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Alpha2 adrenergic agonists for the management of opioid withdrawal

  • Review
  • Intervention

Authors


Abstract

Background

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.

Objectives

To assess the effectiveness of interventions involving the use of alpha2 adrenergic agonists (clonidine, lofexidine, guanfacine) to manage the acute phase of opioid withdrawal.

Search strategy

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.

Selection criteria

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.

Main results

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.

Reviewers' conclusions

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.

Plain language summary

Synopsis

Opioid withdrawal is similar with alpha2 adrenergic agonists and reducing doses of methadone but people stay in treatment longer with methadone and have less adverse effects.

Alpha2 adrenergic agonists (eg. clonidine, lofexidine) moderate the signs and symptoms of opioid withdrawal. Clonidine is used widely as a non-opioid alternative for managing opioid withdrawal. The review of trials found that when withdrawal from heroin or methadone is done with clonidine or lofexidine, compared to reducing doses of methadone, withdrawal signs and symptoms are similar but occur earlier. The chance of completing withdrawal is similar. People stay in treatment longer with methadone regimes. Clonidine has more adverse effects (low blood pressure, dizziness, dry mouth, lack of energy) than reducing doses of methadone. Lofexidine has less effect on blood pressure than clonidine.

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