High-dose Buprenorphine Research Articles

Commentary on Burns et al. (2015): retention in buprenorphine treatment.

Commentary on Burns et al. (2015): retention in buprenorphine treatment.

New developments in the management of opioid dependence: focus on sublingual buprenorphine-naloxone.

Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. Buprenorphine, a partial opioid agonist, has been found by numerous studies to be an effective and safe medication in the treatment of opioid dependence. At present, buprenorphine is available as a monodrug or in a fixed 4:1 ratio combination with naloxone. A diminished risk of diversion and abuse for the buprenorphine–naloxone combination is likely but not firmly established. Conventional formulations are given sublingually to avoid the hepatic first-pass effect. A novel film tablet is available only in the US and Australia. Other novel, sustained-release formulations (implant, depot) are currently being developed and tested. Recent studies, including a Cochrane meta-analysis, suggest that the retention with buprenorphine is lower than for methadone, but that buprenorphine may be associated with less drug use. Higher doses of buprenorphine are associated with better retention rates. Buprenorphine has a ceiling effect at the opioid receptor with regard to respiratory depression, and may cause fewer fatal intoxications than methadone. Possible antidepressant effects of buprenorphine and its use in comorbid psychiatric patients has not been studied in much detail. Clinical implications are discussed.

Crushed and injected buprenorphine tablets: characteristics of princeps and generic solutions.

Self-injection of high-dose buprenorphine is responsible for well-described complications. In 2011, we have been alerted by unusual but serious cutaneous complication among injection buprenorphine users. A prospective data collection identified 30 cases of necrotic cutaneous lesions after injection of filtered buprenorphine solution, among which 25 cases occurred following injection of buprenorphine generics. The main goal of our study was to put forward particularities that could explain the cutaneous complications, by qualitatively and quantitatively confronting particles present in Subutex and generics solutions. We used the same protocol that injected-buprenorphine users: generic or subutex tablets were crushed in sterile water and filtered through 2 filters commonly used (cotton-pad and sterifilt). Solutions were analyzed by laser granulometry, flow cytometry and scanning electron microscopy. We have highlighted the wide variation of the quantity and the size of the particles present in solution between the two drugs after cotton-pad filtration. The proportion of particles <10 µm is systematically higher in the generic solutions than with Subutex. All of the insoluble particles found in generic solutions contain silica, whereas non- organic element was to be identified in the insoluble particles of Subutex. One skin biopsy obtained from one patient who developed a necrotic lesion after intravenous injection of filtrated solution of buprenorphine generic, shows non-organic elements. Identification of particles in situ enables us to confirm the presence of silica in the biopsy. Actually the monitoring of patient receiving generic of buprenorphine must be strengthened.

Psychopathologie des mésusages du Subutex® : le syndrome de Popeye

High dose buprenorphine (HDB), commonly known as Subutex(®), is nowadays largely prescribed as a replacement therapy for major opiate dependence. Its sublingual administration allows a decrease in the withdrawal syndrome accompanying opiate abuse cessation. Over the past few decades, epidemiological data on people on replacement therapy have emphasized an increase in the misuse of Subutex(®) and more specifically intravenous injections of HDB. These growing practices pave the way to major physical consequences or even death. Several studies have highlighted the infectious, vascular, venous and arterial (pseudo-aneurysm) complications stemming from this habit. Among the possible vascular complications, we can notice the presence of abscess, venous thrombosis, phlegmons, skin necrosis, cellulite, and profound and superficial thrombophlebitis at injection sites. These can evolve into chronic edemas of the tips and subcutaneous nodules. The Popeye syndrome is one of the possible complications of this misuse. This syndrome is characterized by the swelling of both sides of the forearms and hands. These edemas tend to become persistent and to be paired with tissue changes such as skin thickening. Besides, the increase in the hands volume can occur bilaterally or sometimes in an asymmetrical way, accentuated on the hand of the non-dominant limb. This syndrome does not decrease, or just a little, after the stoppage of injections. It can have a psychological, social, psychopathological and esthetic impact. In this article, we will focus on the clinical case of a 43-year-old man, who is hospitalized in an addictology unit for massive injections of HDB. This patient suffers from a Popeye syndrome as well as from an alcoholic dependence. Following the description of psychopathological disorders, our analysis will originate from a clarification relative to the specificities of the practice of intravenous HDB injection to better sharpen the understanding of these misuses in their psychopathological and clinical aspects. We will discuss some proposals for interventions aiming at taking better care of the people suffering from a drug addiction characterized by the injection of HDB replacement therapy. Adam requested an admission in an addictology ward for treatment of a self-medication by Subutex started 4 years ago. A certain awkwardness can be perceived when he lays his highly damaged and marked hands on the desk. His upper limbs, thus on display, have tripled in volume: this indicates the presence of a Popeye syndrome, consequence of repeated Subutex injections. These observations lead us to question the function and the sense of this injection behavior in the mental economy, as this repeated behavior engages the body specifically. This bruised body, marked with repeated injection holes has become a place of inscription, of representation that shows the impossibility to access other ways of expression. In this sense, taking action is becoming an act of speech. Within this speech, we can notice the existence of a profound state of uneasiness. To put up with the painful feeling of inner emptiness that is calling for a necessary filling, aiming at re-establishing a frail balance, Adam appeals to repeated injections. However, when the tortured body signifies its incapacity to receive an ultimate injection, thus showing its limits and the destruction it is undergoing, it is no longer possible to resort to Subutex injections. As a consequence, Adam came up with the idea of quitting. The withdrawal was initiated by himself and not coupled with medical care. It has led him to feel a gap, beyond the physical uneasiness. Adam has tried to fill in this unbearable feeling of empty body with tobacco, alcohol and food. The body, highly mobilized, translates the presence of a physical conflict where a massive mental anxiety is expressed in a hidden way. During the interview, Adam also addressed the repetitive familial pattern and the transgeneration effects. He seems to be fully aware of these. Several perspectives can be addressed as part of Adam's treatment and especially cognitive-behavioral therapies as they could prove to be of a certain interest. The aim of this therapy would thus be to assess the motivation for change in order to begin a psychotherapeutic work based on personal adherence to the cessation of this misuse. This could be set up in parallel with an anxiety management work. A better understanding and an extensive knowledge of the possible complications linked to the misuse of HDB seems necessary to sensitize and better inform people who suffer from high-risk behaviors and also to enable a more adapted care.

French Specific Surveillance System for Drug Abuse

ABSTRACTIt is important to assess drug abuse liability in real life by post-marketing surveillance system. In France, to obtain information on drug abuse liability, the Centers for Evaluation and Information on Pharmacodependence (CEIP) network was created in 1990 with the following aims: detection, prevention, evaluation, and information on drug abuse liability. Its specific work is based on a global, scientific assessment involving preclinical data, clinical studies, and post-marketing surveillance. This network has developed several pharmaco-epidemiological approaches to improve knowledge of drug use in real-life. The aim of this article was to describe a French post-marketing surveillance called OPPIDUM (Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse, Observation of Illegal Drugs and Misuse of Psychotropic Medications). OPPIDUM is an annual cross-sectional survey that collects anonymous information on abuse and dependence observed in patients recruited by specialized care centers dedicated to drug dependence. For each patient included sociodemographic data and psychoactive substance consumptions during the previous week were collected. From 1990 to 2010, a total of 50,734 patients were included with descriptions of 102,631 psychoactive substances. This OPPIDUM data has outlined emergent behaviors, such as use of high dosage buprenorphine by intravenous administration. It has contributed to characterize patients under opiate maintenance treatments and to assess abuse liability of emergent drugs as clonazepam. This pharmacoepidemiologic tool has also detected the decrease of flunitrazepam abuse following implementation of regulatory measures. OPPIDUM’s experience clearly demonstrates that collection of valid and useful data on drug abuse is possible. This post-marketing surveillance system offers important and useful information for physicians and health authorities.

Buprenorphine analgesia requires exon 11‐associated mu opioid receptor splice variants (659.11)

Buprenorphine is a potent analgesic with an attractive side effect profile. Although it is considered a partial mu opioid receptor (MOR) agonist and a weak partial agonist or antagonist at kappa opioid receptors, it also competes MOR exon 11‐associated IBNtxA binding with high affinity. We therefore sought to examine the roles of exon 11‐ and exon 1‐associated MOR splice variants in buprenorphine analgesia. Exon 11 knockout animals showed a profound loss of analgesia in the tail flick assay at doses over 300 times the analgesic ED50 in wildtype C57 controls, despite the fact that these animals have intact full length MOR‐1 receptors and other opioids such as morphine and methadone retain full analgesic efficacy. Furthermore, administration of a high dose of buprenorphine actually reversed morphine analgesia in these animals. In exon 1 or triple opioid knockout (MOR exon 1, DOR, and KOR) animals, analgesia was also significantly reduced relative to wildtype controls, suggesting that full buprenorphine analgesic efficacy requires both exon 11‐ and exon 1‐associated MOR splice variants, and that the pharmacology of buprenorphine is more complicated than previously believed.Grant Funding Source: Supported by DA02615, DA06241, DA07242 (GWP); DA013997 (YXP); and the PhRMA Foundation (SGG)

Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence.

Buprenorphine maintenance treatment has been evaluated in randomised controlled trials against placebo medication, and separately as an alternative to methadone for management of opioid dependence. To evaluate buprenorphine maintenance compared to placebo and to methadone maintenance in the management of opioid dependence, including its ability to retain people in treatment, suppress illicit drug use, reduce criminal activity, and mortality. We searched the following databases to January 2013: Cochrane Drugs and Alcohol Review Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Current Contents, PsycLIT, CORK, Alcohol and Drug Council of Australia, Australian Drug Foundation, Centre for Education and Information on Drugs and Alcohol, Library of Congress, reference lists of identified studies and reviews. We sought published/unpublished randomised controlled trials (RCTs) from authors. Randomised controlled trials of buprenorphine maintenance treatment versus placebo or methadone in management of opioid-dependent persons. We used Cochrane Collaboration methodology. We include 31 trials (5430 participants), the quality of evidence varied from high to moderate quality.There is high quality of evidence that buprenorphine was superior to placebo medication in retention of participants in treatment at all doses examined. Specifically, buprenorphine retained participants better than placebo: at low doses (2 - 6 mg), 5 studies, 1131 participants, risk ratio (RR) 1.50; 95% confidence interval (CI) 1.19 to 1.88; at medium doses (7 - 15 mg), 4 studies, 887 participants, RR 1.74; 95% CI 1.06 to 2.87; and at high doses (≥ 16 mg), 5 studies, 1001 participants, RR 1.82; 95% CI 1.15 to 2.90. However, there is moderate quality of evidence that only high-dose buprenorphine (≥ 16 mg) was more effective than placebo in suppressing illicit opioid use measured by urinanalysis in the trials, 3 studies, 729 participants, standardised mean difference (SMD) -1.17; 95% CI -1.85 to -0.49, Notably, low-dose, (2 studies, 487 participants, SMD 0.10; 95% CI -0.80 to 1.01), and medium-dose, (2 studies, 463 participants, SMD -0.08; 95% CI -0.78 to 0.62) buprenorphine did not suppress illicit opioid use measured by urinanalysis better than placebo.There is high quality of evidence that buprenorphine in flexible doses adjusted to participant need,was less effective than methadone in retaining participants, 5 studies, 788 participants, RR 0.83; 95% CI 0.72 to 0.95. For those retained in treatment, no difference was observed in suppression of opioid use as measured by urinalysis, 8 studies, 1027 participants, SMD -0.11; 95% CI -0.23 to 0.02 or self report, 4 studies, 501 participants, SMD -0.11; 95% CI -0.28 to 0.07, with moderate quality of evidence.Consistent with the results in the flexible-dose studies, in low fixed-dose studies, methadone (≤ 40 mg) was more likely to retain participants than low-dose buprenorphine (2 - 6 mg), (3 studies, 253 participants, RR 0.67; 95% CI: 0.52 to 0.87). However, we found contrary results at medium dose and high dose: there was no difference between medium-dose buprenorphine (7 - 15 mg) and medium-dose methadone (40 - 85 mg) in retention, (7 studies, 780 participants, RR 0.87; 95% CI 0.69 to 1.10) or in suppression of illicit opioid use as measured by urines, (4 studies, 476 participants, SMD 0.25; 95% CI -0.08 to 0.58) or self report of illicit opioid use, (2 studies, 174 participants, SMD -0.82; 95% CI -1.83 to 0.19). Similarly, there was no difference between high-dose buprenorphine (≥ 16 mg) and high-dose methadone (≥ 85 mg) in retention (RR 0.79; 95% CI 0.20 to 3.16) or suppression of self-reported heroin use (SMD -0.73; 95% CI -1.08 to -0.37) (1 study, 134 participants).Few studies reported adverse events ; two studies compared adverse events statistically, finding no difference between methadone and buprenorphine, except for a single result indicating more sedation among those using methadone. Buprenorphine is an effective medication in the maintenance treatment of heroin dependence, retaining people in treatment at any dose above 2 mg, and suppressing illicit opioid use (at doses 16 mg or greater) based on placebo-controlled trials.However, compared to methadone, buprenorphine retains fewer people when doses are flexibly delivered and at low fixed doses. If fixed medium or high doses are used, buprenorphine and methadone appear no different in effectiveness (retention in treatment and suppression of illicit opioid use); however, fixed doses are rarely used in clinical practice so the flexible dose results are more relevant to patient care. Methadone is superior to buprenorphine in retaining people in treatment, and methadone equally suppresses illicit opioid use.

EPA-1783 – Comparative study of the addiction to high dose buprenorphine before and after the tunisian revolution

Buprénorphine haut dosage (Subutex) est le médicament le plus couramment utilisé dans le traitement de médicament de substitution. Mais cette molécule est également bien connu pour son usage détourné ou abusif. Depuis la révolution tunisienne, le trafic de plusieurs médicaments a été une montée très dangereux. Pour étudier la prévalence de la dépendance à la buprénorphine haute dose en consultation psychiatrique en 2010 (avant la révolution tunisienne) et 2012 (après la révolution). Comparer les caractéristiques cliniques du patient accro à la buprénorphine haut dosage avant et après la révolution tunisienne. Une étude rétrospective, descriptive et comparative a été effectuée sur les fichiers de patients qui ont consulté le service de consultation externe de l’hôpital Razi à Tunis depuis deux ans: 2010 et 2012 dont diagnostic était la dépendance à la buprénorphine haut dosage. 34 patients dépendants à la buprénorphine haute dose ont été recrutés: six patients en 2010 et 28 patients en 2012. Tous étaient des hommes. L’âge moyen était de 31,83 années en 2010 et 32,13 années en 2012. 44,11% de l’ensemble de la population de l’étude a développé une symptomatologie dépressive: quatre patients en 2010 et 11 patients en 2012. Les groupes d’âge, la période de chômage et le montant des benzodiazépines consommées ont été corrélés avec l’année de consommation. Ces résultats confirment l’impact de la révolution tunisienne sur la prévalence et le profil de dépendance à la buprénorphine haute dose dans notre pays. D’où la nécessité de mesures générales de gestion de ces toxicomanes est imposée.

A Double Blind, within Subject Comparison of Spontaneous Opioid Withdrawal from Buprenorphine versus Morphine

Preliminary evidence suggests that there is minimal withdrawal after the cessation of chronically administered buprenorphine and that opioid withdrawal symptoms are delayed compared with those of other opioids. The present study compared the time course and magnitude of buprenorphine withdrawal with a prototypical μ-opioid agonist, morphine. Healthy, out-of-treatment opioid-dependent residential volunteers (N = 7) were stabilized on either buprenorphine (32 mg/day i.m.) or morphine (120 mg/day i.m.) administered in four divided doses for 9 days. They then underwent an 18-day period of spontaneous withdrawal, during which four double-blind i.m. placebo injections were administered daily. Stabilization and spontaneous withdrawal were assessed for the second opioid using the same time course. Opioid withdrawal measures were collected eight times daily. Morphine withdrawal symptoms were significantly (P < 0.05) greater than those of buprenorphine withdrawal as measured by mean peak ratings of Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), all subscales of the Profile of Mood States (POMS), sick and pain (0-100) Visual Analog Scales, systolic and diastolic blood pressure, heart rate, respiratory rate, and pupil dilation. Peak ratings on COWS and SOWS occurred on day 2 of morphine withdrawal and were significantly greater than on day 2 of buprenorphine withdrawal. Subjective reports of morphine withdrawal resolved on average by day 7. There was minimal evidence of buprenorphine withdrawal on any measure. In conclusion, spontaneous withdrawal from high-dose buprenorphine appears subjectively and objectively milder compared with that of morphine for at least 18 days after drug cessation.

Opioids and Traffic Safety – Focus on Buprenorphine

Opioid maintenance therapy is a well-established first-line treatment approach in opioid dependence. The effects of opioids such as buprenorphine on cognitive functioning and driving ability are a matter of debate. A comprehensive review of studies of the effects of buprenorphine on traffic safety is presented. A number of recent epidemiological and road surveys indicate that opioids have a moderate risk for causing accidents compared to other drugs of abuse, such as alcohol. A number of neuropsychological studies, a few of which were prospective and used a randomized control group, have used standardized test batteries to measure domains relevant for psychomotor functioning and driving ability. Single doses of buprenorphine have been shown to induce some impairment in healthy volunteers, but less than found in chronic users. Some non-randomized studies indicate somewhat better cognitive performance of patients on buprenorphine than of those on methadone but this finding has not been demonstrated in randomized controlled trials. Opioids as a class of drugs induce some impairment of driving ability, but less than other psychotropic agents or drugs of abuse. Personality features such as impulsivity, sensation seeking, low risk perception and antisocial behaviour, comorbid psychiatric and neurological disorders and additional substance use of opioid users are of relevance for traffic safety. Buprenorphine does not cause more cognitive impairment than methadone or may even cause less. Caution is required when initiating treatment with buprenorphine. The risk for driving ability impairment is probably less under steady state conditions. Finally, higher doses of buprenorphine are probably not associated with more impairment.

Pharmacists’ Role in the Continued Care of Patients under Opiate Substitution Treatment

ContextIn France, over 170 000 persons benefit from opiate substitution treatment. The treatment delivery is most often assured by community pharmacies spread out throughout the territory. The aim of this study is to better know the continued care of individuals treated by methadone or high-dose buprenorphine in community pharmacies in Lille (North of France). MethodThis was a cross-sectionnal descriptive study with hand-delivered questionnaires. All pharmacies (n=65) in Lille were included. ResultsFifty-eight of pharmacies (89%) responded to the suvey and 55 of them (95%) followed patients treated by opiate substitution treatment. Addiction was considered as an illness by 53 of pharmacists (91%). Confidential discussions could only be conducted at one of every two treatment delivery work station. ConclusionPharmacists are active in the continued care of individuals treated by opiate substitution treatment. They have a privileged relationship with the general practitioner. A rearrangement of pharmacies’ premises could foster the development of therapeutic patient education within the pharmacy.

An alternative way of managing acute pain in patients who are in buprenorphine opioid substitution therapy programs

Editor, We read with great interest the review article by Stromer et al.1 on the perioperative management of pain in patients who abuse opioids. It adds much to the knowledge base on which we rely to manage such a complex patient group. However, in our experience, there is an alternative and perhaps simpler and more effective way of managing patients who are in buprenorphine opioid substitution therapy (BOST) programs. This is of growing relevance as in many countries the number of such patients is increasing due to the perceived greater safety profile of buprenorphine compared with methadone. We acknowledge that the management of acute perioperative pain in a patient prescribed BOST is controversial.2 We agree that concerns about buprenorphine's long half-life, partial μ-agonist and κ-antagonist effects,1 in addition to its high opioid receptor affinity and slow dissociation from the μ-opioid receptor,3 have led many experts to recommend that it be ceased preoperatively and replaced with methadone or a pure μ-opioid agonist to ensure adequate intraoperative and postoperative pain relief.1,4,5 However, we believe that such concerns are unfounded. Contrary to the management plan suggested by Stromer et al., some authors have recommended that the buprenorphine, even in the high doses of 4 to 32 mg often used in BOST, be continued throughout the perioperative period.2 We, therefore, recently undertook a retrospective cohort study comparing pain relief and patient-controlled analgesia (PCA) opioid requirements in the first 24 h after surgery in 51 patients in methadone opioid substitution therapy (MOST; 29 patients) and BOST (22 patients) programs.3 The patients were further subgrouped into those whose methadone or buprenorphine was given or withheld on the first postoperative day. We found no statistically significant differences in the pain scores (rest and movement) or PCA morphine equivalents used between the MOST and BOST patients, suggesting that even for planned major surgery, adequate intraoperative and postoperative analgesia can be equally achieved for patients taking methadone and buprenorphine. Thus, changing preoperatively from buprenorphine to methadone seems to offer no advantage. Of special interest was that BOST patients who were not given their buprenorphine the day after surgery had statistically significantly higher PCA morphine equivalent requirements in the first 24 h after surgery (though similar pain scores) compared with those who were given their usual dose. As a result, concerns about the ability of high doses of buprenorphine to limit the access of full μ-opioid agonists to opioid receptors and reduce their analgesic efficacy would seem to be unwarranted.3 We also found that the BOST and MOST patients had a higher incidence of increased sedation (a better clinical indicator of early respiratory depression than a decrease in respiratory rate)6 than our opioid-naive patients. Although the reason for this is unclear, it is a finding also noted by Rapp et al.7 in opioid-tolerant patients in general. Thus, when opioid doses are rapidly and significantly escalated to deal with new acute pain in the opioid-tolerant patient2 as recommended by Stromer et al.,1 monitoring for respiratory depression, including using sedation scores, must still be mandated, as these patients may, perhaps counterintuitively, be at greater risk of respiratory depression than the opioid-naive patient. We routinely continue buprenorphine (or any other opioid the patient may be taking in the long-term) throughout the perioperative period, irrespective of its dose or the perceived size of the surgical insult. We manage additional acute pain with a full-agonist PCA opioid in higher-than-usual doses, adjuvant nonopioid analgesic agents including ketamine, and regional analgesia, whenever possible. Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none. Presentation: none.

Comparative Effects of Vasectomy Surgery and Buprenorphine Treatment on Faecal Corticosterone Concentrations and Behaviour Assessed by Manual and Automated Analysis Methods in C57 and C3H Mice

Establishing effective cage-side pain assessment methods is essential if post-surgical pain is to be controlled effectively in laboratory animals. Changes to overall activity levels are the most common methods of assessment, but may not be the most appropriate for establishing the analgesic properties of drugs, especially in mice, due their high activity levels. Use of drugs that can affect activity (e.g. opioids) is also a problem. The relative merits of both manual and automated behaviour data collection methods was determined in two inbred mouse strains undergoing vasectomy following treatment with one of 2 buprenorphine dose rates. Body weights and the effects of surgery and buprenorphine on faecal corticosterone were also measured.Surgery caused abnormal behaviour and reduced activity levels, but high dose buprenorphine caused such large-scale increases in activity in controls that we could not establish analgesic effects in surgery groups. Only pain-specific behaviour scoring using the manual approach was effective in showing 0.05 mg/kg buprenorphine alleviated post-vasectomy pain. The C57 mice also responded better to buprenorphine than C3H mice, indicating they were either less painful, or more responsive to its analgesic effects. C3H mice were more susceptible to the confounding effects of buprenorphine irrespective of whether data were collected manually or via the automated approach. Faecal corticosterone levels, although variable, were higher in untreated surgery mice than in control groups, also indicating the presence of pain or distress.Pain-specific scoring was superior to activity monitoring for assessing the analgesic properties of buprenorphine in vasectomised mice. Buprenorphine (0.01 mg/kg), in these strains of male mice, for this procedure, provided inadequate analgesia and although 0.05 mg/kg was more effective, not completely so. The findings support the recommendation that analgesic dose rates should be adjusted in relation to the potential severity of the surgical procedure, the mouse strain, and the individual animals' response.

Changing patterns of first injection across key periods of the French Harm Reduction Policy: PrimInject, a cross sectional analysis

BackgroundMonitoring of emerging modes of drug consumption in France has identified new patterns of injection among youths with diverse social backgrounds, which may explain the persistence of high rates of hepatitis C virus infection. The circumstances surrounding the first injection have been poorly documented in the group of heavy drug users and in the context of the French opioid substitution treatment (OST) policy that provides expanded access to high-dosage buprenorphine (BHD) MethodsAn Internet survey (Priminject) was conducted from October 2010 to March 2011 with French drug users. Four time periods were compared based on critical dates throughout the implementation of the Harm Reduction Policy in France. ResultsCompared with drug users who injected for the first time prior to 1995, the aspects of drug use for users who recently injected for the first time were as follows: (1) experimentation with miscellaneous drugs before the first injection; (2) an older age at the time of first injection; (3) heroin as the drug of choice for an individual's first injection, notwithstanding the increased usage of stimulant drugs; (4) BHD did not appear to be a pathway to injection; and (5) an increased number of users who injected their first time alone, without the help or presence of another individual. ConclusionThe PrimInject study showed that there is a group of injection drug users that is larger than the group of injection drug users observed in previous studies; therefore, it is necessary to diversify programs to reach the entire spectrum of high-risk users.

Buprenorphine

Buprenorphine

1823 – Addiction to high dose buprenorphine and sexually transmitted diseases in tunisia

Introduction High dosage buprenorphine (Subutex) is actually the principal treatment for substitution medication. Some misappropriations and wrong uses have been seen; the most frequent and sever being using tablets for injections. Since the introduction in different countries, the high dose buprenorphine as a substitition treatment for opioid drug dependence, the number of overdose deaths and heroin users are significantly declined. But the existence of non-use replacement of this processing, mainly intravenously, was born a new scourge of addiction, especially in Tunisia. Besides the risk of overdose, there is a risk of viral contamination. Objectives To study the sexually transmitted diseases among patients addicted to high dose buprenorphine in Tunisia and followed in the outpatient hospital Razi. Materials and methods It is a retrospective study of twenty-three (23) patients (23 men), injection of high dose buprenorphine, having consulted the outpatient clinic of Razi Hospital between January and July of 2012. Results 8 patients had a communicable disease: 1HIV, 5 Hepatitis C, 1Hepatitis B, 1 syphilis. 4 patients had infectious complications: 3 cases of skin infections and 1 case of endocarditis. 9 had never been screened. 8 recognized using a used needle. Conclusion The addiction to high dose buprenorphine is a widespread phenomenon in Tunisia. Lack of information and awareness of companion in Tunisia is at the origin of serious infectious complications. Health professionals have to play an important role in drug addict patients’ education and supervision, to prevent addiction to buprenorphine and related infectious complications.

1611 – Opiate substitution therapy: a retrospective study of an 11-year follow-up depending on the given treatment: methadone and/or buprenorphine

Introduction After 50 years of international experience and 15 years of use in France, the positive impact of drug replacement treatments on the care of patients with opiates dependence is now well established. Even though there is a vast literature on the two existing treatments (methadone and high-dosage buprenorphine), few works have focused on patients who have changed replacement therapy during follow-up. Objectives and aims The aim of our study was to analyze the follow-up of substituted patients throughout an 11-year period. Patients were characterized by the type of treatment: methadone only, high-dosage buprenorphine only, or both treatments. Methods These groups of patients were studied depending on their characteristics at the beginning of the treatment (sociodemographic data, addictive behaviours, psychiatric assessment) and in terms of healthcare and follow-up regularity. We also tried to bring to light predictive factors of unstable follow-ups at the point of entry in healthcare. Results 891 patients were included in our results. Patients having had two substitution treatments initially present with higher severity in terms of socio-professional integration, addictive behaviours and psychiatric comorbidity. Their treatment is more discontinued and they have longer healthcare. Conclusions Psychiatric comorbidities and poly-drug use seem to characterize unstable patients who jeopardize our treatments. They have to be identified very early in order to better adjust healthcare. This preliminary work underlines the necessity of carrying out a prospective study integrating better adapted assessment tools.

Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model: a double-blind, randomized, placebo-controlled, five-arm crossover study

PurposeOpioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain. It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than μ-opioid receptor agonists. The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers. The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia, antihyperalgesia, and descending pain modulation.Subjects and methodsTwenty-eight healthy subjects were included. The study was a double-blind, randomized, placebo-controlled, five-arm crossover study with a multimodal (electrical, mechanical, and thermal stimuli) testing technique. After baseline assessments, intravenous infusions of morphine (10/20 mg), buprenorphine (0.3/0.6 mg), or placebo (normal saline) were administered over a 210-minute period, during which a cold pressor test, heat injury (47°C, 7 minutes, 12.5 cm2), and the first postburn assessment were done. After completion of the drug infusions, two additional postburn assessments were done. The subjects were monitored during each 8-hour session by an anesthesiologist.ResultsFor nearly all tested variables, significant dose-dependent analgesic effects were demonstrated. The median antihyperalgesia/analgesia ratio (secondary hyperalgesia/heat injury relative to placebo) for low-dose morphine was 0.01 (interquartile range: −6.2; 9.9), 0.00 (−2.4; 2.1) for high-dose morphine, 0.03 (−1.8; 2.1) for low-dose buprenorphine, and 0.00 (−3.2; 1.1) for high-dose buprenorphine (P > 0.466). There were no significant differences in opioid responses between high and low pain-sensitive subjects (P > 0.286). High-dose buprenorphine, compared to placebo, was associated with a significantly enhanced action of the descending inhibitory pain control system (P = 0.004).ConclusionThe present study, using multimodal testing technique, could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia. Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system.

High dose of buprenorphine in terminally ill patient with liver failure: Efficacy and tolerability

Pain in terminally ill patients with cancer can be often hard to manage, due to the unpredictable kinetics of drugs caused by progressive kidney and liver dysfunction. Plasma concentrations of active metabolites-also a cause of dangerous side effects--could be difficult to estimate. This case report holds the idea that buprenorphine, a partial agonist of m-receptors, even at high dosage, may be effective and safe to use in terminally ill patients with significant liver and kidney impairment.

Taux de pénétration des génériques de la buprénorphine haut dosage : principales tendances de 2006 à 2008

To assess the national market penetration rate (PR) of generic high-dosage buprenorphine (HDB) in 2008 and its evolution since their marketing (2006), and making a point for each dosage and at regional level. Retrospective study over data using national and regional health reimbursement database over three years (2006-2008). In 2008, the generic HDB's national MPR was 31%. The PR for each dosage were 45% for 0.4 mg, 36% for 2 mg and 19% for 8 mg. The (PR) based on Defined Daily Dose (DDD) was 23% in 2008, 15% in 2007 and 4% in 2006. In 2008, at the regional level, disparities were observed in the adjusted penetration rate from 15% in Île de France to 39% in Champagne Ardennes Lorraine. The national PR of generic HDB has increased. There are differences in MPR in terms of dosage and area. However, this PR is still low (in 2008, 82% of the delivered drugs are generics).