TARGETED NALTREXONE FOR PROBLEM DRINKERS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在美国，大量饮酒经常发生，并与各种与酒精有关的问题有关。现有的治疗问题饮酒的方法疗效有限。这项建议是对200名问题饮酒者进行为期12周的纳曲酮(50毫克口服)的安慰剂对照试验。问题饮酒者是指那些饮酒使他们面临各种心理社会和医疗问题的风险，包括酒精依赖，但身体上不依赖酒精的人。据估计，他们占总人口的20%。这项研究将采用析因设计，研究药物(纳曲酮与安慰剂)、用药时间表(即每日给药与定向给药)的影响，以及这些因素对饮酒行为的相互作用。靶向给药是指使用药物来应对预期的高风险饮酒情况。主要的结果衡量标准将是饮酒天数和酗酒天数。次要结果将包括与酒精有关的问题和酒精消费的生物学措施(即血清伽马谷氨酰转肽酶(GGTP)和碳水化合物缺乏的转铁蛋白CDT)。 这项研究将延长最近完成的一项为期8周的纳曲酮靶向试验的结果，该试验针对早期问题饮酒者。这项研究表明，纳曲酮在重度饮酒日和日常饮酒的靶向给药方面比安慰剂有显著优势。靶向给药的效果随着时间的推移而显著减弱，显然是由于靶向给药所使用的时间表。 在拟议的研究中，靶向用药时间表被修改，样本量增加，治疗持续时间延长，并增加了药物遗传学分析，以检查候选基因座的等位基因变异对纳曲酮疗效的影响。对情绪、饮酒欲望、自我效能感和饮酒行为的日常监测将使深入检查研究变量发挥作用的过程成为可能。 将使用自动电话访谈进行日常监测，并在治疗后3个月和6个月进行面对面跟踪评估，以衡量治疗效果的持久性。基于初步证据的药物遗传学分析表明，编码阿片受体(OPRM1)的基因的功能多态性影响对纳曲酮的反应，这将有助于探索纳曲酮治疗反应的一个重要变异来源。还将进行涉及编码增量阿片受体(OPRD1)的其他基因的探索性分析。对研究假设的仔细评估将为纳曲酮对问题饮酒者的疗效和作用机制提供重要信息。这项研究将使我们能够在多个水平的分析中建立效应模型，以努力应用新的遗传学发现来理解纳曲酮对问题饮酒者治疗效果的精神药理学机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.