The first double-blind, placebo-controlled study to test the efficacy of acamprosate in alcohol-dependent patients took place in France in 1982, and results were published by Lhuintre et al. in 1985 (1). Since then, more than 25 clinical studies have been performed, assessing various efficacy and safety criteria within the context of varying clinical settings and psychosocial support systems. Seventeen of these studies, which included a total of 4523 patients (2371 on acamprosate, 2152 on placebo), were double-blind studies primarily designed to establish efficacy and to evaluate drug safety. The first market authorization was granted in France in 1989. At present, acamprosate is registered in Europe (19 countries), Latin America (14 countries), Mauritius, Australia, and Hong Kong. An application in the United States is pending. This chapter will summarize clinical evidence and other information obtained through the trials on acamprosate. Information was obtained mainly from published data, but when these were incomplete, additional data were obtained through examination of original study reports (2).
Acamprosate is available as gastro-resistant 333-mg tablets at a recommended daily dosage of four to six tablets per day, to be taken three times daily. It is poorly and slowly absorbed from the gastrointestinal tract via the paracellular route (3). The absolute bioavailability is 11.1%. Steady-state plasma levels are reached after 5-7 d of administration. Interaction studies have confirmed that after a single administration with food, absorption is decreased by approx 20%.
Eighteen double-blind, placebo-controlled clinical studies have been completed since 1982. Of these, 17 were performed in Europe (see Table 1) and 1 in the United States. The results of the latter project have not been released by the sponsoring company. Sixteen of the 18 studies employed DSM criteria for diagnosis of alcohol dependence. Patients were between the ages of 18 and 65 and treatment periods varied from 3 to 12 mo. Other drug dependencies were always excluded.
In all but two of the studies, patients had to have already withdrawn from alcohol and started the study medication immediately after the acute period of detoxification (which, on average, lasted between 3 and 14 d). The reason for not starting during the acute withdrawal period was to isolate the drug effect from possible confounding effects of concomitant psychotropic and anticonvulsive detoxification medications. Exceptions to this policy were in the trial performed in Spain by Gual and collaborators (4), who introduced the study medication from the first day of weaning, and in the UK study by Chick and collaborators (5), who allowed a period of "stabilization" or washout of up to 5 wk after the
From: Contemporary Clinical Neuroscience: Glutamate and Addiction Edited by: Barbara H. Herman et al. © Humana Press Inc., Totowa, NJ
Double-Blind Studies with Acamprosate
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