Alpha2-adrenergic agonists for the management of opioid withdrawal

Gowing L, Farrell M, Ali R, White JM

Published Online:

July 8, 2009

Opioid withdrawal is similar with alpha2-adrenergic agonists and reducing doses of methadone but people stay in treatment longer with methadone and have fewer adverse effects.
Managed withdrawal of opioids, or detoxification, is a required first step for longer-term treatments of opioid dependence. The signs and symptoms of opioid withdrawal usually begin 6 to 12 hours after the last dose of heroin or morphine and reach peak intensity within two to four days. Most physical withdrawal signs are no longer obvious after 7 to 14 days. The signs and symptoms develop 36 to 48 hours after the last dose of methadone.
Suppression of withdrawal symptoms with methadone and gradual reduction of the methadone dose requires the use of a drug of dependence to treat opioid dependence and there are often governments restrictions on prescription of methadone. Consumers may also dislike of the protracted nature of methadone withdrawal. The alpha2-adrenergic agonist clonidine is used widely as a non-opioid alternative for managing opioid withdrawal. The review authors identified 24 controlled studies, involving 1631 participants who underwent managed withdrawal in 11 different countries. The review focused on alpha2-adrenergic agonists compared to placebo (four studies), reducing doses of methadone (14 studies), and lofexidine compared to clonidine (three studies).
The alpha2-adrenergic agonists clonidine and lofexidine were more effective than placebo in managing withdrawal from heroin or methadone. Despite having adverse effects, they were associated with higher chances of completing treatment.
Comparing reducing doses of methadone to clonidine or lofexidin for the management of withdrawal from opioids, withdrawal signs and symptoms were similar but occurred earlier with the alpha2-adrenergic agonists, within a few days of cessation of the opioid drugs. The chances of completing withdrawal were similar. People stayed in treatment longer with methadone regimes. Clonidine had more adverse effects (low blood pressure, dizziness, dry mouth, lack of energy) than reducing doses of methadone. Lofexidine had less effect on blood pressure than clonidine.

Abstract (click to read)

Background:

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

Objectives:

To assess the effectiveness of interventions involving the use of alpha2-adrenergic agonists to manage opioid withdrawal.

Search strategy:

We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2008), MEDLINE (January 1966-July 2008), EMBASE (January 1985-2008 Week 31), PsycINFO (1967 to 7 August 2008) and reference lists of articles. We also contacted manufacturers in the field.

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 opioid dependent.

Data collection and analysis:

One author assessed studies for inclusion and undertook data extraction. Inclusion decisions and the overall process were confirmed by consultation between all authors.

Main results:

Twenty-four studies, involving 1631 participants, were included. Twenty-one were randomised controlled trials.Thirteen 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.

Alpha2-adrenergic agonists are more effective than placebo in ameliorating withdrawal, and despite higher rates of adverse effects, are associated with significantly higher rates of completion of treatment.

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. 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 than reducing doses of methadone. Lofexidine does not reduce blood pressure to the same extent as clonidine, but is otherwise similar to clonidine

Authors' conclusions:

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 regimes 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.

This record should be cited as:

Gowing L, Farrell M, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD002024. DOI: 10.1002/14651858.CD002024.pub3

Assessed as up to date:

October 27, 2008

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Primary Review Group:

Drugs and Alcohol Group

Health topics:

Tobacco, drugs, & alcohol dependence > Opioids, opiates, heroin > Dextoxification

Cochrane Summaries^beta

Independent high-quality evidence for health care decision making

Alpha2-adrenergic agonists for the management of opioid withdrawal

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