A Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Acamprosate and Naltrexone

Abstract

Recent efforts to develop pharmacological interventions for relapse-prevention in newly abstinent alcoholics initially focused on acamprosate (Campral ®, Aotal ®) in Europe and naltrexone (ReVia ®) in the United States of America. Acamprosate and naltrexone have each demonstrated efficacy and safety in randomized, double-blind, placebo-controlled trials in alcohol-dependent outpatient volunteers (Garbutt et al. 1999;Litten and Allen 1998;Mason 2001;Mason and Ownby 2000;Swift 1999). Neither medication interacts with alcohol or has abuse potential or rebound effects when discontinued. Despite these similarities, acamprosate and naltrexone induce their action via very different mecha- Address correspondence to: Barbara Mason, Alcohol Disorders Research Unit, 1400 N.W. 10th Avenue, Suite 307A, Miami, FL 33136. Tel.: (305) 243-4059; E-mail: bjmason246@aol.com Received February 12, 2002; revised April 18, 2002; accepted April 22, 2002. Online publication: 5/7/02 at www.acnp.org/citations/Npp 050702298. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 Interaction Study of Acamprosate and Naltrexone 597 nisms and may affect different behavioral aspects of alcohol dependence. Acamprosate is a centrally acting synthetic analog of the naturally occurring amino acid neuromediator taurine (Dahchour and de Witte 2000). Chronic alcohol exposure is associated with decreased GABAergic transmission and increased glutamate activity (Grant et al. 1990;Hoffman and Tabakoff 1994). Although the precise mechanism of action or cellular target of acamprosate is not fully elucidated, acamprosate appears to modulate N-methyl-D -aspartate (NMDA) receptor activity in the glutamate system, and to inhibit the upregulation of voltage-gated Ca 2 ϩ channels that is induced by chronic alcohol ingestion and states of withdrawal (Allgaier et al. 2000;Popp and Lovinger 2000). Thus, acamprosate may act on neurobiological mechanisms that may persist for many months following alcohol withdrawal, and that may contribute to the vulnerability for drinking relapse (Borg 1988).The clinical safety and efficacy of acamprosate was evaluated in 16 placebo-controlled, double-blind trials of 3, 6, or 12 months duration conducted across 11 European countries and involving more than 4,500 male and female outpatients with alcohol dependence (Barrias et al. 1997;Besson et al. 1998;Chick et al. 2000a;Geerlings et al. 1997;Gual and Lehert 2001;Ladewig et al. 1993;Lhuintre et al. 1985Lhuintre et al. , 1990Paille et al. 1995;Pelc et al. 1992Pelc et al. , 1997Poldrugo 1997;Rousseaux et al. 1996;Sass et al. 1996;Tempesta et al. 2000;Whitworth et al. 1996). Fourteen of 16 trials showed a significant advantage for acamprosate over placebo on abstinence measures. There are no serious or rate-limiting adverse effects associated with acamprosate. Mild and transient diarrhea is the only drug-related adverse event that differed consistently from placebo across studies. Acamprosate is not metabolized. It is eliminated by the kidneys and is contra-indicated in cases of re...

The Effects of Acamprosate and Neramexane on Cue-Induced Reinstatement of Ethanol-Seeking Behavior in Rat

“…Interestingly, it has been shown that a combined naltrexone and acamprosate treatment can result in additive effects and improved therapy outcome (Kiefer et al, 2003). Additionally, Mason et al (2002) could demonstrate a significant pharmacokinetic interaction of both compounds, which in turn leads to an increased absorption of acamprosate, when co-administered with naltrexone. Such an increased absorption could predict greater efficacy for the combination than for a single treatment with any of the compounds.…”

Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings

“…Evidence from a human magnetic resonance imaging study does, however, support acamprosate's ability to modulate glutamate neurotransmission as it decreases activity in brain regions rich in N-acetylaspartate and glutamate [95]. Human laboratory studies in both volunteers [104] and alcohol-dependent individuals [105] also have shown that acamprosate -i.e., calcium acetyl homotaurinate -is relatively safe, with the most important adverse events being diarrhea, nervousness, and fatigue, especially at a relatively high dose (3 g/day). Since acamprosate is excreted unchanged in the kidneys, there is no risk of hepatotoxicity, but it should be used with caution in those with renal impairment [104,105].…”

“…Human laboratory studies in both volunteers [104] and alcohol-dependent individuals [105] also have shown that acamprosate -i.e., calcium acetyl homotaurinate -is relatively safe, with the most important adverse events being diarrhea, nervousness, and fatigue, especially at a relatively high dose (3 g/day). Since acamprosate is excreted unchanged in the kidneys, there is no risk of hepatotoxicity, but it should be used with caution in those with renal impairment [104,105]. Acamprosate has no significant clinical interaction with alcohol.…”

“…It is, therefore, tempting to speculate that the combination of naltrexone and acamprosate would make it easier both to abstain and to prevent a "slip" from turning into a relapse. Third, acamprosate can increase blood levels of naltrexone, thereby augmenting its neurochemical effects [104,105].…”

Naltrexone Maintenance Decreases Cannabis Self-Administration and Subjective Effects in Daily Cannabis Smokers

“…Compliance in taking the medications was high under these carefully controlled laboratory conditions, as confirmed by qualitative riboflavin assessments and plasma medication levels: trough levels of 6β − naltrexone (ie, ∼ 24 h after the last naltrexone administration) closely paralleled those reported in studies with confirmed medication administration (Mason et al, 2002;Verebey et al, 1976). Compliance was prioritized in this laboratory study, with a level of oversight that would be difficult to maintain in clinical studies.…”