A Double‐Blind, Placebo‐Controlled Pilot Study to Evaluate the Efficacy and Safety of Oral Nalmefene HCI for Alcohol Dependence

Abstract

A dozen studies have been published showing that opiate antagonists suppress alcohol drinking in animals, and two independent placebo-controlled, double-blind clinical trials of naltrexone found this agent was associated with decreased alcohol craving and consumption in alcohol-dependent patients. Nalmefene is a newer opiate antagonist that has a number of potential advantages over naltrexone in the treatment of alcoholism, including no dose-dependent association with liver toxicity and more effective binding to central opiate receptors. Consequently, a double-blind pilot study was conducted to gather preliminary data on the safety and efficacy of nalmefene for reducing alcohol consumption in alcohol-dependent subjects. Twenty-one alcohol-dependent subjects meeting admission criteria were randomly assigned to 12 weeks of double-blind treatment with 40 mg nalmefene, 10 mg nalmefene, or placebo, resulting in 7 patients/treatment group. Nalmefene was well tolerated, with no serious adverse drug reactions. The 40 mg group had a significantly lower rate of relapse (p < or = 0.05), and a greater increase in the number of abstinent days/week (p < or = 0.09), than the other treatment groups. A significant decrease in the number of drinks/drinking day was noted for both nalmefene groups (p < or = 0.04), but not for placebo. These results were supported by parallel decreases in ALT. These pilot data provide preliminary support for the hypotheses that nalmefene can be safely given to alcoholics, and that nalmefene may have a role in reducing alcohol consumption and preventing relapse, particularly at the 40 mg level. A full-scale study is underway to confirm these preliminary findings.

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).…”

Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing

“…Nalmefene is a more potent antagonist at d-opioid receptors (DeHaven-Hudkins et al, 1990;Emmerson et al, 1994) that have been implicated in alcohol drinking (Ciccocioppo et al, 2002;June et al, 2004), and the plasma terminal half-life of oral nalmefene (Dixon et al, 1987;Gal et al, 1986) markedly exceeds that of naltrexone (Meyer et al, 1984). Single oral nalmefene doses of 20-300 mg and repeated doses of 10-40 mg twice a day have been well tolerated (Dixon et al, 1987;Mason et al, 1994), and there have been no reports of any serious adverse drug reactions on hepatic or other body systems.…”

“…Recent findings indicate that nalmefene and naltrexone are equally effective in reducing subjective responses to alcohol in alcoholics (Drobes et al, 2004), and in clinical studies, nalmefene has been associated with significant decreases vs placebo in reducing relapse to heavy drinking (Mason et al, 1994;Mason et al, 1999). Nevertheless, in a recent multicenter trial in which nalmefene was used in combination with Motivational Enhancement Therapy, there was no statistically significant difference vs placebo in the reduction of heavy drinking (Anton et al, 2004).…”

Treatment of alcohol dependence

“…Another opioid antagonist, nalmefene, has also been evaluated recently in alcohol-dependent subjects. 77 This medication has been found to be well tolerated and superior to placebo in reducing the risk of relapse. Further evaluation of the efficacy of nalmefene, including comparison of that medication with naltrexone, is warranted.…”