Pharmacogenetic Response to Naltrexone For Alcohol Dependence

Despite the well established efficacy of naltrexone, there are significant variations in individual responses to naltrexone. A critical question remains: under what circumstances and for which patients will naltrexone (NTX) be most beneficial? Recent work at our center provides evidence that the mu-opioid receptor (OPRM1) gene polymorphism A118G (Asn40Asp) imparts a significant change in treatment response. We have shown that patients with 1-2 copies of the Asp40 variant have significantly better treatment responses than patients with Asn40 variant (absence of heavy drinking -73.9% v/s 49% response). To further consolidate our knowledge, we wish to test the relationship between A118G polymorphism and the response to treatment with naltrexone. This work is focused on subjects of European or Asian descent as the A118G polymorphism occurs in less than 1% of those of African descent. The study consists of 12 weeks of outpatient treatment with 50mg/day of naltrexone or placebo. Up to 340 subjects will be recruited across four sites. The inclusion criteria include adult males and females of European or Asian descent with DSM-IV diagnosis of alcohol dependence and heavy drinking per TLFB criteria. Patients with major psychiatric disorders or on psychotropic medications, other substance dependence problems (except nicotine), severe cognitive impairment, active suicidal/homicidal thoughts and serious medical conditions (including liver disorders) will be excluded. The ultimate aim of this line of investigation is to further establish a genetic link between alcohol dependence and treatment by defining an endophenotype associated with treatment response. Based upon these very promising findings, the aim of this study is to examine prospectively the interaction between a functional polymorphism of the mu-opioid receptor (A+118G (Asn40Asp)) and response to treatment with naltrexone. A secondary aim of this study is to examine the role of the Asp40 allele in alternating the subjective effects from alcohol use in alcohol dependent individuals that have been demonstrated in human laboratory experiments. We hypothesize that naltrexone - but not placebo - will produce a greater clinical response during the 12 weeks of the trial in subjects with one or two copies of the Asp40 variant ("Asp40 positives") than in subjects homozygous for the Asn40 allele. Response to naltrexone will be measured by a reduction in the number of heavy drinking days (as defined by \>5 drinks/day for males; \>4 for females) during the 12 weeks of the trial. We also expect that there will be an interaction between medication and genotype such that, as compared to the groups on placebo or homozygous for Asn40, Asp40 positive subjects randomized to naltrexone will report less "high" from alcohol consumption (on the Biphasic Alcohol Effects Scale), and the lowest levels of alcohol craving over time (on the Penn Alcohol Craving Scale).