Pharmacogenetic Response to Naltrexone for Alcohol Dependence

描述（由申请人提供）：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。多态性为外显子1 （Asn40Asp）的单核苷酸多态性（SNP）。该SNP几乎只存在于欧洲或亚洲血统的个体中，并且已在体外和体内证明可以改变受体的功能。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）。在接受安慰剂的患者中，反应和基因型之间没有关联。这一发现最近在对COMBINE研究的初步回顾性分析中得到证实，完成试验的Asp40等位基因患者有87%的应答。虽然肯定不是决定性的，但这些数据表明，通过治疗相互作用，基因型的潜力可以更好地定义治疗算法，并消除成瘾不是一种疾病的信念。在与FDA的讨论中，需要进行前瞻性随机安慰剂对照试验，以考虑标签变更或生物标志物的批准。本研究的主要目的是研究Asp40等位基因变异与阿片受体拮抗剂之间的相互作用。我们提出了一项前瞻性、为期12周的双盲随机试验，在与Asn40等位基因纯合子相比，具有一个或两个Asp40多态性拷贝的酒精依赖患者中使用NTX和安慰剂。受试者将根据基因型随机接受药物治疗（2X2细胞设计）。主要结果将是治疗反应。证实与临床反应相关的结果可能会显著促进NTX的使用，并有助于更好地理解酒精依赖的病理生理。前瞻性设计和纳入所有受试者的基因分型将允许对其他可能的候选基因进行次要假设测试，并且获得的样本将促进使用奖励系统药理学探针在特征良好的样本中进行治疗反应的全基因组相关研究。

DESCRIPTION (provided by applicant): 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. The polymorphism is a single nucleotide polymorphism (SNP) in exon 1 (Asn40Asp). The SNP is found almost exclusively in individuals of European or Asian descent and has been demonstrated in vitro and in vivo to alter the function of the receptor. 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). In patients receiving placebo there was no association between response and genotype. This finding was recently confirmed in preliminary retrospective analysis of the COMBINE study with a 87% response in patients with the Asp40 allele who completed the trial. While certainly not definitive, these data suggest the potential for a genotype by treatment interaction that could better define treatment algorithms and dispel the belief that addiction is not a disease. In discussions with the FDA, a prospective randomized placebo controlled trial is required to consider labeling changes or approval of a biomarker. The primary aim of this proposal is to examine the interaction between the Asp40 allele variant and opioid receptor antagonism. We propose a prospective, 12-week, double-blind randomized trial of NTX and placebo among alcohol dependent patients with one or two copies of the Asp40 polymorphism compared to those homozygous for the Asn40 allele. Subjects will be randomized to medication based on genotype (2X2 cell design). The primary outcome will be treatment response. Results confirming the association with clinical response may significantly advance the use of NTX and will lead to a better understanding of the pathophysiology of alcohol dependence. The prospective design and inclusion of genotyping of all subjects will allow secondary hypotheses to be tested for other possible candidate genes and the acquired sample will facilitate whole genome associate studies of treatment response in a well characterized sample using a pharmacological probe of the reward system.