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严重的公共卫生问题，目前还没有已知的有效药物疗法。小型临床试验表明，口服纳曲酮，一种已知在治疗酒精中毒方面有效的阿片类拮抗剂，对苯丙胺成瘾有疗效。在酗酒者中，使用缓释纳曲酮可以提高依从性，减少饮酒。携带-阿片受体(OPRM1)A118G单核苷酸多态性(SNP)的酗酒者对纳曲酮的反应比非携带者更好。我们建议进行纳曲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配方，重点关注A118G SNP在纳曲酮治疗中的作用。进行全面的门诊疗效试验的传统方法是招募同等数量的A118G和野生型受试者，并随机分配给纳曲酮或安慰剂。然而，A1118G多态的频率相对较低(10%-30%)，需要对许多受试者(~800)进行筛查，不适合进行试点试验。如果纳曲酮对甲基苯丙胺成瘾有效，我们预计基于A1118G多态的存在与否，纳曲酮对纳曲酮的反应会有很大差异。发现这样的差异将表明应该进行更大规模的安慰剂对照试验。因此，我们计划进行一项纳曲酮缓释作为甲基苯丙胺成瘾药物疗法的门诊、试点临床试验，比较具有和不具有A118G基因多态的受试者对纳曲酮缓释制剂(380毫克，肌肉注射，持续两个月一次)的反应。比较纳曲酮在这两组中的作用将提供重要的数据，有助于指导后续更明确的研究设计。在这项试点试验中，我们利用几种创新的方法来测试纳曲酮对甲基苯丙胺成瘾的作用。首先，我们使用缓释纳曲酮来提高依从性并减少药物反应的可变性。其次，我们招募了两个药物基因组学定义的群体--A118G SNP携带者和野生型--并通过药物基因组学状态比较纳曲酮的反应。第三，我们利用来自一项类似的、同时进行的平行研究的非随机化安慰剂对照组，以基本上免费的方式进行效应大小估计。第四，我们研究了纳曲酮作用的可能机制，包括减少渴望和冲动。因此，我们提议的试验提供了创新的方法、效率和测试纳曲酮对抗甲基苯丙胺成瘾的强有力的理论基础。 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，目前还没有药物疗法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。纳曲酮阻断阿片受体，这一作用被认为在药物使用的特征，如加强，奖励，冲动和渴望方面很重要。我们计划调查一种长期注射形式的纳曲酮是否有助于防止甲基苯丙胺依赖者的复发。纳曲酮在一些有酒精和其他药物问题的人群中已显示出疗效。

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.