Buprenorphine: blending practice and research

Transcription

1 Journal of Substance Abuse Treatment 23 (2002) Regular article Buprenorphine: blending practice and research Walter Ling, M.D. a, *, David Smith, M.D. b a Integrated Substance Abuse Programs, University of California, Los Angeles, Santa Monica Boulevard, Suite 200, Los Angeles, CA 90025, USA b Haight-Ashbury Free Clinic, Inc., 612 Clayton Street, Second Floor, San Francisco, CA 94117, USA Received 20 March 2002; received in revised form 17 May 2002; accepted 17 May 2002 Abstract Although pharmacotherapy has been a mainstay in opiate addiction, not much research in the development of new opiate medications has been translated into clinical practice. In part, this is because opiate pharmacotherapy has not been an integral element of mainstream medical practice and because new medications developed by research are not available to clinicians. All that will change with the availability of buprenorphine for addiction treatment. For the first time in nearly a century, clinicians will be able to treat opiate addicts in the general medical setting, in the same manner they treat other patients. The unique pharmacological properties of buprenorphine, with its high patient acceptance, favorable safety profile, and ease of clinical administration, should facilitate its clinical integration. However, successful implementation will require changes in the understanding and attitude of clinicians, policymakers, and society. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Buprenorphine; Opiate dependence; Pharmacotherapy; Policy; Research; Practice 1. Introduction Buprenorphine: From Research to Practice was one in a series of workshops presented at the Blending Clinical Practice and Research conference held in Los Angeles, CA November 1 2, This workshop comes at a critical juncture in the history of research in substance abuse and dependence, as treatment is becoming more science based and less ideologically based. There has been considerable new information discovered in clinical research with drug addiction, but few of these research findings have been translated into treatment practices. Some 30 years of research have yielded a rich body of scientific knowledge and understanding of how drugs of abuse behave in the brain and how the effects can be combated with pharmacological and behavioral strategies. Moreover, Dr. Alan Leshner, former director of the National Institute on Drug Abuse (NIDA) has, for some years now, made a point of educating the field with the idea that addiction is a brain disease. Complex as it may be, addiction is a treatable disease, and a number of pharmacological and behavioral strategies * Corresponding author. Tel.: ; fax: address: lwalter@ucla.edu (W. Ling). are available to be implemented at the community level. Nothing exemplifies the readiness, availability, and urgency of this fact more than the anticipated availability of buprenorphine and its implementation into the community treatment settings. For years, clinicians have been frustrated by their inability to deliver an effective treatment for opiate addiction to patients in the normal course of their medical practice because one of the most efficacious means of treatment, namely the delivery of an opiate-based medication, has been unavailable except in very restricted settings. All of this will change with the availability of buprenorphine to physicians in addiction medicine (an injectable form of buprenorphine is currently available in the US for treatment of pain, but it is not yet available for treatment of addiction). Under the Drug Addiction Treatment Act [DATA] of 2000 (US Congress, 2000), clinicians will, for the first time in nearly 8 decades, be able to prescribe an effective opiate-based medication to treat their addicted patients in the same manner they treat any of their other patients. The much anticipated implementation of officebased buprenorphine treatment will signal a defining moment in the history of substance abuse treatment in general and of opiate dependence specifically. The content of this article is divided into a brief introduction of the clinical pharmacology of buprenorphine; /02/$ see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S (02)00257-X

2 88 W. Ling, D. Smith / Journal of Substance Abuse Treatment 23 (2002) research data on the clinical efficacy of buprenorphine; and a discussion of issues raised by the implementation of buprenorphine in community treatment settings. 2. Clinical pharmacology Buprenorphine, a derivative of thebaine, is classified as a partial mu opioid agonist and a weak kappa antagonist. Clinically, the effects of buprenorphine are mostly expressed at the mu receptor, and are similar to those of full agonists like morphine, Levo-Alpha-Acetyl-Methadol (LAAM), and methadone, whose clinical effects are proportional to the dose administered (Jasinski, Pevnick, & Griffith, 1978). Because it is a partial agonist, however, buprenorphine s agonist effects plateau at higher doses and it begins to behave more like an antagonist. This ceiling effect confers on it a high safety profile clinically, a low level of physical dependence, and only mild withdrawal upon cessation after prolonged administration, all characteristics that make buprenorphine especially advantageous for the treatment of opiate dependence (Jasinski et al., 1978; Lewis, 1985; Walsh, Preston, Stitzer, Cone, & Bigelow, 1994). Moreover, buprenorphine s slow dissociation from the receptors provides a long duration of action, allowing dosing schedules to vary from several times daily to several times a week. Taken orally, buprenorphine is not wellabsorbed and much of it is destroyed in the liver, known as the first pass effect (Walter & Inturrisi, 1995). However, buprenorphine is well-absorbed through the lining of the oral cavity and when given sublingually, it reaches 60% 70% of the plasma concentration achieved by the parenteral routes. After absorption, buprenorphine is widely distributed throughout the body with peak plasma concentration of approximately 90 minutes and a terminal half-life of 4 5 hours. It is highly bound to plasma proteins and is inactivated by the enzymatic transformations, N-dealkylation and conjugation (Walter & Inturrisi, 1995). Buprenorphine s metabolites are excreted mainly via the fecal route. 3. Clinical research Early research with buprenorphine for treatment of opiate dependence indicated that it could substitute for heroin, suppress the withdrawal associated with heroin use, and block subsequently administered opiates (Jasinski et al., 1978; Mello & Mendelson, 1980; Mello, Mendelson, & Kuehnle, 1982). Some of the effects of buprenorphine are similar to those seen in patients treated with methadone, such as the suppression of craving and withdrawal, while other effects are reminiscent of those seen in patients receiving naltrexone, such as the blocking of subsequently administered opiates. Thus, it appeared that buprenorphine would have the unique advantage of giving patients an easyto-administer agonist medication that would also act as an antagonist and block the effects of street heroin. These early studies also demonstrated that buprenorphine was safe and free of significant side effects. A series of controlled clinical trials, most conducted in the US, more firmly established buprenorphine s clinical efficacy and safety. Together, these trials involved more than 1000 patients. Each study had an enrollment of at least 100 patients; treatment lasted from 2 weeks to more than 1 year, and most involved systematic data collection over 16 weeks. Some of the study protocols were designed to compare buprenorphine to methadone, and others compared buprenorphine to an active or inactive placebo. Still, others compared different doses of buprenorphine. Abstinence from illicit opiate use, most commonly assessed by urine toxicology, and retention in treatment, were utilized as primary measures of success, but other measures, such as withdrawal symptoms, reduced heroin craving, and improvement on global rating scales were also employed. Several of the studies were considered pivotal from the perspective of a New Drug Application (NDA) to the Food and Drug Administration (FDA). Study results showed that 8 mg buprenorphine is superior to 20 mg methadone, that buprenorphine is superior to placebo on measures of illicit opiate use, treatment retention, and request for dose changes, and that 8 mg buprenorphine is significantly superior to 1 mg buprenorphine on virtually all outcome measures (Ling, Huber, & Rawson, 2001). Nearly all of the early buprenorphine studies and most of the controlled clinical trials utilized a liquid buprenorphine formulation. However, it was discovered during one of the trials that the vials containing the medication became discolored with time, raising the possibility that the liquid formulation might be unstable with long-term storage. As a result, a tablet formulation was developed. To properly interpret the data generated by studies with the liquid formulation, comparison of the bioavailability of buprenorphine in liquid and tablet forms was needed. A single-dose comparison study had indicated that the bioavailability of the tablet formulation varied from 25% 80%, and averaged roughly 50% that of the liquid formulation (Nath et al., 1999) but there were no data on extended dosing. Two subsequent comparison studies showed that the blood level achieved by the tablet formulation approached 65% 70% that of the liquid and suggested that the bioavailability of the tablet formulation improved with continued treatment (Huber, Ling, & Rawson, in preparation). In fact, on chronic dosing, the bioavailability of the two formulations becomes comparable. Concomitant with development of the tablet formulation and in response to reports of buprenorphine abuse in some parts of the world (Singh, Mattoo, Malhotra, & Varma, 1992; Quigley, Bredemeyer, & Seow, 1984) a buprenorphine/ naloxone combination ( combo ) tablet was developed. When the combination tablet is taken orally, buprenorphine is absorbed readily and naloxone is not; therefore only the

3 W. Ling, D. Smith / Journal of Substance Abuse Treatment 23 (2002) buprenorphine effect is apparent. If buprenorphine/naloxone is injected, however, the naloxone effect induces immediate withdrawal, thus deterring intravenous abuse. Early studies had indicated that the combination product became less desirable as a drug of abuse as the ratio of naloxone was increased and that a 4:1 buprenorphine/naloxone combination was sufficient to discourage abuse and retain nearly all of the buprenorphine effect (Mendelson et al., 1999). A pilot study with the combination tablet suggested that induction is easily accomplished and that the formulation is wellaccepted by patients (Bridge et al., in preparation). A large NIDA-sponsored multicenter trial subsequently demonstrated comparable clinical efficacy of the mono- (buprenorphine alone, without naloxone) and combo-tablets and added to the database showing buprenorphine s clinical efficacy (Fudala et al., submitted for publication). Together, these studies supported buprenorphine s effectiveness and safety as an opiate pharmacotherapy in short-term use, detoxification, and long-term maintenance. 4. Clinical use of buprenorphine Clinically, buprenorphine can be used for short-term detoxification from opiates, as a transitional agent to antagonist treatment, or as a long-term maintenance on its own. Induction of patients onto buprenorphine can be done with relative ease and, with the exception of patients maintained on methadone, fear of precipitated withdrawal is largely overstated. A number of specific induction strategies are available and are usually discussed in detail in the many training programs planned for clinicians by various medical and addiction specialty societies. Once stabilized, patients find buprenorphine highly acceptable and clinicians who have experience in using it generally find the practice rewarding since most patients do well. Maintenance doses of 4 32 mg/day are generally sufficient to suppress symptoms of withdrawal and reduce illicit opiate use. With time there is a general trend toward reduction in the required maintenance dose without loss of clinical effectiveness and because of buprenorphine s long duration of action, the dosing interval can be extended to every 2 4 days, although many patients prefer a small nighttime dose. For detoxification, which often involves only several days of medication use, lower doses of 8 12 mg/day generally suffice. Discontinuation of buprenorphine after stabilization and maintenance can be achieved by gradual reduction of doses over time but the availability of followup treatment strategies must be taken into account. For patients with a history of long-term opiate dependence, detoxification alone does not appear to be an adequate treatment strategy since relapses are common following discontinuation of the medication. When used as a first line medication for street heroinaddicted individuals, buprenorphine has a unique advantage over other available opiate pharmacotherapies. It is easy to use and well-liked by patients, and it offers the widest options for subsequent treatment. For example, persons addicted to street heroin can be inducted on 4 8 mg buprenorphine on Day 1 with the dose doubled on Day 2 and increased to a maximum of mg on subsequent days. Patients desiring short-term treatment (i.e., detoxification) can be tapered quickly off buprenorphine, often over several days, provided a long-term treatment plan is in place, such as a combination of psychosocial services (Bickel, Amass, Higgins, Badger, & Esch, 1997) and the use of a medication like naltrexone to reduce craving (Umbricht et al., 1999). Patients who require longer-term treatment can remain on buprenorphine with doses administered once daily to several times a week (Bickel, Amass, & Crean, 1995; Amass, Bickel, & Higgins, 1994; Bickel, Amass, Crean, & Badger, 1999). Those who cannot tolerate the medication or find it insufficient can be transferred to LAAM or methadone (Johnson et al., 2000). For patients in long-term treatment, tapering of buprenorphine can be considered after a sustained period of psychosocial stabilization. Specific treatment guidelines are available and there are a number of trainings being conducted around the country (Buprenorphine Clinical Practice Guidelines: Field Review Draft; US Department of Health and Human Services, Center for Substance Abuse Treatment, 2001). 5. Implementation in community treatment settings Although more than 2 decades of research have provided strong evidence for buprenorphine s clinical safety and efficacy, this alone does not guarantee its availability for clinical use. Other factors relating largely to the societal views of addicted individuals and addiction, which, in turn, shape national political and health policies, also strongly influence the implementation of treatments for opiate dependence. At the writing of this article, buprenorphine is still not approved in the US for treatment of addiction, although its approval is deemed imminent. On the other hand, it has been available in Europe since 1996 and it has also become available in other parts of the world (Ling et al., 2001). An examination of the buprenorphine approval and implementation process in France, Australia, and the US provides some insight into the relationship between social policy and the delivery of buprenorphine as a clinical treatment agent France The most extensive use of buprenorphine is in France where it has been widely available since 1996 in 0.4, 2, and 8-mg tablets without the naloxone combination. During the first 6 months following its availability, the number of patients treated with buprenorphine rose from approximately 100 to some 30,000 (Auriacombe, Franques, & Tignol, 2001) and, at the time of this writing more than

4 90 W. Ling, D. Smith / Journal of Substance Abuse Treatment 23 (2002) ,000 patients in France had received buprenorphine treatment for opiate dependence, more than 10 times the number treated with methadone. Buprenorphine is delivered from a range of treatment settings including general practitioners and specialists offices, and provided by local pharmacies under minimal control (Vignau & Brunelle, 1998). While patients initially receive buprenorphine prescriptions for a few days to 1 week, once stabilized they are allowed up to 4 weeks of medication from their local pharmacy. On the spectrum of buprenorphine implementation, this clearly represents the most liberal approach to date. Some street diversion of buprenorphine has occurred in France and a small number of buprenorphine-related deaths have been reported (Obadia & Perrin, 2001). Most of these cases were not attributed to buprenorphine alone, although a combination of buprenorphine and benzodiazepine was found in some instances. Patients receiving buprenorphine have shown much improvement on social function and quality of life (Bouchez & Vignau, 1998). Moreover, although the number of heroin overdose deaths in France had started to decline in 1995, they plummeted the following year with the availability of buprenorphine in February A review of all deaths reported to the French Police Central Agency on Overdoses for a 5-year period from , showed a decrease from 565 deaths in the first year to 143 in the fifth year. Moreover, the risk of death attributable to methadone was 204 per 100,000 patient years compared to 26 for buprenorphine, making the estimated risk of overdose death at least 5 times higher for methadone than for buprenorphine (Auriacombe et al., 2001). As the number of patients treated with buprenorphine increases relative to the number treated with methadone, it is predicted that the risk of death from heroin overdose will decrease further. Thus, when viewed from a public health standpoint, buprenorphine s availability has greatly reduced the mortality associated with heroin overdose in France. While liberal implementation of buprenorphine is not trouble free, its public health impact is enormous and far outstrips any negative effects Australia The Australian approach to buprenorphine implementation is perhaps the most pragmatic and unburdened by ideology. A number of clinical, largely open studies were conducted in Australia and the authorities readily accepted research data based on controlled clinical studies conducted in the US and Europe. Buprenorphine was approved in Australia in 2001 and is now included in the national formulary. In anticipation, the Australian government, under the auspices of the National Expert Advisory Committee on Illicit Drugs and in consultation with the National Evaluation of Pharmacotherapies for Opioid Dependence, drafted a set of basic policies and clinical practice guidelines for practitioners. This document drew heavily from the Clinical Guidelines for Buprenorphine Trial, a study involving more than 20 medical practitioners and 30 pharmacies with experience in delivering buprenorphine treatment, and from the experiences of numerous other researchers and practitioners worldwide. The final document, National Clinical Guidelines and Procedures for the Use of Buprenorphine in the Treatment of Heroin Dependence (Lintzeris, Clark, Muhleisen, & Ritter, 2001), addresses such issues as pharmacology, maintenance, withdrawal, adverse events and complications of buprenorphine treatment. Thus, with little fuss, the Australian government has taken advantage of the scientific evidence supporting buprenorphine s clinical utility and made it available to its citizens (Ali et al., 2001) US The US approach to buprenorphine implementation has been by far the most conservative. The reasons are legion and have much to do with our traditional views of heroinaddicted individuals and addiction, past and present social and political policy, and the current system of treatment. To date, exposure to buprenorphine treatment in this country has been limited to enrollment in a variety of clinical trials. Several thousand patients have thus benefited from these studies. One such study, which evaluated the buprenorphine/ naloxone combination tablet provided to 326 patients in office-based settings, was terminated early based on definitive evidence that the combination tablet could be effectively used as a first-line opiate dependence treatment in office-based practice. Results of this study have been submitted for publication (Fudala et al., submitted for publication). In an effort to improve treatment options and reach a wider array of potential patients, several other largescale studies in office-based medical practices are being conducted using the buprenorphine/naloxone combination product. One of these now nearing completion involves more than 700 patients across 6 states. The other, now completed, compared the delivery of buprenorphine treatment in an office-based psychosocial treatment setting, a private physician s office, and a narcotic treatment clinic. Also ongoing are protocols at more than a dozen community treatment programs within NIDA s Clinical Trial Network, where the clinical use of buprenorphine for heroin detoxification is being examined in community clinics that have no previous experience using the medication. While no published results from these trials are yet available, informal communication with clinicians and patients suggest that both find the treatment useful and the treatment process satisfactory. It can be anticipated that when buprenorphine finally becomes available for addiction treatment, implementation will not pose significant problems and the treatment will attract a large number of patients. The US government and a number of professional societies are currently conducting physician-training programs in anticipation of buprenorphine s availability as an opiate pharmacotherapy. Unfortunately, it is not yet known for certain when approval will come.

5 W. Ling, D. Smith / Journal of Substance Abuse Treatment 23 (2002) Since the introduction of methadone in the 1960s, treatment of opiate dependence in the US has been virtually limited to methadone clinics. Unfortunately, the methadone treatment system did not arise out of traditional medical practice; it has remained outside mainstream medicine and serves only a small fraction of those who could benefit from short- or long-term opiate-based treatment. Apart from the methadone clinics, most treatment settings in the US are nonmedical in orientation and have little or no infrastructure for the delivery of opiate medications. The treatment philosophy in these facilities is by and large abstinence oriented and medication is often viewed with suspicion. The implementation of buprenorphine treatment into traditional addiction treatment settings will thus require a realignment of treatment philosophy as well as changes in personnel and infrastructure (O Conner & Oliveto, 1998). At a philosophical level, staff will have to be reeducated with respect to the role of medication in the treatment of opiate dependence and its acceptability in a traditionally nonmedical setting. Physicians, pharmacists, nurses and other personnel will need to become part of the treatment team and facilities will have to be created for medication storage, provision of medical evaluation, and maintenance of medication dispensing and other treatment records. Thus far, the experience from several buprenorphine studies that have been implemented at the community clinic level suggests that such adjustments are feasible and that the results can be gratifying even in clinical facilities that traditionally do not embrace medications. Implementation of buprenorphine treatment protocols in community treatment settings has thus far been burdened with a significant amount of paper work and regulatory requirements because these protocols are defined as clinical trials, even though their main purpose is clinical treatment of patients. With formal approval and availability of buprenorphine for general clinical use, these burdens should lighten considerably. In conclusion, the availability of buprenorphine for drug addiction treatment and its implementation in community treatment clinics best exemplifies the shift in treatment of addictive disorders in the US in general, and the treatment of opiate dependence in particular, from an ideologically driven treatment system to a science-based treatment system. The impact of its availability on the treatment system goes beyond the narrow domain of its being a specific medication for treatment of opiate addiction, for it changes not only the treatment of opiate dependence, but also the treatment system as a whole. It is now clear that buprenorphine can be safely implemented in community settings without a great deal of difficulty. Clinicians familiar with treating opiate-addicted individuals can be easily trained to use buprenorphine and there appears to be no shortage of patients desiring such treatment in these settings. Practice guidelines and a number of trainings are available from the Center for Substance Abuse Treatment and the American Society of Addiction Medicine. Buprenorphine is not, however, simply a pharmacological treatment. Rather, it is a treatment strategy within a social and political context. Its special place in the treatment of opiate abuse and dependence depends not only on its unique pharmacological properties but also on the way these properties fit into societal views and policies with respect to opiate addiction and the opiate-addicted persons themselves. On balance, the availability of buprenorphine should add significantly to the armamentarium of treatments for opiate dependence and contribute to the welfare of patients and society as a whole. Acknowledgments The preparation of this article was supported in part by the following grants from NIDA to Dr. Ling: DA ; DA12755; DA50038; DA The authors wish to acknowledge the assistance of Ms. Sandy Dow. Dr. Ling has served as a consultant to Reckitt/Benckaiser, the manufacturer of buprenorphine, and to Schering-Plough, which will market buprenorphine products when approved by the FDA. Dr. Smith has no conflict of interest to declare. 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