13 April 2005

Recent advances in the treatment of alcoholism

Charles O'Brien, MD, PhD.

Uris Auditorium, Cornell Medical School, York Ave, New York City

11am Wednesday 13th April 2005. Summary by Andrew Byrne

Dear Colleagues,

I was privileged to attend this grand rounds presentation in which world expert Dr Charles O'Brien addressed 'recent developments in the treatment of alcoholism'. He separated his talk into three sections: What is addition? Is drug treatment necessary for alcoholism? What treatment should be chosen? Newcomer acamprosate (Campral) has recently joined naltrexone ('Trexan', 'Re-via', now generic) and disulfiram (Antabuse), making three FDA approved medications for alcoholism. Each acts by a different mechanism.

This group of senior psychiatrists at Cornell Medical School was told that Dr O'Brien helped formulate DSM IIIR criteria for alcohol and other dependencies and had worked on the new DSM IV. He said that it was unfortunate that he and his colleagues had originally chosen the term 'dependency' since 'addiction' was more descriptive and was the commonly understood and still accurate scientific term. Rather than the old understanding of tolerance and withdrawals, addiction needed a much more comprehensive delineation. Some people treated for pain over a short period, even conceivably following a single dose of morphine, may develop tolerance and withdrawal, but clearly this is not 'addiction'. Also, some people who are profoundly addicted may show neither tolerance nor withdrawal at certain times. Hence the DSM committee arrived at the modern definitions involving compulsive self-administration of drugs/alcohol despite attempts to avoid them, involving continued harms AND/OR defined detrimental consequences resulting from issues of time spent in drug acquisition, legal, financial, family and vocational matters. Addiction thus involves the drug, person and their community setting.

Dr O'Brien reminded us of the permanent brain changes which occur with all human experience, each potentially involving actual physical, molecular changes as well as synaptic and dendritic alterations. He detailed some of the known sub-cellular mechanisms which end in the common 'reward' pathway for substances whose primary actions are on opioid, GABA or NMDA receptors. They involve the nucleus accumbens, amygdala and connections with the anterior cyngulate gyrus, pre-frontal cortex, etc. As well as for substance use, these pathways operate for other pleasurable behaviors such as gambling and eating. Dr O'Brien showed a number of 'in vivo' PET and other vascular scans showing increased blood flow in both hind-brain and anterior cortex in subjects who were shown pornographic or drug use related images while actually within the imaging machines. He also detailed the close links between alcohol, other drugs and the opioid system.

Likewise, we learned that when measured in rats, the continuously monitored brain dopamine changes in response to drugs such as cocaine or morphine were far greater than the responses found during sex or other pleasurable behavior. This finding exemplifies the intensity of the reward pathways for drugs as well as the 'learned' behaviours which are so hard to change. As a comparison, Dr O'Brien likened it to learned activities � and the younger it is learned, the less likely it is to be forgotten, such as learning to ride a bicycle in childhood. Despite the best will, it is impossible to 'unlearn' this, just as an alcoholic cannot 'unlearn' the experience of drinking to excess (or a hangover, presumably).

We were then told about new findings of 25 discrete alleles of the gene for the �-opiate receptor that have been found at a frequency of 1% or more. One such allele which is functional to the extent that its affinity for �-endorphin in vitro is significantly higher than other alleles and is associated with a higher frequency of alcoholism in a single Swedish study. At least one copy of this allele is found in 30% of European Americans and in a retrospective study of clinical trials of alcoholics with this allele, those randomized to placebo did very poorly but those randomized to naltrexone did very well. The difference was significant and could indicate that alcoholics with this genotype do particularly well on naltrexone. Dr O�Brien emphasized that alcohol is �just another drug� and alcoholism should not be seen as fundamentally different from addiction to illicit drugs or nicotine. He also reminded the audience that it was for �political reasons� that alcohol research in America was funded by a separate authority from illicit drugs.

The speaker then detailed some illuminating Japanese work on alcohol dehydrogenase deficiency which is quite prevalent amongst Asian populations. All homozygous subjects develop severe flushing and distress on consuming alcohol and their incidence of use, abuse and addiction is near zero. However, heterozygous subjects can overcome the similar but less severe effects. And despite some negative effects, some of them nevertheless become regular users, excessive users and/or dependent users of alcohol. This again emphasized the equally strong inputs from each of three domains: (1) drug, (2) host and (3) environment in the causation of addictions.

We were then quoted some figures from a 1994 study by Dr Anthony in which 'ever used' prevalence of addictive drugs was compared with 'became dependent'. For tobacco users 32% became addicted, for alcohol, 15%, and likewise for cocaine 16% heroin 23%, cannabis 9%. These figures are very important for parents and medical people, showing that a highly variable minority of all drug users later become dependent. These figures might be further refined in future research according to at what age subjects were first exposed to the particular drugs.

Next we were given the latest research on naltrexone and acamprosate, both of which reduce alcohol use significantly in 3 to 12 month follow-ups with low rates of side effects and good retention rates. When the total amount of alcohol consumed is compared between placebo and active groups the difference is quite dramatic. Most of the trials used standard psychotherapy, cognitive behavioural or group therapy in addition to drug treatment. Dr O'Brien implied that these therapies were considered essential if not sufficient in some cases yet he did not cite studies showing the effectiveness of such 'talking' therapies for alcoholism. He did quote one study (nearly all were positive) in which the anti-craving drug was given successfully in the absence of any focused psychotherapy (from community practice in Australia).

Such research both in the US and overseas shows similar results despite slightly different criteria for lapse/relapse end points ('just one drink' versus consecutive drinking days). Because these two drugs work by different mechanisms they have been used together by some groups with potentiated effects and minimal side effects. Theoretically at least, disulfiram (Antabuse) could be used as well, comprising a third strand to therapy, although such an approach has apparently not yet been researched.

Topirimate and ondansetron are other drugs with apparent beneficial effects in alcoholics. Thus they might be used "off-label" in certain circumstances. Neurological side effects have limited the use of topirimate, an anticonvulsant. A small randomised trial by Bankole Johnson showed benefits with ondansetron in 'genetic' or life-long alcoholics but no effect in the later onset 'acquired' type. Presently these may be considered promising but still experimental.

We were then told of the intriguing possibilities of the French drug �rimonabant�, a CB-1 (cannabinoid) antagonist. It is currently being promoted for obesity and for nicotine addiction, but animal models suggest that it should benefit alcoholics and cocaine addicts. One experiment showed that it does indeed block the effects of cannabis in human smokers.

Following replies to several diverse questions from the audience, Dr O'Brien was thanked by Dr Robert Millman and his staff. The meeting then broke up as we exited to the warmth and sunlight of York Avenue, East Side of New York City. I walked the block to Sotherby's Auctions where there was a boring showing of antique Rolex watches on the first level with a more engaging sale upstairs entitled "A celebration of the English Country House". There were paintings, brown furniture, rugs, silver, glass and other household meubles and trinkets to turn the eye � and the budget, one suspects.

Comments by Andrew Byrne .. (with some help from and thanks to the speaker)