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方案的重新提交，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。来自我们中心的证据表明，MU-阿片受体(OPRM1)的功能多态性可能与阿片拮抗剂纳曲酮(NTX)治疗酒精依赖的临床反应有关。据报道，NIAAA联合研究也有类似的发现。该多态性是外显子1(Asn40Asp)上的单核苷酸多态性(SNP)。在对服用NTX的患者进行的回顾分析中，携带一个或两个ASP40变异体的患者有73.9%的反应(不再酗酒)；而Asn40等位基因纯合的受试者对治疗的阳性反应率只有49.0%(p=0.040)。虽然这些数据肯定不是决定性的，但这些数据表明，对NTX有反应和没有反应的人之间存在潜在的遗传差异。我们已经提出了一项试验性研究，将人体实验室暴露于酒精和门诊治疗反应结合起来。具体地说，我们将测试特定的遗传标记在多大程度上改变了实验室环境中酒精依赖成年人对酒精摄入反应的主观和客观指标之间的关系。这种酒精反应的内表型将在接下来的12周内与治疗反应进行比较。为了达到这项初步研究的目标，将招募40名酒精依赖男性参与。在两天的住院期间，受试者将接受两次酒精挑战治疗(一次是在接受安慰剂治疗后，另一次是纳曲酮治疗)。在完成挑战阶段后，受试者将接受为期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资助的多地点项目(联合项目)设计的医疗管理(MM)，以支持戒酒，同时以安全、心理教育的形式提供药物治疗。这项试验的结果将有助于开发纳曲酮的药物遗传学试验，这将形成开发治疗匹配的生物标记的基础。

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.