A Pilot Trial of Naltrexone for Methamphetamine Addiction - Role of the A118G SNP

描述（由申请人提供）：甲基苯丙胺成瘾仍然是一个重大的公共卫生问题，没有已知的有效药物治疗。小规模临床试验表明，口服纳洛酮，一种阿片类药物拮抗剂与已知的疗效，在治疗酒精中毒，对苯丙胺成瘾有效。在酗酒者中，使用缓释纳洛酮可提高依从性并减少饮酒。携带阿片受体（OPRM 1）A118 G单核苷酸多态性（SNP）的酗酒者对纳洛酮的反应比非携带者好。我们建议进行纳洛酮治疗甲基苯丙胺成瘾的首次试验。我们将使用可注射的缓释制剂，并专注于A118 G SNP在纳洛酮反应中的作用。全面门诊疗效试验的传统方法是招募相同数量的A118 G和野生型受试者，并将他们随机分配到纳洛酮或安慰剂组。然而，A1118 G多态性的相对低频率（10-30%）将需要筛选许多受试者（约800），并且不适合于初步试验。如果纳洛酮对甲基苯丙胺成瘾有效，我们预计基于A1118 G多态性的存在或不存在，纳洛酮的反应会有很大的差异。发现这样的差异表明应该进行更大规模的安慰剂对照试验。因此，我们计划进行一项门诊，试点临床试验的持续释放纳洛酮作为药物治疗甲基苯丙胺成瘾，比较反应的持续释放制剂（380毫克，肌肉注射，每月一次，超过两个月）的纳洛酮在受试者和没有A118 G多态性。比较纳洛酮在这两组中的作用将为指导后续更明确的研究设计提供重要数据。在这项试点试验中，我们利用几种创新的方法来测试纳洛酮对甲基苯丙胺成瘾。首先，我们使用缓释纳洛酮来提高依从性并减少药物反应的变异性。其次，我们招募了两个药物基因组学定义的组-A118 G SNP携带者和野生型-并通过药物基因组学状态比较对纳洛酮的反应。第三，我们利用一个类似的非随机安慰剂对照组，同时进行平行研究，以允许在基本上没有成本的效果大小估计。第四，我们调查了纳洛酮作用的假定机制，包括减少渴望和冲动。因此，我们提出的试验提供了一个创新的方法，效率和一个强有力的理由来测试纳洛酮对甲基苯丙胺成瘾的组合。 公共卫生相关性：甲基苯丙胺的使用是一个世界性的健康问题，没有药物治疗在降低甲基苯丙胺依赖的高复发率方面显示出很大的希望。纳洛酮阻断阿片受体，这种作用被认为在药物使用的特征中很重要，如强化，奖励，冲动和渴望。我们计划调查是否持久，注射形式的纳洛酮，它已显示出在某些群体与酒精和其他药物问题的疗效，可能有助于防止复发的人谁是甲基苯丙胺依赖。

DESCRIPTION (provided by applicant): Methamphetamine addiction remains a significant public health problem with no known effective pharmacotherapies. Small clinical trials suggest that oral naltrexone, an opioid antagonist with known efficacy in treating alcoholism, has efficacy against amphetamine addiction. In alcoholics, use of sustained release naltrexone improves adherence and decreases drinking. Alcoholics who are carriers of the A118G single nucleotide polymorphism (SNP) of the (-opioid receptor (OPRM1) respond better to naltrexone than do non-carriers. We propose conducting the first trial of naltrexone for methamphetamine addiction. We will use the injectable, sustained release formulation and focus on the role of the A118G SNP in response to naltrexone. The conventional approach to a full-scale outpatient efficacy trial would be to recruit equal numbers of A118G and wild type subjects and assign them randomly to naltrexone or placebo. However, the relative infrequency of the A1118G polymorphism (10-30%) would require screening many subjects (~800), and is not appropriate for a pilot trial. If naltrexone is effective for methamphetamine addiction, we anticipate a large difference in response to naltrexone based on the presence or absence of the A1118G polymorphism. Finding such a difference would indicate that a larger, placebo-controlled trial should be conducted. Therefore, we plan to conduct an outpatient, pilot clinical trial of sustained release naltrexone as a pharmacotherapy for methamphetamine addiction, comparing responses to a sustained release formulation (380 mg, intramuscular, given once per month over two months) of naltrexone in subjects with and without the A118G polymorphism. Comparing the effects of naltrexone in these two groups will provide important data useful in guiding the design of subsequent, more definitive studies. In this pilot trial, we utilize several innovative methods to test naltrexone against methamphetamine addiction. First, we use sustained release naltrexone to improve compliance and decrease variability in drug response. Second, we recruit two pharmacogenomically-defined groups - carriers of the A118G SNP, and wild type - and compare response to naltrexone by pharmacogenomic status. Third, we utilize a non-randomized placebo control group from a similar, simultaneously running parallel study to permit effect size estimation at essentially no cost. Fourth, we investigate putative mechanisms of naltrexone action, which include reduction in craving and impulsivity. Thus, our proposed trial offers a combination of innovative methods, efficiency, and a strong rationale for testing naltrexone against methamphetamine addiction. PUBLIC HEALTH RELEVANCE: Methamphetamine use is a worldwide health problem, and no pharmacotherapy has yet shown much promise in decreasing high rates of relapse seen in methamphetamine dependence. Naltrexone blocks opioid receptors, an action thought to be important in characteristics of drug use such as reinforcement, reward, impulsivity, and craving. We plan to investigate whether a long-lasting, injection form of naltrexone, which has shown efficacy in some groups with alcohol and other drug problems, may help prevent relapse in persons who are methamphetamine dependent.