Pharmacogenetic Response to Naltrexone for Alcohol Dependence

描述（由申请人提供）：来自本中心的证据表明，μ阿片受体（OPRM 1）的功能多态性可能与阿片拮抗剂纳洛酮（NTX）治疗酒精依赖的临床反应相关。该多态性是外显子1（Asn 40 Asp）的单核苷酸多态性（SNP）。SNP几乎仅在欧洲或亚洲血统的个体中发现，并且已经在体外和体内证明可以改变受体的功能。在对NTX依从性患者的回顾性分析中，具有一个或两个Asp 40变体拷贝的人有73.9%的应答（酒精使用无复发）;而Asn 40等位基因纯合子受试者对治疗的阳性应答率仅为49.0%（p=0.040）。在接受安慰剂的患者中，反应与基因型之间没有关联。这一发现最近在联合收割机研究的初步回顾性分析中得到证实，在完成试验的Asp 40等位基因患者中有87%的应答。虽然肯定不是确定的，但这些数据表明基因型与治疗相互作用的潜力，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，需要进行一项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。该建议的主要目的是检查Asp 40等位基因变体和阿片受体拮抗作用之间的相互作用。我们提出了一个前瞻性的，12周，双盲随机试验NTX和安慰剂酒精依赖患者与Asp 40基因多态性的一个或两个拷贝相比，那些纯合子的Asn 40等位基因。受试者将根据基因型（2X2细胞设计）随机接受药物治疗。主要结局为治疗反应。结果证实与临床反应的关联可能会显着推进NTX的使用，并将导致更好地了解酒精依赖的病理生理学。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检验，并且获得的样本将有助于使用奖励系统的药理学探针在充分表征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.