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5 February 2003

The use of anti-craving drugs for alcohol dependence.

Dr Stephen Jurd Concord Dependency Seminar 4th February 2003.


We were reminded of the history of this field and the poor uptake of the two approved drugs, acamprosate and naltrexone both in Australia and overseas. Well under 5% of target subjects are currently being prescribed the drugs for reasons which are not at all clear.

Our speaker detailed the now copious research data on these medications individually as well as one very recent trial using both together, a non-approved but promising innovation.

Dr Jurd described his own personal way of choosing whether to try acamprosate or naltrexone initially. He feels that one can score most alcoholics between two extremes, one end tending to drink to get the blood levels up to high levels and attain pleasurable experiences, the other end drinking to maintain a blood level, thereby avoiding unpleasant and negative feelings, including physical/mental withdrawals. From opiate research we know quite a deal about the pleasure centres, opioid receptors, naltrexone blockers, etcetera, which probably dominate as a causal mechanism in the first type of alcohol dependent subjects. The GABA and glutamate systems are in a rough balance, modulating the level of arousal in the CNS. Acamprosate is active at both GABA and glutamate receptors, in an opposite way to alcohol (decreasing glutamate activity and increasing GABA activity). Thus naltrexone decreases the positive feelings associated with alcohol and acamprosate reduces the negative feelings associated with the lack of alcohol. Naltrexone decreases positive reinforcement and acamprosate probably decreases negative reinforcement.

The research on naltrexone and acamprosate has been performed in numerous ways in different countries. A common end point in American studies was 'time to relapse' where this was defined as '5 standard drinks on one day' or '5 drinking days' (of any quantity). [And to confuse further, an American 'standard' drink has 15g alcohol, not 10!]

Some European acamprosate research used 'time to first drink' (ANY drink) which made interpretation and comparison more difficult but all trials showed substantially higher numbers retained in treatment and abstinent at 3 months with approximately double the numbers being retained. Graphs of treatment population 'decay' are most impressive, showing an even greater response to both drugs used simultaneously. Outcomes have varied widely in different studies, but there have been so many positive studies that it is beyond doubt that these drugs exert an active effect, presumably on cravings.

The Concord audience was also reminded of the definition of the "intention to treat" research principle: It is a preferable way to analyse outcomes in research studies to include the results from all subjects included in the study, not just those who complete the study. In this way, the survival curve displaying the decay of sobriety over the months will have different sample sizes at each point on the graph. Starting say, with 50 subjects in each of the active and placebo group, after a week 4 may have dropped out of the placebo group and 5 may have dropped out the active drug group. What is compared in the graphing of the results is the PROPORTION of sober subjects at 1 week, say 40 out of 45 (or .89) and the PROPORTION of sober subjects in the placebo group, say 35 out of 46 (or .76). Thus at each point on the graph, all available data are used. As each subject drops out, the denominator decreases.

The anti-serotonin (5HT) drug ondansetron (Zofran) seems to act in a manner opposite to SSRI drugs (which had negative effects in alcoholics in the small number of trials so far performed). Ondansetron doses are modest, being only a fraction of the usual anti-emetic dose of 4mg (300ยตg taken twice daily). Further studies on this are needed before it could be accepted as a standard alcoholism treatment. The drug appears to be more effective for the "genetic" type of alcoholism rather than the later onset 'reactive' type.

'Rimonaband' is a French-developed cannabis receptor blocker. It seems to have some effect on alcohol cravings in animals but human research is still quite limited.

General practice was the ideal setting to implement these new drug treatments. Both naltrexone and acamprosate are available on the PBS for alcohol dependence when the patient is 'in a treatment program' (such as a general practice setting) - one month supply and repeats allowed. Naltrexone is a simple once daily administration with few side effects in alcoholics. It is contraindicated with opioid analgesics, unlike acamprosate which needs to be taken as two tablets, three times daily. Acamprosate equally has a low side effect profile and few significant drug interactions. The important issue of when to stop therapy was also broached - without a general consensus. Since most relapses occur in the first 2 to 3 months, by 6-12 months it is probably safe to rely on non-drug means to maintain abstinence in most patients.

We should always remember to utilise support services such as self help groups, counselling and psychological services and liver clinics when appropriate.

comments by Andrew Byrne ..