Alpha2-adrenergic agonists for the management of opioid withdrawal

Withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment.

To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists compared with placebo, reducing doses of methadone, symptomatic medications or with comparison of different alpha2-adrenergic agonists, for the management of the acute phase of opioid withdrawal. Outcomes included the intensity of signs and symptoms and overall withdrawal syndrome experienced, duration of treatment, occurrence of adverse effects and completion of treatment.

We searched the Cochrane Central Register of Controlled Trials (Issue 7, 2013), MEDLINE (1946 to July week 4, 2013), EMBASE (January 1985 to August week 1, 2013), PsycINFO (1806 to July week 5, 2013) and reference lists of articles. We also contacted manufacturers in the field.

Randomised controlled trials comparing alpha2-adrenergic agonists (clonidine, lofexidine, guanfacine, tizanidine) with reducing doses of methadone, symptomatic medications or placebo, or comparing different alpha2-adrenergic agonists to modify the signs and symptoms of withdrawal in participants who were opioid dependent.

One review author assessed studies for inclusion and undertook data extraction. All review authors decided on inclusion and confirmed the overall process.

We included 25 randomised controlled trials, involving 1668 participants. Five studies compared a treatment regimen based on an alpha2-adrenergic agonist with placebo, 12 with a regimen based on reducing doses of methadone, four with symptomatic medications and five compared different alpha2-adrenergic agonists.Alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.18 to 0.57, 3 studies, 148 participants). Completion of treatment was significantly more likely with alpha2-adrenergic agonists compared with placebo (RR 1.95, 95% CI 1.34 to 2.84, 3 studies, 148 participants).Alpha2-adrenergic agonists were somewhat less effective than reducing doses of methadone in ameliorating withdrawal symptoms, as measured by the likelihood of severe withdrawal (RR 1.18, 95% CI 0.81 to 1.73, 5 studies, 340 participants), peak withdrawal score (standardised mean difference (SMD) 0.22, 95% CI -0.02 to 0.46, 2 studies, 263 participants) and overall withdrawal severity (SMD 0.13, 95% CI -0.24 to 0.49, 3 studies, 119 participants). These differences were not statistically significant. The signs and symptoms of withdrawal occurred and resolved earlier with alpha2-adrenergic agonists. The duration of treatment was significantly longer with reducing doses of methadone (SMD -1.07, 95% CI -1.31 to -0.83, 3 studies, 310 participants). Hypotensive or other adverse effects were significantly more likely with alpha2-adrenergic agonists (RR 1.92, 95% CI 1.19 to 3.10, 6 studies, 464 participants) but there was no significant difference in rates of completion of withdrawal treatment (RR 0.85, 95% CI 0.69 to 1.05, 9 studies, 659 participants).There were insufficient data for quantitative comparison of different alpha2-adrenergic agonists. Available data suggest that lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine.

Clonidine and lofexidine are more effective than placebo for the management of withdrawal from heroin or methadone. No significant difference in efficacy was detected for treatment regimens based on clonidine or lofexidine, and those based on reducing doses of methadone over a period of around 10 days but methadone is associated with fewer adverse effects than clonidine, and lofexidine has a better safety profile than clonidine.