This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.In the US, heavy drinking occurs commonly and is associated with a variety of alcohol-related problems. Available treatments for problem drinking have limited efficacy. This proposal is for a 12-week, placebo-controlled trial of naltrexone (50 mg orally) in 200 problem drinkers. Problem drinkers are those individuals whose drinking puts them at risk of a variety of psychosocial and medical problems, including alcohol dependence, but who are not physically dependent on alcohol. They are estimated to comprise up to 20% of the general population. The study will employ a factorial design in which the effects of medication (naltrexone vs. placebo), schedule of medication administration (i.e., daily vs. targeted), and the interaction of these factors on drinking behavior will be examined. Targeted administration refers to the use of medication to cope with anticipated high-risk drinking situations. The primary outcome measures will be drinking days and heavy drinking days. Secondary outcomes will include alcohol-related problems and biological measures of alcohol consumption (i.e., serum Gamma glutamyl transpeptidase (GGTP) and Carbohydrate-Deficient Transferrin CDT). The study will extend the results of a recently completed 8-week trial of targeted naltrexone in early problem drinkers. That study showed a significant advantage of naltrexone over placebo on heavy drinking days and for targeted administration on daily drinking. The effects of targeted administration diminished substantially over time, apparently due to the schedule that was used for targeted medication administration. In the proposed study, the targeted medication schedule has been modified, the sample size increased, the duration of treatment lengthened and a pharmacogenetic analysis added to examine the effect of allelic variation at candidate loci on the response to naltrexone. The daily monitoring of mood, desire to drink, perceived self-efficacy, and drinking behavior will make it possible to examine in depth the processes by which the study variables exert their effects. Daily monitoring will be performed using automated telephone interviews, with in-person follow-up evaluations conducted at 3 and 6 months post-treatment to provide a measure of the durability of treatment effects. A pharmacogenetic analysis based on preliminary evidence showing that a functional polymorphism in the gene encoding the mu-opiate receptor (OPRM1) affects response to naltrexone will serve to explore an important source of variation in the response to naltrexone treatment. Exploratory analyses involving other the gene encoding the delta opioid receptor (OPRD1) will also be conducted. Careful evaluation of the study hypotheses will provide important information on the efficacy and mechanism of the effects of targeted naltrexone in problem drinkers. This study will allow us to model effects across multiple levels of analysis in an effort to apply novel genetic findings to understanding the psychopharmacological mechanisms underlying the therapeutic effects of naltrexone in problem drinkers.
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