Acamprosate

Abstract

Acamprosate (calcium acetylhomotaurinate), a synthetic compound with a similar chemical structure to that of γ-aminobutyric acid, is thought to act via several mechanisms affecting multiple neurotransmitter systems; inhibition of neuronal hyperexcitability by antagonism of excitatory amino acid activity and reduction of calcium ion fluxes has been suggested as its predominant mechanism of action. The drug is the first agent specifically designed to maintain abstinence in alcohol (ethanol)-dependent patients after detoxification. Voluntary oral ethanol consumption in ethanol-preferring or ethanol-dependent rats is dose-dependently reduced by acamprosate; total fluid intake and food consumption are not affected. The drug does not potentiate the acute or chronic toxic effects of ethanol and has no hypnotic, antidepressant, anxiolytic or muscle-relaxant effects in animals. There is no evidence of abuse potential with acamprosate. Oral acamprosate 1.3 or 2 g/day in 3 divided doses administered for 3 to 12 months to alcohol-dependent patients after detoxification was more effective than placebo in preventing alcohol relapse according to abstinence rates, duration of abstinence, γ-glutamyl transferase levels and/or a variety of other clinical or biological end-points. Concomitant psychosocial/behavioural therapies were used in some trials. Compared with those with placebo, the superior abstinence rates and durations of abstinence with acamprosate were maintained during 6-to 12-month post-treatment follow-up periods, and greater abstinence rates with acamprosate were confirmed in a pooled analysis of data from 11 randomised placebo-controlled trials involving a total of 3338 patients with alcohol dependence. The efficacy of acamprosate appears to be dose dependent and enhanced by the addition of disulfiram. Acamprosate was generally well tolerated in placebo-controlled trials. The most common adverse events were gastrointestinal (especially diarrhoea) or dermatological and were mostly mild and transient. The percentage of patient withdrawals because of adverse events was similar in acamprosate and placebo groups. No trials have compared the efficacy or tolerability of acamprosate with those of other treatment approaches (including opiate antagonists or selective serotonin reuptake inhibitors) aimed at maintaining abstinence in detoxified alcohol-dependent patients. Thus, acamprosate, as an adjunct to psychosocial/behavioural therapies, represents a novel advance for the management of alcohol-dependent patients in the postdetoxification period. Longer term and comparative trials with other active therapies are required to confirm these promising results. Acamprosate (calcium acetylhomotaurinate) is a synthetic compound with a chemical structure similar to that of γ-aminobutyric acid (GABA). The exact cellular target of acamprosate is not clear; it has been suggested that inhibition of neuronal hyperexcitability by antagonism of excitatory amino acid activity and reduction of calcium ion fluxes is its predominant mechanism of action. Several other possible mechanisms of action have been suggested, including suppression of conditioned alcohol withdrawal-induced craving. The drug binds preferentially to GABA_B receptors and enhances synaptosomal [³H]GABA uptake. Serotonergic properties of acamprosate have been demonstrated by acamprosate-induced increases in blood and cerebral serotonin (5-hydroxytryptamine; 5-HT) levels in rats exposed to ethanol vapour, intensification of convulsions caused by tryptamine, potentiation of ‘heat twitches’ induced by 5-methoxy-NN-dimethyl-tryptamine and increases in the binding capacity of 5-HT_1D and 5-HT₂ receptors. Noradrenergic antagonist activity is supported by acamprosate-induced increases in the number of adrenergic receptors, antagonism of the effect of ethanol on β-adrenoceptors, antagonism of reserpine-induced hypothermia and potentiation of yohimbine-induced toxicity. Acamprosate dose-dependently reduces or suppresses voluntary oral ethanol consumption in ethanol-preferring or ethanol-dependent rats without affecting total fluid intake or food consumption. This effect is inhibited by the GABA_A-receptor antagonist bicuculline. Long term acamprosate administration (for 15 days) did not potentiate the acute or chronic toxic effects of ethanol in rats. Acamprosate was not self-administered by animals (rhesus monkeys) that freely used cocaine or pentobarbital, and the drug did not induce pentobarbital-or d-amphetamine-appropriate responding in animals (rhesus monkeys or pigeons) trained to discriminate between these agents. The drug also had no hypnotic, antidepressant, anxiolytic or muscle-relaxant effects in animals. Based on pharmacokinetic data from healthy volunteers, the mean maximum plasma concentration (C_max) of acamprosate was 180 μg/L after a single oral dose of 666mg and the area under the plasma concentration-time curve was 3700 μg/L · h. Absorption of acamprosate via the gastrointestinal tract is slow and there is high interindividual variation; however, most of the drug appears to be absorbed within 4 hours. Steady-state acamprosate concentrations are achieved after 7 days’ administration. Concomitant food decreases the bioavailability of acamprosate by approximately 20%; the pharmacokinetics of the drug are unaffected by concomitant alcohol (ethanol) intake. The apparent half-life of acamprosate is 13 hours after oral administration; the drug is not metabolised and is excreted unchanged in the urine. Acamprosate crosses the blood-brain barrier. The pharmacokinetics of acamprosate in alcohol-dependent patients weaned from alcohol are similar to those in healthy volunteers. After single dose administration of acamprosate 666mg, C_max values were significantly higher, time to C_max was significantly...