MEDICATION TO PREVENT RELAPSE
Acamprosate is a putative anti-craving drug, licensed for use in alcohol dependency. Its exact mechanism of action is unknown, but it is thought to act via several mechanisms affecting multiple neurotransmitter systems. During alcohol withdrawal the central nervous system neurones enter a state of hyperexcitability (which leads to a classical withdrawal syndrome characterised by hallucinosis, paranoia, seizures and a generalised overactivity of the autonomic nervous system with high levels of anxiety, insomnia and tremor, sweating and gastrointestinal disturbance). Glutamate-mediated hyperexcitability may also occur, triggered by cues, during the postwithdrawal abstinence period.
At the neurobiochemical level, acamprosate's main action may be to cause a relative inhibition of this hyperexcitable state through a reduction of both glutamate release and receptor activation (glutamate is the major excitatory neurotransmitter). Interaction with the NMDA (glutamate) receptor is also associated with a reduction in calcium ion fluxes (through voltageoperated channels). Activity at the NMDA receptor may be as a 'partial co-agonist': low acamprosate concentrations enhance NMDA activity when this activity is low; but high acamprosate concentrations inhibit NMDA activity, when activity is high. This implies a non-linear dose-dependent effect.Acamprosate has a similar chemical structure to GABA (the major CNS inhibitory transmitter) and it may also act on the GABA presynaptic receptor to increase GABA activity in the synapse. Another inhibitory transmitter, taurine, may also have a role in alcohol withdrawal, and acamprosate has been demonstrated to increase taurine levels in rats.
EFFECTIVENESS
A 1997 review of acamprosate studies concluded the following:
- Oral acamprosate at 1.3 or 2g/day in 3 divided doses for 3 to 12 months was more effective than placebo in preventing alcohol relapse as measured by abstinence rates, duration of abstinence, continued abstinence following cessation of acamprosate (followed for up to 2 years), gamma-glutamyl transferase levels, and other clinical or biological end-points. Retention in treatment was also improved.
- Its efficacy seems dose-dependent.
- Efficacy may be enhanced by addition of disulfiram. One study with a 360 day treatment period, and 360 day acamprosate-free follow-up found more drinkfree days with acamprosate + disulfiram, than with disulfiram alone, or no medication. There was no drug-drug interaction, or increase in side-effects.
SIDE-EFFECT PROFILE
Acamprosate is generally well tolerated; its commonest side-effects are diarrhoea, and mild/transient dermatological effects. Other potential side-effects include nausea, vomiting, abdominal pain, and fluctuation in libido. It has no abuse potential and no sedative, mood or cognitive effects.
PRESCRIBING
666mg tds orally, unless < 60kg when 666mg mane + 333mg bd is recommended. The standard duration of prescribing is one year.Acamprosate may be commenced during alcohol detoxification and the manufacturers recommend commencement on the second day of detoxification. It may also be continued through lapses to alcohol use if this is judged likely to enhance the likelihood of a return to abstinence.
CONCLUSION
Acamprosate has a positive profile in terms of proven effectiveness and good tolerability. Early results from a meta-analysis of randomised controlled trials demonstrate its effectiveness as compared to placebo, but also indicate that up to 17 patients would have to be treated for a single patient to remain abstinent who would otherwise have relapsed. There is no substantial data to indicate which kind of patient is likely to respond. However, acamprosate reduces alcohol consumption (rather than maintains total abstinence) in a greater number of patients.Acamprosate has not been directly compared to its main competitor for alcohol relapse prevention - naltrexone.
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The above information is copyright of Dr Bruce Trathen MBBS MRCPsych (2006). ISBN 0-9545164-0-0. The author grants permission for these guidelines to be downloaded, copied and distributed freely, but does not grant permission for their sale.
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