Abstract: Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed. Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha2-adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine. Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient without indicating the level of care provided. The included studies were heterogeneous in terms of the type of opioid antagonist treatment regimen, the comparator, the outcome measures assessed, and the means of assessing outcomes. As a result, the validity of any estimates of overall effect is doubtful, therefore we did not calculate pooled results for any of the analyses. The quality of the evidence for treatment with an opioid antagonist-adrenergic agonist combination versus an alpha2-adrenergic agonist is very low. Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity over the period of withdrawal. Peak withdrawal induced by opioid antagonists in combination with an adrenergic agonist appears to be more severe than withdrawal managed with clonidine or lofexidine alone, but the average severity over the withdrawal period is less. In some situations antagonist-induced withdrawal may be associated with significantly higher rates of treatment completion compared to withdrawal managed with adrenergic agonists. However, this result was not consistent across studies, and the extent of any benefit is highly uncertain. We could not extract any data on the occurrence of adverse events, but two studies reported delirium or confusion following the first dose of naltrexone. Delirium may be more likely with higher initial doses and with naltrexone rather than naloxone (which has a shorter half-life), but we could not confirm this from the available evidence. Insufficient data were available to make any conclusions on the best duration of treatment. Using opioid antagonists plus alpha2-adrenergic agonists is a feasible approach for managing opioid withdrawal. However, it is unclear whether this approach reduces the duration of withdrawal or facilitates transfer to naltrexone treatment to a greater extent than withdrawal managed primarily with an adrenergic agonist. A high level of monitoring and support is desirable for several hours following administration of opioid antagonists because of the possibility of vomiting, diarrhoea and delirium. Using opioid antagonists to induce and accelerate opioid withdrawal is not currently an active area of research or clinical practice, and the research community should give greater priority to investigating approaches, such as those based on buprenorphine, that facilitate the transition to sustained-release preparations of naltrexone.

Plain-language summary: We identified 10 studies, including six randomised controlled trials (where people are randomly put into one of two or more treatment groups) and four prospective cohort studies (where participants could choose which treatment they received) involving 955 opioid-dependent participants. Four of the studies took place in the UK, three in the USA, two in Italy and one in Australia. Nine of the 10 studies compared treatment with an opioid antagonist (naltrexone or naloxone) plus an adrenergic agonist (clonidine or lofexidine) versus a regimen based on clonidine or lofexidine alone. Other comparisons (placebo, reducing doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. Four studies received some financial support from a pharmaceutical company. We are uncertain whether peak withdrawal induced by opioid antagonists plus clonidine or lofexidine is more severe than withdrawal managed with clonidine or lofexidine alone, or whether the average severity over the withdrawal period is less, as the certainty of the evidence is very low. Clinicians should warn people of the possibility of delirium in the first day of administration of naltrexone, particularly with higher doses (> 25 mg). People should also know that withdrawal will be moderately severe and that symptoms such as muscle aches, vomiting and diarrhoea, and insomnia are likely to persist despite medication. The studies included in this review were diverse and generally of very low quality. As a result there is considerable uncertainty about the value of approaches using opioid antagonists to induce opioid withdrawal as a means of managing withdrawal from opioid dependence.