Value of Opioid Antagonists for Withdrawal Uncertain

Pauline Anderson

June 22, 2017

Combining an opioid antagonist such as naloxone with an alpha2-adrenergic agonist is a feasible approach for managing opioid withdrawal, results of a new Cochrane review suggest.

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.

Studies of antagonist-induced withdrawal with minimal sedation are relatively small and have design limitations with consequent risk for bias, say the review authors, led by Linda Gowing, PhD, University of Adelaide, Australia.

"These limitations, together with diversity in the nature of outcomes and findings reported, make it impossible to draw firm conclusions. Both the extent of potential benefits and the risk of harms associated with antagonist-induced withdrawal remain uncertain," the authors write.

The review was published in the Cochrane Database of Systematic Reviews.

Completing Withdrawal Is Difficult

Managing withdrawal is a necessary first step for longer-term treatment of opioid dependence. The combination of uncomfortable symptoms, such as irritability, anxiety, muscular and abdominal pains, diarrhea, sweating, and insomnia, plus intense craving make completing withdrawal challenging for the majority of patients.

After searching the literature, researchers selected 10 studies – six randomized controlled trials and four prospective cohort studies – with a total of 955 opioid-dependent participants for inclusion in the review.

Five studies took place in an inpatient setting, two were in outpatient settings with day care, and two used day care only for the first day of opioid antagonist administration. One study described the setting as outpatient without indicating the level of care provided.

Nine studies compared treatment with an opioid antagonist, either naltrexone or naloxone, plus an adrenergic agonist, either clonidine or lofexidine, with a regimen based on clonidine or lofexidine alone.

Two studies reported data on peak withdrawal severity, and four studies reported data on the average severity during the period of withdrawal.

Four studies received some financial support from a pharmaceutical company.

Low-Quality Evidence

The included studies were diverse, and the quality of the evidence for a combination approach for withdrawal was very low, the authors note.

"This low quality in addition to the small number of studies, the variability in treatment regimens, and in the means of assessing and reporting withdrawal made it impossible for the reviewers to draw firm conclusions as to the nature and severity of withdrawal induced by an opioid antagonist-adrenergic agonist combination compared to withdrawal managed primarily with an alpha2–adrenergic agonist."

However, the findings did suggest that when combined with an alpha2-adrenergic agonist, the severity of antagonist-induced withdrawal is, at worst, similar to withdrawal managed primarily with an adrenergic agonist and, at best, is less severe. This is probably because of earlier resolution of the signs and symptoms of withdrawal.

Initial administration of an opioid antagonist, particularly naltrexone, may be associated with a peak in withdrawal severity that is greater than the peak that occurs with adrenergic agonist–based regimens, the investigators note.

Data reported on the duration of treatment were minimal, making it impossible to determine whether antagonist-induced withdrawal reduces the duration of withdrawal treatment.

The type of opioid used prior to detoxification might influence the nature and severity of withdrawal. Most studies investigated participants undergoing withdrawal from heroin.

"The small number of studies involving participants withdrawing from methadone and the variability in treatment regimens and means of assessing withdrawal prevented any exploration of the effect of the drug of dependence on withdrawal severity based on studies included in this review," the authors write.

Some opioid-dependent people experience delirium or confusion following administration of an opioid antagonist.

Although only two of the studies included in the review reported delirium as an adverse effect of antagonist-induced withdrawal, six studies that did not meet the criteria for inclusion in the review did report delirium, and other studies have reported delirium or confusion after accidental ingestion of naltrexone by people who are opioid dependent.

Delirium Warning

In all cases, the opioid antagonist administered was naltrexone, and in most cases the initial dose of naltrexone was 25 mg or greater. This suggests that the risk for delirium may be related to the dose of the opioid antagonist and the duration of treatment.

"Clinicians should warn people of the possibility of delirium in the first day of administration of naltrexone," the authors write. "People should also know that withdrawal will be moderately severe and that symptoms such as muscle aches, vomiting and diarrhea, and insomnia are likely to persist despite medication."

The authors concluded that a high level of monitoring and support is desirable for several hours following administration of the first dose of an opioid antagonist.

Adjunct medications, in addition to adrenergic agonists, are likely required to manage the period of peak withdrawal induced by the opioid antagonist, they write.

Adverse effects of alpha2-adrenergic agonists such as dizziness, sedation, and dry mouth are likely to be experienced in the first few days of treatment when high doses of the drug are required to ameliorate the withdrawal symptoms induced by the opioid antagonist.

However, it appears that hypotension necessitating cessation of an adrenergic agonist may be rare when the drug is administered in combination with an opioid antagonist and is even less likely with lofexidine than with clonidine, the authors note.

They note that they did not identify any new studies of the combination approach to managing withdrawal since publication of a review in 2009.

"Clearly, this is not an active area of research, and we believe the approach is not being used in clinical practice," they write.

Buprenorphine has been shown to be more effective than clonidine or lofexidine for managing opioid withdrawal and may facilitate the transition from dependent opioid use to naltrexone maintenance treatment.

There is active research in this area, particularly related to the use of buprenorphine to aid the transition to sustained-release preparations of naltrexone, say the authors.

Facilitating the transition from opioid dependence to naltrexone maintenance is particularly important with sustained-release preparations, because any prolonged experience of opioid withdrawal would likely make this treatment approach unacceptable to opioid-dependent people. It appears that this is the direction currently being taken by research.

"Given that the main reason for considering using opioid antagonists to induce withdrawal would be to initiate naltrexone maintenance treatment, we consider this direction to be appropriate."

The authors have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. Published online May 29, 2017. Abstract

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