Under certain genetic circumstances, naltrexone may increase the urge to drink

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- Findings indicate that Asp carriers of the OPRM1 gene who take NTX have a greater urge to drink, which is contrary to expectations.

Naltrexone (NTX) is able to reduce drinking and craving among many alcoholics and heavy drinkers, but not all of them. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the ì opiate receptor (OPRM1) gene may moderate NTX's effects on craving. New findings indicate that Asp carriers of the OPRM1 gene do indeed have a different response to NTX, albeit contrary to expectations: these individuals have a greater urge to drink.

Results are published in the August issue of Alcoholism: Clinical & Experimental Research.

"We know that NTX does not work for all alcohol-dependent people who take it," said John McGeary, research psychologist at the Providence VA Medical Center. "Some evidence suggests that alcoholics who have a positive family history - other alcoholics in their family - may have a better response to NTX. This can suggest genetic factors, environmental factors, or both. The finding that family history might be related to NTX response gave us the idea to examine specific genes that might account for this effect."

Dr. Raymond F. Anton, Distinguished Professor and director of the Center for Drug and Alcohol Programs at the Medical University of South Carolina believes that the reason why NTX does not work for everyone is due largely to study-related issues.

"There are three meta-analyses all concluding that naltrexone is efficacious in clinical trials taken as a whole," said Anton. "The reason why some are negative are: one, small sample size; two, increased variability in multi-site trials calling for larger samples sizes; three, uneven application of good clinical trial methodology; four; heterogenous study samples; and five, probably the most crucial, the small effect size of NTX leading to some negative trials by chance alone." He also feels that since the current study was done in a small number of subjects who were young and not all alcohol dependent, that the results should be interpreted with caution, especially since they are not consistent with past observations and were not predicted at the beginning of the study. Also, he added, "how this difference in craving related to naltrexone's effects on drinking over the weeks prior to the experiment was not reported."

However, Anton added, "it is clear that gene-by-environment interaction investigations will be with us for a long period of time. Alcohol response is a good place to evaluate these interactions since we know that alcohol is an environmental agent and we can study the interactions with genes more closely than in many diseases."

McGeary and his colleagues analyzed data gathered earlier on 90 participants (50 males, 40 females) who were part of a larger study designed to measure NTX's effects on urge and drinking. All were heavy drinkers who had not sought treatment; all were genotyped. After 10 days of receiving either NTX (50 mg) or a placebo, participants were exposed in a laboratory setting to their favorite alcoholic beverage, smelled it, and looked at it. Their reactions to these cues were then measured in comparison to their reactions to a glass of water.

"Alcohol cue reactivity refers to the response that one has to stimuli," explained McGeary. "For example, if a person always drinks beer with pizza, after several years of this behavior, these stimuli - beer and pizza - can be considered a 'paired set' of stimuli, in that they go together. This means that if the person is presented with pizza only, they may have a desire for beer. Although this example seems innocuous, this may be a real problem for an alcoholic trying not to drink."

Results show that the OPRM1 gene had different moderating effects on NTX's impact on the heavy drinkers' urge to drink: Asp carriers of the OPRM1 gene showed a greater urge to drink when they received NTX, compared to a placebo; whereas NTX had no effect on Asn carriers of the OPRM1 gene. DRD4 polymorphisms did not appear to have any effects on NTX.

Both McGeary and Anton found the results surprising.

"These findings challenge the notion that NTX works by reducing craving and suggest that there may be another mechanism of action for NTX," said McGeary. "Furthermore, we may have identified a genetic variation that predicts response to NTX."

"We need to remember that genes are not deterministic," said Anton. "Having a certain gene makeup does not mean that you will have a disorder. In all complex genetic disorders, such as alcoholism, it is not likely that one gene will cause the problem. It is likely that other genes will add to the risk of having a disorder and some might protect against this risk. Also, it is clear that gene-by-environment interactions - such as family upbringing, education, socioeconomic status, stress responsivity, early life trauma, and certain personality traits - might all interact with genetic makeup to increase or decrease risk of developing alcohol dependence."

However, he conceded, "how people react to alcohol and adapt to chronic use is likely to have some roots in genetic makeup. How medications like NTX interact with that genetic makeup to predict treatment response is an exciting area of investigation that we should be seeing more of in the future."

Both Anton and McGeary spoke of how pharmacogenetic studies of alcohol medications such as NTX may eventually lead to "personalized" or "targeted" medicine. McGeary was especially excited about the Veterans' Administration plan to collect DNA on seven million veterans for inclusion in their medical charts, which "exemplifies some of the real-world potential that exists for targeted medicine," he said.

Alcoholism: Clinical & Experimental Research