A Multi-site Dose Ranging Study of Nalmefene in the Treatment of Alcohol Dependence

Abstract

The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals. This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene (5, 20, or 40 mg) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals. Participants concomitantly received 4 sessions of a motivational enhancement therapy (with a medication compliance component) delivered from trained counselors. Although more subjects in the active medication groups terminated the study early secondary to adverse events, the rates did not differ significantly from that of placebo. The 20-mg/d group experienced more insomnia, dizziness, and confusion, while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group. Most of these symptoms were mild and improved over time. Although all subjects had a reduction in heavy drinking days, craving, gamma-glutamyl transferase, and carbohydrate-deficient transferrin concentrations over the course of the study, there was no difference between the active medication and placebo groups on these measures. The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups. This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics. However, possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmefene treatment.

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

“…While studies of the treatment of alcoholism using nalmefene have been mixed (Mason et al, 1994;Anton et al, 2004), initial studies of nalmefene in the treatment of compulsive gambling have been promising (SW Kim, personal communication). Naltrexone and nalmefene do have comparable affinity at mu-and kappa-opioid receptors.…”

“…Naltrexone's effectiveness is poor for the former and moderate for the latter (San et al, 1991;Volpicelli et al, 1992;O'Malley et al, 1992O'Malley et al, , 2002. Nalmefene also has a moderate treatment effect for alcoholism but is not yet available for this indication (Mason et al, 1994;Anton et al, 2004). Naloxone, naltrexone, and nalmefene are moderately selective ligands for the three opioid receptor subtypes (mu, kappa, and delta).…”

Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol Dependence

“…Naltrexone is now an approved drug for the treatment of alcoholism based on its efficacy in reducing craving for and consumption of ethanol (Volpicelli et al, 1992), and nalmefene has shown clinical utility in the treatment of alcoholism (Mason et al, 1994;Anton et al, 2004). However, naltrexone, although classified as a general opioid receptor antagonist, actually has a higher affinity for the m-opioid receptor subtype than the d and k subtypes at low doses (Abbott et al, 1986;Millan, 1989;Millan et al, 1989;Walker et al, 1994;Stromberg et al, 1998).…”

Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence

“…This found two adverse events reported significantly more frequently by patients on Anton et al [127] compared 5mg, 20mg and 40mg nalmefene with placebo, and Mason et al [125] 20mg and 80mg doses of nalmefene with placebo. Patients on 80mg nalmefene were more likely to withdraw due to adverse effects but the occurrence of adverse drug reactions did not significantly differ between the groups.…”