Neuropharmacology of Tramadol: Clinical Efficacy and Abuse Potential

描述（由申请人提供）：处方阿片类药物误用和滥用在美国日益严重。在2006年全国药物使用和健康调查中，520万美国人在过去一个月内非法使用了处方阿片类药物。全国非法处方类阿片使用率高于海洛因、可卡因或甲基苯丙胺，仅次于大麻。此外，2004年和2005年，开始非法使用处方类阿片的人数多于大麻。这些研究结果表明，非法处方类阿片的使用是一个重大的公共卫生问题，超过可卡因，海洛因或甲基苯丙胺，可能接近大麻。非法处方类阿片使用的增加可能是由于具有显著滥用潜力的类阿片镇痛药物的供应增加。发现和开发滥用可能性降低的阿片类镇痛剂可能有助于减少处方阿片类药物滥用和随后发生的阿片类药物使用障碍。曲马多是一种非预定的非典型镇痛药，具有阿片活性。虽然报告了曲马多滥用和身体依赖的罕见病例，但相对于典型的处方阿片类药物，它降低了滥用的可能性。曲马多的滥用潜力降低归因于其新颖的药理学。曲马多是一种μ阿片类激动剂，但也阻断血清素和去甲肾上腺素的再摄取。本申请的具体目的是阐明μ阿片样物质、5-羟色胺和去甲肾上腺素受体系统对曲马多的作用的相对贡献，使用一系列与其在人类志愿者中的滥用潜力和镇痛功效相关的药理学测量。从拟议的实验中获得的关于曲马多神经药理学的知识将有助于发现和开发其他阿片类药物，降低滥用潜力。具体而言，如果曲马多的非mu介导作用有助于其镇痛疗效和降低滥用可能性，则这些发现将支持开发具有类似神经药理学机制的其他镇痛药。本项目将采用安慰剂对照、随机和双盲试验程序，在三个实验中评价曲马多的行为效应。总的来说，该项目将提供关于曲马多药理学的重要临床信息，与其镇痛功效和减少滥用潜力有关，并提供关于处方阿片类药物对人类行为影响的基本科学信息。公共卫生相关性：本申请中提出的研究旨在更好地了解曲马多的人类神经药理学，曲马多是一种具有阿片类作用的非典型镇痛药，相对于其他阿片类镇痛药，其滥用潜力降低。我们正在寻求了解曲马多的神经药理学如何影响其镇痛疗效和减少滥用的可能性，以帮助开发其他具有减少滥用可能性的镇痛药物。开发滥用可能性降低的镇痛剂可能会降低处方阿片类药物滥用和随后的阿片类药物使用障碍的患病率。

DESCRIPTION (provided by applicant): Prescription opioid misuse and abuse are increasing problems in the United States. In the 2006 National Survey on Drug Use and Health, 5.2 million Americans had illicitly used a prescription opioid in the past month. National rates of illicit prescription opioid use are higher than those for heroin, cocaine or methamphetamine and are exceeded only by marijuana. Moreover, the number of individuals initiating illicit use of prescription opioids was greater than that for marijuana in 2004 and 2005. These findings indicate that illicit prescription opioid use represents a significant public health concern greater than that of cocaine, heroin or methamphetamine and perhaps approaching that of marijuana. The increase in illicit prescription opioid use may be due to increased availability of opioid analgesics medications with significant abuse potential. Discovery and development of opioid analgesics with reduced abuse potential may serve to decrease prescription opioid misuse and the subsequent development of opioid use disorders. Tramadol is an unscheduled atypical analgesic with opioid activity. While rare cases of tramadol abuse and physical dependence have been reported, it has reduced abuse potential relative to typical prescription opioids. The reduced abuse potential of tramadol has been attributed to its novel pharmacology. Tramadol is a mu opioid agonist, but also blocks reuptake of serotonin and norepinephrine. The specific aim of the present application is to elucidate the relative contributions of mu opioid, serotonin and norepinephrine receptor systems to the effects of tramadol using an array of pharmacologic measures relevant to its abuse potential and analgesic efficacy in human volunteers. The knowledge gained about tramadol from the proposed experiments in terms of its neuropharmacology will aid in the discovery and development of other opioid medications with reduced abuse potential. Specifically, if the non-mu mediated effects of tramadol contribute to its analgesic efficacy and reduced abuse potential, these findings would support the development of other analgesics with similar neuropharmacological mechanisms. This project will employ placebo-controlled, randomized and double blind testing procedures to evaluate the behavioral effects of tramadol across three experiments. Overall, this project will contribute important clinical information regarding the pharmacology of tramadol in relation to its analgesic efficacy and reduced abuse potential and provide basic science information about the behavioral effects of prescription opioids in humans. PUBLIC HEALTH RELEVANCE: The research proposed in this application seeks to understand better the human neuropharmacology of tramadol, an atypical analgesic with opioid action that has reduced abuse potential relative to other opioid analgesics. We are seeking to understand how the neuropharmacology of tramadol influences both its analgesic efficacy and reduced abuse potential in an effort to aid development of other analgesic medications with reduced abuse potential. Developing analgesics with reduced abuse potential may reduce the prevalence of prescription opioid misuse and subsequent opioid use disorders.