The results of this study provide strong support for the efficacy of buprenorphine maintenance treatment in sustaining abstinence, delaying time to resumption of heroin use and time to relapse, and retaining patients in treatment, as evidenced by the findings of consistent, significant linear contrasts on all of these measures, with best results for buprenorphine, intermediate results for naltrexone, and worst results for placebo. HIV risk behaviors decreased significantly from baseline for all 3 groups, primarily driven by substantial reductions in injection drug use, but did not differ significantly across treatments. While complete abstinence, elimination of HIV risk behaviors, and recovery of psychosocial functioning would be ideal outcomes, increasing the amount of time abstinent (i.e., consecutive weeks abstinent) and delaying the time to resumption of heroin use or relapse—positive outcomes found with buprenorphine maintenance in this study—are important treatment goals. By these measures, buprenorphine maintenance treatment is significantly more effective than placebo and significantly more effective on some measures than naltrexone. Since patients generally continue to improve the longer they remain in opioid agonist maintenance treatment,32
the significantly greater retention among patients receiving buprenorphine also supports the effectiveness of this medication.
To our knowledge, this is the first randomized clinical trial comparing opioid agonist maintenance treatment (with buprenorphine or methadone) and naltrexone and one of the few (and longest) placebo-controlled trials of buprenorphine or naltrexone. The findings in this study of significant superiority of buprenorphine compared to placebo on all of our primary drug use outcome measures and retention are consistent with the results of other placebo-controlled studies of buprenorphine in the U.S.,18,20,23
The findings of significant superiority of buprenorphine compared to naltrexone for retention and time to resuming heroin use are unique. The results for buprenorphine treated patients in this study regarding retention and maximum duration of opioid abstinence are similar to previous studies of buprenorphine,19
and the results for naltrexone treated patients were comparable to the results of many studies,24,33,34
suggesting that the findings regarding the greater efficacy of buprenorphine compared to naltrexone or placebo may generalize to other populations and settings.
Drug use outcomes and retention for patients treated with naltrexone were consistently better but not significantly different than for placebo-treated patients in this study. The failure to detect significant differences is consistent with several other placebo-controlled studies of naltrexone and meta-analyses11,12
but contrast with the significant differences found in the St. Petersburg studies, where opioid agonist maintenance treatment is not available and there are strong family supports encouraging treatment participation.8,13
Notably, a recent meta-analytic review concluded that retention is the key variable explaining the discrepancies in findings regarding the efficacy of naltrexone in double-blind clinical trials and that significant differences in illicit opioid use are found between naltrexone- and placebo-treated patients in studies with higher retention,12
which may be achieved by enrolling more highly motivated patients or using contingency management, behavioral family therapy, or legal or other pressures to encourage medication adherence and continued treatment participation.35–37
The recent introduction of a long-acting, depot formulation of naltrexone may also improve treatment retention and the effectiveness of naltrexone in clinical practice.38
Despite the favorable findings with regard to buprenorphine, there is still room for improvement, since only 41% of patients remained in treatment and only 25% stayed in treatment and avoided relapse during the 24-week treatment period. Additionally, as found in other studies,3,39
HIV risk behaviors associated with injection drug use were reduced during treatment in all treatment groups, but sexual risk behaviors, including unprotected sex, did not decrease. Providing earlier dose increases, higher doses of buprenorphine, or take-home doses of buprenorphine might have improved retention and drug use outcomes in the buprenorphine group. Training available health care personnel, nurses, to provide the drug counseling is a strength of the study and improves the relevance of the study findings to Malaysia and other developing countries, where there are very few health professionals with advanced training or experience in addictions treatment, but developing and providing more effective counseling or other behavioral interventions might improve treatment outcomes. The added benefits of improved behavioral interventions would be expected in all treatment groups, however, and would not be expected to change the findings regarding the superiority of buprenorphine.
Limitations of this study include early termination of the study, due to the findings of significant superiority of buprenorphine on the primary drug use outcome measures, which resulted in a final sample size that was smaller than initially planned.40,41
The observed, non-significant differences in pair-wise comparisons on some drug use and HIV risk reduction measures and retention (e.g., between naltrexone- and placebo-treated patients on all of these measures or between buprenorphine- and naltrexone-treated patients on some of the measures) would not have been likely to reach the level of statistical significance with the originally planned sample size but could be large enough to be of potential clinical importance if found to differ significantly in a much larger study. Missing data, resulting mainly from the high attrition of patients treated with naltrexone or placebo and subsequent loss to follow-up of some non-completing patients, may have blunted the findings with regard to the efficacy of buprenorphine, since most patients who left treatment prematurely had resumed heroin use prior to leaving treatment, and premature discontinuation of treatment is usually followed by relapse. Drug use outcomes and retention were based on objective measures, but HIV risk behaviors were assessed by self-report and could not be validated by objective measures. Despite efforts to maintain the medication blind, differences in medication effects allowed most patients treated with buprenorphine or naltrexone to break the blind and identify correctly the medication they were receiving. Study eligibility criteria, the requirement that all patients complete a residential detoxification before randomization, and the use of a single study site and limited sample size limit the generalisability of the study findings to other patient populations or settings. Buprenorphine may have even greater effectiveness compared to detoxification followed by drug counseling alone or with naltrexone in “real world” settings where heroin-dependent patients are directly inducted on buprenorphine without first needing to undergo detoxification.
This study has important implications for clinical practice and public health policy. Although opioid agonist maintenance treatment remains unavailable in many areas, the findings of this study provide strong support for the efficacy of buprenorphine maintenance treatment for reducing illicit opioid use and retaining patients in treatment, compared to either naltrexone maintenance treatment or drug counseling only, and some support for the potential efficacy of all 3 treatments to reduce HIV transmission risk associated with injection drug use.3,14,15
The ease of induction onto buprenorphine in ambulatory settings, the low incidence of serious adverse events or medical symptoms leading to treatment discontinuation associated with buprenorphine in this study and previous studies,18,42
and the potential for providing more liberal take home doses than were provided in the clinical trial also facilitate dissemination of this treatment. These considerations support dissemination of opioid agonist maintenance treatment with buprenorphine or methadone (which has at least comparable efficacy, greater ease of induction, and generally lower medication cost compared to buprenorphine) as an important component of an effective public health approach for reducing problems associated with heroin dependence.