Nalmefene for Alcohol Dependence
November 1, 1999
Nalmefene for Alcohol Dependence
Abstract & commentary
Source: Mason BJ, et al. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999;56:719-724.
The first months following cessation of drinking represent the highest risk for relapse and offer the greatest opportunity for pharmacological intervention in outpatients. The first pharmacological intervention for alcohol dependence was adversive therapy (disulfiram [Antabuse]), which was plagued by a high rate of severe adverse drug reactions, medication noncompliance, and drinking relapse. Naltrexone (ReVia), an opioid antagonist, was approved in 1994 as a nonaversive drug and reduces risk for relapse to heavy drinking. However, its limitations are many, including discontinuations from side effects (primarily nausea) in 15% of subjects and dose-dependent hepatotoxic effects, which are particularly concerning considering the damaging effects of alcohol on the liver.
Nalmefene is a newer opioid antagonist that is structurally similar to naltrexone but has a number of potential pharmacologic and clinical advantages. Like naltrexone, it is a pure opioid antagonist with no agonist activity and no abuse potential. In 1300 patients studied for other indications, including patients with liver disorders, there is no known dose-dependent association with liver toxicity. Its duration of action is 8-10 hours, which allows for bid dosing. Finally, it binds more competitively than naltrexone to the delta and kappa opioid receptors (which reinforce alcohol consumption), theoretically suggesting increased efficacy and potentially obviating the need for high doses linked to side effects.
Outpatient subjects for the current 12-week trial were between 18 and 65 years of age and had alcohol dependence by DSM-III-R criteria. Exclusion criteria included use of illicit drugs, use of another agent for alcohol dependence, a comorbid psychiatric disorder, considerable hepatocellular injury (cirrhosis), liver enzymes two times above normal values, and pregnancy. Of patients screened, 105 met criteria; 15 declined participation and 28 met exclusion criteria. Medication compliance was measured by tablet count and by microelectronics to record each time and date the bottle is opened and closed. All patients received manual-guided cognitive behavioral therapy to avoid or cope with high-risk situations. Baseline and ongoing assessments included disorder severity (the alcohol dependence scale, a 25-item instrument with a point range from 0 to 47), quantity of use (self-report, collateral, and breath-alcohol concentrations), craving (the obsessive-compulsive drinking scale [OCDS], a 14-item self-report scale with a point range from 0 to 56), and intrusive thoughts (OCDS subscale). Subjects were randomized to nalmefene 20 mg/d (10 mg bid), nalmefene 80 mg/d (40 mg bid), or placebo. Completion rates, medication compliance, and the number of days in the trial did not differ among the groups; treatment non-completers mainly needed more intensive treatment (13%), were unable to adhere to the study (7%), left for personal/work reasons (12%), or suffered intolerable medication side effects (3%).
| Table-Summary of Significant Results | |||
| Criteria | Intervention Subjects | Control Subjects | P Value |
| Sampling (1+ drink) (odds ratio) | 1 | 2.84 | .04 |
| Patients overall relapsing (%) | 37.1 | 58.8 | .02 |
| Relapse to heavy drinking | |||
| episodes starting with week 1 (%) | 15.7 | 34.3 | .02 |
| Duration of relapse (days) | 0.9 | 1.5 | .06 |
| Time to first relapse (days) | 46.3 | 33.5 | 0.11 |
| Drinks consumed (number per day) | 4.1 | 5.3 | .06 |
| Abstinence from alcohol (days) | 80.3 | 83 | .48 |
Comment by Donald M. Hilty, MD
Nalmefene is a newer opioid antagonist that is structurally similar to naltrexone but with a number of potential pharmacological advantages for the treatment of alcohol dependence, including no dose-dependent association with toxic effects to the liver, a longer duration of antagonist action, and more competitive binding with opioid receptor subtypes that are thought to reinforce drinking. It appears to be as safe as placebo and more efficacious. The subjects treated are similar to those in primary care populations. Limitations include a small sample size and a short duration. Nalmefene should be considered a first-line agent in patients with alcohol dependence, perhaps before naltrexone, because of its side effect profile. For patients stable on naltrexone, a change to nalmefene could be considered if significant side effects are present, or if there is a high risk for hepatic dysfunction.
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