ArticlesMaintenance treatment with buprenorphine and naltrexone for heroin dependence in Malaysia: a randomised, double-blind, placebo-controlled trial
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.
Section snippets
Patients and study setting
Patients met criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM IV)25 for present opiate dependence, and had a urine toxicology test that was positive for opioids. Patients were ineligible if they were dependent on alcohol, benzodiazepines, or sedatives; had concentrations of liver enzymes (alkaline phosphatase or alanine transaminase) greater than three times the upper limit of normal; were dangerous to themselves or others; were psychotic or had major depression; or
Results
Figure 1 shows the trial profile. 44 patients were randomly assigned to buprenorphine, 43 to naltrexone, and 39 to placebo. Table 1 shows the patients' demographic and clinical characteristics, which did not differ between the three groups.
We recorded significant overall differences in retention (p=0·0004), with retention highest for buprenorphine and lowest for placebo (figure 2). In pairwise comparisons, retention was significantly higher with buprenorphine than with naltrexone (hazard ratio
Discussion
The results of this study lend strong support to the efficacy of maintenance treatment with buprenorphine in sustaining abstinence, delaying time to resumption of heroin use and time to relapse, and retaining patients in treatment. HIV risk behaviours decreased significantly from baseline for all three groups, primarily driven by substantial reductions in injection drug use, but did not differ significantly between treatments. Although complete abstinence, elimination of HIV risk behaviours,
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