Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of substitution treatment.
To assess the effects of buprenorphine versus tapered doses of methadone, alpha2-adrenergic agonists, symptomatic medications or placebo, or different buprenorphine regimens for managing opioid withdrawal, in terms of the intensity of the withdrawal syndrome experienced, duration and completion of treatment, and adverse effects.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 11, 2016), MEDLINE (1946 to December week 1, 2016), Embase (to 22 December 2016), PsycINFO (1806 to December week 3, 2016), and the Web of Science (to 22 December 2016) and handsearched the reference lists of articles.
Randomised controlled trials of interventions using buprenorphine to modify the signs and symptoms of withdrawal in participants who were primarily opioid dependent. Comparison interventions involved reducing doses of methadone, alpha2-adrenergic agonists (clonidine or lofexidine), symptomatic medications or placebo, and different buprenorphine-based regimens.
Data collection and analysis
We used standard methodological procedures expected by Cochrane.
We included 27 studies involving 3048 participants. The main comparators were clonidine or lofexidine (14 studies). Six studies compared buprenorphine versus methadone, and seven compared different rates of buprenorphine dose reduction. We assessed 12 studies as being at high risk of bias in at least one of seven domains of methodological quality. Six of these studies compared buprenorphine with clonidine or lofexidine and two with methadone; the other four studies compared different rates of buprenorphine dose reduction.
For the comparison of buprenorphine and methadone in tapered doses, meta-analysis was not possible for the outcomes of intensity of withdrawal or adverse effects. However, information reported by the individual studies was suggestive of buprenorphine and methadone having similar capacity to ameliorate opioid withdrawal, without clinically significant adverse effects. The meta-analyses that were possible support a conclusion of no difference between buprenorphine and methadone in terms of average treatment duration (mean difference (MD) 1.30 days, 95% confidence interval (CI) −8.11 to 10.72; N = 82; studies = 2; low quality) or treatment completion rates (risk ratio (RR) 1.04, 95% CI 0.91 to 1.20; N = 457; studies = 5; moderate quality).
Relative to clonidine or lofexidine, buprenorphine was associated with a lower average withdrawal score (indicating less severe withdrawal) during the treatment episode, with an effect size that is considered to be small to moderate (standardised mean difference (SMD) −0.43, 95% CI −0.58 to −0.28; N = 902; studies = 7; moderate quality). Patients receiving buprenorphine stayed in treatment for longer, with an effect size that is considered to be large (SMD 0.92, 95% CI 0.57 to 1.27; N = 558; studies = 5; moderate quality) and were more likely to complete withdrawal treatment (RR 1.59, 95% CI 1.23 to 2.06; N = 1264; studies = 12; moderate quality). At the same time there was no significant difference in the incidence of adverse effects, but dropout due to adverse effects may be more likely with clonidine (RR 0.20, 95% CI 0.04 to 1.15; N = 134; studies = 3; low quality). The difference in treatment completion rates translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 6), indicating that for every four people treated with buprenorphine, we can expect that one additional person will complete treatment than with clonidine or lofexidine.
For studies comparing different rates of reduction of the buprenorphine dose, meta-analysis was possible only for treatment completion, with separate analyses for inpatient and outpatient settings. The results were diverse, and we assessed the quality of evidence as being very low. It remains very uncertain what effect the rate of dose taper has on treatment outcome.
Buprenorphine is more effective than clonidine or lofexidine for managing opioid withdrawal in terms of severity of withdrawal, duration of withdrawal treatment, and the likelihood of treatment completion.
Buprenorphine and methadone appear to be equally effective, but data are limited. It remains possible that the pattern of withdrawal experienced may differ and that withdrawal symptoms may resolve more quickly with buprenorphine.
It is not possible to draw any conclusions from the available evidence on the relative effectiveness of different rates of tapering the buprenorphine dose. The divergent findings of studies included in this review suggest that there may be multiple factors affecting the response to the rate of dose taper. One such factor could be whether or not the initial treatment plan includes a transition to subsequent relapse prevention treatment with naltrexone. Indeed, the use of buprenorphine to support transition to naltrexone treatment is an aspect worthy of further research.
Most participants in the studies included in this review were male. None of the studies reported outcomes on the basis of sex, preventing any exploration of differences related to this variable. Consideration of sex as a factor influencing response to withdrawal treatment would be relevant research for selecting the most appropriate type of intervention for each individual.
Plain language summary
Buprenorphine for managing opioid withdrawal
We reviewed the evidence about the effect of buprenorphine for managing withdrawal in people who are dependent on opioid drugs (for example, heroin or pharmaceutical opiates).
Managed withdrawal, or detoxification, is a required first step for long-term treatment of opioid dependence. The combination of uncomfortable symptoms and intense craving makes completion of opioid withdrawal difficult for most people. Buprenorphine is one of the medications used to manage withdrawal from opioid drugs. This review considered whether buprenorphine is more effective than methadone in tapered doses, or better than clonidine or lofexidine, which are other medications that have been commonly used for managing opioid withdrawal.
The evidence is current to December 2016.
We identified 27 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups), involving 3048 opioid-dependent participants. For 21 studies the average age of participants was in the range 25 to 40 years − in one study the average age was 47 years, while in two studies involving adolescents, the average age of participants was in the range 17 to 20 years (3 studies did not report the average age of participants). In four studies, all or nearly all participants were male, while in three studies less than half the participants were male. In most studies males comprised between one half and three-quarters of participants, a balance that is typical of the population of people who are opioid dependent. Fourteen of the studies took place in the USA, while the remaining studies were in eight other countries. The studies compared buprenorphine with methadone (6 studies), clonidine or lofexidine (14 studies), or different rates of buprenorphine dose reduction (7 studies).
Fourteen studies reported funding from sources other than industry; in seven studies funding or medications were provided by a pharmaceutical company. The funding source was unclear for seven studies.
Compared to clonidine or lofexidine, people receiving buprenorphine for opioid withdrawal will have less severe signs and symptoms, be likely to stay in treatment longer, experience fewer side effects, and be more likely to complete the scheduled period of treatment. The effectiveness of buprenorphine is probably similar to tapered doses of methadone, but we are uncertain whether withdrawal symptoms resolve more quickly with buprenorphine. We are also uncertain whether rapid reduction in the dose of buprenorphine is more effective than slow reduction and whether this depends on the context of withdrawal.
Quality of the evidence
We assessed the quality of the evidence to be very low to moderate for the comparison of buprenorphine versus clonidine or lofexidine, low to moderate for the comparison of buprenorphine versus methadone, and very low to low for the comparison of different rates of dose reduction. Further evidence could change the findings, particularly for buprenorphine compared to methadone and for different rates of reduction of buprenorphine dose.