Buprenorphine-containing treatments: place in the management of opioid addiction

Although the synthetic opioid buprenorphine has been available clinically for almost 30 years, its use has only recently become much more widespread for the treatment of opioid addiction.The pharmacodynamic and pharmacokinetic profiles of buprenorphine make it unique in the armamentarium of drugs for the treatment of opioid addiction. Buprenorphine has partial mu-opioid receptor agonist activity and is a kappa-opioid receptor antagonist; hence, it can substitute for other micro-opioid receptor agonists, yet is less apt to produce overdose reactions or dysphoria. On the other hand, buprenorphine can block the effects of opioids such as heroin (diamorphine) and morphine, and can even precipitate withdrawal in individuals physically dependent upon these drugs. Buprenorphine has significant sublingual bioavailability and a long half-life, making administration on a less than daily basis possible. Furthermore, its discontinuation is associated with only a mild withdrawal syndrome.Clinical trials have demonstrated that sublingual buprenorphine is effective in both maintenance therapy and detoxification of individuals addicted to opioids. The introduction of a sublingual formulation combining naloxone with buprenorphine further reduces the risk of diversion to illicit intravenous use. Because of its relative safety and lower risk of illegal diversion, buprenorphine has been made available in several countries for treating opioid addiction in the private office setting, greatly enhancing treatment options for this condition.     

The characteristics of heroin users entering treatment: findings from the Australian treatment outcome study (ATOS)

The current study aimed to describe the characteristics (demographics, drug use, mental and physical health) of entrants to treatment for heroin dependence in three treatment modalities; and to compare these characteristics with heroin users not in or seeking treatment. Participants were 825 current heroin users recruited from Sydney, Adelaide and Melbourne: 277 entering methadone/buprenorphine maintenance treatment (MT), 288 entering detoxification (DTX), 180 entering drug-free residential rehabilitation (RR) and 80 not in treatment (NT). Treatment entrants were generally long-term heroin users with previous treatment experience. The majority of the sample (55%) were criminally active in the month preceding interview. Injection-related health problems (74%) and a history of heroin overdose (58%) were commonly reported. There were high degrees of psychiatric co-morbidity, with 49% reporting severe psychological distress, 28% having current major depression, 37% having attempted suicide and 42% having a lifetime history of post-traumatic stress disorder. Personality disorders were also prevalent, with 72% meeting criteria for antisocial personality disorder and 47% screening positive for borderline personality disorder. Striking similarities were noted between the non-treatment and treatment groups in length of heroin use career, drug use and treatment histories. [Ross J, Teesson M, Darke S, Lynskey M, Ali R, Ritter A, Cooke R. The characteristics of heroin users entering treatment: findings from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Rev 2005;24:411-418]     

Retention and attendance with supervised buprenorphine treatment: a case-note review

Since 2001, the Langton Centre has used supervised administration of buprenorphine in treating heroin dependence, without distinguishing between detoxification and maintenance; most people commencing treatment may remain on buprenorphine indefinitely. The aim of this study was to describe retention in treatment, reasons for leaving, re-entry and pattern of attendance, and compare retention in practice with results from research trials, using a file review of sequential presentations for buprenorphine treatment. Retention in treatment was 37% at 6 months, the same as in Australian research trials of buprenorphine maintenance (37%); most people dropped-out without consultation or dose tapering. Repeated episodes of treatment constituted 45% of all episodes; missed scheduled doses were common. Participation in buprenorphine treatment often involves repeated, short episodes and erratic attendance. Measures to improve retention in treatment could improve treatment efficacy. [Bell J, Burrell T. Retention and attendance with supervised buprenorphine treatment: a case-note review. Drug Alcohol Rev 2006;25:161 - 165]     

Buprenorphine treatment of heroin dependence (detoxification and maintenance) in a private practice setting

At the conclusion of a 3-year demonstration project in a medical setting in which refusal to accept methadone was an inclusion criterion, 12 subjects were unable to detoxify from buprenorphine and remained adamant in their refusal to enroll in a MMTP. In order to study the feasibility of expanding opportunities for treatment previously unavailable to this under-served population of heroin addicts, these 12 subjects plus an additional 11 subjects (N = 23) were recruited for a 12 months trial of buprenorphine treatment conducted in an office-based setting on a fee-for-service basis. An additional cohort of 40 heroin dependent subjects were entered in a protocol for detoxification only. The findings demonstrate both feasibility and patient acceptance of office based fee-for-service buprenorphine treatment, supporting the need for (1) additional studies of this population and (2) changes in government regulations to reintroduce addiction treatment under physician auspices in private practice settings.     

Outcomes after detoxification for heroin dependence: findings from the Australian Treatment Outcome Study (ATOS)

As part of the Australian Treatment Outcome Study (ATOS), 177 (88%) heroin users entering detoxification (DTX) and 66 (83%) heroin users not in treatment (NT) were interviewed at baseline and 3 months to examine drug use, risk-taking, overdose, crime and psychopathology outcomes. The majority (76%) of the DTX group had entered additional treatment at 3 months, mainly further detoxification, and 54% were currently in treatment, mainly maintenance and residential rehabilitation. There were reductions in heroin use and other drug use in those entering detoxification. Forty-two per cent were abstinent at 3 months compared to 20% in the NT group. There were also reductions in crime among those entering DTX, and less marked reductions in the NT group. Psychopathology showed less change. Detoxification may, in some part, function as a gateway to further treatment and those entering DTX showed modest but significant improvements across drug use and crime at 3 months. [Teesson M, Havard A, Ross J, Darke S. Outcomes after detoxification for heroin dependence: findings from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Rev 2006;25:241 - 247]     

Practice-based buprenorphine maintenance treatment (BMT): how do French healthcare providers manage the opiate-addicted patients?

France was the first country to promote the extensive use of buprenorphine for the treatment of drug-addicted subjects through the primary care system. To assess both professional commitment and patients' characteristics, all the physicians and pharmacists of a French area having prescribed/dispensed buprenorphine from 2/12/96 (the official release date) to 1/31/98 were identified from data files of the Health Insurance and then interviewed. During the first 61 weeks of buprenorphine maintenance treatment (BMT), 27.5% of physicians and 51.2% of pharmacists of that area were involved; 142 patient records were documented. Features of the clinical routines spontaneously implemented for practice-based BMT were: a high level of on-site supervised dispensation by the pharmacist (71% at treatment induction and 23% thereafter); the absence of objective measurement of illicit drug use; and a low buprenorphine dosage. These features are consistent with the lack of physicians' experience and training, and also the relatively good status of the population treated (no HIV-positives, heroin use duration averaging 4.2 +/- 3.1 years, and 81.7% with stable accommodations). Despite liberal regulations guiding BMT, a negligible proportion of cases had a "nomadic" attitude (multiple buprenorphine prescribers/deliverers). The treatment outcomes (no deaths, three drug overdoses, improvement in occupational status) are encouraging. CONCLUSION: Practice-based BMT appears to be a safe and acceptable response to moderate heroin addiction, but further training of the professionals involved and longitudinal investigations of individual outcomes are needed.     

Short-term buprenorphine maintenance: treatment outcome

Fifty-two heroin addicts were inducted onto buprenorphine under the care of psychiatric residents in a setting modeled on office practice. Subjects were maintained on a protocol of six weeks of 16 mg daily dosing, then tapered to zero dose up to week 16, and maintained on placebo through week 18. Of 44 subjects who continued after the first induction dose, 11 terminated during maintenance, 17 during taper; and 16 while on zero dose. Twice weekly urine toxicologies showed significant successive declines in samples positive for heroin use across these three periods: 70%, 41%, and 20%, respectively. Among historical variables, only prior AA attendance distinguished subjects who achieved zero dose from those who did not. A comparison with recent studies suggests that relatively inexperienced office-based physicians can maintain patients on buprenorphine at a level comparable to that reported for research clinic settings, but with comparable rates of heroin abstinence. These findings are discussed in light of potential options for office-based opioid maintenance.     

Erectile dysfunction in male heroin users, receiving methadone and buprenorphine maintenance treatment

Erectile dysfunction (ED) is common among people in treatment for heroin addiction. The purpose of the study was to examine the frequency of ED among methadone and buprenorphine maintenance therapy patients, and to identify factors associated with ED. Patients - recruited from 7 centres in Italy - underwent: (i) a structured interview on socio-demographic characteristics, drug use and sexual behaviour; (ii) IIEF-15 test, a test of sexual function; (iii) Zung test for depression. The study included 201 males: 42% were on methadone maintenance, 58% were on buprenorphine. Overall, 58% reported no ED, 24% reported mild to moderate ED, and 18% severe ED. In univariate analysis buprenorphine patients had less ED than methadone patients (p=0.0135). Subjects living with a partner had less ED than others (p=0.0018). More depressed subjects had more ED (p<0.001). Heterosexual patients reported less ED than homo/bisexual patients (p=0.0427), and partner's use of heroin was associated with more ED (p=0.0078). The significant univariate predictors were entered into a cumulative logit model. Living with a sexual partner was associated with a lower likelihood of ED, while depression, having a sexual partner with a history of drug use and not having a steady partner were associated with a greater likelihood of ED. The significant association between treatment and ED which appeared in univariate analysis (with buprenorphine patients reporting less ED than methadone patients) was not confirmed by the multivariate analysis. Both psychological and social factors were associated with ED which is an important problem for many males in methadone and buprenorphine treatment.     

New challenges and opportunities in managing substance abuse in Malaysia

Until recently, Malaysia has lagged behind in the treatment of drug addiction and related disorders, despite experiencing severe drug problems. By the end of 2004, 234 000 heroin users or heroin-dependent individuals had been registered in the official government registry, but other estimates exceed 500 000 for heroin abusers in the country. Amphetamine-type stimulant abuse is also increasing and of considerable public and government concern. Among the population of drug users, HIV and other infectious diseases rates are very high. In the Western Pacific regions, Malaysia has the second highest HIV prevalence (after Vietnam) among adult populations (0.62%) and the highest proportion of HIV cases resulting from injection drug use (76.3%). Drug use and related disorders exert a heavy burden on the country's health care and legal systems. Historically, drug abusers were rehabilitated involuntarily in correctional, rather than health-care, facilities. This primarily criminal treatment approach had limited effectiveness which led to widespread public dissatisfaction and the recent introduction of medical treatments for addiction. Naltrexone was introduced in 1999; buprenorphine was introduced in 2001 and methadone in 2003. Agonist maintenance programmes were embraced rapidly by the medical community in Malaysia. Currently, over 30 000 opiate-dependent patients are treated with agonist maintenance treatments by more than 500 medical practitioners in Malaysia. Despite these recent advances, treatments for amphetamine-type stimulant abuse or dependence are underdeveloped, and diversion of agonist medications is an emerging concern. [Mazlan M, Schottenfeld RS, Chawarski MC. New challenges and opportunities in managing substance abuse in Malaysia. Drug Alcohol Rev 2006;25:473 - 478]     

Attempted suicide among entrants to three treatment modalities for heroin dependence in the Australian Treatment Outcome Study (ATOS): prevalence and risk factors

AIMS: To determine the lifetime and recent histories of attempted suicide among entrants to treatment for heroin dependence in three treatment modalities and a non-treatment comparison group; and to ascertain factors associated with a recent history of attempted suicide. DESIGN: Cross-sectional structured interview. SETTING: Sydney, Australia. PARTICIPANTS: Six hundred and fifteen current heroin users: 201 entering methadone/buprenorphine maintenance (MT), 201 entering detoxification (DTX), 133 entering drug free residential rehabilitation (RR) and 80 not in treatment (NT). FINDINGS: A lifetime history of attempted suicide was reported by 34% of subjects, 13% had attempted suicide in the preceding year and 5% had done so in the preceding month. Females were more likely to have lifetime (44% versus 28%) and 12 month (21% versus 9%) suicide attempt histories. The 12 month prevalence of attempted suicide among treatment groups ranged between 11% (MT, NT) and 17% (RR). Factors associated with recent suicide attempts were: being an RR entrant, female gender, younger age, less education, more extensive polydrug use, benzodiazepine use, recent heroin overdose, Major Depression, current suicidal ideation, Borderline Personality Disorder (BPD)and Post-Traumatic Stress Disorder. CONCLUSIONS: Recent suicidal behaviour is a major clinical problem for heroin users, and for females and RR entrants in particular. An essential adjunct to treatment for heroin dependence is routine screening for depression and suicidal ideation, with the provision of appropriate treatment where needed.     

Treatment retention in adolescent patients treated with methadone or buprenorphine for opioid dependence: a file review

The aim of this study was to compare retention and re-entry to treatment between adolescent subjects treated with methadone, those treated with buprenorphine, and those treated with symptomatic (non-opioid) medication only. We used a retrospective file review of all patients aged less than 18 at first presentation for treatment for opioid dependence. The study was conducted at the Langton Centre, Sydney, Australia, an agency specialising in the treatment of alcohol and other drug dependency. Sixty-one adolescents (age range 14 - 17 years at the time of commencing treatment); mean reported age of initiation of heroin use was 14 +/- 1.3 years (range 11 - 16). Sixty-one per cent were female. The first episode of treatment was methadone maintenance in 20 subjects, buprenorphine in 25, symptomatic medication in 15; one patient underwent assessment only. These 61 subjects had a total of 112 episodes of treatment. Subjects treated with methadone had significantly longer retention in first treatment episode than subjects treated with buprenorphine (mean days 354 vs. 58, p<0.01 by Cox regression) and missed fewer days in the first month (mean 3 vs. 8 days, p<0.05 by ttest). Subsequent re-entry for further treatment occurred in 25% of subjects treated with methadone, 60% buprenorphine and 60% symptomatic medications. Time to re-entry after first episode of buprenorphine treatment was significantly shorter than after methadone treatment (p<0.05 by Kaplan - Meier test). Methadone maintenance appears to have been more effective than buprenorphine at preventing premature drop-out from treatment of adolescent heroin users.     

Combating opiate dependence: a comparison among the available pharmacological options

Pharmacotherapies for heroin addiction may target opiate withdrawal symptoms, facilitate initiation of abstinence and/or reduce relapse to heroin use either by maintenance on an agonist or antagonist agent. Available agents include opioid agonists, partial opioid agonists, opioid antagonists and alpha 2 -agonists for use during managed withdrawal and long-term maintenance. Experimental approaches combine alpha 2 -agonists with naltrexone to reduce the time of opiate withdrawal and to accelerate the transition to abstinence. Recently, buprenorphine has been introduced in the US for office-based maintenance, with the hope of replicating the success of this treatment in Europe and Australia. Naloxone has been added to buprenorphine in order to reduce its potential diversion to intravenous use, whilst facilitating the expansion of treatment. Although comprehensive substance abuse treatment is not limited to pharmacotherapy, this review will focus on the rationale, indications and limitations of the range of existing medications for detoxification and relapse prevention treatments. The two major goals of pharmacotherapy are to relieve the severity of opiate withdrawal symptoms during the managed withdrawal of the opioid and to prevent relapse to heroin use either after abstinence initiation or after being stabilised on a long-acting opiate agonist, such as methadone.     

A pilot study of buprenorphine-naloxone combination tablet (Suboxone) in treatment of opioid dependence

In Australia, maintenance treatment for opioid dependence involves supervised daily administration of a dose of methadone or buprenorphine. A sublingual tablet combining buprenorphine and naloxone in a 4 : 1 ratio (Suboxone™) has been developed, designed to deter diversion and intravenous misuse, and may be suitable for unsupervised administration. The aim of this study was to investigate the tolerability of Suboxone, and investigate whether unsupervised administration can be effective in stabilized patients. Employed patients on buprenorphine maintenance, who had ceased heroin use, were switched to Suboxone and provided with weekly supplies of medication to take without supervised administration. Subjects were monitored closely with weekly clinical reviews, and research interviews at baseline, 3 and 6 months. Only 11% of people receiving buprenorphine met eligibility criteria. Seventeen subjects were recruited. Fifteen were retained for the full 6 months. No subject appeared destabilized by unsupervised dosing. Suboxone was well tolerated. The current trial demonstrated that unsupervised administration with regular clinical monitoring can be effective in selected patients. However, using access to unsupervised dosing to promote abstinence from heroin probably limits the potential benefits of unsupervised administration to a very small proportion of patients. [Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine - naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004;23:311-317]     

Behavioral naltrexone therapy: an integrated treatment for opiate dependence

Treatment of opiate dependence with naltrexone has been limited by poor compliance. Behavioral Naltrexone Therapy (BNT) was developed to promote adherence to naltrexone and lifestyle changes supportive of abstinence, by incorporating components from empirically validated treatments, including Network Therapy with a significant other to monitor medication compliance, the Community Reinforcement Approach, and voucher incentives. An overview is presented of the BNT treatment manual. In an uncontrolled Stage I trial (N = 47), 19% completed the 6-month course of treatment. Retention was especially poor in the subsample of patients who were using methadone at baseline (N = 18; 39% completed 1 month, none completed 6 months), and more encouraging among heroin-dependent patients (N = 29; 65% completed 1 month, 31% completed 6 months). Thus, attrition continues to be a serious problem for naltrexone maintenance, although further efforts to develop interventions such as BNT are warranted.     

Non-fatal heroin overdose, treatment exposure and client characteristics: findings from the Australian treatment outcome study (ATOS)

The relationship between treatment exposure, drug use, psychosocial variables and non-fatal heroin overdose was examined among a cohort of 495 heroin users, re-interviewed at 12 months. The 12-month overdose rate declined from 24% to 12%, and the proportion administered naloxone declined from 15% to 7%. There were significant reductions in overdose among those who entered maintenance therapies (22% to 4%) and residential rehabilitation (33% vs. 19%) at baseline, but not among those who entered detoxification or were not entering treatment. The total number of treatment days received over the follow-up period was associated independently with a reduced risk of overdose. Each extra treatment day was associated with a 1% reduction in risk of overdose over the follow-up period. By contrast, more treatment episodes were associated with an increased risk of overdose (OR 1.62). Other independent predictors of overdose over follow-up were more extensive polydrug use (OR 1.40), and having overdosed in the year preceding the study (OR 7.87). [Darke S, Williamson A, Ross J, Teesson M. Non-fatal heroin overdose, treatment exposure and client characteristics: findings from the Australian Treatment Outcome Study (ATOS). Drug Alcohol Rev 2005;24:425-432]     

Corticotropin-releasing factor testing reveals a dose-dependent difference in methadone maintained vs control subjects.

Opiate addiction is associated with abnormal function of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. In general, addiction and withdrawal are associated with abnormal HPA responsivity as demonstrated by baseline, dexamethasone, and metyrapone testing. Following stabilization in methadone maintenance treatment, normalization of HPA axis responsivity is observed. To further investigate HPA axis function associated with heroin addiction and its treatment, saline placebo and human corticotropin-releasing factor (hCRF) were administered intravenously in two doses, one dose lower (0.5 microg/kg) and one dose higher (2.0 microg/kg) than the dose used in standard clinical diagnostics (100 microg), to 16 normal male volunteer controls (NV) and eight male stable-dose methadone-maintained former heroin addicts without ongoing drug or alcohol abuse or dependence (MM). Plasma adrenocorticotrophic hormone (ACTH) and cortisol levels were determined at serial time points. There was no difference in hormonal measurements between the two groups following placebo. NV as well as MM displayed a dose-response effect in plasma ACTH and cortisol levels. MM displayed a significantly greater increase in plasma ACTH levels than the NV following high-dose but not low-dose hCRF (p <0.05). There was no significant difference in plasma cortisol levels between the two groups following high-dose hCRF. Thus, despite earlier documented normalization of behavioral function and of several measures of neuroendocrine function during long-term methadone maintenance, some abnormalities in HPA axis responsivity that may be a consequence of heroin exposure, or that may have existed prior to the addiction, can persist during stable methadone treatment.     

阿片类药物替代疗法:安全性和滥用倾向的比较研究

阿片类药物维持疗法是治疗阿片、海洛因和阿片类制剂依赖的有效方法。美沙酮和丁丙诺啡是世界范围内最常用于替代治疗的阿片类药物,纳曲酮作为一种阿片受体的拮抗剂用于阻断治疗。研究数据显示维持疗法比脱毒疗法疗效更好,但是,存在长期用药剂量的安全性问题,包括对药物的直接反应和滥用风险。对美沙酮和丁丙诺啡(单独使用或与纳曲酮合用)的研究揭示了剂量与效应的关系,以及最佳的用药方案。研究数据提示,在呼吸抑制(过量)和对心血管的直接作用方面丁丙诺啡较美沙酮风险更低。丁丙诺啡,作为一种部分激动剂,可能比美沙酮或者海洛因等完全激动剂的滥用倾向更小。本文提供的数据说明在阿片依赖的个体上丁丙诺啡的滥用风险较美沙酮的更低。最近的数据提示,在阿片依赖和非依赖的使用者中,丁丙诺啡/纳曲酮合用的滥用潜力低于丁丙诺啡单独使用。     

Primary care patient characteristics associated with completion of 6-month buprenorphine treatment

Background

Opioid addiction is prevalent in the United States. Detoxification followed by behavioral counseling (abstinence-only approach) leads to relapse to opioids in most patients. An alternative approach is substitution therapy with the partial opioid receptor agonist buprenorphine, which is used for opioid maintenance in the primary care setting. This study investigated the patient characteristics associated with completion of 6-month buprenorphine/naloxone treatment in an ambulatory primary care office.

Methods

A retrospective chart review of 356 patients who received buprenorphine for treatment of opioid addiction was conducted. Patient characteristics were compared among completers and non-completers of 6-month buprenorphine treatment.

Results

Of the 356 patients, 127 (35.7%) completed 6-month buprenorphine treatment. Completion of treatment was associated with counseling attendance and having had a past injury.

Conclusions

Future research needs to investigate the factors associated with counseling that influenced this improved outcome. Patients with a past injury might suffer from chronic pain, suggesting that buprenorphine might produce analgesia in addition to improving addiction outcome in these patients, rendering them more likely to complete 6-month buprenorphine treatment. Further research is required to test this hypothesis. Combination of behavioral and medical treatment needs to be investigated for primary care patients with opioid addiction and chronic pain.