Coretext

( BUPP09035 - 14 July 2008) Long-term opioid management for chronic noncancer pain.

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effectiveness of long-term opioid therapy for chronic noncancer pain; to identify the adverse effects of long-term opioid therapy for chronic noncancer pain; and to assess withdrawal rates from treatment by reasons for withdrawal based on patient statements. Cochrane Database of Systematic Reviews 2008 Issue 2 (Status: Unchanged) This version first published online: 18 July 2007 in Issue 3, 2007.

( BUPP09034 - 14 July 2008) Test strip handling in screening for drugs of abuse in the clinical toxicological setting.

Test strips are commonly used in rapid screening for drugs of abuse in clinical applications and forensic situations, but the operator does not necessarily have a toxicological qualification. Pharmacological and toxicological knowledge is necessary for interpretation of the results and for technical understanding of the test system (e.g., cutoff values, cross-reactivity). Possible false- negative results have to be considered and strategies for the detection of sample manipulation should be established. Quality controls are indispensable in ensuring results are authentic and reproducible, and proper documentation is mandatory to achieve traceability. Analysis using chromatographic methods should be included to confirm positive test-strip results. National and international regulations for decision limits should also be considered.

( BUPP09033 - 14 July 2008) Enhancing capacities: Right or wrong?

As far as human characteristics or capacities are concerned, much of the debate concerning all methods of enhancement turns on the question: what is normal? Do we take normal to be represented by statistical averages, such as average height? If so, normal height would be markedly greater in some countries, such as Finland or the Netherlands, than in many other European countries and even more so when compared with countries around the world. Whatever value or range is chosen there will always be outliers unless the range is set so wide as to be meaningless.

( BUPP09032 - 14 July 2008) Harm reduction and equity of access to care for French prisoners: A review.

Background: Despite France being regarded as a model of efficient harm reduction policy and equity of access to care in the general community, the health of French inmates is a critical issue, as harm reduction measures are either inaccessible or only partially implemented in French prisons. Method: Using specific inclusion and exclusion criteria, information was collected and analyzed about HIV, HBV and HCV prevalence, risk practices, mortality, access to harm reduction measures and care for French prison inmates. Results: Data about the occurrence of bloodborne diseases, drug use and access to care in prisons remain limited and need urgent updating. Needle exchange programs are not yet available in French prisons and harm reduction interventions and access to OST remain limited or are heterogeneous across prisons. The continuity of care at prison entry and after release remains problematic and should be among the primary public health priorities for French prisoners. Conclusion: Preventive and harm reduction measures should be urgently introduced at least as pilot programs. The implementation of such measures, not yet available in French prisons, is not only a human right for prison inmates but can also provide important public health benefits for the general population.

( BUPP09031 - 14 July 2008) Temporary services for patients in need of chronic care.

Background: A project is a temporary endeavour undertaken to create a product or service. Projects are frequently used for the testing and development of new approaches in social work. Projects can receive grants from central, often national or international institutions, and allow for more experimentation than work placed within existing institutions. Discussion: For socially marginalized groups who need continuing support and care, receiving help in a project means that the clients will have to be transferred to other services when the project ends. There is also a risk that clients will experience a decline in services, as staff members have to seek new employment towards the end of the project, or begin to focus more on the evaluation than the services. This raises some ethical issues concerning the use of human subjects in projects. Conclusion: Project managers should consider ethical issues relating to continuity of services when serving vulnerable patients with a need for continuing care.

( BUPP09030 - 14 July 2008) Diagnostics and therapy of chronic pancreatitis.

Chronic pancreatitis (CP) is characterized by progressive, chronic inflammation of the pancreas, resulting in loss of exocrine and endocrine function and chronic abdominal pain. In most cases, CP is induced by long-term alcoholism. The second most frequent diagnosis is idiopathic CP, in the absence of known causes of CP. However, the identification of genetic and immunological causes continuously reduces the number of cases classified as idiopathic pancreatitis. Common symptoms of CP comprise abdominal pain radiating to the back, diarrhea, steatorrhea and the development of diabetes. The diagnosis is mainly based on clinical features, typical morphological findings such as pancreatic calcifications, duct stenoses and dilatations, as well as pathologic pancreatic function tests. Treatment of CP includes watch and wait strategies in asymptomatic patients, symptomatic treatment of the clinical features such as pain, exocrine and endocrine insufficiency, as well as interventional or surgical therapy of complications such as pseudocysts, pancreatic duct stenosis, stones or biliary obstruction.

( BUPP09029 - 14 July 2008) Variable response to opioid treatment: Any genetic predictors within sight?

The aim of this literature review is to summarize and discuss the available evidence for a relationship between polymorphisms in human genes and variability in opioid analgesia and side effects among patients treated for moderate or severe pain. The evidence supporting a role of certain alleles, genotypes or haplotypes in modulation of opioid analgesia is derived from a limited number of studies, a limited number of genes and a limited number of opioids. Although several interesting candidates have emerged as potentially relevant factors, only for one polymorphism, the prevalent 118A>G of the mu- opioid receptor, the accumulated evidence is sufficient to suggest a clinically relevant effect for an opioid used for moderate or severe pain. Still the data are valid only at the group level and cannot be used to predict treatment outcome in individual patients. Only a few of the symptoms often seen as opioid adverse effects in palliative care, such as nausea, vomiting, constipation and sedation, have been associated with genetic variants in various genes, but the results have been based on case reports, healthy volunteers or post-operative patients. So far, there is no clear evidence that genetic markers can be used to predict opioid efficacy or adverse effects in palliative care patients. This reflects the general lack of studies performed in the context of palliative care, the lack of sufficiently scaled studies and the lack of international standards for the assessment of subjective symptoms.

( BUPP09028 - 14 July 2008) Receptor functions.

Prescribers should have some understanding of receptor mechanisms because many drugs commonly used in modern practice act on receptors, safe drug usage requires an understanding of receptor pharmacology and future advances in pharmacology and therapeutics are likely to develop from the discovery of further receptors and molecular modelling of drugs to interact with them. This article covers basic concepts such as receptors and ligands, agonists and antagonists, dose-response curves, efficacy, potency, selectivity and affinity. It illustrates the different ways that ligand-receptor interactions can be coupled to responses (e.g. channel-linked receptors, G-protein- coupled receptors, kinase-linked receptors and receptors regulating gene transcription). The potential for agonists, partial agonists and antagonists to interact with each other is examined. The importance of understanding the dose-response curve, and its influence on the likelihood of achieving clinical efficacy without causing adverse effects, is emphasized.

( BUPP09027 - 14 July 2008) Thoracic epidural catheterization leading to delayed transient neurological symptoms with normal imaging findings.

Paraparesis after epidural catheterization is rare but may be multifactorial. We report a case of temporary paraparesis in a 32- year-old female patient after thoracic epidural catheterization performed analgesia. A 16 G epidural needle was introduced at the T-7-T-8 interspace but as frank blood came through, it was withdrawn and was reinserted at the T-8-T-9 interspace. An 18 G epidural catheter was introduced and 10 ml of 0.125% bupivacaine with buprenorphine 150 mcg was given. Further top-ups were given for 48 h on complain of pain. There was an episode of hypotension after giving the epidural drug but later on the patient remained haemodynamically stable. On the fourth post-operative day, the patient reported paraparesis with heaviness and tingling sensation in both lower extremities. MRI was normal with no evidence of spinal cord compression, oedema, haematoma or abscess. The patient improved gradually within a period of 3 days. The possible causes of delayed onset of neurological symptoms are discussed.

( BUPP09026 - 14 July 2008) Long-term treatment with buprenorphine/naloxone in primary care: results at 2-5 years.

To examine long-term outcomes with primary care office-based buprenorphine/naloxone treatment, we followed 53 opioid-dependent patients who had already demonstrated six months of documented clinical stability for 2-5 years. Primary outcomes were retention, illicit drug use, dose, satisfaction, serum transaminases, and adverse events. Thirty-eight percent of enrolled subjects were retained for two years. Ninety-one percent of urine samples had no evidence of opioid use, and patient satisfaction was high. Serum transaminases remained stable from baseline. No serious adverse events related to treatment occurred. We conclude that select opioid- dependent patients exhibit moderate levels of retention in primary care office-based treatment.

( BUPP09025 - 14 July 2008) Suicidality in opioid-dependent subjects.

We determined suicide attempt characteristics in 160 opioid-dependent subjects. Three aspects of suicide vulnerability were also examined: familial aggregation of suicidal behaviors, degree of aggression /impulsivity, and smoking. Forty-eight percent of subjects had a personal history of suicide attempt. A personal history of suicide attempt was associated with an early onset of heroin use, but not with gender differences. A family history of suicide was a progressive risk factor for suicide attempt. Subjects with a personal history of suicide attempt had a higher degree of aggression /impulsivity and smoked more cigarettes. In conclusion, opioid- dependent subjects who attempt suicide show familial aggregation and clinical expressions of suicidal liability similar to those described in other psychiatric groups.

( BUPP09024 - 14 July 2008) Oral substitution treatments for opioid dependence (Comments)

Illicit opioid dependence, once largely a problem in developed countries, has become an increasingly important public-health concern over the past few decades in countries such as China, India, Indonesia, Iran, Malaysia, Pakistan, and Russia.1 In 2003, its health effects were estimated to account for 0�7% of global disease burden. Many developing countries have prohibited the use of pharmacological treatments for opioid dependence that are used in developed countries (and in WHO's Model List of Essential Medicines) - ie, oral agonist maintenance treatment with methadone and buprenorphine. The preferred forms of so-called treatment in these countries have often been imprisonment, enforced opioid withdrawal, and a coerced form of drug-free rehabilitation in prison-like settings. Also see BUPP08985 "Maintenance treatment with buprenorphine and naltrexone for heroin dependence in Malaysia: a randomised, double-blind, placebo-controlled trial" Schottenfeld R S, Chawarski M, Mazlan M. Lancet 2008, 371, 2192-2200.

( BUPP09046 - 21 July 2008) Local infiltration analgesia: A technique for the control of acute postoperative pain following knee and hip surgery - A case study of 325 patients.

Background: We have developed a multimodal technique for the control of pain following knee and hip surgery, called "local infiltration analgesia" (LIA). It is based on systematic infiltration of a mixture of ropiva-caine, ketorolac, and adrenaline into the tissues around the surgical field to achieve satisfactory pain control with little physiological disturbance. The technique allows virtually immediate mobilization and earlier discharge from hospital. Patients and methods: In this open, nonrandomized case series, we used LIA to manage postoperative pain in all 325 patients presenting to our service from Jan 1, 2005 to Dec 31,2006 for elective hip resurfacing (HRA), primary total hip replacement (THR), or primary total knee replacement arthroplasty (TKR). We recorded pain scores, mobilization times, and morphine usage for the entire group. Results: Pain control was generally satisfactory (numerical rating scale pain score range 0-3). No morphine was required for postoperative pain control in two- thirds of the patients. Most patients were able to walk with assistance between 5 and 6 h after surgery and independent mobility was achieved 13-22 h after surgery. Orthostatic hypotension, nausea, and vomiting were occasionally associated with standing for the first time, but other side effects were unremarkable. 230 (71%) of the 325 patients were discharged directly home after a single overnight stay in hospital. Interpretation: Local infiltration analgesia is simple, practical, safe, and effective for pain management after knee and hip surgery.

( BUPP09045 - 21 July 2008) Gender issues and the pharmacotherapy of substance abuse.

In the last 25 years, the different disciplines and professions that are involved in managing the issue of substance abuse have recognized that gender-linked factors influence patterns of substance abuse and response to treatment. In 2007, the US National Institute on Drug Abuse (NIDA) concluded that studies of substance abuse should routinely address gender issues. In the field of drug development, gender issues historically have not been an issue of high priority. By outlining the types of evidence that underpin the view of the NIDA and providing evidence of the widespread existence of gender-linked effects from pharmacotherapies (both those marketed and under development), this feature review proposes that drug developers should embrace the opinion of the NIDA regarding gender and substance abuse. To avoid false conclusions, the issue of gender should become a higher priority during the collection and analysis of data on pharmacotherapies. Some gender differences will have more clinical significance than others, but any difference related to gender has the potential to complicate clinical trials and other studies.

( BUPP09044 - 21 July 2008) Prescription of opiates in medical practice.

( BUPP09043 - 21 July 2008) Attitudes and knowledge of substance misusers regarding buprenorphine and methadone maintenance therapy.

Aims: To assess substance users' beliefs and the sources of these beliefs regarding methadone and buprenorphine and to examine how they choose between them. Design: Forty-two opiate-dependent patients seeking treatment chose between open label buprenorphine or methadone maintenance treatment. Prior to treatment patients completed a semi- structured interview or a self-completed questionnaire. Findings: Beliefs were based primarily on their own or other users' experiences. All patients chose their treatment. There was little difference between those choosing MMT and BMT in terms of their beliefs about the drugs, although the BMT group viewed methadone more negatively and buprenorphine more positively than the MMT group. Those choosing MMT appeared to do so on the basis of familiarity whereas those choosing BMT appeared to be attracted by their beliefs that it would block heroin more effectively, reduce craving, give less intoxication and be easier to stop taking. Conclusions: Opiate users rapidly become well informed about a new treatment when it becomes available. They rely more on their own and other users' experience than the information given by agencies. Choices between treatments are based more on individual perceived requirements than different beliefs.

( BUPP09042 - 21 July 2008) Opioids and the control of respiration.

Respiratory depression limits the use of opioid analgesia. Although well described clinically, the specific mechanisms of opioid action on respiratory control centres in the brain have, until recently, been less well understood. This article reviews the mechanisms of opioid-induced respiratory depression, from the cellular to the systems level, to highlight gaps in our current understanding, and to suggest avenues for further research. The ultimate aim of combating opioid-induced respiratory depression would benefit patients in pain and potentially reduce deaths from opioid overdose. By integrating recent findings from animal studies with those from human volunteer and clinical studies, further avenues for investigation are proposed, which may eventually lead to safer opioid analgesia.

( BUPP09041 - 21 July 2008) Simultaneous screening of buprenorphine, ketamine, LSD, MDMA, methaqualone, fentanyl, oxycodone, hydromorphone, propoxyphene and the dilution marker creatinine in urine using Evidence biochip array technology.

( BUPP09040 - 21 July 2008) The buprenorphine Assay* on the Olympus (R) analyzers.

( BUPP09039 - 21 July 2008) Comparison of two Buprenorphine immunoassays and their ability to determine Buprenorphine prevalence, compliance, diversion and abuse.

( BUPP09038 - 21 July 2008) Buprenophine enzyme immunoassay on Synchron systems.

( BUPP09037 - 21 July 2008) Method for reducing pain.

Anonymous, Inventor(s): The present invention is direct to a method of producing analgesia in a mammalian subject. The method includes administering to the subject an omega conopeptide, preferably ziconotide, in combination with an analgesic selected from the group consisting of morphine, bupivicaine, clonidine, hydromorphone, baclofen, fentanyil, buprenorphine, and sufentanil, or its pharmaceutically acceptable salts thereof, wherein the omega-conopeptide retains its potency and is physically and chemically compatible with the analgesic compound. A preferred route of administration is intrathecal administration, particularly continuous intrathecal infusion. The present invention is also directed to a pharmaceutical formulation comprising an omega conopeptide, preferably ziconotide, in combination with an analgesic selected from the group consisting of morphine, bupivicaine, clonidine, hydromorphone, baclofen, fentanyl, buprenorphine, and sufentanil.

( BUPP09036 - 21 July 2008) Driving ability under opioids: current assessment of published studies.

Opioids are more frequently used in the treatment of chronic non- cancer pain. The aim is not only to reduce pain intensity, but also the patients' reintegration into their social environment, including the possibility of driving their own car. Various studies have investigated the impact of opioids on driving ability. Two studies showed that a group of patients with chronic pain receiving sustained treatment with transdermal fentanyl or buprenorphine performed significantly better in tests than healthy persons with legally relevant 0,05% concentration of blood alcohol. These results indicate that stable opioid treatment does not necessarily impair driving ability of patients in chronic pain. However, so far published studies do not provide clear evidence for saying that persons on sustained opioid treatment can drive a car without any problem. Nor do they indicate that such persons should not drive.

( BUPP09059 - 28 July 2008) Case series of buprenorphine injectors in Kuala Lumpur, Malaysia.

Diversion of buprenorphine has been described in settings where it is legally prescribed and has become an increasing concern in Malaysia; it resulted in banning of buprenorphine in Singapore where unsubstantiated case reports suggested that buprenorphine injection was associated with particularly poor outcomes. We therefore conducted a case series of qualitative interviews with buprenorphine injectors in Kuala Lumpur, Malaysia to examine further the issues surrounding buprenorphine injection as well as the abuse of midazolam in combination with buprenorphine. Interviews with 19 men do not suggest significant adverse health consequences from buprenorphine injection alone and injectors have adapted diverted buprenorphine as a treatment modality. A subset of these injectors, however, combined buprenorphine and midazolam for euphoric effects with resultant symptoms of a possible pharmacological interaction. Prospective cohort studies, rather than hospital-derived samples, are needed to better understand the safety of buprenorphine injection. Reapply

( BUPP09058 - 28 July 2008) Pharmacogenetic treatments for drug addiction: Alcohol and opiates.

Aims: Psychiatric pharmacogenetics involves the use of genetic tests that can predict the effectiveness of treatments for individual patients with mental illness such as drug dependence. This review aims to cover these developments in the pharmacotherapy of alcohol and opiates, two addictive drugs for which we have the majority of our FDA approved pharmacotherapies. Methods: We conducted a literature review using Medline searching terms related to these two drugs and their pharmacotherapies crossed with related genetic studies. Results: Alcohol's physiological and subjective effects are associated with enhanced beta-endorphin release. Naltrexone increases baseline beta-endorphin release blocking further release by alcohol. Naltrexone's action as an alcohol pharmacotherapy is facilitated by a putative functional single nucleotide polymorphism (SNP) in the opioid mu receptor gene (Al18G) which alters receptor function. Patients with this SNP have significantly lower relapse rates to alcoholism when treated with naltrexone. Caucasians with various forms of the CYP2D6 enzyme results in a 'poor metabolizer' phenotype and appear to be protected from developing opioid dependence. Others with a "ultra-rapid metabolizer" phenotype do poorly on methadone maintenance and have frequent withdrawal symptoms. These patients can do well using buprenorphine because it is not significantly metabolized by CYP2D6. Conclusions: Pharmacogenetics has great potential for improving treatment outcome as we identify gene variants that affect pharmacodynamic and pharmacokinetic factors. These mutations guide pharmacotherapeutic agent choice for optimum treatment of alcohol and opiate abuse and subsequent relapse.

( BUPP09057 - 28 July 2008) Assessment of differential doses of buprenorphine for long term pharmacotherapy among opiate dependent subjects.

The aim of the present study was to evaluate, two different doses of sublingual buprenorphine (2 mg and 4 mg) among patients on maintenance treatment and to assess the relationship of steady state plasma level with craving. Twenty three male opioid dependent (ICD-10 DCR) subjects, were assigned to double blind randomized controlled trial of 2 and 4 mg/day doses of buprenorphine in an inpatient setting. They were evaluated thrice (2nd, 7th and 14th day) in 2 weeks for withdrawal symptoms (acute and protracted), sedation, euphoria, craving, side effects, global rating of well being and for measurement of plasma levels of buprenorphine. The data showed that there were no significant difference in scores of euphoria and sedation, protracted withdrawal symptoms and side effects, craving and overall well being and plasma level of buprenorphine among the subjects. However, both the groups had significant difference in score on almost all the measurements on final observation in comparison to initial observation. Both 2 mg/day and 4 mg/day dose of buprenorphine were effective in long term pharmacotherapy of opioid dependence without significant difference as compared by different measures used in the study. On waiting list

( BUPP09056 - 28 July 2008) Call for feedback on managing chronic pain and opioid addiction.

( BUPP09055 - 28 July 2008) Prescription opioid abuse and dependence among physicians: Hypotheses and treatment.

Physician impairment is a serious public health issue affecting physicians as well as their families, colleagues, and patients. Though physicians generally display healthier habits than members of the general population, overall rates of impairment are similar among both groups, and prescription drug abuse (including prescription opioids) is particularly problematic among physicians. The current review focuses mainly on prescription opioid abuse and dependence among physicians. It includes a brief history of early physician experiences with anesthetic and analgesic agents, and explores several hypotheses regarding the etiology of prescription opioid abuse and dependence among physicians. Barriers to identification and to treatment entry among physicians are discussed. In addition, methods of assessment and successful treatment in specialized impaired physician programs are described. Medical and psychosocial interventions, 12-step involvement, and extensive use of evaluations are highlighted. Attention is paid to typical follow-up contracting and monitoring strategies, as well as strategies for prevention. Given the extremely positive outcomes demonstrated by specialized programs for treating impaired professionals, it is recommended that their methods be disseminated and utilized in treatment centers for the general public.

( BUPP09054 - 28 July 2008) Prediction of pharmacokinetic drug-drug interactions using human hepatocyte suspension in plasma and cytochrome P450 phenotypic data. II. in vitro-in vivo correlation with ketoconazole.

Traditional cytochrome P450 (P450) based drug-drug interaction (DDI) predictions are based on the ratio of an inhibitor's physiological concentration (I) and its inhibition constant K /sub i/ . Determining (I) at the enzymatic site, although critical for predicting clinical DDIs, remains a technical challenge. In our previous study, a novel approach using cryopreserved human hepatocytes suspended in human plasma was investigated to mimic the in vivo concentration of ketoconazole at the enzymatic site (Lu et al., 2007), effectively eliminating the estimation of the elusive (I) value. P450 inhibition in this system appears to model that in vivo. Using the ketoconazole inhibition information in a human hepatocyte-plasma suspension together with quantitative P450 phenotypic information, we successfully predicted the pharmacokinetic DDIs for a small set of drugs, such as theophylline, tolbutamide, omeprazole, desipramine, midazolam, loratadine, cyclosporine, and alprazolam, as well as an investigational compound. For the applicability of this model on a wider scale the in vitro-in vivo correlation data set needed to be expanded. However, for most drugs in the literature there is not enough quantitative information on the involvement of individual P450s to predict DDIs retrospectively. To facilitate that, in this study we determined quantitative P450 phenotyping for seven marketed drugs: budesonide, buprenorphine, loratadine, sirolimus, tacrolimus, docetaxel, and methylprednisolone. Augmentation of the new data set with the one generated previously produced broader a database that provided further support for the wider applicability of this approach using ketoconazole as a potent CYP3A inhibitor. This application is predicted to be equally effective with other P450 inhibitors that are not substrates of efflux pumps.

( BUPP09053 - 28 July 2008) An emerging trend of buprenorphine abuse resulting in severe neurologic deficits.

( BUPP09052 - 28 July 2008) Combined spinal-epidural anesthesia for renal transplantation.

Introduction. A patient undergoing renal transplantation presents unique problems to the anesthetist, as almost every body system is affected. The combined spinal-epidural technique has become popular in lower abdominal surgeries because it offers the advantages of both spinal and epidural techniques. We review our experience of combined spinal-epidural technique in patients undergoing renal transplantation with respect to demographics, intraoperative anesthesia, hemodynamics, postoperative analgesia, and untoward adverse events.Materials and method. Fifty consecutive patients scheduled for elective renal transplantation over a period of 4 months who consented for combined spinal-epidural anesthesia were enrolled in the study. Combined spinal-epidural anaesthesia was performed using a double-space technique in the right lateral position. Intraoperative monitoring included electrocardiography, pulse oximetry, noninvasive blood pressure, central venous pressure, and urinary output after clamp release. Intravenous fluids, colloids, and blood products were infused so as to keep the central venous pressure between 12 and 15 mm Hg. Postoperative analgesia was provided with buprenorphine via an epidural catheter. We noted intraoperative and postoperative complications.Results. Neuraxial blockade was satisfactory in all but four patients who required supplementation with general anesthesia for unduly prolonged surgery. There were no significant intraoperative hemodynamic changes. The total intravenous fluid used during surgery was 64.24 +/- 12.3 mL/kg. During the postoperative period, all patients had good postoperative pain relief with no incidence of epidural hematoma.Conclusion. Combined spinal-epidural anesthesia proved to be a useful regional anesthetic technique, combining the reliability of spinal block and versatility of epidural block for renal transplantation.

( BUPP09051 - 28 July 2008) A 50-year-old woman addicted to heroin: review of treatment of heroin addiction.

Heroin addiction is a complicated medical and psychiatric issue, with well-established as well as newer modes of treatment. The case of Ms W, a 50-year-old woman with a long history of opiate addiction who has been treated successfully with methadone for 9 years and who now would like to consider newer alternatives, illustrates the complex issues of heroin addiction. The treatment of heroin addiction as a chronic disease is reviewed, including social, medical, and cultural issues and pharmacologic treatment with methadone and the more experimental medication options of buprenorphine and naltrexone.

( BUPP09050 - 28 July 2008) Stepping into the wide world.

( BUPP09049 - 28 July 2008) Community treatment programs take up buprenorphine.

Clinicians have been working out ways to incorporate buprenorphine into their treatment models. Representatives of three addiction treatment programs - a Veterans Affairs methadone clinic, a group of outpatient mental health centers, and a nationwide organization of therapeutic communities - talk about their plans and experiences.

( BUPP09048 - 28 July 2008) Response: integrating buprenorphine therapy into clinical practice.

( BUPP09047 - 24 July 2008) A retrospective evaluation of patients switched from buprenorphine (subutex) to the buprenorphine / naloxone combination (suboxone)

A complete electronic version of this article can be found online at http://www.substanceabusepolicy.com/content/3/1/16 - This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background In Finland, buprenorphine (Subutex) is the most abused opioid. In order to curb this problem, many treatment centres transferred ("forced transfer") their buprenorphine patients to the buprenorphine plus naloxone (Suboxone) combination product in late 2003. Methods Data from a retrospective study involving five different treatment centers, examining the effects of switching patients to Suboxone, were gathered from 64 opioid-dependent patients who had undergone the medication transfer. Results Most patients (90.6%) switched to Suboxone at the same dose of buprenorphine that they had been receiving as Subutex (average 22 mg). The majority of these patients (71.9%) were maintained at the same dose of Suboxone throughout the 4-week study period. During the first 4 weeks, 50% of the patients reported adverse events and at the four month time point, 26.6% reported adverse events. However, due to adverse events one patient only discontinued treatment with Suboxone during the 4-week study period, and five during the four month follow-up period. Of the 26 patients in the follow-up period, Suboxone was misused intravenously once each by 4 patients and twice by 1 patient. These 5 patients all reported that injecting Suboxone was like injecting "nothing" with any euphoria, or that it was a bad experience. Conclusion We conclude that when patients are transferred from high doses (> 22 mg) of buprenorphine to the combination product, dose adjustments may be necessary especially in the later phase of the treatment. We recommend that a transfer from Subutex to Suboxone should be carefully discussed and planned in advance with the patients and after the transfer adverse events should be regularly monitored. With regard of buprenorphine IV abuse, the combination product seems to have a less abuse potential than buprenorphine alone.

( BUPP09082 - 11 August 2008) Endogenous Candida endophthalmitis in drug misusers injecting intravenous buprenorphine.

PURPOSE: To analyze patients presenting ocular candidiasis caused by intravenous drug addiction to buprenorphine. PATIENTS AND METHODS: We have listed all the cases of endogenous fungal endophthalmitis hospitalized between 1996 and 2005 in the ophthalmology department of the university-affiliated hospital of Rouen, France. Posterior vitrectomy was performed for each patient, with direct examination and bacterial and fungal cultures. The treatment was begun both with an intravitreal injection of amphotericin B and oral fluconazole, modified in the event of resistance. RESULTS: Seven men, drug addicts, all using intravenous buprenorphine users, were included in the study. The vitreal culture revealed four cases of Candida albicans candidiasis and one case of Candida tropicalis candidiasis. In two cases, oral fluconazole had to be replaced with oral voriconazole. Of the seven patients, three evolved unfavorably despite treatment. DISCUSSION: Intravenous drug use is known to be a risk factor for ocular candidiasis. However, buprenorphine does not seem to be related to endogenous endophthalmitis, since this was also observed among patients using methadone or heroine. Salivary contact during the preparation of the syringe being used for the injection of the substitute appears to be the source of the candidemia in our series and in the literature. CONCLUSION: Inappropriate intravenous use of oral buprenorphine in drug users is a significant risk factor of endogenous fungal endophthalmitis. Visual monitoring by pharmacists of the oral intake of buprenorphine seems essential. We underline the advantages of removing the vitreous in ocular candidiasis.

( BUPP09081 - 11 August 2008) Pharmacokinetic-pharmacodynamic relationships of cognitive and psychomotor effects of intravenous buprenorphine infusion in human volunteers.

The main objective of the present study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the effects of buprenorphine on cognitive functioning in healthy volunteers. Twenty-three male volunteers received 0.6 mg buprenorphine as an intravenous infusion over 150 min. The cognitive and psychomotor performance was evaluated before and at various times after drug administration by a test battery consisting of trail-making test for visual information processing, finger-tapping test for psychomotor speed, and continuous reaction time for attention. Non-linear mixed effect modelling was used in the analysis of the PK/PD relationships. Buprenorphine caused significant deficits in cognitive and psychomotor functioning. The time course of cognitive and psychomotor impairment was found to have a slow distribution to the biophase from plasma with PK/PD models involving an effect compartment providing the best descriptions of the time course of the data. The values for half-life of biophase equilibration were consistent between the neuropsychological tests in the range of 66.6-84.9 min. The time to onset and duration of the cognitive and psychomotor impairment of buprenorphine was determined by a slow distribution to the biophase.

( BUPP09080 - 11 August 2008) Therapy goals, evaluation and health-economic aspects of the therapy of drug-dependent.

Changes regarding the goal paradigms in the therapy of drug-dependent have substantial influence on the evaluation of the effectiveness and cost effectiveness of such interventions. This overview represents the connection between therapy goals and clinical and health-economic evaluation concepts. In addition, the state of research is summarized concerning the effectiveness and cost-effectiveness of different therapy strategies on the basis by reviews.

( BUPP09079 - 11 August 2008) Transdermal drug delivery systems.

20th August 2008: British Library cannot find a copy of this paper.

( BUPP09078 - 11 August 2008) Addressing Canine and Feline Aggression in the Veterinary Clinic.

Handling aggressive dogs and cats in the veterinary clinic can be frustrating, time consuming, and injurious for both employee and animal. This article discusses the etiology of the aggressive dog and cat patient and how best to approach these cases. A variety of handling techniques, safety products, and drug therapy are reviewed.

( BUPP09077 - 11 August 2008) Neuropathic pain - The view of combined therapy with the use of opioids.

The effective management of chronic pain is a fundamental goal for all clinicians and algesiologists. Potent opioids - such as morphine and the newer-generation agents (fentanyl, buprenorphine, oxycodone and hydromorphone) play an important role in management of pain in patients with chronic pain. The three-step analgesic ladder developed by the World Health Organisation (WHO) outlines these opioids in the management of cancer pain, and these widely accepted and extensively validated guidelines have also been influential in the application of opioid therapy for the treatment of chronic, non-malignant pain. The use of opioids for treatment in neuropathic pain remains somewhat controversial, since early studies indicated that neuropathic pain is generally less responsive to pure mu-opioid analgesia. A growing body of evidence now suggests that different opioids affect different pain pathways, and that opioids are effective under peripheral and central neuropathic pain conditions. Recently emerging data support the possibility of a role for oxycodone and buprenorphine in the management of neuropathic pain. In the article on the use different opioid therapy, the author focuses on the treatment of chronic, non-malignant pain over the course of one year. In the first part of the article, the author describes the separation of the patients in relation to diagnosis and the use of opioid therapy with different opioids. The group comprised 47 patients, whose reactions to the treatment were studied over the course of one year. Neuropathic pain was treated with oxycodone in 53.2% (27 patients), TTS fentanyl was used by 27.6% (13 patients), TDS buprenorphine in 17% (8 patients) and hydromorphone was prescribed for 2.2% (1 patient). In the next part of the article is discussed the efficacy and tolerability of oxycodone in neuropathic pain and greater improvements in the quality of life score. The author emphasizes the preference of using oxycodone in the treatment of neuropathic pain and points to the good analgesic efficacy when using low doses of oxycodone. The author concludes the article by focusing on new clinical studies, which point to the good analgesic effect of using TDS buprenorphine.

( BUPP09076 - 11 August 2008) Opioids and the management of chronic severe pain in the elderly: Consensus statement of an international expert panel with focus on the six clinically most often used world health organization step III opioids (Buprenorphine, Fentanyl, Hydromorphone, Methadone, Morphine, Oxycodone)

1. The use of opioids in cancer pain: The criteria for selecting analgesics for pain treatment in the elderly include, but are not limited to, overall efficacy, overall side-effect profile, onset of action, drug interactions, abuse potential, and practical issues, such as cost and availability of the drug, as well as the severity and type of pain (nociceptive, acute/chronic, etc.). At any given time, the order of choice in the decision-making process can change. This consensus is based on evidence-based literature (extended data are not included and chronic, extended-release opioids are not covered). There are various driving factors relating to prescribing medication, including availability of the compound and cost, which may, at times, be the main driving factor. The transdermal formulation of buprenorphine is available in most European countries, particularly those with high opioid usage, with the exception of France; however, the availability of the sublingual formulation of buprenorphine in Europe is limited, as it is marketed in only a few countries, including Germany and Belgium. The opioid patch is experimental at present in U.S.A. and the sublingual formulation has dispensing restrictions, therefore, its use is limited. It is evident that the population pyramid is upturned. Globally, there is going to be an older population that needs to be cared for in the future. This older population has expectations in life, in that a retiree is no longer an individual who decreases their lifestyle activities. The "baby-boomers" in their 60s and 70s are "baby zoomers" they want to have a functional active lifestyle. They are willing to make trade-offs regarding treatment choices and understand that they may experience pain, providing that can have increased quality of life and functionality. Therefore, comorbidities-including cancer and noncancer pain, osteoarthritis, rheumatoid arthritis, and postherpetic neuralgia-and patient functional status need to be taken carefully into account when addressing pain in the elderly. World Health Organization step III opioids are the mainstay of pain treatment for cancer patients and morphine has been the most commonly used for decades. In general, high level evidence data (Ib or IIb) exist, although many studies have included only few patients. Based on these studies, all opioids are considered effective in cancer pain management (although parts of cancer pain are not or only partially opioid sensitive), but no well-designed specific studies in the elderly cancer patient are available. Of the 2 opioids that are available in transdermal formulation-fentanyl and buprenorphine-fentanyl is the most investigated, but based on the published data both seem to be effective, with low toxicity and good tolerability profiles, especially at low doses. 2. The use of opioids in noncancer-related pain: Evidence is growing that opioids are efficacious in noncancer pain (treatment data mostly level Ib or IIb) , but need individual dose titration and consideration of the respective tolerability profiles. Again no specific studies in the elderly have been performed, but it can be concluded that opioids have shown efficacy in noncancer pain, which is often due to diseases typical for an elderly population. When it is not clear which drugs and which regimes are superior in terms of maintaining analgesic efficacy, the appropriate drug should be chosen based on safety and tolerability considerations. Evidence-based medicine, which has been incorporated into best clinical practice guidelines, should serve as a foundation for the decision-making processes in patient care; however, in practice, the art of medicine is realized when we individualize care to the patient. This strikes a balance between the evidence-based medicine and anecdotal experience. Factual recommendations and expert opinion both have a value when applying guidelines in clinical practice. 3. The use of opioids in neuropathic pain: The role of opioids in neuropathic pain has been under debate in the past but is nowadays more and more accepted; however, higher opioid doses are often needed for neuropathic pain than for nociceptive pain. Most of the treatment data are level II or III, and suggest that incorporation of opioids earlier on might be beneficial. Buprenorphine shows a distinct benefit in improving neuropathic pain symptoms, which is considered a result of its specific pharmacological profile. 4. The use of opioids in elderly patients with impaired hepatic and renal function: Functional impairment of excretory organs is common in the elderly, especially with respect to renal function. For all opioids except buprenorphine, half-life of the active drug and metabolites is increased in the elderly and in patients with renal dysfunction. It is, therefore, recommended that-except for buprenorphine-doses be reduced, a longer time interval be used between doses, and creatinine clearance be monitored. Thus, buprenorphine appears to be the top-line choice for opioid treatment in the elderly. 5. Opioids and respiratory depression: Respiratory depression is a significant threat for opioid-treated patients with underlying pulmonary condition or receiving concomitant central nervous system (CNS) drugs associated with hypoventilation. Not all opioids show equal effects on respiratory depression: buprenorphine is the only opioid demonstrating a ceiling for respiratory depression when used without other CNS depressants. The different features of opioids regarding respiratory effects should be considered when treating patients at risk for respiratory problems, therefore careful dosing must be maintained. 6. Opioids and immunosuppression: Age is related to a gradual decline in the immune system: immunosenescence, which is associated with increased morbidity and mortality from infectious diseases, autoimmune diseases, and cancer, and decreased efficacy of immunotherapy, such as vaccination. The clinical relevance of the immunosuppressant effects of opioids in the elderly is not fully understood, and pain itself may also cause immunosuppression. Providing adequate analgesia can be achieved without significant adverse events, opioids with minimal immunosuppressive characteristics should be used in the elderly. The immunosuppressive effects of most opioids are poorly described and this is one of the problems in assessing true effect of the opioid spectrum, but there is some indication that higher doses of opioids correlate with increased immunosuppressant effects. Taking into consideration all the very limited available evidence from preclinical and clinical work, buprenorphine can be recommended, while morphine and fentanyl cannot. 7. Safety and tolerability profile of opioids: The adverse event profile varies greatly between opioids. As the consequences of adverse events in the elderly can be serious, agents should be used that have a good tolerability profile (especially regarding CNS and gastrointestinal effects) and that are as safe as possible in overdose especially regarding effects on respiration. Slow dose titration helps to reduce the incidence of typical initial adverse events such as nausea and vomiting. Sustained release preparations, including transdermal formulations, increase patient compliance.

( BUPP09075 - 11 August 2008) On drug treatment and social control: Russian narcology's great leap backwards.

The medical discipline of narcology in Russia is a subspecialty of psychiatry from the Soviet era and it is given warrant to define the scope of health activities with regard to alcohol and other drug use, drug users, and related problems. Narcological practice is in turn constrained by the State. The emergence of widespread injection opiate use and associated HIV morbidities and mortalities during the first decade following the collapse of the Soviet Union has brought the contradictions in Russian narcological discourse into high relief. Narcology officials in the Russian Federation have consistently opposed substitution treatment for opiate dependence - the replacement of a short-acting illegal substance with a longer acting prescribed drug with similar pharmacological action but lower degree of risk. Thus, despite the addition of methadone and buprenorphine to WHO's list of essential medicines in 2005 and multiple position papers by international experts calling for substitution treatment as a critical element in the response to HIV (IOM, 2006; UNODC, UNAIDS, and WHO, 2005), methadone or buprenorphine remain prohibited by law in Russia. The authors detail Russian opposition to the prescription of methadone and buprenorphine, describing four phenomena: (1) the dominance of law enforcement and drug control policy over public health and medical ethics; (2) the conflation of Soviet era alcoholism treatment with treatment for opiate dependence; (3) the near universal representation of detoxification from drugs as treatment for dependence; and (4) a framework for judging treatment efficacy that is restricted to "cure" versus "failure to cure, " and does not admit its poor outcomes or recognize alternative frameworks for gauging treatment of opiate dependence. In keeping with this position, Russian narcology officials have taken an implacable ideological stance toward illicit drug use, the people who use drugs, and their treatment. By adopting policies and practices totally unsupported by scientific evidence and inquiry, officials in Russia have rendered narcology (and medical practice) insensitive to the alarming rates and continued spread of HIV, with its dire morbidity and mortality rates in the Russian Federation, turning their backs on all the other health problems posed by opiate use and dependence itself.

( BUPP09074 - 11 August 2008) Controversies in translational research: Drug self-administration

Rationale: Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. Objective: The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. Results: Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. Conclusions: The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect.

( BUPP09073 - 11 August 2008) Mucositis postradiotherapy

( BUPP09072 - 11 August 2008) Comparison of anesthetic induction in cats by use of isoflurane in an anesthetic chamber with a conventional vapor or liquid injection technique.

Objective-To compare 2 techniques for induction of cats by use of isoflurane in an anesthetic chamber.Design-Prospective, randomized study.Animals-51 healthy cats.Procedures-Cats were randomly allocated to 2 induction techniques. Cats were premedicated with acepromazine (0.1 mg/kg (0.045 mg/lb), SC) and buprenorphine (0.01 mg/kg (0.0045 mg/lb), SC) 30 minutes before induction. Cats were then placed into an induction chamber, and anesthetic induction was initiated. One technique involved a conventional flow-through system that used an oxygen flowmeter and an isoflurane vaporizer to flow vapors into the induction chamber. Alternatively, liquid isoflurane was injected into a vaporization tray that was mounted to the interior surface of the chamber lid. Inductions were videotaped for analysis. Five variables (head bobbing, head swinging side to side, paddling, rotating 180 degrees to 360 degrees, and rolling over or flipping) were scored to assess induction quality. Time variables recorded during induction corresponded to the interval until onset of excitatory motion, duration of excitatory motion, interval until recumbency, and interval until complete induction.Results-Compared with cats anesthetized by use of a conventional vapor chamber technique, cats anesthetized by use of the liquid injection technique had a significantly shorter interval until recumbency and interval until complete induction and lower scores for quality of induction, indicating a smoother induction.Conclusions and Clinical Relevance- Anesthetic induction in cats by use of a liquid injection technique was more rapid and provided a better quality of induction, compared with results for cats induced by use of a conventional vapor technique.

( BUPP09083 - 15 August 2008) Sublingual Buprenorphine for Treatment of Neonatal Adstinence Syndrome: A Randomized Trial

Pediatrics published online 11 Aug 2008. Online version of this article, along with updated information and services, is located on the World Wide Web at : http://www.pediatrics.org/cgi/content/full/peds.2008-057v1 OBJECTIVE. In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial u-opioid agonist used for treatment of adult detoxification and maintenance but has never been administered to neonates with opioid abstinence syndrome. The primary objective of this study was to demonstrate the feasibility and, to the extent possible in this size of study, the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered. METHODS.We conducted a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 ug/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system. RESULTS. Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to ~0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. The ratio of buprenorphine to norbuprenorphine was larger than that seen in adults, suggesting a relative impairment of N-dealkylation. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated. CONCLUSIONS. Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome. Pediatrics 2008;122:e601�e607 www.pediatrics.org/cgi/doi/10.1542/ This trial has been registered at www. clinicaltrials.gov (identi.er NCT00521248). Dr Ehrlich�s current af.liation is Departments of Pediatrics and Neurology, Mt Sinai School of Medicine, New York, New York. Accepted for publication May 13, 2008 Address correspondence to Walter K. Kraft, MD, 132 S 10th St, 1170 Main Building, Jefferson Medical College, Philadelphia, PA 19107. E-mail: walter.kraft@jefferson.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright�2008 by the American Academy of Pediatrics

( BUPP09084 - 15 August 2008) Treating Pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates.

Aims: Through a novel synthesis of the literature and our own clinical experience, we have derived a set of evidence based recommendations for consideration as guidance in the management of opioid-dependent pregnant women and infants. Methods: PubMed literature searches were carried out to identify recent key publications in the areas of pregnancy and opioid dependence, neonatal abstinence syndrome (NAS) prevention and treatment, multiple substance abuse and psychiatric comorbidity. Results: Pregnant women dependent on opioids require careful treatment to minimize harm to the fetus and neonate and improve maternal health. Applying multi-disicpinary treatment as early as possible, allowing medication maintenance and regular monitoring, benefits mother and child both in the short and the long term. However, there is a need for randomized clinical trials with sufficient sample sizes. Recommendations: Opioid maintenance therapy is the recommended treatment approach during pregnancy. Treatment decisions must encompass the full clinical picture, with respect to frequent complications approaches to pregnancy, equivalent attention must be given to the treatment of NAS, which occurs frequently after opioid medication. Conclusion: Methodological flaws and inconsistencies confound interpretation to today's literature. Based on this synthesis of available evidence and our clinical experience, we propose recommendations for further discussion.

( BUPP09085 - 18 August 2008) The neurobiology of opioid dependence: implications for treatment.

Opioid tolerance, dependence, and addiction are all manifestations of brain changes resulting from chronic opioid abuse. The opioid abuser's struggle for recovery is in great part a struggle to overcome the effects of these changes. Medications such as methadone, LAAM, buprenorphine, and naltrexone act on the same brain structures and processes as addictive opioids, but with protective or normalizing effects. Despite the effectiveness of medications, they must be used in conjunction with appropriate psychosocial treatments. http://www.nida.nih.gov/PDF/Perspectives/vol1no1/03Perspectives-Neurobio.pd f

( BUPP09086 - 18 August 2008) Comparison of characteristics of opioid-using pregnant women in rural and urban settings.

Historically, research on opioid use during pregnancy has occurred in urban settings and it is unclear how urban and rural populations compare. We examined socio-demographic and other variables in opioid using pregnant women seeking treatment and screened for participation in a multi-site randomized controlled trial. Women screened in rural Burlington, Vermont (n = 54), were compared to those screened in urban Baltimore, Maryland (n = 305). Rural opioid-using pregnant women appear to have some characteristics associated with better treatment outcomes (e.g., less severe drug use, greater employment). However, they may face additional barriers in accessing treatment (e.g., greater distance from treatment clinic). Grant ID: R01DA015764, Acronym: DA, Agency: United States NIDA Grant ID: R01DA018410, Acronym: DA, Agency: United States NIDA.

( BUPP09087 - 18 August 2008) State policy influence on the early diffusion of buprenorphine in community treatment programs.

BACKGROUND: Buprenorphine was approved for use in the treatment of opioid dependence in 2002, but its diffusion into everyday clinical practice in community-based treatment programs has been slow. This study examines the net impact of efforts by state agencies, including provision of Medicaid coverage, on program-level adoption of buprenorphine as of 2006. METHODS: Interviews were conducted with key informants in 49 of the 50 state agencies with oversight responsibility for addiction treatment services. Information from these interviews was integrated with organizational data from the 2006 National Survey of Substance Abuse Treatment Services. A multivariate logistic regression model was estimated to identify the effects of state efforts to promote the use of this medication, net of a host of organizational characteristics. RESULTS: The availability of Medicaid coverage for buprenorphine was a significant predictor of its adoption by treatment organizations. CONCLUSION: Inclusion of buprenorphine on state Medicaid formularies appears to be a key element in ensuring that patients have access to this state-of-the-art treatment option. Other potential barriers to the diffusion of buprenorphine require identification, and the value of additional state-level policies to promote its use should be evaluated.

( BUPP09088 - 18 August 2008) Addiction: a chronic medical condition.

More hapless drug users have paid with their lives, figuratively and literally, as investigators demonstrate yet again that opiate addiction is a treatable but not curable medical condition (1). Thirty-eight of 75 patients given buprenorphine completed the 9 month detoxification protocol, with completion defined as missing less than 2 consecutive weeks of treatment. Completers also included dropouts who returned to agonist maintenance treatment within 30 days. Three patients died during the 9 month detoxification regimen, another died within 12 months of completing treatment and yet one more died 18 months after dropping out, All told, nine of the 75 starting subjects were abstinent at 24 month follow up, and of these an unknown number were incarcerated or in residential care at the time of assessment. Among the authors conclusions: 'Outcomes...do not support the assumption that buprenorphine is a more appropriate agent than methadone in abstinence oriented replacement therapies - an assumption that they attribute to the proposedly mild withdrawal syndrome associated with discontinuation that they attribute to the proposedly mild withdrawal syndrome associated with discontinuation of buprenorphine therapy...' In fact, the problem is not the medication employed, but the nature of this chronic, notoriously relapsing, treatable but (as yet) incurable patients must pay the ultimate price to confirm that which is based so solidly on empirical evidence and common sense.

( BUPP09089 - 18 August 2008) Buprenorphine use by the smoking route in gaols in NSW.

A recent paper in the Journal of Addictive Diseases by Smith and colleagues (1) reports on the abuse of buprenorphine in the United States. The authors cite the unfortunate absence of data regarding the route of administration in assisting then in interpreting their study results. They seem to have focused primarily on the potential for buprenorphine to be injected and the additional aversive potential of the buprenorphine-naloxone combination (Suboxone) in this regard. I wish to raise the issue of smoking as a potential route for misuse and the use of buprenorphine within correctional facilities.

( BUPP09090 - 18 August 2008) Patients' help-seeking behaviours for health problems associated with methadone and buprenorphine treatment.

INTRODUCTION AND AIMS: Clients in opioid substitution therapy often have considerable unmet health-care needs. The current study aimed to explore health problems related to opioid substitution therapy among clients on methadone and buprenorphine treatment. DESIGN AND METHODS: A self-complete, cross-sectional survey conducted among 508 patients receiving methadone and buprenorphine treatment at community pharmacies in New South Wales (NSW), Australia. RESULTS: The most common problems for which participants had ever sought help were dental (29.9%), constipation (25.0%) and headache (24.0%). The most common problems for which participants would currently like help were dental (41.1%), sweating (26.4%) and reduced sexual enjoyment (24.2%). There were no significant differences between those currently on methadone and those currently on buprenorphine for any of the health problems explored, nor differences for gender or treatment duration. Participants on methadone doses 100 mg or above were significantly more likely to want help currently for sedation. DISCUSSION AND CONCLUSIONS: The considerable unmet health care needs among participants in this study suggest that treatment providers should consider improving the detection and response to common health problems related to opioid substitution therapy.

( BUPP09091 - 18 August 2008) The safety of disulfiram for the treatment of alcohol and cocaine dependence in randomized clinical trials: Guidance for clinical practice.

Background: Disulfiram has demonstrated efficacy in six randomized clinical trials for the treatment of cocaine dependence, but is rarely used in clinical settings because of safety concerns. Objective: What are the common and serious side effects of disulfiram in cocaine-dependent individuals with and without alcohol dependence in randomized clinical trials? Methods: We located Phase I and II randomized trials that discussed the safety of disulfiram. Results/conclusions: In randomized clinical trials that eliminated subjects with serious cardiovascular, hepatic, and psychiatric disorders, the most frequent side effects of disulfiram over placebo or index groups include headaches, fatigue, sleepiness, and anxiety. Disulfiram in a dose of 250 mg/day led to only mild interactions with alcohol. When patients are screened for medical and psychiatric stability, and are evaluated for drug interactions, disulfiram has an acceptable side-effect profile for the treatment of cocaine dependence with or without alcohol dependence.

( BUPP09092 - 18 August 2008) Transdermal buprenorphine (Transtec�) for the treatment of severe chronic pain

( BUPP09093 - 18 August 2008) Epidemiology of opioid pharmacy claims in the United States

Objective: To describe opioid pharmacy claims patterns in the United States among an insured population. Design: Information was obtained from the US insurance claims database, IMS Lifelink TM , between 1997 and 2002. Descriptive statistics of opioid claims patterns were described with stratification by gender, age, and year of use. Results: The prevalence of insured people with opioid claims increased from 17.1 percent in 1997 to 18.4 percent in 2002. Among people with an opioid claim, 24 percent had 30 days and 10 percent had 90 days of days supplied based on the insurance claims. Prevalence varied by type of opioid; 56 percent of people with a claim received propoxyphene, 43 percent received codeine, 23 percent received oxycodone, and 17 percent received hydrocodone. Sustained-release opioids were found among 6 percent of those with a claim. With respect to the dose of opioids in the pharmacy claims (expressed as morphine equivalent total daily dose), 71 percent had claims for <50 mg, 55 percent had claims for 50-99 mg, and 24 percent had claims for 100 mg. Women, individuals with cancer, and older patients had significantly more pharmacy claims as well as claims for higher doses of opioids (p < 0.05). Internal medicine and family practice specialists were responsible for 22.4 percent and 20.9 percent of all opioid claims. Conclusions: Opioid pharmacy claims increased slightly over time. Older patients, women and patients with a cancer diagnosis had significantly more opioid claims and claims for higher doses than the younger patients, men, and those without cancer.

( BUPP09094 - 18 August 2008) Opioid-induced hyperalgesia: Pathophysiology and clinical implications.

Background: Opioid-induced hyperalgesia (OIH) refers to a phenomenon whereby opioid administration results in a lowering of pain threshold, clinically manifest as apparent opioid tolerance, worsening pain despite accelerating opioid doses, and abnormal pain symptoms such as allodynia. Aim: The current review, while providing a clinically oriented updated overview on the pathophysiology of OIH, focuses predominantly on evidence-based clinical and management aspects of this important and often baffling phenomenon. Method: Online and manual search using key words such as opioid-induced hyperalgesia, opioid-induced abnormal pain sensitivity, opioid hyperalgesia, opioid-induced paradoxical pain, or opioid-induced abnormal pain, followed by full-text access and further cross-referencing. Results: The underlying pathophysiology of this phenomenon, although still unclear, appears to be related to an opioid-induced imbalance between the internal antinociceptive and pronociceptive systems. Clinical differentiation of an apparent opioid tolerance state includes OIH. Once diagnosed or provisionally considered, treatment strategies could include opioid dose reduction, opioid rotation, use of agents with NMBA receptor antagonism, and a properly timed coxib. Conclusion: Despite initial skepticism and reservations, the phenomenon of OIH in humans is now accepted a clinical reality and a challenge faced by anesthesiologists, intensivists, pain specialists, and other workers in a diverse range of settings from perioperative care to palliative care medicine.

( BUPP09095 - 18 August 2008) A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges.

We carried out a national survey on postoperative pain (POP) management in a representative sample (public/private, teaching/non-teaching, size) of 76 surgical centers in France. Based on medical records and questionnaires, we evaluated adult patients 24 h after surgery, concerning information: pre and postoperative pain, evaluation, treatment and side effects. A local consultant provided information about POP management. Data were recorded for 1900 adult patients, 69.3% of whom remembered information on POP. Information was mainly delivered orally (90.3%) and rarely noted on the patient's chart (18.2%). Written evaluations of POP were frequent on the ward (93.7%) with appropriate intervals (4.1 (4.0) h), but not frequently prescribed (32.7%). Pain evaluations were based on visual analog scale (21.1%), numerical scale (41.2%), verbal scale (13.8%) or non-numerical tool (24%). Pain was rarely a criterion for recovery room discharge (19.8%). Reported POP was mild at rest (2.7 (1.3)), moderate during movement (4.9 (1.9)) and intense at its maximal level (6.4 (2.0)). Incidence of side effects was similar according to patient (26.4%) or medical chart (25.1%) including mostly nausea and vomiting (83.3%). Analgesia was frequently initiated during anesthesia (63.6%). Patient-controlled analgesia (21.4%) was used less frequently than subcutaneous morphine (35.1%) whose prescription frequently did not follow guidelines. Non-opioid analgesics used included paracetamol (90.3%), ketoprofen (48.5%) and nefopam (21.4%). Epidural (1.5%) and peripheral (4.7%) nerve blocks were under used. Evaluation (63.4%) or treatment (74.1%) protocols were not available for all patients. This national, prospective, patient-based, survey reveals both progress and persistent challenges in POP management

( BUPP09096 - 18 August 2008) Normative data of multifrequency tympanometry in rabbits.

In an experimental study, we evaluated acoustic immittance in rabbits in order to use these data as normative values for further experimental investigations. This study is the first experimental evaluation of both conventional 226 Hz and multifrequency tympanometry (MFT) in rabbits. For the investigation, we used 33 female New Zealand rabbits weighing 3.2 - 4.4 kg and aged six months. Bilateral measurements using conventional 226 Hz and MFT were performed under general anaesthetic. A 226 Hz tympanogram was recorded for all animals by conducting an air pressure sweep from +200 to -400 daPa at a rate of 50 daPa/s. Subsequent tympanograms were recorded over a wide frequency range from 250 to 2000 Hz. The acoustic impedance device used in this study provided reproducible and evaluable tympanograms. The applied tone frequency of 226 Hz proved to be especially suitable for determining compliance. Normative data obtained from our study reveal the resonance frequency to be 1368�205 standard deviation (SD) for the right side and 1413�216 SD for the left side. The values for physiological acoustic immittance of the middle ear in the rabbit obtained here can serve as normative data in subsequent experimental animal studies.

( BUPP09097 - 18 August 2008) Pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 polymorphisms: Are we there yet?

Recent changes to the labels of three prescription drugs - irinotecan, 6-mercaptopurine, and warfarin - include recommendations for pharmacogenetic testing in patients. Thus, clinicians are faced with determining the utility and practicality of pharmacogenetic testing in clinical practice. We illustrate the clinical implications that this testing may have using irinotecan, an agent approved for the treatment of metastatic colorectal cancer, as an example. A clinical association between the drug's active metabolite and toxicity has been found. By performing uridine diphosphate lucuronosyltransferase (UGT) 1A1 genetic testing, some studies have been able to predict which patients receiving irinotecan will experience the toxicity. Thus, irinotecan's package insert was revised to include a recommendation for such testing. In addition, the United States Food and Drug Administration approved a clinical test for the UGT1A1*28 allele. These events demonstrate that pharmacogenetics has entered the realm of clinical practice. However, the transition from bench to bedside of these tests has distinct challenges such as population differences, test sensitivity, and the role of other genetic and nongenetic factors that influence drug toxicity. In addition, ethical and logistic implications of pharmacogenetic testing exist.

( BUPP09098 - 18 August 2008) Palliative medicine: Pain management according to time and step-by-step plan.

( BUPP09099 - 18 August 2008) A clinical snapshot of transdermal buprenorphine in pain management.

New and effective analgesics for the treatment of pain are essential. Buprenorphine, a partial mu receptor agonist, offers unique physico-chemical and pharmacological qualities, making it an attractive first-choice opioid for the treatment of acute and chronic pain. Several delivery formulations are available including parental, sublingual tablet, sublingual solution and transdermal. The parental formulation has been administered intravenously, intramuscularly, epidurally and intrathecally. Transdermal patches allow the drug to be continuously absorbed through the skin and into the systemic circulation. This approach has been shown to have clinical benefit, along with high-level patient acceptability, compliance and improved quality of life. However, further randomised controlled trials are needed to focus on defining dose requirements in different pain states and the appropriateness and utilisation of adjuvant analgesics when required.

( BUPP09100 - 18 August 2008) Basic pharmacology of buprenorphine.

Buprenorphine is a derivative of the morphine alkaloid thebaine. The plasma elimination half-life of buprenorphine is three times longer than that of the active metabolite, norbuprenorphine. Although the elimination of norbuprenorphine from the body is more rapid than that of buprenorphine, the plasma concentration of norbuprenorphine was observed to exceed that of buprenorphine with chronic administration of buprenorphine. This plasma level of norbuprenorphine is based on the proportional increase in norbuprenorphine-glucuronide observed after one enterohepatic circulation of buprenorphine due to the first-pass metabolism. When buprenorphine and norbuprenorphine were administered intraventricularly, the analgesic effect of norbuprenorphine was approximately one-fourth that of buprenorphine. After intravenous administration of buprenorphine or norbuprenorphine in rats, the analgesic effect of norbuprenorphine was approximately 1/50th that of buprenorphine. The remarkably weak analgesic effect of norbuprenorphine after intravenous administration may be due to the low permeability of norbuprenorphine into the brain. Therefore, the plasma concentration of norbuprenorphine with chronic administration of buprenorphine has little analgesic effect. The most dangerous side effect of opioid therapy is respiratory depression. In our study of the respiratory effects after intravenous infusion in rats, norbuprenorphine was ten times more potent than the parent drug. However, it is possible that the plasma levels of norbuprenorphine with chronic administration of buprenorphine are not sufficiently high to depress respiratory function. Overall, buprenorphine is a safe and highly effective analgesic opioid for the treatment of chronic pain.

( BUPP09101 - 18 August 2008) Cancer pain management modalities and positioning of oxycodone.

Cancer pain management is centered on opioid therapy. In Japan, 3 types of strong opioid are available for treatment; therefore it is important to use them according to the characteristics of each drug and dosage form. Particularly, oxycodone is suitable as first-line choice of opioid, which can also be employed as opioid switching when symptoms of the central nervous system is manifested following the use of oral morphine. Furthermore, opioid responsiveness should be taken into account when opioid therapy is carried out; assessment of the analgesic effect is particularly important. Recently, we tried to select suitable treatment modalities by speculating on the pathologic conditions of pain relative to the responsiveness to morphine and causes of pain. In the case of pain with low response to morphine, it was possible to attain good pain control not only by opioid therapy but also by a combination of opioid therapy and nerve block therapy. In cancer pain treatment, appropriate assessment of pathologic conditions of pain and selection of adequate and accurate treatment modalities are essential for improvement of the effect of pain relief.

( BUPP09102 - 18 August 2008) Predicting pain and pain responses to opioids.

The mechanisms behind the wide individual variability in pain experience and relief are an area of intense research activity. Predicting individual clinical pain and the responsiveness to analgesics should increase the efficacy and tolerability of analgesic treatments, and improve the overall treatment outcome. Several factors have shown validity in the prediction of pain, with most studies having been performed in postoperative pain. These factors include younger age, female gender, multiple psychosocial contributors (e.g. negative affect, somatisation, depressive mood, expectations, anxiety), pre-existing physical comorbidities and pain, information provided by carers, and the nature of the pain insult. Recent studies have shown quantitiative sensory testing at high stimulus intensity (e.g. pain thresholds), as well as specific genetic factors and the functional testing of the endogenous pain modulatory pathways as emerging useful tools in the study of individual pain variability. Many of the above factors are also relevant in the prediction of analgesic responsiveness. The predominant pain characteristics, pain chronicity and neuroplastic changes, opioid-related genetic factors and psychological factors (including placebo response components) are major determinants of analgesic efficacy. Prediction of analgesia using quantitative sensory tests has been studied with some success. Better prediction of individual pain and analgesic responsiveness promises to improve pain control and general treatment outcome, and reduce adverse events as well as costs. Further prospective studies with interdisciplinary input validating the usefulness of predictive variables within algorithms are encouraged in large patient cohorts.

( BUPP09103 - 18 August 2008) The 3rd Asia Pacific Symposium on Pain Control, Singapore, September 1-3, 2006: Introduction and Overview

The first Asia Pacific Symposium on Pain Control (APSPC) was held in 1991 in Sydney Australia, with the intention of providing the Asia Pacific region with an international platform for discussing emerging concepts in cancer pain management with special regard to oral controlled release morphine. The Proceedings were published in the Postgraduate Medical Journal, Vol 67 S2, 1991. Ten years later followed the 2nd APSPC, also in Sydney and equally successful, with a timely update on further developments in chronic pain management, and with the newly introduced controlled release oxycodone tablets as a novelty in the armamentarium of strong oral opioid analgesics. Proceedings were published in the European Journal of Pain, Vol 5 SA,2001

( BUPP09104 - 18 August 2008) Family 1 uridine-5'-diphosphate glucuronosyltransferases (UGT1A): From Gilbert's syndrome to genetic organization and variability.

The human UDP-glucuronosyltransferase 1A gene locus is organized to generate enzymes, which share a carboxyterminal portion and are unique at their aminoterminal variable region. Expression is tissue-specific and overlapping substrate specificities include a broad spectrum of endogenous and xenobiotic compounds as well as many therapeutic drugs targeted for detoxification and elimination by glucuronidation. The absence of glucuronidation leads to fatal hyperbilirubinemia. A remarkable interindividual variability of UDP-glucuronosyltransferases is evidenced by over 100 identified genetic variants leading to alterations of catalytic activites or transcription levels. Variant alleles with lower carcinogen detoxification activity have been associated with cancer risk such as colorectal cancer and hepatocellular carcinoma. Genetic variants and haplotypes have been identified as risk factors for unwanted drug effects of the anticancer drug irinotecan and the antiviral proteinase inhibitor atazanavir. Glucuronidation and its variability are likely to represent an important factor for individualized drug therapy and risk prediction impacting the drug development and licensing processes

( BUPP09105 - 18 August 2008) Pharmacogenetics of Gilbert's syndrome.

The pharamcogenetics of Gilbert's syndrome is reviewed. Topics discussed are: the uridine diphosphate-5'-glucuronosyltransferase (UGT) 1A gene locus; genetic variation at the UGT1A gene locus; bilirubin metabolism and UGT genes; the UGT1A1 gene; Gilbert's syndrome variants and specific pharmacogenetic risks; disposition to drug toxicity; irinotecan toxicity; and jaundice in proteinase inhibitor therapy (atazanavir). The analysis of transcriptional regulation of the UGT1A genes will offer the potential for therapeutic intervention by identifying druggable inducers that could be co-administered with potentially side effect prone drugs.

( BUPP09106 - 18 August 2008) Monitored anaesthesia care in the elderly - Guidelines and recommendations.

Monitored anesthesia care in the elderly is reviewed with respect to: age-related physiological changes in the elderly; patient preparation; patient-specific monitoring; assessment of the level of sedation; specific agents, doses and related risks for medications used for monitored anesthesia care; specific procedures performed under monitored anesthesia care; potential complications associated with monitored anesthesia care in the elderly; postoperative pain control in the elderly after monitored anesthesia care; and discharge criteria for the elderly after monitored anesthesia care. Anesthetic dosing should be in smaller increments in the elderly, boluses reduced by half and infusions reduced by as much as two-thirds. Caution must be exercised through full monitoring of intra-operative and postoperative mental status, oxygenation and perfusion states.

( BUPP09107 - 18 August 2008) Comparable analgesic efficacy of transdermal buprenorphine in patients over and under 65 years of age.

This prospective age-controlled, open clinical trial compared the efficacy and tolerability of transdermal and sublingual buprenorphine (Transtec patches, Grunenthal GmbH) in 82 elderly patients and younger populations with moderate-to-severe chronic pain. Daily mean pain intensities were even lower in elderly patients vs. younger age-groups. Sleep duration incidences above 6 hr improved from 34% to a plateau above 50% for patients terminating the study as planned. The need for rescue medication was lowest in elderly patients. The opioid typical adverse event profile (predominantly dizziness and nausea) and local skin tolerability were both comparable for younger and elderly patients. Treatment of chronic pain with transdermal buprenorphine in elderly patients above the age of 65 yr is at least as effective, tolerable, and safe as in patients studied in 2 age-groups below that age.

( BUPP09108 - 18 August 2008) Is hepatitis C prevalence decreasing among opiate-substituted drug users attending an addiction outpatient unit in France?

Background and Aims: A previous study conducted in our area in 2003 has shown that HCV prevalence in drug users attending an addiction out patient unit was 66%. The aim of our prospective study is to know if this prevalence has changed in 2007. Methods: A screening for Hepatitis B and C virus, HIV, ALT was offered by the addiction physician to each Opiate Maintenance Treatment (OMT) patient. Samples of venous or capillary blood were collected in the unit. Results: Among the 239 consecutive DU (81 with methadone (MM)- and 158 with buprenorphine (BM)- maintenance), 183 (77%) have been screened without difference according to the type of substitution. 76% were male; mean age was 31.3 years (34.4 vs 29.7 in MM and BM patients respectively, p<0.05). Twenty percent of the samples were performed on capillary blood (41% in MM patients vs 9% in BM patients; p<0.05). While the prevalence of HCV antibodies was 66% in 2003 in this same unit, it was only 19.0% in 2007 (n=35) (37.9% in MM patients vs 8.5% in BM patients; p<0.05). HCV RNA was found in 88.6% of those patients. ALT was higher than the upper limit of normal in 15 out of 26 patients. Daily excessive alcohol intake was observed more frequently in the DU with HCV antibodies (52.9% vs 22.1%; p<0.05) or with MM treatment (44.4% vs 22.8% in BM patients; p=0.03). All patients were antigen HBs-negative and 4 patients were co-infected with HIV-HCV. Conclusion: This study highlights a clear decrease if the hepatitis C prevalence in DU with opiate maintenance treatment in our centre. It can reflect the effectiveness of sanitary guidelines proposed by French authorities in the middle of the 90's and/or a modification of patients' course in the health-care system with a management of highest HVD risk DU apart from our unit. These data underline the need for an extension of systematic screening in other addiction of our town to confirm these results.

( BUPP09109 - 18 August 2008) Relapse rate and outcome after liver transplantation (LT) in former intravenous drug (IVD) abusers.

Background and Aims: Former IVD abusers and patients on methadone of buprenorphine maintenance therapy are accepted in many LT programs. The risks of IVD relapse and the effects on long term survival, however, have been seldom investigated. The aims of the present study wee to address these issues across more transplantation centers in different countries. Methods: Patients with a past history of IVD abuse were identified from the liver transplantation listing protocols from the University Hospitals of Geneva (Switzerland), Grenoble and Lyon (France). Pertinent demographic information and data on survival and relapse were collected and analyzed. Results: Of 1486 liver transplanted patients in these centers between 1985 and 2006, we identified 59 (4.0%) patients with a past history if intravenous drug use. The mean age of transplantation was 46.7 years (range 22-58) and the majority of patients were men (84.7%). The indications for LT were HCV (61%), HBV +HCV (14%), HBV (6.8%), HCV+HIV (3.4%), HBV+HCV+HIV (1.7%), alcohol (5.1%). The mean length of IVD abstinence at the time of listing was 132 months and patients had a mean duration of IVD use before transplantation of 54 months (dependence mode 43%, abuse 15, and occasional use 42%). A substitution therapy with methadone or buprenorphine was administered in 16.9% of patients before transplantation and 6.8% continued after LT. The mean follow up duration was 50 months (range 5 to 168). Post transplant relapse into IVD use was observed in 2 patients (3.4%). Overall survival was 84%, 66% and 61% at 1, 5 and 10 year transplantation, respectively. In 3/17 cases the cause of death was related to a lack of compliance to medication leading to organ loss. Conclusion: Data from the largest cohort of patients with former IVD abuse show a relapse rate of 3.4% after LT. The use of non-IV illicit drugs is not affected by LT. The overall outcome is similar to survival in the general population after LT, but is negatively affected by a major lack of compliance, responsible for the death in 18% of patients.

( BUPP09110 - 26 August 2008) Management of cancer pain: ESMO Clinical Recommendations.

The ESMO clinical recommendations on the management of cancer pain are reviewed. The following topics are discussed: the incidence of cancer pain; the assessment and management of cancer pain; the treatment of mild, moderate, and severe cancer pain (WHO level I, II, and III, respectively); the scheduling and titration of drug treatments; the management of opioid side-effects; radiotherapy, surgery, and other interventions; the treatment of resistant and neuropathic pain; and coanalgesic medication. The drugs discussed are paracetamol, acetylsalicylic acid, ibuprofen, ketoprofen, diclofenac, mefenamic acid, naproxen, dihydrocodeine, tramadol, morphine sulfate, oxycodone, hydromorphone, fentanyl, buprenorphine, methadone, nicomorphine, amitriptyline, clomipramine, nortriptyline, fluoxetine, haloperidol, chlorpromazine, carbamazepine, gabapentin, and pregabalin.

( BUPP09111 - 26 August 2008) Formation of the N-methylpyridinium derivative to improve the detection of buprenorphine by liquid chromatography-mass spectrometry.

The legally defensible identification of the narcotic, analgesic buprenorphine, in biological specimen requires considerable sensitivity due to its low therapeutic dosages and corresponding target concentrations. Application of liquid chromatography-electrospray ionisation-mass spectrometry, which became the default method for buprenorphine detection, is impeded by the disadvantageous fragmentation of the stable precursor ion producing unspecific product ions of comparatively low abundance. A chemical modification to form the N-methylpyridinium ether derivative of buprenorphine is presented to improve the selectivity and sensitivity of its detection by liquid chromatography-mass spectrometry (LC-MS). The reaction of buprenorphine with 2-fluoro-1-methyl-pyridinium-p-toluene-sulfonate and triethylamine as catalyst was accomplished in acetonitrile at an ambient temperature yielding a chemically stable derivative. Fragmentation of the permanently charged precursor ion (m/z = 559) leads to the formation of diagnostic and abundant fragments (e.g. m/z = 443 and 450) representing all parts of the molecule. The application of the technique to the identification of buprenorphine in hair samples demonstrates a high specificity, availability of sufficient qualifier ions and a significant (approximately 8-fold) improvement of detection limits with respect to comparable experiments based on underivatised buprenorphine.

( BUPP09112 - 26 August 2008) Methadone and buprenorphine treatment during pregnancy: what are the effects on infants?

( BUPP09113 - 26 August 2008) Drug-induced dementia: A case/non-case study in the French pharmacovigilance database.

The increased incidence of dementia on the aging population makes this disease a major public health problem. Among known causes of dementia, drug etiology is under considered. We investigated the relationship between exposure to drug therapy and dementia with a case/non-case study using reports of the French Pharmacovigilance database. Among 263 962 adverse effects recorded between 1985 and 2005, 79 (0.03%) are dementia. Median age is 66 (range 3-91). There was 41 women and 37 men. The therapeutic drug class associated with dementia were anticonvulsants, antiparkinsonians, antidepressants, anxiolytics, hypnotics, antipsychotics and morphinics. An association between reporting of dementia and non neurotropic drugs were also found, i.e. interferon alfa-2B, vancomycin and allopurinol. The term "Dementia" is only mentioned in the summary of the characteristics of valproate, but it may concern other drugs. Drug etiology for dementia is a reality but is not necessarily attributed as a cause in aging population, in particular.

( BUPP09114 - 26 August 2008) Pharmacokinetic approaches to treatment of drug addiction.

The pharmacokinetic approach to treatment targets the drug molecules themselves, aiming to reduce their concentration at the site of action, thereby reducing or preventing any pharmacodynamic effect. This approach might be useful in the treatment of acute drug toxicity/overdose and in the long-term treatment of addiction. Early clinical trials with anticocaine and antinicotine vaccines have shown reduced drug use and good tolerability. Also showing promise in animal studies are monoclonal antibodies against cocaine, methamphetamine and phencyclidine, as well as the enhancment of cocaine metabolism with genetic variants of human butyrylcholinesterase, using a bacterial esterase or catalytic monoclonal antibodies. Pharmacokinetic treatments offer potential advantages in terms of patient compliance, absence of medication interactions and benefit for patients who cannot take standard medications.

( BUPP09115 - 26 August 2008) First, Remove the Offending Agent

( BUPP09116 - 26 August 2008) Efficacy and clinical management of buprenorphine.

Objectives. To describe both, the clinical efficacy of buprenorphine in the maintenance treatment of opioid dependence and the most relevants aspects of the clinical use. Material and methods. This review describes the most relevant studies that have evaluated the efficacy of burprenorphine as maintenance treatment of opioid dependence, compared to placebo and other opiate treatments. Other indication for which buprenorphine has been studied are described. Results. Buprenorphine is an opiate that has demonstrated efficacy in the maintenance treatment of opiate dependent patients when compared to placebo as well as to other opiate treatments (methadone, L-alpha-acetyl-methadol (LAAM), morphine and heroin). Buprenorphine is a safe and well tolerated drug and can be used as fixed or flexible doses, which means that is easy to start the treatment and carry on it. Conclusions. Buprenorphine is effective in the treatment of opiate addiction, in maintenance or detoxification programs, specially in patients with affective disorders comorbidity.

( BUPP09117 - 26 August 2008) Interactions between antiretroviral therapy (ART) and substitution medications in HIV-infected drug users.

( BUPP09118 - 26 August 2008) Immunotherapies for drug addictions.

Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders.

( BUPP09119 - 26 August 2008) Hysteresis in drug response.

Hysteresis may be defined as 'the retardation or lagging of an effect behind the cause of the effect'. The two main reasons for the lag phase are limited access to the site of drug action or slow receptor kinetics. Both of these characteristics would produce an anticlockwise hysteresis, in which time moves anticlockwise in the change in the relationship between plasma concentration and observed effect with time. An alternative definition would be 'failure of one of two related phenomena to keep pace with the other', and would include any situation in which the value of one variable depends on whether the other variable is increasing or decreasing. This definition would take in clockwise hysteresis, which is seen in drug tolerance.

( BUPP09120 - 26 August 2008) Addiction and substance misuse.

Alcohol and psychoactive substance misuse has far-reaching social, psychological and physical consequences. The numbers of women and young people exposed to the harmful effects of substances have increased. Substance use, misuse and addiction incur immense cost to the individual and to society. It is paramount to adequately assess substances misuse, and recognize the effects of intoxication, withdrawal and chronic effects. It is also important to diagnose associated disorders to treat promptly and adequately these often life-threatening conditions. Focus should be put on management of the misuse itself, using appropriate pharmacotherapy as an adjunct to psychosocial approaches, but also remember to address any physical and psychiatric sequelae.

( BUPP09121 - 26 August 2008) Characteristics of alcohol-dependent male inmates

Objective: The objective of this study was to compare social and penal characteristics and consumption of psychoactive substances by alcohol-dependent and non-dependent inmates of the Lyon's prison in 2004. Methods: The study was carried out among 2033 male adults incarcerated between January 1st and December 31st 2004. An administered questionnaire was proposed during the arrival visit to record social, administrative and penal data. Use of tobacco, alcohol and illicit drugs was quantified. Results: In all, 1898 questionnaires were analysed. Comparison between alcohol-dependent (n = 356) versus non alcohol-dependent inmates (n = 1542), revealed that the alcohol-dependent population was older, mean age (34 years old versus 30 years, p < 0.001), and had a higher unemployment rate (50% versus 39.4%, p < 0.001). Alcohol addicts were more often repeated offenders (62% versus 50.7%, p = 0.001), had a higher rate of Subutex mixture (11% versus 3.2%, p < 0.001) and presented more psychic suffering (21% versus 6%, p < 0.001). Multivariate analysis identified use of psychotop drugs, use of psychoactive substances, age and familial situation as significantly and independently associated with the abusise alcohol consumption. Conclusion: Because of an elevated prevalence of alcohol dependence among arriving penitentiary inmates, effective screening is needed to prevent withdrawal syndrome and propose care adapted to the specific features of this dependent population: social insecurity and polydrug abuse.

( BUPP09122 - 26 August 2008) The nociceptin/orphanin FQ receptor: A target with broad therapeutic potential.

Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of reverse pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ-NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.

( BUPP09123 - 01 September 2008) ADR news: Buprenorphine abuse. Cerebral embolism (first report) following parenteral administration: case report. Serious.

A woman in her mid-forties (exact age not stated) developed cerebral embolisms while abusing buprenorphine (Subutex) parenterally. The woman had a history of opioid abuse and dependence since age 17 years. She was prescribed sublingual buprenorphine by her physician in 2003 (dosage and indication not stated). However, she quickly began abusing buprenorphine intravenously to achieve a high. She reported crushing 1-3 buprenorphine tablets, mixing the resulting powder in hot water and injecting it. When venous access became a problem she started using her left radial artery. She then reported having a friend inject buprenorphine into her jugular vein and carotid artery, on at least 10 occasions starting 2 months prior to presentation. The most recent occurrence was just days before she presented with blurred vision that waxed and waned (duration of abuse not stated). At time of presentation she had subacute bacterial endocarditis. Ophthalmologic examination revealed no abnormalities. She experienced symptoms of cravings and opioid withdrawal, with a psychiatric interview confirming opioid dependence. She scored 25/30 on the Mini-Mental State Examination. Her score on the Montreal Cognitive Assessment (24/30) was consistent with mild cognitive impairment, and suggested involvement of the visuospatial system. Several foci of T2 and FLAIR hyperintensity were evident upon MRI in the right frontal lobe and bilaterally in the temporal and parietal lobes. Corresponding hyperintensity of these foci were seen during diffusion weighted imaging, suggestive of multiple embolic infarcts. The woman's blurred vision resolved during hospitalisation and she was discharged. Follow up was planned with substance abuse and neuropsychiatry services. Author Comment: "It would not always be possible to distinguish whether the embolic phenomenon is caused by or associated with this patient's subacute endocarditis or the parenteral buprenorphine or both, which, in our view, is most likely the case." Editorial Comment: A search of AdisBase, Medline, Embase and The WHO Adverse Drug Reactions database did not reveal any previous case reports of cerebral embolism associated with buprenorphine.

( BUPP09124 - 01 September 2008) A comparative study of the ventilatory effects of four opioids administered at toxic doses in the rat.

The Authors performed an experimental study in Sprague-Dawley rats, to compare the respiratory effects of the i.p. methadone (MET), buprenorphine (BUP), morphine (MOR), and fentanyl (FEN). MET, MOR and FEN except BUP induced respiratory depression characterized by a increase of inspiratory time (TI) and decrease in respiratory rate, without any modification of tidal volume. MET and FEN increased expiratory time (TE) and decreased minute ventilation. Mechanisms of respiratory depression in relation with opioid toxic doses is not uniform, depending on the molecule. These results suggest, a different control pattern of inspiratory and expiratory times by opioid receptors.

( BUPP09125 - 01 September 2008) Neonatal outcome of 58 infants exposed to maternal buprenorphine in utero.

This prospective study examined the neonatal outcome of 58 infants exposed to buprenorphine (BH) in utero. All infants had BH in their urine. A total of 38 infants required 20 days of morphine HCl (MH) treatment for neonatal abstinence syndrome. The length of hospital stay for all infants was 25 days. The infants' highest urinary nor-BH concentrations across their 1st 3 days of life correlated with the length of hospital stay and duration of MH treatment. The mean birth weight and mean head circumference were below average. 11 Infants were discharged home, 19 were placed in foster care, 28 were discharged with their mothers to Mother and Child homes or to other institutions and 1 infant followed her mother to prison. Maternal BH use at the time of birth may cause neonatal abstinence syndrome, requiring long-term hospitalization.

( BUPP09126 - 01 September 2008) Monitoring of the misuse of prescription drugs by clients of outpatient addiction treatment centres (PHAR-MON, formerly: ebis-med) - Monitoring of medication misuse.

Objectives: The monitoring system PHAR-MON (formerly: ebis-med) documents the misuse of pharmaceuticals in addiction counseling centres as an early warning system. It is described as a diagnostic instrument according to its aims and tasks, implementation and assessing procedures and is evaluated according to the main quality criteria of diagnostic instruments. In addition, selected results are reported about the misuse of medicaments in the year 2004. Methods: In analogy to diagnostic instruments, the main quality criteria objectivity, reliability and validity are applied to evaluate PHAR-MON, they are extended, however, by the validity of the sample of reference outpatient centers. Statistical methods for proving results are applied and discussed concerning their appropriateness for cross-sectional and longitudinal analyses of PHAR-MON data. The selected results are based on the survey data for 2004 of 32 counseling centers with 629 medicaments abused by 500 clients. The representativity was checked by comparison with the outpatient addiction statistics. Results: The sample of counseling centers is representative for all addiction counseling centers in Germany. The dominant influence factor on the abuse of medicaments is the main diagnosis of the clients. Therefore, the analysis is separated for the main diagnoses as to alcohol, illegal drugs and medicaments. The statistical methods of confidence intervals and other statistical procedures are useful in proving data for cross-sectional and longitudinal analyses. In 2004 there was an increase of abused buprenorphine by 5.7% compared to the previous year. The rate of misuse of hypnotics, which is the largest group of abused medicaments, only slightly increased by 2.4%. Conclusions: The monitoring system PHAR-MON is a sensitive and valid monitoring system for the abuse of medicaments in addiction counseling centres. By documenting individual criteria of abuse in the new version of the documentation sheet, the results of medicament abuse can be analyzed in a more valid way. To improve the PHAR-MON system a study about reliability is planned. Because of the health risks associated with the abuse of medicaments, continuous information for physicians about the risks of medicament abuse is helpful to prevent negative consequences.

( BUPP09127 - 01 September 2008) Health care utilization and morbidity associated with methadone and buprenorphine treatment.

Background: Methadone and buprenorphine treatment reduce the high mortality associated with heroin addiction, but even in-treatment, Standardised Mortality Rates are high. Aim: This study investigates the nature of morbidity associated with methadone and buprenorphine treatment, and investigates predictors of health care utilization among people in a variety of treatment settings. Methods: Collation of data from earlier studies, and from published reports. Findings: In a recent study of an entry cohort, the SMR was 5.52 (4.62, 5.65); suicide and overdose accounted for 2/3 of the mortality, but allowing for this, mortality rates remain elevated. Cancer, heart disease and respiratory disease were the three major contributors to mortality. Taken in conjunction with a recent study of medical co-morbidity, this suggests that alcohol, tobacco and other drug use represent the major factors contributing to serious illness in treated opioid addicts. In addition, side-effects of treatment may themselves contribute to some morbidity. Lack of access to health care does not appear to be a contributing factor, as opioid users consult doctors (other than their methadone doctors) at rates far higher than the general population. Predictors of doctor attendance "outside" doctors were psychological distress, and benzodiazepine use. Adjusting for these factors, we found evidence that quality of methadone treatment was a significant predictor of doctor attendance, with better clinical care being associated with less outside doctor attendance. Conclusion: There is a paradox; heroin users have significant physical illness, but their attendance for health care tends to be driven by psychological distress, and can be improved by good care within treatment programs. The priority in addressing health problems of stabilised heroin users is dealing with alcohol and tobacco problems.

( BUPP09128 - 01 September 2008) Effects of epidurally administered morphine or buprenorphine on the thermal threshold in cats.

Objective - To determine the antinociceptive effects of epidural administration of morphine or buprenorphine in cats by use of a thermal threshold model. Animals - 6 healthy adult cats. Procedures - Baseline thermal threshold was determined in duplicate. Cats were anesthetized with isoflurane in oxygen. Morphine (100 mug/kg diluted with saline (0.9% NaCl) solution to a total volume of 0.3 mL/ kg), buprenorphine (12.5 mug/kg diluted with saline solution to a total volume of 0.3 mL/kg), or saline solution (0.3 mL/kg) was administered into the epidural space according to a Latin square design. Thermal threshold was determined at various times up to 24 hours after epidural injection. Results - Epidural administration of saline solution did not affect thermal threshold. Thermal threshold was significantly higher after epidural administration of morphine and buprenorphine, compared with the effect of saline solution, from 1 to 16 hours and 1 to 10 hours, respectively. Maximum (cutout) temperature was reached without the cat reacting in 0, 74, and 11 occasions in the saline solution, morphine, and buprenorphine groups, respectively. Conclusions and Clinical Relevance - Epidural administration of morphine and buprenorphine induced thermal antinociception in cats. At the doses used in this study, the effect of morphine lasted longer and was more intense than that of buprenorphine.

( BUPP09129 - 01 September 2008) Addiction and addiction medicine: Exploring opportunities for the general practitioner.

Addiction medicine deals with problems arising from the use of psychoactive substances, and encompasses the disciplines of general practice and primary care, psychiatry, psychology, internal medicine, public health, pharmacology and sociology. Addiction is a chronic, relapsing illness that is difficult to cure. There are now effective, evidence-based interventions for the prevention and treatment of substance misuse disorders. Harm minimisation and treatment are more cost-effective than policing and supply-reduction methods of responding to substance misuse.

( BUPP09130 - 01 September 2008) Pain in the elderley

05/09/08 Message from the BL: Placed on a waiting list

( BUPP09131 - 01 September 2008) Intravenous regional anesthesia - First century (1908-2008). Beggining, development, and current status.

BACKGROUND AND OBJECTIVES: Intravenous regional block is celebrating its 100 /sup th/ anniversary in 2008. Since this is a widely used technique, this milestone should be recorded, the date celebrated, Brazilian anesthesiologists should be remembered of its evolutive process, especially in the last 40 years, and we should pay homage to the individual who started it: August Karl Gustav Bier. CONTENTS: This report describes the beginning of locoregional anesthesia in general and regional intravenous block in particular, since the introduction of garroting of the extremities to the discovery and improvement of needles, syringes, and local anesthetics. The technical details used initially by Bier, and the pathophysiological and clinical concepts enounced by him at the beginning of the 20 /sup th/ Century are described. It describes the initial evolution and that of the following decades of intravenous regional block, lists national and international pioneers, explains the reasons for the relatively late scientific studies on the technique, and describes the main contributions that made it an effective and safe technique. Finally, it describes the current state of the main knowledge acquired over the years, such as the mechanism and site of action of the anesthetic and ischemia, the use of modern anesthetic solutions, improvement of postoperative analgesia and motor block, pharmacokinetic and pathophysiological concepts, and the best interpretation of possible complications. CONCLUSIONS: Intravenous regional block is the anesthetic technique created by A. K. G. Bier exactly 100 years ago. In the first half of the 20 /sup th/ Century, it evolved little and slowly, but in the last several years, it has seen an accentuated improvement, thanks to countless technical, pathophysiological, pharmacological, pharmacokinetic, and clinical developments, for which Brazilian Anesthesiology has contributed considerably. Since it is celebrating its 100 /sup th/ anniversary in 2008, intravenous regional block deserves to have its story told, and the date should not go unnoticed, but should be remembered and celebrated

( BUPP09132 - 01 September 2008) Early behavioral and histological outcomes following a novel traumatic partial nerve lesion.

A new partial nerve lesion (PNL) model is needed to better simulate traumatic lesions seen clinically that result in both dysfunction and neuropathic pain. We assessed surgical variability and several outcome measures including histology during the acute postoperative period. A surgical lesion was created in the rat tibial nerve by removing a segment, later confirmed by myelinated axon counts. Variability in the model was assessed with four different outcome measures during the first postoperative week (n = 24), with additional histological outcomes at 7 days (n = 13) and pain testing at 21 days (n = 9). At 7 days postoperative, the PNL resulted in a tibial functional index (TFI) of -41.3% distinct from a percent motor deficit (PMD) of -76.3%. However, the respective deficits from 2 to 7 days were similar. Either test could detect outliers, but PMD measurements had a lower coefficient of variation and were easier to perform and analyze. The deleted segment contained 26% of the myelinated axons and resulted in distal degeneration that was either 46% based on axon counts or 54% based on area. Replicated experiments confirmed the PMD, muscle atrophy, and formation of neuropathic pain. In conclusion, our partial lesion histologically progresses twofold during the first postoperative week with profound behavioral deficits involving both motor and sensory loss. These results based on sensitive and correlative outcome measures support the application of this novel model in experimental nerve lesion studies.

( BUPP09133 - 01 September 2008) Buprenorphine treatment in an urban community health center: What to expect.

Background: Despite new opportunities to expand buprenorphine treatment for opioid dependence, use of this treatment modality has been limited. Physicians may question their ability to successfully treat opioid-dependent patients with buprenorphine in a primary care setting. We describe a buprenorphine treatment program and treatment outcomes in an urban community health center. Methods: We conducted retrospective chart reviews on the first 41 opioid-dependent patients treated with buprenorphine/naloxone. The primary outcome was 90-day retention in treatment. Results: Patients' mean age was 46 years, 70.7% were male, 58.8% Hispanic, 31.7% black, 57.5% unemployed, and 70.0% used heroin prior to treatment. Twenty-nine (70.7%) patients were retained in treatment at day 90. Compared to those not retained, patients retained in treatment were more likely to have used street methadone (0% versus 37.9%) and less likely to have used opioid analgesics (54.6% versus 20.7%) and alcohol (50.0% versus 13.8%) prior to treatment. Of the 25 patients with urine toxicology tests, 24% tested positive for opioids. Conclusions: Buprenorphine treatment for opioid dependence in an urban community health center resulted in a 90-day retention rate of 70.7%. Type of substance use prior to treatment appeared to be associated with retention. These findings can help guide program development.

( BUPP09134 - 01 September 2008) Preliminary study of buprenorphine and bupropion for opioid-dependent smokers.

In this double-blind, placebo-controlled trial, bupropion (BUPRO, 300 mg/day) was compared to placebo (PBO) for the concurrent treatment of opioid and tobacco addiction in 40 opioid-dependent smokers stabilized on buprenorphine (BUPRE, 24 mg/day). Participants received contingent, monetary reinforcement for abstinence from smoking, illicit opioids, and cocaine. Significant differences in treatment retention were observed (BUPRE+BUPRO, 58%; BUPRE+PBO, 90%). BUPRO treatment was not more effective than placebo for abstinence from tobacco, opioids, or cocaine in BUPRE-stabilized patients. These preliminary findings do not support the efficacy of BUPRO, in combination with BUPRE, for the concurrent treatment of opioid and tobacco addiction.

( BUPP09135 - 01 September 2008) Key findings from the WHO collaborative study on substitution therapy for opioid dependence and HIV / AIDS

Aims: Opioid substitution treatment has been studied extensively in industrialized countries, but there are relatively few studies in developing / transitional countries. The aim of this study was to examine the effectiveness of opioid substitution treatment (OST) in less resourced countries. Design: Longitudinal cohort study. Setting: Purposively selected OST sites in Asia (China, Indonesia, Thailand). Eastern Europe (Lithuania, Poland, Ukraine), the Middle East (Iran) and Australia. Participants. Seven hundred and twenty-six OST entrants. Measurements. Participants were interviewed at treatment entry, 3 and 6 months. Standardized instruments assessed drug use, treatment history, physical and psychological health, quality of life, criminal involvement, blood-borne virus (BBV) risk behaviours and prevalence of human immunodeficiency virus (HIV) and hepatitis C. Findings. Participants were predominantly male, aged in their early 30s and had attained similar levels of education. Seroprevalence rates for HIV were highest in Thailand (52%), followed by Indonesia (28%) and Iran (26%), and lowest in Australia (2.6%). Treatment retention at 6 months was uniformly high, averaging approximately 70%. All countries demonstrated significant and marked reductions in reported heroin and other illicit opioid use; HIV (and other BBV) exposure risk behaviours associated with injection drug users (IDU) and criminal activity, and demonstrated substantial improvement in their physical and mental health and general wellbeing over the course of the study. Conclusions. OST can similar outcomes consistently in a culturally diverse range of settings in low- and middle-income countries to those reported widely in nigh-income countries. It is associated with a substantial reduction in HIV exposure risk associated with IDU across nearly all the countries. results support the expansion of opioid substitution treatment.

( BUPP09136 - 09 September 2008) ADR news: Buprenorphine. Somnolence and visual hallucinations following transdermal administration in an elderly patient: case report.

An 81-year-old man with oncological neuropathic pain experienced somnolence after treatment with a buprenorphine patch (Transtec). He subsequently experienced visual hallucinations while receiving a reduced buprenorphine dose; when the dose was further reduced, the ADR resolved. The man, who had weakness and progressive pain in his legs, and tumor-like injury in the medullary cone, had received radiotherapy with resolution of the tumor. He continued to experience moderate-to-intense pain and numbness in his legs, and the pain had proved difficult to control during the previous 3 years; he had received various NSAIDs, antiepileptic drugs, opioid analgesics and amitriptyline, and had experienced adverse events. He was subsequently treated with 1/2 a buprenorphine 35 microg/h (20 mg/25cm sup(2)) patch applied every 3.5 days. His pain resolved, however, he experienced great somnolence (duration of therapy to reaction onset not stated). Treatment was reduced to 1/4 of a buprenorphine patch. The man remained wide awake but experienced visual hallucinations and the dose was further reduced to 1/5 of a buprenorphine patch. He continued to use 1/5 of a buprenorphine patch and, at subsequent follow-up, remained free from somnolence and visual hallucinations. Author Comment: "This case reminds us of the importance of individualized treatment of pain and shows that some patients can respond to low doses of opioids."

( BUPP09137 - 09 September 2008) Pharmacogenetics of analgesics: toward the individualization of prescription.

Individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets, and other nonopioid biological systems on central and peripheral analgesics are reviewed. Agents mentioned include morphine, methadone, fentanyl, tramadol, codeine, hydrocodone, oxycodone, dextromethorphan, M3G, M6G, levomethadone, alfentanil, NSAID in general, diclofenac, R-ibuprofen, S-ibuprofen, flurbiprofen, celecoxib, lornoxicam, tenoxicam, piroxicam, aspirin, acetaminophen (paracetamol), aceclofenac, buprenorphine, dihydrocodeine, felbamate, indometacin, mefenamic acid, meloxicam, naproxen, phenylbutazone, and sulfentanil.

( BUPP09138 - 09 September 2008) Recommendations for treatment of neuropathic pain.

Tricyclic antidepressants (TCAs), selective serotonin and norepinephrine reuptake inibitors (SSNRIs), calcium channel alpha2- delta ligands and topical lidocaine are recommended as a first-line treatment for patients with neuropathic pain. In patients who have failed to respond to these first-line medications alone or in combination, opioid analgetics or tramadol can be used as a second-line treatment alone or in combination with one of the first-line medications. In some specific situations, opioid analgetics or tramadol can also be considered for first-line use.

( BUPP09139 - 09 September 2008) The management of neuropathic pain in cancer.

Neuropathic pain is a common problem amongst cancer patients, yet it can be challenging to diagnose and treat successfully. The diagnosis of neuropathic pain has been helped by the identification of common descriptors and symptoms often used by patients and several screening tools now exist to identify neuropathic features. The management of neuropathic pain in cancer is a balance of pharmacological, physical and psychological interventions used skilfully in patients that are often frail and with cognitive, hepatic or renal impairment. Commonly used drugs for the treatment of neuropathic pain include opioids, antidepressants and anti-epileptics, although the evidence for their use in the cancer population is often poor. Other drugs that have shown to be of benefit include NMDA receptor antagonists and local anaesthetic agents, although side effects often limit their use. Physical interventions include intrathecal drug delivery, neurolytic sympathetic plexus blockade and spinal cord stimulation. These therapies should be considered in patients who have refractory pain or intolerable side effects to systemically administered analgesics. New intrathecal drugs, such as the N-type calcium channel blocker ziconotide have shown promise in managing neuropathic pain.

( BUPP09140 - 09 September 2008) Effects of indomethacin and buprenorphine analgesia on the postoperative recovery of mice.

Buprenorphine (Bup) is the most commonly used analgesic in mice, yet few objective assessments address its superiority for postsurgical recovery. In mice, IP implantation of a radiotelemetry device induces decreases in body weight (BW), food and water intake (FI, WI), core temperature (T), and activity levels that persist approximately 14 d in the absence of analgesia. To compare the efficacy of Bup with that of the nonsteroidal antiinflammatory drug indomethacin (Indo) for postsurgical recovery, male C57BL/6J mice were treated on the day of radiotelemetry implantation with Bup (0.3 mg/kg SC) or Indo (1 mg/kg SC) followed by treatment with Indo (1 mg/kg PO) on the next day (Bup-Indo versus Indo-Indo). Responses were compared between treatments in mice implanted with a radiotelemetry device and those that did not undergo surgery. Changes in BW, FI, WI, T, and activity were examined throughout 14 d of recovery. Indo-Indo was more efficacious in inhibiting postsurgical BW, FI, and WI reductions, compared with Bup-Indo. Bup also reduced BW and FI in the absence of surgery, indicating a nonspecific effect of this drug on these variables. Indo-Indo treatment was associated with higher activity levels during lights-on-to-lights-off transition periods compared with that observed with Bup-Indo. According to 5 objective measures of surgical recovery, our data suggest that Indo-Indo treatment is more efficacious than is Bup-Indo for postsurgical recovery of radiotelemetry-implanted mice. Copyright 2008 by the American Association for Laboratory Animal Science.

( BUPP09141 - 09 September 2008) Harm reduction and control of HIV in IDUs in France.

( BUPP09142 - 09 September 2008) Pain therapy in children and adolescents.

Introduction: In children, acute pain occurs predominantly during infectious illnesses or after surgery. Chronic pain, especially headache and abdominal pain, is becoming increasingly common among children and adolescents. Methods: Selective literature review, also including evidence-based guidelines and recommendations. Results: Simple self-reporting and behavioral pain scales are easy to use to assess the intensity of acute pain. To evaluate chronic pain, on the other hand, more complicated, multi-dimensional instruments are necessary (e.g., semi-structured interviews). The most commonly used analgesics are ibuprofen and paracetamol (acetaminophen). When paracetamol is used, its narrow therapeutic window should be kept in mind. Perioperative pain should be treated with balanced analgesia involving a combination of non-pharmacological treatment strategies, non-opioid drugs, opioids, and regional anesthesia. Chronic pain in children can only be treated successfully over the long term with multidisciplinary team intervention based on this biopsychosocial model. Discussion: Pain not only causes children momentary suffering but also threatens to impair their normal development. Therefore, every effort should be made to prevent pain and to treat it effectively once it arises.

( BUPP09143 - 09 September 2008) Oxycodone: A pharmacological and clinical review.

Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma half-life is 3-5 h (half that of morphine) and stable plasma levels are reached within 24 h (2-7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone - which is also a very potent analgesic - and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5-2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3-4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin�) is marketed as 10-, 20-, 40-or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm�) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.

( BUPP09144 - 09 September 2008) QTc interval prolongation and opioid addiction therapy.

( BUPP09145 - 09 September 2008) (Commentary) maintenance treatments across countries.

( BUPP09146 - 09 September 2008) Cetuximab with hepatic arterial infusion of chemotherapy for the treatment of colorectal cancer liver metastases.

Background: Both hepatic arterial infusion (HAI) of chemotherapy and cetuximab (CET) have interesting activity for the treatment of colorectal cancer liver metastases (CRC-LM). Patients and Methods: Intravenous CET with HAI oxaliplatin (OXA) or i.v. Irinotecan (IRI) followed by HAI of infusion of folic acid modulated 5-fluorouracil 5-FU/l-FA was administered to patients (pts) with CRC-LM who had failed at least one line of prior chemotherapy. Results: Eight pts received i.v. CET with HAI-OXA (5 pts) and i.v.-IRI (3 pts) and HAI-S-FU/I-FA. Adverse events: repeated grade 3 skin toxicity (1 pt), abdominal pain with elevated liver enzymes and asthenia (2 pts), duodenal ulcer (2 pts) with catheter migration and intestinal bleeding (1 pt), reversible interstitial pneumonitis (1 pt), and cystic bile duct dilatation (2 pts) with arteriobiliary fistulisation (1 pt). A partial response was documented in 5 pts (62%). The median time to progression was 8.7 months (95% confidence interval 8-14 months). Conclusion: Intravenous administration of CET with HAI of chemotherapy is feasible and has promising activity but is associated with specific toxicity.

( BUPP09147 - 09 September 2008) First meeting of the French CEIP (centres d'evaluation et d'information sur la pharmacodependance). Assessment of the abuse and pharmacodependence potential during drug development.

The French system for the evaluation of abuse and dependence created in 1990 was definitely implemented in 1999 with the decree n�99-249 making in particular mandatory the reporting of all serious cases of abuse or dependence to psychoactive drugs. This decree was also important to define the role of each party (regulatory agencies, pharmaceutical companies, health professionals and the network of the regional Centres for Evaluation and Information of Pharmacodependence) for all marketed psychoactive drugs in France. The first meeting on pharmacodependence was organized during the last annual congress of the French Society of Therapeutic Pharmacology and Physiology (P2T) held in Toulouse in April 2007. The aim of this meeting was that the role of the French system for the evaluation of abuse and dependence during the different steps of drug approval and after marketing in the context of real life would be better known. The French approach includes classical data obtained from experimental and clinical trials, but also and mainly data obtained from the specific tools installed since the creation of the CEIP

( BUPP09148 - 09 September 2008) Efficacy and Safety of Transdermal Buprenorphine: A Randomized, Placebo-Controlled Trial in 289 Patients with Severe Cancer Pain.

Strong opioids are recommended for treating severe cancer pain in the advanced stages of the disease. Few data are available concerning the efficacy of buprenorphine in cancer pain. We compared transdermal buprenorphine 70 mug/h (BUP TDS) to placebo in an enriched design study. Opioid-tolerant patients with cancer pain requiring strong opioids in the dose range of 90-150 mg/d oral morphine equivalents entered a two-week run-in phase, during which they were converted to BUP TDS. Patients who could be stabilized on BUP TDS were randomized to BUP TDS or placebo patch for a two-week maintenance phase. Rescue medication (buprenorphine sublingual tablets 0.2 mg) was allowed as required. Response was defined as a mean pain intensity of <5 (0-10 scale) and a mean daily buprenorphine sublingual tablet intake of 2 tablets during the maintenance phase. Of 289 patients who entered the run-in phase, 100 discontinued treatment due to lack of efficacy or adverse events; 189 patients continued treatment in the maintenance phase (94 BUP TDS, 95 placebo), of whom 31 discontinued treatment (7 BUP TDS, 24 placebo). A significant difference in the number of treatment responders was observed: 70 BUP TDS (74.5%, 65.7-83.3) vs. 47 placebo (50%, 39.9-60.1) (P = 0.0003). This result was supported by a lower daily pain intensity, lower intake of buprenorphine sublingual tablets and fewer dropouts in the BUP TDS group. The incidence of adverse events was slightly higher for BUP TDS. In conclusion, BUP TDS 70 mug/h is an efficacious and safe treatment for patients with severe cancer pain. � 2008 U.S. Cancer Pain Relief Committee.

( BUPP09149 - 09 September 2008) (Commentary) modern treatment for prisoners.

( BUPP09150 - 09 September 2008) Precipitated withdrawal during maintenance opioid blockade with extended release naltrexone

Background: There has been increasing interest in the use of extended release injectable naltrexone for the treatment of opioid dependence. Case description: We report a case of precipitated withdrawal in a 17-year-old adolescent female receiving extended release naltrexone (Vivitrol) for opioid dependence, following her third serial monthly dose of the medication, several days after using oxycodone with mild intoxication. Conclusions: This case suggests that, in some circumstances, the opioid blockade may be overcome when naltrexone levels drop towards the end of the dosing interval, producing vulnerability to subsequent naltrexone-induced withdrawal. This may provide cautionary guidance for clinical management and dosing strategies.

( BUPP09151 - 09 September 2008) Opioid switching from transdermal buprenorphine to oxicodone in delirium: A case report.

The prescription of transdermal buprenorphine for treating moderate to severe chronic pain has shown an important increment in the primary health care of the sanitary region of Lleida being, on 2005, the second strong opioid in Defined Daily Dose (DDD) prescribed (1). Oxycodone is a pure agonist opioid that presents an excellent bioavailability and less adverse effects than morphine. For that reason can be considered a safe alternative when intolerance, adverse effects or lack of analgesia is present (2). Delirium results from the interaction of certain conditions of the patient, leading them to a more vulnerable state, and of some precipiting factors, that can be related to some disease or drug use (3). We present a case of a 75 years old lady diagnosed of epidermoid carcinoma of vagina with regional spreading. While she was treated at home with transdermal buprenorphine, she presented with a cognitive and functional impairment due to the increasing analgesic doses due to incomplete pain relief.

( BUPP09152 - 09 September 2008) Health Care Use in Patients With Chronic Intestinal Dysmotility Before and After Introducing a Specialized Day-Care Unit.

Background & Aims: Patients with chronic intestinal dysmotility (CID) have a lifelong disease, and no curative treatment is available. Interventions are needed to improve the care and support of the patients. The aim of this study was to measure health-care consumption in adult patients with CID before and after the introduction of a specialized day-care unit. Methods: Retrospective analysis was made of medical and nursing records from 3 different health-care delivery systems: period I, traditional care (1987-1996); period II, outpatient clinic (1997-1999); and period III, specialized day-care unit (2000-2002). There were 54 patients (44 women) with a median age of 47 years (range, 22-80 years). Results: The need for admissions to hospital care decreased from 80% to 35% of the patients after the introduction of the specialized day-care unit (P < .002). Also, the mean number of days in hospital care per patient and year was reduced from 39.4 to 3.3 days. The number of outpatient visits remained unaltered. The average cost per patient-year decreased from $32,698 during traditional health-care services to $9,681 after introducing the specialized day-care unit (P < .002). Irrespective of the form of care delivery, the majority of patients (67%-77%) needed daily treatment with analgesics, and 81%-84% needed nutritional support on a regular basis. Conclusions: Individually tailored care at a specialized day-care unit leads to substantially decreased needs for hospital stays and lower costs in patients with CID.

( BUPP09153 - 09 September 2008) The postoperative analgesia procedures in children.

The postoperative analgesia technique which was performed with general anesthesia has gained lot of interest in pediatric patients. Most of regional analgesia techniques which were valid for adults are also valid for the pediatric population. During postoperative period regional analgesia produces considerable amount of analgesia and prevents postoperative complications. 23rd Sept 08 - Message from the British Library - This paper is placed on a waiting list.

( BUPP09154 - 16 September 2008) ADR news: Buprenorphine/naloxone abuse. First report of serotonin syndrome: case report. Serious.

A 54-year-old man developed severe serotonin syndrome after taking unprescribed buprenorphine/naloxone (Suboxone) in order to achieve a euphoric high. He had been taking doxepin, amitriptyline and methadone. The man, who had a history of intravenous drug use, presented with jaw spasm 1.5 hours after consuming a friend's buprenorphine/naloxone (dosage not stated). On presentation, he had been unable to open his mouth for an hour. He was extremely anxious and unable to sit still. Tests revealed the following: rectal temperature 100.4 deg F; HR 130 beats/min; respiratory rate 30 breaths/min; BP 210/93mm Hg. He was responsive to questions and commands but exhibited episodes where he spoke nonsensically. Examination showed masseter spasm with accompanying trismus, spontaneous jerking of his upper extremities and clonus in his lower extremities. He was unable to co-operate with a detailed neurological examination. He continued to be agitated and confused. The man was hydrated with normal saline and received lorazepam, midazolam, diphenhydramine and benzatropine. He also received IV hydromorphone for possible acute opioid analgesic withdrawal. His condition did not change. He was intubated and underwent a CT scan and lumbar puncture. He also received treatment for possible meningitis. Blood tests revealed a calcium level of 7 mg/dL and a creatine kinase level of 1006 U/L. An ECG revealed sinus tachycardia with nonspecific ST segment changes. A urine drug screen was positive for methadone and tricyclic antidepressants. Serotonin syndrome was suspected due to the possible effects of multiple tricyclic antidepressants combined with buprenorphine/naloxone. He was started on cyproheptadine and his mental status improved. On day 3, he self-extubated and was oriented, alert and co-operative. He reported chest pain but was discharged home on day 4 in a stable condition and with baseline mental status. He had not experienced any sequela at 6-months' follow-up. Author Comment: "(T)he temporal relationship between the time the patient took the buprenorphine/naloxone and the onset of symptoms suggests that this medication was the cause of the (serotonin syndrome)." Editorial Comment: A search of AdisBase, Medline and Embase did not reveal any previous case reports of serotonin syndrome associated with buprenorphine or naloxone. The WHO Adverse Drug Reactions database did not contain any reports of serotonin syndrome with buprenorphine/naloxone or naloxone, but did contain 3 reports of serotonin syndrome associated with buprenorphine.

( BUPP09155 - 16 September 2008) Implementation of chronic care management for alcohol and drug dependence: Prescription of addiction and psychiatric medications.

( BUPP09156 - 16 September 2008) Charateristics of individals utilizing 12 step programs while participating in buprenorphine-naloxone outpatient treatment.

( BUPP09157 - 16 September 2008) Buprenorphine-induced respiratory depression reversed by naloxone in a 2-year-old.

The Authors reported a pediatric case of buprenorphine-induced respiratory depression successfully reversed by i.v. naloxone. A continuous infusion of naloxone appeared to prevent recurrent respiratory depression. In conclusion, while buprenorphine is thought to demonstrate slow dissociation from the mu receptor, naloxone was shown to be effective in reversing the respiratory depression in this patient. (conference abstract: Annual Meeting of the North American Congress of Clinical Toxicology, Toronto, ON, Canada, 11/09/2008-16/09/2008).

( BUPP09158 - 16 September 2008) Drug treatment of opiate dependence in primary care - An update.

Opioid dependence is a chronic, relapsing condition associated with significant harms for patients and the wider community. In the broadest sense, the aims of treatment are to reduce the health, social and economic harms that are associated with the misuse of opiates. The available evidence indicates that treatment can lead to substantial improvements in a number of outcomes for many individuals and society. These improvements rely on a multidisciplinary approach using appropriate drugs at sufficient doses to retain patients within treatment programmes, supported by a range of ongoing psychosocial interventions. It is important that all drug misusers are provided with information and advice about harm reduction, both at routine contacts and opportunistically. Drug treatment should only be considered if there is evidence of dependence and tolerance, and at least one positive opiate test. Maintenance treatment is the best option for many individuals in the short, medium and often the long term. Coerced or enforced detoxification is not effective as it leads to relapse, a return to the use of street drugs and the associated risks of overdose, blood-bome viruses, etc. Maintenance treatment Methadone and buprenorphine, using flexible dosing regimens, are both recommended as options for maintenance therapy in the management of opioid dependence. Evidence suggests that methadone maintenance therapy (MMT) is more effective at maintaining patients in treatment than buprenorphine maintenance therapy (BMT). There is little evidence to support the routine use of BMT instead of MMT in terms of other outcome measures such as illicit opiate use whilst on treatment. However, it is generally agreed that there is less risk of opioid overdose associated with the use of buprenorphine than with oral methadone. The decision about which drug to use should be made on a case-by-case basis. If both drugs are equally suitable, methadone should be prescribed as the first choice. Injectable diamorphine and injectable methadone should only be considered for the minority of patients who are genuinely unresponsive to an optimised oral maintenance treatment approach. Close monitoring and regular clinical review are required throughout treatment, and especially during the early stages of treatment and periods of instability. Daily installment prescribing and supervised consumption are useful for ensuring that patients take their treatment as intended and for reducing the diversion of prescribed drugs. Detoxification It is not clear if there is any difference in efficacy between methadone and buprenorphine for opioid detoxification. Either may be offered as the first-line treatment. Risks of drug treatment Methadone carries a risk of QT-interval prolongation, so patients with risk factors (e.g. heart or liver disease, electrolyte abnormalities) and those taking doses over 100mg per day should be carefully monitored. When buprenorphine is initiated, withdrawal symptoms may arise if patients still have opioid drug present in their system. This occurs because buprenorphine has a high affinity for opioid receptors and displaces other opioids, such as heroin or methadone. This gives a rapid reduction in opiate effects because it has less opioid activity. The first dose should therefore be administered when the patient is exhibiting signs of withdrawal, or at least 6-12 hours after the last use of heroin and 24-48 hours after the last use of methadone. Patients should be fully informed of the risks of overdose with the use of prescribed and illicit drugs, They also need to be aware that their previous tolerance to illicit opioids may be lost during detoxification treatment and relapse to illicit drugs may increase their risk of overdose.

( BUPP09159 - 16 September 2008) Evidence of the efficacy of major and minor opioids in the treatment of osteoarticular pain.

Although in normal clinical practice specialists in the locomotor apparatus frequently use opioids for the treatment of osteoarticular pain, there is a lack of scientific evidence regarding their specific recommendation. The purpose of this review is to consider the scientific evidence in the literature regarding the efficacy of major and minor opioids in the treatment of osteoarticular pain, limiting the references as closely as possible to specific rheumatic diseases. The method established to comply with these objectives includes: - Search for evidence. - Analysis of the search. - Results. The search for evidence included: 1) search strategy: random and quasi-random studies in different databases from 1990 to April 2005; 2) inclusion criteria: clinical trials and/or studies of cohorts of more than 100 patients with acute (< 6 weeks) or chronic (> 6 weeks) musculoskeletal pain, of all ages and sexes, and under treatment with major or minor opioids irrespective of the duration of the treatment or route of administration. Control: placebo or any other analgesic, and 3) search criteria: reduction of pain (through the use of qualitative or continuous measures) and improvement of the quality of life. Major opiates resulted in a significantly greater percentage improvement of the pain compared to placebo in patients with chronic pain, with an acceptable evidence level. Major opiates by oral route also resulted in improvement of the WOMAC pain index compared to placebo in patients with osteoarthritis, with an acceptable evidence level. Major opiates by intraarticular route showed a significant improvement in the severity of pain compared to placebo in patients with peripheral osteoarthritis or rheumatoid arthritis, with a good evidence level. Major opiates by intravenous route in general resulted in a higher percentage response compared to placebo in patients with fibromyalgia and radiculopathy, with a slight evidence level. Major opiates by transdermal route resulted in a significantly higher percentage of patients with at least good improvement of the pain, a higher percentage response, and a greater number of patients with more than 6 h of uninterrupted sleep compared to placebo in patients with chronic pain secondary to cancer, musculoskeletal diseases or other situations that cause chronic pain, with a good evidence level. The evidence level is insufficient in regard to major opiates significantly improving pain when compared to anti-inflammatory drugs in patients with chronic lumbago or peripheral osteoarthritis. Tramadol is an efficient treatment for acute and chronic musculoskeletal pain. 23rd Sept 08 - message from the British Library - This paper is placed on a waiting list.

( BUPP09160 - 16 September 2008) Pharmacology of opioids.

Opium comes from the Greek word opos, which means "juice". This juice is also called "latex" and is extracted from the seed pod of a solanaceous plant, commonly known as the opium poppy, Papaver somniferum or "sleep-bringing poppy". Between 10-100 mg of opium, in the form of a milky exudate can be extracted from each seed pod of an opium poppy. It is extracted by carefully cutting the surface of the seed pod capsule without touching the seeds. This juice is then allowed to dry until becoming a rubbery substance from which the opium is later extracted using several chemical processes. Although the word opiate and opioid are often used as synonyms, there is a difference between both terms: - Opiate. This term is applied to all substances derived from opium, with or without a morphine-like activity. - Opioid. This is a much wider term used to refer to any endogenous (opioid peptides) or exogenous substance (natural and semi-synthetic opium derivatives, as well as synthetic opioids) with a capacity to interact with opioid receptors, either as an agonist, antagonist, partial agonist or agonist-antagonist, and of being displaced by the antagonist drug naloxone. Initially, three families of endogenous opioid peptides have been identified: enkephalins, endorphins and dynorphins, which include approximately 20 peptides with opioid activity originating from inactive precursor molecules (pro-enkephalin, pro-opiomelanocortin and pro-dynorphin). Each of the families is derived from a different polypeptide precursor and has a characteristic anatomic distribution. Opioid peptides share the common amino-terminal sequence, which is called "opioid motif". The same precursor may be the origin of different endogenous opioids depending on the tissue where it is found and the stimulus received. Recently, three new endogenous opioid peptides have been isolated: nociceptin/orphanin FQ (N/OFQ) and endomorphins 1 and 2. It has been suggested that endomorphins are selective endogenous ligands of the mu receptor because of their high affinity for this receptor in spite of their structural differences compared to all other endogenous peptides. The antinociceptive effects of opioids are mediated by binding to specific membrane proteins called opioid receptors. There are four known types of opioid receptors called mu (mu), kappa (kappa), delta (delta), and the recently discovered and cloned N/OFQ or opioid receptor like ORL /sub 1/ , which have the peculiarity that no binding takes place with conventional opioids, but which do accept binding with endogenous ligands such as nociceptin/orphanin FQ. The ORL /sub 1/ receptor has been associated with the appearance of hyperalgesia and anti-opioid effects on a supra-spinal level, even though it produces analgesia at spinal level. Different classifications are used to group opioid drugs according to their function and clinical use. They are classified according to their origin in natural opium alkaloids, semi-synthetic derivatives of opium alkaloids and synthetic opioids. They are then divided according to their analgesic power into weak or minor opioids and powerful or major opioids. Oral administration is simple and safe, but has the inconvenience that there is a hepatic first pass effect that considerable reduces bioavailability. Sustained release forms are now available to improve analgesia levels and patient compliance. Transdermal administration has recently acquired great importance in modern pain treatment. 23rd Sept 08 - message from the British Library - This paper is placed on a waiting list.

( BUPP09161 - 16 September 2008) Rapamycin, mycophenolate mofetil, methylprednisolone, and cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-based conditioning regimen to induce partial tolerance to hind limb allografts without cytoreductive conditioning.

BACKGROUND: Composite tissue allograft transplantation may represent the next frontier in the field of reconstructive surgery. However, the main obstacles precluding the routine use of composite tissue allotransplants are rejection and toxicity associated with life-long immunosuppressive therapy. In this study, we investigated a nontoxic immunosuppressant and cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (CTLA4-Ig)-based protocol to induce donor-specific tolerance to hind limb allografts in rats. METHODS: Fully mismatched, 4- to 10-week-old Brown Norway (BN, RT1n) and Lewis (RT1) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with CTLA4-Ig (2 mg/kg/d) on days -30, -28, -26, -24, and -22, rapamycin, mycophenolate mofetil, and methylprednisolone (RAPA/MMF/MP) combined therapy (from days -30 to day 100), a single dose of anti-lymphocyte serum (10 mg, on day -30), and donor bone marrow (10 x 10(7) T-cell-depleted cells) transplantation (BMT, on day -30). Thirty days after BMT, chimeric animals received hind limb allotransplantations (on day 0). The RAPA/MMF/MP combined therapy was changed to Cyclosporine (CsA, 8 mg/kg/d) on day 100 and maintained thereafter at this level. RESULTS: Hematopoietic chimerism of 17.6 + /- 9.5% at day 0, was stable (15.2 +/- 5.6%) at 230 days post-BMT; there was no sign of graft-versus-host disease. Chimeric recipients (Lewis) permanently accepted (>200 days) donor (BN)-specific (RT11, n = 6) hind limbs, yet rapidly rejected (20 +/- 2 days) third-party hind limbs (Wistar Furth (WF)). Lymphocytes of graft-tolerant animals demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner. Tolerant graft histology showed no signs of acute and chronic rejection. CONCLUSIONS: The immunosuppressant and CTLA4-Ig-based conditioning regimen with donor BMT produced mixed chimerism and induced partial donor-specific tolerance to hind limb allografts.

( BUPP09162 - 16 September 2008) (Drug therapy of opioid withdrawal).

Although the opiate dependence is of low frequency in our midst, it is important to know its management because it requires medical treatment in most cases. At present, in our country, we may classify the different patient populations able to submit an opioid withdrawal syndrome in patients undergoing chronic treatment with opioids, patients in intensive care units, neonatal mother addicted patients and addicts from the general population or linked to the health system. Detoxification programs are typically characterized by a low rate of completion of treatment and a high rate of relapse. The opioid withdrawal syndrome is objectively and subjectively severe and moderate and the goals of the therapy for the Opiates Withdrawal Syndrome are: to prevent or reduce the objective and subjective symptoms of abstinence; to prevent or treat its most serious complications; to treat preexisting or concurrent psychiatric disorders; to reduce the frequency or severity of relapses and to rehabilitate in the long term. 30th September 2008 - British Library cannot find this paper at present.

( BUPP09163 - 22 September 2008) Epidural analgesia during brachytherapy for cervical cancer patients.

Aims: To find out the efficacy of epidural analgesia in providing continuous pain relief for patients undergoing brachytherapy for cervical cancer. Settings: Teaching Hospital. Design: Retrospective Study. Materials and Methods: A total of 152 patients of cervical cancer received epidural analgesia during 18 to 21 hours of pelvic brachytherapy. Epidural top up was given using 60-100 mug of buprenorphine every 08-10 hrs. Additional top up or systemic analgesics were given for breakthrough pain. Results: Majority of patients 119 out of 152 received epidural top up twice during their stay in the brachytherapy ward. Only 20 out of 152 needed additional analgesics. Conclusions: Epidural analgesia is safe and provides satisfactory pain relief during brachytherapy and makes patient's stay more comfortable. 30th September 2008 - British Library are unable to get hold of this paper at present.

( BUPP09164 - 22 September 2008) Fentanyl transdermal matrix patch (Durotep� MT patch; Durogesic� DTrans�; Durogesic� SMAT): In adults with cancer-related pain.

The fentanyl transdermal matrix patch is approved in Japan for the management of moderate to severe cancer-related pain in adults. Bioequivalence, in terms of exposure and the maximum and minimum serum concentrations, has been established between the fentanyl transdermal matrix patch 16.8 mg (100 mug/h) and the fentanyl transdermal reservoir patch 10 mg (100 mug/h) after single and multiple applications. The fentanyl transdermal matrix patch 2.1-8.4 mg (12.5-50 mug/h) effectively managed chronic cancer-related pain in adults in a noncomparative, multicentre, phase II study; 89.4% of recipients rated their global assessment of pain as 'very satisfied', 'satisfied' or 'neither satisfied nor dissatisfied'. Adults with cancer-or non-cancer-related chronic pain were switched from fentanyl transdermal reservoir patch to fentanyl transdermal matrix patch therapy without compromising efficacy; no differences in pain intensity or sleep interference scores were seen between the two formulations in an nonblind, multicentre, switching pilot study. Given the nature of the therapy, the tolerability profile of the fentanyl transdermal matrix patch was generally acceptable. Topical adverse events included erythema, application-site irritation and pruritus. In general, patients and physicians preferred the fentanyl transdermal matrix patch over the fentanyl transdermal reservoir patch in the pilot study.

( BUPP09165 - 22 September 2008) Current recommondations on the evaluation of the impact of opioids on driving ability.

( BUPP09166 - 22 September 2008) Candidate gene polymorphisms predicting individual sensitivity to opioids

Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. Studies using gene knockout mice have revealed that genes encoding some metabolic enzymes, opioid transporters, and opioid system signal transduction mediators may be candidate genes to predict appropriate kinds and doses of opioids for individuals. Recently, various databases on knockout mice, pharmacogenetics, and gene polymorphisms have been rapidly consolidated. Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.

( BUPP09167 - 22 September 2008) Opioid addiction and pregnancy: Perinatal exposure to buprenorphine affects myelination in the developing brain.

Buprenorphine is a mu-opioid receptor partial agonist and kappa-opioid receptor antagonist currently on trials for the management of pregnant opioid-dependent addicts. However, little is known about the effects of buprenorphine on brain development. Oligodendrocytes express opioid receptors in a developmentally regulated manner and thus, it is logical to hypothesize that perinatal exposure to buprenorphine could affect myelination. To investigate this possibility, pregnant rats were implanted with minipumps to deliver buprenorphine at 0.3 or 1 mg/kg/day. Analysis of their pups at different postnatal ages indicated that exposure to 0.3 mg/kg/day buprenorphine caused an accelerated and significant increase in the brain expression of all myelin basic protein (MBP) splicing isoforms. In contrast, treatment with the higher dose caused a developmental delay in MBP expression. Examination of corpus callosum at 26-days of age indicated that both buprenorphine doses cause a significant increase in the caliber of the myelinated axons. Surprisingly, these axons have a disproportionately thinner myelin sheath, suggesting alterations at the level of axonglial interactions. Analysis of myelin associated glycoprotein (MAG) expression and glycosylation indicated that this molecule may play a crucial role in mediating these effects. o-immunoprecipitation studies also suggested a mechanism involving a NUG-dependent activation of the Src-family tyrosine kinase Fyn. These results support the idea that opioid signaling plays an important role in regulating myelination in vivo and stress the need for further studies investigating potential effects of perinatal buprenorphine exposure on brain development.

( BUPP09168 - 22 September 2008) Dividing transdermal plaster is not tolerable.

Publisher Hans Marseille Verlag GmbH, PO Box 22 13 41, Munchen, 80503, Germany.

( BUPP09169 - 22 September 2008) Oral versus transdermal treatment of cancer pain.

The treatment of cancer pain can still be improved. Recently new preparations and ways of administration have become available. Still the oral administration remains first choice for the great majority of patients. The oral administration allows indeed an optimal dose titration and adaptation to the varying needs of patients. Finally and compared to the application of transdermal preparations, the intoxication risk is considerably reduced.

( BUPP09170 - 22 September 2008) Late morbidity after duodenum-preserving pancreatic head resection with bile duct reinsertion into the resection cavity.

Background: Reinsertion of the distal common bile duct (CBD) into the pancreatic resection cavity during duodenum-preserving pancreatic head excision (DPPHE) may be an alternative option to Whipple resection or bilioenteric anastomosis when chronic pancreatitis is associated with CBD stenosis. Methods: Outcome in 82 patients with chronic pancreatitis who underwent DPPHE with CBD reinsertion was compared with that in 432 who had DPPHE without reinsertion and 50 who had a Whipple procedure or pylorus-preserving pancreatoduodenectomy (PPPD). Results: There were no deaths after DPPHE with CBD reinsertion, compared with four (0.9 per cent) after DPPHE without reinsertion and three (6 per cent) after classical resection. Overall morbidity rates were 30, 28.9 and 36 per cent respectively. Fifteen patients (18 per cent) who had DPPHE with CBD reinsertion developed a stricture at the reinsertion site, compared with a long-term stricture rate of 2.3 per cent (ten patients) after DPPHE without CBD reinsertion and 4 per cent (two patients) after PPPD/Whipple resection. Conclusion: Although associated with a high incidence of anastomotic stricture, reinsertion of the CBD into the resection cavity as part of DPPHE can be used to preserve duodenal passage and offers an alternative to extended resection for chronic pancreatitis

( BUPP09171 - 22 September 2008) Treatment of chronic osteoarthritis pain: Effectivity and safety of a 7 day matrix patch with a lowdose buprenorphine.

Patients with osteoarthritis often suffer from chronic pain. If pain treatment with NSAIDS and coxibes is no longer indicated, a constant and user friendly opioid analgesia can be achieved with a lowdose buprenorphine patch being applicated using an interval of 7 days. The use of this matrix patch was evaluated in a multicenter observational study on 4263 patients in clinical practice. During treatment a significant decrease of mean pain intensity on a 11-point scale could be observed from 6.9 points before using the patch to 2.9 points at the end of observation. Further effects were a decrease of additional analgetic medication and an improvement of aspects of life quality, e. g. mobility and quality of sleep. Only in 4.5% of the patients adverse effects were observed, reflecting the expected range of adverse effects of opioids. Thus it could be demonstrated that the use of the transdermal patch is an effective, user friendly and safe way of chronic pain relief for osteoarthritis patients.

( BUPP09172 - 22 September 2008) Placebo Response: Relevance to the Rheumatic Diseases.

Recent interest in the neurobiology of the placebo effect has brought about a new awareness of its potential exploitation for patient benefit, framing it as a positive context effect with the power to influence therapy outcome. Among the different placebo effects described in clinical conditions and experimental settings, placebo analgesia is of particular relevance to the rheumatologist. Placebo analgesia is the field that has most contributed to our understanding of the multiple mechanisms underlying this phenomenon. The possible clinical applications of placebo studies range from the design of clinical trials incorporating specific recommendations and minimizing the use of placebo arms to the optimization of the context surrounding the patient so that the placebo component in any treatment is maximized

( BUPP09173 - 22 September 2008) The Pharmacotherapy of Chronic Pain

Most patients with rheumatic diseases experience difficulties with chronic pain. To assist clinicians in directly addressing this pain, this article presents a treatment approach and algorithm based on best evidence. The usual approach for mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate or poorly tolerated, and if there is an element of sleep loss, it is then reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial of one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate a trial of chronic opioid earlier. Cannabinoids and topicals may also be appropriate as single agents or in combination.

( BUPP09174 - 22 September 2008) Regional haemodynamic responses to adenosine receptor activation vary across time following lipopolysaccharide treatment in conscious rats.

Background and purpose: Studies using adenosine receptor antagonists have shown that adenosine-mediated vasodilatations play an important role in the maintenance of regional perfusion during sepsis, but it is unclear whether vascular sensitivity to adenosine is affected. Here, we assessed regional haemodynamic responses to adenosine agonists and antagonists in normal and lipopolysaccharide (LPS)-treated rats to investigate a possible role for adenosine in the haemodynamic sequelae. Experimental approach: Male Sprague-Dawley rats were chronically instrumented with pulsed Doppler flow probes to measure regional haemodynamic responses to adenosine-receptor agonists (adenosine, 2-choloro-N /sup 6/ -cyclopentyladenosine (CCPA)) and antagonists (8-phenyltheophylline (8-PT), 8- cyclopentyl-1,3-dipropylxanthine (DPCPX)), at selected time points in control and LPS-treated rats. Key results: The responses to 8-PT were consistent with endogenous adenosine causing bradycardia, and renal and hindquarters vasodilatation in control rats, whereas in LPS-treated rats, there was evidence for endogenous adenosine causing renal (at 1.5 h) and hindquarters (at 6 h) vasoconstriction. In control animals, exogenous adenosine caused hypotension, tachycardia and widespread vasodilatation, whereas in LPS-treated rats, the adenosine-induced renal (at 1.5 h) and hindquarters (at 6 h) vasodilatations were abolished. As enhanced A /sub 1/ receptor-mediated vasoconstriction could explain the results in LPS-treated rats, vascular responsiveness to a selective A /sub 1/ -receptor agonist (CCPA) or antagonist (DPCPX) was assessed. There was no evidence for enhanced vasoconstrictor responsiveness to CCPA in LPS-treated rats, but DPCPX caused renal vasodilatation, consistent with endogenous adenosine mediating renal vasoconstriction under these conditions. Conclusions and implications: The results show changes in adenosine receptor-mediated cardiovascular effects in endotoxaemia that may have implications for the use of adenosine-based therapies in sepsis

( BUPP09175 - 22 September 2008) Use of buprenorphine for addiction treatment: Perspectives of addiction specialists and general psychiatrists.

Objective: In 2002 buprenorphine (Suboxone or Subutex) was approved by the U.S. Food and Drug Administration for office-based treatment of opioid addiction. The goal of office-based pharmacotherapy is to bring more opiate-dependent people into treatment and to have more physicians address this problem. This study examined prescribing practices for buprenorphine, including facilitators and barriers, and the organizational settings that facilitate its being incorporated into treatment. Methods: Addiction specialists and other psychiatrists in four market areas were surveyed by mail and Internet in fall 2005 to examine prescribing practices for buprenorphine. Respondents included 271 addiction specialists (72% response rate) and 224 psychiatrists who were not listed as addiction specialists but who had patients with addictions in their practice (57% response rate). Results: Three years after approval of buprenorphine for office-based addiction treatment, nearly 90% of addiction specialists had been approved to prescribe it and two-thirds treated patients with buprenorphine. However, fewer than 10% of non-addiction specialist psychiatrists prescribed it. Regression-adjusted factors predicting prescribing of buprenorphine included support of training and use of buprenorphine by the physician's main affiliated organization, less time in general psychiatry compared with addictions treatment, more time in group practice rather than solo, ten or more opiate-dependent patients, belief that drugs play a large role in addiction treatment, and patient demand. Conclusions: Office-based pharmacotherapy offers a promising path to improved access to addictions treatment, but prescribing has expanded little beyond the addiction specialist community.

( BUPP09176 - 23 September 2008) Further investigation of the N-demethylation of tertiary amine alkaloids using the non-classical Polonovski reaction.

Abstract - The iron salt-medicated Polonovski reaction efficiently N-demethylates certain opiate alkaloids. In this process, the use of the hydrochloride salt of the tertiary N-methy amine oxide was reported to give better yields of the desired N-demethylated product. Herein, we report further investigation into the use of N-oxide salts in the iron salt-mediated Polonovski reaction. An efficient approach for the removal of iron salts that greatly facilitates isolation and purification of the N-nor product is also described.

( BUPP09177 - 29 September 2008) Serotonin syndrome triggered by a single dose of suboxone.

Suboxone (buprenorphine/naloxone) is an oral medication used for the treatment of opiate dependence. Because of its mixed properties at the opiate receptors, buprenorphine has a ceiling on its euphoric effects. We report the first case of serotonin syndrome caused by buprenorphine and review other medications implicated in serotonin syndrome. A 54-year-old man on tricyclic antidepressants took an unprescribed dose of buprenorphine/naloxone. He presented to the emergency department with signs and symptoms of severe serotonin syndrome including clonus, agitation, and altered mental status. His agitation was not controlled with benzodiazepines and was electively intubated. At the recommendation of the toxicology service, cyproheptadine, a serotonin receptor antagonist, was administered with improvement in the patient's symptoms. Emergency physicians should be aware of the potential of buprenorphine/naloxone to trigger serotonin syndrome.

( BUPP09178 - 29 September 2008) Pharmacokinetics of buprenorphine following intravenous and oral transmucosal administration in dogs.

Pharmacokinetic analysis of buprenorphine administered to six healthy dogs via the oral transmucosal (OTM) route at doses of 20 and 120 microg/kg was conducted using liquid chromatography-electrospray ionization-tandem mass spectroscopy (LC-ESI-MS/MS). Bioavailability was 38% plus or minus 12% for the 20 microg/kg dose and 47%+/-16% for the 120 microg/kg dose. Maximum plasma concentrations were similar for buprenorphine doses of 20 microg/kg IV and 120 microg/kg OTM. Sedation and salivation were common side effects, but no bradycardia, apnea, or cardiorespiratory depressive effects were seen. When the two OTM dosing rates were normalized to dose, LC-ESI-MS/MS analysis of buprenorphine and its metabolites detected no significant difference (P>.05), indicating dose proportionality. The results of this study suggest that OTM buprenorphine may be an alternative for pain management in dogs.

( BUPP09179 - 29 September 2008) How do you treat fibromyalgia in your practice?

( BUPP09180 - 29 September 2008) 'Topping up' methadone: An analysis of patterns of heroin use among a treatment sample of Scottish drug users.

Objectives: To determine: (a) whether Scottish drug users on methadone maintenance use heroin less frequently than their peers following other forms of drug treatment; and (b) to what extent those on methadone maintenance 'top up' with heroin. Design: A cohort study followed-up for 33 months from 2001 to 2004. Methods: Four hundred and ten interviewees who responded at all four interview sweeps, recruited as new treatment entrants from 28 drug treatment agencies across Scotland. Results: Sixty-eight of the 401 interviewees had commenced an episode of methadone-maintenance treatment at the start of the study. There was no significant difference between the methadone-maintained sample and the other interviewees in their propensity to abstain from heroin use, nor was there any difference between the two groups in the mean reduction over time in their self-reported dependence on drugs. However, if the outcome measure used is the change (between baseline and 33 months) in the number of days that the interviewee reported having used heroin in the previous 3 months, the reduction in the number of days that heroin was used was significantly greater (52 days) in the methadone-maintained group than in the rest of the sample (36.4 days). This fall in the number of days of heroin use was greater still if the comparison was restricted to those who had continued on methadone-maintenance treatment, although 67.4% of those still on methadone maintenance had topped up' with heroin at some point in the 3 months prior to 33-month follow-up. Those on higher maintenance doses were not significantly more likely to have reduced the number of days on which they used heroin compared with those on lower doses, and those still on methadone maintenance were not more likely to have reduced their criminality (measured by the number of days on which they committed acquisitive crimes in the previous 3 months) compared with the rest of the sample. Conclusions: Methadone-maintained drug users are not more likely to achieve abstinence than drug users receiving other forms of treatment, but they are significantly more likely to achieve a reduction in the frequency of their illicit drug use; they 'top up' on methadone, but the frequency of their illicit drug use is less than that of drug users in other treatment modalities. These data confirm the value of methadone-maintenance services as part of a 'mixed economy' of services for the treatment of drug use.

( BUPP09181 - 29 September 2008) Urinary buprenorphine concentrations in patients treated with Suboxone� as determined by liquid chromatography-mass spectrometry and CEDIA immunoassay.

We report on the utility of urine total buprenorphine, total norbuprenorphine, and creatinine concentrations in patients treated with Suboxone� (a formulation containing buprenorphine and naloxone), used increasingly for the maintenance or detoxification of patients dependent on opiates such as heroin or oxycodone. Patients received 8-24 mg/day buprenorphine. Two-hundred sixteen urine samples from 70 patients were analyzed for both total buprenorphine and total norbuprenorphine by liquid chromatography-mass spectrometry (LC-MS-MS). Buprenorphine concentrations in all 176 samples judged to be unadulterated averaged 164 ng/mL, with a standard deviation (SD) of 198 ng/mL. Nine samples (4.2%) had metabolite-parent drug ratios < 0.02, and 33 (15.3%) had no detectable buprenorphine. The metabolite/parent drug ratio in 166 samples had a range of 0.07-23.0 (mean = 4.52; SD = 3.97). Fifteen of 96 available urine samples (16.7%) had creatinine less than 20 mg/dL. We also found sample adulteration in 7 (7.3%) available samples. Using a 5 ng/mL urine buprenorphine cutoff, the sensitivity and specificity of the Microgenics homogeneous enzyme immunoassay versus LC-MS-MS were 100% and 87.5%, respectively. The 5 ng/mL cutoff Microgenics CEDIA buprenorphine assay results agreed analytically with LC-MS-MS in 97.9% of samples.

( BUPP09182 - 29 September 2008) Chronic pain and opioidis dependence syndrome.

Pain is one of the most common complaints among patients seeking medical attention. Chronic pain can present an enormous burden to medical services, and its management has been elusive to clinicians, particularly when one considers the diversity of pain disorders that lack identifiable etiologies. Frequently, the adequate pain treatment is not carried out, because doctors may not aware of the several psychological and organic factors associated with painful syndromes. Pain management has received increased attention from the medical community as a result of societal demands for more effective and comprehensive treatment. Besides, pain management has received greater legal attention. This paper aims to review some aspects of the use of opioids in the treatment for the chronic pain, and some forensic issues pertaining to these problems.

( BUPP09183 - 29 September 2008) Studies on the analgesic and anti-inflammatory properties of crude extracts of sting ray, Dasyatis zugei (Muller and Henle 1841).

Dasyatis zugei (Muller and Henle (1841), the pale-deged sting ray its traditionally used by freshermen community of Puducherry for the treatment of various body ailments. Presently an attempt was made to examine the analgesic and anti-inflammatory properties of crude extract of commonly available ray fish, Dasyatis zugei using mouse assay. The statistically tested data from this experimental study, revealed that the crude petroleum ether and ether extracts of the ray fish exhibited significant pharmacological activities further it was also noticed that, of the extracts ether extract showed higher level of analgesic and anti-inflammatory property in comparison with standard drugs.

( BUPP09184 - 29 September 2008) Pain and U-shaped dose responses: Occurrence, mechanisms, and clinical implications.

This article assesses pain within the context of the dose response. A substantial number of studies indicate that the dose response for pain-related endpoints is commonly biphasic, being independent of the type of biological model employed, endpoint measured, or agent tested. The quantitative features of the dose response are also remarkably consistent regardless of the receptor pathway that mediates the nociceptive response, indicating a likely downstream message convergence. These findings have important implications for drug discovery, development, and clinical evaluation.

( BUPP09185 - 29 September 2008) Effects of various combinations of benzodiazepines with buprenorphine on arterial blood gases in rats.

Fatalities have been attributed to combinations of high-dose buprenorphine with benzodiazepines. In rats, high-dose buprenorphine combined with midazolam was shown to induce sustained respiratory acidosis, while buprenorphine alone did not. However, the effects of buprenorphine combined with pharmacological doses of benzodiazepines remain unknown. Our objective was to compare the acute effects of four selected benzodiazepines used intravenously at equi-efficacious doses in rats, alone and in combination with buprenorphine on sedation, respiratory rate and arterial blood gases. Buprenorphine (30 mg/kg) did not significantly modify sedation level or respiratory rate, but induced mild and transient effects on pH and PaCO /sub 2/(P < 0.05). Similarly, despite having no effects on respiratory rate, nordiazepam (10 mg/kg), bromazepam (1 mg/kg) and oxazepam (12 mg/kg) mildly and transiently altered pH and PaCO /sub 2/ (P < 0.05), whereas clonazepam (5 mg/kg) did not. Buprenorphine combined with each benzodiazepine induced no significant effects on respiratory rate or blood gases, in comparison with buprenorphine alone. However, combinations of oxazepam or nordiazepam with buprenorphine significantly deepened sedation. While both combinations reduced respiratory rate, buprenorphine + 30 mg/kg clonazepam significantly increased PaCO /sub 2/ and buprenorphine + 30 mg/kg nordiazepam decreased PaO /sub 2/ . In conclusion, not all benzodiazepines induce significant respiratory depression at therapeutic doses. We were unable to demonstrate significant effects on rat ventilatory parameters of buprenorphine combined with equi-efficacious pharmacological doses of benzodiazepines in comparison with buprenorphine alone. Our results may suggest that effects of these combinations are rather mild. Respiratory failure may, however, result from the association of buprenorphine with elevated doses of benzodiazepines.

( BUPP09186 - 29 September 2008) Murine renal ischaemia-reperfusion injury.

Ischaemia/reperfusion is a major cause of acute kidney injury in native and transplant kidneys and is associated with significant morbidity and mortality. Murine models of renal ischaemia/reperfusion injury have great potential to improve understanding of the underlying processes and are an important focus of ongoing research into therapeutic and preventative strategies. Like all experimental models, murine models of renal ischaemia/reperfusion are prone to significant variability and results may be influenced by a number of technical and design factors. In this article we review the factors that may influence experimental results and provide a guide to conducting reproducible experiments in murine renal ischaemia/reperfusion

( BUPP09187 - 29 September 2008) Office-based management of opioid dependence with buprenorphine: Clinical practices and barriers.

BACKGROUND: Buprenorphine is a safe, effective and underutilized treatment for opioid dependence that requires special credentialing, known as a waiver, to prescribe in the United States. OBJECTIVE: To describe buprenorphine clinical practices and barriers among office-based physicians. DESIGN: Cross-sectional survey. PARTICIPANTS: Two hundred thirty-five office-based physicians waivered to prescribe buprenorphine in Massachusetts. MEASUREMENTS: Questionnaires mailed to all waivered physicians in Massachusetts in October and November 2005 included questions on medical specialty, practice setting, clinical practices, and barriers to prescribing. Logistic regression analyses were used to identify factors associated with prescribing. RESULTS: Prescribers were 66% of respondents and prescribed to a median of ten patients. Clinical practices included mandatory counseling (79%), drug screening (82%), observed induction (57%), linkage to methadone maintenance (40%), and storing buprenorphine notes separate from other medical records (33%). Most non-prescribers (54%) reported they would prescribe if barriers were reduced. Being a primary care physician compared to a psychiatrist (AOR: 3.02; 95% CI: 1.48-6.18) and solo practice only compared to group practice (AOR: 3.01; 95% CI: 1.23-7.35) were associated with prescribing, while reporting low patient demand (AOR: 0.043, 95% CI: 0.009-0.21) and insufficient institutional support (AOR: 0.37; 95% CI: 0.15-0.89) were associated with not prescribing. CONCLUSIONS: Capacity for increased buprenorphine prescribing exists among physicians who have already obtained a waiver to prescribe. Increased efforts to link waivered physicians with opioid-dependent patients and initiatives to improve institutional support may mitigate barriers to buprenorphine treatment. Several guideline-driven practices have been widely adopted, such as adjunctive counseling and monitoring patients with drug screening

( BUPP09188 - 29 September 2008) Effectiveness of non-steroidal anti-inflammatory drugs and epidural anaesthesia in reducing the pain and stress responses to a surgical husbandry procedure (mulesing) in sheep.

In this study, we examined the potential of several widely used non-steroidal anti-inflammatory drugs ( NSAIDs) and other analgesics to reduce pain and stress in sheep after surgery. Because mulesing involves a greater degree of tissue trauma than other surgical husbandry procedures such as castration or tail-docking, it provides a more rigorous and conservative test to identify potentially useful analgesic strategies in sheep. Merino lambs (5 weeks of age) were randomised into eight treatment groups: (1) carprofen; (2) flunixin; (3) ketoprofen; (4) buprenorphine; (5) xylazine; (6) lignocaine epidural; (7) saline control; (8) sham control. The NSAIDs were administered 1.5 h before mulesing, buprenorphine 0.75 h and xylazine and lignocaine 0.25 h before mulesing. Pain- and discomfort-related behaviours were recorded for 12 h after mulesing, and plasma cortisol concentrations were measured before mulesing and 0.5, 6, 12, 24 and 48 h after mulesing. The results indicated that no single analgesic treatment provided satisfactory analgesia during both the surgical mulesing procedure and the ensuing period of pain associated with the inflammatory phase. However, there were indications that two NSAIDs (carprofen and flunixin) showed good potential as analgesics during the inflammatory phase. A combination of short- and long-acting analgesics may be needed to provide more complete pain relief. In conclusion, the administration of some NSAIDs offers the potential for good analgesia in sheep for the inflammatory phase following the tissue trauma of surgical husbandry procedures. Other analgesic options need to be considered if the acute stress response to the procedure is to be reduced.

( BUPP09189 - 06 October 2008) High cervical epidural neurostimulation for cluster headache: Case report and review of the literature.

Cluster headache belongs to the trigeminal autonomic cephalgias. Clinically, it is characterized by attacks of severe pain localized orbitally, supraorbitally or temporally, lasting for 15-180 min and occuring from once every other day to eight times a day. The attacks are associated with one or more of the following: conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis and eyelid oedema (1). Attacks occur in series (so called cluster periods or bouts) that are usually separated by remission periods lasting for months or years. In chronic cluster headache (CCH) substantial remission periods are lacking. Mean age at onset is 20-40 years and, for unknown reasons, 80% of patients are male. Treatment usually consists of drug therapy. Agents used for acute therapy are inhalation of high flow oxygen, sumatriptan subcutaneous injection or nasal spray and zolmitriptan nasal spray. For transitional or short term prophylaxis, corticosteroids and ergotamine derivatives are used. The cornerstone of maintenance prophylaxis is verapamil, but lithium and methysergide may also be used. Some patients respond to melatonin or topiramate (2). Nevertheless, there are a significant percentage of patients with CCH that do not experience satisfactory pain relief with drug therapy alone. In the last yeas new invasive techniques have emerged, and operational criteria have been proposed to define pharmacologically intractable headache (3)

( BUPP09190 - 06 October 2008) The optimal temperature of first aid treatment for partial thickness burn injuries.

Using our porcine model of deep dermal partial thickness burn injury, various cooling techniques (15 �C running water, 2 �C running water, ice) of first aid were applied for 20 minutes compared with a control (ambient temperature). The subdermal temperatures were monitored during the treatment and wounds observed and photographed weekly for 6 weeks, observing reepithelialization, wound surface area and cosmetic appearance. Tissue histology and scar tensile strength were examined 6 weeks after burn. The 2 �C and ice treatments decreased the subdermal temperature the fastest and lowest, however, generally the 15 and 2 �C treated wounds had better outcomes in terms of reepithelialization, scar histology, and scar appearance. These findings provide evidence to support the current first aid guidelines of cold tap water (approximately 15 �C) for 20 minutes as being beneficial in helping to heal the burn wound. Colder water at 2 �C is also beneficial. Ice should not be used.

( BUPP09191 - 06 October 2008) Overdose training and take-home naloxone for opiate users: Prospective cohort study of impact on knowledge and attitudes and subsequent management of overdoses.

Aim: To examine the impact of training in overdose management and naloxone provision on the knowledge and confidence of current opiate users; and to record subsequent management of overdoses that occur during a 3-month follow-up period. Design: Repeated-measures design to examine changes in knowledge and confidence immediately after overdose management training; retention of knowledge and confidence at 3 months; and prospective cohort study design to document actual interventions applied at post-training overdose situations. Method: A total of 239 opiate users in treatment completed a pre-training questionnaire on overdose management and naloxone administration and were re-assessed immediately post-training, at which point they were provided with the take-home emergency supply of naloxone. Three months later they were re-interviewed. Results: Significant improvements were seen in knowledge of risks of overdose, characteristics of overdose and appropriate actions to be taken; and in confidence in the administration of naloxone. A 78% follow-up rate was achieved (186 of 239) among whom knowledge of both the risks and physical/behavioural characteristics of overdose and also of recommended management actions was well retained. Eighteen overdoses (either experienced or witnessed) had occurred during the 3 months between the training and the follow-up. Naloxone was used on 12 occasions (a trained client's own supply on 10 occasions). One death occurred in one of the six overdoses where naloxone was not used. Where naloxone was used, all 12 resulted in successful reversal. Conclusions: With overdose management training, opiate users can be trained to execute appropriate actions to assist the successful reversal of potentially fatal overdose. Wider provision may reduce drug-related deaths further. Future studies should examine whether public policy of wider overdose management training and naloxone provision could reduce the extent of opiate overdose fatalities, particularly at times of recognized increased risk.

( BUPP09192 - 06 October 2008) Motor cortex rTMS in chronic neuropathic pain: Pain relief is associated with thermal sensory perception improvement.

Background: Improvement in sensory detection thresholds was found to be associated with neuropathic pain relief produced by epidural motor cortex stimulation with surgically implanted electrodes. Objective: To determine the ability of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex to produce similar sensory changes. Methods: In 46 patients with chronic neuropathic pain of various origins, first-perception thresholds for thermal (cold, warm) and mechanical (vibration, pressure) sensations were quantified in the painful zone and in the painless homologue contralateral territory, before and after rTMS of the motor cortex corresponding to the painful side. Ongoing pain level was also scored before and after rTMS. Three types of rTMS session, performed at 1 Hz or 10 Hz using an active coil, or at 10 Hz using a sham coil, were compared. The relationships between rTMS-induced changes in sensory thresholds and in pain scores were studied. Results: Subthreshold rTMS applied at 10 Hz significantly lowered pain scores and thermal sensory thresholds in the painful zone but did not lower mechanical sensory thresholds. Pain relief correlated with post-rTMS improvement of warm sensory thresholds in the painful zone. Conclusions: Thermal sensory relays are potentially dysfunctioning in chronic neuropathic pain secondary to sensitisation or deafferentation-induced disinhibition. By acting on these structures, motor cortex stimulation could relieve pain and concomitantly improve innocuous thermal sensory discrimination. 10th October 2008 - Message from the British Library - They are not allowed to take a copy of this paper so this will not be supplied to us.

( BUPP09193 - 06 October 2008) Coming to terms with complexity: a call to action for HIV prevention.

A quarter of a century of AIDS responses has created a huge body of knowledge about HIV transmission and how to prevent it, yet every day, around the world, nearly 7000 people become infected with the virus. Although HIV prevention is complex, it ought not to be mystifying. Local and national achievements in curbing the epidemic have been myriad, and have created a body of evidence about what works, but these successful approaches have not yet been fully applied. Essential programmes and services have not had sufficient coverage; they have often lacked the funding to be applied with sufficient quality and intensity. Action and funding have not necessarily been directed to where the epidemic is or to what drives it. Few programmes address vulnerability to HIV and structural determinants of the epidemic. A prevention constituency has not been adequately mobilised to stimulate the demand for HIV prevention. Confident and unified leadership has not emerged to assert what is needed in HIV prevention and how to overcome the political, sociocultural, and logistic barriers in getting there. We discuss the combination of solutions which are needed to intensify HIV prevention, using the existing body of evidence and the lessons from our successes and failures in HIV prevention.

( BUPP09194 - 06 October 2008) Drug withdrawal in newborns - Clinical data of 49 infants with intrauterine drug exposure: What should be done?

Background: Infants of drug abusing mothers are at high risk to suffer from neonatal abstinence syndrome (NAS). Depending on the drug signs of neonatal withdrawal vary but mainly include central nervous system irritability. NAS causes long duration of hospital stay. Severe withdrawal signs are seen in infants exposed to methadone, infants exposed to other opioids like heroin or buprenorphine have been shown to be less symptomatic. Between the years 1997 and 2003 following the border opening there was a dramatic increase in drug exposed newborns seen in the area of Leipzig (East Germany). Methods: In a retrospective study maternal and infant characteristics, severity of symptoms, duration of withdrawal and hospital stay, duration and kind of treatment as well as modalities for release from hospital were analyzed. Results: From 1997 to 2003 49 drug exposed newborns were admitted to our neonatal care unit. There was an increase of the number of affected infants within these years (Fig. 1A). Maternal drug abuse (n=48) included mainly methadone (n=33), in second line heroine and benzodiazepines, in a few cases also cocaine and cannabinoides. 3 mothers received substitution therapy with buprenorphine. Additional drug use to substitution therapy was seen in 15 mothers. Drugs of abuse were detected in infant urine specimen (36/48).35 of exposed newborns showed signs of NAS (incidence of NAS 71%). For evaluation of withdrawal signs and conduction of therapy the Finnegan score was used. As first line pharmacological treatment phenobarbitone was administered (n=42), secondary morphine was used (n=14, treatment failure 33%). Mean duration of hospital stay was 21 days. Mean duration of pharmacological treatment was 14 days with longer duration for methadone exposed infants vs. non-methadone exposed infants (16 vs. 10 days). Hospital stay was longer for non-methadone exposed infants. Maternal intake of more than 20 mg methadone per day vs. up to 20 mg per day caused longer duration of hospital stay (28 vs. 20 days, p=0,015). Conclusion: Long duration of hospital stay and pharmacological treatment call for optimised principal guide lines for diagnosis, treatment and long term follow-up. The results also underline the need for further research for an effective pharmacological treatment.

( BUPP09195 - 06 October 2008) Pain therapy Part III. Opioid analgetic drugs.

Opioid are natural or synthetic analgetic drugs. They are divided into two groups: opiates - natural analgesics received from opium - codeine, morphine, heroine; opioids - alfentanil, buprenorphine, fentanyl, methadone, pentazocine, pethidine, remifentanil, sufentanil, tramadol. Opioid receptors are located in the central nervous system and peripheral tissues. There are four main types of the receptors: mu (mi), kappa (kappa), delta (delta) and sigma (sigma), with several subtypes. The mechanism of opioid action can be explained as: presynaptic inhibition due to potassium channels opening and/or calcium channels closing; postsynaptic inhibition as an effect of polarization of the dorsal corns of the spinal cord; influence on the enkephalinergic and GABAergic complexes. Opioids are indicated in the therapy of: acute posttraumatic and postoperative pain; severe pain in certain diseases, e.g. myocardial ischaemia; moderate and strong cancer pain; chronic non-neoplasmatic pain; pain syndromes partly of inflammatory origin; neuropathic pain. Side effects of the opioid therapy: nausea and vomiting; somnolence; dizziness; mood changes (euphoria, dysphoria); respiratory depression; decrease in arterial and venous pressure; obstipation; increased tension of smooth muscles (biliary ducts); urine retention; histamine release. Wide range of the opioid analgetic drugs makes possible to use them according to cause, character, severity and persistence of pain. The knowledge of the undesirable side effects is of crucial value considering safety of the treated patients.

( BUPP09196 - 06 October 2008) Attitudes toward buprenorphine and methadone among opioid-dependent individuals.

Attitudes and beliefs about drug abuse treatment have long been known to shape response to that treatment. Two major pharmacological alternatives are available for opioid dependence: methadone, which has been available for the past 40 years, and buprenorphine, a recently introduced medication. This mixed-methods study examined the attitudes of opioid-dependent individuals toward methadone and buprenorphine. A total of 195 participants (n = 140 who were enrolling in one of six Baltimore area methadone programs and n = 55 who were out-of-treatment) were administered the Attitudes toward Methadone and toward Buprenorphine Scales, and a subset (n = 46) received an ethnographic interview. The in-treatment group had significantly more positive attitudes toward methadone than did the out-of-treatment group (p <.001), while they did not differ in their attitudes toward buprenorphine. Both groups had significantly more positive attitudes toward buprenorphine than methadone. Addressing these attitudes may increase treatment entry and retention.

( BUPP09197 - 06 October 2008) From yeast to alkaloids.

Alkaloids, which include caffeine and morphine, are a large class of pharmacologically active plant compounds that are often difficult to chemically synthesize. Incorporation of benzylisoquinoline alkaloid pathways in yeast will facilitate the production of natural and non-natural alkaloids.

( BUPP09198 - 06 October 2008) beta-Endorphin and drug-induced reward and reinforcement.

Although drugs of abuse have different acute mechanisms of action, their brain pathways of reward exhibit common functional effects upon both acute and chronic administration. Long known for its analgesic effect, the opioid beta-endorphin is now shown to induce euphoria, and to have rewarding and reinforcing properties. In this review, we will summarize the present neurobiological and behavioral evidences that support involvement of beta-endorphin in drug-induced reward and reinforcement. Currently, evidence supports a prominent role for beta-endorphin in the reward pathways of cocaine and alcohol. The existing information indicating the importance of beta-endorphin neurotransmission in mediating the reward pathways of nicotine and THC, is thus far circumstantial. The studies described herein employed diverse techniques, such as biochemical measurements of beta-endorphin in various brain sites and plasma, and behavioral measurements, conducted following elimination (via administration of anti-beta-endorphin antibodies or using mutant mice) or augmentation (by intracerebral administration) of beta-endorphin. We suggest that the reward pathways for different addictive drugs converge to a common pathway in which beta-endorphin is a modulating element. beta-Endorphin is involved also with distress. However, reviewing the data collected so far implies a discrete role, beyond that of a stress response, for beta-endorphin in mediating the substance of abuse reward pathway. This may occur via interacting with the mesolimbic dopaminergic system and also by its interesting effects on learning and memory. The functional meaning of beta-endorphin in the process of drug-seeking behavior is discussed.

( BUPP09199 - 06 October 2008) Pain and medical treatment for pain in gynecology.

Pain is encountered in gynecology in both acute and chronic forms. In addition to causal treatment, appropriate pain therapy should be initiated early for managing acute pain. Chronic pain, including that not caused by tumors, is treated according to WHO guidelines, important components of which include medication according to a fixed schedule, individualized dosage regimens, and prophylaxis for side effects of adjunct medications. Laxatives are indicated for the obstipation frequently accompanying opioid administration. If adequate pain relief cannot be achieved despite oral and transdermal analgetic agents, intravenous morphine should be considered as well as invasive methods such as central or peripheral nerve block. Coanalgetic agents such as corticosteroids, antidepressants, and neuroleptics can help lower the analgetic dosage needed. Acupuncture is possibly useful in certain forms of chronic pain.

( BUPP09200 - 06 October 2008) The role of the opioid receptor-like (ORL1) receptor in motor stimulatory and rewarding actions of buprenorphine and morphine.

We have previously shown that the ability of buprenorphine to activate the opioid receptor-like (ORL1) receptor compromises its antinociceptive effect. Furthermore, morphine has been shown to alter the level of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the ORL1 receptor, raising the possibility that the endogenous OFQ/N/ORL1 receptor system may be involved in the actions of these opioids. Thus, using mice lacking the ORL1 receptor and their wild-type littermates, the present study assessed the role of the ORL1 receptor in psychomotor stimulant and rewarding actions of buprenorphine and morphine. Morphine (5, 10 mg/kg) dose-dependently increased motor activity and induced conditioned place preference. However, the magnitude of each response was comparable for the mutant mice and their wild-type littermates. In contrast, buprenorphine (1mg/kg) induced greater motor stimulation in ORL1 receptor knockout mice as compared with their wild-type littermates. Further, single conditioning with buprenorphine (3 mg/kg) induced place preference in mutant mice but not in their wild-type littermates. The results of binding assay showed that buprenorphine concentration-dependently (0-1000 nM) displaced specific binding of ( /sup 3/ H)-OFQ/N in brain membrane of wild-type mice. Together, the present results suggest that the ability of buprenorphine to interact with the ORL1 receptor modulates its acute motor stimulatory and rewarding effects.

( BUPP09201 - 06 October 2008) The direct comparison of health and ulcerated stomach tissue: A multiple probe microdialysis sampling approach.

The ability to directly compare gastric ulcerated and healthy tissue would aid in the understanding of the physiological differences between these tissue types. Presently, these comparisons can only be drawn by the use of separate animal groups, which results in increased study variability. The focus of this research was to develop a four-probe microdialysis sampling approach to directly compare ulcerated and healthy tissue in the same animal. After controlled chemical ulcer induction, probes were implanted in the ulcerated and healthy stomach submucosa, stomach lumen and in the blood. To assess the significance of this multiple probe approach, drug concentrations in each probe location were monitored after selected compounds were dosed to the ligated stomach by oral gavage. Analysis of the dialysate samples was performed by HPLC-UV and concentration-time curves and pharmacokinetics analyses were used to determine differences between these tissue types.

( BUPP09202 - 06 October 2008) Transdermal buprenorphine in clinical daily practice: Effectiveness and tolerability in patients suffering fom chronic musculoskeletal pain.

( BUPP09203 - 07 October 2008) Commentary on Letter Entitled, "Buprenorphine Comes of Age".

We appreciate the interest that Drs. heit and Gourlay have in our case conference on treating opioid dependence with buprenorphine. we share their hope that increasing numbers of patients will have access to this life-saving treatment. We would like to address their comments of our case discussion. We agree that the limits of toxicology testing for benzodiazepines is a very important clinical issue for addiction physicians to consider in their daily work. in our case discussion, the patient had given a remote history of episodic clonazepam use to self-medicate anxiety and insomnia. There was no mention of her being clonazepam-dependent (prescribed or illicit) and, therefore, the discussants made no assumptions about which benzodiazepine she had used during her relapse during the second month of treatment.

( BUPP09204 - 07 October 2008) The Case for Chronic Disease Management for Addiction

Abstract: chronic disease (care) management (CDM) is a patient-centered model of care that involves longitudinal care delivery; integrated and coordinated primary medical and speciality care; patient and clinician education; explicit evidence-based care plans; and expert care availability. The model, incorporating mental health and speciality addiction care, holds promise for improving care for patients with substance dependence who often receive no care or fragmented ineffective care. We describe a CDM model for substance dependence and discuss a conceptual framework, the extensive current evidence for component elements, and a promising strategy to recognize primary and speciality health care to facilitate access for people with substance dependence. The CDM model goes beyond integrated case management by a professional, colocation of services, and integrated medical and addiction care - elements that individually can improve outcomes. Supporting evidence is presented that: 1) substance dependence is a chronic disease requiring longitudinal care, although most patients with addictions receive no treatment (eg, detoxification only) or short term interventions, and 2) for other chronic diseases requiring longitudinal care (eg, diabetes, congestive heart failure), CDM has been proven effective.

( BUPP09205 - 13 October 2008) Assessment of lung inflammation in a mouse model of smoke inhalation and burn injury: Strain-specific differences.

To test concepts developed in our ovine model of acute respiratory distress syndrome, specifically the roles of neuropeptides and other peptide mediators, a recently developed murine model of combined smoke inhalation and burn (SB) injury was extended by applying methods for quantitative assessment of acute inflammation in the lung. Mice received SB injury per protocol, n = 5 to 7 per group. Mice were anesthetized with i.p. ketamine/xylazine, endotracheally intubated, and exposed to cooled cotton smoke (4 x 30 sec for Balb/C, 2 x 30 sec for C57BL/6). After s.c. injection of 1 mL 0.9% saline, each received a 40% total body surface area (TBSA) flame burn. Buprenorphine (0.1 mg/kg) was given i.p. for postoperative analgesia; 0.9% saline was given i.p. at 4 mL/kg per %TBSA burn. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. In other animals, after vascular perfusion with buffered saline, lungs were sampled and analyzed for myeloperoxidase (MPO), using an EIA kit, and for their content of EB dye. There was a significant (p < 0.05) increase in EB dye content, wet/dry weight ratio, and MPO 24 h after injury in Balb/C mice. Similar increases were seen in C57BL/6 mice 48 h after SB injury, but not at 24 h. C57 mice tolerated less smoke inhalation than Balb/C mice, due to postexposure apnea, and required 48 h to show significant increases in these variables. Direct comparison between animals injured by 40% TBSA burn and 2 x 30 sec smoke exposure and sacrificed after 48 h showed significantly greater abnormality in the C57BL/6 mice. The mouse model can be used effectively to assess acute inflammation in the lung.

( BUPP09206 - 13 October 2008) Opioid-induced hyperalgesia may be more frequent than previously thought

( BUPP0207 - 13 October 2008) Pain treatment with high-dose, controlled-release oxycodone: An Italian perspective.

Objective: To investigate the possible role and tolerability of high-dose (>160 mg/day) oxycodone controlled release (CR) for the treatment of cancer and non-cancer pain. Design: 227 patients with cancer or non-cancer pain were enrolled in an open-label, multi-center, Italian study in order to assess the adequacy of their existing pain management (using a numerical rating scale (NRS)) and the possible benefit high-dose oxycodone CR may offer patients experiencing uncontrolled pain. Results: Pain was poorly controlled at baseline, with only 18.1% of patients reporting adequate pain relief (NRS < 3.5). All other patients reported uncontrolled pain, with an average NRS of 7.81. At baseline assessment, 47.89% of patients had been in pain for up to 3 months, 32.82% for 3-6 months, and 19.19% for more than 6 months. After baseline assessment, patients were switched to oxycodone CR monotherapy. The starting dose was individualized to each patient and titrated up over a 3- to 4-day period until effective pain management was achieved. Treatment was continued for an average of 37.24 days during the study. Pain control (final mean NRS of 2.85) was attained with an average dose of oxycodone CR 221.84 mg/day. Standard adverse events (including constipations, nausea, and vomiting) were recorded in 39.64% of patients receiving high-dose oxycodone CR monotherapy. Side-effects tended to subside after the initial week of treatment and did not result in any participants leaving the study. Conclusion: Higb-dose oxycodone CR can achieve rapid and effective management of moderate to severe cancer and non-cancer pain with minimum side-effects.

( BUPP09208 - 13 October 2008) Efficacy of pethidine and buprenorphine for prevention and treatment of postanesthetic shivering.

Background: Postanesthetic shivering is a distressing postoperative complication. Pharmacological control is an effective method for treatment and prevention of postoperative shivering. Pethidine prevents or manages shivering far better than equianalgesic doses of other opioids. However, buprenorphine is an opioid with a similar structure to morphine but approximately 33 times more potent. This study aimed to assess and compare the effects of these two opioids in preventing post-anesthetic shivering. Materials and Methods: This randomized double- blind clinical trial was designed to compare the efficacy of buprenorphine and pethidine in prevention of post anesthetic shivering. Sixty ASA grade I-II patients undergoing general anesthesia for elective Cesarean section entered the study. Patients received either bupranorphine 3mug/kg (n=30) or pethidine 0.5 mg/kg (n=30) intravenously 30 min before the end of surgery. Heart rate and blood pressure were measured 15 min after the injection. Occurrence of shivering was evaluated for one hour in the recovery room. Also, pain intensity was assessed by using a visual analog scale (VAS; 0-5). Results: Shivering was significantly reduced in the pethidine group (5 of 30 versus 13 of 30, p<0.05). Visual pain scores were similar in both groups. There was no difference between the two groups ragarding hemodynamics. Conclusion: Despite similar in pain control, pethidine is more effective than buprenorphine in prevention of post anesthetic shivering.

( BUPP09209 - 13 October 2008) A new pathway

( BUPP09210 - 13 October 2008) Oxycodone/paracetamol: A guide to its use in the treatment of moderate to severe musculoskeletal pain.

( BUPP09211 - 13 October 2008) Therapeutic strategies for persons addicted to opiates: The role of substitution treatment.

( BUPP09212 - 13 October 2008) A comprehensive review on the mode of action and the use of analgesics in different clinical pain states

Opioids in Medicine Book purchased by Chris Chapleo BBG.

( BUPP09207 - 13 October 2008) Pain treatment with high-dose, controlled-release oxycodone: An Italian perspective.

( BUPP09213 - 27 October 2008) Substitution treatment in Malaysia

( BUPP09214 - 27 October 2008) Accelerating harm reduction interventions to confront the HIV epidemic in the Western Pacific and Asia: The role of WHO (WPRO).

The epidemic of HIV/AIDS linked to injecting drug usage is one of the most explosive in recent years. After a historical epicentre in Europe, South and North America, at present it is clearly the main cause of dissemination of the epidemic in Eastern Europe and some key Asian countries. Recently, 10 African countries reported the spread of HIV through people who inject drugs (PWID), breaking one of the final geographical barriers to the globalization of the epidemic of HIV among and from PWID. Several countries of the Asia and Pacific Region have HIV epidemics that are driven by injecting drug usage. Harm reduction interventions have been implemented in many countries and potential barriers to implementation are being overcome. Harm reduction is no longer a marginal approach in the Region; instead, it is the core tool for responding to the HIV/AIDS epidemic among PWID. The development of a comprehensive response in the Region has been remarkable, including scaling up of needle and syringe programmes (NSPs), methadone maintenance treatment (MMT), and care, support and treatment for PWID. This development is being followed up by strong ongoing changes in policies and legislations. The main issue now is to enhance interventions to a level that can impact the epidemic. The World Health Organization (WHO) is one of the leading UN agencies promoting harm reduction. Since the establishment of the Global Programme on AIDS, WHO has been working towards an effective response to the HIV epidemic among PWID. WHO's work is organized into a number of components: establishing an evidence base; advocacy; development of normative standards, tools and guidelines; providing technical support to countries; ensuring access to essential medicines, diagnostics and commodities; and mobilizing resources. In this paper, we trace the course of development of the HIV/AIDS epidemic among and from PWID in the Western Pacific and Asia Region (WPRO) as well as WHO's role in supporting the response in some of the key countries: Cambodia, China, Lao PDR, Malaysia, the Philippines and Viet Nam.

( BUPP09215 - 27 October 2008) A short review of pharmacy practice in England.

( BUPP09216 - 27 October 2008) Effects of chronic buprenorphine treatment on levels of nucleus accumbens glutamate and on the expression of cocaine-induced behavioral sensitization in rats.

Rationale: Chronic treatment with the mu-opioid receptor agonist, buprenorphine, reduces cocaine-induced behaviors in rats with a history of cocaine self-administration. The mechanisms underlying these actions of buprenorphine remain unclear. Objectives: The objective of this study is to investigate the effects of chronic buprenorphine treatment on cocaine-induced activity and levels of glutamate and dopamine (DA) in the nucleus accumbens (NAc) in rats that were preexposed to cocaine or drug-naive. Materials and methods: In experiment 1, basal levels of NAc glutamate were assessed using in vivo microdialysis in cocaine-naive rats that were treated chronically with buprenorphine (3.0 mg/kg per day) via osmotic minipumps or that underwent sham surgery. In experiment 2, rats were preexposed to seven daily injections of cocaine or saline. After a 12-16-day drug-free period, extracellular levels of NAc glutamate and DA and locomotor activity were assessed simultaneously, before and after an acute injection of cocaine (15 mg/kg, intraperitoneal), in rats under sham and chronic buprenorphine (3.0 mg/kg per day) treatment. Results: Chronic buprenorphine treatment increased basal levels of glutamate in drug-naive and cocaine-preexposed rats, blocked the expression of locomotor sensitization to cocaine, and potentiated the NAc DA response to acute cocaine in cocaine-preexposed rats. Conclusions: These findings suggest that buprenorphine may block the expression of cocaine sensitization and other cocaine-related behaviors by increasing basal levels of glutamate in the NAc, which would serve to decrease the effectiveness of cocaine or cocaine-associated cues.

( BUPP09217 - 27 October 2008) Quantitative analysis of cocaine in human hair by HPLC with fluorescence detection.

Cocaine is currently one of the most widespread abuse drugs in the world. Since hair cocaine concentrations are a reliable marker of exposition to the drug, an original liquid chromatographic method has been developed for the determination of cocaine in human hair. The chromatographic analysis was carried out on a Hydro-RP C18 column, using a mobile phase containing a phosphate buffer (pH 3.0)- acetonitrile-methanol (75:15:10, v/v/v). Native cocaine fluorescence was monitored at 315 nm while exciting at 230 nm. Mirtazapine was used as the internal standard. Sample pre-treatment was carried out by incubative extraction with 0.1 M HCl followed by solid-phase extraction with C2 cartridges. Good linearity was obtained over a working range of 0.3-100.0 ng/mg. Both extraction yield (>89%) and precision values (R.S.D. < 6.2%) were highly satisfactory. The method was successfully applied to hair samples collected from cocaine users. Thus, the method is suitable for the long-term monitoring of cocaine use by means of hair testing.

( BUPP09218 - 27 October 2008) Prevention of Herpes Zoster infections in the elderly and management of post-herpetic neuralgia.

30th October 2008 - Word from the British Library - Been asked to reapply for paper in 3 weeks.

( BUPP09219 - 27 October 2008) Development and validation of a stability indicating HPLC method for the determination of buprenorphine in transdermal patch.

A rapid and sensitive stability indicating HPLC method has been developed and validated for the determination of buprenorphine (BPN) in transdermal patch. Chromatographic separation was achieved isocratically on an XBridge (TM) Shield RP18 column with a mobile phase of acetonitrile / 0.063 M ammonium bicarbonate buffer (pH 9.5) (58:42, v/v) at the flow rate of 1.5 mL/min with UV absorbance monitoring at 230 nm. The system performance was evaluated and the result showed that BPN and degradation products were separated. Buprenorphine was subjected to neutral, acidic and basic hydrolysis as well as chemical oxidation to evaluate the specificity. The calibration curve of buprenorphine was linear in the range of 30-70 mu g/mL (r = 0.9999, n =: 5). The values of RSD (%) for the intra-day and inter-day precision ranged from 0.04 to 0.22 and 0.65 to 0.88%, respectively. The average of the recovery percentage ranged from 98.86 to 99.36%. The detection limit (DL) and quantitation limit (QL) for buprenorphine were 0.008 and 0.024 mu g/mL, separately. The robustness of this method was also evaluated oil the small fluctuations of pH in the mobile phase, the mobile phase compositions, and the flow rate. The results of stability studies showed the hydrolysis reaction of buprenorphine followed zero-order kinetics model in acidic and basic environment and followed first-order kinetics model in the presence of hydrogen peroxide. This analytical method was successfully applied to the determination of buprenorphine in transdermal patch and call be used for routine quality control work.

( BUPP09220 - 27 October 2008) Imaging of opioid receptors in the central nervous system.

In vivo functional imaging by means of positron emission tomography (PET) is the sole method for providing a quantitative measurement of mu-, kappa and delta-opioid receptor-mediated signalling in the central nervous system. During the last two decades, measurements of changes to the regional brain opioidergic neuronal activation - mediated by endogenously produced opioid peptides, or exogenously administered opioid drugs - have been conducted in numerous chronic pain conditions, in epilepsy, as well as by stimulant- and opioidergic drugs. Although several PET-tracers have been used clinically for depiction and quantification of the opioid receptors changes, the underlying mechanisms for regulation of changes to the availability of opioid receptors are still unclear. After a presentation of the general signalling mechanisms of the opioid receptor system relevant for PET, a critical survey of the pharmacological properties of some currently available PET-tracers is presented. Clinical studies performed with different PET ligands are also reviewed and the compound-dependent findings are summarized. An outlook is given concluding with the tailoring of tracer properties, in order to facilitate for a selective addressment of dynamic changes to the availability of a single subclass, in combination with an optimization of the quantification framework are essentials for further progress in the field of in vivo opioid receptor imaging.

( BUPP09221 - 27 October 2008) Differential therapeutic aspects of analgesia with oral sustained-release strong opioids: Application intervals, metabolism and immunosuppression.

The oral "around-the clock" administration of sustained-release strong opioids has been recommended for the long-term treatment of patients suffering from chronic severe pain. At present a plethora of products are available in Germany. Modern galenics even allow for only once-daily oral application without clinically relevant negative chronobiological interference. This application scheme has been shown to improve compliance and sleep quality, factors that influence treatment outcome. Randomized controlled studies revealed no relevant differences between the different strong opioids with respect to efficacy and tolerability. However, hydromorphone and oxycodone appear to be advantageous over morphine due to a lack of immunosuppression. Hydromorphone has the additional benefit of a lower risk of intoxication by accumulation of active metabolites in patients with decreased renal function. As a result, although morphine has been regarded as the standard for the treatment of chronic severe pain, hydromorphone and oxycodone may be better and safer alternatives for certain patient groups (e.g. older age, multimorbidity, cancer).

( BUPP09222 - 27 October 2008) Topical application of morphine and buprenorphine gel has no effect in the sunburn model.

Background. The aim of this placebo-controlled double-blinded cross-over study was to investigate the antihyperalgesic effect of topical morphine and buprenorphine in the sunburn pain model. Material and methods. The study was designed as a double-blind, placebo-controlled cross-over trial, separated into 2 parts each with 16 volunteers. In part A morphine dissolved in Ultrabas-ultrasic ointment at 3 concentrations (0.1, 0.2, 0.4%) and placebo ointment were applied to 4 UVB-induced erythemas on the thighs. In part B buprenorphine at 3 concentrations (0.01, 0.02 and 0.1%) and placebo dissolved in a gel for transcutaneous application, was applied to 4 erythemas on the thighs. Thermal and mechanical hyperalgesia were assessed in the respective erythema by standardized quantitative sensory testing and opioids were compared to the placebo. Results. Neither morphine nor buprenorphine showed any significant reduction of hyperalgesia in comparison to the placebo. Conclusion. The topical application of opioids in this form has no effect on inflamed skin.

( BUPP09223 - 27 October 2008) /sup 153/ Sm: Its use in multiple myeloma and report of a clinical experience.

Background: In the past years the bone seeking radiopharmaceutical samarium lexidronam ( /sup 153/ Sm-EDTMP) has been increasingly used alone or in conjunction with chemotherapy and/or bisphosphonates for the treatment of painful bone metastasis. Objective: Its use has been explored in different solid tumours. In this report we explore its interesting characteristics and describe our experience in multiple myeloma (MM). Methods: /sup 153/ Sm-EDTMP has an affinity for bone and concentrates in areas of bone turnover. It decays as a therapeutic beta-emission and at the same time as gamma-photon that can be used for tracking its concentration with bone scan imaging. Ten patients with symptomatic MM were treated to achieve pain control. Results: Encouraging results were obtained in MM patients. The use of this radioisotope could be largely improved. 30th October 2008 - Message from the Brirtish Library. They are not allowed to copy this piece from the jounral so canot supply.

( BUPP09224 - 27 October 2008) Neuropathic pain - The case for opioid therapy.

For many patients, neuropathic pain (NeP) is arguably more difficult to control than nociceptive or 'normal' pain. We also now recognise the great burden that NeP has on the lives of patients - it is not only a matter of treating pain in isolation, but managing all of the issues that affect the patient's quality of life. Until relatively recently we have had little understanding of the pathophysiology causing NeP and have relied on the secondary effects of non-analgesic drugs as the mainstays of treatment. Greater understanding of the pathophysiology of NeP has led to more appropriate therapy and an increased use of multiple drug therapy - 'rational polypharmacy'. Traditional opinions concerning the treatment of NeP have been challenged and it is because of this that the use of opioids in NeP has been re-evaluated. Opioids will never replace tricyclic antidepressants and anti-epileptic drugs as first-line therapy for Ne P. However, they are now fully established as effective and useful second- or third-line drugs. Many patients in the past have been potentially undertreated as a result of our inertia to use opioids. The case for opioid therapy in NeP has been firmly established.

( BUPP09225 - 27 October 2008) Pharmacotherapeutic guideline for pain management.

( BUPP09226 - 27 October 2008) Illicit drug use and liver transplantation: Is there a problem and what is the solution?

Liver transplantation is indicated in carefully selected patients with alcohol-induced liver disease. There has been less debate to date on the issues surrounding assessment of patients with an illicit drug history and outcome post-transplantation. UK guidelines on assessment and selection have been agreed. Careful assessment and access to treatment should be considered.

( BUPP09227 - 27 October 2008) A survey of cancer pain status in Shanghai

This is a multicenter investigational survey conducted in 76 hospitals in Shanghai between July and August 2004. The objective was to investigate the cancer pain status and physicians' pain management capabilities in Shanghai. A total of 923 cancer patients involved in the investigation completed a questionnaire which included general condition, self-assessment of pain and questions of pain control knowledge. The study results were analyzed concerning: reason for cancer pain, type and intensity of cancer pain, treatment methods, patients' understanding of addiction, patients' request for pain treatment, and patients' and physicians' viewpoint on current cancer pain treatment.

( BUPP09228 - 27 October 2008) The selection and use of essential medicines

This report presents the recommendations of the WHO Expert Committee responsible for updating the WHO Model List of Essential Medicines. The first part contains a summary of the Committee's considerations and justifications for additions and changes to the Model List, including its recommendations. Annexes to the main report include the revised version of the WHO Model List of Essential Medicines (the 14th) and a list of all items on the Model List sorted according to their 5-level Anatomical Therapeutic Chemical (ATC) classification codes.

( BUPP09229 - 27 October 2008) High dose transdermal buprenorphine for moderate to severe pain in Spanish pain centres - A retrospective multicenter safety and efficacy study.

Obectives: To assess the effectiveness of transdermal buprenorphine in patients suffering from moderate to severe pain. Secondary objectives included gathering information about the causes of pain, management of episodic pain, and the safety profile. Methods: Retrospective data were collected from 1,465 patients with moderate to severe pain, ie, 50 mm on a 0 to 100 mm visual analog scale (VAS), that were switched to transdermal buprenorphine, and received a dose 52.5 mug/hour for at least 14 days during the previous 12 months. Pain could have any etiology. Most patients (72.1%) were on tramadol and/or paracetamol (40.7%) before switching to buprenorphine. Using case report forms, efficacy was determined from changes in VAS score compared with 24 hours prior to the first patch application. Safety was evaluated by retrieving information about the nature and incidence of adverse events (AE), whether they were related to the study compound, and the percentage considered being serious. Results: An absolute reduction of 25.1 points in VAS score was seen over a median period of 3.7 months treatment. In addition, the VAS score was reduced by at least 10% in 88.4% of patients and the incidence of episodic pain fell significantly. Treatment was rated as "Good" or "Very Good" by 82.5% of patients. Out of 1,465 patients, 50.2% experienced an AE; this was related to the drug in 48.8%, and considered serious in 4.0%. Conclusions: Transdermal buprenorphine was an effective and considerably safe drug for relieving chronic moderate to severe pain.

( BUPP09230 - 03 November 2008) Opiate treatment in depression refractory to antidepressants and electroconvulsive therapy.

This open-label study examined efficacy of sublingual buprenorphine in 6 patients with nonpsychotic major depressive episode. All depressive patients improved under buprenorphine treatment over 1 wk. This rapid improvement was observed after long-term depressive episodes that had been treated without success with antidepressants and electroconvulsive therapy. Several questions need to be addressed to in further studies (effectiveness in patients with and without treatment resistance, biological or psychopathological predictors for a response to buprenorphine treatment, proper dosage, and treatment duration).

( BUPP09231 - 03 November 2008) Comparison of consumption of opioid analgesics and analgesics-antipyretics in Slovakia and in Finland.

We can classify analgesics according to affinity to opioid receptors into nonopioid and opioid analgesics. We analyse wholesale consumption of analgesics in the ATC group N02 in Slovak medical practice in the years 1996-2007. Obtained results were compared with data based annual health statistics in Finland during 2003-2007. We noticed a significant increase in consumption of metamizol, while consumption of acetylsalicylic acid is decreasing. Fentanyl and buprenorfme consumption significantly increased. These trends in consumption showed a well known accent on effective pain treatment in Scandinavian countries.

( BUPP09232 - 03 November 2008) Effect of selenium compound (selol) on the opioid activity in vincristine induced hyperalgesia.

Purpose: Effect of organoselenium compound (selol), on antinociceptive action of opioid agonists in vincristine neuropathic pain model was investigated. Methods: The changes in pain thresholds were determined using mechanical stimuli - the modification of the classic paw withdrawal test described by Randall-Selitto. Results: Daily administration of VIN (70 mug/kg, iv) resulted in progressive decrease of pain threshold. Neither morphine, fentanyl nor buprenorphine administered alone in 5 consecutives days modified the vincristine-induced hyperalgesia, whereas selol slightly increased the nociceptive threshold. Co-administration of selol with opioids markedly enhanced the analgesic activity of all three investigated compounds. Conclusions: Therefore, concomitant of selenium and opioids may be beneficial in terminal neoplastic states.

( BUPP09233 - 03 November 2008) Interventional pain treatments for cancer pain.

Cancer pain is prevalent and often multifactorial. For a segment of the cancer pain population, pain control remains inadequate despite full compliance with the WHO analgesic guidelines including use of co-analgesics. The failure to obtain acceptable pain or symptom relief prompted the inclusion of a fourth step to the WHO analgesic ladder, which includes advanced interventional approaches. Interventional pain-relieving therapies can be indispensable allies in the quest for pain reduction among cancer patients suffering from refractory pain. There are a variety of techniques used by interventional pain physicians, which may be grossly divided into modalities affecting the spinal canal (e.g., intrathecal or epidural space), called neuraxial techniques and those that target individual nerves or nerve bundles, termed neurolytic techniques. An array of intrathecal medications are infused into the cerebrospinal fluid in an attempt to relieve refractory cancer pain, reduce disabling adverse effects of systemic analgesics, and promote a higher quality of life. These intrathecal medications include opioids, local anesthetics, clonidine, and ziconotide. Intrathecal and epidural infusions can serve as useful methods of delivering analgesics quickly and safely. Spinal delivery of drugs for the treatment of chronic pain by means of an implantable drug delivery system (IDDS) began in the 1980s. Both intrathecal and epidural neurolysis can be effective in managing intractable cancer-related pain. There are several sites for neurolytic blockade of the sympathetic nervous system for the treatment of cancer pain. The more common sites include the celiac plexus, superior hypogastric plexus, and ganglion impar. Today, interventional pain-relieving approaches should be considered a critical component of a multifaceted therapeutic program of cancer pain relief.

( BUPP09234 - 03 November 2008) Cancer pain and analgesia.

Pain ranges in prevalence from 14-100% among cancer patients and occurs in 50-70% of those in active treatment. Cancer pain may result from direct invasion of tumor into nerves, bones, soft tissue, ligaments, and fascia, and may induce visceral pain through distension and obstruction. Cancer pain is multifaceted. Clinicians may describe cancer pain as acute, chronic, nociceptive (somatic), visceral, or neuropathic. Despite implementation of the WHO guidelines, reports of undertreatment of cancer pain persist in various clinical settings and in spite of decades of work to reduce unnecessary discomfort. Substantial obstacles to adequate pain relief with opioids include specific concerns of patients themselves, their family members, physicians, nurses, and the healthcare system. The WHO analgesic ladder serves as the mainstay of treatment for the relief of cancer pain in concert with tumoricidal, surgical, interventional, radiotherapeutic, psychological, and rehabilitative modalities. This multidimensional approach offers the greatest potential for maximizing analgesia and minimizing adverse effects. Primary therapies are directed at the source of the cancer pain and may enhance a patient's function, longevity, and comfort. Adjuvant therapies include nonopioids that confer analgesic effects in certain medical conditions but primarily treat conditions that do not involve pain. Nonopioid medications (over-the-counter agents) are useful in the management of mild to moderate pain, and their continuation through step 3 of the WHO ladder is an option after weighing a drug's risks and benefits in individual patients. Symptomatic treatment of severe cancer pain should begin with an opioid, regardless of the mechanism of the pain. They are very effective analgesics, titrate easily, and offer a favorable risk/benefit ratio. Cancer pain remains inadequately controlled despite the diagnostic and therapeutic means of ensuring that patients feel comfortable during their illness. Therefore, all practitioners need to make control of cancer pain a professional duty, even if they can only use the most basic and least expensive analgesic medications, such as morphine, codeine, and acetaminophen, to reduce human suffering.

( BUPP09235 - 03 November 2008) Sublingual drug delivery.

The sublingual route is one of the early modes of administration for systemic drug delivery. This route avoids first-pass metabolism and affords quick drug entry into the systemic circulation. Attempts have been made to deliver various pharmacologically active agents, such as cardiovascular drugs, analgesics, and peptides, across the sublingual mucosa. In this review, the anatomical structure, blood supply, biochemical composition, transport pathways, permeation enhancement strategies, in vitro / in vivo models, and clinical investigations for the sublingual route of drug delivery is discussed.

( BUPP09237 - 03 November 2008) Neuropsychological functioning of opiate-dependent patients: A nonrandomized comparison of patients preferring either buprenorphine or methadone maintenance treatment

Objectives: In the present study, we investigated whether buprenorphine as a partial mu -opioid receptor agonist is associated with less cognitive impairment than methadone. Methods: Neuropsychological functioning of opioid-dependent patients, previously assigned to methadone (MMP, n = 30) or buprenorphine (BMP, n = 26) maintenance treatment according to their own preference, was compared and dose effects were investigated. Results: MMP and BMP performed equally well on all measures of neuropsychological functioning including the trail making test, the continuous performance test, and a vigilance task. However, patients receiving a higher dose of methadone were impaired in a vigilance task. Conclusions: In a free-choice administration of methadone or buprenorphine, there seems to be no difference in cognitive functioning. Possible explanations are discussed.

( BUPP09238 - 03 November 2008) "Narcotics helped, I thought." Recurrent traumatization and recovery from drug dependence.

( BUPP09239 - 03 November 2008) Office-based treatment in opioid dependence: A critical survey of prescription practices for opioid maintenance medications and concomitant benzodiazepines in Vienna, Austria.

Background: The success of maintenance treatment for opioid dependence in office-based settings is influenced by the extent of treatment coverage, the availability of effective medications and the capacity of general practitioners to prescribe opioids in adequate doses with a minimum of concomitant benzodiazepine prescriptions. Methods: This study compares prescriptions for opioid maintenance and concomitant benzodiazepine from Viennese physicians in 2002 and 2005 using health insurance prescription records (n = 30,309). Results: Between 2002 and 2005, the number of patients prescribed opioids more than doubled (ratio 1:2.3), slow-release oral morphine replaced methadone as the most frequently prescribed medication (57.1 vs. 23.4%; buprenorphine 19.5%), and the ratio of benzodiazepine to opioid prescriptions significantly declined (0.76:1 vs. 0.42:1). Many patients were prescribed concomitant benzodiazepines (27%), in some cases from a secondary physician. Conclusion: Increased utilization of opioid medications in office-based settings will facilitate better treatment coverage. However, safeguards are necessary to ensure that general practitioners have sufficient training and support to safely and appropriately provide treatment, including the reduction in concomitant benzodiazepine use.

( BUPP09240 - 03 November 2008) Post-treatment outcomes of buprenorphine detoxification in community settings: A systematic review.

A systematic review was undertaken to examine studies of buprenorphine detoxification that has included post-treatment outcomes as well as more immediate aspects of progress. Studies were required to report details of buprenorphine withdrawal regime and post-treatment outcomes including abstinence rates. Only five studies met these criteria, with buprenorphine regimes lasting 3 days to several weeks, and with variable follow-up. Detoxification completion rates were 65-100%, but relatively few treatment completers were then drug free at their follow-up appointments. In subsequent prescribing, more patients had returned to opioid maintenance than complied with naltrexone. Our preliminary review indicates that buprenorphine is a suitable medication for the process of opiate detoxification but that this newer treatment option has not led to higher rates of abstinence following withdrawal. Further studies are required to more substantially examine abstinence outcomes, as well as characteristics which predict success.

( 09241 - 03 November 2008) Retention in substitution programmes with buprenorphine.

International and national experiences with substitution programme on buprenorphine are presented. As an advantage, the extension of availability of this treatment modality outside specialized opiate maintenance centres is underlined. Increasing presence of buprenorphine on black market and its misuse are seen as factors that may create a barrier for wider implementation of the programme by general practitioners. Involvement in the programme is crucial for the treatment outcome, therefore specific attention is paid to factors that influence retention.

( BUPP09241 - 03 November 2008) Retention in substitution programmes with buprenorphine.

( BUPP09242 - 03 November 2008) Methadone versus buprenorphine for inpatient detoxification treatment.

Aim: The effects of methadone and buprenorphine on withdrawal from opiates were compared with each other on a drug detoxification unit. Method: 10 female and 50 male patients were randomly assigned; 30 patients received methadone-racemate, and 30 received buprenorphine. Withdrawal symptoms and craving were assessed with standardised measures on Days 1, 2, 3, 7, 14, and 21. Results: During the first 14 days, patients receiving buprenorphine reported fewer withdrawal symptoms, and from Day 7 onward, they reported less craving. The two groups of patients did not differ noticeably in their need for additional medication or in the rate at which they successfully completed the trial. Conclusions: The results show an overall better effect for buprenorphine compared to methadone on withdrawal symptoms and craving.

( BUPP09243 - 03 November 2008) Hair analysis for psychoactive substances in comparison to urine analysis.

Background: Like urine analysis, hair analysis for psychoactive drugs is often regarded as a procedure that is easily performed and interpreted. However, various aspects of either kind of analysis must be considered in order to obtain meaningful results. Variables: Both urine and hair vary widely in their composition. Damage to the hair resulting from weathering or cosmetic treatment is accompanied by a reduction in the concentration of the addictive substance. Urine and hair have quite different analytic patterns that have to be considered during sample preparation and analysis. The interpretation of results from a hair analysis is hampered by the fact that drug incorporation routes are still not known with certainty. The assumption that hair grows at a rate of about 1 cm per month is only a ough estimate. Prospects: The suggestion that hair analysis results be adjusted according to the melanin content of hair should be examined further. Enzyme polymorphisms could partly explain the variability in hair analysis results. There is evidence from several studies that hair analysis is more accurate than urine analysis at identifying drug users. Conclusion: Which kind of analysis is used depends on which kind of specimen is available and on the question that is posed; urine and hair analyses complement each other because of their different detection windows.

( BUPP09244 - 03 November 2008) A national survey of postoperative pain management in France: Influence of type of surgical centres.

Background: The French Society of Anaesthesia and Intensive Care has supported a national survey of postoperative pain (POP) management in various type of surgical centres. Methodology: The survey was cross-checking data on information, evaluation, treatment concerning POP of adult patient within 24 h after surgery in surgical centres randomly selected according to teaching status, public or private funding and size. A local anaesthetist referent provided information on management of POP. Results: One thousand and nine hundred adult patients were audited. Information on POP was better understood in private centres. Rarely prescribed, written evaluation of POP was frequent on the ward (> 90%) without any difference between centres. In all centres, POP evaluation tool were by decreasing frequency, numerical scale, nonspecific tool, visual analog scale and verbal scale. In all institutions, pain was rarely a criterion for recovery room discharge. Reported POP was mild at rest, moderate when moving and intense for maximal pain with no difference between centres. Incidence of side-effects was similar in all centres according to patient or chart, with mainly nausea and vomiting. Analgesics were frequently started during anaesthesia. Patient-controlled analgesia was used less frequently than subcutaneous morphine whose prescription frequently did not follow guidelines especially in small hospital. Non opioid analgesic included paracetamol, ketoprofen mainly in private structure and nefopam mainly in university hospital. Epidural or peripheral nerve blocks were underused similarly in all centres. Evaluation or treatment protocols were less frequent in university hospital. Conclusion: This national, prospective, patient-based, observational survey reveals similar achievements in different surgical centres but also some differences and persistent challenges for POP management.

( BUPP09245 - 03 November 2008) Conscious and anesthetized non-human primate safety pharmacology models: Hemodynamic sensitivity comparison.

Introduction: Drug-induced cardiovascular effects identified in conscious cynomolgus monkeys equipped with tethers and prepared for radiotelemetry were compared with results from anesthetized non-human primate (cynomolgus and rhesus) models. Methods: Remifentanil (4.0 mug/kg, bolus), esmolol (2.0 mg/kg, bolus) and dopamine (0.05 mg/kg /min, 30 min infusion) were given intravenously to all models. Results: Remifentanil decreased heart rate (HR), systolic, mean and diastolic systemic arterial pressures (SAP) in anesthetized animals while conscious monkeys presented an increase in HR, systolic, mean and diastolic SAP, as seen in humans for the respective state of consciousness (conscious and anesthetized). Esmolol decreased HR, systolic, mean and diastolic SAP in anesthetized monkeys while only HR, systolic and mean SAP achieved a statistically significant decrease in the conscious model. The amplitude of SAP reduction was greater in anesthetized models, while the amplitude of HR reduction was greater in the conscious and anesthetized cynomolgus models than in the anesthetized rhesus model. Dopamine induced a significant increase in HR, systolic, mean and diastolic SAP in anesthetized models without any statistically significant effect on HR and SAP in the conscious model. Discussion: The amplitude of hemodynamic and chronotropic alterations induced by positive control drugs was generally greater in anesthetized than in conscious models and statistical significance was achieved more often with the anesthetized models. These results suggest that an anesthetized model may be valuable as part of a drug screening program for cardiovascular safety evaluations in addition to a conscious model

( BUPP09246 - 10 November 2008) Correlations of maternal buprenorphine dose, buprenorphine, and metabolite concentrations in meconium with neonatal outcomes.

For the first time, relationships among maternal buprenorphine dose, meconium buprenorphine and metabolite concentrations, and neonatal outcomes are reported. Free and total buprenorphine and norbuprenorphine, nicotine, opiates, cocaine, benzodiazepines, and metabolites were quantified in meconium from 10 infants born to women who had received buprenorphine during pregnancy. Neither cumulative nor total third-trimester maternal buprenorphine dose predicted meconium concentrations or neonatal outcomes. Total buprenorphine meconium concentrations and buprenorphine/norbuprenorphine ratios were significantly related to neonatal abstinence syndrome (NAS) scores >4. As free buprenorphine concentration and percentage free buprenorphine increased, head circumference decreased. Thrice-weekly urine tests for opiates, cocaine, and benzodiazepines and self-reported smoking data from the mother were compared with data from analysis of the meconium to estimate in utero exposure. Time of last drug use and frequency of use during the third trimester were important factors associated with drug-positive meconium specimens. The results suggest that buprenorphine and metabolite concentrations in the meconium may predict the onset and frequency of NAS.

( BUPP09247 - 10 November 2008) Management of chronic pain in the elderly: Focus on transdermal buprenorphine.

Chronic pain in the elderly is a significant problem. Pharmacokinetic and metabolic changes associated with increased age makes the elderly vulnerable to side effects and overdosing associated with analgesic agents. Therefore the management of chronic cancer pain and chronic nonmalignant pain in this growing population is an ongoing challenge. New routes of administration have opened up new treatment options to meet this challenge. The transdermal buprenorphine matrix allows for slow release of buprenorphine and damage does not produce dose dumping. In addition the long-acting analgesic property and relative safety profile makes it a suitable choice for the treatment of chronic pain in the elderly. Its safe use in the presence of renal failure makes it an attractive choice for older individuals. Recent scientific studies have shown no evidence of a ceiling dose of analgesia in man but only a ceiling effect for respiratory depression, increasing its safety profile. It appears that transdermal buprenorphine can be used in clinical practice safely and efficaciously for treating chronic pain in the elderly.

( BUPP09248 - 10 November 2008) Potent analgesic effect of tissue-engineered skin in a terminal patient with severe leg ulcer pain.

We present herein an elderly and terminal patient suffering from an unusual, extremely severe and disabling pain associated with chronic leg ulcers. This pain, first unresponsive to conventional analgesic treatments, was promptly and totally resolved by applying bilayered low-cost, self-made, noncommercial, allogeneic tissue-engineered skin entirely designed and produced in our hospital. This prototype is based on human plasma as the main component of there dermal layer. keratinocytes and fibroblasts are obtained from skin biopsies from organ donors. After mechanical fragmentation and double enzymatic digestion, we obtain the cells for the primary cultures.Cells coming from trypsin-EDTA (ethylene-diaminetetraacetic acid) digestion are cultured in the presence of lethally irradiated 3T3 cells to generate keratinocytes. Cells coming from collagenase digestion are cultivated without 3T3 to produce cultured fibroblasts. To obtain our skin equivalent, fibroblasts are diluted in human plasma and clot is caused in a culture flask by adding calcium chloride. The resulting dermis is then seeded with previously cultivated keratinocytes. Once keratinocytes have reached confluence, the skin prototype is detached from the flask, fixed to a gauze, and then grafted on the wound bed. The estimated cost of 30 cm2 of this self-made noncommercial artificial skin is approximately $50. Tissue engineered skin is being increasingly used for treating leg ulcers. we report the success of a unique inexpensive bioengineered skin equivalent in controlling pain in the ulcers of a terminally ill patient.

( BUPP09249 - 10 November 2008) The Disease of Addiction: Origins, Treatment, and Recovery.

Addiction can be defined as the continued use of mood-altering addicting substances or behaviors (e.g. gambling, compulsive sexual behaviors) despite adverse consequences. We have learned that alcoholism is a primary, chronic disease with genetic, psychsocial, and environmental factors influencing its development and manifestations. It is characterized by continuous or periodic impaired control over drinking, preoccupation with the alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. This is a definition forwarded in JAMA in 1992, and includes the thinking of the American Society of Addiction Medicine and the National Council of Alcoholism and Drug Dependencies. Since that time, continued exploration of the nature if addiction includes other mood-altering substances aside from alcohol, as well as a number of highly reinforcing behaviors. The common pathways in reward circuitry that affect memory and learning, motivation, control and decision making are also involved in the addictive process. With the more global understanding of addiction come more treatment strategies, such as meditation and mindfulness training, psychosocial interventions, and pharmacologic approaches. Interestingly, our growing understanding of addiction as a disease has not diminished the value of the spiritually driven approaches, such as 12-step-oriented treatments, that are outlined in this article. An understanding of the disease of chemical dependency, and the multiple approaches to treatment, can assist the primary care physician (PCP) in the extended treatment team and at the forefront of patient care. Substance abuse negatively impacts public safety, reduces workers productivity, and contributed to higher healthcare costs, premature deaths, and disability for millions of Americans. Despite this massive health problem, only a fraction of affected people get the help they need. A report released in September 2007, by the Substance Abuse and Mental Health Services Administration (SAMHSA), shows that, in 2006, 23.6 milllion persons aged 12 or older (9.6% of the population) required treatment for alcohol or drug problems with only 2.5 million receiving the help. The PCP is often the first (and sometimes only) clinician to interface with the active addict. This article supplements June 2008 Disease a month, "Substance related disorders in adults" by Jerold B Leiken MD, in which he outlines a practical approach by addressing various clinical presentations of substance abuse, including withdrawal states, potential toxicities, and pharmacologic management stratergies. Hos overview assists the PCP with substance abusing patients in an office, hospital, or medical setting. This article targets the addict in a mental health setting, such as an addiction treatment program.

( BUPP09250 - 10 November 2008) The impact of methadone or buprenorphine treatment and ongoing injection on highly active antiretroviral therapy (HAART) adherence: Evidence from the MANIF2000 cohort study.

Aims: To date, no data exist assessing the impact of either methadone or buprenorphine on adherence to highly active antiretroviral therapy (HAART) in the long term. This study was conducted in order to evaluate whether receiving take-home methadone and buprenorphine may ensure better adherence to HAART in individuals infected with human immunodeficiency virus (HIV) through injection drug use (IDU). Design: Longitudinal data on adherence, opioid substitution treatment (OST) and patient behaviours starting from their first HAART prescription were collected for 276 individuals HIV-infected through drug use (n = 1558 visits). Setting: Out-patient hospital services delivering HIV care in Marseilles, Avignon, Nice and Ile de France. Measurements: At any given visit, patients were classified both according to the type of OST received and ongoing injection. Patients who reported no injection and no OST over the whole study period were considered as 'abstinent' and used as a reference category. A logit model based on generalized estimation equations (GEE) was used to identify predictors of non-adherence. Findings: After adjustment for alcohol consumption, depression and self-reported side effects, patients ceasing injection during OST and abstinent patients exhibited comparable adherence. Patients reporting injection, on OST or not, had a twofold and threefold risk, respectively, of non-adherence compared with abstinent patients (P < 0.01 linear trend). Duration on OST without injecting was associated significantly with virological success. Conclusions: Both access to and effectiveness of OST contribute to sustaining adherence to HAART in HIV-infected IDUs. These results advocate strongly the need of wider use of OST in countries scaling-up HAART where HIV is driven by IDUs.

( BUPP09251 - 10 November 2008) Life-threatening wound treatment.

( BUPP09252 - 10 November 2008) Effect of subcutaneous injection and oral voluntary ingestion of buprenorphine on post-operative serum corticosterone levels in male rats.

Background: Adequate peri-operative analgesia may reduce post-operative stress response and improve recovery in laboratory animals. We have established a method involving repeated automated blood sampling, allowing quantification of serum corticosterone levels in rats for stress assessment without stress-inducing handling or restraint. In the present study, the effects of the commonly used route of buprenorphine administration (0.05 mg/kg injected subcutaneously) were compared with oral administration (0.4 mg/kg mixed with Nutella� and orally administered by voluntary ingestion) in male Sprague-Dawley rats. Methods: A catheter was placed in the jugular vein and attached to an Accusampler� for automated blood sampling. During 96 h after surgery, blood was collected at specified time points. Pre- and post-operative body weights and water consumption were registered. Results: Buprenorphine significantly suppressed levels of circulating corticosterone after the oral but not after the subcutaneous treatment. Both buprenorphine treatments had a positive impact on maintenance of body weight and water consumption, compared to the control group that received no buprenorphine. Conclusion: The present investigation suggests that oral voluntary ingestion ad libitum is an efficacious, convenient and non-invasive way of administering peri-operative buprenorphine to rats, as judged by corticosteroid response and effects on body weight and water consumption.

( BUPP09253 - 10 November 2008) Treatment of opioid dependence via home-based telepsychiatry.

To the Editor: The Food and Drug Administration's approval of the drug buprenorphine in 2002 changed the landscape in terms of our ability to manage opioid dependence. Yet because of the relatively small number of buprenorphine certified physicians and sluggish efforts at public education, a majority of patients with opioid dependence, particularly in rural areas, go without this definitive treatment. Simultaneously, we have seen personal use of broadband Internet expand from 10% of the population in 2002 to its current rate of 55% (1), as well as the release of numerous versions of consumer video conferencing software, such as iChat with secure encryption for the Macintosh and Skype or SightSpeed for both PC and Mac platforms. When combined with broadband Internet and a midrange Webcam, these software packages offer home based telepsychiatry. Over the past two years i have treated approximately 40 opioid dependent patients from communities throughout Colorado, all of whom were seen exclusively via telepsychiatry from their own homes or offices. Many of these patients are affluent professionals seeking treatment for convert addiction to narcotic analgesics, who were relieved to find an option providing both convenience and confidentiality. Few have chronic mental illness other than addiction. The standard of care of general outpatient psychiatry is maintained. After a routine intake, a prescription for buprenorphine is arranged when clinically appropriate by telephone with the patients local pharmacy. Induction is achieved at home, in some cases with intermittent on-camera contact, and follow-up occurs at appropriate intervals. Patients are required to contact their primary care physicians for laboratory tests and physical examinations as indicated. Many are required to participate in ancillary psychosocial treatments, such as Narcotics Anonymous, or in local random urine screening programs. In many cases, the patients spouse or family member appeared on camera to participate and collaborate in treatment.

( BUPP09254 - 10 November 2008) Continuous and intermittent nicotine treatment reduces L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a rat model of Parkinson's disease.

The development of abnormal involuntary movements (AIMs) or dyskinesias is a serious complication of L-DOPA (L-3,4- dihydroxyphenylalanine) therapy for Parkinson's disease. Our previous work had shown that intermittent nicotine dosing reduced L-DOPA- induced dyskinetic-like movements in nonhuman primates. A readily available nicotine formulation is the nicotine patch, which provides a constant source of nicotine. However, constant nicotine administration more readily desensitizes nicotinic receptors, to possibly yield alternate behavioral outcomes. Therefore, we investigated whether constant nicotine administration reduced L-DOPA- induced AIMs in a rat parkinsonian model, with results compared with those with intermittent nicotine dosing. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion were exposed to either intermittent (drinking water) or constant (minipump) nicotine for 2 weeks at doses that yielded plasma levels of the nicotine metabolite cotinine similar to those in smokers. The rats were next treated with L-DOPA /benserazide (8 or 12 mg/kg/15 mg/kg) for 3 weeks to allow for the development of AIMs, with nicotine treatment continued. Both modes of nicotine administration resulted in 50% decline in L-DOPA-induced AIMs. Nicotine treatment also significantly reduced AIMs in L-DOPA- primed rats using either dosing regimen, whereas nicotine removal led to an increase in AIMs. There was no effect of nicotine on various measures of motor performance in 6-OHDA-lesioned rats. In summary, nicotine provided either via the drinking water or minipump reduced L-DOPA-induced AIMs in a rat model of Parkinson's disease. These results suggest that either intermittent or constant nicotine treatment may be useful in the treatment of L-DOPA-induced dyskinesias in patients with Parkinson's disease.

( BUPP09255 - 10 November 2008) The JNK inhibitor XG-102 protects from ischemic damage with delayed intravenous administration also in the presence of recombinant tissue plasminogen activator.

Background: XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide which selectively inhibits the c-Jun N-terminal kinase, is a powerful neuroprotectant in mouse models of middle cerebral artery occlusion (MCAo) with delayed intracerebroventricular injection. We aimed to determine whether this neuroprotection could also be achieved by intravenous injection of XG-102, which is a more feasible approach for future use in stroke patients. We also tested the compatibility of the compound with recombinant tissue plasminogen activator (rtPA), commonly used for intravenous thrombolysis and known to enhance excitotoxicity. Methods: Male ICR-CD1 mice were subjected to a 30-min-suture MCAo. XG-102 was injected intravenously in a single dose, 6 h after ischemia. Hippocampal slice cultures were subjected to oxygen (5%) and glucose (1 mM) deprivation for 30 min. rtPA was added after ischemia and before XG-102 administration, both in vitro and in vivo. Results: The lowest intravenous dose achieving neuroprotection was 0.0003 mg/kg, which reduced the infarct volume after 48 h from 62 � 19 mm /sup 3/ (n = 18) for the vehicle-treated group to 18 � 9 mm /sup 3/ (n = 5, p < 0.01). The behavioral outcome was also significantly improved at two doses. Addition of rtPA after ischemia enhanced the ischemic damage both in vitro and in vivo, but XG-102 was still able to induce a significant neuroprotection. Conclusions: A single intravenous administration of XG-102 several hours after ischemia induces a powerful neuroprotection. XG-102 protects from ischemic damage in the presence of rtPA. The feasibility of systemic administration of this promising compound and its compatibility with rtPA are important steps for its development as a drug candidate in ischemic stroke.

( BUPP09256 - 10 November 2008) Extended vs Short-term Buprenorphine-Naloxone for Treatment of opioid-Addicted Youth - A Randomized Trial

Context The usual treatment for opioid-addicted youth is detoxification and counseling. Extended medication-assisted therapy may be more helpful. Objective To evaluate the efficacy of continuing buprenorphine-naloxone for 12 weeks vs detoxification for opioid-addicted youth. Design, Setting, and Patients Clinical trial at 6 community programs from July 2003 to December 2006 including 152 patients aged 15 to 21 years who were randomized to 12 weeks of buprenorphine-naloxone or a 14-day taper (detox). Interventions Patients in the 12-week buprenorphine-naloxone group were prescribed up to 24 mg per day for 9 weeks and then tapered to week 12; patients in the detox group were prescribed up to 14 mg per day and then tapered to day 14. All were offered weekly individual and group counseling. Main Outcome Measure Opioid-positive urine test result at weeks 4, 8, and 12. Results The number of patients younger than 18 years was too small to analyze separately, but overall, patients in the detox group had higher proportions of opioid-positive urine test results at weeks 4 and 8 but not at week 12 (22 = 4.93, P = .09). At week 4, 59 detox patients had positive results (61%; 95% confidence interval [CI] = 47%-75%) vs 58 12-week buprenorphine-naloxone patients (26%; 95% CI = 14%-38%). At week 8, 53 detox patients had positive results (54%; 95% CI = 38%-70%) vs 52 12-week buprenorphine-naloxone patients (23%; 95% CI = 11%-35%). At week 12, 53 detox patients had positive results (51%; 95% CI = 35%-67%) vs 49 12-week buprenorphine-naloxone patients (43%; 95% CI = 29%-57%). By week 12, 16 of 78 detox patients (20.5%) remained in treatment vs 52 of 74 12-week buprenorphine-naloxone patients (70%; 21 = 32.90, P < .001). During weeks 1 through 12, patients in the 12-week buprenorphine-naloxone group reported less opioid use (21 = 18.45, P < .001), less injecting (21 = 6.00, P = .01), and less nonstudy addiction treatment (21 = 25.82, P < .001). High levels of opioid use occurred in both groups at follow-up. Four of 83 patients who tested negative for hepatitis C at baseline were positive for hepatitis C at week 12. Conclusions Continuing treatment with buprenorphine-naloxone improved outcome compared with short-term detoxification. Further research is necessary to assess the efficacy and safety of longer-term treatment with buprenorphine for young individuals with opioid dependence. Trial Registration clinicaltrials.gov Identifier: NCT00078130

( BUPP09257 - 17 November 2008) Buprenorphine alters desmethylflunitrazepam disposition and flunitrazepam toxicity in rats.

High-dosage buprenorphine (BUP) consumed concomitantly with benzodiazepines (BZD) including flunitrazepam (FZ) may cause life-threatening respiratory depression despite a BUP ceiling effect and BZD' limited effects on ventilation. This study determined the respiratory effects of i.v. BUP (Schering-Plough)/FZ (Roche) and investigated BUP effects on the kinetics of FZ and its main active metabolites, desmethylflunitrazepam (DMFZ), and 7-aminoflunitrazepam (7-AFZ, both Radian Inc.) in catheterized rats. BUP did not alter plasma FZ, 7-AFZ, and DMFZ kinetics, but increased the AUC of DMFZ. BUP or BUP/FZ increased PaCO2, while BUP/FZ decreased Pa02. FZ increased PaCO2, while DMFZ decreased PaO2. Thus, combined high- dosage BUP and FZ is responsible for increased respiratory toxicity in which BUP-mediated alteration in DMFZ disposition may play a significant role.

( BUPP09258 - 17 November 2008) Magnesium ions and opioid agonist activity in streptozotocin-induced hyperalgesia.

Streptozotocin-induced hyperglycemia accompanied by a chronic decrease in the nociceptive threshold is considered a useful model of experimental hyperalgesia. We examined (1) the effect of the opioid receptor agonists and (2) the effect of the magnesium ions (Mg2+) on the antinociceptive action of opioid agonists in a diabetic neuropathic pain model. When administered alone, opioid agonists like morphine (5 mg/kg i.p.) and fentanyl (0.0625 mg/kg i.p.), as well as the partial agonist buprenorphine (0.075 mg/kg) had only little effect on streptozotocin-induced hyperalgesia. However, pretreatment with Mg2+ at a dose of 40 mg magnesium sulfate/kg i.p. markedly enhanced the analgesic activity of all three investigated opioids. Practical aspects of co-administration of magnesium and opioids in diabetic neuropathy are discussed.

( BUPP09259 - 17 November 2008) Propoxyphene: A drug with unfavorable risk-benefit characteristics.

Background: Proxyphene is an opioid analgesic (OA) used to treat mild to moderate pain and approximately equivalent to ibuprofen or acetaminophen in efficacy. Exposures to propoxyphene can result in a major medical outcome or death due to cardiac dysrhythmia. It has been withdrawn from the market in the United Kingdom. Methods: The study aim was to assess the safety of propoxyphene in adults and children by examining the proportions of associated death relative to other known medical outcomes (KMOs) after exposure to propoxythene and compare them to those of other schedule 2 and 3 OAs, using National Poison Data System (NPDS) data 2002-2006. Number of deaths and other KMOs, including no effect, minor, moderate and major effects were abstracted from NPDS database for propoxyphene and other OAs (buprenorphine, hydrocodone, hydromorphone, methadone, morphine and oxycodone). Chi-squared two tail analysis was performed using VassarStats statistics software. Results: Among the schedule 2 and 3 opioids, methadone had the highest proportion of deaths and hydrocodone the lowest. Proxythene had a higher proportion of deaths than hydrocodone. Discussion: Propoxyphene had fewer deaths relative to other KMOs compared to oxycodone, hydromorphone, morphine and methadone which are all schedule 2 controlled substances but more deathsrelative to hydrocodone, which is schedule 3. Conclusion: Because propoxyphene has similar efficacy in the treatment of acute pain relative to non-opioid analgesics such as ibuprofen and acetaminophen the risk of severe adverse outcomes seems unwarranted.

( BUPP09260 - 17 November 2008) Office-based opioid addiction treatment, and the rise in unintentional pediatric buprenorphine ingestions reported to a regional poison center - A new challenge for poison educators.

( BUPP09261 - 17 November 2008) Changes in caller type for drug identification calls reported to a regional poison center over time.

Background: Drug identification (ID) calls to poison centres are common. The purpose of this study was to evaluate the distribution of caller types for several commonly identified substances to the Maryland Poison Center (MPC) between 2005 and 2007. Methods: Calls to the MPC in 2005 to 2007 coded as being drug IDs were reviewed. Substances identified by imprint codes as amphetamines, buprenorphine, or oxycodone were tabulated by caller type by year (total and percentage). Caller types were coded to Health Professional, Law Enforcement, Public or Other. Results: There was variability in there percentage of callers who self identified as low enforcement callers. Calls that were self identified as being from law enforcement increased for all drugs over the study period. Discussion: Drug ID calls to the MPC increased during the study period. The caller type has changed over time with a greater percentage of calls from law enforcement varies by substance. While the overall numbers for buprenorphine calls to the MPC were low, they overwhelmingly came from law enforcement. Conclusion: The caller type for drug ID calls to the MPC changed between 2005 and 2007. We have documented increasing numbers of calls from law enforcement personnel.

( BUPP09262 - 17 November 2008) Persistent toxicity after suboxone ingestion in a toddler.

Background: Suboxone (Buprenorphine/Naloxone) has been approved by the FDA for treatment of opioid addiction. Its advantage over methadone is a thrice weekly dosing and proposed ceiling effect on respiratory depression. We report ingestion in a toddler requiring prolonged supportive care for hyperventilation and persistent sedation. Case Report: A 2 to (14kg) male with a history remarkable only for asthma was witnessed by his mother to ingest a single suboxone (8mg/2mg) tablet. Presentation to the ED 1 hour post-ingestion revealed him to be obtunded with pinpoint pupils. Vital signs were: 37.0C, HE 126 bpm, RR 18/minute, 96%on RA. His O2 saturation then dropped to 91%. He was initially given 1.4mg of naloxone IV and woke slightly but quickly became somnolent again. After being given a total of 7 mg of naloxone he became awake and appropriate. He was then transported by EMS to the nearest PICU after being placed on a naloxone drip. On arrival to the PICU he was awake and interactive with normal vital signs. Initial urine drug screen was negative. Multiple attempts to stop the naloxone drip over the next 48 hours resulted in obtundation and apneic episodes even requiring intubation for respiratory acidosis for 7 hours. A confirmatory urine immunoassay for buprenorphine was confirmed positive. The naloxone drip continued for additional 44 hours. Ninety-six hours post-ingestion the drip was discontinued and he remained asymptomatic. Case Discussion: This is the highest reported dose and duration of naloxone use in a toddler to reverse both somnolence and respiratory depression. His presentation was consistent with an opioid toxidrome, with no other ingestion confirmed by history or urine drug screen. Consistent with other previous reports of toddler ingestion, higher doses of naloxone may be required rather than the recommended 0.1 mg/kg dose. Conclusion: We report an ingestion of suboxone in a toddler requiring prolonged supportive care than had previously been reported. As this medication is becoming more commonly prescribed, clinicians should be aware of the possibility of persistent respiratory depression and somnolence.

( BUPP09263 - 17 November 2008) A retrospective review of unintentional pediatric buprenorphine ingestions reported to a regional poison center.

( BUPP09264 - 17 November 2008) Treatment of adolescent opioid dependence: no quick fix.

The prevalence of adolescent opioid use and dependent is increasing. The epidemiology of opioid use among youth in the 21st century raises concern over the potential far-reaching impact of prescription opioid and heroin use on the current generation of adolescents. In 2007, 232,000 adolescents reported misuse of just one of the many forms of prescription opioids, sustained-release oxycodone. During the same year, heroin, the opioid that is most often associated with illicit use was used by 24,000 adolescents. The prevalence of hydrocodone use is reported to be 3% among 8th graders, 7% in 10th graders, and 10% in 12th graders. Most adolescent users report chewing, swallowing, or insufflating (snorting) opioids, although injection use is reported by 45% of users.

( BUPP09265 - 17 November 2008) Analgesics and palliative care.

Pain is an important and often under-treated symptom of life-threatening illness. A complete evaluation of pain facilitate optimal treatment. Correct use of analgesic medication, following the guidelines of the W.H.O. step ladder, with attention to detail, with addition of adjuvant analgesics, should control the pain in most of the cases. The use of weak and strong opioid analgesics, their tolerance, the breakthrough doses, principle of opioid rotation and the place of adjuvant drugs are discussed. Proper pain management in end-of-life is never easy and require to become more familiar with the use of these analgesics and to surround oneself with a multidisciplinary team.

( BUPP09266 - 17 November 2008) Perioperative Pain Management in Veterinary Patients.

Pain exists; however, we can prevent it, and we can treat it. The fallacy that pain is protective and must be allowed to avoid risk for damage after surgery needs to be eradicated. Preoperative and postoperative analgesia is directed at aching pain, whereas sharp pain associated with inappropriate movements persists. Analgesia provides much more benefit than concern. This article provides suggestions for development of an analgesic plan from the point of admission to discharge. These guidelines can then be adjusted according to the patient's needs and responses.

( BUPP09267 - 17 November 2008) Analgesia for the Critically Ill Dog or Cat: An Update.

Acute pain reliably accompanies severe illness and injury, and when sufficiently severe, it can complicate the recovery of critically ill patients. Because acute pain is closely tied to the neurologic process of nociception, pharmacologic therapy is often essential and effective. This update focuses on two methods of treatment of acute pain-local anesthetic infusion and continuous intravenous infusion of multimodal agents-that can be layered on top of standard care with other drugs

( BUPP09268 - 17 November 2008) Pain Management for the Pregnant, Lactating, and Neonatal to Pediatric Cat and Dog.

Little information on the approach to analgesia in pregnant, nursing, or extremely young animals is available in the veterinary literature. Various analgesics and analgesic modalities are discussed, with emphasis placed on preference and caution for each group. Management of pain is extremely important in all animals but especially in the extremely young, in which a permanent hyperalgesic response to pain may exist with inadequate therapy. Inappropriate analgesic selection in pregnant and nursing mothers may result in congenital abnormalities of the fetus or neonate. Inadequate analgesia in nursing mothers may cause aggressive behavior toward the young. Review of the human and veterinary literature on the various analgesics available for use in this group of patients is discussed.

( BUPP09269 - 17 November 2008) Managing Pain in Feline Patients

This article reviews the current knowledge of pain assessment in cats and the most effective methods for its alleviation. Excellent acute pain management is achievable in cats by using opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), alpha /sub 2/ -agonists, and local anesthetics. A multimodal approach using agents that work at different places in the pain pathway is encouraged because this can have added benefits. Management of chronic pain in cats can be challenging, but there is now an approved NSAID for long-term use. As we gain experience with less traditional analgesics, such as gabapentin, and critically evaluate complimentary therapies, our ability to provide comfort to this population of cats should improve.

( BUPP09270 - 17 November 2008) Control of Cancer Pain in Veterinary Patients.

Control of cancer pain is within the capabilities of most veterinarians and is achievable in most animal patients that have cancer with techniques that are currently available. Great satisfaction can be derived from not only treating the pet's cancer but its pain. Incorporating pain management into oncology practice is good for the well-being of the pet, the owner, the staff, the veterinarians, and the practice.

( BUPP09271 - 17 November 2008) Epidural Analgesia and Anesthesia in Dogs and Cats.

Current knowledge of drugs administered epidurally has allowed an effective way of providing analgesia for a wide variety of conditions in veterinary patients. Proper selection of drugs and dosages can result in analgesia of specific segments of the spinal cord with minimal side effects. Epidural anesthesia is an alternative to general anesthesia with inhalation anesthetics, although the combination of both techniques is more common and allows for reduced doses of drugs used with each technique. Epidural anesthesia and intravenous anesthetics can also be used without inhalation anesthetics in surgical procedures caudal to the diaphragm.

( BUPP09272 - 17 November 2008) Adjunctive Analgesic Therapy in Veterinary Medicine

Adjunctive analgesic therapies are interventions for pain that involve agents or techniques other than the traditional analgesics (opioids, nonsteroidal anti-inflammatory drugs, and local anesthetics). Adjunctive therapies may be pharmacologic or nonpharmacologic in nature. The focus of this article is on pharmacologic interventions with potential utility as adjunctive analgesics in veterinary medicine. Pharmacology of selected agents, including medetomidine, ketamine, amantadine, gabapentin, systemic lidocaine, and pamidronate, is discussed in addition to evidence for their safety and efficacy and guidelines for their use in veterinary patients

( BUPP09273 - 17 November 2008) Pharmacological treatment of schizophrenia and co-occurring substance use disorders.

Substance abuse among individuals with schizophrenia is common and is often associated with poor clinical outcomes. Comprehensive, integrated pharmacological and psychosocial treatments have been shown to improve these outcomes. While a growing number of studies suggest that second-generation antipsychotic medications may have beneficial effects on the treatment of co-occurring substance use disorders, this review suggests that the literature is still in its infancy. Few existing well controlled trials support greater efficacy of second-generation antipsychotics compared with first-generation antipsychotics or any particular second-generation antipsychotic. This article focuses on and reviews studies involving US FDA-approved medications for co-occurring substance abuse problems among individuals with schizophrenia. Comprehensive treatment for individuals with schizophrenia and co-occurring substance use disorders must include specialized, integrated psychosocial intervention. Most approaches use some combination of cognitive-behavioural therapy, motivational enhancement therapy and assertive case management. The research on antipsychotic and other pharmacological treatments is also reviewed, as well as psychosocial treatments for individuals with schizophrenia and co-occurring substance use disorders, and clinical recommendations to optimize care for this population are offered.

( BUPP09274 - 17 November 2008) An interventional study to improve the quality of analgesia in the emergency department.

Objective: We sought to document the adequacy of acute pain management in a high-volume urban emergency department and the impact of a structured intervention. Methods: We conducted a prospective, single-blind, pre- and postintervention study on patients who suffered minor-to-moderate trauma. The intervention consisted of structured training sessions on emergency department (ED) analgesia practice and the implementation of a voluntary analgesic protocol. Results: Preintervention data showed that only 340 of 1000 patients (34%) received analgesia. Postintervention data showed that 693 of 700 patients (99%) received analgesia, an absolute increase of 65% (95% CI 61%-68%), and that delay to analgesia administration fell from 69 (standard deviation (SD) 54) minutes to 35 (SD 43) minutes. Analgesics led to similar reductions in visual analog pain scale ratings during the pre- and postintervention phases (4,5 cm, SD 2.0 cm, and 4.3 cm, SD 3.0 cm, respectively). Conclusion: Our multifaceted ED pain management intervention was highly effective in improving quality of analgesia, timeliness of care and patient satisfaction. This protocol or similar ones have the potential to substantially improve pain management in diverse ED settings.

( BUPP09275 - 17 November 2008) Guidelines of the German Society for Addiction Medicine (DGS e.V.), the German AIDS Society (DAIG) and the German association of physicians in private practice treating HIV-infected persons (DAGNAe) : HIV infection in intravenous drug addicts (IVDA).

( BUPP09276 - 17 November 2008) Addiction and cognitive functions.

Drug addiction is a compulsive behavioral abnormality. In spite of pharmacologic and psychosocial treatments to reduce or eliminate drug taking, addiction tends to persist over time. Preclinical and human observations have converged on the hypothesis that addiction represents the pathologic deterioration of neural processes that normally serve affective and cognitive functioning. The major elements of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie enduring changes in a number of forebrain circuits (involving the ventral striatum and prefrontal cortex) that receive input from midbrain dopamine neurons and are involved in affective and cognitive mechanisms, respectively. Here we review progress in identifying crucial elements useful in understanding the pathophysiology of the disease and its pharmacologic treatment. Pharmacologic targeting of K-opiate receptors, with their discrete distribution within the dopaminergic system(s), and thus different actions on dopaminoceptive areas, may provide beneficial effects at the affective and cognitive level.

( BUPP09277 - 17 November 2008) Step-by-step plan for pain management.

( BUPP09278 - 17 November 2008) Organisation of acute pain therapy.

Orthopaedic and traumatized patients often suffer from severe pain after surgery or trauma. Their early recovery also depends on an efficient acute pain relief based on a combination of systemic medication, local drug application and physical therapy. In 2007, new guidelines for the treatment of perioperative and traumatic pain were published. Based on these guidelines standard operating procedures for each hospital should be developed and implemented. Courses on analgesic concepts should be offered regularly for the involved staff. It is helpful to establish an acute pain service for daily rounds and documentation. The individual patient should be informed about his specific acute pain therapy before the operation. Pain scores should be frequently documented by the patient.

( BUPP09279 - 17 November 2008) New and evidence-based aspects of postoperative pain therapy.

Poorly managed postoperative pain has been recognised to delay patient recovery and hospital discharge. Recent metaanalyses support a multimodal approach with combinations of analgesics from different classes. The pharmacological options of commonly used opioids, nonsteroidal anti-inflammatory drugs, and other nonopioid analgesics in combination have been shown to provide effective pain relief and to reduce opioid consumption. Local, intraarticular, epidural, and, more importantly, modern peripheral regional techniques can be used successfully to enhance perioperative analgesia. The use of continuous perineural techniques with local anaesthetic infusion has been extended beyond hospital discharge in many European countries.

( BUPP09280 - 17 November 2008) Treatment of opioid-dependent pregnant women: Clinical and research issues.

his article addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, which include investigators in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, is provided to aid clinical decision making. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article begins with a discussion of appropriate assessment during pregnancy and then addresses clinical management stages including maintenance medication selection, induction, and stabilization; opioid agonist medication management before, during, and after delivery; pain management; breast-feeding; and transfer to aftercare. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are discussed.

( BUPP09281 - 24 November 2008) Ketamine-based total intravenous anesthesia versus isoflurane anesthesia in a swine model of hemorrhagic shock.

BACKGROUND: Inhalational anesthetics can cause profound hemodynamic effects including decreases in systemic vascular resistance and cardiac inotropy. Although widely used in uncontrolled hemorrhagic shock (UHS), their consequences compared with other anesthetic regimens are not well-studied. Ketamine-based total intravenous anesthesia (TIVA) may produce less profound cardiovascular depression, and has been used during elective surgery but rarely during traumatic shock. The purpose of this study was to compare the effects of isoflurane (ISO) and TIVA regimens in a swine grade V liver injury model. We hypothesized that TIVA would result in less hypotension and dysfunctional inflammation than ISO. METHODS: Twenty swine were randomized blindly to receive either 1% to 3% ISO, or intravenous ketamine, midazolam, and buprenorphine for maintenance anesthesia. Six animals acted as controls. After sedation and intubation, randomized anesthesia was initiated and monitored by an independent animal technician. Invasive lines were placed followed by celiotomy and splenectomy. Baseline mean arterial pressure (MAP) was documented and a grade V liver injury created. After 30 minutes of UHS, animals were resuscitated with 8 mL of Ringer's lactate per milliliter blood loss at 165 mL/min. MAP and tissue oxygen saturation (StO2) were continuously recorded. The animals were sacrificed 120 minutes after injury and lung tissue was harvested. Serum cytokines (interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha)) were quantified with enzyme-linked immunosorbent assay. Lung cytokine mRNA levels were quantified with real time reverse transcriptase polymerase chain reaction. RESULTS: Animal weight, liver injury pattern, and blood loss were similar (p > 0.1). The ISO group had a lower MAP at baseline (p = 0.02), at injury (p = 0.004), and study completion (p = 0.001). After resuscitation, MAP decreased in the ISO group but remained stable in the TIVA group. StO2 was significantly higher in the TIVA group immediately after injury (p = 0.004), but similar between groups throughout the remainder of the study. Animals who received TIVA trended toward higher levels of lactate and lower pH throughout the study, reaching significance at 30 minutes postinjury (p = 0.037 and 0.043). Inflammatory cytokine (IL-6, IL-8, and TNF-alpha) production did not differ between groups, however TNF-alpha mRNA production was significantly lower in the TIVA group (p = 0.04). CONCLUSION: Although a TIVA regimen produced less pronounced hypotension in a swine model of UHS than did ISO, end-organ perfusion with TIVA appeared to be equivalent or inferior to ISO. In circumstances of limited resources, such as those experienced by forward Army surgical teams, a ketamine-based TIVA regimen may be an option for use in UHS.

( BUPP09282 - 24 November 2008) Opioid-induced immunosuppression.

PURPOSE OF REVIEW: This review provides an overview of the immunological effects of commonly used analgesic opioid drugs with particular emphasis on human studies, with the final aim to highlight their potential clinical relevance. RECENT FINDINGS: The immunomodulatory effects of morphine have been characterized in animal and human studies. Morphine decreases the effectiveness of several functions of both natural and acquired immunity, interfering with important intracellular pathways involved in immune regulation. Mainly from animal studies, however, it has emerged that not all opioids induce the same immunosuppressive effects and evaluating each opioid's profile is important for appropriate analgesic selection. The potent opioid fentanyl also exerts a relevant immunosuppression, while the partial agonist buprenorphine appears to have a more favourable immune profile. The impact of the opioid-mediated immune effects could be particularly dangerous in selective vulnerable populations, such as the elderly or immunocompromised patients. SUMMARY: The impact of opioid drug treatment on immunity may be a new safety concern for the physician. Although many advances have been made in understanding the effects of opioid drugs on immune responses, their relevance is not completely clear. The scientific community must be aware that it is about time to perform well designed clinical studies in order to assess the importance of opioid-induced immune suppression.

( BUPP09283 - 24 November 2008) Methadone and buprenorphine related ambulance attendances: A population-based indicator of adverse events.

This study examined the nature and extent of methadone- and buprenorphine-related morbidity through a retrospective analysis of ambulance service records (N = 243) in Melbourne, Australia. Cases in which methadone and buprenorphine were implicated are examined. Demographic and presenting characteristics, transport outcomes, and other substance use were explored. There were 84 buprenorphine-related attendances and 159 methadone-related attendances recorded on the database over the 4-year period. Presenting signs (respiratory rate and Glasgow Coma Scale score) were lower in the methadone-related attendances. Most of the attendances resulted in transport to hospital. Most presentations did not involve traditional signs of opioid overdose, a finding that warrants further investigation. This is the first article to describe characteristics of methadone and buprenorphine-related ambulance attendances, with results suggesting this may be a useful way to monitor harms associated with these medications in the future.

( BUPP09284 - 24 November 2008) Abuse-deterrent opioid formulations: Are they a pipe dream?

The continued need for opioids to treat pain and their unavoidable link to abuse and addiction create a need for risk mitigation approaches that optimize their risk-benefit ratio. Abuse-deterrent formulations (ADFs) have emerged as a means for supporting opioid access while limiting abuse and its consequences. Several different types of ADFs have emerged including physical barriers to tampering, agonist-antagonist formulations, aversion, prodrugs, and alternative methods of administration. Each of these types has the potential to reduce specific forms of prescription opioid abuse. ADFs have the potential to reduce the public health burden of prescription opioid abuse, but they will require not only technically successful formulations, but also appropriate scientific assessment, widespread market penetration, and rational expectations of their benefits.

( BUPP09285 - 24 November 2008) Steps of practical management.

In a more practical than didactic purpose, we are going to describe the successive steps of the management of a leg ulcer. The purpose is to reproduce the stages of the first consultation. Firstly it will be necessary to push aside diagnostic traps (positive and differential diagnosis), then to place the wound in its context (etiologic diagnosis), to grade it (diagnosis of gravity) and finally to build up a plan of treatment according to the various general and local therapeutic means at disposal

( BUPP09286 - 24 November 2008) Analgesia and renal failure.

Chronic kidney disease (CKD) prevalence increases with population aging and makes drugs prescription more difficult. Only a few studies have reported drug dosing adjustment in CKD patients, even in the important field of pain management. We propose an algorithm based on the current literature that helps in selecting right analgesic according to the degree of renal failure. Drug dosing adjustment of the most usually used analgesics (acetaminophen, nonsteroidal anti inflammatory drugs and opioids) is discussed.

( BUPP09287 - 24 November 2008) Managing acute pain in patients with an opioid abuse or dependence disorder.

Assessing and managing patients with acute pain who are addicted to opioids is often challenging. Treatment may be complicated by pharmacological therapies, including methadone, buprenorphine and naltrexone. There is limited evidence to guide the management of acute pain in these patients as they are usually excluded from analgesic studies. Principles of management include thorough assessment of both the pain and the addictive disorder, consultation and referral as appropriate, maximisation of non-opioid analgesics and non-pharmacological therapies, and use of opioids when indicated.

( BUPP09288 - 24 November 2008) Occurrence of ethanol and other drugs in blood and urine specimens from female victims of alleged sexual assault.

Results of toxicological analysis of blood and urine specimens from 1806 female victims of alleged non-consensual sexual activity are reported. After making contact with the police authorities, the victims were examined by a physician for injuries and biological specimens were taken for forensic toxicology and other purposes (e.g. DNA). Urine if available or otherwise on an aliquot of blood after protein precipitation was screened for the presence of drugs by enzyme immunoassay methods (EMIT/CEDIA). All positive results from screening were verified by more specific methods, involving isotope dilution gas chromatography-mass spectrometry (GC-MS) for illicit drugs. A large number of prescription drugs were analyzed in blood by capillary column gas chromatography with a nitrogen-phosphorous (N-P) detector. Ethanol was determined in blood and urine by headspace gas chromatography and concentrations less than 0.1 g/L were reported as negative. The number of reported cases of alleged sexual assault was highest during the warmer summer months and the mean age of victims was 24 years (median 20 years), with 60% being between 15 and 25 years. In 559 cases (31%) ethanol and drugs were negative. In 772 cases (43% of total) ethanol was the only drug identified in blood or urine. In 215 cases (12%) ethanol occurred together with at least one other drug. The mean, median and highest concentrations of ethanol in blood (N = 806) were 1.24 g/L, 1.19 g/L and 3.7 g/L, respectively. The age of victims and their blood-alcohol concentration (BAC) were positively correlated (r = 0.365, p < 0.001). Because BAC decreases at a rate of 0.10-0.25 g/(L h), owing to metabolism the concentration in blood at time of sampling is often appreciably less than when the crime was committed several hours earlier. Licit or illicit drugs were identified in blood or urine in N = 262 cases (15%). Amphetamine and tetrahydrocannabinol were the most common illicit drugs at mean (median) concentrations in blood of 0.22 mg/L (0.1 mg/L) and 0.0012 mg/L (0.0006 mg/L), respectively. Among prescription drugs, sedative- hypnotics such as diazepam and zopiclone were common findings along with SSRI antidepressants and various opiate analgesics. Interpreting the analytical results in terms of voluntary vs. surreptitious administration of drugs and the degree of incapacitation in the victim as well as ability to give informed consent for sexual activity is fraught with difficulties.

( BUPP09289 - 24 November 2008) Successful transition to buprenorphine in a patient with methadone induced torsades de pointes.

A 56-year-old-man presented with syncope and torsades de pointes secondary to methadone-induced QT prolongation. After transition from methadone to buprenorphine, a partial mu-opiate-receptor agonist and a kappa-opiate- receptor antagonist, the QT normalized and ventricular arrhythmias resolved. Buprenorphine should be used for opiate dependence and chronic pain in patients with methadone-induced QT prolongation and as first line therapy in patients with risk factors for torsades de pointes.

( BUPP09290 - 24 November 2008) Ins and outs of neurologic therapy for chronic pain.

Although chronic pain is common, especially in elderly patients, its treatment often remains inadequate. One of many reasons for this is that insufficient therapy of acute pain carries the risk of making the pain chronic. Sooner or later most patients suffering from chronic pain will consult a neurologist. However, in most neurological departments, pain treatment is neither one of the common medical activities nor a subject in medical education. In Germany, only specialised centres have associated pain outpatient clinics, so it is almost impossible for neurologist trainees to improve their knowledge in pain treatment. This review provides a synopsis of procedures regarding chronic pain treatments, with particular focus on the most frequent pain disorders. The treatment recommendations follow the current guidelines of the German Society of Neurology

( BUPP09291 - 24 November 2008) Detecting signs of opioid abuse and treating the addiction.

Opioid dependence is an epidemic that has no prejudice or limits. The number of non-medical users of narcotics has increased steadily over the years, making opioids one of the highest drug classes abused, second only to marijuana. By 2006, the number of users of nonmedical pain relievers was greater than cocaine and heroin users combined (5.2 million vs 2.4 million and 0.6 million, respectively). Pharmacists need to be informed and educate on opioid dependence, so they are able to recognise, confront, and recommend appropriate programs. Classified as an addiction, opioid abuse is recognized in the Diagnostic and Statistical Manual of Mental Disorders, fourth Edition, as a medical disorder with an etiology, pathogenesis, clinical presentation, diagnosis, and treatment options. Understanding the alteration of neurobiology in the brain, as well as the social dispositions that put opioid users at risk, encourages clinical diagnosis and treatment, rather than turning away a "drug seeker", who is judged to have arrived voluntarily at his or her condition.

( BUPP09292 - 01 December 2008) Immune-mediated neuropathies in myeloma patients treated with bortezomib.

Objective: Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. Methods: Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. Results: Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). Conclusions: In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. Significance: This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.

( BUPP09293 - 01 December 2008) Pain and the pharmacogenetics at the fuzzy border between pain physiopathology and pain treatment.

Nociceptive pain is time limited and severe nociceptive pain normally responds well to treatment with opioids, On the contrary, neuropatic pain is frequently chronic, and tends to have a less robust response to treatment with opioids. The unsolved problem of insufficient pain treatment at clinical level, including both wanted analgesic effects and unwanted side effects, is a stimulus to expand the knowledge on the physiophatology of pain and on the involved molecular mechanisms. In particular, it is important not only to better understand the molecular mechanisms associated to drugs effects but also to characterize the genetic traits underlying pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms related to drugs. Literature analysis reveals that there are interesting genetic polymorphisms that are associated either to the sensitivity to pain and to PD response to drugs, or to the metabolic and excretion pathways. Pharmacogenetics/pharmacogenomics holds the promise that drugs might in the next future be tailor-made for individuals and adapted to each person's own genetic background. Collected information, allowing to design combined therapies and to dissect analgesic from addictive properties of opioids within a given patient, will also contribute to contrast the persisting opiophobia in medical practice.

( BUPP09294 - 01 December 2008) Showing-off muscles: Be aware of doping signs.

( BUPP09295 - 01 December 2008) Buccoadhensive drug delivery systems - Extensive review on recent patents.

Peroral administration of drugs, although most preferred by both clinicians and patients has several disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins. Consequently, other absorptive mucosae are considered as potential sites for administration of these drugs. Among the various transmucosal routes studied the buccal mucosa offers several advantages for controlled drug delivery for extended period of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract is avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form, design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is thus a promising area for continued research with the aim of systemic and local delivery of orally inefficient drugs as well as feasible and attractive alternative for non-invasive delivery of potent protein and peptide drug molecules. Extensive review pertaining specifically to the patents relating to buccal drug delivery is currently available. However, many patents e.g. US patents 6, 585,997; US20030059376A1 etc. have been mentioned in few articles. It is the objective of this article to extensively review buccal drug delivery by discussing the recent patents available. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems.

( BUPP09296 - 01 December 2008) Drug addiction in China.

Drug addiction in China began with the importation of Indian opium by the British in the 16th century and brought severe social and health problems. While drug abuse abated following the establishment of People's Republic of China, modernization and Westernization in the 1980s led to the reemergence of this problem. Drug abuse in China became epidemic, facilitating the spread of HIV/AIDS. The Chinese government has made great efforts to address these problems, focusing both on treatments of drug addiction and on harm-reduction programs. Although the new trends of drug addiction in China pose great public health challenges, these government interventions are likely to successfully stem the problem of drug abuse in the future.

( BUPP09297 - 01 December 2008) A French prospective observational study of the treatment of chronic hepatitis C in drug abusers.

The objective of this prospective, multicenter, observational study was to evaluate healthcare for hepatitis C virus (HCV)-infected drug abusers in France and to determine predictors of successful therapeutic intervention. A total of 170 drug users were recruited from 40 French centers. Three centers recruited 66 participants (38.8%), and one to eight patients each were enrolled from 37 other centers (n = 104). A sustained viral response (SVR) was seen in 65 (38.2%) patients. SVR rates were significantly higher in compliant than in non-compliant patients (43.5% versus 23.9%; P = 0.019), in patients from high- rather than low-recruiting centers (54.5% versus 27.9%; P < 0.001) and in patients receiving Buprenorphine /sup �/ rather than methadone (48.1% versus 21.8%; P = 0.001). In patients, who completed both the treatment and follow-up (n = 94), SVR rate was 57.4%. Buprenorphine /sup �/ substitution therapy and genotypes 2 or 3 HCV infection were associated with significantly higher rates of SVR (P < 0.01, for both comparisons). In conclusion, successful care of hepatitis requires an active treatment policy of every center toward drug addicts. Additional studies are needed to explore the difference in SVR with methadone versus Buprenorphine /sup �/ therapy.

( BUPP09298 - 01 December 2008) Substance Abuse and Withdrawal in the Critical Care Setting.

Substance use is common among individuals admitted to the critical care setting and may complicate treatment of underlying disorders. It is imperative for the critical care team to have a high index of suspicion for substance intoxication and withdrawal. This article reviews the epidemiology of substance use in this population and the treatment of common withdrawal syndromes. General principles regarding the management of substance withdrawal syndromes include general resuscitative measures, use of a symptom-triggered approach, and substitution of a long-acting replacement for the abused drug in gradual tapering dose. The authors stress the importance of long-term planning as part of the overall treatment protocol beyond the acute presentation.

( BUPP09299 - 01 December 2008) Transdermal buprenorphine to treat pain in sickle cell crisis.

A specific dosage regimen of buprenorphine achieves pain relief from painful episodes due to sickle cell disease. The dosage regimen comprises administering to a patient in need of pain relief from sickle cell disease at least one BTDS transdermal patch. Alternatively, the dosing regimen comprises administering to the patient (1) a first buprenorphine-containing transdermal dosage form for a first dosing period; (2) administering to the patient a second buprenorphine-containing transdermal dosage form for a second dosing period, where the second dosage form comprises the same dosage of buprenorphine as, or a greater dosage of buprenorphine than, the first dosage form; and (3) administering to the patient a third buprenorphine-containing Inventor(s): Reidenberg Bruce E, Spyker Daniel A.transdermal dosage form for a third dosing period, where the third dosage form comprises a greater dosage of buprenorphine than the second dosage form.

( BUPP09300 - 01 December 2008) Implementation of Drug Substitution Therapy in Georgia

The geopolitical uniqueness of the regional, socioeconomic situation and the existence of territories outside the control of the national government have facilitated the spread of drug use in Georgia. A special problem is injection of opiates, in particular heroin and Subutex (buprenorphine). It has been established that among registered HIV infected individuals the main route of transmission is injecting drug use. Although the prevalence of HIV among IDUs (injecting drug user) is only 1-3%, the high number of IDUs, and the high prevalence of hepatitis C in this population creates high risk of dramatic spread of HIV in Georgia. Beginning at the end of 2005, the GFATM (Global Fund against HIV/AIDS, Tuberculosis and Malaria) supported methadone substitution programmes in Georgia. At present, three programmes are functioning. At the same time, they involve 230 patients altogether. The studies carried out by the Research Institute on Addiction, with the aim to control the efficacy of pilot programmes have revealed a dramatic improvement of psychophysical state of patients, with very high rate of resocialization and decriminalization, significant diminishment of drug-related risky behaviour. Obtained results indicate high efficiency of methadone substitution programmes in Georgia, as an important tool both for treatment of opioid dependence and harm reduction. In order to obtain a more significant impact on public health substitution therapy programmes have to be further expanded.

( BUPP09301 - 01 December 2008) Development and validation of a liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of buprenorphine, norbuprenorphine, and metabolites in human urine.

A liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and norbuprenorphine glucuronide (NBUP-Gluc) in human urine was developed and fully validated. Extensive endogenous and exogenous interferences were evaluated and limits of quantification were identified empirically. Analytical ranges were 5-1,000 ng/mL for BUP and BUP-Gluc and 25-1,000 ng/mL for NBUP and NBUP-Gluc. Intra-assay and interassay imprecision were less than 17% and recovery was 93-116%. Analytes were stable at room temperature, at 4 degrees C, and for three freeze-thaw cycles. This accurate and precise assay has sufficient sensitivity and specificity for urine analysis of specimens collected from individuals treated with BUP for opioid dependence.

( BUPP09302 - 01 December 2008) Electrocardiographic abnormalities in opiate addicts

Aims: To determine in a cross-sectional study the prevalence of electocardiographic (ECG) abnormalities in opiate addicts who were therapy-seeking and its association with demographic, clinical and drug-specific parameters. Methods: In consecutive therapy-seeking opiate addicts, a 12-lead ECG was registered within 24 hours after admission and evaluated according to a pre-set protocol between October 2004 and August 2006. Additionally, demographic, clinical and drug-specified parameters were recorded. Results: Included were 511 opiate addicts, 25% female, with a mean age of 29 years (range 17-59 years). One or more ECG abnormalities were found in 314 patients (61%). In the 511 patients were found most commonly St abnormalities (19%). Qtc prolongation (13%), tall R-and/or S waves (11%) and missing R Progression (10%). ECG abnormalities were more common in males than in females (64 versus 54%, P<0.05), and in patients with positive than negative urine findings for cannabis more often (68 versus 57%, P<0.05). Patients with ST abnormalities were more often males than females (21 versus 11%, P<0.05), had a history of seizures less often (16 versus 27%, P<0.05), had positive urine findings for cannabis more often (26 versus 15%, P<0.01) and had negative than positive urine findings for methadone more often (21 versus 11%, P<0.05). QTc prolongation was more frequent in patients with high dosages of maintenance drugs than in patients with medium or low dosages (27 versus 12 versus 10%, P<0.05) and in patients whose urine findings were positive than negative for methadone (23 versus 11%, P<0.001) as well as for benzodiazepines (17 versus 9%, P<0.05). Limitations of the data are that in most cases other risk factors for the cardiac abnormalities were not known. Conclusion: ECG abnormalities are frequent in opiate addicts. The most frequent ECG abnormalities are ST abnormalities. QTc prolongation and tall R- and/or S-waves. ST abnormalities are associated with cannabis, and QTcprolongation with methadone and benzodiazepines.

( BUPP09303 - 01 December 2008) Opioids and Cardiogram Abnormalities: Providing treatment based on understanding the risks and benefits.

Wallner and colleagues present new and interesting findings on the range of electrocardiographic abnormalities in a sample of opioid-dependent patients receiving a variety of opioid therapies. This paper is especially timely because of increasing concerns over the effect of methadone on cardiac function, specifically cardiac rhythm and possible lengthening of cardiac QT interval. While they report QTc prolongation to occur more frequently with methadone in a dose-dependent fashion, ST abnormalities occurred at greatest frequency in this sample, followed by QTc prolongation, tall R or S waves, and pathologic Q waves, all of which occurred at higher frequencies than fir the general population. However, other abnormalities were observed at rates that do not appear to be substantially greater or were lower than those reported for the general population. Importantly,the association of electrocardiographic abnormalities with illicit substance use by those who are opioid maintained was demonstrated.

( BUPP09304 - 01 December 2008) Letter to the Editor: The use of sublingual Buprenorphine-Naloxone for reversing heroin overdose: A high risk strategy that should not be recommended.

We write with great concern regarding the recent report published in addiction by Welsh and colleagues, and their suggestion that buprenorphine (alone or in combination with naloxone) may be a useful strategy in overdose reversal. While the details surrounding this case are consistent with a buprenorphine-precipitated reversal of heroin effects, there are a number of reasons why buprenorphine should not be recommended for overdose reversal and why such action may, in fact, contribute to increased overdose mortality.

( BUPP09305 - 01 December 2008) Letter to the Editor: The use of Buprenorphine to reverse opioid overdose deserves further evaluation.

Nielsen and Lintzeris express concern over the reported use of Buprenorphine/Naloxone in the reversal of a presumed overdose in A case of heroin overdose reversed by sublingually administered buprenorphine/naloxone (Suboxone). Certainly, their concerns are valid and important to consider. They very correctly point out that one anecdotal report should be treated with extreme caution. The primary purpose of reporting the case was to alert the addiction treatment and public health communities to a practice that is apparently occurring. Since writing the initial case report, i have heard of similar cases in several other American cities as well as other countries.

( BUPP09306 - 01 December 2008) When a New Drug Promotes the Integration of Treatment Modalities: Suboxone and Harm Reduction

In medicine, the introduction of a new drug is often associated with an overall enhanced understanding of the clinical issues that originally stimulated its own development. Sometimes newer drugs must be introduced to counter the improper use of existing drugs. In this paper, we discuss some concepts regarding the pharmacotherapy of heroin addiction (regarding blocking dosages and stabilization dosages), the advantages and disadvantages of opioid agonists in the pharmacotherapy of heroin addiction, the role of motivation for harm reduction strategies, the difficulties of methadone, buprenorphine, naltrexone and naloxone use in harm reduction strategies, and the possible use of buprenorphine-naloxone combination in harm reduction strategies. A buprenorphine-naloxone combination is not only a clinical improvement over pre-existing treatments, but it also represents a good example of a drug designed to limit the misuse of another resulting in the integration of difficult modalities of intervention, previously believed to be in opposition.

( BUPP09307 - 01 December 2008) The Under-Treatment of Pain: A Global Problem. An Educational Approach

In order to undertake comprehensive pain treatment, acute and chronic, all prescribers are required to understand opioid medication, and to appreciate the phenomenon of addiction. Throughout the world there is a major concern with under treatment of pain. This paper aims to assist health professionals in their effort to treat patients pain effectively. It also outlines medications available for use, typical patient situations and strategies for intervention to relieve pain. Barriers to pain treatment are reviewed, in both developed and developing nations.

( BUPP09308 - 01 December 2008) Finnish Experience With Buprenorphine-Naloxone Combination (Suboxone): Survey Evaluations With Intravenous Drug Users

Finland, with a population of around 5.5 million, has four years of prescribing a buprenorphine-naloxone combination product (bup/nx) under its belt, and it already has the most bup/nx experience within Europe. Our data show that the decision to transfer patients from buprenorphine to bup/nx more than halved the street value of an 8mg tablet, in a country where buprenorphine had previously been the most widely intravenously-abused drug. Patients are now maintained on an average daily dose of 16mg bup/nx and, reassuringly, buprenorphine misuse is decreasing. Most importantly, the pre-buprenorphine heroin mortality figures have all but vanished: from 63 deaths in 2000, in the last few years Finland has seen heroin claim just 0-4 lives per annum.

( BUPP09309 - 01 December 2008) Letter to the editor: Fifteen Years of Office Based Prescribing in Croatia. Attitudes, Obstacles and Outcomes.

To the Editor: Like many other European countries, Croatia had to face a heroin addiction epidemic in the early 1990s. However, unlike many of those countries, Croatia gave a prompt medical response to its new public health problem. Methadone for outpatient treatment was introduced in 1991, and by 1995 there were over 1500 patients on methadone. Currently, more than 50% of 2400 GPs in Croatia have patients on maintenance treatment; buprenorphine was introduced in 2004, and by now about 25% of all maintenance patients take buprenorphine.

( BUPP09310 - 05 December 2008) Opiate agonist tretament for addiction (Correspondence letter)

Richard Schottenfeld and colleagues' clinical trial involving maintenance treatment with buprenorphine and naltrexone for heroin dependence (Lancet 28 June 2008. p 2192 - BUPP08985) raises several questions, starting with why it was done in the first place. Enrolment began after buprenorphine (with and without naloxone) had been approved for widespread use by communitybased practitioners in the USA, and at a time whne well over 80,000 patients were receiving buprenorphine maintenance treatment in France.

( BUPP09311 - 08 December 2008) Comparison of sevoflurane and isoflurane in dogs anaesthetised for clinical surgical or diagnostic procedures.

OBJECTIVES: To assess attributes of sevoflurane for routine clinical anaesthesia in dogs by comparison with the established volatile anaesthetic isoflurane.METHODS: One hundred and eight dogs requiring anaesthesia for elective surgery or diagnostic procedures were studied. The majority was premedicated with 0.03 mg/kg of acepromazine and 0.01 mg/kg of buprenorphine or 0.3 mg/kg of methadone before induction of anaesthesia with 2 to 4 mg/kg of propofol and 0.5 mg/kg of diazepam. They were randomly assigned to receive either sevoflurane (group S, n=50) or isoflurane (group I, n=58) in oxygen and nitrous oxide for maintenance of anaesthesia. Heart rate, respiratory rate, indirect arterial blood pressure, haemoglobin saturation, vaporiser settings, end-tidal carbon dioxide and anaesthetic concentration and oesophageal temperature were measured. Recovery was timed. Data were analysed using analysis of variance and non-parametric tests.RESULTS: Heart rate (85 to 140/minute), respiratory rate (six to 27/minute) and systolic arterial blood pressure (80 to 150 mmHg) were similar in the two groups. End- tidal carbon dioxide between 30 and 60 minutes (group S 6.4 to 6.6 and group I 5.8 to 5.9 per cent) and vaporiser settings throughout (group S 2.1 to 2.9 and group I 1.5 to 1.5 per cent) were higher in group S. There was no difference in time to head lift (18 +/- 16 minutes), sternal recumbency (28 +/- 22 minutes) or standing (48 +/-32 minutes). No adverse events occurred.CLINICAL SIGNIFICANCE: Sevoflurane appeared to be a suitable volatile anaesthetic for maintenance of routine clinical anaesthesia in dogs.

( BUPP09312 - 08 December 2008) Sublingual bioavailability of buprenorphine in newborns with neonatal abstinence syndrome - a case study an physiological and developmental changes using SIMCYP.

Background: 60-80% of infants born to opioid dependent mothers require pharmacologic treatment for neonatal abstinence syndrome (NAS). Buprenorphine (BUP) is used as a maintenance agent for adult opioid dependence. There is no data regarding the use of sublingual BUP below the age of 4 years, including in term infants with NAS. Objectives: Characterize pharmacokinetics (PK) of BUP and its metabolite, norbuprenorphine (NBUP), in neonates; Evaluate the developmental changes in neonates to assist dose optimization in ongoing clinical studies. Methods: In silico prediction of PK behaviour and physiological development in neonates were evaluated using SIMCYP. Intravenous clearance was predicted through physiologically based simulation method in SIMCYP. Based on sublingual clearance obtained from a one compartmental model developed previously using NONMEM, individual changes of sublingual bioavailability were evaluated with physiological development in the first two months during the neonatal period. Results: Intrinsic clearance of BUP in neonates was incorporated as 30% and 20% of adult values for CYP3A4 and CYP2C8, respectively. Sublingual bioavailability for individual neonates was evaluated with bioavailability time profiles, and was estimated at 10-30% of adult levels. Conclusion: Developmental considerations for the PK of BUP in neonates are important for the charectirazation of the dose-exposure relationship. We have evaluated this from "bottom up" and "top down" approaches with SIMCYP and NONMEM respectively and found these approaches to be complimentary and valuable for clinical trial design and routine clinical care. Presumably these data will also facilitate rational decision making in pediatric drug development.

( BUPP09313 - 08 December 2008) Population pharmacokinetic investigation of ribavirin in pediatric subjects infected with hepatitis C virus

( BUPP09314 - 08 December 2008) Psychotherapeutic benefits of opioid agonist therapy.

Opioids have been used for centuries to treat a variety of psychiatric conditions with much success. The so-called "opium cure" lost popularity in the early 1950s with the development of non-addictive tricyclic antidepressants and monoamine oxidase inhibitors. Nonetheless, recent literature supports the potent role of methadone, buprenorphine, tramadol, morphine, and other opioids as effective, durable, and rapid therapeutic agents for anxiety and depression. This article reviews the medical literature on the treatment of psychiatric disorders with opioids (notably, methadone and buprenorphine) in both the non-opioid-dependent population and in the opioid-dependent methadone maintenance population. The most recent neurotransmitter theories on the origin of depression and anxiety will be reviewed, including current information on the role of serotonin, N-Methyl d-Aspartate, glutamate, cortisol, catecholamine, and dopamine in psychiatric disorders. The observation that methadone maintenance patients with co-existing psychiatric morbidity (so called dual diagnosis patients) require substantially higher methadone dosages by between 20% and 50% will be explored and qualified. The role of methadone and other opioids as beneficial psychiatric medications that are independent of their drug abuse mitigating properties will be discussed. The mechanisms by which methadone and other opioids can favorably modulate the neurotransmitter systems controlling mood will also be discussed.

( BUPP09315 - 08 December 2008) Electrocardiogram characteristics of methadone and buprenorphine maintained subjects.

There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose standard deviation, 69 +/- 29 mg) and buprenorphine (n = 19, mean daily dose 11 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 +/- 29 mg/day) than methadone subjects without U waves (60 +/- 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 +/- 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 +/- 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.

( BUPP09316 - 08 December 2008) Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence

( BUPP09317 - 08 December 2008) Addiction to Prescription Opioids: Characteristics of the Emerging Epidemic and Treatment With Buprenorphine.

Dependence on and abuse of prescription opioid drugs is now a major health problem, with initiation of prescription opioid abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opioids, there has been an increased emphasis on the treatment of pain. Pain is now the "5th vital sign" and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opioids and the fear of producing addiction in some patients. In this article, the authors characterize the emerging epidemic of prescription opioid abuse, discuss the utility of buprenorphine in the treatment of addiction to prescription opioids, and present illustrative case histories of successful treatment with buprenorphine.

( BUPP09318 - 08 December 2008) Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions

Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain. Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world. In contrast, the long-term administration of an opioid for the treatment of chronic noncancer pain continues to be controversial. Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment. The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities. The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainly about the appropriate role of these drugs in the treatment of pain. This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.

( BUPP09319 - 08 December 2008) Sex Differences in Analgesic, Reinforcing, Discriminative, and Motoric Effects of Opioids.

This review summarizes evidence for sex differences in behavioral effects of opioids, primarily in rats. Whereas mu agonists have been found to be more potent and in some cases more efficacious in producing analgesia and sedation in males than females, females are more sensitive than males to reinforcing and locomotor stimulant effects of opioids. Sex differences in motoric effects of opioids may contribute to sex differences in other behavioral effects of opioids; for example, sex differences in rats' ability to discriminate morphine from saline can be attributed entirely to greater morphine-induced sedation in males. Chronic estradiol blunts females' sensitivity to morphine's analgesic and sedative effects, but enhances females' sensitivity to the reinforcing and locomotor stimulant effects of mu opioids. The neurobiological basis for sex differences in and estradiol modulation of behavioral effects of opioids includes brain opioid receptor density (greater in males and under low-estradiol conditions in females) and dopaminergic function (greater in females and under high-estradiol conditions). Given the significant and growing use of opioids by women, both medicinally and recreationally, understanding how female biology influences analgesic and other effects of opioids is crucial.

( BUPP09320 - 08 December 2008) Comparison between continuous propofol infusion & conventional balanced anaesthesia in neurosurgical patients.

Background: Thiopentone induction and maintenance with an inhalational agent is widely used anaesthetic regimen in most operations including neurosurgeries. Propofol has a favourable effect on neurophysiology and its use during neurosurgeries is advantageous in terms of stable intraoperative vitals and excellent recovery profile. Our study aimed at comparing the conventional technique of thiopentone-isoflurane anaesthesia with propofol anaesthesia in neurosurgeries. Patients & Methods: One hundred twenty ASA grade I and II patients were randomly divided into two groups of sixty each. Group I (conventional ) patients were induced with 5 mg/kg thiopentone and vecuronium bromide and maintained on isoflurane in oxygen and nitrous oxide. Group II (propofol group) patients were induced with titrated dose of propofol (until the loss of verbal commands) and vecuronium bromide and maintained on continuous propofol infusion, oxygen and nitrous oxide. Pulse rates, arterial pressures, recovery profile and postoperative complications were observed. Results: Propofol preserved preoperative pulse rates and provided easily controllable and reversible lowering effect on the mean arterial pressure. Extubation time, sedation scores and PONV were all lesser in the propofol group. Conclusion: We conclude that propofol is good drug for induction & maintenance of general anaesthesia in neurosurgical patients.

( BUPP09321 - 08 December 2008) Pain therapy - Dosing recommendations at beginning and end of treatment

Pain therapy is one of the basic tasks of a clinician. Good knowlegde of the active profile of prescribed analgesics as well as their side effects will facilitate their use and decrease undesired effects. This article discusses currently used analgesics, their indication and practical application with special consideration of dose requirements at the beginning and end of treatment

( BUPP09322 - 16 December 2008) Guidelines: Control of pain in adults with cancer: Summary of SIGN guidelines.

( BUPP09323 - 16 December 2008) Effects of cocaine in the human beings.

Objective. Cocaine abuse still remains a healthy problem in many developed societies. Despite the research efforts of the last decades, the goal of an effective pharmacological cocaine treatment has not been yet achieved. Therefore, it is clear that we should pursue in the search of the psychobiologycal mechanisms that maintain cocaine dependence. New contributions on this particular subject are published every year in scientific journals. A summary of the conclusions of some of these journals may help to other researchers and experience-ded personnel in the field of drug addiction. Material and methods. The availability of behavioral animal models of drug dependence such as self-administration, conditioned place preferente drug discrimination and locomotor sensitization, as well as that of neurobiological methodologies such as intracerebral drug administration, microdialysis, binding and quantitative receptor autoradiography, in situ hibridization, and electrophysiology has increased our knowledge of the neural bases of cocaine dependence. Moreover, recent neuroimage studies in cocaine abusers are providing new insights on the genetic, psychological and social factors that participate in acquisition and maintenance of cocaine addiction. Results. In the last years, several reports have demonstrated that cocaine acts in the brain altering the neurotransmission of different compounds, and specially that of dopamine, serotonine and noradrenaline in cerebral areas related to the reinforcing properties of natural rewards. The anatomical and functional connections between these brain regions constitue a neural circuit, the mesocorticolimbic dopaminergic system, that it is also regulated by psychological and social factors besides the drug. Chronic cocaine abuse change the adequate function of this rewarding system resulting in increased alterations of brain neurotransmission and damage in other corporal tissues. Conclusions. Although cocaine alter the chemicals connections of different neurotransmitters, it seems that of the dopamine is mainly involved in the reinforcing properties of this drug. The psychostimulant feelings induced by this drug are also dependent on the subject expectancies and a chronic cocaine consumption may result in neuroadaptive changes of several neurotransmitter sytems that are maintained even in absence of the drug. It is thought that these neuroadaptive changes could participate too in cocaine relapse. Besides to the nervous tissue, chronic cocaine abuse cause adverse effects on many other corporal tissues, specially in the brain and heart vascular system.

( BUPP09324 - 16 December 2008) Fifteen years of office-based prescribing in Croatia. Attitudes, obstacles and outcomes.

( BUPP09325 - 16 December 2008) The use of buprenorphine to reverse opioid overdose deserves further evaluation.

( BUPP09326 - 16 December 2008) Ciprofloxacin-induced torsades de pointes in a methadone-dependent patient.

Background: Methadone has been associated with QT prolongation and Torsades de pointes. Ciprofloxacin may prolong QT interval and induce Torsades de pointes when other risk factors are present. Case description: A case is described in which a patient receiving methadone treatment developed Torsades de pointes following the addition of ciprofloxacin. Conclusion: Ciprofloxacin should be used with caution in patients receiving methadone.

( BUPP09327 - 16 December 2008) The use of sublingual buprenorphine-naloxone for reversing heroin overdose: A high-risk strategy that should not be recommended.

We write with great concern regarding the recent report published in Addiction y Welsh and colleagues, and their suggestion that buprenorphine (alone or in combination with naloxone) may be a useful strategy in overdose reversal. While the details surrounding this case are consistent with a buprenorphine-precipitated reversal of heroin effects, there are a number of reasons why buprenorphine should not be recommended for overdose reversal and why such action may, in fact, contribute to increased overdose mortality. This is exemplified by a previous case in the literature of a person being administered intravenous buprenorphine in an attempt (unsuccessfully) to reverse a heroin overdose. The authors of this paper note that this action may delay the initiation of proper life-saving actions, and we could concur that this is a grave concern. Welsh and colleagues are incorrect in suggesting that there are no published cases of oral or sublingual buprenorphine related overdoses. There is at least one published fatality following oral buprenorphine and intravenous use of buprenorphine is not suspected in all fatalities.

( BUPP09328 - 16 December 2008) The use of depot naltrexone under legal coercion: The case for caution.

In many developed countries over the past century there have been periodic enthusiasms for legally coerced treatment of addiction: that is, addiction treatment that is offered as an alternative to imprisonment. Between the 1930s and early 1970s, for example, the United States established two Federal public health hospitals where opioid addicts were treated compulsorily for 6 months or over. Enthusiasm for the coerced treatment of addiction has been renewed recently (in the absence of compelling evidence of its efficacy). In the case of heroin addiction, the renewed interest has been stimulated by the development of depot forms of the opioid antagonist, naltrexone, which promises to be more effective in ensuring abstinence from opioids than psychosocial treatment or oral naltrexone. For example, Caplan has argued recently that it would be ethically acceptable to coerce heroin addicts legally into receiving naltrexone implants because heroin addicts are, by definition, incapable of making self-determining autonomous choices about whether or not to use heroin. Naltrexone, he argues, restores heroin addicts autonomy by removing their cravings for heroin and by blocking the euphoric effects of heroin if they succumb to temptation. Caplan also asserts that naltrexone has been used safely and effectively to treat heroin addiction for more than 30 years, so implantable forms of the drug do not present any special ethical issues.

( BUPP09329 - 16 December 2008) Unplanned admissions to two Sydney public hospitals after naltrexone implants.

( BUPP09330 - 16 December 2008) Prevalence of diversion and injection of methadone and buprenorphine among clients opioid treatment at community pharmacies in New South Wales, Australia.

Background: This study aimed to investigate the prevalence of diversion and injection of methadone and buprenorphine among clients receiving opioid pharmacotherapy treatment at community pharmacies in New South Wales (NSW), Australia. Methods: A multi-site cross-sectional survey design was utilised using a self-complete questionnaire. Participants were 508 clients receiving supervised methadone (n=442) and buprenorphine (n=66) at 50 community pharmacies. Participants were surveyed about whether they had diverted their currently prescribed pharmacotherapy, whether they had injected methadone or buprenorphine, the frequency, desirability and duration of action of injecting, and the ease of availability of street-purchased pharmacotherapies. Results: The prevalence of recent diversion was more than 10 times higher among those receiving buprenorphine compared to methadone, with 23.8% of buprenorphine-maintained participants reporting diverting their dose in the preceding 12 months. Seventeen percent of methadone clients had injected methadone on the preceding 12 months compared with 9.1% of buprenorphine clients over the same period. Conclusion: The higher prevalence of buprenorphine diversion compared to methadone diversion is likely to be due to its sublingual tablet formulation and difficulty associated with supervising its consumption compared to that of an oral liquid. Methadone diversion is also less prevalent likely due to high levels of methadone takeaway provision, which also helps to explain the higher levels of recent methadone injecting compared to buprenorphine injecting. A clearer understanding of the motivations for diversion and injection of opioid pharmacotherapies, and the relationship between them is required.

( BUPP09331 - 16 December 2008) Obstiless reports impact of opioid-induced side-effects.

Opioids are widely used to provide analgesia in advanced cancer patients and increasingly being used to treat chronic, non-malignant pain. However, constipation is a major side effect of opioids and can impact significantly on patients quality of life. Constipation is the most adverse effect of long term opioid therapy. Opioid agents mediate their effects through three distinct classes of membrane bound opioid receptors which are expressed throughout the central nervous system, but also in peripheral areas.

( BUPP09332 - 17 December 2008) Opioid maintenance therapy suppresses alcohol intake in heroin addicts with alcohol dependence: Preliminary results of an open randomized study .

Abstract : An open randomized study lasting 12 months was performed to evaluate the efficacy of methadone or buprenorphine to suppress alcohol use in two hundred and eighteen heroin addicts with alcohol dependence. Daily maintenance doses of methadone were 80, 120, 160, and 200 mg/day, while doses of buprenorphine were 8, 16, 24, and 32 mg/day. As expected, both treatments were able to reduce both heroin use and addiction severity (measured with ASI interview). However, although both medications were able to suppress alcohol use, the highest dose of buprenorphine was better than the highest dose of methadone, in reducing alcohol craving, ethanol intake (measured as daily number of drinks), and the ASI subscale of alcohol use. The mechanism underlying the effects of the opioid maintenance therapy on the reduction of alcohol intake is still unclear. The results of the present study may represent the first clinical evidence of the potential effective use of the highest doses of buprenorphine for the suppression of ethanol intake in heroin addicts with alcohol dependence.

( BUPP09333 - 22 December 2008) Cognitive Functioning During Methadone and Buprenorphine Treatment Results of a Randomized Clinical Trial.

Cognitive impairment in drug-dependent patients receiving methadone (MMP) maintenance treatment has been reported previously. We assessed cognitive functioning after at least 14 days of stable substitution treatment with buprenorphine (BUP) or MIMP and after 8 to 10 weeks. We performed a randomized, nonblinded clinical trial in 59 drug dependent patients receiving either BUP or NIMP maintenance treatment and healthy normal controls (n = 24) matched for sex, age, and educational level. Thirteen patients dropped out of the study before the second testing was performed (BUP n = 22; MNIP, n = 24). A neuropsychological test battery was used to measure selective attention, verbal memory, motor/cognitive speed, and cognitive flexibility. In addition, subjective perceived stress was assessed with a questionnaire. Patients in both treatment groups performed equally well in all of the cognitive domains tested. Both BUP and MMP patients showed significantly improved concentration and executive functions after 8 to 10 weeks of stable substitution treatment. The control group achieved better results than the BUP and MMP groups in most cognitive domains, indicating cognitive impairment in the patients. Perceived stress did not show any significant change after 8 to 10 weeks of treatment, and no major differences were detected between the 3 groups. No effects of perceived stress on cognitive function were found. Our results indicate a cognitive impairment in patients receiving maintenance treatment with BUP or MMP compared with healthy controls. Selective attention improved in both patient groups during treatment. We propose that the improvement of attention may facilitate rehabilitation of drug-dependent patients.

( BUPP09334 - 22 December 2008) Urine buprenorphine - A pilot study

( BUPP09335 - 22 December 2008) A simple gas chromatography-mass spectrometry procedure for the simultaneous determination of buprenorphine and norbuprenorphine in human urine.

With the increasing use of buprenorphine in treatment of opiate addiction and pain management, it is important that laboratories be able to assess patient compliance. The presented procedure is simple, efficient, and employs gas chromatography-mass spectrometry (GC-MS) technology available to most laboratories. The specimen is hydrolyzed with beta-glucuronidase prior to liquid-liquid extraction at a basic pH. The evaporated extract is derivatized to form the tertiary-butyl-dimethyl-silyl derivatives of buprenorphine and norbuprenorphine prior to analysis by GC-MS in the electron impact mode. Confirmation of the analytes is based on comparing the ion abundance ratios of the analytes to those of a contemporaneously analyzed standard. The qualitative ion abundance ratios are required to be within 20% of those of the standard for acceptance. Quantification is based on the ion ratios of the analytes to those of their corresponding deuterated analogues. Linearity was obtained for buprenorphine in the range of 1 to 2000 mug/L with a correlation coefficient (R) exceeding 0.999 and or norbuprenorphine from 1 to 1000 mug/L with R exceeding 0.997. Percent recoveries for the buprenorphine and norbuprenorphine were 71% and 75%, respectively. It was found that the recovery of norbuprenorphine could be enhanced to 100% by a simple "salting-out" modification to the procedure.

( BUPP09336 - 22 December 2008) Urinary detection times and metabolite/parent compound ratios after a single dose of buprenorphine.

The objective was to estimate the detection times and metabolite/parent compound ratios in urine after a single dose of buprenorphine. Eighteen healthy volunteers received a single dose of 0.4 mg buprenorphine sublingually. Urine samples were collected prior to dosing and at 2, 4, 6, 8 12, 24, 48, 72, and 96 h post-dose. The samples were screened using cloned enzyme donor immunoassay (CEDIA) reagent and quantitation was performed with liquid chromatography- tandem mass spectrometry (LC-MS-MS) with a cut-off of 0.5 ng/mL for buprenorphine and norbuprenorphine. The mean time of continuous positive results was 9 h (range 4 to 24 h) with CEDIA, whereas for an LC-MS-MS method it was 76 h (range 23-96 h) for buprenorphine, and for norbuprenorphine all samples were positive at 96 h. Some subjects had positive CEDIA results after a negative sample, owing to differences in creatinine concentration. The time when the ratio norbuprenorphine/buprenorphine exceeded 1 was estimated at 7 h. The metabolite/parent ratio may be used to estimate the time of intake even though the individual ratios showed an increased variation the more distant the collection time. We believe that using this ratio, rather than the actual concentrations, it is possible to compensate for urine dilution and different doses, and to improve interpretation.

( BUPP09337 - 22 December 2008) Outbreak of exogenous Cushing's syndrome due to unlicensed medications.

Objective: Despite the widespread medical use of glucocorticoids, reports of factitious administration of these hormones have been uncommon. We herein report an outbreak of Cushing's syndrome in Tehran among the addicts using Tamgesic (a brand of Buprenorphine) to help them through the narcotic withdrawal stage, without knowledge of the glucocorticoid content of the black-market drug. Design and measurements: Case histories of 19 patients with a final diagnosis of iatrogenic Cushing's syndrome were reviewed. Liquid chromatography/mass spectrometry (LC-Mass) method was used to evaluate glucocorticoid existence in the brand. High performance liquid chromatography was used to determine plasma dexamethasone level. Results: No buprenorphine was present in the vials. Each Tamgesic vial contained 0.4 mg of Dexamethasone disodium phosphate; Heroin was also found in them. The duration of injection abuse and the total dexamethasone intake was 4.5 (1-18) months and 2.6 (0.8-8) mg/day, respectively. Median plasma dexamethasone concentration was 5.8 nmol/l, with a range of 5-8.7. Physical findings of the cases were not different from those of the classic endogenous Cushing's syndrome but their serum cortisol and urinary free cortisol were suppressed. Severe life-threatening complications were demonstrated in five cases. Conclusion: Surreptitious use of steroids resulting in Cushing's syndrome may be more common in opium addicts; a high degree of suspicion is needed to uncover this disorder. Whenever facing a cushingoid appearance in addicts, the possibility of using black market drugs with corticosteroid contents should be kept in mind.

( BUPP09338 - 22 December 2008) Transdermal drug delivery has ideal properties in the elderly.

The transdermal route of drug delivery has many advantages over other routes; some of these advantages are particularly applicable to the elderly population.

( BUPP09339 - 22 December 2008) Pain therapy in case of renal disease and chronic renal insufficiency.

Chronic pain patients constitute a problem clientele in every practice. It is decisive to avoid or to break chronification. In case of concomitant renal disease, impaired renal function or patients after renal transplantation, some special precautions have to be taken into account. The following summary shows the current data on therapy recommendations.

( BUPP09340 - 22 December 2008) Transdermal buprenorphine intoxication.

( BUPP09341 - 22 December 2008) Muscle injury, vimentin expression, and nonsteroidal anti-inflammatory drugs predispose to cryptic group A streptococcal necrotizing infection.

Background. Myonecrosis due to group A streptococci (GAS) often develops at sites of nonpenetrating muscle injury, and nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the severity of these cryptic infections. We have previously shown that GAS bind to vimentin on injured skeletal muscles in vitro. The present study investigated whether vimentin up-regulation in injured muscles in vivo is associated with homing of circulating GAS to the injured site and whether NSAIDs facilitate this process. Methods. M type 3 GAS were delivered intravenously 48 h after eccentric contraction (EC)- induced injury of murine hind-limb muscles. Vimentin gene expression and homing of GAS were followed by real-time reversetranscriptase polymerase chain reaction and quantitative bacteriology of muscle homogenates, respectively. In separate experiments, ketorolac tromethamine (Toradol) was given 1 h before GAS infusion. Results. Vimentin was up-regulated 8-fold 48 h after EC. Significantly more GAS were found in moderately injured muscles than in noninjured controls. NSAIDs greatly augmented the number of GAS in injured muscles. Conclusions. Vimentin may tether circulating GAS to injured muscle, and NSAIDs enhance this process. Strategies targeting the vimentin-GAS interaction may prevent or attenuate GAS myonecrosis. Use of NSAIDs should increase suspicion of cryptic GAS infection in patients with increasing pain at sites of nonpenetrating muscle injury.

( BUPP09342 - 22 December 2008) Prenatal buprenorphine exposure: Effects on biochemical markers of hypoxia and early neonatal outcome.

Objective. To evaluate the possible association between prenatal buprenorphine exposure and compromised early neonatal outcome in view of markers of perinatal hypoxia. Design, setting and sample. The study group consisted of 27 full-term neonates exposed to buprenorphine prenatally and prospectively followed up at a special tertiary outpatient clinic for pregnant drug abusers. Serving as controls were 27 full-term neonates exposed prenatally to illicit substances other than opioids and 38 full-term neonates from uncomplicated pregnancies of healthy parturients. Methods and main outcome measures. Apgar scores, cord pH and base excess were recorded. Cord serum samples were collected at birth for analysis of biochemical markers of fetal hypoxic stress: erythropoietin (EPO; chronic hypoxia), cardiac troponin T (cardiac involvement) and S100 (neural damage). Results. All infants were born in good condition according to Apgar scores and pH of cord blood. No statistically significant differences were found between the three groups in cord serum concentrations of EPO (33.0 median, range: 9.0-476.0 U/L in the buprenorphine-exposed group vs 27.0, range: 8.0-114.0U/L in substance-abusing controls vs 28.1, range: 11.6-260.0U/L in healthy controls) or S100 (0.47, range: 0.25-0.91mug/L vs 0.40, range: 0.12-1.22mug/L vs 0.47, range: 0.20-2.15mug/L). No significant differences existed in cardiac TnT levels (0.017, range: 0.010-0.072U/L vs 0.010, range: 0.010-0.075U/L vs 0.024, range: 0.010-0.075U/L). Conclusions. While no significant differences in asphyxia markers were observed between the three groups, a tendency towards higher levels of EPO emerged in the buprenorphine-exposed group.

( BUPP09343 - 05 January 2009) Analysis of a range of narcotic and psychotropic substances.

The registered narcotic and psychotropic drugs has recently tended to reduce in numer. Out of 19 INN registered narcotic and psychotropic agents, buprenorphine, morphine, promedol, prosidol, fentanyl, and sodium oxybate are distinguished by the maximum completeness and depth of their assortment.

( BUPP09344 - 05 January 2009) The prevalence of borderline personality among buprenorphine patients.

OBJECTIVE: In this study, we examined the prevalence of borderline personality disorder (BPD) in a sample of patients seeking outpatient treatment with buprenorphine for opioid addiction. METHOD: To assess for BPD, we used three self-report surveys in a consecutive study sample. RESULTS: Of the 111 participants who completed all three measures of BPD, 49 (44.1%) exceeded the cut-off score indicative of BPD. CONCLUSIONS: Among individuals who are addicted to opioids and seeking treatment with buprenorphine, the prevalence of BPD, as mutually confirmed by three self-report measures, is quite high.

( BUPP09345 - 05 January 2009) Treating opioid dependency and coexistent chronic nonmalignant pain.

As pointed out by Jackman and colleagues in this issue of American Family Physician, opioids are commonly used for the treatment of chronic non-malignant pain (i.e., pain unrelated to cancer that persists beyond the usual course of disease or injury). Although most patients with chronic non-malignant pain may be successfully treated with long-term opioids, there is a risk of drug misuse, abuse, and addiction. One of the most common pain conditions seen in primary care is chronic low back pain. In one systematic review, 5 to 24 percent of patients who were prescribed long-term opioids had aberrant drug-taking behaviour. The review authors noted that, although clinical trials suggest that opioids are effective for the short-term (less than 16 weeks), the effectiveness of long-term opioids (16 weeks or more) for pain relief and improved physical function is less clear. Less is known about the use of long term opioids for another common chronic pain conditions. Recommendations are based on expert opioids for other common chronic pain conditions. Recommendations are based on expert opinion and uncontrolled studies; however, several adverse effects are known to be associated with prolonged treatment with opioids. One study showed that the unintended consequences include accident proneness, impaired judgement and cognitive function, a decline in occupational and social function, and strained family relationships. Physicians should monitor patients for adverse effects. The patients medical history may provide important clues. For example, if the patient is taking unusually large quantities if opioids and still complains of insufficient pain relief, there may be aberrant drug-taking behaviour or drug diversion. This should not be confused with pseudoaddiction, in which patients appear to have drug-seeking behaviour that is actually caused by inadequate pain control.

( BUPP09346 - 05 January 2009) New guidelines against unfair treatment of narcotic addicts necessary

( BUPP09347 - 05 January 2009) Outcomes of DATA 2000 certification trainings for the provision of buprenorphine treatment in the veterans health administration.

Despite the high numbers of veterans with opioid dependence, few receive pharmacologic treatment for this disorder. The adoption of buprenorphine treatment within the Veterans Health Administration (VHA) has been slow. To expand capacity for buprenorphine treatment, the VHA sponsored two eight-hour credentialing courses for the Drug Addiction Treatment Act of 2000. We sought to describe the outcomes of such training. Following the training sessions, 29 participants (18 physicians) were highly satisfied with course content and affirmed their intention to prescribe buprenorphine; after nine-month follow-up, two physicians were prescribing. We conclude that providing credentialing courses, while popular, did not markedly promote the prescription of buprenorphine.

( BUPP09348 - 05 January 2009) Variability and function of family 1 uridine-5'-diphosphate glucuronosyltransferases (UGT1A).

The substrate spectrum of human UDP-glucuronosyltransferase 1A (UGT1A) proteins includes the glucuronidation of non-steroidal anti-inflammatory drugs, anticonvulsants, chemotherapeutics, steroid hormones, bile acids, and bilirubin. The unique genetic organization of the human UGT1A gene locus, and an increasing number of functionally relevant genetic variants define tissue specificity as well as a broad range of interindividual variabilities of glucuronidation. Genetic UGT1A variability has been conserved throughout the protein's evolution and shows ethnic diversity. It is the biochemical and genetic basis for clinical phenotypes such as Gilbert's syndrome and Crigler-Najjar's disease as well as for the potential for severe, unwanted drug side effects such as in irinotecan treatment. UGT1A variants influence the metabolic effects of xenobiotic exposure and therefore have been linked to cancer risk. Detailed knowledge of the organization, function, and pharmacogenetics of the human UGT1A gene locus is likely to significantly contribute to the improvement of drug safety and efficacy as well as to the provision of steps toward the goal of individualized drug therapy and disease risk prediction.

( BUPP09349 - 05 January 2009) Post marketing surveillance study with an analgesic (transdermal buprenorphine patch in patients with moderate to severe chronic pain).

AIM: To obtain information on the efficacy, tolerability and safetyofa transdermal buprenorphine patch (Transtec PRO) in patients with moderate to severe chronic pain. In addition it should be evaluated to what extent the two fixed patch change days per weekare simplifyingthe therapy. METHODS: In this prospective multi-center post marketing surveillance study patients with chronic cancer and non-cancer pain were treated with transdermal buprenorphine for up to eight weeks. The evaluation included pain intensity, the dosage of the applied analgesics and additional therapies, the renal function (by serum creatinine) and adverse events. RESULTS: 3654 patients were treated for a mean of 50.4 days. Using the NRS-11 the mean pain intensity decreased from 6.3 at the time when patients were switched to the transdermal buprenorphine patch to 2.6 at the last treatment evaluation. The matrix patch was safe and well tolerated also in patients with advanced renal insufficiency. Adverse events were reported in 6.7% of the patients. 89.3% of the physicians quoted to prefer transdermal buprenorphine with the two fixed patch change days per week compared to the pre-treatment. CONCLUSION: The buprenorphine-containing matrix patch was effective and well tolerated in patients with moderate to severe chronic cancer and noncancer pain. From the physicians view the two fixed patch change days per week facilitate the guidance of therapy. In patients with advanced renal insufficiency a dose adjustment is not necessary.

( BUPP09350 - 05 January 2009) Transdermal Buprenorphine in Children With Cancer-Related Pain.

We present three cases of children (aged 3-5 years) in which cancer related pain was adequately controlled by Transdermal Buprenorphine. The endpoints for evaluating analgesic efficacy consisted of the assessment of pain using a visual scale and the possibility of reducing other pain treatment. improvement of pain level was demonstrated by the decrease in pain scores, by reduction of the overall amount of medications, especially opioids, and by improvement of uninterrupted sleep. Only limited data is available on the use of Transdermal Buprenorphine in children. In Our experience, Transdermal Buprenorphine allowed good analgesia without significant side effects in these three children with cancer-related pain.

( BUPP09351 - 05 January 2009) Update in Addiction Medicine for the Primary Care Clinician.

The United States Preventive Services Task Force recommends that primary care clinicians assume a major role in screening, identification, treatment, and referral to treatment of unhealthy alcohol and other drugs (AOD) use-the spectrum from use that risks health consequences to AOD disorders (abuse and dependence)-in generalist settings. In the United States, nicotine dependence, alcohol use, and drug use are the first, third and ninth leading causes, respectively, of preventable deaths. Despite the harmful effects of addiction and improved options for office based treatments and referral, not all primary care clinicians routinely address AOD use in their patients. The objectives of this paper are to identify and examine important recent advances in addiction medicine that have implications for primary care clinicians and that emphasize primary care clinicians role in the identification, treatment and/or referral of patients with addictions. We conducted and electronic database (PubMed) search to systematically identify recent (June 1, 2006 to January 1, 2008) human subject, English language, peer-reviewed, research publications that are relevant to generalist care for patients with addiction disorders. We also surveyed the publications that were reviewed by a NIH-funded newsletter that, in an attempt to identify articles that address the health impact of alcohol and drugs, systematically reviews the core general medical, infectious disease, public health, and additional subspecialty journals. Similar to our prior review, authors (A.G., D.F., R.S.) were provided a title listing of articles with addiction-related key words within the reference time frame, and then secondary searches and consensus deliberations were used to identify articles that may impact the care provided by primary care clinicians in the categories of 1) alcohol use and disorders and 2) opioid use and dependence. Articles were categorized as impacting primary care clinicians if they studied primary care settings or could impact such settings and had practice changing findings or implications.

( BUPP09352 - 05 January 2009) Allergic contact dermatitis from transdermal buprenorphine.

Buprenorphine is a low-molecular-weight, lipophilic, opioid analgesic. The transdermal delivery system (TDS) containing it has skin irritation potential, but at least two cases of contact allergy to the active principal have been described previously. To confirm allergic contact dermatitis from transdermal buprenorphine (TDB) in five older patients suffering from chronic pain and who developed persistent, pruritic erythematous plaques at the contact sites, with two of them also presenting with a generalized skin eruption.Besides the baseline patch test series, all five patients were tested with the TDB, four of whom were also tested with the placebo transdermal delivery system as provided by the manufacturer; one patient was also tested with other preparations containing buprenorphine.All reacted to the TDB containing the active principal, the placebo being negative in the four patients tested. The patient tested with the other buprenorphine preparations did react positively to them as well. Tests with TDB in 28 healthy controls were negative.We report five cases of delayed hypersensitivity reactions to a TDS containing buprenorphine. Such adverse reactions might be under-reported. A fentanyl-containing TDS is a good alternative in these cases.

( BUPP09353 - 05 January 2009) Challenges in providing drug user treatment services in Russia: Providers' views.

The estimated number of opiate users in Russia is 2,000,000 and heroin consumption is continuing to increase. The Russian government is discussing the initiation of compulsory treatment to bring illegal drug users to the treatment services. At the same time, there is no access to the evidence-based treatment for opiate addiction such as methadone and buprenorphine maintenance programs. Qualitative interviews were conducted with drug user treatment service providers (N = 35) in Barnaul, Volgograd, and Yekaterinburg, Russia, in 2003-2004 to examine their views on drug user treatment services in Russia. The framework approach was used in data collection and analysis. Study participants identified major challenges in service provision for drug using population, including lack of resources, rehabilitation programs, and social support. It also depicted ambivalent attitudes toward compulsory treatment and clients' registration. The Russian drug user treatment system desperately needs resources allocation to provide quality care and diversify in its services in order to achieve long-term recovery. At this stage, it seems unreasonable to initiate compulsory treatment as is advocated by some government officials.

( BUPP09354 - 05 January 2009) Long-term recovery from heroin use among female ex-offenders: Marisol's story.

Ex-offenders experience various difficulties in successfully reentering communities post-incarceration. For those with a history of opioid misuse, despite various interventions, long-term recovery rates are relatively low. Additionally, the difficulties ex-offenders experience reintegrating with their families and communities are further compounded by the stigma and structural barriers posed by prior criminal and drug use histories. This qualitative study, using in-depth interviews conducted during an 18-month period between mid 2004 and late 2005 examines the process of creating and maintaining abstinence among 25 former heroin users, mostly Latino and African American New York City ex-offenders who have remained abstinent from heroin use for a period of 5 yr or longer. Focusing primarily on the story of one female respondent and in participants' own words, the factors that they found to be most salient in enhancing their recovery efforts (positive peer support, motivational tools, exercise, meditation, skills enhancement) are examined. The study findings suggest that reentry programs and policies can help ex-offenders sustain long-term abstinence and prosocial lifestyles by supporting the various coping strategies that they identify as being particularly valuable.

( BUPP09355 - 05 January 2009) Substance Use & Misuse: Editorial.

Use of the term "recovery" when it comes to addiction has a long history. Its use remains virtually invisible in the scientific literature however. The bulk of what we know about addiction processes emanates from research conducted in the United States and other "developed" nations; most of the work adopts a Western perspective and tends to focus on symptoms and the effectiveness of professional treatment at reducing symptoms. This literature as been useful in guiding policy and funding decisions and service development as well as refining theory that contributes to innovations in treatment. However, there are critical gaps in the addiction knowledge base, chiefly the pervasive under representation of research on the wellness perspective and on recovery. To date, addiction researchers, treatment providers, and public and private funders of services have emphasized the absence of symptom (i.e., abstinence from drugs and alcohol in the United States). Wellness goes beyond absence of illness (Breslow, 2006; World Health Organization, 1985). Recovery goes beyond not using drugs or alcohol. A participant in one of our studies defined recovery thus: My definition of recovery is life. Cause i didn't have no life before i got into recovery. Ultimately, recovery is about quality of life.

( BUPP09356 - 05 January 2009) Views and models about addiction: Differences between treatments for alcohol-dependent people and for illicit drug consumers in Italy.

Treatment of people who are alcohol-dependent and treatment of users of illicit drugs differ remarkably in Italy, in keeping with the perception of the general public that drinking alcoholic beverages is a time-honored behavior, while consumption of illicit drugs is a deviant behavior. From a clinical perspective, the treatment for alcoholism essentially stands on the principle of free choice, motivation to change, and a family approach, while the treatment of people who are illicit drug users is characterized by control, pharmacotherapy, and individual therapy approaches. From a socio-political viewpoint both were established in the 1970s, the former being a "bottom-up" movement that started as "spontaneous" responses that mutual help groups and a few clinicians and institutions gave to alcoholics and their families; while the latter was provided "top-down" as a political response of the Government confronting the increase of illegal drug consumption among youngsters.

( BUPP09357 - 05 January 2009) Endogenous opiates and behavior: 2007.

This paper is the thirtieth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2007 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.

( BUPP09359 - 12 January 2009) Hospital morbidity associated with the natural history of heroin use.

Objective: To assess changes in hospital morbidity associated with heroin use from pre-initiation, recreational to dependent use, and changes following treatment. Design: Analysis of hospital admission data assessed over six, 6-month periods (before and after heroin initiation; two dependent heroin use periods; and post-oral and post-sustained release naltrexone treatment). Participants: A sequential cohort of 139 patients for whom date of initial heroin use, regular heroin use, and two periods of heroin dependence (prior to treatment with oral and implant naltrexone) were known. Outcome Measures: The West Australian Data Linkage System was used to assemble hospital admission data. Admissions were analyzed as follows: "all cause" admissions and then subgrouped as "mental health (MH) other, " "MH opioid related, " "MH non-opioid drug related, " and "opioid overdoses." Results: The database identified 130 (94 percent) of the participants with 76 (59 percent) being male. The mean length of follow-up from first heroin use was 9.4 (SD 4.9) years. Significant increases in morbidity were not found in the periods pre-first and post-first heroin use, but were found from pre-heroin use to dependent use for "all cause, " "MH opioid related, " and "opioid over-dose" admissions. A significant decline in these measures was observed from the first dependent period to the post-implant period. "MH opioid related" admissions declined from the first to the second period of dependent heroin use. Conclusions: Findings suggest that the movement to dependent heroin use increases hospital morbidity; that morbidity in the presence of treatment does not necessarily increase; and the treatment with a sustained release preparation may be more effective than oral naltrexone in arresting morbidity.

( BUPP09360 - 12 January 2009) Intrathecal drug delivery for management of cancer and noncancer pain.

Intrathecal drug delivery (ITDD) has been an option for the management of persistent pain since the 1980s. The discovery of opioid receptors in the central nervous system was the impetus for early attempts to deliver opioids intraspinally. Approximately, 10-20 percent patients with cancer pain get inadequate analgesia from conventional medical management; this group particularly may benefit from ITDD. However, there is also some evidence for the use of ITDD in those with noncancer pain. This review presents options for ITDD, available drugs, evidence for efficacy, principles of patient selection, and problems with the intrathecal route.

( BUPP09361 - 12 January 2009) Opiate agonist treatment for addiction - Authors' reply.

( BUPP09362 - 12 January 2009) Multiple bone lesions resembling a metastatic origin. An unexpected diagnosis.

Lytic and blastic lesions have been associated to malignant tumours, such as solid cancer (breast cancer, renal cancer, prostate cancer, malignant melanoma or thyroid tumours). Although a mixed pattern with lytic and blastic lesions is due to metastatic tumour, this is not the only possible origin. The following case shows a systematic. This case report shows the number of tests that were made in order to discover the origin of osteolytic and osteoblastic lesions and it is notable that there is not an occult neoplasia on every occasion.

( BUPP09363 - 12 January 2009) Oral or transdermal opioids for osteoarthritis of the knee or hip.

Osteoarthritis is a degenerative joint disease characterized by pain and inflammation and primarily involves degeneration of the articular cartilage. Oral paracetamol and non-sterodial anti-inflammatory drugs (NSAIDS) are far the most common pharmacological treatment of pain in patients with osteoarthritis of the knee or hip. However, paracetamol is often inadequate to treat osteoarthritis pain on a daily basis and more chronic NSAID use may cause serious gastrointestinal and may be associated with cardiovascular adverse events. Therefore, opioids may often be a reasonable alternative for patients suffering from severe pain or for which other analgesics are contraindicated. Opioids are potent analgesics that work by targeting opioid receptors. Cellular studies have shown that there are opioid receptors in inflamed osteoarthritis synovial tissue. The American College of Rheumatology guidelines on management of osteoarthritis, updated in 2000, suggest that opioids can be used as a last resort. Guidelines from the UK also propose opioids as an alternative, if inadequate pain relief is achieved with ibuprofen and paracetamol, However, the use of strong opioids for the treatment of non-cancer pain remains controversial. Concerns about long-term use of opioids for chronic non-cancer pain have been expressed mainly due to the risks of dependence and addiction to opioids. Additionally, evidence on the long-term effects of the use of opioids in patients with knee or hip osteoarthritis is still lacking. he objective of this review is to systematically look at the effectiveness of pain reduction and improvement of physical function, and at the safety of opioid therapy for osteoarthritis.

( BUPP09364 - 12 January 2009) Maintenance treatments for opiate dependent adolescent.

Several studies have been demonstrated that the adolescent (less than 18 years old) substance abuse is a serious and growing problem. In Europe, estimate of cumulative use of drugs by young people under eighteen vary greatly by Countries, ranging from 3% to 20%. School survey of adolescents in seven countries of Latin America, found an estimate 5% of the youths in this region have tried drugs. In the USA, recent household survey data indicate that drugs are used on estimate 9% of 12-17 years old. The most common drugs used by young people worldwide are cannabis and inhalants. The prevalence of use of heroin and other opioid among adolescents has markedly increased in the last decade, reaching levels not observed since the 1960s. The percentage of young people aged between 13 to 18 years who have used heroin doubled from 0.4% in the early 1990s to 1.0%-1.6% in the recent years.

( BUPP09365 - 12 January 2009) Consumer satisfaction with opioid treatment services at community pharmacies in Australia.

Objective: To explore consumer satisfaction with, and experiences of, a range of issues associated with the delivery of opioid substitution treatment at community pharmacies in New South Wales, Australia. Setting: 50 community pharmacies providing opioid substitution treatment in New South Wales. Method: Self-completion survey completed by 508 clients during supervised dosing. Main outcome measure: Satisfaction with opioid substitution treatment delivery at community pharmacies. Results: Sixty-one percent of participants reported being satisfied with their treatment programme. Participants expressed a high level of satisfaction with most aspects of opioid substitution treatment delivery at their pharmacy (aggregate mean = 8.1/10; 10 = excellent). However, participants were less satisfied with the level of privacy afforded at the pharmacy. Thirty-four percent reported that they were made to wait longer than other customers, and 25% reported that the pharmacy staff did not treat them the same as other customers. However, 87% reported that they felt welcomed by the pharmacy staff. Twenty-three percent of clients were currently in debt to the pharmacy for nonpayment of dispensing fees. The mean amount of current debt was $71.75, equivalent to approximately 2 weeks of pharmacy dispensing fees. Conclusion: Community pharmacies providing opioid substitution treatment in New South Wales appear to be providing a level of service that is satisfactory to the clients of those services. However, many participants were concerned about a lack of privacy, the high cost of treatment, and being treated differently to other customers.

( BUPP09366 - 12 January 2009) Comparison of nonhydrolysis and hydrolysis methods for the determination of buprenorphine metabolites in urine by liquid chromatography-tandem mass spectrometry.

A highly sensitive and selective method for the direct determination of buprenorphine (BUP), norbuprenorphine (NBUB), buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide in urine was developed and validated. Analytes of interest were extracted by solid-phase extraction on Bond Elut C18, followed by liquid chromatography-electrospray ionization tandem mass spectrometry analysis using a Synergy Polar RP column. Gradient elution was based on a mobile phase consisting of 10 mM ammonium formate adjusted to pH 3 and acetonitrile. Acceptance criteria for linearity, precision, and recovery were achieved for all analytes. Intraday and interday precisions were better than 12% and 14%, respectively. Calibration curves were linear for BUP and its metabolites over the concentration range of 5-250 ng/mL, and correlation coefficients (R(2)) were better than 0.999. Limits of detection and lower limits of quantification were 0.2-0.4 and 0.7-1.2 ng/mL, respectively. Recoveries were in the range of 76-96%. No interference was detected with other common drugs. The described method was compared with an in-house hydrolysis method using 21 real urine case samples. BUP and NBUP were detected using both methods, with higher concentrations obtained using the direct method. Both methods were linear with correlation coefficients of 0.994 and 0.986 for total BUP and total NBUP, respectively. The comparison between the direct detection of BUP and its metabolites with the analysis of total BUP and total NBUP using the hydrolysis method is reported for the first time in this work.

( BUPP09380 - 26 January 2009) Effects of transdermal buprenorphine in cancer patients. Results from the Cancer Pain Outcome Research (CPOR) Study Group.

Pain still afflicts most cancer patients, mainly in the metastatic phases, and undertreatment is well documented. Transdermal delivery systems (TDS) could potentially have advantages over oral and parental routes, but evidence from comparative trials are scanty. In the framework of a wider initiative, an Outcome Research Study was carried out in Italy in 2006 to evaluate the effects of various analgesic options, particularly TDS Buprenorphine. Despite the limitations due to the observational design, these findings may be useful to clinicians to better judge the value of the drug under evaluation and to help researchers to design further comparative studies.

( BUPP09381 - 26 January 2009) Opioid dependent patients' experiences of and attitudes towards having their injecting sites examined.

Background: This study explored the attitude towards, and experiences of, injection site examination among injecting drug users in opioid treatment and the potential impact of this routine examination on information disclosure and future injection practices. Methods: A self-complete, anonymous, cross-sectional questionnaire was used with 153 patients recruited from three public clinics in Sydney, Australia. Results: The vast majority (97%) had ever injected in their upper limb, 19% in their leg, 16% in their neck, and 7% in their groin. The majority were 'happy to have their sites inspected' (78%), and felt it was an 'appropriate part of routine examination' (72%). Seventy-seven percent said they would be more honest about recent injecting, and 25% would inject in other sites if upper limb inspection occurred at every clinical review. Conclusions: The examination of injecting sites can provide useful corroboration of self-reported injecting drug use and an opportunity to offer harm reduction advice. The inspection of injecting sites was acceptable to most patients and should form part of routine clinical reviews.

( BUPP09382 - 26 January 2009) An enhanced method for the review of CD prescribing, based on ePACT data

Following the murders committed by Harold Shopman over a period of 23 years, there have been recommendations and legislation of tighten the management and monitoring of Controlled Drug prescriptions to prevent such a tragedy recurring. The recommendations in the Fourth Report of the Shipman Inquiry were wide ranging and the Government responded by issuing the command paper "Safer management of Controlled Drugs". Stakeholders went on to develop safer methods of monitoring and handling of CDs and the role of the "accountable officer" was developed. Legislation was passed by Parliament in July 2006 and January 2007 that enacted these changes. Their arms were: to ensure patients have timely access to the drugs prescribed for them: to promote the safe and effective use management of CDs; to limit the opportunities for CDs to be abused or diverted, causing possible harm to patients; and to share good practice and pick up poor performance quickly.

( BUPP09383 - 26 January 2009) Interventions to reduce HIV transmission related to injecting drug use in prison.

The high prevalence of HIV infection and drug dependence among prisoners, combined with the sharing of injecting drug equipment, make prisons a high-risk environment for the transmission of HIV. Ultimately, this contributes to HIV epidemics in the communities to which prisoners return on their release. We reviewed the effectiveness of interventions to reduce injecting drug use risk behaviours and, consequently, HIV transmission in prisons. Many studies reported high levels of injecting drug use in prisons, and HIV transmission has been documented. There is increasing evidence of what prison systems can do to prevent HIV transmission related to injecting drug use. In particular, needle and syringe programmes and opioid substitution therapies have proven effective at reducing HIV risk behaviours in a wide range of prison environments, without resulting in negative consequences for the health of prison staff or prisoners. The introduction of these programmes in countries with an existing or emergent epidemic of HIV infection among injecting drug users is therefore warranted, as part of comprehensive programmes to address HIV in prisons.

( BUPP09384 - 26 January 2009) Medications for Stimulant Abuse: Agonist-Based Strategies and Preclinical Evaluation of the Mixed-Action D(2) Partial Agonist Aripiprazole (Abilify(R)).

Agonist-based strategies and preclinical evaluation of the mixed-action D2 partial agonist aripiprazole (Abilify) as medications for stimulant abuse are reviewed. Topics discussed include: pharmacological strategies for medications development; monoaminergic psychomotor stimulants (cocaine and methamphetamine) as agonist-based strategies for medications development; partial agonist-based strategies for medications development; preclinical evaluation of aripiprazole in nonhuman primates; and aripiprazole and D2 partial agonist-based strategies for medications development. Findings indicate that agonist and antagonist effects of aripiprazole are evident under different experimental conditions and that, like D2 full agonists, aripiprazole may have limited value for treating monoaminergic stimulant abuse and addiction.

( BUPP09385 - 26 January 2009) Local Inhibition of Rho Signaling by Cell-Permeable Recombinant Protein BA-210 Prevents Secondary Damage and Promotes Functional Recovery following Acute Spinal Cord Injury.

Spinal cord injury (SCI) leads to robust Rho activation at the lesion site. Here, we demonstrate that BA-210, a cell-permeable fusion protein derived from C3 transferase, formulated in fibrin sealant and delivered topically onto the dura matter, diffuses into the spinal cord and inactivates Rho in a dose-dependent manner. Treatment with BA-210 in rats with thoracic spinal cord contusion increased tissue sparing around the lesion area and led to significant improvement of locomotor function. In mice, BA-210 improved functional outcome when treatment was either applied at the time of injury or delayed by 24 h. In both rats and mice, treatment with BA-210 was well tolerated. Rats gained body weight normally, and BA-210 treatment had no impact on the development of allodynia. Inactivating Rho with BA-210 holds promise for treating patients with SCI.

( BUPP09386 - 26 January 2009) Neonatal outcome following buprenorphine maintenance for opiate dependency.

Methadone substitution improves maternal and neonatal outcomes. However methadone induced neonatal abstinence syndrome (NAS) is common. Buprenorphine-exposed neonates may be at a lower risk of NAS. Currently in the Republic of Ireland, buprenorphine does not have a special licence for use in pregnancy. We describe here the history and neonatal outcomes of the first Irish woman maintained on buprenorphine during two pregnancies.Supervised urinanalysis on this mother between and throughout both pregnancies did not reveal any illicit drug use. She delivered two post-term babies of normal birth weight and length. The second infant required treatment for NAS for 21 days with morphine sulphate. Although the use of buprenorphine in pregnancy does not remove the possibility of NAS, neonatal outcomes of buprenorphine-maintained women compares favourably to methadone. As the use of buprenorphine becomes more established in Ireland, the management of buprenorphine-exposed neonates will become more common.

( BUPP09387 - 26 January 2009) Pegylated interferon alfa-2a (peg-2a) plus ribavirin (rbv) for patients with chronic Hepatitis C virus (HCV) on opioid pharmacotherapy: virological outcomes, psychological impact and safety.

( BUPP09388 - 26 January 2009) High rates of sustained virological response in HCV-infected injection drug users receiving directly observed therapy with peginterferon alfa-2a and once daily ribavirin.

( BUPP09389 - 26 January 2009) Prediction of Drug Clearance by Glucuronidation from in Vitro Data: Use of Combined Cytochrome P450 and UDP-Glucuronosyltransferase Cofactors in Alamethicin-Activated Human Liver Microsomes.

Glucuronidation via UDP-glucuronosyltransferase (UGT) is an increasingly important clearance pathway. In this study intrinsic clearance (CLint) values for buprenorphine, carvedilol, codeine, diclofenac, gemfibrozil, ketoprofen, midazolam, naloxone, raloxifene, and zidovudine were determined in pooled human liver microsomes using the substrate depletion approach. The in vitro clearance data indicated a varying contribution of glucuronidation to the clearance of the compounds studied, ranging from 6 to 79% for midazolam and gemfibrozil, respectively. The CLint was obtained using either individual or combined cofactors for cytochrome P450 (P450) and UGT enzymes with alamethicin activation and in the presence and absence of 2% bovine serum albumin (BSA). In the presence of combined P450 and UGT cofactors, CLint ranged from 2.8 to 688 mu l/min/mg for zidovudine and buprenorphine, respectively; the clearance was approximately equal to the sum of the CLint values obtained in the presence of individual cofactors. The unbound intrinsic clearance (CLint, u) was scaled to provide an in vivo predicted CLint; the data obtained in the presence of combined cofactors resulted in 5-fold underprediction on average. Addition of 2% BSA to the incubation with both P450 and UGT cofactors reduced the bias in the clearance prediction, with 8 of 10 compounds predicted within 2-fold of in vivo values with the exception of raloxifene and gemfibrozil. The current study indicates the applicability of combined cofactor conditions in the assessment of clearance for compounds with a differential contribution of P450 and UGT enzymes to their elimination. In addition, improved predictability of microsomal data is observed in the presence of BSA, in particular for UGT2B7 substrates.

( BUPP09390 - 26 January 2009) Buprenorphine transdermal system in chronic pain due to osteoarthritis.

Objective: Evaluate the safety and efficacy of the Buprenorphine Transdermal System (BTDS) compared to placebo in subjects with chronic pain due to osteoarthritis of the hip/knee. Methods: Randomized, double-blind, placebo-controlled, maintenance-of-analgesia design study consisting of 3 phases: open-label run-in (21 days), double-blind evaluation (28 days), open-label extension (6 months), During the open-label run-in period, subjects were titrated to a dose of BTDS (5mg, 10mg or 20mg) that provided adequate analgesia with acceptable tolerability. The subjects meeting protocol-specified criteria for "adequate analgesia" were randomized to BDTS or placebo in the double-blind phase. The subjects continued taking their pre-study chronic, stable non-opioid analgesics, discontinued all intermittent analgesics, and were provided acetaminophen for breakthrough pain. The primary efficacy parameter was time to development of inadequate analgesia. Pain relief was also assessed with mean daily maximum pain right now' scores over last 7 days of study drug treatment. Results: 326 subjects age 36-76 with OA for 1 year, currently treated with stable doses of non-opioid analgesics or intermittent doses of opioid and non-opioid analgesics were randomized and analyzed for efficacy and safety. Subjects reported moderate to severe pain during the 14 days prior to enrollment. the median time to inadequate analgesia was 7 days in placebo versus 21 days in BTDS-treated subjects (p=0.0026,Cox regression). In total, 66% of placebo and 51% of BTDS-treated subjects met the protoc-specified criteria for inadequate analgesia. Mean daily maximum 'pain right now' scores were lower in BDTS (3.2 +0.14) compared to placebo-treated subjects (3.8 + 0.15; P = 0.0066). Adverse events reported were those typically observed with other opioids, No clinically important changes in labs, ECGs or vitals were noted. Conclusion: BTDS treatment in this study showed greater efficacy than placebo and was generally well tolerated in patients with chronic pain die to OA of the hip/knee.

( BUPP09391 - 03 February 2009) Pharmacokinetics of buprenorphine after single-dose subcutaneous administration in red-eared sliders (Trachemys scripta elegans).

Buprenorphine, a mu opioid receptor agonist, is expected to be a suitable analgesic drug for use in reptiles. However, to date, dosage recommendations have been based on anecdotal observations. The aim of this study was to provide baseline pharmacokinetic data in red-eared sliders (Trachemys scripta elegans) targeting a plasma level of 1 ng /ml reported effective for analgesia in humans. Serial blood samples were taken after subcutaneous injection of buprenorphine, and plasma buprenorphine levels were measured by radioimmunoassay. Pharmacokinetic parameters of a lower dose (0.02 mg/kg) injected into the forelimb were compared with a higher dose (0.05 mg/kg) given in the same forelimb as well as a lower dose (0.02 mg/kg) given in the hind limb of the same animals with 2 wk between studies. After administration of 0.05 mg/kg in the front limb, 85% of animals maintained the minimum effective plasma level for 24 hr, while only 43% of animals maintained this level after 0.02 mg/kg. After hind limb injection at 0.02 mg/kg, maximum plasma concentrations and areas under the buprenorphine concentration-time curve were less than 20% and 70%, respectively, of values after forelimb injection, consistent with substantial first pass extraction by the liver. Furthermore, a secondary rise in the buprenorphine level was found after having only a hind limb injection, probably from enterohepatic recirculation of glucuronidated drug. In conclusion, buprenorphine dosages of at least 0.075 mg/kg s.i.d. should be appropriate for evaluation of analgesia efficacy, and front limb administration may be preferable to hind limb administration for optimal drug exposure.

( BUPP09392 - 03 February 2009) DOTS in drug addicts with TB : Delhi experience.

BACKGROUND: Drug abuse is on the rise. Drug addiction lowers the general immunity of the body. Tuberculosis is known to be one of the major infectious diseases with a high incidence among drug addicts. Treatment of drug addicts suffering from tuberculosis is a challenge to the treating physician. METHODS: An interventional prospective study which involved free de-addiction drugs and motivation along with free anti tubercular drugs under Revised National Tuberculosis Programme was undertaken among drug addicts. Sixty drug addicts suffering from tuberculosis, registered under RNTCP in SPM marg TB Clinic (Pili Kothi) between 2002-2007 and treated under DOTS along with de-addiction treatment by an NGO (Sharan) formed the study sample. OBJECTIVES: Objectives of the study were: a) To study the profile of drug addicts with tuberculosis, b) To assess the success results of DOTS in drug addicts with tuberculosis (along with de-addiction treatment). RESULTS: Extensive counselling for de-addiction and motivation of the study patients along with nutritional food supplements improved the compliance and adherence to treatment with equal success rates as in non-addict tuberculosis patients. The overall success rate in drug addicts was 83.3%. The default rate of 3.3% and failure rate of just 1.7% among study group were also within the permissible range of RNTCP (< 4%). CONCLUSION: DOTS along with supplementary intervention was observed to be quite effective in drug addicts with TB.

( BUPP09393 - 03 February 2009) Integration of viral hepatitis services into opioid treatment programs.

Opioid treatment programs (OTPs) dispense methadone and buprenorphine under specific federal regulations to individuals diagnosed with opioid dependence. OTPs can provide a comprehensive therapeutic milieu, often including primary medical care, psychosocial counseling, vocational rehabilitation, ongoing performance monitoring, and other vital services. Because of the high prevalence of infectious diseases, particularly hepatitis C virus infection, model OTPs are developing comprehensive care and treatment programs that integrate general medical and infectious disease-related medical care with substance abuse and mental health services. Integrating hepatitis care services in the substance abuse treatment settings fosters access to care for patients with multiple comorbidities, many who otherwise would not receive needed care. Improving health related outcomes for this patient population with complex medical problems requires an advanced integrated model of care for OTPs that can be exemplified through establishing resources needed to prevent hepatitis infection as standard of care. Outcomes management becomes possible through enhancing current capability of existing dispensing programs. This may serve as a national model for highly cost-efficient healthcare that has a measurable outcome of improved health.

( BUPP09394 - 03 February 2009) Adverse reactions to drug withdrawal.

Withdrawal from a wide range of drugs may precipitate clinical syndromes in susceptible individuals. We review recent advances in the understanding of the pathophysiology of some of these reactions, the clinical features and consider the available treatment options.

( BUPP09395 - 03 February 2009) Low-dose strong opioid (LDSO) - Treatment of pain in osteoarthritis.

( BUPP09396 - 03 February 2009) Medications, drugs and alcohol in road traffic.

( BUPP09397 - 03 February 2009) "Maintenance" treatment of addiction: To whose credit, and why it matters.

It has been stated that credit for introducing methadone "maintenance" treatment of opiate dependence does not belong to Drs. Vincent Dole and Marie Nyswander, but rather to a Canadian. Dr. Robert Halliday. One writer put it this way: "Halliday began methadone treatment for heroin addiction in Vancouver, British Columbia, in the late 1950s and introduced a methadone maintenance program in 1963" (Bayes, 2007). Can and should he, in fact, be credited with first introducing the concept and practice of "maintenance" treatment of addiction? The answer seems to be "no".

( BUPP09398 - 09 February 2009) Treatment of opioid withdrawal

( BUPP09399 - 09 February 2009) General practitioner views on drug-assisted rehabilitation and the Norwegian substance abuse reform

Due to increased use of injected heroin in Norway the official policy has shifted from an ideal drug-free position to a more realistic harm reduction, where one element is substitution therapy. This implies controlled distribution of opiates, methadone and buprenorfine to selected individuals, combined with close follow-up and social rehabilitation. After the "substance abuse reform" was implemented in 2004, a number of treatment facilities have been included in the ordinary specialist health care system, and the clients who can document their right to <> have obtained ordinary patient rights according to the Patients Rights Act. General practitioners are supposed to follow up these patients, by prescribing opiates to those eligible for substitution therapy, and by participating in local <>. We wanted to investigate how general practitioners' perceive their involvement in substitution therapy, and to see whether this view had changed from 2000 to 2006. MATERIAL AND METHODS: Postal questionnaires were sent to 1606 doctors in 2000 and to 1400 of the same doctors in 2006. Of the 1318 (82 %) who responded in 2000, 227 were general practitioners and 78 were municipal medical officers; of the 966 (69 %) who responded in 2006, 227 were regular general practitioners. 208 of these had also responded in 2000. In 2006 we also asked the doctors about the recent substance abuse reform. RESULTS: 53 % of the general practitioners were in favour of substitution therapy with methadone or buprenorfine; 50 % said they might prescribe the drugs themselves and 77 % were positive towards participating in "responsibility groups". Two thirds felt that transferral of responsibility for patients with substance abuse problems to the specialist health care service, was a necessary and useful reform. The fraction of doctors with a positive attitude towards substitution therapy increased slightly from 2000 to 2006, but individual viewpoints varied largely. INTERPRETATION: Political and cultural rather than medical arguments seem to dominate doctors' views on these issues.

( BUPP09400 - 09 February 2009) Tolerance to the antinociceptive effects of peripherally administered opioids. Expression of beta-arrestins

Tolerance to peripheral antinociception after chronic exposure to systemic morphine was assessed in mice with chronic CFA-inflammation; cross-tolerance to locally administered mu, delta and kappa-opioid agonists and levels of beta-arrestins in the injured paw, were also evaluated. Tolerance was induced by the subcutaneous implantation of a 75 mg morphine-pellet, and antinociception evaluated with the Randall-Selitto test, 5 min after the subplantar injection of morphine, fentanyl, buprenorphine, DPDPE, U-50488H or CRF. Experiments were performed in the absence and presence of CFA-inflammation, in animals implanted with a morphine or placebo pellet. Beta-arrestin protein levels were determined by western blot. In mice without inflammation, subplantar opioids did not induce antinociception, while during CFA-inflammation, all drugs generated dose-response curves with an order of potency of: U-50488H < DPDPE < morphine < buprenorphine < fentanyl << CRF. During CFA-inflammation plus morphine-pellet, the potency of fentanyl decreased 1.25 times, while that of DPDPE, U-50488H and CRF diminished approximately 2.5-4.3 times. For each drug, the ratio between the ED(50)'s in tolerant and naive animals, was significantly higher than 1 (except for buprenorphine and fentanyl), demonstrating partial cross-tolerance to systemic morphine. Inflammation induced a twofold increase in beta-arrestin expression (p<0.01), and the levels decreased after acute morphine exposure (p<0.05). Tolerance did not alter beta-arrestins, but partially prevented the increase induced by inflammation. The results suggest that peripheral beta-arrestins could facilitate peripheral OR-desensitization and tolerance development. Clinically, the experiments could be useful to establish the effectiveness of local opioid administration in patients with musculoskeletal pain, chronically receiving morphine analgesia.

( BUPP09401 - 09 February 2009) Impact of a prescription monitoring program on doctor-shopping for high dosage buprenorphine

Doctor-shopping (simultaneous use of several physicians by a patient) is one of the most frequent ways of diversion for prescription drugs. A specific method was used to assess the evolution of doctor-shopping for High Dosage Buprenorphine (HDB) in a French region from 2000 to 2005 and the impact of a prescription monitoring program for HDB implemented in 2004. METHODS: Data from eight periods (semesters of years 2000, 2002, 2004, and 2005) were extracted from a prescription database. Three quantities (the delivered, the prescribed, and the doctor-shopping quantity) were computed for each patient. The total doctor-shopping quantity and the doctor-shopping ratio (percentage of buprenorphine obtained through doctor-shopping) were used to evaluate the diversion of HDB among the population. The total prescribed quantity and the number of patients treated regularly were used as indicators of the access to treatment. RESULTS: The doctor-shopping ratio increased from 1st semester 2000 to 1st semester 2004 (from 14.9 to 21.7%) and then decreased to 16.9% in 2nd semester 2005. The total doctor-shopping quantity followed the same evolution. The number of patients treated remained stable from 1st semester 2000 to 2nd semester 2005. The prescribed quantity increased from 1st semester 2000 to 2nd semester 2002, decreased in 1st semester 2004 (4163 g) and then remained stable. CONCLUSIONS: After a four-year increase of the diversion through doctor-shopping for buprenorphine the beginning of the prescription monitoring program was concomitant with a marked decrease of doctor-shopping indicators without notable impact on the access to treatment.

( BUPP09402 - 09 February 2009) Methicillin-Susceptible Staphyloccocus aureus (MSSA) Bacteremias in Intravenous Buprenorphine Abusers: An Emerging Pathogen in Highly Regulated Singapore

Buprenorphine was licensed in Singapore in 2002 for treatment of opiate addiction. MSSA bacteremia has occurred in intravenous drug addicts (IVDAs) in Singapore who crush and inject buprenorphine intended for sublingual use. We attempted to quantify this phenomenon in our 900 bed teaching hospital. Method: All cases of community acquired MSSA bacteremias in 2005 were retrospectively reviewed to identity patients who abused buprenorphine. Overall hospitalizations for substance abuse at our hospital based on International Classification of Disease-9 (ICD-9) coding of discharge diagnoses was accessed. Results: 12/99 (12.1%) of our community based MSSA bacteremias were patients using iv buprenorphine. They were young (32.9 + 8.8years) and 11/12 males. 11 patients had endocarditis, 9 had septic pulmonary emboli. 6 had musculoskeletal complications (pyomyositis, epidural abscess, septic arthritis). 4 deaths (33%) ensued. Since 2002 there is a rise in substance abuse hospitalizations (Fig 1). this is reasonably explained by this spate of buprenorphine misuse cases. Discussions: Though therapy of opiate dependence is critical, unsupervised use of buprenorphine can be associated with considerable infections complications. Hence the need for strict control measures including supervised dispensing of buprenorphine and meticulous post marketing surveillance.

( BUPP09403 - 09 February 2009) Novel medications to treat addictive disorders

Recent discoveries about the effects of drugs of abuse on the brain and the mechanisms of their addictions; new chemical compounds, including immunotherapies; and new actions of available medications are offering many opportunities for the discovery and development of novel medications to treat addictive disorders. Furthermore, advancements in the understanding of the genetic and epigenetic basis of drug addiction and the pharmacogenetics of the safety and/or efficacy of the medications are providing opportunities for more individualized pharmacotherapy approaches. Although multiple medications have been investigated for treating addictions, only a handful have shown acceptable safety and efficacy and are approved by the US Food and Drug Administration. This article reviews the current medications that are medically safe and have shown promising results for treating opioid, cocaine, methamphetamine, and cannabis addictions.

( BUPP09404 - 09 February 2009) A French prospective observational study of the treatment of chronic hepatitis C in drug abusers: A commentary.

( BUPP09405 - 09 February 2009) Potential use of dopamine partial agonists in cocaine addiction

( BUPP09424 - 16 February 2009) Buprenorphine tapering schedule and illicit opioid use

To compare the effects of a short or long taper schedule after buprenorphine stabilization on participant outcomes as measured by opioid-free urine tests at the end of each taper period.This multi-site study sponsored by Clinical Trials Network (CTN, a branch of the US National Institute on Drug Abuse) was conducted from 2003 to 2005 to compare two taper conditions (7 days and 28 days). Data were collected at weekly clinic visits to the end of the taper periods, and at 1-month and 3-month post-taper follow-up visits.Eleven out-patient treatment programs in 10 US cities.Non-blinded dosing with Suboxone (R) during the 1-month stabilization phase included 3 weeks of flexible dosing as determined appropriate by the study physicians. A fixed dose was required for the final week before beginning the taper phase.The percentage of participants in each taper group providing urine samples free of illicit opioids at the end of the taper and at follow-up.At the end of the taper, 44% of the 7-day taper group (n = 255) provided opioid-free urine specimens compared to 30% of the 28-day taper group (n = 261; P = 0.0007). There were no differences at the 1-month and 3-month follow-ups (7-day = 18% and 12%; 28-day = 18% and 13%, 1 month and 3 months, respectively).For individuals terminating buprenorphine pharmacotherapy for opioid dependence, there appears to be no advantage in prolonging the duration of taper.

( BUPP09423 - 16 February 2009) Comparison of Side Effects between Buprenorphine and Meloxicam Used Postoperatively in Dutch Belted Rabbits (Oryctolagus cuniculus)

( BUPP09422 - 16 February 2009) Model for Clinical Evaluation of Perioperative Analgesia in the Rabbit

( BUPP09421 - 16 February 2009) Castration Eliminates Conspecific Aggression in Group-housed Male Surveillance Mice

( BUPP09419 - 16 February 2009) Evaluation of Perioperative Analgesia on Behavioral Tests in the Chronic Constriction Injury Neuropathic Pain Model

( BUPP09418 - 16 February 2009) In Vitro Skin Permeation of Buprenorphine Transdermal Patch.

This study was aimed to develop the new transdermal formulation to improve the permeability of buprenorphine. The apparent partition coefficients of buprenorphine were measured using the buffers at pH 1.2 to 10.0 as aqueous phase. The solubility of buprenorphine was 12.97 mu g/mL in the 0.1 M phosphate buffer at pH 6.8. The influences of vehicles at different pH, adhesives, and permeation enhancers on the penetration of buprenorphine through nude mouse skin were investigated using the static Franz diffusion cells. The permeation parameter J(ss) of buprenorphine increased along with the reduction of the pH of receptor fluid, and the vehicle at pH 6.8 was used in the following skin permeation studies. The pressure sensitive adhesives (PSA) including polyisobutylene (PIB), polystyrene-block- polyisoprene-block-polystyrene (SIS), and acrylic adhesives were evaluated. The permeability of buprenorphine was higher in the PIB or SIS adhesives than that in the acrylic adhesives under the condition without enhancer. When combined the enhancers with propylene glycol (PG) to improve the penetration of buprenorphine, the permeation- enhancing effects of enhancers were in the following order: lauric acid > linolenic acid > menthol > oleic acid > N-methyl-2-pyrrolidone (NMP) > laurocapram > glabridin. Finally, a matrix-type transdermal delivery system for buprenorphine was formulated using acrylic adhesive, PG, and lauric acid. The J(ss) parameter was 2.68 +/- 0.20 mu g/cm(2)/h and buprenorphine permeated across the nude mouse skin was 31.68%.

( BUPP09417 - 16 February 2009) The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders?

( BUPP09415 - 16 February 2009) Mucositis in the treatment of haematological malignancies.

Mucositis in the treatment of hematological malignancies is reviewed. Topics discussed include epidemiology, pathobiology, clinical features and diagnostic tools, and therapeutic approach. Mucosal response to cytotoxic insults appears to be controlled by both global factors and tissue-specific factors. Interactions between these elements, coupled with underlying genetic influences, most likely govern the risk, course, and severity of regimen-related mucosal injury. Thus far, there is no predictive model of the risk of mucositis, at the beginning of therapy. However, by exploiting molecular diagnostic methods, pharmacogenomics will eventually allow routine determination of a patient's genotype, enabling the physician to tailor the drug and dosage to every patient.

( BUPP09414 - 16 February 2009) The clinical content of preconception care: alcohol, tobacco, and illicit drug exposures.

Substance abuse poses significant health risks to childbearing-aged women in the United States and, for those who become pregnant, to their children. Alcohol is the most prevalent substance consumed by childbearing-aged women, followed by tobacco, and a variety of illicit drugs. Substance use in the preconception period predicts substance use during the prenatal period. Evidence-based methods for screening and intervening on harmful consumption patterns of these substances have been developed and are recommended for use in primary care settings for women who are pregnant, planning a pregnancy, or at risk for becoming pregnant. This report describes the scope of substance abuse in the target population and provides recommendations from the Clinical Working Group of the Select Panel on Preconception Care, Centers for Disease Control and Prevention, for addressing alcohol, tobacco, and illicit drug use among childbearing-aged women.

( BUPP09413 - 16 February 2009) Introduction to a Symposium on Recent Advances in the Development of Medications for Drug Abuse Treatment in Honor of Jack H. Mendelson, MD.

( BUPP09411 - 16 February 2009) Treating drug abuse and addiction in the criminal justice system: Improving public health and safety.

Despite increasing evidence that addiction is a treatable disease of the brain, most individuals do not receive treatment. Involvement in the criminal justice system often results from illegal drug-seeking behavior and participation in illegal activities that reflect, in part, disrupted behavior ensuing from brain changes triggered by repeated drug use. Treating drug-involved offenders provides a unique opportunity to decrease substance abuse and reduce associated criminal behavior. Emerging neuroscience has the potential to transform traditional sanction-oriented public safety approaches by providing new therapeutic strategies against addiction that could be used in the criminal justice system. We summarize relevant neuroscientific findings and evidence-based principles of addiction treatment that, if implemented in the criminal justice system, could help improve public heath and reduce criminal behavior.

( BUPP09410 - 16 February 2009) Delayed-onset neutropenia associated with divalproex sodium; Acute psychosis induced by clarithromycin; Acute phase reaction with ibandronate; Duloxetine-associated tachycardia; Hepatotoxicity with valerian; Serotonin syndrome with a single dose of buprenorphine /naloxone.

Publisher: Facts and Comparisons, 111 W. Port Plaza, Ste. 300, St. Louis, MO 6314603098.

( BUPP09409 - 16 February 2009) Short- and intermediate-term efficacy of buprenorphine TDS in chronic painful neuropathies: Research report.

Buprenorphine is a potent opioid available as a transdermal delivery system (TDS) formulation. This open-label study investigated its safety, tolerability, and efficacy in 30 patients with chronic painful neuropathy. Subjects with visual analogue scale (VAS) score 5 under stable analgesic treatment were entered. The starting dosage of 35 mug/h was increased up to 70.0 mug/h in case of unsatisfactory pain control as assessed by fortnightly visits. The primary endpoint was the number of patients achieving at least 30% pain relief at day 42 visit. Treatment was safe over the study period. Nine patients dropped out for side effects, mostly nausea and daily sleepiness. Buprenorphine TDS was well tolerated in 21 patients. Thirteen patients achieved >30% of pain relief at day 42 visit. Five patients needed to increase the dosage to 52.5 mug/h. Eight patients did not meet the primary outcome, but none allowed increasing the dosage to 70 mug/h, and four patients withdrew consent to continue the study before day 42 visit because of a 'fear to become addicted,' although 40% had obtained VAS reduction. In our study, which needs to be confirmed by a controlled trial, buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third-line treatment.

( BUPP09408 - 16 February 2009) Inhibition of inducible nitric oxide synthase reduces an acute peripheral motor neuropathy produced by dermal burn injury in mice: Research report.

The systemic inflammatory response produced by a full-thickness dermal burn injury is associated with a peripheral motor neuropathy. We previously reported that a 20% body surface area (BSA) full-thickness dermal burn in C57BL6 mice produced structural and functional deficits in motor axons at a distance from the burn site. The etiology of the neuropathy, however, is not well characterized. Burn injury leads to an increase in production of a number of proinflammatory mediators, including nitric oxide (NO). We tested the hypothesis that dermal burn-induced motor neuropathy is mediated by increased production of NO. NO synthase (NOS) activity was inhibited following a 20% BSA full-thickness burn by injection of non-specific NOS inhibitor, nitro-l-arginine methyl ester or inducible NOS (iNOS) inhibitors, l-N6-(1-iminoethyl) lysine, and aminoguanidine. NOS inhibitors also prevented the reduction in ventral roots mean axon caliber and the decrease in a motor nerve conduction velocity (MCV) following burn. iNOS knockout mice prevented MCV decrease in the first 3 days post-burn, but iNOS knockout MCV was significantly reduced at 7-14 days post-burn. These results suggest that an increase in NO production generated by systemic inflammatory response pathways after burn injury contributes to the development of structural and functional deficits in peripheral motor axons.

( BUPP09407 - 16 February 2009) Substance-related problems and treatment among men who have sex with men in comparison to other men in Chicago.

This study compares a sample of urban men who have sex with men (MSM) with a general population sample of men in the same city on self-reported problems with substance use indicative of dependence and history of substance use treatment. Both samples were randomly selected using multistage probability methods. All participants completed audio computer-assisted self-interviews, including questions on substance use, problems related to substance use experienced in the past 12 months, and substance treatment. Problem use of alcohol, marijuana, and cocaine did not differ between samples. Compared to men in the general population sample, MSM were significantly more likely to experience problems related to the use of sedatives, tranquilizers, or prescription pain relievers. Among MSM, history of substance treatment was associated with a positive HIV test, and treatment usually preceded HIV diagnosis. Research is needed on effective methods for integrating HIV prevention for MSM into substance treatment settings, including physician-administered buprenorphine treatment for opiate addiction.

( BUPP09420 - 16 February 2009) Effect of Buprenorphine Analgesia on Growth in Neonatal Mice

( BUPP09416 - 16 February 2009) (<< Puffy hands >> syndrome)

( BUPP09412 - 16 February 2009) Reinforcing Effects of Stimulants in Humans: Sensitivity of Progressive-Ratio Schedules.

Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of schedules of reinforcement, including progressive-ratio schedules. As the name implies, in a progressive-ratio schedule, the response requirement for each subsequent delivery of drug increases, and the primary outcome variable is often the break point (i.e., the last ratio completed to receive a drug delivery). These schedules have been used in a number of human laboratory studies evaluating the reinforcing effects of stimulants. The results of these studies have demonstrated that progressive-ratio schedules are sensitive to manipulation of a pharmacological variable, dose, and to nonpharmacological variables contributing to stimulant drug effects. In addition, findings with progressive-ratio schedules are largely concordant with clinical findings, suggesting that drug self-administration under these schedules has predictive validity in terms of drug abuse and dependence. Future research is necessary, however, to understand better how pharmacological factors like route of administration, onset of effects, and pretreatment influence the reinforcing effects of stimulants under progressive-ratio schedules.

( BUPP09406 - 16 February 2009) Home buprenorphine/naloxone induction in primary care

Buprenorphine can be used for the treatment of opioid dependence in primary care settings. National guidelines recommend directly observed initial dosing followed by multiple in-clinic visits during the induction week. We offered buprenorphine treatment at a public hospital primary care clinic using a home, unobserved induction protocol. Participants were opioid-dependent adults eligible for office-based buprenorphine treatment. The initial physician visit included assessment, education, induction telephone support instructions, an illustrated home induction pamphlet, and a 1-week buprenorphine/naloxone prescription. Patients initiated dosing off-site at a later time. Follow-up with urine toxicology testing occurred at day 7 and thereafter at varying intervals. Primary outcomes were treatment status at week 1 and induction-related events: severe precipitated withdrawal, other buprenorphine-prompted withdrawal symptoms, prolonged unrelieved withdrawal, and serious adverse events (SAEs). Patients (N = 103) were predominantly heroin users (68%), but also prescription opioid misusers (18%) and methadone maintenance patients (14%). At the end of week 1, 73% were retained, 17% provided induction data but did not return to the clinic, and 11% were lost to follow-up with no induction data available. No cases of severe precipitated withdrawal and no SAEs were observed. Five cases (5%) of mild-to-moderate buprenorphine-prompted withdrawal and eight cases of prolonged unrelieved withdrawal symptoms (8% overall, 21% of methadone-to-buprenorphine inductions) were reported. Buprenorphine-prompted withdrawal and prolonged unrelieved withdrawal symptoms were not associated with treatment status at week 1. Home buprenorphine induction was feasible and appeared safe. Induction complications occurred at expected rates and were not associated with short-term treatment drop-out.

( BUPP09367 - 15 January 2009) Cost analysis of clinic and office-basaed treatment of opioid dependence: Results with methadone and buprenorphine in clinically stable patients.

The cost of providing and receiving treatment for opioid dependence can determine its adoption. To compare the cost of clinic-based methadone (MC, n=23), office-based methadone (MO, n=21), and office-based buprenorphine (BO, n=34) we performed an analysis of treatment and patient costs over 6 months of maintenance in patients who had previously been stabilized for at least 1 year. We performed statistical comparisons using ANOVA and chi-square tests and performed a sensitivity analysis varying cost estimates and intensity of clinical contact. The cost of providing 1 month of treatment per patient was $147 (MC), $220 (MO) and $336 (BO) (p<0.001). Mean monthly medication cost was $93 (MC), $86 (MO) and $257 (BO) (p<0.001). The cost to patients was $92 (MC), $63 (MO) and $38 (BO) (p=0.102). Sensitivity analyses, varying cost estimates and clinical contact, result in total monthly costs of $117 to $183 (MC), $149 to $279 (MO), $292 to $499 (BO). Monthly patient costs were $84 to $133 (MC), $55 to $105 (MO) and $34 to $65 (BO). We conclude that providing clinic-based methadone is least expensive. The piece of buprenorphine accounts for a major portion of the difference in costs. For patients, office-based treatment may be less expensive.

( BUPP09368 - 15 January 2009) Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence.

This article was received in December 06, but has been revised in June 2008. Few studies in community settings have evaluated predictors, meditators, and moderators of treatment success for medically supervised opioid withdrawal treatment. This report presents new findings about these factors from a study of 344 opioid-dependent men and women prospectively randomized to either buprenorphine-naloxone or clonidine in an open-label 13 day medically supervised withdrawal study. Subjects were either in-patient or outpatient in community treatment settings; however not randomized by treatment setting. Medication type (buprenorphine-naloxone versus clonidine) was the single best predictor of treatment retention and treatment success, regardless of treatment setting. Compared to the outpatient setting, the in-patient setting was associated with higher abstinence but similar retention rates when adjusting for medication type. Early opioid withdrawal severity medicated the relationship between medication type and treatment outcome with buprenorphine-naloxone being superior to clondine at relieving early withdrawal symptoms. In-patient subjects on clonidine with lower withdrawal scores at baseline than those with lower withdrawal scores. No relationship was found between treatment outcome and age, gender, race, education, employment, marital status, legal problems, baseline depression, or length/severity of drug use. Tobacco use was associated with worse opioid treatment outcomes. Severe baseline anxiety symptoms doubled treatment success. Medication type (buprenorphine-naloxone) was the most important predictor of positive outcome; however the paper also considers other clinical and policy implications of other results, including that in-patient setting predicted better outcomes and moderate medication outcomes.

( BUPP09369 - 16 January 2009) Buprenorphine and methadone maintenance in jail and post-release: A randomized clinical trial.

Buprenorphine has rarely been administered as an opioid agonist maintenance therapy in a correctional setting. This study introduced buprenorphine maintenance in a large urban jail, Rikers Island in New York City. Heroin-dependent men not enrolled in community methadone treatment and sentenced to 10-90 days in jail (N=116) were voluntarily randomly assigned either to buprenorphine or methadone maintenance, the latter being the standard of care for eligible inmates at Rikers. Buprenorphine and methadone maintenance completion rates in jail were equally high, but the buprenorphine group reported for their designated post-release treatment in the community significantly more often than did the methadone group (48% vs. 14%, p<0.001). Consistent with this result, prior to release from Rikers, buprenorphine patients stated an intention to continue treatment after release more often than did methadone patients (93% vs.44%, p<.001). Buprenorphine patients were also less likely than methadone patients to withdraw voluntarily from medication while in jail (3% vs. 16%, p<.05). There were no post-release differences between the buprenorphine and methadone groups in self-reported relapse to illicit opioid use, self-reported re-arrests, self-reported severity of crime to re-incarceration in jail. After initiating opioid agonist treatment in jail, continuing buprenorphine maintenance in the community appears to be more acceptable to offenders than continuing methadone maintenance in the community appears to be more acceptable to offenders than continuing methadone maintenance.

( BUPP09370 - 16 January 2009) Benzodiazepine use among opiate-dependent subjects in buprenorphine maintenance treatment: Correlates of use, abuse and dependence.

Background: Previous studies from North America, Europe and Australia have reported high levels of benzodiazepine use among opiate-dependent patients in opiate maintenance treatment. However, to date, there are no available data on patterns of abuse and dependence on benzodiazepines according to DSM criteria among these patients. Aims: To describe the independent correlates of use, abuse and dependence on benzodiazepines among buprenorphine patients selected from standard treatment settings. Methods: Cross-sectional study in France between June 2001 and June 2004. buprenorphine patients treated for over 3 months were recruited via physicians prescribing buprenorphine. Patients answered a self-administered questionnaire, the DSM-IV criteria for benzodiazepine abuse and dependence, the Beck Anxiety and Depression Inventories (BAI, BDI and the Nottingham Health Profile (NHP). Main outcome was modalities of benzodiazepine use: no use vs. simple use vs. problematic use (Abuse or dependence according to (DSM-IV). Results: 170 patients were recruited. 54% did not use benzodiazepines the previous month, 15% were simple users and 31% were problematic users. Benzodiazepine use (all modalities) were associated with poly-use of psychotropics. Simple users of Benzodiazepines were not statistically different from non-users for the other factors explored. Problematic users of benzodiazepines had higher depression and anxiety levels, correlated with quality of life impairment and precariousness. They used higher dosages of benzodiazepines than simple users. Conclusions: Characteristics of simple benzodiazepine users were distinct from problematic users but not from non-users in this sample of buprenorphine patients. This should be taken into account in the clinical management of benzodiazepine use among buprenorphine patients=

( BUPP09371 - 19 January 2009) Maintenance of anaesthesia in sheep with isoflurane, desflurane or sevoflurane.

Rapid recovery from anaesthesia is advantageous in small ruminants, to reduce the risk of regurgitation. Theoretically, the least soluble inhalation agents should result in the fastest recoveries, but using additional injectable agents may negate this advantage. This study compared three inhalation agents for the maintenance of anaesthesia in sheep. Eighteen ewes that were to undergo orthopaedic surgery were allocated to one of three groups. Each group was premedicated with xylazine (0.1 mg/kg intramuscularly), anaesthesia was induced using ketamine (2 mg/kg) and midazolam (0.03 mg/kg) intravenously and analgesia provided by buprenorphine (0.008 mg/kg intramuscularly). Anaesthesia was then maintained with either isoflurane, sevoflurane or desflurane. Cardiopulmonary parameters were monitored throughout. All three inhalation agents provided adequate stable anaesthesia and there was no significant difference between the groups in their cardiopulmonary parameters or their recovery times. The mead (sd) postanaesthetic times to first swallow, first chewing attempts and ability to maintain their head lifted for five minutes were, respectively, 3.95 (2.53), 6.37 (3.68) and 32.8 (18.1) minutes for isoflurane, 3.62 (0.98), 7.66 (0.78) and 38.8 (16.6) minutes for sevoflurane, and 4.37 (1.65), 6.95 (1.52) and 29.8 (11.5) minutes for desflurane. Two sheep had poor quality recoveries after the use of sevoflurane, but all the other sheep recovered uneventfully. All three inhalation agents were suitable for the maintenance of anaesthesia in sheep but, as used in this study, there were no differences between them in speed of recovery.

( BUPP09372 - 19 January 2009) Clinical trial: a primary-care-based model for the delivery of anti-viral treatment to injecting drug users infected with hepatitis C.

Background Injecting drug use is the main risk factor for hepatitis C virus (HCV) infection. Secondary-care-based strategies for the management of HCV do not effectively target this vulnerable population.Aims To evaluate the feasibility, safety and efficacy of a primary-care-based model for the delivery of HCV services including anti-viral therapy to injecting drug users. Methods A partnership between a clinical nurse specialist employed by, and working under the supervision of, a secondary-care-based hepatitis service and drug workers and general practitioners. Three hundred and fifty-three clients attending opiate substitution clinics in primary care were evaluated. Outcomes were: number of new diagnoses of HCV infection, number of clients assessed as suitable for anti-viral treatment, and number of patients treated. Results 174 HCV antibody positive clients were identified. Of these, 124 were chronically infected with HCV of whom only six had been previously identified. Of 118 new chronically-infected individuals, 86 entered the care pathway, 43 were assessed as suitable for anti-viral treatment and 30 have so far been treated. Outcomes of anti-viral treatment are comparable with those obtained in secondary care settings.Conclusion A primary-care-based model offers a new paradigm for the treatment of HCV in injecting drug users.

( BUPP09373 - 19 January 2009) Preparation and characteristics of anti-buprenorphine monoclonal antibodies.

Objective: To prepare anti-buprenorphine monoclonal antibodies through hybridoma cell line technique, and identify their immunological characteristics. Methods: After introduced an active carboxyl group, the hapten buprenorphine was linked to the blue blood (KLH) and bovine serum albumin (BSA) through condensation reaction to form a complete antigen. Immunized the Balb/c mice with the complete antigen, the hybridoma cell line which could secrete anti-buprenorphine monoclonal antibodies was acquired via cell fusion and screening. Then, the anti-buprenorphine monoclonal antibody was produced by intraperitoneal injection with the hybridoma cell. After purified with octoic acid-ammonium sulfate and affinity chromatography, the anti-buprenorphine monoclonal antibody was tested for the affinity and specificity by ELISA and Gold colloid immunochromatographic method. Results: A total of three cell lines, named as 7E6, 6G4 and 3C2 respectively, were finally obtained. For 7E6 and 6G4, the sensitivity for detecting buprenorphine was 10. 0 ng/ml, and 3C2 was 20.0 ng/ml. The affinity constants of 7E6, 6G4 and 3C2 antibodies were 3.6 � 10 /sup -9/ mol/L, 4.3 � 10 /sup -9/ mol/L and 6.3 � 10 /sup -9/ mol/L respectively. Except for 3C2 antibody with morphine, no any more cross reaction was observed for these antibodies with 40 control substances. Conclusion: The anti-buprenorphine monoclonal antibodies produced by hybridoma cell lines 7E6 and 6G4 are of high sensitivity and specificity.

( BUPP09374 - 19 January 2009) Substance-abuse related emergencies - Illegal drugs, part I.

( BUPP09375 - 19 January 2009) Cancer patients and pain control - Current aspects of diagnosis and therapy.

n 1986 the World Health Organization (WHO) developed a three-step analgesic ladder, according to which the pain of about 80-90% cancer patients could be treated sufficiently. Up to today, this analgesic stepladder is seen as a guide for initiating analgesic drugs and dosages that correspond to the patient's reported level of pain. The ladder starts with non-opioid oral drugs for mild pain and progresses to strong opioids, adjuvants and invasive therapies for severe and/or intractable pain. However, treatment by the ladder must not be started with step I in patients with moderate or severe pain. Even though oral morphine remains the reference drug, various new opioids, formulations of opioids (immediate and slow-release), and a greater variety of application modes have broadened the range of options in modern cancer pain therapy. Pain, i.e. chronic, acute and breakthrough pain, is said to be one of the most feared and distressing symptoms of cancer and one that disrupts all aspects of life. Therefore, good quality of cancer pain treatment is of utmost importance and includes the necessity of both, basic knowledge and regular updates.

( BUPP09376 - 19 January 2009) Age-dependent relationship between bispectral index and sedation level.

Study Objective: To determine the relationship between bispectral index (BIS) and sedation. Design: Prospective, observational clinical study. Setting: Intensive care unit of a public hospital in Japan. Patients: 22 ASA physical status I, II, and III middle-aged (18-65 yrs) and elderly (>65 yrs) patients receiving postoperative sedation with midazolam. Interventions: Patients were allocated to two groups: Group M was composed of middle-aged patients (<65 yrs) and Group H elderly patients (>65 yrs). Midazolam was administered at a bolus dose of 0.1 mg/kg, followed by a continuous dose of 0.04 mg/kg per hour, which was adjusted every two hours to achieve a target level of sedation at 3-6 on the Ramsay Sedation Scale (RSS); buprenorphine was administered at a constant rate (0.625 mug kg /sup -1/ hr /sup -1/ ). Measurements: BIS value, RSS, midazolam dose, body temperature (BT), heart rate, dopamine dose, and mean arterial pressure were recorded every two hours by an independent nurse. Data were analyzed using Spearman rank correlation and the Mann-Whitney U test. Main Results: BIS values decreased depending on depth of sedation; a significant correlation was noted between groups in RSS and BIS. The BIS values at levels of RSS 5 and 6 were significantly lower in Group H than Group M. Conclusion: BIS correlated with sedation depth, with BIS scores in group H than group M at a deep sedation depth.

( BUPP09377 - 19 January 2009) Mouse and rat anesthesia and analgesia.

Many animal models used in neuroscience research must be surgically created and/or anesthetized for imaging studies. The purpose of this unit is to review the advantages and disadvantages of various anesthetic and analgesic agents in rodents; to discuss state-of-the-art methods for monitoring anesthesia; and to provide tips for troubleshooting problems with anesthesia.

( BUPP09378 - 19 January 2009) Chapter 8 Noninvasive Imaging of Blood Vessels.

ngiogenesis is a key component in several major clinical conditions including cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis. All these diseases could be managed much more effectively if their angiogenic capacities were somehow curtailed. Hence there is great interest in developing a fuller understanding of angiogenesis and designing agents to suppress, guide, and normalize this process. Although much has been learned from in vitro methods, the perspective is limited because angiogenesis depends on active blood flow and a variety of circulating precursor cells provided by the intact host. Therefore, noninvasive in vivo methods that provide information over days and weeks are needed. Accordingly, the rodent dorsal skinfold tissue window chamber facilitates the imaging of new vessels around implanted cells, around an injury, or around a simple device impregnated with growth factors. Tissue oxygen levels can be measured during the course of angiogenesis using a window chamber that is also fitted with a miniature multiple electrode sensor. The present review describes window chamber methods and hardware, the measurement of oxygen, and the introduction into the chamber of tumors, growth factors, and organs to induce angiogenesis. The application of multiphoton microscopy to intravital imaging is discussed, along with a description of how to modify a standard brightfield or fluorescence microscope for multiphoton imaging of window chamber microvessels

( BUPP09379 - 19 January 2009) Alcohol and opioid dependence medications: Prescription trends, overall and by physician specialty.

Over the past decade, advances in addiction neurobiology have led to the approval of new medications to treat alcohol and opioid dependence. This study examined data from the IMS National Prescription Audit (NPA) Plus TM database of retail pharmacy transactions to evaluate trends in U.S. retail sales and prescriptions of FDA-approved medications to treat substance use disorders. Data reveal that prescriptions for alcoholism medications grew from 393,000 in 2003 ($30 million in sales) to an estimated 720,000 ($78 million in sales) in 2007. The growth was largely driven by the introduction of acamprosate in 2005, which soon became the market leader ($35 million in sales). Prescriptions for the two buprenorphine formulations increased from 48,000 prescriptions ($5 million in sales) in the year of their introduction (2003) to 1.9 million prescriptions ($327 million in sales) in 2007. While acamprosate and buprenorphine grew rapidly after market entry, overall substance abuse retail medication sales remain small relative to the size of the population that could benefit from treatment and relative to sales for other medications, such as antidepressants. The extent to which substance dependence medications will be adopted by physicians and patients, and marketed by industry, remains uncertain.

( BUPP09435 - 23 February 2009) Methadone capsules: A long-awaited formulation

( BUPP09434 - 23 February 2009) Buprenorphine and pregnancy

The authors concluded that buprenorphine is an acceptable alternative for the treatment of opiate dependence in pregnant women, despite an apparent increase in the risk of threatened preterm delivery.

( BUPP09433 - 23 February 2009) Transplantation of pancreatic islets into the kidney capsule of diabetic mice

Our protocol was developed to cleanly and easily deliver islets or cells under the kidney capsule of diabetic or normal mice. We found that it was easier to concentrate the islets or cells into pellets in the final delivery tubing (PE50) used to transplant the cells under the kidney capsule. This technique provides both speed and ease while reducing any undue stress to the cells or to the mouse. LOADING: Settled, hand picked, islets or pelleted cells are carefully aspirated off the bottom of a 1.5 mL microcentrifuge tube using a p200 pipetteman and a straight, thin-wall pipette tip. A length of PE50 tubing is attached to the pipette tip using a small silicone adapter tubing. Cells are allowed to settle, in the tip, and then are transferred to the PE50 tubing by slowly dialing the pipetteman. Once the cells are near the end of the PE50 tubing, a kink is made and the silicone adaptor tubing is placed over the kink. The PE50 tubing is transferred to a 15 mL conical containing a cut 5 mL pipet, and the PE50 tubing is taped over the side of the 5 mL pipet to prevent curling during centrifuging. Cells are allowed to reach 1,000 rpm and stopped. TRANSPLANTATION: Recipient mice are anesthetized, shaved, and cleaned. A small incision is made on the left flank of the mouse and the kidney is exposed. The kidney, fat, and tissue are kept moist with normal saline swab. The distal end of the PE50 is attached to a Hamilton screw drive syringe, containing a pipette tip, using the silicone adaptor tubing. A small nick is made on the right flank side of the kidney, not too large nor too deep. The beveled end of the PE50 tubing, nearest the cells, is carefully placed under the capsule, the tubing is moved around gently to make space while swabbing normal saline; a dry capsule can tear easily. A small air bubble is delivered under the capsule by slowly dialing the syringe screw drive. Islets are then slowly delivered behind the air bubble. Once the islets have been delivered kidney homeostasis is maintained and the knick is cauterized with low heat. The kidney is placed back into the cavity and the peritoneum and skin are sutured and stapled. Mice are immediately treated with Flunixin and Buprenorphine s.q. and placed in a cage on a heating pad.

( BUPP09432 - 23 February 2009) Injectable methadone, methadone and naltrexone, or buprenorphine and naltrexone microparticle compositions and their use in reducing consumption of abused substances.

An injectable slow-release methadone, partial opioid agonist or opioid antagonist formulation is provided comprising methadone, a partial opioid agonist or opioid antagonist in a poly(D, L-lactide) excipient with a small amount of residual ethyl acetate. Upon intramuscular or subcutaneous injection of the composition, methadone, a partial opioid agonist or opioid antagonist is released in a controlled manner over an extended period of time. The composition finds use in the treatment of heroin addicts and alcoholics to reduce consumption of the abused substances. Of particular interest are the drugs buprenorphine, methadone and naltrexone.

( BUPP09431 - 23 February 2009) A meta-analysis of chinese herbal medicine in treatment of managed withdrawal from heroin

Chinese herbal medicine has shown promise for heroin detoxification. This review extends a prior meta-analysis of Chinese herbal medicine for heroin detoxification, with particular attention to the time course of symptoms. Both English and Chinese databases were searched for randomized trials comparing Chinese herbal medicine to either alpha2-adrenergic agonists or opioid agonists for heroin detoxification. The methodological quality of each study was assessed with Jadad's scale (1-2 = low; 3-5 = high). Meta-analysis was performed with fixed- or random-effect models in RevMan software; outcome measures assessed were withdrawal-symptoms score, anxiety, and adverse effects of treatment. Twenty-one studies (2,949 participants) were included. For withdrawal-symptoms score relieving during the 10-day observation, Chinese herbal medicine was superior to alpha2-adrenergic agonists in relieving opioid-withdrawal symptoms during 4-10 days (except D8) and no difference was found within the first 3 days. Compared with opioid agonists, Chinese herbal medicine was inferior during the first 3 days, but the difference became non-significant during days 4-9. Chinese herbal medicine has better effect on anxiety relieving at late stage of intervention than alpha2-adrenergic agonists, and no difference with opioid agonists. The incidence of some adverse effects (fatigue, dizziness) was significantly lower for Chinese herbal medicine than for alpha2-adrenergic agonists (sufficient data for comparison with opioid agonists were not available). Findings were robust to file-drawer effects. Our meta-analysis suggests that Chinese herbal medicine is an effective and safety treatment for heroin detoxification. And more work is needed to determine the specific effects of specific forms of Chinese herbal medicine.

( BUPP09430 - 23 February 2009) Practical perioperative pain control in children and adults

Poorly managed pain affects virtually every organ system. Successful pain management requires a continuum of care and change of delivery systems as the process of recovery takes place. Opiates are the mainstay of perioperative pain management, and are administered by a variety of routes. Antagonists are available which reverse actions of both endogenous and exogenous opioid ligands. Side-effects should be anticipated and treated. Use of local anaesthetic techniques should be considered in every case, especially in children, where LA blocks are usually performed under GA. Other management approaches include physical therapies, non-opioid medications, and psychosocial modalities. Rehabilitative therapies aimed at improved function after surgery should be the long-term aim, with these being done within the pain threshold of each patient. Do the simple things well: this may generate great benefits for patients without requiring expensive high-tech interventions.

( BUPP09429 - 23 February 2009) Penn/VA center for studies of addiction

The Penn/VA Center was founded in 1971 because of great concern over the number of Vietnam veterans returning home addicted to heroin. At that time little was known about the science of addiction, so our program from the very beginning was designed to gather data about the nature of addiction and measure the effects of available treatments. In other words, the goals were always a combination of treatment and research. This combination has continued to the present day. A human laboratory for the study of addiction phenomena such as conditioned responses was also founded in 1971. The key clinician investigators in this group have remained in the Center since the 1970s with most of the research staff continuing to work together. Important new investigators have been added over the years. Treatment was empirically based with randomized, controlled clinical trials as the gold standard for determining evidence-based treatment. The patients coming to treatment do not distinguish between abuse of alcohol and other drugs, so the treatment and research programs have always focused on all drugs including ethyl alcohol and the combination of ethyl alcohol with other drugs such as cocaine and opioids. Most of the patients coming for treatment also suffered from additional psychiatric disorders such as depression, anxiety, bipolar disorder or schizophrenia. Thus, the addiction treatment program in 1980 absorbed the rest of the VA Psychiatry Service into the Substance Abuse Program forming a new Behavioral Health Service with responsibility for over 9000 patients. The integration of substance abuse treatment with overall mental health care was the most efficient way to handle patients with complicated combinations of disorders. While this continues to be the best way to treat patients, it has proven difficult in practice. The main reason for this difficulty is that most mental health therapists whether they are psychiatrists, psychologists or social workers feel very inadequate to handle substance abuse problems. Unless they have had specialized training in addictive disorders, therapists are likely to be uncomfortable if substance abuse is one of the diagnoses while they may be quite comfortable treating other complex disorders such as schizophrenia. This lack of education of clinicians remains a major problem for our field. Some of the findings that came out of both the Penn/VA laboratory and clinical studies are now widely accepted and form the basis of standard clinical practice. These concepts and evidence will be briefly reviewed below.

( BUPP09428 - 23 February 2009) Role of active metabolites in the use of opioids

The opioid class of drugs, a large group, is mainly used for the treatment of acute and chronic persistent pain. All are eliminated from the body via metabolism involving principally CYP3A4 and the highly polymorphic CYP2D6, which markedly affects the drug's function, and by conjugation reactions mainly by UGT2B7. In many cases, the resultant metabolites have the same pharmacological activity as the parent opioid; however in many cases, plasma metabolite concentrations are too low to make a meaningful contribution to the overall clinical effects of the parent drug. These metabolites are invariably more water soluble and require renal clearance as an important overall elimination pathway. Such metabolites have the potential to accumulate in the elderly and in those with declining renal function with resultant accumulation to a much greater extent than the parent opioid. The best known example is the accumulation of morphine-6-glucuronide from morphine. Some opioids have active metabolites but at different target sites. These are norpethidine, a neurotoxic agent, and nordextropropoxyphene, a cardiotoxic agent. Clinicians need to be aware that many opioids have active metabolites that will become therapeutically important, for example in cases of altered pathology, drug interactions and genetic polymorphisms of drug-metabolizing enzymes. Thus, dose individualisation and the avoidance of adverse effects of opioids due to the accumulation of active metabolites or lack of formation of active metabolites are important considerations when opioids are used.

( BUPP09427 - 23 February 2009) Palliative Care in the Elderly Breast Cancer Patient.

Breast cancer is most common in the elderly and their needs are distinctly different from their younger counterparts. Although tumoricidal treatment may be given, a palliative approach to disease management will probably occur. Palliative and supportive care is an integral component of the management of the elderly breast cancer patient. Common problems include pain, cognitive impairment, depression, lymphoedema and ulcerating disease. End of life care and dignity therapy are also of great importance. Elderly patients with breast cancer are a unique cohort whose nuances with regard to palliative care issues rightly deserve special consideration. The main issues affecting the elderly breast cancer patient are discussed within this overview.

( BUPP09426 - 23 February 2009) Cutaneous complications among i.v. buprenorphine users

i.v. buprenorphine hydrochloride (Subutex) misuse has been creating a number of medical complications, and cutaneous manifestations such as soft tissue infection are one of the commonest consequences. Between January 2004 and December 2006, amongst 130 i.v. buprenorphine abusers who presented to the National University Hospital, Singapore, cutaneous complications were identified in 45 patients (prevalence, 31%) with cellulitis and skin abscess being the commonest complications. Tissue and blood culture were positive in 19 (42%) patients and Methicillin-sensitive Staphylococcus aureus was the commonest microbiological isolate (20%). Univariate linear regression revealed significant relationships between body temperature (P = 0.03), heart rate (P = 0.02), respiratory rate (P < 0.001), total peripheral white cell count (P = 0.011), absolute neutrophil count (P < 0.001) and serum C-reactive protein (CRP) level (P < 0.001) on admission and through the duration of hospitalization. In multivariate analysis, respiratory rate on admission remained significantly associated with longer duration of hospitalization (P = 0.01). i.v. cloxacillin, i.v. crystallized penicillin and oral cloxacillin were the most commonly prescribed antibiotics while 11 (24%) patients required surgical treatment. The mean duration of hospitalization was 8 � 11 days and repeated cutaneous complications occurred in eight (18%) patients. In conclusion, cutaneous complications are common among i.v. buprenorphine users. Respiratory rates on admission predict duration of hospital stay. A high index of suspicion coupled with a correct choice of antibiotics based on local bacteriological surveillance is necessary in an attempt to reduce cutaneous complications and length of hospitalization.

( BUPP09069 - 04 August 2008) Effect of tramadol use on three point-of-care and one instrument- based immunoassays for urine buprenorphine.

We report that use of the popular analgesic tramadol can cause false- positive urine buprenorphine results. We examined the extent of tramadol cross-reactivity in three point-of-care urine buprenorphine immunoassays (ACON, QuikStrip, and ABMC) and an instrument-based one (Cedia). We tested 29 urine samples from patients known to be taking tramadol. Ten different samples tested positive for urine buprenorphine by at least one immunoassay. Samples with positive buprenorphine screens by immunoassay were tested for total buprenorphine and total norbuprenorphine content by liquid chromatography-tandem mass spectrometry (LC-MS-MS), which confirmed that seven of the 10 positive samples were false-positives. The remaining three positive immunoassay samples had insufficient quantity for LC-MS-MS testing. No false-positives were detected with the ACON (10 ng/mL calibration cutoff) or the Cedia assay (using a 20 ng/mL calibration cutoff). All four false-positive Cedia results (using a 5 ng/mL cutoff) in this study tested negative using the ACON device. Our data suggest that tramadol use can cause false-positive urine buprenorphine immunoassays, and this effect appears to be assay-dependent. Tramadol interference with the Cedia assay is clinically relevant, especially if the 5 ng/mL calibration cutoff is used.

( BUPP09425 - 18 February 2009) Integrating buprenorphine treatment into office-based practice: A qualitative study

Despite the availability and demonstrated effectiveness of office-based buprenorphine maintenance treatment (BMT), the systematic examination of physicians' attitudes towards this new medical practice has been largely neglected. To identify facilitators and barriers to the potential or actual implementation of BMT by office-based medical providers. Qualitative study using individual and group semi-structured interviews. Twenty-three practising office-based physicians in New England. Interviews were audiotaped, transcribed, and entered into a qualitative software program. The transcripts were thematically coded using the constant comparative method by a multidisciplinary team. Eighty percent of the physicians ere white; 55% were women. The mean number of years since graduating medical school was 14 (SD = 10). The primary areas of clinical specialization were internal medicine (50%), infectious disease (20%), and addiction medicine (15%). Physicians identified physician, patient, and logistical factors that would either facilitate or serve as a barrier to their integration of BMT into clinical practice. Physician facilitators included promoting continuity of patient care, positive perceptions of BMT, and viewing BMT as a positive alternative to methadone maintenance. Physician barriers included competing activities, lack of interest, and lack of expertise in addiction treatment. Physicians' perceptions of patient-related barriers included concerns about confidentiality and cost, and low motivation for treatment. Perceived logistical barriers included lack of remuneration for BMT, limited ancillary support for physicians, not enough time, and a perceived low prevalence of opioid dependence in physicians' practices. Addressing physicians' perceptions of facilitators and barriers to BMT is crucial to supporting the further expansion of BMT into primary care and office-based practices.

( BUPP09445 - 02 March 2009) Pregnancy under high-dose buprenorphine

Objective: This study was first conducted to compare the consequences of the use of methadone and high-dose buprenorphine in pregnancy in France and secondly to describe the heterogeneity of women under high-dose buprenorphine. This paper focuses on the second point only. Study design: From October 1998 to September 1999, data on pregnancy, delivery outcomes and neonatal parameters were collected for 251 addicted women on methadone or high-dose buprenorphine (HDB) substitution followed in 35 hospitals and clinics in continental France. Then the data of 159 women who had been taking HDB during pregnancy and had delivered 160 live infants were analyzed. Results: Most of these women were treated as outpatients by general practitioners. 43% of them belong to what we considered a "hidden population" of drug users: most of them were native French citizens, who lived with the future fathers in their own homes, had at least some secondary education, and were usually not followed in specialized centers for drug addicts. Almost all the women smoked every day during their pregnancies; 20% used heroin during the last 4 weeks preceding delivery; 16% admitted having injected HDB at least once. Notably, neither the severity nor the duration of the neonatal abstinence syndrome (NAS) seemed to be related to the daily doses of the substitution agent. Half of the newborns were treated for NAS, mainly with morphine hydrochloride. Conclusion: Although two different populations of women were clearly identified, 64 with no social disadvantage and 95 socially disadvantaged, there was no difference between the groups as for the severity of NAS which was only related to the mothers' compliance with a programme of treatment against addiction. � 2008 Elsevier Ireland Ltd. All rights reserved.

( BUPP09444 - 02 March 2009) Authors' response

( BUPP09443 - 02 March 2009) Balancing the costs and benefits of opioid analgesics in the United States

( BUPP09442 - 02 March 2009) Thinking the unthinkable: Could the increasing misuse of prescription opioids among street drug users offer benefits for public health?

( BUPP09441 - 02 March 2009) The role of binding kinetics in therapeutically useful drug action

Binding kinetics help define how a medicine will communicate with physiology to produce a desired therapeutic response. Clinical efficacy, duration of action, clinical differentiation and safety may all be influenced by binding kinetics. The optimization of binding kinetics can be used to maximize a drug's therapeutic index and thereby decrease drug attrition. The gap between basic scientific principles and the potential medical value of a drug is currently bridged by the use of empirical assays. The value of binding kinetics to drug discovery will be increased through an improved ability to identify optimal kinetic mechanisms and define kinetic structure activity relationships.

( BUPP09440 - 02 March 2009) BUPRENORPHINE VS. METHADONE FOR TREATMENT FOR OPIOID ADDICTION DURING PREGNANCY: A RETROSPECTIVE STUDY OF PRENATAL COMPLIANCE AND NEONATAL OUTCOMES

( BUPP09439 - 02 March 2009) Right-sided Infective Endocarditis in Singapore.

Aim: To study the epidemiology of right-sided Infective Endocarditis in a regional hospital of Singapore Methods: Retrospective study on data of subjects diagnosed with infective endocarditis as the principal diagnosis for the last 5 years from January 2001 to July 2006. Summary of Results: A total of 38 right- sided Infective Endocarditis (IE) cases (possible and definite by Duke's criteria) were admitted during the study period. An analysis of the data revealed rising incidences from 2001 to 2006. Mean age is 33.7 years old. Majorities of them (73.7%) were in younger age group between 20 to 40 years old. Ethic majorities were Malay (73.7%), male (81.6%), previously healthy subjects (73.7%) and intravenous drug abusers (84.2%). The commonest drug of abuse was Subutex (60.5%) or buprenorphine hydrochloride. Six patients have recurrent IE and all were intravenous drug abusers. Majorities have abused drugs for less than 2 years (71.1%). We found 15 patients (39.5%) were concomitantly Hepatitis C positive. Only 2 were Hepatitis B positive and none were HIV positive. The main presenting symptoms was fever (84.2%) for less than 2 weeks (94.7%). The commonest valve involved was tricuspid (89.5%). 6 patients (15.8%) have more than 1 valves involved. The commonest organism was Staphylococcus aureus (79.9%). Complications arose in 33 cases (86.8%) namely embolic phenomenon (71.1%) and valve destruction (23.7%). The mortality rate was 10.5%. The cure rate was 65.8% with mainly intravenous antibiotics but 4 cases (10.5%) needed surgical intervention. There was also a high incidence of " against medical advice" discharges (23.7%). Conclusion: Right- sided Endocarditis is increasing in prominence over the last few years, likely attributed to IV drug abuse. The organisms causing IE have also changed as a result. This may result in increasing morbidity and mortality of infective endocarditis.

( BUPP09438 - 02 March 2009) Development and validation of a HPLC method for the determination of buprenorphine hydrochloride, naloxone hydrochloride and noroxymorphone in a tablet formulation

A simple isocratic reversed-phase high-performance liquid chromatographic method (RP-HPLC) was developed for the simultaneous determination of buprenorphine hydrochloride, naloxone hydrochloride dihydrate and its major impurity, noroxymorphone, in pharmaceutical tablets. The chromatographic separation was achieved with 10 mmol L-1 potassium phosphate buffer adjusted to pH 6.0 with orthophosphoric acid and acetonitrile (17:83, v/v) as mobile phase, a C-18 column, Perfectsil Target ODS3 (150 mm x 4.6 mm i.d., 5 mu m) kept at 35 degrees C and UV detection at 210 run. The compounds were eluted isocratically at a flow rate of 1.0 ml min(-1). The average retention times for naloxone, noroxymorphone and buprenorphine were 2.4, 3.8 and 8.1 min, respectively. The method was validated according to the ICH guidelines. The validation characteristics included accuracy, precision, linearity, range, specificity, limit of quantitation and robustness. The calibration curves were linear (r> 0.996) over the concentration range 0.22-220 mu g mL(-1) for buprenorphine hydrochloride and 0.1-100 mu g mL(-1) for naloxone hydrochloride clihydrate and noroxymorphone. The recoveries for all three compounds were above 96%. No spectral or chromatographic interferences from the tablet excipients were found. This method is rapid and simple, does not require any sample preparation and is suitable for routine quality control analyses. (C) 2008 Elsevier B.V. All rights reserved.

( BUPP09437 - 02 March 2009) The effect of norbuprenorphine on gastrointestinal transit in mice lacking mu opioid receptors

The Authors investigated the the effect of s.c. norbuprenorphine (NOR) on gastrointestinal transit in mice lacking mu opioid receptors (MOR). NOR was effective in arresting transit with doses close to the antinociceptive ED50 value in mice. Irrespective of dose, transit was constant only to a limited extent. In conclusion, NOR can nonetheless slow transit but only to a limited extent in mice that lacks MORs. Therefore, NOR influenced transit in at least 2 different ways, via MORs and the other by an undetermined mechanism. (conference abstract: EPHAR 2008 Congress of the Federation of European Pharmacological Societies, Manchester, UK, 13/07/2008-17/07/2008).

( BUPP09436 - 02 March 2009) (Substitution treatment of drug addicts during pregnancy: consequences for the children?)

BACKGROUND: Substitution treatment of opioid-dependent addicts was introduced in Norway in 1998. During the last 10 years, approximately 150 infants have been born to mothers taking part in this programme. MATERIAL AND METHODS: 10 mothers, who took part in the substitution treatment programme, gave birth to 15 infants at Haukeland University Hospital in the period 1999-2005. The infants were observed and monitored at the Department of Pediatrics, Haukeland University Hospital. RESULTS: During pregnancy, six of the infants were only exposed to opiates, i.e methadone or buprenorphine. Eight infants were also exposed to heroine, benzodiazepines or cannabis. As a group, these infants had lower birth weight than the national average. 14 of the 15 children developed neonatal abstinence syndrome (NAS), 10 needed treatment and two children died from sudden infant death syndrome (SIDS). Long-term follow-up showed that six of 13 children had normal psychomotor development, five had various degrees of delayed psychomotor development and two children had symptoms indicating a hyperkinetic disorder. Five children were in foster care. INTERPRETATION: Infants of women included in substitution treatment programmes for drug addicts are at high risk compared to infants of women without such addiction. For the newborn, NAS was a frequent complication. The study also showed that symptoms of hyperkinetic disorder and delayed psychomotor development were common. Children who had been exposed to opiates in combination with additional drugs seemed to have a high risk of delayed development and behaviour disorders. As they get older many were placed in foster care, despite well-coordinated, multidisciplinary treatment for the mother.

( BUPP09461 - 10 March 2009) Brief buprenorphine detoxification for the treatment of prescription opioid dependence: A pilot study

We examined the feasibility of brief outpatient detoxification as a treatment for prescription opioid (PO) abusers. Fifteen PO-dependent adults were enrolled to receive buprenorphine stabilization, a 2-week buprenorphine taper. and subsequent naltrexone for those who completed the taper. Subjects also received behavioral therapy, urinalysis monitoring, and double-blind drug administration. Subjects provided 83.8%. 91.7% and 31.2% opioid-negative samples during stabilization. taper and naltrexone phases, respectively. Inspection of individual subject data revealed systematic differences in whether subjects successfully completed the taper without resumption of illicit opioid use. Post-hoc analyses were used to examine the characteristics of subjects who successfully completed the taper (Responders, n = 5 ) vs. those who failed to do so (Nonresponders, n = 9). These pilot data suggest a subset of PO abusers may respond to brief buprenorphine detoxification, though future efforts should aim to improve outcomes, investigate individual differences in treatment response and identify characteristics that may predict those for whom longer-term agonist treatment is warranted.

( BUPP09460 - 10 March 2009) Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious rats

Background and purpose: The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined. Experimental approach: We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-(2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo(1,2,3-de)-1,4-benzoxazin-6-yl)-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.Key results: Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB1 receptor antagonist, AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyr azole-3- carboxamide).Conclusions and implications: These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB1 receptor-mediated mechanisms in the actions of anandamide

( BUPP09459 - 10 March 2009) SUBLINGUAL DOSE PROPORTIONALITY OF BUPRENORPHINE AND NALOXONE

Background: Buprenorphine / Naloxone (BUP/NAL) sublingual tablets, approved for opioid-dependence treatment, contain a mu-opioid partial agonist (buprenorphine) combined with naloxone. Two tablet strengths are marketed, 2/0.5 and 8/2mg. For intermediate dose (eg 12/3mg), multiple tablets are combined. The purpose of this report is to assess dose proportionality of Cmax and AUC values from 2/0.5 to 16/4mg doses.

( BUPP09458 - 10 March 2009) Effect of selol on the opioids activity in streptozotocin induced hyperalgesia

We examined the effect of the opioid receptor agonists and the effect of an antioxidant selol, which is an organoselenium compound on antinociceptive action of opioid agonists in diabetic neuropathic pain model. Streptozotocin (STZ) induced hyperglycemia accompanied by a prolonged decrease in nociceptive threshold is considered a useful model of experimental hyperalgesia. The changes in pain thresholds were determined using mechanical stimuli--the modification of the classic paw withdrawal Randall-Selitto test. Neither morphine, fentanyl nor buprenorphine administered alone in 7 consecutives days modified the STZ induced hyperalgesia, whereas selol slightly increased the nociceptive threshold. Pretreatment with selol markedly enhanced the analgesic activity of all three investigated opioids. Concomitant administration of selol and opioids in alleviation of neoplastic pains seems to be justified.

( BUPP09457 - 10 March 2009) Opioid abstinence reinforcement delays heroin lapse during buprenorphine dose tapering

A positive reinforcement contingency increased opioid abstinence during outpatient dose tapering (4, 2, then 0 mg/day during Weeks 1 through 3) in non-treatment-seeking heroin-dependent volunteers who had been maintained on buprenorphine (8 mg/day) during an inpatient research protocol. The control group (n=12) received $4.00 for completing assessments at each thrice-weekly visit during dose tapering; 10 of 12 lapsed to heroin use 1 day after discharge. The abstinence reinforcement group (n=10) received $30.00 for each consecutive opioid-free urine sample; this significantly delayed heroin lapse (median, 15 days).

( BUPP09456 - 10 March 2009) Treatment of pain in chronic pancreatitis

Abdominal pain is the most frequent symptom in patients with chronic pancreatitis. Between 70 and 90% of patients experience pain at some point in the course of their disease. In patients with alcoholic pancreatitis, pain is usually experienced at disease onset. Two distinct forms of idiopathic chronic pancreatitis can be distinguished: in early-onset (juvenile) idiopathic chronic pancreatitis, pain occurs initially, while in late-onset (senile) idiopathic chronic pancreatitis, pain is delayed or may even be absent. According to several authors, between 27 and 67% of patients require surgery due to lack of response to medical treatment. Pain may reoccur in more than 30% of patients who have undergone surgery and consequently, reintervention is not uncommon. Several treatment options are currently available: medical, endoscopic and surgical. The most appropriate treatment for each patient should be chosen on an individualized basis.

( BUPP09455 - 10 March 2009) Pharmacological treatments for tobacco dependence

There are currently three licensed therapies for smoking cessation: nicotine replacement (NR), bupropion and varenicline.NR can be indicated for: 1) aid in abrupt cessation; 2) gradual reduction in order to quit smoking; 3) temporary abstinence; and 4) smoking reduction maintenance. A meta-analysis has found that the relative risk of abstinence for any form of NR relative to control was 1.6. It has been found that starting NR treatment 1-3 weeks before smoking cessation and combining NR products, usually patch and gum, increases efficacy. Recently some new nicotine administration forms, i.e. lozenge, mouth spray and a pouch, have been developed. They seem to have the potential to relieve cravings faster than the current high-dose gum, and also be more preferred. Varenicline is a selective partial agonist at the alpha /sub 4/ beta /sub 2/ nicotinic acetylcholine receptors (nAChR). It decreases cravings and alleviates the symptoms of withdrawal. It can also reduce the rewarding and reinforcing effects of nicotine. Trials have shown varenicline to have increased efficacy relative to bupropion. Varenicline has also been compared with NR (21 mg transdermal patch) in one randomised study. Abstinence at the end of treatment at 12 weeks was significantly increased for varenicline (56%) compared with for nicotine patch (43%). Some post-marketing reports have expressed concern about psychiatric adverse effects, such as aggression, depression and suicides. The European Medicines Agency and the Food and Drug Administration of the USA are monitoring reported side-effects, but so far no confirmed casual relationship between these adverse effects and varenicline has been established. Bupropion inhibits neuronal re-uptake of dopamine and norepinephrine and is an antagonist on the nAChR. Its efficacy, compared with placebo, has been proved in several meta-analyses. A recent study suggests that longer pre-cessation use of bupropion, e.g. for 4 weeks, can improve efficacy results. Under development for the treatment of tobacco dependence are cannabinoid antagonists, immunotherapy against nicotine, monoaminooxidase inhibitors, dopamine receptor D3 receptor antagonists and partial agonists, glutamatergic and GABA-ergic compounds and novel selective nicotine cholinergic receptor agonists and antagonists.

( BUPP09454 - 10 March 2009) Clinical update on the pharmacology, efficacy and safety of transdermal buprenorphine

Buprenorphine was not used widely in clinical practice over many years, mainly due to analgesic potency and clinical safety concerns based on misinterpreted animal data. Contrary to previous concerns, however, no analgesic ceiling effect and no antagonism of combined pure mu-opioid receptor agonists is seen within the therapeutic dose range. In recent studies, buprenorphine could be effectively and safely combined with full mu-agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses. Moreover, buprenorphine exerts an antihyperalgesic effect, which is due-at least in part-to antagonistic activity at kappa-opioid receptors. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction. In addition, the risk of respiratory depression is lower than with other opioids including morphine, hydromorphone, methadone and fentanyl. Unlike morphine and fentanyl, there is no immunosuppressive activity with buprenorphine at therapeutic analgesic doses. Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous buprenorphine release for up to 96 h. In clinical trials, patients receiving transdermal buprenorphine experienced significantly greater pain relief, better sleep, and a reduced need for rescue therapy, compared to placebo. Large-scale post-marketing studies have confirmed the effectiveness of transdermal buprenorphine in treating moderate-to-severe cancer and non-cancer pain including neuropathic syndromes. Finally, the comparably low incidence of CNS adverse events and constipation, and the possibility of use in severe renal dysfunction without a need for dose adjustment make buprenorphine well suited for chronic pain management in at-risk patients, such as diabetics, elderly or renally impaired individuals including those requiring haemodialysis.

( BUPP09453 - 10 March 2009) Antinociceptive activity of buprenorphine and lumiracoxib in the rat orofacial formalin test: A combination analysis study

Combination of two or more analgesics is widely used for the treatment of moderate and severe pain syndromes, allowing usage of lower doses of each compound and thereby limiting side effects; there is currently a large interest in investigating the potential advantages of combinations between opioids and non-steroidal inflammatory drugs (NSAIDs), coxibs in particular. The rat orofacial formalin test is a useful pre-clinical model of inflammatory trigeminal pain for evaluating antinociceptive activity of analgesics and their combinations. Injection of formalin in the rat wiskerpad induces a stereotyped response (rubbing), consisting of two distinct phases: a first 'phasic' phase and a second 'tonic' phase. In this work we tested a partial agonist to mu-opioid receptors, buprenorphine, and a selective cyclo-oxygenase-2 inhibitor, lumiracoxib, each of which given i.p. either alone or in combination. Buprenorphine reduced nociception both in the first and in the second phase, whereas lumiracoxib induced antinociception in the second phase only. The interaction between the two drugs was assessed through isobolographic analysis after combined administration at a fixed dose ratio. Such combination produced a dose-dependent antinociceptive effect in both phases. We observed a statistical difference between the theoretical and the experimental ED /sub 50/ , which indicated synergistic interaction in the second phase. Concerning the first phase, we assumed that the antinociceptive effects were almost completely to be attributed to buprenorphine, since lumiracoxib was ineffective when administered alone. However, we found an unexpected difference between the theoretical and experimental ED /sub 50/ , suggesting synergism in the first phase as well.

( BUPP09452 - 10 March 2009) Unusual complication of intravenous Subutex abuse: Two cases of septic sacroiliitis

We report two unusual cases of septic sacroiliitis resulting from intravenous Subutex abuse that initially masqueraded as low back pain. Both patients, a 48-year-old Malay man and a 30-year-old Malay woman, presented with chills, rigor and progressive lower back pain, and eventually experienced difficulty in ambulating. The Malay woman also developed severe pain in her left elbow, with swelling and restriction of movement. Blood investigations and cultures revealed an infective process. Imaging of the pelvis and lower back confirmed t he diagnosis of septic arthritis of the sacroiliac joints. The first patient underwent computed tomography-guided drainage of the abscess and was administered intravenous antibiotics via a peripherally-inserted central catheter (PICC) line. The second patient underwent an arthrotomy for her elbow and her left sacroiliac joint was managed conservatively with intravenous antibiotics, also via a PICC line. The diagnostic difficulty and the need for a high index of suspicion are discussed.

( BUPP09451 - 10 March 2009) Pharmaceutical advice for substitute drugs

( BUPP09450 - 10 March 2009) Learning and scoring: Substitution therapy

( BUPP09449 - 10 March 2009) Review: Influence of preoperative feeding on the healing of colonic anastomoses in malnourished rats

Background: Malnutrition influences healing of gastrointestinal anastomoses. The authors hypothesize that colonic anastomotic healing is decreased by malnutrition and might be improved by preoperative feeding. Methods: Eighty adult male Wistar rats were divided into 4 groups: (1) control rats 1 (C1), fed regular chow ad libitum for 21 days; (2) malnourished pair-fed rats (M), fed 50% of the food ingested by the control rats for 21 days; (3) preoperative nutrition rats (PRE), fed 50% of the average of the controls for 21 days and then fed preoperative nutrition with regular chow ad libitum for 1 week before the operation; and (4) control rats 2 (C2), fed regular chow ad libitum for 28 days. On days 21 (C1 and M) and 28 (PRE and C2), rats underwent 2 colonic transections and, subsequently, 2 end-to-end anastomoses. Rats were killed on postoperative day 5. The anastomoses were ressected for tensile strength and histological analysis. Results: PRE rats showed increased maximal tensile strength vs the M group (0.09 � 0.01 vs 0.15 � 0.01; P <.05) and similar values of maximal tensile strength as the controls (0.15 � 0.01 vs 0.15 � 0.02; P =.91). Collagen type I was higher in controls vs the PRE group (6.13 � 0.39 vs 4.90 � 1.53; P <.05); nevertheless, the PRE group showed higher collagen type I than M rats (4.90 � 0.36 vs 3.83 � 0.35; P <.05). Conclusions: Preoperative feeding for 7 days increases the maximal tensile strength, as well as the percentage area of mature collagen, approaching similar values as the control group.

( BUPP09448 - 10 March 2009) The ORL-1 receptor system: Are there opportunities for antagonists in pain therapy?

Following the cloning of the classical opioid receptors (mu, delta and kappa), the opioid receptor like-1 (ORL-1) was identified as a G-protein coupled receptor (GPCR) with 65% structure homology to the other members of the opioid family. Its endogenous ligand nociception / orphanin FQ (N/ OFQ) was discovered shortly thereafter, becoming the subject of investigation in numerous studies. Since activation of the ORL-1 receptor by N/OFQ leads to G i-coupling and signal transduction similar to that of opioid receptors, N/OFQ was thought to have a role in pain modulation, similar to that of the endogenous opioids. Surprisingly, studies characterizing N/OFQ's effects on pain transmission yielded conflicting results, attributing to N/OFQ both pronociceptive and antinociceptive actions, depending on doses and routes of administration as well as species and sex of the subjects. With the development of selective and potent ORL-1 antagonists, many scientists believed these contradicting actions would be elucidated. Here we review the recent literature reporting the use of novel ORL-1 antagonists, both peptide and non-peptide, in different models of pain and discuss their use as research tools or potential drug candidates.

( BUPP09447 - 10 March 2009) Post-operative epidural analgesia - Comparison of bupivacaine plus buprenorphine with bupivacaine alone

Objective: The study was conducted to investigate whether the combination of epidural bupivacaine and buprenorphine provides longer duration of post-operative analgesia than epidural bupivacaine alone. Methods: Sixty adult patients were divided into 2 groups of 30 patients each. 2 hours after spinal anaesthesia group A patients received 8ml of 0.25% bupivacaine along with 0.1 mg buprenorphine, and group B patients received 8 ml of 0.25% bupivacaine alone through prefixed epidural catheter. Results: Duration of post-operative analgeslia with epidural combination of bupivacaine plus buprenorphine and epidural bupivacaine alone, were 12.23 � 1.72 hours and 4 � 0.69 hours respectively. Conclusion: Combination of epidural bupivacaine and 0.1 mg of buprenorphine provides longer duration of post-operative analgesia thign epidural bupivacaine alone and is recommended in patients undergoing gynaecological and lower limb orthopaedic surgery.

( BUPP09446 - 10 March 2009) Working with opioid analgesics does not have to be a pain) The basics of pain management

( BUPP09071 - 04 August 2008) Pregnancy and injecting drug use.

( BUPP09472 - 18 March 2009) Combination of Mn /sup 2+/ enhanced and diffusion tensor MR imaging gives complementary information about injury and regeneration in the adult rat optic nerve

Purpose: To evaluate manganese (Mn /sup 2+/ )-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) as tools for detection of axonal injury and regeneration after intravit-real peripheral nerve graft (PNG) implantation in the rat optic nerve (ON).Materials and Methods: In adult Fischer rats, retinal ganglion cell (RGC) survival was evaluated in Flurogold (FG) back-filled retinal whole mounts after ON crush (ONC), intravitreal PNG, and intravitreal MnCl /sub 2/ injection (150 nmol) at 0 and 20 days post lesion (dpl). MEMRI and echo-planar DTI (DTI-EPI) was obtained of noninjured ON one day after intravitreal MnCl /sub 2/ injection, and at 1 and 21 dpl after ONC, intravitreal PNG, and intravitreal MnCl2 injections given at 0 and 20 dpl. GAP-43 immunohistochemistry was performed after the last MRI.Results: ONC reduced RGC density in retina by 94% at 21 dpl compared to noninjured ON without MnCl2 injections. Both intravitreal PNG and intravitreal MnCl2 injections improved RGC survival in retina, which was reduced by 90% (ONC + MnCl /sub 2/ ), 82% (ONC+PNG), and 74% (ONC+PNG+MnCl /sub 2/ ) compared to noninjured ON. DTI-derived parameters (fractional anisotropy (FA), mean diffu-sivity, axial diffusivitylambda??, and radial diffusivity lambda ) were unaffected by the presence of Mn /sup 2+/ in the ON. At 1 dpl, CNR /sub MEMRI/ and lambda??were reduced at the injury site, while at 21 dpl they were increased at the injury site compared to values measured at 1 dpl. GAP-43 immunoreactive axons were present in the ON distal to the ONC injury site.Conclusion: MEMRI and DTI enabled detection of functional and structural degradation after rat ON injury, and there was correlation between the MRI-derived and immu-nohistochemical measures of axon regeneration.

( BUPP09471 - 18 March 2009) Psychological symptoms of opioid dependent patients in substitution treatment - Occurrence and degree at entry and 1-year follow-up.

Background: The measurement of mental wellbeing in persons getting substitution sustained treatment (SST) is of interest for clinical and scientific reasons as well as for the implementation of quality management measures. Method: Psychological symptoms were assessed with the SCL-27 instrument at entry (n = 435) and in a one year follow-up (n = 130). The change in occurrence and degree of the respective psychological symptoms in opioid dependent patients during SST were examined using T-test and Wilcoxon-test for paired samples. Results: We found that opioid dependent persons starting an SST had a substantial load of psychological symptoms. The most often mentioned were symptoms of melancholia, hot and cold shivers, suspiciousness against most people, hopelessness, and lack of energy, problems to concentrate, and the fear to be exploited. The number of not prescribed drugs as well as the presence and extent of benzodiazepine use before treatment start correlated slightly with a higher load of psychological symptoms. At the average the total burden of symptoms and especially depressive symptoms reduced slightly during the first year of treatment. Conclusion: The symptom checklist SCL-27 has various limitations as an instrument for monitoring mental wellbeing of patients in opioid maintenance treatment. Additional research efforts are needed to find a more satisfying solution.

( BUPP09470 - 18 March 2009) The prevalence of childhood trauma among those seeking buprenorphine treatment

In this study, the authors examined the prevalence of five types of childhood trauma among a sample of adult patients who were addicted to opioids and seeking treatment with buprenorphine. Using a survey methodology, the authors examined a consecutive sample of 113 participants and found that 20.4% reported having experienced sexual abuse, 39.8% reported having experienced physical abuse, 60.2% reported having experienced emotional abuse, 23.0% reported having experienced physical neglect, and 65.5% reported having witnessed violence. Only 19.5% of the sample denied having experienced any of the five forms of childhood trauma. Most respondents (60.2%) reported having experienced one, two, or three different forms of childhood trauma. A minority reported having experienced four (13.3%) or all five (7.1%) forms of childhood trauma. These data indicate that among individuals with opioid dependence who are seeking treatment with buprenorphine, the prevalence rates of various types of childhood trauma are quite high.

( BUPP09469 - 18 March 2009) Methods and motivations for buprenorphine diversion from public opioid substitution treatment clinics

This study aimed to develop a better understanding of the motives for suspected buprenorphine diversion during supervised dosing. Structured interviews were conducted with clients after 71 episodes of diversion at 3 opioid substitution treatment clinics in Sydney, Australia. Interviews were conducted by the clinic manager. An equivalent number of suspected episodes involved diversion via removal of buprenorphine from the mouth (n = 35), and secretion of buprenorphine in the mouth (n = 32). Denial of diversion occurred in 45% of suspected episodes and was significantly associated with secretion of buprenorphine in the mouth (P <.0001), suggesting a possible misunderstanding between clinicians and clients to what constitutes diversion. Motivations for diversion included "stockpiling" for later sublingual use (n = 15), discarding buprenorphine (n = 11), and giving it to another person (n = 5). A consistent definition of diversion of supervised dosed of buprenorphine is required. Diversion of supervised doses may represent a single episode of nonadherence to dosing instructions or more significant ambivalence over treatment. Responses to suspected diversion should aim to minimise harm and maximise treatment outcomes.

( BUPP09468 - 18 March 2009) Swiss recommendations for substitution treatment: A report that "got it right"

( BUPP09467 - 18 March 2009) Treatment of ischemic pain in patients suffering from peripheral vasculopathy with transdermal buprenorphine plus epidural morphine with ropivacaine vs. epidural morphine with ropivacaine

Aim: This study compared the efficacy and safety of buprenorphine transdermal delivery system with peridural infusion of morphine and ropivacaine to peridural infusion alone for the control of ischemic pain in patients suffering from peripheral vasculopathy. Methods: Eighty-sixpatients were randomized into two groups. In the first group, a buprenorphine patch 35mug/hour TTDS (transtec transdermal device plus ropivacaine and morphine) was applied, and a peridural infusion of ropivacaine/morphine (200mg + 2mg) was established. In the second group, ropivacaine and morphine analgesia was obtained using a peridural infusion and a placebo patch. The primary efficacy parameter was the visual analog scale score for pain. Secondary parameters of efficacy were the short-form McGill Pain Questionnaire scores and a score for pain interference with sleep obtained from patient diaries evaluated every week for a period of 4weeks. Results: Subjects in the TTDS group reported a reduction in pain, increased sleep, and a lower incidence of side effects compared with the control group. Conclusion: Transdermal buprenorphine use resulted in significant pain relief with excellent patient satisfaction, which may translate into improvement in mood and quality of life.

( BUPP09466 - 18 March 2009) Chronic pain treatment: A high moral imperative with offsetting personal risks for the physician-a medical student's perspective

There is a clear need for physicians who specialize in the treatment of chronic pain, and these specialists must be empowered to use legally available and medically acceptable pain therapies, including opioids. However, prescribing opioids (or not prescribing them) for chronic pain treatment exposes pain physicians to medicolegal risks with serious personal consequences. This article summarizes, from a medical student's perspective, the basis for the specialization in pain medicine, and actions that place pain physicians at risk for serious professional harm. Regulatory issues of opioid prescription, physician litigation, and the ethical and legal implications on pain management from the perspective of a medical student are discussed. Existing data suggest that legal and regulatory issues have impacted and will continue to impact the treatment of pain. Creating uncertainty about legal issues and instilling fear in the prescribing physician are the best ways to discourage the use of opioids for legitimate medical purposes. In addition, the personal risks associated with the treatment of pain are likely to deter medical students from choosing pain management as their specialty. It is concluded that pain management is both a moral imperative and a moral obligation of clinicians that stems from the Hippocratic Oath. It is clear that there are many misconceptions and ethical concerns surrounding the use of opioids to treat pain. It is imperative that legal and regulatory issues do not discourage medical students from specializing in pain medicine.

( BUPP09465 - 18 March 2009) Investigating medetomidine-buprenorphine as preanaesthetic medication in cats

The objective of this study was to investigate medetomidine-buprenorphine preanaesthetic medication in cats.Forty American Society of Anesthesiologists (ASA) I female cats were enrolled in this prospective, blinded, clinical study. Cats were randomised into one of four groups: group M30 were injected intramuscularly with 30 mu g/kg medetomidine, groups M10+B, M30+B and M50+B received 10, 30 and 50 mu g/kg of medetomidine, respectively, each in combination with 20 mu g/kg buprenorphine. After 30 minutes, a sedation score was allocated. Anaesthesia was induced using intravenous propofol and maintained using is oflurane in oxygen, while cats underwent ovariohysterectomy. Heart rate, respiratory rate, end-tidal carbon dioxide tension and oxygen saturation of haemoglobin were recorded. Atipamezole was administered intramuscularly at volatile agent discontinuation. Time taken to lift their head, sit in sternal and stand were recorded along with quality of recovery.M30+B cats required significantly less isoflurane compared with M30 cats. Heart rate and oxygen saturation of haemoglobin were significantly lower in M50+B cats than in M30 cats. All M+B groups experienced significantly better recoveries compared with the medetomidine only M30 control group.The addition of buprenorphine to medetomidine preanaesthetic medication in cats reduces volatile agent vaporiser setting and improves the quality of recovery from anaesthesia.

( BUPP09464 - 18 March 2009) Influence of early neonatal experience on nociceptive responses and analgesic effects in rats

Early maternal separation has profound effects on nociception in rats. Cross-fostering is a standard husbandry procedure used by some commercial breeders. This study aimed to determine if cross-fostering altered nociception and the analgesic efficacy of buprenorphine and morphine. At seven and nine weeks of age, an elevated plus maze was used to assess anxiety and Hargreaves apparatus was used to measure thermal nociception at two intensities in cross-fostered and naturally-reared rats. At 10 weeks of age these rats were assigned to one of three treatment groups: saline, buprenorphine or morphine. The Hargreaves apparatus was used to evaluate the effect of analgesics on nociception. Differences were observed in nociception between the cross-fostered and naturally-reared rats at both intensities. At the lower intensity no significant differences were seen between the cross-fostered and naturally-reared rats post-administration of an analgesic. At the higher intensity significant differences were apparent. Morphine was less effective in inducing analgesia to thermal stimuli in cross-fostered rats compared with naturally-reared rats, whereas the opposite was found with buprenorphine which had a more pronounced analgesic effect in the cross-fostered rats. No significant differences in performance on an elevated plus maze were demonstrated between the cross-fostered and naturally-reared rats.

( BUPP09463 - 18 March 2009) Earlier warning: a multi-indicator approach to monitoring trends in the illicit use of medicines

BACKGROUND: The availability of medicines on the illicit drug market is currently high on the international policy agenda, linked to adverse health consequences including addiction, drug related overdoses and injection related problems. Continuous surveillance of illicit use of medicines allows for earlier identification and reporting of emerging trends and increased possibilities for earlier intervention to prevent spread of use and drug related harm. This paper aims to identify data sources capable of monitoring the illicit use of medicines; present trend findings for Rohypnol and Subutex using a multi-indicator monitoring approach; and consider the relevance of such models for policy makers. METHODS: Data collection and analysis were undertaken in Bergen, Norway, using the Bergen Earlier Warning System (BEWS), a multi-indicator drug monitoring system. Data were gathered at six monthly intervals from April 2002 to September 2006. Drug indicator data from seizures, treatment, pharmacy sales, helplines, key informants and media monitoring were triangulated and an aggregated differential was used to plot trends. RESULTS: Results for the 4-year period showed a decline in the illicit use of Rohypnol and an increase in the illicit use of Subutex. CONCLUSION: Multi-indicator surveillance models can play a strategic role in the earlier identification and reporting of emerging trends in illicit use of medicines.

( BUPP09462 - 18 March 2009) Practice, problems and perspectives of opioid substitution treatment (OST) in Germany

Opioid dependency is a complex and chronically relapsing disease with high risks of morbidity and mortality. Frequent relapses and in most of the cases a long process of maturing out characterize this disease. Opioid substitution programs with methadone, buprenorphine and other opioids are a suitable intervention and form the first choice in the treatment of this disease. In Germany, compared to its neighboring countries, this treatment was introduced relatively late. However, in the last five years, the number of patients in substitution treatment has increased significantly to more than 70,000 patients, which marks an increase of 50%, meaning that one third to one half of the estimated opiate users are being reached. Despite the widely acknowledged success with respect to the improvement of the quality of life, survival rates, and accessibility of the target groups for ongoing treatments of drug-related diseases (such as HIV/HCV infections), opioid substitution treatment is still discussed controversially. In this contribution, problems in the areas of service provision, juristic, social, health and research policies are discussed and possibilities of increasing the access and quality of this treatment are introduced.

( BUPP09482 - 23 March 2009) QTc Interval Prolongation in Patients on Long-Term Methadone Maintenance Therapy

Objective: the aim of the present study was to assess the incidence of abnormal QTc interval values in a population of subjects on a long-term methadone maintenance treatment, as a single therapy, and with methadone dosages ranging between 10 and 600mg/daily (mean + SD = 87 + 76). Method: Basal ECG recordings were carried out in 83 former heroin addicts on long-term successful methadone maintenance therapy for a least 6 months, while no other known QT-prolonging agent was being administered. Results: Eighty-three percent of the subjects had a more prolonged QT interval than the reference values for persons of the same sex and age. Only 2 patients displayed a QTc interval of >500 ms. No correlation emerged between QTc interval values. This data, associated with the finding that methadoen is a rather potent inhibitor of HERG potassium channels and that it may induce torsade de pointes in predisposed subjects, supports the recommendation that patients entering methadone treatment (MT) are screened for cardiac risk factors. ECG might be considered in ongoing MT patients especially before starting QT-prolonging medications.

( BUPP09481 - 23 March 2009) Determination of colchicine in urine and blood by liquid chromatography-tandem mass spectrometry with multiple-reaction monitoring

Objective To establish a method of liquid chromatography-tandem mass spectrometry for determination of colchicine in blood and urine. Methods 0. 5mL of blood or urine sample was extracted using a liquid-liquid extraction (ethyl acetate) at pH 9.2 with buprenorphine as internal standard. The extract was separated on a ZORBAX SB-C18 column (150mm � 2. 1mm �5mum) using 20 mmol/L ammonium acetate with 0.1% formic acid(pH 4)/ methanol (20/80) as mobile phase with a flow-rate of 0.2mL/min, confirmed and quantified by MS-MS in the multiple reaction monitoring (MRM) mode via positive electrospray ionization mode(+ESI). Results Colchicine and buprenorphine in blood and urine were separated well. Calibration curves were linear within the range of 0. 1-50ng/mL(r > 0. 9990), and the limits of detection were 0.05ng /mL. The recoveries were between 94%-116%, the inter-day and intra-day precisions were less than 8. 5%. Conclusion This method is sensitive, fast and accurate, and suitable for determination of trace colchicine in blood and urine

( BUPP09480 - 23 March 2009) Quetiapine-induced peripheral edema

Quetiapine fumarate is an atypical antipsychotic with relatively benign side-effect profile. Here we report a rare side-effect of quetiapine use. This is the second reported case of peripheral edema with quetiapine use. Unaware of this rare side-effect, patient had to endure extensive investigations.

( BUPP09479 - 23 March 2009) Letters to the editor

( BUPP09478 - 23 March 2009) Example of complementarities between evaluation of the Regional Pharmacovigilance Department and Center of Evaluation and Information on Pharmacodependence

( BUPP09477 - 23 March 2009) A meta-analysis of retention in methadone maintenance by dose and dosing strategy

Objective: To estimate, via meta-analysis, the influence of different methadone dose ranges and dosing strategies on retention rates in methadone maintenance treatment (MMT). Methods: A systematic literature search identified 18 randomized controlled trials (RCTs) evaluating methadone dose and retention. Retention was defined as the percentage of patients remaining in treatment at a specified time point. After initial univariate analyses of retention by Pearson chi-squares, we used multilevel logistic regression to calculate summary odds ratios (ORs) and 95% confidence intervals for the effects of methadone dose (above or below 60 mg/day), flexible vs. fixed dosing strategy, and duration of follow-up. Results: The total number of opioid-dependent participants in the 18 studies was 2831, with 1797 in MMT and 1034 receiving alternative mediations or placebo. Each variable significantly predicted retention with the other variables controlled for. Retention was greater with methadone doses 60 than with doses < 60 (OR: 1.74, 95% CI: 1.43-2.11). Similarly, retention was greater with flexible-dose strategies than with fixed-dose strategies (OR: 1.72, 95% CI: 1.41-2.11). Conclusions: Higher doses of methadone and individualization of doses are each independently associated with better retention in MMT.

( BUPP09476 - 23 March 2009) Fast-tracking implementation through trial design: The case of buprenorphine treatment in Victoria

Objectives: We investigated how a randomised controlled trial (RCT) could be designed to incorporate features known or thought likely to enhance the uptake of the new treatment into clinical practice post-trial. Method and Results: Between 1999 and 2001, we trialled buprenorphine treatment for heroin dependence in community settings throughout Victoria, using 28 experienced methadone prescribers and 34 pharmacists across 19 sites. In this case study, we describe how we incorporated seven features considered important in treatment uptake: skilled and experienced practitioners, government and policy support, incentives to prescribe the new treatment, specialist support services, clinical guidelines, training programs and patient involvement and information. We also present information showing that uptake of buprenorphine treatment was substantially boosted in Victoria compared with other Australian jurisdictions immediately after the trial in 2001 and that this increase was sustained until at least 2006. Conclusion: While we cannot prove that our trial design was responsible for the increased uptake of buprenorphine treatment in Victoria, we do show that design has been a neglected aspect of clinical trials in terms of enhancing post-trial uptake of the treatment being tested. Implications: Those interested in closing the 'know-do' gap between research and practice may wish to further explore this very promising lead. Imaginative linking of features known to enhance treatment uptake to pressing research questions may lead to new information on efficacy, as well as getting valuable drugs into the treatment system more rapidly.

( BUPP09475 - 23 March 2009) Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth

( BUPP09474 - 23 March 2009) No longer only a young man's disease - Illicit drugs and older people

( BUPP09473 - 23 March 2009) A comparison of epidural buprenorphine plus detomidine with morphine plus detomidine in horses undergoing bilateral stifle arthroscopy

OBJECTIVE: To compare the analgesic efficacy of buprenorphine plus detomidine with that of morphine plus detomidine when administered epidurally in horses undergoing bilateral stifle arthroscopy. STUDY DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: Twelve healthy adult horses participating in an orthopedic research study. Group M (n = 6) received morphine (0.2 mg kg(-1)) and detomidine (0.15 mg kg(-1)) epidurally; group B (n = 6) received buprenorphine (0.005 mg kg(-1)) and detomidine (0.15 mg kg(-1)) epidurally. METHODS: Horses received one of two epidural treatments following induction of general anesthesia for bilateral stifle arthroscopy. Heart rate (HR), mean arterial blood pressure (MAP), end-tidal CO(2) (Pe'CO(2)), and end-tidal isoflurane concentrations (E'Iso%) were recorded every 15 minutes following epidural administration. Post-operative assessment was performed at 1, 2, 3, 6, 9, 12, and 24 hours after standing; variables recorded included HR, respiratory rate (f(R)), abdominal borborygmi, defecation, and the presence of undesirable side effects. At the same times post-operatively, each horse was videotaped at a walk and subsequently assigned a lameness score (0-4) by three ACVS diplomates blinded to treatment and who followed previously published guidelines. Nonparametric data were analyzed using Wilcoxon's rank-sum test. Inter- and intra-rater agreement were determined using weighted kappa coefficients. Statistical significance was set at p

( BUPP09517 - 31 March 2009) Buprenorphine-Naloxone Versus Methadone Maintenance Therapy: A Randomised Double-Blind Trial With Opioid-Dependent Patients

This is the first randomised study comparing buprenorphine-naloxone with methadone for maintenance treatment of opioid dependence. A 17 week, double-blind, double-dummy trial of daily dosing compared buprenorphine-naloxone (8/2mg and 16/4mg) with methadone (45mg and 90mg) in 268 participants. the percentage of opioid-free urine samples over time did not differ by drug or dosage. The percentage of patients with > 12 consecutive opioid-negative urine samples did not differ by drug and was significantly greater for patients receiving higher doses of either agent. Induction success, compliance, nonopioid drug sue, retention and Addiction Severity Index scores did not differ among groups. Buprenorphine-naloxone is a viable alternative to methadone in clinical practice.

( BUPP09514 - 31 March 2009) Hypogonadism in men receiving methadone and buprenorphine maintenance treatment

The aim of this study was to determine the prevalence and investigate the aetiology of hypogonadism in men on methadone or buprenorphine maintenance treatment (MMT, BMT). 103 men (mean age 37.6 � 7.9) on MMT (n = 84) or BMT (n = 19) were evaluated using hormone assays, body mass index (BMI), serological, biochemical, demographic and substance use measures. Overall 54% of men (methadone 65%; buprenorphine 28%) had total testosterone (TT) <12.0 nm; 34% (methadone 39%; buprenorphine 11%) had TT <8.0 nm. Both methadone- and buprenorphine-treated men had lower free testosterone, luteinising hormone and estradiol than age-matched reference groups. Methadone-treated men had lower TT than buprenorphine-treated men and reference groups. Prolactin did not differ between methadone, buprenorphine groups, and reference groups. Primary testicular failure was an uncommon cause of hypogonadism. Yearly percentage fall in TT by age across the patient group was 2.3%, more than twice that expected normally. There were no associations between TT and opioid dose, cannabis, alcohol and tobacco consumption, or chronic hepatitis C viraemia. On multiple regression higher TT was associated with higher alanine aminotransferase and lower TT with higher BMI. Men on MMT have high prevalence of hypogonadotrophic hypogonadism. The extent of hormonal changes associated with buprenorphine needs to be explored further in larger studies. Men receiving long term opioid replacement treatment, especially methadone treatment, should be screened for hypogonadism. Wide interindividual differences in methadone metabolism and tolerance may in a cross-sectional study obscure a methadone dose relationship to testosterone in individuals. Future studies of hypogonadism in opioid-treated men should examine the potential benefits of dose reduction, choice of opioid medication, weight loss, and androgen replacement.

( BUPP09513 - 31 March 2009) New medications for the treatment of substance use disorders

Can new medications help in the treatment of substance use disorders? The short answer to that question is yes. Despite the historical resistance of addiction treaters to using medications in their treatment of addicted people, recent advances and more sophisticated methods for integrating medications into standard addiction treatment have led to a surge in new anti-addiction medications available to the addicted person. Medications like depot naltrexone and acamprosate have shown substantial effects in decreasing alcohol craving, while suboxone has provided relief to opiate addicts who simply would not have come to treatment in the past. Despite the apparent post-marketing emergence of side effects like agitation and nightmares, varenicline is a step in the right direction for those looking for help with their nicotine addiction. Although not yet available to the public, the pipeline of investigational medications includes several cocaine vaccines. In addition to these vaccines and the Food and Drug Administration-approved medications, other addiction remedies have been touted in the press and should be understood by the general physician; in this widely publicized but unproven category is the proprietary medication "cocktail" offered by Prometa. Clinicians can provide substantial benefit to their addicted patients by making newly developed medications part of the treatment package. This article reviews the clinical use of these new medications.

( BUPP09512 - 31 March 2009) Changing practice to improve pain control for renal patients.

Pain is a common symptom described by patients with end-stage kidney disease (ESKD) but remains ineffectively managed. The aim of this audit was to determine what proportion of these patients report pain, then introduce the use of an analgesic ladder adapted specifically for ESKD, and finally re-evaluate the prevalence of pain symptoms, looking for an improvement. A cohort of inpatients on the renal wards of a West London teaching hospital was studied. The number of patients reporting pain and the severity of their pain on a scale of 1-10 were recorded. A considerable number of patients were barred from participating because of a language barrier. Interpreters were introduced, and the phase was repeated. The World Health Organization (WHO) three-step analgesic ladder was adapted for patients with ESKD and introduced to medical staff on the renal wards. The number of patients reporting pain and the severity of their pain were re-recorded. There was a significant reduction in the number of patients reporting pain and the severity of their pain. Pain control in patients with ESKD is improved through the use of an adapted version of the WHO analgesic ladder. Strategies must be in place for effective communication with foreign patients.

( BUPP09510 - 31 March 2009) Retention rate and side effects in a prospective trial on hepatitis C treatment with pegylated interferon alpha-2a and ribavirin in opioid-dependent patients

Hepatitis C viral (HCV) infection is present in 30 to 98% of intravenous drug users. Intravenous substance abuse represents the main route of HCV transmission in industrialized countries. A multi-centre, randomized, controlled, prospective study assessed sustained virological response (SVR), adverse events such as depressive episodes and retention rate of HCV treatment in opioid-dependent patients. Stabilized, opioid-dependent patients with chronic HCV infection (genotype 2 or 3) received pegylated interferon alpha-2a in combination with ribavirin 800 mg/day (Group A) or 400 mg/day (Group B). Participants were randomized, blocked and stratified by genotype and viral load. A standardized psychiatric assessment, Beck Depression Inventory (BDI) and Van Zerssen's list of complaints were administered at each study visit. In 31 months, 300 opioid-dependent patients were screened; 190 (63.3%) were hepatitis C antibody positive. According to study protocol, out of 75 'potential-to-treat' patients with genotype 2 or 3, 17 stable patients (22.6%) were included in the study. All participants completed the study. Significant haemoglobin decreases occurred in both Groups A (P = 0.001) and B (P = 0.011). All the patients had an end-of-treatment (week 24) HCV RNA negativity. Fifteen (88.2%) achieved SVR at week 48. Overall, 52.9% developed depressive symptoms during treatment. Because of the prompt initiation of antidepressant medication at first appearance of depressive symptoms, no severe depressive episodes occurred. Our data show a high retention rate and reliability, and good viral response for both treatments. Hepatitis C treatment in stable opioid-dependent patients was efficacious, suggesting that addiction clinics can offer antiviral therapy in combination with agonistic treatment as part of multi-disciplinary treatment.

( BUPP09509 - 31 March 2009) Peginterferon plus Ribavirin for chronic hepatitis C in opiate addicts on methadone/buprenorphine maintenance therapy

Background: In developed countries hepatitis C is prevalently transmitted by intravenous drug users (IDUs). The problems associated with management of HCV hepatitis in these patients have, in the past, discouraged treatment. Aim: To evaluate efficacy, safety and tolerability of a standard Peginterferon (Peg-IFN) alpha-2b or alpha-2a plus Ribavirin treatment in IDUs who were receiving methadone or buprenorphine. Methods: A multi-centre prospective observational study performed from September 2003 to September 2006 in Central Italy (Umbria and Marches regions). A shared care model of HCV management was used which integrated a multidimensional, multidisciplinary approach. Results: Sixty-five subjects were evaluated and 52 satisfied inclusion criteria. Forty-five completed treatment (25 with Peg-IFN alpha-2b, 20 with Peg-IFN alpha-2a), a total of 37 showed a biochemical/virological response at the end of treatment (ITT 71.1%), 26 had a sustained virological response (ITT 50%; 38.4% of cases genotype 1-4, 61.6% genotype 3-2). Conclusions: The results indicate that patients on maintenance treatment with methadone/buprenorphine can be treated for HCV. The success rate was fairly good; tolerability and side effects were similar to those reported in non-IDU patients. Close cooperation with specialists in drug addiction and psychiatrists is however essential for success.

( BUPP09508 - 31 March 2009) Treating chronic hepatitis C in recovering opiate addicts: yes, we can

Hepatitis has been a major problem identified in intravenous drug users (IDUs) since the 1950's. Pioneering research leading to methadone maintenance treatment as effective pharmacotherapy of opiate addiction was conducted among IDUs in New York city in the 1960s; prospective studies conducted between 1964 and 1972 reported that 60-70% of all heroin addicts entering methadone treatment had evidence of liver disease (1). At the time, it was ascertained that many of these patients had hepatitis B virus (HBV) infection, a disorder then only recently characterized. However, it was quite clear that other forms of "non-A non-B hepatitis" and alcoholic liver disease were also present among these patients. By the end of the 1980s, studies from several laboratories identified that the major risk group for contracting the newly identified hepatitis C virus (HCV) infection were parenteral opiate and cocaine abusers (2). It is now well known that a history of intravenous drug use is the single strongest risk factor for acquiring HCV infection and that prevalence of HCV, particularly in IDUs older than 40 years of age, is over 70% (3-5). Methadone or buprenorphine maintenance treatment can be equated to a long-term therapy for opiate addiction equivalent to that employed for other chronic diseases (ie, diabetes, hypertension); however, stigma towards patients receiving treatment for addiction is still widespread. both in the general public as well as among physicians and health providers. In this issue of Digestive and Liver Disease, the study by Belfiori et al demonstrates that IDUs treated with pegylated interferon and ribavirin can achieve sustained virological response rates that are equivalent tot hose obtained in registration trials using these therapies. To obtain these responses, IDUs were treated by a multidisciplinary group consisting of infectious disease physicians, addiction medicine specialists, and psychiatrists. The success of their approach raises the question: why so many former opiate addicts are still not considered suitable candidates for antiviral therapy?

( BUPP09507 - 31 March 2009) Factors affecting willingness to provide buprenorphine treatment.

Buprenorphine is an effective long-term opioid agonist treatment. As the only pharmacological treatment for opioid dependence readily available in office-based settings, buprenorphine may facilitate a historic shift in addiction treatment from treatment facilities to general medical practices. Although many patients have benefited from the availability of buprenorphine in the United States, almost half of current prescribers are addiction specialists suggesting that buprenorphine treatment has not yet fully penetrated general practice settings. We examined factors affecting willingness to offer buprenorphine treatment among physicians with different levels of prescribing experience. Based on their prescribing practices, physicians were classified as experienced, novice, or as a nonprescriber and asked to assess the extent to which a list of factors impacted their prescription of buprenorphine. Several factors affected willingness to prescribe buprenorphine for all physicians: staff training; access to counseling and alternate treatment; visit time; buprenorphine availability; and pain medications concerns. Compared with other physicians, experienced prescribers were less concerned about induction logistics and access to expert consultation, clinical guidelines, and mental health services. They were more concerned with reimbursement. These data provide important insight into physician concerns about buprenorphine and have implications for practice, education, and policy change that may effectively support widespread adoption of buprenorphine.

( BUPP09506 - 31 March 2009) Herpes zoster and post-herpetic nevralgia in old adults

Varicella-Zoster virus is responsible for chickenpox and, after reactivation, herpes zoster. Herpes zoster causes a vesicular dermatomal rash, traditionally metameric. Old adults can present severe pain during the acute phase, and late complications, such as post-herpetic neuralgia that can trying and crippling. Initiated within the first 72 hours of the rash, antivirals accelerate rash healing, reducing both rash and acute pain severity but incompletely the onset of other complications. Complementary therapeutic drug is often necessary. However, their application in old, frail, co-morbid and often poly-medicated patients have to be carefully considered as their use may be contraindicated. A specific vaccine is enable to reduce herpes zoster-related morbidity.

( BUPP09505 - 31 March 2009) Nephrogenic systemic fibrosis: The first Italian gadolinium-proven case

Nephrogenic systemic fibrosis (NSF) is a systemic disease, recently described in patients with advanced chronic kidney disease (CKD), characterized by progressive scleromyxedema-like fibrotic involvement mainly of the skin. We describe the case of a 66-year-old woman on chronic hemodialysis for end-stage renal failure, also affected by hypothyroidism, secondary hyperparathyroidism and occluding arteriopathy, for which she underwent a contrast-enhanced magnetic resonance angiography of the lower limbs in February 2007. One month later, she began complaining of progressive, painful distal lower limb stiffness, which sub-sequently spread to all four limbs and to the whole trunk. A deep-skin biopsy, taken from an affected area, showed gadolinium deposits. The case reported is, to best of our knowledge, the first Italian case of NSF. This diagnosis should be considered with care in CKD patients with a recent exposure to a gadolinium-based contrast agent, complaining of limb stiffness, especially in the presence of risk factors.

( BUPP09504 - 31 March 2009) Self-administration of cocaine, cannabis and heroin in the human laboratory: Benefits and pitfalls

The objective of this review is to describe self-administration procedures for modeling addiction to cocaine, cannabis and heroin in the human laboratory, the benefits and pitfalls of the approach, and the methodological issues unique to each drug. In addition, the predictive validity of the model for testing treatment medications will be addressed. The results show that all three drugs of abuse are reliably and robustly self-administered by non-treatment-seeking research volunteers. In terms of pharmacotherapies, cocaine use is extraordinarily difficult to disrupt either in the laboratory or in the clinic. A range of medications has been shown to significantly decrease cocaine's subjective effects and craving without decreasing either cocaine self-administration or cocaine abuse by patients. These negative data combined with recent positive findings with modafinil suggest that self-administration procedures are an important intermediary step between pre-clinical and clinical studies. In terms of cannabis, a recent study suggests that medications that improve sleep and mood during cannabis withdrawal decrease the resumption of marijuana self-administration in abstinent volunteers. Clinical data on patients seeking treatment for their marijuana use are needed to validate these laboratory findings. Finally, in contrast to cannabis or cocaine dependence, there are three efficacious Food and Drug Administration-approved medications to treat opioid dependence, all of which decrease both heroin self-administration and subjective effects in the human laboratory. In summary, self-administration procedures provide meaningful behavioral data in a small number of individuals. These studies contribute to our understanding of the variables maintaining cocaine, marijuana and heroin intake, and are important in guiding the development of more effective drug treatment programs.

( BUPP09503 - 31 March 2009) Swiss multicenter study evaluating the efficacy, feasibility and safety of peginterferon-alfa-2a and ribavirin in patients with chronic hepatitis C in official opiate substitution programs

Background: Though patients in opiate substitution programs are commonly infected with HCV, due to safety and efficacy concerns, they are rarely treated with interferon and ribavirin. Methods: In a multicenter study, HCV-infected patients in opiate maintenance treatment programs received 180 mug pegylated interferon-alfa-2a once weekly, plus daily ribavirin for 24 weeks (genotypes 2, 3), or 48 weeks (genotypes 1, 4). Results: Of the 67 patients enrolled, 31 (46%) had HCV genotypes 1 or 4, and 36 (54%) had genotypes 2 or 3. Intent-to-treat analysis showed end-of-treatment virologic response in 75% of patients (81% of genotypes 2 or 3; 65% of genotypes 1 or 4), and a sustained virologic response in 61% of patients (72% of genotypes 2 or 3; 48% of genotypes 1 or 4). Fifteen patients (22%) did not complete the study, in 5 (8%) cases because of severe adverse events. Conclusions: Drug users with chronic HCV infection, regularly attending an opiate maintenance program in which close collaboration between hepatologists/internists and addiction specialists is assured, can be treated effectively and safely with pegylated interferon-alfa-2a and ribavirin. Treatment results are very similar to those in other patient groups, and thus therapy should also be considered for this population.

( BUPP09502 - 31 March 2009) Evaluation of transdermal buprenorphine for the treatment of chronic pain in cancer patients

Introduction: The concern with chronic severe pain in cancer patients is growing as antineoplastic therapeutic advances are procuring prolonged survival in many patients. This necessitates the development of new effective and safe analgesic treatments. For this purpose, the comparison of therapeutic outcomes with that obtained in non-cancer patients may be helpful. Methods: A prospective, uncontrolled observational study that included a 3 month follow-up of patients starting transdermal buprenorphine was performed. Information was collected systematically on pain relief, quality of life (EuroQol-5D questionnaire), comfort of patch use and adverse events. Missing data were imputed by carrying forward former observations. This article refers to the comparative results of a subgroup of 207 cancer patients with that of 968 non-cancer patients that participated in the same study. Results and conclusions: 30% of cancer patients switched to transdermal buprenorphine from other opioid drug. Dose increases were required by 44% of patients, and most occurred in the first month; this proportion being significantly greater (p<0.001) than among non-cancer patients (18.8%). More than two third achieved satisfactory pain relief, regardless of the origin of pain. There was a significant increase of quality of life score that was, nevertheless, lower among cancer patients (by an average of 12.2 mm in a visual analogue scale) than among non-cancer patients (17.1 mm); that was mainly attributed to pain improvement. The proportion of patients with adverse events was significantly lower among cancer (42.0%) than non-cancer patients (49.1%), p=0.010. This was true also for related adverse events and withdrawals because of adverse events. Conversely, more cancer patients had serious adverse events or died during follow-up; although in none case these were related to buprenorphine treatment. Conclusions: Within the opioid class, the transdermal formulation of buprenorphine is effective and safe for the treatment of moderate to severe chronic pain in non-terminal cancer patients.

( BUPP09501 - 31 March 2009) Process tnanagetnent in pain treattnent

The treatment of severe cancer pain is an obligation in addition to a necessity. In the paper we show a review of the pharmacological armamentarium we can use at the present time, to once consider based on the type of pain before which we were and established the opportune valuation the patient with the available instruments. In the therapeutic management one sets out in addition to the pharmacological treatment, the interventional one that can be benefitted some from these patients.

( BUPP09500 - 31 March 2009) Community-based treatment for chronic hepatitis C in drug users: High rates of compliance with therapy despite ongoing drug use

Chronic hepatitis C infection is common in drug users. Treatment of injectors is possible under controlled conditions, but many have not yet been included in treatment programmes as there are concerns about their ability to comply with therapy. It is not known which factors influence compliance. Aim: To examine the hypothesis that active drug users would comply with anti-viral therapy if treatment was delivered in a convenient manner. Methods: We established a community-based treatment programme and offered anti-viral therapy to all drug users who wanted it. Few pre-treatment requirements were imposed and, by design, compliance with therapy was reviewed after 50 patients had completed treatment. Results: Of the 441 patients who were known to be HCV RNA positive and attended the specialist addiction services during the period of this study, eighty three patients considered therapy. Twenty patients did not undergo treatment: 14 declined and 6 had medical conditions that precluded it. In 60 episodes (58 patients) where treatment had been completed, compliance was greater than 80% and homelessness, active illicit drug use and pre-treatment antidepressant therapy were not associated with noncompliance. In 25 of 49 treatment episodes that were assessed 6 months after treatment cessation, a sustained virological response (51%) was seen. Conclusion: Active drug users using illicit drugs can be successfully treated in community-based clinics.

( BUPP09499 - 31 March 2009) Transdermal buprenorphine: A current overview of pharmacological and clinical data

Our understanding of the pathophysiologic mechanisms of chronic pain progresses; the complexity of the problem justifies our need for new molecules and new ways of administration that will help to further optimise and better individualize our pharmacologic therapies. Whereas acute pain can be considered an alarm signal, chronic pain constitutes, per se, a syndrome that requires a meticulous selection of the analgesic drug(s). Since pain is permanent, the continuous administration of the analgesic is recommended rather than an on demand administration. Transdermic modes of administration are of value for the treatment of chronic pain because they allow a progressive delivery of the active compound together with the maintenance of stable plasma levels of the drug. Buprenorphine is a semi-synthetic opioid that is available in the sublingual, injectable, or transdermic forms. The matrix patch of buprenorphine represents a major asset for the treatment of chronic pain, whether it be cancerous in origin, or not. Its efficacy and safety have been clearly demonstrated in randomised double blind trials as well as in post-marketing surveillance observations. Buprenorphine, administered as a transdermal therapeutic system, induces a dose-related pain relief, whatever the nature of the pain and the age of the patient. Buprenorphine also exerts an analgesic action on neuropathic pain. It differs from other opioids by its affinity as a partial agonist on mu and kappa receptors, and as a complete agonist of ORL-1 receptors. Therefore, transdermal buprenorphine will be useful to all physicians having to control severe pain by powerful opioids.

( BUPP09498 - 31 March 2009) Effects of indomethacin and buprenorphine analgesia on the postoperative recovery of mice

( BUPP09497 - 31 March 2009) Response to Dr. Farris' letter to the editor

( BUPP09496 - 31 March 2009) Ad hoc Committee of the Croatian Society for Neurovascular Disorders, Croatian Medical Association: Recommendations for neuropathic pain treatment

Damage to the somatosensory nervous system poses a risk for the development of neuropathic pain. Such an injury to the nervous system results in a series of neurobiological events resulting in sensitization of both the peripheral and central nervous system. The symptoms include continuous background pain (often burning or crushing in nature) and spasmodic pain (shooting, stabbing or "electrical"). The diagnosis of neuropathic pain is based primarily on the history and physical examination finding. Although monotherapy is the ideal approach, rational polypharmacy is often pragmatically used. Several classes of drugs are moderately effective, but complete or near-complete relief is unlikely. Antidepressants and anticonvulsants are most commonly used. Opioid analgesics can provide some relief but are less effective than for nociceptive pain; adverse effects may prevent adequate analgesia. Topical drugs and a lidocaine-containing patch may be effective for peripheral syndromes. Sympathetic blockade is usually ineffective except for some patients with complex regional pain syndrome.

( BUPP09495 - 31 March 2009) Symptom management in geriatric oncology: Practical treatment considerations and current challenges

Symptom management of the actively treated elderly cancer patient represents an undertreated and disproportionately understudied cohort in oncology. There is a dearth of specific recommendations or guidelines regarding drug selection, dosing, and side effects which account for changes in aging physiology, pharmacokinetics, and idiosynchratic reactions. In treating cardinal symptoms and clusters of symptoms including pain, constipation, fatigue/weakness, nausea /vomiting, mucositis/xerostomia, and nutritional depletion syndromes such as malabsorption and anorexia/cachexia, most clinicians base their therapeutic decisions on individual experience. Depending on relative interest and level of competency, symptom management is often narrow in scope, frequently ineffective, and not based on evidence. We discuss these issues in a practical format, by surveying and comparing available core literature to the extent that it readily exists and by incorporating our own experiences.

( BUPP09494 - 31 March 2009) A 'pain-free' death

Background: The time around a patient's death is often filled with sadness, but good medical and nursing care can provide comfort to patients and their carers at this critical time. For many, a 'pain-free' death is a priority although there are other aspects to providing good care at the end of life. Honest, open discussion with patients and carers about their wishes is an essential prerequisite to individualized care. Sources of data: Relevant literature was reviewed with regards to policy, education and delivery of end of life care. Areas of agreement: Pain management must be tailored to the individual with due regard to the route of analgesic administration in those unable to swallow, and consideration to the other circumstances surrounding a person's care. All staff caring for dying patients should address pain as a priority in managing end of life care, to promote the best possible death for patients and prevent undue distress for carers and staff. Areas of controversy: This review has approached patient care at the end of life within current UK legislation, outlining what can be done to promote a 'pain-free' death. Debate continues about the role of euthanasia within end of life care and the use of analgesics and sedatives in pain management in terminal care. Growing points: There is a range of tools available to help staff to care for dying patients, such as the Liverpool Care Pathway (LCP) for the Dying. It is most effective when introduced as part of a wider system of staff education in relation to terminal care. Areas timely for developing research: Research into care of the dying will continue to be challenging. Priorities include; whether the use of tools such as the LCP improve the care patients receive, and the development of routine outcome measures including validated reports from patients and proxies.

( BUPP09493 - 30 March 2009) Long-term effects of bupivacaine on cartilage in a rabbit shoulder model

Background: Previous investigations have reported on the chondrotoxicity of bupivacaine in short-term in vivo and in vitro models. This study was designed to provide additional information on the long-term effects of bupivacaine infusion on articular cartilage in an established rabbit shoulder model. Hypothesis: Infusion of bupivacaine into the rabbit shoulder will have long-term deleterious effects on articular cartilage. Study Design: Controlled laboratory study. Methods: Thirty-six rabbits were randomized into 3 groups and were infused over 48 hours with saline (S), bupivacaine alone (B), or bupivacaine with epinephrine (B+E) into the glenohumeral joint. Animals were sacrificed after 3 months, and tissue samples were analyzed with live/dead cell assay, proteoglycan (PG) synthesis and content assays, and conventional histological evaluation. Results: No macroscopic or radiographic changes were detected in the infused shoulders. Sulfate uptake of infused shoulders relative to controls was elevated to 112% � 39% (S), 166% � 67% (B), and 210% � 127% (B+E). Statistical analysis of PG content demonstrated significantly increased levels in bupivacaine groups compared with saline. There were no significant differences among groups in cell count, percentage of living cells, or histological grade. Conclusions: No permanent impairment of cartilage function was detected 3 months after intra-articular infusion of bupivacaine. Cartilage metabolism was increased, indicating a possible reparative response. This suggests that, at least in the model used, articular cartilage has the ability to recover from the chondrotoxic effects of bupivacaine infusion. Before extrapolating these results to human cartilage, other factors including underlying cartilage injury or disease, decreased chondrocyte density, and increased bupivacaine dosing need to be taken into account. Clinical Relevance: Bupivacaine toxicity has recently been implicated in the development of chondrolysis after arthroscopic shoulder procedures, but these findings suggest that additional noxious stimuli might be required before permanent damage ensues.

( BUPP09492 - 30 March 2009) Screening for drug-facilitated sexual assault by means of liquid chromatography coupled to atmospheric-pressure chemical-ionisation- mass spectrometry (LC-APCI-MS)

Drug-facilitated crimes (sexual assaults, robbery) are common in many countries. The low concentration of date-rape drugs in blood and (often) the long delay between the crime and clinical examination make analysis of biological fluids collected from victims of rapes for presence of these drugs very difficult. The aim of this study was to develop and apply an LC-APCI-MS screening procedure for date-rape drugs in blood. The elaborated method allows simultaneous screening and detection of forty-two compounds. Target analytes were isolated using liquid-liquid extraction. Analyses were carried out using LC-MS operating in APCI mode. Detection of all compounds was based on pseudomolecular ions that were monitored in 6 groups, up to 19 ions in each group. The developed procedure can easily be expanded for more substances. The LC-APCI-MS procedure was successfully applied in routine casework to the analysis of authentic blood samples collected from victims of rapes.

( BUPP09491 - 30 March 2009) Seizures, illicit drugs, and ethanol

Recreational substance users are at risk for seizures by indirect mechanisms, including cerebral trauma, central nervous system infection, ischemic and hemorrhagic stroke, and metabolic derangements such as hypoglycemia, hypocalcemia, and renal failure. Drugs and ethanol can also cause seizures more directly, either as a feature of intoxication (eg, psychostimulants) or of withdrawal (eg, sedatives, including ethanol). In any patient with a seizure, clinicians should consider illicit drug or ethanol use. Seizures in known alcoholics or illicit drug users require workup to exclude treatable coexisting conditions.

( BUPP09490 - 30 March 2009) Assessment and management of breakthrough pain in cancer patients: Current approaches and emerging research.

Cancer pain is highly prevalent and often severe. Fortunately, most cancer pain can be readily managed, with up to 90% of patients responding well to standard interventions. However, breakthrough cancer pain - brief flares of severe pain superimposed on baseline pain - is common, difficult to manage, and often negatively impacts patients' quality of life. Breakthrough cancer pain is traditionally managed with oral, immediaterelease opioids. However, because of its sudden onset and severity, oral opioids often fall short of providing adequate control. Research into novel approaches to pain management has identified several innovative strategies for this difficult cancer pain problem. We describe current approaches to assess, define, characterize, and treat breakthrough cancer pain, and summarize recent clinical research on novel agents, novel routes of drug delivery, and other advances in its management.

( BUPP09489 - 30 March 2009) Training physicians to treat substance use disorders

The importance of training physicians to effectively assess and manage substance use disorders has become increasingly recognized. Studies highlighting the effort to enhance curricula are described and common practices identified. Preferable curricula incorporate interactive teaching methods along with experiential and didactic components. Addiction specialists serve an important role in training programs designed for medical students and residents (ie, role models) and practicing physicians (ie, clinical support). Further integration of online training into current programs may expand and enhance training opportunities.

( BUPP09488 - 30 March 2009) Caudal epidural block versus other methods of postoperative pain relief for circumcision in boys

Background: Techniques to minimize the postoperative discomfort of penile surgery, such as circumcision, include caudal block; penile block; systemic opioids and topical local anaesthetic cream, emulsion or gel. Objectives: To compare the effects of caudal epidural analgesia with other forms of postoperative analgesia following circumcision in boys. Search strategy: We searched CENTRAL (The Cochrane Library 2008, Issue 1), MEDLINE (to April 2008) and EMBASE (to April 2008). Selection criteria: Randomized and quasi-randomized trials of postoperative analgesia by caudal epidural block compared with non-caudal analgesia in boys, aged between 28 days and 16 years, having elective surgery for circumcision. Data collection and analysis: Two review authors independently carried out assessment of study eligibility, data extraction and assessment of the risk of bias in included studies. Main results: We included 10 trials involving 721 boys. No difference was seen between caudal and parenteral analgesia in the need for rescue or other analgesia (relative risk (RR) 0.41, 95% confidence interval (CI) 0.12 to 1.43; 4 trials, 235 boys; random-effects model) or on the incidence of nausea and vomiting (RR 0.61, 95% CI 0.36 to 1.05; 4 trials, 235 boys). No difference in the need for rescue or other analgesia was seen for caudal compared with dorsal nerve penile block (DNPB) (RR 1.25, 95% CI 0.64 to 2.44; 4 trials, 336 boys; random-effects model). No differences were seen between caudal block and DNPB in the incidence of nausea and vomiting (RR 1.88, 95% CI 0.70 to 5.04; 4 trials, 334 boys; random effects model) or individual complications except for motor block (RR 17.00, 95% CI 1.01 to 286.82; 1 trial, 100 boys) and motor or leg weakness (RR 10.67, 95% CI 1.32 to 86.09; 2 trials, 107 boys). These were significantly more common in the caudal block groups than with DNPB. No differences were seen between caudal and rectal or intravenous analgesia in the need for rescue analgesia or any other outcomes (2 trials, 162 boys). Authors' conclusions: Differences in the need for rescue or other analgesia could not be detected between caudal, parenteral and penile block methods. In day-case surgery, penile block may be preferable to caudal block in children old enough to walk due to the possibility of temporary leg weakness after caudal block. Evidence from trials is limited by small numbers and poor methodology. There is a need for properly designed trials comparing caudal epidural block with other methods such as morphine, simple analgesics and topical local anaesthetic creams, emulsions or gels.

( BUPP09487 - 30 March 2009) Psychosocial combined with agonist maintenance treatments versus agonist maintenance treatments alone for treatment of opioid dependence

Background: Maintenance treatments are effective in retaining patients in treatment and suppressing heroin use. Questions remain regarding the efficacy of additional psychosocial services offered by most maintenance programs. Objectives: To evaluate the effectiveness of any psychosocial plus any agonist maintenance treatment versus standard agonist treatment for opiate dependence in respect of retention in treatment, use of substances, health and social status. Search strategy: We searched: Cochrane Drugs and Alcohol Group's Register of Trials (February 2008), Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library issue 1, 2008), MEDLINE (January 1966 to February 2008), EMBASE (January 1980 to February 2008), CINAHL (January 2003-February 2008), PsycINFO (January 1985 to April 2003), reference lists of articles. Selection criteria: Randomised studies comparing any psychosocial plus any agonist with any agonist alone intervention for opiate dependence. Data collection and analysis: Three reviewers independently assessed trial quality and extracted data. Main results: Twenty eight trials, 2945 participants, were included. These studies considered twelve different psychosocial interventions and three pharmacological maintenance treatments. Comparing any psychosocial plus any maintenance pharmacological treatment to standard maintenance treatment, results do not show benefit for retention in treatment, 23 studies, 2193 participants, Relative Risk (RR) 1.02 (95% CI 0.97 to 1.07), use of opiate during the treatment, eight studies, 681 participants, RR 0.86 (95% CI 0.65 to 1.13), compliance, three studies, MD 0.43 (95% CI -0.05 to 0.92), psychiatric symptoms, four studies, MD 0.02 (-0.19 to 0.23), depression, four studies, MD -1.30 (95% CI -3.31 to 0.72) and results at follow up as number of participants still in treatment at the end of the follow-up , 289 participants, RR 0.91 (95% CI 0.77 to 1.06). In spite of results at follow up as number of participants abstinent at the end of the follow-up, five studies, 232 participants, show a benefit in favour of the associated treatment RR1.15 (95% CI 1.01 to 1.32). The remaining outcomes were analysed only in single studies considering a limited number of participants.Comparing the different psychosocial approaches, results are never statistically significant for all the comparisons and outcomes. Authors' conclusions: Results suggest that adding any psychosocial support to maintenance treatments improve the number of participants abstinent at follow up; no differences for the other outcome measures. Data do not show differences between different psychosocial interventions also for contingency approaches, contrary to all expectations. Duration of the studies was too short to analyse relevant outcomes such as mortality.

( BUPP09486 - 30 March 2009) Improve treatment of multiple sclerosis by defining specific pain syndromes and analysing their relationship to the disease

Pain, a common symptom in patients with multiple sclerosis, is frequently underestimated and poorly treated. Careful patient assessment and monitoring improves diagnosis of pain symptoms, while analysing these pain symptoms in the context of the disease improves analgesic therapy and enhances health-related quality of life.

( BUPP09485 - 30 March 2009) A French prospective observational study of the treatment of chronic hepatitis C in drug abusers: Answer to commentary

( BUPP09484 - 30 March 2009) Opioid therapy and restoration of the immune function in heroin-addicted patients

There are several reports suggesting that opioid compounds may influence the immune response. Studies carried out in experimental animals and in humans have shown that both innate and acquired immunity are significantly affected by opioids. From a molecular viewpoint, opioids behave like cytokines, modulating the immune response by interacting with their receptors both in the central nervous system and in the periphery. One of the main features of opioid-mediated modulation of the immune function is the development of immunosuppression, which has been documented in injecting heroin abusers. Over the last few years, however, evidence has been provided to suggest that various opioid drugs may have distinctive effects on the immune function. Data obtained from animal studies have demonstrated, for instance, that long-acting opioids, such as methadone and buprenorphine, are devoid of any intrinsic immunosuppressive activity. In this connection, the hypothesis, which was first put forward some years ago, that the normalization of altered cellular immunity can, in injecting heroin abusers, be achieved through long-term methadone or buprenorphine treatment, has been positively re-evaluated in recent times. Our group has recently investigated the immune response in heroin-addicted patients currently under methadone or buprenorphine maintenance treatment, comparing them with untreated heroin addicts and healthy controls. In agreement with the data obtained by other groups, our study has provided evidence confirming the 'immunoprotective' effect of longacting opioid drugs. From a pathophysiological viewpoint, the ability of opioids to modulate the immune function may have some bearing on the development of the infectious diseases that are often associated with drug abuse. The high percentage of infections among injecting drug users is partly related to injection methods and life-style practices, but it is now accepted that heroin-induced immunosuppression may contribute as a co-factor in the contraction of several microbial and viral infections, such as Hepatitis C virus (HCV) infection. Conversely, in view of the 'immunoprotective' action of some opioids, such as buprenorphine, it has now been proposed that the administration of these latter compounds may improve the outcome of chronic HCV virus infections

( BUPP09483 - 30 March 2009) Major policy and clinical developments in the use of methadone and buprenorphine treatment in the U.S.

( BUPP09521 - 06 April 2009) Pain management with opioid analgesics: Balancing risk & benefit

The "opioid pendulum" swings between providing adequate pain relief and preventing addiction, without solving either problem sufficiently. Policies to address prescription drug abuse in the United States sometimes appear to contradict a practice environment in which chronic pain can be adequately treated. Pharmacovigilance when prescribing controlled substances for chronic pain requires physicians to first make a risk/benefit analysis and then to reassess during ongoing treatment. It is important that physicians document this analysis with transparency so regulators can see that risk is being assessed and managed. Physicians must balance the benefits and risks of COAT so that they can continue to treat pain effectively and improve functional outcomes, while at the same time avoid indiscriminate prescribing. Physicians have an obligation to be thorough, thoughtful, logically consistent, and careful - but there is no realistic expectation that they will always be "right." Advances in the science and art of medicine emphasize rational patient assessment and selection for treatment, the benefits and limitations of pharmacologic and nonpharmacologic management, and careful monitoring. Even small changes to clinical practice can promote safe controlled substances prescribing, and will likely improve the overall standard of care.

( BUPP09520 - 06 April 2009) A rodent model of metabolic surgery for study of type 2 diabetes and positron emission tomography scanning of beta cell mass

Background: Type 2 diabetes mellitus is a worldwide healthcare problem with major socioeconomic implications. Metabolic surgical procedures have been shown to improve diabetes, but the mechanism of action is poorly understood. The Goto-Kakizaki (GK) rodent is a type 2 diabetic animal model that is ideally situated for studying the effect of surgery on diabetes; however, the operative mortality is high. The aim of this study was to describe the operative technique, improvements in perioperative management, and the technique of micro-positron emission tomography (PET) scanning of the beta-cell mass in GK rodents. Methods: A total of 53 GK rats were divided into 1 of 3 operative groups: sham, sleeve gastrectomy, and duodenojejunal bypass. A subset of animals underwent micro-PET scanning with (11C)-dihydrotetrabenazine to determine the vesicular monoamine transporter 2 binding index, an indicator of beta-cell mass. Results: The 30-day mortality in the sham and sleeve gastrectomy rodents was 0; however, 2 sleeve gastrectomy rodents developed enterocutaneous fistula and 1 developed an abscess. In the duodenojejunal bypass group, the initial mortality rate was close to 90%; however, refinements in the surgical technique and perioperative management (fluids, antibiotics, pain control) lowered the mortality rate to 60%. The surgical technique is discussed in detail. (11C)-Dihydrotetrabenazine uptake in the pancreas was demonstrated on micro-PET scanning in the sham and duodenojejunal bypass rodents. Conclusion: Intensive medical management in the perioperative period and attention to the operative technique lowered the mortality. (11C)-Dihydrotetrabenazine micro-PET scanning is a feasible method for assessing the beta-cell mass in GK rodents and could prove to be an important modality for evaluating beta-cell performance in type 2 diabetes.

( BUPP09519 - 06 April 2009) Infective endocarditis secondary to intravenous Subutex abuse

Introduction: Subutex (buprenophine) was approved by the Health Science Authority of Singapore for heroin detoxification in 2002. The number of heroin addicts has decreased in Singapore since the introduction of Subutex. However, Subutex abuse and its associated complications became arising medical problems. We report the management of a series of infective endocarditis cases secondary to Subutex abuse. Methods: We identified 12 cases of infective endocarditis in former heroin addicts treated with Subutex from August 2005 to April 2006. All patients were interviewed by the research coordinator and prospectively followed-up for two years. Results: The treatment period of Subutex endocarditis was often prolonged with a mean hospitalisation stay of 48 days, with 3.8 days in the intensive care unit. Multiple medical complications were noted. Staphylococcus aureus septicaemia accounted for 92 percent of cases. Mortality rate was 42 percent. Failure rate of medical therapy alone was common. 25 percent underwent open heart valve surgery. All patients were subsidised. Mean hospitalisation expenses was S$31,218. Conclusion: Subutex endocarditis causes signifcant morbidity and mortality. It imposes a heavy medical and financial burden to the patient and society. Multidisciplinary treatment involving cardiologists, infectious disease physicians, psychiatrists, surgeons, medical counsellors and social workers is required to manage these patients.

( BUPP09518 - 06 April 2009) The Underrecognized Toll of Prescription Opioid Abuse on Young Children

Study objective: The impact of prescription opioid abuse on young children is underrecognized and poorly documented. We hypothesize that poisoning of young children from prescription opioids occurs regularly in the United States and is associated with serious health events, including death. Methods: Using data from poison centers participating in the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System, exposures in children younger than 6 years, involving buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone (January 2003 to June 2006), were quantified and described. Results: We identified 9,179 children exposed to a prescription opioid. The median age was 2.0 years (range newborn to 5.5 years), and 54% were boys. Nearly all exposures involved ingestion (99%) and occurred in the home (92%). Exposures to any opioid were associated with 8 deaths, 43 major effects, and 214 moderate effects. Of 51 patients who experienced a major effect or death, 35 were treated with naloxone: a beneficial response was documented in 34 patients. All 5 exposures to buprenorphine associated with a major effect were treated with naloxone, and a beneficial response was recorded in all 5. Nearly all exposures were to medications prescribed for adults in the household. The number of prescriptions filled for an opioid in an area correlated well with exposures in young children in the same area; children have access to household members' prescription drugs. Conclusion: Young children are exposed to prescription opioids, typically prescribed for other patients, resulting in major health effects and death.

( BUPP09516 - 06 April 2009) Buprenorphine and methadone maintenance treatment - Sexual behaviour and dysfunction prevalence

Buprenorphine maintenance treatment has become a major intervention in the care and treatment of drug dependence in Europe. Still little is known about sexual behaviour and sexual dysfunction especially under buprenorphine or methadone maintenance treatment. Our study aimed to evaluate patterns of sexual behaviour and dysfunction prevalence within buprenorphine and methadone maintenance treatment. Significant differences between both groups could be observed regarding sexual excitation disturbances and ability to orgasm. 33.3% of the methadone-maintained group showed significantly higher sexual excitation disturbances (p = 0.006). Future studies of sexual dysfunction in opioid-treated persons should examine the potential benefits of dose reduction, androgen replacement, and choice of opioid.

( BUPP09515 - 06 April 2009) QTc interval screening in methadone treatment

Description: An independent panel developed cardiac safety recommendations for physicians prescribing methadone. Methods: Expert panel members reviewed and discussed the following sources regarding methadone: pertinent English-language literature identified from MEDLINE and EMBASE searches (1966 to June 2008), national substance abuse guidelines from the United States and other countries, information from regulatory authorities, and physician awareness of adverse cardiac effects. Recommendation 1 (Disclosure): Clinicians should inform patients of arrhythmia risk when they prescribe methadone. Recommendation 2 (Clinical History): Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope. Recommendation 3 (Screening): Obtain a pretreatment electrocardiogram for all patients to measure the QTc interval and a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures. Recommendation 4 (Risk Stratification): If the QTc interval is greater than 450 ms but less than 500 ms, discuss the potential risks and benefits with patients and monitor them more frequently. If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy. Recommendation 5 (Drug Interactions): Clinicians should be aware of interactions between methadone and other drugs that possess QT interval-prolonging properties or slow the elimination of methadone.

( BUPP09511 - 06 April 2009) First do no harm . . . reduction?

( BUPP09532 - 14 April 2009) Pediatric palliative care: Use of opioids for the management of pain

Pediatric palliative care (PPC) is provided to children experiencing life-limiting diseases (LLD) or life-threatening diseases (LTD). Sixty to 90% of children with LLD/LTD undergoing PPC receive opioids at the end of life. Analgesia is often insufficient. Reasons include a lack of knowledge concerning opioid prescribing and adjustment of opioid dose to changing requirements. The choice of first-line opioid is based on scientific evidence, pain pathophysiology, and available administration modes. Doses are calculated on a bodyweight basis up to a maximum absolute starting dose. Morphine remains the gold standard starting opioid in PPC. Long-term opioid choice and dose administration is determined by the pathology, analgesic effectiveness, and adverse effect profile. Slow-release oral morphine remains the dominant formulation for long-te rm use in PPC with hydromorphone slow-release preparations being the first rotation opioid when morphine shows severe adverse effects. The recently introduced fentanyl transdermal therapeutic system with a drug-release rate of 12.5 mug/hour matches the lower dose requirements of pediatric cancer pain control. Its use may be associated with less constipation compared with morphine use. Though oral transmucosal fentanyl citrate has reduced bioavailability (25%), it inherits potential for breakthrough pain management. However, the gold standard breakthrough opioid remains immediate-release morphine. Buprenorphine is of special clinical interest as a result of its different administration routes, long duration of action, and metabolism largely independent of renal function. Antihyperalgesic effects, induced through antagonism at the kappa-receptor, may contribute to its effectiveness in neuropathic pain. Methadone also has a long elimination half-life (19 'SD 14' hours) and NMDA receptor activity although dose administration is complicated by highly variable morphine equianalgesic equivalence (1 : 2.5-20). Opioid rotation to methadone requires special protocols that take this into account. Strategies to minimize adverse effects of long-term opioid treatment include dose reduction, symptomatic therapy, opioid rotation, and administration route change. Patient- or nurse- controlled analgesia devices are useful when pain is rapidly changing, or in terminal care where analgesic requirements may escalate. In this article, we present detailed pediatric pharmacokinetic and pharmacodynamic data for opioids, their indications and contraindications, as well as dose-administration regimens that include practical strategies for opioid switching and dose reduction. Additionally, we discuss the problem of hyperalgesia and the use of adjuvant drugs to support opioid therapy.

( BUPP09530 - 14 April 2009) Management of HIV infection in patients with substance use problems.

Although highly active antiretroviral therapy (HAART) has greatly reduced overall morbidity and mortality in patients with HIV, patients with substance use issues have been less likely than other patients with HIV to realize these benefits. Social obstacles (eg, lack of housing, minimal social support), and medical comorbidities (eg, mental illness, hepatitis), complicate the management of this group of patients. Not only are drug and alcohol users less likely to access medical care, initiation of HAART may be delayed due to concerns for adherence and the potential development of drug resistance. Ultimately, a multidisciplinary comprehensive approach is needed to both engage and retain this population in care. Through the integration of case management, addiction therapy, and medical treatment of HIV, we may be able to improve out-comes for patients with HIV and addiction. � Current Medicine Group LLC 2008.

( BUPP09529 - 14 April 2009) Comparison of the effects of intrathecal administration of levobupivacaine and lidocaine on the prostaglandin E /sub 2/ and glutamate increases in cerebrospinal fluid: A microdialysis study in freely moving rats

Background: Bupivacaine has a lower incidence of transient neurological symptoms than lidocaine after intrathecal (i.t.) injection. The increased toxic potential of lidocaine does not support its use in the clinical setting and could be related to augmented levels of spinal prostaglandin E /sub 2/ (PGE /sub 2/ ). We tested whether levobupivacaine leads to lower PGE /sub 2/ levels than lidocaine. Moreover, we compared the release of PGE /sub 2/ and glutamate after i.t. injections of levobupivacaine or lidocaine. Methods: Rats were anaesthetized for implantation of an i.t. dialysis catheter. This allowed sampling dialysates of cerebrospinal fluid (CSF) for measuring PGE /sub 2/ and glutamate levels. The microdialysis setting included baseline sampling and was followed by an i.t. injection of levobupivacaine 250 mug, 100 mug, or saline. PGE /sub 2/ and glutamate levels in CSF were analysed for 4 h. In addition, the residual effect of a second i.t. injection on, respectively, of PGE /sub 2/ and glutamate changes was compared after injection of either 250 or 100 mug levobupivacaine, 1000 or 400 mug lidocaine, or saline.Results: Prolonged spinal PGE /sub 2/ increases lasting 50-120 min were observed after levobupivacaine injection. Higher PGE /sub 2/ concentrations were observed after the second lidocaine 1000 mug injection. Glutamate release after the second injection did not vary between the local anaesthetic groups. Conclusions: Spinal PGE /sub 2/ levels are similarly increased after i.t. levobupivacaine injection of 250 and 100 mug. A higher PGE /sub 2/ response was observed after a second i.t. injection in the animals receiving 1000 mug lidocaine than those receiving 400 mg lidocaine or either dose of levobupivacaine.

( BUPP09528 - 14 April 2009) Comparison of the analgesic properties of transdermally administered fentanyl and intramuscularly administered buprenorphine during and following experimental orthopedic surgery in sheep

Objective - To evaluate the analgesic properties of transdermally administered fentanyl and IM administered buprenorphine in sheep undergoing unilateral tibial osteotomy. Animals - 20 mature sheep. Procedures - Fentanyl patches (n = 15 sheep) or placebo patches (5 sheep) were applied 12 hours before sheep underwent general anesthesia and a unilateral tibial osteotomy. Buprenorphine was administered to the placebo group every 6 hours commencing at time of induction. Signs of pain were assessed every 12 hours after surgery by 2 independent observers unaware of treatment groups. Results - There were no differences in preoperative and intraoperative physiologic data between the 2 groups. Sheep treated with fentanyl required less preoperative administration of diazepam for sedation and had significantly lower postoperative pain scores, compared with those treated with buprenorphine. No complications associated with the antebrachium at the site of patch application were detected. Conclusions and Clinical Relevance - Under the conditions of this study, transdermally administered fentanyl was a superior option to IM administered buprenorphine for alleviation of postoperative orthopedic pain in sheep. This information can be used to assist clinicians in the development of a rational analgesic regimen for research and clinical patients.

( BUPP09527 - 14 April 2009) Activities of hospital drug committees

( BUPP09526 - 14 April 2009) Case 9-2009: An 81-year-old man with massive rectal bleeding

( BUPP09525 - 14 April 2009) Adjunctive medical therapy with an alpha-1A-specific blocker after shock wave lithotripsy of lower ureteral stones

Introduction: We assessed the efficacy of using an alpha-1A-specific blocker for improving the success rate in shock wave lithotripsy (SWL) for lower ureteral stones. Materials and Methods: This prospective study was conducted from June 2005 to December 2006 and involved 107 patients. All the patients underwent SWL with the PCK Stonelith. The patients were randomly divided into 3 groups: group 1 (34 patients) received tamsulosin, group 2 (35 patients) received terazosin, and group 3 (38 patients) received placebo. All patients were diagnosed by kidney-ureter-bladder X-ray, abdominal ultrasonography and intravenous urography. The number of colic episodes, lower urinary tract symptoms, analgesic dosage and days for spontaneous passage of the stones through the ureter were recorded by diary. Statistical analyses were performed using ANOVA, the chi /sup 2/ test, Fisher's exact test and the non-parametric Wilcoxon 2-sample t test. Results: There were no differences between the groups regarding age, stone size, expulsion time and expulsion rate. The number of colic episodes and the analgesic dosage were significantly lower in group 1 compared with groups 2 and 3. A statistically significant difference was observed in lower urinary tract symptoms: lower urinary tract symptoms were observed in 4 of 34 patients in group 1 (12%), in 8 of 35 in group 2 (23%), and in 13 of 38 in group 3 (34%). Adverse effects were noted in 5 of 32 patients in group 2 (16%), which was significantly different in comparison with group 3. Conclusions: Administration of an alpha-1A-specific blocker reduced analgesic dosage and colic episodes after SWL of lower ureteral stones. There was no benefit with regard to increasing stone expulsion rate or decreasing expulsion time.

( BUPP09523 - 14 April 2009) Psychopathological changes and quality of life in hepatitis C virus-infected, opioid-dependent patients during maintenance therapy

To examine among maintenance patients (methadone or buprenorphine) with and without hepatitis C virus (HCV) infection (i) the frequency of psychopathological symptoms at baseline and 1-year follow-up; (ii) the association between antiviral interferon (IFN) treatment and psychopathological symptoms; and (iii) to explore whether IFN therapy has an effect on 1-year outcome of maintenance treatment. Naturalistic prospective longitudinal cohort design. A total of 223 substitution centres in Germany.A nationally representative sample of 2414 maintenance patients, namely 800 without and 1614 with HCV infection, of whom 122 received IFN therapy.HCV infection (HCV+/HCV-), IFN (IFN+/IFN-) treatment status and clinical measures. Diagnostic status and severity (rated by clinician), psychopathology (BSI-Brief Symptom Inventory) and quality of life (EQ-5D-EuroQol Group questionnaire). HCV+ patients revealed indications for a moderately increased psychopathological burden and poorer quality of life at baseline and follow-up compared to HCV- patients. HCV+ patients showed a marked deterioration over time only in the BSI subscale somatization (P = 0.002), and the frequency of sleep disorders almost doubled over time (12.8% at baseline; 24.1% at follow-up; P < 0.01). IFN treatment, received by 10% of HCV+ patients, did not impair efficacy or tolerability of maintenance therapy and was associated overall with neither increased psychopathological burden nor reduced quality of life. Findings suggest no increased risk among HCV+ patients on maintenance therapy for depressive or other psychopathological syndromes. In our patient sample, IFN treatment was not associated with increased psychopathological burden, reduced quality of life or poorer tolerability and efficacy of maintenance treatment.

( BUPP09522 - 14 April 2009) Haemodynamic and electrocardiographic changes after spinal administration of combinations ketamine with bupivacaine, xylazine or buprenorphine at lumbosacral space in healthy buffalo calves

The study was undertaken to evaluate the haemodynamic and electrocardiographic changes following spinal administration of combinations of ketamine with bupivacaine, xylazine or buprenorphine in buffalo calves. Eighteen buffalo calves were used in three equal groups A, B and C. The combinations of ketamine (2.5 mg/kg b.wt.) with bupivacaine (0.25 mg/kg b.wt.) were administered spinally at lumbosacral space in group A, B and C, respectively. The MAP CVP and ECG were recorded at different intervals up to 180 min of drugs injection.The results indicated least alterations in haemodynamic and ECG parameters after spinal administration of bupivacaine and ketamine combination, as compared to others. Combination of buprenorphine and ketamine produced irregular ECG pattern. pattern.

( BUPP09560 - 05 May 2009) Window to other specialties: Maximum dosage of high risk drugs

11 May 2009 - copy not available from the Birtish Library

( BUPP09559 - 29 April 2009) Oxymorphone and opioid rotation

To obtain the durable benefits of opioid analgesia, physicians must develop strategies to manage the negative attributes of opioid therapy. Side effects, opioid tolerance, and toxicity limit the use of opioids, yet specific guidelines have not emerged for appropriate doses. Furthermore, there are wide variations in interindividual responsiveness to opioid analgesia. Opioid rotation is an effective, emerging strategy to help manage the negative effects of opioids by limiting doses required to obtain pain relief with tolerable side effects. Tolerance to one particular type of opioid does not necessarily develop at the same rate as tolerance to another opioid (incomplete cross-tolerance). Side effects may vary and generally are reduced at lower doses. Oxymorphone is a highly potent molecule that offers linear dose proportionality, multiple preparations (IV, immediate release, extended release) and good analgesic effect. Strategies for rotating a patient from an opioid to oxymorphone require dose calculation based on equianalgesia, a conversion period and dose titration. In addition to converting a patient from other oral opioids to oxymorphone, special strategies are needed for particular preparations (extended release to extended release; extended release to immediate release to extended release; cross-titration; in-patient titration). Issues in opioid rotation involving oxymorphone are common to other opioid rotation plans: side effects, in particular nausea and constipation, as well as toxicity concerns. While pain patients present a unique challenge to physicians, opioid analgesia involving oxymorphone and opioid rotation strategies have been shown to be effective in pain management in some patients with tolerable side effects.

( BUPP09558 - 29 April 2009) Immunoassays for drugs of abuse: Limitations

( BUPP09557 - 29 April 2009) Reported analgesic and anaesthetic administration to rodents undergoing experimental surgical procedures

A structured literature review was carried out to assess recent trends in the administration of analgesics and anaesthetics to laboratory rats and mice undergoing surgical procedures. The Science Direct database was used to systematically identify studies published in peer-reviewed journals over two periods (2000-2001 and 2005-2006), 86 studies from each time period were included in the review. The total number of animals that underwent surgery, species used, type of procedure, anaesthetic regimen and analgesic administration were noted for each study. There was an increase in the reported administration of systemic analgesics from 10% in 2000-2001 to 20% in 2005-2006. Buprenorphine was the most commonly reported analgesic in both periods (2000-2001: 78%, 2005-2006: 35%) and reporting the use of non-steroidal anti-inflammatory drugs increased from 11% to 53%. There was also a change in reported anaesthetic practices, notably a decrease in the use of pentobarbital and an increase in the use of isoflurane and ketamine/xylazine. Although reported administration of analgesics has increased and there has been some refinement in the selection of anaesthetic agents used, the findings of this review suggest that there is still significant scope for improvement with respect to the perioperative care of laboratory rodents.

( BUPP09556 - 29 April 2009) Relative Importance of Intestinal and Hepatic Glucuronidation-Impact on the Prediction of Drug Clearance

Purpose: To assess the extent of intestinal and hepatic glucuronidation in vitro and resulting implications on glucuronidation clearance prediction. Methods: Alamethicin activated human intestinal (HIM) and hepatic (HLM) microsomes were used to obtain intrinsic glucuronidation clearance (CL /sub int, UGT/ ) for nine drugs using substrate depletion. The in vitro extent of glucuronidation (fm /sub UGT/ ) was determined using P450 and UGT cofactors. Utility of hepatic CL /sub int/ for the prediction of in vivo clearance was assessed. Results: fm /sub UGT/ (8-100%) was comparable between HLM and HIM with the exception of troglitazone, where a nine-fold difference was observed (8% and 74%, respectively). Scaled intestinal CL /sub int, UGT/ (per g tissue) was six- and nine-fold higher than hepatic for raloxifene and troglitazone, respectively, and comparable to hepatic for naloxone. The remaining drugs had a higher hepatic than intestinal CL /sub int, UGT/ (average five-fold). For all drugs with P450 clearance, hepatic CL /sub int, CYP/ was higher than intestinal (average 15-fold). Hepatic CL /sub int, UGT/ predicted on average 22% of observed in vivo CL /sub int/ ; with the exception of raloxifene and troglitazone, where the prediction was only 3%. Conclusion: Intestinal glucuronidation should be incorporated into clearance prediction, especially for compounds metabolised by intestine specific UGTs. Alamethicin activated microsomes are useful for the assessment of intestinal glucuronidation and fm /sub UGT/ in vitro.

( BUPP09555 - 29 April 2009) Magnetic Resonance Imaging of Acute Injury in Rats and the Effects of Buprenorphine on Limb Volume

The purposes of this study were to determine 1) whether magnetic resonance imaging (MRI)-based T2 mapping and measurements of limb volume can differentiate injured and uninjured tissue after blunt trauma to rat hindlimbs and 2) whether administration of buprenorphine influences these assessments. Male Wistar rats (age, 3 to 4 mo) underwent blunt contusion injury to the posterior aspect of the hindlimb; MRI was conducted at 6,12,24,48, 72, and 96 h after injury. The imaging results showed that administration of buprenorphine had no effect on the T2 value {area under the receiver operating characteristic (ROC) curve: with drug, 0.869 (95% confidence interval (CI), 0.78 to 0.96); without drug, 0.809 (95% CI, 0.72 to 0.90)} but did influence limb volume (area under the ROC curve; without drug, 0.954 (95% CI, 0.92 to 0.99); with drug, 0.713 (95% CI, 0.61 to 0.82)). When using MRI to determine the extent of injury or to track injury over time, calculated limb volumes may lose sensitivity to detect injury, due to the intrinsic increase in volume from morphine-derived drugs. During administration of morphine derivatives, T2 maps may provide more accurate assessments of muscle tissue injury both initially after injury and over time.

( BUPP09554 - 29 April 2009) Comparison of Buprenorphine and Butorphanol Analgesia in the Eastern Red-Spotted Newt (Notophthalmus viridescens)

The experimental use of amphibian models in biomedical research increases yearly, but there is a paucity of reports concerning analgesic use in many of these species. In this study, buprenorphine given by intracoelomic injection and butorphanol added to the tank water were compared for analgesic effect in the eastern red-spotted newt after bilateral forelimb amputations. Newts undergoing anesthesia but not surgery and newts having surgery but not given analgesia postoperatively were used as control groups. Animals were tested for food consumption, spontaneous movement, response to tapping on the tank, response to being touched, and body posture. Both buprenorphine by intracoelomic injection and butorphanol in tank water significantly promoted resumption of normal behavior after bilateral surgical amputation of the forelimbs. The difference between analgesic treatment and no analgesic treatment was maintained until 72 h after surgery.

( BUPP09553 - 29 April 2009) (Infants of drug-addicted mothers: pitfalls of replacement therapy)

Maternal drug addiction can cause problems for the fetus and the newborn, and hamper long-term development. The prevalence of drug addiction during pregnancy varies from 1 % to more than 10 % depending on the country and the maternity unit. Management of these mothers can be further complicated by medical, social and psychological problems. Compared to methadone, heroin replacement therapy with buprenorphine provides better stabilization of the mother and causes fewer withdrawal symptoms in the newborn. Despite numerous publications on the effects of this partly preventive medication, data on buprenorphine pharmacology at birth are scarce. In this study, 20 newborns of mothers using oral buprenorphine were observed until the end of the withdrawal syndrome, when present. Buprenorphine plasma levels were determined with HPLC and mass spectrometry in the mother at delivery and in the newborn at birth (cord blood), 24 and 48 hours. Fifteen newborns were born at term (mean +/- SD birth weight 3029 +/- 273 g), and the other five between 32 and 36 weeks. All Apgar scores were > or =7. Withdrawal symptoms were observed in 8 of the 15 infants born to mothers taking buprenorphine alone, and lasted between 5 and 35 days. The newborns were classified in three groups. Groups I (N8) and II (N7) comprised newborns with and without withdrawal symptoms, respectively. In group III (N5), the mothers were polyintoxicated (as shown by urinary drug or neurotropic substance screening) and the newborns were symptomatic for 1 to 69 days. Buprenorphine plasma levels in the mothers ranged from 0 to 2.9 microg/L, suggesting large differences in adherence. At birth there was no significant difference in the mean plasma buprenorphine level between newborns with and without withdrawal symptoms; the respective values were 0.7 (0.4-1.3) and 0.5 (0-0.6) microg/L. In asymptomatic newborns (group II), buprenorphine was no longer detectable at 48 h, whereas in symptomatic newborns (group I), the mean level rose from 0.7 microg/l at birth to 1.5 microg/L at 48 h (+114 %). In the absence of breastfeeding, this increase appears to be related to tissue release of this strongly lipophilic compound. The difference in plasma buprenorphine kinetics between groups I and II might be explained by genetic polymorphism of drug-metabolizing enzymes. The paradoxically high plasma buprenorphine levels at 48 hours in infants with withdrawal symptoms are intriguing. One possibility is that the mothers missed one or several doses of buprenorphine around the time of delivery, in the same way that smoking mothers tend to cut down during the last days of their pregnancy. If buprenorphine plasma levels at birth appear to reflect maternal adherence, cord blood levels do not predict the risk of a withdrawal syndrome. In contrast, the level at 48 h might help to discriminate between high- and low-risk newborns. Pregnant women on opiate replacement therapy must be delivered in maternity units with adequate neonatal facilities.

( BUPP09552 - 29 April 2009) Brief vs. Extended Buprenorphine Detoxification in a Community Treatment Program: Engagement and Short-Term Outcomes

Background: Despite evidence supporting the efficacy of buprenorphine relative to established detoxification agents such as clonidine, little research has examined: 1) how best to implement buprenorphine detoxification in outpatient settings; and 2) whether extending the length of buprenorphine detoxification improves treatment engagement and outcomes. Objectives: The current study examined the impact on 1) successful detoxification completion; 2) transition to longer-term treatment; and 3) treatment engagement of two different length opioid detoxifications using buprenorphine. Methods: The study compared data obtained from two consecutive studies of early treatment engagement strategies. In one study (n = 364), opioid-addicted participants entered treatment through a Brief (5-day) buprenorphine detoxification. In the other study (n = 146), participants entered treatment through an Extended (i.e., 30-day) buprenorphine detoxification. Results: Results indicated a greater likelihood of successful completion and of transition among participants who received the Extended as compared to the Brief detoxification. Extended detoxification participants attended more counseling sessions and submitted fewer drug-positive urine specimens during the first 30 days of treatment, inclusive of detoxification, than did Brief detoxification participants. Conclusions: Results demonstrate that longer periods of detoxification improve participant engagement in treatment and early treatment outcomes. Scientific Significance: Current findings demonstrate the feasibility of implementing an extended buprenorphine detoxification within a community-based treatment clinic

( BUPP09551 - 29 April 2009) Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market

Background: Diversion of buprenorphine (BPN) has been described in settings where it is legally prescribed and has resulted in increasing concern. To address this concern, co-formulation of buprenorphine/naloxone (BPN/NLX) replaced buprenorphine alone in Malaysia in December 2006. Methods: To assess the significance of BPN/NLX introduction, 41 BPN/NLX injectors in Kuala Lumpur, Malaysia were recruited using a modified snowball recruitment technique. Results: In January 2007, all subjects had previously injected BPN alone. During the transition from injecting BPN alone to co-formulated BPN/NLX, the mean daily BPN injection dose increased from 1.88 mg (range 1.0-4.0 mg) to 2.49 mg/day (p .001). Overall, 18 (44%) subjects increased their daily amount of injection while 22 (54%) had no change in dose; only one subject reduced the amount of injection. Development of opioid withdrawal symptoms was the primary outcome, however the only symptom that was significantly associated with BPN/NLX dosage was the report of stomach pains (p = .01). In logistic regression analysis, the development of opioid withdrawal symptoms was associated with increased benzodiazepine injection and increased syringe sharing. Conclusion and Scientific Significance: These data suggests that the introduction of BPN/NLX did not reduce injection related risk behaviors such as syringe sharing and was associated with increased benzodiazepine use. Evidence-based approaches to treat BPN injection are urgently needed.

( BUPP09550 - 29 April 2009) Evaluation of buprenorphine in a postoperative pain model in rats

We evaluated the commonly prescribed analgesic buprenorphine in a postoperative pain model in rats, assessing acute postoperative pain relief, rebound hyperalgesia, and the long-term effects of postoperative opioid treatment on subsequent opioid exposure. Rats received surgery (paw incision under isoflurane anesthesia), sham surgery (anesthesia only), or neither and were treated postoperatively with 1 of several doses of subcutaneous buprenorphine. Pain sensitivity to noxious and nonnoxious mechanical stimuli at the site of injury (primary pain) was assessed at 1, 4, 24, and 72 h after surgery. Pain sensitivity at a site distal to the injury (secondary pain) was assessed at 24 and 72 h after surgery. Rats were tested for their sensitivity to the analgesic and locomotor effects of morphine 9 to 10 d after surgery. Buprenorphine at 0.05 mg /kg SC was determined to be the most effective; this dose induced isoalgesia during the acute postoperative period and the longest period of pain relief, and it did not induce long-term changes in opioid sensitivity in 2 functional measures of the opioid system. A lower dose of buprenorphine (0.01 mg/kg SC) did not meet the criterion for isoalgesia, and a higher dose (0.1 mg/kg SC) was less effective in pain relief at later recovery periods and induced a long-lasting opioid tolerance, indicating greater neural adaptations. These results support the use of 0.05 mg/kg SC buprenorphine as the upper dose limit for effective treatment of postoperative pain in rats and suggest that higher doses produce long-term effects on opioid sensitivity

( BUPP09549 - 29 April 2009) Buprenorphine: a review

A significant breakthrough in the treatment of opioid addiction occurred with the passage of the Data Addiction Treatment Act of 2000 (DATA 2000), signed into law by President Clinton, which allowed physicians for the first time in more than eight decades to prescribe opioid medications for the treatment of opioid addiction in the normal course of their practice. Two years later, on October 8, 2002, Suboxone (Buprenorphine/Naloxone) and Subutex (Buprenorphine) received FDA approval for the treatment of opioid addiction. Prior to DATA 2000, opioid maintenance treatment was available through highly regulated methadone clinics. This article discusses opioid addiction in the United States today and the principles of buprenorphine therapy.

( BUPP09548 - 29 April 2009) Opiates

( BUPP09547 - 29 April 2009) Interventions Used With Cholescintigraphy for the Diagnosis of Hepatobiliary Disease

Since the early 1980s interventions have been used in conjunction with /sup 99m/ Tc-iminodiacetic acid (IDA) radiopharmaceuticals in many different clinical situations, eg, to prepare the patient for the study, to reduce the time of a study, to improve its diagnostic accuracy, and to make diagnoses not otherwise possible. Interventions all have underlying physiological rationales. Some of these interventions are as simple as having the patient fast before the study or eat a meal with high fat content. However, most are pharmacologic interventions, eg, morphine sulfate, cholecystokinin, and phenobarbital. Although these are probably the most common interventions used today, numerous other interventions have been used during the years and likely will be in the future. Interventions have aided in the diagnosis of acute cholecystitis, chronic cholecystitis, biliary obstruction, and sphincter of Oddi dysfunction. This review will discuss in detail the interventions commonly is use today and in somewhat less detail many that have been successfully used on an investigational basis and may have some larger role in the future.

( BUPP09546 - 29 April 2009) Pain therapy

Cancer-related pain is a major issue of healthcare systems worldwide. The reported incidence, considering all stages of the disease, is 51%, which can increase to 74% in the advanced and terminal stages. For advanced cancer, pain is moderate to severe in about 40-50% and very severe or excruciating in 25-30% of cases. Pain is both a sensation and an emotional experience. Pain is always subjective; and may be affected by emotional, social and spiritual components thus it has been defined as "total pain". From a pathophysiological point of view, pain can be classified as nociceptive (somatic and visceral), neuropathic (central, peripheral, sympathetic) idiopathic or psychogenic. A proper pain assessment is fundamental for an effective and individualised treatment. In 1986 the World Health Organisation (WHO) published analgesic guidelines for the treatment of cancer pain based on a three-step ladder and practical recommendations. These guidelines serve as an algorithm for a sequential pharmacological approach to treatment according to the intensity of pain as reported by the patient. The WHO analgesic ladder remains the clinical model for pain therapy. Its clinical application should be employed only after a complete and comprehensive assessment and evaluation based on the needs of each patient. When applying the WHO guidelines, up to 90% of patients can find relief regardless of the settings of care, social and/or cultural environment. This is the standard treatment on a type C basis. Only when such an approach is ineffective are interventions such as spinal administration of opioid analgesics or neuroinvasive procedures recommended.

( BUPP09545 - 29 April 2009) Betting on Change: Modeling Transitional Probabilities to Guide Therapy Development for Opioid Dependence

This study investigated the process of change by modeling transitions among four clinical states encountered in 64 detoxified opiate-dependent individuals treated with daily oral naltrexone: no opiate use, blocked opiate use (i.e., opiate use while adhering to oral naltrexone), unblocked opiate use (i.e., opiate use after having discontinued oral naltrexone), and treatment dropout. The effects of baseline characteristics and two psychosocial interventions of differing intensity, behavioral naltrexone therapy (BNT) and compliance enhancement (CE), on these transitions were studied. Participants using greater quantities of opiates were more likely than other participants to be retained in BNT relative to CE. Markov modeling indicated a transition from abstinence to treatment dropout was approximately 3.56 times greater among participants in CE relative to participants in BNT, indicating the more comprehensive psychosocial intervention kept participants engaged in treatment longer. Transitions to stopping treatment were more likely to occur after unblocked opiate use in both treatments. Continued opiate use while being blocked accounted for a relatively low proportion of transitions to abstinence and may have more deleterious effects later in a treatment episode.

( BUPP09544 - 29 April 2009) Frequency, Indications, Outcomes, and Predictive Factors of Opioid Switching in an Acute Palliative Care Unit

The aim of this study was to prospectively evaluate the frequency, indications, outcomes, and predictive factors associated with opioid switching, using a protocol that had been clinically applied and viewed as effective for many years. A prospective study was carried out on a cohort of consecutive cancer patients who were receiving opioids but had an unacceptable balance between analgesia and adverse effects, despite symptomatic treatment of side effects. The initial conversion ratio between opioids and routes was as follows (mg/day): oral morphine 100 = intravenous morphine 33 = transdermal fentanyl 1 = intravenous fentanyl 1 = oral methadone 20 = intravenous methadone 16 = oral oxycodone 70 = transdermal buprenorphine 1.3. The switch was assisted by opioids used as needed, and doses were changed after the initial conversion according to clinical response in an acute care setting. Intensity of pain and symptoms associated with opioid therapy were recorded. A distress score (DS) was calculated as a sum of symptom intensity. A switch was considered successful when the intensity of pain and/or DS, or the principal symptom necessitating the switch, decreased to at least 33% of the value recorded before switching. One hundred eighteen patients underwent opioid substitutions. The indications for opioid switching were uncontrolled pain and adverse effects (50.8%), adverse effects (28.8%), uncontrolled pain (15.2%), and convenience (4.2%). Overall, 103 substitutions were successful. Ninety-six substitutions were successful after the first switching, and a further substitution was successful in seven patients who did not respond to the first switch. The mean time to achieve dose stabilization after switching was 3.2 days. The presence of both poor pain control and adverse effects was related to unsuccessful switching (P < 0.004). No relationship was identified between unsuccessful switching and the opioid dose, opioid sequence, pain mechanism, or use of adjuvant medications. Opioid switching was an effective method to improve the balance between analgesia and adverse effects in more than 80% of cancer patients with a poor response to an opioid. The presence of both poor pain relief and adverse effects is a negative factor for switching prognosis, whereas renal failure is not.

( BUPP09533 - 29 April 2009) Considerations on the use of opioids in chronic pain of elderly patients

The number of elderly patients is increasing every day in our society. Old age, formerly a privilege of the few, is now reached by many people, who often lead social and active lives and who are also in good health. However, as one reaches sixty-five years of age and beyond, there is a gradual reduction in one's functional abilities and, as a result, chronic diseases are common leading to disabilities. Medical care seeks to extend the lives of the elderly but, more importantly, to improve their quality of life. We believe, as the main objective of our work, that it is essential to learn the physiological, pharmacokinetic and pharmacodynamic characteristics of elderly patients for the proper management and control of analgesic use while ensuring minimal risk. Similarly, we believe that increasing an elderly patient's functional abilities and quality of life are also of the utmost importance. Opioid analgesics represent a key therapeutic weapon in the management of moderate-severe pain. Despite the reluctance to use opioids in dealing with the chronic pain of elderly patients, its analgesic efficacy and high safety profile have now been proven. Thus, we must be guided by the risk-benefit equation when it comes to considering analgesic treatments for elderly patients, always mindful of their physiological, pharmacokinetic and pharmacodynamic characteristics. As a final thought, we acknowledge the high prevalence of pain in the elderly but would like to stress that many of them do not receive proper treatment. Pharmacological research has helped to develop a great amount of therapeutic drugs for pain treatment, demonstrating that opioid analgesics represent a key therapeutic weapon in the management of moderate-severe pain with a high rate of analgesic efficacy and a high safety profile. elderly, chronic pain, opioids.

( BUPP09565 - 05 May 2009) Drug Abuse Treatment Beyond Prison Walls

The period surrounding release from prison is a critical time for parolees, bearing the potential for a drug-free and crime-free life in the community but also high risks for recidivism and relapse to drugs. The authors describe two projects. The first illustrates the sue of a formal Delphi process to elicit and combine the expertise of treatment providers, researchers, corrections personnel, and other stakeholders in a set of statewide guidelines for facilitating re-entry.The second project is a six-session intervention to enable women to protect themselves against acquiring or transmitting HIV in their intimate relationships.

( BUPP09564 - 05 May 2009) Commentary - What more do we need to know about medication - assisted treatment for prescription opioid abusers?

( BUPP09563 - 05 May 2009) Retention in methadone maintenance drug treatment for prescription-type opioid primary users compared to heroin users

Aims - To assess retention in methadone maintenance treatment for prescription-type opioid primary (PTOP) users compared to heroin users. Design and participants - A retrospective cohort study was carried out to examine the association between opiate types used on 12-month retention. The study population consisted of adults admitted to one of 11 not-for-profit methadone maintenance clinics in 2004 and 2005 throughout Washington State (n = 2308). Logistic regression analyses with fixed effects for treatment agencies were conducted. Measurements - Opiate use type in past 30 days: any heroin use of primary prescription opioid without heroin use. Demographics, other drugs used, self-reported medical and psychiatric concerns, social, familial and legal issues, public assistance type and housing stability were documented at intake using a comprehensive biopsychosocial instrument, the Treatment and Assessment Reports Generation Tool. Findings - the odds of being retained in treatment for PTOP compared to heroin users not adjusting for other factors was 1.33 (95% confidence interval [CI]. 1.03, 1.71) In the final logistic regression model the odds of retention for PTOP compared to heroin users was 1.25 (95% CI, 0.93, 1.67), indicating that there was no statistically significant difference in treatment retention by opiate type after adjusting for demographics, treatment agencies, other drug use, public assistance type, medical, psychiatric, social, legal and familial factors. Conclusion - The finding of this study suggest that PTOP can be treated at methadone maintenance treatment facilities at least as effectively as heroin users in terms of treatment retention.

( BUPP09562 - 05 May 2009) First reports of serious adverse drug reactions in recent weeks

( BUPP09561 - 05 May 2009) Commentary: What more do we need to know about medication-assisted treatment for prescripton opioid abusers?

( BUPP09584 - 12 May 2009) Expert Reviews - Buprenorphine for opioid dependence

As a treatment agent for opioid dependence, buprenorphine is a nearly ideal medication at our current stage of medication development. Unlike methadone, buprenorphine dosage can be rapidly adjusted with minimal potential for inducing severe consequences. In addiction to its intrinsic safety, buprenorphine's relatively low abuse liability in the combination product (ie with naloxone as Suboxone) makes it even more acceptable in regulatory quarters as well as to prescribing physicians. The approval of buprenorphine as a pharmacotherapy for opioid dependence returns to physicians the ability to treat their opioid-dependent patients with an effective opioid-baed treatment for the first time in nearly 100 years. Buprenorphine is an opioid, however, and potential for misuse remains, even in combination with naloxone. Whether buprenorphine will be increasingly accepted as a treatment for opioid-dependent patients depends on clinicians recognising the advantages of its uniquely useful properties while still heeding the need to mange their patients' therapy with reasonable vigilance.

( BUPP09583 - 12 May 2009) High-dose buprenorphine for outpatient palliative pain therapy

The case of a 78-year-old patient with cancer-related pain and additionally mixed-pain syndrome is presented. Pain therapy with buprenorphine TTS 210 mug/h every 3 days was sufficient in the beginning, later the therapy was changed because of increasing problems of tape fixing during fever periods under chemotherapy to a continuous infusion of buprenorphine intravenously via an external medication pump. During the course of therapy it became necessary to increase the dose to 99.9 mg/day buprenorphine. Under this medication a sufficient pain reduction (median NRS 2-3) over a period of 135 days could be achieved. At the same time the patient was vigilant and cooperative without signs of intoxication until the end of life at home in the presence of his family. If no signs of intoxication occur under extreme opioid therapy and a sufficient pain therapy can be achieved, a rotation to another opioid is not necessary. However, outpatient palliative care requires a frequent adaption to the individually varying opioid demand of the patient and time-consuming nursing care.

( BUPP09582 - 12 May 2009) Puffy hand syndrome

Puffy hand syndrome is an unrecognized complication of intravenous drug abuse. This painless syndrome appears during or after a long period of drug addiction. It involves the hands and sometimes the forearms, and may cause functional, aesthetic and social disturbances when the hand volume is important. Physiopathological mechanisms of the puffy hand syndrome are unclear and include venous and lymphatic insufficiencies, infectious complications and direct toxicity of injected drugs and their adulterants. Low-stretch bandage and elastic garment, usually used in lymphedema treatment, are proposed to treat the puffy hand syndrome.

( BUPP09581 - 12 May 2009) Opiate-using patients: Intake in the emergency rooms. Patients interviews in the Gironde's emergency rooms and drug rehabilitation facilities

Aim: To establish the current problems encountered, the questions raised and proposed suggestions regarding the intake of opiate-addicted patients in Gironde's emergency rooms. Methods: Expert interviews with all emergency room directors of major hospitals in Bordeaux and its neighbourhood, as well as directors of drug rehabilitation facilities in Gironde. Evaluation of emergency management and analysis of present intake methods of drug-dependent patients. All results were recorded in a comparative chart. Discussion: To create a common protocol for the most frequent situations regarding the intake of patients who arrive in emergency rooms and pose an implicit or explicit problem related to opiate addictions. Conclusion: Implementation of an evaluative study in the field regarding commonly agreed-upon protocol such as Evidence-Based Medicine based on the literature's findings.

( BUPP09580 - 12 May 2009) Buprenorphine inhibits bradykinin-induced release of calcitonin gene-related peptide from rat trigeminal neurons via both mu-opioid and nociceptin/orphanin peptide receptors

In this study we used the dual opioid and nociceptin/orphanin peptide (NOP) agonist buprenorphine to investigate the relative contributions of opioid and NOP systems in regulating bradykinin-stimulated calcitonin-gene related peptide (CGRP) release from primary cultures of neonatal rat trigeminal neurons. We found that: bradykinin stimulates CGRP secretion either by a direct effect or after applying so-called "bradykinin-priming" protocol. In both cases, buprenorphine was able to inhibit bradykinin-stimulated CGRP secretion; however, inhibition was mediated by NOP receptors when buprenorphine was added to the incubation medium along with bradykinin, whereas it appeared to be mediated by mu-opioid receptors in bradykinin priming experiments. Bradykinin treatments also caused an increase in neuronal prostaglandin production; prostanoids appeared to be involved in the stimulatory effects of bradykinin as well as in buprenorphine inhibition, through apparently unrelated mechanisms.

( BUPP09579 - 12 May 2009) Drug-induced liver injury through mitochondrial dysfunction: Mechanisms and detection during preclinical safety studies

Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be associated with profound hypoglycaemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clinical trials, or drug withdrawal after marketing, it should be detected during the preclinical safety studies. Several in vitro and in vivo investigations can be performed to determine if newly developed drugs disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.

( BUPP09578 - 12 May 2009) Buprenorphine naloxone

Buprenorphinenaloxone is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone, although more data are needed. Less frequent dispensing of buprenorphinenaloxone (e.g. thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Buprenorphinenaloxone is more effective than clonidine as a medically-supervised withdrawal therapy. Moreover, buprenorphinenaloxone is a generally well tolerated medically-supervised withdrawal and maintenance treatment. Thus, sublingual buprenorphinenaloxone is a valuable pharmacotherapy for the treatment of opioid dependence.

( BUPP09577 - 12 May 2009) Management of Complications in Multiple Myeloma

Multiple myeloma (MM) is characterized by the presence of osteolytic bone disease, renal impairment, anemia, and immune dysfunction. Adequate supportive care is considered an essential part of anti-myeloma therapy. The administration of bisphosphonates has been shown to reduce skeletal related events and hypercalcemia. Bisphosphonates are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). Adequate pain control is of crucial importance for the quality of life of MM patients. Local radiotherapy may rapidly ameliorate symptoms of painful MM bone lesions, and vertebroplasty and kyphoplasty are able to control symptoms and restore the original height of vertebral fractures. Symptomatic chemotherapy-induced anemia should preferentially be treated with erythropoietic growth factors, but further studies are required to confirm the long-term safety of this approach. Light-chain-induced renal impairment should be treated without delay with a highly effective anti-myeloma regimen consisting of novel drugs. Prophylaxis of infections should be considered particularly in patients with poorly controlled disease and documented infections should be treated aggressively as they contribute significantly to morbidity and mortality. The concerted action of these supportive therapies can significantly improve the quality of life of MM patients during the different phases of their disease.

( BUPP09576 - 12 May 2009) Chronic neuropathic pain in patients with spinal cord injury. What is the efficacy of regional interventions? Sympathetic blocks, nerve blocks and intrathecal drugs

Objective: To elaborate recommendations regarding neuropathic pain management in spinal cord injury patients. The goal was to evaluate the efficacy of local anesthetic therapeutics including intrathecal or epidural treatments, sympathetic and nerve blocks. Method: The methodology, proposed by the French Society of Physical Medicine and Rehabilitation (SOFMER), includes a systematic revue of the literature, the gathering of information regarding current clinical practice and a validation by a multidisciplinary panel of experts. Results: The results of the literature review do not validate the efficacy of clonidine, baclofen, morphine or lidocaine administered via intrathecal (IT) drug delivery or epidural injections on neuropathic pain in spinal cord injury patients. One reason could be the methodological limitations of the studies. Another reason could be that in most cases the evaluation is done after one single dose injection, thus preventing the authors from assessing the efficacy of the treatments on the long-term. Various clinical practices experiences lead us into thinking that there is, in some cases, a real efficacy for IT baclofen delivery, but this still remains to be properly defined in terms of patients characteristics and type of neuropathic pain. Regarding anesthetic nerve root blocks and sympathetic blocs, no element is available to validate the efficacy of these techniques. Conclusion: There is not a sufficient level of proof to recommend using IT or epidural drug delivery for treating neuropathic pain. However, according to the clinical practices data reviewed, we can suggest to conduct further studies on the impact of IT baclofen delivery that seems to have a pain-relieving impact in some situations. It would be interesting to identify the subgroups of patients that could benefit from this treatment.

( BUPP09575 - 11 May 2009) Comparing between bupremorphine and peridural morphine to manage post-ceasarean section pain

Objective: The postoperatory analgesia in the obstetric patient is controversial for the adverse effects that can happen with the elimination of medicaments in the breast milk. One must find a suitable line of managing, which can be provided by the peridural opioids. Material and methods: 60 patients submitted to Caesarean, 30 for the group A (peridural morphine) and 30 for the group B (peridural buprenorphine). Administering 2 mg of morphine or 300 mu of buprenorphine in the moment of the cut the umbilical cord, realizing measurements of the Visual Analogous Scale and adverse effects: nausea, vomit, pruritus, urinary retention and Ramsay to the moment of revenue to recovery, at 2, 4, 6, 12 and 24 h. Results: The group of morphine was top for presenting at 12 h, 56% of the patients with minor EVA of 5. One presented pruritus in 14% of the patients of the group A and nausea in 14% of the patients of the group B only to his revenue to recovery. Conclusions: The epidural morphine was effective for 8 to 12 h in average but not sufficiently in the only dose for the control of postoperatory pain. Analgesia of rescue was needed.

( BUPP09574 - 11 May 2009) The state of the art on the use of oral fluid as alternative specimen in forensic toxicology

Oral fluid is a readily available specimen which can be collected by non invasive procedures and contains many drugs of interest in screening and diagnosis. It is obtained by a painless and non invasive method of sampling; it contains the free fraction of drugs and therefore it could be a good indicator of intoxication state. Oral fluid in fact has the potential for supplying interpretation with respect to blood concentration and impairment with similar detection windows to blood. Drugs of abuse have been investigated in oral fluid for more than twenty years, because of a number of advantages compared to the body fluids traditionally used as substrates for therapeutic drug monitoring, that is blood and plasma, and actually their analysis is becoming more widely used and accepted across a number of testing disciplines. This review summarizes the studies on the determination of different drugs of abuse in oral fluid in the last eight years to elucidate the current status in this area. To obtain useful information about the correct employ of oral fluid in forensic toxicology, the study of some parameters such as collection, storage and stability of drugs, is required. Moreover analytical aspects and interpretation of results must be evaluated. For this purpose the analysis of the latter scientific literature is discussed in detail for the knowledge of the state of the art, with respect to some forensic aspects such as driving impairment or workplace drug testing.

( BUPP09573 - 11 May 2009) Opioid Imaging

Many beakthrough scientific discoveries have been made using opioid imaging. Developments include the application of ever higher resolution whole-brain positron emission tomography (PET) scanners, the availability of several radioligands, the combination of PET with advanced structural imaging, advances in modeling macroparameters of PET ligand binding, and large-scale statistical analysis of imaging datasets. Suitable single-photon emission computed tomography (SPECT) tracers are lacking, but with the increase in the number of available PET (or PET/CT) cameras and cyclotrons thanks to the clinical successes of PET in oncology, PET may become widespread enough to overcome this. In the coming decade, there should be a more widespread application of the available techniques to patients and an impact in clinical medicine.

( BUPP09572 - 11 May 2009) Forensic aspects of therapeutic drug-monitoring in psychiatry

Therapeutic drug monitoring (TDM) has been an integral part of a differentiated psychopharmaco- therapy for many years now. Its contribution to improvement, individualisation and risk reduction of psychopharmacological treatment is beyond question. Consensus guidelines have been established for TDM in psychiatry. It is not known yet, whether these consensus guidelines are also applicable for forensic patients. In this article the relevance of TDM for the medical treatment of psychiatric patients in the forensic context including addictive patients is discussed with respect to the forensic medical care in Hes- sen and Austria. Potential additional indications for TDM in forensic psychiatry are shown.

( BUPP09571 - 11 May 2009) Performances of an automated dispensing system combined with a computerized prescription order entry

Introduction. - Performances of an automated dispensing system Pillpick(R) (Swisslog) coupled with the computerized - prescribing - order-entry software and dispensing software Pharma(R) (Computer Engineering) implemented at the opening of a new prison facility in Meaux were quantitatively and qualitatively evaluated. Pillpick(R) allows the treatment of different and varied pharmaceutical forms without imposing bulk handling or depackaging.Method. - This study conducted between July and September 2006 focused on the performances of the automated dispensing system in terms of single dose packaging, single dose dispensing, dispensing error rate and security of the medication circuit.Results. - Seventy-six plus or minus five percent of the prescribed medications were automated dispensed. Packaging working flow rate was 377 units doses per hour, dispensing working flow rate was 537 doses per hour. Dispensing error rate was 0.5%, due to wrong delivery orders mainly generated by the Pharma(R) computer-order entry software.Discussion. - Automated dispensing systems Pillpick(R) ensure safe drug dispensing. Potential drug errors can possibly be generated by the computerized-prescribing - order-entry software and dispensing software.Conclusion. - The robot-software combination constitutes the key performance parameter.

( BUPP09570 - 11 May 2009) French pharmacoepidemiological observatory of buprenorphine delivery and good use in community pharmacy

Objective: to describe the buprenorphine delivery in community pharmacies and its good use in daily practice. Methods: cross sectional pharmacoepidemiological study conducted in community pharmacies. Each pharmacist was asked to include the next 10 opioid-dependant patients coming with a prescription of buprenorphine. Results: 3772 opioid-dependant patients, 35 years old among whom 73,9% were male, have been included in the study. The name of the pharmacy was written on the prescription in 67,7% of them, the average duration of the prescription was 24 days and the average dosage was 8 mg, and the intake was once a day in 78,8%. Three quarters of patients (75,5%) use the sublingual way, 14,3% inject buprenorphine and 5,3% sniff it; 35,5% are also taking benzodiazepines; 12,5% have more than one medical prescribers; 4,6% have already shown false prescriptions et 12,7% have sometime some hostile reactions. The good use of buprenorphine appears statistically correlated with patient socialization. Conclusion: the good use of buprenorphine can still be improved and the pharmacist may provide an important contribution to a better practice, and especially if specific continuous training are proposed to all staff members.

( BUPP09569 - 11 May 2009) Epidemiological Trends in Abuse and Misuse of Prescription Opioids

The authors evaluated trends between social, geographic, and demographic factors and cases of select scheduled drugs (buprenorphine, fentanyl, hydrocodone, hydromorphone, morphine, methadone, and oxycodone) using the Researched Abuse, Diversion and Addiction-Related Surveillance System poison center data and census data. Spontaneous calls from the public and healthcare professionals are recorded by poison centers using a standardized, electronic data collection system. We compared the annual incidence of total prescription opioid drug cases to annual data from the U.S. Department of Labor and U.S. Census Bureau by year and by state for unemployment rate, poverty rate, population density, high school graduation rate, and bachelor's degree proportion using the best least square fit in an evaluation for trends for 2003 to 2006. Two strong positive trends were found between poverty rate, unemployment rate, and prescription opioid drug rates, with prescription opioid drug rates increasing as poverty rate and unemployment rate increased. This trend was consistent over the 4 years of study and strongly influenced by the hydrocodone and methadone rates, with less influence from oxycodone rates. The high school graduation rate trend was consistent over the 4 years and was strongly influenced by the hydrocodone and methadone rate. No consistent trend was identified with population density and prescription opioid drug rates. Understanding trends may help guide distribution of scarce resources and prevention efforts to where they may have their greatest impact.

( BUPP09568 - 11 May 2009) Potent analgesic effects of buprenorphine in a rat neuropathic pain model

( BUPP09567 - 11 May 2009) Successful Treatment of Encephalopathy Associated with Autoimmune Thyroiditis: A Case Report

( BUPP09566 - 11 May 2009) The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) prisons project: a randomised controlled trial comparing dihydrocodeine and buprenorphine for opiate detoxification

BACKGROUND: Many opiate users entering British prisons require prescribed medication to help them achieve abstinence. This commonly takes the form of a detoxification regime. Previously, a range of detoxification agents have been prescribed without a clear evidence base to recommend a drug of choice. There are few trials and very few in the prison setting. This study compares dihydrocodeine with buprenorphine. METHODS: Open label, pragmatic, randomised controlled trial in a large remand prison in the North of England. Ninety adult male prisoners requesting an opiate detoxification were randomised to receive either daily sublingual buprenorphine or daily oral dihydrocodeine, given in the context of routine care. All participants gave written, informed consent. Reducing regimens were within a standard regimen of not more than 20 days and were at the discretion of the prescribing doctor. Primary outcome was abstinence from illicit opiates as indicated by a urine test at five days post detoxification. Secondary outcomes were collected during the detoxification period and then at one, three and six months post detoxification. Analysis was undertaken using relative risk tests for categorical data and unpaired t-tests for continuous data. RESULTS: 64% of those approached took part in the study. 63 men (70%) gave a urine sample at five days post detoxification. At the completion of detoxification, by intention to treat analysis, a higher proportion of people allocated to buprenorphine provided a urine sample negative for opiates (abstinent) compared with those who received dihydrocodeine (57% vs 35%, RR 1.61 CI 1.02-2.56). At the 1, 3 and 6 month follow-up points, there were no significant differences for urine samples negative for opiates between the two groups. Follow up rates were low for those participants who had subsequently been released into the community. CONCLUSION: These findings would suggest that dihydrocodeine should not be routinely used for detoxification from opiates in the prison setting. The high relapse rate amongst those achieving abstinence would suggest the need for an increased emphasis upon opiate maintenance programmes in the prison setting.

( BUPP09588 - 13 May 2009) En route to 90% Retention. 'Active Rehabilition' in Central Norway

( BUPP09587 - 13 May 2009) Preferences for Buprenorphine/Naloxone (Suboxone) and Buprenorphine (Subutex) in Patients Receiving Buprenorphine Maintenance Therapy in France: A Prospective, Multicentre Study

( BUPP09586 - 13 May 2009) Use and Abuse of High-Dose Buprenorphine (HDB) Obtained Without a Prescription: a French Survey

Objectives: To gain information of the profile of patients using High-Dose Buprenorphine in France without a medical prescription. Methods: This was a naturalistic survey on 27 survey sites (n=298) comprising three different groups: people who had always obtained their HDB without a prescription, people who had obtained HDB both with and without a prescription over the previous month and an intermediary group who had previously obtained it on prescription, but not over the course of the previous month. Results: In terms of treatment and supervision objectives, significant differences were found between the group of patients who were under the supervision of a doctor and those who continued to obtain HDB without any prescription. Discussion: Medical supervision is a central factor in treatment. Conclusion: Treatment education for patients, medical training for prescribers, and pharmaceutical form appear to me means that need to be developed simultaneously to optimise the treatment.

( BUPP09585 - 13 May 2009) Treatment of Opioid Dependence and ADHS/ADD with Opioid Maintenance and Central Stimulants

Since Jan 2005 Medically Assisted Rehabilitation of opiate addicts (MAR) is a regular treatment by the Nat Board of Health and Welfare in Sweden. At the addiction medicine unit in Jonkoping, high dose buprenorphine has been used since 1999, and methadone was added in 2005, when the previously separate regulations for the use of those two substances were merged in the present regulations. ADHD and ADD, together with OCD, are relatively common disorders among drug addicts. Since 2004 we have diagnosed over 150 patients with these disorders at the addiction medicine unit. By Nov 2007, treatment with long-acting methylphenidate or modafinil had been initiated in 85 subjects. Of those 85, 12 had also met the criteria for opioid substitution. This paper will discuss our experiences with the combine treatment with opioids and central stimulants, as administered to those drug addicts. In this naturalistic study, all 12 subjects (1 female), mean age 38 (range 20 - 52) were evaluated before starting Central Stimulant (CS) treatment with clinical interviews, self-assessments and formal computerised tests (EuroCog). The ambition is to follow each patient's development through the use of drug tests, interviews (subjects and relatives/significant others), and a retest to evaluate the outcome of the combined treatment.

( BUPP09601 - 20 May 2009) Psychopathological changes and quality of life in hepatitis C virus-infected, opioid-dependent patients during maintenance therapy

Aims: To examine among maintenance patients (methadone or buprenorphine) with and without hepatitis C virus (HCV) infection (i) the frequency of psychopathological symptoms at baseline and 1-year follow-up; (ii) the association between antiviral interferon (IFN) treatment and psychopathological symptoms; and (iii) to explore whether IFN therapy has an effect on 1-year outcome of maintenance treatment. Design: Naturalistic prospective longitudinal cohort design. Setting: A total of 223 substitution centres in Germany. Participants: A nationally representative sample of 2414 maintenance patients, namely 800 without and 1614 with HCV infection, of who 122 received IFN therapy. Measures: HCV infection (HCV+/HCV-), IFN (IFN+/IFN-) treatment status and clinical measures. Diagnostic status and severity (rated by clinician), psychopathology (BSI---Brief Symptom Inventory) and quality of life (EQ-5D---EuroQol Group questionnaire). Findings: HVC+ patients revealed indications for a moderately increased psychopathological burden and poorer quality of life at baselien and follow-up compared to HCV- patients. HCV+ patients showed a marked deterioration over time only in the BSI subscale somatization (P = 0.0002), and the frequency of sleep disorders almost doubled over time (12.8% at baseline 24.1% at follow-up; P <0.01). IFN treatment, received by 10% of HCV+ patients, did not impair efficacy or tolerability of maintenance therapy and was associated overall with neither increased psychopathological burden nor reduced quality of life. Conclusions: Findings suggest no increased risk among HCV+ patients on maintenance therapy for depressive or other psychopathological syndromes. In our patient sample, IFN treatment was not associated with increased psychopathological burden, reduced quality of life or poorer tolerability and efficacy of maintenance treatment.

( BUPP09600 - 19 May 2009) Pain syndromes in sickle cell disease: An update

Objective. Pain has a critical role in the management of sickle cell disease (SCD). Patients may suffer from several pain syndromes, which may be or not may be associated with other clinical complications, such as anemia, organ failures, and infections. Design. Data for review were identified by using PubMed to search MEDLINE, limiting the search to abstract/articles in English, Italian, French, and Dutch. The key words pain, sickle cell disease, anemia, hemoglobin, hemoglobinopathy, analgesics, opioids, morphine, acetaminophen, paracetamol, nonsteroidal anti-inflammatory drugs, hematology, and quality of life were variously combined in the title, abstract, and key word search list. The abstract database of most hematological congresses and the bibliographies of most relevant articles were also considered. Results. There are two major types of SCD pain: acute and chronic. Sometimes, mixed and neuropathic pain can be also observed. Acute pain is mostly related to vaso-occlusion. Chronic pain may be due to some SCD complications, such as leg ulcers and avascular necrosis. Conclusions. Pain management in the SCD setting needs multidisciplinary approaches, given the several syndromes and the pathogenic mechanisms that are likely involved. Pain management is not standardized and often difficult, so that many patients with SCD are still poorly treated. Further efforts to develop care plans and treatment protocols as well as management guidelines are required.

( BUPP09599 - 19 May 2009) Efficacy and safety of low-dose transdermal buprenorphine patches (5, 10, and 20 mug/h) versus prolonged-release tramadol tablets (75, 100, 150, and 200 mg) in patients with chronic osteoarthritis pain: A 12-week, randomized, open-label, controlled, parallel-group noninferiority study

Objective: This study compared the efficacy and safety of low-dose 7-day buprenorphine patches and prolonged-release tramadol tablets in patients with chronic, moderate to severe osteoarthritis (OA) pain of the hip and/or knee. Methods: Eligible patients were adults with a clinical and radiologic diagnosis of OA of the hip and/or knee and moderate to severe pain, as confirmed by a mean Box Scale 11 (BS-11) score 4 while using paracetamol 4000 mg/d for pain during the screening week. Patients were randomized in a 1:1 ratio to receive either low-dose 7-day buprenorphine patches (patch strengths of 5, 10, and 20 mug/h, with a maximum dosage of 20 mug/h) or twice-daily prolonged-release tramadol tablets (tablet strengths of 75, 100, 150, and 200 mg, with a maximum dosage of 400 mg/d) over a 12-week open-label treatment period. Supplementary paracetamol was available as rescue medication throughout the study. The primary end point was the difference in BS-11 scores from baseline to the completion of treatment. Noninferiority was assumed if the treatment difference on the BS-11 scale was -1.5 boxes, indicating a clinically meaningful result. Secondary efficacy variables were rescue medication use, sleep disturbance and quality of sleep, and patients' and investigators' global assessments of pain relief. In addition, patient preference was assessed at the completion visit by asking patients whether, given equal pain relief, they would prefer basic treatment for OA pain with a patch applied once weekly or a tablet taken twice daily. Exploratory variables included investigators' assessments of patients' pain, stiffness, and ability to perform daily activities (Western Ontario and McMaster Universities Osteoarthritis Index); patients' quality of life (EuroQol EQ-5D health states index and EuroQol visual analog scale); and abuse and diversion of study drug. Results: One hundred thirty-four patients (69 receiving 7-day buprenorphine patches and 65 receiving tramadol tablets) were randomized and received 1 dose of study medication. A respective 98.6% and 100% of the 2 treatment groups were white, with mean (SD) ages of 64.4 (11.1) and 64.2 (9.3) years. Both treatments were associated with a clinically meaningful reduction in pain from baseline to study completion. The least squares mean change from baseline in BS-11 scores in the 7-day buprenorphine patch and tramadol tablet groups was -2.26 (95% CI, -2.76 to -1.76) and -2.09 (95% CI, -2.61 to -1.58). The efficacy of 7-day buprenorphine patches was noninferior to that of prolonged-release tramadol tablets. The incidence of adverse events (AEs) was comparable in the 2 treatment groups: 226 AEs were reported in 61 patients (88.4%) in the 7-day buprenorphine patch group, and 152 AEs were reported in 51 patients (78.5%) in the tramadol group. Ten patients (14.5%) in the 7-day buprenorphine patch group and 19 (29.2%) in the tramadol tablet group withdrew from the study due to AEs. The most common AEs in the 7-day buprenorphine patch group were nausea (30.4%), constipation (18.8%), and dizziness (15.9%); the most common AEs in the tramadol tablet group were nausea (24.6%), fatigue (18.5%), and pain (12.3%). Most patients (47/67 (70.1%) in the 7-day buprenorphine patch group and 43 /61 (70.5%) in the tramadol tablet group) reported that they would prefer a 7-day patch to a twice-daily tablet for future pain treatment. Conclusions: In these patients with chronic, moderate to severe OA pain of the hip and/or knee, 7-day low-dose buprenorphine patches were an effective and well-tolerated analgesic. The buprenorphine patches were noninferior to prolonged-release tramadol tablets.

( BUPP09598 - 19 May 2009) Effects of intravenous patient-controlled analgesia with buprenorphine and morphine alone and in combination during the first 12 postoperative hours: A randomized, double-blind, four-arm trial in adults undergoing abdominal surgery

Background: Intense pain in the first 12 hours after major abdominal surgery requires the use of large amounts of analgesics, mainly opioids, which may produce undesirable effects. Buprenorphine (BUP) is not typically used intravenously in this setting, particularly in combination with morphine (MO), due to concerns that BUP might inhibit the analgesic effect of MO. Objective: This study compared the analgesic effect of BUP and MO separately and in combination for postoperative pain control in patients undergoing abdominal surgery. Methods: In this double-blind study, adult patients were randomized to receive 1 of 4 regimens for 12 hours: a basal BUP infusion (BUP-i) of 0.4 mug/kg/h + BUP boluses (BUP-b) of 0.15 mug/kg each; a basal MO infusion (MO-i) of 10 mug/kg/h + MO boluses (MO-b) of 5 mug/kg each; a basal BUP-i of 0.4 mug/kg/h + MO-b of 5 mug/kg each; or a basal MO-i of 10 mug/kg/h + BUP-b of 0.15 mug/kg each. Bolus doses were delivered by intravenous patient-controlled anesthesia, with a bolus lockout time of 7 minutes. Diclofenac 75 mg IM q6h was available as rescue pain medication. Every 15 minutes during the first 2 postoperative hours and hourly thereafter, patients used visual analog scales to rate their pain (from 0 = totally free of pain to 10 = unbearable pain), level of sedation (from 1 = totally awake to 10 = heavily sedated), and satisfaction with treatment (from 1 = totally unsatisfied to 10 = fully satisfied). Blood pressure, heart rate, respiration rate, and arterial blood oxygen saturation (SpO /sub 2/ ) were monitored, and adverse effects reported by patients or noted by clinicians were recorded at the same times. Study end points included total opioid consumption (infusion + boluses), demand:delivery ratio, and use of rescue medication. Results: One hundred twenty patients (63 men, 57 women; age range, 21-80 years; weight range, 40-120 kg) were included in the study. Seventy-four percent had other mild, treated diseases (American Society of Anesthesiologists physical class 2). Pain visual analog scale ratings were comparably high in all groups during the first 2 postoperative hours. Pain intensity ratings at 3 to 12 hours were significantly lower in those who received BUP-i + BUP-b compared with the other treatment groups (P = 0.018). The drug requirement during the postoperative period decreased significantly in all groups (P = 0.01); however, there was a significant difference between groups in the demand:delivery ratio at 3 to 12 hours (group * psydrug interaction, P = 0.026). The numerically lowest demand:delivery ratio was seen with BUP-i + BUP-b. BUP-i was associated with a significantly lower heart rate compared with the other groups (P = 0.027); there were no drug-related differences in respiration rate, SpO /sub 2/ , or sedation. Patients' level of satisfaction with treatment was significantly higher in the group that received BUP-i + BUP-b compared with the other 3 groups (P < 0.001). Postoperative nausea and vomiting were mild and occurred at a similar incidence in all groups, as did rescue diclofenac use. Conclusions: In these patients undergoing abdominal surgery, the BUP-i + BUP-b regimen controlled postoperative pain as well as did MO-i + MO-b or the combinations of BUP and MO. BUP neither inhibited the analgesia provided by MO nor induced undesired sedation or hemodynamic or respiratory effects.

( BUPP09597 - 19 May 2009) Opioid substitution treatment with sublingual buprenorphine in Manipur and Nagaland in Northeast India: What has been established needs to be continued and expanded

Manipur and Nagaland in northeast India report an antenatal HIV prevalence of > 1% and the current HIV prevalence among injecting drug users is 24% and 4.5% respectively. Through support from DFID's Challenge Fund, Emmanuel Hospital Association (EHA) established thirteen drop-in-centres across the two states to deliver opioid substitution treatment with sublingual buprenorphine for 1200 injecting drug users. Within a short span of time the treatment has been found to be attractive to the clients and currently 1248 injecting opioid users are receiving opioid substitution treatment. The project is acceptable to the drug users, the families, the communities, religious as well as the militant groups. The treatment centres operate all days of the week, have trained staff members, utilize standardized protocols and ensure a strict supervised delivery system to prevent illicit diversion of buprenorphine. The drug users receiving the substitution treatment are referred to HIV voluntary counselling and testing. As this treatment has the potential to change HIV related risk behaviours, what has been established in the two states needs to be continued and expanded with the support from the Government of India.

( BUPP09596 - 19 May 2009) Peripheral subcutaneous neurostimulation in the management of neuropathic pain: Five case reports

Introduction. Spinal cord stimulation (SCS) is an effective treatment option for neuropathic pain. However, because of the obvious procedural issues, SCS is unable to reach certain areas, such as the face, thorax, coccyx, the cervico-dorsal and lumbar areas, and the sacral, abdominal, and inguinal regions. On the other hand, these areas are easily reached by subcutaneous field stimulation. Methodology. We report the analgesic results, using a visual analog scale (VAS), of five patients with neuropathic pain treated with subcutaneous field stimulation to the area. We also discuss the probable mechanism of action, and highlight the technical issues inherent to this approach. Results. Significant pain reduction and reduction in analgesic medication were reported in all patients during the study period, with VAS scores consistently lowered by more than 50% from baseline levels. As a result of pain reduction, the patients' quality of life improved. There were no adverse events reported except for early electrode array displacement in two of our patients. Conclusion. When SCS is not appropriate for certain neuropathic pain syndromes, subcutaneous field stimulation may be used with some degree of efficacy.

( BUPP09595 - 19 May 2009) Criminal justice sector prescribing

( BUPP09594 - 19 May 2009) Patterns of major depression and drug-related problems amongst heroin users across 36 months

The study aimed to determine patterns of major depression (MD) across 36 months, and the relationship to outcomes for the treatment of heroin dependence. As part of a longitudinal cohort study, 429 heroin users were interviewed at 36 month follow-up. MD declined from 23.8% at baseline to 8.2% at 36 months. Females were more likely to have MD at both baseline (31.1 vs. 19.8) and 36 months (11.9 vs. 6.1%). Those with MD at baseline were significantly more likely to be diagnosed with MD at a follow-up interview (40.2 vs. 15.9%) and at 36 months (14.7 vs. 6.1%). Antidepressant use did not decrease across 36 months amongst either gender. Baseline MD was not related to treatment exposure across 36 months. There were large and significant declines in drug use and drug-related problems, and improvements in physical health with no group differences evident at 36 months. Despite improvements in global mental health, at both baseline and 36 months those with MD at baseline had significantly lower SF12 mental health scores. It was concluded that, with the exception of depression, the prognosis of depressed heroin users is not worse than that of non-depressed users.

( BUPP09593 - 19 May 2009) Satisfaction guaranteed? What clients on methadone and buprenorphine think about their treatment

INTRODUCTION AND AIMS: A consumer satisfaction survey was conducted among clients receiving methadone or buprenorphine treatment for opioid dependence. The survey aimed to assess client perceptions across a number of treatment domains, including the clinic environment, service provision, clinical relationships, medication and treatment outcomes. DESIGN AND METHODS: Participants were 432 clients receiving treatment at nine public clinics in New South Wales, Australia. An interviewer-administered questionnaire was utilised, designed by the researchers. Participation was voluntary and anonymous. All participants received $10 remuneration. RESULTS: Seventy-eight per cent of participants were on methadone treatment. Overall satisfaction with treatment was high (mean: 3.8; very satisfied = 5). Participants were mainly satisfied with service provided by the clinic, although had concerns over the inflexibility associated with the clinic atmosphere, frequency of clinic attendance, dosing hours and lack of takeaway doses. While relationships with prescribers and case managers were rated positively, 16% and 21% of participants wanted to see their prescriber and case manager more often, respectively; 53% reported that they did not have input into their care plan. Regarding the helpfulness of case managers in assisting clients with problems experienced in identified domains of case management (e.g. drug use, physical and mental health, psychosocial supports), the mean rating was 5.2 (excellent = 10). DISCUSSION AND CONCLUSIONS: While Participants reported being mainly satisfied with their treatment, results must be viewed within the context of what a consumer reasonably expects to receive from a service. The concept of 'expectation' and 'relative experience' is crucial in measuring consumer satisfaction among pharmacotherapy consumers.

( BUPP09592 - 19 May 2009) Correlation between body weight changes and postoperative pain in rats treated with meloxicam or buprenorphine

It is essential to identify objective and efficient methods of evaluating postoperative pain in rodents. The authors investigated whether postoperative changes in rates of body weight gain could serve as a measure of the efficacy of meloxicam or buprenorphine analgesia in growing rats. Young adult male Lewis rats underwent general endotracheal anesthesia and thoracotomy and were treated postoperatively for 3 d with saline (no analgesia), buprenorphine (six doses of 0.1 mg per kg) or meloxicam (three doses of 1 mg per kg). The authors evaluated rats' daily growth rates for 5 d after surgery and compared them with baseline (preoperative) growth rates. To discriminate between the effects of postoperative pain and other concurrent physiologic effects associated with anesthesia, thoracotomy or analgesia, the authors evaluated weight changes in multiple control groups. Treatment with buprenorphine in the absence of any other procedure or with anesthesia alone significantly affected rats' body weight. Notably, growth rate was maintained at near normal levels in rats treated postoperatively with meloxicam. These findings suggest that growth rate might serve as an efficient index of postoperative pain after major surgical procedures in young adult rats treated with meloxicam but not in rats treated with buprenorphine.

( BUPP09591 - 19 May 2009) (Accompanying patients in substitution treatment for opiates: consulting and coaching in the office))

( BUPP09590 - 19 May 2009) Simultaneous screening and quantification of 25 opioid drugs in post-mortem blood and urine by liquid chromatography-tandem mass spectrometry

A method for simultaneous screening and quantification was developed for the fentanyls alfentanil. fentanyl. p-fluorofentanyl, cis-3-methylfentanyl, trans-3-methylfentanyl, alpha-methylfentanyl, norfentanyl, remifentanil, sufentanil. and the other opioid drugs 6-acetylmorphine, buprenorphine, codeine, dextropropoxyphene, ethylmorphine, heroin, methadone, morphine, naloxone, naltrexone, norbuprenorphine, normethadone. oxycodone, pentazocine, pethidine, and tramadol in post-mortem blood and urine samples by LC-MS/MS. Samples were extracted with butyl acetate at pH 7. The drugs were separated by LC on a Genesis C-18 reversed-phase column. with a gradient consisting of acetonitrile and ammonium acetate at pH 3.2. The mass spectrometric analysis was performed with a quadrupole-linear ion-trap mass spectrometer equipped with a turbo ion spray interface in positive mode using multiple reaction monitoring (MRM). Quantification was performed based on five isotope-labelled internal standards. Validation included assessment of linearity, limit of quantification, inaccuracy, precision, and matrix effects. The limits of quantification were adequate for screening and quantification of opioid drugs at low therapeutic or abuse concentration levels, with inaccuracy less than 23% and precision better than 24% both in blood and urine samples. When this method was applied to autopsy cases, its results were in agreement with those of reference methods

( BUPP09589 - 19 May 2009) Aerosol formulations and aerosol delivery of buprenorphine

A liquid aerosol formulation comprising at least one thermally stable active ingredient selected from the group consisting of buspirone, buprenorphine, triazolam, cyclobenzaprine, zolpidem, pharmaceutically acceptable salts and esters thereof and derivatives thereof. The liquid formulation can include an organic solvent such as propylene glycol and one or more optional excipients. The active ingredient can be present in an amount of 0.01 to 5 wt. % and the formulation can be heated to provide a vapor which forms an aerosol having a mass median aerodynamic diameter of less than 3 mu m.

( BUPP09620 - 08 June 2009) The role of flumazenil in the treatment of benzodiazepine dependence: Physiological and psychological profiles

Two-related studies are presented here, detailing our early experience with benzodiazepine-dependent patients treated with a four-day flumazenil infusion using a novel delivery technique. Patients with long-term benzodiazepine dependence who attended the Australian Medical Procedures Research Foundation (AMPRF, Perth, Australia) for treatment were recruited for these studies. Self-reported psychological and physical symptoms, as well as objective vital signs data were collected at intervals before, during and 2 weeks postinfusion. Study A is a case series with cardiovascular measures; study B is an open trial that tracks the psychological profiles of 13 subjects. Withdrawal symptoms were tracked, however, the nature and severity of these symptoms differed between patients. No major complications or discomfort prompting study dropout was observed. Significant benzodiazepine abstinence occurred with this flumazenil infusion method despite high levels of initial dependence, comorbid substance use and comorbid psychiatric illness. Low-dose flumazenil infusion appears to be a safe and effective treatment resulting in withdrawal symptoms of lesser severity than any other cessation method currently available. Recommendations for future research are discussed.

( BUPP09619 - 08 June 2009) Ensuring the safety of new medications and devices: Are naltrexone implants safe?

( BUPP09618 - 08 June 2009) Hepatitis after intravenous injection of sublingual buprenorphine in acute hepatitis C carriers: Report of two cases of disappearance of viral replication after acute hepatitis

OBJECTIVE: To report 2 cases of acute hepatitis related to intravenous administration of buprenorphine in hepatitis C-infected patients. CASE SUMMARY: Two patients, aged 33 and 50 years, respectively, who were hepatitis C virus (HCV) carriers were treated with sublingual buprenorphine 8 mg/day for addiction. Several years after initiation of buprenorphine, they were hospitalized because of clinical hepatitis with jaundice that developed after intravenous injection of buprenorphine. Serum alanine aminotransferase rose to 100 times the upper limit of normal (ULN) in the first patient and to 21 times the ULN in the second. As cofactors, the first patient had consumed alcohol, and the second patient took aspirin 600 mg in addition to the injection of buprenorphine 20 mg 4 days before the onset of jaundice. After stopping the intravenous injections, both patients continued sublingual buprenorphine therapy, with no relapse of hepatitis. Interestingly, in these 2 patients, buprenorphine-induced hepatitis was followed by the disappearance of HCV RNA. DISCUSSION: Most cases of hepatotoxicity related to buprenorphine have occurred in hepatitis C-infected patients. The main mechanism for buprenorphine-induced hepatitis is a mitochondrial defect, exacerbated by cofactors with additional potential to induce mitochondria dysfunction (eg, HCV, alcohol, concomitant medications). According to the Naranjo probability scale, buprenorphine was found to be the probable cause of acute hepatitis in both patients. In addition, we assessed the relationship between intravenous buprenorphine and acute hepatitis using 2 scales for causality assessment of hepatotoxicity (the Council for International Organizations of Medical Sciences scale and the Maria & Victorino scale). The diagnosis of intravenous buprenorphine-induced hepatitis was classified as probable in both cases. In addition, these 2 cases illustrate that acute hepatitis in a carrier of chronic HCV may occasionally facilitate the clearance of virus. CONCLUSIONS: Although buprenorphine is well tolerated when used at recommended sublingual doses, patients should be informed about the risk of acute hepatitis with misuse of the drug by the intravenous route. These cases illustrate that, in carriers of chronic HCV, acute hepatitis may modify the host's immunotolerance and facilitate clearance of the virus.

( BUPP09617 - 08 June 2009) Outcome after Injections of Crushed Tablets in Intravenous Drug Abusers in the Helsinki University Central Hospital

Objective: To retrospectively analyse injection drug users (IDUs) with complications after intra- or extra-vasal administration of dissolved tablets. Design: A retrospective study. Methods: The hospital discharge registers were used to identify the patients admitted in different clinics in Helsinki University Central Hospital during 2000-2005. The patient demographics and social background were clarified. The type of the crushed drugs, the injection route and the timing of administration were registered. Medical interventions, examinations and surgical procedures were recorded. Results: Between January 2000 and December 2005, 24 patients had been treated on 30 occasions for manifestations caused by injecting crushed tablets. The main types of manifestations were acute limb ischaemia (16 patients) and infection (eight patients), and eight cases led to distal or proximal amputations. Men (19 of 24) were affected more frequently than were women (5 of 24). Their ages ranged between 20 and 39 years (mean: 26 years). All the patients had a previous history of intravenous drug abuse, and they lived in Greater Helsinki region. The incidence of seropositivity for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) was 33% (n = 8), 88% (n = 21) and 4% (n = 1), respectively. The time between injection and presentation to the Emergency Department varied between 3 h and 10 days (mean: 62 h). Buprenorphine was the most commonly used drug in 10 of the 24 patients, and benzodiazepine derivatives were also used in 11 of the 24 patients. Conclusions: Intra- or extra-vasal administration of dissolved tablets leads to serious consequences, including limb amputations. Vascular and soft-tissue imaging may be helpful in the diagnosis. Prompt drainage of any abscess and fasciotomies for compartment syndrome treatment are essential. Controversy exists over the best medical therapy.

( BUPP09616 - 08 June 2009) Pharmacokinetics of buprenorphine after intravenous administration of clinical doses to dogs

The purpose of this study was to evaluate plasma concentrations and pharmacokinetic parameters of buprenorphine in dogs following intravenous (IV) administration of clinical doses of the opioid. An IV bolus of 0.02 mg/kg buprenorphine was administered to six healthy Beagles and blood samples were collected through a jugular catheter before and at 1, 5, 10, 15, 20, 30 and 45 min, and 1, 2, 4, 6, 8 and 12 h after administration. Plasma buprenorphine concentrations, measured using a commercial radioimmunoassay (RIA), decreased following a three-exponential curve. The two distribution and the elimination half-lives were 2.9 � 1.8 min, 16.5 � 3.7 min, and 266.6 � 82.0 min, respectively; the clearance was 329.6 � 62.2 mL/min, and the steady state volume of distribution was 83.7 � 26.5 L. The results demonstrated the feasibility of the RIA assay to analyse buprenorphine in dog plasma samples. Following IV administration buprenorphine showed a three-compartment kinetic profile, as has been described previously in humans, rabbits and cats. The relationship between plasma concentrations and dynamic effects in dogs remains to be established.

( BUPP09615 - 08 June 2009) Diabetes mellitus and subclinical neuropathy: A call for new paths in peripheral nerve block research

( BUPP09614 - 08 June 2009) Opioid therapy: Everyone reacts differently

( BUPP09613 - 08 June 2009) Comparison of costs and utilization among buprenorphine and methadone patients

Buprenorphine is an effective alternative to methadone for treatment of opioid dependence, but economic concerns represent a barrier to implementation. The economic impacts of buprenorphine adoption by the US Veterans Health Administration (VHA) were examined.Prescriptions of buprenorphine, methadone treatment visits, health-care utilization and cost, and diagnostic data were obtained for 2005.VHA dispensed buprenorphine to 606 patients and methadone to 8191 other patients during the study year. An analysis that controlled for age and diagnosis found that the mean cost of care for the 6 months after treatment initiation was $11 597 for buprenorphine and $14 921 for methadone (P < 0.001). Cost was not significantly different in subsequent months. The first 6 months of buprenorphine treatment included an average of 66 ambulatory care visits, significantly fewer than the 137 visits in methadone treatment (P < 0.001). In subsequent months, buprenorphine patients had 8.4 visits, significantly fewer than the 21.0 visits of methadone patients (P < 0.001). Compared to new methadone episodes, new buprenorphine episodes had 0.634 times the risk of ending (95% confidence interval 0.547-0.736). Implementation of buprenorphine treatment was not associated with an influx of new opioid-dependent patients.Despite the higher cost of medication, buprenorphine treatment was no more expensive than methadone treatment. VHA methadone treatment costs were higher than reported by other providers. Although new buprenorphine treatment episodes lasted longer than new methadone episodes, buprenorphine is recommended for more adherent patients

( BUPP09612 - 08 June 2009) Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study

To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme.Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997-December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT.The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross-matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient-years in OMT.In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results < 450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient-years. Only one death among 3850 OMT initiations occurred within the first month of treatment.Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient-years.

( BUPP09611 - 08 June 2009) Compliance and detection of illicit drug use among opioid dependent subjects maintained on sublingual buprenorphine substitution therapy

( BUPP09610 - 08 June 2009) Prescription of opioids in Italy: everything, but the morphine

( BUPP09609 - 08 June 2009) A new pattern of buprenorphine misuse may complicate perioperative pain control

( BUPP09608 - 08 June 2009) Prophylaxis of severe oral mucositis with tramadole and buprenorphine in patients with lymphoproliferative diseases undergoing high-dose chemotherapy with autologous haematopoietic progenitor cells rescue: a single centre experience

( BUPP09607 - 08 June 2009) Allometric Scaling of Chemical Restraint Associated with Inhalant Anesthesia in Giant Anteaters

This study describes the use of allometric scaling in five giant anteaters (Myrmecophaga tridactyla) submitted for osteosynthesis, gastrostomy, or treatment of burns, Chemical restraint was performed by allometric Scaling using the dog its it reference; acepromazine (0.06 mg/kg), diazepam (0.3 mg/kg), ketamine (8.8 mg/kg), and buprenorphine (5.9 mu g/kg) were combined, and the animals were maintained under isoflurane anesthesia. Heart rate, respiratory rate, hemoglobin oxygen saturation, temperature, and anesthetic depth were measured. Postoperative treatment consisted of ketoprofen, buprenorphine, and ceftiofur Anesthetic induction was obtained in 10-15 min, achieving muscle relaxation and absence of excitement. Physiologic parameters were stable during the procedures, and post- operative treatment was effective. Allometric scaling was effective for chemical restraint and postoperative treatment.

( BUPP09606 - 08 June 2009) Pharmaceutical formulation comprising ziconotide

The present invention is direct to a method of producing analgesia in a mammalian subject. The method includes administering to the subject an omega conopeptide, preferably ziconotide, in combination with an analgesic selected from the group consisting of morphine, bupivacaine, clonidine, hydromorphone, baclofen, fentanyil, buprenorphine, and sufentanil, or its pharmaceutically acceptable salts thereof, wherein the omega-conopeptide retains its potency and is physically and chemically compatible with the analgesic compound. A preferred route of administration is intrathecal administration, particularly continuous intrathecal infusion. The present invention is also directed to a pharmaceutical formulation comprising an omega conopeptide, preferably ziconotide, an antioxidant, in combination with an analgesic selected from the group consisting of morphine, bupivacaine, clonidine, hydromorphone, baclofen, fentanyl, buprenorphine, and sufentanil.

( BUPP09605 - 08 June 2009) Diagnosis, Management, and Treatment of Hepatitis C: An Update

Diagnosis, management, and treatment of hepatitis C are reviewed. Topics discussed are: testing and counseling; laboratory testing; diagnosis of acute and chronic HCV infection and interpretation of assays; utility of the liver biopsy and non-invasive tests of fibrosis; initial treatment of HCV infection; optimal treatment of chronic HCV; viral kinetics; early virological response; rapid virological response; assessment prior to treatment and monitoring during and after therapy; retreatment of persons who failed to respond to previous treatment; special patient groups; treatment of persons with acute hepatitis C; treatment of active injection drug users; and treatment of persons with psychiatric illnesses; general management issues. Thus, reasonable physicians may deviate from the strategy and remain within acceptable standards of treatment.

( BUPP09604 - 08 June 2009) The effects of nitrous oxide on recovery from isoflurane anaesthesia in dogs

OBJECTIVES: To assess rate and quality of recovery from anaesthesia where isoflurane was delivered in oxygen or oxygen/nitrous oxide. METHODS: Dogs anaesthetised with propofol were randomly allocated to receive isoflurane maintenance in either 100 per cent oxygen (group 1) or 66 per cent nitrous oxide (N(2)O)/34 per cent oxygen (group 2). Time from end of anaesthesia to achieving sternal recumbency was recorded. Incidence of adverse behaviours (vocalisation, uncontrolled head movement and restlessness) were assessed. Recovery quality was recorded on a visual analogue scale (VAS) (anchored at 0 with "best possible" recovery and "did not recover" at 100 mm). Age, weight, gender, anaesthetic duration, mean vaporiser setting, VAS scores, recovery times, postoperative temperature and behavioural scores were compared (chi-squared test, Mann-Whitney U test or t-test as appropriate, significance P< or =0.05). RESULTS: Objective data from 54 dogs were analysed, only VAS data where the observer was unaware of treatment group were used (n=33). Recovery was faster in group 2 dogs (median 10 min (range 4 to 31) compared with 14 minutes (3 to 43) in group 1, P=0.049) with less restlessness (0 (0 to 4) compared with 2 (0 to 4) in group 1, P=0.013) and uncontrolled head movement (0 (0 to 4) compared with 1 (0 to 3) in group 1, P<0.001). However, VAS scores were not statistically different between groups (group 1: mean 39.4 mm (s.d. 24.0)); group 2: 30.1 mm (25.9); P=0.303). CLINICAL SIGNIFICANCE: Addition of N(2)O to isoflurane anaesthesia results in a lower incidence of adverse behaviour (for example restlessness) and marginally faster recovery.

( BUPP09603 - 08 June 2009) Treatment of herpes zoster in immunocompetent and immunosuppressed patients

Herpes zoster (HZ) is a clinical manifestation of the reactivation of latent varicella zoster virus infection. Patients may have acute neuritic pain, together with cutaneous vesicular lesions in a dermatomal distribution. Recently, new antiviral drugs have been highly useful in the treatment of patients with HZ, avoiding many of the secondary complications that can appear after this herpetic infection. In addition, the rational and early use of these antiviral drugs may reduce the virulence of postherpetic neuralgia in a substantial proportion of patients. Consequently, guidelines for the management and treatment of patients with HZ should be established. Specifically, guidelines should be established for certain patient groups at risk for an atypical or severe clinical course, such as immunosuppressed patients (those with solid organ transplants, HIV infection or AIDS, or patients under immunosuppressive treatment) or pregnant and pediatric patients. In addition, antiviral treatment must be administered with analgesic drugs to control neuritic pain in all patients with HZ, whether in the acute phase or in the form of postherpetic neuralgia.

( BUPP09602 - 08 June 2009) Simultaneous quantification of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in human placenta by liquid chromatography mass spectrometry

A LCMS method was developed and validated for the determination of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and norbuprenorphine glucuronide (NBUP-Gluc) in placenta. Quantification was achieved by selected ion monitoring of m/z 468.4 (BUP), 414.3 (NBUP), 644.4 (BUP-Gluc), and 590 (NBUP-Gluc). BUP and NBUP were identified monitoring MS2 fragments m/z 396, 414 and 426 for BUP, and 340, 364 and 382 for NBUP, and glucuronide conjugates monitoring MS3 fragments m/z 396 and 414 for BUP-Gluc, and 340 and 382 for NBUP-Gluc. Linearity was 1-50 ng/g. Intra-day, inter-day and total assay imprecision (% RSD) were <13.4%, and analytical recoveries were 96.2-113.1%. Extraction efficiencies ranged from 40.7-68%, process efficiencies 38.8-70.5%, and matrix effect 1.3-15.4%. Limits of detection were 0.8 ng/g for all compounds. An authentic placenta from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. BUP was not detected but metabolite concentrations were NBUP-Gluc 46.6, NBUP 15.7 and BUP-Gluc 3.2 ng/g.

( BUPP09631 - 16 June 2009) Medical expulsive therapy for distal ureteral stones

Although minimally invasive treatments for ureteral stones are efficacious, they are not free of complications and are associated with high cost. Medical expulsive therapy (MET) has recently emerged as an alternative strategy for the initial management of small distal ureteral stones. A MEDLINE search was undertaken to evaluate all currently available data on efficacy and safety of MET therapy in such patients. The specific mechanism of action on the ureteral smooth muscle and the emerging evidence of the efficacy (defined as either an increase in expulsion rate or decrease in time to expulsion) and low-risk profile suggest that alpha-adrenergic receptor antagonists (alpha-blockers) and calcium channel antagonists should be the initial medical treatment in patients amenable to conservative therapy. NSAIDs and anticholinergics have not shown efficacy as single agents or in combination with alpha-blockers or nifedipine. Corticosteroids may provide a small additive effect when combined with either alpha-blockers or nifedipine.

( BUPP09630 - 16 June 2009) Pain treatment with opioids: Achieving the minimal effective and the minimal interacting dose

Appropriate and successful management of pain with opioid analgesics is based on tailoring pharmacologic treatment to the individual and identifying the minimal effective dose at which pain is controlled with minimal adverse effects. Morphine and morphine-like-agonists exhibit similar pharmacodynamic profiles, but substantially different receptor affinities and pharmacokinetic properties, which dictate the dosage, route and regimen required to achieve analgesic effect. Opioids exhibit differences in drug elimination resulting in marked variations in the plasma half-life value. Although fentanyl is more potent than morphine, with a shorter duration of action than parenteral morphine, its oral bioavailability is poor and it is administered transdermally. Morphine, with a short half-life and a time to steady-state plasma concentrations of 1012 hours is better suited than transdermal fentanyl for initial opioid therapy and for the treatment of unstable pain, which requires a fluctuating opioid dose. International guidelines recommend normal-release morphine for initial optimization of individual dose because its pharmacokinetics allow 'real-time' dose regimen changes and rapid identification of the dose required for pain control. Once an effective normal-release morphine dosage is achieved, other administration routes, formulations and opioids can be considered as required. Despite guidelines advocating that transdermal fentanyl should only be used in patients who are shown to be tolerant to strong opioid therapy, in Italy and other European countries, controlled-release or transdermal opioids are often used when starting opioid therapy. Opioids are associated with a wide range of adverse reactions, but these can be minimized with careful drug titration and maintenance. A major challenge with pain control is polypharmacy and the risk of pharmacokinetic or pharmacodynamic drug-drug interactions. Prevention and management of interactions rely on careful and timely adjustment of drug regimens involved, according to the severity of the effect. Dose titration is the key to successful therapy initiation with strong opioids in patients with moderate-to-severe pain. It is the only way to establish the optimal and minimal effective dose and provides the best protection against adverse effects. Committed physicians should adhere to guidelines on the appropriate use of opioids in all patients, particularly those with a high risk of adverse reactions.

( BUPP09629 - 16 June 2009) Social and structural aspects of the overdose risk environment in St. Petersburg, Russia

Background: While overdose is a common cause of mortality among opioid injectors worldwide, little information exists on opioid overdoses or how context may influence overdose risk in Russia. This study sought to uncover social and structural aspects contributing to fatal overdose risk in St. Petersburg and assess prevention intervention feasibility. Methods: Twenty-one key informant interviews were conducted with drug users, treatment providers, toxicologists, police, and ambulance staff. Thematic coding of interview content was conducted to elucidate elements of the overdose risk environment. Results: Several factors within St. Petersburg's environment were identified as shaping illicit drug users' risk behaviours and contributing to conditions of suboptimal response to overdose in the community. Most drug users live and experience overdoses at home, where family and home environment may mediate or moderate risk behaviours. The overdose risk environment is also worsened by inefficient emergency response infrastructure, insufficient cardiopulmonary or naloxone training resources, and the preponderance of abstinence-based treatment approaches to the exclusion of other treatment modalities. However, attitudes of drug users and law enforcement officials generally support overdose prevention intervention feasibility. Modifiable aspects of the risk environment suggest community-based and structural interventions, including overdose response training for drug users and professionals that encompasses naloxone distribution to the users and equipping more ambulances with naloxone. Conclusion: Local social and structural elements influence risk environments for overdose. Interventions at the community and structural levels to prevent and respond to opioid overdoses are needed for and integral to reducing overdose mortality in St. Petersburg.

( BUPP09628 - 16 June 2009) Postoperative complications in the seriously mentally ill: A systematic review of the literature

To determine the knowledge base on clinical outcomes of surgery among persons diagnosed with serious mental illness. BACKGROUND:: Despite a burgeoning literature during the last 20 years regarding perioperative risk management, little is known about intraoperative and postoperative complications among patients with schizophrenia and other serious mental illnesses. METHODS:: A systematic literature search of Medline (1966-August 2007) and review of studies was conducted. Eligible studies were of any design with at least 10 patients diagnosed with serious mental illness, reporting perioperative medical, surgical, or psychiatric complications. RESULTS:: The search identified 1367 potentially relevant publications; only 12 met eligibility criteria. Of 10 studies of patients with schizophrenia, 9 had fewer than 100 patients, whereas one large retrospective study reported higher rates of postoperative complications among 466 schizophrenia patients compared with 338,257 controls. These studies suggest that patients with schizophrenia, compared with those without mental illness, may have higher pain thresholds, higher rates of death and postoperative complications, and differential outcomes (eg, confusion, ileus) by anesthetic technique. Two studies evaluated outcomes in patients with major depressive disorder and found higher rates of postoperative delirium and postoperative confusion. Both schizophrenia and depression patients experienced more postoperative confusion or delirium when psychiatric medications were discontinued preoperatively. We identified no studies of perioperative outcomes in patients with bipolar or posttraumatic stress disorder. CONCLUSIONS:: There are few studies of perioperative outcomes in patients with serious mental illness. Future research should assess surgical risks among patients with serious psychiatric conditions using rigorous methods and well-defined clinical outcomes.

( BUPP09627 - 16 June 2009) Opioid treatment programs in the Clinical Trials Network: Representativeness and buprenorphine adoption

As the Clinical Trials Network (CTN) begins to focus efforts on disseminating the results of its research studies to the addiction treatment field, it is important to begin to assess the capacity of programs outside the CTN to integrate with fidelity these endorsed treatment practices. To date, no data exist to assess the representativeness of opioid treatment programs (OTPs) participating in the CTN, nor potential barriers to the effective diffusion of practices aimed at the treatment of opioid-dependent patients, including buprenorphine. Using data obtained from OTPs within the CTN (n = 49) and a sample drawn from the population of U.S. OTPs (n = 50) , this study compares the two groups on their organizational, clinical, and client characteristics, as well as their adoption of buprenorphine. The study finds that the populations differ significantly on numerous variables but that structural characteristics appear more predictive of buprenorphine adoption than either staff or caseload differences. Implications for studying the diffusion and implementation of evidence-based research findings are discussed.

( BUPP09626 - 16 June 2009) Factors associated with the prescribing of buprenorphine or methadone for treatment of opiate dependence

The study investigates patient preferences and beliefs and treatment program factors related to the decision to prescribe either buprenorphine or methadone to opiate-dependent patients. The sample (N = 192) was recruited from 10 addiction treatment services in London. Data were collected by means of a single structured interview conducted with patients commencing a treatment episode at the participating agencies. Data on patient demographics, beliefs, attitudes, and preferences were collected using a structured interview. Data regarding treatment goals and prescribed medication were collected from interviews with clinical staff. Oral methadone had a higher preference rating than buprenorphine. Clinical prescribing practices were influenced by patient preferences (both positive and negative), by prior treatment experiences, and by current treatment goals. Patient preferences and beliefs about opioid agonist medications served as an important influence upon clinical prescribing practices. The odds of being prescribed buprenorphine were three times greater among those patients who reported a preference for buprenorphine. The odds of receiving a prescription for methadone were about twice as great among those for whom methadone was the more preferred medication. Preferences were related to previous treatment experiences with these opioid agonists, and for patients in both groups, personal experience was the most important source of information about the treatment options. Buprenorphine was more likely to be prescribed for short-term detoxification and methadone for maintenance treatment.

( BUPP09625 - 16 June 2009) Evaluation of recombinant cytochrome p450 enzymes as an in vitro system for metabolic clearance predictions

The aim of this study was to explore the potential of recombinant cytochrome P450 (P450) enzymes for human metabolic clearance prediction. The relative abundance and relative activity approaches were compared as methods to bridge the gap between catalytic activities in recombinant P450 enzymes and human liver microsomes (HLMs). Relative activity factors were measured by determining the intrinsic clearance (CL /sub int/ ) of probe substrates (bu- furalol-CYP2D6, diclofenac-CYP2C9, midazolam-CYP3A4, and phenacetin-CYP1A2) in recombinant P450s and 16 HLM donors. Simultaneous determination of drug depletion and metabolite formation profiles has enabled a direct comparison of these methods for CL /sub int/ determination. Of the 110 drugs tested, 66% were metabolized by one or more P450 enzymes; of these 44% of were metabolized by CYP3A4 (0.3-21 fil/min/pmol of P450), 41% by CYP2D6 (0.6-60 ft l/min/pmol of P450), 26% by CYP2C19 (0.4-8.1 fil/min/pmol of P450), 9% by CYP1A2 (0.4-2.5 fil/min/pmol of P450), and 4% by CYP2C9 (0.9-6.4 ft l/min/pmol of P450). Recombinant enzymes demonstrated improved prediction reliability relative to HLMs and hepatocytes. The most reliable correlations in terms of lowest bias and highest precision were observed by comparing in vivo CL /sub int/ , calculated using the parallel-tube model and incorporating fraction unbound in blood, with in vitro CL /sub int/ determined using relative activity factors and adjusted for nonspecific binding. Predictions were less reliable using the relative abundance approach. For these drugs, recombinant P450 enzymes offer improved assay sensitivity compared with HLMs and cryo- preserved hepatocytes for CL /sub int/ determination using the drug depletion method.

( BUPP09624 - 16 June 2009) Mortality among injection drug users in Chennai, India (2005-2008)

Background: Injection drug users (IDUs) have estimated mortality rates over 10 times higher than the general population; much of this excess mortality is HIV-associated. Few mortality estimates among IDUs from developing countries, including India, exist.Methods: IDUs (1158) were recruited in Chennai from April 2005 to May 2006; 293 were HIV positive. Information on deaths and causes was obtained through outreach workers and family/network members. Mortality rates and standardized mortality ratios were calculated; multivariate Poisson regression was used to identify predictors of mortality. Results: We observed 85 deaths over 1998 person-years (p-y) of follow-up (mortality rate (MR) 4.25 per 100 p-y; 95%. confidence interval (CI) = 3.41-5.23). The overall standardized mortality ratio was 11.1; for HIV-positive IDUs, the standardized mortality ratio was 23.9. Mortality risk among HIV-positive IDUs (MR: 8.88 per 100 p-y) was nearly three times that of negative IDUs (MR: 3.03 per 100 p-y) and increased with declining immune status (CD4 cells > 350: 5.44 per 100 p-y vs. CD4 cells <= 200: 34.5 per 100 p-y). This association persisted after adjustment for confounders. The leading causes of mortality in both HIV negative and positive IDUs were overdose (n = 22), AIDS (n = 14), tuberculosis (n = 8) and accident/trauma (n = 9). Conclusion: Substantial mortality was observed in this cohort with the highest rates among HIV-positive IDUs with CD4 counts of less than 350 cells/mu l. Although, in these 2 years, non-AIDS deaths outnumbered AIDS-related deaths, the relative contribution of AIDS-associated mortality is likely to increase with advancing HIV disease progression. These data reinforce the need for interventions to reduce the harms associated with drug use and increase HAART access among IDUs in Chennai. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

( BUPP09623 - 16 June 2009) Is there a better way to match patients to opioid maintenance treatment: a case report

( BUPP09622 - 16 June 2009) Acceptability of technology-based methods substance abuse counseling in office based buprenorphine maintenance for opioid dependence

( BUPP09621 - 16 June 2009) New opioids for general anaesthesia and in- and out-hospital analgesia

Over the last 30 years, three new opioids of the piperidine family have been introduced to anaesthesia clinical practice: sufentanil, alfentanil and remifentanil. Alfentanil is a derivative of fentanyl, with quicker onset than that of fentanyl and with shorter duration and more intense vagomimetic properties than those of fentanyl and sufentanil. It may cause less intense respiratory depression than equianalgesic doses of fentanyl. Clinical trials indicate that alfentanil can be used effectively as an analgesic, as an analgesic supplement to anaesthesia, and as the major component of a general anaesthetic. Its short duration of effect makes it attractive as an analgesic supplement for short ambulatory surgical procedures. Sufentanil is a more potent and more lipophilic analgesic than fentanyl. It would appear to maintain haemodynamic stability during surgery better than other opioids. Epidural sufentanil produces a rapid onset and good quality of analgesia. In addition, low doses administered intravenously via a PCA pump seem to have a potential role for analgesia during labour. Remifentanil is an opioid analgesic that is rapidly metabolized by non-specific blood and tissue esterases. According to its unique pharmacokinetic profile, remifentanil-based anaesthesia combines high-dosage opioid analgesia intraoperatively with a rapid and predictable postoperative awakening, even after long procedures. Its vagomimetic properties are especially pronounced in small children, the elderly and hypovolaemic patients, and in these groups atropine should be always given before remifentanil administration. Remifentanil also minimises the adrenergic response to endotracheal intubation. Three mju agonist-antagonists have been used for pain treatment: nalbuphine, butorphanol and buprenorphine. They can be used in ambulatory settings. Nalbuphine can be used parenterally. It reverses morphine-induced respiratory depression while maintaining adequate analgesic effect. Buprenorphine can be given sublingually, percutanenously, epidurally and parenterally. It is a potent analgesic, recommended for strong postoperative pain. Butorphanol is a potent analgesic that increases heart rate, arterial and pulmonary blood pressures and cardiac output. It should be given carefully in patients with coronary disease.

( BUPP09648 - 22 June 2009) Bioavailability of veterinary drugs in vivo and in silico

The physical and chemical properties of a drug determine the behaviour of its molecule in a living organism. In this paper, the relationship between selected physical and chemical parameters and drug bioavailability in vivo was investigated. Data sets from 75 compounds, which can be administered per os to 11 various animal species were analyzed. The selected parameters for the prediction of the in vivo bioavailability were the lipophilicity (LogP) and the polar surface area (PSA) or apolar surface area (aPSA) of a molecule. It was shown that the calculation of the hybrid parameters aPSA/PSA and LogP + (aPSA/PSA) allows to estimate the oral bioavailability of a drug and its allocation to clusters with either an oral bioavailability of <70% or >70%. The performed analysis also showed that an extreme low value of the PSA of a molecule (<40 square angstroems) combined with the extreme high value of LogP (>4) is associated with a lower oral bioavailability (<50%). The results obtained indicate the existence of a relationship between the mean LogP value and aPSA/PSA in silico, and the bioavailability of veterinary drugs as determined in vivo.

( BUPP09647 - 22 June 2009) The cyclic GMP modulators YC-1 and zaprinast reduce vessel remodeling through antiproliferative and proapoptotic effects

Guanosine-specific cyclic nucleotide signaling is suggested to serve protective actions in the vasculature; however, the influence of selective pharmacologic modulation of cyclic guanosine monophosphateg Euro" synthesizing soluble guanylate cyclase or cyclic guanosine monophosphateg Euro"degrading phosphodiesterase on vessel remodeling has not been thoroughly examined. In this study, rat carotid artery balloon injury was performed and the growth-modulating effects of the soluble guanylate cyclase stimulator YC-1 or the cyclic guanosine monophosphategEuro" dependent phosphodiesterase-V inhibitor zaprinast were examined. YC-1 or zaprinast elevated vessel cyclic guanosine monophosphate content, reduced medial wall and neointimal cell proliferation, stimulated medial and neointimal cellular apoptosis, and markedly attenuated neointimal remodeling in comparable fashion. Interestingly, soluble guanylate cyclase inhibition by 1H-(1,2,4) oxadiazolo(4,3-a)quinoxalin-1-one failed to noticeably alter neointimal growth, and concomitant zaprinast with YC-1 did not modify any parameter compared to individual treatments. These results provide novel in vivo evidence that YC-1 and zaprinast inhibit injury-induced vascular remodeling through antimitogenic and proapoptotic actions and may offer promising therapeutic approaches against vasoproliferative disorders.

( BUPP09646 - 22 June 2009) Forensic toxicology

( BUPP09645 - 22 June 2009) Protein-losing enteropathy post-valvular surgery with severe tricuspid regurgitation in Subutex-related endocarditis

We report a 25-year-old Malay man with Subutex-related endocarditis, complicated by protein-losing enteropathy from severe tricuspid regurgitation and congestive heart failure. The intestinal protein loss was reversed with surgical valvular intervention. This case highlights the importance of recognising the rare association between protein-losing enteropathy and congestive heart failure in the setting of endocarditis.

( BUPP09644 - 22 June 2009) Phantom limb pain: From physiopathology to prevention

First described in 1545, phantom limb pain is a frequent complication after limb amputation, described by 60 to 85% of amputees. Stump pain, phantom limb sensation and phantom limb pain are often combined. Physiopathology is complex and peripheral, medullar and cortical mechanisms are combined. Pharmacological preventive treatments as well as regional anaesthesia techniques have equivalent results. Such treatments must be investigated more precisely as postoperative rehabilitation of amputees mostly depends on pain relief.

( BUPP09643 - 22 June 2009) Long-term outcomes of composite auricle as a neurosensorial facial subunit allotransplant

A total of 22 composite auricle transplantations were performed in allogeneic experimental (group I, n = 10), allogeneic control (group IIa, n = 5), and isogeneic control (group IIb, n = 7) groups. Allotransplantations were carried out across major histocompatibility complex barrier from Lewis Brown Norway rats to Lewis rats. Isotransplantations were performed between Lewis rats. Group II group received no treatment. Allotransplant recipients in group I were immunosupressed by tapered dose of cyclosporine A for 100 days. Then the treatment was discontinued and immunologic, histopathologic, and clinic assessments including neurosensory recovery were carried out . Group IIa rejected their allografts within 7 to 9 days. All 10 animals from group I and 6 animals from group IIb survived for 100 days without infection, illness, signs of rejection, and graft versus host disease. Satisfactory sensory recovery was attained. Suppressed mixed lymphocyte reaction reactivity under CsA treatment was increased 10 days after cessation of the treatment. CD4-positive/RT1 and CD8-positive/RT1 chimeric cell rates were detected as 0.9% and 1.2% respectively at day 100.

( BUPP09642 - 22 June 2009) A review of barriers and facilitators of HIV treatment among injection drug users

Globally, injection drug use continues to account for a substantial proportion of HIV infections. There have not, however, been any evidence-based reviews of the barriers and facilitators of HIV treatment among injection drug users. For this review, published studies were extracted from nine academic databases, with no language or date specified in the search criteria. Existing evidence demonstrates that, although injection drug users often have worse outcomes from HIV treatment than non-injection drug users, major antiretroviral-associated survival gains still have been observed among this population. Inferior outcomes are explained by a range of barriers to antiretroviral access and adherence, which often stem from the negative influences of illicit drug policies, as well as issues within medical systems, including lack of physician education about substance abuse. Evidence demonstrates that several under- utilized interventions and novel antiretroviral delivery modalities have helped to greatly address these barriers in several settings, and there is sufficient evidence to support immediate scale-up of these programmes. These interventions include coupling antiretroviral therapy with opioid substitution therapies as well as directly administered antiretroviral therapy programmes. Of particular interest for future evaluation is the coupling of HIV treatment programmes within comprehensive services, which also provide low-threshold (harm reduction) HIV prevention programmes. Scale-up of evidence-based HIV treatment and prevention to injection drug users, however, will require increasing political will among both national policy-makers and international public health agencies.

( BUPP09641 - 22 June 2009) Psychiatrists for medically complex patients: bringing value at the physical health and mental health/substance-use disorder interface

Background: In their current configuration, traditional reactive consultation-liaison services see a small percentage of the general-hospital patients who could benefit from their care. These services are poorly reimbursed and bring limited value in terms of clinical improvement and reduction in health-service use. Method: The authors examine models of cross-disciplinary, integrated health services that have been shown to promote health and lower cost in medically-complex patients, those with complicated admixtures of physical, mental, social, and health-system difficulties. Conclusion: Psychiatrists who specialize in the treatment of medically-complex patients must now consider a transition from traditional consultation to proactive, value-added programs and bill for services from medical, rather than behavioral, insurance dollars, since the majority of health-enhancement and cost-savings from these programs occur in the medical sector. The authors provide the clinical and financial arguments for such program-creation and the steps that can be taken as psychiatrists for medically-complex patients move to the next generation of inter- disciplinary service.

( BUPP09640 - 22 June 2009) Buprenorphine is a weak partial agonist that inhibits opioid receptor desensitization

Buprenorphine is a weak partial agonist at mu-opioid receptors that is used for treatment of pain and addiction. Intracellular and whole-cell recordings were made from locus ceruleus neurons in rat brain slices to characterize the actions of buprenorphine. Acute application of buprenorphine caused a hyperpolarization that was prevented by previous treatment of slices with the irreversible opioid antagonist beta-chlornaltrexamine (beta-CNA) but was not reversed by a saturating concentration of naloxone. As expected for a partial agonist, subsaturating concentrations of buprenorphine decreased the (Met) /sup 5/ enkephalin (ME)-induced hyperpolarization or outward current. When the ME-induced current was decreased below a critical value, desensitization and internalization of beta-opioid receptors was eliminated. The inhibition of desensitization by buprenorphine was not the result of previous desensitization, slow dissociation from the receptor, or elimination of receptor reserve. Treatment of slices with subsaturating concentrations of etorphine, methadone, oxymorphone, or beta-CNA also reduced the current induced by ME but did not block ME-induced desensitization. Treatment of animals with buprenorphine for 1 week resulted in the inhibition of the current induced by ME and a block of desensitization that was not different from the acute application of buprenorphine to brain slices. These observations show the unique characteristics of buprenorphine and further demonstrate the range of agonist-selective actions that are possible through G-protein-coupled receptors.

( BUPP09639 - 22 June 2009) Pain therapy in practice

( BUPP09638 - 22 June 2009) Management of Acute Postpartum Pain in Patients Maintained on Methadone or Buprenorphine During Pregnancy

Background: Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients. Objectives: To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate postpartum period. Methods: Pain control adequacy and amount of non-opioid and opioid medication Needed in buprenorphine- (n = 8) and methadone-maintained (n = 10) patients over the first five days postpartum were examined. Results: Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use. Conclusions and Scientific Significance: Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.

( BUPP09637 - 22 June 2009) Pulmonary Hypertension in First Episode Infective Endocarditis among Intravenous Buprenorphine Users: Case Report

Background: Since the Food and Drug Administration (FDA) approved the use of buprenorphine hydrochloride (Subutex) for the treatment of opiate dependence in 2002, there has been a global trend of its IV abuse which led to life-threatening medical complications such as infective endocarditis (IE), cardiac failure, and death. Methods: First episode IE were identified in 14 patients (prevalence of 10.8%) among 130 IV buprenorphine abusers who presented to the National University Hospital, Singapore between 2004 to 2006. The variables that were examined in the present study included age, gender, ethnicities, duration of symptoms, types of valves, laboratory, microbiology, echocardiographic features, types of antibiotics given, duration of hospitalization, and the mortality rate. Results: While the majority of these patients presented predominantly with pleuropneumonic symptoms and had tricuspid-valve vegetations with Staphylococcus aureus being the commonest causative organism as reported in other IV drug abusers, pulmonary arterial hypertension (PHT) seemed peculiarly common (79%), and the mortality (21%) was higher in our patients compared to previously reported series (5-10%). Univariate linear regression revealed no relationship between PHT and the presence of septic pulmonary emboli (p =.284) and pulmonary embolism (p =.777). Conclusion and Scientific Significance: PHT may contribute to morbidity and mortality amongst IV buprenorphine abusers. A high index of suspicion of PHT is required in treating IV buprenorphine abusers who presented with pleuropneumonic symptoms. The absence of a relationship between PHT and pulmonary embolism underscores the possibility of the contribution of buprenorphine to PHT, which have been demonstrated in a number of animal studies.

( BUPP09636 - 22 June 2009) Comparison of Side Effects between Buprenorphine and Meloxicam Used Postoperatively in Dutch Belted Rabbits (Oryctolagus cuniculus)

One of the challenges facing veterinarians and investigators who use rabbits (Oryctolagus cuniculus) as a surgical model in biomedical research is choosing an appropriate and efficacious postoperative analgesic without systemic complications and side effects. The objective of this study was to evaluate the gastrointestinal side effects associated with the postoperative use of buprenorphine in Dutch Belted rabbits. We also evaluated the analgesic meloxicam as an alternative to opioid administration during the postoperative period. Rabbits were assigned to 1 of 3 treatment groups during the postoperative period after routine ovariohysterectomy: buprenorphine (n = 10), meloxicam (n = 10), and incisional infiltration with bupivicaine (no treatment control; n = 10). Feed intake, fecal production, weight loss, urine output, and other physiologic parameters were monitored and behavior and pain assessments were performed for 7 d after surgery and compared with baseline values collected before surgery. All rabbits showed decreased pellet consumption, fecal production, and weight on day 1 after surgery. This effect was severe in some rabbits that received bupivicaine; therefore treatment of this entire group with metoclopramide, fluids, and hay was instituted to reverse gut stasis. No significant difference in feed consumption and fecal production was present between the buprenorphine- and meloxicam-treated groups. On the basis of these results, meloxicam appears to be a suitable alternative or adjunct to buprenorphine for alleviating postoperative pain with minimal risk of anorexia and gastrointestinal ileus

( BUPP09635 - 22 June 2009) The 'Mill-Wheel' Murmur and Computed Tomography of Intracardiac Air Emboli

The 'water-wheel' or 'mill-wheel' murmur is classically associated with large intracardiac air emboli and described as a "characteristic splashing auscultatory sound due to the presence of gas in the cardiac chambers." We used 64-slice computed tomography (slice thickness, 0.5 mm; revolution time, 400 msec) and 3D fly-through software imagery to capture previously unreported intracardiac air-blood interface dynamics associated with this murmur and ineffective right ventricular contraction in a porcine model.

( BUPP09634 - 22 June 2009) False-positive ethyl glucuronide immunoassay screening associated with chloral hydrate medication as confirmed by LC-MS/MS and self-medication

BACKGROUND: Urine-ethyl glucuronide (EtG) concentrations are considered as a specific marker of recent alcohol consumption. We describe false-positive EtG screening results by the DRI ethyl glucuronide enzyme immunoassay caused by chloral hydrate intake. METHODS: Urine-EtG-screening: DRI EtG enzyme immunoassay (Thermo Fisher Scientific Microgenics) on a Hitachi 912 analyzer. EtG- and ethyl sulfate (EtS) confirmatory analysis: LC-MS/MS with an ESI source in the negative ionization, selective reaction monitoring mode. Patient: ethanol-abstaining women under buprenorphine-treatment (medication with levetiracetam, gabapentin, clomethiazol and chloral hydrate). Proband: self-medication with 500 mg chloral hydrate after a 5-day ethanol abstinence. EtG analysis for both in subsequent urines. Check for cross reactions of the pharmaceuticals with the EtG immunoassay by addition of pure substance (2 g/L each) to EtG-free urine. RESULTS: EtG concentrations up to 8.0 mg/L or 7.0 mg/g creatinine (cut-off 0.5 mg/L or mg/g) for the patient and up to 0.28 mg/L or 0.35 mg/g for the control subject (after 500 mg chloral hydrate) were obtained by the immunoassay. LC-MS/MS could not confirm these EtG results. In fact, EtG and/or EtS were not detectable in any of the urine samples by LC-MS/MS (lower limit of detection 0.01 mg/L). Cross reactions of the pharmaceuticals, incl. the chloral hydrate metabolites trichloroethanol and trichloroacetic acid, with the DRI EtG immunoassay results were ruled out (by spiking experiments) as the underlying cause for the false-positive EtG immunoassay results. CONCLUSIONS: Trichloroethyl glucuronide as an important chloral hydrate metabolite remains the most probable cross reacting substance with the DRI EtG immunoassay (unproven because of lack in pure standard). The chloral hydrate self-medication experiment clearly points to an association of the false-positive EtG immunoassay results and chloral hydrate intake. Chloral hydrate medication has to be considered as a cause for false-positive EtG screening results by the DRI EtG immunoassay even in cases with regular chloral hydrate treatment (250-1000 mg) and the more in patients with chloral hydrate tolerance (taking g/day). It is recommended that positive EtG immunoassay results always be confirmed by a more specific technique such as LC-MS/MS, including ethyl sulfate as a second minor ethanol metabolite.

( BUPP09633 - 22 June 2009) Opioids switching with transdermal systems in chronic cancer pain

BACKGROUND: Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapy OBJECTIVE: To assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment. METHODS: A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeks RESULTS: Pain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 + /- 20.5 (mean +/- SD) to 3.75 +/- 8.06, and 33.8 +/- 18.9 to 3.75 +/- 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment. CONCLUSION: Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer.

( BUPP09632 - 22 June 2009) Urinary excretion of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide in pregnant women receiving buprenorphine maintenance treatment

BACKGROUND: Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum. METHODS: We measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 microg/L for BUP and BUP-Gluc and 25 microg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy. RESULTS: NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly Higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy. CONCLUSIONS: These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation.

( BUPP09668 - 29 June 2009) Transfer of buprenorphine into breast milk and calculation of infant drug dose

( BUPP09667 - 29 June 2009) Open-label dose-finding trial of buprenorphine implants (Probuphine) for treatment of heroin dependence

Buprenorphine, a u-opiod receptor partial agonist, has been shown to be safe and effective for treatment of opioid dependence. A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion. The goal of the current study was to conduct an initial, open-label, evaluation of the safety, pharmacokinetics, and efficacy of two doses of Probuphine in subjects with opioid dependence maintained on sublingual buprenorphine. Two doses of Probuphine were evaluated in 12 heroin-dependent volunteers switched from daily sublingual buprenorphine dosing to either two or four Probuphine implants based upon their buprenorphine daily maintenance dose of 8mg of 16mg respectively, and were monitored for 6 months. Probuphine implants provided continuous steady state delivery of buprenorphine until their removal at 6 months. Withdrawal symptoms and craving remained low throughout the 6 months. For the 12 subjects, an average of 50% of urines were opioid-negative across the 6 month treatment period. Injection site reactions were present in half of patients, but none were serious. No safety concerns were evident. These results suggest that Probuphine implants offer significant promise for enhancing delivery of effective opioid substitution treatment while minimizing risk for abuse of medication.

( BUPP09666 - 29 June 2009) Combined use of pregabalin and memantine in fibromyalgia syndrome treatment: A novel analgesic and neuroprotective strategy?

Fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome that is estimated to affect 4-8 million US adults. The exact molecular mechanisms underlying this illness remain unclear, rendering most clinical treatment and management techniques relatively ineffective. It is now known that abnormalities in both nociceptive and central pain processing systems are necessary (but perhaps not sufficient) to condition the onset and maintenance of FMS. These same systemic abnormalities are thought to be responsible for the loss of cephalic gray matter density observed in all FMS patients groups studied to date. The current scope of FMS treatment focuses largely on analgesia and does not clearly address potential neuroprotective strategies. This article proposes a combined treatment of pregabalin and memantine to decrease the pain and rate of gray matter atrophy associated with FMS. This dual-drug therapy targets the voltage-gated calcium ion channel (VGCC) and the N-methyl d-aspartate receptor (NMDAR) (respectively), two primary components of the human nociceptive and pain processing systems.

( BUPP09665 - 29 June 2009) Simultaneous quantification of buprenorphine, norbuprenorphine, buprenorphine-glucuronide and norbuprenorphine-glucuronide in human umbilical cord by liquid chromatography tandem mass spectrometry

A LCMS method was developed and validated for the simultaneous determination of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) in human umbilical cord. Quantification was achieved by selected ion monitoring of precursor ions m/z 468.4 for BUP; 414.3 for NBUP; 644.4 for BUP-Gluc and 590 for NBUP-Gluc. BUP and NBUP were identified by MS /sup 2/ , with m/z 396, 414 and 426 for BUP, and m/z 340, 364 and 382 for NBUP. Glucuronide conjugates were identified by MS /sup 3/ with m/z 396 and 414 for BUP-Gluc and m/z 340 and 382 for NBUP-Gluc. The assay was linear 1-50 ng/g. Intra-day, inter-day and total assay imprecision (%RSD) were <14.5%, and analytical recovery ranged from 94.1% to 112.3% for all analytes. Extraction efficiencies were >66.3%, and process efficiency >73.4%. Matrix effect ranged, in absolute value, from 3.7% to 7.4% (CV < 21.8%, n = 8). The method was selective with no endogenous or exogenous interferences from 41 compounds evaluated. Sensitivity was high with limits of detection of 0.8 ng/g. In order to prove method applicability, an authentic umbilical cord obtained from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. Interestingly, BUP was not detected but concentrations of the other metabolites were NBUP-Gluc 13.4 ng/g, BUP-Gluc 3.5 ng/g and NBUP 1.2 ng/g.

( BUPP09664 - 29 June 2009) Management of cancer pain: ESMO Clinical Recommendations

( BUPP09663 - 29 June 2009) Harm reduction for injecting opiate users: An update and implications in China

The harm associated with high-risk injected opiate use and the threat of the HIV epidemic among injecting drug users has become a worldwide problem. Twenty years ago, in the face of a rapid increase in mortality rates among injecting drug users and the upcoming threat of HIV, the first harm-reduction programs were implemented in the Western world. This paper is a literature review describing four forms of harm reduction currently in use in Europe, North America, and Australia. Each represents a reasonable counterapproach to the threat of increased prevalence of HIV among injecting drug users in transitional and developing countries. The paper attempts to explain the concepts behind the most commonly used types of harm reduction and provides a brief overview of the advantages and disadvantages of each and the reasons for their implementation. The main focus of the review is on the definition and the practical aspects of harm reduction; it includes a brief introduction of Chinese harm-reduction efforts and their implications.

( BUPP09662 - 29 June 2009) Lives to save: PEPFAR, HIV, and injecting drug use in Africa

( BUPP09661 - 29 June 2009) Using molecular similarity to highlight the challenges of routine immunoassay-based drug of abuse/toxicology screening in emergency medicine

Background: Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often used in emergency medicine, generally utilize antibody-based tests (immunoassays) to detect classes of drugs such as amphetamines, barbiturates, benzodiazepines, opiates, and tricyclic antidepressants, or individual drugs such as cocaine, methadone, and phencyclidine. A key factor in assay sensitivity and specificity is the drugs or drug metabolites that were used as antigenic targets to generate the assay antibodies. All DOA/Tox screening immunoassays can be limited by false positives caused by cross-reactivity from structurally related compounds. For immunoassays targeted at a particular class of drugs, there can also be false negatives if there is failure to detect some drugs or their metabolites within that class. Methods: Molecular similarity analysis, a computational method commonly used in drug discovery, was used to calculate structural similarity of a wide range of clinically relevant compounds (prescription and over-the-counter medications, illicit drugs, and clinically significant metabolites) to the target ('antigenic') molecules of DOA/Tox screening tests. These results were compared with cross-reactivity data in the package inserts of immunoassays marketed for clinical testing. The causes for false positives for phencyclidine and tricyclic antidepressant screening immunoassays were investigated at the authors' medical center using gas chromatography/mass spectrometry as a confirmatory method. Results: The results illustrate three major challenges for routine DOA/ Tox screening immunoassays used in emergency medicine. First, for some classes of drugs, the structural diversity of common drugs within each class has been increasing, thereby making it difficult for a single assay to detect all compounds without compromising specificity. Second, for some screening assays, common 'out-of-class' drugs may be structurally similar to the target compound so that they account for a high frequency of false positives. Illustrating this point, at the authors' medical center, the majority of positive screening results for phencyclidine and tricyclic antidepressants assays were explained by out-of-class drugs. Third, different manufacturers have adopted varying approaches to marketed immunoassays, leading to substantial inter-assay variability. Conclusion: The expanding structural diversity of drugs presents a difficult challenge for routine DOA/Tox screening that limit the clinical utility of these tests in the emergency medicine setting.

( BUPP09660 - 29 June 2009) Acute liver and renal failure during treatment with buprenorphine at therapeutic dose

Buprenorphine is a semi-synthetic opioid derivative commonly used in the treatment of heroin addiction. Life-threatening complications have been described following overdoses while few cases of hepatotoxicity due to drug use at therapeutic doses have been recently described in hepatitis C virus carriers. In these cases, however, histological assessment was not exhaustive and no extra-hepatic organ failure was observed. We describe herein a case of acute liver and kidney failure in a patient with previously latent hepatitis C virus chronic infection following recommended doses of buprenorphine. Histology did not demonstrate any feature compatible with hepatitis C virus reactivation or liver cirrhosis and suspension of the treatment led to the resolution of both liver and kidney failure. Causality criteria fulfillment indicates a high probability of buprenorphine-induced liver toxicity. No signs of pre-existant kidney impairment or of pre- or post-renal causes were observed. Since buprenorphine is metabolized through cytochrome P450 3A4, we genotyped six genetic polymorphisms previously described in poor metabolizers but could not confirm these pharmacogenetic bases in this case. In conclusion, we surmise that buprenorphine at suggested doses can induce liver and kidney failure in susceptible individuals, possibly through direct mitochondrial toxicity.

( BUPP09659 - 29 June 2009) Retax pitfall narcotic substances

( BUPP09658 - 29 June 2009) A review of addiction

Addiction to drugs and alcohol is often undiagnosed and untreated. Physicians are often unaware or have negative attitudes regarding these patients, such as the perception that treatment is ineffective. Addiction - psychological dependence with or without tolerance and withdrawal - is essentially compulsive uncontrolled substance use despite physical, psychological, or social consequences. Wc now have an understanding of the 2 major neurological pathways involved in addiction. First, the mcsolimbic dopamine reward pathway, which is essential for survival, can be physically altered by drug abuse to result in uncontrolled cravings. Second, the decision-making prefrontal cortex, which suppresses inappropriate reward response, can also be altered by drug abuse. Thus, accelerated "go" signals and impaired "stop" signals result in uncontrolled use despite severe consequences. Further, addicts can be predisposed to addiction by genetic defects in reward pathway neurotransmission and stress-related developmental brain abnormalities. Relapse to drug use can occur because of stress or cue-related reward pathway stimulation or even by a single drug dose. Individualized treatment of addiction, including pharmacological and cognitive-behavioral interventions, can be as successful as treatment of other chronic diseases. Several pharmaceuticals are available or under study for these disorders. Waiting for the addict to "be ready" for treatment can be dangerous and detoxification alone is often ineffective. The physician's role in treating addiction includes prevention, diagnosis, brief intervention, motivational interviewing, referral, and follow-up care. An understanding of the biological reality of addiction allows physicians to understand addicts as having a brain disease. Further, the reality of effective pharmacological and cognitive-behavioral treatments for addiction allows physicians to be more optimistic in treating addicts. The challenge to the physician is to embrace the reality of addictive disease and fulfill his or her role in its treatment.

( BUPP09657 - 29 June 2009) Prescription of heroin for the management of heroin dependence: Current status

The prescription of heroin (diamorphine) for the management of heroin dependence is a controversial treatment approach that was limited to Britain until the 1990s. Since then a number of countries have embarked upon clinical trials of this approach, and it is currently licensed and available in several European countries. To date, six randomized controlled trials (RCTs) with over 1600 patients and several cohort studies have examined injected (or inhaled) heroin treatment. This article reviews relevant clinical pharmacology, how heroin treatment programmes are delivered, and the evidence regarding safety, efficacy and cost-effectiveness from RCTs. Heroin is usually prescribed in intravenous dosages of 300500 mgday, divided in two or three doses. Uncommon but serious side effects include seizures and respiratory depression immediately following injection. Despite methodological shortcomings, RCTs generally indicate that heroin treatment results in a comparable retention, improved general health and psychosocial functioning, and less self-reported illicit heroin use than oral methadone treatment. Cost-effectiveness studies indicate heroin treatment to be more expensive to deliver but to result in savings in the criminal justice sector. There has been debate regarding how heroin treatment should be positioned within the range of treatment approaches for this condition. There is increasing consensus that, in countries that have robust and accessible treatment systems for heroin users, heroin treatment is suited to a minority of heroin users as a second-line treatment for those individuals who do not respond to methadone or buprenorphine treatment delivered under optimal conditions.

( BUPP09656 - 29 June 2009) Progress in pharmacological pain treatment with opioid analgesics

The role of opioids in pharmacological cancer pain treatment is essential, especially strong opioids - in Poland morphine, fentanyl, buprenorphine, methadone and recently oxycodone are available. Currently weak opioids are infrequently used worldwide; however, in Poland (tramadol and dihydrocodeine) and in Germany (tramadol) play a significant role in moderate cancer pain treatment. Weak opioids' role in education and easier availability of tramadol are emphasized. Combining weak or strong opioids with non-opioids and adjuvant analgesics (co-analgesics) improves analgesia. Opioid switching (rotation) plays an important role in patients with poor analgesia and intense adverse effects of opioid. Combining two or more opioids (semi-switch) remains controversial but more studies support such an approach. Opioid pharmacokinetic and pharmacodynamic interactions should be emphasized as they may impair analgesia and intensify opioid adverse effects. In this paper cancer pain treatment rules and properties of tramadol, codeine, dihydrocodeine, morphine, fentanyl, methadone, oxycodone, buprenorphine, hydromorphone and tapentadol are discussed.

( BUPP09655 - 29 June 2009) Current situation and trends of drug abuse and HIV/AIDS in China

Drug abuse re-emerged in mainland China in the 1980s and has spread dramatically over the last decades; the cumulative number of registered drug users increased to 1.16 million by the end of 2005. Among them, 78.3% were heroin addicts and the majority of them (50-70%) were injecting drug users. The abuse of amphetamine-type stimulants emerged at the end of the 1990s and spread quickly. Injecting drug use and unsafe sexual behavior among drug users have been the key factors in the spread of HIV/AIDS. By the end of September 2008, the cumulative total of reported HIV/AIDS cases was 264,302 in China. The Chinese government takes great measures and strategies to prevent HIV/AIDS transmission and reduce drug-related harms, including methadone-maintenance treatment and needle-exchange programs. Moreover, antiretroviral therapy has been provided for AIDS patients. The Chinese government will continue to implement strategies to prevent the spread of HIV/AIDS among drug users in the future.

( BUPP09654 - 29 June 2009) Methadone-associated Q-T interval prolongation and torsades de pointes

Purpose. The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided. Summary. Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and chlorobutanol, oral methadone should be used whenever possible. Conclusion. Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary.

( BUPP09653 - 29 June 2009) Development of pharmacotherapies for drug addiction: A Rosetta stone approach

Current pharmacotherapies for addiction represent opportunities for facilitating treatment and are forming a foundation for evaluating new medications. Furthermore, validated animal models of addiction and a surge in understanding of neurocircuitry and neuropharmacological mechanisms involved in the development and maintenance of addiction - such as the neuroadaptive changes that account for the transition to dependence and the vulnerability to relapse - have provided numerous potential therapeutic targets. Here, we emphasize a 'Rosetta Stone approach', whereby existing pharmacotherapies for addiction are used to validate and improve animal and human laboratory models to identify viable new treatment candidates. This approach will promote translational research and provide a heuristic framework for developing efficient and effective pharmacotherapies for addiction.

( BUPP09652 - 29 June 2009) Detoxification treatments for opiate dependent adolescents

BACKGROUND: The scientific literature examining effective treatments for opioid dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component of effective treatments for opioid dependence. Nevertheless no studies have been published which systematically assess the effectiveness of the pharmacological detoxification among adolescents. OBJECTIVES: To assess the effectiveness of any detoxification treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions on completion of treatment, reducing the use of substances and improving health and social status. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (August 2008), MEDLINE (January 1966 to August 2008), EMBASE (January 1980 to August 2008), CINHAL (January 1982 to August) and reference lists of articles. SELECTION CRITERIA: Randomised and controlled clinical trials comparing any pharmacological interventions alone or associated with psychosocial intervention aimed at detoxification with no intervention, placebo, other pharmacological intervention or psychosocial intervention in adolescents (13-18 years). DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: One trial involving 36 participants was included. It compares buprenorphine with clonidine for detoxification. No difference was found for drop out: RR 0.45 (95%CI: 0.20 - 1.04) and acceptability of treatment: withdrawal score WMD: 3.97 (95%CI -1.38, 9.32). More participants in the buprenorphine group initiated naltrexone treatment: RR 11.00 (95%CI 1.58, 76.55). AUTHORS' CONCLUSIONS: It is difficult to draft conclusions on the basis of only one trial with few participants. Furthermore, the only study included did not consider the efficacy of methadone that is still the most frequent drug utilized for the treatment of opioid withdrawal. One possible reason for the lack of evidence could be the difficulty in conducting trials with young people for to practical and ethical reasons.

( BUPP09651 - 29 June 2009) Maintenance treatments for opiate dependent adolescent.

BACKGROUND: The scientific literature examining effective treatments for opioid dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component of effective treatments for opioid dependence. Nevertheless no studies have been published which systematically assess the effectiveness of the pharmacological maintenance treatment among adolescent. OBJECTIVES: To assess the effectiveness of any maintenance treatment alone or in combination with psychosocial intervention compared to no intervention, other pharmacological intervention or psychosocial interventions on retaining adolescents in treatment, reducing the use of substances and reducing health and social status SEARCH STRATEGY: We searched the Cochrane Drugs and Alcohol Group's trials register (august 2008), MEDLINE (January 1966 to august 2008), EMBASE (January 1980 to august 2008), CINHAL (January 1982 to august 20 08) and reference lists of articles SELECTION CRITERIA: Randomised and controlled clinical trials comparing any maintenance pharmacological interventions alone or associated with psychosocial intervention with no intervention, placebo, other pharmacological intervention included pharmacological detoxification or psychosocial intervention in adolescent (13-18 years) DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data MAIN RESULTS: Two trials involving 187 participants were included. One study compared methadone with LAAM for maintenance treatment lasting 16 weeks after which patients were detoxified, the other compared maintenance treatment with buprenorphine - naloxone with detoxification with buprenorphine. No meta-analysis has been performed because the two studies assessed different comparisons. Maintenance treatment seems more efficacious in retaining patients in treatment but not in reducing patients with positive urine at the end of the study. Self reported opioid use at 1 year follow up was significantly lower in the maintenance group even if both group reported high level of opioid use and more patients in the maintenance group were enrolled in other addiction treatment at 12 month follow up. AUTHORS' CONCLUSIONS: It is difficult to draft conclusions on the basis of only two trials. One of the possible reason for the lack of evidence could be the difficulty to conduct trial with young people due to practical and ethic reasons.

( BUPP09650 - 29 June 2009) Long-acting opioid-agonists in the treatment of heroin addiction: why should we call them "substitution"?

Many studies have documented the safety, efficacy, and effectiveness of long-acting opioids (L-AOs), such as methadone and buprenorphine, in the treatment of heroin addiction. This article reviews the pharmacological differences between L-AO medications and short-acting opioids (heroin) in terms of reinforcing properties, pharmacokinetics, effects on the endocrine and immune systems. Given their specific pharmacological profile, L-AOs contribute to control addictive behavior, reduce craving, and restore the balance of disrupted endocrine function. The use of the term "substitution" referring to the fact that methadone or buprenorphine replace heroin in binding to brain opioid receptors, has been generalized to consider L-AOs as simple replacement of street drugs, thus contributing to the widespread misunderstanding of this treatment approach.

( BUPP09649 - 29 June 2009) Comparison of Five Benzodiazepine-Receptor Agonists on Buprenorphine-Induced mu-Opioid Receptor Regulation

In this study, we compared the effects of five short-, medium, or long-acting benzodiazepine-receptor agonists (BZDs) (alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)), at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of mu-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. Using 0.312 - 5 nM (H-3)-DAMGO concentrations and Scatchard plot analysis, B-max (maximal receptor density) and K-d (dissociation constant) were determined at different brain regions of interest (amygdala, cortex, hippocampus, hypothalamus, thalamus). Acute BPN induced an expected down- regulation and addition of each of the BZDs to BPN induced less down-regulation than did BPN alone, sometimes while altering affinity. Some significant differences in the intensity of these effects were observed between BZDs. FLZ that is widely abused and enlarges BPN toxicity appeared the most potent to increase mu-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on mu-opioid-receptor regulation appeared lower is considered to have a low risk of dependence in the epidemiological data banks. CLZ and ZLP (2 mg/kg) induced the strongest modification on mu-opioid-receptor density, but a substantial decrease in affinity could minimize the functional consequences. The reported changes were maximal in the amygdala, hippocampus, and thalamus. Among people using BPN and BZDs, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the BZD.

( BUPP09680 - 06 July 2009) Invited comment

( BUPP09679 - 06 July 2009) Successful methadone maintenance treatment for opioid dependency requires carefully individualized dosages

Methadone is used as a substitute opioid in the long-term maintenance treatment of opioid addiction. It occupies the opioid receptors, preventing withdrawal symptoms and physical cravings, but without the 'highs' associated with other opioids. As the response to methadone varies, the dosage should be individualize.

( BUPP09678 - 06 July 2009) Opioid use in an Israeli health maintenance organization: 2000-2006

Objective. The objective of this study was to assess opioid use during 7 years (2000-2006) among Clalit Health Services (CHS) members. Design. Purchasing data of opioids authorized for use in Israel were obtained from the computerized databases of CHS. Patient demographics and cancer morbidity were also extracted. The data were analyzed by converting the purchased opioids to oral morphine equivalents (OMEs). Setting. CHS is the largest health maintenance organization in Israel (3,774,600) and insures almost 54% of the Israeli population. Patients.All CHS members who purchased an opioid at least once during the 7-year study period (2000-2006). Intervention. There were no interventions in this study. Outcome Measures. The ourcome measures of this study were total OME purchased per year, OME (mg) per capita/per year, and OME (mg) daily dose. Results. There were 119,562 patients who purchased an opioid at least once (3.2% of CHS population). Of them, 57.4% were women, 69.0% aged 65 years and above (average age 56.05 years � 26.7), 7.7% purchased opioids for more than 12 months, and 81.3% purchased opioids for only 1-4 months. A 96% increase in total OME purchased was found between 2000 and 2006 (from 56.4 kg to 110.6 kg). The annual OME purchased per capita increased from 15.7 mg in the year 2000 to 29.3 mg in 2006. The total number of patients who received at least one opioid prescription increased by 60%, while the growth in total number of CHS members was smaller (4.8%). Conclusions. There is a growing use of opioids at CHS during the 7-year period, a potential indicator of the progress made in improving accessibility and availability of opioids in our health care organization in Israel.

( BUPP09676 - 06 July 2009) Drug abuse and hepatitis C infection as comorbid features of HIV associated neurocognitive disorder: Neurocognitive and neuroimaging features

Substance abuse and co-infection with hepatitis C (HCV) are two highly relevant determinants of neurocognitive and neuroimaging abnormalities associated with HIV. Substance abuse and HCV are common in the HIV population and there is increasing evidence that the CNS is directly compromised by these comorbid conditions via additive or synergistic processes. In this article we review the current literature regarding mechanisms of neuronal injury as well as the neuropsychological and neuroimaging signatures associated with substance abuse and HCV status among HIV patients. We discuss specific methodological challenges and threats to validity associated with studies of HIV and comorbid substance use disorders or HCV and review potential strategies for minimizing their confounding effects. Efforts to understand the interactions between HIV, substance abuse and HCV co-infection will lead to more complete models of neuropathogenesis of HIV and a greater understanding of the variability in neuropsychological expression of HIV Associated Neurocognitive Disorder.

( BUPP09675 - 06 July 2009) Case report: postoperative analgesia and preserved motor function with clonidine and buprenorphine via a sciatic perineural catheter

Two cases of posterolateral corner reconstruction of the knee with postoperative sciatic perineural analgesia using a mixture of clonidine and buprenorphine, are presented. Numeric rating scores for pain with movement were 0-2 out of 10 postoperatively after injection. Gross motor function below the knee was maintained in both cases.

( BUPP09674 - 06 July 2009) Comparing retention in treatment and mortality in people after initial entry to methadone and buprenorphine treatment

To compare retention in treatment and mortality among people entering methadone and buprenorphine treatment for opioid dependence.The Pharmaceutical Drugs of Abuse System (PHDAS) database records start-and end-dates of all episodes of methadone and buprenorphine treatment in New South Wales, and the National Death Index (NDI) records all reported deaths.Data linkage study. First entrants to treatment between June 2002 and June 2006 were identified from the PHDAS database. Retention in treatment was compared between methadone and buprenorphine. Names were linked to the NDI database, and 'good matches' were identified. Deaths were classified as occurring during induction, maintenance and either post-methadone or post-buprenorphine, depending on the latest episode of treatment prior to death. The numbers of inductions into treatment, of total person-years spent in each treatment, and person-years post-methadone or buprenorphine, were calculated. Risk of death in different periods, and different treatments, was analysed using Poisson regression.A total of 5992 people entered their first episode of treatment-3349 (56%) on buprenorphine, 2643 on methadone. Median retention was significantly longer in methadone (271 days) than buprenorphine (40 days). During induction, the risk of death was lower for buprenorphine (relative risk = 0.114, 95% confidence interval = 0.002-0.938, P = 0.02, Fisher's exact test). Risk of death was lowest during treatment, significantly higher in the first 12 months after leaving both methadone and buprenorphine. Beyond 12 months after leaving treatment, risk of death was non-significantly higher than during treatment.Buprenorphine was safer during induction. Despite shorter retention in treatment, buprenorphine maintenance was not associated with higher risk of death.

( BUPP09673 - 06 July 2009) Maintenance therapy and 3-year outcome of opioid-dependent prisoners: a prospective study in France (2003-06)

To describe the profile of imprisoned opioid-dependent patients, prescriptions of maintenance therapy at imprisonment and 3-year outcome in terms of re-incarceration and mortality.Prospective, observational study (France, 2003-06).Health units of 47 remand prisons.A total of 507 opioid-dependent patients included within the first week of imprisonment between June 2003 and September 2004, inclusive.Physicians collected socio-demographic data, penal history, history of addiction, maintenance therapy and psychoactive agent use, general health status and comorbidities. Prescriptions at imprisonment were recorded by the prison pharmacist. Re-incarceration data were retrieved from the National Register of Inmates, survival data and causes of death from the National Registers of vital status and death causes.Prison maintenance therapy was delivered at imprisonment to 394/507 (77.7%) patients. These patients had poorer health status, heavier opioid use and prison history and were less socially integrated than the remaining 113 patients. Over 3 years, 238/478 patients were re-incarcerated (51.3 re-incarcerations per 100 patient-years, 95% confidence interval (CI) 46.4-56.2). Factors associated independently with re-incarceration were prior imprisonment and benzodiazepine use. After adjustment for confounders, maintenance therapy was not associated with a reduced rate of re-incarceration (adjusted relative risk 1.28, 95% CI 0.89-1.85). The all-cause mortality rate was eight per 1000 patient-years (n = 10, 95% CI 4-13).Prescription of maintenance therapy has increased sharply in French prisons since its introduction in the mid-1990s. However, the risk of re-imprisonment or death remains high among opioid-dependent prisoners. Substantial efforts are needed to implement more effective preventive policies.

( BUPP09672 - 06 July 2009) A new illicit opioid dependence outbreak, evidence for a combination of opioids and steroids

Opioid abuse is common in Iran. In 2005, a new version of locally produced illicit opioid vials, so called Norgesic, appeared in the illicit market, which gained popularity rapidly and led to an improvement of stigmatizing the general appearance of dependent cases. Later, some cases suffered Cushing's-like problems. A prospective case series was designed to evaluate 18 Norgesic- dependent subjects who volunteered for abstinence therapy in a rehabilitation clinic from November 1, 2005, to December 30, 2005. In this study, we aimed to describe the clinical and paraclinical findings in detail and define the potential determinants of this Cushing's syndrome outbreak. History, physical examination, plasma cortisol level, and urine screen tests were used to describe the patients. All subjects were male with a mean (SEM) age of 29.8 +/- 1.6 years. The opioid-dependence period was 8.4 +/- 0.9 years. In an average of 4.7 +/- 0.3 months, subjects increased their usage to 5.5 +/- 0.5 vials a day. Patients claimed to gain weight. Striae were seen in 38.9%, previously documented psychological problems in 33.3%, weakness in 27.8%, high systolic blood pressure in 22.2%, moon face in 16.7%, hirsutism in 11.1%, extensive dermal infection in 11.1%, gynecomastia in 5.6%, back pain in 5.6%, insomnia in 5.6%, and lack of potency in 5.6%. Their cortisol level, on average, was 4.8 +/- 1.1 mu g/dL. Hepatitis C virus was positive in 22.2%. Urine-screening tests were positive for morphine and negative for buprenorphine. In conclusion, these new vials contain steroids as well as opioids. This combination could be more dangerous than opioids themselves.

( BUPP09671 - 06 July 2009) Imaging Human Brain Opioid Receptors: Applications to Substance Use Disorders

Three types of opioid receptors (ORs: mu (mu), kappa (kappa), and delta (delta)) are differentially distributed throughout the brain. Historically, the mu OR has been of greatest clinical interest because it mediates therapeutic effects (e.g., analgesia and cough suppression) and nontherapeutic effects (e.g., abuse and physical dependence) of opioid agonists. This "dual-edged sword" underlies the classical dilemma of balancing safety and efficacy when mu OR agonists are administered systemically to human subjects. Preclinical studies suggest that kappa OR- and delta OR-specific agonists and antagonists could be useful in treating human substance use disorders, but the lack of such Food and Drug Administration (FDA)-approved medications significantly limits our understanding of the role of these molecular targets in the clinical setting. However, the mu OR-specific radiotracer (C-11)-carfentanil has been used with positron emission tomography (PET) to elucidate the function of this endogenous system as it relates to substance use disorders, both with antagonists (e.g., naltrexone) and agonists (e.g., buprenorphine). The delta OR-specific tracer (C-11)-methyl-naltrindole is also available for human use, but has not yet been applied to substance use disorders, and a kappa OR-specific tracer has shown promise in preclinical testing. Advances in neuroscience and medication development are likely to yield significant progress that will improve our understanding of these disorders and clinical outcomes in the near future.

( BUPP09670 - 06 July 2009) Experimental Utility and Clinical Potential of Irreversible Opioid Antagonists

In opioid pharmacology, irreversible, insurmountable antagonists have been critical experimental tools to characterize mu-opioid receptors and receptor function with respect to such important concepts of receptor theory as spare receptors, affinity, and efficacy. In the present chapter, we present the specific pharmacological characteristics of four insurmountable antagonists with primary actions at mu-opioid receptors: beta-chlornaltrexamine (beta-CNA), beta-funaltrexamine (beta-FNA), buprenorphine, and clocinnamox. After alkylation or long-lasting blockade, fewer receptors are available for agonist interaction, and an agonist may produce a reduced maximum effect. After insurmountable antagonist administration, the method of partial irreversible blockade can be applied to estimate the apparent affinity constant for an agonist (K-A), relative efficacy estimates for agonists, and the fraction of receptors remaining for agonist interaction after alkylation (o). Insurmountable antagonists have been exploited to uncover how compounds bind within receptors, to help understand such phenomena as tolerance and dependence, and to determine the rate of turnover of mu-opioid receptors in different species. Probably the most frequent use of opioid insurmountable antagonists has been the estimate of agonist efficacy values with the goal of understanding the relationship of agonist efficacy to functional outcomes. More recently, investigators in clinical experimental pharmacology are using these tools, principles, and results generated from preclinical laboratory animal experiments to understand the role of agonist relative efficacy to behavioral data collected in humans. The development of tools that allow the quantitative assessment of multiple dependent measures (analgesia, reinforcing effects, and respiratory suppression) within and between different medications clearly has important clinical applications.

( BUPP09669 - 06 July 2009) Naltrexone for Initiation and Maintenance of Opiate Abstinence

Pharmacotherapies for opiate dependence first involve detoxification from physical dependence on opiates and then maintenance of that abstinent state. There are now three agents of distinct pharmacological classes available to achieve both phases: the opiate agonist methadone, the partial opioid agonist buprenorphine, and the opioid antagonist naltrexone. This chapter reviews the role of naltrexone in current opiate detoxification strategies and its use in long-term maintenance of sobriety from opiates.

( BUPP09685 - 13 July 2009) Commentary: Database linkage: Outside reflections on health care inside prisons

( BUPP09684 - 13 July 2009) The use of motion analysis to measure pain-related behaviour in a rat model of degenerative tendon injuries

Chronic tendinopathy is characterized with longstanding activity-related pain with degenerative tendon injuries. An objective tool to measure painful responses in animal models is essential for the development of effective treatment for tendinopathy. Gait analysis has been developed to monitor the inflammatory pain in small animals. We reported the use of motion analysis to monitor gait changes in a rat model of degenerative tendon injury. Intratendinous injection of collagenase into the left patellar tendon of Sprague Dawley rat was used to induce degenerative tendon injury, while an equal volume of saline was injected in the control groups. Motion analyses with a high speed video camera where performed on all rats at pre-injury, 2, 4, 8, 12 or 16 weeks post injection. In the end-point study, the rats were sacrificed to obtain tendon samples for histological examination after motion analyses. In the follow-up study, repeated motion analyses were performed on another group of collagenase-treated and saline-treated rats. The results showed that rats with injured patellar tendon exhibited altered walking gait as compared to the controls. The change in double stance duration in the collagenase-treated rats was reversible by administration of buprenorphine (p = 0.029), it suggested that the detected gait changes were assocated with pain. Comparisons of end-point and follow-up studies revealed the confounding effects of training, which led to higher gait velocities and probably a different adaptive response to tendon pain in the trained rats. The results showed that motion analysis could be used to measure activity-related chronic tendon pain.

( BUPP09683 - 13 July 2009) A meta-analysis of acupuncture combined with opioid receptor agonists for treatment of opiate-withdrawal symptoms.

This review extends a prior meta-analysis of acupuncture's utility for treating opioid detoxification, addressing the efficacy of acupuncture when combined with allopathic therapies. Both English and Chinese databases were searched for randomized trials comparing acupuncture combined with opioid agonist treatment versus opioid agonists alone for treating sympttoms of opioid withdrawal. The methodological quality of each study was assessed with Jadad's scale (1-2 = low; 3-5 = high). Meta-analysis was performed with fixed- or random-effect models in RevMan software; the outcome measures assessed were withdrawal-symptoms score, relapse rate, side effects, and medication dosage. Withdrawal-symptom scores were lower in combined treatment trials than in agonist-alone trials on withdrawal days 1, 7, 9 and 10. Combined treatment also produced lower reported rates of side effects and appeared to lower the required dose of opioid agonist. There was no significant difference on relapse rate after 6 months. This meta-analysis suggests that acupuncture combined with opioid agonsts can effectively be used to manage the withdrawal symptoms. One limitation of this meta-analysis is the poor quality of the methodology of some incuded trials. High-quality studies are needed to confirm findings regarding the side effects and medication dosage.

( BUPP09682 - 13 July 2009) Medicines submitted to narcotics regulations in France, 1992-2007

The objective was to study the current narcotics regulations which are the msot restictive regarding prescription and dispensation practice in France, and their evolution over the period 1992-2007. This is an example of regulation in a European member state regarding medicines with a risk of abuse or dependence. Narcotics regulations were studied in the French public health code. Status and indications of medicines concerned were found on the French medicine agency website, and the retrospective part of the study was conducted using the Franch public statute law website. Seventeen medicines were found. Three were psychotropics and fourteen narcotics. The prescription rules could be different for a given substance according to the route of administration or indication. In 2007, half of the narcotic opioids could be prescribed for 28 days, whereas in 1992, most of them could be prescribed for only 7 days. These rsults show the adaption of French narcotics regulations, with the development of medicines indicated in acute or chronic pain treatment of opioid maintenance treatment.

( BUPP09681 - 13 July 2009) Transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs.

Described herein are opioid prodrugs, methods of making opioid prodrugs, formulations comprising opioid prodrugs, and methods of using opioid prodrugs. One embodiment described herein relates to the transdermal administration of a buprenorphine prodrug in an abuse-resistant formualtion for treating and preventing diseases and/or disorders.

( BUPP09698 - 20 July 2009) Incorporating receptor theory in mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling

Pharmacokinetic-Pharmacodynamic (PK-PD) modeling helps to better understand drug efficacy and safety and has, therefore, become a powerful tool in the learning-confirming cycles of drug-development. In translational drug research, mechanism-based PK-PD modeling has been recognized as a tool for bringing forward early insights in drug efficacy and safety into the clinical development. These models differ from descriptive PK-PD models in that they quantitatively characterize specific processes in the causal chain between drug administration and effect. This includes target site distribution, binding and activation, pharmacodynamic interactions, transduction and homeostatic feedback mechanisms. Compared to descriptive models mechanism-based PK-PD models that utilize receptor theory concepts for characterization of target binding and target activation processes have improved properties for extrapolation and prediction. In this respect, receptor theory constitutes the basis for 1) prediction of in vivo drug concentration-effect relationships and 2) characterization of target association-dissociation kinetics as determinants of hysteresis in the time course of the drug effect. This approach intrinsically distinguishes drug- and system specific parameters explicitly, allowing accurate extrapolation from in vitro to in vivo and across species. This review provides an overview of recent developments in incorporating receptor theory in PK-PD modeling with a specific focus on the identifiability of these models.

( BUPP09697 - 20 July 2009) A systematic review of randomized trials evaluating regional techniques for postthoracotomy analgesia

BACKGROUND:: Thoracotomy induces severe postoperative pain and impairment of pulmonary function, and therefore regional analgesia has been intensively studied in this procedure. Thoracic epidural analgesia is commonly considered the "gold standard" in this setting; however, evaluation of the evidence is needed to assess the comparative benefits of alternative techniques, guide clinical practice and identify areas requiring further research. METHODS:: In this systematic review of randomized trials we evaluated thoracic epidural, paravertebral, intrathecal, intercostal, and interpleural analgesic techniques, compared to each other and to systemic opioid analgesia, in adult thoracotomy. Postoperative pain, analgesic use, and complications were analyzed. RESULTS:: Continuous paravertebral block was as effective as thoracic epidural analgesia with local anesthetic (LA) but was associated with a reduced incidence of hypotension. Paravertebral block reduced the incidence of pulmonary complications compared with systemic analgesia, whereas thoracic epidural analgesia did not. Thoracic epidural analgesia was superior to intrathecal and intercostal techniques, although these were superior to systemic analgesia; interpleural analgesia was inadequate. CONCLUSIONS:: Either thoracic epidural analgesia with LA plus opioid or continuous paravertebral block with LA can be recommended. Where these techniques are not possible, or are contraindicated, intrathecal opioid or intercostal nerve block are recommended despite insufficient duration of analgesia, which requires the use of supplementary systemic analgesia. Quantitative meta-analyses were limited by heterogeneity in study design, and subject numbers were small. Further well designed studies are required to investigate the optimum components of the epidural solution and to rigorously evaluate the risks/benefits of continuous infusion paravertebral and intercostal techniques compared with thoracic epidural analgesia.

( BUPP09696 - 20 July 2009) Mechanism-based medication development for the treatment of nicotine dependence

Tobacco use is a global problem with serious health consequences. Though some treatment options exist, there remains a great need for new effective pharmacotherapies to aid smokers in maintaining long-term abstinence. In the present article, we first discuss the neural mechanisms underlying nicotine reward, and then review various mechanism-based pharmacological agents for the treatment of nicotine dependence. An oversimplified hypothesis of addiction to tobacco is that nicotine is the major addictive component of tobacco. Nicotine binds to alpha4BETA2 and alpha7 nicotinic acetylcholine receptors (n AChRs) located on dopaminergic, glutamatergic and GABAergic neurons in the mesolimbic dopamine (DA) system, which causes an increase in extracellular DA in the nucleus accumbens (NAc). That increase in DA reinforces tobacco use, particularly during the acquisition phase. Enhanced glutamate transmission to DA neurons in the ventral tegmental area appears to play an important role in this process. In addition, chronic nicotine treatment increases endocannabinoid levels in the mesolimbic DA system, which indirectly modulates NAc DA release and nicotine reward. Accordingly, pharmacological agents that target brain acetylcholine, DA, glutamate, GABA, or endocannabonoid signaling systems have been proposed to interrupt nicotine action. Furthermore, pharmacokinetic strategies that alter plasma nicotine availability, metabolism and clearance also significantly alter nicotine's action in the brain. Progress using these pharmacodynamic and pharmacokinetic agents is reviewed. For drugs in each category, we discuss the mechanistic rationale for their potential anti-nicotine efficacy, major findings in preclinical and clinical studies, and future research directions.

( BUPP09695 - 20 July 2009) Gastrointestinal symptoms under opioid therapy: A prospective comparison of oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine

Introduction: The purpose of this trial was to evaluate the effect of long-term treatment with oral sustained-release hydromorphone, transdermal fentanyl, and transdermal buprenorphine on nausea, emesis and constipation. Patients and methods: Randomly selected outpatients with cancer pain receiving one of the study medications were enrolled in a prospective, open-labeled, controlled trial (n = 174). Mobility, pain, and gastrointestinal symptoms were assessed directly and per selected item on the ECOG (Eastern Cancer Oncology Group), EORTC (European Organisation for Research and Treatment of Cancer) questionnaires, NRS (Numerical Rating Scales), and analyzed statistically. Results: Demographic and medical data were comparable in all groups. Only 15% of patients suffered from constipation. 59% took the prescribed laxatives. The incidence of stool free periods >72 h was significantly higher with transdermal opioids (transdermal fentanyl: 22%; transdermal buprenorphine: 21%; oral hydromorphone: 2%; p = 0.003). 21% of patients revealed nausea and emesis. The mean NRS for nausea (transdermal fentanyl:1.3; transdermal buprenorphine: 1.2; oral hydromorphone: 1.5; p = 0.6), the consumption of antiemetics (transdermal fentanyl: 42%; transdermal buprenorphine: 33%; oral hydromorphone: 36%; p = 0.6) and laxatives (transdermal fentanyl:53%; transdermal buprenorphine:66%; oral hydromorphone: 61%; p = 0.2) did not differ significantly, in contrast to the score for emesis (transdermal fentanyl: 16%; transdermal buprenorphine:13%; oral hydromorphone: 33%; p = 0.02). Morphine equivalent opioid doses differed (mg/d transdermal fentanyl: 183; transdermal buprenorphine: 89; oral hydromorphone: 143; p = 0.001), because of obvious tolerance varying after long-term treatment. Conclusions: Gastrointestinal symptoms of cancer pain patients undergoing an opioid therapy are related to multifactorial causes. Transdermal opioids showed no benefit over oral controlled-release hydromorphone with regard to gastrointestinal symptoms. The conversion ratios for transdermal fentanyl, transdermal buprenorphine, and oral hydromorphone did not accord to the literature, because of differing occurrences of opioid tolerance after long-term therapy.

( BUPP09694 - 20 July 2009) Cost-effectiveness of strong opioids focussing on the long-term effects of opioid-related fractures: A model approach

Opioid analgesics are known to impact on the central nervous system (CNS). These CNS side effects, such as dizziness and confusion, have been shown to lead to an increased risk of falling with subsequent fractures in elderly patients being treated with opioids. The risk of experiencing fractures has been shown to be dependent on the substance administered. Therefore, a health economic model was developed to investigate the cost-effectiveness of the most commonly used strong opiods in Germany, focussing on opioid-related fractures. By means of a Markov model, the consequences of hip, spine and forearm fractures due to the prior administration of transdermal (TD) buprenorphine, TD fentanyl, oral oxycodone as well as oral morphine were assessed from the perspectives of the German statutory health insurance (SHI) and the German social security (GSS) system over a time horizon of 6 years. The most frequently prescribed strength/package-size combinations of these opioids were taken into consideration, including generics where available. The results of the present analysis predict that TD buprenorphine is dominant compared to TD fentanyl and oxycodone by showing better effects (life years gained/quality adjusted life years (QALY) gained) at lower cost. From the SHI perspective, the incremental cost-effectiveness ratio (ICER) compared to morphine is Euro 6,801.61 per life year gained, and Euro 7,766.11 per QALY gained. From the GSS perspective, the ICER is Euro 2,496.77 per life year gained and Euro 2,850.83 per QALY gained. The model is robust regarding probabilistic variations of all parameters in the sensitivity analyses. Focussing on fractures due to the prior administration of strong opioids, TD buprenorphine is less costly and more effective than TD fentanyl and oxycodone and represents a cost-effective treatment option versus morphine in patients with chronic pain from both the SHI and GSS perspective in Germany.

( BUPP09693 - 20 July 2009) Pharmacotherapy of substance dependence and withdrawal syndromes

Substance use disorders (SUD) include substance abuse and dependence as well as acute intoxication, withdrawal, and various psychiatric disorders. In the course of the SUD, severe comorbid disorders and somatic consequences can occur. The treatment of withdrawal symptoms focuses on the relief of immediate symptoms and the prevention of complications. The treatment of SUDs should achieve long-term abstinence with relapse prevention or harm reduction using maintenance treatment strategies. Beside psychosocial interventions, the pharmacotherapy has become an important factor for the treatment of SUDs and withdrawal syndromes. This review reports evidence-based pharmacologic treatment strategies of the most frequent SUDs according to current guidelines for SUDs. In the pharmacological treatment of alcohol dependence long-lasting benzodiazepines or clomethiazole for alcohol withdrawal, and acamprosate or naltrexone for relapse prevention are preferable. There exists no effective relapse prevention for cannabis dependence. During cocaine withdrawal tricyclic antidepressants demonstrated the highest efficacy. For cocaine dependence no medication can be recom mended, so far. However, mood stabilizers such as topiramate and tiagabine or disulfirame were found to be efficacious in preliminary studies. There is consistent evidence for methylphenidate in treating cocaine dependence co-occurring with attention-deficit/hyperactivity disorder. For opioid dependence, methadone or buphrenorphine treatment is the pharmacotherapy of first choice. Nicotine replacement therapy, Bupropion and Vareniclin are efficacious in smoking cessation.

( BUPP09692 - 20 July 2009) Inflammation-induced increase in hyperpolarization-activated, cyclic nucleotide-gated channel protein in trigeminal ganglion neurons and the effect of buprenorphine

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are active at resting membrane potential and thus contribute to neuronal excitability. Their increased activity has recently been demonstrated in models of nerve injury-induced pain. The major aim of the current study was to investigate altered HCN channel protein expression in trigeminal sensory neurons following inflammation of the dura. HCN1 and HCN2 channel immunoreactivity was observed on the membranes of medium- to large-sized trigeminal ganglion neurons with 76% and 85% of HCN1 and HCN2 expressing neurons also containing the 200 kDa neurofilament protein (associated with myelinated fibers). Western immunoblots of lysates from rat trigeminal ganglia also showed bands with appropriate molecular weights for HCN1 and HCN2. Three days after application of complete Freund's adjuvant (CFA) to the dura mater, Western blot band densities were significantly increased; compared to control, to 166% for HCN1 and 284% for HCN2 channel protein. The band densities were normalized against alpha-actin. In addition, the number of retrogradely labeled neurons from the dura expressing HCN1 and HCN2 was significantly increased to 247% (HCN1) and 171% (HCN2), three days after inflammation. When the opioid receptor partial agonist, buprenorphine, was given systemically, immediately after CFA, the inflammation-induced increase in HCN protein expression in both Western blot and immunohistochemical experiments was not observed. These results suggest that HCN1 and HCN2 are involved in inflammation-induced sensory neuron hyperexcitability, and indicate that an opioid receptor agonist can reverse the protein upregulation.

( BUPP09691 - 20 July 2009) Naltrexone implants after in-patient treatment for opioid dependence: Randomised controlled trial

Background: Naltrexone has considerable potential in helping to prevent relapse in heroin dependency. A longer-lasting formulation for naltrexone treatment is desirable to further reduce non-adherence and relapse during treatment of opiate dependence. Aims: To evaluate the safety and effectiveness of a 6-month naltrexone implant in reducing opioid use after in-patient treatment. Method: A group of 56 abstinence-oriented patients who completed in-patient treatment for opioid dependence were randomly and openly assigned to receive either a 6-month naltrexone implant or their usual aftercare. Drug use and other outcomes were assessed at 6-month follow-up. Results: Patients receiving naltrexone had on average 45 days less heroin use and 60 days less opioid use than controls in the 180-day period (both P<0.05). Blood tests showed naltrexone levels above 1 ng/ml for the duration of 6 months. Two patients died, neither of whom had received an implant. Conclusions: Naltrexone implant treatment safely and significantly reduces opioid use in a motivated population of patients.

( BUPP09690 - 20 July 2009) A literature review of international implementation of opioid substitution treatment in prisons: equivalence of care?

BACKGROUND/AIMS: Opioid substitution treatment (OST) is an effective treatment for heroin dependence. The World Health Organization has recommended that OST be implemented in prisons because of its role in reducing drug injection and associated problems such as HIV transmission. The aim of this paper was to examine the extent to which OST has been implemented in prisons internationally. METHODS: Literature review. RESULTS: As of January 2008, OST had been implemented in prisons in at least 29 countries or territories. For 20 of those countries, the proportion of all prisoners in OST could be calculated, with results ranging from less than 1% to over 14%. At least 37 countries offer OST in community settings, but not prisons. CONCLUSION: This study has identified an increase in the international implementation of OST in prisons. However, there remain large numbers of prisoners who are unable to access OST, even in countries that provide such programs. This raises issues of equivalence of care for prisoners and HIV prevention in prisons.

( BUPP09689 - 20 July 2009) Cross-reactivity of naloxone with oxycodone immunoassays: implications for individuals taking Suboxone

( BUPP09688 - 20 July 2009) Role of phospholipase D2 in the functional selectivity of mu-opioid receptor ligands

( BUPP09687 - 20 July 2009) Nanoparticle dispersions of opioids for local pain reduction - influence on wound healing

( BUPP09686 - 20 July 2009) Mechanisms of toxic smoke inhalation and burn injury: Role of neutral endopeptidase and vascular leakage in mice

The effects of neutral endopeptidase (NEP) in acute inflammation in the lung were studied using a newly developed murine model of smoke and burn (SB) injury. C57BL/6 mice were pretreated with an i.v. dose of a specific NEP antagonist CGS-24592 (110 mg/Kg) I h prior to SB injury (n = 5-8/group). Mice were anesthetized with i.p. ketamine /xylazine, intubated, and exposed to cooled cotton smoke (2 x 30s). After s.c. injection of 1 ml 0.9% saline, each received a 40% total body surface area (TBSA) flame burn. Buprenorphene (2 mg/kg) was given i.p. and resuscitated by saline. Evans Blue dye (EB) was injected i.v. 15 min before sacrifice. Lung wet/dry weight ratio was measured. After vascular perfusion, lungs were analyzed for their levels of EB dye and myeloperoxidase (MPO). In mice pretreated with CGS-24592 followed by SB injury the EB levels were significantly higher (61%, p = 0.043) than those with SB injury alone. There was a significant increase (144%, p = 0.035) in EB dye in animals with SB injury alone as compared to shams. In mice pretreated with CGS-24592 prior to SB injury wet/dry weight ratios were significantly (27%, p = 0.042) higher compared to animals with SB injury alone. CGS-24592 pretreatment also caused a significant increase in MPO (29%, p = 0.026) as compared to mice with SB injury alone. In conclusion the current study indicates that specific NEP inhibitor CGS 24592 exacerbates the SB-induced lung injury and inflammation in mice.

( BUPP09708 - 27 July 2009) Anaesthetic and analgesic considerations in drug abusing pregnant women

( BUPP09707 - 27 July 2009) Acute pain in clinical praxis

Pain is one of the main reasons for visiting a doctor. Before we start to treat pain, we have to evaluate it, with one of the many pain scales. The best way to treat pain is to remove its cause. We can treat the pain in many different ways, by using medicaments, or with some other techniques. Our main goal in acute pain treatment is to achive pain score bellow 3 on VAS.

( BUPP09706 - 27 July 2009) Morphine and fentanyl: Use in acute pain?

Pain has a detrimental effect on patient quality of life, thus its good control is essential. As healthcare professionals, pharmacists meet patients treated with opioids every day, and may have an important role in assuring good pain control in these patients. When dispensing opioid drugs, patients should be asked about their level of pain control as well as consulted about the possible adverse effects of these drugs and their treatment. This level of pharmaceutical care can be achieved only by pharmacists with adequate competences in pain management. This article is the first step towards the needed theoretical basis: the role of opioids in the treatment of pain is presented and the guidelines recommendations are reinforced with the pharmacodynamic and pharmacokinetic properties of these drugs.

( BUPP09705 - 27 July 2009) Therapy of pain in multiborbid elderly patients

All human organ systems are prone to age-related physiological changes. Functional impairment is especially found in the liver, the kidneys, the nervous system, the gastrointestinal tract and the blood vessels. Changes in metabolism cause, e. g., changes in the composition of blood, reduction in neurotransmitters and the respective receptors, changes in calcium homeostasis with consequences for the stability of bones. As with any pharmacotherapy, the treatment of pain must consider these age-related factors. Adequate pain treatment is especially important in elderly patients, because the number of morbidities increases together with the number of pain conditions of different origin. In Germany, most patients with severe pain are undertreated. Although tumor pain, e. g., can be relieved in up to 95 % of patients, up to 40% of patients under medical treatment still have pain, the German Pain League states. The WHO's pain ladder, developed in the 1980ies, is still regarded as an appropriate guideline, albeit too often disregarded by physicians, reflecting the reserve of patients and doctors towards opioids. With progress in opioid therapy, however, experts tend to early prescription of step-III-analgesics without sticking to the steps of the WHO ladder. Constipation, the major side effect of opioids, can be overcome by co-medication with laxatives. The combination of slow-release oxycodone with naloxone, an orally given antagonist of intestinal mu-receptors is effective as analgesic and maintains the normal bowel function.

( BUPP09704 - 27 July 2009) PecSys: In situ gelling system for optimised nasal drug delivery

PecSys TM (PS) is a proprietary pectin-based drug delivery system designed to gel when applied to mucosal surfaces and with potential areas of application for drugs used in local and systemic disease therapy. The current area of focus is intranasal drug delivery where PS is being used to optimise absorption of lipophilic drugs into the systemic circulation. Pectin is described as GRAS (generally regarded as safe) with an excellent regulatory position through its long history of pharmaceutical and food usage. Tests to measure the functional gelling properties of pectin raw material and PS have been devised and validated. The PS-based products at the most advanced stages of development are intranasal formulations containing opioid analgesics intended to provide rapid pain relief with simple and convenient dosing and minimal side effects. The profile of such drugs may not be optimal through current routes of delivery and the ability of PS to modulate their pharmacokinetic profiles, such as attenuation of the peak plasma concentration (C /sub max/ ), has been demonstrated in clinical testing. The lead product using PS is a fentanyl nasal spray formulation (NasalFent�), which has successfully met the primary objective in a pivotal Phase III clinical study and is scheduled for regulatory filings in the first half of 2009.

( BUPP09703 - 27 July 2009) Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine

Background and purpose: Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl. Experimental approach: The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G(z) protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally. Key results: Spinal naloxone (20 mu g) or PTX (1 mu g) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G(z) protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G(z)-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G(z)-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mg center dot kg(-1), i.p.) enhanced the ascending (3 mg center dot kg(-1)) and descending (30 mg center dot kg(-1)) portions of buprenorphine's dose-response curve, but only spinal, not supraspinal, nociceptin (10 nmol center dot L-1) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001-10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mg center dot kg(-1), s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception. Conclusions and implications: Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G(z) protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.

( BUPP09702 - 27 July 2009) Use of cytostatic and antalgic drugs for the terminal oncological patients: comparison between the years 2000 and 2004

Although we cannot yet explain the reason why a person falls sick with cancer and another one does not, we know today environmental factors and characteristics of the lifestyle than can increase our probability of developing the cancer (OI, II). General term by which we define pathologies characterised by a new formation (neoplasy) of a tissue, i.e. the abnormal development of one or more cell masses increasing in an uncontrolled manner. Possible therapies are: surgery, radiotherapy, ormonal therapy, chemoterapy. Pain is one of the most common collateral effects, and the most difficult to resolve with cancer, and it is particularly intense in the terminal patient, i.e. in the cancer patient where the illness has invaded a great part of the organism, and who does not react to any therapy any more.

( BUPP09701 - 22 July 2009) Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence

Nonserial publication Free Download These WHO Guidelines review the use of medicines such as methadone, buprenorphine, naltrexone and clonidine in combination with psychosocial support in the treatment of people dependent on heroin or other opioids. Based on systematic reviews of the literature and using the GRADE approach to determining evidence quality, the guidelines contain specific recommendations on the range of issues faced in organising treatment systems, managing treatment programmes and in treating people dependent on opioids. Developed in collaboration with internationally acclaimed experts from the different regions of the globe, this book should be of interest to policy makers, program managers, and clinicians everywhere who seek to alleviate the burden of opioid dependence.

( BUPP09700 - 22 July 2009) Surgical Management of Infected Pseudoaneurysms in Intravenous Drug Abusers: Single Institution Experienc e and a Proposed Algorithm

Background: Vascular complications from intravenous drug abuse pose significant challenges to vascular surgeons. No formalised policies have been reached on surgical management of the resultant infected pseudoaneurysm. Methods: A retrospective review of all patients who underwent surgery for pseudoaneurysms due to chronic intravenous drug abuse from July 2005 to February 2008 was performed. Results: A total of 15 patients with infected pseudoaneurysms from chronic intravenous drug abuse were operated on during the study period. The sites of involvement were restricted to the femoral (86.7%) and brachial (13.3%) areas. The drug involved was buprenorphine (Subutex) in all cases. Pain over the limb swelling (100%), pulsatility (60%), and symptoms suggestive of septicemia (46.7%) were the most common symptoms. Staphylococcus aureus was present in 93.3%. Diagnosis was achieved clinically in 26.7% by duplex ultrasonography in 60.0%, and by computed tomography (CT) angiography in 13.3%. In the two patients with brachial pseudoaneurysms, the brachial artery was ligated in one, and a basilic vein patch was used in the other. In the 13 patients with femoral pseudoaneurysms, the pseudoaneurysm was ligated and excised in 8 (61.5%), and immediate reconstructive bypass surgery was performed in 5 (38.5%). Two patients had critical ischemia after ligation and required reconstructive bypass surgery a few weeks later. Postoperative complications included claudication, digital gangrene, localised would infection, and rebleeding. There was no associated mortality. Conclusions: Pseudoaneurysm from intravenous drug abuse continues to pose significant challenges to surgeons worldwide, ranging from an accurate diagnosis to the choice of surgery. The aims of surgery must be to achieve adequate debridement and control infection and haemorrhage. Any associated postoperative complications must be identified and dealt with.

( BUPP09699 - 21 July 2009) Exploring prison buprenorphine misuse in the United Kingdom: A qualitative study of former prisoners

The United Kingdom Ministry of Justice recently highlighted the extent of buprenorphine (Subutex) misuse in English and Welsh prisons, naming it the third most misused drug overall. Yet little is known regarding how illicit buprenorphine is obtained in prison and what influences prisoners to use it. Qualitative research was used to explore prison drug using practices. Thirty men who were former prisoners with a history of injecting drug use were interviewed in depth about their illicit prison drug use, including buprenorphine. Interviews were conducted over 18 months, from August 2006 to January 2008 and were analysed using Framework. The misuse of Subutex by snorting emerged as a significant theme. Accounts suggested that the diversion of prison prescribed Subutex was widespread and prisoners used various tactics to obtain the medication. Various complex and interlinked reasons were given to explain why Subutex was snorted in prison. The main motivation for snorting was to experience a prolonged euphoric opiate effect, believed to help to combat the boredom of being in prison. The price of illicit Subutex in prison was linked to its availability, but it was generally cheaper than heroin, thus contributing to its use. Participants narratives identified the belief that snorting Subutex in prison was not risk free, but risks were lower than continuing to use other drugs, particularly injecting illicit opiates. The implications of prison Subutex misuse for prisoners, prison medical services, commissioners, and prescribing policy and practice are discussed.

( BUPP09721 - 04 August 2009) The role of transdermal buprenorphine in the treatment of cancer pain: An expert panel consensus

Background: The semi-synthetic opioid, buprenorphine, has the general structure of morphine but differs from it in significant ways, both pharmacologically and clinically. A number of longterm studies have shown effective, long-lasting analgesia in moderate to severe cancer and non-cancer pain, including neuropathic pain, with a low incidence of constipation, nausea, dizziness and tiredness. The treatment of moderate to severe chronic pain has improved as a result of the development of new methods of administration of this substance, particularly the introduction of the transdermal drug delivery system, which offers a number of advantages over the usual oral and parenteral routes. Scope: A panel of experts specialising in palliative care and pain treatment was convened in November 2007 to discuss their clinical experiences with transdermal buprenorphine and other analgesics. The aim was to provide practical guidance on the treatment of cancer pain with transdermal buprenorphine, particularly when there is a need for increasing pain relief leading to high and increasing doses. A literature search on the use of transdermal buprenorphine was carried out for the panel meeting (based on a search of PubMed to November 2007 - since updated by an additional search for the period to February 2009) and a number of case histories were presented and discussed. This commentary article presents this evidence and the consensus findings of the expert panel. Findings: The Panel reached consensus that transdermal buprenorphine was a valuable treatment for chronic cancer pain, including its neuropathic components. A number of general recommendations were made. Large-scale, randomised clinical studies are needed to provide product comparisons on the use of analgesics in the treatment of neuropathic pain although it was recognised that such studies may not be practicable. Data on the treatment of acute and chronic pain should be kept separate in general. Physicians should be made more aware of the problem of hyperalgesic effects of some opioids in long term use. Buprenorphine in contrast has been described to exert an antihyperalgesic effect. The development of analgesic tolerance with some opioids in long term use and the lack of it with buprenorphine requires further studies. The registered dose range of 35-140 mg/h was considered adequate to achieve sufficient pain relief in most patients although some members of the panel presented data showing that increases beyond this dose range provided improved pain relief if slow titration is used. However, it was generally felt that more evidence was needed before this could become generally acceptable. Conclusion: The consensus was that transdermal buprenorphine has a valuable role to play in the treatment of chronic cancer pain because of its efficacy and good safety and tolerability profile, including a low risk of respiratory depression, a lack of immunosuppression and a lack of accumulation in patients with impaired renal function.

( BUPP09720 - 04 August 2009) Zona incerta: A role in central pain

Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

( BUPP09719 - 04 August 2009) Factors limiting successful buprenorphine treatment with inner city heroin users: A patient survey

OBJECTIVES: Little is known about barriers to maintenance outpatient buprenorphine treatment specific to inner city heroin addicts. We identified potential barriers to implementation of outpatient treatment with buprenorphine in an inner city population. METHODS: Twenty-one patients admitted to a community teaching hospital with acute heroin use were identified in 1 month in 2005. Each patient was interviewed using a survey that evaluated familiarity with buprenorphine, heroin use, and obstacles to quitting. RESULTS: All 21 patients agreed to participate. Mean age was 45 years. Patients had used heroin for an average of 18 years (range, 1 to 40 y). Personal cost for heroin ranged from $40 to $200/d, with some patients using occasionally and others daily. Eight patients had been incarcerated, and 8 reported being homeless. All patients expressed interest in quitting heroin. Five of twenty-one patients reported being encouraged by a healthcare provider to obtain buprenorphine maintenance therapy; only one described this encouragement as enthusiastic. Cost of buprenorphine was cited as an obstacle by 13 patients. CONCLUSIONS: Lack of healthcare worker referral and cost of treatment were major obstacles to implementation of buprenorphine outpatient maintenance treatment for inner city heroin users.

( BUPP09718 - 04 August 2009) Sex-specific responses to opiates: Animal and human studies

It is widely reported that analgesic drugs acting at mu, kappa, and delta opioid-receptors display quantitative and qualitative differences in effect in males and females. These sex-related differences are not restricted to the analgesic/antinociceptive properties of opioids, but are also present in opioid-induced side effects, such as changes in respiration, locomotor activity, learning /memory, addiction, and changes in the cardiovascular system. An increasing number of well-controlled animal and human studies directly examining the issue of sex in the potency of opioids show that, although sex may affect opioid analgesia, the direction and magnitude of sex differences depend on many interacting variables. These include those specific to the drug itself, such as dose, pharmacology, and route and time of administration, and those particular to the subject, such as species, type of pain, genetics, age, and gonadal/hormonal status. In the current review, we systematically present these animal and human studies and discuss the data in relation to the depending variables. Although the observed sex differences in opioid effect may be clinically relevant, lack of knowledge on other factors involved in the large variability in patient opioid analgesic sensitivity should compel practitioners to customize their dosing regimens based on individual requirements.

( BUPP09717 - 04 August 2009) Sex, gender, and pain: An overview of a complex field

Traditionally, biomedical research in the field of pain has been conducted with male animals and subjects. Over the past 20-30 yr, it has been increasingly recognized that this narrow approach has missed an important variable: sex. An ever-increasing number of studies have established sex differences in response to pain and analgesics. These studies have demonstrated that the differences between the sexes appear to have a biological and psychological basis. We will provide brief review of the epidemiology, rodent, and human experimental findings. The controversies and widespread disagreement in the literature highlight the need for a progressive approach to the questions involving collaborative efforts between those trained in the basic and clinical biomedical sciences and those in the epidemiological and social sciences. In order for patients suffering from acute and/or chronic pain to benefit from this work, the approach has to involve the use or development of clinically relevant models of nociception or pain to answer the basic, but complex, question. The present state of the literature allows no translation of the work to our clinical decision-making.

( BUPP09716 - 04 August 2009) Dilemmas in chronic/persistent pain management

The burden of chronic/persistent pain is substantial for the patient and society as a whole. Although a variety of pharmacologic treatments are available, chronic/persistent pain remains inadequately treated. Many pharmacologic treatment options provide analgesic efficacy for 4 to 6 hours, requiring multiple doses for continuous pain relief. The inconvenience of multiple doses may prevent many patients from achieving adequate pain relief. Other limitations to the current pharmacologic treatment options include gastrointestinal effects, cardiovascular effects, and organ toxicity, as well as fear of abuse or addiction. The purpose of this review is to highlight the burden of chronic/persistent pain in today's society and discuss the limitations of short-acting pharmacologic therapies used in the treatment of chronic/persistent pain.

( BUPP09715 - 04 August 2009) The impact of opioids on the endocrine system

Objectives: Opioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. Methods: A review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. Results: Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. Conclusions: Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on longterm opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.

( BUPP09714 - 04 August 2009) Buprenorphine sniffing as a response to inadequate care in substituted patients: results from the Subazur survey in south-eastern France

BACKGROUND: Despite the safety profile of buprenorphine, which makes this treatment highly acceptable for many countries, the risk of its diversion raises several public health and drug policy concerns. Although buprenorphine injection has been investigated quite extensively, diversion by sniffing has been overlooked. The Subazur survey gave us the opportunity to identify factors associated with buprenorphine sniffing in patients receiving buprenorphine in primary care. METHODS: We studied a population of 111 stabilized patients receiving office-based buprenorphine in south-eastern France. The design of the study consisted of two longitudinal assessments by phone interviews (at enrollment and 6 months later) detailing patients' socio-demographic characteristics, addictive behaviors, treatment experience and general health status. We used a logistic regression based on generalized estimating equations (GEE) to identify factors associated with buprenorphine sniffing at any interview. RESULTS: Among the 111 interviewed subjects, 33 (30%) patients reported sniffing buprenorphine after having initiated treatment. After multivariate analysis, 4 variables remained significantly associated with buprenorphine sniffing: not living in a stable relationship, having had only one or no parents during childhood, a history of drug sniffing and dissatisfaction with buprenorphine treatment. CONCLUSIONS: Our findings underline the need to address these patients to appropriate social and mental services as well as diversifying therapeutic options, in order to provide them with adequate care and minimize diversion. The issues highlighted in the study reflect the need for recommendations for physicians prescribing OST in primary care to consider buprenorphine diversion during treatment more as non-adherence behavior than an abuse.

( BUPP09713 - 04 August 2009) Effect of buprenorphine on the cardiovascular and respiratory response to visceral pain in conscious rabbits

OBJECTIVE: To evaluate the effect of buprenorphine administration on the cardiovascular and respiratory responses to noxious colorectal distension in conscious rabbits. STUDY DESIGN: Prospective experimental trial. ANIMALS: Fifteen healthy, young adult New Zealand white rabbits (eight female). METHODS: Experiments were performed on conscious rabbits that were instrumented with intraabdominal arterial and venous catheters, and diaphragmatic and abdominal electromyographic electrodes. Colorectal distension was achieved by inflation of an acutely placed colorectal balloon catheter until mean arterial pressure increased 10-15 mmHg. Buprenorphine (0.06 mg) or saline was administered intravenously prior to, or during colorectal distension. Arterial blood pressure, heart rate, respiratory rate, abdominal electromyographic activity, and intra-balloon pressure were monitored. RESULTS: In the absence of colorectal distension, buprenorphine increased arterial blood pressure and decreased respiratory rate but did not change heart rate. Colorectal distension increased arterial blood pressure and heart rate, and decreased respiratory rate. The increase in arterial blood pressure associated with colorectal distension was attenuated following preemptive buprenorphine, but was not changed by buprenorphine administered during distension. CONCLUSIONS AND CLINICAL RELEVANCE: If cardiovascular changes reflect the intensity of noxious stimulation, then these results support the preemptive administration of buprenorphine for visceral analgesia.

( BUPP09712 - 04 August 2009) Respiratory and cardiovascular effects of buprenorphine in conscious rabbits

OBJECTIVE: To quantify the respiratory and cardiovascular effects of intravenous or subcutaneous buprenorphine in conscious rabbits. STUDY DESIGN: Prospective experimental trial. ANIMALS: Eight healthy, young adult New Zealand white rabbits (four female). METHODS: Rabbits were instrumented with intraabdominal arterial and venous catheters and diaphragmatic electromyographic electrodes 2 weeks before experiments. Arterial blood pressure, arterial blood gases, heart rate and respiratory rate were monitored during experiments. Buprenorphine (0.06 mg) was administered either intravenously or subcutaneously to conscious rabbits. Respiratory and cardiovascular parameters were compared to baseline at 10 and 22 minutes after intravenous buprenorphine administration, and at 30, 60, and 90 minutes after subcutaneous buprenorphine administration. RESULTS: Buprenorphine administration, at a dose of approximately 0.02 mg kg (-1), did not change blood pressure or heart rate. However, respiratory rate decreased from 252 +/- 26 to 39 +/- 26 breaths minute(-1) (mean +/- SD), and from 306 +/- 38 to 90 +/- 38 breaths minute(-1) following intravenous and subcutaneous administration of buprenorphine, respectively. Subsequent to intravenous and subcutaneous buprenorphine, arterial oxygen tension decreased from 88 +/- 4 to 72 +/- 4 mmHg (11.7 +/- 0.5 to 9.6 +/- 0.5 kPa) and from 87 +/- 3 to 77 +/- 3 mmHg (11.6 +/- 0.4 to 10.3 +/- 0.4 kPa), respectively. Buprenorphine, by either route of administration, increased arterial carbon dioxide tension from 36 to 41 mmHg (4.8-5.5 kPa) and increased the alveolar-arterial oxygen gradient from 15 to > or =20 mmHg (2 to > or =2.7 kPa). CONCLUSIONS AND CLINICAL RELEVANCE: Buprenorphine administration decreased respiratory rate and produced mild hypoxemia in conscious rabbits. While these changes were well tolerated by healthy animals, caution should be exercised when administering buprenorphine to rabbits predisposed to respiratory depression.

( BUPP09711 - 04 August 2009) Evaluation of Bio-Rad TOX/See (TM) Buprenorphine Rapid Urine Drug Screen SO, JUN 2009, vol. 55, no. 6, Suppl. S, p. A244-A245, ISSN: 0009-9147. LG English.

( BUPP09710 - 04 August 2009) Analysis and Interpretation of Drug Testing Results from Patients on Chronic Pain Therapy: A Clinical Laboratory Perspective

( BUPP09709 - 04 August 2009) Performance of Two Buprenorphine Immunoassays in Urines with Low Concentrations of Buprenorphine and/or Opiates/Opioids

( BUPP09732 - 12 August 2009) Comparing overdose mortality associated with methadone and buprenorphine treatment

Aim: To compare overdose mortality associated with methadone and buprenorphine treatment for opioid dependence. Methods: Data linkage study. Since 1 April 2006, the Division of Analytic Laboratories (DAL) has routinely tested all New South Wales (NSW) coronial post-mortem samples for both methadone and buprenorphine. Names of all methadone or buprenorphine-positive cases between April and December 2006 inclusive were linked to the National Coroners Information System (NCIS) database, which provided information on cause of death, autopsy findings and circumstances of death. Names were linked to the Pharmaceutical Services Branch Drugs of Addiction System (PHDAS) database to identify whether people were in treatment and in decedents not registered in treatment, the source of methadone or buprenorphine was presumed to be diversion from treatment programs. Mean number in treatment during 2006 for methadone and buprenorphine were derived from the PHDAS database. Rate of opioid overdose per thousand people in treatment were calculated for methadone and buprenorphine. Results: In the 9-month period there were 13,718 in methadone treatment and 2716 people in buprenorphine. There were 60 sudden deaths positive for methadone (32 in-treatment) and 7 buprenorphine-positive decedents (none in treatment). Most out-of-treatment deaths occurred in people with known histories of drug misuse. Forty-three methadone positive cases - 19/32 in treatment, and 24/28 out-of-treatment - and 2 of the 7 buprenorphine-positive deaths were due to overdose. The risk of overdose death per thousand people in treatment was lower for buprenorphine than for methadone (RR 4.25 [1.03, 17.54]). Conclusions: In this short-term study, buprenorphine was associated with lower overdose risk that methadone.

( BUPP09731 - 12 August 2009) Sequencing of DSM-IV criteria of nicotine dependence

Aims: To determine whether there is a sequence in which adolescents experience symptoms of nicotine dependence (ND) as per the DSM-IV. Design: A two-stage design was implemented to select a multi-ethnic target sample of adolescents from a school survey of 6th-10th graders from the Chicago Public Schools. The cohort was interviewed at home five times with structured computerised interviews at 6-month intervals over a 2-year period. Participants: Subsample of new tobacco users (n=353) who had started to use tobacco within 12 months prior to wave 1 or between waves 1 and 5. measurements and statistical methods: Monthly histories of DSM-IV symptoms of ND were obtained. Log-linear quasi-independence models were estimated to identify the fit of different cumulative models of progression among the four most prevalent dependence criteria (tolerance, impaired control, withdrawal, unsuccessful attempts to quit), indexed by specific symptoms, by gender and race/ethnicity. Findings: Pathways varied slightly across groups. The proportions who could be classified in a progression pathway not by chance ranged from 50.7% to 68.8%. overall, tolerance and impaired control appeared first and preceded withdrawal; impaired control preceded attempts to quit. For males, tolerance was experienced first, with withdrawal a minor path of entry; for females withdrawal was experienced last, tolerance and impaired control were experienced first. For African Americans tolerance by itself was experienced first; for other groups an alternative pathway began with impaired control. Conclusions: The prevalence and sequence of criteria of ND fit our understanding of the neuropharmacology of ND. The order among symptoms early in the process of dependence may differ from the severity order of symptoms among those who persist in smoking.

( BUPP09730 - 12 August 2009) Supply reduction's hidden casualties: A view from the trenches

( BUPP09729 - 12 August 2009) Retarded highly effective opioid analgesics

( BUPP09728 - 12 August 2009) The ability of anaesthetists to identify generic medications from trade names

The recent proliferation of brand names for prescription medications has made the clinician's task of identifying the corresponding generic drug substances more difficult. A survey of 86 anaesthetists and anaesthetic trainees at two Melbourne hospitals was conducted to measure the extent to which this was perceived to be a clinical problem. In addition, a theoretical test was administered to examine the ability of these anaesthetists to correctly identify generic drugs and therapeutic groups when only the brand name is provided. The results indicated this is perceived to be a genuine clinical problem, with more than 80% of respondents encountering unfamiliar trade names 'often' or 'always' and the test revealing that fewer than one third of commonly prescribed brand names were identified correctly. LG English.

( BUPP09727 - 12 August 2009) Cisplatin-induced non-convulsive posterior reversible encephalopathy syndrome in a 41-year-old woman with metastatic malignant melanoma

Background. Cisplatin, a widely used antineoplastic agent usually induces peripheral neuropathy, but can rarely also complicate with encephalopathy, with or without seizures.Case report. We report a case of a young patient with metastatic malignant melanoma with signs and symptoms of cisplatin-induced non-convulsive posterior reversible encephalopaty syndrome. Within the days shortly after the first cycle of cisplatin based chemotherapy the patient suffered from nausea, vomitus, headache, severe pain at the site of sub-cutaneous metastases and confusion. She later experienced somnolence, cortical blindness and aphasia, but without epileptic seizures.Conclusions. Cisplatin is an effective chemotherapeutic drug but also very toxic one and physicians using it must also be aware of possible encephalopathy.

( BUPP09726 - 12 August 2009) Why should addiction medicine be an attractive field for young physicians?

Aims: The clinical practice and science of addiction are increasingly active fields, which are attracting professionals from diverse disciplines such as psychology and neurobiology. Our scientific knowledge of the pathophysiology of addiction is rapidly growing, along with the variety of effective treatments available to clinicians. Yet, we believe that the medical specialties of addiction medicine/psychiatry are not attracting the interest and enthusiasm of young physicians. What can be done? Methods: We offer the opinions of two experience addiction psychiatrists. Results: In the US, there has been a decline in the number of psychiatrists seeking training or board certification in addiction psychiatry; about one-third of graduates with such training are not practicing in an addiction psychiatry setting. There is widespread neglect of addiction medicine /psychiatry among the medical profession, academia and national health authorities. This neglect is unfortunate, given the enormous societal costs of addiction (3-5% of the gross domestic product in some developed countries), the substantial unmet need for addiction treatment, and the highly favourable benefit to cost yield (at least 7:1) from treatment. Conclusions: We believe that addiction medicine /psychiatry can be made more attractive for young physicians. Helpful steps include widening acceptance as a medical specialty or subspecialty, reducing the social stigma against people with substance use disorders, expanding insurance coverage and increasing the low rates of reimbursement for physicians. These steps would be easier to take with broader societal (and political) recognition of substance use disorders as a major cause of premature death, morbidity and economic burden.

( BUPP09725 - 12 August 2009) Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis

Objective. We evaluated the effectiveness and safety of adalimumab in a large cohort of patients with active ankylosing spondylitis (AS) and identified clinical predictors of good clinical response. Methods. Patients with active AS (Bath AS Disease Activity Index (BASDAI) 4) received adalimumab 40 mg every other week in addition to their standard antirheumatic therapies in a multinational 12-week, open-label study. We used 3 definitions of good clinical response: 50% improvement in the BASDAI (BASDAI = 50), 40% improvement in the ASsessments of SpondyloArthritis International Society criteria (ASAS40), or ASAS partial remission. Response predictors were determined by logistic regression with backward elimination (selection level 5%). Results. Of 1250 patients, 1159 (92.7%) completed 12 weeks of adalimumab treatment. At Week 12, 57.2% of patients achieved BASDAI 50, 53.7% achieved ASAS40, and 27.7% achieved ASAS partial remission. Important predictors of good clinical response (BASDAI 50, ASAS40, and partial remission) were younger age (p < 0.001), and greater C-reactive protein (CRP) concentration (p 0.001), HLA-B27 positivity (p 0.01), and tumor necrosis factor (TNF) antagonist naivety (p < 0.001). Conclusion. Adalimumab was effective in this large cohort of patients with AS, with more than half of patients achieving a BASDAI 50 or ASAS40 response and more than a quarter of patients reaching partial remission at Week 12.Younger age, greater CRP concentrations, HLA-B27 positivity, and TNF antagonist naivety were strongly associated with BASDAI 50, ASAS40, and partial remission responses. Clinical Trials.gov identifier: NCT00478660.

( BUPP09724 - 10 August 2009) Validation of bioanalytical LC-MS/MS assays: Evaluation of matrix effects

Liquid chromatography coupled to atmospheric pressure ionization tandem mass spectrometry is currently the method of choice for the quantitative determination of drugs in biological matrices. The advantages of this technique include high specificity, sensitivity and throughput. However, co-eluting matrix components, which are not observed in the chromatogram, can have a detrimental effect on the analysis, since they can cause ion suppression or enhancement of the analyte. The evaluation of matrix effects on the quantitative analysis of drugs in biological fluids is an important and sometimes overlooked aspect of assay validation. In this review, the influence of matrix effects on bioanalytical LC-MS/MS methods is discussed and illustrated with some examples. In addition, possible solutions to reduce or eliminate matrix effects are highlighted. A literature overview of validated LC-MS/MS methods published from January till June 2008 is also included. Although matrix effects are investigated in most papers, there is no consensus on how matrix effects should be evaluated during method validation. In addition, the definition of specificity should be changed for LC-MS/MS based methods.

( BUPP09723 - 10 August 2009) Memory function in opioid-dependent patients treated with methadone or buprenorphine along with benzodiazepine: longitudinal change in comparison to healthy individuals

BACKGROUND: Opioid-substitution treatment (OST) for opioid dependence (OD) has proven effective in retaining patients in treatment and reducing illegal opiate abuse and crime. Consequently, the World Health Organization (WHO) has listed the opioid agonists methadone and buprenorphine as essential drugs for OD that should be available worldwide. In many areas of the world, OD is often associated with concomitant benzodiazepine (BZD) dependence and abuse, which complicates treatment. However, possible changes in the cognitive functioning of these patients are not well-known. The present study is the first to examine longitudinal stability of memory function in OST patients with BZD use, thus providing a new tool for health policy authorities in evaluating the usefulness of OST. METHODS: Within the first two months (T1) and between 6-9 months (T2) after OST admission, we followed the working memory, immediate verbal memory, and memory consolidation of 13 methadone- and 15 buprenorphine- or buprenorphine/naloxone-treated patients with BZD dependence or abuse disorder. The results were compared to those of fifteen normal comparison participants. All participants also completed a self-reported memory complaint questionnaire on both occasions. RESULTS: Both patient groups performed statistically significantly worse than normal comparison participants in working memory at time points T1 and T2. In immediate verbal memory, as measured by list learning at T1, patients scored lower than normal comparison participants. Both patient groups reported significantly more subjective memory problems than normal comparison participants. Patients with more memory complaints recalled fewer items at T2 from the verbal list they had learned at T1 than those patients with fewer memory complaints. The significance of the main analyses remained nearly the same when the statistical tests were performed without buprenorphine-only patients leaving 12 patients to buprenorphine /naloxone group. CONCLUSION: Working memory may be persistently affected in OST patients with BZD use. A high number of memory complaints among OST patients with BZD use may indicate memory consolidation impairment. These findings show that recovery of memory function in OD patients treated along with BZDs takes time, and their memory complaints may have practical relevance.

( BUPP09722 - 10 August 2009) Opioid agonist pharmacotherapy in New South Wales from 1985 to 2006: patient characteristics and patterns and predictors of treatment retention

AimsThe aims of this study were to: examine the number and characteristics of patients entering and re-entering opioid replacement treatment between 1985 and 2006, to examine select demographic and treatment correlates of leaving treatment between 1985 and 2000, and to compare retention rates in methadone and buprenorphine maintenance treatment from 2001 to 2006.Design A retrospective cohort study using register data from the Pharmaceutical Drugs of Addiction System.SettingOpioid substitution treatment in New South Wales (NSW), Australia.ParticipantsA total of n = 42 690 individuals prescribed opioid replacement treatment between 1985 and 2006 in NSW.MeasurementsClient characteristics over time, retention in days in first treatment episode, number of episodes of treatment and proportion switching medication.Findings Overall, younger individuals were significantly more likely to leave their first treatment episode than older individuals. In 2001-06, after controlling for age, sex and first administration point, the hazard of leaving treatment was 1.9 times for those on buprenorphine relative to those on methadone. Retention in treatment varied somewhat across historical time, with those entering during 1995-2000 more likely to leave at an earlier stage than those who entered before that time.ConclusionsRetention in treatment appears to fluctuate in inverse proportion to the availability of heroin. Individuals in contemporary treatment are older users with a lengthy treatment history. This study has provided population-level evidence to suggest that retention in methadone and buprenorphine differ in routine clinical practice. Future work might investigate ways in which patient adherence and retention may be improved.

( BUPP09750 - 17 August 2009) Application of mechanism-based CYP inhibition for predicting drug-drug interactions

Background: A mechanism-based inhibition of CYPs is characterized by NADPH-, time- and concentration-dependent enzyme inactivation and substrate protection. A significant inactivation of CYPs and particularly the main human hepatic and intestinal CYPs could result in clinical drug-drug interactions (DDIs) and adverse drug reactions. Objective: To address whether DDIs owing to mechanism-based CYP inhibition is predictable based on in vitro inhibitory data. Method: Medline (by means of PubMed up to 26 March 2009) has been searched using proper relevant terms. Result/conclusion: It is possible to predict DDIs caused by mechanism-based CYP inhibition, although the in vitro data do not necessarily translate directly into relative extents of inhibition in vivo because in vivo clinical consequences depend on additional factors that are not easily accounted for in vitro and for reversible inhibition. Incorporation of other important parameters such as CYP degradation rate (k /sub deg/ ), relative contribution of the CYP inactivated to the victim drug elimination (f/sub m(CYP)/ ) and inhibition of intestinal CYP-mediated first-pass metabolism of the object drug (F' /sub gut/ /F /sub gut/ ratio) into the prediction models significantly improves the prediction. Uncertainty of the prediction is mainly from the variability in the estimates of these critical parameters.

( BUPP09749 - 17 August 2009) Substance use at admission to an acute psychiatric department

Substance use is prevalent in patients with psychiatric disorders and may cause severe symptoms in addition to complicating the diagnosis of psychiatric disorders. The aims of the study were to find the prevalence in use of alcohol, drugs, benzodiazepines, hypnotics, opiates and stimulants, and to find the prevalence of substance use disorders at admission to an acute psychiatric department receiving all admissions from a catchment area. Patients were interviewed about use of medications and intoxicating substances during the last week before admission in 227 consecutive admissions. Urine samples were analysed with the liquid chromatography with mass spectrometry (LC- MS) method. Use of substances was determined from reported use and findings in urine samples. Diagnoses were set at discharge according to ICD-10 research criteria. In 81.9% of the admissions, the patient had used alcohol, drugs, benzodiazepines, hypnotics, opiates or stimulants prior to admission. More men used alcohol, cannabis and stimulants, whereas more women used benzodiazepines. In 31.7% of the admissions, 49.5% of men and 16.4% of women, the patients had a substance use disorder (ICD-10, F10-19). Patients with substance use disorders had a shorter stay in hospital than other patients, and patients with no psychiatric disorder other than substance use disorders had a median length of stay of 2 days. Most patients had used psychoactive substances before admission to the acute psychiatric department, and half of the men had a substance use disorder.

( BUPP09748 - 17 August 2009) Effects of specific alpha-1A/1D blocker on lower urinary tract symptoms due to double-J stent: A prospectively randomized study

The aim of our study was to evaluate the effect of tamsulosin in improving symptoms in patients with indwelling double-J ureteral stents. This prospective study lasted from April 2006 to March 2008. All the patients with symptomatic lower ureteral stones with <15 mm diameter were enrolled, and were prospectively randomized (random numbers table) into two groups. A total of 154 patients, with insertion of a double-J ureteral stent after ureteroscopic stone removal. In group 1, 75 patients were enrolled and received placebo for 2 weeks. Group 2 included 79 patients who received 0.4 mg of tamsulosin, once daily for 2 weeks. All patients completed the validated ureteral stent symptom questionnaire (USSQ) and quality of life of international prostate symptom scale (IPSS) for evaluating the symptoms of double-J stents and quality of life after double-J stent insertion and removal, respectively. The analysis of the questionnaire at W1 revealed a significant difference in the main score index of urinary symptoms, body pain and general health between groups 1 and 2. When comparing W1 evaluation with that of W4 after double-J removal, both groups showed significant worsening of urinary symptoms, body pain, general health and work performance, except sexual performance. The mean score of quality of life in IPSS was 4.21 in group 1 and 1.6 in group 2. Tamsulosin can improve a subset of stent-related urinary symptoms and quality of life effectively and may be applied in routine clinical practice.

( BUPP09747 - 17 August 2009) High-risk pregnancy in rhesus monkeys (Macaca mulatta): A case of ectopic, abdominal pregnancy with birth of a live, term infant, and a case of gestational diabetes complicated by pre-eclampsia

Background: Cases of abdominal pregnancy, in the form of intra-abdominal mummified fetuses, have been described in nonhuman primates. Gestational diabetes and pre-eclampsia are common pregnancy complications in women. Methods: Two timed-bred rhesus monkeys had high-risk pregnancies, an abdominal pregnancy with delivery of a live term infant, and a case of gestational diabetes that later developed pre-eclampsia. Results: The monkey that had abdominal pregnancy later died from septic peritonitis. The monkey had a colonic adenocarcinoma that may have allowed leakage of intestinal contents into the abdomen. Her infant was fostered to another female and survived. The monkey with gestational diabetes and pre-eclampsia was treated with a regimen similar to that used in women, and a live infant was delivered at day 157 of gestation by Caesarian section. Conclusions: These cases underscore the value of timed-breeding and the similarities between pregnancy complications in women and in nonhuman primates.

( BUPP09746 - 17 August 2009) Acute pain and availability of analgesia in the prehospital emergency setting in Italy: A problem to be solved

Objectives: The treatment of acute pain in the prehospital emergency setting remains a significant problem. We evaluated the incidence, site, and possible cause of acute pain in the prehospital period and also the current state of prehospital pain management by evaluating analgesic availability in emergency vehicles in Italy. Methods: First aid volunteers documented the presence, intensity, and site of acute pain by questionnaire for over 3 months. Emergency service operations completed a questionnaire on analgesic availability in ambulances and helicopters. Results: Pain symptoms were present in two-thirds of the patients (n = 383) and ranked as moderate to unbearable in 41.75%. Results of the analgesic availability survey indicate that 10.6% of the ambulance services carry no pain killers (including non-steroidal anti-inflammatory drugs (NSAIDs)and/or paracetamol) and 11.5% are without an opioid. The emergency helicopter survey showed a significant difference in analgesic availability compared with ambulances, with 97.6% having at least one opioid agent available (weak or strong). A wide geographical variation in the availability of analgesic agents in ambulance and helicopter services was seen. Conclusions: There is a high prevalence of pain among patients receiving prehospital emergency treatment in Italy and treatment for acute pain during emergency treatment of trauma patients is inadequate. All emergency vehicles, without distinction, should carry opioids and other analgesic drugs (NSAIDs and paracetamol) and there should be no geographic differences in the availability of pain medications.

( BUPP09745 - 17 August 2009) Symptomatic treatments (pain management excluded) for adults in palliative care

Patients with evolutive and terminal desease often present 4 to 5 annoying symptoms, linked to the desease and implying a rigorous assessment as well as a treatment of the cause whenever possible. When all etiologic treatments have been used, the symptomatic treatments often allow to relieve the patient. This demands allying care and medication as well as mastering the available therapeutics so as to adapt the prescriptions at best. The present work essentially approaches the etiologies and symptomatic treatments of nausea and vomiting, hiccup, constipation, bowel obstruction, dyspnoea, congestion and death rattle and neuropsychic disfunctionning, in particular anxiety, depression and delirium. For the situations where the oral, transdermic and intravenous routes become difficult or impossible, medication to be administrated through subcutaneous routes are listed, with prudence, for not regulated.

( BUPP09744 - 17 August 2009) Pain management for adult patients relative to palliative care

Pain management for a patient in palliative care requires a multi-functional approach that entails the physical, psychological, social and spiritual dimensions. It is based on a deep understanding of the pain physiopatology and its accurate assessment to optimize the treatment. This article provides guidelines to manage nociceptive and neuropathic pains, along with tips in case of refractory pains. It gives detailed instructions relative to the use of strong opiods taking advantage of the availability of new types of galenics. It proposes a decision tree relative to neuropatic pain management.

( BUPP09743 - 17 August 2009) Strong opioids in the management of chronic pain of the elderly

40-60% of the elderly suffer from chronic pain that significantly affects their overall quality of life. The prevalence of chronic pain among the elderly is 40-60%. Management of chronic pain in this population involves a combination of pharmacological and non-pharmacological methods. The previous clear-cut classification of chronic pain as malignant or non-malignant is today viewed as relative. The basic therapeutic approaches to the treatment of severe chronic pain are the same, regardless of etiology. Opioid analgesics are the mainstay of pharmacotherapy of severe chronic pain regardless of age. Aging is characterized by important physiological changes that may significantly affect the efficacy and safety of analgesics. The progressive decline in renal and hepatic function can affect the pharmacology of analgesics: onset of action, rate of elimination and effect duration. Thus, drugs whose elimination is independent of glomerular filtration may prove useful Moreover, total body water decreases and body fat relatively increases with age. This significantly affects the distribution volume of lipophilic drugs. This delays the onset of action and decreases the rate of elimination without affecting plasma concentration. In the case of hydrophilic drugs, there is a decrease in the volume of distribution with age. This can lead to a rapid increase in the plasma concentrations of these drugs and the development of serious adverse events. Older age is also associated with a higher incidence of other, concomitant diseases requiring a great number of other drugs. Thus, the risk of drug interactions and adverse events increases, including e.g. vertigo, disorientation and confusion and the associated risk of falls and severe trauma. When selecting the preparation, the unique character of each individual patient and his/her state of pain must be taken into consideration. The article discusses the practical consequences of these physiological changes associated with aging for the selection of opioids and their safe dosing. Due to its demonstrated efficacy and safety, transdermal buprenorphine appears to be a good candidate for the management of severe chronic pain in older patients.

( BUPP09742 - 17 August 2009) Management of pain due to sickle cell disease

Assessment of pain in sickle cell disease is briefly described and a case of a 32-year-old Nigerian woman who had sickle cell pain is presented. The management and outcomes of her care in the UK are described and commentaries are presented on this case of sickle cell pain by specialists from Spain and The Netherlands.

( BUPP09741 - 17 August 2009) Update on treatments for neuropathic pain

Pharmacotherapy for which there is evidence of efficacy in neuropathic pain management is described. The role of opioids is discussed in the context of recent controlled trials. Evidence to support combination pharmacotherapy for neuropathic pain management is presented.

( BUPP09740 - 17 August 2009) Animal models for pediatric circulatory support device pre-clinical testing: National heart, lung, and blood institute pediatric assist device contractor's meeting animal models working group

The National Heart, Lung, and Blood Institute (NHLBI) convened a meeting of NIH contractors funded under the Pediatric Circulatory Support program in February 2008. Working groups were formed on major areas of common interest, including a group discussing animal models used for pediatric VAD testing. Animal testing is typically a component of preclinical assessment of circulatory support devices. In the case of devices intended for the pediatric population, the choice of animal model is especially important and challenging. The choice of animal model and the test protocol are dictated by the objectives of the study, which may be multi-factorial. The working group outlined the important factors to consider in designing the animal study. Compromises are required, and no single animal model or study design was recommended for all groups. This report discusses important general study objectives, issues related to specific animal models, and methods that may be utilized to meet study objectives.

( BUPP09739 - 17 August 2009) (Prospective study on anesthesia for lumbar spine surgery--the effectiveness of the perioperative epidural anesthesia with buprenorphine)

We prospectively evaluated the efficacy of perioperative epidural buprenorphine for lumbar spinal surgery under general anesthesia. Twenty-eight patients were allocated into two groups; in one group (buprenorphine group), patients underwent the surgery under general anesthesia with perioperative epidural buprenorphine 0.2 mg, in the other group (control group), patients underwent the surgery under general anesthesia only. The epidural injection was within 2 levels of the cephalad segment of the operating site. In both groups, fentanyl and flurbiprofen were intravenously injected intermittently in the same manner. In buprenorphine group, requirement of analgesics was less during and after surgery compared with the control group. Neurological evaluation immediately after surgery revealed no neurological side effects in both groups. We conclude that general anesthesia with perioperative epidural buprenorphine for lumbar spinal surgery is safe and useful.

( BUPP09738 - 17 August 2009) The implications of medication development in the treatment of substance use disorders in developing countries

PURPOSE OF REVIEW: To enquire as to how applicable are the latest developments in pharmacotherapy of substance use disorders (SUDs) to patients in developing countries. We review the latest literature regarding the magnitude of the problem in developing countries. We then present a review of recent developments in pharmacotherapy of SUDs, especially from developing countries. Finally, we discuss the barriers that prevent patients in developing countries from benefiting from these developments. RECENT FINDINGS: The problem of SUDs is increasing in developing countries and there is a severe shortage of manpower to manage it. Disulfiram, naltrexone and acamprosate are useful in treating alcohol dependence, and likewise methadone and buprenorphine in treating opioid dependence. Strategies of matching patients to medications and combining the medications have shown promise. There is a parallel benefit of reduction in the risk of HIV spread among injecting drug users. However, many barriers prevent an average patient with SUD from benefiting from these developments. CONCLUSION: Medication treatment can improve the outcome of SUDs. Research in this field is catching up in developing countries. However, due to issues of availability, affordability, manpower and governmental policies, a large number of patients in these countries are unable to benefit from recent developments. Urgent efforts are required to fill this gap between research and practice.

( BUPP09737 - 17 August 2009) Buprenorphine for the management of opioid withdrawal

BACKGROUND: Managed withdrawal is a necessary step prior to drug-free treatment or as the end point of substitution treatment. OBJECTIVES: To assess the effectiveness of interventions involving the use of buprenorphine to manage opioid withdrawal, for withdrawal signs and symptoms, completion of withdrawal and adverse effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), MEDLINE (January 1966 to July 2008), EMBASE (January 1985 to 2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials of interventions involving the use of buprenorphine to modify the signs and symptoms of withdrawal in participants who were primarily opioid dependent. Comparison interventions involved reducing doses of methadone, alpha(2)-adrenergic agonists, symptomatic medications or placebo, or different buprenorphine-based regimes. DATA COLLECTION AND ANALYSIS: One author assessed studies for inclusion and methodological quality, and undertook data extraction. Inclusion decisions and the overall process was confirmed by consultation between all authors. MAIN RESULTS: Twenty-two studies involving 1736 participants were included. The major comparisons were with methadone (5 studies) and clonidine or lofexidine (12 studies). Five studies compared different rates of buprenorphine dose reduction.Severity of withdrawal is similar for withdrawal managed with buprenorphine and withdrawal managed with methadone, but withdrawal symptoms may resolve more quickly with buprenorphine. It appears that completion of withdrawal treatment may be more likely with buprenorphine relative to methadone (RR 1.18; 95% CI 0.93 to 1.49, P = 0.18) but more studies are required to confirm this.Relative to clonidine or lofexidine, buprenorphine is more effective in ameliorating the symptoms of withdrawal, patients treated with buprenorphine stay in treatment for longer (SMD 0.92, 95% CI 0.57 to 1.27, P < 0.001), and are more likely to complete withdrawal treatment (RR 1.64; 95% CI 1.31 to 2.06, P < 0.001). At the same time there is no significant difference in the incidence of adverse effects, but drop-out due to adverse effects may be more likely with clonidine. AUTHORS' CONCLUSIONS: Buprenorphine is more effective than clonidine or lofexidine for the management of opioid withdrawal. Buprenorphine may offer some advantages over methadone, at least in inpatient settings, in terms of quicker resolution of withdrawal symptoms and possibly slightly higher rates of completion of withdrawal.

( BUPP09736 - 17 August 2009) Recent Developments in the Chemistry of Thebaine and its Transformation Products as Pharmacological Targets

The most practical synthetic routes to the preparation of as important pharmaceuticals as oxycodone, naloxone, naltrexone, nalbuphine and buprenorphine have utilized the alkaloid, thebaine, as a starting material. This review intends to focus on chemical transformations of morphinans which resulted in morphinandiene derivatives with well-established and novel pharmacological potencies. These chemical transformations were mainly associated with the formation and substitution of the unique diene structure of the ring C of the morphinan backbone.

( BUPP09735 - 17 August 2009) mu-Opioid receptor-stimulated synthesis of reactive oxygen species is mediated via Phospholipase D2

We have recently shown that the activation of the rat mu-opioid receptor (MOPr, also termed MOR1) by the mu-agonist (d-Ala(2), Me Phe (4), Glyol(5))enkephalin (DAMGO) leads to an increase in phospholipase D2 (PLD2) activity and an induction of receptor endocytosis, whereas the agonist morphine which does not induce opioid receptor endocytosis fails to activate PLD2. We report here that MOPr-mediated activation of PLD2 stimulates production of reactive oxygen molecules via NADH/NADPH oxidase. Oxidative stress was measured with the fluorescent probe dichlorodihydrofluorescein diacetate and the role of PLD2 was assessed by the PLD inhibitor d-erythro-sphingosine (sphinganine) and by PLD2-small interfering RNA transfection. To determine whether NADH/NADPH oxidase contributes to opioid-induced production of reactive oxygen species, mu-agonist-stimulated cells were pre-treated with the flavoprotein inhibitor, diphenylene iodonium, or the specific NADPH oxidase inhibitor, apocynin. Our results demonstrate that receptor-internalizing agonists (like DAMGO, beta-endorphin, methadone, piritramide, fentanyl, sufentanil, and etonitazene) strongly induce NADH/NADPH-mediated ROS synthesis via PLD-dependent signaling pathways, whereas agonists that do not induce MOPr endocytosis and PLD2 activation (like morphine, buprenorphine, hydromorphone, and oxycodone) failed to activate ROS synthesis in transfected human embryonic kidney 293 cells. These findings indicate that the agonist-selective PLD2 activation plays a key role in the regulation of NADH/NADPH-mediated ROS formation by opioids.

( BUPP09734 - 17 August 2009) Treatment of Chronic Non-Malignant Pain in the Elderly Safety Considerations

The safety considerations in the treatment of chronic non-malignant pain in elderly are reviewed. Topics discussed are: aging of the global population; geriatric syndromes, frailty and dementia; an inadequate evidence base for treatment of elderly people; pharmacokinetics and pharmacodynamics in elderly people; prevalence of chronic pain in the elderly; incidence of adverse drug reactions; analgesic drug safety in the elderly, pharmacological interventions for the treatment of chronic pain; paracetamol; NSAID, opioid analgesics; adjuvant analgesics; and approaches in improving safety. The absence of trial data, specific to the elderly, is substantially offset by information based on clinical experience and expert consensus statements.

( BUPP09733 - 17 August 2009) The role of methadone in cancer pain treatment - a review

The role of methadone in cancer pain treatment is reviewed with reference to: general characteristics of methadone; pharmacodynamics and pharmacokinetics; drug interactions; equianalgesic dose ratio with other opioids; dosing and breakthrough pain treatment; routes of administration; adverse effects; and summary of methadone studies in cancer pain. Methadone is an important opioid analgesic at step 3 of the World Health Organization analgesic ladder. Future controlled studies may focus on establishment of methadone equianalgesic dose ratio with other opioids and its role as the 1st strong opioid in comparative studies with analgesia, adverse effects and quality of life taken into consideration.

( BUPP09783 - 02 September 2009) Opioid maintenance treatment during pregnancy: Occurrence and severity of neonatal abstinence syndrome

Background: Opioid maintenance treatment (OMT) is widely used to treat pregnant women with a history of opioid dependence. This study investigated whether maternal methadone/buprenorphine dose and nicotine use in pregnancy affects the occurrence and duration of neonatal abstinence syndrome (NAS) in the infant. Methods: Forty-one pregnant women from OMT programmes in Norway who gave birth between January 2005 and January 2007 were enrolled in a national prospective study. Thirty-eight women (81% of the population) were interviewed in the last trimester of pregnancy and 3 months after delivery. Data from the European Addiction Severity Index and a questionnaire measuring enrolled birth information were compared with medical records and urine analyses. Results: Treatment requiring NAS occurred in 58% of the methadone-exposed and in 67% of the buprenorphine-exposed infants. There was no significant relationship between a maternal dose of methadone or buprenorphine in pregnancy and NAS treatment duration for the infant. The mean number of cigarettes consumed correlated significantly with NAS treatment duration for the methadone group. Birth weight for the methadone group was approximately 200 g above international findings despite high doses during pregnancy. Conclusions: Maternal methadone/ buprenorphine dose predicted neither the occurrence nor the need for NAS treatment for the infant.

( BUPP09782 - 02 September 2009) Association between prenatal tobacco exposure and outcome of neonates born to opioid-maintained mothers

Background: Prenatal nicotine exposure is associated with increased neonatal mortality, low birth weight, and smaller head circumference. Opioid-dependent pregnant women show a particularly high prevalence of tobacco smoking and are at greater risk for additional adverse events. However, little is known about the impact of tobacco smoking on opioid-maintained pregnant women and neonatal outcomes. Patients and Methods: This study examined the effect of cigarette smoking on 139 opioid-maintained pregnant women and their neonates. Forty-five percent of the participants were maintained on slow-release oral morphine (SROM), 39% received methadone maintenance, and 16% received buprenorphine. Participants were divided into two groups: (1) women who reported a low cigarette consumption of 10 cigarettes/day (56.8%) and (2) those reporting heavy consumption of 20 cigarettes/day (43.2%). Neonatal outcome measures were assessed, and a standardized Finnegan score was applied to determine the neonatal abstinence syndrome (NAS). Results: Fifty-two percent of the newborns did not require treatment for NAS (54% of neonates born to methadone-maintained mothers, 30% born to SROM-maintained mothers, and 95% born to buprenorphine-maintained mothers; p < 0.001). Heavy cigarette consumption was associated with significantly lower neonatal birth weight (p < 0.001), smaller birth length (p = 0.017) as well as with the severity of NAS (p = 0.03). With regard to concomitant consumption of opioids (p = 0.54), cocaine (p = 0.25), amphetamines (p = 0.90) or benzodiazepines (p = 0.09), no significant differences between heavy or low nicotine consumption were noted. Conclusion: Heavy tobacco smoking in opioid-maintained pregnant women is associated with adverse medical and developmental consequences for the newborn. Future treatment programs for this target group should focus on an individualized approach to opioid maintenance therapy in addition to offering specially tailored counseling for smoking cessation.

( BUPP09781 - 02 September 2009) Feasibility of buprenorphine maintenance therapy programs in the Ukraine: First promising treatment outcomes

Background: Opiate substitution therapy (OST) in the Ukraine was not provided until 2004. As part of the introduction of OST, the first feasibility study was conducted in 2007. Six clinics in 6 cities were involved in providing OST and collecting data. Methods: A total of 151 opiate-dependent patients were given buprenorphine as a substitute, and a survey of substance use, HIV transmission risks, and legal and social status was conducted at baseline and at 6 and 12-month follow-up. Results: Illegal substance use and illegal activities and incomes were highly reduced, whereas employment rates and psychiatric problems improved. Retention was comparatively high (79.5%) after 12 months. No significant adverse events were reported. Conclusion: A successful implementation of OST in the Ukraine is feasible.

( BUPP09780 - 02 September 2009) Tramadol hydrochloride use and acute deterioration in Parkinson's disease tremor

( BUPP09779 - 02 September 2009) Effect of melatonin on burn-induced gastric mucosal injury in rats

We studied the effect of melatonin treatment on gastric mucosal damage induced by experimental burns and its possible relation to changes in gastric lipid peroxidation status. Melatonin was intraperitoneally applied immediately after third-degree burns over 30% of total body skin surface area of rats. Malondialdehyde (MDA), uric acid (UA) and sulphydril (SH) levels were determined in gastric mucosa and blood plasma and used as biomarkers of the oxidative stress. The results showed that the skin burn caused oxidative stress evidenced by accumulation of MDA and UA as well as the depletion of SHs in gastric mucosa. Plasma MDA concentrations were elevated, while plasma SH concentrations were decreased after burns. Melatonin (10 mg per kg body weight) protected gastric mucosa from oxidative damage by suppressing lipid peroxidation and activating the antioxidant defence. It may be hypothesised that melatonin restores the redox balance in the gastric mucosa and protects it from burn-induced oxidative injury. Melatonin has no significant influence on the concentrations of plasma MDA and antioxidants after burn; therefore, it should largely be considered as a limiting factor for tissue-damage.

( BUPP09778 - 02 September 2009) Mexican drug violence intertwined with US demand for illegal drugs

( BUPP09777 - 02 September 2009) Psychopharmacologic management of opioid-dependent women during pregnancy

Illicit drug use during pregnancy presents complex clinical challenges, including reducing drug use and treating psychiatric disorders. Pharmacologic treatment of psychiatric disorders in a pregnant woman requires an evaluation of the balance between potential clinical benefit and the risk of potential neonatal consequences. This study describes psychiatric symptoms in 111 opioid-dependent pregnant women and their prescribed psychotropic medications. Hypomania, generalized anxiety disorder and depression were the most common disorders for which psychiatric symptoms were endorsed. Over half of women studied were prescribed some form of psychoactive medication during pregnancy. Pharmacologic vs. non-pharmacologic treatment approaches in this patient population are discussed.

( BUPP09776 - 02 September 2009) Early outcomes following low dose naltrexone enhancement of opioid detoxification

Although withdrawal severity and treatment completion are the initial focus of opioid detoxification, post-detoxification outcome better defines effective interventions. Very low dose naltrexone (VLNTX) in addition to methadone taper was recently associated with attenuated withdrawal intensity during detoxification. We describe the results of a seven-day follow-up evaluation of 96 subjects who completed inpatient detoxification consisting of the addition of VLNTX (0.125 or 0.250 mg per day) or placebo to methadone taper in a double blind, randomized investigation. Individuals receiving VLNTX during detoxification reported reduced withdrawal and drug use during the first 24 hours after discharge. VLNTX addition was also associated with higher rates of negative drug tests for opioids and cannabis and increased engagement in outpatient treatment after one week. Further studies are needed to test the utility of this approach in easing the transition from detoxification to various follow-up treatment modalities designed to address opioid dependence.

( BUPP09775 - 02 September 2009) Substance-dependent professional drivers in Iran: a descriptive study

OBJECTIVE: To determine characteristics of a nationwide sample of Iranian dependent drug users whose main profession is driving. METHODS: Data were derived from a larger study, which aimed to describe pattern of drug dependency in Iran. A "driver" was defined as a person whose main profession was driving a motor vehicle to earn a living. Nine hundred twenty individuals were interviewed by a trained drug abuse team in all provinces of Iran during a 5-month period, from April to August 2007. Socioeconomic characteristics, substance abused, and high-risk behaviors were collected by a checklist. RESULTS: All drivers were male and their mean (+/- standard deviation) age was 35.1 (+/- 8.6) years. Opioids (434 cases, 46.8%) and kerack (256 cases, 27.6%) were the two most common drugs used. Except for buprenorphine, which was used via intravenous injection, inhalation was the dominant method of us in other substances including opioids (56%), heroin (51.4%), kerack (80.1%), methamphetamine (73.9%), and cannabis (77.8%). Extramarital sexual relationships (414 cases, 45%) and nonfatal intoxication (362 cases, 39.3%) were the two most frequent high-risk behaviors. CONCLUSIONS: There are people with drug dependencies who drive for living in Iran. Deterrence programs through screening and random drug testing at police stations and legislation regarding charges of drugged drivers and prohibition from driving for long time periods are essential priorities in traffic safety.

( BUPP09774 - 02 September 2009) Buprenorphine: a safe agent for opioid dependent patients who are under the increased risk of stroke?

( BUPP09773 - 02 September 2009) Dexmedetomidine as a novel therapeutic for postoperative pain in a patient treated with buprenorphine

Buprenorphine is a partial agonist/antagonist used for the outpatient management of pain and addiction. It avidly binds to the opioid receptors and has a long and varied half-life. Its effects can impair the efficacy of opioids used for postoperative pain. The authors present a case of a patient managed with buprenorphine as an outpatient who presented for revision spine surgery and had significant postoperative pain that was successfully treated with hydromorphone and dexmedetomidine. This is the first reported use of dexmedetomidine for postoperative pain in a patient treated with buprenorphine.

( BUPP09772 - 02 September 2009) Relative bioavailability of two formulations of buprenorphine spray compared with sublingual tablets (Temgesic (R))

( BUPP09771 - 02 September 2009) Optimizing the galenical formulation of analgetics for the treatment of chronic pain conditions: possible effects on sleep disorders

( BUPP09770 - 02 September 2009) Behavioral economic analysis of opioid consumption in heroin-dependent individuals: Effects of alternative reinforcer magnitude and post-session drug supply

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand were influenced by HYD unit price (UP), alternative money reinforcement magnitude and post-session HYD supply. Heroin-dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day first sampled two HYD doses (12 and 24 mg IM, labeled Drug A (session 1) and Drug B (session 2)). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could earn a HYD unit dose (2 mg, fixed) or money ($2 or $4, varied across sessions), administered immediately after the work session. Before the PR task, volunteers were told which HYD supplemental dose (none, Drug A or B) would be available 3 h after receiving the PR-contingent dose. PR-contingent HYD choice significantly decreased when $4 relative to $2 was concurrently available. Information about the post-session HYD supplement moderated this effect: when subjects were told a supplemental dose was available, HYD-seeking behavior decreased when the money alternative was smaller ($2), but this information did not further attenuate HYD choice, which was already low, when the money alternative was higher ($4). HYD demand elasticity was only increased by the $4 relative to $2 alternative without the HYD supplement. In summary, opioid-seeking behavior is influenced by the availability of concurrent non-drug and drug alternatives. These findings show that drug availability and non-drug alternatives interact to modulate drug-seeking behavior.

( BUPP09769 - 02 September 2009) The Intensive Treatment Unit: A brief inpatient detoxification facility demonstrating good postdetoxification treatment entry

Inpatient detoxification is frequently used to treat substance use disorders, despite consistent findings that drug use soon after detoxification is the norm. A number of lines of evidence suggest the most rational means of improving outcomes after detoxification is to improve postdetoxification treatment entry. This report presents outcomes from the Intensive Treatment Unit (ITU), a brief inpatient detoxification unit in Baltimore, MD, found to have good postdischarge treatment entry outcomes. The patients followed were predominantly male African Americans in early middle age who were sequentially admitted to the unit (N = 134) and demonstrated severe social disruption and psychiatric comorbidity. More than 80% of the patients discharged from the ITU were admitted to treatment postdetoxification, with most going to long-term residential settings or recovery houses. Success was associated with seeking residential treatment, and failure was concentrated among the minority discharged with no plan for aftercare and those seeking outpatient treatments. The report explores patient and process factors associated with these outcomes and discusses the possibility that the ITU may be a model system for improving outcomes postdetoxification.

( BUPP09768 - 02 September 2009) Medical consequences of drug abuse and co-occurring infections: Research at the national institute on drug abuse

Substance abuse still remains one of the major problems in the world today, with millions of people abusing legal and illegal drugs. In addition, a billion people may also be infected with one or more infections. Both drugs of abuse and infections are associated with enormous burden of social, economic, and health consequences. This article briefly discusses a few medical consequences of drugs of abuse and infections such as human immunodeficiency virus, hepatitis C virus, psychiatric complications in hepatitis C infection, pharmacokinetic drug-drug interactions among medications used in the treatment of addiction and infections, and new drugs in development for the treatment of infections. Research is encouraged to study interactions between infections, drugs of abuse, and underlying pathophysiologic and molecular/genetic mechanisms of these interactions.

( BUPP09767 - 02 September 2009) Comparing buprenorphine 'tapers' - To what end?

( BUPP09766 - 02 September 2009) Long-suffering or prolonged suffering? Time matters

( BUPP09765 - 02 September 2009) European pain management discussion forum

Queries from European physicians about analgesic pharmacotherapy and responses from the author are presented. The topics addressed the management of trigeminal neuralgia in primary care and the association between long-term opioid use and osteoporosis.

( BUPP09764 - 02 September 2009) Relationship between exposure of (-)-N-{2-((R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino)ethyl }-4-fluorobenzamide (YM758), a "funny" if current channel inhibitor, and heart rate reduction in tachycardia-induced beagle dogs

(-)-N-{2-((R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidino)ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel (If channel) inhibitor, is developed as a treatment for stable angina and atrial fibrillation. In this study, the pharmacokinetic/ pharmacodynamic (PK/PD) relationship after intravenous administration of YM758 to tachycardia-induced dogs was investigated and described based on the simplified compartment model. The PK of YM758 in dogs did not differ between the nontreated and tachycardia-induced groups. A drug-induced reduction in heart rate (HR) was clearly observed, and the half-life of the duration of the effect (approximately 4.0 h) was longer than that of the plasma concentration of the unchanged drug. The fitting and simulation procedure from the PK/PD relationship between the time profiles for YM758 plasma concentration and HR reduction had an ECe50 value (YM758 concentration in the effective compartment resulting in a 50% decrease of the maximum effect) of 6.0 ng/ml, which did not agree with the results of the in vitro experiment using right atria isolated from guinea pigs (EC30, 70.4 ng/ml). In addition, in the in vitro experiments, YM758 metabolites had a weak inhibitory effect, if any, on the spontaneous beat rate of the right atria from guinea pigs. These data, along with the previous finding that YM758 and its metabolites are eliminated rapidly from rat hearts, indicate that the duration of the pharmacological effect of YM758 (compared with the rapid elimination of the plasma drug concentration) may be the result of strong binding and/or slower dissociation of YM758 in the If channel. Such PK/PD analyses allow the pharmacological profiles of many drugs, especially cardiovascular drugs, to be more readily understood and better predicted during the clinical stages.

( BUPP09763 - 02 September 2009) Xenon reduces neurohistopathological damage and improves the early neurological deficit after cardiac arrest in pigs

OBJECTIVE: Treatment options to ameliorate brain damage following cardiopulmonary resuscitation from cardiac arrest are limited. DESIGN: In a porcine model, we evaluated the effects of xenon treatment on neuropathologic and functional outcomes after cardiopulmonary resuscitation. SETTING: Prospective, randomized laboratory animal study. SUBJECTS: Male pigs. INTERVENTIONS: Following successful resuscitation from 8 mins of cardiac arrest and 5 mins of cardiopulmonary resuscitation, 24 pigs were randomized to one of three groups receiving either 70% xenon for 1 or 5 hrs or untreated controls receiving 70% nitrogen. MEASUREMENTS AND MAIN RESULTS: Gas exchange, hemodynamics, and lactate and glucose levels were measured at baseline and in the postresuscitation period. On four postoperative days, neurocognitive and overall neurologic deficits were assessed before day 5, when the brains were harvested for histologic analysis of predefined regions using a semiquantitative score (0-10% 1, 10-20% 2, 20-50% 3, 50-80% 4, 80-100% 5). No differences in gas exchange, hemodynamics, or lactate and glucose levels were observed among the groups. Animals exposed to 1 and 5 hrs of xenon showed significantly reduced scores for necrotic neurons in the putamen (1.25 � 0.5 and 1.25 � 0.5 vs. 2.5 � 1.2; p < 0.05), accompanied by significantly lesser scores for perivascular inflammation in putamen (0.8 � 0.5 and 1.1 � 0.8 vs. 2.1 � 1.1; p < 0.05) and caudate nucleus (1.0 � 0.8 and 0.6 � 0.7 vs. 2.0 � 1.1; p < 0.05). This resulted in improved neurocognitive and neurologic function on day 1 to 3 after cardiopulmonary resuscitation in xenon-treated animals. CONCLUSIONS: In this experimental study of cardiac arrest-induced neurologic damage, xenon conferred neurohistopathologic protection, translating in transiently improved functional outcome.

( BUPP09762 - 02 September 2009) Improving adherence to antiviral therapy in injecting drug users with chronic hepatitis C virus

( BUPP09761 - 02 September 2009) Concerns about consensus guidelines for QTc interval screening in methadone treatment (1)

( BUPP09760 - 02 September 2009) Concerns about consensus guidelines for QTc interval screening in methadone treatment (4)

( BUPP09759 - 02 September 2009) In response

( BUPP09758 - 01 September 2009) Medication Assisted Treatment in the Treatment of Drug Abuse and Dependence in HIV/AIDS Infected Drug Users

Drug use and HIV/AIDS are global public health issues. The World Health Organization (WHO) estimates that up to 30% of HIV infections are related to drug use and associated behaviors. The intersection, of the twin epidemics of HIV and drug/alcohol use, results in difficult medical management issues for the health care providers and researchers who work in the expanding global HIV prevention and treatment fields. Access to care and treatment, medication adherence to multiple therapeutic regimens, and concomitant drug-drug interactions of prescribed treatments are difficult barriers for drug users to overcome without directed interventions. Injection drug users are frequently disenfranchised from medical care and suffer sigma and discrimination creating additional barriers to care and treatment for their drug abuse and dependence as well as HIV infection. In an increasing number of studies, medication assisted treatment of drug abuse and dependence has been shown to be an important HIV prevention intervention. Controlling the global transmission of HIV will require further investment in evidence-based interventions and programs to enhance access to care and treatment of individuals who abuse illicit drugs and alcohol. In this review, we present the cumulative evidence of the importance of medication assisted treatment in the prevention, care, and treatment of HIV infected individuals who also abuse drugs and alcohol.

( BUPP09757 - 01 September 2009) Incidence of and risk factors for postoperative pneumonia in dogs anesthetized for diagnosis or treatment of intervertebral disk disease.

Objective-To determine incidence of and risk factors for postoperative pneumonia in dogs anesthetized for diagnosis or treatment of intervertebral disk disease (IVDD).Design-Retrospective case-control study.Animals-707 dogs that underwent general anesthesia for the diagnosis or treatment of IVDD between 1992 and 1996 or between 2002 and 2006.Procedures-Postoperative pneumonia was diagnosed if compatible clinical signs (cough or hypoxemia) and radiographic abnormalities (alveolar infiltrates) developed within 48 hours after anesthesia. To identify risk factors for postoperative pneumonia, findings for dogs that developed postoperative pneumonia between 2002 and 2006 were compared with findings for a randomly selected control group of unaffected dogs from the same population. Results- there were no significant differences in age, breed, body weight, sex, location of IVDD, or survival rate between the 2 time periods, but there were significant differences in the use of magnetic resonance imaging, computed tomography, and hemilaminectomy and in the percentage of dogs that developed postoperative pneumonia in the later (4.6%) versus the earlier (0.6%) years. Significant risk factors for postoperative pneumonia included preanesthetic tetraparesis, cervical lesions, undergoing magnetic resonance imaging, undergoing > 1 anesthetic procedure, longer duration of anesthesia, and postanesthetic vomiting or regurgitation.Conclusions and Clinical Relevance-Results suggested that at this institution, the incidence of postoperative pneumonia in dogs anesthetized for diagnosis or treatment of IVDD had increased in recent years.

( BUPP09756 - 01 September 2009) The Effects of Repeated Opioid Administration on Locomotor Activity: I. Opposing Actions of mu and kappa Receptors

Repeated administration of many addictive drugs leads to a progressive increase in their locomotor effects. This increase in locomotor activity often develops concomitantly with increases in their positive-reinforcing effects, which are believed to contribute to the etiology of substance use disorders. The purpose of this study was to examine changes in sensitivity to the locomotor effects of opioids after their repeated administration and to determine the role of mu and kappa receptors in mediating these effects. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and changes in locomotor activity were measured. Repeated administration of the mu agonists, morphine and buprenorphine, produced a progressive increase in locomotor activity during the treatment period, and this effect was blocked by coadministration of the opioid antagonist naltrexone. The kappa agonist spiradoline decreased locomotor activity when administered alone and blocked the progressive increase in locomotor activity produced by morphine. The ability of spiradoline to block morphine- induced increases in locomotor activity was itself blocked by pretreatment with the kappa antagonist nor-binaltorphimine. Repeated administration of high doses, but not low or moderate doses, of the mixed mu/kappa agonists butorphanol, nalbuphine, and nalorphine produced a progressive increase in locomotor activity during the treatment period. Doses of butorphanol, nalbuphi ne, and nalorphine that failed to produce a progressive increase in locomotor activity when administered alone did so when subjects were pretreated with nor-binaltorphimine. These findings suggest that mu and kappa receptors have functionally opposing effects on opioid-mediated locomotor activity and sensitization-related processes.

( BUPP09755 - 01 September 2009) The Effects of Repeated Opioid Administration on Locomotor Activity: II. Unidirectional Cross-Sensitization to Cocaine

Sensitization refers to an increase in sensitivity to the effects of a drug and is believed to play a role in the etiology of substance use disorders. Cross-sensitization has been observed between drugs from different pharmacological classes and may play a role in the escalation of drug use in polydrug-abusing populations. The purpose of this study was to examine cross-sensitization between opioids and cocaine and to determine the extent to which cross-sensitization is mediated by an opioid's selectivity for mu, kappa, and delta receptors. Separate groups of rats were treated with opioid receptor agonists and antagonists every other day for 10 days, and the locomotor effects of cocaine were tested 8 days later. The mu agonists, morphine and buprenorphine, and the delta agonist, BW373U86 ((+/-)-4-((R*)((2S*, 5R*)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl)-(3-hydroxyphenyl) methyl)-N, N-diethylbenzamide hydrochloride), produced cross-sensitization to cocaine, such that repeated administration of these drugs over a 10-day period significantly enhanced cocaine's locomotor effects when tested later. Coadministration of the opioid antagonist naltrexone prevented morphine and buprenorphine from producing cross-sensitization. Coadministration of naltrexone, but not the delta antagonist naltrindole, also prevented BW373U86 from producing cross-sensitization. The kappa agonist spiradoline failed to produce cross-sensitization, but coadministration of spiradoline prevented morphine and buprenorphine from producing cross-sensitization. The ability of spiradoline to block cross-sensitization was itself blocked by the kappa antagonist nor-binaltorphimine. The mixed mu/kappa opioids butorphanol, nalbuphine, and nalorphine did not produce cross-sensitization under any condition examined. These data indicate that agonist activity at mu receptors positively modulates cross-sensitization between opioids and cocaine, whereas agonist activity at kappa receptors negatively modulates this effect.

( BUPP09754 - 01 September 2009) Structural and Physicochemical Profiling of Morphine and Related Compounds of Therapeutic Interest

A concise account of the physicochemical properties of morphine and its derivatives of therapeutic interest is provided. Such properties include macroscopic and microscopic acid/base parameters, lipophilicity, solubility, permeability that all influence the fate of drugs in the body. The dependence of these parameters on pH is discussed and subsequent implications in drug administration and formulation are presented.

( BUPP09753 - 01 September 2009) Prescription Opioid Aberrant Behaviors A Pilot Study of Sex Differences

This pilot study assessed the sex differences in specific types of aberrant behaviors or sex-specific predictors of such behaviors in 121 chronic pain patients. More men than women were taking a prescribed opioid. Women were more likely than men to hoard unused medication and to use additional medications to enhance the effectiveness of pain medication. Among men, high rates of aberrant prescription use behaviors were associated with current alcohol use and the use of oxycodone and morphine. Among women, use of hydrocodone was associated with high rates of aberrant prescription use behaviors. These findings indicate that a substantial proportion of chronic pain patients engage in aberrant prescription opioid behaviors, which range along a continuum of severity. Aberrant prescription use behaviors as well as the predictors of these behaviors may be sex-specific.

( BUPP09752 - 01 September 2009) (Experience of using injectable formulation of buprenorphine for the detoxification treatment of heroin dependence patients)

Forty-four heroin dependence patients took detoxification treatment in Fukko-kai Tarumi Hospital from October 1998 to April 2008 (total of 80 admissions). Injectable formulation of buprenorphine (0.2 mg) was used intramuscularly to relieve withdrawal symptoms from October 2002. In the initial phase, small dosage of buprenorphine (0.4 mg per day) was dispensed but obvious effects were not confirmed. Therefore, the dosage was increased to 0.6 mg (3 ampoules), possibly more for 27 patients (total of 53 admissions) from October 2005. While treatment was interrupted by various reasons in 6 patients (total of 10 admissions), the rest completed detoxification. Dosage of buprenorphine given to the patients varied from 0.6 mg (3 ampoules) to 1.6 mg (8 ampoules) per day, and only 4 patients required over 1.0 mg. While duration of administration ranged from 5 days to 15 days, it was between 7 days and 10 days in over the half cases. When sufficient amount of buprenorphine was administered, severity and duration of heroin withdrawal symptoms was distinctly reduced. Since the introduction of heroin detoxification with buprenorphine, number of patients who request the treatment voluntarily increased including those who relapsed, but the length of hospital stay was shortened. One patient rejected buprenorphine injection for unknown reason and one patient left the hospital because of insufficient effect due to insufficient amount of buprenorphine dose, serious adverse effect was not observed. Detoxification treatment with buprenorphine cannot ensure sustained abstinence but can motivate heroin-using patients to receive treatment and strive for abstinence.

( BUPP09751 - 01 September 2009) (Abuse of alcohol and benzodiazepine during substitution therapy in heroin addicts: a review of the literature)

INTRODUCTION: In spite of its seriousness, dependence on alcohol and benzodiazepines during substitution treatment are poorly documented. Its frequency is nonetheless significant. According to studies, between one and two thirds of patients are affected. This consumption is under verbalized by patients and underestimated by carers. In one study, where the average diazepam doses were from 40 to 45 mg per day, 30% of the patients were taking 70 to 300 mg per day, two thirds having experimented with a fixed dose of 100mg. Benzodiazepines, especially diazepam and flunitrazepam, were studied versus placebo. Thus, 10 to 20mg of diazepam gave rise to euphoria, a sensation of being drugged, sedation and lessening of cognitive performance. The aim of this consumption is to potentiate the euphoria induced by opioids, a "boost" effect during the hour after taking it, or the calming of the outward signs of withdrawal. The most sought after molecules are the most sedative, those with pronounced plasmatic peaks, and the most accessible. LITERATURE FINDINGS: In multidependant subjects, opioid dependence had been earlier in adolescence, with a number of therapeutic failures. They had been faced with repetitive rejection and separation during childhood, medicolegal and social problems. Somatization, depression, anxiety and psychotic disorders are frequent in this subgroup. Heavy drinkers under methadone treatment are highly vulnerable to cocaine. Their behaviour is at risk, with exchange of syringes; their survival rate is 10 years less than that of moderate consumers of alcohol. Most are single, with a previous prison, psychiatric or addictive cursus and they present significant psychological vulnerability. For some authors, benzodiazepines indicate a psychiatric comorbidity. Methadone significantly reduces the consumption of alcohol by nonalcoholic heroin addicts. Although alcohol is an enzymatic inductor of methadone catabolism, with bell-shaped methadone plasma curves over 24 hours, a substitution treatment is recommended. It has a minimum impact on care, in spite of efficiency and retention in therapeutical programs, allowing the subject's inclusion in the framework of a more regular and sustained medical follow-up. Treatment of benzodiazepine dependence by a progressive regression of doses has little efficacy in subjects which cannot control how much medication they are taking. Certain authors have suggested maintenance treatments of clonezepam. The most appropriate therapeutic propositions are: (1) maintenance of therapeutic links though a framework of deliverance from flexible substitution treatment; (2) prevention by cautious prescribing and control of dispensing medication; (3) parallel treatment of psychiatric comorbidities and related personality disorders; (4) individual psychiatric treatment, either institutional or in consistent networks.

( BUPP09800 - 08 September 2009) The opioid-exposed newborn: Assessment and pharmacologic management

The infant exposed to opioids in utero frequently presents a challenge to the neonatal care provider in the assessment and treatment of symptoms of Neonatal Abstinence Syndrome (NAS) after birth. This review is intended to provide the healthcare professional with a brief review of current evidence and practical guidelines for optimal evaluation and pharmacologic management of the opioid-exposed newborn.

( BUPP09799 - 08 September 2009) Update in cancer pain

Cancer-related pain is a major issue of healthcare systems worldwide. The reported incidence, considering all stages of the disease, is 51%, which can increase to 90% in the advanced and terminal stages. For advanced cancer, pain is moderate to severe in about 40-50% and very severe or excruciating in 25-30% of cases. In 1986 the World Health Organization (WHO) published analgesic guidelines for the treatment of cancer pain based on a three-step ladder and practical recommendations. These guidelines serve as an algorithm for a sequential pharmacologic approach to treatment according to the intensity of pain as reported by the patient. The WHO analgesic ladder remains the clinical model for pain therapy. The experience gained since its implementation has shown that pain intensity at initial assessment is a significant predictor of pain management complexity and length of time to stable pain control. These and similar data suggest that a direct move to the third step of the WHO analgesic ladder is feasible. Despite great advances in the fields of pain management and palliative care, pain directly or indirectly associated with a cancer diagnosis remains significantly undertreated. The present paper reviews the current standard for cancer pain management and highlights new treatments and targeted techniques.

( BUPP09798 - 08 September 2009) Methadone-induced mortality in the treatment of chronic pain: Role of QT prolongation

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual's propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone- associated arrhythmia and to assess the feasibility of current risk mitigation strategies.

( BUPP09797 - 08 September 2009) The impact of neuropsychological functioning on adherence to HAART in HIV-infected substance abuse patients

This study assessed the frequency of neuropsychological impairment and its relationship to adherence in a sample of HIV-infected injection drug users (IDUs) in treatment. One hundred eight participants recruited between September 2006 and October 2008 completed psychodiagnostic and neuropsychological assessments and monitored HAART adherence over a 2-week period via the use of Medication Event Monitoring System (MEMS) electronic pill caps and self-report. Assessment of concurrent functioning included clinician-rated scales of depression and substance use severity, and a battery of neuropsychological tests. Findings from individual neuropsychological tests were converted to Z scores relative to standard norms and averaged to form a composite score (NPZ). NPZ was generally poor (mean/-1.505, standard deviation/1.120), with 76.9% of the sample being classified as highly impaired. Self-reported adherence was significantly higher than MEMS cap adherence. In contrast with previous studies, overall neuropsych logical functioning was not a significant predictor of electronically monitored or self-reported adherence. However, examiner-rated current global severity of substance use and delayed word list recall emerged as significant predictors of self-reported adherence. Additionally, estimated premorbid verbal intelligence emerged as a significant predictor of the discrepancy between electronically monitored and self-reported adherence. Given the extent of neuropsychological impairment in this sample, future studies should examine the degree to which the impact of neuropsychological impairment may moderate interventions for this population, and the extent to which skills to cope with neuropsychological problems may boost the potential efficacy of such interventions.

( BUPP09796 - 08 September 2009) Anaesthesia at remote location: Use of modified bain circuit (Mapleson D) at Kunri Christian Hospital (KCH).

Objective: To develop a safe general anaesthesia technique for remote areas with lack of facilities. Methods: Four types of anaesthesia techniques using TIVA and modified Bain circuit were planned. Monitoring facility was limited to manual sphygmomanometer, palpation of radial pulse and monitoring of colour of skin and blood. Depth of anaesthesia was assessed using EVANs, RPST scoring system. Patients were asked in recovery room for awareness. Results: Surgeries done were cesarean sections, laparotomies, gynaecological, urological, hernia and burn contractures. Six patients had RPST score of 5 or more and three patients in recovery room complained of awareness. Cost per Anaesthesia was Rs225. Conclusion: TIVA with modified Bain circuit provided effective anaesthesia in remote area at low cost.

( BUPP09795 - 08 September 2009) Comment on outcomes of DATA certification trainings for the provision of buprenorphine treatment in the veterans health administration

( BUPP09794 - 08 September 2009) Physician training is never a failure

( BUPP09793 - 08 September 2009) The kappa-opiate receptor impacts the pathophysiology and behavior of substance use

There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and behavior. As dopamine activity is upregulated through chronic substance use, kappa receptor activity, mediated through the peptide dynorphin, is upregulated in parallel. Dynorphin causes dysphoria and decreased locomotion, and the upregulation of its activity on the kappa receptor likely dampens the excitation caused by increased dopaminergic activity. This feedback mechanism may have significant clinical implications for treating drug dependent patients in various stages of their pathology.

( BUPP09792 - 08 September 2009) The pharmaceutical benefits scheme and implications for paediatric prescribing

Aims: To evaluate the impact of the Pharmaceutical Benefits Advisory Committee (PBAC) decisions on access to medicines listed on the Pharmaceutical Benefits Scheme (PBS) for children. Methods: We analysed all public summary documents from PBAC meetings from July 2005 to November 2006 and compared these with the Therapeutic Goods Administration (TGA) recommendations for children for the same medicine. Main outcome measures stratified by age, the total number of medicines for specific indications (accepted and rejected) by therapeutic class; estimated cost to the PBS per annum for each medicine recommended for listing; comparison of TGA-approved product information and PBS listing for recommended medicines. Results: Of the 102 medicines for specific indications considered by the PBAC, 7% (7/102) of submissions were for new paediatric indications. Most submissions (60%, 61/102) did not specify age for the PBS recommendation and were for conditions which only affect adults. Listings which specifically included children were more likely to have a positive PBAC recommendation. Of the six recommended medicines for children, four were estimated to cost between $10-30 million per year. There was fair concordance between PBS- and TGA-approved product information for age (kappa 0.21) but in 46%, PBAC recommendations were for age-unrestricted listing compared with adults-only use in the TGA-approved product information. Conclusion: Access to new subsidised medicines for children in Australia lags behind adults because most applications to the PBAC for new medicines are for conditions which only affect adults. PBS processes facilitate access for children to new medicines by avoiding age restrictions.

( BUPP09791 - 08 September 2009) General management in ambulatory medicine of osteoarthritis and crystal deposition diseases

( BUPP09790 - 08 September 2009) Opioid dependence treatment: Options in pharmacotherapy

The development of effective treatments for opioid dependence is of great importance given the devastating consequences of the disease. Pharmacotherapies for opioid addiction include opioid agonists, partial agonists, opioid antagonists, and alpha-2-adrenergic agonists, which are targeted toward either detoxification or long-term agonist maintenance. Agonist maintenance therapy is currently the recommended treatment for opioid dependence due to its superior outcomes relative to detoxification. Detoxification protocols have limited long-term efficacy, and patient discomfort remains a significant therapy challenge. Buprenorphine's effectiveness relative to methadone remains a controversy and may be most appropriate for patients in need of low doses of agonist treatment. Buprenorphine appears superior to alpha-2 agonists, however, and office-based treatment with buprenorphine in the USA is gaining support. Studies of sustained-release formulations of naltrexone suggest improved effectiveness for retention and sustained abstinence; however, randomized clinical trials are needed.

( BUPP09789 - 08 September 2009) Swedish use and misuse of the Dole & Nyswander treatment

For 23 years (1966-1989) Sweden had a National Methadone Maintenance treatment of opioid addicts, delivering 70-80 % vocationally rehabilitated patients, taxpaying citizens, with no drug abuse and a great reduction in mortality rates. This treatment was changed in 1990 into a short-term methadone program, resulting in numerous discharges for disciplinary reasons, a high mortality rate among the newly discharged and poor rehabilitation results. Politically, the short-term treatment is called "restrictive", which is regarded as commendable by the Swedish mass media.

( BUPP09788 - 08 September 2009) Methadone-treated patients after switching to buprenorphine in residential therapeutic communities: An addiction-specific assessment of quality of life

Background: evaluating the addiction-related quality of life of a sample of opiate-dependent patients in treatment with buprenorphine in therapeutic communities after a switch from methadone. Design and participants: observational (descriptive), open longitudinal prospective study ('before-after' design); a non-probabilistic consecutive sampling procedure was used. After their admission to five therapeutic communities, a sample of patients in treatment with methadone switched to buprenorphine induction (Subutex /sup R/ ). When considered appropriate, a gradual reduction in buprenorphine dose was begun, so as to bring it down to 0 mg within 16 weeks. The patients met DSM-IV-TR criteria for Opiate Dependence, were adults and had signed an informed consent release. All the patients were evaluated at three times; baseline assessment (Mo), after one month of treatment (M1) and after three months (M2). The study protocol was approved by the Andalusian Regional Committee for Clinical Trials, and was conducted in accordance with the Declaration of Helsinki. Measurements: The Objective Opiate Withdrawal Scale (OOWS), the Subjective Opiate Withdrawal Scale (SOWS), the Health Related Quality of Life for Drug Abusers Test (HRQoLDA Test), the General Health Questionnaire (GHQ-28), the Opiate Treatment Index (OTI) and the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). Results: A total of 119 patients met the selection criteria. Of these, 46 subjects transferred from methadone to buprenorphine, while the remaining 73 decided to stay on their methadone maintenance treatment. A statistically significant increase was observed in scores on the quality of life scale after one month of treatment with buprenorphine (from 0.62 to 0.99; p<0.05) and at three months (from 0.43 to 0.77; p<0.05). One month after the start of treatment, statistically significant improvements were observed in "general state of health" (from 10.7 to 4.3; p<0.05), in "severity of dependence" (11.7 to 4.1; p<0.05) and in "psychological adjustment" (from 7.5 to 3.7; p<0.05). At the three-month assessment, statistically significant differences were again observed in the same variables, except for "psychological adjustment". Conclusions: the patients who were in treatment with methadone after their admission to a therapeutic community and switched to buprenorphine were able to experience ongoing improvement in their quality of life.

( BUPP09787 - 08 September 2009) Substitution therapy. A new problem of biomedical ethics and medical law

Substitution maintenance therapy can be judged from different perspectives focused on its medical, legal, social, economic and ethical aspects. A subject that attracts special attention is the ethical side of substitution therapy. In the opinion of the opponents of substitution maintenance therapy, there are several key ethical problems that make this therapy immoral. From our point of view, it is unethical to refuse a patient this kind of help (substitution therapy). Substitution therapy for opioid dependence should be seen as the most ethical and humane of all methods. The absence of substitution therapy in the Russian Federation puts Russian patients in an awkward position.

( BUPP09805 - 07 September 2009) Diversion of Buprenorphine/Naloxone Coformulated Tablets in a Region with High Prescribing Prevalence

The purpose of this article was to characterize practices of buprenorphine/naloxone (B/N) diversion in a region with a high prescribing prevalence. A cross-sectional, open-ended survey was administered to individuals entering opioid addiction treatment programs in two New England states. The authors obtained formative information about the knowledge, attitudes, beliefs, practices, and street economy of B/N diversion. The authors interviewed 51 individuals, 49 of which were aware of B/N medication. Of that number, 100% had diverted B/N to modulate opiate withdrawal symptoms arising from attempted "self-detoxification, " insufficient funds to purchase preferred illicit opioids, or inability to find a preferred source of drugs. Thirty of 49 (61%) participants obtained the illicit drug from an individual holding a legitimate prescription for B/N. A high proportion of individuals in the study locations who sought treatment for opioid addiction self-reported the purchase and use of diverted B/N. The diversion of B/N may be minimized by modifying educational, treatment, monitoring, and dispensing practices.

( BUPP09804 - 07 September 2009) What Is Diversion of Supervised Buprenorphine and How Common Is It?

This study aimed to identify the practices of community pharmacists regarding the provision of buprenorphine for opioid dependence and explore behaviors pharmacists considered indicative of buprenorphine diversion. A cross-sectional survey of 669 community pharmacists authorized to dispense buprenorphine or methadone was conducted in New South Wales and Victoria, Australia. There was wide variation between pharmacies in the level of supervision provided during supervised buprenorphine dosing and a lack of clarity between pharmacists regarding what behaviors are examples of buprenorphine diversion. Compared to New South Wales, a higher proportion of Victorian pharmacists detected I or more episodes of buprenorphine diversion in the past year (65% vs. 28%; p < .001) and in the past month (20% vs. 7%; p < .001). Detection of buprenorphine diversion was associated with the administration of crushed tablets (odds ratio = 2.77), broken tablets (odds ratio = 2.69), and having more buprenorphine clients (odds ratio = 1.24). Future research investigating the prevalence of buprenorphine diversion should include a clear definition of what behaviors constitute diversion.

( BUPP09803 - 07 September 2009) Distribution of Saquinavir, Methadone, and Buprenorphine in Maternal Brain, Placenta, and Fetus During Two Different Gestational Stages of Pregnancy in Mice

Efflux transporters such as P-glycoprotein (P-gp) play a critical role in the maternal-to-fetal and blood-to-brain transfer of many drugs. Using a mouse model, the effects of gestational age on P-gp and MRP expression in the placenta and brain were evaluated. P-gp protein levels in the placenta and brain were greater at mid-gestation (gd 13) than late-gestation (gd 18). Likewise, brain MRP1 levels were greater at mid-gestation, whereas, placental levels were greater at late-gestation. To evaluate these effects on drug disposition, concentrations of (H-3)saquinavir, (H-3)methadone, (H-3) buprenorphine, and the paracellular marker, (C-14)mannitol were measured in plasma, brain, placenta, and fetal samples after i.v. administrations to nonpregnant and pregnant mice. Following i.v. administration, (H-3)saquinavir placenta-to-plasma and fetal-to-plasma ratios were significantly greater in late-gestation mice versus mid-gestation. Furthermore, late-gestation mice experienced significant increases in the (H-3)saquinavir and (H-3)methadone brain-to-plasma ratios 60 min after dosing relative to mid-gestation (p<0.05). No significant differences were observed in these tissue-to-plasma ratios for buprenorphine or mannitol. Repeated dosing (three doses, once daily) decreased the differential uptake of (H-3) saquinavir in brain but potentiated it in the fetus. These results suggest that differential expression of P-gp and possibly MRP1 contributes to the gestational-induced changes in brain and fetal uptake of saquinavir.

( BUPP09802 - 07 September 2009) Misuse of Psychotropic Medications in a Population of Subjects Held for Custody in the City of Paris

Misuse of Psychotropic Medications in a Population of Subjects Held for Custody in the City of Paris. Objective: Identify which psychotropic medications are misused and peddled in a population of subjects held for custody in the city of Paris. Methods: Subjects held for custody in the Medico-Legal Emergency Unit of the Paris Hotel-Dieu hospital were examined and interrogated between March 2006 and March 2007 in order to assess their consumption of psychotropic medications. Results: Sixty one of the 659 subjects (9.2%) interrogated were included in the study. Their main source of psychotropic medications was street dealers. The most frequently misused psychotropic agent was clonazepam (42.6%), followed by buprenorphine (30.65%) and methadone (21.3%). Clonazepam appears to have replaced flunitrazepam which now only comes in fifth position (11.4%). The finding that methadone is the third most misused drug should lead us to query this medication's dispensing method. Conclusions: Practitioners should remain vigilant regarding the potential misuses of psychotropic medications, particularly since they may induce severe undesirable events (addiction, neurological disorders, possibly lethal overdosage).

( BUPP09801 - 07 September 2009) Effects of Tamsulosin on Lower Urinary Tract Symptoms due to Double-J Stent: A Prospective Study

Objective: To evaluate the effect of tamsulosin in improving symptoms in, and quality of life of, patients with indwelling double-J ureteral stents. Patients and Methods: This prospective study lasted from January 2005 to February 2007. All the patients with symptomatic lower ureteral stones with <15 mm diameter were enrolled in this prospective study, and were prospectively randomized (programs Plus 1.0 and Plus 2.10; S-Plus, Taiwan) into two groups. There was a total of 146 patients with insertion of a double-J ureteral stent after ureteroscopic stone removal. In group 1, 71 patients were enrolled and they received placebo for 2 weeks. Group 2 included 75 patients who received 0.4 mg of tamsulosin, once daily for 2 weeks. All patients completed a 10-cm linear visual analogue scale (VAS) for evaluating pain and voiding flank pain, and irritative domain of the International Prostate Symptom Scale (IPSS) before double-J stent removal 2 weeks later. Results: The mean VAS for pain was 4.01 in group 1, 1.52 in group 2, and for voiding flank pain it was 3.3 in group 1 and 1.93 in group 2. The mean score of frequency in IPSS was 3.7 in group 1 and 1.55 in group 2. The mean score of urgency in IPSS was 3.82 in group 1 and 1.43 in group 2. The mean score of nocturia in IPSS was 2.01 in group 1 and 0.65 in group 2. The mean score of quality of life in IPSS was 4.21 in group 1 and 1.6 in group 2. All p values are <0.0001 with statistical significances. Conclusions: Tamsulosin improved a subset of stent-related urinary symptoms, pain, voiding flank pain and quality of life.

( BUPP09786 - 07 September 2009) New approaches in the treatment of opioid dependency during the pregnancy

( BUPP09785 - 07 September 2009) Expanded access to seps and other harm reduction measures in France: Commentaries on des Jarlais et al. (2009)

( BUPP09784 - 07 September 2009) The Leeds evaluation of efficacy of detoxification study (LEEDS) prisons project study: Protocol for a randomised controlled trial comparing methadone and buprenorphine for opiate detoxification

Background: In the United Kingdom (UK), there is an extensive market for the class 'A' drug heroin and many heroin users spend time in prison. People addicted to heroin often require prescribed medication when attempting to cease their drug use. The most commonly used detoxification agents in UK prisons are currently buprenorphine and methadone, both are recommended by national clinical guidelines. However, these agents have never been compared for opiate detoxification in the prison estate and there is a general paucity of research evaluating the most effective treatment for opiate detoxification in prisons. This study seeks to address this paucity by evaluating the most routinely used interventions amongst drug users within UK prisons. Methods/Design: This study uses randomised controlled trial methodology to compare the open use of buprenorphine and methadone for opiate detoxification, given in the context of routine care, within three UK prisons. Prisoners who are eligible and give informed consent will be entered into the trial. The primary outcome will be abstinence status eight days after detoxification, as determined by a urine test. Secondary outcomes will be recorded during the detoxification and then at one, three and six months post-detoxification.

( BUPP09817 - 15 September 2009) The In Vivo Response of Novel Buprenorphine Metabolites, M1 and M3, to Antiretroviral Inducers and Inhibitors of Buprenorphine Metabolism

Buprenorphine metabolism was recently expanded by in vitro identification of a number of hydroxylated metabolites. The identification of two, M1 and M3, in urine suggests that they may be quantitatively significant metabolites. To further understand the in vivo regulation of this mode of metabolism, we evaluated 24-hr urine from subjects (10 per treatment group) on buprenorphine alone or with the antiretroviral agents: efavirenz, delavirdine, nelfinavir, ritonavir, and lopinavir/ritonavir. Quantitative analysis for buprenorphine and traditional metabolites and semi-quantitative analysis of M1 and M3 in urine were performed by liquid chromatography-electrospray ionization-tandem mass spectrometry. The renal clearance of buprenorphine and traditional metabolites were similar for all treatments except for lopinavir/ritonavir, suggesting that urine amounts of M1 and M3 would adequately reflect systemic changes (except lopinavir/ritonavir). Efavirenz decreased M1 and increased M3 consistent with its ability to induce cytochrome P450 (CYP) 3A. Delavirdine increased M1 and decreased M3 consistent with its ability to inhibit CYP3A. Both nelfinavir and ritonavir decreased both M1 and M3, consistent with their ability to inhibit CYP3A and 2C8. These results provide further information on the in vivo response of novel secondary metabolites of buprenorphine to metabolic inhibitors and inducers.

( BUPP09816 - 15 September 2009) Kappa-opioid ligands in the study and treatment of mood disorders

The biological basis of mood is not understood. Most research on mood and affective states has focused on the roles of brain systems containing monoamines (e.g., dopamine, norepinephrine, serotonin). However, it is becoming clear that endogenous opioid systems in the brain may also be involved in the regulation of mood. In this review, we focus on the potential utility of kappa-opioid receptor (KOR) ligands in the study and treatment of psychiatric disorders. Research from our group and others suggests that KOR antagonists might be useful for depression, KOR agonists might be useful for mania, and KOR partial agonists might be useful for mood stabilization. Currently available KOR agents have some unfavorable properties that might be addressed through medicinal chemistry. The development of KOR-selective agents with improved drug-like characteristics would facilitate preclinical and clinical studies designed to evaluate the possibility that KORs are a feasible target for new medications

( BUPP09815 - 15 September 2009) Transverse shifting of the esophagus according to the patient's position helped achieve a safe and successful pulmonary vein isolation procedure

Although the incidence of causing an atrioesophageal fistula during pulmonary vein isolation is very low, this type of injury results in a very high mortality rate. To prevent this complication, keeping a safe distance from the esophagus to the ablation lesion is a simple but safe method. We report a case in which we were able to shift the position of the esophagus by positioning the patient in a lateral posture in order to keep the esophagus at a safe distance from the pulmonary vein antrum, resulting in performance of a safe and successful pulmonary vein antrum isolation.

( BUPP09814 - 15 September 2009) Anesthesia for Endoscopy in Small Animals

This article discusses considerations for general anesthesia for various endoscopic procedures in small animals. Specific drug and monitoring recommendations are made. Special physiologic concerns of individual procedures affecting the anesthetized patient are discussed.

( BUPP09813 - 15 September 2009) Substitution without border. Methadone and subutex� prescriptions across the Belgium-France border

Mobility of persons and goods in cross-border zones is frequent, for multiple purposes (such as for tobacco, fuel, chocolate or medication purchase). In the context of substitution treatments prescriptions for opiate dependence (methadone and Subutex�), patients' flows of varying intensity transit in both directions along the cross-border zones of North of France and West Hainaut in Belgium. The border, turning point between two territories, is also the turning point between two distinctive legislative worlds. This difference between legislations also offers the main reason for the above-mentioned mobility or flows. This paper addresses those cross-border flows and differences in legislation.

( BUPP09812 - 15 September 2009) Bad use, but use

The nursing of drug users treated by opiate substitute medicines seems to put in an awkward position the medical model, which recommends a strict compliance with the treatments, and the psychoanalytic approach, which specifies that the misuse of opiate substitute medicines may form a part of the patient's uniqueness in his drug user's evolution. In the nowadays context, the risk of inconsiderate substitute users being branded by nursing staff is that the therapeutic relationship could be called into question. It may be appropriate to put these "bad practices" into perspective in order to better understand the sense drug users under substitution treatment want or can give to them.

( BUPP09811 - 15 September 2009) Use and misuse of substitution medicines and doping substances: A literature review

The resources compiled in this article are dedicated to the use and the misuse of doping and substitution products (4-methyl-thioamphetamine and buprenorphine). They include french books and scientific articles on those topics, some english literature and a selection of internet websites where papers can be accessed for free.

( BUPP09810 - 15 September 2009) Erratum: Very long acting buprenorphine for opioid dependence (Journal of Pain and Palliative Care Pharmacotherapy 21:1).

( BUPP09809 - 15 September 2009) A comparative study of epidural tramadol hydrochloride and epidural buprenorphine hydrochloride for postoperative analgesia following combined spinal epidural anaesthesia

Objective: The study was conducted to compare the efficacy of postoperative analgesia of epidural tramadol hydrochloride and buprenorphine hydrochloride. Methods: One hundred patients of either sex of ASA I and II who were to undergo routine lower abdominal and lower limb surgeries under combined spinal and epidural analgesia (CSEA) were chosen randomly for the study in the department of Anaesthesiology, Regional Institute of Medical Sciences(RIMS), Imphal and divided into two groups of 50 patients each - Group I, to receive hydrochloride while Group II received 150mug of epidural buprenorphine hydrochloride. Results: The pain scores (VAS and verbal rating scores) at different corresponding time interval was better (lower) and statistically highly significant with p value<0.001in Group II as compared with Group I. The onset of analgesic action was significantly faster (P<0.001) in Group II (8.00�0.00 mins) than in Group I(9.96�0.50 mins). Group II(14.55� 1.11hrs) also had longer duration of analgesia as compared with Group I(11.17�1.21hrs) which was found to be highly statistically significant (p- alue< 0.001). Conclusion: Epidural buprenorphine hydrochloride offers superior analgesic effect/quality than epidural tramadol hydrochloride for relieving post-operative pain in lower abdominal and lower limb surgeries.

( BUPP09808 - 15 September 2009) Buprenorphine improves the efficacy of bupivacaine in nerve plexus block: A double blind randomized evaluation in subclavian perivascular brachial block

Background: Studies examining the benefit of adding analgesic to brachial plexus block have produced mixed results. Although the mechanism of action of these analgesics remains unclear, buprenorphine have been used successfully in brachial block for prolonged postoperative pain relief. We compared the onset, quality and duration of analgesia produced by bupivacaine, either alone or combined with buprenorphine. Patients & Methods: A prospective, randomized double blind study was conducted on forty patients scheduled to undergo surgery for upper limb under Supraclavicular subclavian perivascular brachial plexus block (SSPB). Group-I (control group) (n=20) patients received 30 ml 0.3% bupivacaine+ 1 ml saline and intramuscular 1ml drug (3mugkg /sup -1/ buprenorphine + saline to make volume= 1 ml). Group-II (study group) (n=20) patients received 30 ml 0.3% bupivacaine + 1 ml study drug (3mugk.kg-1 bupivacaine + saline to make volume= 1 ml ) and 1 ml of intramuscular injection of saline. Results: In Group-I the onset time for motor block was 4.05+0.944 min. and sensory block was 6.65+ 1.182 min. Group-II the onset time for motor block was 3.75+1.208 min. and sensory block was 4.25+1.25 min. This difference was not significant (p<0.404) for sensory and (p<0.152) for motor block. The mean duration of satisfactory analgesia was 331.2+33.54 minutes in Group-I and 680.6+86.27 minutes in Group-II the difference in duration between two groups was significant (p<0.0001). The mean duration of motor block was not significant, 309+26.1 minutes in Group-I and 329+ 28.4 minutes in Group-II (p<0.352). Conclusion: We conclude that the addition 3 mugkg /sup -1/ buprenorphine to 0.3% bupivacaine for perivascular brachial block in upper limb orthopedic surgery increase the time for complete sensory block. It improves the quality of block and lengthens the duration of analgesia without affecting the duration of motor block.

( BUPP09807 - 15 September 2009) Influences of opioids and nanoparticles on in vitro wound healing models

For efficient pain reduction in severe skin wounds, topical opioids may be a new option - given that wound healing is not impaired and the vehicle allows for slow opioid release, since long intervals of painful wound dressing changes are intended. We investigated the influence of opioids on the wound healing process via in vitro models, migration assay and scratch test. In fact, morphine, hydromorphone, fentanyl and buprenorphine increased the number of migrated HaCaT cells (spontaneously transformed keratinocytes) twofold. In the scratch test, morphine accelerated the closure of a monolayer wound (scratch). As possible slow release application forms are nanoparticulate systems like solid lipid nanoparticles (SLN) and dendritic core-multishell (CMS) nanotransporters, we evaluated the effect of unloaded nanoparticles on HaCaT cell migration, too. CMS nanotransporters did not inhibit migration, SLN even enhanced it (twofold). Applying morphine plus unloaded nanoparticles reduced morphine effects possibly due to uptake into CMS nanotransporters and adsorption to the surface of SLN. In contrast to SLN, TGF-beta1 was taken up by CMS nanotransporters, too. Both nanoparticles are tolerable by skin and eye as derived from Episkin-SM /sup TM/ skin irritation test and HET-CAM assay. No acute toxic effects were observed either. In conclusion, opioids as well as the investigated nanoparticulate carriers conform the essential conditions for topical pain reduction.

( BUPP09806 - 15 September 2009) Opioid induced hyperalgesia: clinical implications for the pain practitioner

Opioids have been and continue to be used for the treatment of chronic pain. Evidence supports the notion that opioids can be safely administered in patients with chronic pain without the development of addiction or chemical dependency. However, over the past several years, concerns have arisen with respect to administration of opioids for the treatment of chronic pain, particularly non-cancer pain. Many of these involve legal issues with respect to diversion and prescription opioid abuse. Amongst these, opioid induced hyperalgesia (OIH) is becoming more prevalent as the population receiving opioids for chronic pain increases. OIH is a recognized complication of opioid therapy. It is a pro-nocioceptive process which is related to, but different from, tolerance. This focused review will elaborate on the neurobiological mechanisms of OIH as well as summarize the pre-clinical and clinical studies supporting the existence of OIH. In particular, the role of the excitatory neurotransmitter, N-methyl-D-aspartate appears to play a central, but not the only, role in OIH. Other mechanisms of OIH include the role of spinal dynorphins and descending facilitation from the rostral ventromedial medulla. The links between pain, tolerance, and OIH will be discussed with respect to their common neurobiology. Practical considerations for diagnosis and treatment for OIH will be discussed. It is crucial for the pain specialist to differentiate amongst clinically worsening pain, tolerance, and OIH since the treatment of these conditions differ. Tolerance is a necessary condition for OIH but the converse is not necessarily true. Office-based detoxification, reduction of opioid dose, opioid rotation, and the use of specific NMDA receptor antagonists are all viable treatment options for OIH. The role of sublingual buprenorphine appears to be an attractive, simple option for the treatment of OIH and is particularly advantageous for a busy interventional pain practice.

( BUPP09828 - 21 September 2009) Pediatric analgesia

Introduction: Children suffer pain due to various causes. Acute pain is usually due to trauma, infectious diseases or following operations, in which pain occurs as a side effect. Chronic pain is usually headache or stomachache. Trauma is the main cause of pain in the particular case of emergency medicine. Methods: Evaluation of existing literature, with a particular focus on evidence-based recommendations and guidelines. Results: Acute pain of whatever origin should be treated as soon as possible. If necessary, simple observation or self-evaluation scales can be used to help assess the degree of pain. Children with chronic pain should be treated by specialized teams. The most commonly used analgetics are paracetamol, ibuprofen and morphine. Ibuoprofen appears to be more effective than paracetamol and to have fewer side effects. In emergency medicine, the resources available must be used. The origin of the pain usually requires the administration of opioids or ketamine.

( BUPP09827 - 21 September 2009) Opioid-based multimodal care of patients with chronic pain: Improving effectiveness and mitigating risks

( BUPP09826 - 21 September 2009) The burden of the nonmedical use of prescription opioid analgesics

An increase in the prescribing of opioids over the past several years often has been perceived as the primary reason for the increase in the nonmedical use of prescription opioids. Determining the prevalence of this illicit use has been difficult, because of varied methodologies and terminologies that are used to estimate the number of people directly contributing to or affected by this burden. Despite these discrepancies, the findings from several nationally recognized surveys have demonstrated that the prevalence of nonmedical prescription opioid use is indeed significant and has been increasing in recent years. The considerable burden on society imposed by misuse and abuse of these drugs is largely due to the monetary costs associated with nonmedical use (e.g., strategies implemented to prevent or deter abuse, treatment programs for misusers, etc.), decreased economic productivity, and the indirect effect on access to appropriate health care. However, using various nonpharmacologic and pharmacologic approaches to treat patients who use prescription opioids illicitly can decrease its overall prevalence and associated impact, with the development of novel opioid formulations designed to reduce nonmedical use providing valuable clinical tools as part of an overall risk management program. In addition, prescription monitoring programs are a prevalent drug control system designed to identify and address abuse and diversion of prescription medications, including opioids. Such resources, along with an accurate understanding of the problem, extend greater hope that the public health challenge of nonmedical prescription opioid use can be ffectively mitigated.

( BUPP09825 - 21 September 2009) Update on abuse-resistant and abuse-deterrent approaches to opioid formulations

The number of opioid analgesic prescriptions has increased since 1990. Opioids are being prescribed for longer periods of time for both cancer- and noncancer-associated moderate to severe chronic pain. Concurrent with the increased prescribing of opioids has been an increase in their diversion from prescribed use and their abuse; frequently, this abuse occurs after the opioid analgesic has been physically or chemically manipulated to increase the concentration or bioavailability of the active ingredient. Formulations of opioids have been designed to resist the extraction of the active opioid from prescribed products through the incorporation of physical barriers or to deter the reinforcing effects of opioids through the incorporation of antagonists or other ingredients that only become active when the analgesic is used improperly. However, none of these formulations are currently commercially available in the United States. This paper describes the formulations now under development and their potential clinical utility and impact on society. These emerging opioid formulations designed to reduce the risk of misuse and/or abuse may be useful to physicians in meeting the important goals of maximizing pain relief and minimizing prescription opioid abuse.

( BUPP09824 - 21 September 2009) Safe and probably safe drugs in acute hepatic porphyria

Acute porphyrias are caused by enzyme defects along the heme synthesis pathway. Patients usually present with abdominal pain, impaired intestinal motility, neurological and psychiatric symptoms, hypertension, tachycardia, hyponatriemia and reddish urine. This article gives an overview over drugs that are recommended in patients with acute hepatic porphyrias and represents a compilation of four so far existing lists.

( BUPP09823 - 21 September 2009) Equipotent doses to switch from high doses of opioids to transdermal buprenorphine

INTRODUCTION: The aim of this study was to evaluate the equianalgesic ratio of transdermal buprenorphine (TD BUP) with oral morphine and TD fentanyl in a sample of consecutive cancer patients receiving stable doses of 120-240 mg of oral morphine or 50-100 microg of TD fentanyl, reporting adequate pain and symptom control. MATERIALS, METHODS, AND RESULTS: Patients receiving daily stable doses of opioids for more than 6 days, with no more than two doses of oral morphine (20 and 40 mg, respectively) as needed, were switched to TD BUP using a fentanyl-BUP ratio of 0.6:0.8 and an oral morphine-BUP ratio of 70:1. Opioid doses, pain and symptom intensity, global satisfaction, and number of breakthrough medication were recorded before switching (T0) , 3 days after (T3), and 6 days after (T6). Eleven patients were recruited in a period of 1 year, and data were complete for ten patients. The mean age was 61.6 (SD 9.5), and five patients were males. No significant changes in pain and symptom intensity were found, except improvement in reported constipation (p = 0.014), as well as in global satisfaction with the analgesic treatment. No significant changes in breakthrough pain medication were observed. CONCLUSION: The results of this study suggest that stable patients receiving relatively high doses of oral morphine or TD fentanyl could be safely switched to TD BUP, by using a ratio of 70:1 and 0.6:0.8, respectively, maintaining the same level of Analgesia.

( BUPP09822 - 21 September 2009) Optimized surgical techniques and postoperative care improve survival rates and permit accurate telemetric recording in exercising mice

BACKGROUND: The laboratory mouse is commonly used as a sophisticated model in biomedical research. However, experiments requiring major surgery frequently lead to serious postoperative complications and death, particularly if genetically modified mice with anatomical and physiological abnormalities undergo extensive interventions such as transmitter implantation. Telemetric transmitters are used to study cardiovascular physiology and diseases. Telemetry yields reliable and accurate measurement of blood pressure in the free-roaming, unanaesthetized and unstressed mouse, but data recording is hampered substantially if measurements are made in an exercising mouse. Thus, we aimed to optimize transmitter implantation to improve telemetric signal recording in exercising mice as well as to establish a postoperative care regimen that promotes convalescence and survival of mice after major surgery in general. RESULTS: We report an optimized telemetric transmitter implantation technique (fixation of the transmitter body on the back of the mouse with stainless steel wires) for subsequent measurement of arterial blood pressure during maximal exercise on a treadmill. This technique was used on normal (wildtype) mice and on transgenic mice with anatomical and physiological abnormalities due to constitutive overexpression of recombinant human erythropoietin. To promote convalescence of the animals after surgery, we established a regimen for postoperative intensive care: pain treatment (flunixine 5 mg/kg bodyweight, subcutaneously, twice per day) and fluid therapy (600 microl, subcutaneously, twice per day) were administrated for 7 days. In addition, warmth and free access to high energy liquid in a drinking bottle were provided for 14 days following transmitter implantation. This regimen led to a substantial decrease in overall morbidity and mortality. The refined postoperative care and surgical technique were particularly successful in genetically modified mice with severely compromised physiological capacities. CONCLUSION: Recovery and survival rates of mice after major surgery were significantly improved by careful management of postoperative intensive care regimens including key supportive measures such as pain relief, administration of fluids, and warmth. Furthermore, fixation of the blood pressure transmitter provided constant reliable telemetric recordings in exercising mice.

( BUPP09821 - 21 September 2009) Buprenorphine withdrawal in a toddler

( BUPP09820 - 21 September 2009) ANTI-INFLAMMATORY ADJUVANT IMPROVES SURVIVAL DURING RESUSCITATION

The Authors characterized the effects of opioids (tramadol, buprenorphine, morphine) in a cecal ligation and puncture (CLP) mice model of sepsis. Cell counts in the blood were lower for high dose tramadol compared to buprenorphine. Differences in TNF-alpha in the lungs and peritoneum were seen for buprenorphine compared to either morphine or high dose tramadol. There were no differences in WBC counts for any treatment group compared to control.

( BUPP09819 - 21 September 2009) ANALYSIS OF WHITE MATTER DAMAGE IN THE RAT SPINAL CORD FOLLOWING INJURY

( BUPP09818 - 21 September 2009) Incorrect comments regarding the use of butorphanol-medetomidine as a premedicant in cats

( BUPP09841 - 28 September 2009) Percutaneous imaging-guided ablation therapies in the treatment of symptomatic bone metastases: Preliminary experience

The treatment of pain in bone metastases is currently multidisciplinary. Among the various therapies, local radiotherapy is the gold standard for pain palliation from single metastasis, even though the maximum benefit is obtained between 12 and 20 weeks from initiation. In carefully selected patients, several ablation therapies achieve this objective in 4 weeks. The purpose of this study was to assess the technical success, effectiveness and possible complications of percutaneous ablation therapies in patients with symptomatic bone metastases. From November 2003 to May 2008, ten ablation treatments were performed in ten patients with acute pain from metastatic bone lesions. Patient selection and choice of the most appropriate ablation treatment was made based on lesion characteristics. Three patients were treated with radiofrequency, one with plasma-mediated radiofrequency, two with plasma-mediated radiofrequency and cementoplasty, three with radiofrequency and cementoplasty and one with microwave. Assessments were based not only on imaging but also on the visual analogue scale (VAS) score for determining pain and on changes in morphine-equivalent doses. In both cases, 3-month follow-up showed a statistically significant reduction of pain. In no case did local complications occur either during or after treatment. Only one patient treated with radiofrequency (1/9, 11%) developed low-grade fever and general malaise during the 6 days following the procedure, compatible with a post-radiofrequency syndrome, which was treated with acetaminophen (paracetamol) only and resolved on day 7. Percutaneous ablation therapies represent a safe and valuable alternative for treating localised pain from single bone metastasis, providing rapid (4-week) relief of symptoms and a significant reduction in morphine doses. This contributes to improving the quality of life of patients with metastatic disease.

( BUPP09840 - 28 September 2009) Clinical trial literacy among injecting drug users in Sydney, Australia: A pilot study

This pilot study examined knowledge, understanding and perceived acceptability of key methodological concepts in clinical trials among injecting drug users (IDUs) in Sydney, Australia. Participants were clinical trial-experienced (n = 17) and trial-naive (n = 99) IDUs recruited from community needle and syringe programs, and through institutions involved in clinical trials with IDU participants. Cross-sectional data were collected via a study-specific interviewer- administered survey. Following detailed verbal explanations, higher proportions of trial-experienced than trial-naive participants demonstrated an understanding of all clinical trial concepts assessed, including single blinding (94% versus 60%); placebo (94% versus 49%); equipoise (71% versus 60%); comparison (59% versus 46%); randomisation (59% versus 21%); and double blinding (47% versus 3%). Multivariate analyses indicated a better understanding among trial-experienced participants. Participants who demonstrated an understanding of 'placebo' and 'double blinding' were significantly more likely to perceive these concepts to be acceptable than those who did not. Results indicate the need for targeted education programs that adequately inform IDUs about clinical trial concepts prior to recruitment to a clinical trial, and support adaptations of informed consent procedures to ensure trial participants' comprehensive understanding of methodologies and their implications.

( BUPP09838 - 28 September 2009) Opiate replacement therapy in France

France has been implementing a harm reduction based policy toward drug users, mainly based on opiate replacement therapy. The opiate substitution treatment appeared at the beginning of 1990's and was implemented at a large scale to avoid the spread of HIV among injecting drug users and to reduce the large number of drug abuse related deaths. The 15-year experience is conclusive when access to health care had been greatly improved. Moreover, this policy has made a considerable impact on substance users' health in general. It has contributed to the reduction of fatal overdoses, almost brought an end to HIV transmission through needle-sharing; the numbers of offenders for heroine use dramatically decreased. In the same way, adverse consequences occurred, mainly linked to the misuse of buprenorphine. Policy measures have been set up at the end of the consensus conference on June 2004: a national health insurance action plan - aiming at reducing the volume of diverted medicines -, a working group dedicated to opiate replacement therapy on behalf of the Ministry of Health (commission on addiction), regulatory measures to reduce the misuse of opiate maintenance medicines, risk management plan of the French Medicines Agency. The Government Action Plan 2008-11 on drugs and drug addiction provides for proposals aiming at reducing the diversion and the misuse of medicines and protecting their therapeutic value. French advocacy in favour of opiate replacement therapy remains a national and international priority.

( BUPP09837 - 28 September 2009) Opioid substitution therapy in France: A physician's overview

Widespread diffusion of opiate substitution therapy (OST), particularly with high-dose buprenorphine (BHD) has led to a considerable decline in the number of intravenous drug users (IVDU) in France, in parallel with a reduction in the volume of over-the-counter syringe sales, the number of overdoses, the use of heroin, and the associated delinquency, and HIV prevalence. OST also plays a crucial role in improving observance of anti-HIV, and anti-HCV treatments as well as an improvement in the quality-of-life of IVDUs. But fraudulent behavior (resellers, dealers), and misuse (sniff, inhalation, injection for BHD, fractionated or excessive doses, association with other psychoactive products for BHD and methadone) have also developed. Misuse is related either to the difficult, and progressive adhesion process during the early phases of OST or to a situation of therapeutic failure after long-term appropriate OST. Unless access to care is facilitated with new therapeutic options capable of matching the benefits of OST, healthcare professionals will have little to offer in the event of therapeutic failure.

( BUPP09836 - 28 September 2009) Opiate substitution: The users' point of view

The needs of drug users for substitution therapy and drug-use-related care can vary greatly, a source of conflict between users and health care professionals and sometimes generating dysfunction of the health care system. For example, in France the lack of injection formulations for substitution therapy has led users to inject their substitution product (Subutex /sup �/ or Skenan /sup �/ ) creating a bogus relationship with the pharmacist or physician who do not know how they should react. Beliefs held by health care professionals and the lack of drug abuse training in the pharmacy and medicine curricula can also lead to a dangerous situation for users: physicians may prescribe a dose too low for substitution with the risk of pushing the user into the black market to search for a complement. We detail here the way users would like to use substitution, focusing on the points where they are in agreement or disagreement with health care professionals. We explain why, in our opinion, it is fundamental to take into consideration the users' point of view.

( BUPP09835 - 28 September 2009) New antidepressant drugs: Beyond monoaminergic mechanisms

( BUPP09834 - 28 September 2009) An overview of principles of effective treatment of substance use disorders and their potential application to pregnant cigarette smokers

Cigarette smoking remains a leading preventable cause of poor pregnancy outcomes and infant morbidity and mortality. Despite three decades of research encompassing more than 60 trials and 20,000 pregnant women, cessation rates produced by existing interventions are often low (<20%), especially among socioeconomically disadvantaged women. This has led to a call for the development and testing of novel interventions. One strategy for identifying novel interventions for pregnant smokers is to examine efficacious interventions for other types of substance use disorders (SUDs). Pregnant smokers share many sociodemographic similarities with other sub-populations of individuals with SUDs, suggesting that interventions efficacious with the latter may also benefit the former. The National Institute on Drug Abuse's guide, "Principles of Drug Addiction Treatment: A Research-based Guide", presents empirically validated principles of effective treatments for other SUDs. The present report enumerates these principles, briefly describes some of the empirical evidence supporting them, and explores their potential application to the treatment of smoking during pregnancy. Overall, the results of this exercise suggest much promise for enhancing treatment outcomes for pregnant smokers by borrowing from and extending what has been learned with other populations with SUDs.

( BUPP09833 - 28 September 2009) A patient's journey: Persistent pain

( BUPP09832 - 28 September 2009) Chronic pain, breakthrough pain: Challenges

This article focuses on three key challenges for the management of chronic pain and breakthrough pain for cancer and non cancer patients. The first question concerns the use of transdermal fentanyl in the management of severe chronic pain. The second question approaches the problem of breakthrough pain in cancer patients discussing its identification and management in clinical practice. The third question focuses on the treatment options available for breakthrough pain, and the pharmacological aspects of mucosal administration of fentanyl. Each question examined in detail by one of the three authors of this article.

( BUPP09831 - 28 September 2009) Pain: Basics and relevance in dermatology: Academy CME

Scientific progress in pathophysiology and differentiation of pain, functional diagnostic of pain and emerging treatments highlight this subject. Basics of development of pain, as well as differentiation of nociceptive and neuropathic pain are depicted; the latter is illustrated with the example of postherpetic neuralgia. Complex regional pain syndromes are described as a third pain complex. Principles of differentiated pain management are given. Substance groups from the WHO scheme including antipyretic analgesics, non-steroidal antiinflammatory drugs (NSAIDs) and opioids are discussed. Recommendations of the Drug Commission of the German Medical Association concerning NSAIDs and of the International Association for the Study of Pain (IASP) concerning new treatment options for cancer pain are cited. Overviews amongst others from the Cochrane library for local anesthetics, opioids and for the treatment of postherpetic neuralgia are included. Tables are provided to simplify use in daily practice. The goal of this overview is a conceptual development of pain diagnosis and therapy in dermatology.

( BUPP09830 - 28 September 2009) The risk of tramadol abuse and dependence: findings in two patients

( BUPP09829 - 28 September 2009) Buprenorphine medication versus voucher contingencies in promoting abstinence from opioids and cocaine

During a 12-week intervention, opioid dependent participants (N = 120) maintained on thrice-a-week (M, W, F) buprenorphine plus therapist and computer-based counseling were randomized to receive: (a) medication contingencies (MC = thrice weekly dosing schedule vs. daily attendance and single-day 50% dose reduction imposed upon submission of an opioid and/or cocaine positive urine sample); (b) voucher contingency (VC = escalating schedule for opioid and/or cocaine negative samples with reset for drug-positive samples); or (c) standard care (SC), with no programmed consequences for urinalysis results. VC resulted in better 12-week retention (85%) compared to MC (58%; p = 0.009), but neither differed from SC (76% retained). After adjusting for baseline differences in employment, and compared to SC, the MC group achieved 1.5 more continuous weeks of combined opioid/cocaine abstinence (p = 0.030), while the VC group had 2 more total weeks of abstinence (p = 0.048). Drug use results suggest that both the interventions were efficacious, with effects primarily in opioid rather than cocaine test results. Findings should be interpreted in light of the greater attrition associated with medication-based contingencies versus the greater monetary costs of voucher-based contingencies.

( BUPP09861 - 07 October 2009) Methadone and buprenorphine prescribing and referral practices in US prison systems: Results from a Nationwide Survey

Background: More than 50% of incarcerated individuals have a history of substance use, and over 200,000 individuals with heroin addiction pass through American correctional facilities annually. Opiate replacement therapy (ORT) with methadone or buprenorphine is an effective treatment for opiate dependence and can reduce drug-related disease and recidivism for inmates. Provision of ORT is nevertheless a frequently neglected intervention in the correctional setting. Objective and methods: We surveyed the 50 state: Washington; District of Columbia (DC); and Federal Department of corrections medical directors or their equivalents about their facilities ORT prescribing policies and referral programs for inmates leaving prison. Results: We received responses from 51 of 52 prison systems nationwide. Twenty eight prison systems (55%) offer methadone to inmates in some situations. Methadone use varies widely across states: over 50% of correctional facilities that offer methadone do so exclusively for pregnant women or for chronic pain management. seven states prison systems (14%) offer buprenorphine to some inmates. The most common reason cited for not offering ORT was that facilities "prefer drug free detoxification over providing methadone or buprenorphine". Twenty three states prison systems (45%) provide referrals for some inmates to methadone maintenance programs after release, which increased from 8% in 2003; 15 states prison systems (29%) provide some referrals to community buprenorphine providers. Conclusion: Despite demonstrated social, medical and economic benefits of providing ORT to inmates during incarceration and linkage to ORT upon release, many prison systems nationwide still do not offer pharmacological treatment for opiate addiction or referrals for ORT upon release.

( BUPP09860 - 07 October 2009) Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: Risk factors and lives saved

Background: The small size of previous studies of mortality in opioid dependent people has prevented as assessment of the extent to which elevated mortality risks are consistent across time, clinical and/or patient groups. The current study examines reductions in mortality related to treatment in an entire treatment population. Methods: Data from the new South Wales (NSW) Pharmaceutical Drugs of Addiction System, recording every "authority to dispense" methadone or buprenorphine as opioid replacement therapy, 1985-2006, was linked with data from the national Deaths Index, a record of all deaths in Australia. Crude mortality rates and standardized mortality ratios were calculated according to age, sex, calendar year, period in or out-of-treatment, medication type, previous treatment exposure and cause of death. Results: mortality among 42,676 people entering opioid pharmacotherapy was elevated compared to age and sex peers. Drug overdose and trauma were the major contributors. Mortality was higher out-of-treatment, particularly during the first weeks, and it was elevated during induction onto methadone but not buprenorphine. Mortality during these risky periods changed across time and treatment episodes. Overall, mortality was similarly reduced (compared to out-of-treatment time periods. Despite periods of elevated risk,this large-scale provision of pharmacotherapy is estimated to have resulted in significant reductions in mortality.

( BUPP09859 - 07 October 2009) Chronic Pain Management in Older Adults: Special Considerations

The rising prevalence of neuropathic pain and the multifaceted sequelae of pain particularly within older adults are part of the increasing challenges in providing good geriatric pain management. Aging can lead to a higher sensitivity to pain within older adults, whereas physiological changes modify the absorption, bioavailability, and transit time of pharmaceutical agents. Ultimately, these differences within older adults require clinicians treating them to provide individually tailored analgesic approaches. Progressive age increases the variance in physiology among people; thus, the management approach should reflect an individual's unique requirements and limitations based on findings at the time of assessment.

( BUPP09858 - 07 October 2009) Moving away from addiction

( BUPP09857 - 07 October 2009) Substitution treatments from the drug users' point of view: Which path for which way out?

The present paper focuses on a specific method for getting out of drug addiction: substitution treatments for opiates. It is based on afield investigation of patients involved in high-dosage methadone or buprenorphine treatment in specialist care centres for drug addicts or who are followed by general practitioners. About sixty patients took part in individual face-to-face interviews. In addition, professionals from three methadone centres and GPs working in Bordeaux and Paris were interviewed. On the basis of the material gathered, the paper offers a comprehensive analyse of the way of getting out of drug addiction from the point of view of patients in treatment. At the same time, the paper points out the internal means and resources that patients use in their development. In this way, the individual treatment is structured around personal behaviour. Great strides are made. However, it is difficult for them to find an identity other than that of the drug addict. This slows down their change and brings into question the real improvement afforded by their treatment.

( BUPP09856 - 07 October 2009) Druq users' care strategies

Drug users'consumptions of legal and illegal drugs when they are in a treatment process has always been seen as a persistence of their addiction, which is itself considered as the symptom of a psychological unbalance. With the advent of the harm reduction policy, and especially with the advent of the substitution treatments, the figure of the drug user has been modified, as the user is now more viewed as a responsible person able to control his consumptions and their related risks with the help of institutions. Meanwhile, in both cases, drug consumptions during treatment are still more or less anchored in fluctuating interpretations that are generally related to already ongoing addiction processes. But we could consider that the care services cannot simultaneously take charge of all the aspects of drug-taking cessation, and that some of these aspects are directly catered for by the drug users themselves. In this perspective, consumptions no longer are anomalies and representatives of an ongoing addiction, but become the supports of more complex and diverse care strategies.

( BUPP09855 - 06 October 2009) Opiate replacement therapy in France: Assessment of the public policies

( BUPP09854 - 06 October 2009) Mechanisms of opioid-induced overdose: Experimental approach to clinical concerns

The widely used term "overdose" denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO /sub 2/ . However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO /sub 2/ ). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO /sub 2/ . This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO /sub 2,/ even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.

( BUPP09853 - 06 October 2009) Lipid nanoparticles with different oil/fatty ester ratios as carriers of buprenorphine and its prodrugs for injection

Buprenorphine is a promising drug for the treatment of chronic pain and opioid dependence. The aim of the present work was to evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for injection of buprenorphine. To improve the release properties and analgesic duration of the drug, ester prodrugs were also incorporated into the nanoparticles for evaluation. Linseed oil and cetyl palmitate were respectively chosen as the liquid lipid and solid lipid in the inner phase of the nanoparticulate systems. Differential scanning calorimetry (DSC) was performed, and the particle size, zeta potential, molecular environment, and lipid/water partitioning were determined to characterize the state of the drug /prodrug and lipid modification. The in vitro release kinetics were measured by a Franz assembly. DSC showed that systems without oil (solid lipid nanoparticles, SLNs) had a more ordered crystalline lattice in the inner matrix compared to those with oil (nanostructured lipid carriers, NLCs and lipid emulsion, LE). The mean diameter of the nanoparticles ranged between 180 and 200 nm. The in vitro drug/prodrug release occurred in a delayed manner in decreasing order as follows: SLN > NLC > LE. It was found that the release rate was reduced following an increase in alkyl ester chains in the prodrugs. The in vivo antinociception was examined by a cold ethanol tail-flick test in rats. Compared to an aqueous solution, a prolonged analgesic duration was detected after an intravenous injection of buprenorphine-loaded SLNs and buprenorphine propionate (Bu-C3)-loaded NLCs (with 10% linseed oil in the lipid phase). The Bu-C3 in NLCs even showed a maximum antinociceptive activity for 10 h. In vitro erythrocyte hemolysis and lactate dehydrogenase (LDH) release from neutrophils demonstrated a negligible toxicity of these carriers. Our results indicate the feasibility of using lipid nanoparticles, especially SLNs and NLCs, as parenteral delivery systems for buprenorphine and its prodrugs.

( BUPP09852 - 06 October 2009) Assessment of risk associated with medication-related problems in elderly outpatients

Background: The Society of Hospital Pharmacists of Australia's (SHPA) Standards of Practice for Clinical Pharmacy provide a risk-classification system for interventions made by pharmacists in hospital inpatients. These standards are based on Australian standards for risk management, where risk is based on an estimate of the likelihood and consequences of an adverse outcome from a medication-related problem, if no intervention was made. Aim: To adapt and validate the SHPA risk-classification system for use in geriatric ambulatory care and to explore differences in classifications of risk made by pharmacists and geriatricians. Method: The SHPA risk-classification system was modified, piloted and reviewed by experts to assess face validity. 113 medication-related problems identified by an outpatient clinical pharmacist in aged care were independently classified by a senior clinical pharmacist, a geriatrician and the outpatient clinical pharmacist. When there was disagreement, the case was discussed and consensus reached. A random sample of 30 medication-related problems, stratified by consensus risk classification was classified by a second geriatrician. Results: Face validity of the adapted risk-classification system was established. Agreement between pharmacists on medication-related problem risk was moderate and agreement between pharmacists and geriatricians was fair. Risk of adverse outcomes was rated lower by geriatricians than pharmacists. Consensus was easily reached through case discussion. Conclusion: A system for classifying risk associated with pharmacist-identified medication-related problems in geriatric ambulatory care was developed. Differences were identified between pharmacists and geriatricians in the way medication-related risks are perceived. Classification of pharmacist-identified medication-related problems/interventions may need to be based on consensus between at least one doctor and pharmacist.

( BUPP09851 - 06 October 2009) Pharmacokinetic-pharmacodynamic modeling in anesthesia, intensive care and pain medicine

PURPOSE OF REVIEW: Studies from the anesthesiology literature published in the last 2 years were selected to illustrate the most important developments in the field of pharmacokinetic-pharmacodynamic modeling. RECENT FINDINGS: The pharmacokinetic models focused on incorporating covariate, especially age for pediatric- geriatric use, and altered physiological states. The pharmacodynamic models studied the effect of rate of anesthetic administration, a g experimental conditions, and delay within the monitor on estimation of drug concentration in the biophase. Models for the surrogate measure of the components of general anesthesia, hypnosis (bispectral index scale, entropy), immobility (limb tetanic stimulus-induced withdrawal reflex) and antinociception (surgical stress index, skin conductance algesimeter) were developed and validated. Response surface models were used to study drug interactions for important end-points during surgery and also to optimize dosing of anesthetic agents to maximize the desired/undesired effect ratio. The models for target-controlled infusions were improved by incorporating more covariates, and the closed-loop system was refined by using adaptive controllers that individualize the pharmacokinetic/pharmacodynamic parameters to the particular patient by using Bayesian, Kalman filters, fuzzy logic or neural networks. SUMMARY: Progress was made by improving population Pharmacokinetic/pharmacodynamic models, developing new indexes to measure drug effect and using them in an adaptive delivery system to the individual patient.

( BUPP09850 - 06 October 2009) SMARCAL1 mutations: A cause of prepubertal idiopathic steroid-resistant nephrotic syndrome

Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal-recessive multisystem disorder with disproportionate growth failure, impaired T cell function, and steroid-resistant nephrotic syndrome. Recently, we presented the typical anthropometric features of SIOD. We now present data on two siblings who were initially classified as suffering from familial steroid-resistant nephrotic syndrome of unknown genetic origin. Apart from growth failure, no Syndrome-specific symptoms were found until the age of 10 y. However, serial anthropometric examinations showed the development of a SIOD-like pattern with a decreased ratio of trunk to leg length in early adolescence. The growth pattern was significantly different from that seen in children with chronic renal failure of other origins. In prepuberty the siblings had proportionate short stature but developed disproportion only during adolescence. Molecular genetic analysis revealed compound heterozygosity for a known and a new mutation in the SMARCAL1 gene. Conclusion: the disease spectrum associated with SMARCAL1 mutations includes previously undescribed milder phenotypes that may be clinically overlooked, particularly before puberty. Serial anthropometric assessment can eventually identify patients with a growth pattern similar to that of SIOD. These patients should be tested for SMARCAL1 mutations to avoid overtreatment with immunosuppressive agents.

( BUPP09849 - 06 October 2009) Opioid use in osteoarthritis: From guidelines to clinical care

Three treatment guidelines for the treatment of knee and hip osteoarthritis (OA) which pick up the aspects of treatment supported by evidence have been published. Opioid drugs have an important role in symptomatic treatment. The guidelines, the effectiveness, and the safety of opioid analgesics in osteoarthritis, as well as its implications in clinical practice are reviewed. Tramadol is the opioid with the biggest evidence of effectiveness and safety, besides being the most used in clinical practice. Strong opioids (transdermic brupenorphine or fentanyl, oxycodone, and morphine) can be used in severe pain that does not respond to other treatments. Opioids can be used in patients that have moderate or severe pain or in those with inadequate response or intolerance to NSAID's. The opioids also have a sedative effect that facilitates sleep and can improve functional limitations and anxiety. The side effects are frequent; they usually appear at the beginning of treatment and are rarely severe, but frequently force to stop treatment.

( BUPP09848 - 06 October 2009) Attitude and concern of Italian veterinary practitioners toward management of pain in dogs and cats

( BUPP09847 - 06 October 2009) Update on Cancer Pain Guidelines

( BUPP09846 - 06 October 2009) Opioid Rotation: The Science and the Limitations of the Equianalgesic Dose Table

Opioid rotation refers to a switch from one opioid to another in an effort to improve the response to analgesic therapy or reduce adverse effects. It is a common method to address the problem of poor opioid responsiveness despite optimal dose titration. Guidelines for opioid rotation are empirical and begin with the selection of a safe and reasonably effective starting dose for the new opioid, followed by dose adjustment to optimize the balance between analgesia and side effects. The selection of a starting dose must be based on an estimate of the relative potency between the existing opioid and the new one. Potency, which is defined as the dose required to produce a given effect, differs widely among opioids, and among individuals under varying conditions. To effectively rotate from one opioid to another, the new opioid must be started at a dose that will cause neither toxicity nor abstinence, and will be sufficiently efficacious in that pain is no worse than before the change. The estimate of relative potency used in calculating this starting dose has been codified on "equianalgesic dose tables, " which historically have been based on the best science available and have been used with little modification for more than 40 years. These tables, and the clinical protocols used to apply them to opioid rotation, may need revision, however, as the science underlying relative potency evolves. Review of these issues informs the use of opioid rotation in the clinical setting and defines key areas for future research.

( BUPP09845 - 05 October 2009) Injection of medications used in opioid substitution treatment in Australia after the introduction of a mixed partial agonist-antagonist formulation

OBJECTIVES: To examine the levels and predictors of injection of buprenorphine-naloxone (BNX)--a combination of a partial opioid agonist and an opioid antagonist for treating opioid dependence--which was specifically developed to limit injecting. Comparison was made with injecting of two other opioid substitution treatment medications, methadone and buprenorphine (BPN); severe harms have been documented after injection of the latter. DESIGN AND PARTICIPANTS: Injecting was studied in regular injecting drug users ("IDUs") and current opioid substitution treatment clients ("clients"). Regular IDUs are interviewed annually in each Australian capital city (about 900 per year) and data for 2003-2007 were used; 399 clients were interviewed in 2007. Data on injection of opioid substitution treatment medications between 2003 and 2007 were adjusted for availability of medications (from national sales data for methadone, BPN and BNX). Predictors of injecting were analysed by multiple regression analyses. SETTING: Capital cities of all Australian states and territories. MAIN OUTCOME MEASURE: Injection of opioid substitution treatment medications among individuals both in and out of treatment. RESULTS: In the year after its introduction in Australia, BNX was injected less frequently and by fewer regular IDUs and clients compared with BPN, particularly when differences in the availability of medications were taken into account. Some individuals did nonetheless regularly inject BNX. Injection of methadone, BPN and BNX was more likely to occur among those injecting other pharmaceutical opioids. CONCLUSIONS: A partial opioid agonist-antagonist combination appears to be less commonly and less frequently injected by clients in treatment and IDUs who are not. Further studies are needed to evaluate longer-term trends in use and harms.

( BUPP09844 - 05 October 2009) What more do we need to know about medication-assisted treatment for prescription opioid abusers?

( BUPP09843 - 05 October 2009) Animal Models in Cardiovascular Research, Third Edition

This 394-page book presents and describes Animal Models in Cardiovascular Research, in which it reviews genetic, molecular, and protein-based information. The book is organized into 14 individually authored chapters, which are further divided into different sections and subsections. The first chapter deals with general principles of animal selection and normal physiological valure. The second chapter deals with preanesthesia, anesthesia, chemical restraint, and the recognition and treatment of pain and distress. The third chapter deals with normal cardiac function parameters. Remaining chapters include measuring cardiac function, measuring vascular function and ventricular/arterial coupling dynamics, isolated heart preparations, problems, and pitfalls, cardiovascular effects of anesthetics, sedatives, postoperative analgesic agents, and other pharmaceuticals, iatrogenic models of ischemic heart disease, and other transgenic animal models used in cardiovascular studies. The book highlights a list of contributors and their respective institutions. Each chapter contains a list of references. The text is written in English and indexed by subject with tables and figures. Users of this book will include cardiologists, molecular biologists, and biotechnologists.

( BUPP09842 - 05 October 2009) Embolic stroke associated with injection of buprenorphine tablets

Background: Drug users who crush, dissolve, and inject buprenorphine tablets parenterally may be at risk of severe thromboembolic complications or death. We describe patients with neurologic complications after injecting buprenorphine tablets.Methods: Brain MRI including diffusion-weighted imaging (DWI) in patients admitted to the neurologic department after injecting buprenorphine tablets were reviewed.Results: Seven men had neurologic complications after buprenorphine tablet injection. In 5 patients, multiple small scattered hyperintense lesions were detected on DWI in the cortex, white matter, and basal ganglia of the cerebral hemisphere; one patient had a single small lesion. The side of MRI abnormality corresponded to the side of needle marks on the neck except in one patient who had bilateral injections. One patient, who denied injecting into the neck, had DWI abnormalities in the middle cerebral artery territory on one side and occlusion of the ipsilateral internal carotid artery.Conclusions: Buprenorphine tablets can be intentionally or inadvertently injected into the carotid artery, causing a characteristic appearance on diffusion-weighted imaging, consistent with embolic cerebral infarction.

( BUPP09867 - 13 October 2009) Transdermal buprenorphine in chronic pain: Indications and clinical experience

Transdermal buprenorphine has been shown to be effective in managing moderate-to-severe cancer pain and severe pain that is unresponsive to nonopioid analgesics. In clinical trials, it provided better pain relief than placebo, despite a higher consumption of rescue analgesia by placebo patients. Analgesia was rated as satisfactory or better by 90% of patients in a long-term follow-up study and 94.6% considered the buprenorphine matrix patch to be user friendly. Transdermal buprenorphine is well tolerated; most adverse events are transient local reactions to the patch or systemic effects typical of treatment with opioids. Even in opioid-experienced volunteers, buprenorphine does not cause respiratory depression at doses up to 70-times higher than those used for analgesia. No problems have been encountered when switching from another opioid to transdermal buprenorphine, or in combining the buprenorphine patch with intravenous morphine or tramadol for breakthrough pain. There is a growing body of evidence that transdermal buprenorphine may be particularly useful for managing neuropathic pain. Most notably, it appears to be effective in treating hyperalgesic states and syndromes characterized by pronounced central sensitization.

( BUPP09866 - 13 October 2009) Comparative treatment and mortality correlates and adverse event profile of implant naltrexone and sublingual buprenorphine

There is increasing interest in the use of implantable naltrexone as a new treatment for opiate dependence. This center has been one of the leaders in this form of treatment in Australia and has recently completed a registry-controlled review of our mortality data. As part of the study of the safety profile of this therapy, we were interested to review both the treatment correlates of previously presented mortality data and of adverse events. A total of 255 naltrexone implant therapy (NIT) and 2,518 buprenorphine (BUP) patients were followed for 1,322.22 and 8,030.02 patient-years, respectively. NIT patients had significantly longer days in treatment per episode (mean � standard deviation, 238.32 � 110.11 vs. 46.96 � 109.79), total treatment duration (371.21 � 284.64 vs. 162.50 � 245.76), and mean treatment times but fewer treatment episodes than BUP (all p < .0001). Serious local tissue reaction or infection each occurred in 1% of 200 NIT episodes. These data show that NIT economizes treatment resources without compromising safety concerns.

( BUPP09865 - 13 October 2009) Buprenorphine adoption in the National Drug Abuse Treatment Clinical Trials Network

The National Drug Abuse Treatment Clinical Trials Network (CTN), a collaborative federal research initiative that brings together universities and community-based treatment programs (CTPs), has conducted multiple clinical trials of buprenorphine for opioid dependence. Part of the CTN's mission is to promote the adoption of evidence-based treatment technologies. Drawing on a data collected during face-to-face interviews with administrators from a panel of 206 CTPs, this research examines the adoption of buprenorphine over a 2-year period. These data indicated that the adoption of buprenorphine doubled between the baseline and 24-month follow-up interviews. Involvement in a buprenorphine protocol continued to be a strong predictor of adoption at the 2-year follow-up, although adoption of buprenorphine tripled among those CTPs without buprenorphine-specific protocol experience. For-profit CTPs and those offering inpatient detoxification services were more likely to adopt buprenorphine over time. A small percentage of programs discontinued using buprenorphine. These findings point to the dynamic nature of service delivery in community-based addiction treatment and the continued need for longitudinal studies of organizational change.

( BUPP09864 - 13 October 2009) Inquiries about and initiation of buprenorphine treatment in an inner-city clinic

Despite increases in opioid dependence, availability of buprenorphine treatment remains limited. Reasons may include health center concerns about becoming overwhelmed or attracting patients who differ from the local community. This study documents inquiries about and initiation of buprenorphine treatment in an inner-city health center. From 2006-2008, we collected demographic information and subsequent treatment data for everyone who inquired about treatment. Of the 324 people who inquired, 55.6% initiated treatment. The number of inquiries increased gradually over time, and most came from local community residents (80.4%). These results may allay health center concerns, and can help planning for buprenorphine treatment.

( BUPP09863 - 13 October 2009) Evaluation of buprenorphine and tramadol as pre-emptive analgesics following ovariohysterectomy in female dogs

Ovariohysterectomy from right flank region, was performed tinder atropine, diazepam and propofol general anaesthesia on twelve healthy female dogs randomly divided into two groups of six animals each. In one group tramadol was administered and in another group buprenorphine was administered 30 minute prior to atropine sulphate. Tramadol was repeated after every six hours and buprenorphine was repeated after every twelve hours up to second postoperative day. Postoperative pain assessment (0-20 multifactorial numerical rating scale) was made and clinico-biochemicohematological parameters Were measured at preoperative, immediate post-recovery and 8, 24 and 48 hours postoperative stages. Mean total pain score at immediate post-recovery stage was slightly lower in tramadol than the buprenorphine group. As compared to tramadol group, plasma glucose concentration (at immediate post-recovery stage), neutrophil count (at 48 hours postoperative stage) and respiration rate (at immediate post-recovery stage) were significantly higher (P<0.05) and heart rate (at eight hours postoperative stage) was significantly lower (P<0.05) in buprenorphine group.

( BUPP09862 - 13 October 2009) Integrating nine prescription opioid analgesics and/or four signal detection systems to summarize statewide prescription drug abuse in the United States in 2007

Purpose Integrate statewide rankings of abuse across different drugs and/or signal detection systems to summarize prescription drug abuse in each state in 2007.Methods Four signal detection systems (Opioid Treatment Programs, Key Informants, Drug Diversion, and Poison Centers) that covered heterogeneous populations collected data on the abuse of nine opioids: hydrocodone, immediate-release oxycodone, tramadol, extended-release (ER) oxycodone, fentanyl, morphine, methadone, hydromorphone, and buprenorphinc). We introduce here linearized maps which integrate nine drugs within each system; four systems for each drug; or all drugs and systems.Results When rankings were integrated across drugs, Rhode Island, New Hampshire, Maine, West Virginia, and Michigan were in the highest tertile of abuse in three systems. When rankings were integrated across signal detection systems, there was a geographic clustering of states with the highest rates for ER oxycodone (in Tennessee, Mississippi, Kentucky, Ohio, Indiana, Michigan, and in Massachusetts, New Hampshire, Maine, and Vermont) and methadone (Massachusetts, Rhode Island, New Hampshire, Maine, Vermont, Connecticut, and New Jersey). When rankings were integrated across both drugs and signal detection systems, states with 3-digit ZIP codes below 269 (i.e., from Massachusetts to West Virginia): Massachusetts, New Hampshire, Maine, Vermont, Washington DC, Virginia, and West Virginia were in the highest tertile and only Delaware was in the lowest tertile.Conclusions We have presented methods to integrate data on prescription opioid abuse collected by signal detection systems covering different populations. Linearized maps are effective graphical summaries that depict differences in the level of prescription opioid abuse at the state level.

( BUPP09880 - 20 October 2009) Management of injecting drug users admitted to hospital

( BUPP09879 - 20 October 2009) Effectiveness of community treatmetns for heroin and crack cocaine addiction in England: a prospective, in-treatment cohort study

( BUPP09878 - 20 October 2009) Chronic pain management

Pain is one of the major complaints leading to doctor visits. Therefore basic knowledge of frequent pain diagnoses and possible treatment approaches is essential. Numerous medical and interventional therapeutic options are available for causal or symptomatic treatment of pain. The treatment of neuropathic pain is often difficult and demands special knowledge. Antidepressants like amitriptyline and anticonvulsive drugs are the first choice in these cases. Also interventional approaches are useful, such as spinal cord stimulation for angina pectoris. For the treatment of complex regional pain syndrome and phantom pain the use of mirror feed-back is a new effective method for pain relief. The only way to prevent from development of chronic pain is the early and effective treatment of acute pain.

( BUPP09877 - 20 October 2009) Chronic pain therapy

Chronic pain represents a considerable health problem in developed countries, too. This fact is especially important in the socio-economic perspective.The nowadays at least partially known fundamental processes of the development of chronic pain allow for a mechanism-oriented therapeutical approach. This drug oriented approach has to be improved. Themanagement of complex chronic pain states should basically be interdisciplinary, including all involved medical and paramedical disciplines. Semi-invasive and invasive approaches of pain therapy should be the last resort.

( BUPP09876 - 20 October 2009) Perioperative pain management in patients receiving chronic opioid therapy

Historically, opioids have been used for the transient management of acute pain, whereas chronic administration has been reserved for patients with malignancy or terminal disease. Recently, however, greater emphasis has been placed on pain as an important health problem. As a result, opioids now play a greater role in the treatment of chronic pain of various causes, resulting in a rapid increase in the annual sales of opioid analgesics in all developed countries. All anesthesiologists are likely to be confronted with the difficult acute perioperative pain management in these patients, since they can experience greater postoperative pain and have markedly increased opioid requirements. Therefore, anesthesiologists must acquire the necessary skills and understanding to effectively treat these patients.

( BUPP09875 - 20 October 2009) Note on treatment history of heroin addicts receiving a methadone treatment

The authors are describing a group of 74 heroin addicts who receive methadone treatment. Two sub-groups of 37 subjects are compared. In the first group, methadone treatment was initiated 10 years ago or more; in the second group, methadone treatment was initiated more recently, one year ago or less at the time of the study. The study confirms that methadone treatment - in both groups - occurs very late in the treatment history of the subjects.

( BUPP09874 - 20 October 2009) Interferon-based hepatitis C treatment in patients with pre-existing severe mental illness and substance use disorders

Hepatitis C infection in patients with mental illness and drug addiction is highly prevalent and infrequently treated. Over the past 5 years, a wealth of studies specifically focused on these groups have demonstrated comparable rates of sustained virological response, compliance and adverse events. Optimization of psychotropic and opioid-replacement therapy with integrated psychiatric/addiction treatment prior to and during IFN-alpha initiation produces optimal results. Experience in treating these populations demonstrates clinical outcomes comparable with those without these comorbidities. Patients with mental illness and drug addiction should have routine screening and treatment for HCV infection to prevent associated morbidity and mortality.

( BUPP09873 - 20 October 2009) The challenges of postoperative pain

Postoperative pain causes deleterious physiological and psychological effects leading to prolonged recovery and hospitalisation. Patients with postoperative pain should be judiciously prescribed analgesics and, when necessary, referred to pain medicine specialists.

( BUPP09872 - 20 October 2009) Instilled or injected purified natural capsaicin has no adverseeffects on rat hindlimb sensory-motor behavior or osteotomy repair

BACKGROUND: A novel formulation of 98% pure capsaicin (4975) is currently undergoing clinical investigation using novel routes of delivery to provide selective analgesia lasting weeks to months with a single dose. We conducted this study to assess the safety and effects of instilled and injected 4975 in rat models of wound healing osteotomy repair and sensory-motor nerve function. METHODS: Adult male and female Sprague-Dawley rats were used. To assess the effects of 4975 on nerve or muscle, 0.0083 or 0.025 mg 4975 or vehicle (25% polyethylene glycol-300) was applied to exposed sciatic nerve, or 0.1 mg 4975 or vehicle was injected into the surrounding muscle (Group 1). To assess the effect of 4975 on bone healing, an osteotomy was made in one femur and 0.5 mg of 4975 or vehicle was instilled into the site (Group 2). Behavioral testing was performed on both groups of rats and histological evaluation of the sciatic nerve, and surrounding soft tissue and bone was done at days 3, 14, and 28 after surgery. Femurs from osteotomy rats were assessed using peripheral quantitative computed tomography and biomechanical testing. Standard statistical tests were used to compare groups. RESULTS: Rats with direct application of 4975 to the sciatic nerve and surrounding muscle were no different from the controls in nociceptive sensory responses (F = 0.910, P = 0.454), grip strength (F = 0.550, P = 0.654), or histology of the muscle or sciatic nerve. In osteotomy rats, there were no statistical differences between 4975 and vehicle-treated rats for bone area (H = 2.858, P = 0.414), bone mineral content (F = 0.945, P = 0.425), or bone mineral density (F = 0.87, P = 0.462) and no difference in soft tissue healing. There were neither differences in bone stiffness (F = 1.369, P = 0.268) nor were there noticeable differences in the macro- or microscopic appearance of the right femur osteotomy healing site and surrounding soft tissues between the control group and the 4975-treated animals. CONCLUSION: A single, clinically relevant application of instilled or injected 4975 has no observable adverse effect on wound and bone healing after osteotomy or on the structural integrity of exposed muscle and nerve.

( BUPP09871 - 20 October 2009) Muscle injection of AAV-NT3 promotes anatomical reorganization of CST axons and improves behavioral outcome following SCI

Here we propose the use of adeno-associated virus (AAV) vectors as a non-invasive vehicle for the nervous system to deliver genes to spinal motoneurons, based on their retrograde transport from muscle. Long-term protein expression in lower cervical motoneurons was achieved after injections of AAV into the triceps, independently of serotypes 1, 2, or 5. Muscle injections of AAV5-neurotrophin 3 (NT3) resulted in a significant increase in the levels of NT3 in the cervical enlargement, compared to those obtained after injections of AAV5-GFP. Following a dorsal lesion at C4/C5, animals injected with AAV5-NT3 made fewer errors (footslips) in the horizontal ladder test compared to those injected with AAV5-GFP. In parallel, the number and length of corticospinal tract (CST) fibers circumventing the injury site were significantly increased in rats injected with AAV5-NT3. Compared to controls, we observed less astrogliosis and less CST axonal retraction and/or enhanced sprouting in animals injected with AAV5-NT3. In sum, we demonstrate here that the delivery of nt3 via retrograde transport of AAV from triceps to cervical motoneurons leads to reduced functional loss and anatomical reorganization of the CST following injury, without introducing additional injury to the spinal cord.

( BUPP09870 - 20 October 2009) Effect of VEGF treatment on the blood-spinal cord barrier permeability in experimental spinal cord injury: Dynamic contrast-enhanced magnetic resonance imaging

Compromised blood-spinal cord barrier (BSCB) is a factor in the outcome following traumatic spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis and vascular permeability. The role of VEGF in SCI is controversial. Relatively little is known about the spatial and temporal changes in the BSCB permeability following administration of VEGF in experimental SCI. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies were performed to noninvasively follow spatial and temporal changes in the BSCB permeability following acute administration of VEGF in experimental SCI over a post-injury period of 56 days. The DCE-MRI data was analyzed using a two-compartment pharmacokinetic model. Animals were assessed for open field locomotion using the Basso-Beattie-Bresnahan score. These studies demonstrate that the BSCB permeability was greater at all time points in the VEGF-treated animals compared to saline controls, most significantly in the epicenter region of injury. Although a significant temporal reduction in the BSCB permeability was observed in the VEGF-treated animals, BSCB permeability remained elevated even during the chronic phase. VEGF treatment resulted in earlier improvement in locomotor ability during the chronic phase of SCI. This study suggests a beneficial role of acutely administered VEGF in hastening neurobehavioral recovery after SCI.

( BUPP09869 - 20 October 2009) Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: What are the key messages for clinical practice?

Safe and effective chronic opioid therapy (COT) for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and in the assessment and management of risks associated with opioid abuse, addiction, and diversion. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on COT for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations based on the best available evidence. This article summarizes key clinical messages from this guideline regarding patient selection and risk stratification, informed consent and opioid management plans, initiation and titration of COT, use of methadone, monitoring of patients, use of opioids in high-risk patients, assessment of aberrant drug-related behaviors, dose escalations and high-dose opioid therapy, opioid rotation, indications for discontinuation of therapy, prevention and management of opioid-related adverse effects, driving and work safety, identifying a medical home and when to obtain consultation, and management of breakthrough pain.

( BUPP09868 - 19 October 2009) Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases

We investigated the enzyme kinetics of buprenorphine and norbuprenorphine glucuronidation in human liver microsomes and UDP-glucuronosyltransferase (UGT) Supersomes. The involvement of UGT 1A1, 1A3 and 2B7 in buprenorpine and 1A3 in norbuprenorphine glucuronidation were confirmed. Novel involvement of 2B17 with buprenorphine and 1A1 with norbuprenorphine were demonstrated. Scaling of buprenorphine clearance with, or without, correction for the nonspecific microsomal protein binding of buprenorphine (f(u) = 0.42) suggested glucuronidation was a significant route for hepatic clearance of buprenorphine.

( BUPP09895 - 29 October 2009) Subcutaneous pre-anaesthetic medication with acepromazine - buprenorphine is effective as and less painful than the intramuscular route

Objectives: To compare reaction to injection, sedation and propofol induction dose in dogs receiving acepromazine-buprenorphine pre-anaesthetic medication by the intramuscular or subcutaneous routes. Methods: Fifty-two client owned dogs of American Society of Anaesthesiologists grade I or II anaesthetised for diagnostic imaging. Dogs were randomly assigned to receive acepromazine 0.03mg/kg and buprenorphine 0.02mg/kg either intramuscular or subcutaneous. Reaction to injection was scored. Sedation was compared before and one hour after pre-anaesthetic medication. Propofol was administered in 1mg/kg incremental injections until tracheal intubation was achieved. Total propofol dose was recorded. Results: Reaction to injection was significantly greater (P=0.009) in the intramuscular group compared to the subcutaneous group. Sedation scores were not significantly different (P-0.523) between the intramuscular and the subcutaneous group. There was no statistically significant difference in propofol dose for induction (P=0.7). Clinical Significance: Acepromazine-buprenorphine pre-anaesthetic mediation provides a similar degree of sedation whether administered by the intramuscular of subcutaneous route. The intramuscular route is more painful compared to the subcutaneous route.

( BUPP09894 - 29 October 2009) Dose-related antinociceptive effects of intravenous buprenorphine in cats

The dose-related antinociceptive effects of intravenous (IV) buprenorphine were evaluated in cats. Thermal (TT) and mechanical threshold (MT) devices were used for nociceptive stimulation. After baseline threshold recordings, buprenorphine was administered IV (0.01, 0.02 or 0.04 mg/kg; B1, B2 and B4, respectively) in a randomised, blinded and cross-over study. Data were analysed by ANOVA (P < 0.05) using 95% confidence intervals (CI). TT increased 15, 30, 45 min and 1 (5.2 � 2.7 �C), 2, 3 and 4 h after B1; 15, 30, 45 min and 1 (5.1 � 3.9 �C) and 2 h after B2, and 15, 30, 45 min and 1 (5.4 � 3.3 �C), 2, 3, 6 and 8 h after B4. MT increased 15 and 45 min after B2 (260 � 171 mmHg), and 30 (209 � 116 mmHg) and 45 min and 1 and 2 h after B4. At 45 min, MT values were significantly higher after B2 compared to B1 (P < 0.05). With MT, B2 and B4 produced more antinociception and longer duration of action than B1, respectively. No dose response to thermal stimulation was detected.

( BUPP09893 - 29 October 2009) Continuous Buprenorphine Delivery Effect in Streptozotocine-Induced Painful Diabetic Neuropathy in Rats

Diabetic peripheral neuropathy (DPN) can induce loss of nociception as well as mechanical hyperalgesia and tactile allodynia. Pharmacological and clinical studies have shown that buprenorphine, a low-molecular-weight, lipophilic, opioid analgesic available as a transdermal matrix patch formulation, acts on neuropathic pain. To assess the role of buprenorphine in the treatment of DPN-associated neuropathic pain, we used a well-established experimental rat model of DPN in which buprenorphine at doses of 1.2 and 2.4 mug/kg/h was administered by implantable Alzet osmotic pumps for 3 weeks. After 6 weeks of diabetes, nerve conduction velocity (NCV) and behavioural responses to noxious mechanical and thermal stimuli were assessed. Diabetic rats showed an impairment of NCV, mechanical allodynia, and thermal hypoalgesia. Both doses of buprenorphine significantly reversed the diabetes-induced allodynia up to day 7 of treatment. Buprenorphine did not alter either thermal perception or NCV. Perspective: This study evaluated, through a multimodal approach, the analgesic effect of buprenorphine in an experimental rat model of painful DPN. Our results suggest a possible role for buprenorphine in the management of DPN-associated neuropathic pain.

( BUPP09892 - 29 October 2009) Local anaesthetic adjuvants: Neuraxial versus peripheral nerve block

Purpose of review: To present a review of the literature on the importance and the clinical characteristics relevant to adjuvants added to local anaesthetics in neuraxial and peripheral nerve blocks. Recent findings: In neuraxial anaesthesia, both opioids and alpha-2 receptor agonists have beneficial effects. Intrathecally, fentanyl and sufentanil not only improve the postoperative analgesia but also make it possible to allow a decrease in the local anaesthetic dose. When clonidine or dexmedetomidine was added to intrathecal local anaesthetics, the regression of sensory, motor block increased dose-dependently and postoperative analgesia was prolonged. The potency of intrathecal clonidine: dexmedetomidine seems to be 10: 1. In peripheral nerve block, when opioid was combined with local anaesthetics, no increased improvement in analgesia was reported in comparison with systemic controls in most of the studies, except buprenorphine. Also clonidine is controversial as an analgesic adjuvant. Special factors, such as type of local anaesthetics, block of upper or lower limb, are important for its the beneficial effect. Other adjuvants, except neuraxial low-dose neostigmine, are of minor importance. Summary: Opioids and alpha-2 receptor agonists are important as neuraxial adjuvants to improve the quality of peroperative and postoperative analgesia in high-risk patients and in ambulatory procedures. In peripheral nerve blocks, however, some benefit is found only when clonidine is added to local anaesthetics under certain circumstances.

( BUPP09891 - 29 October 2009) Antiviral treatment for chronic hepatitis C in illicit drug users: A systematic review

According to recent World Health Organization data, approximately 170-200 million people worldwide are infected with hepatitis C virus (HCV). At present, illicit drug users (IDUs) constitute the largest group of individuals infected with HCV in industrial countries. Between 50% and 90% of IDUs are estimated to be positive for anti-HCV antibodies and most of the new infections occur in IDUs. The aim of our review is to focus on tertiary prevention of HCV infection among IDUs. We review strategies to prevent HCV infection and disease progression, attitude to antiviral treatment, access to specific HCV therapy and data of efficacy and safety of antiviral treatment among IDUs.

( BUPP09890 - 29 October 2009) Antalgic treatments usually prescribed in otolaryngological conditions

( BUPP09889 - 29 October 2009) 2007 update of the 3rd Consensus Conference in Emergency Medicine (Creteil, April 1993): Medicinal treatment of pain in adults in the emergency setting

A questionnaire was posted on the SFMU website from February 15 through April 15 2007 in order to assess the impact of the 1993 Consensus Conference. Four hundred and seventy-three questionnaires were available for study. Among the main findings, it was noted that most of the emergency physicians had a mixed activity, with a predominance of the adult population. Numeric and analogue scales were widely used. Dolopus and the Edin scale were not employed. Sixty-two percent of persons interrogated used the unit protocol. Seventy-two percent of the interrogated persons had an initial dose of morphine then titration with repeated boluses. Management of adults with pain thus appears to be in compliance with the guidelines. An analysis of the literature, using Medline, Cochrane and ScienceDirect /sup �/ was based on decreasing level of proof. As for the preceding updates, the articles were classified as follows: randomized controlled studies, practical guidelines, meta-analysis, review articles. Data concerning medication used in the emergency setting for pain relief were selected.

( BUPP09888 - 29 October 2009) Inadequate dose of opioid-agonist medication is related to misuse of benzodiazepines

Objectives: To evaluate whether misuse of nonprescribed substances is related to dose-adequacy of opioid-agonist medication (OAM) in opioid substitution treatment. Methods: Opioid-dependent patients undergoing a substitution treatment program of the Helsinki University Central Hospital. Opioid-dependent patients evaluated their dose of OAM (methadone or buprenorphine combined with naloxone) as either too low (group 1) or adequate (group 2). Instead of being limited to the main drug classes detectable by standard immunoassay techniques, this study systematically investigated the incidental use of a very broad spectrum of therapeutic and illicit drugs both from blood and urine samples. Results: Of the 65 participating patients 21 (32%) completed the study. Their doses and blood concentrations of OAM showed no differences between the 2 groups. The group 1 patients, however, showed more positive laboratory findings for nonprescribed benzodiazepines (7/10 vs. 1/11, P=0.008). Diazepam was present in all positive samples of nonprescribed benzodiaze pines, alprazolam in 4, clonazepam in 3, and midazolam in 2 samples. There was no difference in misuse of opiates, amphetamine, cannabis, barbiturates, designer drugs, or psychotropic drugs between groups 1 and 2. Conclusions: The inadequate dose of OAM in opioid substitution treatment for opioid- dependent patients seems to be related to the misuse of benzodiazepines.

( BUPP09887 - 29 October 2009) Adherence to substitute opioid prescribing: Survey of inner-London drug services

AIMS AND METHOD: To investigate non-adherence to substitute opioid treatment, using a cross-sectional study design, with 630 patients from three London community drug services. Adherence was measured as the number of doses collected from the pharmacy as a proportion of the total number of doses stipulated on the prescription during a 28-day period and was further investigated through laboratory urine drug screens. RESULTS: Overall, 30.5% (n = 191) of individuals failed to pick up at least one dose of medication from the pharmacy over 1 month, but only 1.6% (n = 10) missed 50% or more of their doses. Non-adherence was associated with supervised consumption, more frequent pick-up, shorter duration of treatment, younger age, a lower dose of methadone and a recent urinalysis result positive for opiates. CLINICAL IMPLICATIONS: Treatment services need to monitor levels of adherence to treatment and develop strategies to improve it so that treatment can be optimised effectively.

( BUPP09886 - 28 October 2009) Pain following a stroke

Pain is a well-known condition following stroke and includes central neuropathic pain, complex regional pain syndrome and hemiplegic shoulder pain. After a brief recall of physiology, the diagnostic criteria, the general management and the pharmacologic treatment that have demonstrated efficacy are reviewed.

( BUPP09885 - 28 October 2009) Pediatric Suboxone Exposure: How Long is the Initially Symptomatic Child at Risk for Sequellae after Naloxone Reversal? A Case Report and Literature Review

A case of pediatric suboxone toxicity and management with naloxone (i.m. and intranasal) to avoid recurrent opioid effect is reported. Intranasal naloxone showed improvement in respirations and consciousness. Additional 0.2 mg doses of i.m. naloxone were given. The patient remained asymptomatic. The results indicated that naloxone reversed the buprenorphine-induced opioid effects in this patient. In conclusion symptomatic children exposed to suboxone who were treated with naloxone, should be monitored overnight to avoid recrudescence of opioid effect as naloxone is eliminated.

( BUPP09884 - 28 October 2009) Involvement of the Different Opioid Receptors in Respiratory Depression in Rats

This study investigated the involvement of the different opioid receptors in respiratory depression in vivo in rat exposed to morphine, fentanyl, methadone, buprenorphine (all i.p.), i.v. naloxonazine, naltrindole and nor-binaltorphimine (both s.c.). The results indicated that the mechanisms of respiratory depression in relation to toxic doses of opioids was not uniform, depending on the molecule with different control patterns of PaCO2 and PaO2 as well as inspiratory and expiratory times by opioid receptors.

( BUPP09883 - 28 October 2009) Utilization Characteristics and Treatment Persistence in Patients Prescribed Low-Dose Buprenorphine Patches in Primary Care in the United Kingdom: A Retrospective Cohort Study

Background: The 7-day, low-dose buprenorphine patch has been available in the United Kingdom since 2005 for the treatment of chronic nonmalignant pain that is unresponsive to nonopioid analgesics. Osteoarthritis pain, a significant cause of pain and disability in the elderly, is a common reason for prescribing buprenorphine patches.Objectives: The goals of this study were to investigate utilization and treatment persistence in patients receiving low-dose buprenorphine patches and the expected patterns of treatment 12 months after the initiation of treatment.Methods: This was a retrospective cohort study of patients who were prescribed low-dose buprenorphine patches in general practice in the United Kingdom. Patients in this cohort were matched by age, sex, and practice with comparator cohorts prescribed oral codeine, dihydrocodeine, or tramadol. Data on baseline characteristics, utilization, and adverse events were obtained from the General Practice Research Database, which contains computerized medical records from UK general practice. Treatment persistence was determined based on repeat prescribing within 90 days after the expected end of a prescription; rates of persistence were compared between the buprenorphine and comparator cohorts. Cox proportional hazards regression models were used to compare the incidence of typical opioid adverse effects (constipation, dizziness, and nausea and/or vomiting) between cohorts .Results: The study cohort included 4968 patients who were prescribed low-dose buprenorphine patches. The majority of patients (64.2%) were aged >65 years, and the most frequently recorded indication for low-dose buprenorphine patches was osteoarthritis (48.7%). Most patients (76.1%) started treatment at the lowest patch strength (5 mu g/h). The mean patch strength prescribed over time stabilized at 10 to 12 mu g/h. Persistence with low-dose buprenorphine patches over 6 months was significantly higher than with codeine, dihydrocodeine, and tramadol (28.9%,22.4%,24.4%, and 23.8%, respectively; P < 0.01). Persistence over 12 months also was significantly higher with low-dose buprenorphine patches compared with the comparators (18.5%, 16.1%, 18.0%, and 17.6%; P < 0.01). After 12 months, the difference in persistence levels between cohorts was not statistically significant. In the Cox proportional hazards regression models, patients using buprenorphine patches had an increased incidence of constipation, dizziness, and nausea and vomiting compared with those who used the comparator opioids (P < 0.05). Conclusions: Significantly more patients receiving low-dose buprenorphine patches in this study persisted with treatment at 6 and 12 months compared with those receiving other opioid analgesics. Treatment with low-dose buprenorphine patches was most frequently initiated at the lowest patch strength and stabilized at a mean of 10 to 12 mu g/h.

( BUPP09882 - 28 October 2009) Antinociceptive effects of epidural buprenorphine or medetomidine, or the combination, in conscious cats

The aim of this study was to compare the antinociceptive effects of epidural buprenorphine (EB), epidural medetomidine (EM) or epidural buprenorphine-medetomidine (EBM). Eight cats were studied. Thermal thresholds (TT) were measured by increasing the temperature of a probe placed on the thorax. Mechanical thresholds (MT) were measured through inflation of a modified blood pressure bladder to the cat's forelimb. After baseline measurements, EB (0.02 mg/kg), EM (0.01 mg /kg) or half of the doses of each drug (EBM) were administered. Data were analysed using anova (P < 0.05) and 95% confidence interval (CI). TT increased from 30 min to 1 h after EB and at 45 min after EM. MT increased from 45 min to 2 h after EB, from 15 min to 1 h after EM and at 30, 45 min and at 2 h after EBM. MT were significantly lower after EB than EM at 30 min. TT were above the upper 95%CI from 15 min to 24 h after EB, from 15 min to 4 h after EM and from 15 min to 8 h after EBM. MT were above the upper 95%CI from 15 min to 5 h, and at 8, 12 and 24 h after EB, from 15 min to 6 h after EM and from 15 min to 6 h and at 12 and 24 h after EBM. All treatments had similar onset. Overall, EB presented longer period of action than EBM and EM. The same magnitude of analgesia was achieved, but with fewer side effects when EBM was compared with EM.

( BUPP09881 - 28 October 2009) Plasma buprenorphine concentrations after the application of a 70 mu g/h transdermal patch in dogs. Preliminary report

The objective of the present study was to evaluate the plasma concentrations and pharmacokinetics of buprenorphine after transdermal application in dogs (n = 4). A 70 mu g/h transdermal buprenorphine patch was applied to the ventral abdomen of four healthy beagles. Blood samples were collected through a preplaced jugular catheter before and at 1, 2, 4, 8, 12, 24, 36, 48 and every 6h until 108 h after the patch application. Plasma buprenorphine concentrations were measured using a

( BUPP09907 - 03 November 2009) Antidotes for poisonings: More need of evidence to improve clinical practice

( BUPP09906 - 03 November 2009) Mechanisms of disulfiram-induced cocaine abstinence: Antabuse and cocaine relapse

The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake. Recent clinical trials, initiated to investigate whether disulfiram could be used to treat individuals who abuse both alcohol and cocaine, have indicated that disulfiram effectively decreases cocaine consumption. Yet the ability of disulfiram to curb cocaine intake cannot be explained by the disruption of ethanol metabolism. Here, we synthesize clinical and animal data that point to dopamine beta-hydroxylase inhibition as a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence.

( BUPP09905 - 03 November 2009) Alpha /sub 2/ -adrenergic agonists for the management of opioid withdrawal

Background: Withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment. Objectives: To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists to manage opioid withdrawal. Search strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), Psyc INFO (1967 to 7 August 2008) and reference lists of articles. We also contacted manufacturers in the field. Selection criteria: Controlled trials comparing alpha /sub 2/ -adrenergic agonists with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha /sub 2/ -adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent. Data collection and analysis: One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors. Main results: Twenty-four studies, involving 1631 participants, were included. Twenty-one were randomised controlled trials. Thirteen studies compared a treatment regime based on an alpha2-adrenergic agonist with one based on reducing doses of methadone. Diversity in study design, assessment and reporting of outcomes limited the extent of quantitative analysis. Alpha2-adrenergic agonists are more effective than placebo in ameliorating withdrawal, and despite higher rates of adverse effects, are associated with significantly higher rates of completion of treatment. For the comparison of alpha2-adrenergic agonist regimes with reducing doses of methadone, there were insufficient data for statistical analysis, but withdrawal intensity appears similar to or marginally greater with alpha2-adrenergic agonists, while signs and symptoms of withdrawal occur and resolve earlier. Participants stay in treatment longer with methadone. No significant difference was detected in rates of completion of withdrawal with adrenergic agonists compared to reducing doses of methadone, or clonidine compared to lofexidine. Clonidine is associated with more adverse effects than reducing doses of methadone. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine Authors' conclusions: Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. No significant difference in efficacy was detected for treatment regimes based on clonidine or lofexidine, and those based on reducing doses of methadone over a period of around 10 days but methadone is associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.

( BUPP09904 - 03 November 2009) Pharmacological therapies for maintenance treatments of opium dependency

( BUPP09903 - 03 November 2009) Nalfurafine hydrochloride: A new drug for the treatment of uremic pruritus in hemodialysis patients

Uremic pruritus in hemodialysis patients is intractable and no effective treatments have been established yet. Although the precise mechanism of the pruritus is still unclear, accumulating evidence suggests that activation of the mu-opioid receptors may induce pruritus in hemodialysis patients. On the other hand, activation of kappa-opioid receptors is known to control or inhibit the signals activated through mu-opioid receptors; therefore, it was expected that kappa-opioid receptor agonists would be able to reduce pruritus in patients undergoing hemodialysis. Nalfurafine hydrochloride is a novel derivative of the opioid receptor antagonist naltrexone. Nalfurafine hydrochloride is a selective kappa-opioid receptor agonist and has a potent antipruritic effect on various types of pruritus through central kappa-opioid receptor activation in non-clinical pharmacological studies. Moreover, clinical studies have demonstrated that nalfurafine hydrochloride possesses efficacy and safety in hemodialysis patients with uremic pruritus. In this review, we provide a detailed description of the activity of nalfurafine hydrochloride using published data of in vitro, in vivo nonclinical pharmacological and clinical studies in hemodialysis patients with uremic pruritus.

( BUPP09902 - 03 November 2009) Incidence of hepatitis C in drug injectors: The role of homelessness, opiate substitution treatment, equipment sharing, and community size

A prospective cohort study estimated the incidence of hepatitis C virus (HCV) in drug injectors in South Wales (UK). In total, 286/481 eligible seronegative individuals were followed up after approximately 12 months. Dried blood spot samples were collected and tested for anti-HCV antibody and behavioural data were collected at baseline and follow-up. HCV incidence was 5.9/100 person-years (95% confidence interval (CI) 3.4-9.5). HCV incidence was predicted by community size (incident rate ratio (IRR) 6.6, 95% CI 2.11-20.51, P = 0.001), homelessness (IRR 2.9, 95% CI 1.02.-8.28, P = 0.047) and sharing injecting equipment (IRR 12.7, 95% CI 1.62-99.6, P = 0.015). HCV incidence was reduced in individuals in opiate substitution treatment (IRR 0.34, 95% CI 0.12-0.99, P = 0.047). In order to reduce follow-up bias we used multiple imputation of missing data using switching regression; after imputation estimated HCV incidence was 8.5/100 person-years (95% CI 5.4-12.7). HCV incidence varies with community size, equipment sharing and homelessness are associated with increased HCV incidence and opiate substitution treatment may be protective against HCV.

( BUPP09901 - 03 November 2009) Opiates inhibit paclitaxel uptake by P-glycoprotein in preparations of human placental inside-out vesicles

The use of either methadone or buprenorphine for treatment of the pregnant opiate-dependent patient improves maternal and neonatal outcome. However, patient outcomes are often complicated by neonatal abstinence syndrome (NAS). The incidence and severity of NAS should depend on opiate concentration in the fetal circulation. Efflux transporters expressed in human placental brush border membranes decrease fetal exposure to medications by their extrusion to the maternal circulation. Accordingly, the concentration of either methadone or buprenorphine in the fetal circulation is, in part, dependent on the activity of the efflux transporters. The objective of this study was to characterize the activity of P-gp and its interaction with opiates in the placental apical membrane. Therefore, brush border membrane vesicles were prepared from human placenta. The vesicles were oriented approximately 75% inside-out, exhibited saturable ATP-dependent uptake of P-gp substrate ( /sup 3/ H)-paclitaxel with an apparent K /sub t/ of 66 � 38 nM and V /sub max/ of 20 � 3 pmol mg protein /sup -1/ min /sup -1/ . Methadone, buprenorphine, and morphine inhibited paclitaxel transport with apparent K /sub i/ of 18, 44, and 90 muM, respectively. Our data indicate that a method has been established to determine the activity of the efflux transporter P-gp, expressed in placental brush border membranes, and the kinetics for the transfer of its prototypic substrate paclitaxel. Furthermore, the method was used to determine the effects of methadone, buprenorphine, and morphine on paclitaxel transfer by placental P-gp and revealed that they have higher affinity to the transporter than its classical inhibitor verapamil (K/sub i/ , 300 muM). � 2009 Elsevier Inc. All rights reserved. LG English.

( BUPP09900 - 03 November 2009) Anti-relapse medications: Preclinical models for drug addiction treatment

Addiction is a chronic relapsing brain disease and treatment of relapse to drug-seeking is considered the most challenging part of treating addictive disorders. Relapse can be modeled in laboratory animals using reinstatement paradigms, whereby behavioral responding for a drug is extinguished and then reinstated by different trigger factors, such as environmental cues or stress. In this review, we first describe currently used animal models of relapse, different relapse triggering factors, and the validity of this model to assess relapse in humans. We further summarize the growing body of pharmacological interventions that have shown some promise in treating relapse to psychostimulant addiction. Moreover, we present an overview on the drugs tested in cocaine or methamphetamine addicts and examine the overlap of existing preclinical and clinical data. Finally, based on recent advances in our understanding of the neurobiology of relapse and published preclinical data, we highlight the most promising areas for future anti-relapse medication development.

( BUPP09899 - 03 November 2009) Predicting falls among psychiatric inpatients: A case-control study at a state psychiatric facility

Objective: The purpose of the study was to add to the research on risk of falling in an understudied population of psychiatric inpatients in an acute setting. Methods: Five years of fall data in an inpatient psychiatric facility, where falls were frequent but benign, were examined for patient and treatment characteristics that might be associated with falls. This was a retrospective analysis, which matched 1:1 the medical records of fallers and nonfallers on primary psychiatric diagnoses. The total sample consisted of 148 patients. Statistical analysis was conducted on patient demographic characteristics, summed medical history items reported, summed physical complaints on the day of the fall, the number and types of medications taken within a 24-hour period of the fall, and the patient's vital signs. Multivariate logistic regression was used to identify the most salient associations with faller status. Results: Univariate analyses revealed that fallers were prescribed significantly more medications and complained of more physical symptoms on the day of their fall. Fallers were more likely to have a current acute medical condition and to be currently prescribed clonazepam or antihypertensive medication. Multivariate logistic regression analysis revealed that current physical complaints and current clonazepam treatment had significant associations with faller status. Conclusions: Risk factors identified in this study should be assessed in replication studies. Psychiatric clinicians can use such risk factors to create evidence-based fall prevention programs.

( BUPP09897 - 03 November 2009) Increase in expiratory time is characteristic of the respiratory response in rat to toxic doses of methadone and fentanyl but not morphine and buprenorphine

( BUPP09896 - 03 November 2009) Development and validation of a GC/MS method for the determination of buprenorphine and norbuprenorphine in blood

( BUPP09924 - 10 November 2009) A model for functional recovery and cortical reintegration after hemifacial composite tissue allotransplantation

Background: The ability to achieve optimal functional recovery is important in both face and hand transplantation. The purpose of this study was to develop a functional rat hemifacial transplant model optimal for studying both functional outcome and cortical reintegration in composite tissue allotransplantation. Methods: Five syngeneic transplants with motor and sensory nerve appositions (group 1) and five syngeneic transplants without nerve ppositions (group 2) were performed. Five allogeneic transplants were performed with motor and sensory nerve appositions (group 3). Lewis (RT /sup 1/ ) rats were used for syngeneic transplants and Brown-Norway (RT /sup n/ ) donors and Lewis (RT /sup 1/ ) recipients were used for allogeneic transplants. Allografts received cyclosporine A monotherapy. Functional recovery was assessed by recordings of nerve conduction velocity and cortical neural activity evoked by facial nerve and sensory (tactile) stimuli, respectively. Results: All animals in groups 1 and 3 showed evidence of motor function return on nerve conduction testing, whereas animals in group 2, which did not have nerve appositions, did not show electrical activity on electromyographic analysis (p < 0.001). All animals in groups 1 and 3 showed evidence of reafferentation on recording from the somatosensory cortex after whisker stimulation. Animals in group 2 did not show a cortical response on stimulation of the whiskers (p < 0.001). Conclusion: The authors have established a hemiface transplant model in the rat that has several modalities for the comprehensive study of motor and sensory recovery and cortical reintegration after composite tissue allotransplantation.

( BUPP09923 - 10 November 2009) Trends in opioid consumption in the Nordic countries 2002-2006

Objective: The purpose of the study was to examine the trends in opioid consumption in the five Nordic countries between 2002 and 2006 and to explore possible explanations for changes in the quality and quantity of opioids consumed. Methods: Data on opioid consumption were extracted from the databases of the respective national authorities. Six strong and four weak opioids were included in the analysis. Data were presented as DDDs/1000 inhabitants/day. In addition, information on the reimbursement system and opioid prescription regulations in respective countries was obtained. Also, the cost of analgesic medication in the Nordic countries was compared as equipotent doses of CR morphine, CR oxycodone and transdermal fentanyl. Results: During the five year period examined the total use of opioids showed some increase in all countries except Sweden. In Finland and Norway the increase in the total consumption was mainly due to an increase in the consumption of strong opioids while in Denmark the rise was due to increased consumption of weak opioids. The consumption of morphine was stabile or decreased slightly in all countries while the use of transdermal fentanyl increased in Denmark, Finland and Sweden and oxycodone in all countries except Iceland. The consumption of dextropropoxyphene decreased in all countries. Reimbursement policies or prescription regulations do not seem to explain the kind/type of opioids consumed or changes in their consumption. Conclusions: Consumption of opioid analgesics in the Nordic countries showed changes over the five year period that cannot be explained by pharmacology, price, reimbursement or prescription regulations. Marketing has most likely significantly influenced the type and amount of opioids consumed.

( BUPP09922 - 10 November 2009) Introduction of low dose transdermal buprenorphine - Did it influence use of potentially addictive drugs in chronic non-malignant pain patients?

The aim was to study the introduction of the new low dose transdermal buprenorphine (LD-TD-BUP) in Norway, particularly with regard to former use and co-medication with other potentially addictive drugs. The nationwide Norwegian Prescription Database contains information on all prescription drugs dispensed to individual non- institutionalised patients, and we may follow all individuals who received LD-TD-BUP (Norspan /sup �/ ) after marketing on the Norwegian market on 15/11/05. We studied all prescriptions of opioids and other potentially addictive drugs to patients receiving at least two LD-TD-BUP prescriptions during 2004-2006. Poisson regressions were run with concomitant use of addictive drugs (yes, no) as the endpoint. Overall, 1884, non cancer individuals received at least two prescription of LD-TD-BUP. Of these 91.7% received prescriptions of other opioids and 58.6% of them had also been prescribed benzodiazepines/carisoprodol before the prescription of LD-TD-BUP. Of the LD-TD-BUP users who received more than one prescription, 60% co-medicated with at least one other potentially addictive drug, and 24% with at least two. In the multivariate analysis, the variables associated with a higher likelihood of using co-medicated drugs were: previous use of benzodiazepines/carisoprodol relative risk RR = 16.7 (95% CI 10.4-26.9), previous use of opioids RR = 4.0 (1.9-8.7) and younger age 20-40 years RR = 1.9 (1.6-2.3). So far, it is questionable whether the introduction of LD-TD-BUP actually has stabilised opioids consumption or whether it has complicated and increased the consumption of potentially addictive drugs.

( BUPP09921 - 10 November 2009) Pharmacologic management of cancer pain

Recent surveys report that up to two-thirds of cancer patients suffer from severe pain in their last months, although most could be treated successfully by consequent pharmacologic pain management. This review describes the basis of pain classification, differences between nociceptive and neuropathic pain, and pain measurement. The use of nonopioid and opioid drugs as well as co-analgesics and NMDA receptor antagonists is summarized. Opioid rotation, side effects, and the treatment of breakthrough pain are highlighted. Tables give a brief overview of dosing and the characteristics of particular drugs. However, pharmacologic management should always be embedded in a holistic approach comprising appropriate cancer-specific therapies as well as the psychosocial and spiritual needs of the patient.

( BUPP09920 - 10 November 2009) Screening for illicit drug use: Recommendation statement - Summary of recommendations and evidence

( BUPP09919 - 10 November 2009) Traumatic rectal perforation presenting as necrotising fasciitis of the lower limb

Necrotising fasciitis is a life-threatening soft tissue infection that is associated with high mortality and morbidity. It has been described in the form of Fournier's gangrene following rectal perforations related to colorectal cancer. In these rare instances, spontaneous perforation of locallyadvanced rectal carcinoma provides an entry point for bacterial seeding to the surrounding soft tissues, resulting in Gram-negative sepsis of the perineum. To our knowledge, necrotising fasciitis extending beyond the perineum due to rectal perforation has not been previously described. We report an unusual self-induced traumatic rectal perforation presenting with severe necrotising fasciitis of the lower limb in a 73-year-old Chinese man. Our patient was successfully treated with a multidisciplinary approach that involved a defunctioning colostomy as well as prompt and rigorous debridement of the affected limb. We also review the literature on the management of retroperitoneal rectal perforations and their sequalae, as well as discuss the various surgical options commonly applied and their outcomes.

( BUPP09918 - 10 November 2009) An empirical study on the selection of analytes and corresponding cutoffs for immunoassay and GC-MS in a two-step test strategy - Buprenorphine example

(i) Standard solutions of buprenorphine (B) and three metabolites; (ii) immunoassay (IA) reagents designed for the analysis of B and/or its metabolites; and (iii) clinical urine specimens collected from patients (under B-treatment), constitute the B-System for fundamental study of parameters critical to the two-step test strategy, an analytical approach designed for a high-volume testing environment. The cross-reacting characteristics of IA reagents were examined using standard solutions of B and its metabolites. Resulting data were used as the basis for selecting target analytes suitable for the preliminary and the confirmatory test steps. Test data derived from IA and GC-MS analysis of clinical urine specimens (with natural distribution of B and its metabolites) were quantitatively correlated. Correlation parameters were examined: (i) to verify whether the analyte-pair targeted by the IA and GC-MS test steps has been properly selected; and (ii) to decide on appropriate cutoffs for the two test steps. In conclusion, this study has demonstrated that the most effective analyte(s) that should be targeted in the GC-MS determination step vary with the IA selected in the preliminary test step. All analytes that generate significant responses to the IA reagent should be targeted in the GC-MS test step. LG English.

( BUPP09917 - 10 November 2009) Vascular ultrasound studies for the non-invasive assessment of vascular flow and patency in experimental surgery in the pig

Vascular ultrasound is a reliable non-invasive tool used for the routine assessment of vascular flow and patency in human recipients. We describe the use at three different time points (immediately, 1 week and 4 weeks postsurgery) of ultrasound studies and its validation by angiographic studies in 37 swine undergoing carotid graft replacement. We calculated predictive values (>92%), sensitivity (>85%) and specificity (>92%) with high results at all time points. Ultrasound appeared as an accessible non-invasive technique, providing rapid, safe, repeatable and reliable results. It is an excellent alternative to angiography, avoiding risks inherent to invasive methods and therefore contributing to animal welfare.

( BUPP09916 - 10 November 2009) Development of perioperative care for pigs undergoing laryngeal transplantation: A case series

Pigs are ideal animal models for airway surgical research, facilitating the successful translation of science into clinical practice. Despite their ubiquitous use, there is a paucity of information on the perioperative care of pigs, especially for major procedures. In a series of experiments to investigate laryngeal transplantation, we combined veterinary and medical experience to develop protocols for perioperative management of pigs, including high dependency care. Novel airway management methods were developed. A pain scoring system was used to direct analgesia use. Fluid balance and electrolytes were monitored closely. Recent animals received a central venous line via the femoral vein two days prior to transplantation to facilitate blood sampling and drug delivery. Intensive monitoring and airway management were required to ensure a successful outcome. Methods for optimal perioperative care are proposed. These results will help future groups wishing to use pigs in airway research, will reduce numbers of animals used and improve animal welfare.

( BUPP09915 - 10 November 2009) Codeine-induced generalized dermatitis and tolerance to other opioid

( BUPP09914 - 10 November 2009) Could anaesthesia, analgesia and sympathetic modulation affect neoplasic recurrence after surgery? A systematic review centred over the modulation of natural killer cells activity

Objective: The Natural Killer cells (NK) are an important part of non-specific cellular-mediated and antitumoral immunity. The goal of this review is to recapitulate data published over NK activity during the perioperative period and the influence of anaesthesia, analgesia and modulation of sympathetic system. Data sources: Pubmed/Medline database. Study selection and data extraction: Keywords-based selection, without limit of date: fundamental studies, randomized controlled trials and non-randomized comparative studies. Data synthesis: In human as in animal studies, an important correlation exists between NK activity and prognosis linked to the development of metastasis. The great depression of this cytotoxicity during the perioperative period could be able to compromise host defenses. The influence of anaesthetics and analgesics is important. The effects of the opioids, the agonists and the antagonists of the sympathetic nervous system, the prostaglandins, the NSAIDs, the ketamine, the hypnotics and the locoregional anaesthesia are systematically reviewed. The limits of experimental model presented are covered. Conclusion: The effects of anaesthetic/analgesic drugs and techniques, the consequences of sympathomodulation on NK activity are numerous and sometimes opposite. It is important for the anaesthesiologist to keep in mind that the long term consequences of his techniques on the patients' outcome must be clarified.

( BUPP09913 - 10 November 2009) Prescription of psychotropic drugs in incarcerated patients treated with methadone or high dose buprenorphine for opioid substitution therapy

This retrospective study assessed the prescription of psychotropic drugs in 262 incarcerated patients treated with methadone (MET) or high dose buprenorphine (BUP) for opioid substitution therapy (OST). Mean number of associated drugs was 3.74 for MET and 3.42 for BUP. The results suggest that a high level of association of pyschotropic drugs were observed with OST.

( BUPP09912 - 10 November 2009) Benzodiazepine influence on buprenorphine-induced conditioned place preference in mice

This study evaluated the influence of i.p. benzodiazepine (BZD) on buprenorphine (BPN)-induced conditioned place preference in vivo in mice. The mice treated with BPN + dipotassium clorazepate (CRZ) increased the time spent in the drug paired chamber compared to the group treated with BPN alone. The results indicated that CRZ influenced BPN induced place preference. Thus joint comumption of BZD with CRZ may increase the addidive properties of BPN alone.

( BUPP09911 - 10 November 2009) Haemodynamic changes in acute opiate withdrawal

( BUPP09910 - 10 November 2009) The effects of sevoflurane and propofol on glucose metabolism under aerobic conditions in fed rats

BACKGROUND: Recent studies reported that intraoperative hyperglycemia is an independent risk factor for mortality and morbidity related to surgery. Volatile anesthetics, such as sevoflurane, impair glucose use, suggesting their possible contributions to intraoperative hyperglycemia. However, the effects of IV anesthetics, such as propofol, on glucose metabolism are poorly understood. Thus, we compared the effects of sevoflurane and propofol on glucose metabolism under aerobic conditions in fed rats. METHODS: We first examined changes in blood glucose levels in rats undergoing sigmoid colostomy under sevoflurane, sevoflurane/buprenorphine, propofol, and propofol/buprenorphine anesthesia. We then examined changes in blood glucose levels after glucose administration using awake rats, rats under sevoflurane anesthesia, and rats under propofol anesthesia. RESULTS: Blood glucose levels increased markedly after sigmoid colostomy under sevoflurane anesthesia; the marked increases could not be prevented by the coadministration of buprenorphine. Under propofol anesthesia, blood glucose levels did not change after sigmoid colostomy at the highest dose, but increased slightly at the lowest and intermediate doses; the slight increases were completely prevented by the coadministration of buprenorphine. Whereas changes in blood glucose levels after glucose administration in rats under sevoflurane anesthesia were significantly greater than those in awake rats, the changes in rats under propofol anesthesia were similar to those in awake rats. CONCLUSIONS: During surgery, hyperglycemia was observed under sevoflurane and sevoflurane/buprenorphine anesthesia, but blood glucose levels were relatively stable under propofol and propofol/buprenorphine anesthesia. Whereas sevoflurane exaggerates glucose intolerance, propofol has no significant effects on glucose tolerance. We speculate that this feature of propofol contributes, at least in part, to the stable glucose metabolism during surgery observed in this study. The results of this study confirm the marked difference in the effects of sevoflurane and propofol on glucose metabolism.

( BUPP09909 - 10 November 2009) Pediatric Buprenorphine/Naloxone Poisoning: A Case Series

( BUPP09908 - 10 November 2009) Novel Approach to the Treatment of Opiate Addiction in Adolescents

( BUPP09931 - 18 November 2009) Predictors for Non-Relapsing in Methadone- and Buprenorphine-maintained heroin Addicts: A Comparative Study

( BUPP09929 - 18 November 2009) The clinical efficacy and abuse potential of combination buprenorphine-naloxone in the treatment of opioid dependence

Background: Opioid dependence is a chronic relapsing condition for which long-term opioid substitution treatment (OST) is effective. However, safety and community acceptance of OST is compromised by diversion of prescribed medication. The development of a formulation combining buprenorphine and naloxone is designed to reduce the likelihood of intravenous misuse, and the therefore the value of the medication if diverted to the black market. Objective: To evaluate the evidence for 4:1 buprenorphine-naloxone as an efficacious OST, and as a deterrent to diversion and intravenous misuse. Methods: The literature on buprenorphine-naloxone in a 4:1 ratio is reviewed. Results/conclusion: The addition of naloxone does not appear to affect the efficacy of buprenorphine as a maintenance drug. While offering some deterrence of injection through precipitated withdrawal, there are many circumstances where injecting of buprenorphine-naloxone is reinforcing rather than aversive. The combination will reduce, but not eliminate, intravenous misuse; clinicians therefore need to monitor patients in OST, and be selective in providing patients with medication to be taken without observation.

( BUPP09928 - 18 November 2009) Translational Pain Research: Achievements and Challenges

The achievements in both preclinical and clinical pain research over the past 4 decades have led to significant progress in clinical pain management. However, pain research still faces enormous challenges and there remain many obstacles in the treatment of clinical pain, particularly chronic pain. Translational pain research needs to involve a number of important areas including: 1) bridging the gap between pain research and clinical pain management; 2) developing objective pain-assessment tools; 3) analyzing current theories of pain mechanisms and their relevance to clinical pain; 4) exploring new tools for both preclinical and clinical pain research; and 5) coordinating research efforts among basic scientists, clinical investigators, and pain-medicine practitioners. These issues are discussed in this article in light of the achievements and challenges of translational pain research. Perspective: The subjective nature of clinical pain calls for innovative research approaches. As translational pain research emerges as an important field in pain medicine, it will play a unique role in improving clinical pain management through coordinated bidirectional research approaches between bedside and bench.

( BUPP09927 - 18 November 2009) Barbed suture for gastrointestinal closure: A randomized control trial

In an effort to make laparoscopic suturing more efficient, the V-Loc advanced wound closure device (Covidien, Mansfield, MA) has been produced. This device is a self-anchoring barbed suture that obviates the need for knot tying. The goal of this initial feasibility study was to investigate the use of the barbed suture in gastrointestinal enterotomy closure. A randomized study of 12 pigs comparing enterotomy closure with barbed versus a nonbarbed suture of similar tensile strength was performed. To this end, 25 mm enterotomies were made in the stomach (1 control, 1 treatment), jejunum (2 controls, 2 treatments), and descending colon (1 control, 1 treatment). Animals were killed at 3, 7, and 14 days postoperatively (4 each group) and their gastrointestinal tracts harvested; 6 of the 8 enterotomies from each pig underwent burst strength testing. The remaining 2 were fixed in formalin and sent for histological examination. All 12 pigs survived until they were killed without any major complications. Enterotomy closure with barbed suture revealed adhesion scores, burst strength pressures, and histology scores that were similar to those for control. Jejunal closures resulted in 6 failures at 7 days (3 control, 3 barbed) and 4 failures at 14 days (2 control, 2 barbed). The barbed suture significantly reduced suturing time in the stomach, jejunum, and colon. The V-Loc wound closure device appears to offer comparable gastrointestinal closure to 3-0 Maxon while being significantly faster. Further studies with V-Loc are required to assess its use in laparoscopic surgery.

( BUPP09926 - 18 November 2009) Vaccines against morphine/heroin and its use as effective medication for preventing relapse to opiate addictive behaviors

Current pharmacotherapies for treating morphine/heroin dependence are designed to substitute or block addiction by targeting the drug itself rather than the brain. The heroin addict is still being exposed to addictive opiates, and consequently may develop tolerance to and experience withdrawal and drug's toxic effects from the treatment with high incidence of relapse to addictive drug consumption. As for other drugs of abuse, an alternative approach for morphine/heroin addiction is an antibody-based antagonism of heroin's brain entry. This review summarizes the literature examining important aspects of neurobiological and pharmacological processes involved in opiate dependence. Thereafter, classical pharmacological interventions for opiate dependence treatment and its major clinical limitations are reviewed. Finally, relevant preclinical studies are examined for comparisons in the design, use, immunogenic profile and efficacy of several models of morphine/heroin vaccine as immunologic interventions on the pharmacokinetics and behavioral of morphine /heroin in the rat as animal model.

( BUPP09925 - 18 November 2009) Buprenorphine strongly attenuates neuropathic pain induced by spinal nerve injury or chemotherapy in laboratory animals

( BUPP09942 - 10 December 2009) Analgesia misuse: Pharmacy's challenge

( BUPP09941 - 10 December 2009) Detection of corneal fibrosis by imaging second harmonic-generated signals in rabbit corneas treated with mitomycin C after excimer laser surface ablation

( BUPP09940 - 10 December 2009) Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers

( BUPP09939 - 10 December 2009) Opioids in cancer pain

( BUPP09938 - 10 December 2009) Orotransmucosal drug delivery systems: A review

( BUPP09937 - 10 December 2009) Decompressive craniectomy for intracerebral hemorrhage

( BUPP09936 - 10 December 2009) Eosinophilic panniculitis: a new form of local reaction with specific immunotherapy

( BUPP09935 - 10 December 2009) Retention in Opioid Substitution Treatment: A Major Predictor of Long-Term Virological Success for HIV-Infected Injection Drug Users Receiving Antriretroval Treatment

( BUPP09934 - 10 December 2009) Spotlight on Buprenorphine/Naloxone in the Treatment of Opioid Dependence

( BUPP09933 - 10 December 2009) Neuropsychological functioning in buprenorphine maintained patients versus abstinent heroin abusers on naltrexone hydrochloride therapy

( BUPP09932 - 10 December 2009) Molecular, Anatomical, Physiological, and Behavioural Studies of Rats Treated with Buprenorphine after Spinal Cord Injury

Acute pain is a common symptom experiended after spinal cord injury (SCI). The presence of this pain calls for treatment with analgesics, such as buprenorphine. However, there are concerns that the drug may exert other

( BUPP09952 - 10 December 2009) Nitrous oxide-induced analgesia does not influence nitrous oxide's immobilizing requirements

BACKGROUND: Nitrous oxide (N2O) acts on supraspinal noradrenergic neurons to produce analgesia, but it is unclear if analgesia contributes to N2O's immobilizing effects. We tested the hypothesis that N2O minimum alveolar anesthetic concentration (MAC) is unchanged after selective ablation of supraspinal noradrenergic neurons, or in naive animals at N2O exposure timepoints when analgesia is absent. METHODS: We determined tailflick latency (TFL) and hindpaw withdrawal latency (HPL) under 70% N2O, N2O MAC, and isoflurane MAC before and after intracerebroventricular injections of anti-dopamine-beta hydroxylase conjugated to saporin (SAP-DBH; n = 7), or a control antibody conjugated to saporin (n = 5). In a separate group of naive rats (n = 8), N2O MAC was determined at 25-45 min after initiation of N2O exposure (during peak analgesia) and again at 120-140 min (after TFL and HPL returned to baseline). RESULTS: After 30 min of N2O exposure, TFL and HPL increased significantly but declined back to baseline within 120 min. N2O did not produce analgesia in rats that received SAP-DBH. However, N2O and isoflurane MAC were not significantly different between SAP-DBH and control-injected animals (Mean � sd for N2O: 1.7 � 0.1 atm vs 1.7 � 0.2 atm; isofurane: 1.6 � 0.2% vs 1.7 � 0.2%). In naive animals, N2O MAC was not different at the 30 min period compared with the 120 min period (1.8 � 0.1 atm vs 1.8 � 0.2 atm). CONCLUSIONS: Destroying brainstem noradrenergic neurons or prolonged exposure to N2O removes its analgesic effects, but does not change MAC. The immobilizing mechanism of N2O is independent from its analgesic effects.

( BUPP09951 - 10 December 2009) Substance misuse during pregnancy: Its effects and treatment.

( BUPP09950 - 10 December 2009) Pharmacological therapies for management of opium withdrawal

( BUPP09949 - 10 December 2009) Intravenous Naloxone Plus Transdermal Buprenorphine in Cancer Pain Associated with Intractable Cholestatic Pruritus

( BUPP09948 - 10 December 2009) Determination of naloxone and nornaloxone (noroxymorphone) by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry

A highly sensitive method was developed to measure naloxone and its metabolite nornaloxone in human plasma, urine, and human liver microsomes (HLM). Naltrexone-d /sub 3/ and oxymorphone-d /sub 3/ were used as respective internal standards. Solid-phase extraction, using mixed mode extraction columns and 0.1 M phosphate buffer (pH 5.9), was combined with high-performance liquid chromatography interfaced by electrospray ionization to tandem mass spectrometry. The calibration range in plasma was 0.025 to 2 ng/mL for naloxone and 0.5 to 20 ng/mL for nornaloxone. It was 10 to 2000 ng/mL in urine and 0.5 to 20 ng/mL in HLM for both. Enzymatic hydrolysis of urine was optimized for 4 h at 40� C. Intra- and interrun accuracy was within 15% of target; precision within 13.4% for all matrices. The mean recoveries were 69.2% for naloxone and 32.0% for nornaloxone. Analytes were stable in plasma and urine for up to 24 h at room temperature and in plasma after three freeze-thaw cycles. In human subjects receiving 16 mg buprenorphine and 4 mg naloxone, naloxone was detected for up to 2 h in all three subjects and up to 4 h in one subject. Mean AUC /sub 0-24/ was 0.303 � 0.145 ng/mL h; mean C /sub max/ was 0.139 � 0.062 ng/mL; and T /sub max/ was 0.5 h. In 24-h urine samples, about 55% of the daily dose was excreted in either conjugated or unconjugated forms of naloxone and nornaloxone in urine. When cDNAexpressed P450s were incubated with 20 ng of naloxone, nornaloxone formation was detected for P450s 2C18, 2C19, and 3A4. Naloxone utilization exceeded nornaloxone formation for 2C19 and 3A4, indicating they may produce products other than nornaloxone. These results demonstrate a new method suitable for both in vivo and in vitro metabolism and pharmacokinetic studies of naloxone.

( BUPP09947 - 10 December 2009) Buprenorphine maintenance treatment in a primary care setting: Outcomes at 1 year.

The purposes of this study were to assess outcomes of patients prescribed buprenorphine at a primary care practice and to identify factors associated with favorable outcomes. All 255 patients given at least one prescription for buprenorphine between August 2003 and September 1, 2007, at a primary care practice in Baltimore were included. Data regarding demographics and comorbidities were collected retrospectively. Patients were classified as "opioid-positive" or "opioid-negative" each month based on patient report, urine toxicology, and provider assessment. After 12 months, 145 (56.9%) patients remained in treatment, and 64.7% of their months were opioid-negative. Patients using heroin were less likely to be opioid-negative, whereas those using prescription opioids were more likely to be opioid-negative. Polysubstance use was associated with increased treatment retention. The prescription of buprenorphine for opioid dependence treatment can be incorporated into primary care practice, and many patients, including polysubstance users, benefit from this treatment.

( BUPP09946 - 10 December 2009) Effect of plasma proteins on buprenorphine transfer across dually perfused placental lobule

Objective. The aim of this investigation is to determine the effect of human serum albumin HSA and alpha-acid glycoprotein AAG on buprenorphine BUP transplacental transfer and distribution. Methods. The technique of dual perfusion of placental lobule DPPL was utilised. BUP was co-perfused with the marker compound antipyrine AP. In each experiment, the radiolabelled isotopes /sup 3/ H-BUP and /sup 14/ C-AP were added to enhance their detection limits. Human plasma proteins, HSA and AAG, were added to both the maternal and fetal circuits separately and in combination at their physiological concentrations in maternal and fetal circulations close to term. Results. Transplacental transfer of BUP, in absence of plasma proteins, is a two-step process: the first is its uptake by the syncytiotrophoblast from the maternal circuit, and the second is its transferrelease from the tissue to the fetal circuit. The addition of HSA to the perfusion medium affected only the second step of BUP transfer, but AAG affected both steps. The combined effect of HSA and AAG was not different from that observed in presence of the latter alone. Conclusions. Binding of BUP to circulating A AG could have an important role in the transfer of the drug from the maternal to fetal circulation.

( BUPP09945 - 10 December 2009) Self-perceived motivation for benzodiazepine use and behavior related to benzodiazepine use among opiate-dependent patients

Clinical observations have shown a high prevalence of benzodiazepine use among opiate-dependent patients. Our objective was to identify if distinct patterns of behavior could be associated with three different self-perceived motivations for benzodiazepine use: (a) exclusive self-therapeutic motivation, (b) exclusive hedonic motivation, and (c) combined self-therapeutic and hedonic motivation. Data were collected through a self-administered questionnaire in 92 opiate users in treatment in France (Aquitaine). The behaviors associated with exclusive self-therapeutic motivation included the search for an anxiolytic effect, oral administration, use within the context of a medical prescription, and use without other substances. The behaviors associated with exclusive hedonic motivation were use in combination with other substances, the obtaining of benzodiazepines by the black market, and use of other routes of administration in search of a "blackout." Among patients who reported both motivations, there were distinct trends of behavior according to motivation.

( BUPP09944 - 10 December 2009) Determinants of successful chronic hepatitis C case finding among patients receiving opioid maintenance treatment in a primary care setting

AimsInjection drug users are at high risk for chronic hepatitis C virus infection (CHC). Opioid maintenance treatment (OMT) offers a unique opportunity to screen for CHC. This study proposed the hypothesis that a general practitioner (GP) with special interest in addiction medicine can achieve CHC screening rates comparable to specialized centres and aimed to investigate determinants for a successful CHC case finding in a primary care setting.Design and participantsRetrospective medical record analysis of 387 patients who received opioid maintenance therapy between 1 January 2002 and 31 May 2008 in a general practice in Zurich, Switzerland.Measurements Successful CHC assessment was defined as performance of hepatitis C virus (HCV) serology with consecutive polymerase chain reaction-based RNA and genotype recordings. The association between screening success and patient characteristics was assessed using multiple logistic regression.FindingsMedian (interquartile range) age and duration of OMT of the 387 (268 males) patients was 38.5 (33.6-44.5) years and 34 (11.3-68.0) months, respectively. Fourteen patients (3.6%) denied HCV testing and informed consent about screening was missing in 13 patients (3.4%). In 327 of 360 patients (90.8%) with informed consent a successful CHC assessment has been performed. Screening for HCV antibodies was positive in 136 cases (41.6%) and in 86 of them (63.2%) a CHC was present. The duration of OMT was an independent determinant of a successful CHC assessment. Conclusions: In addicted patients a high CHC assessment rate in a primary care setting in Switzerland is feasible and opioid substitution provides an optimal framework.

( BUPP09943 - 10 December 2009) Comparative Immunovirological Study between Buprenorphine and Methadone Using Human Lymphocytes and Glial Cells

( BUPP09964 - 16 December 2009) Articular cartilage degeneration following the treatment of focal cartilage defects with ceramic metal implants and compared with microfracture

Background: Localized cartilage defects are frequently associated with joint pain, reduced function, and a predisposition to the development of osteoarthritis. The purposes of the current study were to investigate the feasibility of the application of defect-sized femoral implants for the treatment of localized cartilage defects and to compare this treatment, in terms of joint degeneration, with the use of microfracture in a goat model of established cartilage defects. Methods: In nine Dutch milk goats, a defect in the medial femoral condyle was created in both knees. After ten weeks, the knees were randomly treated by microfracture or by placement of an oxidized zirconium implant. At twenty-six weeks after surgery, the animals were killed. The joints were evaluated macroscopically. Implant osseointegration was measured by automated histomorphometry, and cartilage repair (after microfracture) was scored histologically. Cartilage quality was analyzed macroscopically and histologically. Glycosaminoglycan content and release were measured by alcian blue assay, and the synthesis and release of newly formed glycosaminoglycans were measured by liquid scintillation analysis of the incorporation of /sup 35/ SO /sub 4/ /sup 2-/ in tissue and medium. Results: The mean bone-implant contact (and standard error) was appropriate (14.6% � 5.4%), and the amount of bone surrounding the implantwas extensive (mean, 40.3% � 4.0%). The healing of themicrofracture-treated defects was extensive, although not complete (mean, 18.38 � 0.43 points of a maximum possible score of 24 points). The macroscopic cartilage evaluation did not show any significant differences between the treatments. On histologic evaluation, the cartilage of the medial tibial plateau articulating directly against the treated defects demonstrated significantly more degeneration in the microfracture-treated knees than in the implant-treated knees (p < 0.05). This was in accordance with a significantly higher glycosaminoglycan content, higher synthetic activity, and decreased glycosaminoglycan release of the medial tibial plateau cartilage of the implant-treated knees (p < 0.05 for all). On histological analysis, degeneration was also found in the cartilage of the lateral tibial plateau and condyle, but no significant difference was found between the treatments. Conclusions: Both microfracture and the use of implants as a treatment for established localized cartilage defects in the medial femoral condyle caused considerable (p < 0.05) degeneration of the directly articulating cartilage as well as in more remote sites in the knee. However, in themedial tibial plateau, themetal implants caused less damage than the microfracture technique. Clinical Relevance: Although this study shows that small metal implants may be more suitable than microfracture in the treatment of localized cartilage defects in the knee, the generalized degeneration found following both treatments should be addressed first.

( BUPP09963 - 16 December 2009) Detection of abused drugs in urine by GC-MS

This paper reviews gas chromatography-mass spectrometry (GC-MS) methods for the analysis of amphetamines, ketamines, opioids, cocaine, and other abused drugs in urine that were developed by authors in Taiwanese institutions, and published during the 2000 to early 2008 period. Information on sample preparation, derivatization, internal standard, GC column, detection mode, and validation data for the reported methods are summarized in table format to facilitate readers' reference and adaptation.

( BUPP09962 - 16 December 2009) Examination of opioid prescribing in Australia from 1992 to 2007: ORIGINAL ARTICLE

Background: Opioid prescribing is controversial with evidence of both significant under-utilization and over-utilization. There is some evidence to support efficacy for chronic non-malignant pain, but community and individual harms are increasingly reported. Aims: To review availability of opioid preparations and prescription patterns of opioids through the subsidized Pharmaceutical Benefits Scheme in Australia from 1992 to 2007. Methods: Interrogation of the Health Insurance Commission database from 1992 to 2007. Item numbers for all available opioid preparations were identified, and frequency of dispensing was collected and collated. Results: The number of opioids on the Pharmaceutical Benefits Scheme (PBS) increased from 11 preparations of four medications to 70 preparations of eight medications during this period. The total number of PBS opioid prescriptions increased from 2 397 006 in 1992 to 6 998 556 in 2007. We identified a dramatic and continuing increase in prescription of oxycodone in all dose ranges. Fentanyl prescribing is increasing to a lesser degree. Morphine and tramadol prescribing appears to have plateaued. Conclusion: Opioid use is increasing. There is a pressing need for co-ordinated assessment of efficacy and harms to facilitate quality usage of opioids.

( BUPP09961 - 16 December 2009) State of Consciousness During the Last Days of Life in Patients Receiving Palliative Care

( BUPP09960 - 16 December 2009) Therapy of perioperative pain in pediatric urology

Difficulties in estimating the kind and inten-sity of pain as well as uncertainty in drug se-lection and dosing are often responsible for a suboptimal treatment of pain therapy in the various age groups in childhood. The follow-ing article will help to minimize these deficits by contributing full details of safe and ef-fective concepts for perioperative pain therapy in childhood.

( BUPP09959 - 16 December 2009) Cancer pain therapy

Pain belongs to the most prevalent symp-toms that require patients with urological tumours to seek medical help. The treatment of cancer pain requires standardized guidelines that are best reflected by the WHO'S three-step ladder of cancer pain relief. This implies an individualized approach, a detailed history taking of underlying pain and thor-ough clinical examination, as well as a consistent and forceful therapy of constant and breakthrough pain episodes, using pharmacological substances and non-pharmacological techniques.This requires the choice of the correct drug, an application "by the clock " an individualized dose titration, and the use of coanalgesics. For constant "backg round" pain, slow release substances are needed, whilst fast acting pain medication is given on demand for breakthrough pain episodes. Be sides symptomatic analgesic therapy, cancer pain therapy may also comprise tumor specific treatment modalities, whenever ap-propriate and requested by the patient. This comprises radiation therapy, e.g. for bone or soft tissue processes or brain metastases, as well as radionuclide techniques, surgical pro cedures, chemotherapy, new substances or antihormonal therapy. Furthermore, pain is considered a multimodal experience that requires the consideration of psychical and so-cial factors. This chapter describes the differ-ent facets of cancer pain, its epidemiology, pathophysiology, diagnostics and therapeutic principles.

( BUPP09958 - 16 December 2009) Disproportionately high rate of epileptic seizure in patients abusing dextropropoxyphene dextropropoxyphene

Dextropropoxyphene (DPP), a weak opioid, is often abused as a psychoactive substance. In this retrospective chart review to document, characterize and put in perspective the often-obtained history of epileptic seizures in patients with DPP abuse, we analyzed the case files of all patients with DPP abuse registered in our center (a tertiary-care drug de-addiction clinic in north India) from May 1, 2001 until April 30, 2007 and those with use of other opioids during the same period. Non-drug-related seizures were excluded from analysis. Out of 312 patients with DPP abuse, 63 (20.2) had epileptic seizures related to DPP use, in contrast to 0.4 4.2 of other opioid users. The seizures were mostly characterized as generalized tonic-clonic seizures (87.3), occurring around two hours following a higher-than-usual dose of DPP. Those with seizures had significantly greater duration of DPP use and higher rates of medical comorbidity compared to patients without seizure. Age, duration of use and medical comorbidity were better predictors of seizure than dosage of drug or use of multiple drugs. Thus, DPP-induced epileptic seizures are common (one in five), and much more frequent than seizures in patients using other opioids. The awareness of this phenomenon has implications for diagnosis and management, as well as for drug regulation policy.

( BUPP09957 - 16 December 2009) Analgesic patches and defibrillators: A cautionary tale

Implantable cardioverter defibrillator (ICD) insertions have increased significantly over the last decade. Transdermal patches are increasingly used for drug delivery. Skin burns associated with metal containing transdermal patches have been reported with magnetic resonance imaging and external cardiac defibrillation. However, there are no reports of dermal injury secondary to an ICD shock and a transdermal drug delivery patch. We report the first known case of a patient who suffered a dermal burn following a defibrillation due to a transdermal patch being positioned over the ICD.

( BUPP09956 - 16 December 2009) Are differences in guidelines for the treatment of nicotine dependence and non-nicotine dependence justified?

Despite the many similarities between nicotine dependence and other drug dependences, national guidelines for their treatment differ in several respects. The recent national guideline for the treatment of nicotine dependence has (i) less emphasis on detailed assessment; (ii) less emphasis on treatment of psychiatric comorbidity; (iii) less acceptance of reduction of use as an initial treatment goal; (iv) greater emphasis on pharmacological interventions; and (v) less emphasis on psychosocial treatment than national guidelines for non-nicotine dependences. These treatment differences may occur because (i) nicotine does not cause behavioral intoxication; (ii) psychiatric comorbidity is less problematic with nicotine dependence; (iii) psychosocial problems are less severe with nicotine dependence; and (iv) available pharmacotherapies for nicotine dependence are safer, more numerous and more easily available. However, it is unclear whether these treatment differences are, in fact, justifiable because of the scarcity of empirical tests. We suggest several possible empirical tests.

( BUPP09955 - 16 December 2009) Uses of diverted methadone and buprenorphine by opioid-addicted individuals in Baltimore, Maryland

This study examined the uses of diverted methadone and buprenorphine among opiate-addicted individuals recruited from new admissions to methadone programs and from out-of-treatment individuals recruited from the streets. Self-report data regarding diversion were obtained from surveys and semi-structured qualitative interviews. Approximately 16 (n = 84) of the total sample (N = 515) reported using diverted (street) methadone twothree times per week for six months or more, and for an average of 7.8 days (SD = 10.3) within the past month. The group reporting lifetime use of diverted methadone as compared to the group that did not report such use was less likely to use heroin and cocaine in the 30 days prior to admission (ps <.01) and had lower ASI Drug Composite scores (p <.05). Participants in our qualitative sub-sample (n 22) indicated that street methadone was more widely used than street buprenorphine and that both drugs were largely used as self-medication for detoxification and withdrawal symptoms. Participants reported using low dosages and no injection of either medication was reported.

( BUPP09954 - 15 December 2009) Estrogen prevents norepinephrine alpha-2a receptor reversal of stress-induced working memory impairment

Understanding effects of estrogen on the medial prefrontal cortex (PFC) may help to elucidate the increased prevalence of depression and post-traumatic stress disorder in women of ovarian cycling age. Estrogen replacement in ovariectomized (OVX) young rats amplifies the detrimental effects of stress on working memory (a PFC-mediated task), but the mechanisms by which this occurs have yet to be identified. In male rats, stimulation of norepinephrine alpha-2 adrenoceptors protects working memory from stress-induced impairments. However, this effect has not been studied in females, and has not been examined for sensitivity to estrogen. The current study asked whether OVX females with estrogen replacement (OVXEst) and without replacement (OVXVeh) responded differently to stimulation of alpha-2 adrenoceptors after administration of the benzodiazepine inverse agonist FG7142, a pharmacological stressor. The alpha-2 agonist, guanfacine, protected working memory from the impairing effects of FG7142 in OVXVeh, but not in OVXEst rats. Western Blot analysis for alpha-2 receptors was performed on PFC tissue from each group, but no changes in expression were found, indicating that the behavioral effects observed were likely not due to changes in receptor expression. These findings point to possible mechanisms by which estrogen may enhance the stress response, and hold implications for the gender discrepancy in the prevalence of stress-related mental illness.

( BUPP09953 - 15 December 2009) Improvement of analgesic protocols in renal xenotransplantation procedures

( BUPP09994 - 22 December 2009) Assessing Social Risks Prior to Commencement of a Clinical Trial: Due Diligence or Ethical Inflation?

Assessing social risks has proven difficult for IRBs. We undertook a novel effort to empirically investigate social risks before an HIV prevention trial among drug users in Thailand and China. The assessment investigated whether law, policies and enforcement strategies would place research subjects at significantly elevated risk of arrest, incarceration, physical harm, breach of confidentiality, or loss of access to health care relative to drug users not participating in the research. The study validated the investigator's concern that drug users were subject to serious social risks in the site localities, but also suggested that participation in research posed little or no marginal increase in risk and might even have a protective effect. Our experience shows that it is feasible to inform IRB deliberations with actual data on social risks, but also raises the question of whether and when such research is an appropriate use of scare research resources.

( BUPP09993 - 22 December 2009) Low Doses of Transdermal Buprenorphine in Opioid-Naive Patients With Cancer Pain: A 4-Week, Nonrandomized, Open-Label, Uncontrolled Observational Study

Objective: The aim of this study was to evaluate the effect and tolerability of low doses of transdermal (TD) buprenorphine patches in opioid-naive patients with cancer pain.Methods: This was a nonrandomized, open-label, uncontrolled study in consecutive opioid-naive patients with advanced cancer and moderate pain. TD buprenorphine was initiated at a dose of 17.5 mu g/h (0.4 mg/d), with patch changes every 3 days. Doses were then adjusted according to the clinical response. Pain intensity, opioid-related adverse effects, TD buprenorphine doses, and quality of life were monitored over 4 weeks. The time to dose stabilization and indexes of dose escalation were also calculated.Results: Thirty-nine consecutive patients completed all 4 weeks of the study. Low doses of TD buprenorphine were well tolerated and effective in these opioid-naive patients with cancer pain. Pain control was achieved within a mean of 1.5 days after the start of TD buprenorphine therapy. The mean TD buprenorphine dose was significantly increased from baseline beginning at 2 weeks after the start of therapy and had doubled by 4 weeks (P < 0.05). Pain intensity was significantly decreased from baseline beginning at 1 week and continuing through the remaining weekly evaluations (P < 0.05). The mean buprenorphine escalation index, calculated as a percentage and in milligrams, was 41.2% and 0.2 mg, respectively. Quality of life improved significantly over the study period (P 0.007). There were no significant changes in opioid-related symptoms between weekly evaluations.Conclusion: Observations from this study suggest that randomized, controlled, double-blind studies of TD buprenorphine 17.5 mu g/h in opioid-naive patients with cancer pain may be warranted.

( BUPP09992 - 22 December 2009) Introduction to College on Problems of Drug Dependence special conference on risk management and post-marketing surveillance of CNS drugs

( BUPP09991 - 22 December 2009) Case histories in pharmaceutical risk management

The development and implementation of programs in the U.S. to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration (FDA) since the mid 1990s. This paper provides fourcase histories of risk management and post-marketing surveillance programs utilized recently to address problems associated with possible abuse, dependence and diversion. The pharmaceutical sponsors of each of these drugs were invited to present their programs and followed a similar template for their summaries that are included in this article. The drugs and presenting companies were OxyContin (R), an analgesic marketed by Purdue Pharma L.P., Daytrana (R) and Vyvanse (R), ADHD medications marketed by Shire Pharmaceuticals, Xyrem (R) for narcolepsy marketed by Jazz Pharmaceuticals, and Subutex (R) and Suboxone (R) for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc. These case histories and subsequent discussions provide invaluable real-world examples and illustrate both the promise of risk management programs in providing a path to market and /or for keeping on the market drugs with serious potential risks. They also illustrate the limitations of such programs in actually controlling unintended consequences, as well as the challenge of finding the right balance of reducing risks without posing undue barriers to patient access. These experiences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies (REMS).

( BUPP09990 - 22 December 2009) Unilateral Scrotal Enlargement in a Naive Dorset Sheep (Ovis aries)

( BUPP09989 - 22 December 2009) Implementation of Self-Administered Oral Analgesic Treatment in Rats Subjected to Invasive Procedures

( BUPP09988 - 22 December 2009) Assessment of the Efficacy and Duration of Buprenorphine and Carprofen Analgesia in a Mouse Model of Acute Incisional Pain

( BUPP09987 - 22 December 2009) Postoperative Analgesia in a Mouse Mammary Cancer Model

( BUPP09986 - 22 December 2009) Multimodal Analgesia for Ruminants Undergoing Lateral Thoracotomy for Ventricular Assist Device Implantation

( BUPP09985 - 22 December 2009) The Effects of Postoperative Analgesia on Alcohol Consumption in Mice

( BUPP09984 - 22 December 2009) Pharmacokinetics of Buprenorphine in Mice Administered Subcutaneously, Intravenously, Orally by Gavage, and Orally by Voluntary Ingestion

( BUPP09983 - 22 December 2009) A comparison of subarachnoid buprenorphine or xylazine as an adjunct to lidocaine for analgesia in goats

OBJECTIVE: To test the hypothesis that subarachnoid administration of buprenorphine and lidocaine provides more intense and longer lasting perioperative analgesia with less side effects than xylazine and lidocaine in goats. STUDY DESIGN: Randomized, blinded, controlled study. STUDY ANIMALS: Ten healthy female goats randomly assigned to two groups of five animals each. METHODS: After sedation with acepromazine (0.1 mg kg(-1)) intravenously (i.v.), lidocaine 2% (0.1 mL kg(-1)) combined with either xylazine (0.05 mg kg(-1); Group X) or buprenorphine (0.005 mg kg(-1); Group B) were injected intrathecally at the lumbo-sacral junction prior to stifle surgery. Electrocardiogram, heart rate, direct systolic, mean, and diastolic arterial blood pressures, rectal temperature and arterial blood gases were recorded as were post-operative sedation and pain scores using a visual analogue and numeric rating scale, respectively. Data were analyzed with one-way ANOVA for repeated measures, one-way anova, Friedman's and Kruskal-Wallis tests as necessary (p < 0.05). RESULTS: Surgery was successfully performed under both analgesia protocols. Total pain and sedation scores were significantly lower in the B as compared with X group from 3-24 hours and 30-120 minutes, respectively after subarachnoid drug administration (SDA). Heart rate and arterial blood pressures decreased post SDA and were consistently lower in X versus B (p < 0.05). In B arterial blood gas parameters did not change post SDA, but in group X PaCO(2) increased slightly within 15 minutes of SDA and remained elevated for at least 3 hours (p < 0.05). CONCLUSION: In these goats intrathecal administration of buprenorphine and lidocaine produced more profound and longer lasting analgesia with less sedation and hemodynamic and respiratory impairment than xylazine with lidocaine. CLINICAL RELEVANCE: In these goats undergoing hind limb surgery, subarachnoid buprenorphine /lidocaine offered more intense and longer lasting analgesia than a xylazine/lidocaine combination, with less sedation and impairment of cardiopulmonary function.

( BUPP09982 - 22 December 2009) (A political order)

( BUPP09981 - 22 December 2009) Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats

Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD(50) in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg(-1)-naloxonazine at 5 min (mu-OR antagonist), subcutaneous 30 mg kg(-1)-naloxonazine at 24 h (mu1-OR antagonist), subcutaneous 3 mg kg(-1)-naltrindole at 45 min (delta-OR antagonist), and subcutaneous 5 mg kg(-1)-Nor-binaltorphimine at 6 h (kappa-OR antagonist) were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO(2) (P<0.001) and increased PaCO(2) (P<0.05), while buprenorphine only decreased PaO(2) (P<0.05). While all opioids significantly increased inspiratory time (T(I), P<0.001), methadone and fentanyl also increased expiratory time (T(E), P<0.05). Intravenous 10 mg kg(-1)-naloxonazine at 5 min completely reversed opioid-related effects on PaO(2) (P<0.05), PaCO(2) (P<0.001), T(I) (P<0.05), and T(E) (P<0.01) except in buprenorphine. Subcutaneous 30 mg kg(-1)-naloxonazine at 24 h completely reversed effects on PaCO(2) (P<0.01) and T(E) (P<0.001), partially reversed effects on T(I) (P<0.001), and did not reverse effects on PaO(2). Naltrindole reversed methadone-induced T(E) increases (P<0.01) but worsened fentanyl's effect on PaCO(2) (P<0.05) and T(I) (P<0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T(I) increases (P<0.001) but worsened methadone's effect on PaO(2) (P<0.05) and morphine (P<0.001) and buprenorphine's (P<0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T(I) and T (E) are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD(50), all drugs increased T(I). Methadone and fentanyl induced hypoxemia, hypercapnia, and T(E) increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.

( BUPP09980 - 22 December 2009) (Interactions with methadone and buprenorphine)

In Norway, about 5000 patients receive opioid maintenance treatment; 60 % receive methadone and 40 % buprenorphine. An increasing number of regular general practitioners and hospital doctors are in contact with this group of patients. This article presents a short overview of drug interactions with methadone and buprenorphine, as an aid to medical doctors in contact with these patients.

( BUPP09979 - 22 December 2009) Buprenorphine with bupivacaine for intraoral nerve blocks to provide postoperative analgesia in outpatients after minor oral surgery

PURPOSE: The demonstration that opioid receptors exist in the peripheral nervous system offers the possibility of providing postoperative analgesia in the ambulatory surgical patient. Over the previous decade, many investigators have studied this approach and have compared the efficacy of various opioids added to the local anesthetic near the brachial plexus; and it appears from several of these studies that buprenorphine provides the longest duration of analgesia, the most important parameter of postoperative analgesia in outpatients. One of these studies indicated that the agonist-antagonist, buprenorphine, added to bupivacaine provided a longer period of postoperative analgesia than the traditional opiates, but none of the studies was performed in patients undergoing minor oral surgery to check the efficacy of buprenorphine to provide postoperative analgesia in dental patients. The present study was undertaken to ascertain the efficacy of buprenorphine in providing prolonged postoperative analgesia when added to 0.5% bupivacaine with epinephrine 1:200,000. PATIENTS AND METHODS: Fifty healthy, consenting adult patients scheduled for upper extremity surgery were enrolled in the study. Patients were assigned randomly to 1 of 2 equal groups based on the agents used for the blocks. Patients in group I received 40 mL of a local anesthetic alone, and those in group II received the same local anesthetic plus buprenorphine 0.3 mg. The study was kept double-blind by having one dentist prepare the solutions, a second dentist perform the blocks, and a third dentist monitor the anesthesia and analgesia thereafter, up to and including the time of the first request for an analgesic medication. The data were reported as means +/- standard errors of the mean, and differences between groups were determined using t test. A P value less than .01 was considered statistically significant. RESULTS: The mean duration of postoperative pain relief after injection of the local anesthetic alone was 8.34 +/- 0.11 hours compared with 28.18 + /- 1.02 hours after buprenorphine was added, a difference that was statistically (and clinically) significant (P < .001). CONCLUSION: The addition of buprenorphine to the local anesthetic used for intraoral nerve blocks in the present study provided a 3-fold increase in the duration of postoperative analgesia, with complete analgesia persisting 30 hours beyond the duration provided by the local anesthetic alone in 75% of patients. This practice can be of particular benefit to patients undergoing minor oral surgery by providing prolonged analgesia after discharge from the hospital.

( BUPP09978 - 22 December 2009) Osteoporosis pain management

( BUPP09977 - 22 December 2009) Palliative care in advanced breast cancer

Breast cancer is currently one of the most frequent malignant neoplasms in Polish women. Since the '80s of past century, breast cancer is the leading cause of mortality in women aged 40-59. Patients are usually admitted to the stationary palliative care facilities in a far advanced stage of neoplastic disease originating primarily in the breast and are mostly in a poor general condition. Their overall condition is a resultant of development and severity of the tumour itself with possible distant metastases, coexisting diseases, as well as late complications of cause-oriented or palliative treatment implemented. In the setting of palliative treatment the primary goal is relief of pain, according to the recommendations of the so-called "analgetic ladder", conforming with general principles of analgetic management This consists in determination of cause of pain, evaluation of its type and severity, regular pace of administration of analgetic drugs, careful titration of dose of strong analgetics, oral administration of drugs, as this is the most physiologic and recommended route of administration, if only the patient can tolerate it. An important issue is also to relieve other bothersome ailments, both somatic, mental, spiritual and social. According to the WHO definition, palliative care ensures the patients a comprehensive and active care, improves their quality of life and, when justified, includes all oncologic therapeutic modalities. In the setting of palliative care, oncologic treatment aims at arresting or slowing-down of development of primary tumour and metastatic foci, thus improving the patient's comfort and quality of life, obviously taking into account current state of the patient and toxicity of drugs.

( BUPP09976 - 22 December 2009) Sensitivity analysis in economic evaluation: An audit of NICE current practice and a review of its use and value in decision-making

Objectives: To determine how we define good practice in sensitivity analysis in general and probabilistic sensitivity analysis (PSA) in particular, and to what extent it has been adhered to in the independent economic evaluations undertaken for the National Institute for Health and Clinical Excellence (NICE) over recent years; to establish what policy impact sensitivity analysis has in the context of NICE, and policy-makers' views on sensitivity analysis and uncertainty, and what use is made of sensitivity analysis in policy decision-making. Data sources: Three major electronic databases, MEDLINE, EMBASE and the NHS Economic Evaluation Database, were searched from inception to February 2008. Review methods: The meaning of 'good practice' in the broad area of sensitivity analysis was explored through a review of the literature. An audit was undertaken of the 15 most recent NICE multiple technology appraisal judgements and their related reports to assess how sensitivity analysis has been undertaken by independent academic teams for NICE. A review of the policy and guidance documents issued by NICE aimed to assess the policy impact of the sensitivity analysis and the PSA in particular. Qualitative interview data from NICE Technology Appraisal Committee members, collected as part of an earlier study, were also analysed to assess the value attached to the sensitivity analysis components of the economic analyses conducted for NICE. Results: All forms of sensitivity analysis, notably both deterministic and probabilistic approaches, have their supporters and their detractors. Practice in relation to univariate sensitivity analysis is highly variable, with considerable lack of clarity in relation to the methods used and the basis of the ranges employed. In relation to PSA, there is a high level of variability in the form of distribution used for similar parameters, and the justification for such choices is rarely given. Virtually all analyses failed to consider correlations within the PSA, and this is an area of concern. Uncertainty is considered explicitly in the process of arriving at a decision by the NICE Technology Appraisal Committee, and a correlation between high levels of uncertainty and negative decisions was indicated. The findings suggest considerable value in deterministic sensitivity analysis. Such analyses serve to highlight which model parameters are critical to driving a decision. Strong support was expressed for PSA, principally because it provides an indication of the parameter uncertainty around the incremental cost-effectiveness ratio. Conclusions: The review and the policy impact assessment focused exclusively on documentary evidence, excluding other sources that might have revealed further insights on this issue. In seeking to address parameter uncertainty, both deterministic and probabilistic sensitivity analyses should be used. It is evident that some cost-effectiveness work, especially around the sensitivity analysis components, represents a challenge in making it accessible to those making decisions. This speaks to the training agenda for those sitting on such decision-making bodies, and to the importance of clear presentation of analyses by the academic community.

( BUPP09975 - 22 December 2009) Doctors, nurses, and patients create barriers: Cancer pain is often underestimated

( BUPP09974 - 22 December 2009) What's new in... Toxicity of drugs of abuse

Toxicity caused by drugs of abuse is a frequent reason for presentation to hospital. Cannabis is the most widely used recreational agent. Although not often associated with acute toxicity requiring hospital admission, there is increasing recognition of its cardiovascular, respiratory and central effects. Strong opioids like heroin and methadone are still the most common causes of fatal recreational drug poisoning, but morbidity and mortality caused by cocaine has been increasing. Numerous hospital presentations continue to occur following ecstasy use. Although less common, episodes of toxicity relating to other drugs of abuse, such as newer stimulants (e.g. piperazines), gamma hydroxybutyrate and its precursors, and ketamine, are increasingly encountered by medical staff. This article is an update on the toxicity of recreational drugs, concentrating on recent research findings and emerging issues.

( BUPP09973 - 22 December 2009) Editorial

( BUPP09972 - 22 December 2009) Psychophysiological disorders among buprenorphine patients

In this study, we examined the prevalence of 14 psychophysiological disorders among 114 opioid-dependent individuals (a sample that previously evidenced high rates of borderline personality) as well as the relationship between these disorders and borderline personality. In the aftermath of analyses, only migraine headaches (28.9%) and chronic pain (33.3%) demonstrated relatively high frequency rates in this sample. Only migraine headaches showed a significant relationship with the diagnosis of borderline personality symptoms. In conclusion, in an opioid-dependent population, the prevalence of psychophysiological disorders appears to be rather unremarkable.

( BUPP09971 - 22 December 2009) Fibromyalgia Mechanisms and management

( BUPP09970 - 22 December 2009) Postherpetic neuralgia - Case report

The article summarises questions of postherpetic neuralgia, which is typically occurs up to fifty percent pacient after acute stage of herpes zoster. We described guidelines for treatment, specific examination techniques and new scales for testing neuropathic pain. Discussion about prevention of postherpetic neuralgia is still missing, there is represent by clinical studies aimed at vaccinations of patient with risk of postherpetic nauralgia. The important part of this article is case of postherpetic neuralgia.

( BUPP09969 - 22 December 2009) Comparative study of efficacy of IV magnesium sulphate v/s buprenorphine for attenuating the pressor response to laryngoscopy and intubation

Background: Magnesium is well known to inhibit catecholamine release and attenuate vasopressin-stimulated vasoconstriction. Present study was done to evaluate efficacy of i/v magnesium sulfate compared with inj. Buprenorphine for attenuation of pressure response to laryngoscopy & endotracheal intubation. Patients & Methods: 90 patients belonging to ASA Grade I & II, equally divided in three groups I, II, III . Magnesium sulphate 30 mg / kg in Group I, Buprenorphine 3 mug / kg in Group II and normal saline 4ml in Group III was administered intravenously 3 minutes before laryngoscopy and intubation and the effects were evaluated .Premedication was given with inj. Glycopyrrolate 0.2 mg & inj. Phenargan 0.5 mg/kg i/m 30min before induction of anaesthesia maintained on 33% Oxygen, 66% N2O, and vecuronium. Pulse rate, blood pressure, rate pressure product SPO2, ECG were monitored before and immediately after intubation and then every 15 min intraoperatively. Results: The mean pulse rate rise in group III and I was more than group II. Statistically it was highly significant (P<0.001) and it remained highly significant up to 5 minutes. After 30 minutes of intubation it was non-significant (P>0.05). Mean arterial pressure at 1 minute after intubation was raised in group III in comparison to group I and II and remained high (P>0.001) up to 30 minutes, after 30 minutes it was not significant. So, in group - I and II there was a good pressure attenuation response to IV magnesium sulphate and buprenorphine respectively. Conclusion: Low dose of magnesium sulphate given before 3 minutes before intubation attenuates the pressor response to laryngoscopy and intubation, more adequately and comparably to Buprenorphine.

( BUPP09968 - 22 December 2009) Thoracic epidural for modified radical mastectomy in a valvular heart disease patient

( BUPP09967 - 22 December 2009) Skin permeation of buprenorphine and its ester prodrugs from lipid nanoparticles: Lipid emulsion, nanostructured lipid carriers and solid lipid nanoparticles

The aim of this study was to develop and characterize lipid nanoparticle systems for the transdermal delivery of buprenorphine and its prodrugs. A panel of three buprenorphine prodrugs with ester chains of various lengths was synthesized and characterized by solubility, capacity factor (log K'), partitioning between lipids and water and the ability to penetrate nude mouse skin. Colloidal systems made of squalene (lipid emulsion, LE), squalene Precirol (nanostructured lipid carriers, NLC) and Precirol (solid lipid nanoparticles, SLN) as the lipid core material were prepared. Differential scanning calorimetry showed that the SLN had a more ordered crystalline lattice in the inner matrix compared to the NLC. The particle size ranged from 220300 nm, with NLC showing the smallest size. All prodrugs were highly lipophilic and chemically stable, but enzymatically unstable in skin homogenate and plasma. The in vitro permeation results exhibited a lower skin delivery of drug /prodrug with an increase in the alkyl chain length. SLN produced the highest drug/prodrug permeation, followed by the NLC and LE. A small inter-subject variation was also observed with SLN carriers. SLN with soybean phosphatidylcholine (SLN-PC) as the lipophilic emulsifier showed a higher drug/prodrug delivery across the skin compared to SLN with Myverol, a palmitinic acid monoglyceride. The in vitro permeation of the prodrugs occurred in a sustained manner for SLN-PC. The skin permeation of buprenorphine could be adjusted within a wide range by combining a prodrug strategy and lipid nanoparticles.

( BUPP09966 - 22 December 2009) Stress-related neuropeptides and alcoholism: CRH, NPY, and beyond

This article summarizes the proceedings of a symposium held at the conference on "Alcoholism and Stress: A Framework for Future Treatment Strategies" in Volterra, Italy, May 6-9, 2008. Chaired by Markus Heilig and Roberto Ciccocioppo, this symposium offered a forum for the presentation of recent data linking neuropetidergic neurotransmission to the regulation of different alcohol-related behaviors in animals and in humans. Dr. Donald Gehlert described the development of a new corticotrophin-releasing factor receptor 1 antagonist and showed its efficacy in reducing alcohol consumption and stress-induced relapse in different animal models of alcohol abuse. Dr. Andrey Ryabinin reviewed recent findings in his laboratory, indicating a role of the urocortin 1 receptor system in the regulation of alcohol intake. Dr. Annika Thorsell showed data supporting the significance of the neuropeptide Y receptor system in the modulation of behaviors associated with a history of ethanol intoxication. Dr. Roberto Ciccocioppo focused his presentation on the nociceptin/orphanin FQ (N/OFQ) receptors as treatment targets for alcoholism. Finally, Dr. Markus Heilig showed recent preclinical and clinical evidence suggesting that neurokinin 1 antagonism may represent a promising new treatment for alcoholism. Collectively, these investigators highlighted the significance of neuropeptidergic neurotransmission in the regulation of neurobiological mechanisms of alcohol addiction. Data also revealed the importance of these systems as treatment targets for the development of new medication for alcoholism.

( BUPP09965 - 22 December 2009) Recourse to psychotropic medication in the nord - Pas-de-Calais region (France)

The prescriptions for psychoactive drugs presented to the Health Insurance system for reimbursement of charges are a source of information about some psychological illnesses and disorders in the context of the overuse of these drugs in France. In Nord - Pas-de-Calais Region, out of a total of 5 070 160 prescriptions in 2007, 576493 individuals benefited from at least one such drug. Over the period of the study, 15.6% of the population of the region covered took at least one psychotropic medication. The rate of use was 11.7% for benzodiazepines, 7.6% for anti-depressants, 1.8% for anti-psychotics, 0.5% for treatment of alcohol dependence and 0.3% for opiate substitution therapy (OST). For the first three of these classes rate of use increased steadily with age. It was invariably much higher in women than in men. Men were treated more frequently for alcoholism and heroin dependency; the proportion taking medication initially increased with age (up to 40-49 years for alcohol dependency and 30-39 years for OST), before falling thereafter.

( BUPP10006 - 04 January 2010) (A study in extraction method of buprenorphine in urine)

OBJECTIVE: The extraction method for separating buprenorphine from urine was described. METHODS: Buprenorphine was extracted with chloroform at pH7 or with SPE (extracted by organic support 401 at pH10.8, then eluted with chloroform), finally determined by GC-NPD. RESULTS: The extracted yields of the analyte in specimens were 86.6% by solution-phase extraction and 83.0% by solid-phase extraction (SPE) respectively. CONCLUSION: These two methods are simple and accurate for separating buprenorphine from urine.

( BUPP10005 - 04 January 2010) HIV provider endorsement of primary care buprenorphine treatment: A vignette study

Background and Objectives: Opioid dependence is common among HIV-infected persons in the United States. Factors associated with HIV care providers recommending buprenorphine for opioid dependence are poorly defined. Using vignettes, we sought to identify HIV provider characteristics associated with endorsing buprenorphine treatment in primary care. Methods: We used a cross-sectional survey of HIV providers, including 497 physicians, nurse practitioners, and physician assistants attending HIV educational conferences in 2006. Anonymous questionnaires distributed to conference attendees contained one of two vignettes depicting opioid-dependent patients. Respondents recommended type of substance abuse treatment for the vignette patient. Using logistic regression, we tested patient and provider factors associated with HIV provider endorsement of buprenorphine in primary care. Results: Sixteen percent of providers endorsed buprenorphine treatment in primary care for vignette patients. Family physicians and general internists (AOR=2.8, CI=1.1-7.1), African American providers (AOR=3.0, CI=1.3-6.8), and those with previous buprenorphine prescribing experience (AOR=4.6, CI=1.2-17.9) were more likely to endorse buprenorphine treatment in primary care. Conclusions: HIV providers infrequently endorsed buprenorphine treatment in primary care for vignette patients. Generalist and African American providers and those with previous buprenorphine prescribing experience are more likely to endorse buprenorphine treatment in primary care. Targeting generalist and minority providers may be one strategy to promote effective integration of HIV care and opioid addiction treatment.

( BUPP10004 - 04 January 2010) Pain therapy: Modern dosage forms for potent analgesic agents

( BUPP10003 - 04 January 2010) Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists

Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-((3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl)-3-ethyl-1,3-dihy dro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1- (2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl) piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)- cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetra hydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.

( BUPP10002 - 04 January 2010) Take multiple factors into account when choosing the best opioid for pain therapy in paediatric palliative care

Many children receiving palliative care require opioid treatment for pain. The choice of opioid should be based on scientific evidence, pain pathophysiology, and available administration modes, with doses calculated on the basis of weight up to a maximum starting dose. Morphine remains the gold standard starting opioid in paediatric palliative care; however, other opioids may also be used as long-term therapy and/or to treat breakthrough pain.

( BUPP10001 - 04 January 2010) City's racial composition shapes treatment center characteristics and services

We assessed the extent to which a city's racial composition shapes the characteristics of substance abuse treatment centers. We utilized both the 2004 National Survey of Substance Abuse Treatment Services, which provides information on treatment center characteristics such as availability of comprehensive substance abuse evaluation, and 2000 Census data on the percentage of African Americans and Latinos in a city. We found that a city's racial composition influences treatment center characteristics and services available, but the pattern is complex in that there are inequalities in treatment for certain types of services but not in others. For instance, cities with high percentages of Latinos and African Americans provide more treatment options, such as employment and domestic violence counseling or programs for gay/lesbian clients. However, minority cities have fewer integrated treatment centers that provide comprehensive assessment for substance abuse and mental health problems. We discuss the implications of these findings for service providers, especially those working with Latino and African American clients, as well as provide avenues for future research.

( BUPP10000 - 04 January 2010) Medical expulsive therapy is an effective treatment for small distal ureteral stones

Minimally invasive treatments, such as shock wave lithotripsy, are effective treatments for ureteral stones, but are associated with high cost and the need for specialized equipment and personnel. Small distal ureteral stones can alternatively be treated with medical expulsive therapy, which promotes relaxation of the ureter in the region of the stone. Based on current clinical evidence, initial medical treatment in appropriate patients should involve a-adrenergic receptor antagonists and calcium channel antagonists.

( BUPP09999 - 04 January 2010) Neurologic Aspects of Drug Abuse

Neurologic aspects of drug abuse vary. This article explains the general nature of drug abuse, identifies the physiologic effects of certain drugs, and briefly describes the neurobiology of addiction. This article also reviews available treatment options for those addicted to substances of abuse, and clarifies common misconceptions, including the differences between tolerance, abuse, and addiction.

( BUPP09998 - 04 January 2010) Puffy hand syndrome due to drug addiction. Chronic Lymphoedema and long-term intravenous drug addiction

( BUPP09997 - 04 January 2010) Effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes

We tested the hypothesis that primary cultures of human hepatocytes could predict potential drug interactions with methadone and buprenorphine. Hepatocytes (five donors) were preincubated with dimethyl sulfoxide (DMSO) (vehicle), rifampin, or nelfinavir before incubation with methadone or buprenorphine. Culture media (0-60 min) was analyzed by liquid chromatography-tandem mass spectrometry for R-and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) or for buprenorphine, norbuprenorphine, and their glucuronides (buprenorphine-3-glucuronide (B-3-G) and norbuprenorphine-3-glucuronide (N-3-G)). R- and S-EDDP were detected in three of five, four of five, and five of five media from cells pretreated with DMSO, nelfinavir, and rifampin. R-EDDP increased 3.1- and 26.5-fold, and S-EDDP increased 2.5- and 21.3-fold after nelfinavir and rifampin. The rifampin effect was significant. B-3-G production was detected in media of all cells incubated with buprenorphine and accounted for most of the buprenorphine loss from culture media; it was not significantly affected by either pretreatment. Norbuprenorphine and N-3-G together were detected in three of five, four of five, and five of five donors pretreated with DMSO, nelfinavir and rifampin, and norbuprenorphine in one of five, one of five, and two of five donors. Although there was a trend for norbuprenorphine (2.8- and 4.9-fold) and N-3-G (1.7- and 1.9-fold) to increase after nelfinavir and rifampin, none of the changes were significant. To investigate low norbuprenorphine production, buprenorphine was incubated with human liver and small intestine microsomes fortified to support both N-dealkylation and glucuronidation; N-dealkylation predominated in small intestine and glucuronidation in liver microsomes. These studies support the hypothesis that methadone metabolism and its potential for drug interactions can be predicted with cultured human hepatocytes, but for buprenorphine the combined effects of hepatic and small intestinal metabolism are probably involved.

( BUPP09996 - 04 January 2010) Neurochemical aspects of possible therapeutic interventions of opiate medications in schizophrenia patients

( BUPP09995 - 04 January 2010) The "Black Box" of Prescription Drug Diversion

A variety of surveys and studies are examined in an effort to better understand the scope of prescription drug diversion and to determine whether there are consistent patterns of diversion among various populations of prescription drug abusers. Data are drawn from the RADARS System, the National Survey of Drug Use and Health, the Delaware School Survey, and a series of quantitative and qualitative studies conducted in Miami, Florida. The data suggest that the major sources of diversion include drug dealers, friends and relatives, smugglers, pain patients, and the elderly, but these vary by the population being targeted. In all of the studies examined, the use of the Internet as a source for prescription drugs is insignificant. Little is known about where drug dealers are obtaining their supplies, and as such, prescription drug diversion is a "black box" requiring concentrated, systematic study.

( BUPP10019 - 11 January 2010) Efficacy of Opiate Maintenance Terapy and Adjunctive Interventions for Opioid Dependence with Comorbid Cocaine Use Disorders: A Systematic Review and Meta-Analysis of Controlled Clinical Trials

( BUPP10018 - 11 January 2010) Systemic opioid and chronic pain

Opioid analgesic drugs currently represent the most powerful choice in pain therapy. They elicit their effects by mimicking endogenous substances - opioid peptides - the natural ligands of the opioid receptors. These analgesic drugs interact with specific receptors physiologically present in the central nervous system (CNS) and in the periphery, where they serve different functions. The opioid receptors modulate well-known functions related to nociceptive transmission, but this system is also involved in the regulation of gastrointestinal, endocrine, and autonomic functions. Opioids are being prescribed more frequently for treating pain, and physicians should be able to control pain before it becomes intractable. Recent research on new endogenous opioid pathways, the development of several administration routes, and the development of new drugs with reduced ability for abuse, will allow a deeper scientific understanding, better targeted therapy, and safer use of opiate drugs for the pharmacological control of pain. The goals in this field of research are important and future knowledge will help physicians to use all analgesic drugs correctly and effectively in the treatment of pain.

( BUPP10017 - 11 January 2010) Time for serious Rx abuse treatment

( BUPP10016 - 11 January 2010) Interindividual variability of drug transporters: Impact on opioid treatment in chronic renal failure

Some transmembrane transporters influence the absorption, the tissue distribution and the elimination of opioids, and their genetic variants may be an important factor in therapeutic efficacy and toxicity. Uptake and efflux transporters may facilitate or limit access of opioids to blood-brain barrier (BBB), modulating pain relief. As renal function is crucial in the metabolism and pharmacokinetic profile of any drug, renal failure and end-stage renal disease may alter drug disposition by affecting protein and tissue binding, and reducing systemic clearance of drugs.

( BUPP10015 - 11 January 2010) Confirmatory analysis of buprenorphine, norbuprenorphine, and glucuronide metabolites in plasma by LCMSMS. Application to umbilical cord plasma from buprenorphine-maintained pregnant women

An LCMSMS method was developed and fully validated for the simultaneous quantification of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-glucuronide (BUP-Gluc), and norbuprenorphine-glucuronide (NBUP-Gluc) in 0.5 mL plasma, fulfilling confirmation criteria with two transitions for each compound with acceptable relative ion intensities. Transitions monitored were 468.3 > 396.2 and 468.3 > 414.3 for BUP, 414.3 > 340.1 and 414.3 > 326.0 for NBUP, 644.3 > 468.1 and 644.3 > 396.3 for BUP-Gluc, and 590.3 > 414.3 and 590.3 > 396.2 for NBUP-Gluc. Linearity was 0.1-50 ng/mL for BUP and BUP-Gluc, and 0.5-50 ng/mL for NBUP and NBUP-Gluc. Intra-day, inter-day, and total assay imprecision (%RSD) were <16.8%, and analytical recoveries were 88.6-108.7%. Extraction efficiencies ranged from 71.1 to 87.1%, and process efficiencies 48.7 to 127.7%. All compounds showed ion enhancement, except BUP-Gluc that demonstrated ion suppression: variation between 10 different blank plasma specimens was <9.1%. In six umbilical cord plasma specimens from opioid-dependent pregnant women receiving 14-24 mg/day BUP, NBUP-Gluc was the predominant metabolite (29.8 � 7.6 ng/mL), with BUP-Gluc (4.6 � 4.8 ng/mL), NBUP (1.5 � 0.8 ng/mL) and BUP (0.4 � 0.2 ng/mL). Although BUP biomarkers can be quantified in umbilical cord plasma in low ng/mL concentrations, the significance of these data as predictors of neonatal outcomes is currently unknown.

( BUPP10014 - 11 January 2010) Diacetylmorphine versus methadone for opioid addiction (9)

( BUPP10013 - 11 January 2010) Endogenous opiates and behavior: 2008

This paper is the 31st consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2008 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

( BUPP10012 - 11 January 2010) The aldose reductase inhibitor fidarestat suppresses ischemia-reperfusion- induced inflammatory response in Rat Retina

Recent studies suggest that increased aldose reductase (AR) activity plays an important role in ischemia-reperfusion injury in the retina. The mechanisms are not completely understood, but may be linked to inflammation. In the present study, we investigated whether the AR inhibitor fidarestat suppressed the retinal inflammatory response induced by ischemia-reperfusion in a rat model. The inflammatory response was manifested by increased gene expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 (ICAM-1) as well as elevated protein levels of soluble ICAM-1. This response was partially suppressed by the AR inhibitor fidarestat. The findings may reveal beneficial effects of AR inhibition on retinal inflammation associated with ischemia-reperfusion and are in agreement with recent developments in pharmacological research suggesting that pathological conditions other than diabetes may benefit from AR inhibitors.

( BUPP10011 - 11 January 2010) Substance Abuse Among Reproductive Age Women

Substance abuse poses significant health risks to reproductive age women in the United States and, for those who become pregnant, to their children. Substance abuse or dependence is defined as a maladaptive pattern of substance use marked by recurrent and significant negative consequences related to the repeated use of substances. Alcohol is the most prevalent substance consumed by childbearing-aged women, followed by tobacco and various illicit drugs. Substance use in the preconception period predicts continued but often limited substance use during the prenatal period. Providers must be aware of reproductive age women's unique physiologic, psychological, and social needs and the related legal and ethical ramifications surrounding substance abuse before referral to a community-based multidisciplinary team for often long-term treatment.

( BUPP10010 - 11 January 2010) Rhabdomyolysis developing after transcatheter arterial chemoembolization for hepatocellular carcinoma

A 25-year-old man with hepatocellular carcinoma developed severe muscular weakness and pain 15 days after transcatheter arterial chemoembolization (TACE). The diagnosis of rhabdomyolysis was made based on myalgia localized in the bilateral upper extremities (bilateral trapezius, deltoid, biceps brachii, and teres major muscles) on magnetic resonance imaging and increased levels of muscle-derived serum enzymes. In this case, some drugs administered during the clinical course of TACE (diclofenac, famotidine, and cefotiam dihydrochloride) were suspected to be involved in the rhabdomyolysis, but the exact cause of rhabdomyolysis was not identified. The symptoms were completely improved by right trisegmentectomy of the liver following conservative treatment.

( BUPP10009 - 11 January 2010) Patterns in sleep-wakefulness in three-month old infants exposed to methadone or buprenorphine

Background: Infants exposed to opioides in-utero frequently demonstrate withdrawal symptoms in the neonatal period and have difficulties with state regulation. Aim: This study examines sleep-wakefulness-distress patterns as indicators of regulatory mechanisms at 3 months of age. Participants: A national infant cohort (N = 35) born to women in high-dose maintenance treatment during pregnancy and a comparison group (N = 36) of low-risk infants born in the same period. Outcome measures: Distributions and frequencies of sleep, wakefulness and distress measured in hours and episodes on sleep charts recorded by the mothers in the two groups. Results: Women in maintenance treatment were monitored closely during pregnancy to avoid illicit drug use and to be prepared for motherhood. They were also offered residential treatment before pregnancy and after the child was born. There were no statistical differences between the two groups in any of the 10 measures reflecting diurnal and nocturnal rhythmicity at 3 months despite of neonatal abstinence syndrome in 47% of the exposed infants and significant differences in infant characteristics with respect to birth weight, gestational age and maternal characteristics. Conclusions: Follow-up procedures combining drug monitoring and counseling during pregnancy and in the first months after birth enhance the development of state regulation in terms of sleep-wakefulness patterns.

( BUPP10008 - 11 January 2010) Estimation of clonazepam abuse liability: a new method using a reimbursed drug database

Some observations suggest the existence of clonazepam abuse. The aim of this study was to assess its magnitude in real life by a new method, using a prescription database, and to assess its evolution between 2001 and 2006. Individuals from a region affiliated to the French health reimbursement system, who had a prescription of clonazepam reimbursed between 1 January and 15 February of two selected years were included. Their deliveries were monitored over a 9-month period. After a descriptive analysis, a clustering method illustrated by a factorial analysis was used to identify different subgroups of clonazepam consumers. An increase of 82% in participants who had a delivery of clonazepam between 2001 and 2006 was observed. Using the clustering method, this study identified some deviant participants. This group comprises a higher proportion of males, benzodiazepine users, and buprenorphine users. The number of deliveries by different prescribers and pharmacies are higher. The proportion of deviant participants increased between 2001 and 2006 (from 0.86 to 1.38%). Our method can be used to assess the magnitude of abuse liability of clonazepam and is also interesting for following its evolution, two important keys for assessing patterns of abuse.

( BUPP10007 - 11 January 2010) Developing an Internet-based practice tool to assist physicians associated with buprenorphine treatment of opioid addiction

The Buprenorphine Practice Advisor (BPA) is a new web-based tool for primary care physicians who see opioid-dependent patients in their practices. The website (BupPractice.com) provides physicians with information and resources on referring patients for buprenorphine treatment, medical management of patients on buprenorphine, and setting up and managing office-based buprenorphine treatment.

( BUPP10028 - 19 January 2010) Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: A prospective, multicenter study

Maintenance treatment with buprenorphine tablets (Subutex) has been associated with reductions in heroin use; however, concerns for intravenous misuse exist. A buprenorphine/naloxone formulation (Suboxone) was designed to reduce this misuse risk while retaining buprenorphine's efficacy and safety. This prospective, open-label, multicenter trial compared preferences for buprenorphine and buprenorphine/naloxone in 53 opioid-dependent patients stabilized on buprenorphine. Buprenorphine was first administered at the patient's current dose (Days 1-2), followed by a direct switch to buprenorphine /naloxone (Days 3-5). Global satisfaction rates were high and similar between buprenorphine and buprenorphine/naloxone; however, patients preferred the tablet taste, size, and sublingual dissolution time of buprenorphine/naloxone. At the end of the study, 54% of patients preferred buprenorphine/naloxone, 31% preferred buprenorphine, and 15% had no preference; most patients (71%) wished to continue treatment with buprenorphine/naloxone. This study did not identify any impediments to a direct buprenorphine-to-buprenorphine/naloxone switch and revealed some characteristics that may facilitate treatment with buprenorphine/naloxone.

( BUPP10027 - 19 January 2010) Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: In vitro and in vivo evaluation

Conclusions based on either in vitro or in vivo approach to evaluate the P-gp affinity status of opioids may be misleading. For example, in vitro studies indicated that fentanyl is a P-gp inhibitor while in vivo studies indicated that it is a P-gp substrate. Quite the opposite was evident for meperidine. The objective of this study was to evaluate the P-gp affinity status of methadone, buprenorphine and diprenorphine to predict P-gp-mediated drug-drug interactions and to determine a better candidate for management of opioid dependence. Two in vitro (P-gp ATPase and monolayer efflux) assays and two in vivo (tissue distribution and antinociceptive evaluation in mdr1a/b (-/-) mice) assays were used. Methadone stimulated the P-gp ATPase activity only at higher concentrations, while verapamil and GF120918 inhibited its efflux (p < 0.05). The brain distribution and antinociceptive activity of methadone were enhanced (p < 0.05) in P-gp knockout mice. Conversely, buprenorphine and diprenorphine were negative in all assays. P-gp can affect the PK/PD of methadone, but not buprenorphine or diprenorphine. Our report is in favor of buprenorphine over methadone for management of opioid dependence. Buprenorphine most likely is not a P-gp substrate and concerns regarding P-gp-mediated drug-drug interaction are not expected.

( BUPP10026 - 19 January 2010) Effective Treatment of Injecting Drug Users With Recently Acquired Hepatitis C Virus Infection

Background & Aims: Patients with acute hepatitis C virus (HCV) infection who receive treatment achieve high rates of sustained virologic response (SVR), but few studies have examined outcomes among injecting drug users (IDUs). We evaluated the efficacy of treatment of recent HCV infection in IDUs with acute and early chronic HCV. Methods: We analyzed data from the Australian Trial in Acute Hepatitis C-a prospective study of the natural history and treatment outcomes of patients with recent HCV infection. Participants eligible for the study had their first anti-HCV antibody-positive test result within the past 6 months and either acute clinical HCV within the past 12 months or documented anti-HCV seroconversion within 24 months. Participants with HCV received pegylated interferon-alfa-2a (180 mug/wk, n = 74); those with HCV /human immunodeficiency virus (HIV) co-infection received pegylated interferon-alfa-2a (180 mug/wk) with ribavirin (n = 35) for 24 weeks. Results: From June 2004 to February 2008, 167 participants were enrolled in the Australian Trial in Acute Hepatitis C; 79% had injected drugs in the previous 6 months. Among 74 with only HCV, the SVRs were 55% and 72% by intention-to-treat and per-protocol analysis, respectively. In multivariate analyses, baseline factors independently associated with lower SVR included decreased social functioning and current opiate pharmacotherapy. Adherent participants had higher SVR rates (63% vs 29%; P = .025). Of the 35 participants with HCV/HIV co-infection, the SVRs were 74% and 75% by intention-to-treat and per-protocol analysis, respectively. Conclusions: Treatment of recent HCV infection among IDUs, including those with HIV co-infection, is effective. Strategies to engage socially marginalized individuals and increase adherence should improve treatment outcomes in this population.

( BUPP10025 - 19 January 2010) Efficacy and safety of deep, continuous palliative sedation at home: A retrospective, single-institution study

Goals: The goal of this study is to evaluate the feasibility and efficacy of palliative sedation at home (PSH) to approach refractory symptoms in dying cancer patients. Materials and methods: Charts of 121 patients, observed by "L'Aquila per la Vita" Home Care Unit, from August 2006 to May 2008, were reviewed. Sixteen patients out of 44 who died at home (36.4%) were sedated. Indication for sedation was agitated delirium in 13 patients and dyspnea in three patients. A multistep midazolam-based protocol was administered. Results: In all patients, a deep, prolonged, continuous sedation was obtained. No treatment-related complications were registered. Conclusion: A midazolam-based protocol for PSH is feasible and effective. Our results need to be confirmed by prospective, multicentric, controlled studies.

( BUPP10024 - 19 January 2010) Syphilis in drug users in low and middle income countries

Background: Genital ulcer disease (GUD), including syphilis, is an important cause of morbidity in low and middle income (LMI) countries and syphilis transmission is associated with HIV transmission. Methods: We conducted a literature review to evaluate syphilis infection among drug users in LMI countries for the period 1995-2007. Countries were categorized using the World Bank Atlas method (The World Bank. (2007). Data and statistics: Country groups. Retrieved online October 18, 2007 at http://go.worldbank.org/D7SN0B8YU0) according to 2006 gross national income per capita. Results: Thirty-two studies were included (N = 13,848 subjects), mostly from Southeast Asia with some from Latin America, Eastern Europe, Central and East Asia, North Africa and the Middle East but none from regions such as Sub-Saharan Africa. The median prevalence of overall lifetime syphilis (N = 32 studies) was 11.1% (interquartile range: 6.3-15.3%) and of HIV (N = 31 studies) was 1.1% (interquartile range: 0.22-5.50%). There was a modest relation (r = 0.27) between HIV and syphilis prevalence. Median syphilis prevalence by gender was 4.0% (interquartile range: 3.4-6.6%) among males (N = 11 studies) and 19.9% (interquartile range: 11.4-36.0%) among females (N = 6 studies) . There was a strong relation (r = 0.68) between syphilis prevalence and female gender that may be related to female sex work. Conclusion: Drug users in LMI countries have a high prevalence of syphilis but data are limited and, in some regions, entirely lacking. Further data are needed, including studies targeting the risks of women. Interventions to promote safer sex, testing, counselling and education, as well as health care worker awareness, should be integrated in harm reduction programs and health care settings to prevent new syphilis infections and reduce HIV transmission among drug users and their partners in LMI countries.

( BUPP10023 - 19 January 2010) Endocrine consequences of opioid therapy

Gonadal hormones are known to be affected by morphine and other opioids. In this paper, we summarize data collected in recent years which clearly indicate that the opioid-induced effects on steroid hormones depend on the opioid used and in some cases on the sex of the subject. Indeed morphine is able to reduce hormones like testosterone and cortisol in both male and female subjects in just a few hours, probably acting directly on peripheral glands. These depressant effects of morphine on hormones are also present in the treatment of surgical pain and are quickly reversible once opioid administration is suspended. Similar actions were also found to occur in experimental animals and in vitro in glial cells, further confirming the morphine-induced reduction of testosterone cell content. Testosterone and its metabolites are well known substances involved in the development and maintenance of the brain and all body structures. Thus when treating pain with opioids, their effects on hypothalamo-pituitary-gonadal and hypothalamo-pituitary-adrenal-related hormones must be considered and, where possible, hormone replacement therapy should be started.

( BUPP10022 - 19 January 2010) Review: A systematic review and empirical analysis of the relation between dose and duration of drug action

There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentration versus time curve from zero to infinity (AUC) are abstracted and analyzed by panel data regression modeling, with within-study fixed effects. Duration of drug action is defined as the time during which a pharmacodynamic effect (or response) exceeds a nominal threshold. The generalized models of all observations from 33 publications, with duration of action as the dependent variable and the logarithm of the dose (or AUC) as the explanatory variable, yield significant log-linear relationships. The regressions for individual studies are correctly specified in 27 cases; there are insufficient data for analysis in 10 studies, and a log-linear specification is deemed inappropriate in 6. Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs, extending a result that was previously documented for very few compounds.

( BUPP10021 - 19 January 2010) A randomized trial of transcutaneous electric acupoint stimulation as adjunctive treatment for opioid detoxification

This pilot study tested the effectiveness of transcutaneous electric acupoint stimulation (TEAS) as an adjunctive treatment for inpatients receiving opioid detoxification with buprenorphine-naloxone at a private psychiatric hospital. Participants (N = 48) were randomly assigned to active or sham TEAS and received three 30-minute treatments daily for 3 to 4 days. In active TEAS, current was set to maximal tolerable intensity (8-15 mA); in sham TEAS, it was set to 1 mA. By 2 weeks postdischarge, participants in active TEAS were less likely to have used any drugs (35% vs. 77%, p < .05). They also reported greater improvements in pain interference (F = 4.52, p <.05) and physical health (F = 4.84, p < .01) over time. TEAS is an acceptable, inexpensive adjunctive treatment that is feasible to implement on an inpatient unit and may be a beneficial adjunct to pharmacological treatments for opioid detoxification.

( BUPP10020 - 19 January 2010) Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression

Opioid treatment of pain is generally safe with 0.5% or less events from respiratory depression. However, fatalities are regularly reported. The only treatment currently available to reverse opioid respiratory depression is by naloxone infusion. The efficacy of naloxone depends on its own pharmacological characteristics and on those (including receptor kinetics) of the opioid that needs reversal. Short elimination of naloxone and biophase equilibration half-lives and rapid receptor kinetics complicates reversal of high-affinity opioids. An opioid with high receptor affinity will require greater naloxone concentrations and/or a continuous infusion before reversal sets in compared with an opioid with lower receptor affinity. The clinical approach to severe opioid-induced respiratory depression is to titrate naloxone to effect and continue treatment by continuous infusion until chances for renarcotization have diminished. New approaches to prevent opioid respiratory depression without affecting analgesia have led to the experimental application of serotinine agonists, ampakines, and the antibiotic minocycline.

( BUPP10047 - 26 January 2010) Neurocircuitry of addiction

Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: binge /intoxication, withdrawal/negative affect, and preoccupation /anticipation (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

( BUPP10046 - 26 January 2010) Treating substance dependency in the UAE: A case study

There is increasing concern about alcohol and drug problems in the Middle East, but addiction treatment models largely rely on evidence from Western countries with limited support for good-practice models in local addiction settings. Importantly, culturally sensitive aspects need to be explored for their influence on patients' perceptions, behaviors, and treatments. The aim of this article is to present a case report detailing the cultural elements and treatment delivery. Service provision occurred in the United Arab Emirates-based National Rehabilitation Centre, where a multidisciplinary team delivers specialist care to male nationals suffering from drug /alcohol use disorders.

( BUPP10045 - 26 January 2010) Simultaneous screening and quantification of 29 drugs of abuse in oral fluid by solid-phase extraction and ultraperformance LC-MS/MS

BACKGROUND: The European DRUID (Driving under the Influence of Drugs, Alcohol And Medicines) project calls for analysis of oral fluid (OF) samples, collected randomly and anonymously at the roadside from drivers in Denmark throughout 2008-2009. To analyze these samples we developed an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for detection of 29 drugs and illicit compounds in OF. The drugs detected were opioids, amphetamines, cocaine, benzodiazepines, and DELTA-9-tetrahydrocannabinol. METHOD: Solid-phase extraction was performed with a Gilson ASPEC XL4 system equipped with Bond Elut Certify sample cartridges. OF samples (200 mg) diluted with 5 mL of ammonium acetate /methanol (vol/vol 90: 10) buffer were applied to the columns and eluted with 3 mL of acetonitrile with aqueous ammonium hydroxide. Target drugs were quantified by use of a Waters ACQUITY UPLC system coupled to aWaters Quattro Premier XE triple quadrupole (positive electrospray ionization mode, multiple reaction monitoring mode). RESULTS: Extraction recoveries were 36%-114% for all analytes, including DELTA-9-tetrahydrocannabinol and benzoylecgonine. The lower limit of quantification was 0.5 mug/kg for all analytes. Total imprecision (CV) was 5.9%-19.4%.With the use of deuterated internal standards for most compounds, the performance of the method was not influenced by matrix effects. A preliminary account of OF samples collected at the roadside showed the presence of amphetamine, cocaine, codeine, DELTA-9-tetrahydrocannabinol, tramadol, and zopiclone. CONCLUSIONS: The UPLC-MS/MS method makes it possible to detect all 29 analytes in 1 chromatographic run (15 min), including DELTA-9- tetrahydrocannabinol and benzoylecgonine, which previously have been difficult to incorporate into multicomponent methods.

( BUPP10044 - 26 January 2010) Elderly need an adapted cancer pain therapy

( BUPP10043 - 26 January 2010) The need for chemical compatibility studies of subcutaneous medication combinations used in palliative care

When a person with a life-limiting illness is unable to swallow, the subcutaneous route of administration is a widely used way of administering many medications, either as repeated bolus injections or by continuous infusions to complement transdermal, sublingual, or rectal routes of administration. To optimize symptom control as changes are made from other routes of administration to subcutaneous delivery, basic principles for ensuring optimal net clinical benefit (therapeutic benefit and minimizing side effects) must be understood as fully as science will allow. Despite the widespread use of combinations of injectable medications in this clinical setting and the availability of the technology to do the studies, the limited work done suggests that there may be significant drug loss with some combinations of medications without any visual or physical changes apparent. Work needs to be done urgently to evaluate a wide range of medication combinations used extensively in hospice and palliative care for chemical compatibility, while ensuring the work that has been done in other areas (anesthetics, chronic pain) is adopted into practice as results become available. Almost all of these medications are off-patent and there is therefore no financial incentive for the pharmaceutical industry to do the studies on medications now produced generically. Other sources of funding need to be identified. At best, it is likely that optimal symptom control is at times compromised in palliative care without chemical compatibility data for combinations of injectable medications and, at worst, toxicity is generated unknowingly.

( BUPP10042 - 26 January 2010) Impact of constipation on opioid use patterns, health care resource utilization, and costs in cancer patients on opioid therapy

Patterns of opioid use, resource utilization, and costs in cancer patients with and without constipation were compared using retrospective insurance claims data. Inclusion criteria were 30 days of opioid use and continuous plan coverage for 6 months before and 12 months following first opioid claim (index date). Constipation was defined as 1 ICD-9-CM diagnosis codes in the range of 564.0x during the 12 months postindex date. Of the 8836 opioid initiators with cancer initially considered, approximately 9.3 (n 821) had a diagnosis of constipation during follow-up. Opioid use patterns were compared between patients with constipation and matched controls. Two-part semilogarithmic regression models assessed the impact of constipation on resource utilization and associated costs. Compared with controls without constipation, patients with constipation had higher rates of concurrent use of 2 opioids (P < .0001), opioid discontinuation (P .0002), opioid switching (P < .0001), nausea with vomiting (P < .0001), and respiratory depression (P .0003). Compared with controls, more patients with constipation received inpatient (P < .0001), hospice (P .0086), home health (P < .0001), laboratory (P .0015), other outpatient (P < .0001), emergency (P < .0001), office visit (P < .0001), and nursing home care (P .0266). Compared with controls, patients with constipation had substantially higher total costs (P < .0001). This study suggests that in opioid-treated cancer patients, constipation significantly impacts opioid-use patterns, resource utilization, and costs. Alleviation of constipation may optimize opioid therapy and reduce costs.

( BUPP10041 - 26 January 2010) The challenge of pain management in patients with myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. The complexity of the disease and its treatments make MG patients particularly susceptible to adverse effects of drugs. MG is not a painful condition; however, as pain management armamentarium includes drugs from diverse pharmacological groups and with potential for drug-drug interactions, managing pain in patients with MG can be challenging. The underlying disease and the concomitant medications of each patient must be considered and the analgesic treatment individualized. This review presents an update on the various aspects of pain pharmacotherapy in patients with MG, focusing primarily on medications used to treat chronic pain. Drugs discussed are opioids, nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants, muscle relaxants, benzodiazepines, intravenous magnesium, and local anesthetics. Drug interactions with agents used for MG treatment (acethylcholinesterase inhibitors, corticosteroids, immunosuppressants) and plasmapheresis are discussed. The clinical usefulness and limitations of each of the drug classes and agents are described.

( BUPP10040 - 26 January 2010) Guidelines for the diagnosis and management of neuropathic pain: Consensus of a group of latin american experts

These consensus guidelines have been developed by a group of Latin American experts in pain management, to point out patterns and make practical recommendations to guide the diagnosis, identify warning signs (yellow and red flags), and establish comprehensive medical management (pharmacologic and nonpharmacologic treatment) and monitoring plans for patients enduring neuropathic pain. From the viewpoint of pharmacologic management, drugs are classified into groups according to efficacy, availability/accessibility, and safety criteria. Drugs are recommended for use depending on the disease and particular circumstances of each patient, with an approach that favors multimodal treatment while taking into consideration the idiosyncrasies of medical practice in Latin America.

( BUPP10039 - 26 January 2010) The chemical neuromodulation of pain: A review

The chronic pain is a true emergency. In fact, the study "Pain in Europe 2005" showed that 26% of the Italian population is suffering by it. Chronic pain can be benign, when caused by a tissular damage, or malignant when cancer-related. The study of the pain has made a lot of progress in the last years. An example is the chemical neuromodulation, that interferes with the transmission of the pain afferences toward the brain, through the administration of chemical substances in the spinal or cranial compartment in well selected patients. This allows the use of doses lower than those required for other ways of administration, with less collateral effects and a more rapid response.

( BUPP10038 - 26 January 2010) Heroin assisted treatment

( BUPP10037 - 26 January 2010) Two-stage enriched enrolment pain trials: A brief review of designs and opportunities for broader application

Clinical Trail registration number: NCT00472303 (ClinicalTrials.gov); NCT00713323 (ClinicalTrials.gov); NCT00713817 (ClinicalTrials.gov).

( BUPP10036 - 26 January 2010) Buprenorphine for opioid dependence

Buprenorphine is a partial mu agonist opioid that is FDA-approved to manage opioid addiction in settings outside of traditional methadone clinics. The clinical uses, pharmacokinetics, pharmacodynamics, toxicology, and management of overdoses of buprenorphine are reviewed.

( BUPP10035 - 26 January 2010) Commentary from Dr Jan Vranken

( BUPP10034 - 26 January 2010) Quantification of drugs of abuse and some stimulants in hair samples by liquid chromatography-electrospray ionization ion trap mass spectrometry

A qualitative and quantitative method for the analysis of drugs of abuse (cocaine and benzoylecgonine, opiates) and some stimulants in human hair was developed and validated. Hair samples were incubated with phosphate buffer (pH 5.0), chosen as the extraction medium, extracted with Bond Elut Certify cartridges and analyzed by LC-MS-MS and LC-MS /sup 3/ as confirmation for positive results. The method proved to be specific, accurate and precise across the calibration range (0.1-30 ng/mg) where good linearity was observed. Total extraction recovery, intra-assay accuracy and precision, limits of detection and limits of quantitation were estimated. The method was successfully applied to the analysis of hair samples collected from drug abusers and it was suitable for routine analytical applications in the Antidoping Laboratory of Public Health Laboratory.

( BUPP10033 - 26 January 2010) Relations among psychopathology, substance use, and physical pain experiences in methadone-maintained patients

Objective: Differences in psychiatric distress and substance use (licit and illicit) were examined in methadone maintenance treatment (MMT) patients with a variety of pain experiences. Method: Parametric and nonparametric statistical tests were performed on data obtained from 150 patients currently enrolled in MMT. Assessments were carried out at the 3 opioid agonist treatment programs operated by the APT Foundation, New Haven, Connecticut. Participants were recruited between March 2007 and March 2008. Results: In comparison to MMT patients reporting no pain in the previous week, those with chronic severe pain (CSP) (ie, pain lasting at least 6 months with moderate to severe pain intensity or significant pain interference) exhibited significantly higher (P < .01) levels of depression, anxiety, somatization, overall psychiatric distress, and personality disorder criteria but reported comparable rates of substance use. A third group, ie, non-CSP MMT patients reporting some pain in the past week, differed significantly (P < .05) from the other 2 pain groups on somatization and global psychiatric distress but reported comparable rates of substance use. Conclusions: Pain-related differences in psychiatric problems exist in MMT patients and may have implications for program planning and outreach efforts.

( BUPP10032 - 26 January 2010) Analgesic prescribing for palliative care patients with renal impairment

Analgesic use in renally impaired palliative care patients, including but not restricted to cancer patients, is discussed. Dosage adjustment strategies, including use of the Cockcroft-Gault equation, are described. Opioids, nonsteroidal antiinflammatory drugs, and drugs for neuropathic pain are addressed.

( BUPP10031 - 26 January 2010) The role of opioids in managing chronic non-cancer pain

The use of opioids for the treatment of chronic non-cancer pain has become more widespread recently. Available data support the short-term use of opioids in clearly defined nociceptive and neuropathic pain states. Their use in 'pathological' pain states without a clear diagnosis, such as chronic low back pain, is more contentious. A decision to initiate opioid treatment in these conditions requires careful consideration of benefits and risks; the latter include not only commonly considered adverse effects such as constipation, but also opioid-induced hyperalgesia, abuse, addiction and diversion. Ideally, treatment goals should not only be relief of pain, but also improvement of function. Opioid treatment of chronic non-cancer pain requires informed consent by, and preferably a treatment contract with, the patient. Treatment should be initiated by a trial period with defined endpoints using slow-release or transdermal opioids. Ongoing management of the patient requires ideally a multi-disciplinary setting. Treatment should not be regarded as life-long and can be discontinued by tapering the dose.

( BUPP10030 - 26 January 2010) THERAPEUTIC RESPONSE IN OUTPATIENT OPIOID SUBSTITUTION TREATMENT

Aim: The aim of the study was to compare the success of buprenorphine therapy induction between two groups of outpatients.Subjects and Methods: The analysis was retrospective, based on medical documentation from the Centre for Prevention of Drug Addiction, Public Health Institute of the Split-Dalmatia County, Split, Croatia. The success of buprenorphine treatment induction and maintenance was compared between two groups of outpatients treated in 2006 (group 1, n=24) and 2007 (group 2, n=28), observed for the first four months of both years and only patients that presented to the Centre once a week for at least one month were included. The dose of buprenorphine was 2-4 mg per day in group 1 and 6-8 mg per day in group 2. Between group differences were compared using X-2-test with Yates correction and Mann-Whitney U-test. The probability value of P<0.05 was considered significant.Results: There was no significant difference between groups in demographic characteristics (sex, age, employment, education and marital status) and duration of heroin use. In group 1, 12 (50%) patients continued buprenorphine substitution treatment after 30 days, whereas in group 2 this figure was 21 (75%) patients (P<0.05). A significant difference between groups was also recorded in positive urine opiate test in the first and second week (P<0.05). Conclusion: Pharmacotherapy alone is rarely sufficient treatment for drug addiction, but it is an essential part of opioid substitution treatment. Therefore it is important to recommend an adequate dose of agonist or agonist/antagonist medication. As the cost of buprenorphine therapy has been reimbursed by the Croatian Health Insurance Institute in full amount since the beginning of 2007, a higher ("adequate") dose of buprenorphine is recommended to improve the success of buprenorphine treatment induction and maintenance.

( BUPP10029 - 26 January 2010) (Comparison between analytic and anamnestic data about drug consumption among opiate addicts with substitutes therapy. A feasibility study)

In this feasibility study of an observational nature, we used the protocol 'AnalyTox-Op' to compare analytical data with anamnestic reports gathered from specialized drug addiction treatment centers. These data were collected from 32 drug addicts who were patients undergoing treatment with addictive drug substitutes or prescribed psychotropic drugs. Urine toxicology screens were performed using immunological methods followed by confirmation with more specific techniques, i.e. gas chromatography coupled with mass spectrometry (GC-MS) and liquid chromatography with diode array detection (HPLC-DB). While complete agreement between patient reports of drug consumption (obtained from a questionnaire) and analytical data was only observed in 13 out of the 32 cases, a very good concordance was seen with opiate substitutes (88% with methadone and high-dosage buprenorphine, combined) and legally prescribed psychotropic drugs. Of note, however, was the omission of illicit drug use in patient questionnaires, especially with cocaine (22%) and recreational opiates (22%), causing discordance in the comparison. This study is currently being expanded to include a large number of participants across the country with the aim of obtaining data under homogeneous conditions, verifying the discordance we found and determining its significance.

( BUPP10069 - 02 February 2010) Does opioid substitution in prisons reduce injecting-related HIV risk behaviours? A systematic review

Objectives: To review systematically the evidence on opioid substitution treatment (OST) in prisons in reducing injecting-related immunodeficiency virus (HIV) risk behaviours. Methods: Systematic review in accordance with guidelines of the Cochrane Collaboration. Electronic databases were searched to identity studies of prison-based opioid substitution treatment programmes that included assessment of effects of prison OST on injecting drug use, sharing of needles and syringes and HIV incidence. Published data were used to calculate risk ratios for outcomes of interest. Risk ratios were not pooled due to the low number of studies and differences in study designs. Results: Five studies were included in the review. Poor follow-up rates were reported in tow studies, and representativeness of the sample was uncertain in the remaining three studies. Compared to inmates in control conditions, for treated inmates the risk of injecting drug use was reduced by 55 - 75% and risk of needle and syringe sharing was reduced by 47-73%. No study reported a direct effect of prison OST on HIV incidence. Conclusions: There may be a role for OST in preventing HIV transmission in prisons, but methodologically rigorous research addressing this question specifically is required. OST should be implemented in prisons as part of comprehensive HIV prevention programmes that also provide condoms and sterile injecting and tattooing equipment.

( BUPP10068 - 02 February 2010) Internet blockade in Xinjiang puts a strain on science

( BUPP10067 - 02 February 2010) Evidence that opioids may have toll-like receptor 4 and MD-2 effects

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and behavioral consequences resulting, in part, via TLR4 signaling.

( BUPP10066 - 02 February 2010) Managing chronic osteoarthritic pain in primary care: An update

A review of current osteoarthritis management focused on primary care is presented. Epidemiological and diagnostic issues and both pharmacological and nonpharmacological therapeutic interventions are described. A three-step pharmacotherapy paradigm beginning with acetaminophen (paracetamol) and proceeding to use of opioids is provided.

( BUPP10065 - 02 February 2010) Opioids in older people: A realistic option for pain management?

Pain is common in older persons, with a reported prevalence of 40 to 80. Undertreatment is frequent. Common pain syndromes seen in elders and management with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are discussed. The effects of age on physiology and drug disposition are described.

( BUPP10064 - 02 February 2010) Commentary from Poland

( BUPP10063 - 02 February 2010) Therapy of chronic HCV-infection in psychotic drug users from clinical perspective

Even when treated with neuroleptica, psychotic patients under pegIFN /RBV therapy develop mild psychotic symptoms. Nevertheless, in most cases there is no need to stop HCV-Therapy, provided that the patients have been selected according to certain criteria. The selection should be based on the severity and frequency of precedent psychotic episodes. At least one year should have passed since the last acute psychotic episode. Patients should have achieved a stable social situation and they should be willing to start a phrophylactical neuroleptic therapy. Also non-psychotic patients may develop a psychosis under pegIFN/RBV-Therapy. The risk is increased by following factors: HIV-coinfection, psychic side-effects of antiretroviral therapy, borderline structure, precedent alcohol- or drug-addiction, especially long-term use of hallucinogenic drugs (cannabis, LSD, mescaline, ecstasy) (Lynch et al. 1998, Schaefer et al. 2000). During therapy the triad of depression, suicidal tendencies and persistent insomnia indicate the possible begin of psychotic decompensation (Lynch et al. 1998). The few available casuistics suggest that the early onset of neuroleptic treatment allieviates psychotic episodes significantly. If hepatological diagnostics indicate a high risk of lethal liver failure, psychotic patients should also be treated with pegIFN/RBV. The possible risks of a necessary in-patient treatment or enduring neuroleptical therapy after HCV-therapy have to be considered as far less dangerous. The risk adapted selection of patients should be based on the psychiatric competence and experience of the particular treatment center. Most qualified are those centers who combine addiction medicine, psychiatric and infectiological competence. But also centers without these features can treat these multimorbid patients in close and defined interdisciplinary cooperation with other institutions. A long lasting trusting relationship of physician and patient-as can be found frequently in substitution therapy-makes it easier to guide the patient also in psychotic phases.

( BUPP10062 - 02 February 2010) Consensus statement "Substitution-based treatment of opioid-dependent persons"

This consensus statement represents the position of the "Austrian society for medication assisted treatment" (OEGABS) concerning the substitution based treatment of opiod dependent individuals. It has been developed to serve as a professional basis for high quality interdisciplinary treatment of opiod dependence. To be useful for the development of individualised treatment approaches the actual scientific knowledge and the clinical experience regarding the complex situation of patients had to be brought together and had to be presented in a format that is relevant for practical treatment tasks. The statement therefore had to be based on an integrated and comprehensive evidence based approach using not only the results of clinical (experimental) research but also clinical expertise from the different health professions which are involved in the treatment of opioid dependent individuals. The final version of the statement has been developed using a quasi Delphi design. Substitution treatment represents an important treatment option that is a part of a comprehensive harm reduction model. In that sense it does not compete against abstinence oriented treatment programmes but complements them. To implement the principle of demand orientation and to stimulate good compliance of the patients the treatment offers have to be well-grounded on low threshold admission, multi-professional co-operation and coordination of diversified treatment and care offers and have to provide the patients with well-tolerated medications.

( BUPP10061 - 02 February 2010) Perioperative pain management in the patient treated with opioids: Continuing Professional Development

Purpose: The objective of this continuing professional development module is to describe the perioperative anesthesia and pain management of patients taking opioids because of chronic pain or drug addiction. Principal findings: The number of patients under opioid treatment is increasing. Pain management is problematic in these patients, because regular opioid intake is associated with mechanisms of tolerance and dependence. More recently, opioid-induced hyperalgesia phenomena have been brought to light. As a rule, the usual opioid dose should be administered with the appropriate conversions, and additional requirements should be anticipated because of the surgical procedure. Local and regional anesthesia, and multimodal analgesia are indicated whenever possible. For the patient addicted to heroin or other opioids, the perioperative period is not a suitable time to initiate weaning. Conclusion: The physiological and pharmacological changes caused by chronic opioid intake must be understood in order to provide optimal pain management with respect to each individual and the type of procedure

( BUPP10060 - 02 February 2010) Obstiless reports impact of opioid-induced side effects

A study of opioid induced constipation conducted by the German Society for Pain Therapy and the German Pain League is described. Prevalence of this problem and implications for practice are discussed.

( BUPP10059 - 02 February 2010) Comparison of tuberculin skin testing reactivity in opioid-dependent patients seeking treatment with methadone versus buprenorphine: Policy implications for tuberculosis screening

Background: Buprenorphines availability in primary care settings offers increased access to treatment and linkage to primary care for opioid-dependent patients. Currently, tuberculin skin testing (TST) is recommended for patients enrolling in methadone maintenance treatment (MMT), but not for those enrolling in buprenorphine maintenance treatment (BMT). Objectives: To compare TST screening results in enrollees in BMT and MMT programs and assess the correlates of TST positivity among these subjects. Methods: A cross-sectional analysis of a retrospective cohort study was conducted to compare concurrent TST results among contemporaneously matched groups of MMT and BMT patients in the same community. Results: TST positivity was 9% in both MMTand BMTsettings (p=.27). Increased TST positivity was associated with being Black (AOR = 3.53, CI = 1.28-9.77), Hispanic (AOR = 3.11, CI = 1.12-8.60), and having higher education (AOR = 3.01, CI = 1.20-7.53). Conclusions: These results confirm a similar high prevalence of TST positivity in opioid-dependent patients enrolling in MMT and BMT programs. Racial and ethnic health disparities remain associated with TST positivity, yet a relationship between higher education and tuberculosis requires further investigation. Scientific significance: These data suggest the importance of incorporating TST screening in emerging BMT programs as a mechanism to provide increased detection and treatment of tuberculosis infection in opioid-dependent patient populations.

( BUPP10058 - 02 February 2010) Placenta for Monitoring in utero Drug Exposure to Buprenorphine and Correlation with Neonatal Outcomes

This study monitored the in utero drug exposure to buprenorphine (BUP) and its correlation with neonatal outcomes in placenta of 5 BUP-maintained pregnant women. In placenta specimens, the concentrations were less with BUP and BUP-glucuronide than with nor BUP and norBUP-glucuronide. BUP, metabolite concentrations and maternal mean daily dose showed correlation. Thus, placenta can be used to monitor in utero drug exposure to BUP with uniform drug distribution throughout the tissue. Specific BUP biomarker concentrations were highly predictive of gestational exposure and neonatal abstinence syndrome (NAS) onset, duration and degree, which could be useful in treating BUP-exposed neonates. (conference abstract: 11th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology, Montreal, Quebec, Canada, 03/10/2009-08/10 /2009).

( BUPP10057 - 02 February 2010) Urine Buprenorphine: Compliance Monitoring - A Clinical Evaluation

This study evaluated the dose response with Buprenorphine (BUP) urine samples using a quantitative assay. Urine samples randomly collected were analyzed for urine creatinine and BUP. Urine BUP levels gradually increased with dose in the patient samples. No interference was found with high levels of opiate, methadone and cocaine. In conclusion, there is good correlation between dose and both BUP ng/mL and urine corrected BUP levels. This suggests that compliance monitoring is possible when creatinine corrected quantitative BUP levels are used (No EX). (conference abstract: 11th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology, Montreal, Quebec, Canada, 03/10/2009-08/10/2009).

( BUPP10056 - 02 February 2010) Identification of the UDP-Glueuronosyltransferase (UGT) Isoforms involved in Buprenorphine Glucuronidation and Evaluation of the Inhibitory Potential of this Drug on UGTs

This study evaluated the specific contribution of individual UDP-glucuronosyltransferase (UGT) isoforms to the hepatic glucuronidation (HG) of buprenorphine (BUP) and the inhibitory capacity of BUP on the different UGT in human liver microsomes (HLM). UGT 1A1, 1A3 and 2B7 produced BUP-glucuronide at detectable levels. UGT 2B7 showed high affinity towards BUP. BUP inhibited the activities of UGT 2B7, UGT 1A3, UGT 1A4 and UGT 1A1. Thus, UGT2B7 is the main isoform involved in BUP HG and showed an inhibitory effect on several hepatic UGT. The IC50 observed are much higher than usual therapeutic levels suggesting that drug-drug interactions might not be clinically relevant. (conference abstract: 11th International Congress of Therapeutic Drug Monitoring & Clinical Toxicology, Montreal, Quebec, Canada, 03/10/2009-08/10/2009).

( BUPP10055 - 02 February 2010) Contribution of the Different UDP-Glucuronosyltransferase (UGT) Isoforms to Buprenorphine and Norbuprenorphine Metabolism and Relationship with the Main UGT Polymorphisms in a Bank of Human Liver Microsomes

The goal of this study was to evaluate the specific contribution of individual UDP-glucuronosyltransferase (UGT) isoforms in the metabolism of buprenorphine (BUP) and norbuprenorphine (NorBUP), as well as the impact of their genetic variations. The glucuronidation of BUP and Nor-BUP was examined using human liver microsomes (HLMs) and heterologously expressed UGTs. The individual contribution of UGT isoforms was estimated using enzyme kinetic experiments combined with the relative activity factor (RAF). Phenotype-genotype relationships were investigated in a bank of 52 HLMs. Among the six hepatic UGT isoforms tested, UGT1A1, UGT1A3, and UGT2B7 metabolized BUP and Nor-BUP. Using the RAF approach, we found that UGT1A1 and UGT2B7 accounted for approximately 10 and 41% of BUP glucuronidation, respectively. Nor-BUP glucuronidation involved predominantly UGT1A3 (approximately 63%) and UGT1A1 (34%), whereas UGT2B7 had only a minor role. The UGT1A1 promoter (TA)(6/7)TAA mutation (UGT1A*28) resulted in a 28% decrease of BUP glucuronidation V-max in pooled HLMs but was not statistically associated with glucuronidation rate in 52 individual HLMs. The presence of the UGT2B7 promoter (G-842A) mutation resulted in higher BUP glucuronidation V-max in pooled HLMs (+80% on average) and in a significant higher glucuronidation rate in noncarriers (but not in carriers) of the UGT1A1*28 allele (P = 0.0352). This study represents a functional basis for further clinical pharmacogenetic studies.

( BUPP10054 - 02 February 2010) Why do the clients of Georgian needle exchange programmes inject buprenorphine?

AIM: The aim of the study was to understand the prevalence and patterns of the non-medical injecting use of buprenorphine among drug injectors in Georgia. METHOD: A self-administered questionnaire was distributed among injecting drug users enrolled in Georgian needle exchange programmes. The questions covered topics related to drug use career, patterns (frequency, history, dosage) and reasons for the use of buprenorphine. RESULTS: Pharmaceutical buprenorphine in the form of Subutex was the most commonly injected drug in terms of lifetime (95.5%) and last-month (75%) prevalence of use. 48% of those study participants who had injected Subutex at some point reported having used it to cope with withdrawal or to give up other opioids. 90.5% of Subutex injectors used 1-2 mg as a single dose, and the mean frequency of its injection was 6 times per month. 75% of Subutex injectors had used 3 or more types of illegal drugs during the last 30 days. CONCLUSION: While widely misused by Georgian drug injectors, Subutex is neither the principal nor the favourite drug, and it is rather used as self-treatment. The authors consider the introduction of buprenorphine maintenance treatment to be a promising effective measure to decrease its non-medical and illegal use.

( BUPP10053 - 02 February 2010) Suboxone (buprenorphine/naloxone) as an agonist opioid treatment in Spain: a budgetary impact analysis

OBJECTIVE: To evaluate the economic impact of buprenorphine/naloxone (B/N) as an agonist opioid treatment for opiate dependence. METHODS: A budgetary impact analysis model was designed to calculate the annual costs (drugs and associated costs) to the Spanish National Healthcare System of methadone versus B/N. Data for the model were obtained from official databases and expert panel opinion. RESULTS: It was estimated that 86,017 patients would be in an agonist opioid treatment program each of the 3 years of the study. No increase in the number of patients is expected with the introduction of B/N combination. The budgetary impact (drugs and associated costs) for agonist opiate treatment in the first year of the study would be 89.53 million EUR. In the first year of B/N use, the budgetary impact would rise by 4.39 million EUR (4.6% of the total impact), with an incremental cost of 0.79 million EUR (0.9% of the total impact). The budgetary increase would be 0.6% (0.48 million EUR increase) and 0.6% (0.49 million EUR increase) in the second and third years of use, respectively. The mean cost per patient in the first year with and without B/N would be EUR 1,050 and 1,041, respectively. The most influential variables in the sensitivity analysis were logistics and production costs of methadone and the percentage use of B/N. CONCLUSION: With an additional cost of only EUR 9 per patient, B/N is an efficient addition to the therapeutic arsenal in the drug treatment of opiate dependence, particularly when considering clinical aspects of novel pharmacotherapy.

( BUPP10052 - 02 February 2010) Postoperative analgesic effect of preoperative intravenous flurbiprofen in arthroscopic rotator cuff repair

PURPOSE: This study was carried out to evaluate the postoperative analgesic effects of preoperative intravenous flurbiprofen in patients undergoing arthroscopic rotator cuff repair under general anesthesia. METHODS: We studied 44 patients who underwent an elective arthroscopic rotator cuff repair in a prospective, randomized, and double-blind fashion. The patients were divided into two groups. Group A (n = 22) received lipid emulsion 0.1 ml kg(-1) as a placebo, and group B (n = 22) received flurbiprofen 1 mg kg(-1) before the surgery. Intralipid or flurbiprofen was given intravenously 5 min before the surgery. General anesthesia was maintained with sevoflurane and nitrous oxide, and 10 ml of 0.75% ropivacaine was administered intraarticularly at the end of the surgery. Postoperative analgesia was supplied with intravenous 0.1 mg buprenorphine according to the patient's demand. The effectiveness of flurbiprofen's analgesic effect was measured by a visual analog scale (VAS) and by the amount of buprenorphine consumption at 0.5, 1, 2, 4, 6, 12, and 24 h after the surgery. Time to the first analgesic was also recorded. RESULTS: VAS in group B was significantly (P < 0.01) lower than that in group A during the first 6 h postoperatively. The amount of buprenorphine consumption in group B was also significantly (P < 0.01) less than that in group A within the first 2 h postoperatively. The time to first analgesic request in group B was significantly (P < 0.01) longer than that in group A. CONCLUSION: These results show that preoperative intravenous flurbiprofen facilitates the analgesic effect in the early postoperative period after arthroscopic rotator cuff repair.

( BUPP10051 - 02 February 2010) Integrated Opioid Use Disorder and HIV Treatment: Rationale, Clinical Guidelines for Addiction Treatment and Review of Interactions of Antiretroviral Agents and Opioid Agonist Therapies

Abstract Injection drug use (IDU) is an important vector of HIV infection in the United States. Many patients with HIV infection have comorbid substance use disorders. Integrated treatment for HIV and substance use disorders has been shown to improve HIV and other health outcomes, but significant barriers to integrated treatment exist. For individuals who are dependent on injection opioid drugs, agonist therapies of methadone or buprenorphine maintenance are available as part of a treatment program. Patients who are infected with HIV and require antiretroviral therapy (ART) are at risk for drug-drug interaction between ART and methadone or buprenorphine. We present a programmatic approach to the evaluation and treatment of opioid use disorders for HIV care providers, as well as a summary of the available knowledge of interactions of methadone and buprenorphine with ART, along with the level of evidence for each actual or potential interaction. Based on the available information of practice and the level of clinical significance of drug-drug interactions, we conclude that buprenorphine-based maintenance treatment for opioid dependent patients is the preferred maintenance therapy for integrated treatment systems.

( BUPP10050 - 02 February 2010) Development of nociceptin receptor (NOP) agonists and antagonists

The nociceptin opioid (NOP) receptor is the most recently discovered member of the family of the opioid receptors; its endogenous agonist is the peptide nociceptin. Due to the subsequent elucidation of its physiological role in both central and peripheral nervous system and in some non-neural tissues, there is a rapidly growing interest in the pharmacological application of substances active on this receptor. Despite the current clinical use of a morphinane-based NOP /MOP mixed ligand (buprenorphine) as an analgesic and in the treatment of drug addictions, so far just a few clinical trials have been made with selective NOP ligands. However, the perspective of their utilization is rapidly growing. Agonists can find applications in the treatment of neuropathic pain, anxiety, cough, drug addition, urinary incontinence, anorexia, congestive heart failure, hypertension; and antagonists for pain, depression, Parkinson's disease, obesity, and as memory enhancers. Besides peptide ligands, which are still subjected to many pharmacological investigations, many different chemical classes of NOP ligands have been discovered: piperidines, nortropanes, spiropiperidines, 4-amino-quinolines and quinazolines, and others. The new advances in establishing structure-activity relationships, also with the help of modeling studies, can permit the development of more active and selective molecules.

( BUPP10049 - 02 February 2010) Future considerations for pharmacologic adjuvants in single-injection peripheral nerve blocks for patients with diabetes mellitus

As the epidemics of obesity and diabetes expand, there are more patients with these disorders requiring elective surgery. For surgery on the extremities, peripheral nerve blocks have become a highly favorable anesthetic option when compared with general anesthesia. Peripheral blocks reduce respiratory and cardiac stresses, while potentially mitigating untreated peripheral pain that can foster physiologic conditions that increase risks for general health complications. However, local anesthetics are generally accepted to be a rare but possible cause of nerve damage, and there are no evidence-based recommendations for dosing local anesthetic nerve blocks in patients with diabetes. This is important because anesthesiologists do not want to potentially accelerate peripheral nerve dysfunction in diabetic patients at risk. This translational vignette (i) examines laboratory models of diabetes, (ii) summarizes the pharmacology of perineural adjuvants (epinephrine, clonidine, buprenorphine, midazolam, tramadol, and dexamethasone), and (iii) identifies areas that warrant further research to determine viability of monotherapy or combination therapy for peripheral nerve analgesia in diabetic patients. Conceivably, future translational research regarding peripheral nerve blocks in diabetic patients may logically include study of nontoxic injectable analgesic adjuvants, in combination, to provide desired analgesia, while possibly avoiding peripheral nerve toxicity that diabetic animal models have exhibited when exposed to traditional local anesthetics.

( BUPP10048 - 02 February 2010) A pilot study about the feasibility and cost-effectiveness of electronic compliance monitoring in substitution treatment with buprenorphine-naloxone combination

OBJECTIVES: The purpose of the study was to investigate whether or not compliance monitoring by microchip could offer a feasible method for reducing abuse and/or diversion of medication from unsupervised substitution treatment for opioid addiction. DESIGN: Naturalistic, 4-week pilot study in out patients. PATIENTS AND INTERVENTIONS: All our patients (N = 12) on buprenorphine-naloxone combination (Suboxone) received their medication for 6 days in a compliance-monitoring device (PharmaDDSi, StoraEnso), which registers date and time of tablet removal. Patients were instructed to take all tablets as one dose. Time cues were displayed and discussed with the patients during their weekly visits for supervised drug administration and counseling. MAIN OUTCOME MEASURES: Regularity of registered time cues, treatment costs in comparison with routine treatment, patients' answers from a questionnaire on acceptability, and effect on drug diversion. RESULTS: Six patients showed good compliance, in two patients irregularities were minor, but in two others lack of adherence to treatment instructions was detected. Patients with several comorbid psychiatric diagnoses showed on an average the longest intervals between removal of first and last tablet of the daily dose. One-fourth of the patients reported that compliance monitoring had helped to avoid diversion. Total cost savings during the 4-week period was a reduction of 39 percent, which was mainly due to fewer visits to the clinic. CONCLUSIONS: Compliance monitoring by PharmaDDSI with weekly feedback was well accepted and subjectively increased compliance with substitution treatment. Future studies will show whether a technical solution for compliance monitoring in real time can help to reduce drug abuse and noncompliance in substitution treatment and other opioid treatments.

( BUPP10086 - 10 February 2010) Buprenorphine for neuropathic pain--targeting hyperalgesia

Opioids are well known to relieve severe, acute, and chronic nociceptive pain, but neuropathic pain shows a relatively poor response to opioids. Buprenorphine, a partial mu and ORL-1-receptor agonist, kappa-delta receptor antagonist, interacts with different G proteins than potent mu agonists and hence is not cross-tolerant to standard opioids. Buprenorphine blocks central sensitization (hyperalgesia) that is commonly found with neuropathic pain. We present a patient with neuropathic pain and tactile allodynia in which buprenorphine alleviated the hyperalgesia to a greater extent than pain severity. We found buprenorphine to be effective in reducing hypersensitivity in neuropathic pain when pure mu agonists fail to produce a response or in individuals who are intolerant to pure mu agonists.

( BUPP10085 - 10 February 2010) Bioavailability of Buprenorphine from Crushed and Whole Buprenorphine (Subutex) Tablets

Background: Buprenorphine (Subutex) is the most abused opioid in Finland. In order to curb the abuse potential of this drug, many treatment centres and prisons crush Subutex tablets before administering them to patients. To date, there are no published studies comparing the efficacy and bioavailability of crushed and whole Subutex tablets. methods: A total of 16 opioid-dependent patients stabilised on 24mg of buprenorphine were enrolled in a double-blind, double-dummy, randomised cross-over study comparing crushed and whole buprenorphine tablets on a range of pharmacokinetic and pharmacodynamic variables. Buprenorphine tablets (either crushed or whole) and placebo tablets (either crushed or whole) were administered to subjects simultaneously. Buprenorphine and norbuprenorphine serum levels were measured at 30, 60, 90, 120, 180, 240 and 360 min, as well as 24h, after tablet administration. After 1 week, the experiment was repeated in a cross-over design so that, by the end of the study, each patient had received the active drug (buprenorphine) as both crushed and whole tablets. Results: Pharmacokinetic parameters (mean serum levels, Cmax' Tmax' AUC) of buprenorphine or norbuprenorphine did not differ significantly between crushed and whole tablets, although serum levels were slightly higher after administration of the crushed tablets. There were also no significant differences in dissolution/absorption time, withdrawal signs of opiate craving. Conclusion: We conclude that crushing Subutex tables does not significantly alter serum buprenorphine or norbuprenorphine levels or the drug's clinical effect. Our results indicate that crushing Subutex tablets may be used as an alternative method to counter the risk of buprenorphine diversion.

( BUPP10084 - 10 February 2010) (Guideline 'Medicinal care for drug addicts in penal institutions')

In the Netherlands, the policy on care for prisoners who are addicted to opiates is still heterogeneous. The recent guidelines entitled 'Medicinal care for drug addicts in penal institutions' should contribute towards unambiguous and more evidence-based treatment for this group. In addition, it should improve and bring the care pathways within judicial institutions and mainstream healthcare more into line with one another. Each rational course of medicinal treatment will initially be continued in the penal institution. In penal institutions the help on offer is mainly focused on abstinence from illegal drugs while at the same time limiting the damage caused to the health of the individual user. Methadone is regarded at the first choice for maintenance therapy. For patient safety, this is best given in liquid form in sealed cups of 5 mg/ml once daily in the morning. Recently a combination preparation containing buprenorphine and naloxone - a complete opiate antagonist - has become available. On discontinuation of opiate maintenance treatment intensive follow-up care is necessary. During this period there is considerable risk of a potentially lethal overdose. Detoxification should be coupled with psychosocial or medicinal intervention aimed at preventing relapse. Naltrexone is currently the only available opiate antagonist for preventing relapse. In those addicted to opiates, who also take benzodiazepines without any indication, it is strongly recommended that these be reduced and discontinued. This can be achieved by converting the regular dosage into the equivalent in diazepam and then reducing this dosage by a maximum of 25% a week.

( BUPP10083 - 10 February 2010) Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT(1) receptor blockade

Heart failure (HF) was induced by ligation of the left anterior descending artery (LAD). Left ventricular end-diastolic pressure (LVEDP) >25 mmHg (at day 23 after LAD ligation) was the inclusion criterion. The rats were divided into three groups: sham-operated (Sham, n = 23, LVEDP: 5.6 +/- 0.6 mmHg), HF (n = 14, LVEDP: 29.4 +/- 1.4 mmHg), and candesartan (1 mg.kg(-1).day(-1) sc)-treated HF (HF + Can, n = 9, LVEDP: 29.2 +/- 1.2 mmHg). After 7 days (i.e., 29 days after LAD ligation) semiquantitative immunoblotting revealed increased abundance of inner medulla aquaporin-2 (AQP2) and AQP2 phosphorylated at Ser(256) (p-AQP2) in HF. There was also markedly enhanced apical targeting of AQP2 and p-AQP2 in inner medullary collecting duct (IMCD) in HF compared with Sham rats, shown by immunocytochemistry. Candesartan treatment significantly reversed the increases in both AQP2 and p-AQP2 expression and targeting. In contrast, there were only modest changes in other collecting duct segments. Semi-quantitative immunoblots revealed increased expression of type 3 Na+/H+ exchanger (NHE3) and Na+-K+-2Cl(-) cotransporter (NKCC2) in kidneys from HF compared with Sham rats: both effects were reversed or prevented by candesartan treatment. The protein abundance of alpha-epithelial sodium channel (alpha-ENaC) was increased while beta-ENaC and gamma-ENaC expression was decreased in the cortex and outer stripe of the outer medulla in HF compared with Sham rats, which was partially reversed by candesartan treatment. These findings strongly support an important role of angiotensin II in the pathophysiology of renal water and sodium retention associated with HF.

( BUPP10082 - 10 February 2010) Long-term outcomes of office-based buprenorphine/naloxone maintenance therapy

Background: Buprenorphine/naloxone was approved by the FDA for office-based opioid maintenance therapy (OMT), with little long-term follow-up data from actual office-based practice. 18-Month outcome data on the office-based use of buprenorphine/naloxone (bup/nx) and the impact of socioeconomic status and other patient characteristics on the duration and clinical effects of bup/nx are reported. Methods: This retrospective chart review and cross-sectional telephone interview provide treatment retention of opioid-dependent patients receiving bup/nx-OMT in an office-based setting. 176 opioid-dependent patients from two different socioeconomic groups (high and low SES) were begun on bup/nx, started intensive outpatient treatment, and followed-up after a minimum of 18 months (18-42 months) by telephone interview to assess treatment outcome. Results: 110 subjects (67%) completed the interview, 77% remained on bup/nx with no difference in retention between high and low SES groups. Those on bup/nx at follow-up were more likely to report abstinence, to be affiliated with 12-step recovery, to be employed and to have improved functional status. Conclusions: Bup/nx-OMT is a viable treatment option and when coupled with a required abstinence oriented addiction counseling program is effective in promoting abstinence, self-help group attendance, occupational stability, and improved psychosocial outcomes in both low SES and high SES patient populations over an 18-42-month period.

( BUPP10081 - 10 February 2010) New horizons for therapeutics in drug and alcohol abuse

Alcohol, tobacco and illicit drug dependence represents a serious health and social issue within the community. As drug dependence has become more widely recognized as a clinical disorder and the severity of the problem been fully realized, options available for treatment have grown along with our understanding of the neurobiological mechanisms underlying the development and persistence of addiction. Treatment has progressed from purely social and behavioral approaches to now encompass pharmacotherapy to attempt to disrupt the mechanisms underlying these disorders. Despite these advances, many forms of addiction lack effective therapeutics and the prevalence of this disorder remains unacceptably high. As a result, a significant effort within the research community has been dedicated to the identification of novel targets for the development of therapeutics based upon our understanding of the pathological processes underlying addiction. The current review aims to provide an overview of existing and clinically trialed pharmacotherapies for alcohol, opiate, psychostimulant, nicotine, cannabis and inhalant addictions. Further, we discuss some of the potential targets that have been recently indentified from basic studies that may hold promise for the development of novel treatments.

( BUPP10080 - 10 February 2010) Cross-sectional assessment of the consequences of a GTP cyclohydrolase 1 haplotype for specialized tertiary outpatient pain care

OBJECTIVES: Reduced-function variants of the guanosine triphosphate cyclohydrolase gene (GCH1) have been associated with reduced pain in well-defined cohorts of patients and healthy volunteers. We addressed the question whether this genetic association plays a role in outpatient pain therapy. METHODS: In a cross-sectional observational study, 523 patients were enrolled in 3 different tertiary care outpatient pain centers at German University hospitals. Of the 519 Caucasian patients, data from 424 could be analyzed for functional associations of the formerly named pain-protective GCH1 haplotype with the key characteristics of pain therapy being (1) actual pain, (2) opioid dosing, and (3) pain therapy duration. RESULTS: With an allelic frequency of 14.2% the pain-protective haplotype was not rarer among pain patients than in the general population (P=0.344). However, a tendency toward gene dose-dependent effects of the GCH1 haplotype was observed in all the 3 therapy parameters. Carriers of the haplotype tended to have lower actual 24-hour pain scores (n=424; P=0.18), require lower opioid doses (P=0.096), and were significantly shorter on specialized pain therapy (P=0.004). The latter applied predominantly to differences between homozygous carriers and heterozygous (alpha-corrected t test: P=0.06) or non-carriers (P=0.011) of the haplotype. CONCLUSIONS: The results strength the support for a modest yet reproducible and consistent pain-protective effect associated with a GCH1 haplotype known to reduce GCH1 and thus BH4 up-regulation. Pending independent verification, the results might point to a prophylactic role of decreased GCH1 up-regulation delaying the need for pain therapy.

( BUPP10079 - 09 February 2010) Blasch-kolinear psoriasis revealed by infliximab therapy

Background: Blaschko-linear psoriasis is a rare disease about which only a few publications have appeared in the literature. This form of psoriasis poses problems of differential diagnosis with regard to other forms of inflammatory Blaschko-linear dermatoses. Herein, we report an original case, the linear nature of which was revealed by treatment with infliximab. Case report: A 29-year-old man presented chronic psoriasis present for 17 years and resistant to various forms of systemic therapy. Treatment with infliximab 5 mg/kg given on D1, D15 and two-monthly, thereafter resulted in practically complete resolution of all skin lesions after the fourth infusion. The only remaining lesions were psoriatic erythematous-squamous, non-pustular lesions with a Blaschko-linear pattern, limited to one side, on the left arm and left leg. These lesions persisted after 10 courses of infliximab, although no other lesions reappeared. Discussion: This case was original in terms of the revelation of Blaschko-linear lesions during treatment with infliximab, despite the complete disappearance of diffuse psoriatic plaques, thus suggesting the existence in this patient of two cell populations, each having a different response to biotherapy.

( BUPP10078 - 09 February 2010) Critical factors influencing the in vivo performance of long-acting lipophilic solutions-impact on in vitro release method design

Parenteral long-acting lipophilic solutions have been used for decades and might in the future be used in the design of depots with tailored delivery characteristics. The present review highlights major factors influencing the in vivo performance of lipophilic solutions. Furthermore, an account is given of the characteristics of employed in vitro release methods with a focus on the "state" of sink condition, the stirring conditions, and the oil-water interfacial area. Finally, the capability of in vitro release data to predict the in vivo performance of drug substances administrated in the form of lipophilic solutions is discussed. It is suggested that as long as the major rate-limiting in vivo release mechanism is governed by the drug partitioning between the oil vehicle and the tissue fluid, the use of in vitro release testing in quality control appears to be realistic. With increasing lipophilicity of the drug substances and longer duration of action, the in vivo drug release process may become more complex. As discussed, practical analytical problems together with the inability of release methods to mimic two or more concomitant in vivo events may constitute severe impediments for establishment of in vitro in vivo correlations.

( BUPP10077 - 09 February 2010) Recommendations for the treatment of neuropathic pain

The introduction and development of new products with demonstrated efficacy in neuropathic pain has generated a clear need for an evidence-based algorithm to treat the different types of neuropathic pain. The present article aims to provide recommendations on the treatment of neuropathic pain supported by the scientific evidence and agreed on by consensus by a multidisciplinary group of experts in methodology and pain management. The evidence was obtained from meta-analyses including the greatest amount of information available for each type of neuropathic pain. The literature search was performed by 5 reviewers, who focussed individually on the distinct forms of presentation of neuropathic pain. The databases consulted were the Cochrane Library, EMBASE (from 2000 onwards), and PUBMED (from 2000 onwards). Meta-analyses and randomized, controlled clinical trials were selected. Finally, retrieved articles were evaluated and clinical recommendations for the treatment of neuropathic pain were designed by the pain specialists. For some types of neuropathic pain, there is insufficient information. In these types of pain, recommendations based on scientific publications without evidence were included to provide the greatest possible amount of information on their treatment. Studies of safety and efficacy in postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), and trigeminal neuralgia (TN) were reviewed as paradigms of peripheral neuropathic pain. The scarce available information on central neuropathic pain (CNP) and sympathetic pain (SP) was also gathered. Based on the results obtained with this literature review and the evidence extracted, a decision algorithm was designed with the drugs currently available in the Spanish pharmacopeia for PHN and PDN, and separate decision algorithms were designed for TN and finally for CNP and SP. These recommendations take into account the treatments that should be used initially - first line treatments - and subsequently the alternatives are outlined in order of preference, based on daily clinical practice according to the consensus of the pain specialists.

( BUPP10076 - 09 February 2010) Pain clinics and palliative care in Mexico: Management of opioid-induced constipation. Conclusions of an expert group

At the end of September 2008, 15 leading figures in pain treatment and palliative care in Mexico met in Mexico City to design a clinical guideline on the use of opioids and the secondary effects of these drugs, with special emphasis on constipation. A new treatment scheme was proposed. The participants currently work in pain or palliative care units throughout Mexico and some are active participants in the design of regulatory measures on opioid use. During the drafting of this guideline, the law reforming palliative treatment in Mexico was passed and came into effect on 6 /sup th/ January, 2009.

( BUPP10075 - 09 February 2010) When the progression of disease lowers opioid requirement in cancer patients

OBJECTIVE: To describe 2 cases in which an abrupt progression of disease compromising pain pathways and inducing some relief of existing pain or limiting drug delivery to central nervous system. METHODS: Case reports which a significant decrease of opioid requirement was reported, either systematically and spinally. RESULTS: The progression of disease produced changes in pain input or limited the effects of opioids given spinally. DISCUSSION: The data presented suggest that physicians should be aware of the possibility that opioid doses have to be reduced, where presumably specific events related to the progression of disease can change the pain syndrome or reduce the delivery of opioids when using particular routes of administration. This problem needs to be recognized and treated appropriately when it occurs.

( BUPP10074 - 09 February 2010) Anesthesia and the microcirculation

There is increasing evidence that the microcirculation and its regulation are severely compromised during many pathological conditions, such as hemorrhage, sepsis, or trauma. The effects of anesthetic agents on macrohemodynamics were investigated intensively in the last several decades. Research regarding modern anesthetics and anesthesia techniques has increased knowledge regarding the nonanesthetic effects of anesthetic agents, including those on organ perfusion and the microcirculation. Alterations in microvascular reactivity, nitric oxide pathways, and cytokine release are presumably the main mechanisms of anesthetic-induced tissue perfusion changes. This review summarizes current methods of microcirculatory status assessment and current knowledge regarding the microcirculatory effects of intravenous and potent volatile anesthetics and anesthesia-related techniques under both normal and pathophysiological conditions.

( BUPP10073 - 09 February 2010) Non-invasive systemic drug delivery: Developability considerations for alternate routes of administration

Over the past few decades alternate routes of administration have gained significant momentum and attention, to complement approved drug products, or enable those that cannot be delivered by the oral or parenteral route. Intranasal, buccal/sublingual, pulmonary, and transdermal routes being the most promising non-invasive systemic delivery options. Considering alternate routes of administration early in the development process may be useful to enable new molecular entities (NME) that have deficiencies (extensive first-pass metabolism, unfavorable physicochemical properties, gastro-intestinal adverse effects) or suboptimal pharmacokinetic profiles that are identified in preclinical studies. This review article describes the various delivery considerations and extraneous factors in developing a strategy to pursue an alternate route of administration for systemic delivery. The various delivery route options are outlined with their pros and cons; key criteria and physicochemical attributes that would make a drug a suitable candidate are discussed; approaches to assess delivery feasibility, toxicity at the site of delivery, and overall developability potential are described; and lastly, product trends and their disease implications are highlighted to underscore treatment precedence that help to build scientific rationale for the pursuit of an alternate route of administration.

( BUPP10072 - 09 February 2010) Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect

To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using ( /sup 3/ H)pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of ( /sup 3 / H)pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit ( /sup 3/ H)pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentrationdependent manner by amitriptyline, fluvoxamine and mexiletine with K /sub i/ values of 13, 65, and 44 muM, respectively. These K /sub i/ values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations.

( BUPP10071 - 09 February 2010) Second meeting of the French CEIP (Centres d'Evaluation et d'Information sur la Pharmacodependance). Part I: How to evaluate and prevent the abuse and dependence on hypnotic/anxiolytic drugs?

The second meeting of the French CEIP (Centres d'Ivaluation et d'Information sur la Pharmacodependance) was organized during the annual congress of the French Society of Pharmacology Therapeutics and Physiology in 2008. The aim of this meeting was to update the knowledge on abuse and dependence of the anxiolytics and hypnotics from different points of view (pharmacoepidemiology, epidemiology and treatment). The first part of this meeting summarized the pharmacological data obtained by the pharmacoepidemiological tools developed by the CEIP network. Even if the abuse liability of these agents is not a new problem, it remains always present and characterized by differences of misuse between drugs in real-life settings. The second part targeted to a subtype of consumers, the elderly population, because older patients are more likely to be prescribed with multiple prescriptions and also more at risk for prescription abuse. Despite this evidence, there is a scarcity of information on the factors associated with a such behaviour and its screening, assessment, diagnosis and treatment.

( BUPP10070 - 09 February 2010) Influential factors in regular and intensive use of psychoactive drugs

The article attempts to construct a typology to the use of psychoactive drugs and the study of the various factors linked to their use, whether heavy or regular. The results draw on the exploitation of databases containing medicines presented for reimbursement by medical insurance in the Nord - Pas-de-Calais region. In 2007 and 2008, 20.7% of the insured population (764,650 people) benefited from reimbursements for this type of medication. Among the beneficiaries, about a third (30.5%) had an intense consummation. Age, the CMUs benefits and the fact that a person is or not followed by a psychiatrist are the most influential variables on the intensity and the regularity of intake. The observed regularity of the recourse to benzodiazepines does not conform with the current recommendations.

( BUPP10094 - 17 February 2010) The highs and lows of my years at NIDA (1986-1992)

( BUPP10093 - 17 February 2010) Methadone treatment in Italy in the third millennium: Continuing fear of treatment

( BUPP10092 - 17 February 2010) Pharmacology and neurochemistry of methadone

Contrary to what might be thought initially, the pharmacology of methadone is only partly known, and current research continues to investigate into its distinctive aspects. Clinical evidence provides key guidance to pharmacological research on the opiate system; on the other hand, evolving expectations from therapeutic drugs or putative agents for addiction treatment provide a key incentive to the broadening of pharmacological knowledge. Apart from the classic description of receptorial opioid agonism, narcotic blockade and tolerance/withdrawal dynamics, some crucial issues need to be clarified in a comprehensive way. For instance, studies have proved the importance of metabolic polymorphism in treatment planning and offered interpretations of apparent resistance to normal dosages, so authorizing the employment of high dosages on a sound pharmacological basis. Also, dosages should not be regarded as stable through time, especially in the first few months, and clinicians may schedule dose variations that take into account such expected variations while pursuing stabilization. Methadone's action profile in the central nervous system is not exclusively based on opioid receptors, and a thorough knowledge of its 'collateral' effects may explain its beneficial action against specific psychopathological abnormalities. The role of the inactive enantiomer in the context of racemous methadone's tolerability and action profile has also been outlined. Lastly, some of the therapeutic effects of methadone endure without being neutralized by the emergence of tolerance; one of these is its crucial anticraving property. In order to clarify this issue, the mechanisms of cell membrane endocytosis and signal transduction have been illustrated and compared between different opiates.

( BUPP10091 - 17 February 2010) An in vivo evaluation of surface polishing of TAN intermedullary nails for ease of removal

Fractures of the tibia and femoral diaphysis are commonly repaired by intra-medullary (IM) nailing. Currently IM nails are available in either electropolished stainless steel (SS) or in Titanium-Aluminium-Niobium (TAN). After healing, removal of the nails still is common but removal of TAN IM nails often has complications whereas SS IM nails of the same design are less often associated with problems. We believe the differences in removal are due to the ability of TAN to promote strong bone on-growth. We have previously shown in vivo that polishing cortical screws reduces removal torque and the percentage of bone-implant contact. Therefore, we postulate that bony on-growth onto IM nails can be reduced by means of surface polishing, for ease of removal. Here we aim to compare the pull-out forces for removal of standard TAN (TAN-S) compared to experimental paste polished TAN (TAN-PP) IM nails from a bilateral non-fracture sheep tibia model after 12 months implantation. Histological analysis was also performed to assess tissue on-growth to the nails. We show that polishing significantly reduces (p=0.05) the extraction force required for TAN IM nail removal. This effect in part is attributable to the distinct tissue-material reaction produced. For TAN-S nails direct bone contact was observed while for TAN-PP nails a fibrous tissue interface was noted. Since TAN is preferred over SS for IM nailing due to superior biocompatibility and mechanical properties, we believe these findings could be used to recommend changes to current surface technologies of intramedullary nails to reduce complications seen with nail removal especially in rapidly growing bone in children.

( BUPP10090 - 17 February 2010) Tissue reaction to implants of different metals: A study using guide wires in cannulated screws

Cannulated screws, along with guide wires, are typically used for surgical fracture treatment in cancellous bone. Breakage or bending deformation of the guide wire is a clinical concern. Mechanically superior guide wires made of Co-Cr alloys such as MP35N and L605 may reduce the occurrence of mechanical failures when used in combination with conventional (316L stainless steel) cannulated screws. However the possibility of galvanic or crevice corrosion and adverse tissue reaction, exists when using dissimilar materials, particularly in the event that a guide wire breaks, and remains in situ. Therefore, we designed an experiment to determine the tissue reaction to such an in vivo environment. Implant devices were designed to replicate a clinical situation where dissimilar metals can form a galvanic couple. Histological and SEM analyses were used to evaluate tissue response and corrosion of the implants. In this experiment, no adverse in vivo effects were detected from the use of dissimilar materials in a model of a broken guide wire in a cannulated screw.

( BUPP10089 - 17 February 2010) Gilbert-Meulengracht's syndrome and pharmacogenetics: Is jaundice just the tip of the iceberg?

Gilbert's syndrome is characterized by mild unconjugated nonhemolytic hyperbilirubinemia, without hepatic inflammation, fibrosis, chronic liver disease, or liver failure. It is readily diagnosed by genetic variants of the UGT1A1 gene, mainly UGT1A1*28, and is also associated with abnormalities of hepatobiliary transport and additional UGT1A gene variants. Apart from representing a potential risk factor in irinotecan and protease inhibitor therapy, it appears to exert protective effects in Hodgkin's lymphoma and cardiovascular disease. Gilbert's syndrome is part of a continuous spectrum of altered glucuronidation that extends to fatal Crigler-najjar disease. The complexity hidden behind this pharmacogenetic abnormality is of profound significance for drug development and therapy.

( BUPP10088 - 17 February 2010) The potential of pharmacogenomics to treat drug addiction

( BUPP10087 - 17 February 2010) Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphrine-induced respiratory depression shows a marked ceiling effect at higher closes, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is in excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8%, 92.3% +/- 22.8% of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

( BUPP10104 - 23 February 2010) Predictors of buprenorphine-naloxone dosing in a 12-week treatment trial for opioid-dependent youth: Secondary analyses from a NIDA Clinical Trials Network study

Introduction: The present investigation examines baseline patient characteristics to predict dosing of buprenorphine-naloxone, a promising treatment for opioid addiction in youths. Methods: This study of 69 opioid-dependent youths is a secondary analysis of data collected during a National Institute on Drug Abuse (NIDA) Clinical Trials Network study. Outpatients aged 15-21 were randomised to a 12-week buprenorphine-naloxone dosing condition (including 4 weeks of taper). Predictors of dosing included sociodemographic characteristics (gender, race, age, and education), substance use (alcohol, cannabis, cocaine, and nicotine use), and clinical characteristics (pain and withdrawal severity). Results: Most (75.4%) reported having either "some" (N=40, 58.0%) or "extreme" (n=12, 17.4%) pain on enrolment. Maximum daily dose of buprenorphine-naloxone (19.7mg) received by patients reporting "extreme" pain at baseline was significantly higher than the dose received by patients reporting "some" pain (15.0mg) and those without pain (12.8mg). In the adjusted analysis, only severity of pain and withdrawal significantly predicted dose. During the dosing period, there were no significant differences in opioid use, as measured by urinalysis, by level of pain. Conclusion: These data suggest that the presence of pain predicts buprneoprhine-naloxone dose levels in opioid-dependent youth, and that patients with pain have comparable opioid use outcomes to those without pain, but require higher buprenorphine-naloxone doses.

( BUPP10103 - 22 February 2010) Problems experienced by community pharmacists delivering opioid substitution treatment in New South Wales and Victoria, Australia

AimsTo explore service provision and the range of problems that New South Wales (NSW) and Victoria (VIC) community pharmacists providing opioid substitution treatment (OST) have experienced with clients and prescribers.DesignCross-sectional postal survey.SettingAll community pharmacies providing OST in NSW (n = 593) and VIC (n = 393), Australia.ParticipantsCompleted questionnaires were received from 669 pharmacists (68% response rate).MeasurementsThe questionnaire addressed pharmacy characteristics, recent problems experienced with clients including refusal to dose, provision of credit for dispensing fees, termination of treatment, responses of pharmacists to problems experienced with clients, as well as problems experienced with OST prescribers.FindingsIn the preceding month, 41% of pharmacists had refused to dose a client for any reason, due most commonly to expired prescriptions (29%), or >= 3 missed doses (23%). Terminating a client's treatment in the past month was reported among 14% of respondents, due most commonly to inappropriate behaviour and missed doses. Treatment termination was reported by a significantly higher proportion of pharmacists in VIC (P < 0.001). Treatment termination in last month was predicted having more clients (P < 0.001), the provision of buprenorphine treatment (P = 0.008), having a separate dosing area (P = 0.021), and being a female pharmacist (P = 0.013). Past month refusal to dose was predicted by the pharmacy being in VIC (P < 0.001) and having more clients (P < 0.001). Problems experienced most commonly in the past month with prescribers were difficulty contacting prescriber (21%) and provision of takeaway doses to clients considered unstable by the pharmacist (19%) (higher in VIC: both P < 0.001).ConclusionsThis study highlights the range of problems experienced by community pharmacists in the delivery of OST and the consequences for people in treatment. Particular attention should be focused upon considering number of clients per pharmacy and improving professional communication between pharmacists and prescribers.

( BUPP10102 - 22 February 2010) An Increase in Glycinergic Quantal Amplitude and Frequency During Early Vestibular Compensation in Mouse

The process of vestibular compensation includes both behavioral and neuronal recovery after unilateral loss of peripheral vestibular organs. The mechanisms that underlie this process are poorly understood. Previous research has shown the presence of both gamma-aminobutyric acid type A (GABA(A)) and glycine receptors in the medial vestibular nuclei (MVN). It has been suggested that inhibitory transmission mediated by these receptors may have a role in recovery during vestibular compensation. This study investigated changes in fast inhibitory synaptic transmission of GABA(A)ergic and glycinergic quantal events after unilateral labyrinthectomy (UL) at three different time points. Mice were anesthetized and peripheral vestibular organs were removed from one side of the head. After recovery, transverse brain stem sections (300 mu m) were prepared from mice that had undergone UL either 4 hours, 2 days, or 7 days earlier. Our experiments do not show evidence for alterations in synaptic GABA(A) receptor properties in MVN neurons after UL at any time point investigated. In contrast, during early vestibular compensation (4 hours post UL) there is a significant increase in the glycinergic quantal current amplitude in contralesional MVN neurons compared with control. Our results also show an increase in the frequency of glycinergic quantal events of both ipsi-and contralesional MVN neurons during this early period. We suggest that changes in both pre- and postsynaptic glycine receptor mediated inhibitory synaptic transmission after sensory loss is an important mechanism by which neuronal discharge patterns can be modulated.

( BUPP10101 - 22 February 2010) A review of opioid dependence treatment: Pharmacological and psychosocial interventions to treat opioid addiction

Opioid dependence is a problem of national concern, especially with dramatically increased rates of abuse and dependence of prescription opioids. The current article provides an up-to-date review of the literature on opioid dependence treatment, with a focus on conclusions drawn by experts in the field (e.g., Cochrane reviews and meta-analyses) and methodologically rigorous studies (e.g., randomized controlled trials). We describe the major classes of drug treatments available, including opioid agonist (e.g., methadone, buprenorphine, LAAM), antagonist (e.g., naltrexone) and non-opioid pharmacotherapies (e.g., alpha2 adrenergic agonists). These treatments are discussed in the context of detoxification and long term treatment options such as abstinence-based and maintenance strategies. We review the state of the literature as to prevention of opioid overdose and discuss the widespread problem of comorbidity among opioid-dependent populations. We also focus prominently on evidence for inclusion of psychosocial approaches in treatment regimens, either as stand-alone or in conjunction with psychopharmacological options.

( BUPP10100 - 22 February 2010) Ondansetron: An effective treatment for the withdrawal symptoms of opioids?

( BUPP10099 - 22 February 2010) Opioids: Now and the future

( BUPP10098 - 22 February 2010) Endogenous opioids and addiction to alcohol and other drugs of abuse

There is significant experimental evidence implicating the endogenous opioid system (opioid peptides and opioid receptors) with the processes of reward and reinforcement. Indeed, many behaviors associated with reward and reinforcement, for example feeding behavior, are controlled by distinct components of the endogenous opioid system located in relevant brain regions. It has also been shown that regardless of their initial site of action many drugs of abuse, such as morphine, nicotine, cocaine, alcohol and amphetamines, induce an increase in the extracellular concentration of dopamine in the nucleus accumbens. This, increased secretion of dopamine in the nucleus accumbens seems to be a common effect of many drugs of abuse, and it was proposed that may mediate their rewarding and reinforcing properties. Furthermore, activation of mu opioid receptors in the ventral tegmental area, or of mu and delta opioid receptors in the nucleus accumbens enhances the extracellular concentration of dopamine in the nucleus accumbens. Thus, stimulation of the activity of distinct components of the endogenous opioid system either by opioid or by other drugs of abuse, may mediate some of their reinforcing effects. In this review article, a brief description of the endogenous opioid system and its implication in the processes of reward and reinforcement of opioid and other drugs of abuse will be presented. Furthermore, the use of opioid antagonists in the treatment of drug addiction will be discussed. Special emphasis will be given to ethanol addiction, the drug mainly studied in my laboratory.

( BUPP10097 - 22 February 2010) Psychotropic drugs of today and basis for development of future drug

Psychopharmacology is a 60-year-old specialized branch of pharmacology. Its first discoveries were fortuitous but, progressively, with the development of neurobiology, it has transformed and modified its research modalities, imposing a rational approach and scientific rigour. It has also been automatized, especially with the "high throughput screening", which measures the affinity of a very large number of molecules to be tested for a number of biological targets, followed by the determination of the manner of interaction, especially intrinsic activity. Commonly, a molecule is not specific to a determined biological target, and one is prompted to take advantage of composite actions for an appropriate manipulation of disturbed cerebral functions. These in vitro studies now precede in vivo studies. The studies favour behavioural models which closely mimic definite psychiatric diseases. We have chosen for illustration the development of a "depressive" line of mice. When a potential efficacy has been observed, before performing the clinical studies necessary to fulfil the criteria characteristics of a true drug, further information, dealing with toxicity and pharmacokinetics, should be obtained. Finally, we have also presented various putative targets which should inspire the development of new antidepressant drugs. � 2009 Elsevier Masson SAS.

( BUPP10096 - 22 February 2010) Improvement in psychosocial outcomes in chronic pain patients receiving intrathecal morphine infusions

BACKGROUND: When conventional multimodal analgesic therapy is unsuccessful, more aggressive analgesic treatments are required for patients with intractable chronic pain. Despite extensive clinical experience with implanted morphine pumps, there is still controversy regarding the psychosocial effects of this invasive analgesic therapy. In this prospective study, we evaluated the impact of intrathecal (IT) morphine infusions on pain perception and psychosocial functionality. A secondary objective of this pilot study was to assess the effect of IT morphine infusion on the patient's level of functional activity. METHODS: Thirty patients with chronic nonmalignant pain that failed to respond to multimodal analgesic regimens were evaluated using the McGill Pain Questionnaire before and at 3-, 12-, and 24-mo intervals after implantation of an IT morphine infusion pump. At each clinic visit, the patient's level of pain was assessed using an 11-point visual analog scale, with 0 = no pain and 10 = worse pain imaginable. The mean initial morphine infusion rate was 0.23 � 0.14 mg/day (with a range from 0.09 to 0.75 mg/day) and was subsequently adjusted to maintain their pain score at a value <50% of the initial value. Adverse side effects and complications, as well as activity levels, were recorded at each clinic visit. RESULTS: Both evaluative and affective components of the pain assessment demonstrated a significant improvement over the 24-mo study period. The evaluative component of the McGill Pain Questionnaire improved 66%, the affective component 59%, and the sensory component 32%. The average morphine infusion rate increased to 0.44 � 0.29, 0.66 � 0.39, and 0.80 � 0.45 mg/day at the 3-, 12-, and 24-mo follow-up intervals (P < 0.05). The reduced level of chronic pain leads to improved social, work, and family relationships and quality of life. Among 13 patients of working age, 12 returned to work full time, and among 17 retired patients, 14 had a reduced need for assistance. CONCLUSIONS: IT infusion of morphine using an implantable pump was helpful in improving psychosocial function in patients with intractable pain that had failed to respond to standard multimodal analgesic therapy.

( BUPP10095 - 22 February 2010) Opioid treatment and "Long-QT Syndrome (LQTS)": A critical review of the literature

The present paper aims to provide a critical survey of the current literature on QT-related cardiac safety in cases of methadone treatment. On the whole, case reports, whether single or multiple, do not seem to offer a reliable basis for drawing conclusions about the weight of any putative risk factor in QT prolongation. Systematic studies, on the other hand, do allow certain statements to be made about the extent and the the importance of QT prolongation during methadone maintenance treatment for heroin addiction. There do not seem to be any major concerns about cardiac safety arising from methadone itself in the average addict. Higher risk conditions due to multiple and polydrug treatments deserve more intensive surveillance. From a risk/benefit perspective, there is no clear rationale for applying a dose ceiling.

( BUPP10119 - 04 March 2010) Withdrawal Symptoms Following the Onset of a Naltrexone Treatment for Ethanol Dependence During Opioid Addiction Substitution

( BUPP10118 - 04 March 2010) Buprenorphine and major metabolites in blood specimens collected for drug analysis in law enforcement purposes

A liquid chromatographic/electrospray ionization tandem mass spectrometric method for the quantification of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-3-beta-D-glucuronide (BUPG) and norbuprenorphine-3-beta-D-glucuronide (NBUPG) in serum samples was developed and validated. Pre-treatment of BUP and NBUP was by liquid-liquid extraction, while glucuronides were favourably isolated by solid phase extraction. Separation in 2 separate runs (2 x 5 min) was achieved using isocratic elution. The method was applied to 20 authentic serum specimens collected for law enforcement purposes where BUP intake had been indicated. The parent drug was not detectable in half of the specimens at a lower limit of detection of 0.2 ng/mL, whereas NBUP could be determined from any sample but one. NBUPG is the major metabolite present, which could be identified along with BUPG in all samples under investigation. In authentic specimens it could be advisable to monitor BUP metabolites along with the parent drug.

( BUPP10117 - 03 March 2010) Prescription and administration of opioids to hospital in-patients, and barriers to effective use

Objective: This study aimed to describe prescribing and administration of opioids in a tertiary referral teaching hospital. Secondary aims were assessment of staff knowledge of opioid pharmacology and available preparations, and of perceived barriers limiting opioid use. Design: A cross-sectional survey of in-patients requiring opioid analgesia was performed. An anonymous semi-structured questionnaire was administered to medical and nursing staff. Setting: Australian tertiary referral teaching hospital. Patients: All patients prescribed opioids on study wards over 3 months (N = 190). Results: Oxycodone was the most frequently prescribed opioid (51.4%). The majority (64.7%) of participants had incomplete pain relief, which was significantly associated with having opioid related side effects. There was no association between pain relief and prescribed daily dose or received daily dose of opioids. Limited understanding of opioid preparations, tolerance, and dependence was demonstrated by staff. The most common perceived barriers to opioid use included difficulties in identifying the right dose, staff time required to prescribe and monitor, and large numbers of preparations. While prescription of inadequate doses was perceived as a barrier, this study identified that submaximal doses were administered. An opioid educational session improved knowledge of opioid formulations. Conclusion: The majority of participants had incomplete pain relief and the maximum prescribed doses of opioids were not administered. Reported barriers included staff knowledge of opioid dose titration and opioid preparations, and time constraints. Identified barriers included poor knowledge of opioid preparations.

( BUPP10116 - 03 March 2010) Effect of low level capacitive-coupled pulsed electric field stimulation on mineral profile of weight-bearing bones in ovariectomized rats

Mineral content, mineral composition, and crystalline pattern of bone in osteoporosis are different from those of normal individuals. Present management of bone mineral loss is rather unsatisfactory primarily because of socioeconomic factors and untoward effects of the treatment drugs. We report the efficacy of capacitive-coupled pulsed electric field (CCPEF) to prevent bone loss in an ovariectomized rat model of osteoporosis. One month postsurgery either leg was stimulated with CCPEF, whereas the other leg did not receive any stimulation (sham exposed). The treatment was given in 60 sessions each of 2 h/d (5 days a week). The control group of rats was sham operated. At the end of the observation period, femur and tibia bones were removed. Their bone mineral content (BMC), calcium, phosphorus, and carbon contents were analyzed and bone mineral density (BMD) was calculated. The BMC data were supported by X-ray diffraction (XRD) method. In shamexposed bones, a statistically significant decrease in BMC, BMD, calcium, and phosphorus contents were obtained as compared to the control. Although in CCPEF bones, there was an attenuation of decrement in the noted parameters except phosphorus. XRD pattern supported these observations. The results suggest that chronic, 60 sessions of 2 h/d, 5 d/wk CCPEF (14 MHz with 16 Hz modulation 16 Hz and 10 V peak to peak) is effective in attenuating the ovariectomy-induced bone mineral loss in rats.

( BUPP10115 - 03 March 2010) Advances in pain treatment. Clinical applications

( BUPP10114 - 03 March 2010) Pharmacological treatment of neuropathic pains

( BUPP10113 - 03 March 2010) Morphine analgesics

( BUPP10112 - 03 March 2010) Medication-assisted treatment and HIV/AIDS: Aspects in treating HIV-infected drug users

Drug use and HIV/AIDS remain serious public health issues in the US. The intersection of the twin epidemics of HIV and drug/alcohol use, results in difficult medical management issues for the healthcare providers who work in the HIV prevention and treatment fields. Access to care and treatment, medication adherence to multiple therapeutic regimens and concomitant drug-drug interactions of prescribed treatments are difficult barriers for drug users to overcome without directed interventions. Injection drug users are frequently disenfranchised from medical care and suffer stigma and discrimination creating additional barriers to care and treatment for their substance use disorders as well as HIV infection. Controlling the transmission of HIV will require access to care and treatment of individuals who abuse illicit drugs and alcohol. Improving health outcomes (e.g. access to and adherence to antiretroviral therapy) among HIV-infected substance users will also require access to evidenced-based pharmacological therapies for the treatment of drug abuse and dependence. The current review presents an overview of issues regarding the use of medication-assisted treatments for substance abuse and dependence among HIV-infected individuals, providing medical management paradigms for their care and treatment.

( BUPP10111 - 03 March 2010) Recent advances in the pharmaceutical management of pain

Pain is an unpleasant sensory and emotional experience for patients. Management of pain is the most frequent issue encountered by clinicians and treatment is usually with pharmacological therapy. This review discusses recent pharmaceutical advances in pain management with respect to new modes of analgesic delivery, as well as new analgesic agents and adjuvants that are currently being investigated for their analgesic properties. New modes of administration include transdermal delivery in the form of skin patches, transmucosal delivery, inhalational administration, various patient-controlled devices and extended-release analgesic formulations. Up-to-date research is presented on classical analgesics, such as opioids, anti-inflammatory agents, including cyclo-oxygenase-2 inhibitors and paracetamol (acetaminophen), local anesthetics and ketamine. In addition, newer agents such as antidepressants and antiepileptic drugs as well as medicinal cannabinoids are discussed. As our understanding of the multiple pain pathways involved in the pathogenesis of pain expands, further compounds with analgesic properties will be developed.

( BUPP10110 - 03 March 2010) Pro-con debate: Is codeine a drug that still has a useful role in pediatric practice?

( BUPP10109 - 03 March 2010) Influence of preferred foodstuffs on the antinociceptive effects of orally administered buprenorphine in laboratory rats

Oral administration of buprenorphine is becoming a popular method of providing analgesia for laboratory rodents. The mixing of buprenorphine with flavoured jello, which rodents find palatable, is becoming a commonly used method as it is thought to improve the efficacy of oral buprenorphine by increasing the time available for it to be absorbed via the oral mucosa. The aim of this study was to assess the effect of various methods of buprenorphine administration (subcutaneous saline, subcutaneous buprenorphine (0.05 mg/kg), buprenorphine gavage (0.5 mg/kg), buprenorphine in jello (0.5 mg/kg) and buprenorphine in golden syrup (0.5 mg/kg)) on thermal antinociceptive thresholds in laboratory rats. Buprenorphine administered subcutaneously, by gavage, in jello and in syrup induced significant increases in thermal antinociceptive thresholds compared with saline. This effect was observed up to 5 h postadministration for buprenorphine administered subcutaneously and by gavage, but only for one hour postadministration for buprenorphine administered in jello and in syrup.

( BUPP10108 - 03 March 2010) Evaluation and management of substance abuse emergencies

This article focuses on the clinical evaluation and initial treatment of patients with substance abuse problems who present to an emergency department. The importance of making an accurate differential diagnosis and consideration of all relevant biopsychosocial factors is highlighted. The authors offer a treatment algorithm for emergency department clinicians and psychiatrists working in an emergency department setting to consider when assessing patients with intoxication or withdrawal from drugs of abuse. As emergency departments serve an important triage function, level of care determinates are highlighted. Three important clinical federal guidelines developed by the Center for Substance Abuse Treatment are presented and discussed, which are relevant to all emergency department clinicians who evaluate patients who are intoxicated or in withdrawal. These include the following: First, never give medications to an intoxicated patient and immediately discharge them. Second, avoid discharging any intoxicated patient to the street. Last, differentiate between acute intoxication and withdrawal and assess the potential for self harm, intentional and non-intentional.

( BUPP10107 - 03 March 2010) Editorial: Improving healthcare for incarcerated women

( BUPP10106 - 02 March 2010) Use of health information technology to advance evidence-based care: Lessons from the VA QUERI program

Background: As the Department of Veterans Affairs (VA) Health Services Research and Development Service's Quality Enhancement Research Initiative (QUERI) has progressed, health information technology (HIT) has occupied a crucial role in implementation research projects. Objectives: We evaluated the role of HIT in VA QUERI implementation research, including HIT use and development, the contributions implementation research has made to HIT development, and HIT-related barriers and facilitators to implementation research. Participants: Key informants from nine disease-specific QUERI Centers. Approach: Documentation analysis of 86 implementation project abstracts followed up by semi-structured interviews with key informants from each of the nine QUERI centers. We used qualitative and descriptive analyses. Results: We found: (1) HIT provided data and information to facilitate implementation research, (2) implementation research helped to further HIT development in a variety of uses including the development of clinical decision support systems (23 of 86 implementation research projects), and (3) common HIT barriers to implementation research existed but could be overcome by collaborations with clinical and administrative leadership. Conclusions: Our review of the implementation research progress in the VA revealed interdependency on an HIT infrastructure and research-based development. Collaboration with multiple stakeholders is a key factor in successful use and development of HIT in implementation research efforts and in advancing evidence-based practice.

( BUPP10105 - 02 March 2010) (Family practitioner and the heroin addict)

( BUPP10136 - 09 March 2010) Biologic treatments for drug and alcohol dependence

Drug and alcohol dependence continue to be significant public health problems in the United States. The high rates of relapse associated with the psychosocial treatment of addiction have encouraged the development of medications to augment counseling for the prevention of relapse. Current medications have been developed to help prevent relapse by numerous different mechanisms, including making drug use aversive, reducing the euphoric effects of abused drugs, and reducing drug craving. Medications that can reduce drug craving have been the most effective. Effective medications for the treatment of alcohol dependence include disulfiram, naltrexone, and acamprosate. For opioid dependence, methadone, buprenorphine, and acamprosate have been shown to be effective. For nicotine dependence, nicotine replacement therapy is available as well as bupropion and varenicline. No medications have thus far been proven to be effective for stimulant dependence, but several promising leads have emerged.

( BUPP10135 - 09 March 2010) A survey of community drug team prescribing policies and client views

Aims and methods: A postal and telephone survey of 140 community drug teams in England and Wales was performed to survey existing prescribing policies for substitute prescriptions, including prevalence of supervised methadone consumption, use of methadone higher doses, injectables and prescribed benzodiazepines. Questionnaires were directed to the prescribing doctor. A second survey involved questionnaires distributed to clients at three community drugs teams in Essex. Participants were asked to comment on various aspects of prescribing policies. Results: Results were obtained from 120 community drug teams (86%) and 104 clients who had received substitute prescribing. Around 22% of teams reported that methadone was supervised in a minority of new patients. Low doses (under 60 mg methadone per day) were rarely used (fewer than 10 patients) in 45% of services. Buprenorphine was prescribed in 97% of services. Fewer than half of community drug teams prescribed benzodiazepines (other than alcohol detoxification) or injectable drugs. A total of 104 responses were received from service users in Essex. The majority were opposed to supervised consumptions, although they were in broad agreement with other policies. Conclusion: Regulations concerning supervised consumption of methadone are ignored in at least one-fifth of community drug teams. The opposition of service users to supervised consumption may lead to the continued popularity of methadone to take away in England and Wales. Service users in Essex were generally in agreement with other aspects of prescribing policy including the reluctance to use higher doses of methadone.

( BUPP10134 - 09 March 2010) What is recovery? Revisiting the Betty Ford Institute Consensus Panel Definition. The Betty Ford Consensus Panel and Consultants

( BUPP10133 - 09 March 2010) Current issues in palliative care: Third national conference

This recent conference provided an all-round review of the current issues to be considered in palliative care. A list of the top 10 points that one hospital physician found most useful is presented.

( BUPP10132 - 09 March 2010) Pharmacotherapy and pregnancy: Highlights from the second international conference for individualized pharmacotherapy in pregnancy

To address provider struggles to provide evidence-based, rational drug therapy to pregnant women, a second conference was convened to highlight the current research in the field. Speakers from academic centers and institutions spoke about: the unique physiology and pathology of pregnancy; pharmacokinetic changes in pregnancy; thyroid disorders in pregnancy; pharmacogenetics in pregnancy; the role of CYP2D6 in pregnancy; treating addiction in pregnancy; the power of teratology networks to inform clinical decisions; the use of anti-depressants in pregnancy; and how to utilize computer-based modeling to aid with individualized pharmacotherapy in pregnancy. The Conference highlighted several areas of collaboration with the current Obstetrics Pharmacology Research Units Network (OPRU) and hoped to stimulate further collaboration and knowledge in the area with the common goal to improve the ability to safely and effectively use individualized pharmacotherapy in pregnancy.

( BUPP10131 - 09 March 2010) Persistent pain in the older adult: What should we do now in light of the 2009 American Geriatrics Society Clinical Practice Guideline?

The recent publication of revised guidelines for the management of persistent pain in the older adult (American Geriatric Society, 2009) has posed a dilemma for clinicians. In essence, these revised guidelines now downplay the use of nonsteroidal anti-inflammatory drugs (NSAIDs) relative to prior year's recommendations. The strong recommendation for caution when employing NSAIDs is because of the numerous, well-documented, potential adverse effects including renal failure, stroke, hypertension, heart failure exacerbations, and gastrointestinal complications. Nevertheless, physicians still have a substantial arsenal for combating chronic pain due to such conditions as degenerative arthritis and back problems. Options for intervention include physical therapy, topical nonsteroidals, capsaicin, topical lidocaine, intra-articular therapies, and judicious use of narcotics. In the future, cyclooxygenase-inhibiting nitric oxide-donating drugs may represent a technical improvement in the toxicity profile of traditional NSAIDs.

( BUPP10130 - 09 March 2010) Harms associated with psychoactive substances: Findings of the UK national drug survey

Nutt and colleagues rational scale to assess the harms of commonly used drugs was based on ratings by a panel of experts. This survey aimed to assess drug users views of the harms of drugs using the same scale. As users drug choices are not solely based on harms, we additionally assessed perceived benefits. The survey was hosted at http://www.nationaldrugsurvey.org. UK residents reported their experience of 20 commonly used substances; those with direct experience of a substance rated its physical, dependence-related and social harms as well as benefits. A total of 1501 users completed the survey. There was no correlation between the classification of the 20 drugs under the Misuse of Drugs Act and ranking of harms by users. Despite being unclassified substances, alcohol, solvents and tobacco were rated within the top ten most harmful drugs. There was a remarkably high correlation (r = 0.896) overall between rankings by users and by experts. Ecstasy, cannabis and LSD were ranked highest by users on both acute and chronic benefits. These findings imply that users are relatively well informed about the harms associated with the drugs they use. They also suggest that the current UK legal classification system is not acting to inform users of the harms of psychoactive substances.

( BUPP10129 - 09 March 2010) Antagonist-agonist combinations as therapies for heroin addiction: Back to the future?

Psychopharmacology is a powerful approach to the treatment of many psychiatric disorders. In this article I discuss the conceptual and practical issues in relation to the use of mu opioid receptor agonist, antagonist and partial agonist drugs in the treatment of opioid addiction, as this is one therapeutic area where all three types of agents are currently available. The choice of pharmacological agent is largely determined by patient profile, existence of ongoing drug misuse, and the kinetics of the drugs available. These principles, however, can be applied to other disorders as and when other pharmacological approaches become refined in these areas.

( BUPP10128 - 09 March 2010) Livedoid and necrotic skin lesions due to intra-arterial buprenorphine injections evidenced by maltese cross-shaped histologic bodies

( BUPP10127 - 09 March 2010) Biological, clinical, and ethical advances of placebo effects

For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects.

( BUPP10126 - 09 March 2010) A review of the clinical pharmacokinetics of opioids, benzodiazepines, and antimigraine drugs delivered intranasally

Background: Interest in the development of drug delivery devices that might improve treatment compliance is growing. A dosage formulation that is easy to use, such as intranasal application with transmucosal absorption, may offer advantages compared with other routes of drug delivery. The literature concerning intranasal application is diffuse, with a large number of published studies on this topic. Some cerebroactive pharmaceuticals delivered intranasally might follow the pathway from the nose to the systemic circulation to the brain. To determine the suitability of these drugs for intranasal drug delivery, a systematic review was performed. Objective: The aim of this review was to compare the pharmacokinetic properties of intranasal, intravenous, and oral formulations in 3 classes of cerebroactive drugs that might be suitable for intranasal delivery-opioids, benzodiazepines, and antimigraine agents. Methods: A search of MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature, EMBASE, and Cochrane Database of Systematic Reviews (dates: 1964-April 200 9) was conducted for pharmacokinetic studies of drugs that might be suitable for intranasal delivery. A comparison of pharmacokinetic data was made between these 3 routes of administration. Results: A total of 45 studies were included in this review. Most of the opioids formulated as an intranasal spray reached a T /sub max/ within 25 minutes. The bioavailability of intranasal opioids was high; in general, >50% compared with opioids administered intravenously. Intranasal benzodiazepines had an overall T /sub max/ that varied from 10 to 25 minutes, and bioavailability was between 38% and 98%. T /sub max/ for most intranasal antimigraine drugs varied from 25 to 90 minutes. Intranasal bioavailability varied from 5% to 40%. Conclusions: This review found that intranasal administration of all 3 classes of drugs was suitable for indications of rapid delivery, and that the pharmacokinetic properties differed between the intranasal, oral, and intravenous formulations (intravenous > intranasal > oral).

( BUPP10125 - 09 March 2010) Effects of opioids and anesthetic drugs on body temperature in cats

OBJECTIVE: To determine which class of opioid alone or in conjunction with other anesthetic drugs causes post-anesthetic hyperthermia in cats. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: Eight adult, healthy, cats (four spayed females and four castrated males weighing 3.8 +/- 0.6 kg). METHODS: Each cat was instrumented with a wireless thermistor in the abdominal cavity. Temperature in all phases was recorded every 5 minutes for 5 hours. Population body temperature (PBT) was recorded for approximately 8 days. Baseline body temperature is the final 24 hours of the PBT. All injectable drugs were given intramuscularly. The cats were administered drugs in four phases: 1) hydromorphone (H) 0.05, 0.1, or 0.2 mg kg(-1); 2) morphine (M) (0.5 mg kg(-1)), buprenorphine (BUP) (0.02 mg kg(-1)), or butorphanol (BUT) (0.2 mg kg(-1)); 3) ketamine (K) (5 mg kg(-1)) or ketamine (5 mg kg(-1)) plus hydromorphone (0.1mg kg(-1)) (KH); 4) isoflurane in oxygen for 1 hour. Fifteen minute prior to inhalant anesthetic, cats received either no premed (I), hydromorphone (0.1 mg kg(-1)) (IH), or hydromorphone (0.1 mg kg(-1)) plus ketamine (5 mg kg(-1)) (IHK). RESULTS: Mean PBT for all unmedicated cats was 38.9 +/- 0.6 degrees C (102.0 +/- 1 degrees F). The temperature of cats administered all doses of hydromorphone increased from baseline (p < 0.03) All four opioids (H, M, BUP and BUT) studied increased body temperature compared with baseline (p < 0.005). A significant difference was observed between baseline temperature values and those in treatment KH (p < 0.03). Following recovery from anesthesia, temperature in treatments IH and IHK was different from baseline (p < 0.002). CONCLUSIONS AND CLINICAL RELEVANCE: All of the opioids tested, alone or in combination with ketamine or isoflurane, caused an increase in body temperature. The increase seen was mild to moderate (<40.1 degrees C (104.2 degrees F) and self limiting.

( BUPP10124 - 09 March 2010) Diversion and injection of methadone and buprenorphine among clients in public opioid treatment clinics in New South Wales, Australia

A survey of 448 clients receiving opioid treatment in public clinics in Australia was conducted during 2005, exploring diversion and injection of supervised methadone and buprenorphine, frequency and reported effects of injecting, and the cost and availability of street-purchased pharmacotherapies. The rates of diversion in the preceding 12 months were over three times higher among participants receiving supervised buprenorphine (15.3%) than among those receiving supervised methadone (4.3%). While 26.5% of participants currently prescribed buprenorphine had ever injected buprenorphine, 65.9% of those prescribed methadone reported ever injecting methadone. The majority of participants did not appear to have extensive experience of injecting their medication and most expressed a preference for taking it as directed. Further research is required to determine the optimal approach for the supervised administration of buprenorphine that maximizes the benefits of treatment and minimizes harm and the risk of diversion. The study's limitations are noted.

( BUPP10123 - 09 March 2010) Improved quality of life, clinical, and psychosocial outcomes among heroin-dependent patients on ambulatory buprenorphine maintenance

AIM: A prospective longitudinal design was employed to examine the effects of buprenorphine maintenance on quality of life (QOL), clinical, and psychosocial characteristics of heroin-dependent patients. METHOD: Between 2003 and 2005 data were collected on 259 patients attending the outpatient centers for treatment of drug addictions across Israel, of which 157 were reevaluated 16 weeks later and 105 reevaluated 32 weeks later using the Clinical Global Impression, Distress Scale for Adverse Symptoms, Quality of Life Enjoyment and Satisfaction Questionnaire, General Health Questionnaire, General Self-Efficacy Scale, and the Multidimensional Scale of Perceived Social Support. Univariate and multivariate analyses were conducted to examine the association between the parameters and the cross-sectional and longitudinal predictions of the QOL outcomes. RESULTS: The groups did not differ in baseline values and their post-treatment ratings revealed significant improvement on virtually all the scales. Perceived self-efficacy and social support from friends and significant others at baseline as well as their changes over time were the best predictors of the QOL in the short and long terms. The study's limitations are noted. CONCLUSIONS: The beneficial effects on the QOL were associated with improvement in the psychosocial parameters and a reduction in buprenorphine-related side effects and psychological distress. This study could stimulate research to compare the QOL related to buprenorphine and methadone treatment and serve as a basis on which a controlled study should be performed.

( BUPP10122 - 09 March 2010) Drug Addiction

Many drugs of abuse, including cannabinoids, opioids, alcohol and nicotine, can alter the levels of endocannabinoids in the brain. Recent studies show that release of endocannabinoids in the ventral tegmental area can modulate the reward-related effects of dopamine and might therefore be an important neurobiological mechanism underlying drug addiction. There is strong evidence that the endocannabinoid system is involved in drug-seeking behavior (especially behavior that is reinforced by drug-related cues), as well as in the mechanisms that underlie relapse to drug use. The cannabinoid CB1 antagonist/inverse agonist rimonabanthas been shown to reduce the behavioral effects of stimuli associated with drugs of abuse, including nicotine, alcohol, cocaine, and marijuana. Thus, the endocannabinoid system represents a promising target for development of new treatments for drug addiction.

( BUPP10121 - 09 March 2010) No hyperalgesia following opioid withdrawal after the oripavine derivative etorphine compared to remifentanil and sufentanil

Background and objective The concept of opioid-induced hyperalgesia has recently gained prominence as a contributing factor for long-term treatment failure.Methods To evaluate possible differences of opioids used in anaesthesia, cumulative doses of sufentanil and remifentanil were compared with escalating doses of the oripavine derivative etorphine, in awake and trained canines. This was followed by naloxone unmasking a possible hyperalgesic state, which had developed during opioid administration. Heart rate, blood pressure and propagation of nociceptive volleys in somatosensory-evoked potentials as well as the skin-twitch reflex were evaluated.Results Opioid-related hypotension and bradycardia were reversed by naloxone with a late (30 min) overshoot of +43 and +17% after remifentanil and sufentanil, respectively. Following etorphine, overshoot in mean blood pressure was +9%, whereas heart rate still remained below -9% when compared with control. Peak hyperalgesia, as detected in the somatosensory-evoked potential and skin-twitch, increased by +70% after remifentanil and by +43% after sufentanil. This reflected a significant (P<0.005) increase in propagation of nociceptive afferents as late as 30 min after naloxone reversal. Such potentiation was not observed in the etorphine group, as peak somatosensory-evoked potential deflection and skin-twitch remained below -80% when compared with control.Conclusion The pure mu-agonists sufentanil or remifentanil seem to induce a 'bimodal' inhibitory followed by an excitatory effect. The latter is unmasked by naloxone in the postadministration period. In contrast, this is not seen with etorphine, a close congener of buprenorphine. The proposed mode of action of such hyperexcitatory effects may involve second-messenger-mediated G-protein activation, originally proposed by others. Ligands of the oripavine series may present an alternative for prevention of opioid-induced hyperalgesia in patients.

( BUPP10120 - 09 March 2010) Post-operative analgesia in the dog: a comparison of morphine, buprenorphine and pentazocine

The efficacy of buprenorphine and pentazocine in controlling pain in dogs following orthopaedic surgery was compared with that of morphine. All three analgesics provided effective pain relief with no undesirable side effects.

( BUPP10152 - 17 March 2010) The Nordic Countries as a Cohort for Pharmacoepidemiological Research

The Nordic countries have a long tradition of registry-based epidemiological research. Many population-based health registries were established in the 1960s, with use of unique personal identifiers facilitating linkage between registries. In recent years, each country has established a national database to track prescription drugs dispensed to individuals in ambulatory care. The objectives were to present an overview of the prescription databases established in the Nordic countries, as well as to elaborate on their unique potential for record linkage and cross-national comparison of drug utilization. Five Nordic countries collect drug exposure data based on drugs dispensed at pharmacies and have the potential to link these data to health outcomes. The databases together cover 25 million inhabitants (Denmark: 5.5 million; Finland: 5.3 million; Iceland: 0.3 million; Norway: 4.8 million; and Sweden: 9.2 million). In 2007, the registries encompassed 17 million prescription drug users (68% of the total population). We provide examples of how these databases have been used for descriptive drug utilization studies and analytical pharmacoepidemiological studies linking drug exposure to other health registries. Comparisons are facilitated by many similarities among the databases, including data source, content, coverage and methods used for drug utilization studies and record linkage. There are, however, some differences in coding systems and validity, as well as in some access and technical issues. To perform cross-national pharmacoepidemiological studies, resources, networks and time are needed, as well as methods for pooling data. Interpretation of results needs to account for inter-country heterogeneity and the possibility of spurious relationships. The Nordic countries have a unique potential for collaborative high-quality cross-national pharmacoepidemiological studies with large populations. This research may assist in resolving safety issues of international interest, thus minimizing the risk of either over-reacting on possible signals or underestimating drug safety issues.

( BUPP10151 - 17 March 2010) Efficacy and safety of different techniques of paravertebral block for analgesia after thoracotomy: A systematic review and metaregression

Various techniques and drug regimes for thoracic paravertebral block (PVB) have been evaluated for post-thoracotomy analgesia, but there is no consensus on which technique or drug regime is best. We have systematically reviewed the efficacy and safety of different techniques for PVB. Our primary aim was to determine whether local anaesthetic (LA) dose influences the quality of analgesia from PVB. Secondary aims were to determine whether choice of LA agent, continuous infusion, adjuvants, pre-emptive PVB, or addition of patient-controlled opioids improve analgesia. Indirect comparisons between treatment arms of different trials were made using metaregression. Twenty-five trials suitable for metaregression were identified, with a total of 763 patients. The use of higher doses of bupivacaine (890-990 mg per 24 h compared with 325-472.5 mg per 24 h) was found to predict lower pain scores at all time points up to 48 h after operation (P=0.006 at 8 h, P=0.001 at 24 h, and P<0.001 at 48 h). The effect-size estimates amount to around a 50 decrease in postoperative pain scores. Higher dose bupivacaine PVB was also predictive of faster recovery of pulmonary function by 72 h (effect-size estimate 20.1% more improvement in FEV /sub 1/ , 95% CI 2.08%-38.07%, P=0.029). Continuous infusions of LA predicted lower pain scores compared with intermittent boluses (P=0.04 at 8 h, P=0.003 at 24 h, and P<0.001 at 48 h). The use of adjuvant clonidine or fentanyl, pre-emptive PVB, and the addition of patient-controlled opioids to PVB did not improve analgesia. Further well-designed trials of different PVB dosage and drug regimes are needed.

( BUPP10150 - 17 March 2010) Impact of opioid rescue medication for breakthrough pain on the efficacy and tolerability of long-acting opioids in patients with chronic non-malignant pain

Background. There is little evidence that short-acting opioids as rescue medication for breakthrough pain is an optimal long-term treatment strategy in chronic non-malignant pain. We compared clinical studies of long-acting opioids that allowed short-acting opioid rescue medication with those that did not, to determine the impact of opioid rescue medication use on the analgesic efficacy and tolerability of chronic opioid therapy in patients with chronic non- malignant pain. Methods. We searched MEDLINE (1950 to July 2006) and EMBASE (1974 to July 2006) using terms for chronic non-malignant pain and long-acting opioids. Independent review of the search results identified 48 studies that met the study selection criteria. The effect of opioid rescue medication on analgesic efficacy and the incidence of common opioid-related side-effects were analysed using meta-regression. Results. After adjusting for potentially confounding variables (study design and type of opioid), the difference in analgesic efficacy between the 'rescue' and the 'no rescue' studies was not significant, with regression coefficients close to 0 and 95% confidence intervals that excluded an effect of more than 18 points on a 0-100 scale in each case. There was also no significant difference between the 'rescue' and the 'no rescue' studies for the incidence of nausea, constipation, or somnolence in both the unadjusted and the adjusted analyses. Conclusions. We found no evidence that rescue medication with short-acting opioids for breakthrough pain affects analgesic efficacy of long-acting opioids or the incidence of common opioid-related side-effects among chronic non-malignant pain patients.

( BUPP10149 - 17 March 2010) Gluten content of the top 200 medications of 2008: A follow-up to the impact of celiac sprue on patients' medication choices

( BUPP10148 - 17 March 2010) Medications used in opioid maintenance treatment

( BUPP10147 - 17 March 2010) Narcotics: Aut idem and discount contracts

( BUPP10146 - 17 March 2010) A Contingency-Management Intervention to Promote Initial Smoking Cessation Among Opioid-Maintained Patients

Prevalence of cigarette smoking among opioid-maintained patients is more than threefold that of the general population and associated with increased morbidity and mortality. Relatively few studies have evaluated smoking interventions in this population. The purpose of the present study was to examine the efficacy of contingency management for promoting initial smoking abstinence. Forty methadone- or buprenorphine-maintained cigarette smokers were randomly assigned to a contingent (n = 20) or noncontingent (n = 20) experimental group and visited the clinic for 14 consecutive days. Contingent participants received vouchers based on breath carbon monoxide levels during Study Days 1 to 5 and urinary cotinine levels during Days 6 to 14. Voucher earnings began at $9.00 and increased by $1.50 with each subsequent negative sample for maximum possible of $362.50. Noncontingent participants earned vouchers independent of smoking status. Although not a primary focus, participants who were interested and medically eligible could also receive bupropion (Zyban). Contingent participants achieved significantly more initial smoking abstinence, as evidenced by a greater percentage of smoking-negative samples (55% vs. 17%) and longer duration of continuous abstinence (7.7 vs. 2.4 days) during the 2 week quit attempt than noncontingent participants, respectively. Bupropion did not significantly influence abstinence outcomes. Results from this randomized clinical trial support the efficacy of contingency management interventions in promoting initial smoking abstinence in this challenging population.

( BUPP10145 - 17 March 2010) Infectious adverse events related to misuse of high-dose buprenorphine: A retrospective study of 42 cases

Purpose: Misuse of high-dose buprenorphine (HDB), mainly by injection, is responsible of frequent infectious adverse events. Methods: This is a retrospective study of infectious complications occurring in patients using HDB by injection. Forty-two cases were identified (29 men and ten women) and the data were collected between March 1999 and December 2008. Results: The infectious complications included cutaneous infections (27 cases), endocarditis (nine cases), osteoarticular infections (four spondylodiscitis and one sacroiliitis), and a vascular embolism with decrease in visual acuity. Conclusion: The results of HDB maintenance treatment must be improved, both from the point of view of substitution and to limit its misuse by intravenous route injection. Health professionals have to play an important role in drug addict patients' education and supervision, to prevent buprenorphine injection and related infectious complications.

( BUPP10144 - 17 March 2010) Addiction

The 2009 news in medicine regarding dependence confirm the bio-psycho-social field of addiction medicine and psychiatry. First a statement is made about the risk of cardiac arythmy in opioid substitution treatments. Then a review of the treatment of C hepatitis shows its importance in an addicted population. In the field of cognitive neuroscience, progress has been made in the knowledge of <> and of its endophenotypical components. Electronic medias related disorders are on the border of addiction : a case study is exploring this new domain. At last, recent datas are presented on the relationship between cannabis and psychosis.

( BUPP10143 - 17 March 2010) Deconstructing the drug development process: The new face of innovation

Forged in the early 1960s, the paradigm for pharmaceutical innovation has remained virtually unchanged for nearly 50 years. During a period when most other researchbased industries have made frequent and often sweeping modifications to their R & D processes, the pharmaceutical sector continues to utilize a drug development process that is slow, inefficient, risky, and expensive. Few who work in or follow the activities of the pharmaceutical industry question whether change is coming. They know that the pharmaceutical sector, as currently structured, is unable to deliver enough new products to market to generate revenues sufficient to sustain its own growth. Nearly all major drug developers are critically examining current R & D practices and, in some cases, considering a radical overhaul of their R & D models. But key questions remain. What will the landscape for pharmaceutical innovation look like in the future? And, who will develop tomorrow's medicines?

( BUPP10142 - 17 March 2010) Application of quantitative structure-activity relationships for modeling drug and chemical transport across the human placenta barrier: A multivariate data analysis approach

Pharmacological agents and environmental pollutants can transfer from mother to fetus across the placental barrier, leading to reproductive toxic effects. Ex vivo human placental perfusion constitutes the most widely used method to study placental transfer and metabolism of drugs and chemicals. The aim of the present study was to evaluate whether quantitative structure-activity relationship (QSAR) methodology could serve as an effective alternative tool to estimate drugs and chemicals transport across the human placental barrier on the basis of easily interpretable molecular, physicochemical and structural properties. Multivariate data analysis (MVDA) was applied to a set of 88 structurally diverse drugs and chemicals to model placental transfer expressed by clearance index values compiled from literature sources. An adequate and robust QSAR model (r /sup 2/ = 0.73, Q /sup 2/ = 0.71, RMSEE = 0.15) was established, providing an informative illustration of the contributing physicochemical, molecular and structural properties of the compounds in placental transfer process. Descriptors reflecting the polarity of compounds proved to be the most important with a negative sign. Lipophilicity and, at a lower extent, molecular size parameters exerted positive contribution in the model. Thus, QSAR analysis may be considered as a promising alternative tool to support high-throughput screening of drugs and chemicals in respect to their transport across placental barrier.

( BUPP10141 - 17 March 2010) Prevention and treatment of hepatitis C in illicit drug users

Drug use is a complex behavior with multidimensional determinants, including social, psychological, cultural, economic, and biological factors. Blood borne viral infections including hepatitis C virus are transmitted when an uninfected intravenous drug user (IVDU) uses injection equipment, especially syringes, that have previously been used by an infected person. The transmission can also result from sharing other injection equipment such as 'cookers' and 'cottons'. Recent studies have shown that the prevalence and incidence of drug abuse have declined substantially since the introduction of needle exchange. Infection with hepatitis C may spontaneously resolve during the acute stage and never progress to chronic infection, or the infection may become chronic without medical complications, or the infection may become chronic with progressive medical complications. Regular testing for infection is an important strategy for secondary prevention of chronic hepatitis C infection. Care for hepatitis C is a vital component of a comprehensive health program for persons using illicit drugs. Such care includes screening for transmission risk behavior, prevention counseling and education, testing for HCV antibody and RNA. IDUs found to have chronic HCV infection should be assessed for the presence and degree of liver disease and evaluated for treatment for HCV. Hepatitis C care also requires providing access to treatment for substance use and abuse. Therapy with opioid agonists, including methadone maintenance treatment, has been shown to diminish and often eliminate opioid use and reduce transmission of infection. Approval of buprenorphine makes office-based pharmacotherapy for opioid addiction possible. When considering treatment for hepatitis C, particular attention must be paid to mental health conditions. As a group, IDUs exhibit higher rates of comorbid psychiatric disorders than the general population. IFN-based regimens for hepatitis C are often complicated by neuropsychiatric adverse effects, including depression, insomnia, and irritability. Strong linkages with mental health services, whether on-site or within the community, are a vital component of comprehensive health programs for IDUs and are particularly important during treatment for hepatitis C. Past episodes of depression or other psychiatric disorders are not absolute contraindications for the treatment for HCV infection. Some authors recommend prophylactic antidepressant therapy before initiating treatment for HCV in patients thought to be at a high risk of depression.

( BUPP10140 - 17 March 2010) The analgesic potential of cannabinoids

Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as antiemetic, appetite modulating, and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. As opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis-based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.

( BUPP10139 - 17 March 2010) Comparison of clonazepam compliance by measurement of urinary concentration by immunoassay and LC-MS/MS in pain management population

Background: Physicians determine patient compliance with their medications by use of urine drug testing. It is known that measurement of benzodiazepines is limited by immunoassay specificity and cutoff limits and therefore does not offer physicians an accurate picture of their patients' compliance with these medications. A few studies have used lower cutoffs to demonstrate patient compliance. Objectives: To define more appropriate cutoffs for compliance monitoring of patients prescribed clonazepam as determined using immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Study Design: A diagnostic accuracy study of the urinary excretion of clonazepam. Methods: Millennium Laboratories performed measurements on the urinary excretion of pain patients prescribed clonazepam as the indicator test. This benzodiazepine was chosen because it forms one major metabolite, 7-aminoclonazepam which is specific for that drug. Patients whose only benzodiazepine medication was clonazepam were selected as the test population. The Millennium Laboratories test database was filtered first to select patients on clonazepam, then a second filter was used to eliminate patients with any other listed benzodiazepine medications. Samples were tested using the Microgenics DRI � benzodiazepine assay with a 200 ng/mL cutoff. The same samples were quantitatively assessed for 7-aminoclonazepam by LC-MS/MS with a cutoff of 40 ng/mL. The results from the immunoassay were scored as positive or negative while the quantitative results from the LC-MS/MS were also scored as positive or negative depending upon their concentration. Results: Samples from 180 patients met these medication criteria. The positivity rates were 21% (38 samples) by immunoassay. The positivity rate was 70% (126 samples) if the LC-MS/MS cutoff was set at 200 ng/mL. However, the positivity rate was 87% (157 samples) if the LC-MS/MS was set at 40 ng/mL. Concentration distributions revealed a significant fraction (7%) in the 40 - 100 ng/mL range. Limitations: A limitation of the study was the inability to measure lower than 40 ng/mL. There may be another fraction of the population that was positive below the cutoff value. Conclusions: The difference in positivity rate between the immunoassay and the LC-MS/MS result showed that the nominal 200 ng/mL cutoff of the immunoassay did not apply to 7-aminoclonazepam. This low immunoassay positivity rate is inconsistent with the manufacturer's published cross reactivity data for clonazepam and 7-aminoclonazepam. These data illustrate the limitations of using a 200 ng/mL cutoff to monitor clonazepam compliance and suggest that a cutoff of 40 ng/mL or less is needed to reliably monitor use of this drug.

( BUPP10138 - 17 March 2010) POTENT ANTI-HYPERALGESIC EFFECT OF BUPRENORPHINE IN TWO DISTINCT NEUROPATHIC PAIN MODELS INDUCED BY SPINAL NERVE INJURY AND BY PACLITAXEL

( BUPP10137 - 17 March 2010) A Review of the Community Reinforcement Approach m the Treatment of Opioid Dependence

This article reviews the Community Reinforcement Approach (CRA) in the treatment of opioid dependence. It covers the use of CRA with both methadone maintenance patients and patients withdrawing from opioids. The data reviewed in the use of CRA in combination with methadone maintenance shows improvement in a number of areas. These include the reduction of opioid use, as well as other drugs of abuse, improved legal status, less psychiatric symptoms, and improved vocational and social functioning. CRA coupled with vouchers can assist in retaining patients in treatment long enough to improve opioid detoxification rates from buprenorphine and coupled with naltrexone may sustain abstinence. Further, the use of a standardized computerized format may extend the utility of CRA.

( BUPP10163 - 24 March 2010) Crushing sublingual buprenorphine-naloxone tablets: Impact upon dissolution time for supervised dispensing

Introduction/aims: The practice of crushing sublingual buprenorphine tablets has been implemented in a number of jurisdictions both in response to concerns about diversion and to reduce the time required to supervise dosing. there is, however, little evidence regarding the impact of dispensing crushed tablets. This study aims to: 1) Evaluate the dissolution time of crushed versus whole buprenorphine preparations in buprenorphine maintained individuals, 2) Examine the impact of dose upon dissolution time. Methods: the study involved a comparison of dissolution time for crushed versus whole buprenorphine-naloxone tablets. Study pharmacists measured dissolution time in 31 patients dispensed crushed or whole tablets. Each patient received both crushed and whole tablets. Analysis compared crushed versus whole tablet dissolution time and examined the relationship between dissolution time and dose. Results: The mean dose was 14.1mg buprenorphine. The mean time t dissolve whole buprenorphine tables was approximately 6 minutes, compared to 3� for the crushed preparation. Time to dissolution was significantly correlated to buprenorphine dose dispensed., both as whole (r=0.520, p>0.005) and crushed (r=0.582, p>0.005) tablets. Conclusions: the study confirmed that crushing of buprenorphine tablets significantly reduced the dissolution time, and hence the time required to supervise buprenorphine doses. A guide for pharmacists for supervision time for whole and crushed dosing is provided.

( BUPP10162 - 24 March 2010) Unobserved versus observed office buprenorphine/naloxone induction: A pilot randomised clinical trial

Physician adoption of buprenorphine treatment of opioid dependence may be limited in part by concerns regarding the induction process. Although national guidelines recommend observed induction, some physicians utilize unobserved induction outside the office. The aim of this pilot randomized clinical trial was to assess preliminary safety and effectiveness of unobserved versus observed office buprenorphine/naloxone induction among patients entering a 12-week primary care maintenance study. Participants (N = 20) with DSM-IV opioid dependence were randomly assigned to unobserved or office induction, stratifying by past buprenorphine use. All patients received verbal and written instructions. A withdrawal scale was used during initiation and to monitor treatment response. Clinic visits occurred weekly for 4 weeks then decreased to monthly. The primary outcome, successful induction one week after the initial clinic visit, was defined as retention in buprenorphine/naloxone treatment and being withdrawal free. Secondary outcomes included prolonged withdrawal beyond 2 days after medication initiation and stabilization at week 4, defined as being in treatment without illicit opioid use for the preceding 2 weeks. Outcome results were similar in the two groups: 6/10 (60%) successfully inducted in each group, 3/10 (30%) experienced prolonged withdrawal, and 4/10 (40%) stabilized by week 4. These pilot study results suggest comparable safety and effectiveness of unobserved and office induction and point toward utilization of non-inferiority design during future definitive protocol development. By addressing an important barrier for physician adoption, further validation of the unobserved buprenorphine induction method will hopefully lead to increased availability of effective opioid dependence treatment.

( BUPP10161 - 24 March 2010) Opioid treatment: Inhibiting pain memory

( BUPP10160 - 24 March 2010) Current situation and trends of drug abuse and HIV/AIDS in China

( BUPP10159 - 23 March 2010) Chronic pancreatitis: Diagnosis and treatment

Diagnosis and treatment of chronic pancreatitis still pose a serious problem especially in general care medicine. Over the last years, a frequency of this disease in developed countries has increased, which is associated with increased alcohol consumption as well as with progress in determination of genetic mutations in subjects previously diagnosed as suffering from idiopathic chronic pancreatitis. Although this disease is still difficult to recognize in its early stages, the introduction of new diagnostic options such as magnetic resonance imaging and positron emission tomography are expected to improve diagnostic procedures. The principle of the modern treatment is supplementation with new pancreatic enzyme formulas, with high enzymatic activity, especially of lipase, and fast release after reaching the duodenum. Pancreatic enzyme formula treatment is indicated mainly in the malabsorption syndrome caused by exocrine pancreatic insufficiency, and in pain complaints in the course of chronic pancreatitis. Therapeutic endoscopy plays an important role in the treatment of complications, but long term results of the procedures are still unknown. The question of a connection between chronic pancreatitis and pancreatic cancer remains unanswered. Gene mutations characteristic of pancreatic carcinogenesis have been found to occur, though less frequently, also in chronic pancreatitis. Promising evidence suggests a possibility of predicting the risk of cancer in the course of chronic pancreatitis by mea ns of evaluation of changes in the genetic profile, mainly mutations of the K-ras, p53, p16 and DPC4 genes. A better understanding of these mutations may be useful in diagnosis and treatment of pancreatic neoplasm.

( BUPP10158 - 23 March 2010) The concept of palliative care practice among Iranian general practitioners.

Introduction: General Practitioners (GPs) have the main responsibility in medical and particularly palliative care provision in most of countries, though this is not the current case in Iran. Development of 'family physician' approach in rural and most of the urban areas in Iran, GPs will have the main role in care provision. There is no formal palliative care education during general medical training in the country so far. Regarding the increasing number of people in need of palliative care services, it is essential to assess GPs' knowledge about palliative care to develop special palliative care educational programmes. Method: A cross-sectional questionnaire survey was conducted on general practitioners participated in a formal Continuous Medical Education programme, using three scales. Results: 216 GPs returned the completed questionnaires. More than half scored their knowledge about palliative care as weak, which was significantly related to their previous experience in caring of a terminally ill patient (p=0.001). Less than one third stated their good ability to either assess or manage pain in end of life. Major gender differences were seen in different subscales such as communication with patients and carers, patient management, palliative care knowledge and skills, and psychological stress. Conclusion: This study revealed a profound lack of knowledge and experience among Iranian general practitioners about palliative care which was mostly in more complicated areas rather than common symptoms relief.

( BUPP10157 - 23 March 2010) Co-infections and co-therapies: Treatment of HIV in the presence of hepatitis C and hepatitis B

An increasing number of people are chronically infected with HIV and HCV, and/or HBV owing to shared routes of transmission. With the advent of HARRT, liver disease secondary to hepatitis co-infections has emerged as a leading cause of morbidity and mortality in HIV-infected persons. There is increasing need to manage dual infection, but treatment is complicated by co-morbidities, overlapping toxicities, drug activities and resistance. A model of treatment that builds on the lessons learned from the treatment of HIV has evolved to maximise success of treating dual infections. This review will address current strategies for the managmetn of HIV in the setting of HCV and HBV co-infection and discuss future treatment directions and challenges.

( BUPP10156 - 23 March 2010) Substance abuse treatment organisations as mediators of social policy: slowing the adoption of a congressionally approved medication.

Most substance abuse treatment occurs in outpatient treatment centers, necessitating an understanding of what motivates organizations to adopt new treatment modalities. Tichy's framework of organizations as being comprised of three intertwined internal systems (technical, cultural, and political) was used to explain treatment organizations' slow adoption of buprenorphine, a new medication for opiate dependence. Primary data were collected from substance abuse treatment organizations in four of the ten metropolitan areas with the largest number of heroin users. Only about one fifth offered buprenorphine. All three internal systems were important determinants of buprenorphine adoption in our multivariate model. However, the cultural system, measured by attitude toward medications, was a necessary condition for adoption. Health policies designed to encourage adoption of evidence-based performance measures typically focus on the technical system of organizations. These findings suggest that such policies would be more effective if they incorporate an understanding of all three internal systems.

( BUPP10155 - 23 March 2010) Who rules the roost?

CASE: Adam's mother was concerned about her 3-year-old son's hyperactivity, violence, and activity level. Adam and his mom had recently moved into a shelter for pregnant women. The rest of the residents are primarily in their early 20s, whereas Adam's mom is 42. She had found about 3 months ago that she was pregnant. This was her fourth pregnancy, second with this father, and he had recently left her when she refused an abortion. Her other children are 22 and 24 and live out of state. She has a history of opioid addiction. She had been on methadone during Adam's gestation and had recently started on buprenorphine to treat her addiction during this pregnancy as well. Adam is here today for his 3-year-old checkup and you had not seen him for a year. Mom states that he has been healthy but has become progressively active over the last year. He is very angry about his dad leaving, and according to Adam's mother "blames her" for sending him away. They are living in 1 room at the shelter, and mom is finding it increasingly difficult to keep him busy all day. When she goes out looking for a job, he is very challenging at the shelter, and she constantly receives complaints that he is "too loud" in the common rooms. She feels like she is at the end of her rope with him, he is constantly climbing, bolting from her, and taking risks.When you examine Adam, you find a robust, healthy young boy. His eye contact is good, and he is socially related but does actively explore your office. When he begins taking the instruments off your wall, his mother sits passively watching him. When he begins playing with the faucet, she half heartedly tells him to "stop" but he looks at her and continues splashing. He then begins flicking the light switch on and off in the room with no response from mom. When you ask about discipline, mom states "nothing works." When you ask about supports, she states "I have nobody except Adam and the new baby now."Adam was born after an uneventful full-term pregnancy with his mother on 100mg methadone daily. She denies cigarette smoking, drugs, alcohol, or other medications. Urine testing throughout was positive only for opioids. Motor milestones were achieved at the appropriate time. Language milestones at the 2-year-old visit consisted of 10 single words. Now, he has a 50 single-word vocabulary but no 2-word combinations. He primarily takes whatever he wants and has a tantrum if mom cannot figure out what he desires. Adam's medical history is unremarkable. Family history is significant for drug abuse by her father and mother; mental illness in the father's family consisting of bipolar disorder in several uncles. Where do you go from here?

( BUPP10154 - 23 March 2010) Home versus office based buprenorphine inductions for opioid dependent patients

Recent legislation permits the treatment of opioid-dependent patients with buprenorphine in the primary care setting, opening doors for the development of new treatment models for opioid dependence. We modified national buprenorphine treatment guidelines to emphasize patient self-management by giving patients the opportunity to choose to have buprenorphine inductions at home or the physician's office. We examined whether patients who had home-based inductions achieved greater 30-day retention than patients who had traditional office-based inductions in a study of 115 opioid-dependent patients treated in an inner-city health center. Retention was similar in both groups: 50 (78.1%) in office-based group versus 40 (78.4%) in home-based group, p = .97. Several patient characteristics were associated with choosing office- versus home-based inductions, which likely influenced these results. We conclude that opioid dependence can be successfully managed in the primary care setting. Approaches that encourage patient involvement in treatment for opioid dependence can be beneficial. (C) 2010 Elsevier Inc. All rights reserved.

( BUPP10153 - 23 March 2010) Buprenorphine formulations for intranasal delivery

Aqueous formulations suitable for intranasal administration comprise buprenorphine or a physiologically acceptable salt or ester thereof and (a) a pectin having a degree of esterification of less than 50%, (b) chitosan and a polyoxyethylene-polyoxypropylene copolymer (poloxamer) or (c) chitosan and hydroxypropylmethylcellulose. Such formulations can induce rapid and prolonged analgesia when delivered intranasally to a patient. The buprenorphine or buprenorphine salt or ester may be delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration of buprenorphine, C-ther, of 0.2 ng/ml or greater which is maintained for a duration T(maint ) of at least 2 hours.

( BUPP10211 - 15 April 2010) Subutex can be no substitute because it is "stupefying"

When economic, political and scientific interests mingle with moral or religious views, dominant discourse tends to dwell within the limited province of unifying thinking what the French call La Pensee unique supporting propaganda. The way in which institutional therapy seeks to control rampant drug addiction is a most blatant illustration of language manipulation. The displacement of meaning breeds a general sense of confusion, destroying the faculty to think and encouraging the incapacity to think.

( BUPP10210 - 15 April 2010) Pharmacy willingness to partner with office based opioid dependence treatment providers in conducting random buprenorphine pill counts

( BUPP10209 - 15 April 2010) Conducting clinical research with prescription opioid dependence: Defining the population

Most treatment studies of opioid dependent populations have focused predominantly on heroin users, despite a recent increase in those dependent upon prescription opioids. A key methodological challenge involved in studying the latter group involves defining the population. Specifically, researchers must decide whether to include (1) concurrent heroin users and (2) individuals with pain. The multi site Prescription Opioid Addiction Treatment Study is examining treatments for this population. This paper describes various inclusion criteria considered by the study team related to heroin use and pain. The goal was to recruit a distinct but generalizable population of individuals dependent upon prescription opioids.

( BUPP10208 - 15 April 2010) Liaison psychiatry in a general hospital: Seven paradigmatic cases

Through the use of case reports, this article reviews frequent causes that origin the need for psychiatric intervention in patients hospitalized in medical and surgical wards. Particular diagnosis aspects are focused, so is the necessity of integration of the biological, psychological and social dimensions of the patient. The integrated approach by the various members of the medical staff is also emphasised. The cases presented were observed in the Liaison Psychiatry Consult of the Psychiatry Service of Hospital Santa Maria, in Lisbon, between November 2007 and January 2008. Seven cases were selected because they reflect paradigms in the intervention of the Liaison Psychiatrist, and reflect the following psychiatric diagnosis: Panic Disorder; Paranoid Schizophrenia; Bipolar Disorder; Personality Disorder; Major Depression, Dementia and Abstinence Syndrome.

( BUPP10207 - 15 April 2010) Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: A report from the ESMO/EAPC opioid policy initiative

Background: Many patients in Europe do not receive adequate relief of pain because of excessive regulatory restrictions on the availability and accessibility of opioids. This is a major public health problem. The aim of the study is to evaluate and report on opioid availability and the legal and regulatory barriers to accessibility across the countries of Europe. Methods: European Society for Medical Oncology and European Association for Palliative Care national representatives reported data regarding survey of opioid availability and accessibility. Formulary adequacy is evaluated relative to the World Health Organization (WHO) essential drugs list and the International Association for Hospice and Palliative Care list of essential medicines for palliative care. Overregulation is evaluated according to the guidelines for assessment of national opioid regulations of the WHO. Results: Data were reported on the availability and accessibility of opioids for the management of cancer pain in 21 Eastern European countries and 20 Western European countries. Results are presented describing the availability and cost of opioids for cancer pain in each surveyed country and nine forms of regulatory restrictions. Conclusions: Using standards derived from the WHO and International Narcotics Control Board, this survey has exposed formulary deficiencies and excessive regulatory barriers that interfere with appropriate patient care in many European countries. There is an ethical and public health imperative to address these issues.

( BUPP10206 - 15 April 2010) Harm reduction healthcare: From an alternative to the mainstream platform?

Despite a plethora of health related problems, access to primary healthcare is often limited for drug users (DUs). Many seek care at emergency departments and tertiary hospitals because of late presentation of illness. The costs to both DUs and the health system are such that harm reduction based healthcare centres (HRHCs) have been established in various settings and utilising a variety of models. These provide a range of medical and sometimes social services, in one, integrated, low threshold facility, including (or closely linked with) programs such as needle syringe provision. In some countries these HRHCs are becoming an alternative healthcare system for DUs. However, the need to provide such services on a broad, public health scale, in a sustainable, cost effective manner, raises the question as to whether such programmes should be mainstreamed. This commentary provides insights on advantages and disadvantages to mainstreaming HRHCs, and approaches and barriers to achieving this. Two approaches suggest themselves: (i) providing harm reduction services through the regular healthcare system, or (ii) more closely integrating HRHCs with mainstream services. Funding and stigma are major barriers to mainstreaming. Diverse national policies towards DUs, healthcare systems and contexts, necessitate different approaches. Because of the various barriers to mainstreaming, any steps towards mainstreaming should be taken whilst maintaining the option of continuing the current targeted harm reduction services.

( BUPP10205 - 15 April 2010) Pharmacotherapy in cancer pain management

Cancer related pain affects approximately about 30 to 80% of all patients, according to primary and metastatic sides and stage of disease. Cancer pain management depends on the underlying pathophysiological mechanisms. Current pain treatment is still based on the World Health Organisation (WHOladder) guidelines, opioid therapy beeing the cornerstone. The present overview article focuses on different opioids, as well as on the various adjuvants. Advantages and side effects of the different nonopioids, anticonvulsants, and antidepressants are discussed. The recommendations are limited for the adult outpatient treatment.

( BUPP10204 - 15 April 2010) Doppler ultrasonography for the noninvasive measurement of uterine artery volume blood flow through gestation in the pregnant sheep

Accurate noninvasive quantification of volume blood flow in the uterine arteries (UtAs) would have clinical and research benefits. We evaluated the correlation and agreement between uterine artery volume blood flow (UtABF) as calculated (cUtABF) from color/pulsed wave Doppler acquisitions and that measured (mUtABF) by bilateral perivascular transit time flow probes in 6 pregnant sheep at 2 gestational ages. Out of 22 Doppler acquisitions, 19 were successful. The overall correlation between cUtABF and mUtABF was 0.55 (n = 19, P=.01). Calculated UtABF and mUtABF were significantly correlated in late gestation (n = 11, r = 0.71, P =.01) but not at mid gestation (n = 8, r =.02, P =.96). By Bland Altman analysis, the mean cUtABF/mUt ABF was 1.15 with 95% limit of agreement ( 0.26 to 2.56), similar to results previously achieved using power/pulsed wave Doppler. Despite the acceptable correlation, the limits of agreement between Doppler and transit time flow probe measurements remain wide. This makes Doppler ultrasonography less than a desirable method to quantify Ut ABF in studies where accurate quantification is required.

( BUPP10203 - 15 April 2010) Harm reduction: Moving through the third decade

( BUPP10202 - 15 April 2010) Effect of cocaine use on buprenorphine pharmacokinetics in humans

The effect of chronic cocaine use on buprenorphine pharmacokinetics was investigated to identify drug interactions and potential toxicities. In a retrospective analysis, pharmacokinetics were compared for 16 studies completed on subjects who were regular cocaine users and 74 studies on subjects who used cocaine only occasionally or not at all. All participants were stably maintained on buprenorphine/naloxone 16/4 mg daily. Participants who used cocaine regularly had lower buprenorphine exposure (AUC 34% lower; C /sub max/ 27% lower and C /sub 24/ 37% lower; p .001 for all comparisons). Regular cocaine users were younger (p =.0007), and used more heroin (p =.004) and cocaine (p <.0001). Regular cocaine use may result in lower buprenorphine plasma concentrations with potential for adverse clinical outcomes.

( BUPP10201 - 15 April 2010) Drug interactions of clinical importance with methadone and buprenorphine

( BUPP10199 - 15 April 2010) The association between cocaine use and treatment outcomes in patients receiving office based buprenorphine/naloxone for the treatment of opioid dependence

Cocaine use in patients receiving methadone is associated with worse treatment outcomes. The association between cocaine use and office based buprenorphine/naloxone treatment outcomes is not known. We evaluated the association between baseline and in treatment cocaine use, treatment retention, and urine toxicology results in 162 patients enrolled in a 24 week trial of primary care office based buprenorphine/naloxone maintenance. Patients with baseline cocaine metabolite negative urine toxicology tests compared with those with cocaine metabolite positive tests had more mean weeks of treatment retention (18.3 vs. 15.8, p =.04), a greater percentage completed 24 weeks of treatment (50% vs. 33%, p =.04) and had a greater percentage of opioid negative urines (47% vs. 34%, p =.02). Patients with in treatment cocaine metabolite negative urine toxicology tests compared with cocaine metabolite positive patients had more mean weeks of treatment retention (19.0 vs. 16.5, p =.003), a greater percentage completed 24 weeks of treatment (60% vs. 30%, p <.001), and had a greater percentage of opioid negative urines (51% vs. 35%, p =.001). We conclude that both baseline and in treatment cocaine use is associated with worse treatment outcomes in patients receiving office based buprenorphine/naloxone and may benefit from targeted interventions.

( BUPP10198 - 15 April 2010) Interactions between buprenorphine and antiretrovirals: Nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine, lamivudine, and tenofovir

To improve outcomes among injection drug users with HIV and/or chronic hepatitis B, it is important to identify drug interactions between antiretroviral and opiate therapies. We report the results of a study designed to examine the interaction between buprenorphine and the nucleos(t)ide reverse transcriptase inhibitors (NRTI) didanosine (ddI), lamivudine (3TC), and tenofovir (TDF). Opioid dependent, buprenorphine/naloxone maintained, HIV negative volunteers (n = 27) participated in two 24 hour sessions to determine (1) pharmacokinetics of buprenorphine alone and (2) pharmacokinetics of both buprenorphine and either ddI, 3TC, or TDF. Among buprenorphine /naloxone maintained study participants, no significant changes in buprenorphine pharmacokinetics were observed following ddI, 3TC, or TDF administration. Buprenorphine had no significant effect on NRTI concentrations. Concomitant use of buprenorphine with ddI, 3TC, or TDF results in neither a significant pharmacokinetic nor pharmacodynamic interaction.

( BUPP10197 - 15 April 2010) Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: A review

Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area.

( BUPP10196 - 15 April 2010) Lack of clinically significant drug interactions between nevirapine and buprenorphine

This study was conducted to determine whether drug interactions of clinical importance occur between buprenorphine, an opioid partial agonist medication used in treatment of opioid dependence, and the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine. Opioid dependent, buprenorphine/naloxone maintained, HIV negative volunteers (n = 7) participated in 24 hour sessions to determine the pharmacokinetics of buprenorphine alone and of buprenorphine and nevirapine following administration of 200 mg nevirapine daily for 15 days. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined prior to and following nevirapine administration. Modest decreases were observed for AUC for buprenorphine and its metabolites. There was a trend for more rapid clearance of both buprenorphine (p =.08) and buprenorphine 3 glucuronide (p =.08). While no single effect reached statistical significance, the joint probability that the consistent declines in all measures of exposure were due to chance was extremely low, indicating that nevirapine significantly reduces overall exposure to buprenorphine and buprenorphine metabolites. Clinically significant consequences of the interaction were not observed. Buprenorphine did not alter nevirapine pharmacokinetics. Dose adjustments of either buprenorphine or nevirapine are not likely to be necessary when these drugs are coadministered for the treatment of opiate dependence and HIV disease.

( BUPP10195 - 15 April 2010) Benzodiazepines, methadone and buprenorphine: Interactions and clinical management

Benzodiazepines (BZDs) are widely used by heroin users not in treatment, and by patients in methadone and buprenorphine (BPN) treatment. This review examines the epidemiology of BZD use by opioid users, and the range of harms that are associated with BZD use in this group, including the association of BZD use with opioid related mortality. Preclinical and clinical data regarding pharmacokinetic and pharmacodynamic interactions between methadone, buprenorphine, and BZDs are reviewed. An overview of treatment approaches for managing BZD use in this population is presented, including strategies for minimizing abuse and addressing BZD dependence.

( BUPP10194 - 15 April 2010) Indicators of buprenorphine and methadone use and abuse: What do we know?

Abuse of prescription opioids is a growing problem. The number of methadone pain pills distributed now exceeds liquid methadone used in opioid treatment, and the increases in buprenorphine indicators provide evidence of the need to monitor and intervene to decrease the abuse of this drug. The need for additional and improved data to track trends is discussed, along with findings as to the characteristics of the users and combinations of drugs. Data on toxicities related to methadone or buprenorphine, particularly in combination with other prescribed drugs, are presented and clinical implications and considerations are offered. These findings underscore the need for physicians to be aware of potential toxicities and to educate their patients regarding these issues.

( BUPP10193 - 15 April 2010) Effect of cocaine use on methadone pharmacokinetics in humans

Chronic cocaine use has been shown to significantly decrease buprenorphine concentrations in the blood with potential for adverse events and poor treatment response. In this study, we investigated whether a similar drug interaction occurred between cocaine and methadone. In a retrospective analysis, methadone pharmacokinetics were compared for those who were either regular cocaine users (N = 16) or with intermittent or no cocaine use (N = 23). Participants who used cocaine regularly showed a significant decrease in C /sub min/(p =.04) and a trend for decreased AUC (p =.09) and more rapid methadone clearance (p =.08). Regular cocaine use may adversely impact treatment outcomes for opioid dependence in those receiving methadone maintenance by decreasing methadone exposure.

( BUPP10192 - 15 April 2010) Recently patented and promising ORL 1 ligands: Where have we been and where are we going?

Importance of the field: The interactions of nociceptin/orphanin FQ (N/OFQ) and the opioid receptor like receptor 1 (nociceptin opioid peptide NOP) have been implicated in a variety of systems including cardiovascular, respiratory, immune, and the central and peripheral nervous systems. Areas covered in this review: To elucidate the endogenous role of the N/OFQNOP system through the use of knockout and knockdown animal preparations, though most advances have been made using a host of synthetic agonists and antagonists. This review gives a brief history of the receptorligand discovery, the development of these agonists and antagonists within the last 10 years as published, and the therapeutic indications thereof focusing on pain. What the reader will gain: The use of NOP ligands in pain has been controversial at best; however, there are indications that both agonists and antagonists have a place in the clinical setting for acute and chronic pain. NOP ligands have potential as novel therapeutics, interestingly, when incorporated into a rationally designed multi target agent. Take home message: The discovery of N /OFQ and NOP opened a new option for the treatment of pain with the potential for a decreased side effect profile. Numerous compounds have been designed to target this system, the most promising of which have mixed profiles.

( BUPP10191 - 15 April 2010) Opioid induced constipation: Physiopathology and treatment

Constipation is the most common and bothersome side effect occurring during any opioid treatment. In some cases, its occurrence leads to a reduction of opioid doses and an incomplete pain control. Bowel dysfunction is the consequence of the opioid effect on mu receptors at the enteric nervous system level that promotes both motor and secretory effects due to a reduced neuron excitability and an impaired neurotransmitter (mainly acetylcholine) release. Opioids increase the number of segmental colonic contractions, reduce the frequency of peristaltic contractions, enhance the colonic storage of stools via an effect on colonic tone, impair rectal sensitivity and the feeling to defecate and promote an anal hypertony. In the same time, water and electrolyte intestinal absorption is increased leading to hard stools, difficult to expel. From a therapeutic point of view, opioid induced constipation remains a therapeutic challenge and most of the laxatives fail to improve large bowel dysfunction. Stimulant laxatives (sennosides, bisacodyl) are a possible solution while the treatment of a fecal impaction is often needed. The concomitant administration of naloxone with opioids is another option despite the risk of an impaired pain control, even when naloxone is given at lowdoses (2mg). Peripheral opioid antagonists acting on mu receptors are now available. These drugs, such as methylnaltrexone, are a significant therapeutic advance to obtain an effective control of pain without significant digestive side effects that impair patients'quality of life.

( BUPP10190 - 15 April 2010) Early experiences with Suboxone maintenance therapy in Hungary

Background: Suboxone (Buprenorphine/naloxone) is a novel drug used in opiate substitution therapy. In Hungary, it was introduced in November 2007. Suboxone is a product for sublingual administration containing the partial mu receptor agonist buprenorphine and antagonist naloxone in a 4:1 ratio. Objective: Objectives of our study were to monitor and evaluate the effects of Suboxone treatment. Method: 6 outpatient centers participated in the study, ; 3 from Budapest and 3 from smaller cities in Hungary. At thes e centers, all patients entering Suboxone maintenance therapy between November 2007 and March 2008, altogether 80 persons (55 males, 35 females, mean age = 30,2 years, SD=5,48) were included in the study sample. During the 6 month period of treatment, data were collected 4 times; when entering treatment, 1 month, 3 months, and 6 months after entering treatment. Applied measures were the Addiction Severity Index, SCID I, SCID II, Hamilton Depression Scale, Hamilton Anxiety Scale, STAI S State Anxiety Inventory, Beck Depression Inventory, Heroin Craving Questionnaire, WHO Well being Inventory, Perceived Stress Scale, ADHD retrospective questionnaire, TCI short version, and Ways of Coping questionnaire. Results: Nearly fourth of the altogether 80 heroin dependent patients (18 persons, 22.5%) dropped out of treatment during the first month (the majority, 12 persons (15%) during the first week) or chose methadone substitution instead. Following this period however, dropout rate decreased and the six month treatment period was completed by 32 patients (40%). During the first month of treatment significant positive changes were experienced in all studied psychological and behavioral dimensions that proved to be stabile throughout the studied period. Conclusions: According to the early experience with Suboxone treatment, it is a well tolerable and successfully applicable drug in the substitution therapy of opiate addicts. A critical phase seems to be the first one or two weeks of treatment. Dropout rate is high during this early period, while after a successful conversion clients presumably remain in therapy for a long period. At the beginning of administration special emphasis must be put on informing patients, especially concerning withdrawal symptoms that might be present during the first week, which highly contributes to better retention in treatment.

( BUPP10189 - 14 April 2010) Reply from the authors

( BUPP10188 - 14 April 2010) Maximising the treatment outcomes of opioid substitution treatment

( BUPP10187 - 14 April 2010) Review: buprenorphine better than alpha2 adrenergic agonists for managing opioid withdrawal

( BUPP10186 - 14 April 2010) Buprenorphine detection in hair samples by immunometric screening test: Preliminary experience

The recent introduction of buprenorphine use by the Drug Addiction Services has induced toxicology laboratories to develop new qualitative or semiquantitative screening assay for its determination in hair samples. The aim of this preliminary study was to verify the correlation between the buprenorphine intake and the immunometric screening test results (VMA-T Comedical and buprenorphine CEDIA /Thermo-Fisher/Microgenics reagents) and therefore their comparison with the liquid chromatography coupled with mass spectrometry (LC/MS) results. Hair samples were obtained from 32 subjects without buprenorphine-therapy reported and 17 in treatment. In glass test tube with hermetic cap were weighed 33 mg of 49 finely cut hair samples, washed with 1 mL of SLV-VMA-T washing solution, which is then completely sucked and eliminated. The samples were extracted with 400 mu L of VMA-T reagent for an hour at 100 degrees C. The extracts were analysed by immunometric screening test on ILab 650 chemistry analyser, using buprenorphine CEDIA reagent assay. From the 32 non-takers of drug, 30 semiquantitative results were less than 10 pg/mg and 2 were over 10 pg/mg; from the 17 subjects with therapy, all were over 10 pg/mg (range 13-50 pg/mg); no samples were false-negative. Results suggest that exist a good relationship between the administration of buprenorphine and its concentration in hair, detectable through this method and reagents line.

( BUPP10185 - 14 April 2010) Efavirenz: a decade of clinical experience in the treatment of HIV

The pharmacokinetics, long-term efficacy, resistance development, safety and cost-effectiveness of efavirenz are reviewed. Topics discussed are: pharmacokinetics; efficacy; safety and tolerability; use of efavirenz in special patient populations; resistance; drug interactions; adherence; QOL; and cost-effectiveness. Drugs mentioned are efavirenz, didanosine, emtricitabine, nelfinavir, ritonavir, lopinavir, stavudine, tenofovir, zidovudine, nevirapine, lamivudine, vicriviroc, raltegravir, rilpivirine, etravirine, and abacavir. Efavirenz is generally well tolerated during prolonged therapy, although neuropsychiatric symptoms are common in the 1st few wk of treatment and lead to discontinuation in a relatively small proportion of patients. (No EX).

( BUPP10183 - 12 April 2010) Urine drug screening: a valuable office procedure

Urine drug screening can enhance workplace safety, monitor medication compliance, and detect drug abuse. Ordering and interpreting these tests requires an understanding of testing modalities, detection times for specific drugs, and common explanations for false-positive and false-negative results. Employment screening, federal regulations, unusual patient behavior, and risk patterns may prompt urine drug screening. Compliance testing may be necessary for patients taking controlled substances. Standard immunoassay testing is fast, inexpensive, and the preferred initial test for urine drug screening. This method reliably detects morphine, codeine, and heroin; however, it often does not detect other opioids such as hydrocodone, oxycodone, methadone, fentanyl, buprenorphine, and tramadol. Unexpected positive test results should be confirmed with gas chromatography/mass spectrometry or high-performance liquid chromatography. A positive test result reflects use of the drug within the previous one to three days, although marijuana can be detected in the system for a longer period of time. Careful attention to urine collection methods can identify some attempts by patients to produce false-negative test results.

( BUPP10182 - 12 April 2010) A comparison of methadone, buprenorphine and alpha /sub 2/ adrenergic agonists for opioid detoxification: A mixed treatment comparison meta-analysis

Objectives: The aim of this systematic review was to compare the efficacy of methadone, buprenorphine, clonidine and lofexidine for opioid detoxification. Mixed treatment comparison meta-analyses were used to synthesise the data as it is designed for data-sets where limitations in standard pairwise meta-analyses make comparisons difficult to interpret. Data sources: A systematic search was conducted using the following databases: CENTRAL, CINAHL, Embase, HMIC, Medline and PsycINFO. Review methods: RCTs that included opioid dependent participants over a mean age of 16 receiving opioid detoxification using buprenorphine, methadone, clonidine or lofexidine were included in the systematic review. Included studies were quality assessed and the completion of treatment data was extracted by the author and a research assistant independently. Mixed treatment comparison methods were used to synthesise the data. Results: There were 23 RCTs included in the systematic review (and 20 included in the meta-analysis) comprising a total of 2112 participants. Buprenorphine and methadone were ranked as the most effective methods of opioid detoxification followed by lofexidine and clonidine respectively. Conclusion: Buprenorpine and methadone appear to be the most effective detoxification treatments. While the analysis suggests buprenorphine is the most effective method of detoxification there is some uncertainty on whether it is more effective than methadone and requires further research to confirm this result.

( BUPP10181 - 12 April 2010) Issues pertaining to the analysis of buprenorphine and its metabolites by gas chromatography-mass spectrometry.

"Substitution therapy" and the use of buprenorphine (B) as an agent for treating heroin addiction continue to gain acceptance and have recently been implemented in Taiwan. Mature and widely utilized gas chromatography-mass spectrometry (GC-MS) technology can complement the low cost and highly sensitive immunoassay (IA) approach to facilitate the implementation of analytical tasks supporting compliance monitoring and pharmacokinetic/pharmacogenetic studies. Issues critical to GC-MS analysis of B and norbuprenorphine (NB) (free and as glucuronides), including extraction, hydrolysis, derivatization, and quantitation approaches were studied, followed by comparing the resulting data against those derived from IA and two types of liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. Commercial solid-phase extraction devices, highly effective for recovering all metabolites, may not be suitable for the analysis of free B and NB; acetyl-derivatization products exhibit the most favorable chromatographic, ion intensity, and cross-contribution characteristics for GC-MS analysis. Evaluation of IA, GC-MS, and LC-MS/MS data obtained in three laboratories has proven the 2-aliquot GC-MS protocol effective for the determination of free B and NB and their glucuronides.

( BUPP10180 - 12 April 2010) Implementing harm reduction for heroin users in Afghanistan, the worldwide opium supplier

Afghanistan has suffered decades of war, occupation and unrest. It is also the world's greatest producer of opium and drug production and trafficking account for a third of the total Afghan economy. Currently alongside the "War on Terrorism", the control and eradication of opium production and related trafficking is a main concern of the international community. However, this focus on supply reduction has meant scant attention has been paid to increasing drug use problems within the country; it is estimated there are up to 25,000 opium users and 20,000 heroin users in Kabul city. Drug use is often a response to war, poverty and under-development, however, street opium and heroin manufactured in the country are widely available, affordable and of high purity. This paper documents the efforts of non-governmental organisations to promote and develop harm reduction and treatment services for problem drug users in Afghanistan in this difficult context.

( BUPP10179 - 12 April 2010) Tramadol as an analgesic for mild to moderate cancer pain

In most cancer patients, pain is successfully treated with pharmacological measures such as opioid analgesics alone or opioid analgesics combined with adjuvant analgesics (co-analgesics). Opioids for mild-to-moderate pain (formerly called weak opioids) are usually recommended in the treatment of cancer pain of moderate intensity. There is a debate whether the second step of the WHO analgesic ladder, which, in Poland, is composed of opioids such as tramadol, codeine, dihydrocodeine (DHC), is still needed for cancer pain treatment. One of the most interesting and useful drugs in this group is tramadol. Its unique mechanism of action, analgesic efficacy and profile of adverse effects are responsible for its successful use in patients with different types of acute and chronic pain, including neuropathic pain. The aim of this article is to summarize the data regarding pharmacodynamics, pharmacokinetics, possible drug interactions, adverse effects, dosing guidelines, equipotency with other opioid analgesics and clinical studies comparing efficacy, adverse reactions and safety of tramadol to other opioids in cancer pain treatment.

( BUPP10178 - 12 April 2010) Magnesium ions and opioid agonists in vincristine-induced neuropathy

Neuropathic pain is difficult to treat. Classic analgesics (i.e., opioid receptor agonists) usually possess low activity. Therefore other agents such as antidepressants, anticonvulsants, and corticosteroids are used. It is commonly known that NMDA antagonists increase analgesic activity of opioids. Unfortunately, clinical use of NMDA antagonists is limited because of the relatively frequent occurrence of adverse effects e.g., memory impairment, psychomimetic effects, ataxia and motor in-coordination. Magnesium ions (Mg /sup 2+ / ) are NMDA receptor blockers in physiological conditions. Therefore, in this study the effect of opioid receptor agonists and the influence of Mg /sup 2+/ on the action of opioid agonists in vincristine-induced hyperalgesia were examined. Opioid agonists such as morphine (5 mg/kg, ip), and fentanyl (0.0625 mg/kg, ip), as well as the partial agonist buprenorphine (0.075 mg/kg, ip) administered alone on 5 consecutives days did not modify the hyperalgesia in vincristine rats. In contrast, pretreatment with a low dose of magnesium sulfate (30 mg/kg, ip) resulted in a progressive increase of the analgesic action of all three investigated opioids. After discontinuation of drug administration, the effect persisted for several days.

( BUPP10177 - 12 April 2010) Drug abuse by adolescents: General considerations

Research evidence shows that early onset of substance use is significantly correlated with risk of developing alcohol dependence later in life. (17) Research evidence shows that the primary factors appearing to contribute to a teenager's choice of selecting one drug over another are its perceived availability, the perceived degree of social approval associated with its use, and how risky the drug is perceived to be. (3)(22) Strong research evidence shows that the CRAFFT is a valid and reliable method of screening adolescents for substance abuse in medical settings. (27)(29) Strong research evidence shows that psychiatric comorbidity in adolescents who misuse psychoactive substances is the rule rather than the exception, with comorbidities, including unipolar or bipolar depression, anxiety, conduct disorder, oppositional-defiant disorder, and ADHD. (33)(34) (35)(36) Adolescent substance use differs from that of adults in that progression from casual use to dependence occurs more quickly, adolescents are more likely to use multiple substances, and adolescents often are at higher risk of presenting with psychiatric comorbidities. Treatment always should be tailored to each adolescent's particular needs. Strong research evidence shows that family-based treatments are effective for adolescents who abuse substances and depend on them. (58)(59)(60) (61)(62)(63)(64).

( BUPP10176 - 12 April 2010) Optimizing pain control through the use of implantable pumps

Intrathecal therapy represents an effective and well established treatment of nonmalignant as well as malignant pain. Devices available include mechanical constant flow pumps as well as electronic variable flow pumps with patient-controlled bolus release. The latter provide faster dose finding, individual pain control, and good acceptance by patients. New technologies such as membrane pumps and rechargeable devices are expected to be developed to clinical perfection. The available drugs for intrathecal therapy are listed according to the polyanalgesic consensus on intrathecal therapy. The integration of remote patient-controlled analgesia into electronic implantable devices, and the peptide analgesic ziconotide, have significantly improved intrathecal therapy. Complications include infections, catheter ruptures or disconnections, catheter granulomas, and technical dysfunctions. Further possibilities for optimizing intrathecal therapy include development of new drugs, drug side effects, catheter and pump technologies, and surgical techniques.

( BUPP10175 - 30 March 2010) Lofexidine, an alpha /sub 2/ -receptor agonist for opioid detoxification

OBJECTIVE: To review the pharmacology, toxicology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines for lofexidine, an alpha /sub 2/ -agonist, for opioid detoxification. DATA SOURCES: Primary literature was identified through a MEDLINE search (1950-September 2009), EMBASE (1988-July 2009), International Pharmaceutical Abstracts (1970-September 2009), and the Cochrane Library (1996-September 2009) using the key words lofexidine and opioid withdrawal. Abstracts were included in the absence of published results of studies. STUDY SELECTION AND DATA EXTRACTION: Studies published in English-language literature reporting on animal and human pharmacology, toxicology, and pharmacokinetics were included in addition to clinical trials using lofexidine for opioid detoxification in comparison to placebo or active controls. DATA SYNTHESIS: Lofexidine is an alpha /sub 2/ -agonist structurally related to clonidine. It is not an effective antihypertensive agent; however, it decreases the sympathetic outflow responsible for many opioid withdrawal symptoms. Nine clinical studies were reviewed representing 354 patients receiving lofexidine including a recent Phase 3 clinical trial. Eight studies involved comparisons of lofexidine to an opioid receptor agonist or clonidine for opioid detoxification. In these trials, lofexidine dosing was titrated to a maximum of 1.6-3.2 mg/day in divided doses for a total of 5-18 days. The data suggest that lofexidine has positive efficacy in reducing opioid withdrawal symptoms and is at least as effective as the opioid receptor agonists utilized for detoxification. Not all withdrawal symptoms are alleviated by alpha /sub 2/ -agonists, with many patients complaining of insomnia and aching. The most common adverse event with lofexidine in the Phase 3 trial was insomnia. Hypotension was also reported; however, the studies comparing clonidine with lofexidine suggest decreased incidence and severity of adverse events with lofexidine. CONCLUSIONS: Lofexidine appears to be a promising agent for opioid detoxification. If approved, it would be the first nonopioid agent approved for this indication. Further large-scale controlled studies are needed to identify the safest, most effective dosage regimen required to achieve opioid detoxification.

( BUPP10184 - 30 March 2010) Bradycardia, absent radial pulse and convulsion following intramyometrial vasopressin

( BUPP10174 - 30 March 2010) Intrathecal buprenorphine for post-operative analgesia: A prospective randomised double blind study

Background: The use of intrathecal narcotics for pain relief is now an established technique, the drug most used being Morphine. Buprenorphine is a mixed agonist antagonist narcotic with high affinity at both mu and k opiate receptors. This study was conducted to assess the efficacy of intrathecal buprenorphine for postoperative pain relief and to study the incidence of side-effects. Patients & Methods : A prospective randomized double blind study was conducted in 100 patients, who underwent surgery of the lower abdomen and lower extremities. One group received (Control Group) 15 mg of heavy bupivacaine (0.5%), while the other group (Study Group) received 15mg of heavy bupivacaine (0.5%) with 1 mug kg /sup -1/ buprenorophine intrathecally upto a maximum of 50 mug. Results: Prolonged post-operative analgesia was observed in the study group (475.6 � 93.7 min) compared with Control Group (195.2 � 29.52 min). The side effects were minimal. Conclusion : This study shows that buprenorphine is an effective analgesic suitable for the management of post-operative pain.

( BUPP10173 - 30 March 2010) Sirolimus in Kidnery Transplant Donors and Clinical and Histologic Improvement in Recipients: Rat Model

Background: Ischemia-reperfusion (I/R) injury is one of the risk factors for delayed graft function, acute rejection episodes, and impaired long-term allograft survival after kidney transplantation. This antigen-independent inflammatory process produces tissue damage. Isogeneic transplantation in a rat model is a useful method for study of nonimmunologic risk factors for kidney damage. Objective: To study the effect of sirolimus on I/R injury using only 1 dose of the drug in the donor. Materials and Methods: Eighteen rats were allocated to 3 groups of 6 rats each: sham group, control group, and rapamycin group. Results: Improved renal function and systemic inflammatory response were observed in the rapamycin group compared with the control group (DELTAurea, DELTAcreatinine, and DELTAC3, all P < .01). The number of apoptotic nuclei in the renal medulla in the control group was higher than in the rapamycin group (P < .01). Tubular damage was less severe in the rapamycin group compared with the control group (P < .01). Complement 3 and tumor necrosis factor-alpha expression in the kidney samples were significantly decreased when rapamycin was given to the donor rats (P > .01). Bcl-2 protein was upregulated in the rapamycin group compared with the control group (P < .01). Conclusion: Administration of rapamycin in donors attenuates the I/R injury process after kidney transplantation in a rat model.

( BUPP10171 - 30 March 2010) The management of acute pain

Unrelieved acute pain produces undesirable effects that may influence a patient's recovery and even survival after surgery. It may also lead to the long-term problem of chronic post-surgical pain. Pain management techniques themselves carry risks so a careful consideration of the risk:benefit ratio is essential. An acute pain service should provide education and training to all staff members involved in pain control and advice on the management of more complex problems. The responsibility for assessing and addressing pain lies with the whole of the team, and the patient themselves play an important part in this process. Pain should be anticipated wherever possible and appropriate measures taken to prevent it. Communication is an essential part of optimizing safe, effective pain control. There are many simple measures using familiar drugs and techniques that can enhance pain control. Sometimes pain control measures fail and a suitable response should be implemented to address severe pain. Some patient groups offer particular challenges, but understanding possible difficulties often helps in managing these challenges. Pain should be considered the fifth vital sign.

( BUPP10170 - 30 March 2010) Transdermal buprenorphine - A critical appraisal of its role in pain management

This paper reviews the current clinical data for the role of transdermal buprenorphine (BUP TDS) in the treatment of diverse acute and chronic pain syndromes. Literature searches were carried out using PubMed (1988 to June 2009). The published findings seem to support hypotheses regarding the rather unique analgesic mechanisms of buprenorphine as compared with pure mu-opioids like morphine and fentanyl. However, the exact mechanism of this analgesic efficacy still remains largely unknown despite recent advances in preclinical pharmacological studies. Such assessments have demonstrated the sustained antihyperalgesic effect of buprenorphine in diverse animal pain models. These findings are supported in a growing number of clinical studies of oral, intrathecal, intravenous, and Bup TDS. This review paper focuses almost entirely on the clinical experience concerning the transdermal administration of buprenorphine, although preclinical aspects are also addressed in order to provide a complete picture of the unique pharmacological properties of this analgesic drug. Mounting evidence indicates the appropriateness of Bup TDS in the treatment of diverse acute and chronic pain syndromes which have been less or not responsive to other opioids. Additionally, BUP TDS seems to hold great promise for other difficult-to-treat (pain) conditions, such as patients in the intensive care setting. However, its use is somewhat tempered by the occurrence of local skin reactions which have been shown to be often therapy resistant. Further studies are certainly warranted to identify even more precisely the clinical syndromes that are most sensitive to buprenorphine treatment, and to compare buprenorphine to other opioids in head-to-head trials of acute and chronic pain conditions.

( BUPP10169 - 30 March 2010) Burden of disease and level of patient's medical care in substitution treatment for opiates

Background and Purpose: Within the framework of an interdisciplinary cooperation, the authors set up an on-site medical service provider in a specialized methadone substitution center in Germany. Here, they report on the prevalence of infectious and noninfectious diseases, and the vaccination status of substituted heroin-dependent patients. Patients and Methods: All patients who visited the medical care service provider between February 2008 and December 2008 were included in this study. Results: Ten patients (7%) were seropositive for the hepatitis A virus. Two patients (1.3%) suffered from chronic hepatitis B; 40 patients (27%) were cured after a hepatitis B infection. Additionally, 99 patients (68%) were infected with hepatitis C virus (HCV), and 41 patients (28%) had active hepatitis C. Furthermore, 48 hepatitis C patients (33%) were cured. Of those, 25 patients (17%) cleared the virus spontaneously and 23 (16%) after ribavirin/interferon combination therapy. Ten (7%) of 146 patients were infected with the human immunodeficiency virus (HIV). Of those, four patients had active hepatitis C, and five patients were cured after a hepatitis C infection. 18 patients (12%) were vaccinated against hepatitis A and 28 (19%) against hepatitis B. Two of the 41 patients with chronic hepatitis C were vaccinated against hepatitis A. The most frequent noninfectious diagnoses were arterial hypertension (n = 28), bronchial asthma (n = 8), and diffuse liver parenchymal damage (n = 12). Conclusion: These results emphasize that i.v. drug users on substitution therapy are an underserved collective with a high prevalence of disease. The challenge consists in facilitating this population access to internistic and infectious disease service. The offer of an on-site medical service was well accepted. This is essential for an ongoing reduction of HIV and HCV prevalence in the drug users.

( BUPP10168 - 30 March 2010) Transdermal opiates in the treatment of moderate-severe cancer pain

Although oral morphine is the gold standard in the front-line approach to moderate-severe cancer pain, transdermal opiates are largely used in clinical practice. Aims of our work were to review the evidences of literature supporting these different habits and to suggest an evidence-based criterion to guide clinical research and clinical practice. A systematic review of literature with meta-analysis of the safety data reported in randomized clinical trials comparing slow releasing oral morphine and transdermal opiates was performed using the random effect model. The quality of the evidences supporting the use of the different strategies and the strength of the recommendations was analyzed using the GRADE method. A significant advantage in favor of transdermal opiates was observed for constipation, urinary retention, need of laxative use and patient's preferences; a significant advantage in favor of slow releasing oral morphine was observed for diarrhea and sweating. The quality of the evidences supporting a front-line use of transdermal fentanyl was considered low, while those supporting the use of transdermal buprenorphine was considered very low. For the use of transdermal fentanyl and for that of transdermal buprenorphine a weak and a strong recommendation against their us as front-line treatment of moderate-severe cancer pain can be respectively obtained from the literature data. Transdermal opiates represent a safety and effective alternative to oral morphine against cancer pain, but they can not replace oral morphine as the gold standard first-line treatment of moderate-severe cancer pain.

( BUPP10167 - 30 March 2010) Factors associated with uptake of treatment for recent hepatitis C virus infection in a predominantly injecting drug user cohort: The ATAHC study

Despite that the majority of hepatitis C virus (HCV) infection occurs among injection drug users (IDUs), little is known about HCV treatment uptake in this group, particularly during recent infection. We evaluated uptake of treatment for recent HCV infection, including associated factors, within a population predominantly made up of IDUs. The Australian Trial in Acute Hepatitis C was a study of the natural history and treatment of recent HCV infection. All participants with detectable HCV RNA at screening were offered HCV treatment, assessed for eligibility and those initiating treatment were identified. Logistic regression analyses were used to identify predictors of HCV treatment uptake. Between June 2004 and February 2008, 163 were enrolled, with 146 positive for HCV RNA at enrolment. The mean age was 35 years, 77% (n=113) participants had ever injected illicit drugs and 23% (n=34) reported having ever received methadone or buprenorphine treatment. The uptake of HCV treatment was 76% (111 of 146) among those who were eligible on the basis of positive HCV RNA. Estimated duration of HCV infection (OR=1.03 per week, 95% CI=1.00-1.06, P=0.035) and log /sub 10/ HCV RNA (OR=1.92 per log /sub 10/ increase, 95% CI=1.36-2.73, P<0.001) were independently associated with treatment uptake whereas injection drug use was not. This study demonstrates that a high uptake of HCV treatment can be achieved among participants with recently acquired HCV infection. Decisions about whether to initiate treatment for recently acquired HCV were mainly driven by clinical factors, rather than factors related to sociodemographics or injecting behaviors.

( BUPP10166 - 30 March 2010) Pain in patients with lung cancer: Pathophysiology and treatment

This review analyses the characteristics of the principal pain syndromes associated with lung cancer, their physiopathology and causes, and provides updated information on available treatments. Pain associated with lung cancer is characterized by multiple expressions, due to either the progression of disease and/or induced by oncological treatment. The analgesic treatment is principally based on the use of opioids. Other than the oral route, which is the preferred one, alternative modalities to administer opioids may be helpful in different clinical circumstances. According to the opioid response, other routes and other opioids, may improve the balance between analgesia and adverse effects providing the best individual response to a specific opioid drug. More complex strategies, such as interventional procedures, are seldom necessary and require an appropriate selection of patients.

( BUPP10165 - 30 March 2010) A multi-site, two-phase, Prescription Opioid Addiction Treatment Study (POATS): Rationale, design and methodology

The National Institute on Drug Abuse Clinical Trials Network launched the Prescription Opioid Addiction Treatment Study (POATS) in response to rising rates of prescription opioid dependence and gaps in understanding the optimal course of treatment for this population. POATS employed a multi-site, two-phase adaptive, sequential treatment design to approximate clinical practice. The study took place at 10 community treatment programs around the United States. Participants included men and women age 18 who met Diagnostic and Statistical Manual, 4th Edition criteria for dependence upon prescription opioids, with physiologic features; those with a prominent history of heroin use (according to pre-specified criteria) were excluded. All participants received buprenorphine/naloxone (bup/nx). Phase 1 consisted of 4 weeks of bup/nx treatment, including a 14-day dose taper, with 8 weeks of follow-up. Phase 1 participants were monitored for treatment response during these 12 weeks. Those who relapsed to opioid use, as defined by pre-specified criteria, were invited to enter Phase 2; Phase 2 consisted of 12 weeks of bup/nx stabilization treatment, followed by a 4-week taper and 8 weeks of post-treatment follow-up. Participants were randomized at the beginning of Phase 1 to receive bup/nx, paired with either Standard Medical Management (SMM) or Enhanced Medical Management (EMM; defined as SMM plus individual drug counseling). Eligible participants entering Phase 2 were re-randomized to either EMM or SMM. POATS was developed to determine what benefit, if any, EMM offers over SMM in short-term and longer-term treatment paradigm. This paper describes the rationale and design of the study.

( Bupp10164 - 30 March 2010) Pain therapy with opiods

There is a worldwide consensus about the efficacy of opioids in the treatment of moderate to severe cancer pain. Pain therapy with strong opioids requires the choice of the appropriate drug and its administration in the right dose at the right time interval. At the beginning, the opioid must be titrated up to the individually necessary dose. Opioids are substances with morphine-like effects, binding to opioid receptors in the CNS and peripheral organs. These substances, apart from morphine itself, are hydromorphone, fentanyl, oxycodone, buprenorphine and methadone. Opioid rotation may be necessary because of great inter - and intra-individual differences in response to certain substances, insufficient pain control or refractory adverse effects. This article presents the principles of pain therapy with opioids according to guidelines, their modes of action, effects and indications, as well as prophylaxis and therapy of possible side-effects.

( BUPP10240 - 22 April 2010) Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin users

Background: Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomised, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Methods: Intravenous heroin users (n=12) lived in the hospital for 8-9 weeks and were maintained on each of three different sublingual buprenorphine doses (2mg, 8mg, 24mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results: Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (p<0.00005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of 'drug liking' and 'desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P=0.00001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P,0.05). Seven adverse events were reported: most were mild and transient. Conclusions: These data suggest that although the buprenorphine/naloxone has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.

( BUPP10239 - 22 April 2010) Young Opioid Abusers Benefit from Extended Buprenorphine-Naloxone Treatment

( BUPP10223 - 22 April 2010) Increasing use of opioids from 2004 to 2007 Pharmacoepidemiological data from a complete national prescription database in Norway

Background: A high opioid consumption for cancer related and acute pain may indicate adequate pain treatment. Analysis of a national, compulsory and complete database of all dispensed prescription drugs in Norway (NorPD) may reveal important epidemiological data on prescription pattern of opioids. This study investigated the prevalence of opioid dispensions in 2004 2007 and explored patterns of use. Methods: All pharmacies in Norway submit data electronically to NorPD on all dispensed prescriptions. All prescriptions to any individual are identified by a unique pseudonym. All persons who were dispensed opioids from 2004 to 2007 are included in the study. Cancer patients are identified by a reimbursement code. Non cancer pain indications are inferred from pattern of prescriptions. Results: 470,638 Norwegians were dispensed opioids in 2007, corresponding to 9.7% of the population (13.0% of adults). Only 13,220 persons (2.8% of all patients) received opioids for cancer pain, accounting for 10% of all dispensed opioids measured in defined daily doses (DDDs). Among persons with non cancer pain 77% received only one dispension per year or less than 50 DDDs/year. Fifteen percent received from 50 to 200 DDDs/year. Only 13,846 (4%) received >400 DDDs/year and are likely to be daily users for chronic non cancer pain. From 2004 to 2007 a 9 % increase was observed in the number of persons receiving opioids and the number of dispensions, whereas opioid types, doses, and indications appeared stable. Interpretation: From these prescription patterns it can be concluded that the majority of patients received opioids for acute, non cancer pain.

( BUPP10222 - 22 April 2010) Current developments in intraspinal agents for cancer and noncancer pain

Since the late 1980s, intrathecal (IT) analgesic therapy has improved, and implantable IT drug delivery devices have become increasingly sophisticated. Physicians and patients now have myriad more options for agents and their combination, as well as for refining their delivery. As recently as 2007, The Polyanalgesic Consensus Conference of expert panelists updated its algorithm for drug selection in IT polyanalgesia. We review this algorithm and the emerging therapy included. This article provides an update on newly approved as well as emerging IT agents and the advances in technology for their delivery.

( BUPP10221 - 22 April 2010) Editorial: Effective pain management in hematological malignancies

( BUPP10220 - 22 April 2010) Mood disturbance and withdrawal severity in substitution treatment for opioid dependence: Their association and impact on continued illicit drug use

Objectives: This study explored the relationship between withdrawal severity and mood disturbance, and their links with continued illicit drug use during the first 3 months of opioid substitution treatment (ST). Methods: Sixteen participants undergoing opioid ST with methadone (n=7) or buprenorphine (n=9) were recruited through outpatient units in South Australia. In a within groups repeated measures design, the Opiate Treatment Index was administered at baseline and again at 3 months. Participants also completed the Methadone Symptoms Checklist and the Profile of Mood States at baseline and fortnightly throughout the 3 month measurement period. Results: Withdrawal severity and mood disturbance were observed to co vary over the 3 months. Statistically significant reductions in both withdrawal severity and mood disturbance were observed. The direction of association between withdrawal severity and mood disturbance was positive and was statistically significant at all measurement points. Continued use of illicit drugs was associated with higher levels of both mood disturbance and withdrawal severity. Conclusions: Withdrawal severity and mood disturbance co vary over time and have important implications for treatment outcomes in ST.

( BUPP10219 - 22 April 2010) Rapid and selective enzymatic debridement of porcine comb burns with bromelain derived Debrase�: Acute phase preservation of noninjured tissue and zone of stasis

Deep burns are associated with the formation of an eschar, which delays healing and increases the risk of infection. Surgical debridement of the eschar is, at present, the fastest means to achieve an eschar free bed, but the process can not differentiate between the viable tissue and the eschar and follow the minute irregularities of the interface between the two. We evaluated the efficacy and selectivity of a novel enzymatic bromelain based debriding agent, Debrase� Gel Dressing (Debrase�), in a porcine comb burn model. We hypothesized that Debrase� would result in rapid debridement of the eschar without adverse effects on the surrounding uninjured skin. This is a prospective, controlled, animal experiment. Five domestic pigs (20 25 kg) were used in this study. Sixteen burns were created on each animal's dorsum using a brass comb with four rectangular prongs preheated in boiling water and applied for 30 seconds, resulting in four rectangular 10 � 20 mm full thickness burns and separated by three 5 � 20 mm unburned interspaces representing the zone of stasis. The burned keratin layer (blisters) was removed, and the burns were treated with a single, topical, Debrase� or control vehicle application for 4 hours. The Debrase� /control was then wiped off using a metal forceps handle, and the burns were treated with a topical silver sulfadiazine (SSD). The wounds were observed, and full thickness biopsies were obtained at 4 and 48 hours for evidence of dermal thickness, vascular thrombosis, and burn depth, both within the comb burns and the unburned interspaces in between them. Chi square and t tests are used for data analysis. A single 4 hour topical application of Debrase� resulted in rapid and complete eschar dissolution of all the burns in which the keratin layer was removed. The remaining dermis was thinner (1.1 � 0.7 mm) than in the control burns (2.1 � 0.3 mm; difference 0.9 mm (95% confidence interval: 0.3 1.4)) and was viable with no injury to the normal surrounding skin or to the unburned interspaces between the burns, which represents the zone of stasis. In control burns, the entire thickness of the dermis was necrotic. At 48 hours, Debrase� treated areas were found partially desiccated under SSD treatment. The unburned interspaces demonstrated partial thickness necrosis in two third and full thickness necrosis in one third of wounds. In contrast, full thickness necrosis was noted in all control interspaces (P = .05). In a porcine comb burn model, a single, 4 hour topical application of Debrase� resulted in rapid removal of the necrotic layer of the dermis with preservation of unburned tissues. At 48 hours, SSD treatment resulted in superficial tissue damage and partial preservation of the unburned interspaces.

( BUPP10218 - 22 April 2010) Allergie contact dermatitis to from per transdermic buprenorphine administration

The administration of molecules per transdermic way offers many advantages: ousting of an effect of first pass metabolism in the liver and constant release of various active ingredients ensuring consequently perfectly stable plasmatic concentrations. Nevertheless, cutaneous reactions, in particular allergic, can compromise the use of these transdermal therapeutic systems. We report the case of a patient having presented an allergic contact dermatitis, with secondary generalization, from transdermal buprenorphine (Transtec�). An assessment with patch tests was made and it confirmed hypersensitivity to buprenorphine itself and excluded any reaction to the adhesives or excipients. The transdermal systems of buprenorphine can be responsible for localised but also generalized allergic contact reactions, testifying the systemic absorption of the molecule.

( BUPP10217 - 22 April 2010) Impact of surgical severity and analgesic treatment on plasma corticosterone in rats during surgery

Tissue injury and anaesthesia during surgery induce a stress response associated with increased glucocorticoid secretion from the adrenal glands. This response alters the normal physiology and may cause postoperative morbidity, as well as affect the results during acute experiments. The aim of the present investigation was to study the effect of surgical severity and analgesic treatment on circulating corticosterone in male Sprague Dawley rats. Male rats were treated with either lidocaine infiltrated during surgery, buprenorphine (0.05 or 0.1 mg/kg subcutaneously) or saline subcutaneously. Each treatment group was subjected to either arterial catheterisation or arterial catheterisation and laparotomy. A catheter was inserted in the common carotid artery and blood was collected during surgery and during anaesthesia 6 h after surgery. Lidocaine treatment reduced the corticosterone levels compared to saline treatment after catheterisation but not after laparotomy. Buprenorphine treatment reduced the corticosterone levels during the first hour after surgery after both catheterisation and laparotomy. The higher buprenorphine dose led to an earlier and more pronounced reduction, especially after laparotomy. In the present study, the corticosterone response during surgery in laboratory rats is correlated with the severity of the procedure, and buprenorphine reduces the surgical stress response more effectively than lidocaine treatment.

( BUPP10216 - 22 April 2010) Opioids for the Treatment of Chronic Non Cancer Pain in Older People

Chronic pain occurs in 45 85% of the geriatric population and the need to treat chronic pain is growing substantially. Unfortunately, treatment for chronic pain is not always correctly targeted, which leads to a reduced quality of life, with decreased socialization, depression, sleep disturbances, cognitive impairment, disability and malnutrition. Considering these consequences, healthcare professionals should aim at improving the diagnosis and treatment of chronic pain in older persons. One of the most important limitations in achieving successful pain management is that older people are not aware that pain management options exist or medications for pain, such as opioids, have associated benefits and adverse effects. Importantly, opioids do not induce any organ failure and if adequately used at the right dosage may only present some predictable and preventable adverse effects. Treating and controlling chronic pain is essential in elderly patients in order to maintain a good quality of life and an active role in both the family and society. To date there are only a few randomized clinical trials testing opioid therapy in elderly patients, and the aim of the present review is to highlight the efficacy and tolerability of opioid use through a literature search strategy in elderly people with chronic non cancer pain.

( BUPP10215 - 22 April 2010) Provision of Ancillary Medications During Buprenorphine Detoxification Does Not Improve Treatment Outcomes

For individuals dependent on opioids, recovery efforts begin with a period of withdrawal that typically includes discomfort from symptoms, possibly precipitating a return to drug use. The study described here investigated whether the provision of ancillary medications for opioid withdrawal symptoms affected treatment outcomes in 139 participants receiving buprenorphine in a 13 day detoxification trial. Outcome measures include the number of opioid free urine samples collected and retention in treatment. Ancillary medications were provided to 70% of participants: 59% received medication for insomnia, 45% for anxiety, 40% for bone pain, 35% for nausea, and 28% for diarrhea. Findings indicate no difference in the number of opioid free urine samples between the group receiving ancillary medication and the group who did not, although tests of specific ancillary medications indicate that those who received diarrhea medication had fewer opioid free urines than those who did not (P = .004). Results also indicate that participants attended fewer days of treatment if they received anxiety, nausea, or diarrhea medication compared to no medication (all P values < .05).

( BUPP10214 - 22 April 2010) Favorable Mortality Profile of Naltrexone Implants for Opiate Addiction

Several reports express concern at the mortality associated with the use of oral naltrexone for opiate dependency. Registry controlled follow up of patients treated with naltrexone implant and buprenorphine was performed. In the study, 255 naltrexone implant patients were followed for a mean (+/- standard deviation) of 5.22 + /- 1.87 years and 2,518 buprenorphine patients were followed for a mean (+/- standard deviation) of 3.19 +/- 1.61 years, accruing 1,332.22 and 8,030.02 patient years of follow up, respectively. The crude mortality rates were 3.00 and 5.35 per 1,000 patient years, respectively, and the age standardized mortality rate ratio for naltrexone compared to buprenorphine was 0.676 (95% confidence interval = 0.014 to 1.338). Most sex, treatment group, and age comparisons significantly favored the naltrexone implant group. Mortality rates were shown to be comparable to, and intermediate between, published mortality rates of an age standardized methadone treated cohort and the Australian population. These data suggest that the mortality rate from naltrexone implant is comparable to that of buprenorphine, methadone, and the Australian population.

( BUPP10213 - 22 April 2010) Investigation of Temporal Changes of Abuse and Misuse of Prescription Opioids

We analyzed intentional exposures to prescription opioids (buprenorphine, fentanyl, hydrocodone, hydromorphone, morphine, methadone and Oxycodone) using the Research Abuse, Diversion and Addiction Related Survllience System (RADARS (R)) Poison Center data over a 5 year period 2003 2007 to see if there were temporal trends in the abuse and misuse of prescription drugs associated with (1) weekends vs. weekdays and (2) during select holiday periods vs. non holiday periods. Over the study period 25 of 120 holiday period days showed a decrease of at least 1 SD from the mean and 9 of 120 holiday period days showed an increase of at least 1 SD from the mean. Over the study period there were 144,653 intentional exposures. Mean percent of cases by day of week ranged from 14.03% to 14.39%, with slightly higher use on weekend days. There was no significant difference when evaluating prevalence of intentional exposures by day of week (p = 0.99). There was no significant difference when evaluating weekend versus weekday (p > 0.05). In summary, the prevalence of abuse and misuse of prescription drugs was not impacted by day of the week or difference between weekday and weekend. The impact of 8 traditional holidays appeared to be associated with a minor decrease in abuse and misuse of prescription drugs. No temporally related increase in abuse and misuse of prescription drugs was noted and conversely a trend toward decreased abuse and misuse of prescription drugs was suggested.

( BUPP10212 - 22 April 2010) Opioid dependence treatment and guidelines

BACKGROUND: In response to the growing incidence of opioid dependence, guidelines have been created, and new treatments are being developed to assist physicians in treating dependence and withdrawal of opioids. OBJECTIVE: To review treatment modalities and guidelines utilized in opioid dependence. SUMMARY: Guidelines for the treatment of opioid dependence have been developed by organizations such as the American Society of Interventional Pain Physicians (ASIPP) and the American Psychiatric Association (APA). Current guidelines recommend comprehensive treatment with pharmacological agents such as methadone, buprenorphine, or buprenorphine combined with naloxone as well as psychosocial therapy. These guidelines stress the need for an integrated approach to treatment. Office-based opioid treatment is currently being utilized to treat opioid dependent patients in a physician's office setting with buprenorphine /naloxone replacement therapy as an alternative to entering patients into a methadone clinic. These office-based programs offer a breakthrough in access to care for dependent patients. CONCLUSION: Physicians need to be aware of and adhere to currently accepted guidelines and recommendations for treating opioid dependent patients, including integrating psychosocial treatments and behavior modification strategies for optimal results. Clinicians must be educated on the new treatment modalities and regulations surrounding the use of these therapies.

( BUPP10249 - 27 April 2010) Therapy for opioid dependence - An update

After the heroin-wave in Switzerland in the 1980s and 1990s and the establishment of successful maintenance therapies for harm reduction in many western countries, the first evidence-based guidelines for the treatment of opioid dependence appeared. Prevalence of heroin use in Switzerland has decreased subsequently in recent years with a large proportion of patients enrolled in maintenance therapies. In this review, pharmacological and psychosocial treatment strategies for opioid dependence are described and discussed with particular regard to current guidelines from European and American medical societies. Opioid dependence is a chronic brain disease associated with neuroadaptive processes and structural changes that lead to substance craving and relapses despite of negative consequences. Like all substance use disorders, opioid-related disorders comprise acute intoxication, harmful use, dependency and withdrawal states. These diagnoses are discussed in short. Comorbid psychiatric disorders as well as multiple substance use are frequent among opioid-dependent subjects and may complicate an effective treatment. Diagnosis and treatment of comorbidity are therefore crucial and necessary to fundamentally improve the prognosis of opioid dependence. Standardised questionnaires and interviews can be used for this purpose. Treatment in acute phases usually begins with the assessment of physical complications and detailed drug anamnesis. It is followed by the withdrawal of additionally consumed substances like cocaine, benzodiazepines and alcohol. Opioid withdrawal can be treated with agonists as well as other medication directed at specific symptoms. Already at this stage, patients should be motivated to begin maintenance treatment, although abstinence can be a reasonable goal for patients with a short history of opioid abuse as well as in subsequent stable phases of the disorder. Agonist maintenance treatment with methadone or buprenorphine constitutes the first-line therapy at this time. Maintenance treatment with slow-release morphine is currently still carried out as "off-label use". Maintenance with diacetylmorphine (Heroin) is regarded as an important treatment alternative after aborted or failed maintenance therapy and has been established in diverse European countries. Motivational interviewing and contingency management are well-examined psychotherapeutic interventions effective in the treatment of substance-related disorders. Furthermore, disorder-specific psychotherapies enable the integrated treatment of comorbid personality disorders or depressive disorders in parallel to substance use and show positive effects on the course of opioid dependence. Further research is needed to improve our understanding of the neurobiological mechanisms underlying this disorder. Moreover it should aim to advance the efficacy of medical and psychotherapeutic treatments and identify subgroups of patients that can be targeted by specific interventions. Innovative techniques like neuroimaging will provide new options and insights.

( BUPP10248 - 27 April 2010) Buprenorphine prescription, misuse and service provision: A global perspective

Buprenorphine, a partial mu-opioid agonist and kappa-opioid antagonist, is recommended as safe and effective maintenance treatment for opioid dependence. It offers the possibility of management in primary care settings. However, its prescription has led to diversion for illicit recreational use and resulted in medical complications and, rarely, fatal overdose in combination with other sedatives. The outcome of buprenorphine maintenance programmes varies from country to country and it is determined by the local therapeutic traditions, regulatory restrictions and existing service provision for opioid misusers. This article addresses the pharmacology of buprenorphine, the benefits and drawbacks of its prescription, service provision for opioid misuse around the world, policy recommendations, and prescribing training requirements.

( BUPP10247 - 27 April 2010) The judicious use of opioids in managing chronic noncancer pain

Symptom control in the patient with chronic pain is an important aim of treatment, as part of a multimodal approach and as a passport to improved quality of life. Consider the use of opioids for managing chronic pain when non-opioid drugs have been found to be ineffective or not tolerated. Before prescribing opioids, assess psychological status, history of substance abuse and social context. Opioid treatment is an ongoing trial of therapy: response to opioids and problems with opioids are difficult to predict. Regularly assess the six As: analgesia, activity, adverse effects, affect, aberrant behaviours and accurate records. Seek advice if an apparent increase in opioid requirement is occurring.

( BUPP10246 - 27 April 2010) Heroin-assisted treatment in the Netherlands: History, findings, and international context

This monograph describes the history, findings and international context of heroin-assisted treatment (HAT) in the Netherlands. The monograph consists of (1) a short introduction and seven paragraphs describing the following aspects of HAT in the Netherlands: (2) history of HAT studies and implementation of routine HAT in the Netherlands; (3) main findings on efficacy, safety and cost- effectiveness from the two randomized controlled HAT trials in the Netherland; (4) new findings from a large cohort study on the effectiveness of HAT in routine clinical practice in the Netherlands; (5) unique data on the patient's perspective of HAT; (6) data on the pharmacological and pharmaceutical basis for HAT in the Netherlands; (7) description of the registration process; and (8) account of the international context of HAT. Together, these data show that HAT can now be considered a safe and proven-effective intervention for the treatment of chronic, treatment-resistant heroin dependent patients.

( BUPP10245 - 27 April 2010) Managing severe cancer pain: The role of transdermal buprenorphine: A systematic review

Pain is a frequent and important symptom in cancer patients. Among the available strong opioids, transdermal buprenorphine has been licensed in Europe since 2002, and results from a few clinical studies suggest that it may be a good alternative to the other oral or transdermal opioids. To assess the best available evidence on its efficacy and safety, we carried out a systematic literature review with the aim of pooling relevant studies. We identified 19 eligible papers describing 12 clinical studies (6 randomized controlled trials and 6 observational prospective studies), including a total of about 5000 cancer patients. Given the poor quality of reports and the heterogeneity of methods and outcomes, pooling was not feasible as the type of data was not appropriate for combining the results statistically. A meta-analysis based on individual data is ongoing in the context of the Cochrane Collaboration. In conclusion, although the narrative appraisal of each study suggests a positive risk benefit profile, well designed and statistically powered controlled clinical trials are needed to confirm this preliminary evidence.

( BUPP10244 - 27 April 2010) Adverse effects of chronic opioid therapy for chronic musculoskeletal pain

The use of opioids for the treatment of chronic pain has increased dramatically over the past decade. Whether these drugs provide considerable benefits in terms of pain reduction and improved function to balance the risks associated with their use, however, is unclear. Of particular importance to clinicians treating chronic musculoskeletal pain is opioid-induced hyperalgesia, the activation of pronociceptive pathways by exogenous opioids that results in central sensitization to pain. This phenomenon results in an increase in pain sensitivity and can potentially exacerbate pre-existing pain. Opioids also have powerful positive effects on the reward and reinforcing circuits of the brain that might lead to continued drug use, even if there is no abuse or misuse. The societal risk of increased opioid prescription is associated with increased nonmedical use, serious adverse events and death. Patients with chronic musculoskeletal pain should avoid the long-term use of opioids unless the benefits are determined to outweigh risks, in which case, the use of chronic opioids should be regularly re-evaluated.

( BUPP10243 - 27 April 2010) Myoclonia in an oldest old woman: A frequent and reversible etiology

A 98-year-old woman was referred to our hospital because of myoclonia. The concentration of calcium and vitamin D in the serum was low. In this context, we concluded of neuromuscular irritability secondary to hypocalcaemia. The symptoms disappeared after a treatment of intravenous calcium. This case shows how important it is to investigate electrolytes in case of neuromuscular irritability symptoms in elderly people.

( BUPP10242 - 27 April 2010) Uzbekistan: government discontinues pilot opiate substitution therapy program

In this decade, with support from the international community, most countries of the former Soviet Union introduced opiate substitution therapy (OST) programs, using methadone or buprenorphine, in order to curb the spread of HIV and to introduce more efficient drug dependence treatment options. However, the development is uneven: While some countries have expanded their pilot projects, others have not gone beyond the pilot stage. One Central Asian country--Uzbekistan--has recently closed its pilot OST project.

( BUPP10241 - 27 April 2010) Effects of Voluntarily-ingested Buprenorphine on Plasma Corticosterone Levels, Body Weight, Water Intake, and Behaviour in Permanently Catheterised Rats

This study investigated the peri- and postoperative effect of pre-emptive analgesia through voluntary ingestion of buprenorphine in Nutella (R), in male Sprague-Dawley rats. An arterial catheter was inserted and the rats were connected to an automated blood sampling device (AccuSampler (R)). Blood samples were drawn up to 18 h after surgery and the plasma concentrations of corticosterone were quantified. Postoperative changes in water intake and body weight were recorded, and the behaviour of the rats was analysed during two 30-min periods. Pre-emptive oral buprenorphine treatment reduced the plasma corticosterone levels in the postoperative period, compared to controls treated with local anaesthetics. Buprenorphine-treated rats consumed more water and maintained body weight better. Behavioural observations indicated that buprenorphine changed the behaviour in non-operated rats but there was no difference in the operated rats. The present study strengthens the hypothesis that pre-emptive oral buprenorphine in Nutella is suitable for treatment of postoperative pain in rats.

( BUPP10284 - 20 May 2010) Recent Advances in Transdermal Drug Delivery.

Transdermal delivery of pharmacologically active agents has been extensively studied for the past 40 years. Despite the strong efforts, currently, only about 40 products are in market on about 20 drug molecules, due to the requirements that the patch area should be small enough for the patients to feel comfortable, and to the barrier properties of the stratum corneum. Various approaches to overcome the barrier function of skin through physical and chemical means have been broadly studied. The development of an effective transdermal delivery system is dictated by the unique physicochemical property each drug molecule possesses. In this review, we have summarized various physical and chemical approaches for transdermal flux enhancement, including the application of electricity, ultrasound, microneedle and chemical enhancers. Pressure sensitive adhesive such as acrylics, rubbers and silicones are described together with recent developments. Factors affecting dosage form design, particularly for drug in adhesive system, like adhesion and crystallization are also discussed.

( BUPP10283 - 20 May 2010) Prevention of HIV Infection among Injection Drug Users in Resource Limited Settings

Injection drug use contributes to considerable global morbidity and mortality associated with human immunodeficiency virus (HIV) infection and AIDS and other infections due to blood borne pathogens through the direct sharing of needles, syringes, and other injection equipment. Of similar to 16 million injection drug users (IDUs) worldwide, an estimated 3 million are HIV infected. The prevalence of HIV infection among IDUs is high in many countries in Asia and eastern Europe and could exacerbate the HIV epidemic in sub Saharan Africa. This review summarizes important components of a comprehensive program for prevention of HIV infection in IDUs, including unrestricted legal access to sterile syringes through needle exchange programs and enhanced pharmacy services, treatment for opioid dependence (ie, methadone and buprenorphine treatment), behavioral interventions, and identification and treatment of noninjection drug and alcohol use, which accounts for increased sexual transmission of HIV. Evidence supports the effectiveness of harm reduction programs over punitive drug control policies.

( BUPP10282 - 20 May 2010) APPROACH RABBIT ANAESTHESIA WITH CONFIDENCE

( BUPP10281 - 20 May 2010) The Development of New Analgesics Over the Past 50 Years: A Lack of Real Breakthrough Drugs.

The development of new analgesics over the past 50 yr is reviewed. The drugs discussed include pentazocine, fentanyl, butorphanol, indometacin, mefenamic acid, ibuprofen, naproxen, tolmetin, sulindac, meclofenamate, sumatriptan, pentosan, zolmitriptan, naratriptan, nalbuphine, buprenorphine, sufentanil, piroxicam, diflunisal, ketoprofen, diclofenac, fenoprofen, rizatriptan, almotriptan, frovatriptan, alfentanil, tramadol, remifentanil, nabumetone, oxaprozin, ketorolac, bromfenac, celecoxib, meloxicam, nepafenac, eletriptan, zicotonide, pregabalin, carbamazepine, phenytoin, clonazepam, amitriptyline, doxepin, imipramine, propranolol, capsaicin, cyclobenzaprine, lidocaine, valproate, gabapentin, topiramate, desipramine, venlafaxine, duloxetine, mexiletine, ketamine, dronabinol, and dexamethasone. There appears to be a lack of real breakthroughs in analgesic drug development. (No EX).

( BUPP10280 - 20 May 2010) Buprenorphine in maintenance treatment: Experience among italian physicians in drug addiction centers

The aim of this study was to assess the attitudes of Italian physicians regarding buprenorphine and its clinical use approximately 6 years after the medication was introduced into clinical practice. The sample consisted of 305 randomly selected physicians, working in public centers of drug addiction. In Italy buprenorphine seems a valid tool in the field of drug addiction treatment, although it is far from replacing methadone even though it seems to guarantee better compliance. Interviewees follow clinical experience more than international guidelines, with pharmaceutical company representatives as the most cited source for information about the medication. The data also suggests a need for the development of formal guidelines for treatment with buprenorphine in Italy.

( BUPP10279 - 20 May 2010) Clinical pharmacology of analgesics in old age and frailty

Summary There is a high prevalence of pain in older people. Optimal assessment and management of pain in this population is challenging. The pharmacokinetics and pharmacodynamics of analgesic medications are affected by ageing and frailty, as well as by intercurrent medical conditions and their treatments. This review describes what is currently understood about the impacts of old age and frailty on the clinical pharmacology of commonly used analgesics, to provide a rational basis for the use of these medicines. In view of the wide age related inter individual variability in pharmacokinetics and pharmacodynamics of analgesic medications, monitoring of clinical response and adverse effects is essential to optimize pain control in older people.

( BUPP10278 - 20 May 2010) Opioids affect focal contact mediated cell substrate adhesion.

Earlier observations suggested that opioids modify cell substrate adhesion on agar. In this study, we wanted to investigate whether opioids also interfere with cell adhesion to biologically relevant substrates, including interstitial matrix and basement membrane components. Human embryonic kidney 293 cells stably transfected with FLAG tagged mu opioid receptor were used as an experimental model. The cells were cultured on tissue culture plastic, collagen types I and IV, fibronectin, laminin and human amnion fragments in the absence or presence of morphine. Cultures were immunolabelled with antivinculin to visualize focal contacts. Morphine treated cultures on tissue culture plastic, collagen types I and IV and fibronectin, but not on laminin, covered less substrate than untreated cultures; individual cells were difficult to distinguish and their nuclei piled up in contrast to untreated cultures. The same effects were observed on human amnion fragments: morphine changed the morphotype of cultures on the stromal side, but not on the basement membrane side. Cultures that were treated with morphine displayed fewer focal contacts than untreated cultures on collagen type I, whereas untreated and morphine treated cultures were indistinguishable on laminin. In conclusion, morphine can modify focal contact mediated cell substrate adhesion on some extracellular matrix ligands, but not on laminin. We suggest that after activation of the mu opioid receptor by morphine a signalling network is activated that ultimately leads to suppression of integrin activation, which results in a reduction of focal contacts. Modified cell substrate adhesion by opioids changes cell morphology and migration.

( BUPP10277 - 20 May 2010) Chronic in utero buprenorphine exposure causes prolonged respiratory effects in the guinea pig neonate.

Our laboratory studies the effects of in utero opioid exposure on the neonate. In this work we test the effects of chronic in utero exposure to buprenorphine on the neonate. Buprenorphine is a promising candidate for treatment of opioid addiction during pregnancy and it has been suggested to decrease the neonatal abstinence syndrome in human infants. In our guinea pig model, we focused not only on the respiratory effects of in utero exposure on the neonate, but also studied withdrawal signs in the neonate, a major concern of all opioid treatment during pregnancy. Pregnant guinea pigs were treated with daily subcutaneous injections of 0.1mg /kg buprenorphine during the second half of gestation. We measured weight, locomotor activity and respiratory function in pups of ages 3 to 14days. Respiratory response was recorded using a two chamber plethysmograph, while pups were breathing either room air or 5% CO /sub 2/ . Our results show that chronic in utero exposure to buprenorphine induces respiratory effects up to day 14 after birth, while earlier studies have shown that effects of either in utero methadone or morphine only persist in the first week after birth in the guinea pig model. These data provide important information for clinical trials of buprenorphine treatment suggesting that duration and severity of respiratory effects of in utero buprenorphine exposure should be monitored.

( BUPP10276 - 20 May 2010) Possible interactions of analgesics with liver microsomal cytochromes P450.

Cytochromes P450 (CYP), the most important enzymes of phase I of drug metabolism, are involved in the biotransformation of many drugs used in the treatment of pain. Knowledge of the metabolic pathways of drugs is essential to minimise the possible adverse side effects. Simultaneous use of drugs can cause drug interactions mediated by CYP. Another important factor of the effect of the drugs is the genetic polymorphism of CYP forms (especially CYP2D6 and CYP2C9), which can cause enormous individual differences in the effects of drugs. CYP2D6 metabolises approximately 25% of drugs including opioids, antidepressants and beta blockers. This form is important from the view of genetic polymorphism, since approximately 7% of Czech Republic inhabitants are so called poor metabolisers, which are susceptible to drug overdose by parent compounds or they can show insufficient formation of active metabolites in the case of pro drugs. To the contrary, about 3% of inhabitants of the Czech Republic are ultra rapid metabolisers, which need a higher dose of drugs to reach the analgesic effect or can be intoxicated by higher amounts of the active metabolite formed. CYP2C9 is responsible for the metabolism of non steroidal anti inflammatory drugs (NSAID) and warfarin and this enzyme has also been found to be polymorphic. When using NSAIDs in pain treatment, it is necessary to take into account the possibility of GIT related adverse side effects, which are most probably not related with CYP polymorphism, but with dose and individual drug used. Other enzymes involved in pain treatment are CYP1A2, CYP2C19 and CYP3A4. The role of these CYPs in the metabolism is discussed together with the individual drugs used in the pharmacotherapy of pain. This work is focused on the most common drugs in algesiology metabolised via CYP and also on description of the possible interactions and risks associated with the use of drugs.

( BUPP10275 - 20 May 2010) HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage.

BACKGROUND: Previous reviews have examined the existence of HIV prevention, treatment, and care services for injecting drug users (IDUs) worldwide, but they did not quantify the scale of coverage. We undertook a systematic review to estimate national, regional, and global coverage of HIV services in IDUs. METHODS: We did a systematic search of peer reviewed (Medline, BioMed Central), internet, and grey literature databases for data published in 2004 or later. A multistage process of data requests and verification was undertaken, involving UN agencies and national experts. National data were obtained for the extent of provision of the following core interventions for IDUs: needle and syringe programmes (NSPs), opioid substitution therapy (OST) and other drug treatment, HIV testing and counselling, antiretroviral therapy (ART), and condom programmes. We calculated national, regional, and global coverage of NSPs, OST, and ART on the basis of available estimates of IDU population sizes. FINDINGS: By 2009, NSPs had been implemented in 82 countries and OST in 70 countries; both interventions were available in 66 countries. Regional and national coverage varied substantially. Australasia (202 needle syringes per IDU per year) had by far the greatest rate of needle syringe distribution; Latin America and the Caribbean (0.3 needle syringes per IDU per year), Middle East and north Africa (0.5 needle syringes per IDU per year), and sub Saharan Africa (0.1 needle syringes per IDU per year) had the lowest rates. OST coverage varied from less than or equal to one recipient per 100 IDUs in central Asia, Latin America, and sub Saharan Africa, to very high levels in western Europe (61 recipients per 100 IDUs). The number of IDUs receiving ART varied from less than one per 100 HIV positive IDUs (Chile, Kenya, Pakistan, Russia, and Uzbekistan) to more than 100 per 100 HIV positive IDUs in six European countries. Worldwide, an estimated two needle syringes (range 1 4) were distributed per IDU per month, there were eight recipients (6 12) of OST per 100 IDUs, and four IDUs (range 2 18) received ART per 100 HIV positive IDUs. INTERPRETATION: Worldwide coverage of HIV prevention, treatment, and care services in IDU populations is very low. There is an urgent need to improve coverage of these services in this at risk population.

( BUPP10274 - 20 May 2010) (Study on colloidal gold labeled anti buprenorphine monoclonal antibody for rapid test kit to detect buprenorphine)

OBJECTIVE: To develope an easy to use, rapid and accurate test for detecting buprenorphine based on the principle of competitive immunoassay. METHODS: Monoclonal antibody against buprenorphine was conjugated with colloidal gold and dispensed on the glass fiber. The complete antigen Buprenorphine BSA and the goat anti mouse IgG polyclonal antibody were separately sprayed on the nitrocellulose membrane as the test line (T line) and the control line (C line). The rapid test kit was the final assembled product of test strip with the plastic cover. RESULTS: A total of 100 urine samples were tested for buprenorphine by immunochromatographic and GC/ MS methods. The accuracy was 99.0%. It is found the test kit can only detect by cross reaction with other 45 kind drugs. CONCLUSION: Rapid test kit can detect buprenorphine in the samples in 5 minutes. The cut off value of the test is 100 ng/mL.

( BUPP10273 - 20 May 2010) (Simultaneous screening for 22 poisonous alkaloids in blood by liquid chromatography tandem mass spectrometry with multiple reaction monitoring).

OBJECTIVE: To establish a liquid chromatography tandem mass chromatography (LC MS/MS) method for the simultaneous screening for 22 poisonous alkaloids in blood. METHODS: This method involves a liquid liquid extraction (LLE) followed by liquid chromatography tandem mass spectrometry with multi ple reaction monitoring (MRM). After blood was extracted with buprenorphine as the internal standard, the target compounds were analyzed with LC MS/MS ESI in the positive ionization mode. RESULTS: Identification was based on the compound's retention time and two precursor to product ion transitions. The limits of detection ranged from 0.1 ng/mL to 20 ng/m L in blood. CONCLUSION: The method was sufficiently selective and sensitive to detect poisonous alkaloids and can be applied in forensic and clinical toxicology.

( BUPP10272 - 20 May 2010) In Silico Prediction of Biliary Excretion of Drugs in Rats Based on Physicochemical Properties

Evaluating biliary excretion, a major elimination pathway for many compounds, is important in drug discovery. The bile duct cannulated (BDC) rat model is commonly used to determine the percentage of dose excreted as intact parent into bile. However, a study using BDC rats is time consuming and cost ineffective. The present report describes a computational model that has been established to predict biliary excretion of intact parent in rats as a percentage of dose. The model was based on biliary excretion data of 50 Bristol Myers Squibb Co. compounds with diverse chemical structures. The compounds were given intravenously at < 10 mg/kg to BDC rats, and bile was collected for at least 8 h after dosing. Recoveries of intact parents in bile were determined by liquid chromatography with tandem mass spectrometry. Biliary excretion was found to have a fairly good correlation with polar surface area (r = 0.76) and with free energy of aqueous solvation (Delta G(solv) (aq)) (r = 0.67). In addition, biliary excretion was also highly corrected with the presence of a carboxylic acid moiety in the test compounds (r = 0.87). An equation to calculate biliary excretion in rats was then established based on physiochemical properties via a multiple linear regression. This model successfully predicted rat biliary excretion for 50 BMS compounds (r = 0.94) and for 25 previously reported compounds (r = 0.86) whose structures are markedly different from those of the 50 BMS compounds. Additional calculations were conducted to verify the reliability of this computation model.

( BUPP09068 - 04 August 2008) Drug screening of hair by liquid chromatography-tandem mass spectrometry.

Hair has become an important matrix for drug analysis, complementary to blood and urine as a matrix. A prolonged detection window makes hair analysis suitable for the detection of exposure to illegal and medicinal drugs for periods up to 12 months. In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for drug screening in hair was developed and validated. To 20 mg of hair, 0.45 mL of acetonitrile/25 mM formic acid (5:95 v/v) and 50 muL of deuterated internal standards were added, and the sample was incubated in a water bath at 37�C for 18 h. LC separation was achieved with a Zorbax SB-Phenyl column (2.1 x 100 mm, 3.5-mum particle). Mass detection was performed by positive ion mode electrospray LC-MS-MS and included the following drugs/metabolites: nicotine, cotinine, morphine, 6-monoacetylmorphine, codeine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, benzoylecgonine, 7-aminonitrazepam, 7-aminoclonazepam, 7- aminoflunitrazepam, oxazepam, diazepam, alprazolam, zopiclone, zolpidem, carisoprodol, meprobamate, buprenorphine, and methadone. Within- and between-assay relative standard deviations varied from 2.0% to 12% and 2.7% to 15%, respectively. The accuracies were in the range of -24% to 16%, and recoveries ranged from 25% to 100%. The LC- MS-MS method proved to be simple and robust for the determination of drugs in hair. It has been used for authentic samples in our laboratory in the past year.

( BUPP09067 - 04 August 2008) Retention rate and substance use in methadone and buprenorphine maintenance therapy and predictors of outcome: Results from a randomized study.

This was a 6-month, randomized, flexible-dose study comparing the effects of methadone (Meth) and buprenorphine (Bup) on retention rate and substance use in a sample of 140 opioid-dependent, primarily heroin-addicted, patients who had been without opioid substitution therapy in the 4 weeks prior to the study. The major aims were to compare the efficacy of Bup and Meth in a flexible dosing regimen and to identify possible predictors of outcome. There were no major inhomogeneities between treatment groups. All patients also received standardized psychosocial interventions. Mean daily dosages after the induction phase were 44-50 mg for Meth and 9-12 mg for Bup. Results from this study indicate a favourable outcome, with an overall retention rate of 52.1% and no significant differences between treatment groups (55.3% vs. 48.4%). Substance use decreased significantly over time in both groups and was non-significantly lower in the Bup group. Predictors of outcome were length of continuous opioid use and age at onset of opioid use, although these were only significant in the Bup group. Mean dosage and other parameters were not significant predictors of outcome. Overall, the results of this study give further evidence that substitution treatment is a safe and effective treatment for drug dependence. Meth and Bup are equally effective. Duration of continuous opioid use and age at onset were found to have predictive value for negative outcome. The intensity of withdrawal symptoms showed the strongest correlation with drop-out. Future studies are warranted to further address patient profiles and outcome under different substitution regimens.

( BUPP09066 - 04 August 2008) Transdermal systems in practice.

( BUPP09065 - 04 August 2008) What sense in cannabinoid use as regulated by Italian DM 18/04/07? Pharmacological and giuridical considerations.

The present article relates to the Italian Ministerial Decree (DM) 18 /04/2007 referring to what was established by the Financial Law 2007 on the matter of the use of drugs for the so cal led "off-label" uses. This law introduces three cannabinoid substances, with the common name of Delta 9 and Trans-delta 9 tetrahydrocannabi nol and Nabilone, within the possible therapies for the treatment of "severe pain". The authors underline the absence of a sufficient pharma cokinetical and pharmacodynamical knowledge supporting the use of cannabinoid substances in the "severe pain" therapy. Further more the professional prescriber could go against judicial conseguences if the drugs causes as verified the onset of collateral effects even severe that, for the scientific knowledge in possess at the pre sent state, the authors know could take place.

( BUPP09064 - 04 August 2008) Buprenorphine rediscovered: From pharmacology to transdermal administration.

The management of chronic pain syndromes often requires an individualized pharmacological treatment, procuring adequate pain relief without provoking intolerable side effects. Transdermal administration of opioid analgesics provides, after the dose titration phase, stable plasma levels. The strong opioid buprenorphine is available as well in sublingual as in injectable formulations. The recently introduced matrix patch which is available in 3 different dose delivery strengths (35, 52.5 and 70 mug/h) offers a valuable alternative to oral dosing. The efficacy and safety of the buprenorphine transdermal patch have been studied in randomized and large double-blind and prospective post-marketing follow-up studies. The use of the buprenorphine patch leads to a dose-dependent pain reduction irrespective of the type of pain or the age of the patient. The effect of buprenorphine on neuropathic pain syndromes has been attributed to the differences in opioid receptor affinities. An analgesic ceiling effect has not been noted in clinical practice, though such an effect is observed for the side effects. The characteristics of transdermal buprenorphine render it particularly suitable for the management of chronic pain syndromes which are unsatisfactorily controlled with non-opioid analgesics or other strong opioids. In many clinical studies a linear dose analgesia response was noticed, which did not occur for the side effects. Thus the buprenorphine matrixpatch is a valuable tool for every clinician treating severe cancer and non cancer pain.

( BUPP09063 - 04 August 2008) The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: Review of human and animal data.

Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current "gold standard", and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a mu-opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial mu-opioid receptor agonist and a kappa-opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

( BUPP09062 - 04 August 2008) Selective portal vein embolization and ligation trigger different regenerative responses in the rat liver.

Two strategies are clinically available to induce selective hypertrophy of the liver: portal vein embolization (PVE) and portal vein ligation (PVL). The aim of this study was to compare the impact of PVE and PVL on liver regeneration. Rats were subjected to 70% PVL, 70% PVE, 70% partial hepatectomy (PH) (positive control), or sham operation (negative control). PVL and PVE of liver segments were validated by portography and histology, demonstrating obstruction of the involved portal branches. Liver weight and markers of regeneration were assessed at 24, 48, and 72 hours, and 7 days after surgery (n = 5). Sinusoidal perfusion was examined by intravital microscopy. The weight of the regenerating liver segments increased continuously in all groups, with the highest weight gain after PH, which also disclosed the strongest proliferative activity. In Ki-67 and PCNA stainings, hepatocyte proliferation after PVL was more pronounced than after PVE (P = 0.01). Volumetric blood flow and functional sinusoidal density were lower after PVE than after PVL (P = 0.006, P = 0.02, respectively). The accumulation of Kupffer cells 24 hours after the intervention was highest after PH. Transcript levels of cytokines (interleukin-1beta, tumor necrosis factor-alpha, interleukin-6) peaked at 24 hours and were highest after PH. The embolized part of the liver after PVE showed prominent foreign body reaction in the portal triad with accumulation of macrophages. Conclusion: PVL is superior to PVE in inducing a regenerative response of the remnant liver. The impairment of liver regeneration after PVE may be a consequence of macrophage trapping in the occluded segment due to a foreign body reaction. Lower blood flow and lower accumulation of macrophages, particularly Kupffer cells, in the regenerating part of the liver likewise causes impaired liver regeneration after PVE.

( BUPP09061 - 29 July 2008) A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal

( BUPP09060 - 29 July 2008) Buprenorphine in primary care: Risk factors for treatment injection and implications for clinical management

( BUPP10302 - 27 May 2010) Utilizing nature as a source of new probes for opioid pharmacology

Background: Traditional and current opioid pharmacology is fundamentally based on interactions between opioid receptors and compounds isolated from natural sources. Adverse effects associated with opioids have led to the search for compounds with diminished side effects. Discussion: Recent discoveries of non nitrogenous and structurally diverse alkaloids as novel opioid ligands have led to renewed interest in the development of novel chemotypes for opioid receptors. Conclusion: The strong history of natural products as opioid receptor ligands suggests that nature is one of the most promising for the identification of novel opioids. This review highlights the vast potential of investigating natural products as novel probes of opioid receptors.

( BUPP10301 - 27 May 2010) Other drugs acting on nervous system associated with QT interval prolongation

Several drugs acting on the nervous system have been implicated in the prolongation of the QT interval. Leaving aside the antidepressant and antipsychotic drugs, some have shown to prolong the QT interval in vivo. These include opioids, particularly methadone, inhalational anesthetics, and some preparations used for treatment of cough. These drugs have a narrow therapeutic interval or possible drug interactions that lead to clinical toxicity manifested by arrhythmias. They share the ability to block potassium channels (HERG), prolong the action potential and QT interval, and generate arrhythmias and Torsades de Pointes like other typicality recognized like antiarrhythmics, antihistamines, prokinetics, psychotropics and anti infectives agents. Muscle relaxants like alcuronium, pancuronium and atracurium associated with or without atropine prolong significantly the QT interval. Methadone is the opiod most tightly associated with QTc prolongation; with much lesser potency buprenorphine and oxycodone can block HERG channels and depress the IKr current in vitro. Antineoplastic chemotherapy like anthracyclines, alkylating drugs, alkilants and cisplatin are associated with electrocardiographic alterations including prolongation of QT and emesis of different grades. It's very important take in account the synergic effects over the QT prolongation when effective antiemetics like 5 HT3 receptor antagonist (granisetron, ondansetron, and dolasetron) are administered. The Knowledge of their pharmacological properties is of vital importance to avoid exposing particularly vulnerable individuals as those with congenital long QT syndrome, and even the general public to unnecessary risk of potentially fatal arrhythmias.

( BUPP10300 - 27 May 2010) On line desorption of dried blood spots coupled to hydrophilic interaction/reversedphase LC/MS/MS system for the simultaneous analysis of drugs and their polar metabolites

An assay for the simultaneous analysis of pharmaceutical compounds and their metabolites from micro whole blood samples (i.e. 5 muL) was developed using an on line dried blood spot (on line DBS) device coupled with hydrophilic interaction/reversed phase (HILIC/RP) LC/MS /MS. Filter paper is directly integrated to the LC device using a homemade inox desorption cell. Without any sample pretreatment, analytes are desorbed from the paper towards an automated system of valves linking a zwitterionic HILIC column to an RP C18 column. In the same run, the polar fraction is separated by the zwitterionic HILIC column while the non polar fraction is eluted on the RP C18. Both fractions are detected by IT MS operating in full scan mode for the survey scan and in product ion mode for the dependant scan using an ESI source. The procedure was evaluated by the simultaneous qualitative analysis of four probes and their relative phase I and II metabolites spiked in whole blood. In addition, the method was successfully applied to the in vivo monitoring of buprenorphine metabolism after the administration of an intraperitoneal injection of 30 mg/kg on adult female Wistar rat.

( BUPP10299 - 27 May 2010) Managing chronic nonmalignant pain

In 2007 there were 3.2 million people in Australia experiencing chronic pain, defined as pain lasting more than three months. The causes of pain behaviour are nociceptive pain, neuropathic pain or pain disorders. Chronic pain is very unlikely to resolve spontaneously and in most cases treatment can be assumed to be ongoing. An opioid trial should be considered in patients with nociceptive pain; anticonvulsants should be the treatment of choice for patients with neuropathic pain; and psychological management should be used for the treatment of patients with pain disorders in the absence of nociceptive and neuropathic pain. The common chronic pain management pitfalls such as resting when in pain and treating the site of referred pain should be avoided.

( BUPP10298 - 27 May 2010) Respiratory Chest Pain: Diagnosis and Treatment

Chest pain from respiratory causes is a common complaint and may indicate the presence of a serious or even life threatening pathologic condition. Most chest pains are the result of irritation or inflammation of the parietal pleura, as the visceral pleura is insensate, although pain may arise from direct malignant invasion or trauma to the chest wall. Rapid recognition with appropriate understanding of the anatomy and physiology of chest pain from respiratory causes is vital to ensure timely and appropriate therapy.

( BUPP10297 - 27 May 2010) Hemodynamics and bispectral index (BIS) of dogs anesthetized with midazolam and ketamine associated with medetomidine or dexmedetomidine and submitted to ovariohysterectomy

Purpose: To evaluate hemodynamics and bispectral index (BIS) in bitches anesthetized with ketamine and midazolam in combination with dexmedetomidine or medetomidine and submitted to ovariohysterectomy. Methods: Twenty bitches pretreated with levomedetomidine and buprenorphine were anesthetized with 5 mg.kg /sup 1/ ketamine and 0.2 mg.kg /sup 1/ midazolam i.v. Continuous infusion of 0.4 mg.kg 1.h 1 midazolam and 20 mg.kg /sup 1/ .h /sup 1/ ketamine was initiated in combination with DEX (n=10): 20 mug.kg /sup 1/ .h /sup 1/ dexmedetomidine or MED (n=10): 30 mug.kg /sup 1/ .h /sup 1/ medetomidine over 30 minutes. A pharmacokinetic study provided dexmedetomidine plasma concentration, set to be 3.0 ng.mL /sup 1/ . Results: BIS decreased in both groups (P<0.05), but it was lower in DEX (P<0.05) as compared to MED. No differences were found in hemodynamic parameters (heart rate, systolic, diastolic and mean arterial pressure) between groups (P>0.05), but heart rate decreased in both groups, as compared to control values (P<0.05). Respiratory rate decreased (P<0.05) and expired end tidal CO /sub 2/ increased progressively (P<0.05) and similarly in both groups. Anesthetic recovery period was similar between groups (P<0.05) with no adverse effects. Conclusion: Continuous administration of dexmedetomidine with calculated plasma concentration equal to 3 ng.mL /sup 1/ in combination with midazolam and ketamine provides suitable anesthesia for spay surgery in bitches, hemodynamic stability and calm awakening with no adverse effects.

( BUPP10296 - 27 May 2010) Pain management in multiple myeloma

Pain is a prominent feature of multiple myeloma (MM) and may be caused by different underlying causes and mechanisms. Indeed, pain may be due to disease related complications, iatrogenic causes or may be associated with other unrelated medical conditions. This symptom may be particularly devastating and can negatively affect the quality of life of the afflicted patients and their functional status. For most MM patients suffering from continuous nociceptive pain, the WHO's three step analgesic ladder can provide adequate relief with oral options, although the high prevalence in MM patients of difficult to treat pains, such as pains due to skeletal mechanical instability or sustained by neuropathic mechanisms, makes the treatment approach a challenging concern. The management of pain in this setting requires a multidisciplinary approach integrating analgesics and causal interventions. This review focuses on the most common syndromes afflicting MM patients, attempting to provide an understanding of the underlying pain mechanisms and a discussion of the most commonly used treatment strategies.

( BUPP10295 - 27 May 2010) Neurons in area 5 of the posterior parietal cortex in the cat contribute to interlimb coordination during visually guided locomotion: A role in working memory

We tested the hypothesis that area 5 of the posterior parietal cortex (PPC) contributes to interlimb coordination in locomotor tasks requiring visual guidance by recording neuronal activity in this area in three cats in two locomotor paradigms. In the first paradigm, cats were required to step over obstacles attached to a moving treadmill belt. We recorded 47 neurons that discharged in relationship to the hindlimbs. Of these, 31/47 discharged between the passage of the fore and hindlimbs (FL HL cells) over the obstacle. The activity of most of these neurons (25/31) was related to the fore and hindlimb contralateral to the recording site when the contralateral forelimb was the first to pass over the obstacle. In many cells, discharge activity was limb independent in that it was better related to the ipsilateral limbs when they were the first to step over the obstacle. The other 16/47 neurons discharged only when the hindlimbs stepped over the obstacle with the majority of these (12/16) discharging between the passage of the two hindlimbs over the obstacle. We tested 15/47 cells, including 11/47 FL HL cells, in a second paradigm in which cats stepped over an obstacle on a walkway. Discharge activity in all of these cells was significantly modulated when the cat stepped over the obstacle and remained modified for periods of 1 min when forward progress of the cat was delayed with either the fore and hindlimbs, or the two hindlimbs, straddling the obstacle. We suggest that neurons in area 5 of the PPC contribute to interlimb coordination during locomotion by estimating the spatial and temporal attributes of the obstacle with respect to the body. We further suggest that the discharge observed both during the steps over the obstacle and in the delayed locomotor paradigm is a neuronal correlate of working memory.

( BUPP10294 - 27 May 2010) Drug safety problems in association with the use of opioid containing patches for the management of pain

( BUPP10293 - 27 May 2010) Buprenorphine maintenance therapy hinders acute pain management in trauma

Buprenorphine is a mixed opiate receptor agonist antagonist growing in popularity as an office based treatment for opioid dependent patients. It has high affinity, but only partial agonism at the mu opioid receptor resulting in a ceiling analgesic effect. At higher doses, buprenorphine potentiates antagonism at the kappa opioid receptor. These properties make buprenorphine an effective maintenance treatment for opioid dependent patients. These same properties, however, can interfere with the management of acute pain in patients on maintenance buprenorphine therapy.We present a case of a young multisystem trauma patient in whom adequate analgesia could not be achieved due to buprenorphine treatment before and through the early course of admission. Discontinuation of buprenorphine allowed for appropriate pain management and successful analgesia. Further education of acute care clinicians about buprenorphine pharmacology and careful selection of patients for buprenorphine maintenance therapy are needed to avoid delays of pain control in trauma patients.

( BUPP10292 - 27 May 2010) The use of opioids for breakthrough pain in acute palliative care unit by using doses proportional to opioid basal regimen

To determine the efficacy and safety of different opioids used in doses proportional to the basal opioid regimen for the management of breakthrough pain (BP). METHODS: In 66 patients consecutive patients admitted to a pain relief and palliative care unit, the efficacy and safety of different opioids used in doses proportional to the basal opioid regimen for the management of breakthrough pain (BP) were assessed. The choice of the opioid to be administered as rescue medication was based on the characteristics of patients, clinical stability, compliance, preference, and so on. For each episode, nurses were instructed to routinely collect changes in pain intensity and emerging problems when pain became severe (T0), and to re assess the patient 15 minutes after the opioid given as a rescue medication (T15). RESULTS: Six hundred twenty four episodes of BP were recorded during admission. Intravenous morphine (IV MO) and oral transmucosal fentanyl (OTFC) were most frequently administered. Of 503 events available, 427 episodes were defined as successfully treated, while 76 episodes required a further administration of opioids. Pain intensity significantly decreased at T15 in all the groups (P<0.001). In 97.2% and 90.7% of cases treated with IV MO, BP events had a reduction in pain intensity of more than 33% and 50%, respectively. In 99.2% and 97.6% patients receiving OTFC, BP events had a reduction in pain intensity of more than 33% and 50%, respectively. DISCUSSION: This survey suggests that doses of opioids for BP proportional to the basal opioid regimen, are very effective and safe in clinical practice, regardless the opioid and modality used.

( BUPP10291 - 27 May 2010) Different activation of opercular and posterior cingulate cortex (pcc) in patients with complex regional pain syndrome (crps i) compared with healthy controls during perception of electrically induced pain: A functional MRI study.

Although the etiology of complex regional pain syndrome type 1 (CRPS 1) is still debated, many arguments favor central maladaptive changes in pain processing as an important causative factor. METHODS: To look for the suspected alterations, 10 patients with CRPS affecting the left hand were explored with functional magnetic resonance imaging during graded electrical painful stimulation of both hands subsequently and compared with healthy participants. RESULTS: Activation of the anterior insula, posterior cingulate cortex (PCC), and caudate nucleus was seen in patients during painful stimulation. Compared with controls, CRPS patients had stronger activation of the PCC during painful stimulation of the symptomatic hand. The comparison of insular/opercular activation between controls and patients with CRPS I during painful stimulation showed stronger (posterior) opercular activation in controls than in patients. DISCUSSION: Stronger PCC activation during painful stimulation may be interpreted as a correlate of motor inhibition during painful stimuli different from controls. Also, the decreased opercular activation in CRPS patients shows less sensory discriminative processing of painful stimuli.These results show that changed cerebral pain processing in CRPS patients is less sensory discriminative but more motor inhibition during painful stimuli. These changes are not limited to the diseased side but show generalized alterations of cerebral pain processing in chronic pain patients.

( BUPP10290 - 27 May 2010) Pharmacotherapy in the treatment of addiction: Methadone

Methadone maintenance treatment (MMT) is the most widely available pharmacotherapy for opioid addiction and has been shown to be an effective and safe treatment over a period of 40 years. Although women comprise approximately 40% of clients currently being treated in MMT programs, comparatively little research geared specifically toward this group has been published. This article begins with an overview of neurobiological studies on opioid addiction, including a discussion of gender differences, followed by a review of the pharmacology of methadone. The authors then examine the particular needs and differences of women being treated in MMTs, including co dependence with other substances, women's health issues, and psychosocial needs unique to this population. Research shows that women have different substance abuse treatment needs in comparison to their male counterparts. One New York City MMT program that has attempted to address these differences is highlighted.

( BUPP10289 - 27 May 2010) Introduction to women, children and addiction.

( BUPP10288 - 27 May 2010) Prenatal drug exposure: Infant and toddler outcomes

This manuscript provides an overview of the current scientific literature on the impact of maternal drug use, specifically opioids and cocaine, during pregnancy on the acute and long term outcomes of infants and toddlers from birth through age 3 years. Emphasis with regard to opioids is placed on heroin and opioid substitutes used to treat opioid addiction, including methadone, which has long been regarded as the standard of care in pregnancy, and buprenorphine, which is increasingly being investigated and prescribed as an alternative to methadone. Controlled studies comparing methadone at high and low doses, as well as those comparing methadone with buprenorphine, are highlighted and the diagnosis and management of neonatal abstinence syndrome is discussed. Over the past two decades, attention of the scientific and lay communities has also been focused on the potential adverse effects of cocaine and crack cocaine, especially during the height of the cocaine epidemic in the United States. Herein, the findings are summarized from prospective studies comparing cocaine exposed with non cocaine exposed infants and toddlers with respect to anthropometric growth, infant neurobehavior, visual and auditory function, and cognitive, motor, and language development. The potentially stigmatizing label of the so called crack baby preceded the evidence now accumulating from well designed prospective investigations that have revealed less severe sequelae in the majority of prenatally exposed infants than originally anticipated. In contrast to opioids, which may produce neonatal abstinence syndrome and infant neurobehavioral deficits, prenatal cocaine exposure appears to be associated with what has been described as statistically significant but subtle decrements in neurobehavioral, cognitive, and language function, especially when viewed in the context of other exposures and the caregiving environment which may mediate or moderate the effects. Whether these early findings may herald more significant learning and behavioral problems during school age and adolescence when the child is inevitably confronted with increasing social and academic challenges is the subject of ongoing longitudinal research.

( BUPP10287 - 27 May 2010) Gender issues in the pharmacotherapy of opioid addicted women: Buprenorphine

Gender, a biological determinant of mental health and illness, plays a critical role in determining patients' susceptibility, exposure to mental health risks, and related outcomes. Regarding sex differences in the epidemiology of opioid dependence, one third of the patients are women of childbearing age. Women have an earlier age of initiation of substance use and a more rapid progression to drug involvement and dependence than men. Generally few studies exist which focus on the special needs of women in opioid maintenance therapy. The aim of this paper is to provide an overview of treatment options for opioid dependent women, with a special focus on buprenorphine, and to look at recent findings related to other factors that should be taken into consideration in optimizing the treatment of opioid dependent women. Issues addressed include the role of gender in the choice of medication assisted treatment, sex differences in pharmacodynamics and pharmacokinetics of buprenorphine drug interactions, cardiac interactions, induction of buprenorphine in pregnant patients, the neonatal abstinence syndrome and breastfeeding. This paper aims to heighten the awareness for the need to take gender into consideration when making treatment decisions in an effort to optimize services and enhance the quality of life of women suffering from substance abuse.

( BUPP10286 - 27 May 2010) Substance Abuse in Women

Gender differences in substance use disorders (SUDs) and treatment outcomes for women with SUDs have been a focus of research in the last 15 years. This article reviews gender differences in the epidemiology of SUDs, highlighting the convergence of male/female prevalence ratios of SUDs in the last 20 years. The telescoping course of SUDs, recent research on the role of neuroactive gonadal steroid hormones in craving and relapse, and sex differences in stress reactivity and relapse to substance abuse are described. The role of co occurring mood and anxiety, eating, and posttraumatic stress disorders is considered in the epidemiology, natural history, and treatment of women with SUDs. Women's use of alcohol, stimulants, opioids, cannabis, and nicotine are examined in terms of recent epidemiology, biologic and psychosocial effects, and treatment. Although women may be less likely to enter substance abuse treatment than men over the course of the lifetime, once they enter treatment, gender itself is not a predictor of treatment retention, completion, or outcome. Research on gender specific treatments for women with SUDs and behavioral couples treatment has yielded promising results for substance abuse treatment outcomes in women.

( BUPP10285 - 26 May 2010) Anesthetic considerations in bariatric surgery

The occurrence of obesity is rising worldwide. Being overweight and obesity are becoming endemic, particularly because of increasing nourishment and a reduction in physical activities. Insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, liver steatosis, gastroesophageal reflux, certain forms of cancer, obstructive sleep apnea, degenerative joint disease, gout, lower back pain, and polycystic ovary syndrome are all associated with overweight and obesity. There are several surgical procedures for obese, morbidly obese and ultra obese patients that have been used for the last 3 decades. For severely obese patients, bariatric surgery is the only treatment to effectively have sustained weight loss and associated health improvement. Therefore, the number of obese patients requesting bariatric surgical procedures have being growing exponentially. Efficient knowledge on the pharmacokinetics and pharmacodynamics of anesthetic drugs needs a full up to date information on obese (body mass index (BMI) 40-49 kg/m2)) and super obese patients (BMI > 50 kg/m2) in order to perform the proper anesthesia care. Following certain anesthesia guidelines will ease the management and enhance outcomes of the morbidly obese patient presenting for any surgery.

( BUPP10337 - 10 June 2010) Two cases of psoas abscesses caused by group A beta haemolytic streptococcal infection with a cutaneous portal of entry

Background: Psoas abscess is a rare clinical entity that occurs chiefly after intra abdominal or retroperitoneal infection. We report two cases of psoas abscesses caused by group A beta haemolytic streptococcal infection having a cutaneous portal of entry. Case reports: The first patient, a 50 year old man, was feverish and had ulcerative and necrotic cutaneous lesions evocative of ecthyma that were progressing for three months and were recently associated with a painful mass in the left iliac fossa, leading to difficulties in walking. The second patient, a 35 year old woman with a medical history of intravenous drug addiction, was admitted to intensive care for sepsis syndrome following group A beta haemolytic streptococcal infection with a cutaneous portal of entry (swelling on left lower limb). She remained unaccountably subfebrile 10 days after the start of antibiotic therapy with amoxicillin. Abdominal CAT scans for each patient confirmed the diagnosis of left psoas abscess. For the first patient, the same group A beta haemolytic streptococcus was isolated in drainage fluid and at the cutaneous injury site. The outcome was favourable in both cases following extensive intravenous antibiotic therapy (amoxicillin) combined with percutaneous drainage (in the first case). Discussion: Psoas abscess can occur after locoregional infection and the portals of entry are usually gastro intestinal, musculoskeletal or genitourinary, with many organisms capable of causing such secondary abscesses. Psoas abscess can also be a primary clinical event. Staphylococcus aureus is the most common causative organism. The presented cases comprised secondary psoas abscesses with a cutaneous portal of entry. Since the complete set of three evocative symptoms (prolonged fever, pain and psoitis) is frequently seen late, diagnosis must be made on the basis of prolonged infectious state or unaccountable feverish abdominal pain. Diagnosis is based on abdominal CAT scan and treatment involves the use of appropriate antibiotics as well as percutaneous or surgical drainage of the abscess. The mortality rate in this patient population remains high with survival being dependent on prompt initiation of therapy.

( BUPP10336 - 10 June 2010) Opioids for neuropathic pain

( BUPP10335 - 10 June 2010) Drug addiction and anaesthesia: Most popular recreational drugs in Germany and anaesthesiological management of drug addicts

Drug addicts need special anesthesiological care due to their co morbidities, their modified need for analgesics and anesthetics and /or their specific substitution therapies. In spite of the high incidence of addiction worldwide controlled studies and evidence based recommendations for the anaesthesiological management of the patients are missing. The perioperative care is not the treatment of addiction, on the contrary the specific aspects of a chronic disease have to be accepted. Equally important perioperative treatment strategies for the management of drug addicts include: 1. stabilisation of the physical dependence by substitution therapies. 2. avoidance of distress or craving.3. perioperative stress relief.4. strict avoidance of inadequate analgesic treatment.5. postoperative optimization with regional or systemic analgesia with non opioids, opiods and co analgesics. 6. consideration of specific physical or psychological comorbidities. Inadequate analgesic treatment is known to be responsible for relapses into addiction and has strictly to be avoided. This holds true even for people with long term drug abstinence.

( BUPP10334 - 10 June 2010) Naloxone for administration by peers in cases of heroin overdose

( BUPP10333 - 10 June 2010) Intraspinal techniques for pain management in cancer patients: A systematic review

Purpose This systematic review outlines current evidence regarding the effectiveness of intraspinal techniques for cancer pain and addresses practical implementation issues. Methods A search of electronic databases identified systematic reviews and randomized controlled trials (RCTs) evaluating the effectiveness of intraspinal techniques in the setting of cancer pain. An environmental scan was completed via the internet to identify practice guidelines and resource documents addressing organizational and implementation issues in the delivery of intraspinal analgesia. Elements reviewed included patient selection, contraindications, monitoring, aftercare, follow up, hospital discharge equipment, health personnel, patient education, and safety. Main results Three systematic reviews, three consensus conferences, and 12 RCTs met the inclusion criteria for evidence of effectiveness. No single systematic review or consensus conference included all relevant RCTs or specifically addressed the use of intraspinal techniques for cancer pain. Six RCTs compared intraspinal techniques alone or combined with other interventions alone or in combination, four compared different intraspinal medications, and two compared different intraspinal techniques. In general, the evidence supported the use of intraspinal techniques for cancer pain management. The two main indications consistently identified were intractable pain not controlled by other conventional medical routes and/or side effects from conventional pain management strategies preventing dose escalation. Reports indicate intraspinal analgesia is equally or more effective than conventional medical management and often associated with fewer side effects. Thirteen resource documents addressed issues surrounding the delivery of intraspinal analgesia and program implementation. Conclusions Intraspinal techniques monitored by an interprofessional health care team should be included as part of a comprehensive cancer pain management program.

( BUPP10332 - 10 June 2010) Differentiated pharmacological consideration of modern opioids

( BUPP10331 - 10 June 2010) Effectiveness of a polysubstance dependence detoxification protocol for patients with co occurring disorders

Patients with polysubstance dependence and co occurring psychiatric and substance use disorders represent a growing population. This study investigates the safety and effectiveness of a single scale, symptom triggered protocol for patients undergoing inpatient detoxification from alcohol, opioids, sedatives, or polysubstance dependence. Medical records staff generated a list of all charts containing a principal discharge diagnosis of alcohol, sedative, opioid, or polysubstance dependence between 2002 and 2004, when the Butler Instrument for Withdrawal Assessment protocol was administered. This list was arranged by terminal digits of the medical record numbers to randomize the selection, and staff pulled the first 100 charts for review. De identified medical data were recorded from the charts to obtain information about medications, length of stay, and adverse events during hospitalization. The main outcome measures were adverse events and length of stay. The average length of stay was 4.2 days (SD = 2.3), rate of discharge against medical advice was 4% (exactly 4 patients out of 100), and no seizures or delirium tremens were reported. The results of this study suggest that a single scale, symptom triggered detoxification protocol can facilitate safe and rapid detoxification and stabilization, even for patients with polysubstance dependence and co occurring psychiatric and substance use disorders.

( BUPP10330 - 10 June 2010) Prevention of HIV transmission among intravenous drug users

( BUPP10329 - 10 June 2010) Clinically relevant doses of lidocaine and bupivacaine do not impair cutaneous wound healing in mice

Background. Lidocaine and bupivacaine are commonly infiltrated into surgical cutaneous wounds to provide local anaesthesia after surgical procedures. However, very little is known about their effects on cutaneous wound healing. If an inhibitory effect is demonstrated, then the balance between the benefits of postoperative local anaesthesia and the negatives of impaired cutaneous wound healing may affect the decision to use local anaesthesia or not. Furthermore, if a difference in the rate of healing of lidocaine and bupivacaine treated cutaneous wounds is revealed, or if an inhibitory effect is found to be dose dependent, then this may well influence the choice of agent and its concentration for clinical use.Methods. Immediately before incisional wounding, we administered lidocaine and bupivacaine intradermally to adult female mice, some of which had been ovariectomized to act as a model of post menopausal women (like post menopausal women, ovariectomized mice heal wounds poorly, with increased proteolysis and inflammation). Day 3 wound tissue was analysed histologically and tested for expression of inflammatory and proteolytic factors.Results. On day 3 post wounding, wound areas and extent of re epithelialization were comparable between the control and local anaesthetic treated animals, in both intact and ovariectomized groups. Both tested drugs significantly increased wound activity of the degradative enzyme matrix metalloproteinase 2 relative to controls, while lidocaine also increased wound neutrophil numbers.Conclusions. Although lidocaine and bupivacaine influenced local inflammatory and proteolytic factors, they did not impair the rate of healing in either of two well established models (mimicking normal human wound healing and impaired age related healing).

( BUPP10328 - 09 June 2010) Comparison of epidural xylazine ketamine and buprenorphine for post traumatic pain management in goats (Capra hircus)

The comparative efficacy of epidural xylazine and ketamine (0.05 mg /kg and 2 mg/kg body wt) and buprenorphine (1 mg/kg body wt) and was studied in goats. Model of acute pain and inflammation was created by the injection of turpentine oil (0.15 mL) in the left hock joint under thiopental anaesthesia in 12 non descript goats of either sex divided into three groups i.e. A (control), B (xylazine and ketamine) and C (buprenorphine). These drugs were administered at lumbosacral epidural space at an interval of 2, 24, 48 and 72 hr after the induction of arthritis. Analysis of clinical and haemato biochemical data suggested severe post traumatic changes and stress response in animals of group A as evidenced by increased HR, RR, RT, joint warmth, hyperalgesia, swelling, pain, leukocytosis, hyperglycemia, neutrophilia, increased trypsin inhibition, fibrinogen and decreased lymphocytes. The post traumatic treatment with epidural xylazine ketamine and buprenorphine resulted in early suppression of changes in these parameters compared to control animals. Both treatments protected the animals from noxious stimuli and acute pain.

( BUPP10327 - 09 June 2010) Seizure risk associated with neuroactive drugs: Data from the WHO adverse drug reactions database

The data from the WHO adverse drug reactions on seizure risk associated with neuroactive drugs are reviewed. Based on the reports in VigiBase, adverse drug reactions reports relating to antidepressants, antipsychotic and cholinomimetic drugs included seizures more often than other neuroactive drugs.

( BUPP10326 - 09 June 2010) Combination of Cell Culture Assays and Knockout Mouse Analyses for the Study of Opioid Partial Agonism

Nonselective opioid partial agonists, such as buprenorphine, butorphanol, and pentazocine, have been widely used as analgesics and for anti addiction therapy. However, the precise molecular mechanisms underlying the therapeutic and rewarding effects of these drugs have not been clearly delineated. Recent success in developing mu opioid receptor knockout (MOP KO) mice has elucidated the molecular mechanisms underlying the effects of morphine and other opioids. We have revealed the in vivo roles of MOPs in the effects of opioid partial agonists by using MOP KO mice for behavioral tests (e.g., several kinds of antinociceptive tests for analgesic effects, conditioned place preference test for dependence). The combination of the cell culture assays using cDNA for mu, delta, and kappa opioid receptors and the behavioral tests using MOP KO mice has provided novel theories on the molecular mechanisms underlying the effects of opioid ligands, especially opioid partial agonists.

( BUPP10325 - 09 June 2010) The Use of Major Analgesics in Patients with Renal Dysfunction

Pain in patients with impaired renal function may be a significant problem requiring treatment with opioids. However, pharmacokinetic and metabolic changes associated with an impaired renal function may raise some concerns about side effects and overdosing associated with opioid agents in this patient's population. In order to give recommendations on this issue, we review the available evidences on the pharmacokinetics and side effects of most common opioids used to treat pain. The results of this review show that the half life of the parent opioid compounds and of their metabolites is increased in the presence of renal dysfunction, for which careful monitoring of the patient, dose reduction and a longer time interval between doses are recommended. Among opioids, morphine and codeine used with great caution and possibly avoided in renal failure/dialysis patients; tramadol, hydromorphone and oxycodone can be used with caution and close patient's monitoring, whereas transdermal buprenorphine, methadone and fentanyl/sufentanil appear to be safe to use in patients with renal failure.

( BUPP10324 - 09 June 2010) Tolerance and Withdrawal From Prolonged Opioid Use in Critically III Children

OBJECTIVE: After prolonged opioid exposure, children develop opioid induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal.PATIENTS AND METHODS: Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid, " "opiate, " "sedation, " "analgesia, " "child," "infant newborn, " "tolerance, " "dependency, " "withdrawal, " "analgesic, " "receptor, " and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis.RESULTS: Mechanisms of opioid induced hyperalgesia and tolerance suggest important drug and patient related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short acting opioids. Treatment options include slowly tapering opioid doses, switching to longer acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia.CONCLUSIONS: Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal. Pediatrics 2010; 125: e1208 e1225.

( BUPP10323 - 09 June 2010) Medical interventions for addictions in the primary care setting

Primary care physicians treating HIV-infected patients should not be afraid or reluctant to engage in medication-assisted treatment for substance dependence. Effective medications are available for many types of substance addictions, including buprenorphine for opioid dependence, disulfiram for cocaine dependence, bupropion for methamphetamine dependence, and naltrexone for alcohol dependence. Physician use of medications coupled with encouragement to adhere to all aspects of treatment including counseling and other psychosocial interventions can produce substantial rewards in terms of keeping patients involved in their HIV care and improving overall patient health and functioning. This article summarizes a presentation made by R. Douglas Bruce, MD, MA, MSc, at the 12th Annual Clinical Conference for the Ryan White HIV/AIDS Program held in October 2009 in Dallas, Texas. The original presentation is available as a Webcast at www.iasusa.org.

( BUPP10322 - 09 June 2010) Clinical characteristics of central european and North American samples of pregnant women Screened for opioid agonist treatment

Background: Little comparable information is available regarding clinical characteristics of opioid dependent women from different countries. In the present study, women from the USA, Canada and a Central European country, Austria, screened for participation in the Maternal Opioid Treatment Human Experimental Research study, were compared with respect to their demographic and addiction histories. Methods: Pregnant women (n = 1,074) were screened for study participation using uniformed clinical criteria and instruments. The screening results were compared with regard to exclusion, demographics, drug use, and psychosocial and treatment histories. Results: Compared to the screened US and Canadian women, Austrian women were more likely to be younger (p < 0.001), white (p < 0.001), had significantly lower levels of educational attainment (p < 0.001), were less likely to use opioids daily (p < 0.001) and more likely to have been prescribed buprenorphine (p < 0.001). Compared to both rural and urban US groups, the Austrian group was less likely to have legal issues (p < 0.001) and was younger when first prescribed agonist medication (p < 0.001). Conclusion: The differences between North American and European groups may offer unique insights concerning treatment and pregnancy outcomes for opioid dependent pregnant women.

( BUPP10321 - 09 June 2010) Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: Pharmacodynamics, acute cardiovascular effects, and preliminary toxicology

Background: CW002 is a neuromuscular blocking drug that is inactivated by endogenous l cysteine. This study determined the exogenous l cysteine dose response relationship for CW002 reversal along with acute cardiovascular effects and organ toxicity in dogs. METHODS:: Six dogs were each studied four times during isoflurane nitrous oxide anesthesia and recording of muscle twitch, arterial pressure, and heart rate. CW002 (0.08 mg/kg or 9 � ED /sub 95/ ) was injected, and the time to spontaneous muscle recovery was determined. CW002 was then administered again followed 1 min later by 10, 20, 50, or 100 mg/kg l cysteine (1 dose/experiment). After twitch recovery, CW002 was given a third time to determine whether residual l cysteine influenced duration. Preliminary toxicology was performed in an additional group of dogs that received CW002 followed by vehicle (n = 8) or 200 mg/kg l cysteine (n = 8). Animals were awakened and observed for 2 or 14 days before sacrificing and anatomic, biochemical, and histopathologic analyses. Results:l Cysteine at all doses accelerated recovery from CW002, with both 50 and 100 mg/kg decreasing median duration from more than 70 min to less than 5 min. After reversal, duration of a subsequent CW002 dose was also decreased in a dose dependent manner. Over the studied dose range, l cysteine had less than 10% effect on blood pressure and heart rate. Animals receiving a single 200 mg/kg dose of l cysteine showed no clinical, anatomic, biochemical, or histologic evidence of organ toxicity. CONCLUSION:: The optimal l cysteine dose for rapidly reversing the neuromuscular blockade produced by a large dose of CW002 in dogs is approximately 50 mg/kg, which has no concomitant hemodynamic effect. A dose of 200 mg/kg had no evident organ toxicity.

( BUPP10320 - 09 June 2010) BioPartnering north America Spotlight on Canada

The BioPartnering North America conference, held in Vancouver, included presentations covering drug pipeline developments from both large and small pharmaceutical companies. This conference report highlights selected presentations from drug developers from Canada. Investigational drugs discussed include davunetide (Allon Therapeutics Inc), ANG 1005 (Angiochem Inc), AQX 1125 (Aquinox Pharmaceuticals Inc), and Sertolin (Sernova Corp), APG 2305 (Allostera Pharma Inc). The DepoVax liposomal vaccine delivery platform from Immunovaccine Inc is also highlighted.

( BUPP10319 - 09 June 2010) Use of hydromorphone, with particular reference to the OROS /sup �/ formulation, in the elderly

The prevalence of pain increases with age. However, pain is often inadequately managed in elderly people, which undermines quality of life. Pain has been associated with depression, sleep disturbances, impaired ambulation, and increased healthcare use and costs.Effective treatment of pain improves the overall quality of life. However, pain management is complicated by the presence of multiple co morbidities in elderly people, which increases the likelihood of polypharmacy, and therefore increases the chance of potential drug drug interactions. Polypharmacy is also associated with poor adherence to therapy. Age related pharmacokinetic and pharmacodynamic changes reduce the therapeutic index of drugs. Therefore, elderly people are more likely to suffer from adverse events and increased sensitivity to the analgesic properties of opioids.OROS /sup �/ hydromorphone (Jurnista /sup �/ ) is a once daily, extended release formulation that uses the OROS /sup �/ push pull technology to provide controlled release of the semi synthetic opioid hydromorphone. Compared with conventional immediate release hydromorphone, OROS /sup �/ hydromorphone provides more consistent delivery of hydromorphone with lower peak concentrations and less variability in plasma concentrations over time. The bioavailability of hydromorphone from OROS /sup �/ hydromorphone is minimally affected by food or alcohol (ethanol).Hydromorphone is mainly metabolized in the liver and is excreted in the urine. Unlike morphine, hydromorphone does not have an active 6 glucuronide metabolite. This metabolite of morphine can accumulate in the presence of renal failure; therefore, the lack of an active 6 glucuronide metabolite makes hydromorphone a useful alternative to morphine in elderly patients with renal failure. However, hydromorphone is similar to morphine in that it is metabolized to hydromorphone 3 glucuronide, which may be neuroexcitatory. Because of its low plasma protein binding and low probability of interfering with the metabolism of other drugs, hydromorphone may be especially suitable for patients taking multiple medications.OROS /sup �/ hydromorphone is an effective analgesic that is well tolerated and provides more stable plasma concentrations than immediate release forms of hydromorphone. Its once daily administration offers an advantage over immediate release forms and longer acting formulations that require twice daily administration. This means OROS /sup �/ hydromorphone will be more convenient for elderly patients and may improve adherence, resulting in improved pain relief and quality of life.

( BUPP10318 - 09 June 2010) Enhanced HIV testing, treatment, and support for HIV infected substance users

( BUPP10317 - 09 June 2010) Management of chronic

( BUPP10316 - 09 June 2010) Methadone maintenance dosing guideline for opioid dependence, a literature review

To date, methadone dosing is still an issue of debate and controversy among clinicians who are involved in methadone maintenance programs. The authors conducted a literature review to update clinicians about this issue and provide recommendations for proper methadone dosing. Studies eligible for inclusion in the review were retrieved from the PubMed database by searching for reports published between 1990 and September 2008 using the major medical subject headings Methadone (all fields) and dose. Only articles written in English were included. Additional reports were identified from the reference lists of retrieved articles and by manual review of the tables of contents of journals on drug of abuse included in the psychiatry and substance abuse subject category listing 2008 of the Journal Citation Reports. Abstracts of medical meetings were excluded. Twenty four articles were included in the review. Twelve are randomized, controlled, or double blind clinical trials, 10 are non randomized and observational studies, and 2 are meta analyses. Currently, the consensus is to have a goal for methadone dosing in the range of 60 to 100 mg daily. For patients who continue to use illicit opiates while prescribed this dose range, clinicians may consider doses greater than 100 mg daily. However, this is not the current consensus but rather is based on the limited promising data the authors have; it could be considered if the benefits outweigh the risks for some patients.

( BUPP10315 - 09 June 2010) Transdermal buprenorphine for oropharyngeal mucositis associated pain in patients treated with radiotherapy for head and neck cancer

( BUPP10314 - 09 June 2010) Long acting depot formulations of naltrexone for heroin dependence: A review

Purpose of review The major problem with the oral formulation of naltrexone for heroin dependence is poor compliance (adherence). Long acting sustained release formulations of naltrexone (implantable and injectable) might help to improve compliance and, thus, increase the efficacy of abstinence oriented treatment of heroin dependence with naltrexone. Recent findings There have been several implantable and injectable formulations of naltrexone developed within the last decade. It was demonstrated that some of them are effective and relatively well tolerated medications for relapse prevention in heroin addicts. However, advantages and disadvantages of these new medications have never been systematically analyzed. Summary Long acting sustained release formulations of naltrexone are well tolerated and more effective for relapse prevention in heroin addicts than the oral ones.

( BUPP10313 - 09 June 2010) Peripheral nerve conditions in diabetes

Tight glycaemic control is needed to help prevent the development of diabetic peripheral neuropathy. However, once the condition has occurred patients should be protected against the development of foot ulceration. Patient education and preventive podiatric care are priorities in people with diabetic peripheral neuropathy.

( BUPP10312 - 09 June 2010) Early development of opioid exposed infants born to mothers in buprenorphine replacement therapy

MDI) and mother child interaction (using the Emotion Availability Scales, 3rd edition) among infants of opioid abusing mothers. Participants were 87 dyads (15 opioid exposed, 15 maternal depression and 57 unexposed mother infant dyads). The study group included 15 infants (mean age=7.0 months, sd=2.8 months) of mothers who participated in buprenorphine replacement therapy. Study variables were evaluated during the second half of the first year and compared with the infants of depressed (mean age = 8.06 months, sd =2.4 months) and nonabusing mothers (mean age = 9.96 months, sd = 2.9 months). The opioid exposed infants earned the lowest Bayley II MDI scores. Furthermore, they scored the lowest in infant involvement. The role of environmental risk factors, in turn, was highlighted in that the opioid abusing mothers scored the lowest in maternal sensitivity, structuring and nonintrusiveness. Maternal childhood foster care and criminal record were significantly related to lower sensitivity and higher intrusiveness. Finally, the environmental risk status of the opioid exposed infants was further underlined in that there were more separations from the mother in the end of the first year as well as an elevated risk for physical abuse.

( BUPP10311 - 09 June 2010) Clinical veterinarian's perspective of non human primate (NHP) use in drug safety studies

Owing to their size, cost, and availability, the cynomolgus macaque (Macaca fascicularis) has surpassed the rhesus macaque in its use as a non human primate preclinical model for drug safety studies. There are three major regions where cynomolgus macaques are bred: China, Southeast Asia, and the island of Mauritius. Country of origin of the macaque is important, as disease status and background disease incidence in non human primates from each of these sites can differ. Once a source of macaque has been decided, careful monitoring of the animal during breeding and by the importing vendor while the animals are in quarantine is important. During vendor quarantine, the animals should be monitored and evaluated for disease, response to tuberculosis testing, retroviral status, and both ecto and endoparasites. After animals arrive at the test facility, additional quarantine and acclimation are important to ascertain health status further and to reduce stress on the animals, thereby providing a better research model. The type of caging, food, water, and enrichment should be carefully selected to best suit the needs of the study while working within Federal Regulations (i.e., Animal Welfare Act and Good Laboratory Practices). Careful prescreening by performing tests (such as physical, neurologic, and ophthalmologic examinations), complete blood count, biochemical profile, urinanalysis, electrocardiograms, and pulse oximetry is important when selecting the most appropriate animals for the study. After the in life portion of the study begins, animals that present with clinical signs should be examined and an appropriate treatment course begun while maintaining study objectives. As many commonly used medications have immunomodulatory effects, having an understanding of the mechanism of action of test articles will aid in the appropriate choice of treatment of study animals. A tiered approach to the treatment of these animals is a conservative and usually acceptable approach.

( BUPP10310 - 09 June 2010) Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: A systematic review

Background: Present practice guidelines recommend sedative analgesic and neuromuscular blocking administration during therapeutic hypothermia in comatose patients after cardiac arrest. However, none suggests the best administration protocol. In this study, we evaluated intensivists' preferences regarding administration. Methods: A systematic literature review was conducted to identify clinical studies published between 1997 and July 2009. Selected articles had to meet the following criteria: use of hypothermia to improve neurologic outcome after cardiac arrest, and specific mention of the sedative protocol used. We checked drugs and dose used, the reason for their administration, and the specific type of neurologic and neuromuscular monitoring used. Results: We identified 44 studies reporting protocols used in 68 intensive care units (ICUs) from various countries. Midazolam, the sedative used most often, was used in 39 ICUs at doses between 5 mg/h and 0.3 mg/kg/h. Propofol was used in 13 ICUs at doses up to 6 mg/kg/h. Eighteen ICUs (26%) did not report using any analgesic. Fentanyl was the analgesic used the most, in 33 ICUs, at doses between 0.5 and 10 mug/kg/h, followed by morphine in 4 ICUs. Neuromuscular blocking drugs were routinely used to prevent shivering in 54 ICUs and to treat shivering in 8; in 1 ICU, their use was discouraged. Pancuronium was used the most, in 24 ICUs, followed by cisatracurium in 14. Four ICUs used neuromuscular blocking drug administration guided by train of four monitoring and 3 ICUs used continuous monitoring of cerebral activity. Conclusions: There is great variability in the protocols used for anesthesia and analgesia during therapeutic hypothermia. Very often, the drug and the dose used do not seem the most appropriate. Only 3 ICUs routinely used electroencephalographic monitoring during paralysis. It is necessary to reach a consensus on how to treat this critical care population.

( BUPP10309 - 09 June 2010) Addiction to the opioids. Consequences on the pain treatment

Addiction is a chronic disease of the central nervous system. Numerous neuroadaptations occur following chronic exposure to drugs of abuse. The progress in numerous domains, neuroimaging, molecular biology, animal models, allowed these last years to understand better the neurobiological and neurochemical mechanisms of addictions. The activity of the central nervous system is globally regulated by excitatory and inhibitory ligands. The very fine balance which exists between these two groups of neurotransmitters and neuropeptides allows maintaining the equilibrium of the brain. The acute drug exposure is strongly destabilizing this balance. If the exposure is repeated, the brain is going to try to oppose to these effects to maintain the balance. We have neuroadaptations of the brain. These mechanisms, which are mechanisms of re equilibrium, are relatively stable, and explain the necessity of using pharmacotherapy to help in the abstinence. The maintenance treatments in the management of opioid dependence showed its utility during the last years, with a reduction of the consumption of opiates as well as to a decrease of the rates of morbidity and mortality bound to the taking of drugs. Nevertheless thesemaintenance treatments are opioid agonists (buprenorphine or methadone), with specific pharmacodynamic and pharmacokinetic properties. Adequate treatment of painful conditions is an essential dimension of quality medical care. Physicians will frequently encounter patients receiving agonist therapy treatment with methadone or buprenorphine and who develop acutely or chronically painful conditions, requiring effective treatment strategies.

( BUPP10308 - 09 June 2010) Effectiveness and safety of high dose opioids for chronic pain

( BUPP10307 - 09 June 2010) Functional interactions between endogenous cannabinoid and opioid systems: Focus on alcohol, genetics and drug addicted behaviors

Although the first studies regarding the endogenous opioid system and addiction were published during the 1940s, addiction and cannabinoids were not addressed until the 1970s. Currently, the number of opioid addiction studies indexed in PubMed Medline is 16 times greater than the number of cannabinoid addiction reports. More recently, functional interactions have been demonstrated between the endogenous cannabinoid and opioid systems. For example, the cannabinoid brain receptor type 1 (CB1) and mu opioid receptor type 1 (MOR1) co localize in the same presynaptic nerve terminals and signal through a common receptor mediated G protein pathway. Here, we review a great variety of behavioral models of drug addiction and alcohol related behaviors. We also include data providing clear evidence that activation of the cannabinoid and opioid endogenous systems via WIN 55,512-2 (0.4-10 mg/kg) and morphine (1.0-10 mg/kg), respectively, produces similar levels of relapse to alcohol in operant alcohol self administration tasks. Finally, we discuss genetic studies that reveal significant associations between polymorphisms in MOR1 and CB1 receptors and drug addiction. For example, the SNP A118G, which changes the amino acid aspartate to asparagine in the MOR1 gene, is highly associated with altered opioid system function. The presence of a microsatellite polymorphism of an (AAT)n triplet near the CB1 gene is associated with drug addiction phenotypes. But, studies exploring haplotypes with regard to both systems, however, are lacking.

( BUPP10306 - 09 June 2010) Case Studies

( BUPP10305 - 09 June 2010) Recent development in therapeutics for breakthrough pain

Breakthrough pain is defined as transitory flares of pain. Breakthrough pain is caused by cancer, cancer complications, treatment or comorbidities. The usual onset to maximum breakthrough pain intensity time is 3 min and duration is 30 min; therefore, the assessment for response needs to be at short intervals. The rapid onset and offset of pain results in inadequate responses when oral opioids are used to manage pain flares. Several strategies have been used to manage breakthrough pain: titration of the chronic opioid, independent titration of rescue opioids and alternative routes. Buccal fentanyl has a rapid onset to analgesia and appears to be superior to oral morphine. Newer fentanyl preparations have been released to manage breakthrough pain in the opioid tolerant individual. Other routes of administration that have a rapid onset to analgesia include intranasal hydrophilic and lipophilic opioids, inhaled opioids delivered by special delivery devices and parenteral morphine. In a small series of patients experiencing severe flares of pain with spinal opioids unrelieved by parenteral opioids, sublingual ketamine and bolus doses of intrathecal local anesthetics have been effective. Nonpharmacological approaches to managing activity related pain include radiation therapy, surgical correction of impending fractures, kyphoplasty and radioisotopes.

( BUPP10304 - 09 June 2010) Opioids in chronic noncancer pain

Chronic noncancer pain is highly prevalent with associated negative effects on function and quality of life of the individuals involved. Opioids have been shown to decrease pain and improve function in some patients with chronic noncancer pain, but they are not always effective and are associated with multiple complications, including drug misuse, abuse and diversion. Furthermore, the effectiveness of opioids in decreasing pain and improving function has not been proven conclusively, resulting in continued uncertainty about long term benefits of opioids for chronic noncancer pain. Ideally, in modern medicine, clinical decisions are made based on information derived from high quality evidence. Since no such evidence exists for chronic opioid therapy in chronic noncancer pain, this review describes various aspects of opioid therapy in chronic noncancer pain, including adherence monitoring, along with a ten step process outlining the principles of effective and safe opioid use.

( BUPP10303 - 08 June 2010) Douleur et Analgesie: Editorial

( BUPP10352 - 17 June 2010) Reducing the abuse potential of controlled substances

Prescription drugs, principally opioid analgesics, now account for more fatal drug overdoses in the US than heroin and cocaine. Experts offer several theories for this, including the introduction within the past decade of high dosage, extended release drug formulations that have proven easy to manipulate for abuse purposes. At the same time, the prescribing of immediate and extended release pain relievers the most highly abused category of prescription drugs has increased significantly. Regulatory agencies, in turn, have increased their oversight of prescribers, dispensers and manufacturers of controlled substances. For its part, the pharmaceutical industry has shown a modest but growing interest in developing abuse deterrent drugs. In this article, we review the progress being made through the use of technology and design in mitigating the abuse potential of currently marketed and newly approved drugs, as well as several pipeline candidates. We discuss obstacles facing the future of this novel approach to reducing prescription drug abuse and conclude with policy recommendations intended to encourage the development of abuse deterrent drugs.

( BUPP10351 - 17 June 2010) Basic measures and systemic medical treatment of patients with toxic epidermal necrolysis

Background: With an incidence of 1.5 1.8/1 million inhabitants per year, toxic epidermal necrolysis is a rare but life threatening disease. It is almost always drug induced and its lethality is pronounced with up to 50 %. Several therapeutic options are described in literature; however, there is still lack of a universally accepted and specific therapy of toxic epidermal necrolysis. Methods: This survey considers 8 cases of toxic epidermal necrolysis diagnosed and treated in our clinic from 2003 to 2007. The epidermal sloughing was > 30 % of the body surface in each case. Results: After immediately discontinuing the drug suspected of being responsible for toxic epidermal necrolysis, we treated with systemic corticosteroids in an initial dose of up to 1.5 mg/kg. Moreover, special emphasis was put on basic measures such as control of vital parameters. With this treatment we reached good results; none of the patients died.

( BUPP10350 - 17 June 2010) Acute pain management Foreword

( BUPP10349 - 17 June 2010) Nicotinic receptor mediated reduction in L DOPA induced dyskinesias may occur via desensitization

L-DOPA-induced dyskinesias in Parkinson's disease are a significant clinical problem for which few therapies are available. We recently showed that nicotine reduces L-DOPA-induced abnormal involuntary movements (AIMs) in parkinsonian animals, suggesting it may be useful for the treatment of L-DOPA-induced dyskinesias. The present experiments were performed to understand the mechanisms whereby nicotine reduces L-DOPA-induced AIMs. We used a well established model of dyskinesias, L-DOPA treated unilateral 6 hydroxydopamine lesioned rats. Dose ranging studies showed that injection of 0.1 mg /kg nicotine once or twice daily for 4 or 10 days most effectively reduced AIMs, with no worsening of parkinsonism. Importantly, a single nicotine injection did not reduce AIMs, indicating that nicotine's effect is caused by long term rather than short term molecular changes. Administration of the metabolite cotinine did not reduce AIMs, suggesting a direct effect of nicotine. Experiments with the nicotinic receptor (nAChR) antagonist mecamylamine were done to determine whether nicotine acted via a receptor mediated mechanism. Unexpectedly, several days of mecamylamine injection (1.0 mg/kg) alone significantly ameliorated dyskinesias to a comparable extent as nicotine. The decline in AIMs with combined nicotine and mecamylamine treatment was not additive, suggesting that nicotine exerts its effects via a nAChR interaction. This latter finding, combined with data showing that mecamylamine reduced AIMs to a similar extent as nicotine, and that nicotine or mecamylamine treatment both decreased alpha6beta2* and increased alpha4beta2* nAChR expression, suggests that the nicotine mediated improvement in L-DOPA-induced AIMs may involve a desensitization block. These data have important implications for the treatment of L-DOPA-induced dyskinesias in Parkinson's disease.

( BUPP10348 - 17 June 2010) Clinical Drug Investigation: Foreword

( BUPP10347 - 17 June 2010) Intravenous misuse of buprenorphine: Characteristics and extent among patients undergoing drug maintenance therapy.

Background and objective: Sublingual buprenorphine (Subutex�) is used to treat opioid dependence. However, illicit intravenous (IV) injection of buprenorphine is a widespread problem. This survey investigated the IV misuse of buprenorphine among patients receiving drug replacement therapy at the Drug Addiction Centre in Udine, Italy. Study design: All patients who were receiving treatment with buprenorphine or methadone at the Drug Addiction Centre were invited to fill in a voluntary and anonymous questionnaire consisting of five questions. The questions asked if the patient had ever misused buprenorphine intravenously, when the misuse had occurred, the patient's reasons for misusing buprenorphine, the patient's perception of their experience, and the patient's perception of how widespread IV misuse of buprenorphine is. 307 patients completed the questionnaire, 93 and 214 of whom, respectively, were receiving buprenorphine and methadone. Results: In total, 23.12% of patients admitted an IV misuse of buprenorphine, with a significantly greater prevalence among patients currently receiving buprenorphine (35.48%) than those receiving methadone (17.75%; p < 0.001). Younger patients were also more likely to have misused buprenorphine, and tended to have done so before coming to the Drug Addiction Centre. The most frequent motivation for IV misuse was treatment of heroin addiction or withdrawal symptoms (50.71%), while only 12.67% of patients reported that their motivation was to experience pleasure or euphoria. The majority of patients who had misused buprenorphine intravenously (53.52%) had a negative experience, and methadone recipients were significantly more likely to find the experience negative than buprenorphine recipients (68.42% vs 36.36%; p = 0.007). Almost half of the patients (45.93%) thought that at least 50% of patients had taken buprenorphine by IV injection. Conclusion: The results of our study confirm the widespread IV misuse of buprenorphine. Misuse was most common among patients currently receiving buprenorphine treatment and younger patients. For the majority of patients, the reason for IV misuse was to treat their dependence. We believe that the prevalence of buprenorphine misuse could be reduced by adopting appropriate clinical practices and treating patients with the buprenorphine/naloxone combination rather than buprenorphine alone.

( BUPP10346 - 17 June 2010) Therapeutic switch to buprenorphine/naloxone from buprenorphine alone: Clinical experience in an Italian addiction centre

Background: Pharmacological therapy has an important place in the management of opioid dependence. Methadone has been the mainstay of therapy but has a number of limitations. Buprenorphine monotherapy is another option, but misuse and diversion can have negative consequences. The opioid receptor antagonist, naloxone, has been added to buprenorphine to create a combination product with a reduced potential for misuse and diversion. Objectives: This study evaluated the use of buprenorphine/naloxone for 24 weeks as a pharmacological management of opioid dependent patients after therapeutic switch from buprenorphine alone. Methods: Patients (n = 43) received sublingual tablets of buprenorphine/naloxone. The buprenorphine dose was 2 24 mg (mean 16). Patients saw a physician, including an interview using a structured data sheet, and had counselling each week. Assessments were performed at week 2 (period 1), week 6 (period 2), week 16 (period 3) and week 24 (period 4). Laboratory immunoenzymatic testing was performed weekly to detect drugs in the urine. Results: The management of withdrawal symptoms was rated as 'satisfactory' by 67% of patients during period 1 and 91% during period 4. The majority of patients was highly satisfied with therapy and considered that buprenorphine/naloxone provided good control of cravings. Two patients dropped out of therapy, but all others continued to receive buprenorphine throughout the study. Approximately 50% of patients stated that they disliked the sensory properties (taste, colour, odour and feel) of buprenorphine/naloxone. Adverse effects were as would be expected on the basis of the mechanism of action of buprenorphine (i.e. opioid induced constipation) and for patients undergoing drug withdrawal. Only 2% of patients attempted the intravenous misuse of buprenorphine/naloxone, none of whom experienced any gratifying effects. Conclusions: Opioid dependent patients maintained on buprenorphine monotherapy can be safely switched to a sublingual buprenorphine/naloxone tablet without any loss of treatment effectiveness. Buprenorphine/naloxone can be administered in an outpatient or primary care setting, and effectively controls cravings and withdrawal symptoms. Patient satisfaction was high, making retention in treatment more likely.

( BUPP10345 - 17 June 2010) Safety and efficacy of buprenorphine/naloxone in opioid dependent patients: An Italian observational study

Background: Opioid dependence is a growing problem. Methadone is an established agent for the treatment of opioid dependence, but there is a risk of this agent being abused, a potential for interaction with antiretroviral agents and a risk of cardiac toxicity. Another option is the partial mu opioid receptor opioid agonist buprenorphine, which has been used successfully to manage opioid dependence. While the risk of abuse is lower than that for methadone, there is still a risk. The sublingual combination formulation of buprenorphine and the opioid receptor antagonist naloxone (buprenorphine/ naxolone) is a newer agent with reduced abuse potential, and has been shown to have promising efficacy for opioid dependence. Objectives: We describe the results of an observational study investigating the safety and efficacy of buprenorphine/naloxone in opioid dependent patients. Methods: A total of 77 patients were included and were switched from buprenorphine to sublingual tables of buprenorphine/naloxone; the buprenorphine dosage was titrated to achieve good control of withdrawal symptoms. The prevalence of withdrawal symptoms, craving, constipation, cramps, insomnia, sexual activity, depression, sweating, distress, bone/joint pain and drowsiness were compared over the first 30 days of treatment (period 1) and the total 120 day study duration (period 2). Results: The average buprenorphine/naloxone dose in period 1 was 7.3 mg/day and 12.7 mg/day in period 2. Most patients did not experience any withdrawal symptoms in either period 1 or period 2. Fewer than 20% of patients experienced any cravings over the 120 day study period. Importantly, the adverse effects observed were usually mild, with very few patients experiencing significant adverse effects. Conclusions: This study shows that buprenorphine/naloxone is an effective and well tolerated treatment for opioid withdrawal when the dosage is titrated to achieve good control of withdrawal symptoms. Switching from buprenorphine alone to buprenorphine/naloxone was possible with very little discomfort for the patient and effective retained patients in treatment.

( BUPP10344 - 17 June 2010) Safety and tolerability of the switch from buprenorphine to buprenorphine/naloxone in an Italian addiction treatment centre

Background: Abuse and misuse of pharmacological therapies represent major challenges in the healthcare system, particularly in patients receiving longacting opioid drugs for the treatment of heroin or opioid addiction. The partial mu opioid receptor agonist buprenorphine is used to treat opioid dependence, but diversion and misuse may occur. The sublingual combination formulation of buprenorphine and the opioid receptor antagonist naloxone (buprenorphine/naxolone) is associated with a reduced abuse potential, and has been shown to have promising efficacy for the treatment of opioid dependence. Objectives: This observational study assessed the safety and efficacy of sublingual buprenorphine/naloxone combination therapy in patients with opioid dependence after therapeutic switch from buprenorphine monotherapy. Methods: A total of 94 patients being treated with buprenorphine monotherapy (average dose 8 mg/day; mean duration of therapy 840 days) were switched to buprenorphine/naloxone combination therapy. Patients were asked to rate their level of satisfaction with buprenorphine/naloxone combination treatment with respect to the management of withdrawal symptoms, and urinary toxicology tests were carried out before and 14 days after switching to combination therapy. Results: Within 3 months, 75/94 patients (80%) previously treated with buprenorphine monotherapy had switched to sublingual buprenorphine/naloxone combination treatment (average dose buprenorphine 8 mg). Among patients receiving combination treatment for >3 months, 83% were receiving medication either weekly or fortnightly, based on the results of toxicological testing. A reduction in positive urinary toxicology tests was observed in patients within two weeks after being switched to combination treatment (before switch: 28, 9 and 2 positive tests for heroin, cocaine and heroin + cocaine, respectively vs 11, 3 and 1 after switch) and a total of 64 patients of the 75 who switched to combination therapy (85%) were satisfied with the management of withdrawal symptoms during buprenorphine/naloxone treatment. Few adverse events were reported and no patients dropped out of treatment. Conclusions: This study shows that switching from buprenorphine monotherapy to sublingual buprenorphine/naloxone combination therapy is effective and well tolerated, and associated with good control of withdrawal symptoms in the majority of patients. In addition, combination therapy reduced illicit drug use (based on negative urinary toxicology texts) and allowed the time between clinic visits to be increased.

( BUPP10343 - 17 June 2010) Clinical experience with fortnightly buprenorphine/naloxone versus buprenorphine in Italy: Preliminary observational data in an office based setting

Background and objective: Buprenorphine/naloxone is a new option for the management of opioid dependence. It has a reduced potential for abuse or misuse compared with methadone and buprenorphine alone, and has a long half life allowing less frequent dosing. Buprenorphine /naloxone appears to be well suited for the management of opioid dependence in an office based setting. The aim of this study was to evaluate the efficacy and safety of a buprenorphine/naloxone combination treatment in an office based setting. Therefore, we evaluated the effect on misuse/diversion, quality of care, quality of life and service delivery. Study design: Seventy eight patients were switched to buprenorphine/naloxone from either methadone or buprenorphine alone; the median duration of previous buprenorphine or methadone treatment was 10 years. Patients received buprenorphine /naloxone and were evaluated throughout a 1 year follow up period. Treatment was self administered by the patients every 2 weeks and the mean buprenorphine dosage at 1 year was 8mg/day. Comparisons were made before and after the switch for patients who switched from buprenorphine alone to buprenorphine/naloxone. Results: Switching to buprenorphine/naloxone was not associated with clinically relevant problems in 50% of patients studied. Buprenorphine/naloxone provided satisfactory coverage of withdrawal symptoms in 78.1% of patients, and 50% of patients were satisfied with buprenorphine/ naloxone therapy. Seventy eight per cent of patients reported improved psychosocial functioning. The majority of patients (approximately 85%) were negative for opioids during toxicological testing. A significantly higher proportion of treatment recipients were highly satisfied during buprenorphine/naloxone administration (p < 0.001 compared with buprenorphine given before the switch). Other outcomes were similar during buprenorphine and buprenorphine/naloxone administration. Fortnightly self administration of buprenorphine /naloxone appeared to be cost saving for the clinic. Conclusion: Buprenorphine/naloxone is an effective and safe treatment option for the outpatient management of opioid dependence.

( BUPP10342 - 17 June 2010) Taking care of drug addict in odontology

In the dental surgery practice, a drug addicted patient declares suffering from high pain and asks with insistency to be examined in emergency. The clinical examination shows a pity overall dental status: an important dental deterioration, a periodontal disease. At the end of the examination, the patient suffering withdrawal syndrome, asks with a high demand up to physical threat, to get a prescription of psychotropic medicines, and especially opiates (high dose buprenorphine). In front of this situation, the dental surgeon will face two aspects: first of all, clinical issues, as taking care of the odontological pathologies, management of the pain and of the withdrawal syndrome and second of all, the legislation issues related to its responsibility of prescription writer and the specific attitude to adjust in front of a patient with withdrawal syndrome at the dental surgery practice.

( BUPP10341 - 17 June 2010) Penile and scrotal skin necrosis after injection of crushed buprenorphine tablets

( BUPP10340 - 17 June 2010) Haemato biochemical response to buprenorphine or xylazine along with lignocaine for epidural analgesia in buffalo calves

The study was conducted in 15 healthy male buffalo calves to assess the safety of intercoccygeal epidural buprenorphine and xylazine in combination with lignocaine by estimating various haemato biochemical parameters. Epidural administration of lignocaine alone or along with buprenorphine caused nonsignificant changes in various haematological parameters whereas lignocaine with xylazine resulted in significant decrease in haemoglobin, packed cell volume, total leucocyte count, total erythrocyte count, lymphocytes and significant increase in neutrophil count in buffaloes. Serum glucose, urea nitrogen, creatinine, amino alaninetransferase and amino aspartate transferase increased significantly in animals of group C (lignocaine + xylazine) whereas a nonsignificant decrease in serum total protein was observed, however, in animals of group A (lignocaine alone) and group B (lignocaine + buprenorphine) increase was non significant. The increase in various haematological and biochemical parameters returned to base values within 24 h. Thus, epidural buprenorphine and xylazine along with local anaesthetic can be safely used in buffaloes as it caused transient haematobiochemical alterations, which attained normal physiological values within few hours.

( BUPP10339 - 17 June 2010) High rates of sustained virological response in hepatitis C virus infected injection drug users receiving directly observed therapy with peginterferon alpha 2a (40KD) (PEGASYS) and once daily ribavirin

This retrospective study evaluated the efficacy and tolerability of directly observed therapy with peginterferon alfa 2a and once daily ribavirin (RBV) for chronic hepatitis C in 49 opioid addicted injection drug users (IDUs) participating in a drug treatment program at a specialized outpatient center. Patients also received prophylactic citalopram to minimize the risk of interferon induced depression. Patients had daily access to and support from specialist physicians, nurses and counseling services at the center, and a 24 hour helpline. Sustained virological response was achieved by 48 of 49 patients (98%) overall, including 20 of 21(95%) hepatitis C virus (HCV) Genotype 1/4 infected patients and 28 of 28 (100%) Genotype 2 /3 infected patients. Treatment was well tolerated, and no unexpected side effects of peginterferon treatment were seen. The safety profile of once daily RBV was not different from twice daily dosing. Decline in hemoglobin levels was similar to those reported in clinical trials including once daily RBV and did not lead to dose reduction or treatment withdrawal. Our data demonstrate that HCV infected IDUs on stable L polamidone (methadone) or buprenorphine maintenance can be successfully and safely treated with peginterferon alfa 2a and RBV in an optimal substitution setting.

( BUPP10338 - 17 June 2010) Prospective comparative assessment of buprenorphine overdose with heroin and methadone: Clinical characteristics and response to antidotal treatment

Buprenorphine is a partial opioid agonist with a "ceiling effect" for respiratory depression. Despite this, it has been associated with severe overdoses. Conflicting data exist regarding its response in overdose to naloxone. We compared clinical overdose characteristics of buprenorphine with heroin and methadone and assessed responses to naloxone and flumazenil. Patients admitted to two intensive care units with severe opioid overdoses were enrolled into this 4 year prospective study. Urine and blood toxicological screening were performed to identify overdoses involving predominantly buprenorphine, heroin, or methadone. Eighty four patients with heroin (n = 26), buprenorphine (n = 39), or methadone (n = 19) overdoses were analyzed. In the buprenorphine group, sedative drug coingestions were frequent (95%), whereas in the methadone group, suicide attempts were significantly more often reported (p =.0007). Buprenorphine overdose induced an opioid syndrome not differing significantly from heroin and methadone in mental status (as measured by Glasgow Coma Score) or arterial blood gases. Mental status depression was not reversed in buprenorphine overdoses with naloxone (0.4 0.8 mg) but did improve with flumazenil (0.2 1 mg) if benzodiazepines were coingested. In conclusion, buprenorphine overdose causes an opioid syndrome clinically indistinguishable from heroin and methadone. Although mental status and respiratory depression are often unresponsive to low dose naloxone, flumazenil may be effective in buprenorphine overdoses involving benzodiazepines.

( BUPP10370 - 24 June 2010) The pharmacological treatment of opioid addiction-a clinical perspective

This article reviews the main pharmacotherapies that are currently being used to treat opioid addiction. Treatments include detoxification using tapered methadone, buprenorphine, adrenergic agonists such as clonidine and lofexidine, and forms of rapid detoxification. In opioid maintenance treatment (OMT), methadone is most widely used. OMT with buprenorphine, buprenorphine-naloxone combination, or other opioid agonists is also discussed. The use of the opioid antagonists naloxone (for the treatment of intoxication and overdose) and oral and sustained-release formulations of naltrexone (for relapse prevention) is also considered. Although recent advances in the neurobiology of addictions may lead to the development of new pharmacotherapies for the treatment of addictive disorders, a major challenge lies in delivering existing treatments more effectively. Pharmacotherapy of opioid addiction alone is usually insufficient, and a complete treatment should also include effective psychosocial support or other interventions. Combining pharmacotherapies with psychosocial support strategies that are tailored to meet the patients' needs represents the best way to treat opioid addiction effectively.

( BUPP10369 - 24 June 2010) Total intravenous anesthesia with propofol and S(+)-ketamine in rabbits

OBJECTIVE: To evaluate total intravenous anesthesia with propofol alone or in combination with S(+)-ketamine in rabbits undergoing surgery. STUDY DESIGN: Prospective, randomized, blinded trial. ANIMALS: Nine 6-month-old New Zealand white rabbits, weighing 2.5-3 kg. METHODS: Animals received acepromazine (0.1 mg kg(-1)) and buprenorphine (20 microg kg(-1)) IM, and anesthesia was induced with propofol (2 mg kg(-1)) and S(+)-ketamine (1 mg kg(-1)) IV. Rabbits received two of three treatments: propofol (0.8 mg kg(-1) minute(-1)) (control treatment, P), propofol (0.8 mg kg(-1) minute(-1)) + S(+)- ketamine (100 microg kg(-1) minute(-1)) (PK100) or propofol (0.8 mg kg(-1) minute(-1)) + S(+)-ketamine (200 microg kg(-1) minute(-1)) (PK200). All animals received 100% O(2) during anesthesia. Heart rate, mean arterial pressure, hemoglobin oxygen saturation and respiratory rate were measured every 5 minutes for 60 minutes. Blood-gas parameters were measured at zero time and 60 minutes. Additional propofol injections, if necessary, and recovery time were recorded. RESULTS: An increase in heart rate was observed in P and PK200 up to 10 minutes after induction of anesthesia. Blood pressure decreased from baseline values during the first 10 minutes in P and PK200, and during the first 15 minutes and between 45 and 55 minutes in PK100. A reduction in respiratory rate was observed after 5 minutes in all treatments. Respiratory acidosis was observed in all treatments. Six (2.8) (median (interquartile range)) further propofol injections were necessary in P, which differed statistically from PK100 (1 (0.2)) and PK200 (2 (0.6)). Recovery time was shorter in P compared with PK100 and PK200, being (7.5 minutes (4.11)), (17.5 minutes (10.30)), and (12 minutes (10.30)), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: S(+)-ketamine potentiates propofol-induced anesthesia in rabbits, providing better maintenance of heart rate. All of these techniques were accompanied by clinically significant respiratory depression.

( BUPP10368 - 24 June 2010) Combination of dexmedetomidine with buprenorphine enhances the antinociceptive effect to a thermal stimulus in the cat compared with either agent alone

OBJECTIVE: To evaluate the sedative and antinociceptive effects of combinations of dexmedetomidine and buprenorphine in cats. STUDY DESIGN: Experimental randomized study. ANIMALS: Twelve purpose-bred neutered domestic short-hair cats (4 male and 8 female) weighing 4.6 kg (range 3.7-5.5 kg) aged from 2 to 5 years. METHODS: Six cats per group were administered buprenorphine (B) at 10 (B10) or 20 microg kg (-1) (B20) or dexmedetomidine (D) at 20 (D20) or 40 microg kg(-1) (D40) or a combination of B10/D20. A feline thermal nociceptive threshold testing device was used to evaluate the antinociceptive effects of the drugs before and up to 24 hours after drug treatment. Sedation was scored using a 100 mm visual analogue scale (VAS). RESULTS: Thermal thresholds increased significantly after administration of all but D20. Area under the curve (AUC, hours degrees C) for the first 6 hours (mean +/- SD) for B20 (281 +/- 17.8) was significantly greater than B10 (260 +/- 11.4), D20 (250 +/- 7.9) and D40 (255 +/- 11.4). The AUC for B10/D20 (273 +/- 12.2) was significantly greater than D20 but not the other treatments. No sedation was seen after administration of B10 or B20 and maximal sedation was seen for all animals in the D40 and B10/D20 groups and most animals in the D20 group. CONCLUSIONS: D20 alone had the smallest analgesic effect; B10 alone provided no sedation but their combination gave good sedation with analgesia comparable with B20. CLINICAL RELEVANCE: This combination could be a useful multimodal sedative/analgesic regimen in cats.

( BUPP10367 - 24 June 2010) Clinic-based treatment of opioid-dependent HIV-infected patients versus referral to an opioid treatment program: A randomized trial

BACKGROUND: Opioid dependence is common in HIV clinics. Buprenorphine-naloxone (BUP) is an effective treatment of opioid dependence that may be used in routine medical settings. OBJECTIVE: To compare clinic-based treatment with BUP (clinic-based BUP) with case management and referral to an opioid treatment program (referred treatment). DESIGN: Single-center, 12-month randomized trial. Participants and investigators were aware of treatment assignments. (ClinicalTrials.gov registration number: NCT00130819) SETTING: HIV clinic in Baltimore, Maryland. PATIENTS: 93 HIV-infected, opioid-dependent participants who were not receiving opioid agonist therapy and were not dependent on alcohol or benzodiazepines. INTERVENTION: Clinic-based BUP included BUP induction and dose titration, urine drug testing, and individual counseling. Referred treatment included case management and referral to an opioid-treatment program. MEASUREMENTS: Initiation and long-term receipt of opioid agonist therapy, urine drug test results, visit attendance with primary HIV care providers, use of antiretroviral therapy, and changes in HIV RNA levels and CD4 cell counts. RESULTS: The average estimated participation in opioid agonist therapy was 74% (95% CI, 61% to 84%) for clinic-based BUP and 41% (CI, 29% to 53%) for referred treatment (P < 0.001). Positive test results for opioids and cocaine were significantly less frequent in clinic-based BUP than in referred treatment, and study participants receiving clinic-based BUP attended significantly more HIV primary care visits than those receiving referred treatment. Use of antiretroviral therapy and changes in HIV RNA levels and CD4 cell counts did not differ between the 2 groups. LIMITATION: This was a small single-center study, follow-up was only moderate, and the study groups were unbalanced in terms of recent drug injections at baseline. CONCLUSION: Management of HIV-infected, opioid-dependent patients with a clinic-based BUP strategy facilitates access to opioid agonist therapy and improves outcomes of substance abuse treatment. PRIMARY FUNDING SOURCE: Health Resources and Services Administration Special Projects of National Significance program. Grant ID: K01AI071754, Acronym: AI, Agency: NIAID NIH HHS, United States Grant ID: K23DA015616, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: K24DA000432, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01AA016893, Acronym: AA, Agency: NIAAA NIH HHS, United States Grant ID: R01DA011602, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01DA018577, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01DA019511, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01DA020576, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01DA025991, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: UL1 RR 025005, Acronym: RR, Agency: NCRR NIH HHS, United States

( BUPP10366 - 24 June 2010) Drug testing in oral fluid

Over the last decade there have been considerable developments in the use of oral fluid (saliva) for drug testing. Oral fluid can provide a quick and non-invasive specimen for drug testing. However, its collection may be thwarted by lack of available fluid due to a range of physiological factors, including drug use itself. Food and techniques designed to stimulate production of oral fluid can also affect the concentration of drugs. Current applications are mainly focused on drugs of abuse testing in employees at workplaces where drug use has safety implications, in drivers of vehicles at the roadside and in other situations where drug impairment is suspected. Testing has included alcohol (ethanol) and a range of clinical tests eg antibodies to HIV, therapeutic drugs and steroids. Its main application has been for testing for drugs of abuse such as the amphetamines, cocaine and metabolites, opioids such as morphine, methadone and heroin, and for cannabis. Oral fluid concentrations of basic drugs such as the amphetamines, cocaine and some opioids are similar or higher than those in plasma. Tetrahydrocannabinol (THC), the major species present from cannabis use, displays similar concentrations in oral fluid compared to blood in the elimination phase. However, there is significant local absorption of the drug in the oral cavity which increases the concentrations for a period after use of drug. Depot effects occur for other drugs introduced into the body that allow local absorption, such as smoking of tobacco (nicotine), cocaine, amphetamines, or use of sub-lingual buprenorphine. Screening techniques are usually an adaptation of those used in other specimens, with an emphasis on the parent drug since this is usually the dominant species present in oral fluid. Confirmatory techniques are largely based on mass spectrometry (MS) with an emphasis on Liquid Chromatography-Mass Spectrometry (LC-MS), due to low sample volumes and the low detection limits required. Drug testing outside laboratory environments has become widespread and provides presumptive results within minutes of collection of specimens. This review focuses on the developments, particularly over the last 10 years, and outlines the roles and applications of testing for drugs in oral fluid, describes the difficulties associated with this form of testing and illustrates applications of oral fluid testing for specific drugs.

( BUPP10365 - 24 June 2010) Medication helps make therapy work for teens addicted to prescription opioids

( BUPP10364 - 24 June 2010) Opioid antagonists for smoking cessation

Background: The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. Objectives: To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longeracting opioid antagonist naltrexone. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in June 2009. We also contacted investigators, when possible, for information on unpublished studies. Selection criteria: We considered randomized controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psychobiological mediating variables associated with nicotine dependence. Data collection and analysis: We extracted data in duplicate on the type of study population, the nature of the drug therapy, the outcome measures, method of randomization, and completeness of follow up. The main outcome measure was cotinine- or carbon monoxide-verified abstinence from smoking after at least six months follow up in patients smoking at baseline. Where appropriate, we performed meta-analysis using a fixed-effect model (Mantel-Haenszel odds ratios). Main results: Four trials of naltrexone met inclusion criteria for meta-analyses for long-term cessation. All four trials failed to detect a significant difference in quit rates between naltrexone and placebo. In a pooled analysis there was no significant effect of naltrexone on longterm abstinence, and confidence intervals were wide (odds ratio 1.26, 95% confidence interval 0.80 to 2.01). No trials of naloxone or buprenorphine reported long-term follow up. Authors' conclusions: Based on limited data from four trials it is not possible to confirm or refute whether naltrexone helps people who smoke, to quit. The confidence intervals are compatible with both clinically significant benefit and possible negative effects of naltrexone in promoting abstinence. Data from larger trials of naltrexone are needed to settle the question of efficacy for smoking cessation.

( BUPP10363 - 24 June 2010) Opioid antagonists with minimal sedation for opioid withdrawal

Background: Managed withdrawal is a necessary step prior to drug-free treatment or as the end point of long-term substitution treatment. Objectives: To assess the effectiveness of opioid antagonists in combination with minimal sedation to manage opioid withdrawal. Search strategy: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2008), MEDLINE (January 1966 to July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. Selection criteria: Controlled studies of interventions involving the use of opioid antagonists in combination withminimal sedation tomanage withdrawal in opioid-dependent participants compared with other approaches or different opioid antagonist regimes. Data collection and analysis: One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors. Main results: Nine studies (6 randomised controlled trials), involving 837 participants, met the inclusion criteria for the review. The quality of the evidence is low, but suggests that withdrawal induced by opioid antagonists in combination with an adrenergic agonist is more intense than withdrawal managed with clonidine or lofexidine alone, while the overall severity is less. Delirium may occur following the first dose of opioid antagonist, particularly with higher doses (> 25mg naltrexone). In some situations antagonist-induced withdrawal may be associated with significantly higher rates of completion of treatment, comp(ared to withdrawal managed primarily with adrenergic agonists. However, this outcome has not been produced consistently, and the extent of any benefit is highly uncertain. Authors' conclusions: The use of opioid antagonists combined with alpha2-adrenergic agonists is a feasible approach to themanagement of opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist. A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium. Further research is required to confirmthe relative effectiveness of antagonist-induced regimes, aswell as variables influencing the severity of withdrawal, adverse effects, the most effective antagonist-based treatment regime, and approaches that might increase retention in subsequent naltrexone maintenance treatment.

( BUPP10362 - 24 June 2010) Buprenorphine for cancer pain

( BUPP10361 - 24 June 2010) New frontiers in alcoholism and addiction treatment

Drug addiction and alcoholism are behavioural disorders characterized by a profound alteration of several brain circuits induced by chronic drug use. Their treatment is yet based on empiricism and today only few pharmacological strategies are fully effective to control both drug use and relapse. The present paper reviews the most updated pharmacotherapies able to contrast both alcoholism and drug addiction including the new patented drugs and the future therapeutic trends.

( BUPP10359 - 24 June 2010) Pharmacological management of pain in older persons

Objective: Evaluate the efficacy and safety of pharmacological pain management treatments to minimize adverse events and optimize pain relief. Data Sources: Symposium presentation based on clinical practice and research and current clinical guidelines. Conclusions: Pain is a common problem among elderly long-term care residents and is vastly undertreated. Even when pain medication is prescribed, often residents do not receive the most appropriate drug, or prescribers fail to adjust the dose and frequency of administration to tailor therapy to the individual's compromised physiology and needs. This places elders at risk, for not only unnecessary suffering, but also for drug toxicity. Consultant pharmacists are in a key position to identify underuse and inappropriate use of analgesic drugs and assist prescribers with individualizing each resident's medication regimen to provide optimal therapeutic outcomes.

( BUPP10358 - 24 June 2010) Pharmacogenetics of drug dependence: Role of gene variations in susceptibility and treatment

Drug dependency is a highly prevalent mental health disorder that imposes a significant burden on those directly affected, health care systems, and society in general. There is substantial heritability in the susceptibility to drug addiction, which indicates that there are genetic risk factors. Variation in the human genome is abundant and can directly affect drug dependency phenotypes, for example, by altering the function of a gene product or by altering gene expression. Pharmacogenetic studies can assess the effects of genetic variation on the risk for a particular phenotype (e.g., being an alcoholic). In addition, pharmacogenetic variability in treatment efficacy and adverse reactions can be investigated to identify particular genetic variants associated with altered responses. This review highlights examples of genetic variations that are important in the development and maintenance of specific drug dependencies as well as those that affect the response to treatment.

( BUPP10357 - 24 June 2010) Empirical view of opioid dependence

BACKGROUND: The impact of opioid dependence on employers, managed care, and society is significant. Inappropriate use of narcotic analgesics leads to uncontrolled pain management, dependence, and may lead to patient deaths, creating a tremendous cost burden to the health care system. OBJECTIVE: To provide an overview of the clinical and economic impact of treating opioid dependence on managed care, employers, and society. SUMMARY: An estimated 6% to 15% of people in the United States abuse drugs, and approximately 20% of Americans report using prescription opioids for nonmedical use. This is associated with an annual cost of nearly half a trillion dollars, taking into account the medical, economic, social, and criminal impact of this abuse. A recent study showed that patients who abuse opioids generate mean annual direct health care costs 8.7 times higher than nonabusers. The National Survey on Drug Use and Health (NSDUH), conducted by the Substance Abuse and Mental Health Services Administration (SAMHSA), found that patients who report opioid abuse miss more than 2.2 days of work monthly, compared with the 0.83 days per month reported for the average person. Presenteeism and productivity are also affected by misuse and dependence on opioids. CONCLUSION: The costs associated with opioid dependence are significant. Physicians, employers, and managed care organizations must be proactive in appropriately diagnosing and treating patients who suffer from substance abuse disorders in order to lessen this economic burden.

( BUPP10356 - 24 June 2010) Patient perspective, complexities, and challenges in managed care

BACKGROUND: Lack of coordination of care is one of the largest obstacles involved with treating opioid dependence. Physicians also face the challenges of managing comorbidities and dealing with relapse. OBJECTIVE: To examine the clinical, economic, and humanistic factors involved in treating opioid dependence. SUMMARY: Despite the extensive utilization of narcotic analgesics, pain is often uncontrolled. Effective pain management and coordination of care is essential in treating pain patients, as patients who abuse pain medications consume more health care resources than nonabusers. Patients who abuse are 2.3 times more likely to present at the emergency department and 6.7 times more likely to be hospitalized than nonabusers. Managed care organizations are now incorporating integrated approaches to treating pain and substance abuse disorders, realizing that patients must be looked at as a whole, considering alternative and behavioral therapies in addition to pharmacological treatments. They are also able to assess patterns of abuse using pharmacy claims data and alert physicians to potential problems by making use of prescription monitoring programs. Physicians who treat chronic pain must utilize strategies to minimize the risk of developing dependence on opioids, and practitioners treating opioid dependence must employ policies to optimize outcomes. Such strategies include developing pain contracts; performing random urine screenings and pill counts; and setting goals of therapy and re-evaluating patients throughout treatment. Plans must be in place in the event of relapse, as well. CONCLUSION: In order to be successful in managing opioid dependence, physicians, employers, and managed care organizations must work together to provide an integrated approach to treatment.

( BUPP10355 - 24 June 2010) Practice strategies to improve compliance and patient self-management.

BACKGROUND: Failure in treating opioid dependence is costly to the patient, the employer, managed care organizations, and the overall health care system. Opioid dependent patients tend to be less productive at work and in society and utilize a great many health care resources. Optimizing outcomes is essential. OBJECTIVE: To introduce the benefit of integrated strategies and patient support in the treatment of opioid dependence. SUMMARY: Health Analytics is currently studying the benefit of HereToHelp, a behavioral support program in which registered nurses or addiction treatment counselors with specialized training in addiction education provide information and encouragement to patients receiving pharmacologic treatment for opioid dependence. A total of 470 physicians in 41 states have been enlisted to participate in this patient support study. The study hypothesis is that patients who receive behavioral support and encouragement will be more compliant with their opioid replacement therapy, leading to better outcomes. Additional treatment strategies are also being developed to minimize the risk of abuse and diversion. Prodrugs and vaccines are also being investigated. CONCLUSION: A coordinated team approach is essential in treating pain patients and opioid-dependent patients. Offering behavior modification in addition to pharmacotherapy and utilizing strategies such as prescription monitoring programs, pain contracts, and screening are all vital components necessary for positive outcomes.

( BUPP10354 - 24 June 2010) (All methadone therapy must be safer)

( BUPP10353 - 24 June 2010) Symposium report "Modern substitution therapy"

( BUPP10381 - 01 July 2010) Developing of LC/MS method with microwave assisted extraction for determination of methadone and it major metabolite (EDDP) in the blood of patients of methadone maintenance treatment

Opium derivatives as the addictive substances cause many medical and social problems. In treatment of opiates addiction except psychotherapy a long time pharmacotherapy with methadone or buprenorphine are apply. In a recent study both moderate- and high- dose methadone treatment resulted in reductions in illicit opioid use. The aim of the study was develop fast high sensitive liquid chromatography coupled with mass spectrometry for determination of methadone and EDDP after microwave assisted extraction. Developed method for methadone and EDDP determination were linear over the range 5 to 1000 ng/ml for methadone and its metabolite. The method exhibit a good intra and inter day precision, the microwave assisted extraction was also satisfactory with recovery superior to 80%. The mean concentration of methadone in plasma of patients receiving 40 mg of drug per day was 194 ng/ml but in second group (receiving 90 mg of methadone/day) 263 ng/ml. The ratio of the doses was 2.25 but for methadone concentration only 1.36. The much higher ratio (3.25) of concentrations was noticed for EDDP. This observation can support opinion other authoress about polymorphism of methadone pharmacokinetics and pharmacodynamics.

( BUPP10380 - 01 July 2010) A prospective multi-centre clinical trial to compare buprenorphine and butorphanol for postoperative analgesia in cats

One hundred and fifty-three cats undergoing surgery in seven veterinary practices in Great Britain were studied. They were randomly allocated to receive either 10-20 microg/kg buprenorphine or 0.4 mg/kg butorphanol with acepromazine before anaesthesia with propofol, Saffan or thiopentone and isoflurane or halothane. Routine monitoring was undertaken. Pain and sedation were assessed blind using a four point (0-3) simple descriptive scale (SDS) at 1, 2, 4, 8 and 24h. Pain and sedation data were compared using non-parametric statistical tests and continuous data using t tests or analysis of variance (ANOVA). Anaesthesia and surgery were uneventful, and cardiorespiratory data were within normal limits. After surgery, overall, more cats had pain score 0 after buprenorphine and more had pain score 3 after butorphanol (P=0.0465). At individual time points, more cats had lower pain scores after buprenorphine at 2 (P=0.040) and 24 (P=0.036)h. At 24h 83% after buprenorphine and 63% after butorphanol had pain score 0 (P<0.04). Buprenorphine provided better and longer lasting postoperative analgesia than butorphanol.

( BUPP10379 - 01 July 2010) On deriving the dose-effect relation of an unknown second component: An example using buprenorphine preclinical data

Buprenorphine, like many other drugs, displays a biphasic dose-response relation ('hormesis'), viz., its antinociceptive effect in some preclinical models increases up to some dose level (often achieving 100% effect) and decreases at high-doses. A decreasing component was evident in the tail-flick tests described here, occurring in both the mouse and the rat. While the mechanism of dose-related decline in antinociceptive effect, when observed, might be related to nociceptin/orphanin-FQ, the precise mechanism remains unknown. Regardless of the mechanism, the values of this dose-related decline yield data that can be used to calculate the dose-effect relation of the decreasing (unknown second) component. The calculation, which uses the same concept of dose equivalence that underlies additivity in isobolographic analysis, was employed here from tail-flick data obtained in mouse and rat. The derived dose-effect curves of the second component, though differing in efficacy between mouse and rat, displayed a very notable similarity. This novel technique offers possible insight into the dual low-dose (analgesic), high-dose (addiction medication) uses of buprenorphine.

( BUPP10378 - 01 July 2010) Acute Pancreatitis part 1: Approach to Early Management

( BUPP10377 - 01 July 2010) Characterization and classification of matrix effects in biological samples analyses

An exhaustive classification of matrix effects occurring when a sample preparation is performed prior to liquid-chromatography coupled to mass spectrometry (LC-MS) analyses was proposed. A total of eight different situations were identified allowing the recognition of the matrix effect typology via the calculation of four recovery values. A set of 198 compounds was used to evaluate matrix effects after solid phase extraction (SPE) from plasma or urine samples prior to LC-ESI-MS analysis. Matrix effect identification was achieved for all compounds and classified through an organization chart. Only 17% of the tested compounds did not present significant matrix effects.

( BUPP10376 - 01 July 2010) Quantitative prediction of regioselectivity toward cytochrome P450/3A4 using machine learning approaches

In the drug discovery process, it is important to know the properties of both drug candidates and their metabolites. Fast and precise prediction of metabolites is essential. However, it has been difficult to predict metabolites because of the complexity of the mechanism of cytochrome P450/3A4 (CYP 3A4), which is the main metabolite enzyme of drugs. In this study, we focus on the regioselectivity of CYP 3A4, i.e., the selectivity of metabolic sites. We have developed a model to predict the regioselectivity of drug candidates by using machine learning (ML) approaches.

( BUPP10375 - 01 July 2010) European perspectives on upcoming analgesics: What do they have that we don't - and what do they think about them?

Regulatory climate, medical culture, and history have created geographic distinctions in analgesics. In particular, Europe has experience with many commercially available analgesics that have recently been introduced or may soon be introduced to the USA market. The authors selected 4 analgesics widely used in Europe that may be less familiar to American clinicians: transdermal buprenorphine, essential oxygen oil, tapentadol ER, and intravenous diclofenac. These agents are far from the only such agents worthy of consideration but were selected as they range from a new formulation for a familiar drug, an over-the-counter topical product, an oral opioid, and a very popular nonsteroidal anti-inflammatory agent. The clinical studies performed on these agents can help inform physician prescribing choices, when these drugs are available in the USA.

( BUPP10374 - 01 July 2010) Robust, unbiased general linear model estimation of phMRI signal amplitude in the presence of variation in the temporal response profile

Purpose: To determine a simple yet robust method to generate parsimonious design matrices that accurately estimate the "pharmacological MRI" (phMRI) response amplitude in the presence of both confounding signals and variability in temporal profile. Variability in the temporal response profile of phMRI time series data is often observed. If not properly accounted for, this variation can result in inaccurate and unevenly biased signal amplitude estimates when modeled within a general linear model (GLM) framework. Materials and Methods: The approach uses a low-rank singular value decomposition (SVD) approximation to a set of vectors capturing anticipated variations of no interest around the signal model to generate additional regressors for the design matrix. The method is demonstrated for both plateau and bolus type phMRI response profiles in the presence of variation in signal onset and/or shape, and applied to an in vivo blood oxygenation level-dependent (BOLD) phMRI study of buprenorphine in healthy human subjects. Results: In general, 2-3 additional regressors, capturing >75% of the anticipated variance, resulted in robust and unbiased signal amplitude estimates in the presence of substantial variability. Conclusion: This method provides a simple and flexible means to provide robust phMRI amplitude estimates within a GLM framework.

( BUPP10373 - 01 July 2010) Oropharyngeal Mucositis Pain Treatment with Transdermal Buprenorphine in Patients After Allogeneic Stem Cell Transplantation

( BUPP10372 - 01 July 2010) Transdermal analgesics: Advantages compared to oral pain therapy?

( BUPP10371 - 01 July 2010) Cancer pain: Therapy according to the pain relief ladder

( BUPP10409 - 22 July 2010) Effect of dexamethasone on postoperative symptoms in patients undergoing elective laparoscopic cholecystectomy: randomized clinical trial

BACKGROUND: Dexamethasone has been reported to reduce postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy (LC). However, its effects on other surgical outcomes, such as pain and fatigue, have been unclear. We evaluated the efficacy of preoperative dexamethasone for ameliorating postoperative symptoms after LC. METHODS: In this prospective, double-blind, placebo-controlled study, 210 patients scheduled for elective LC were analyzed after randomization to intravenous dexamethasone (8 mg) or a placebo. All patients underwent standardized procedures for general anesthesia and surgery. Episodes of PONV and the pain and fatigue scores were recorded on a visual analog scale. Analgesic and antiemetic requirements were also recorded. RESULTS: There were no significant differences between groups with regard to medical or demographic variables. Significantly fewer patients experienced PONV in the dexamethasone group immediately after LC and at 6 and 12 h. The need for ondansetron to relieve PONV was higher in the placebo group (P = 0.001). Patients in the study group reported less postoperative pain during the first 24 h and less fatigue after 6, 12, and 24 h. The need for buprenorphine to relieve intolerable pain was also less in this group (P = 0.009). There were no side effects, and the morbidity similar in the two groups (6.7 vs. 7.6%). CONCLUSIONS: The regimen we employed is safe and without apparent side effects. Thus, preoperative dexamethasone can significantly reduce the incidence of PONV, pain and fatigue after elective LC.

( BUPP10408 - 22 July 2010) (Necrosis of the glans penis: a complication of an injection of buprenorphin in a opioid abuser)

Necrosis of the penis glans is commonly described after circumcision or strangulation. We report the case of a patient, opioid abuser, who presented an isolated glans necrosis after an injection of buprenorphin. The buprenorphin (Subutex) is a sublingual partial mu-opioid agonist used for the treatment of heroin dependance. Its intravenous or subcutaneous abuse is associated with local infection. The patient require a surgical intervention. After the failure of a mucosal graft, a soft skin graft was done.

( BUPP10407 - 22 July 2010) Approaches to Improve Pain Relief While Minimizing Opioid Abuse Liability

Two strategies should greatly improve pain management while minimizing opioid abuse. The first strategy involves the systematic implementation in every clinical practice of "universal precautions, " a set of procedures that help physicians implement opioid therapy in a safe and controlled manner. These procedures include: 1) carefully assessing the patient's risk for opioid abuse; 2) selecting the most appropriate opioid therapy; 3) regularly monitoring the patient to evaluate the efficacy and tolerability of the treatment and to detect possible aberrant behaviors; and 4) mapping out solutions if abuse and/or addiction is detected, or in case of treatment failure. The second strategy involves the use of opioid formulations designed to deter or prevent product tampering and abuse. Results of clinical trials of new formulations of existing opioids (including oxycodone, morphine, and hydromorphone) suggest the potential for reduced abuse liability and, if approved, will be evaluated after launch for reduced real-world abuse. Integration of these formulations in clinical practices based on universal precautions should help further minimize the risk of opioid abuse while fostering appropriate prescribing to patients with indications for opioid therapy. Perspective: Undertreated pain and prescription opioid abuse remain important public health problems. In the absence of strong empirical evidence, common sense dictates that a universal-precautions approach-a systematic and easily adopted process that clinicians can quickly put into practice-is advised to promote safe opioid prescribing. Abuse- and tamper-resistant opioid formulations are emerging tools that may enhance safe opioid prescribing; further research and postmarketing analysis will clarify their utility and role in clinical practice.

( BUPP10406 - 22 July 2010) Pain in cancer patients: Summary results of a five-years project

Aims. To promote an increase knowledge on cancer pain and start initiatives to improve quality of care and patient's outcomes. Methods. A series of activities were launched between 2003 and 2008 including: 1) systematic literature review in order to acquire information necessary to plan and carry out research and training activities; 2) meetings, workshops and training sessions with stakeholders; 3) design and conduct of a prospective epidemiological study to collect empirical information on the epidemiology, quality of care and outcomes of cancer pain management in Italy. Results. This article presents the results of the 3 systematic reviews conducted to study the undertreatment, the prevalence of breakthrough pain and effectiveness of transdermal buprenorphine in patients with cancer pain. It also describes the main results of prospective epidemiological study and introduces the ongoing RCT. Conclusion. On the basis of results archived, a RCT will be hunched to compare the effectiveness of 4 strong opioids. The trial will include 80 centers and about 1000 patients.

( BUPP10405 - 22 July 2010) Paradigm shift in pain therapy - New concepts versus old WHO stage scheme

( BUPP10403 - 22 July 2010) Efficacy of sedation in outpatient procedures performed by pediatric residents.

Objective. To determine the efficacy of sedation in outpatient procedures performed by Pediatric Residents. Material and methods. Observational, analytic, cross-sectional study in patients that require diagnostic and therapeutic procedures. Data were collected during the period between June 01 and September 2007 in the Pediatrics Department. Patients from 1 month to 15 years of age that required sedation were included. Results. 97 sedations were carried out, with an average age of 3.5years. 59.3% were males and 40.7% were females. 100% of the procedures were carried out with 12.3% adverse effects. Conclusions. The procedures were done successfully; the pediatric residents demonstrated the required preparation for sedating and reverting adverse effects

( BUPP10402 - 22 July 2010) Palliative and end-of-life care in advanced renal failure

( BUPP10401 - 22 July 2010) Estimation of illicit drugs consumption by wastewater analysis in Paris area (France)

Illicit drugs consumption is actually an important public health concern that needs to be well defined to be managed. A new method, expressed as sewage epidemiology has been proposed by Daughton and developed by Zuccato. This method involves estimating the consumption from the measurement of drug residues in sewage. Several studies have been carried out, leading to an assessment of drugs consumption in some European countries. This work, carried out in Paris area (France) brings new data to this assessment and allows a comparison of cocaine and MDMA consumptions with European estimations. Four wastewater treatment plants (WWTPs) have been retained for the study, taking into account biological treatment, volume capacity, geographic location and social environment. Cocaine and its major metabolite benzoylecgonine (BZE), amphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and buprenorphine were measured in raw water and WWTP effluent using HPLC-MS/MS after SPE extraction. Amphetamine was rarely detected. Cocaine and BZE were quantified at levels from 5 to 282 ng L-1 and 15 to 849 ng L-1, respectively. MDMA and buprenorphine concentrations remained under 20 ng L-1. Cocaine consumption was estimated from cocaine or BZE concentrations measured in raw water and the results showed significant difference in drug taking during week or weekend. The estimated doses observed in this study are lower than those reported for others countries, especially Spain and Italy. MDMA consumption was estimated at lower levels than cocaine.

( BUPP10400 - 08 July 2010) Principes de la Therapeutique et des prises en charge en addictologie

( BUPP10399 - 06 July 2010) Opiaces: epidemiologie, etiologie et clinique

( BUPP10398 - 06 July 2010) Outils d'evaluation pour les troubles addicifs

( BUPP10397 - 06 July 2010) Relationship between anxiety disorders and opiate dependence - A systematic review of the literature: Implications for diagnosis and treatment

Our objective was to evaluate the prevalence and temporal sequence of co-occurrence of anxiety disorders with opiate dependence in order to better define the relationship between these two disorders and to improve diagnosis and treatment. The search used Medline and Toxibase up to January 1, 2009, and was based on a systematic review method. Eighteen studies ere found. Prevalence of anxiety disorders assessed by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria was high in opiate-dependent treated persons (lifetime prevalence ranged from 26% to 35%). Among anxiety disorders, phobic disorders have been shown to often precede the onset of opiate dependence. The identification of substance-induced versus independent anxiety disorder has important treatment implication. The monitoring of anxiety symptoms after several weeks of abstinence may allow physicians to determine the relationship between dependence and anxiety and make a reliable diagnosis of any initial anxious disorder. Specific management of anxiety disorder may then be used.

( BUPP10396 - 06 July 2010) Drug Policy and the Public Good: A summary of the book

Drug Policy and the Public Good was written by an international group of scientists from the fields of addiction, public health, criminology and policy studies to improve the linkages between drug research and drug policy. The book provides a conceptual basis for evidence-informed drug policy and describes epidemiological data on the global dimensions of drug misuse. The core of the book is a critical review of the cumulative scientific evidence in five general areas of drug policy: primary prevention programmes in schools and other settings: health and social services for drug suers: attempts to control the supply of drugs, including the international treaty system: ; lay enforcement and ventures into decriminalisation; and control of the psychotropic substance market through prescription drug regimes. The final chapters discuss the current state of drug policies in different parts of the world and describe the need for future approaches to drug policy that are coordinated and informed by evidence.

( BUPP10395 - 06 July 2010) Sex differences in opioid analgesia, hyperalgesia, tolerance and withdrawal: Central mechanisms of action and roles of gonadal hormones

This article reviews sex differences in opiate analgesic and related processes as part of a Special Issue in Hormones and Behavior. The research findings on sex differences are organized in the following manner: (a) systemic opioid analgesia across mu, delta and kappa opioid receptor subtypes and drug efficacy at their respective receptors, (b) effects of the activational and organizational roles of gonadal steroid hormones and estrus phase on systemic analgesic responses, (c) sex differences in spinal opioid analgesia, (d) sex differences in supraspinal opioid analgesia and gonadal hormone effects, (e) the contribution of genetic variance to analgesic sex differences, (f) sex differences in opioid-induced hyperalgesia, (g) sex differences in tolerance and withdrawal-dependence effects, and (h) implications for clinical therapies.

( BUPP10394 - 06 July 2010) Mixing pleasures: Review of the effects of drugs on sex behavior in humans and animal models

Drugs of abuse act on the brain circuits mediating motivation and reward associated with natural behaviors. There is ample evidence that drugs of abuse impact male and female sexual behavior. First, the current review discusses the effect of drugs of abuse on sexual motivation and performance in male and female humans. In particular, we discuss the effects of commonly abused drugs including psychostimulants, opiates, marijuana/THC, and alcohol. In general, drug use affects sexual motivation, arousal, and performance and is commonly associated with increased sexual risk behaviors. Second, studies on effects of systemic administration of drugs of abuse on sexual behavior in animals are reviewed. These studies analyze the effects on sexual performance and motivation but do not investigate the effects of drugs on risk-taking behavior, creating a disconnect between human and animal studies. For this reason, we discuss two studies that focus on the effects of alcohol and methamphetamine on inhibition of maladaptive sex-seeking behaviors in rodents. Third, this review discusses potential brain areas where drugs of abuse may be exerting their effect on sexual behavior with a focus on the mesolimbic system as the site of action. Finally, we discuss recent studies that have brought to light that sexual experience in turn can affect drug responsiveness, including a sensitized locomotor response to amphetamine in female and male rodents as well as enhanced drug reward in male rats.

( BUPP10393 - 06 July 2010) Recent advances in the use of opioids for cancer pain

Opioids are the mainstay of treatment for moderate to severe cancer pain. In recent years there have been many advances in the use of opioids for cancer pain. Availability and consumption of opioids have increased and opioids other than morphine (including methadone, fentanyl, oxycodone) have become more widely used. Inter individual variation in response to opioids has been identified as a significant challenge in the management of cancer pain. Many studies have been published demonstrating the benefits of opioid switching as a clinical maneuver to improve tolerability. Constipation has been recognized as a significant burden in cancer patients on opioids. Peripherally restricted opioid antagonists have been developed for the prevention and management of opioid induced constipation. The phenomenon of breakthrough pain has been characterized and novel modes of opioid administration (transmucosal, intranasal, sublingual) have been explored to facilitate improved management of breakthrough cancer pain. Advances have also been made in the realm of molecular biology. Pharmacogenetic studies have explored associations between clinical response to opioids and genetic variation at a DNA level. To date these studies have been small but future research may facilitate prospective prediction of response to individual drugs.

( BUPP10392 - 06 July 2010) Development of a method to measure methadone enantiomers and its metabolites without enantiomer standard compounds for the plasma of methadone maintenance patients.

A liquid chromatography-photodiode array (LC-PDA) method using a chiral analytical column was developed to determine the plasma levels of enantiomers of methadone and its chiral metabolite, 2- ethylidene-1,5-dimethyl-3,3- diphenylpyrrolidine (EDDP), without the standard compounds of R-form or S-form enantiomers. This method was established by the characteristics of recombinant cytochrome P-450 (CYP) isozymes, where CYP2C19 prefers to metabolize R-methadone and CYP2B6 prefers to metabolize S-methadone. We incubated the racemic methadone standard with either enzyme for 24 h. We identified the retention times of R- and S-methadone to be around 10.72 and 14.46 min, respectively. Furthermore, we determined the retention times of R- and S-EDDP to be approximately 6.76 and 7.72 min, respectively. No interferences were shown through the retention times of morphine, buprenorphine and diazepam. With the high recovery rate of a solid-phase extraction procedure, this method was applied in analyzing plasma concentrations of seven methadone maintenance patients where R- and S-methadone and R- and S-EDDP were 233.4 � 154.9 and 185.9 � 136.3 ng/mL and 84.4 � 99.4 and 37.6 � 22.9 ng/mL, respectively. These data suggest that the present method can be applied for routine assay for plasma methadone and EDDP concentrations for patients under treatment.

( BUPP10391 - 06 July 2010) Drug regimen review: Herpes zoster and neuralgia

( BUPP10390 - 06 July 2010) Hydromorphone: An option in the treatment of pain

The analgesics opioids are one of the fundamental props in the pharmacological treatment of the moderate and severe pain, particularly in chronic oncology pain. The hydromorphone molecule is structurally very similar to morphine and it may be administered enterally or parenterally. It binds mainly to mu opioid receptors and to a lesser extent to delta receptors. The binding to the mu receptor is responsible for the analgesic effect as well as for the appearance of side effects. Hydromorphone is available in 12-hour and 24-hour slowrelease presentations. A 24-hour sustained release preparation has recently come available on the market in Spain which uses the OROS push-pull system. In the treatment of the acute pain, the clinical evidence demonstrates that hydromorphone has similar analgesic equivalence to other opioids. Treatment of oncological pain has been evaluated compared to other opioids and with different formulations, demonstrating it to be a drug equivalent to morphine as regards its analgesic effectiveness and side effects. There are no controlled clinical trials on the use of hydromorphone in the treatment of chronic nononcological pain. Conclusions, hydromorphone has a pharmacological profile, analgesic properties and side effects similar to morphine, but there is still controversy as regards hydromorphone-morphine equivalent doses and the oral-parenteral dose.

( BUPP10389 - 06 July 2010) Is the WHO analgesic ladder still valid? Twenty-four years of experience

( BUPP10388 - 06 July 2010) First-trimester fetal heart rate in mothers with opioid addiction

AimTo investigate the difference in fetal heart rate of opioid-dependent mothers compared to non-dependent mothers in the first trimester of pregnancy.DesignThe data of 74 consecutive singleton pregnancies of mothers enrolled in a maintenance programme for opioid-dependent women was matched to 74 non-exposed singleton pregnancies by maternal age, crown-rump length, smoking status, ethnic background and mode of conception.MeasurementFetal heart rate measured as part of first-trimester screening by Doppler ultrasound between 11+0 and 13+6 gestational weeks was compared retrospectively .FindingsThe mean fetal heart rate in opioid-dependent mothers was 156.0 beats per minute (standard deviation 7.3) compared to 159.6 (6.5) in controls. The difference in fetal heart rate was significant (P = 0.02). There was a significant difference in mean maternal body mass index (P = 0.01) but not in mean nuchal translucency (P = 0.3), gestational age (0.5), fetal gender (P = 0.3) and parity (P = 0.3) between both groups. Fifty-five per cent (41 of 74) of cases were taking methadone, 30% (22 of 74) buprenorphine and 15% (11 of 74) were taking slow-release morphines throughout the pregnancy .ConclusionsIn fetuses of opioid-dependent mothers a decreased fetal heart rate can already be observed between 11+0 and 13+6 gestational weeks. The effect of opioid intake needs to be taken into consideration when interpreting fetal heart rate in opioid-dependent mothers at first-trimester screening.

( BUPP10387 - 06 July 2010) Implications of Opioid Analgesia for Medically Complicated Patients

Opioid analgesics have an established role in the management of postoperative pain and cancer pain, and are gaining acceptance for the management of moderate to severe chronic noncancer pain, most notably chronic low back pain and osteoarthritis, that does not respond to other interventions. Many patients with chronic pain have co-morbid medical conditions that may complicate opioid therapy. Selecting the appropriate opioid requires knowledge of how individual opioids differ with respect to metabolism and interaction with concurrent medications, as well as the reasons why specific medical conditions may influence their efficacy and tolerability. Polypharmacy is a common complicating condition in the elderly and in patients with psychiatric illness, cancer, cardiovascular disease, diabetes mellitus or other chronic illnesses. Polypharmacy, though often necessary for patients with multiple medical conditions, also multiplies the risk of drug interactions. Pharmacokinetic drug interactions can increase or reduce exposure to the opioid or concurrent medications, reducing efficacy and/or tolerability and increasing toxicity. Pharmacodynamic interactions can enhance the depressive effects of opioids, compromising safety. Patients with impaired renal or hepatic function may have difficulty clearing or metabolizing opioids and concurrent medications, leading to increased risk of adverse events. Patients with cardiovascular, cerebrovascular or respiratory disease (including smokers of >= 2 packs/day with no other diagnosis) may be more susceptible to respiratory depression, bradycardia and hypotension with any opioid, and a few specific opioids pose additional risks. Patients with cerebrovascular disease, dementia, brain injury or psychiatric illness are more susceptible to opioid effects on the CNS, which can include euphoria, cognitive impairment and sedation. Appropriate opioid selection may mitigate these effects. Even in older patients, addiction, abuse and misdirection of prescribed opioids are of concern. Higher risk exists for patients with psychiatric illness, history of substance abuse, and identifiable substance abuse risk factors. Screening for abuse potential and vigilant patient monitoring should be routine. Opioids differ in their ability to produce euphoria, based on opioid receptor agonism, but substance abusers may be more influenced by availability, familiarity and cost factors. Consequently, opioid selection has limited influence on abuse potential but can facilitate ease of monitoring. This review provides an overview of opioid use in medically complicated patients and recommendations on how to optimize analgesia while avoiding adverse events and drug interactions in the clinical setting. Articles cited in this review were identified via a search of EMBASE and PubMed. Articles selected for inclusion discussed characteristics of specific opioids and general physiological aspects of opioid therapy in important patient populations.

( BUPP10386 - 06 July 2010) PREDICTORS OF HEPATITIS C TREATMENT OUTCOME IN GENOTYPE 1 PATIENTS IN A "REAL WORLD" SETTING

( BUPP10385 - 06 July 2010) An in vitro approach to estimate putative inhibition of buprenorphine and norbuprenorphine glucuronidation

An in vitro inhibition study was performed to investigate potential drug-drug interactions on glucuronidation of buprenorphine (BUP) and norbuprenorphine (NBUP), which represents the major elimination pathway of the drug using cDNA-expressed uridine 5'-diphosphate glucuronosyltransferases (UGTs) and human liver microsomes (HLMs). Following identification of major UGT enzymes for BUP and NBUP glucuronidation, substrates were incubated with drugs (amitriptyline, nortriptyline, lamotrigine, oxazepam, and temazepam), which are extensively cleared by glucuronidation as well as are often used during maintenance treatment. To evaluate the inhibitory potential, the half maximal inhibitor concentration (IC50), the inhibition constant (K (i)), and the inhibitor concentration (K (I)) that yield half the maximum rate of inactivation and the enzyme inactivation rate constant (k (inact)) were determined, if appropriate. Amitriptyline and temazepam are inhibitors of NBUP glucuronidation (UGT1A3, HLMs), whereas BUP glucuronidation was affected by amitriptyline (HLMs), oxazepam, and temazepam (UGT2B7). Additionally, BUP inhibits NBUP glucuronidation (UGT1A1, 1A3, HLMs) and vice versa (UGT1A3). A decrease in the metabolic clearance of NBUP may increase the risk of adverse effects such as respiratory depression. Further investigations are needed to evaluate whether inhibition of BUP and NBUP glucuronidation contributes to adverse events.

( BUPP10384 - 06 July 2010) Effect of Incarceration History on Outcomes of Primary Care Office-based Buprenorphine/Naloxone

Behaviors associated with opioid dependence often involve criminal activity, which can lead to incarceration. The impact of a history of incarceration on outcomes in primary care office-based buprenorphine /naloxone is not known.The purpose of this study is to determine whether having a history of incarceration affects response to primary care office-based buprenorphine/naloxone treatment.In this post hoc secondary analysis of a randomized clinical trial, we compared demographic, clinical characteristics, and treatment outcomes among 166 participants receiving primary care office-based buprenorphine /naloxone treatment stratifying on history of incarceration. Participants with a history of incarceration have similar treatment outcomes with primary care office-based buprenorphine/naloxone than those without a history of incarceration (consecutive weeks of opioid-negative urine samples, 6.2 vs. 5.9, p = 0.43; treatment retention, 38% vs. 46%, p = 0.28).Prior history of incarceration does not appear to impact primary care office-based treatment of opioid dependence with buprenorphine/naloxone. Community health care providers can be reassured that initiating buprenorphine/naloxone in opioid dependent individuals with a history of incarceration will have similar outcomes as those without this history.

( BUPP10383 - 06 July 2010) Pharmacokinetic (PK) Interaction Between Darunavir in Combination with Low- Dose Ritonavir (DRV/r) and Buprenorphine/Naloxone (bup/nlx)

( BUPP10382 - 06 July 2010) Buprenorphine Transdermal System in Adults With Chronic Low Back Pain: A Randomized, Double-Blind, Placebo-Controlled Crossover Study, Followed by an Open-Label Extension Phase

Background: Buprenorphine is a mixed-activity, partial p-opioid agonist. Its lipid solubility makes it well suited for transdermal administration.Objective: This study assessed the efficacy and safety profile of a 7-day buprenorphine transdermal system (BIDS) in adult (age >18 years) patients with moderate to severe chronic low back pain previously treated with tablet daily of an opioid analgesic. Methods: This was a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. After a 2- to 7-day washout of previous opioid therapy, eligible patients were randomized to receive BTDS 10 mu g/h or matching placebo patches. The dose was titrated weekly using 10- and 20-mu g/h patches (maximum, 40 mu g/h) based on efficacy and tolerability. After 4 weeks, patients crossed over to the alternative treatment for another 4 weeks. Patients who completed the double-blind study were eligible to enter the 6-month open-label phase. Rescue analgesia was provided as acetaminophen 325 mg to be taken as 1 or 2 tablets every 4 to 6 hours as needed. The primary outcome assessments were daily pain intensity, measured on a 100-mm visual analog scale (VAS), from no pain to excruciating pain, and a 5-point ordinal scale, from 0 = none to 4 = excruciating. Secondary outcome assessments included the Pain and Sleep Questionnaire (100-mm VAS, from never to always), Pain Disability Index (ordinal scale, from 0 = no disability to 11 = total disability), Quebec Back Pain Disability Scale (categorical scale, from 0 = no difficulty to 5 = unable to do), and the 36-item Short Form Health Survey (SF-36). Patients and investigators assessed overall treatment effectiveness at the end of each phase; they assessed treatment preference at the end of double-blind treatment. After implementation of a precautionary amendment, the QTc interval was measured 3 to 4 days after randomization and after any dose adjustment. All assessments performed during the double-blind phase were also performed every 2 months during the open-label extension. Adverse events were collected by non-directed questioning throughout the study.Results: Of 78 randomized patients, 52 (66.7%) completed at least 2 consecutive weeks of treatment in each study phase without major protocol violations (per-protocol (PP) population: 32 women, 20 men; mean (SD) age, 51.3 (11.4) years; mean weight, 85.5 (19.5) kg; 94% white, 4% black, 2% other). The mean (SD) dose of study medication during the last week of treatment was 29.8 (12.1) mu g/h for BTDS and 32.9 (10.7) mu g/h for placebo (P = NS). During the last week of treatment, BTDS was associated with significantly lower mean (SD) pain intensity scores compared with placebo on both the VAS (45.3 (21.3) vs 53.1 (24.3) mm, respectively; P = 0.022) and the 5-point ordinal scale (1.9 (0.7) vs 2.2 (0.8); P = 0.044). The overall Pain and Sleep score was significantly lower with BTDS than with placebo (177.6 (125.5) vs 232.9 (131.9); P = 0.027). There were no treatment differences on the Pain Disability Index, Quebec Back Pain Disability Scale, or SF-36; however, BTDS was associated with significant improvements compared with placebo on 2 individual Quebec Back Pain Disability Scale items (get out of bed: P = 0.042; sit in a chair for several hours: P = 0.022). Of the 48 patients/physicians in the PP population who rated the effectiveness of treatment, 64.6% of patients (n = 31) rated BTDS moderately or highly effective, as did 62.5% of investigators (n = 30). Among the 50 patients in the PP population who answered the preference question, 66.0% of patients (n = 33) preferred the phase in which they received BTDS and 24.0% (n = 12) preferred the phase in which they received placebo (P = 0.001), with the remainder having no preference; among investigators, 60.0% (n = 30) and 28.0% (n = 14) preferred the BTDS and placebo phases, respectively (P = 0.008), with the remainder having no preference. The mean placebo-adjusted change from baseline in the QTc interval ranged from -0.8 to +3.8 milliseconds (P = NS). BIDS treatment was associated with a significantly higher frequency of nausea (P < 0.001), dizziness (P < 0.001), vomiting (P = 0.008), somnolence (P = 0.020), and dry mouth (P = 0.003), but not constipation. Of the 49 patients completing 8 weeks of double-blind treatment, 40(81.6%) entered the 6-month, open-label extension study and 27 completed it. Improvements in pain scores achieved during the double-blind phase were maintained in these patients.Conclusions: In the 8-week, double-blind portion of this study, BIDS 10 to 40 mu g/h was effective compared with placebo in the management of chronic, moderate to severe low back pain in patients 11 had previously received opioids. The improvements in pain scores were sustained throughout the 6-month, open-label extension. (Current Controlled Trials identification number: ISRCTN 06013881) (Clin Then 2010; 32:844-860) (C) 2010 Excerpta Medica Inc.

( BUPP10426 - 28 July 2010) Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling

Ligand-directed signaling has been suggested as a basis for the differences in responses evoked by otherwise receptor-selective agonists. The underlying mechanisms are not understood, yet clearer definition of this concept may be helpful in the development of novel, pathway-selective therapeutic agents. We previously showed that kappa-opioid receptor activation of JNK by one class of ligand, but not another, caused persistent receptor inactivation. In the current study, we found that the mu-opioid receptor (MOR) could be similarly inactivated by a specific ligand class including the prototypical opioid, morphine. Acute analgesic tolerance to morphine and related opioids (morphine-6-glucuronide and buprenorphine) was blocked by JNK inhibition, but not by G protein receptor kinase 3 knockout. In contrast, a second class of mu-opioids including fentanyl, methadone, and oxycodone produced acute analgesic tolerance that was blocked by G protein receptor kinase 3 knockout, but not by JNK inhibition. Acute MOR desensitization, demonstrated by reduced D-Ala(2)-Met(5)-Glyol-enkephalin-stimulated ((35)S)GTPgammaS binding to spinal cord membranes from morphine-pretreated mice, was also blocked by JNK inhibition; however, desensitization of D-Ala(2)-Met(5)-Glyol- enkephalin-stimulated ((35)S)GTPgammaS binding following fentanyl pretreatment was not blocked by JNK inhibition. JNK-mediated receptor inactivation of the kappa-opioid receptor was evident in both agonist-stimulated ((35)S)GTPgammaS binding and opioid analgesic assays; however, gene knockout of JNK 1 selectively blocked kappa-receptor inactivation, whereas deletion of JNK 2 selectively blocked MOR inactivation. These findings suggest that ligand-directed activation of JNK kinases may generally provides an alternate mode of G protein-coupled receptor regulation. Grant ID: K99-DA025182, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: KO5 DA20570, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R37-DA11672, Acronym: DA, Agency: NIDA NIH HHS, United States.

( BUPP10425 - 28 July 2010) Why do patients report transferring between methadone and buprenorphine?

( BUPP10424 - 28 July 2010) Buprenorphine may boost HIV treatment

( BUPP10423 - 28 July 2010) Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain

OBJECTIVE: The present randomized, double-blinded, crossover study compared the efficacy and safety of a seven-day buprenorphine transdermal system (BTDS) and placebo in patients with low back pain of moderate or greater severity for at least six weeks. METHODS: Prestudy analgesics were discontinued the evening before random assignment to 5 mug/h BTDS or placebo, with acetaminophen 300 mg /codeine 30 mg, one to two tablets every 4 h to 6 h as needed, for rescue analgesia. The dose was titrated to effect weekly, if tolerated, to 10 mug/h and 20 mug/h BTDS. Each treatment phase was four weeks. RESULTS: Fifty-three patients (28 men, 25 women, mean (� SD) age 54.5�12.7 years) were evaluable for efficacy (completed two weeks or more in each phase). Baseline pain was 62.1�15.5 mm (100 mm visual analogue scale) and 2.5�0.6 (five-point ordinal scale). BTDS resulted in lower mean daily pain scores than in the placebo group (37.6�20.7 mm versus 43.6�21.2 mm on a visual analogue scale, P=0.0487; and 1.7�0.6 versus 2.0�0.7 on the ordinal scale, P=0.0358). Most patients titrated to the highest dose of BTDS (59% 20 mug/h, 31% 10 mug/h and 10% 5 mug/h). There were improvements from baseline in pain and disability (Pain Disability Index), Pain and Sleep (visual analogue scale), Quebec Back Pain Disability Scale and Short-Form 36 Health Survey scores for both BTDS and placebo groups, without significant differences between treatments. While there were more opioid-related side effects with BTDS treatment than with placebo, there were no serious adverse events. A total of 82% of patients chose to continue BTDS in a long-term open-label evaluation, in whom improvements in pain intensity, functionality and quality of life were sustained for up to six months without analgesic tolerance. CONCLUSION: BTDS (5 mug/h to 20 mug/h) represents a new treatment option for initial opioid therapy in patients with chronic low back pain.

( BUPP10422 - 28 July 2010) Consensus guidelines for the selection and implantation of patients with noncancer pain for intrathecal drug delivery

Intrathecal therapy offers an invasive alternative for the long-term management of select patients with intractable pain associated with various disease states, including those of noncancer origin. It is commonly accepted that proper patient selection is essential to optimizing treatment outcomes, yet the practice of candidate selection for device implantation varies widely. A multifaceted approach-with consideration of preexisting medical comorbidities; psychological status; associated social, technical, and economic issues; and response to intrathecal trialing-enables practitioners to fully evaluate the appropriateness of implanting a patient with an intrathecal drug delivery system. Yet, to date no standard set of guidelines have been developed to aid practitioners in navigating this evaluation process. Using experience- and knowledge-based expert opinion to systematically evaluate the available evidence, this article provides consensus guidelines aimed at optimizing the selection of patients with noncancer pain for intrathecal therapy. In conclusion, complete assessment of a patient's physical, psychological, and social characteristics, can guide practitioners in determining the appropriateness of initiating intrathecal therapy. These consensus guidelines are intended to assist with weighing this risk/benefit ratio of intrathecal therapy, thereby minimizing the potential for treatment failure, unacceptable adverse effects, and excess mortality.

( BUPP10421 - 28 July 2010) Ethical perspectives in caring for people living with addictions: The European experience

European policy and practice in caring for people living with addictions is based on defined values (human rights, medical ethics) and on research evidence for the effects and impact of interventions. The focus of the paper is on risk management approaches to reduce the negative consequences of continued illicit drug use, being the ethically most debatable issue. The legal and policy positions are set by the European Council and Commission, and their translation into practice is documented centrally in the European Monitoring Centre on Drugs and Drug Addiction, showing the general trends as well as national differences. The European experience with the risk management approaches is presented in terms of research evidence on their effects and side-effects; this evidence is justifying the present practice. The perspectives for the future are set to follow the same lines, in a continued effort to find a balance of interests, in cooperation of authorities and civil society, and guided by ongoing research.

( BUPP10420 - 28 July 2010) Alterations in brain structure and functional connectivity in prescription opioid-dependent patients

A dramatic increase in the use and dependence of prescription opioids has occurred within the last 10 years. The consequences of long-term prescription opioid use and dependence on the brain are largely unknown, and any speculation is inferred from heroin and methadone studies. Thus, no data have directly demonstrated the effects of prescription opioid use on brain structure and function in humans. To pursue this issue, we used structural magnetic resonance imaging, diffusion tensor imaging and resting-state functional magnetic resonance imaging in a highly enriched group of prescription opioid-dependent patients ((n=10); from a larger study on prescription opioid dependent patients (n=133)) and matched healthy individuals (n =10) to characterize possible brain alterations that may be caused by long-term prescription opioid use. Criteria for patient selection included: (i) no dependence on alcohol or other drugs; (ii) no comorbid psychiatric or neurological disease; and (iii) no medical conditions, including pain. In comparison to control subjects, individuals with opioid dependence displayed bilateral volumetric loss in the amygdala. Prescription opioid-dependent subjects had significantly decreased anisotropy in axonal pathways specific to the amygdala (i.e. stria terminalis, ventral amygdalofugal pathway and uncinate fasciculus) as well as the internal and external capsules. In the patient group, significant decreases in functional connectivity were observed for seed regions that included the anterior insula, nucleus accumbens and amygdala subdivisions. Correlation analyses revealed that longer duration of prescription opioid exposure was associated with greater changes in functional connectivity. Finally, changes in amygdala functional connectivity were observed to have a significant dependence on amygdala volume and white matter anisotropy of efferent and afferent pathways of the amygdala. These findings suggest that prescription opioid dependence is associated with structural and functional changes in brain regions implicated in the regulation of affect and impulse control, as well as in reward and motivational functions. These results may have important clinical implications for uncovering the effects of long-term prescription opioid use on brain structure and function.

( BUPP10419 - 28 July 2010) Dual-emissive quantum dots for multispectral intraoperative fluorescence imaging.

Fluorescence molecular imaging is rapidly increasing its popularity in image guided surgery applications. To help develop its full surgical potential it remains a challenge to generate dual-emissive imaging agents that allow for combined visible assessment and sensitive camera based imaging. To this end, we now describe multispectral InP/ZnS quantum dots (QDs) that exhibit a bright visible green/yellow exciton emission combined with a long-lived far red defect emission. The intensity of the latter emission was enhanced by X-ray irradiation and allows for: 1) inverted QD density dependent defect emission intensity, showing improved efficacies at lower QD densities, and 2) detection without direct illumination and interference from autofluorescence.

( BUPP10418 - 28 July 2010) Do opioids affect the ability to drive safely

The literature on the impact of opioid pharmacotherapy on driving ability and safety is reviewed. Recommendations for safe driving while taking opioids and limitations of the data are discussed.

( BUPP10417 - 28 July 2010) Development of acute pain service in an Indian cancer hospital

Postoperative pain relief continues to be a major challenge for all health care professionals caring for such patients in India. Acute pain services are almost nonexistent, even in large private and university hospitals. As per our estimate not more than 10 such services are available. Tata Memorial Hospital is a tertiary care cancer center that started one of the first Acute Pain Services (APS) in India in 2002 to provide safe and effective postoperative pain management. APS guidelines and protocols have since been implemented and patients are monitored by a team of a consultant physician, a nurse, and a medical resident. Audits are done at regular intervals to evaluate the efficacy of service and patient satisfaction. Pain scores declined yet the patient satisfaction has not improved. Postoperative outcome studies are yet to be undertaken. The development and current activities of the APS that can be implemented in a country that does not have sophisticated acute pain management teams are described.

( BUPP10416 - 28 July 2010) Dihydrocodeine as an opioid analgesic for the treatment of moderate to severe chronic pain

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule. DHC is used as an analgesic, antitussive and antidiarrhoeal agent; it is also used for the treatment of opioid addiction. Limited data is available on the relative potency of DHC to other opioids. The analgesic effect of DHC is probably twice as potent as codeine for the parenteral and slightly stronger for an oral route. DHC possesses approximately 1/6 /sup th/ of the morphine analgesic effect when drugs are administered orally. In this article pharmacokinetics, pharmacodynamics, dosing guidelines, adverse effects and clinical studies of DHC in pain management are shown with focus on cancer pain. The impact of CYP2D6 activity on DHC analgesia was discussed and a proposal of calculation equianalgesic doses of DHC to other opioids was put forward.

( BUPP10415 - 27 July 2010) Enhancement of tolerance development to morphine in rats prenatally exposed to morphine, methadone, and buprenorphine

Background: Abuse of addictive substances is a serious problem that has a significant impact on areas such as health, the economy, and public safety. Heroin use among young women of reproductive age has drawn much attention around the world. However, there is a lack of information on effects of prenatal exposure to opioids on their offspring. In this study, an animal model was established to study effects of prenatal exposure to opioids on offspring.Methods: Female pregnant Sprague-Dawley rats were sub-grouped to receive (1) vehicle, (2) 2-4 mg/kg morphine (1 mg/kg increment per week), (3) 7 mg/kg methadone, and (4) 3 mg/kg buprenorphine, subcutaneously, once or twice a day from E3 to E20. The experiments were conducted on animals 8-12 weeks old and with body weight between 250 and 350 g.Results: Results showed that prenatal exposure to buprenorphine caused higher mortality than other tested substance groups. Although we observed a significantly lower increase in body weight in all of the opioid- administered dams, the birth weight of the offspring was not altered in all treated groups. Moreover, no obvious behavioral abnormality or body-weight difference was noted during the growing period (8-12 weeks) in all offspring. When the male offspring received morphine injection twice a day for 4 days, the prenatally opioid-exposed rats more quickly developed a tolerance to morphine (as shown by the tail-flick tests), most notably the prenatally buprenorphine-exposed offspring. However, the tolerance development to methadone or buprenorphine was not different in offspring exposed prenatally to methadone or buprenorphine, respectively, when compared with that of the vehicle controlled group. Similar results were also obtained in the female animals.Conclusions: Animals prenatally exposed to morphine, methadone, or buprenorphine developed tolerance to morphine faster than their controlled mates. In our animal model, prenatal exposure to buprenorphine also resulted in higher mortality and much less sensitivity to morphine-induced antinociception than prenatal exposure to morphine or methadone. This indicates that buprenorphine in higher doses may not be an ideal maintenance drug for treating pregnant women. This study provides a reference in selecting doses for clinical usage in treating pregnant heroin addicts.

( BUPP10414 - 27 July 2010) ANTIHCV TREATMENT OUTCOME IN DRUG USERS IS ASSOCIATED WITH BUPRENORFINE USE AND ADHERENCE TO TREATMENT

( BUPP10413 - 27 July 2010) Self-treatment: Illicit buprenorphine use by opioid-dependent treatment seekers

Outpatient-based opioid treatment (OBOT) with buprenorphine is an important treatment for people with opioid dependence. No quantitative empirical research has examined rationales for use of illicit buprenorphine by U.S. opioid-dependent treatment seekers. The current study sequentially screened OBOT admissions (n = 129) during a 6-month period in 2009. This study had two stages: (a) a cross-sectional epidemiological analysis of new intakes and existing patients already receiving a legal OBOT prescription (n = 78) and (b) a prospective longitudinal cohort design that followed 76% of the initial participants for 3 months of treatment (n = 42). The primary aims were to establish 2009 prevalence rates for illicit buprenorphine use among people seeking OBOT treatment, to use quantitative methods to investigate reasons for this illicit use, and to examine the effect of OBOT treatment on illicit buprenorphine use behavior. These data demonstrate a decrease in illicit use when opioid-dependent treatment seekers gain access to legal prescriptions. These data also suggest that the use of illicit buprenorphine rarely represents an attempt to attain euphoria. Rather, illicit use is associated with attempted self-treatment of symptoms of opioid dependence, pain, and depression.

( BUPP10412 - 27 July 2010) Factors associated with complicated buprenorphine inductions

Despite data supporting its efficacy, barriers to implementation of buprenorphine for office-based treatment are present. Complications can occur during buprenorphine inductions, yet few published studies have examined this phase of treatment. To examine factors associated with complications during buprenorphine induction, we conducted a retrospective chart review of the first 107 patients receiving buprenorphine treatment in an urban community health center. The primary outcome, defined as complicated induction (precipitated or protracted withdrawal), was observed in 18 (16.8%) patients. Complicated inductions were associated with poorer treatment retention (than routine inductions) and decreased over time. Factors independently associated with complicated inductions included recent use of prescribed methadone, recent benzodiazepine use, no prior experience with buprenorphine, and a low initial dose of buprenorphine/naloxone. Findings from this study and further investigation of patient characteristics and treatment characteristics associated with complicated inductions can help guide buprenorphine treatment strategies.

( BUPP10411 - 27 July 2010) Anesthesia for Patients with Renal/Hepatic Disease

General anesthesia may be necessary for patients with significant disease processes such as renal disease or hepatic disease. A basic understanding of the effects of general anesthetics on these organs and the anticipated problems of renal and hepatic impairment on the anesthetic process is necessary to optimize conditions for patients with renal or hepatic disease. Patient preparation, drug selection, and monitoring strategies will be discussed for patients with renal and liver disease.

( BUPP10410 - 27 July 2010) Anesthetic Considerations in Orthopedic Patients with or without Trauma

Anesthetic management of orthopedic patients could vary from normal routine management to more challenging critical management depending on the state in which the patient is presented. Multimodal pain management strategies incorporating opioids, which are the mainstay drugs for pain management, along with adjunctive drugs like local anesthetics (eg, lidocaine), dissociative anesthetics (eg, ketamine), and alpha-2 agonists (eg, dexmedetomidine), could improve overall patient comfort and help prevent establishment of chronic pain pathways. Also, use of local nerve blocks can prevent nociception right a the point of origin. Orthopedic patients with multiple organ traumas like head injuries, spinal injuries, pulmonary fat embolism, compartment syndrome, of thoracic injuries are high-risk patients in which any life-threatening organ pathology should be addressed before the patient is put under general anesthesia. Interactions of various drugs like antibiotics and neuromuscular blocking agents used in the peroperative period in orthopedic patients should warrant a careful consideration with respect to their interactions with each other and other anesthetic drugs used.

( BUPP10444 - 09 August 2010) Transitioning Stable Methadone Maintenance Patients to Buprenorphine Maintenance

Objectives: Little data exists on psychosocially stable patients maintained long term on methadone maintenance treatment who attempt to transition their maintenance treatment to buprenorphine. The aims of this study were (1) to determine whether there is a correlation between baseline methadone maintenance dose and final buprenorphine maintenance dose, (2) to investigate subjective and objective outcomes over time in psychosocially stable opioid-dependent patients who transitioned their long-term maintenance treatment from methadone to buprenorphine. Methods: In this retrospective study, 104 such patients on dosages of methadone 5 - 80 mg/d were offered the opportunity to convert their maintenance treatment to buprenorphine, of which 25 accepted. Results: All patients (n = 25, 100%) who readily attempted transition to buprenorphine succeeded. A low-moderate association was found between patients' pretransfer methadone dose and pretransfer buprenorphine dose (Spearman correlation coefficient p = 0.46, P = 0.02). At a mean 30.3 months duration (SD 16.5), 22 patients (88%) remained on buprenorphine maintenance, 1 patient (4%) tapered off buprenorphine under clinician supervision, 1 patient (4%) died of hepatitis C, and 1 patient (4%) relapsed to cocaine and was lost to follow-up. Conclusions: the results demonstrate a low to moderate association between methadone and buprenorphine treatment for opioid dependence for psychosocially stable patients on long-term methadone maintenance dosages up to 80 mg/d.

( BUPP10443 - 09 August 2010) Law enforcement and drug treatment: a culture clash

( BUPP10442 - 09 August 2010) Ventricular arrhythmias in patients treated with methadone for opioid dependence

PURPOSE: Over the last decade, there has been a significant rise in reported cases of methadone induced QT prolongation (QTP) and Torsades de Pointes (TdP) in patients treated for opioid dependence. Optimal management of these patients is challenging. METHODS: We report a case series of 12 consecutive patients admitted to our institution with methadone-induced QTP and ventricular arrhythmias. RESULTS: All patients survived the presenting arrhythmia. Successful transition to buprenorphine was accomplished in three patients. QT interval normalized and none of these patients had recurrent arrhythmias. Methadone dose was reduced in five patients with improvement of QT interval and resolution of arrhythmia. Four patients, including two with ICDs, refused or did not tolerate a reduction in their methadone dose. CONCLUSION: Ventricular arrhythmias in patients on methadone are an uncommon but important problem. Buprenorphine, a partial micro-opiate-receptor agonist and a kappa-opiate-receptor antagonist does not cause QTP or TdP. Buprenorphine is a useful and effective alternative to methadone in a select group of patients, including those with documented ventricular arrhythmias on methadone. Pacemakers or defibrillators should be reserved for patients who have failed buprenorphine or a reduced methadone dose.

( BUPP10441 - 09 August 2010) (Post-operative analgesia in case of ano-rectal diseases)

BACKGROUND: The aim of the study was that to evaluate the post-operative pain in case of ano-rectal diseases wether treated by ketorolac, or buprenorphine or tramadol. MATERIALS AND METHODS: The intensity of post-operative pain was evaluated in 60 patients with hemorrhoidal diseases, fistulae, abscesses and anal neoplasms, divided into three homogenous groups and treated with intramuscular ketorolac (Group I), transdermal buprenorphine (Group II) and tramadol in elastomeric pump (Group III). RESULTS: The average index of the visual analogue scale, as mean to evaluate the intensity of the post-operative pain, was 1,85 in the first group, 1,20 in the second one and 1,40 in the third group. DISCUSSION: In patients treated with transdermal buprenorphine or with tramadol in elastomeric pump there has been a more quick psycho-physical recovery than in those treated with ketorolac; the management of elastomeric pump represents however for patients cause of concern while the transdermal system is a kind of rational and comfortable way of treatment of the pain, with the advantage of being non-invasive. CONCLUSIONS: Better compliance and lower operating costs have given the preference to the use of transdermal buprenorphine for the treatment of diseases of the post-operative pain in the diseases of the anal canal.

( BUPP10440 - 09 August 2010) Current use of sedation and analgesia: 218 resuscitations in France services practices survey

Objectives: To assess the current use of sedation and analgesia in a large sample of French intensive care units (ICUs) and to define structural characteristics of the units that use a written procedure. Study design: Self-reported survey. Participants: Three hundred and sixty French ICUs were presented the questionnaire in September 2007. Results: Surveys were received from 228 (60.6%) ICUs. Midazolam was used in more than 50% of the patients in 79.2% of the ICUs and propofol in 22.2% of the ICUs. Sufentanil was the most frequently used morphinic. A sedation-scale was used in 68.8% of the units (80.3% Ramsay score). Sedation was assessed at least every 4. hours in 61% of ICUs. A pain-scale was used in 88.9% of the ICUs, but only 12.5% in the non-communicant patients. A written procedure was used in 29.4% of the units only. In multivariate analysis, use in the ICU of a written procedure for the early management of patients with septic shock and/or intensive insulin therapy was the single variable significantly associated with presence of a written procedure for sedation and analgesia (respectively OR 4.37; p<0.0001 and OR 5.64; p =0.032). Conclusion: Although more than two-third of the responding ICUs reported the use of sedation-and-pain-scales, frequency of assessment was low, and objective assessment of pain in the non- communicating patients was extremely uncommon. Similarly, the use of written procedure was low. The use of sedation-analgesia written procedure in an ICU seems strongly influenced by a more global involvement of the ICU in the protocolisation of complex care. These findings support the reinforcement of educational programs.

( BUPP10439 - 09 August 2010) Cancer-related breakthrough pain

( BUPP10438 - 09 August 2010) Pharmacotherapies for Adolescent Substance Use Disorders

There is a paucity of research on pharmacotherapies in adolescents with substance use disorders. This paucity is partly because of the fact that most people with substance dependence do not get diagnosed until early adulthood, that is, after 18 years of age. This article reviews pharmacotherapies used for aversion, substitution, anti-craving, and detoxification of alcohol, nicotine, cocaine, and opioids dependence. Adult research is referenced when applicable and generalized to adolescents with caution. Continued evaluation and development of pharmacotherapy for youth in controlled studies are needed to examine medication effectiveness, safety, potential for abuse, compliance, and potential interactions with other medications or substances of abuse.

( BUPP10437 - 09 August 2010) Management of cancer pain: ESMO Clinical Practice Guidelines

( BUPP10436 - 09 August 2010) Editorial: Toward a potential paradigm shift for the clinical care of diabetic patients requiring perineural analgesia: Strategies for using the diabetic rodent model

( BUPP10435 - 09 August 2010) Functional deficits after intraneural injection during interscalene block

OBJECTIVE: We present an occurrence of a severe but transient neurologic complication after intraneural injection during an ultrasound-guided interscalene block. CASE REPORT: A 36-year-old man underwent ultrasound-guided interscalene nerve blockade before shoulder incision and drainage. On postoperative day 1, he exhibited new-onset arm weakness with dysesthesias. Intraneural injection was recognized based on a retrospective review of the recorded ultrasound imaging. The symptoms persisted for more than 2 weeks and completely resolved by 6 weeks. Conclusions: Our report suggests that intraneural injection during ultrasound-guided interscalene block carries a risk of neurologic complications.

( BUPP10434 - 09 August 2010) Recovery from Chronic Musculoskeletal Pain with Psychodynamic Consultation and Brief Intervention: A Report of Three Illustrative Cases

Objective: Most physicians are unaware of the potential for complete remission from chronic musculoskeletal pain through a purely psychological approach. We report three cases in which various types of chronic musculoskeletal pain were successfully treated using a small-group psychological workshop combined with a single consultative session. Design: Case report. Setting and Patients: Hospital-based clinic; retrospectively selected cases among patients with at least a 4-year history of chronic musculoskeletal pain prior to intervention. Measures: Structured interview. Results: Each of three patients discussed reported pain-free status at last follow-up, which was at least 6 months following the intervention. Conclusion: Certain individuals with chronic musculoskeletal pain may greatly benefit from a primarily psychodynamic approach to treatment, even when standard approaches to pain treatment have failed.

( BUPP10433 - 09 August 2010) The French internet forums: Chatting and looking for information about pregnancies under Subutex.

Pregnant women look for information on internet forums and share their experiences, even though the subject can be sensitive when it involves opiate maintenance treatments for instance. Their free use of this source of information enables researchers to know the experiences about the Subutex (high-dose buprenorphine) use in pregnancy of the women they would not normally have the opportunity of questioning: young women, pregnant or mothers, using internet, living with a partner, working, using an opiate substitution treatment, mostly prescribed by their GPs'. The analysis of the contents of these messages, realized by a thematic tree construction, shows five categories of interventions from the participating people. First, we identified their opinions and representations about Subutex in general and in the particular context of pregnancy. Secondly, we examined their shared knowledge on subjects about which they deplore the lack of information. Thirdly, they had more technical conversations, on how to stop Subutex before the end of pregnancy or on at least how to decrease the doses. The fourth point is that fear and guilty about Subutex intakes during pregnancy carry out an ideal of abstinence, leading women to flout medical advice when faced with the necessity to continue or even to increase the doses. Finally, a closer inspection of the children's future, the newborn withdrawal and maternal lactation, in the context of this treatment, complete this spectrum.

( BUPP10432 - 09 August 2010) The transdermal 7-day buprenorphine patch - An effective and safe treatment option, if tramadol or tilidate/naloxone is insufficient. Results of a non-interventional study

The transdermal 7-day buprenorphine matrix patch provides a constant and user-friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7-day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p 0,001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user-friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets.

( BUPP10431 - 09 August 2010) A randomized, placebo-controlled, double-blinded, parallel-group, 5-week study of buprenorphine transdermal system in adults with osteoarthritis.

Background: This multicenter, parallel-group, 35-day study in adults with osteoarthritis (OA) pain evaluated the analgesic efficacy and safety of buprenorphine transdermal system (BTDS) designed for 7-day wear. Methods: Patients with OA pain inadequately controlled with nonsteroidal antiinflammatory drugs or patients who had taken opioids for OA pain within the past year entered a 7-day run-in period during which they took ibuprofen only. Patients with pain 7 on a 0-10 scale had their ibuprofen discontinued and were randomized into a 28-day double-blinded period to receive either BTDS at 1 of 3 dose levels (5, 10, or 20 mug/h) or placebo. Doses were titrated to effectiveness over a period of 21 days and maintained for 7 days. No rescue medication was allowed during the study. The primary efficacy measure was the proportion of patients who achieved treatment success, defined as a patient satisfaction score of good, very good, or excellent (on day 28 or at early discontinuation) for those who did not discontinue due to ineffective treatment. Results: More BTDS-treated patients experienced treatment success than placebo TDS- treated patients (44 percent and 32 percent; odds ratio = 1.66, p = 0.036). Fewer patients taking BTDS titrated to the highest dose compared with placebo (p < 0.05). There were two serious adverse events (both in the placebo group) and no deaths. The most common ( 5 percent) adverse events reported in BTDS-treated patients were nausea, headache, dizziness, somnolence, application site pruritus, and vomiting. Conclusion: Compared with placebo, BTDS treatment was effective in treating patients with moderate to severe pain due to OA of the knee or hip. BTDS was well-tolerated.

( BUPP10430 - 09 August 2010) Postoperative analgesia

( BUPP10429 - 09 August 2010) Characteristics of opiate users leaving detoxification treatment against medical advice

Substance-dependent patients leaving against medical advice (AMA) pose a unique challenge to detoxification programs. Most notably, AMA patients fail to access residential or outpatient treatment needed after detoxification and often return to detoxification treatment multiple times which has deleterious results for the patient and is taxing to the healthcare system. Using retrospective data from 89 daily opiate-using detoxification patients completing detoxification and 95 patients leaving AMA, we sought to identify patient characteristics useful in predicting AMA discharges from detoxification. Bivariate analyses indicated that AMA patients reported drug use did not impair their health, were injection drug users, younger and had fewer previous treatment admissions. Binomial logistic regression indicated that AMA patients were more likely to be unemployed and report that drug use did not impair their health. Patients completing detoxification were less likely to be injection drug users and less likely to be self-referred to treatment. Identifying patients at risk of leaving AMA provides an opportunity for clinicians to intervene in an effort to increase treatment engagement for these patients.

( BUPP10428 - 05 August 2010) President's message

( BUPP10427 - 05 August 2010) Implantable polymeric device for sustained release of buprenorphine

The present invention provides compositions, methods, and kits for treatment of opiate addiction and pain. The invention provides a biocompatible nonerodible polymeric device which releases buprenorphine continuously with generally linear release kinetics for extended periods of time. Buprenorphine is released through pores that open to the surface of the polymeric matrix in which it is encapsulated. The device may be administered subcutaneously to an individual in need of continuous treatment with buprenorphine.

( BUPP10454 - 12 August 2010) Intravenous Procaine Is Effective Pain Therapy in Acute Pancreatitis: A Randomized, Placebo-Controlled, Double Blind Study.

Background: IV procaine hydrochloride (PH) has been widely used for analgesia in acute pancreatitis (AP) in several countries, but its efficacy is unknown, as double-blinded placebo-controlled controlled trials are lacking. Hypothesis: PH is effective for pain control and reduces demand for additional analgesic medication compared with placebo in AP. Methods: Consecutive patients with AP or acute inflammatory bouts in chronic pancreatitis (ACP) received 500 mg metamizole and were then randomly assigned to receive PH (2 g/24 h) i.v. or placebo over 72 h in a double blind fashion. Patients were instructed to demand for additional pain medication (standardized: metamizole and/or buprenorphine), and administration was recorded. Pain severity (visual analogue scale, VAS), complications and laboratory parameters were also recorded at baseline and every 24h. Pain control was defined as >= 50% reduction of pain severity compared with baseline. Results: 44 patients (17 E, 27 M) participated (PH: N=23, placebo: N=21) in 6 centers, Baseline characteristics did not differ between both treatment arms, Quantitative pain reduction was significantly greater with PH, compared with placebo (VAS PH -70.8% vs. placebo -51.1%, p=0.028), and more patients achieved pain control (PH, 80% vs, placebo, 57%; p <0.05), despite greater use of additional analgesia in the placebo- group. Subgroup analyses revealed that PH was particularly effective in patients with AP (rather than ACP), BMI >25 kg/m2, and presence of complications at baseline. Conclusions: PH is effective analgesia and decreases demand tor additional pain medication compared with placebo in AP. The effect is more pronounced in obese patients and/or severe disease, These findings justify larger randomized trials.(GRAPHICS) Reduction of pain severity in response to 72 h treatment with i.v. procain or placebo in acute pancreatitis (vertical line marks % of patients who achieve 50% reduction of the pain score compared with baseline).

( BUPP10453 - 12 August 2010) Addiction and Related Disorders Introduction

( BUPP10452 - 12 August 2010) Buprenorphine in the Treatment of Opiate Dependence

Compelling clinical evidence establishes that buprenorphine is similar to methadone in efficacy for opiate detoxification and maintenance but safer than methadone in an overdose situation. The Drug Abuse Treatment Act of 2000 (DATA 2000) enabled US physicians with additional training to prescribe buprenorphine to a limited number of opiate-dependent patients. The sublingual tablets Subutex (R) (buprenorphine alone) and Suboxone (R) (a combination of buprenorphine and naloxone) meet the specifications of DATA 2000. Suboxone is intended to discourage intravenously administration and has less abuse potential than buprenorphine alone. Suboxone is generally recommended for maintenance treatment except for women who are pregnant. Subutex is recommended in treatment of pregnant women. A buprenorphine opiate withdrawal syndrome can occur in newborns. Although intravenous buprenorphine abuse is a significant public health problem in some countries, buprenorphine alone or in combination with naloxone has less potential for abuse than heroin and some prescription opiates, such as oxycodone. Pharmacotherapy from physicians' offices makes buprenorphine treatment acceptable to some opiate-dependent patients who would not accept treatment in traditional opiate-maintenance clinics. For reasons not adequately understood, some patients find discontinuation of buprenorphine following long-term use difficult. This article reviews the pharmacology of buprenorphine, summarizes evidence supporting the safety and efficacy of buprenorphine and provides clinical guidelines for treatment.

( BUPP10451 - 12 August 2010) Chronic Pain: Pathophysiology and Treatment Implications

An examination of the current understanding of the processes and related therapies aimed at treatment of chronic pain in animals is presented. Discussion focuses on mechanisms involved in the neural pathways of chronic pain, differences between acute and chronic pain, and pharmacologic options for chronic pain as they relate to inflammatory, neoplastic, and neuropathic processes.

( BUPP10450 - 12 August 2010) Preclinical evidence of new opioid modulators for the treatment of addiction

Importance of the field: Addiction to opiates is one of the most severe forms of substance dependence, and despite a variety of pharmacological approaches to treat it, relapse is observed in a high percentage of subjects. New pharmacological compounds are necessary to improve the outcome of treatments and reduce adverse side effects. Moreover, drugs that act on the opioid system can also be of benefit in the treatment of alcohol or cocaine addiction. Area covered by this review: Recent preclinical studies of pharmacological agents for the treatment of opiate addiction (2008 to the present date). What the reader will gain: The reader will be informed of the latest drugs shown in animal models to modify dependence on opiates and the reinforcing effects of these drugs. In addition, reports of the latest studies to test these compounds in models of other drug addictions are reviewed. Take home message: The classic clinical pharmacotherapy for opiate dependence, involving mu-opioid receptor agonists or antagonists, has not yielded a high success rate in humans. In pharmacotherapy for opioid dependence, new options are emerging and different pharmacological strategies are now being tested.

( BUPP10449 - 12 August 2010) A key role of the basal ganglia in pain and analgesia - insights gained through human functional imaging

The basal ganglia (BG) are composed of several nuclei involved in neural processing related to the execution of motor, cognitive and emotional activities. Preclinical and clinical data have implicated a role for these structures in pain processing. Recently neuroimaging has added important information on BG activation in conditions of acute pain, chronic pain and as a result of drug effects. Our current understanding of alterations in cortical and sub-cortical regions in pain suggests that the BG are uniquely involved in thalamo-cortico-BG loops to integrate many aspects of pain. These include the integration of motor, emotional, autonomic and cognitive responses to pain.

( BUPP10448 - 12 August 2010) Anaesthesia in a patient with "von recklinghausen's disease"

( BUPP10447 - 12 August 2010) Intrathecal buprenorphine for post-op analgesia

( BUPP10446 - 12 August 2010) Reply: Intrathecal Buprenorphine for Post-op Analgesia

( BUPP10445 - 12 August 2010) Pharmacological feature of buprenorphine: Research advances

Buprenorphine is a semisynthetic opioid derived from thebaine. It has been shown to nteract in vivo and in vitro with multiple opioid receptors with slow receptor binding kinetics. It can act as an agonist and/or antagonist when interacting with different classes of opioid receptors, which contributes to the distinctive pharmacological feature of buprenorphine. This review summarizes the recent research data on the pharmacology of buprenorphine, aiming to accurately understand the efficacy and safety of its clinical use.

( BUPP10468 - 19 August 2010) Buprenorphine Duration of Action: Mu-opioid Receptor Availability and Pharmacokinetic and Behavioural Indices

Background: Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of mu opioid receptors (muORs). This study examined the duration of action of BUP at muORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers. Methods: Availability of muOR (measured with positron emission tomography and [11C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere. Results: Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain muOR availability was 30%, 54% 67% and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of muOR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade. Conclusions: Togehter with our previous findings, it appears that muOR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50% - 60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.

( BUPP10467 - 19 August 2010) Outcomes associated with opioid use in the treatment of chronic noncancer pain in older adults: A systematic review and meta-analysis

This systematic review summarizes existing evidence regarding the efficacy, safety, and abuse and misuse potential of opioids as treatment for chronic noncancer pain in older adults. Multiple databases were searched to identify relevant studies published in English (1/1/80-7/1/09) with a mean study population age of 60 and older. Forty-three articles were identified and retained for review (40 reported safety and efficacy data, the remaining 3 reported misuse or abuse outcome data). The weighted mean subject age was 64.1 (mean age range 60-73). Studies enrolled patients with osteoarthritis (70%), neuropathic pain (13%), and other pain-producing disorders (17%). The mean duration of treatment studies was 4 weeks (range 1.5-156 weeks), and only five (12%) lasted longer than 12 weeks. In meta-analyses, effect sizes were -0.557 (P<.001) for pain reduction, -0.432 (P<.001) for physical disability reduction, and 0.859 (P=.31) for improved sleep. The effect size for the Medical Outcomes Study 36-item Health Survey was 0.191 (P=.17) for the physical component score and -0.220 (P=.04) for the mental component score. Adults aged 65 and older were as likely as those younger than 65 to benefit from treatment. Common adverse events included constipation (median frequency of occurrence 30%), nausea (28%), and dizziness (22%) and prompted opioid discontinuation in 25% of cases. Abuse and misuse behaviors were negatively associated with older age. In older adults with chronic pain and no significant comorbidity, short-term use of opioids is associated with reduction in pain intensity and better physical functioning but poorer mental health functioning. The long-term safety, efficacy, and abuse potential of this treatment practice in diverse populations of older persons remain to be determined.

( BUPP10466 - 19 August 2010) Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that elicits complex biological effects in humans. One plausible mechanism for this phenomenon is that racemic MDMA is composed of two stereoisomers that exhibit qualitatively different pharmacological effects. In support of this, studies have shown that R(-)-MDMA tends to have hallucinogen-like effects, whereas S(+)-MDMA tends to have psychomotor stimulant-like effects. However, relatively little is known about whether these stereoisomers engender different endocrine and neurochemical effects. In the present study, the endocrine and neurochemical effects of each stereoisomer and the racemate were assessed in four rhesus monkeys after intravenous delivery at doses (1-3 mg/kg) that approximated voluntary self-administration by rhesus monkeys and human recreational users. Specifically, fluorescence-based enzyme-linked immunosorbent assay was used to assess plasma prolactin concentrations, and in vivo microdialysis was used to assess extracellular dopamine and serotonin concentrations in the dorsal striatum. R(-)-MDMA, but not S(+)-MDMA, significantly increased plasma prolactin levels and the effects of S, R(�)-MDMA were intermediate to each of its component stereoisomers. Although S (+)-MDMA did not alter prolactin levels, it did significantly increase extracellular serotonin concentrations. In addition, S(+)-MDMA, but not R(-)-MDMA, significantly increased dopamine concentrations. Furthermore, as in the prolactin experiment, the effects of the racemate were intermediate to each of the stereoisomers. These studies demonstrate the stereoisomers of MDMA engender qualitatively different endocrine and neurochemical effects, strengthening the inference that differences in these stereoisomers might be the mechanism producing the complex biological effects of the racemic mixture of MDMA in humans.

( BUPP10465 - 19 August 2010) Erratum to " Infectious adverse events related to misuse of high-dose buprenorphine: A retrospective study of 42 cases" (Rev Med Int 2010; 31:188-193)

( BUPP10464 - 19 August 2010) Regional anaesthesia practice for total knee arthroplasty: French national survey - 2008.

Background and objective: Improved pain management techniques and rehabilitation programs have significantly modified outcome for total knee arthroplasty (TKA). Objective: The aim of the survey was to describe the French practice patterns in regional anaesthesia for TKA. Methods: Twenty-item questionnaires were distributed to units with significant orthopaedic activity across France. The content referred to the type of orthopaedic activity; anaesthetic and analgesic management; preoperative patient information; technical aspects describing regional anaesthesia and postoperative analgesia. Results: Response rate was 54%. Combined general anaesthesia and perineural catheter was the most frequently used anaesthetic technique. Most of respondents used multimodal analgesia (including femoral nerve catheter by 80%). Written hygiene protocols were rarely available. Sterile gowns were seldom worn. Among antiseptic agents, povidone iodine was most often used. Sedative agents were systematically used by 36% of respondents. Ropivacaine was the preferred local anaesthetic agent. Finally, adjuvants were rarely used. In most cases (58%) the femoral block was performed before induction of general anaesthesia. The catheter was commonly threaded to a length between 5 and 8. cm. The correct position of the catheter tip was verified clinically by majority of respondents. Local anaesthetics were administered by continuous infusion, continuous infusion plus boluses and boluses alone in 44, 36 and 8% of cases. Catheter duration was 48 and 72. h in 45 and 33% of the units and was independent of pain scores. Conclusion: This national survey showed practices in accordance with recent guidelines as well as persistent challenges in regional anaesthesia for TKA.

( BUPP10463 - 19 August 2010) Is methadone substitution the best treatment of choice for opioid dependence?

( BUPP10462 - 19 August 2010) Singapore's experience with buprenorphine (Subutex)

Buprenorphine (Subutex) has been used to treat opioid dependency in the past 16 years. Subutex (or buprenorphine hydrochloride) was approved by the Singapore's Ministry of Health (MOH) in 2000 as a substitution treatment for opiate-dependent drug abusers within the framework of medical, social and psychological treatments. It was subsequently introduced into the Singapore market in 2002. In spite of the promise of improvement in the lives of addicts with medical care, a distinct trend of buprenorphine abuse has occurred. A cascade of events from 2002 to 2006 led to discontinuation of Subutex treatment programs in the country. In this paper, firstly reports on morbidity and mortality caused by Subutex IV abuse will be reviewed and secondly, the MOH response to the situation will be outlined and finally, implications of Singapore's experience with Subutex will be discussed.

( BUPP10461 - 19 August 2010) Distribution of vestibulospinal contacts on the dendrites of ipsilateral splenius motoneurons: an anatomical substrate for push-pull interactions during vestibulocollic reflexes

Excitatory and inhibitory synapses may control neuronal output through a push-pull mechanism--that is, increases in excitation are coupled to simultaneous decreases in inhibition or vice versa. This pattern of activity is characteristic of excitatory and inhibitory vestibulospinal axons that mediate vestibulocollic reflexes. Previously, we showed that medial vestibulospinal tract (MVST) neurons in the rostral descending vestibular nucleus (DVN), an excitatory pathway, primarily innervate the medial dendrites of contralateral splenius motoneurons. In the present study, we tested the hypothesis that the counterparts of the push-pull mechanism, the ipsilateral inhibitory MVST synapses, are distributed on the dendritic tree such that the interactions with excitatory MVST synapses are enhanced. We combined anterograde tracing and intracellular staining in adult felines and show that most contacts (approximately 70%) between inhibitory MVST neurons in the rostral DVN and ipsilateral splenius motoneurons are also located on medial dendrites. There was a weak bias towards proximal dendrites. Using computational methods, we further show that the organization of excitatory and inhibitory MVST synapses on splenius motoneurons increases their likelihood for interaction. We found that if either excitatory or inhibitory MVST synapses were uniformly distributed throughout the dendritic tree, the proportion of inhibitory contacts in close proximity to excitatory contacts decreased. Thus, the compartmentalized distribution of excitatory and inhibitory MVST synapses on splenius motoneurons may be specifically designed to enhance their interactions during vestibulocollic reflexes. This suggests that the push-pull modulation of motoneuron output is based, in part, on the spatial arrangement of synapses on the dendritic tree.

( BUPP10460 - 19 August 2010) The diverse clinical uses of opioid receptor drugs

Opioid receptors are widely distributed throughout the nervous system. In addition to their central role in brain pathways mediating pain, endogenous opioid peptides function as neuromodulators and opioid systems are involved in many physiological functions. Opioid receptor drugs, including methadone (Dolophine), buprenorphine (Buprenex, Subutex), naltrexone (Revia), naloxone (Narcan), and buprenorphine/naloxone (Suboxone), are the focus of this article. This class of drugs is likely to be further developed for the treatment of addictions and mood disorders.

( BUPP10459 - 19 August 2010) Pharmacokinetic interactions between buprenorphine/naloxone and once-daily lopinavir/ritonavir

BACKGROUND: This study was conducted to examine the pharmacokinetic interactions between buprenorphine/naloxone (BUP/NLX) and lopinavir /ritonavir (LPV/r) in HIV-seronegative subjects chronically maintained on BUP/NLX. METHODS: This study was an open labeled pharmacokinetic study in twelve HIV-seronegative subjects stabilized on at least 3 weeks of BUP/NLX therapy. Subjects sequentially underwent baseline and steady-state pharmacokinetic evaluation of once-daily LPV/r (800/200 mg). RESULTS: Compared to baseline values, BUP AUC0-24h (46.8 vs. 46.2 ng*hr/mL) and Cmax (6.54 vs. 5.88 ng/mL) did not differ significantly after achieving steady-state LPV/r. Similar analyses of norBUP, the primary metabolite of BUP, demonstrated no significant difference in norBUP AUC0-24 hours (73.7 vs. 52.7 ng x h/mL); however, Cmax (5.29 vs. 3.11 ng/mL) levels were statistically different (P < 0.05) after LPV/r administration. Naloxone concentrations were similarly unchanged for AUC0-24 hours (0.421 vs. 0.374 ng x hr/mL) and Cmax (0.186 vs. 0.186 ng/mL). Using standardized measures, no objective opioid withdrawal was observed. The AUC0-24 hours and Cmin of LPV in this study did not significantly differ from historical controls (159.6 vs. 171.3 microg x hr/mL) and (2.3 vs. 1.3 microg/mL). CONCLUSIONS: The addition of LPV/r to stabilized patients receiving BUP/NLX did not affect buprenorphine pharmacokinetics but did increase the clearance of norbuprenorphine. Pharmacodynamic responses indicate that the altered norbuprenorphine clearance did not lead to opioid withdrawal. Buprenorphine/naloxone and LPV/r can be safely coadministered without need for dosage modification. Grant ID: K23 DA022143-04, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: K23DA022143, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: K24 DA017072, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01 DA025932, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: RR024139, Acronym: RR, Agency: NCRR NIH HHS, United States

( BUPP10458 - 19 August 2010) A case of poppy tea dependence in an octogenarian lady

While poppy seed and poppy tea dependence has been described, it is unusual to see such patients actively seek treatment in India. We report the case of an 82-year-old client with dependent use of poppy for 55 years. She was brought for treatment as access to poppy became difficult following legal restrictions. She was successfully maintained on buprenorphine maintainence.

( BUPP10457 - 17 August 2010) HIV/AIDS How Ukraine is tackling Europe's worst HIV epidemic

( BUPP10456 - 17 August 2010) Effect of Buprenorphine and Methadone on Human Cd4(+) T Lymphocytes and Glial Cells

( BUPP10455 - 17 August 2010) Method of providing sustained analgesia with buprenorpine

A method of effectively treating pain in humans is achieved by administering buprenorphine in accordance with first order kinetics over an initial three-day dosing interval, such that a maximum plasma concentration from about 20 pg/ml to about 1052 pg/ml is attained, and thereafter maintaining the administration of buprenorphine for at least an addition two-day dosing interval in accordance with substantially zero order kinetics, such that the patients experience analgesia throughout the at least two-day additional dosing interval.

( BUPP10501 - 01 September 2010) Were the changes to Sweden's maintenance treatment policy 2000 - 06 related to changes in opiate-related mortality and morbidity?

Aims: To analyse whether changes in maintenance treatment of opiate-dependent subjects in Sweden were related to changes in opiate-related mortality and in-patient care from 1998 to 2006. Design: We collected data from surveys of methadone maintenance treatment units, of buprenorphine and methadone sales, and of mortality and in-patient care in Sweden. Setting: Sweden. Participants: Patients in maintenance treatment. Measurements: Survey data of in-patient care and forensic investigations. Findings: The surveys showed a marked change to a less restrictive policy, with increased use of 'take-away doses' and a reduction of discharges due to side misuse. The one-year retention rate stayed high. Sales of buprenorphine and methadone and the number of patients in treatment increased more than threefold from 2000 to 2006, with the greatest increase for buprenorphine, introduce in year 2000. There was a significant 20-30% reduction in opiate-related mortality and in-patient care between 2000 -2002 and 2004-2006 but not of other drug-related mortality and in-patient care. This decline was larger in Stockholm County, which had a less restricted treatment policy. However, a significant increase in buprenorphine- and methadone-related mortality occurred. For the study period 1998-2006, statistically significant declines occurred only in Stockholm County. Conclusions: The liberalisation of Sweden's drug policy correlated with an increase in maintenance treatment, a decrease in opiate-related mortality and in-patient care and an increase in deaths with methadone and buprenorphine in the tissues.

( BUPP10500 - 01 September 2010) Cost-effectiveness of extended buprenorphine-naloxone treatment for opioid-dependent youth: data from a randomised trial

Aims: The objective is to estimate cost, net social cost and cost-effectiveness in a clinical trial of extended buprenorphine-naloxone (BUP) treatment versus brief detoxification treatment in opioid-dependent youth. Design: Economic evaluation of a clinical trial conducted at six community out-patient treatment programs from July 2003 to December 2006, who were randomised to 12 weeks of BUP or a 14-day taper (DETOX). SUP patients were prescribed up to 24mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14mg per day and then tapered to zero on day 14. All were offered twice-weekly drug counselling. Participants: 152 patients aged 15-21 years. Measurements: Data were collected prospectively during the 12-week treatment and at follow-up interviews at months 6, 9 and 12. Findings: The 12-week out-patient study treatment cost was $1514 (P,0.001) higher for BUP relative to DETOX. One-year total direct medical cost was only $83 higher for BUP (P=0.97). The cost-effectiveness ratio of BUP relative to DETOX was $1376 in terms of 1-year direct medical cost per quality-adjusted life year (QALY) and $25 049 in terms of out-patient treatment program cost per QALY. There acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost-effective for a threshold of $100 000 per QALY. Conclusions: Extended BUP treatment relative to brief detoxification is cost effective in the US health-care system for the outpatient treatment of opioid-dependent youth

( BUPP10499 - 01 September 2010) Practice Misalignments in Randomized Controlled Trials: Identification, Impact, and Potential Solutions

Appropriate control group selection in a randomized controlled trial (RCT) is a critical factor in generating results, which are both interpretable and generalizable. Control groups ideally encompass and realistically reflect prevailing medical practices. This goal can be challenging in investigations of standard therapies that are routinely titrated. To eliminate the heterogeneity in clinical practice from the trial design, recent investigations of titrated therapies have randomized patients to fixed-dose regimens. Although this approach may produce statistically significant differences, the results may not be interpretable or generalizable.In this trial design, randomization disrupts the normal relationship between clinically important characteristics and therapy titration, thereby creating subgroups of patients within each study arm that receive levels of therapy inconsistent with current practices outside of the clinical study. These misaligned subgroups may have worse outcomes than usual care. Practice misalignments can occur in any clinical trial of a preexisting therapy that is typically adjusted based on severity of illness or other patient characteristics.In this study, we review three recent RCTs to demonstrate how practice misalignments can affect the safety, results, and conclusions of RCTs. Furthermore, we discuss methods to prospectively identify potentially important relationships between therapy titration and patient- and disease-specific characteristics. Finally, we review trial design options that may minimize the occurrence and impact of practice misalignments. Because these designs may limit the feasibility of a clinical trial, a thorough characterization of usual care is necessary to determine whether one of these designs should be used to protect patient safety.

( BUPP10498 - 01 September 2010) The Effects of Perioperative Analgesia on Litter Size in Crl:CD1(ICR) Mice Undergoing Embryo Transfer

The objective of this study was to evaluate the effect on litter size of 2 analgesics used perioperatively during mouse embryo transfer surgery. Day 2.5 pseudopregnant CD1 mice (n = 96) were divided equally into 2 analgesic treatment groups and a saline control group. Each mouse received a single, subcutaneous dose of buprenorphine hydrochloride (0.1 mg/kg), flunixin meglumine (2.5 mg/kg), or saline immediately after induction of anesthesia with 2.5% isoflurane. Each mouse then was prepared for aseptic surgery. Blastocysts had previously been collected from C57BL/6NCrl female mice that were synchronized and superovulated by using pregnant mare serum gonadotropin and human chorionic gonadotropin and mated with C57BL /6NTac male mice 3.5 d before collection. Viable blastocysts were pooled, and 8 were selected arbitrarily and transplanted into the right uterine horn of each pseudopregnant CD1 mouse. Mice were monitored throughout pregnancy, and the number of pups at birth was documented. No statistically significant difference was found between the 3 groups. These results indicate that perioperative analgesic treatment with buprenorphine or flunixin in the CD1 mouse undergoing embryo transfer is not associated with increased embryonic loss.

( BUPP10497 - 01 September 2010) Better MURs for patients with chronic pain

This paper describes improved MUR for the management of patients with chronic pain. The recommended incremental dose increases for opioid products commonly prescribed in the Midlands are presented (buprenorphine (BuTrans patches, Temgesic sublingual tablets), fentanyl (Abstral sublingual tablets, Actiq lozenges, Durogesic DTrans patches), morphine (Morphgesic SR tablets, MST Continus tablets, MXL capsules, Zomorph capsules, MST Continus suspension, Oramorph liquid), and oxycodone (Oxycontin tablets, Oxynorm capsules, and Oxynorm liquid and concentrate). The key points for MUR for patients with chronic pain are outlined. Other drugs discussed include paracetamol, NSAID, co-codamol, and co-dydramol. It is suggested that community pharmacists can play a valuable role in the management of patients with pain and MUR are an ideal opportunity to do this. (No EX).

( BUPP10496 - 01 September 2010) (Status quo of opioid agonist maintenance therapy in Germany)

Neurobiological evidence and clinical experience indicate that opioid dependence is a chronic relapsing disorder. Crisis intervention, abstinence-oriented treatment (including detoxification and relapse prevention), and agonist maintenance treatment are the current treatment options depending on the individually pursued treatment goals. Agonist maintenance therapy is considered the first-line treatment for severe chronic opioid dependence. Numerous studies demonstrated evidence of a growing number of different agonist maintenance agents, such as methadone, buprenorphine and also new options like slow-release morphine, intravenous, inhalable and oral diamorphine. Despite the proven effectiveness of agonist maintenance therapy, the number of comprehensive care facilities nationwide is still not adequate. The growing number of patients in maintenance-treatment has not been accompanied by an increase in the number of specialized German physicians actively taking part in substitution treatment. Further efforts are needed to ensure adequate health care provision for opiate addicts in Germany.

( BUPP10495 - 01 September 2010) Outpatient opioid addiction treatment using buprenorphine

( BUPP10494 - 01 September 2010) Heroin maintenance for chronic heroin-dependent individuals Cochrane Review

BACKGROUND: Several types of medications have been used for stabilizing heroin users: Methadone, Buprenorphine and levo-alpha-acetyl-methadol (LAAM.) The present review focuses on the prescription of heroin to heroin-dependent individuals. OBJECTIVES: To compare heroin maintenance to methadone or other substitution treatments for opioid dependence regarding: efficacy and acceptability, retaining patients in treatment, reducing the use of illicit substances, and improving health and social functioning. SEARCH STRATEGY: A review of the Cochrane Central Register of Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to 2008), EMBASE (1980 to 2005) and CINAHL until 2005 (on OVID) was conducted. Personal communication with researchers in the field of heroin prescription identified other ongoing trials. SELECTION CRITERIA: Randomised controlled trials of heroin maintenance treatment (alone or combined with methadone) were compared with any other pharmacological treatment for heroin-dependent individuals. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. MAIN RESULTS: Eight studies involving 2007 patients were included. Results show marginal significance in favour of heroin for remaining in treatment until the end of the study (8 studies, N= 2007, RR=1.23, 95%CI=0.96-1.57; heterogeneity P < 0.01). Adverse events are significantly more frequent in the heroin group. Heroin plus methadone prescription for maintenance treatment in adult chronic opioid users who failed previous methadone treatment attempts decreases the use of other illicit substances (3 Studies, N=1289, RR=0.63, 95%CI=0.49, 0.81, heterogeneity P=0.21), and reduces the risk of being incarcerated (2 studies, N=1103, RR=0.64, 95%CI=0.51-0.79, heterogeneity P=0.31). In addition, we also found a marginally significant protective effect of heroin prescription plus methadone for the use of street heroin (3 studies, N=1512, RR=0.70, 95%CI=0.49-1.00, heterogeneity P < 0.01) and for criminal activity (4 studies, N=1377, RR=0.80, 95%CI=0.61-1.04, heterogeneity P=0.31). There was not enough power to detect statistically significant results for the risk of death (5 studies, N=1817, RR=0.77, 95%CI=0.32-1.87, heterogeneity P=0.79). AUTHORS' CONCLUSIONS: The available evidence suggests a small added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment-refractory opioid users, considering a decrease in the use of street heroin and other illicit substances, and in the probability of being imprisoned; and an increase in retention in treatment. Due to the higher rate of serious adverse events, heroin prescription should remain a treatment of last resort for people who are currently or have in the past failed maintenance treatment.

( BUPP10493 - 01 September 2010) Self-harm behaviors among buprenorphine-treated patients

( BUPP10516 - 08 September 2010) Induction of a Buprenorphine Substitution Treatment with Temporary Overlap of Heroin Use: A New Approach ("Bernese Method")

A constant finding in all international recommendations on substitution treatment with buprenorphine is that people should be induced onto buprenorphine only after at least 4h since the last intake of heroin and when they show clear signs of withdrawal. However, regardless of these precautions some patients show significant symptoms of withdrawal on induction, which are caused by the antagonistic effect of buprenorphine. There are 2 important findings in the scientific literature. A large number of patients on buprenorphine substitution continue to use heroin without adverse effects and the maximum effect of antagonists is reduced by applying repetitive small doses. For these reasons, repeated doses of buprenorphine, beginning with a very small dose, shouldn't release a severe withdrawal syndrome in patients, who continue to use heroin. At the same time, the effect of heroin should diminish over time (displacement of opiates from receptors by buprenorphine). We present a case of an addicted woman with PTSD, who had suffered from a severe withdrawal syndrome using the "traditional" method of induction (general faintness and malady, diarrhoea, flash backs, dissociation of thoughts). After stop of the buprenorphine treatment and relapse into heroin she wished to restart this treatment but showed great fear of the induction. We proposed her the "Bernese method": starting with 0.2mg buprenorphine without currently stopped heroin use (overlap) increasing slowly the buprenorphine dose day by day at sufficient dose of buprenorphine terminating the heroin sue with relevant withdrawal symptoms As a matter of fact, the patient could give up heroin use abruptly taking 8mg/d of buprenorphine on day 6. this induction of the treatment was possible with only minor stress and distress for the patient.

( BUPP10515 - 08 September 2010) Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats

This study characterized and compared the severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine (all i.p.) in vivo in rats. Methadone, morphine, and fentanyl decreased partial pressure of oxygen in arterial blood (Pa O2) and increased partial pressure of carbon-di-oxide in arterial blood (PaCO2). Methadone and fentanyl increased expiratory time while morphine and buprenorphine did not. In conclusion, opioid-related respiratory pattern is not uniform. (conference abstract: 14th Annual Meeting of the French Society of Pharmacology and Therapeutics, the 77th Annual Meeting of the Society of Physiology, the 31st Pharmacovigilance Meeting, the 11th APNET Seminar and the 8th CHU CIC Meeting, Bordeaux, France, 23/03/2010-25/03/2010).

( BUPP10514 - 08 September 2010) The cognitive effects of opioids in chronic non-cancer pain

( BUPP10513 - 08 September 2010) Postoperative pain treatment SIAARTI recommendations 2010 short version

The aim of these recommendations is the revision of data published in 2002 in the "SIAARTI Recommendations for acute postoperative pain treatment". In this version, the SIAARTI Study Group for acute and chronic pain decided to grade evidence based on the "modified Delphi" method with 5 levels of recommendation strength. Analgesia is a fundamental right of the patient. The appropriate management of postoperative pain (POP) is known to significantly reduce perioperative morbidity, including the incidence of postoperative complications, hospital stay and costs, especially in high-risk patients (ASA III-V), those undergoing major surgery and those hospitalized in a critical unit (Level A). Therefore, the treatment of POP represents a high-priority institutional objective, as well as an integral part of the treatment plan for <>, which includes analgesia, early mobilization, early enteral nutrition and active physiokinesitherapy (Level A). In order to improve an ACUTE PAIN SERVICE organization, we recommend: - a plan for pain management that includes adequate preoperative evaluation, pain measurement, organization of existing resources, identification and training of involved personnel in order to assure multimodal analgesia, early mobilization, early enteral nutrition and active physiokinesitherapy (Level A); - the implementation of an Acute Pain Service, a multidisciplinary structure which includes an anesthetist (team coordinator), surgeons, nurses, physiotherapists and eventually other specialists; - referring to high-quality indicators in establishing an APS and considering the following key points in its organization (Level C): service adoption; identifying a referring anesthetist who is on call 24 hours a day; patient care during the night and weekend; sharing, drafting and updating written therapeutic protocols; continuous medical education; systematic pain assessment; data collection regarding the efficacy and safety of the implemented protocols; at least one audit per year. - a preoperative evaluation, including all the necessary information for the management of postoperative analgesia (Level C); - to adequately inform the patient about the risks and benefits of drugs and procedures used to obtain the maximum efficacy from the administered treatments (Level D). We describe pharmacological and loco-regional techniques with special attention to day surgery and difficult populations. Risk management pathways must be the reference for early identification and treatment of adverse events and chr onic pain development.

( BUPP10512 - 08 September 2010) Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs. SO , {Lancet}, 2010, vol. 376, no. 9738, p. 367-387, 166 refs, CODEN: LANCA, ISSN: 0140-6736. Publisher: Elsevier Limited, 32 Jamestown Road, London, NW1 7BY, UK. AU

HIV-infected drug users have increased age-matched morbidity and mortality compared with HIV-infected people who do not use drugs. Substance-use disorders negatively affect the health of HIV-infected drug users, who also have frequent medical and psychiatric comorbidities that complicate HIV treatment and prevention. Evidence- based treatments are available for the management of substance-use disorders, mental illness, HIV and other infectious complications such as viral hepatitis and tuberculosis, and many non-HIV-associated comorbidities. Tuberculosis co-infection in HIV-infected drug users, including disease caused by drug-resistant strains, is acquired and transmitted as a consequence of inadequate prescription of antiretroviral therapy, poor adherence, and repeated interfaces with congregate settings such as prisons. Medication-assisted therapies provide the strongest evidence for HIV treatment and prevention efforts, yet are often not available where they are needed most. Antiretroviral therapy, when prescribed and adherence is at an optimum, improves health-related outcomes for HIV infection and many of its comorbidities, including tuberculosis, viral hepatitis, and renal and cardiovascular disease. Simultaneous clinical management of multiple comorbidities in HIV-infected drug users might result in complex pharmacokinetic drug interactions that must be adequately addressed. Moreover, interventions to improve adherence to treatment, including integration of health services delivery, are needed. Multifaceted, interdisciplinary approaches are urgently needed to achieve parity in health outcomes in HIV-infected drug users.

( BUPP10511 - 08 September 2010) Restless legs syndrome: Limited therapeutic possibilities

( BUPP10510 - 08 September 2010) Pain management in the paediatric population: The regulatory situation in Europe

This study compared the availability and the licensing status of analgesic drugs marketed in three European countries (Italy, France and the UK) and evaluated the evidence on safety and efficacy in the paediatric population of the drugs reported in the European Medicines Evaluation (EMA) document "Assessment of Pediatric Needs: Pain" (2005). Ten of 17 drugs reported in the EMA document were marketed with a paediatric licence in all three countries but with wide differences concerning age groups. In all, 594 randomised controlled trials (RCTs) concerning the 17 drugs in the EMA list were found through biomedical literature databases. Bupivacaine was the drug with the most trials retrieved (171 RCTs, 29%); 32 (5%) RCTs concerned clonidine not licensed for pain control, and 51 (9%) concerned ketamine licensed for paediatric use only in the UK. Access to, and the rational use, of drugs to prevent or control pain and its functional consequences pose a considerable challenge. There is a pressing need for further research and clinical development in the assessment and management of pain in children.

( BUPP10509 - 07 September 2010) Injection drug use before and after liver transplantation: A retrospective multicenter analysis on incidence and outcome

Background and aims: Injecting drug use (IDU) before and after liver transplantation (LT) is poorly described. The aim of this study was to quantify relapse and survival in this population and to describe the causes of mortality after LT. Methods: Past injection drug users were identified from the LT listing protocols from four centers in Switzerland and France. Data on survival and relapse were collected and used for uni- and multivariate analysis. Results: Between 1988 and 2006, we identified 59 patients with a past history of IDU. The mean age at transplantation was 42.4 yr and the majority of patients were men (84.7%). The indication for LT was for the vast majority viral cirrhosis accounting for 91.5% of cases, while alcoholic cirrhosis was 5.1%. There were 16.9% of patients who had a substitution therapy before and 6.8% who continued after LT. Two patients (3.4%) relapsed into IDU after LT and died at 18 and 41 months. The mean follow-up was 51 months. Overall survival was 84%, 66%, and 61% at 1, 5, and 10 yr after transplantation. Conclusions: Documented IDU was rare in liver transplanted patients. Past IDU was not associated with poorer survival after LT, and relapse after LT occurred in 3.4%.

( BUPP10508 - 07 September 2010) Co-occurring psychiatric symptoms are associated with increased psychological, social, and medical impairment in opioid dependent pregnant women

The interaction of psychiatric symptoms with drug dependence during pregnancy is not well understood. This study examines the relationship of psychiatric symptoms to severity of drug use and drug-related problems among participants in a clinical trial of pharmacologic treatment of opioid dependence during pregnancy (N = 174). A total of 64.6% reported additional psychiatric symptoms (48.6% mood symptoms, 40.0% anxiety symptoms, and 12.6% suicidal thinking). Women who endorsed co-occurring psychiatric symptoms showed more severe impairment on the Addiction Severity Index. Further investigation is warranted to understand the effect of psychiatric symptoms on long-term maternal and neonatal outcomes.

( BUPP10507 - 07 September 2010) Generic and therapeutic substitutions in the UK: Are they a good thing?

There is considerable interest and debate concerning the place of generic substitution (switching from a brand to generic product); and on therapeutic substitution, that is, switching to a cheaper, but apparently equivalent, product, usually within the drug class. Generic substitution by pharmacists is standard practice in UK hospital settings, and is being proposed for implementation in primary care. Although most prescriptions are already written generically (83% in the community in England in 2008), there are still cost savings that could be made if generic medicines are substituted against prescriptions written by branded name or by getting prescribers to adhere to advice to prescribe generically. Therapeutic substitution is more contentious, as direct evidence to support equivalence is normally lacking. However, the price differential between established drugs whose patents have expired and for which generics are available and newer, branded medicines within the same therapeutic class, makes therapeutic substitution an attractive application of cost-minimization analysis for the more efficient use of healthcare resources. Here we explore the tension that exists between the clinical appropriateness and safety of switching from an individual patient perspective and the consideration of value for money which is required to maximize population health from a health service perspective. Although substitution may affect individual patients (such as, for instance, reduced adherence, increased potential for medication error), it might be a price worth paying given the opportunity cost associated with the use of medicines that are clinically no better than cheaper alternatives.

( BUPP10506 - 07 September 2010) What is recovery?

( BUPP10505 - 07 September 2010) Treatment of substance-abuse patients in Germany: Results from the 2007 statistical report on substance-abuse treatment facilities.

Aims: To report treatment and patient characteristics from the 2007 data from substance-abuse treatment facilities and to assess treatment demand based on population statistics. Method: The analysis was based on aggregated data from 220,669 patients in 720 outpatient centres and 34,186 patients in 147 inpatient substance-abuse treatment facilities in Germany. 77% and 60% of all inpatient and outpatient treatment centres, respectively, were included. Results: Inpatient facilities offered treatment for a wide range of disorders. Patients with alcohol-, opioid-, or cannabis-use disorders represented the largest groups in both outpatient (57%, 19%, and 12%, respectively) and inpatient (70%, 14%, and 5%, respectively) treatment centres. Planned treatment completion varied considerably, but patients with alcohol-use disorders achieved the highest rate (outpatient: 63%, inpatient: 83%). Trend analyses showed that the number of patients treated for alcohol-related disorders and pathological gambling had increased slightly since 2002. Conclusions: Although similarities between inpatient and outpatient treatment were observed, there were numerous differences with respect to patient, treatment, and outcome characteristics. Compared to population estimates, only a small percentage of persons with substance-use disorders receive psychosocial or medical support.

( BUPP10504 - 07 September 2010) The Global Diversion of Pharmaceutical Drugs

AimTo provide a clinician's perspective on the problem of diversion of prescribed pharmaceuticals.MethodsThe paper provides a personal account of working in a treatment context where diversion from opioid substitution treatment (OST) became a political issue potentially compromising the continued delivery of OST. It summarizes evidence on the impact of diversion, and measures to contain it, from the United Kingdom 1986-2006, Australia 1996-2008 and the United States and France from the mid-1990s.ResultsOpioid diversion to the black market occurs in proportion to the amount of opioids prescribed to be taken without supervision, and in inverse proportion to the availability of heroin. Diversion for OST programmes using supervision of dosing is less than diversion of opioids prescribed for pain, which is now a growing public health problem. Adverse consequences of diversion include opioid overdose fatalities, an increased incidence of addiction (particularly in jurisdictions where heroin is scarce) and compromising the public acceptance of long-term opioid prescribing. All long-term opioid prescribing requires monitoring of risk and appropriate dispensing arrangements-including dilution of methadone take-aways, supervision of administration for high-risk patients and random urine testing. Clinical guidelines influence practice, although prescribing often deviates from guidelines.Conclusion Clinical guidelines and clinical audit to enhance compliance with guidelines are helpful in maintaining the quality and integrity of the treatment system, and can contribute to keeping diversion within acceptable levels.

( BUPP10503 - 07 September 2010) The Physician Clinical Support System-Buprenorphine (PCSS-B): a Novel Project to Expand/Improve Buprenorphine Treatment.

Opioid dependence is largely an undertreated medical condition in the United States. The introduction of buprenorphine has created the potential to expand access to and use of opioid agonist treatment in generalist settings. Physicians, however, often have limited training and experience providing this type of care. Some physicians believe having a mentoring relationship with an experienced provider during their initial introduction to the use of buprenorphine would ease implementation. Our goal was to describe the development, implementation, resources, and evaluation of the Physician Clinical Support System-Buprenorphine (PCSS-B), a federally funded program to improve access to and quality of treatment with buprenorphine. We provide a description of the PCSS-B, a national network of 88 trained physician mentors with expertise in buprenorphine treatment and skills in clinical education. We provide information regarding the use the PCSS-B core services including telephone, email and in-person support, a website, clinical guidances, a warmline and outreach to primary care and specialty organizations. Between July 2005 and July 2009, 67 mentors and 4 clinical experts reported providing mentoring services to 632 participants in 48 states, Washington DC and Puerto Rico. A total of 1,455 contacts were provided through email (45%), telephone (34%) and in-person visits (20%). Seventy-six percent of contacts addressed a clinical issue. Eighteen percent of contacts addressed a logistical issue. The number of contacts per participant ranged from 1-125. Between August 2005 and April 2009 there were 72,822 visits to the PCSS-B website with 179,678 pages viewed. Seven guidances were downloaded more than 1000 times. The warmline averaged more than 100 calls per month. The PCSS-B model provides support for a mentorship program to assist non-specialty physicians in the provision of buprenorphine and may serve as a model for dissemination of other types of care.

( BUPP10502 - 07 September 2010) Buprenorphine for the Treatment of Opioid Dependence: a Study on Generic Substitution Conducted in Community Pharmacies

Buprenorphine for the Treatment of Opioid Dependence: a Study on Generic Substitution Conducted in Community Pharmacies. Objective. To describe the evolution of buprenorphine prescription form characteristics before and after the application of a measure of the French Social Security system aimed to encourage the use of generic drugs.Method. All buprenorphine prescription forms issued to sixty-two patients subjected to follow-up in 6 community pharmacies were analysed between October 2007 and February 2008.Results. Patients maintained on Subutex (R) during the whole follow-up were more numerous (n=39), younger, and received a higher daily dose of buprenorphine (10.5 mg versus 7.8 mg), compared to patients maintained on generic (n=13). For patients receiving again Subutex (R) after have been treated by a generic (n=10), daily doses remained unchanged.Conclusion. It seems that the patients stabilized on generic present less serious pharmacodependence and less psychiatric comorbidity than those maintained on Subutex (R). Substituting a buprenorphine speciality with another should not induce any treatment unsettlement.

( BUPP10531 - 16 September 2010) Mechanism-based PK/PD Modelling of the Respiratory Depressant Effect of Buprenorphine and Fentanyl in Healthy Volunteers

The objective of this study was to characterise the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed PETO2 of 50mm Hg and PETO2 of 110mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase 1 studies (50 volunteers received buprenorphine:0.05-0.6mg/7-kg and 24 volunteers received fentanyl: 0.075-0.5mg/70kg). The PK/PD correlations were analysed using nonlinear mixed effects modelling. A two- and three-compartment pharmacokinetic model characterised the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid Emax pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution-receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hystereses is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half-time values of biophase equilibration (t1/2,keo) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of Kon was 0.246ml/ng/min and the value of Koff was 0.0102 min -1. The concentration-effect relationship of buprenorphine was characterised by a ceiling effect at higher concentrations (intrinsic activity x=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (x=0.91, 95% CI: 0.19-1.62).

( BUPP10530 - 16 September 2010) Serious morbidity associated with misuse of over-the-counter codeine-ibuprofen analgesics: a series of 27 cases

Objective: To investigate morbidity related to misuse of over-the-counter (OTC) codeine-ibuprofen analgesics. Design and setting: Prospective case series collected from Victorian hospital-based addiction medicine specialists between may 2005 and December 2008. Main outcome measures: Morbidity associated with codeine-ibuprofen misuse. Results: Twenty seven patients with serious morbidity were included, mainly with gastrointestinal haemorrhage and opioid dependence. The patients were taking mean daily doses of 435-602mg of codeine phosphate and 6800-9400mg ibuprofen. Most patients had no previous history of substance sue disorder. The main treatment was opioid substitution treatment with buprenorphine-naloxone or methadone. Conclusions: Although codeine can be considered a relatively weak opioid analgesic, it is nevertheless addictive, and the significant morbidity and specific patient characteristics associated with overuse of codeine-ibuprofen analgesics support further awareness, investigation and monitoring of OTC codeine-ibuprofen analgesic use.

( BUPP10529 - 16 September 2010) A Clinical Trial Comparing Tapering Doses of Buprenorphine with Steady Doses for Chronic Pain and Co-existent Opioid Addiction

Objectives: Effective strategies are needed to manage individuals with chronic non-cancer pain and coexistent opioid addiction. This study compared opioid discontinuation and opioid replacement protocols. Methods: We planned to enroll 60 individuals into an open-label trial who had been treated with opioids for chronic non-cancer pain, and who also had opioid addiction. Participants were randomly assigned to one of two 6-month treatment protocols of buprenorphine/naloxone sublingual tablets: 1)tapering doses for opioid weaning or "detoxification" (active comparator group) or 2) steady doses for opioid replacement (experimental group). They were followed monthly for the study outcomes: completion of the 6-month treatment protocol and self-reported pain control, physical functioning, alcohol consumption and illicit drug use. Results: Enrolment was terminated after enrolling 12 participants because none of the 6 assigned to receive tapering doses could successfully complete the protocol (5 were given steady doses and 1 was admitted to an in-patient chemical dependency treatment program): whereas, of the 6 assigned to receive steady doses, 5 completed the protocol (1 withdrew). This difference between the 2 treatment conditions was significant (P = 0.015). Of the 10 participants who completed the 6 month follow-up, 8 reported improved pain control and physical functioning and 5 used alcohol and/or illicit drugs. Conclusions: We conclude that over 6 months, these participants with chronic pain and co-existent opioid addiction were more likely to adhere to an opioid replacement protocol than an opioid weaning protocol and that opioid replacement therapy with steady doses of buprenorphine/naloxone is associated with improved pain control and physical functioning.

( BUPP10528 - 16 September 2010) Tramadol/paracetamol fixed-dose combination: A review of its use in the management of moderate to severe pain

--- 12 --- TI AB Tramadol/paracetamol 37.5mg325mg (Tramacet /sup �/ , Zaldiar /sup �/ , Ixprim /sup �/ , Kolibri /sup �/ ) is an orally administered fixed-dose combination of the atypical opioid tramadol and paracetamol, which is indicated in the EU for the symptomatic treatment of moderate to severe pain. This article reviews the pharmacological properties, clinical efficacy and tolerability of Tramadol /paracetamol in adults with moderate to severe pain.Fixed-dose Tramadol/paracetamol is a rapidly-acting, longer-duration, multimodal analgesic, which is effective and generally well tolerated in patients with moderate to severe pain. In several well designed, clinical studies, single- or multiple-dose Tramadol/paracetamol was effective in providing pain relief in adult patients with postoperative pain after minor surgery, musculoskeletal pain (acute, subacute or chronic), painful diabetic peripheral neuropathy or migraine pain. It was also effective as an add-on analgesic in patients who were experiencing moderate to severe musculoskeletal pain (e.g. osteoarthritis or rheumatoid arthritis pain) despite ongoing NSAID and or disease-modifying antirheumatic drug therapy. Moreover, in patients with postoperative pain, ankle sprain pain or subacute lower back pain, the analgesic efficacy of Tramadol /paracetamol was better than that of paracetamol, generally similar to, or better than that, of tramadol, and generally similar to that of ibuprofen or the fixed-dose combinations hydrocodoneparacetamol, codeineparacetamol and codeineparacetamolibuprofen. In addition, the analgesic efficacy of Tramadol/paracetamol did not differ significantly from that of gabapentin in patients with chronic pain associated with diabetic peripheral neuropathy. Tramadol/paracetamol had no additional tolerability issues relative to its components and, overall, the tolerability profile of Tramadol/paracetamol was generally similar to that of other active comparators (fixed-dose combinations or single-agents); however, incidences of some adverse events were lower in Tramadol/paracetamol than in active comparator recipients. Although additional comparative and long-term studies would help to definitively position Tramadol/paracetamol with respect to other analgesics, available clinical data suggest that Tramadol /paracetamol is a useful treatment option for providing multimodal analgesia in patients with moderate to severe pain. LG English.

( BUPP10527 - 16 September 2010) Opioid maintenance treatment during pregnancy under consideration of evidence-based research using the example of the <> study

Background: Opioid addiction during pregnancy constitutes a growing problem in the healthcare system because of the overall increasing rate of women developing opioid dependence. The use of illicit substances during pregnancy is associated with a range of adverse effects in newborns, mostly because of difficult life circumstances and the presence of medical and psychiatric comorbidities. Method: We conducted a literature research via pubmed.gov database and included recent studies on opioid maintenance treatment (OMT) during pregnancy and occurrence of neonatal abstinence syndrome (NAS). Results: Methadone maintenance therapy (MMT) is currently the preferable treatment, although it is associated with NAS in 60-80% of newborns. Buprenorphine appears to be an attractive treatment option, a lower rate of NAS being observed in some studies. Conclusions: Because previous findings are based mainly on retrospective studies and include methodological flaws, it is difficult to determine a valid interpretation of the advantages and disadvantages regarding the development and severity of NAS. The <> study can be seen as a model example for prospectively evidence-based research in this field.

( BUPP10526 - 16 September 2010) Musculoskeletal pain from multiple causes with a commentary from Germany and a commentary from Sweden

A case is presented of an individual with opioid-induced constipation that exacerbated the musculoskeletal pain for which the opioids were prescribed. Use of an opioid antagonist to help resolve this effect is described. Commentaries on the Irish case are provided by German and Swedish pain clinicians.

( BUPP10525 - 15 September 2010) Refractory fibromyalgia in a young woman with a commentary from Sweden and a commentary from Romania

A case report of fibromyalgia in a young woman who did not respond to traditional analgesic therapy is described. The use of transdermal buprenorphine and oral pregabalin did provide some relief as part of an interdisciplinary care plan. The commentary from Sweden addresses central sensitization and the preference for nonpharmacological therapy. The commentary from Romania discusses possible mechanisms of the pharmacotherapy used.

( BUPP10524 - 15 September 2010) What's new in shock september 2010?

( BUPP10523 - 15 September 2010) Effects of tramadol and buprenorphine on select immunologic factors in a cecal ligation and puncture model

Sepsis research relies on animal models. The models that most closely resemble clinical disease, such as cecal ligation and puncture, require surgery. After surgery, analgesics may not be included in experimental protocols because of concern over effects on inflammatory responses. This often generates animal welfare controversies within institutions; however, there are no scientific studies directly addressing the effects of analgesics on surgical models of sepsis. The purpose of this study was to characterize the effects of opioids on key parameters used in sepsis research. Female ICR mice were divided into four treatment groups (Ringer's lactate solution, high-or low-dose tramadol, buprenorphine) for 3-week mortality studies (n = 12 per treatment). Experimental groups were then repeated, and mice were killed at 12, 24, and 48 h postsurgery for cell counts, differentials, and cytokine levels in blood, peritoneum, and airways. Mortality studies demonstrated no significant differences between controls and any treatment group. However, significant differences were noted between buprenorphine and high-dose tramadol, revealing more and later deaths with tramadol. For comparison of immune parameters, Mann-Whitney U or Student t test was performed, emphasizing comparisons between treatment and control. Although several results were significant, comparisons between control and any treatment group yielded no differences that remained consistently apparent during the observation period. Again, differences were observed between the treatments. The results suggest that judicious and limited use of some analgesics may not dramatically affect the outcome of similarly conducted cecal ligation and puncture studies when compared with those not using analgesics. However, when different analgesics are used, comparisons between studies may be complicated.

( BUPP10522 - 15 September 2010) Impact of anesthesia, analgesia, and euthanasia technique on the inflammatory cytokine profile in a rodent model of severe burn injury

ABSTRACT: Anesthetics used in burn and trauma animal models may be influencing results by modulating inflammatory and acute-phase responses. Accordingly, we determined the effects of various anesthetics, analgesia, and euthanasia techniques in a rodent burn model. Isoflurane (ISO), ketamine-xylazine (KX), or pentobarbital (PEN) with or without buprenorphine were administered before scald-burn in 72 rats that were euthanized without anesthesia by decapitation after 24 h and compared with unburned shams. In a second experiment, 120 rats underwent the same scald-burn injury using KX, and 24 h later were euthanized under anesthesia or carbon dioxide (CO /sub 2/ ). In addition, we compared euthanasia by exsanguination with that of decapitation. Serum cytokine levels were determined by an enzyme-linked immunosorbent assay. In the first experiment, ISO was associated with elevation of cytokine-induced neutrophil chemoattractant 2 (CINC-2) and monocyte chemotactic protein 1 (MCP-1) , and KX and PEN was associated with elevation of CINC-1, CINC-2, IL-6, and MCP-1. Pentobarbital also decreased IL-1beta. IL-6 increased significantly when ISO or PEN were combined with buprenorphine. In the second experiment, euthanasia performed by exsanguination under ISO was associated with reduced levels of IL-1beta, CINC-1, CINC-2, and MCP-1, whereas KX reduced CINC-2 and increased IL-6 levels. Meanwhile, PEN reduced levels of IL-1beta and MCP-1, and CO /sub 2/ reduced CINC-2 and MCP-1. In addition, decapitation after KX, PEN, or CO /sub 2/ decreased IL-1beta and MCP-1, although we found no significant difference between ISO and controls. Euthanasia by exsanguination compared with decapitation using the same agent also led to modulation of several cytokines. Differential expression of inflammatory markers with the use of anesthetics and analgesics should be considered when designing animal studies and interpreting results because these seem to have a significant modulating impact. Our findings indicate that brief anesthesia with ISO immediately before euthanasia by decapitation exerted the least dampening effect on the cytokines measured. Conversely, KX with buprenorphine may offer a better balance during longer procedures to avoid significant modulation. Standardization across all experiments that are compared and awareness of these findings are essential for those investigating the pathophysiology of inflammation in animal models.

( BUPP10521 - 15 September 2010) Quality of life among opiate-dependent individuals: A review of the literature.

Quality of life (QoL) has become an important outcome indicator in health care evaluation. A clear distinction has to be made between Qo L - focussing on individuals' subjective satisfaction with life as a whole and different life domains - and health-related QoL (HRQoL), which refers to the absence of pathology. As opiate dependence is the primary drug of most persons entering treatment and as the attention for QoL in addiction research is growing, this review of the literature intends to summarise and differentiate the available information on QoL in opiate-dependent individuals. A comprehensive literature review was conducted, including database searches in Web of Science, Pubmed and Cochrane Database of Systematic Reviews. Articles were eligible for review if they assessed QoL or HRQoL of opiate-dependent individuals, used a QoL or HRQoL instrument and reported at least one specific outcome on QoL or HRQoL. In total, 38 articles have been selected. The review showed that various instruments (n=15) were used to measure QoL, mostly HRQoL instruments. Opiate-dependent individuals report low (HR)QoL compared with the general population and peo ple with various medical illnesses. Generally, participation in substitution treatment had a positive effect on individuals' (HR)QoL, but long-term effects remain unclear. Psychological problems, older age and excessive alcohol use seem to be related with lower (HR)QoL scores. The assessment of QoL in research on opiate dependence is still in its infancy. Still, the chronic nature of drug use problems creates the necessity to look at outcomes beyond the direct consequences of drug dependence and based on clients' needs. HRQoL, with its unilateral focus on the functional status of clients, does not give information on clients' own experiences about the goodness of life, and is as a consequence unsuitable for measuring QoL. Future research starting from a subjective, multidimensional approach of the concept of QoL is required.

( BUPP10520 - 15 September 2010) Transverse cordotomy and cuneiform cartilage amputation for the management of laryngeal paralysis in a dog

This paper describes the novel approach of transverse cordotomy and cuneiform cartilage amputation for the surgical management of laryngeal paralysis in a dog.

( BUPP10519 - 15 September 2010) Composition, purity and perceived quality of street cocaine in France

Background: There is little knowledge about the composition and cocaine content of street cocaine, nor about what users know about it. Method: 373 cocaine users were face to face interviewed between May and December 2006 about the last sample of cocaine they had consumed and residual amounts of the substances actually used were analysed using gas phase chromatography coupled to mass spectrometry (GC-MS). Users rated the perceived quality of their product (" good", " average" , " poor" ), its " estimated percentage of cocaine" and any cutting agents it contained. Price, quantity, place of purchase (street, dealer's premise, appointment), mode of administration (sniffing, injection, smoking) and the supposed nature of the sample (natural, synthetic, no distinction ever made) were also reported. Perceived quality was modelled using multivariate multinomial regression. Results: The median cocaine content was 22%. Altogether, 343 samples contained cocaine, among which 75% contained at least one adulterant. The most frequently occurring were phenacetin (54% of the samples), caffeine (17%), paracetamol (14%), diltiazem and lidocaine (11%). Users showed relatively poor discrimination concerning cocaine purity, and only 12% reported at least one of the detected adulterants. The major determinants of their perception of cocaine quality were: place of purchase, natural origin, price per gram, actual cocaine content and mode of administration. Conclusion: The composition of street cocaine is largely unknown to users. Users' perceptions of cocaine quality are based partly on false beliefs and certain administration modes. This may contribute to favouring very risky practices. The effects of adulterants on users' health should be investigated.

( BUPP10518 - 15 September 2010) Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia

Background: Buprenorphine maintenance is efficacious for treating opioid dependence, but problems with diversion and misuse of buprenorphine (BUP) may limit its acceptability and dissemination. The buprenorphine/naloxone combination tablet (BNX) was developed to reduce potential problems with diversion and abuse. This paper provides data regarding the characteristics of BUP injection drug users in Malaysia and preliminary data regarding the impact of withdrawing BUP and introducing BNX. BUP was introduced in 2002 and subsequently withdrawn from the Malaysian market in 2006. BNX was introduced in 2007. Methods: A two wave survey of BUP IDUs was conducted shortly prior to BUP withdrawal from the Malaysian market (n=276) and six months after BNX was introduced (n=204). Six focus groups with BUP and/or BNX IDUs were also conducted shortly before the second wave. Results: In addition to current BUP or BNX IDU, 96% of first wave participants and 97% second wave participants reported lifetime heroin IDU preceding the onset of their BUP/BNX IDU. Additionally, 58% of first and 64% of second wave survey participants reported current heroin IDU. Benzodiazepine abuse, often injected with BUP, was reported in both the surveys. Focus group participants reported that BNX was not as desirable as BUP, nonetheless, the results of the second wave survey suggest a continuing widespread BNX IDU, at least in Kuala Lumpur. Conclusions: In Malaysia, BUP and BNX IDU occur among heroin IDUs. The introduction of BNX and withdrawal of BUP may have helped to reduce, but did not eliminate the problems with diversion and abuse.

( BUPP10517 - 15 September 2010) Out of the medicine closet: Time to talk straight about prescription drug abuse

( BUPP10543 - 22 September 2010) Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)

Drug interaction with P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may influence its tissue disposition including blood-brain barrier transport and result in potent drug drug interactions. The limited data obtained using in-vitro models indicate that methadone, buprenorphine, and cannabinoids may interact with human P-gp; but almost nothing is known about drugs of abuse and BCRP. We used in vitro P-gp and BCRP inhibition flow cytometric assays with hMDR1- and hBCRP-transfected HEK293 cells to test 14 compounds or metabolites frequently involved in addiction, including buprenorphine, norbuprenorphine, methadone, ibogaine, cocaine, cocaethylene, amphetamine, N-methyl-3,4-methylenedioxyamphetamine, 3,4-methylenedioxyamphetamine, nicotine, ketamine, Delta(9)-tetrahydrocannabinol (THC), naloxone, and morphine. Drugs that in vitro inhibited P-gp or BCRP were tested in hMDR1- and hBCRP-MDCKII bidirectional transport studies. Human P-gp was significantly inhibited in a concentration-dependent manner by norbuprenorphine >buprenorphine> methadone > ibogaine and THC. Similarly, BCRP was inhibited by buprenorphine >norbuprenorphine> ibogaine and THC. None of the other tested compounds inhibited either transporter, even at high concentration (100 mu m). Norbuprenorphine (transport efflux ratio similar to 11) and methadone (transport efflux ratio similar to 1.9) transport was P-gp-mediated; however, with no significant stereo-selectivity regarding methadone enantiomers. BCRP did not transport any of the tested compounds. However, the clinical significance of the interaction of norbuprenorphine with P-gp remains to be evaluated.

( BUPP10542 - 22 September 2010) HIV Risk Behavior in Treatment-Seeking Opioid-Dependent Youth: Results From a NIDA Clinical Trials Network Multisite Study

Objective: To assess baseline rates of and changes in HIV drug and sexual risk behavior as a function of gender and treatment in opioid-dependent youth.Methods: One hundred fifty participants were randomly assigned to extended buprenorphine/naloxone therapy (BUP) for 12 weeks or detoxification for 2 weeks; all received drug counseling for 12 weeks. HIV risk was assessed at baseline and 4-week, 8-week, and 12-week follow-ups. Behavioral change was examined using generalized estimating equations.Results: Baseline rates of past-month HIV risk for females/males were 51%/45% for injection drug use (IDU) (ns), 77% /35% for injection risk (P < 0.001), 82%/74% for sexual activity (ns) , 14%/24% for multiple partners (ns), and 68%/65% for unprotected intercourse (ns). IDU decreased over time (P < 0.001), with greater decreases in BUP versus detoxification (P < 0.001) and females versus males in BUP (P < 0.05). Injection risk did not change for persistent injectors. Sexual activity decreased in both genders and conditions (P < 0.01), but sexual risk did not.Conclusions: Overall, IDU and sexual activity decreased markedly, particularly in BUP patients and females, but injection and sexual risk behaviors persisted. Although extended BUP seems to have favorable effects on HIV risk behavior in opioid-dependent youth, risk reduction counseling may be necessary to extend its benefits.

( BUPP10541 - 22 September 2010) Bortezomib-induced neuropathic pain: Evaluation of anti nociceptive effect of a new analgesic compound

( BUPP10540 - 21 September 2010) Assessment and management of acute pain in adult medical inpatients: A systematic review

Objective: To review the literature addressing effective care for acute pain in inpatients on medical wards. Methods: We searched Medline, PubMed Clinical Queries, and the Cochrane Database for systematic reviews published in 1996 through April 2007 on the assessment and management of acute pain in inpatients, including patients with impaired self-report or chemical dependencies. We conducted a focused search for studies on the timing and frequency of assessment, and on the use of patient-controlled analgesia (PCA) for nonsurgical pain. Two investigators performed a critical analysis of the literature and compiled narrative summaries to address the key questions. Results: We found no evidence that directly linked the timing, frequency, or method of pain assessment with outcomes or safety in medical inpatients. There is good evidence that treating abdominal pain does not compromise timely diagnosis and treatment of the surgical abdomen. Pain management teams and other systemwide interventions improve assessment and use of analgesics, but do not clearly affect pain outcomes. The safety and effectiveness of PCA in medical patients have not been studied. There is weak evidence that most cognitively impaired individuals can understand at least one self-assessment measure. Almost no evidence is available to guide management of pain in delirium. Evidence for managing pain in patients with substance abuse disorders or chronic opioid use is weak, being derived from case reports, retrospective studies, and expert opinion. Conclusions: Pain is a prevalent problem for medical inpatients. Clinical research is needed to guide the assessment and management of pain in this setting.

( BUPP10539 - 21 September 2010) Pain behavior measures to quantitate joint pain and response to neurotoxin treatment in murine models of arthritis

To evaluate the validity of newly developed pain behavior measures in two murine models of inflammatory arthritis and to determine the ability of these measures to evaluate the analgesic effectiveness of intra-articular (IA) botulinum toxin type A (BoNT/A) for treatment of arthritis pain. Design: Acute inflammatory arthritis was produced in adult female mice by IA injection of carrageenan and chronic inflammatory arthritis by IA injection of CFA. The presence of arthritis was confirmed by the presence of swelling and erythema. A menu of pain behavior measures was devised for quantitating pain in these models including tenderness, and spontaneous nocturnal wheel running. Toxicity due to neurotoxin was measured as gross limb weakness and impaired functional ability during wheel running. Results: Tenderness measures and spontaneous nocturnal wheel-running are valid measures of arthritis pain and are sensitive to the effects of analgesia. Narcotic analgesics are effective, but in fully analgesic doses impair wheel-running. IA BoNT/A is an effective analgesic for chronic arthritis pain, but not for acute arthritis pain. High doses can produce local limb muscle weakness, which impairs wheel-running function. Doses of botulinum toxin that are not toxic retain their analgesic function. Conclusions: Tenderness and spontaneous pain behavior measures are valid and sensitive for the measurement of pain and analgesia in murine models of inflammatory arthritis. Effective narcotic analgesia produces a decline in function in mice similar to that seen in humans. A neurotoxin is a promising therapy for chronic inflammatory arthritis but may not be effective for acute arthritis pain.

( BUPP10538 - 21 September 2010) Opioid formulations designed to resist/deter abuse

Physicians who prescribe opioid analgesics for patients with moderate to severe chronic pain face a balancing act in the wake of the current publicity regarding abuse (nonmedical use) of prescription pain killers. There is a spectrum of opioid abuse ranging from those who misuse the drug by not following doctors orders to those who take the drugs to achieve a high or divert the drugs to the street market for profit. Formulations of opioid analgesics designed to resist or deter abuse have been proposed, and are now either on the market or in the pipeline. These are innovative formulations that make the drug less convenient or less desirable to abusers. This article examines three such new products along with clinical studies that report on their safety and effectiveness. These drugs include extended-release morphine with sequestered naloxone (Embeda�), controlled-release oxycodone in a high-viscosity hard gelatin capsule (Remoxy�) and an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent (Acurox� with niacin tablets).Extended-release morphine with sequestered naltrexone offers a pharmacological barrier in that pellets of morphine surround an internal core of naltrexone (ratio 100:4 of morphine:naltrexone), which is released if the tablet is compromised by chewing or crushing. The hard gelatin capsule of controlled-release oxycodone was designed to resist tampering and the drug cannot be extracted with a needle. The immediate-release oxycodone formulation with subtherapeutic niacin uses a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The subtherapeutic niacin is intended to induce flushing and other unpleasant effects if the drug is taken in an excessive quantity. While these drugs hold individual promise, it remains undetermined if they can truly prevent abuse. Drug-seeking individuals are extremely resourceful and show little loyalty to a particular drug when other drugs are available. It is possible that abuse-deterring formulations may divert such individuals to find other drugs that are easier to compromise. Nevertheless, these formulations are important innovations and warrant further study to assess their appropriate role as analgesics.

( BUPP10537 - 21 September 2010) Substance misuse in pregnancy. SO , {Obstet-Gynaecol- Reprod-Med}, September 2010, vol. 20, no. 9, p. 278-283, 11 refs, ISSN: 1751-7214. Publisher: Churchill Livingstone, 1-3 Baxter's Place, Leith Walk, Edinburgh, EH1 3AF, UK. AU .

Substance misuse is a common problem complicating pregnancy and childbirth. Multidisciplinary care is necessary to optimize outcomes because the financial, psychological, social and domestic problems associated with drug misuse are often of greater importance than the physical and medical concerns. A specialist midwife is ideally placed to coordinate the involvement of acute hospital trusts, community midwives, general practitioners, mental health and drug services, social services and sometimes the police. The aim during pregnancy is to engage the client with these multiple agencies, to help bring a degree of order, and to reduce the harm associated with substance misuse. Abstinence and detoxification are not necessarily the priority. This review illustrates the general principles of managing substance misuse in pregnancy using three case scenarios covering both drug and alcohol misuse

( BUPP10536 - 21 September 2010) Methadone, buprenorphine, and street drug interactions with antiretroviral medications

While street drugs appear unlikely to alter the metabolism of antiretroviral (ARV) medications, several ARVs may induce or inhibit metabolism of various street drugs. However, research on these interactions is limited. Case reports have documented life-threatening overdoses of ecstasy and gamma-hydroxybutyrate after starting ritonavir, an ARV that inhibits several metabolic enzymes. For opioid addiction, methadone or buprenorphine are the treatments of choice. Because a number of ARVs decrea se or increase methadone levels, patients should be monitored for methadone withdrawal or toxicity when they start or stop ARVs. Most ARVs do not cause buprenorphine withdrawal or toxicity, even if they alter buprenorphine levels, with rare exceptions to date including atazanavir/ritonavir associated with significant increases in buprenorphine and adverse events related to sedation and mental status changes in some cases. There are newer medications yet to be studied with methadone or buprenorphine. Further, there are many frequently used medications in treatment of complications of HIV disease that have not been studied. There is need for continuing research to define these drug interactions and their clinical significance.

( BUPP10535 - 21 September 2010) Effects of experimental Unemployment, Employment and Punishment analogs on opioid seeking and consumption in heroin-dependent volunteers

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only+Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8mg/day) volunteers first sampled two HYD doses (0 and 24mg IM in randomized, counterbalanced order, labeled Drug A (session 1) and Drug B (session 2)). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3h after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only+Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased P /sub max/ (i.e., lower " essential value" of HYD) and O /sub max/ (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability. Clinical Trail registration number: NCT00608504 (ClinicalTrials.gov).

( BUPP10534 - 21 September 2010) The PRISCUS list. SO , {Dtsch-Apoth-Ztg}, 19 August 2010, vol. 150, no. 33, p. 44-53, 17 refs, CODEN: DAZEA, ISSN: 0011-9857. Publisher: Deutscher Apotheker Verlag, Birkenwaldstr.44,, Stuttgart, 70191, Germany. AU . LG German.

( BUPP10533 - 21 September 2010) Repeated psychological stress-induced alterations of visceral sensitivity and colonic motor functions in mice: influence of surgery and postoperative single housing on visceromotor responses

Visceral pain modulation by chronic stress in mice has been little studied. Electromyography (EMG) recording of abdominal muscle contractions, as a proxy to the visceromotor response (VMR), requires electrode implantation and post-surgical single housing (SH) which could affect the VMR to stress. To test this hypothesis, male mice had electrode implantation surgery (S) plus SH, or no surgery and were group housed (NS-GH) or single housed (NS-SH) and exposed to either water avoidance stress (WAS, 1 h/day) or left undisturbed in their home cages for 10 days. The VMR to phasic ascending colorectal distension (CRD) was assessed before (basal) and 24 h after 10 days of WAS or no stress using a surgery-free method of intraluminal colonic pressure (ICP) recording (solid-state manometry). WAS heightened significantly the VMR to CRD at 30, 45, and 60 mmHg in S-SH vs. NS-GH, but not compared to NS-SH conscious mice. Compared to basal CRD, WAS increased VMR at 60 mmHg in the S-SH group and decreased it at 30-60 mmHg in NS-GH mice, while having no effect in NS-SH mice. The average defecation during the hour of repeated WAS over 10 days was 1.9 and 2.4 fold greater in S-SH vs. NS-GH and NS-SH mice, respectively. These data indicate that the combination of S-SH required for VMR monitoring with EMG is an important component of repeated WAS-induced post-stress visceral hypersensitivity and defecation in mice. Grant ID: AM41301, Acronym: AM, Agency: NIADDK NIH HHS, United States Grant ID: DK-33061, Acronym: DK, Agency: NIDDK NIH HHS, United States Grant ID: DK-78676, Acronym: DK, Agency: NIDDK NIH HHS, United States Grant ID: DK41301, Acronym: DK, Agency: NIDDK NIH HHS, United States Grant ID: P50 DK-64539, Acronym: DK, Agency: NIDDK NIH HHS, United States Grant ID: R01DK-57238, Acronym: DK, Agency: NIDDK NIH HHS, United States Grant ID: T32 DK07180-33, Acronym: DK, Agency: NIDDK NIH HHS, United States

( BUPP10532 - 21 September 2010) Case management: ongoing evaluation of patients' needs in an opioid treatment program

PURPOSE/OBJECTIVE: Case management has been widely used in mental health and substance abuse services. There have been only a few studies that have examined the use of case management in opioid-treatment programs. In a project funded by the Centers of Substance Abuse Treatment, we looked at the use of case managers and specifically at the treatment needs of this unique population. Our case managers, with the aid of research assistants, surveyed the treatment needs of 189 patients entering an opioid-treatment program over a 3-year period. Patients completed the Needs Assessment Instrument at intake, 6 months, and 12 months. PRIMARY PRACTICE SETTING(S): The use of case managers to assess the needs of opioid-dependent patients is applicable to substance abuse treatment setting especially in opioid-treatment programs that provide methadone or buprenorphine maintenance. FINDINGS/CONCLUSIONS: The critical services most requested were vocational, employment, transportation, dental, emotional, and smoking cessation. There were changes over the 12-month follow-up period in the types and priority of services requested. IMPLICATION FOR CASE MANAGEMENT PRACTICE: The Needs Assessment Instrument is a useful tool for case mangers to assess treatment needs of patients and the overall clinic population. Once sufficient patients have been surveyed, the opioid-treatment program can plan needed services for the clinic. Specific social agencies can be contacted to provide key services. Service needs are not static and as patients improve they may need a different mix of services to support their continued abstinence.

( BUPP10556 - 29 September 2010) From methadone to buprenorphine or back to methadone. The Croatian experience

In Croatia maintenance treatment is made widely available through a network of GP offices that covers the whole of the country. More than 50% of all GPs in Croatia have at least one patient in MT. Methadone was the only opioid agonist used for over a decade, but this changed when buprenorphine was introduced 4 years ago. There is little difference in the regimen for the prescription and provision of the two medications: both are free of charge and are prescribed by GPs; in addition, there are not restrictions on the dose to be used or on 'take-home' policy. The decision on which medication will be sued is based exclusively on the clinical assessment and patient-doctor agreement. The example of Croatia gives an opportunity to compare the acceptance of this medication by patients and doctors in situations of equal availability.

( BUPP10555 - 29 September 2010) Additional take-home dosages

Objectives: The objective of the study was to analyse the practice e of giving take-home dosages of opioid medications to patients with reference to the reasons for and the quantity of the medications given as additional or extra take-home dosages. Methods: All the patients were checked regarding the kind of medication, urine samples, reasons for extra take-home dosages and their quantity. Results: Of the 150 patients selected for the group in the programme, 27 needed one or more extra take-home dosages in 2007. 10 (11*) of those patients had negative urine samples for all illicit drugs and never used alcohol at any stage of the year of the study. 7 used alcohol and benzodiazepines more often. Among the reasons for extra take-home dosages, hard physical work was listed 7 times, vomiting because of the bad taste of the medication 3 times, difficulties in initiating medical therapy after entering the programme 3 times, vomiting as a part of illness twice and lowering the dosage too quickly twice. Other reasons were listed once each. Altogether, the percentage of the overall quantity of medications received by patients during the year as extra take-home dosages was: 0.47% for methadone, 0.75% for buprenorphine and 0.10% for SR morphine. Conclusions: Reviewing the fairly good results of treatment at the centre, therapeutic decisions to give additional take-home dosages to the patients have proved to be reasonable and usually correct. Throughout this study a continual therapeutic wish to achieve a better understanding of opioid addiction as just one among other chronic diseases has been made evident.

( BUPP10554 - 29 September 2010) (Impact of slow-release oral morphine on drug abusing habits in Austria)

A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is therefore objected.

( BUPP10553 - 29 September 2010) Effect of opiate maintenance therapy on intrapartum fetal heart rate patterns

( BUPP10552 - 29 September 2010) Buprenorphine dose changes during gestation

( BUPP10551 - 29 September 2010) Perioperative analgesia for opioid tolerant patients

In this review article the special anesthesiological problems of opioid tolerance and surgical interventions will be presented. These affect patients with a long-term opioid therapy of chronic pain, addicts with long-term substitution therapy and addicts with current or previous heroin addiction ("clean"). For all patient groups a guarantee of continuous and adequate analgesia (avoidance of fear and increasing patient compliance), exploiting suitable regional anesthesia or regional analgesia procedures when possible, and prevention of a physical opioid withdrawal syndrome have utmost priority. The necessary optimization of perioperative pain therapy only succeeds when based on a thorough preoperative examination of the clinical history which subtly inquires into the drug taking habits with respect to opioids and associated medications. Systemic and/or regional analgesia procedures are possible. Regional procedures are more effective for analgesia. Systemic analgesia procedures do not basically differ from those routinely used for patients without opioid tolerance. However, higher doses of opioids are necessary as well as individual titration according to needs. Special conditions apply to patients previously addicted to opioids (clean) when they are to be operated on. Non-opioids are sufficiently effective for low level pain and opiates can be avoided. Opioid therapy with inclusion of a non-opioid is necessary following major operations or for severe postoperative pain, even as i.v. patient-controlled analgesia (i.v. PCA) if needed. For these patients a relapse to addiction can be provoked by insufficient administration of analgesics, not by pain management including opioids.

( BUPP10550 - 29 September 2010) Report from the USA

( BUPP10549 - 29 September 2010) Rifaximin.

( BUPP10548 - 29 September 2010) Testing for illicit drug use in mental health services

Testing for illicit drug use is used in pre-employment checks, the criminal justice system, sports medicine and for screening and confirmatory purposes in patients with physical and mental illnesses. The types of drugs tested for and the methods used vary depending on the indication. This article focuses primarily on blood, urine and oral fluids, which are specimens more commonly used in mental health settings, although hair and sweat are increasingly used in medico-legal cases and in child protection issues. The main drugs and their metabolism are discussed to gain a better understanding of the methods used and for accurate interpretation. Methods to ensure validity during sample collection are explored. False-positive and false-negative tests are common and possible confounders are discussed.

( BUPP10547 - 29 September 2010) Acute effects of sublingual buprenorphine on brain responses to heroin-related cues in early-abstinent heroin addicts: An uncontrolled trial

Replacement therapy with buprenorphine is clinically effective in reducing withdrawal and craving for heroin during detoxification but not in decreasing the probability of relapse after detoxification. This study examined the acute effects of buprenorphine on brain responses to heroin-related cues to reveal the neurobiological and therapeutic mechanisms of addiction and relapse. Fifteen heroin addicts at a very early period of abstinence, were studied in two separate periods 10-15 min apart: an early period (5-45 min) and a later period (60-105 min) after sublingual buprenorphine, roughly covering the onset and peak of buprenorphine plasma level. During both periods, fMRI scanning with heroin-related visual stimuli were performed followed by questionnaires. Under effect of buprenorphine, brain responses to heroin-related cues showed decrease in amygdala, hippocampus, ventral tegmental area (VTA) and thalamus but no changes in ventral striatum and orbital-prefrontal-parietal cortices. As an uncontrolled trial, these preliminary results suggest that buprenorphine has specific brain targets in reducing withdrawal and craving during early abstinence, and that ventral striatum and orbital-prefrontal-parietal cortices may be the key targets in developing therapy for drug addiction and relapse.

( BUPP10546 - 29 September 2010) Medication reviews and deprescribing: Consideration to case medications

( BUPP10545 - 29 September 2010) New drugs approved by the FDA; New dosage forms and indications approved by the FDA; Agents Pending FDA Approval; New Drug/Biologics License Applications Filed by Manufacturer; Significant Labeling Changes or "dear Health Professional" Letters Related to Safety.

( BUPP10544 - 29 September 2010) A signal for an abuse liability for pregabalin-results from the Swedish spontaneous adverse drug reaction reporting system.

AB Purpose: Pregabalin is a gamma-aminobutyric acid (GABA) analogue approved for the treatment of epilepsy, neuropathic pain and generalised anxiety disorder. As a GABA analogue, there has been some concern about an abuse liability. We aimed to investigate the possible abuse liability of pregabalin. Methods: By applying a Bayesian data-mining algorithm to reports of possible drug abuse or addiction in the Swedish national register of adverse drug reactions (SWEDIS), we calculated the information component (IC) for pregabalin and reports of abuse and addiction. Results: Out of 198 reports indicative of abuse or addiction to any drug, 16 concerned pregabalin. The IC became significantly elevated in the fourth quarter of 2008, rising to 3.99 (95% confidence interval 3.21-4.59) at the end of 2009. Conclusion: Based on the signal from the present study, we conclude that pregabalin is likely to be associated with an abuse potential.

( BUPP10577 - 14 October 2010) Pregnancy under subutex (buprenorphine): opinions expressed on French internet forums

Internet forums record the opinions and advice exchanged about pregnancy under Subutex. Two hundred and fourteen messages under 92 nicknames from four forums, especially dedicated to this subject in France, from August 2005 to July 2008 were collected and analyzed with QSR NIVIVO8. Most of the Internet users were women, pregnant, or with children, using Subutex. Very few professionals took part in them. The analysis of the opinions and representations of this substance, of medical practices, of exchanged advice, particularly on posology, was realized by the construction of a thematic tree.

( BUPP10576 - 14 October 2010) Buprenorphine: a more accessible treatment for opioid dependence

( BUPP10575 - 14 October 2010) Transdermal drug delivery

Transdermal drug delivery is a validated technology contributing significantly to global pharmaceutical care. Since 1980, impressive growth in this field has been observed with many commercial successes; importantly, a new chemical entity was recently developed and approved for transdermal administration without having first been given as an injectable or oral dosage form. The progress achieved has been based on the clearer understanding of skin barrier function, and of the physicochemical, pharmacokinetic and physiological factors which underpin the feasibility of transdermal administration. Novel, non-invasive approaches to enhance and control drug transport across the skin are under intensive investigation, and some technologies, e.g. iontophoresis, have reached true maturity. The "local", subcutaneous delivery of drugs (for example, to underlying muscle and other tissues) is gaining increasing acceptance, and new opportunities in this under-subscribed area may be envisaged

( BUPP10574 - 14 October 2010) Mechanism-based selection of compounds for the development of innovative in vitro approaches to hepatotoxicity studies in the LIINTOP project

The 6th European Framework Programme project LIINTOP was specifically raised to optimise and provide established protocols and experimental in vitro models for testing intestinal and liver absorption, metabolism and toxicity of molecules of pharmacological interest. It has been focused on some of the most promising existing liver and intestine in vitro models with the aim of further improving their performance and thus taking them to a pre-normative research stage. Regarding the specific area of the liver, a first basic approach was the optimisation of in vitro hepatic models and the development and optimisation of in vitro approaches for toxicity screening. New advanced technologies have been proposed and developed in order to determine cellular and molecular targets as endpoints of drug exposure. A key issue in the development and optimisation of in vitro hepatotoxicity screening methods was the selection of structurally diverse suitable hepatotoxic reference model compounds to be tested. To this end, a number of solid selection criteria were defined (drugs preferably than chemical agents, well-documented hepatotoxicity in man and well-defined mechanism/s of hepatotoxicity, commercially available no volatile compounds with unequivocal CAS number and chemical structure), the strategy followed, including all resources consulted, is described and the selected compounds are extensively illustrated.

( BUPP10573 - 14 October 2010) Buprenorphine maintenance in pregnancy

( BUPP10572 - 14 October 2010) Disparity between heroin addicts enrolled in maintenance treatment and detoxification treatment and its implication

Fundamentally, detoxification treatment aims to stop substance use behavior among the opioid addicts, while maintenance treatment aims to promote a healthier addiction behavior among the subjects by providing safer chemical substitutes. In this study, we evaluated the differences of social-demographics and clinical features between heroin addicts enrolled in detoxification and maintenance treatment. Data of 748 heroin addicts admitted for maintenance treatment or detoxification treatment between January 2004 and October 2007 were retrieved. Statistical analyses showed that older mean age, school dropout, drug offence, property offence, HCV and HIV infections, and older age of 3,4-methylenedioxymethamphetamine co-use, were significantly associated with maintenance treatment. Only a small number of patients chose detoxification treatment to treat their problems. The preference of maintenance treatment rather than detoxification treatment can be partially explained by financial concerns, either because the maintenance treatment is free or cheaper. Overall speaking, patients in detoxification treatment were relatively healthier in the aspects of social-demographics and clinical features compared to patients in maintenance treatment. Finding of this study should be concerned when designing treatment profiles, modifying of original treatment profiles or identifying target problems of a treatment profile.

( BUPP10571 - 14 October 2010) Pain and analgesia in domestic animals

The biggest challenge to the use of analgesic agents in animals is the determination of the efficacy of these agents. In humans, the verbal communication of the alleviation of pain is fundamental to the effective use of analgesics. In animals, the lack of verbal communication not only confounds the diagnosis and characterisation of the experience of pain, but also challenges the evaluation of the analgesic therapy. As animals possess the same neuronal pathways and neurotransmitter receptors as humans, it seems reasonable to expect that their perceptions of painful stimuli will be similar, and this is a basis for the use of laboratory animals for screening of analgesics for human use. However, as the evaluation in the laboratory animal tests is based mainly on behavioural responses, and although some physiological responses do occur, it is often difficult to separate these from stress responses. The use of behavioural responses to evaluate analgesics in a range of species is complicated by the fact that different species show different behaviours to a similar pain stimulus, and different pain stimuli produce different pain responses in the same species. Thus behaviours may be species-and pain-specific and this can complicate analgesic evaluation. As most animals possess similar neuronal mechanisms to humans for pain perception, it is not surprising that the standard human pain control strategies can be applied to animals. For instance, local anaesthetics, opioids, non-steroidal anti-inflammatory drugs (NSAIDs) , as well as other analgesics used in humans are all found to be effective for animal use. Differences in metabolism and distribution between various species, as well as financial considerations in larger animals can affect efficacy and thus limit their use. In addition, the use of any drug in a species that may be intended for human consumption will be limited by residue considerations. The treatment of pain in animals presents many challenges, but the increasing public concerns regarding animal welfare will ensure that studies into the nature and control of animal pain will continue to have a high profile.

( BUPP10570 - 14 October 2010) Misuse of alcohol during opiate substitution treatment

Context: Although alcohol misuse is a common phenomenon during opiate substitution treatment, the etiologic explanations advanced for it are generally no more than speculative. OBJECTIVES: To identify differences in alexithymia, self-esteem, and temperament among patients undergoing methadone or buprenorphine substitution treatment having excessive alcohol consumption from those who have not. DESIGN: This was an open prospective study conducted from September 2007 to January 2008. SETTING: The cohort was recruited from 9 drug addiction treatment centers in 2 regions of France, Alsace and Moselle. PARTICIPANTS: The study was based on 203 patients on opiate substitution programs whose dosage had been stable for at least 1 month and who had given their consent to take part. MAIN MEASUREMENT TOOLS: The participants completed a series of self-administered questionnaires in the treatment centers: Alcohol Use Disorders Identification Test (AUDIT), Toronto Alexithymia Scale (TAS-20), Coopersmith's Self-Esteem Inventory (SEI), Temperament and Character Inventory (TCI-R). RESULTS: We observed high alexithymia scores, low self-esteem scores, and low self-directedness scores among patients with excessive alcohol consumption. CONCLUSIONS: We make some recommendations for new therapeutic approaches.

( BUPP10569 - 14 October 2010) Impact of setting of care on pain management in patients with cancer: A multicentre cross-sectional study

Background: No study has so far addressed whether differences do exist in the management of cancer-related pain in patients admitted to oncology and non-oncology settings. Patients and methods: A multicentre cross-sectional study in 48 Italian hospitals has enrolled 819 patients receiving analgesic therapy for cancer-related pain. Demographics and clinical and analgesic therapy information have been prospectively collected by standardized forms. Adequacy of pain management has been evaluated by the Pain Management Index (PMI) .Results: Differences in the analgesic drug administration according to settings of care have been evident, non-opioids more frequently being administered in non-oncology units (19.6% versus 7.0%; P <0.0001), while strong opioids are more frequently used in the oncology units (69.5% versus 51.9%; P < 0.0001). The number of patients receiving inadequate therapy (PMI < 0) has lowered in oncology compared with non-oncology units (11.3% versus 18.8%; P = 0.0024). Results of multiple logistic regression analysis have shown that the admission to non-oncology setting (odds ratio (OR) = 1.75, 95% confidence interval (CI) = 1.15-2.67; P = 0.0096) and the absence of metastatic disease (OR = 1.60, 95% CI = 1.04-2.44; P = 0.0317) were independent factors associated with an increased risk of receiving an inadequate analgesic therapy.Conclusion: Oncology wards provide the most adequate standard of analgesic therapy for cancer-related pain.

( BUPP10568 - 14 October 2010) Methadone treatment for pregnant heroin addicted women. SO , {Heroin-Addict-Relat- Clin-Probl}, June 2010, vol. 12, no. 2, p. 29-36, 72 refs, ISSN: 1592-1638. Publisher: Pacini Editore s.r.l., Via A. Gherardesca 1, Ospedaletto (Pisa), 56121, Italy. AU .

A review of methadone-related issues and the approach to heroin addicted patients is presented with the aim to clarify what is practiced by the establishment of anti-craving treatment and what is expected within a history of addiction. A series of clinical situations occurring throughout pregnancy to early child development are described, and the etiological hypothesis discussed. Moreover, some methodological considerations are described in order to better understand some ambiguity about the effectiveness and harmlessness of methadone treatment, particularly with regard to neonatal opiate withdrawal. Limitations to the outcome of pregnancies in heroin addicted women seems to be due to misconceptions about methadone toxicity and neonatal damage, which may lead to the mishandling of methadone as a therapeutic modality, especially with regard to maintenance at effective dosages.

( BUPP10593 - 20 October 2010) Ranking the harm of alcohol, tobacco and illicit drugs for the individual and the population

Drug policy makers continuously face a changing pattern of drug use, i.e. new drugs appear on the market, the popularity of certain drugs changes or drugs are used in another way or another combination. For legislative purposes, drugs have mostly been classified according to their addictive potency. Such classifications, however, lack a scientific basis. The present study describes the results of a risk assessment study where 19 recreational drugs (17 illicit drugs plus alcohol and tobacco) used in the Netherlands have been ranked by a Dutch expert panel according to their harm based on the scientific state of the art. The study applies a similar approach as recently applied by Nutt et al. (Lancet 2007; 369:1047-1053), so that the results of both studies could be compared. The harm indicators scored are acute and chronic toxicity, addictive potency and social harm. The aim of this study is to evaluate whether the legal classification of drugs in the Netherlands corresponds with the ranking of the drugs according to their science-based ranking of harm. Based on the results, recommendations are formulated about the legal classification of recreational drugs at national and international level which serves a rational approach for drug control.

( BUPP10592 - 20 October 2010) Aetiology and management of diabetic peripheral neuropathy.

Aetiology: Painful diabetic neuropathy affects approximately 25% of diabetic patients, those treated with insulin and/or glucose lowering drugs, and is characterised by presenting as a distal symmetric neuropathy associated with chronic pain. Pathophysiology: The cause is generally vascular, which produces a lesion of the primary sensory nerves due to neuronal hypoxia and lack of nutrients. Symptoms: The onset is usually bilateral in the toes and feet. In cases where it is asymmetric, it progresses to be bilateral. It can gradually progress to the calves and the knees, in which case the patient may experience symptoms of pain and/or paresthesia both in the hands and feet ("glove-stocking" pattern). They describe the pain using diverse terms: burning, electric, deep, etc. Allodynia and hyperalgesia are less common. The pain intensity is usually gets worse at night. Other symptoms: vascular claudication, dysautonomic signs (skin colour, abnormal temperature, sweating), depression and anxiety, sleep disorders. Physical findings: Sensory loss and the loss or decrease in Achilles tendon reflex is characteristic in "glove-stocking", although some patients who only have small nerve fibres involvement may have normal reflexes and vibratory sensitivity. Diagnosis: It is clinical. There is no need for electro-physiological studies when the history and physical findings are consistent with the diagnosis of painful diabetic neuropathy. Natural history: The natural history of painful diabetic neuropathy varies and its clinical course unpredictable. In some patients, the pain may improve after months or years, while in others it persists and gets worse. Treatment: Due the great number of causal and contributing factors in the pathogenesis of diabetic neuropathy, there is no single satisfactory treatment. The maintenance of a glycosylated haemoglobin between 6.5 and 7.5% can slow down and even prevent the progression of neuropathy. The current treatment recommendations for painful diabetic neuropathy can be seen in table 5 and figure 1.

( BUPP10591 - 20 October 2010) Kidney transplantation in mice using left and right kidney grafts

Background. Mouse kidney transplantation is a powerful tool for scientific research. The conventional method uses only the left donor kidney for grafting because of shorter renal vessels on the right side. Materials and Methods. We developed a new technique of harvesting both left and right kidneys from one donor mouse, and separately transplanted them into two recipients. Forty-six kidney grafts (23 left, 23 right kidneys) were transplanted to 46 recipient mice. Life-supporting kidney transplantation (in which both recipient kidneys were removed) was performed in 12 recipients (six of each group). Results. Cold ischemia times were considerably longer for the second kidney graft (2.5-3 versus 1 h), which resulted in reduced graft function at early time points. However, the 14 d survival rate was comparable with 80% for right and 70% for left kidney grafts. Recipient animals were sacrificed between 1 and 6wkafter transplantation. Histologic examination of surviving grafts showed intact renal parenchyma, whereas total necrosis was usually seen in failed grafts. The causes of graft failurewerethrombosis of the renal artery, narrowoutflow of the renal vein, and fistula of the ureter. In a subgroup of animals, specific staining for apoptosis was performed. A tendency for a higher rate of apoptosis was seen at 1 wk compared with 6 wk post-transplant, but no correlation with cold ischemia time was found. Conclusion. We report a new microsurgical technique of mouse kidney transplantation using both right and left donor kidneys as grafts for two recipient mice. Right kidney grafts showed equal survival compared with left kidney grafts. Thus, this technique reduces overall operating time and costs for microsurgery experiments.

( BUPP10590 - 20 October 2010) Oxymorphone extended-release tablets (Opana ER) for the management of chronic pain: A practical review for pharmacists.

( BUPP10589 - 20 October 2010) Buprenorphine: A new alternative in the treatment of opioid addiction

Opioid addiction is a complex disease with severe biological, psychological, and social impacts in the life of the individual, his family and the society. Besides heroin, misuse and abuse of prescription opioid pain medications are rising. Current pharmacological maintenance therapy with methadone accompanied by appropriate psychosocial treatments is a highly effective treatment for opioid addiction. However, due to strict regulations, limited availability, and abuse risk of methadone, new and practical approaches are required. Buprenorphine, a high affinity partial mu opioid agonist, allows qualifying physicians to offer treatment in office-based settings for the detoxification or maintenance of individuals with opioid addiction.

( BUPP10588 - 20 October 2010) Analgesic requirements after major abdominal surgery are associated with OPRM1 gene polymorphism genotype and haplotype

Aims: The association between SNPs of the human OPRM1 gene encoding the -opioid receptor and postoperative analgesic requirements in surgical patients remains controversial. Here, we evaluate whether any of the five tag SNPs (A118G, IVS2+G691C, IVS3+G5953A, IVS3+A8449G and TAA+A2109G) representing the four linkage disequilibrium blocks of the OPRM1 gene influences postoperative analgesic requirements. Materials & methods: We studied 138 adult Japanese patients who underwent major open abdominal surgery under combined general and epidural anesthesia and received continuous postoperative epidural analgesia with opioids. Results: The 118G homozygous (GG) patients required 24-h postoperative analgesics more than 118A homozygous (AA) and heterozygous (AG) patients. Tag SNP haplotypes also were associated with 24-h postoperative analgesic requirements. Conclusions: These results suggest that OPRM1 gene tag SNP genotypes and haplotypes can primarily contribute to prediction of postoperative analgesic requirements in individual patients undergoing major open abdominal surgery.

( BUPP10587 - 20 October 2010) Pharmacotherapy of pain

Pain is a subjective unpleasant sensation. When acute, pain serves its fundamental protective function, alerting the body to possible damage. Chronic pain, however, loses this very function and becomes a disease in itself. Pharmacotherapy is one of the most effective therapeutic options. The main strategies for pain management are derived from the WHO three-step analgesic ladder or, more recently, the "lift system" has been used. Strong opioids play a major role in the treatment of intense pain. Strict rules have to be followed when these opioids are commenced, used and discontinued. It is the only way to achieve the maximum therapeutic effect and minimize the risk of developing adverse effects or psychic dependence.

( BUPP10586 - 20 October 2010) Inpatients farmacotherapy of acute pain, overview

Acute pain may result from injury, trauma, surgery, or medical procedures, and can lead to significant emotional, cognitive, and sensory consequences. Though acute pain, by definition, is short-lived and intensive, it can have significant and detrimental effects on the patient's quality of life, postoperative period and can lead to chronic pain states if left undertreated. The main goal of this article, is to provide the readers actually perspective of drugs which are used in acute pain management.

( BUPP10585 - 20 October 2010) Pharmacotherapy of neuropathic pain

Pathophysiologically, neuropathic pain (NPP) is one of the types of pain. It can occur alone or together with nociceptive pain, as mixed pain, in tumorous disease as well as for non-tumorous reasons. It is caused by a dysfunction of or damage to neural tissue at various sites, ranging from the periphery to central structures. Neuropathic pain has a typical clinical presentation which is very diverse. An underlying anatomic basis is not invariably found. One neuropathic syndrome may present with different symptoms. The treatment of NPP is difficult and not always successful. Pharmacotherapy is the mainstay of treatment that may help achieve an acceptable intensity of the pain. Anticonvulsants and tricyclic antidepressants (amitriptyline) are the first choice with opioids being the second. Some neuropathic pain syndromes are so difficult to manage that invasive procedures have to be used, such as spinal blockage, sympathetic or peripheral plexus blockage, and modern neuromodulation and radiofrequency techniques. Local treatment with lidocaine or capsaicin can be used as adjunct therapy for NPP; local NSAIDs are minimally effective.

( BUPP10584 - 20 October 2010) mu-opioid receptors: Correlation of agonist efficacy for signalling with ability to activate internalization

We have compared the ability of a number of mu-opioid receptor (MOPr) ligands to activate G proteins with their abilities to induce MOPr phosphorylation, to promote association of arrestin-3 and to cause MOPr internalization. For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. Our results show that overall there is a very good correlation between efficacy for G protein activation and arrestin-3 recruitment, whereas a few agonists, in particular endomorphins 1 and 2, display apparent bias toward arrestin recruitment. The agonist-induced phosphorylation of MOPr at Ser /sup 375/ , considered a key step in MOPr regulation, and agonist-induced internalization of MOPr were each found to correlate well with arrestin-3 recruitment. These data indicate that for the majority of MOPr agonists the ability to induce receptor phosphorylation, arrestin-3 recruitment, and internalization can be predicted from their ability as agonists to activate G proteins. For the prototypic MOPr agonist morphine, its relatively weak ability to induce MOPr internalization can be explained by its low agonist efficacy.

( BUPP10583 - 19 October 2010) Targeting murine small bowel and colon through selective superior mesenteric artery injection

Administration of molecular, pharmacologic, or cellular constructs to the intestinal epithelium is limited by luminal surface mucosal barriers and ineffective intestinal delivery via systemic injection. Many murine models of intestinal disease are used in laboratory investigation today and would benefit specific modulation of the intestinal epithelium. Our aim was to determine the feasibility of a modified microsurgical approach to inject the superior mesenteric artery (SMA) and access the intestinal epithelium. We report the detailed techniques for selective injection of the SMA in a mouse. Mice were injected with methylene blue dye to grossly assess vascular distribution, fluorescent microspheres to assess biodistribution and viral vector to determine biological applicability. The procedure yielded good recovery with minimal morbidity. Tissue analysis revealed good uptake in the small intestine and colon. Biodistribution analysis demonstrated some escape from the intestine with accumulation mainly in the liver. This microsurgical procedure provides an effective and efficient method for delivery of agents to the small intestine and colon, including biological agents.

( BUPP10582 - 19 October 2010) Pain management in older people

At times providing pain relief in elderly patients can prove troublesome. Their tolerance and perception of pain can differ from that of younger patients, while the incidence of pain is above that found in those of less advanced years. Conventional approaches to providing pain relief can be successful, but the tolerance to the side-effects of those drugs used to provide pain relief can be less. Furthermore, polypharmacy can have implications for the range of analgesic drugs that can be considered. Fortunately there are an increasing range of medicinal products with reduced potential for side-effects that can be considered when treating older patients with pain.

( BUPP10581 - 19 October 2010) Why variability facilitates spinal learning

Spinal Wistar Hannover rats trained to step bipedally on a treadmill with manual assistance of the hindlimbs have been shown to improve their stepping ability. Given the improvement in motor performance with practice and the ability of the spinal cord circuitry to learn to step more effectively when the mode of training allows variability, we examined why this intrinsic variability is an important factor. Intramuscular EMG electrodes were implanted to monitor and compare the patterns of activation of flexor (tibialis anterior) and extensor (soleus) muscles associated with a fixed-trajectory and assist-as-needed (AAN) step training paradigms in rats after a complete midthoracic (T8-T9) spinal cord transection. Both methods involved a robotic arm attached to each ankle of the rat to provide guidance during stepping. The fixed trajectory allowed little variance between steps, and the AAN provided guidance only when the ankle deviated a specified distance from the programmed trajectory. We hypothesized that an AAN paradigm would impose fewer disruptions of the control strategies intrinsic to the spinal locomotor circuitry compared with a fixed trajectory. Intrathecal injections of quipazine were given to each rat to facilitate stepping. Analysis confirmed that there were more corrections within a fixed-trajectory step cycle and consequently there was less coactivation of agonist and antagonist muscles during the AAN paradigm. These data suggest that some critical level of variation in the specific circuitry activated and the resulting kinematics reflect a fundamental feature of the neural control mechanisms even in a highly repetitive motor task.

( BUPP10580 - 19 October 2010) Prediction of human metabolic clearance from in vitro systems: Retrospective analysis and prospective view

Purpose: To provide a definitive assessment of prediction of in vivo CL /sub int/ from human liver in vitro systems for assessment of typical underprediction. Methods: A database of published predictions of clearance from human hepatocytes and liver microsomes was compiled, including only intravenous CL /sub b/ . The influence of liver model (well-stirred (WS) or parallel tube (PT)), plasma protein binding and clearance level on the relationship between in vitro and in vivo CL /sub int/ was examined. Results: Average prediction bias was about 5- and 4-fold for microsomes and hepatocytes, respectively. Reduced bias using the PT model, in preference to the popular WS model, was only marginal across a wide range of clearance with a consequential minor impact on prediction. Increasing underprediction with decreasing fu /sub b/ , or increasing CL /sub int/ , was found only for hepatocytes, suggesting fundamental in vitro artefacts rather than failure to model potentially unequilibrated binding during rapid extraction. Conclusions: In contrast to microsomes, hepatocytes give a disproportionate prediction with increasing clearance suggesting limitations either at the active site, such as cofactor exhaustion, or with intracellular concentration equilibrium, such as rate-limiting cell permeability. A simple log linear empirical relationship can be used to correct hepatocyte predictions.

( BUPP10579 - 19 October 2010) A hybrid liquid chromatography-mass spectrometry strategy in a forensic laboratory for opioid, cocaine and amphetamine classes in human urine using a hybrid linear ion trap-triple quadrupole mass spectrometer

A rapid method has been developed to analyse morphine, codeine, morphine-3-glucuronide, 6-monoacetylmorphine, cocaine, benzoylegonine, buprenorphine, dihydrocodeine, cocaethylene, 3,4- methylenedioxyamphetamine, ketamine, 3,4-methylenedioxymethamphetamine, pseudoephedrine, lignocaine, benzylpiperazine, methamphetamine, amphetamine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine and methadone in human urine. Urine samples were diluted with methanol:water (1:1, v/v) and sample aliquots were analysed by hybrid linear ion trap-triple quadrupole mass spectrometry with a runtime of 12.5min. Multiple reaction monitoring (MRM) as survey scan and an enhanced product ion (EPI) scan as dependent scan were performed in an information-dependent acquisition (IDA) experiment. Finally, drug identification and confirmation was carried out by library search with a developed in-house MS/MS library based on EPI spectra at a collision energy spread of 35�15 in positive mode and MRM ratios. The method was validated in urine, according to the criteria defined in Commission Decision 2002 /657/EC. At least two MRM transitions for each substance were monitored in addition to EPI spectra and deuterated analytes were used as internal standards for quantitation. The reporting level was 0.05mugmL /sup -1/ for the range of analytes tested. The regression coefficients (r /sup 2/ ) for the calibration curves (0-4mugmL /sup -1/ ) in the study were 0.98. The method proved to be simple and time efficient and was implemented as an analytical strategy for the illicit drug monitoring of opioids, cocaines and amphetamines in criminal samples from crime offenders, abusers or victims in the Republic of Ireland. To the best of our knowledge there are no hybrid LC-MS applications using MRM mode and product ion spectra in the linear ion trap mode for opioids, cocaines or amphetamines with validation data in urine.

( BUPP10578 - 19 October 2010) Opioid-dopamine interactions: Implications for substance use disorders and their treatment

( BUPP10606 - 27 October 2010) Research for Recovery: A review of the Drugs Evidence Base

( BUPP10605 - 27 October 2010) Cochrane Review: What's there and what should be

The Cochrane Drugs and Alcohol Group aims to produce, update, and disseminate systematic reviews on the prevention, treatment, and rehabilitation of problematic drug and alcohol use. The objective of the present paper was to summarise the main characteristics of the published systematic reviews in the field of drug and alcohol dependence., in terms of the topics covered, methods used to produce the reviews, and available evidence. By Jan 2010, the Group had published 52 reviews with 694 primary studies included out of 2059 studies considered for inclusion. Of these publications, 44% were published in 12 journals, including Drug and Alcohol Dependence (11%) with the highest number of publications, and 68% were conducted in North America. The majority of included studies (90%) were randomised controlled trials. Evaluation their methodological quality, we found that allocation concealment methods were not properly described in the majority of studies (18% adequate, 73% unclear, 9% inadequate). The percentage of interventions shown to be beneficial varied according to the substance considered: 42% for opioids, 37% for alcohol, 14% for psychostimulants, 7% for polydrugs, and 33% for prevention. Furthermore, 75% of the reviews provided specific information on further research needs. Cochrane reviews provide information on the most effective treatments, particularly in the area of opioid and alcohol dependence, and help clarify areas for further research.

( BUPP10604 - 26 October 2010) A Randomized, Double-Blind, Double-Dummy Comparison of the Efficacy and Tolerability of Low-Dose Transdermal Buprenorphine (BuTrans(R) Seven-Day Patches) With Buprenorphine Sublingual Tablets (Temgesic (R)) in Patients With Osteoarthritis Pain

This randomized, double-blind, double-dummy, parallel-group study compared the efficacy and tolerability of 7-day, low-dose transdermal buprenorphine (BU) patches (BuTrans, Napp) with those of sublingual BU (Temgesic, Schering-Plough) in 238 patients (PX) with moderate /severe pain caused by osteoarthritis (OA) of the hips and/or knees. Transdermal BU patches and sublingual BU similarly reduced pain, as shown by Box Scale-11 (BS-11) pain scores. Use of escape medication was low in both treatments. Both treatments decreased sleep disturbance caused by pain. Both treatments also improved QOL, as measured by the Western Ontario and McMaster Universities Arthritis (WOMAC) OA Index. Fewer group A PX reported nausea, dizziness, and vomiting than group B PX. These findings suggest that transdermal BU patches are as effective as sublingual BU, with a better tolerability profile.

( BUPP10603 - 26 October 2010) Intrapartum and postpartum analgesia for women maintained on buprenorphine during pregnancy

Objective: To determine whether buprenorphine maintenance alters intrapartum or postpartum pain or medication requirements. Methods: Sixty three patients treated with buprenorphine for opioid dependence during pregnancy (vaginal n = 44; cesarean n = 19) were matched retrospectively to control women. Analgesic medication and pain scores (0-10) were extracted from the medical record. Primary endpoint: opioid utilization postpartum (oxycodone equivalents). Secondary endpoints: pain scores and intrapartum analgesia. Results: There were no differences in intrapartum pain or analgesia. Following vaginal birth, buprenorphine maintained women had increased pain (buprenorphine 2.7 (1.7, 4.0); control 2.1 (1.2, 3.0), p = 0.006) but no increase in opioid utilization (buprenorphine: 11.8 � 24.8; control 5.4 � 10.4 mg/24 h, p = 0.10); following cesarean delivery both pain (buprenorphine: 5.1 (4.1, 6.1); control: 3.3 (2.5, 4.1), p = 0.009) and opioid utilization (buprenorphine: 89.3 � 38.0, control: 60.9 � 13.1 mg/24 h, p = 0.004) were increased. Conclusion: Buprenorphine maintained women have similar intrapartum pain and analgesic needs during labor, but experience more postpartum pain and require 47% more opioid analgesic following cesarean delivery.

( BUPP10602 - 26 October 2010) Burden of opioid-associated gastrointestinal side effects from clinical and economic perspectives: A systematic literature review

Opioid analgesia is the mainstay of treatment for moderate to severe acute and chronic pain and is highly effective in relieving pain but can be limited by side effects, the most common of which affect the gastrointestinal (GI) and central nervous systems. A growing body of evidence demonstrates that opioid-associated GI side effects constitute an important health problem with significant humanistic and economic consequences that warrant consideration by healthcare professionals and administrators in optimizing patients' pain management. This article documents the frequency of opioid-associated GI side effects and describes its clinical and economic burdens based on a systematic review of the medical literature between 1966 and 2008.

( BUPP10601 - 26 October 2010) Care of rats with complete high-thoracic spinal cord injury

The complications of spinal cord injury (SCI) increase in number and severity with the level of injury. A recent survey of SCI researchers reveals that animal models of high SCI are essential. Despite this consensus, most laboratories continue to work with mid- or low-thoracic SCI. The available data on cervical SCI in animals characterize incomplete injuries; for example, nearly all studies published in 2009 examine discrete, tract-specific lesions that are not clinically-relevant. A primary barrier to developing animal models of severe, higher SCI is the challenge of animal care, a critical determinant of experimental outcome. Currently, many of these practices vary substantially between laboratories, and are passed down anecdotally within institutions. The care of animals with SCI is complex, and becomes much more challenging as the lesion level ascends. In our experience, the care of animals with high-thoracic (T3) SCI is much more demanding than the care of animals with low-thoracic SCI, even though both injuries result in paraplegia. We have developed an animal care regimen for rats with complete high-thoracic SCI. Our practices have been refined over the past 7 years, in collaboration with animal care centre staff and veterinarians. During this time, we have cared for more than 300 rats with T3 complete transection SCI, with experimental end-points of up to 3 months. Here we provide details of our animal care procedures, including acclimatization, housing, diet, antibiotic prophylaxis, surgical procedures, post-operative monitoring, and prevention of complications. In our laboratory, this comprehensive approach consistently produces good outcomes following T3 complete transection SCI: using body weight as an objective indicator of animal health, we have found that our rats typically return to pre-operative weights within 10 days of T3 complete SCI. It is our hope that the information provided here will improve care of experimental animals, and facilitate adoption of models that directly address the complications associated with higher level injuries.

( BUPP10600 - 26 October 2010) Sexual activities of metamphetamine and buprenorphin users

In an inquiry 30 males - frequent metamphetamine users and the same number of buprenorphin users were asked questions about their sexuality. We have been inquiring into differences in sexual behaviour (e.g. number of sexual partners and frequency of intercourses, as well as feelings about their sexual life - e.g. estimated duration of sexual activities, satisfaction with their quality or sexual appetite). Some findings have been compared with data from the last representative survey of sexual behaviour in the Czech Republic in 2003. Among others, we have found that only 53 % of buprenorphin users, in comparison with 87 % of metamphetamine users, are satisfied with their sexual life. The average age of first sexual intercourse was 15 years (14.8 and 15.0, respectively) while in Czech men from general population it was 18 years. The drug users also admit much more sexual partners during their lives - with the average number of 11.6 in buprenorphin users and 31.7 in metamphetamine users, comparing with 8.8 in Czech men. The findings indicate significant differences between the two drug-user groups especially in their satisfaction with sexual life, which is lower in buprenorphin users. In the comparison with the general population of Czech men we have found much more risky sexual behaviour of drug users.

( BUPP10599 - 26 October 2010) Lnk-dependent axis of SCF-cKit signal for osteogenesis in bone fracture healing

The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)-cKit signaling during stem cell self-renewal, and Lnk-deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/ angiogenesis and osteogenesis were promoted in Lnk-deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF-cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF-cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing.

( BUPP10598 - 26 October 2010) Causes of delirium in elderly Post-heart cardiac surgery

The delirium is perhaps one of the most frequent forms of presentation of acute illness in the elderly patient and the complications observed in the postoperative cardiac surgery and during the course of their hospitalization. It is a disease in itself but a syndrome characterized by alterations in consciousness, attention and perception, accompanied by a change in cognitive function that develops acutely, fluctuates throughout the day and not attributable to a demented state.

( BUPP10597 - 26 October 2010) Buprenorphine implants for treatment of opioid dependence: a randomized controlled trial

CONTEXT: Limitations of existing pharmacological treatments for opioid dependence include low adherence, medication diversion, and emergence of withdrawal symptoms. OBJECTIVE: To determine the efficacy of buprenorphine implants that provide a low, steady level of buprenorphine over 6 months for the treatment of opioid dependence. DESIGN, SETTING, AND PARTICIPANTS: A randomized, placebo-controlled, 6-month trial conducted at 18 sites in the United States between April 2007 and June 2008. One hundred sixty-three adults, aged 18 to 65 years, diagnosed with opioid dependence. One hundred eight were randomized to receive buprenorphine implants and 55 to receive placebo implants. INTERVENTION: After induction with sublingual buprenorphine-naloxone tablets, patients received either 4 buprenorphine implants (80 mg per implant) or 4 placebo implants. A fifth implant was available if a threshold for rescue use of sublingual buprenorphine-naloxone treatment was exceeded. Standardized individual drug counseling was provided to all patients. MAIN OUTCOME MEASURE: The percentage of urine samples negative for illicit opioids for weeks 1 through 16 and for weeks 17 through 24. RESULTS: The buprenorphine implant group had significantly more urine samples negative for illicit opioids during weeks 1 through 16 (P = .04). Patients with buprenorphine implants had a mean percentage of urine samples that tested negative for illicit opioids across weeks 1 through 16 of 40.4% (95% confidence interval (CI), 4.2%-46.7%) and a median of 40.7%; whereas those in the placebo group had a mean of 28.3% (95% CI, 20.3%-36.3%) and a median of 20.8%. A total of 71 of 108 patients (65.7%) who received buprenorphine implants completed the study vs 17 of 55 (30.9%) who received placebo implants (P <.001). Those who received buprenorphine implants also had fewer clinician-rated (P <.001) and patient-rated (P = .004) withdrawal symptoms, had lower patient ratings of craving (P <.001), and experienced a greater change on clinician global ratings of severity of opioid dependence (P<.001) and on the clinician global ratings of improvement (P < .001) than those who received placebo implants. Minor implant site reactions were the most common adverse events: 61 patients (56.5%) in the buprenorphine group and 29 (52.7%) in the placebo group. CONCLUSION: Among persons with opioid dependence, the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks as assessed by urine samples. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00447564.

( BUPP10596 - 26 October 2010) Advances in the treatment of opioid dependence: continued progress and ongoing challenges

( BUPP10595 - 26 October 2010) Improved HIV and substance abuse treatment outcomes for released HIV-infected prisoners: the impact of buprenorphine treatment

HIV-infected prisoners fare poorly after release. Though rarely available, opioid agonist therapy (OAT) may be one way to improve HIV and substance abuse treatment outcomes after release. Of the 69 HIV-infected prisoners enrolled in a randomized controlled trial of directly administered antiretroviral therapy, 48 (70%) met DSM-IV criteria for opioid dependence. Of these, 30 (62.5%) selected OAT, either as methadone (N = 7, 14.5%) or buprenorphine/naloxone (BPN /NLX; N = 23, 48.0%). Twelve-week HIV and substance abuse treatment outcomes are reported as a sub-study for those selecting BPN/NLX. Retention was high: 21 (91%) completed BPN/NLX induction and 17 (74%) remained on BPN/NLX after 12 weeks. Compared with baseline, the proportion with a non-detectable viral load (61% vs 63% log(10) copies/mL) and mean CD4 count (367 vs 344 cells/mL) was unchanged at 12 weeks. Opiate-negative urine testing remained 83% for the 21 who completed induction. Using means from 10-point Likert scales, opioid craving was reduced from 6.0 to 1.8 within 3 days of BPN/NLX induction and satisfaction remained high at 9.5 throughout the 12 weeks. Adverse events were few and mild. BPN/NLX therapy was acceptable, safe and effective for both HIV and opioid treatment outcomes among released HIV-infected prisoners. Future randomized controlled trials are needed to affirm its benefit in this highly vulnerable population. Grant ID: K23 DA019381, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: K23 DA019381-01A1, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: K23 DA019381-05, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: K24 DA017072, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R01 DA017059, Acronym: DA, Agency: NIDA NIH HHS, United States Grant ID: R21 DA019843, Acronym: DA, Agency: NIDA NIH HHS, United States

( BUPP10594 - 26 October 2010) Addiction treatment in Russia

( BUPP10667 - 15 December 2010) The Effect of Voluntarily Ingested Buprenorphine on Rats Subjected to Surgically Induced Global Cerebral Ischaemia

The effect of perioperatively administered buprenorphine analgesia on rats subjected to surgically induced global ischaemia was assessed. Rats supplied with buprenorphine, mixed in nut paste for voluntary ingestion, displayed significant reductions in postoperative excretions of faecal corticosterone, in both magnitude and variance. This is indicative of lowered stress levels and less inter-animal metabolic variation. Although corticosterone has been reported to modulate the extent of cerebral damage, histology of coronal sections exhibited no differences in the extent of the ischaemia in buprenorphine-treated and untreated animals. A part from a slightly higher hyperthermia immediately after surgery and typical opiate- associated behaviour, the buprenorphine treatment had no apparent adverse effects on the experimental model. In contrast, the analgesic treatment improved the model by minimizing stress-associated confounding variables in the experimental animals.

( BUPP10666 - 15 December 2010) Utility of saccadic eye movement analysis as an objective biomarker to detect the sedative interaction between opioids and sleep deprivation in opioid-naive and opioid-tolerant populations

Analysis of saccadic eye movements (SEMs) has previously been used to detect drug- and sleep-deprivation-induced sedation, but never in combination. We compared the effects of sleep deprivation and opioids on 10 opioid-naive with nine opioid-tolerant participants. The naive- participant study evaluated the effects of sleep deprivation alone, morphine alone and the combination; the tolerant-participant study compared day-to-day effects of alternate-daily-dosed buprenorphine and the combination of buprenorphine on the dosing day with sleep deprivation. Psychomotor impairment was measured using SEMs, a 5-minute pupil adaptation test (PAT), pupil light reflex (PLR) and alertness visual analogue scale (AVAS). The PAT and PLR did not detect sleep deprivation, in contrast to previous studies. Whilst consistently detecting sleep deprivation, the AVAS also detected buprenorphine in the tolerant study, but not morphine in the naive study. SEMs detected morphine alone and sleep deprivation alone as well as an additive interaction in the naive study and the effect of sleep deprivation in the tolerant study. The alternate-day buprenorphine dosing did not alter SEMs. The current study revealed greater SEMs, but not AVAS impairment in tolerant versus naive participants. The current study demonstrates that objective measures provide additional information to subjective measures and thus should be used in combination.

( BUPP10665 - 14 December 2010) Endogenous opiates and behavior: 2009

This paper is the 32nd consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2009 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration and thermoregulation (Section 16); and immunological responses (Section 17).

( BUPP10664 - 14 December 2010) Corrigendum to "A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of 7 day buprenorphine transdermal patch in osteoarthritis patients naive to potent-opioids"

( BUPP10663 - 14 December 2010) Herpes zoster-related pain in aged individuals: How to manage it safely.

Varicella-Zoster virus, an exclusively human herpes virus is responsible for chickenpox and herpes zoster. After the primary infection, the virus becomes permanently latent in the dorsal-root sensory ganglias and may be reactivated several decades later causing a vesicular dermatomal rash, traditionally metameric. Old adults can present severe pain during the acute phase, and late complications, such as postherpetic neuralgia that can be trying and crippling. Initiated within the first 72 hours of the rash, antivirals accelerate rash healing, reducing both rash and acute pain severity as well as avoiding the onset of other complications. The combination of antivirals and corticosteroids may further alleviate short-term zoster pain, increasing the risk of serious adverse effects, especially among older adults. Recently, some therapeutic recommendations focused on analgesic treatments (NSAIDs, opioid agonists, antidepressive drugs, calcium channel alpha2-delta ligands, corticosteroids and even antiviral agents) were published. However, their applications in old, frail, comorbid and often polymedicated patients have to be consciously pondered and are sometimes contraindicated (as tricyclic antidepressants). Specific recommendations for the therapeutic management of acute and post herpes zoster-related neuralgias, in older adults are proposed.