Adrenergic agonists alone and in combination with opioid antagonists for the management of opioid withdrawal

Evidence Summaries

Level of Evidence = B
Clonidin and lofexidine appear to be more effective than placebo and may have similar efficacy than reducing doses of methadone in the management of withdrawal from heroin or methadone. Combinining adrenergic agonists (naltrexone, naloxone) to the regime can reduce withdrawal symptoms, resulting in more intense early withdrawal but less overall severity.

A Cochrane review 1 included 26 studies (21 RCTs) with a total of 1,728 subjects. Alpha2-adrenergic agonists were more effective than placebo in ameliorating withdrawal in terms of the likelihood of severe withdrawal (RR 0.32, 95% CI 0.18 to 0.57; 3 studies, n=148), and despite higher rates of adverse effects, are associated with significantly higher rates of completion of treatment (RR 1.95, 95% CI 1.34 to 2.84; 3 studies, n=148). Alpha2 adrenergic agonist (clonidine, lofexidine, guanfacine) regimes were somewhat less effective than reducing doses of methadone (12 studies). However, these differences were not statistically significant. The signs and symptoms of withdrawal occur and resolve earlier in treatment with alpha2-adrenergic agonists. The duration of treatment was longer with methadone (SMD -1.07, 95% CI -1.31 to -0.83; 3 studies, n=310). 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.

Another Cochrane review 2 (abstract , review ) included 10 studies (6 randomised controlled trials and 4 prospective cohort studies), involving 955 participants. 9 studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha2-adrenergic agonist (clonidine or lofexidine). In six studies the treatment regime based on naltrexone. In 6 studies, naloxone was used to induce withdrawal. The resulst suggested that withdrawal induced by opioid antagonists in combination with an adrenergic agonist is more intense than withdrawal managed with clonidine or lofexidine alone, but the overall severity is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of completion of treatment, compared to withdrawal managed primarily with adrenergic agonists. However, this outcome has not been produced consistently, and the extent of any benefit is highly uncertain.

Comment: The quality of evidence is downgraded by study limitations.

The following decision support rules contain links to this evidence summary:


1. Gowing L, Farrell M, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev 2009;(2):CD002024 [Review content assessed as up-to-date: 7 January 2016].  [PMID:19370574]

2. Gowing L, Ali R, White JM. Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev 2017;(5):CD002021.  [PMID:28553701]

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