Pharmacology of Acamprosate

The Clinical Pharmacology of Acamprosate.

Br J Clin Pharmacol. 2012 Dec 25

Kalk N, Lingford-Hughes A.

This is a nice review of pharmacokinetics, mechanism and clinical use of acamprosate.

Kinetics and Dosing

The authors note these surprising facts for a medicine usually dosed TID

• oral bioavailability is quite low 11%
• absorption of acamprosate is so slow that it acts as though it were a modified-release medication with a tmax of 6.3 hours in enteric coated form
• half-life is around 32 hours with complete elimination occurring only four days after cessation of therapy

Acamprosate is renally cleared and renal impairment is related to increased plasma concentrations. Acamprosate is contra-indicated in severe renal impairment and dose reduction advised in mild renal impairment



The usual dose of acamprosate prescribed is 1998g daily (666 mg TID) for those over, and 1332g for those under 60 kg  Higher doses i.e. 3g/day have been reported to be more efficacious. However, a small study compared 3g daily with a 2g dose and found more nervousness at the higher dose. 

In general, acamprosate is a well-tolerated drug, with self-limiting diarrhea being the main side-effect. Unlike naltrexone there is not report of hepatic concerns.

Mechanism

The authors demonstrate that GABA and NMDA effects are likely indirect.  They note some evidence of inhibition of GABA-B receptors and more compelling evidence of antagonism at a (non NMDA) metabotropic glutamate receptor.  

Animal Studies

It is noted that acamprosate can decrease some alcohol withdrawal symptoms including hypermobility, anxiety and seizures. 

Acamprosate decreased drinking for alcohol dependent rats when alcohol was given immediately or after a few days’ deprivation.  This effect was not seen three weeks after alcohol was stopped, suggesting the primary effect was to decrease withdrawal symptoms.  Acamprosate also does not have as pronounced an effect in alcohol naive animals.

Clinical use

Acamprosate increased the chance of abstinence after detoxification by about 15%.  The ‘number needed to treat’ (NNT) to result in one more patient becoming abstinent was calculated as 9-11.


The smaller effect sizes in later published reviews is a consequence of recent studies done in America and Australia where acamprosate was not superior to placebo .


Some studies and reviews have found that acamprosate reduces heavy drinking in those patients who do relapse. Effects on symptoms associated with alcohol withdrawal have also been reported.  

Acamprosate has been shown to be effective in decreasing sleep disturbance in withdrawal and during abstinence up to six months.  A slight anxiolytic effect in abstinent alcohol dependent patients has been reported and it has been noted that acamprosate treatment may offset the poorer prognosis conferred by higher anxiety.


Acamprosate was less effective when the start of treatment was delayed long after detoxification.  Although preliminary data have suggested that some drinking outcomes may worsen if acamprosate is started during detoxification, this is still recommended based on the other trial evidence, and pre-clinical evidence of its neuroprotective effect.  Less severe withdrawal symptoms with acamprosate therapy have been reported.   


However comparison of naltrexone and acamprosate in reducing cue-induced craving found that naltrexone reduced subjective craving more than acamprosate.