Maintenance Treatment with Buprenorphine and Naltrexone for Heroin Dependence in Malaysia: A Randomised, Double-Blind, Placebo-Controlled Trial

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
The Lancet (Impact Factor: 45.22). 07/2008; 371(9631):2192-200. DOI: 10.1016/S0140-6736(08)60954-X
Source: PubMed


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.
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, number NCT00383045.
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.
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.

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Available from: Marek C Chawarski, Aug 27, 2014
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    • "While some studies provide a detailed description of conditions that would deem patients ineligible for inclusion, other studies lacked such sufficient detail thus jeopardizing the reproducibility of their trial. For instance, one of the higher quality studies published in the Lancet by Schottenfeld et al. (2008) provides a list of conditions they deemed problematic for inclusion into the trial without once discussing how such conditions were measured, " 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 had life-threatening medical problems, " [19]. This type of description was not uncommon, whereby the majority of studies lacked any explanation of the methods used to assess for different physical conditions or demographic characteristics. "
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    ABSTRACT: Eligibility criteria that result in the exclusion of a substantial number of patients from randomized trials jeopardize the generalizability of treatment effect to much of the clinical population. This is important when evaluating opioid substitution and antagonist therapies (OSATs), especially given the challenges associated with treating the opioid-dependent population. We aimed to identify OSAT trials' eligibility criteria, quantify the percentage of the clinical population excluded by these criteria, and determine how OSAT guidelines incorporate evidence from these trials. We performed a systematic review to identify the eligibility criteria used across trials. We searched Medline, EMBASE, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry (CTR), World Health Organization International CTR Platform Search Portal, and the National Institutes of Health CTR databases from inception to January 1, 2014. To quantify the effect of trials' eligibility criteria on generalizability, we applied these criteria to data from an observational study of opioid-dependent patients (n = 394). We then accessed the Canadian, American, British, and World Health Organization (WHO) OSAT guidelines to evaluate how evidence is used in the recommendations. Among the 60 trials identified the majority (≥50 % of trials) exclude patients with psychiatric (60 %) and physical comorbidity (51.7 %). Additionally, we found 19 trials exclude patients with current alcohol/substance-use problems (31.7 %), and 29 (48.3 %) exclude patients taking psychotropic medications. These criteria were restrictive and in some cases rendered 70 % of the observational sample ineligible. North American OSAT guidelines made strong recommendations supported by evidence with poor generalizability. National Institute of Health and Care Excellence (NICE) and WHO guidelines for opioid misuse provide a critical assessment of the literature used to inform their recommendations. Trials assessing OSATs often exclude patients with concurrent disorders. If the excluded patients respond differently to treatment, results from these trials are likely to overestimate the true effectiveness of OSATs. North American guidelines should consider these limitations when drafting clinical recommendations.
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    • "Effects of the three treatment arms on primary and secondary outcomes were reported previously (Schottenfeld, Chawarski, and Mazlan 2008). All ICERs for primary outcomes – days in treatment, days in treatment without heroin use, days in treatment without heroin relapse, and maximum consecutive days abstinent --were below $50 per additional day (Figure 1). "
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    ABSTRACT: To aid public health policymaking, we studied the cost-effectiveness of buprenorphine, naltrexone, and placebo interventions for heroin dependence in Malaysia. We estimated the cost-effectiveness ratios of three treatments for heroin dependence. We used a microcosting methodology to determine fixed, variable, and societal costs of each intervention. Cost data were collected from investigators, staff, and project records on the number and type of resources used and unit costs; societal costs for participants' time were estimated using Malaysia's minimum wage. Costs were estimated from a provider and societal perspective and reported in 2004 US dollars. Muar, Malaysia. 126 patients enrolled in a randomized, double-blind, placebo-controlled clinical trial in Malaysia (2003-2005) receiving counseling and buprenorphine, naltrexone, or placebo for treatment of heroin dependence. Primary outcome measures included days in treatment, maximum consecutive days of heroin abstinence, days to first heroin use, and days to heroin relapse. Secondary outcome measures included treatment retention, injection drug use, illicit opiate use, AIDS Risk Inventory total score, and drug risk and sex risk subscores. Buprenorphine was more effective and more costly than naltrexone for all primary and most secondary outcomes. Incremental cost-effectiveness ratios were below $50 for primary outcomes, mostly below $350 for secondary outcomes. Naltrexone was dominated by placebo for all secondary outcomes at almost all endpoints. Incremental treatment costs were driven mainly by medication costs, especially the price of buprenorphine. Buprenorphine appears to be a cost-effective alternative to naltrexone that might enhance economic productivity and reduce drug use over a longer term.
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    • "The short version of AIDS Risk Inventory, assessing drug-related and sexual risk behaviors associated with HIV transmission (Chawarski et al., 1998), was administered at baseline and 3 and 6 months after study enrollment. A Mandarin Chinese version of this assessment, translated by native Mandarin Chinese-speaking co-investigators in previous studies in Malaysia and China and then back translated and checked for accuracy and equivalence, has been used in several previous studies (Chawarski et al., 2008, Schottenfeld at al., 2008). Illicit drug use was measured by at least monthly urine testing using rapid/instant urine tests for opiates (morphine). "
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