A Double-blind, Placebo-Controlled Study of Oral Nalmefene for Alcohol Dependence

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Abstract
THE FIRST months following cessation of drinking represent the highest risk for relapse and offer the greatest opportunity for pharmacological intervention in outpatients with alcohol dependence.1 Pharmacological treatment options for this indication have been limited. Aversive therapy with disulfiram (Antabuse) was the only pharmacological treatment for alcohol dependence available in the United States until recently, despite high rates of severe adverse drug reactions, drinking relapse, and medication noncompliance.2 The drug 3-acetamido-1-pro-panesulfonic acid, calcium salt (acamprosate), is available internationally and is being studied in the United States as a nonaversive pharmacotherapy to maintain abstinence in recently detoxified alcoholics.3 Naltrexone (ReVia), an opioid antagonist, was approved in 1994 as a nonaversive prescription drug for alcohol dependence on the basis of 2 small placebo-controlled trials (N=186)4,5 and a large open-label safety study (N=570).6 The results of recent naltrexone studies are more modest but reinforce earlier reports regarding reduced risk of relapse to heavy drinking among subjects who are highly compliant with treatment.7-9 Use of naltrexone has certain limitations, eg, 15% of patients participating in the open-label safety study terminated treatment owing to adverse events, primarily intolerable nausea.6 Additionally, naltrexone is associated with dose-dependent hepatotoxic side effects, which may make use problematic and contraindicated in alcoholic patients with liver disease.10 Replicating naltrexone results with a structurally similar but better tolerated compound would validate opioid antagonist treatment of alcohol dependence and identify an alternative form of drug for patients with medical contraindications, adverse drug experiences, or nonresponse to naltrexone.