Maintenance treatment with buprenorphine and naltrexone for heroin dependence in Malaysia: a randomised, double-blind, placebo-controlled trial

Summary

Background

Expansion of access to effective treatments for heroin dependence is a worldwide health priority that will also reduce HIV transmission. We compared the efficacy of naltrexone, buprenorphine, and no additional treatment, in patients receiving detoxification and subsequent drug counselling, for maintenance of heroin abstinence, prevention of relapse, and reduction of HIV risk behaviours.

Methods

126 detoxified heroin-dependent patients, from an outpatient research clinic and detoxification programme in Malaysia, were randomly assigned by a computer-generated randomisation sequence to 24 weeks of manual-guided drug counselling and maintenance with naltrexone (n=43), buprenorphine (n=44), or placebo (n=39). Medications were administered on a double-blind and double-dummy basis. Primary outcomes, assessed by urine testing three times per week, were days to first heroin use, days to heroin relapse (three consecutive opioid-positive urine tests), maximum consecutive days of heroin abstinence, and reductions in HIV risk behaviours over 6 months. The study was terminated after 22 months of enrolment because buprenorphine was shown to have greater efficacy in an interim safety analysis. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00383045.

Findings

We observed consistent, linear contrasts in days to first heroin use (p=0·0009), days to heroin relapse (p=0·009), and maximum consecutive days abstinent (p=0·0007), with all results best for buprenorphine and worst for placebo. Buprenorphine was associated with greater time to first heroin use than were naltrexone (hazard ratio 1·87 [95% CI 1·21–2·88]) or placebo (2·02 [1·29–3·16]). With buprenorphine, we also recorded significantly greater time to heroin relapse (2·17 [1·38–3·42]), and maximum consecutive days abstinent than with placebo (mean days 59 [95% CI 43–76] vs 24 [13–35]; p=0·003); however, for these outcomes, differences between buprenorphine and naltrexone were not significant. Differences between naltrexone and placebo were not significant for any outcomes. HIV risk behaviours were significantly reduced from baseline across all three treatments (p=0·003), but the reductions did not differ significantly between the three groups.

Interpretation

Our findings lend support to the widespread dissemination of maintenance treatment with buprenorphine as an effective public-health approach to reduce problems associated with heroin dependence.

Funding

US National Institute on Drug Abuse.

Introduction

Heroin and injection drug use are worldwide problems that substantially increase HIV transmission in Malaysia, many other developing and transitional countries (including China, India, Indonesia, Iran, Pakistan, and Russia), and in high-income countries (USA, England, Europe, and Australia).1, 2, 3, 4, 5, 6, 7 Until recently, Malaysia, along with many other developing countries, implemented a largely punitive approach to drug problems, relying on imprisonment or long-term detention in so-called rehabilitation programmes and prohibiting medical treatments for heroin dependence.3, 7 In Malaysia, the failure of this approach to stem drug problems and HIV transmission led to the introduction in 1996 of some medical treatments, which were limited to medically-supervised detoxification, drug counselling, and maintenance treatment with the opioid antagonist naltrexone.⁷

Malaysia continued to prohibit maintenance treatment with opioid agonists, however, until the start of this study, which introduced maintenance treatment with buprenorphine and led to the subsequent approval of maintenance treatment with methadone. Concerns about the potential abuse liability of methadone, misconceptions about the therapeutic mechanisms of maintenance treatment with opioid agonists (some believe that it simply substitutes one addiction for another), and poor understanding of its effectiveness contributed to prohibition of this treatment approach. Notably, maintenance treatment with an opioid agonist remains prohibited in some countries, including Russia,3, 8 and is provided only to an estimated 240 000 of 800 000 or more heroin addicts in the USA.⁹ Dissemination of medical treatments will partly depend on assessment of the comparative efficacy of the different treatments.

Heroin detoxification followed by drug counselling or referral to self-help groups is a common treatment approach in the USA, Malaysia, and elsewhere, despite little strong empirical evidence to lend support to this approach.¹⁰ Naltrexone, a fairly long-acting (24–72 h after oral administration) opioid antagonist, was approved by the US Food and Drug Administration for the treatment of opioid dependence in 1984, on the basis of its safety and pharmacological efficacy at blocking effects of opiods, and it was introduced in Malaysia in 1996. Several meta-analyses and reviews concluded, however, that placebo-controlled studies have provided insufficient evidence to support the efficacy of naltrexone,11, 12 although two placebo-controlled studies undertaken in St Petersburg, Russia, showed significantly larger retention and reductions in relapse with naltrexone.8, 13 However, poor treatment retention and difficulties with patient acceptance have restricted its effectiveness in clinical practice.¹¹

Strong and consistent findings from randomised, placebo-controlled clinical trials and observational and quasi-experimental studies indicate the effectiveness of maintenance treatment with a partial opioid agonist, buprenorphine, or a full agonist, methadone, in reduction of illicit opioid use and risk of HIV transmission.3, 14, 15, 16 Studies directly comparing buprenorphine and methadone report comparable or greater efficacy of methadone.15, 17 Advantages of buprenorphine—including decreased overdose risk, possibly reduced risk of abuse (especially when provided as a tablet containing naloxone), and potential for dosing three times per week18, 19—facilitated its introduction in Malaysia at a time when methadone was still prohibited. No studies have directly compared the efficacy of treatment with an opioid agonist (either buprenorphine or methadone) and maintenance treatment with naltrexone. The absence of direct comparisons could contribute to policy makers' assumption that the introduction of maintenance treatment with opioid agonists has no advantages, if maintenance treatment with naltrexone is available. Additionally, not very many placebo-controlled clinical trials of maintenance with either buprenorphine18, 20, 21, 22, 23 or naltrexone8, 11, 12, 13, 24 exist.

Consequently, we undertook a double-blind, double-dummy, placebo-controlled randomised clinical trial to compare the efficacy of detoxification followed by drug counselling alone (placebo), or combined with maintenance treatment with naltrexone or buprenorphine, for maintenance of heroin abstinence, prevention of relapse, and reduction of HIV risk behaviours.