Defining an endophenotype for opioid dysregulation: A pilot study

描述（由申请人提供）：本申请是我们的试点提案的重新提交，旨在测试基因型，对酒精挑战的反应和治疗反应之间的关系。我们中心的证据表明，在治疗酒精依赖时，阿片受体（OPRM1）的功能多态性可能与阿片拮抗剂纳曲酮（NTX）的临床反应有关。NIAAA联合研究报告也有类似的发现。多态性为外显子1 （Asn40Asp）的单核苷酸多态性（SNP）。在对坚持NTX治疗的患者的回顾性分析中，有一个或两个Asp40变异拷贝的患者有73.9%的应答（没有复发的酒精使用）；而Asn40等位基因纯合的受试者对治疗的阳性反应率仅为49.0% （p=0.040）。虽然肯定不是决定性的，但这些数据表明，对NTX有反应和没有反应的人之间可能存在遗传差异。我们提出了一项结合人类实验室酒精暴露和门诊治疗反应的初步研究。具体而言，我们将在实验室环境中测试特定遗传标记改变酒精依赖成人对酒精摄入反应的主观和客观测量之间关系的程度。在接下来的12周内，这种酒精反应内表型将与治疗反应进行比较。为了达到试点研究的目的，将招募40名酒精依赖者参加。在2天的住院期间，受试者将接受两次酒精挑战（一次接受安慰剂治疗后，另一次接受纳曲酮治疗）。在完成挑战环节后，受试者将接受12周的纳曲酮门诊治疗。在门诊治疗期间，所有患者还将接受为niaaa资助的多站点项目（COMBINE）设计的医疗管理（MM），以支持禁欲，同时以安全、心理教育的形式提供药物治疗。该试验的结果将有助于开展纳曲酮的药理学试验，这将为开发治疗匹配的生物标记奠定基础。

DESCRIPTION (provided by applicant): This application is a resubmission of our pilot proposal aimed at testing the relationship between genotype, response to an alcohol challenge and treatment response. Evidence from our center suggests that a functional polymorphism of the mu-opioid receptor (OPRM1) may be associated with clinical response to the opioid antagonist, naltrexone (NTX) in the treatment of alcohol dependence. A similar finding has been reported from the NIAAA COMBINE study. The polymorphism is a single nucleotide polymorphism (SNP) in exon 1 (Asn40Asp). In retrospective analyses of patients adherent to NTX, persons with one or two copies of the Asp40 variant had a 73.9 % response (no relapse to alcohol use); whereas subjects homozygous for the Asn40 allele only had a 49.0 % positive response rate to treatment (p=0.040). While certainly not definitive, these data suggest the potential for a genetic difference between those who do and do not respond to NTX. We have proposed a pilot study combining a human laboratory exposure to alcohol and outpatient treatment response. Specifically, we will test the degree to which specific genetic markers alter the relationship between subjective and objective measures of response to alcohol ingestion among alcohol dependent adults in a laboratory environment. This alcohol response endophenotype will then be compared to treatment response over the next 12 weeks. To meet the aim of the pilot study, 40 alcohol dependent men will be recruited for participation. During a 2 day inpatient stay, subjects will administered two alcohol challenge sessions (one session after receiving a placebo and one session treatment with naltrexone). After completion of the challenge sessions, subjects will receive 12 weeks of outpatient treatment with naltrexone. During outpatient treatment, all patients will also receive Medical Management (MM) as designed for the NIAAA-funded, multi-site project (COMBINE), to support abstinence while providing pharmacotherapies in a safe, psycho-educational format. Results from this trial will assist in developing a pharmacogenetic trial of naltrexone which would form the basis for developing a biological marker for treatment matching.