Licit & Illicit Opioids: Comparative Studies in Humans

描述(申请人提供)：虽然海洛因依赖率在过去几年中相当稳定，但处方阿片类药物滥用、依赖和转移的比率显著上升。最初的5年奖通过对最广泛滥用的阿片类药物(氢可酮、羟考酮和奥施康定)的临床药理学进行一系列研究，重点关注新出现的处方阿片滥用流行。这些研究调查了相对滥用潜力的估计、相对效力、疼痛对滥用倾向的影响，以及这些药物在口服、鼻腔和静脉途径滥用时的药代动力学和药效学。本申请通过开展一系列研究，收集关于阿片类药物的新数据，这些阿片类药物据称具有较低的滥用倾向，但根据监测研究，正在成为新的滥用药物，包括曲马多、丁丙诺啡(Subutex(R))和丁丙诺啡/纳洛酮(Suboxone(R))。将进行三项研究，招募零星的阿片类药物滥用者和阿片类药物依赖者，以考察曲马多、丁丙诺啡和丁丙诺啡/纳洛酮在不同给药途径滥用时的相对滥用潜力和增强疗效。这些研究包括谨慎的双盲、随机、安慰剂对照、交叉设计，并将创新的方法学添加到标准的滥用责任方法中，包括1)使用人类自我管理程序对这些化合物的直接强化效果进行同时评估，以评估“黄金标准”方法与直接检查吸毒行为的模型之间的一致性；2)多个相关的比较药物；3)安全性、主观报告、观察者评级和精神运动表现的多维结果。这三项拟议的住院研究将考察1)口服曲马多在非依赖阿片类药物滥用者中与羟可酮(一种高效激动剂)、可待因(中效激动剂)和安慰剂的比较滥用易感性和增强疗效，2)丁丙诺啡和丁丙诺啡/纳洛酮在鼻腔内相互比较以及在非依赖阿片滥用者中与羟可酮、可待因和安慰剂的比较，以及3)鼻腔注射丁丙诺啡和丁丙诺啡/纳洛酮在维持短效阿片类药物依赖的受试者中的相互比较和与羟可酮、纳洛酮和安慰剂的比较。这些研究将提供关于两种新出现的滥用药物--曲马多和丁丙诺啡--的重要新信息，这两种药物在美国都有可能被重新安排到更严格的限制状态。至关重要的是，在保护公众安全的同时，为其目标患者群体(即分别寻求以办公室为基础的药物依赖治疗的疼痛患者和阿片依赖患者)保留这些药物的供应。这些研究将提供关于这些药物在相关人群中的相对滥用风险的经验数据，并可为基于证据的监管决策提供信息和支持。 与公共卫生相关：处方阿片类药物滥用在美国急剧增加，是一个严重的公共卫生问题。重要的是要了解处方阿片类药物的药理作用，以便预测和控制其滥用和其他对健康不利的后果。这些研究将提供关于曲马多(用于疼痛)和丁丙诺啡单独以及与纳洛酮(用于治疗阿片依赖)联合使用的滥用相关特征的新信息。

DESCRIPTION (provided by applicant): While rates of heroin dependence have been fairly stable over the last several years, rates of prescription opioid abuse, dependence and diversion have risen significantly. The initial 5-year award focused on the emerging prescription opioid abuse epidemic by conducting a series of studies on the clinical pharmacology of the most widely abused opioids (hydrocodone, oxycodone and Oxycontin(R)). These studies investigated relative abuse potential estimates, relative potency, effects of pain on abuse liability, and pharmacokinetics and pharmacodynamics of these drugs when misused by the oral, intranasal and intravenous routes. The present application extends these findings by conducting a series of studies to collect new data on opioids purported to have low abuse liability but, based upon surveillance studies, are emerging as new drugs of abuse, including tramadol, buprenorphine (Subutex(R)) and buprenorphine/naloxone (Suboxone(R)). Three studies will be conducted, enrolling both sporadic opioid abusers and opioid dependent individuals, to examine the relative abuse potential and reinforcing efficacy of tramadol, buprenorphine and buprenorphine/naloxone when misused by various routes of administration. These studies include careful double-blind, randomized, placebo- controlled, crossover designs and incorporate innovative methodological additions to the standard abuse liability approach, including 1) concurrent evaluation of the direct reinforcing efficacy of these compounds using human self-administration procedures to assess the concordance of findings between the "gold standard" approach to a model that examines drug-taking behavior directly, 2) multiple relevant comparator agents, and 3) multi-dimensional outcomes of safety, subjective reports, observer-rating and psychomotor performance along. The three proposed inpatient studies will examine the comparative abuse liability and reinforcing efficacy of 1) oral tramadol over a range of doses in comparison to oxycodone (a high efficacy agonist), codeine (an intermediate efficacy agonist), and placebo in non-dependent opioid abusers, 2) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone, codeine and placebo in non-dependent opioid abusers, and 3) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone, naloxone and placebo in opioid-dependent subjects maintained on a short-acting pharmaceutical opioid. These studies will provide important new information on two emerging drugs of abuse- tramadol and buprenorphine- both drugs at risk for being rescheduled to more restrictive status in the U.S. It is critical that availability of these drugs be preserved for their target patient groups (i.e., pain patients and opioid dependent individuals seeking office- based treatment for drug dependence, respectively) while protecting the public safety. These studies will provide empirical data on the relative abuse liability of these drugs in a relevant population and can inform and support evidence-based regulatory decision-making. PUBLIC HEALTH RELEVANCE: Prescription opioid abuse has increased dramatically in the United States and is a significant public health problem. It is important to understand the pharmacological effects of prescribed opioids in order to predict and control their abuse and other negative health consequences. These studies will provide new information on the abuse-related features of tramadol (used for pain) and buprenorphine alone and in combination with naloxone (used for treatment of opioid dependence).