Withdrawal (detoxification) is necessary prior to drug-free treatment. It may also represent the end point of long-term treatment such as methadone maintenance. The availability of managed withdrawal is essential to an effective treatment system.
To assess the effectiveness of interventions involving the use of alpha2 adrenergic agonists (clonidine, lofexidine, guanfacine) to manage the acute phase of opioid withdrawal.
Multiple electronic databases (including MEDLINE, EMBASE, PsycINFO, Australian Medical Index, Cochrane Clinical Trials Register) were systematically searched. Reference lists of retrieved studies, reviews and conference abstracts were handsearched and relevant pharmaceutical companies contacted.
Controlled trials comparing alpha2 adrenergic agonists 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 primarily opioid dependent.
Data collection and analysis
One reviewer assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all four reviewers.
Twenty-two studies, involving 1691 participants, were included. Eighteen were randomised controlled trials; for the remaining studies allocation was by participant choice in one, another used alternate allocation and in two the method of allocation was unclear.
Eleven studies compared a treatment regime based on an alpha2 adrenergic agonist with one based on reducing doses of methadone.
Diversity in study design, assessment and reporting of outcomes limited the extent of quantitative analysis.
For the comparison of alpha2 adrenergic agonist regimes with reducing doses of methadone, there were insufficient data for statistical analysis, but withdrawal intensity appears similar to, or marginally greater with alpha2 adrenergic agonists, while signs and symptoms of withdrawal occur and resolve earlier in treatment. Participants stay in treatment longer with methadone. No significant difference was detected in rates of completion of withdrawal with adrenergic agonists compared to reducing doses of methadone, or clonidine compared to lofexidine. Clonidine is associated with more adverse effects (low blood pressure, dizziness, dry mouth, lack of energy) than reducing doses of methadone. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine.
No significant difference in efficacy was detected for treatment regimes based on the alpha2 adrenergic agonists clonidine and lofexidine, and those based on reducing doses of methadone over a period of around 10 days, for the management of withdrawal from heroin or methadone. Participants stay in treatment longer with methadone regimes and experience less adverse effects. The lower incidence of hypotension makes lofexidine more suited to use in outpatient settings than clonidine. There are insufficient data available to support a conclusion on the efficacy of other alpha2 adrenergic agonists.