Licit & Illicit Opioids: Comparative Studies in Humans

描述（由申请人提供）：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年期奖项侧重于新出现的处方阿片类药物滥用流行病，对滥用最广泛的阿片类药物（氢可酮、羟考酮和奥施康定（R））的临床药理学进行了一系列研究。这些研究调查了相对滥用潜力估计值、相对效力、疼痛对滥用倾向的影响，以及这些药物在经口、鼻内和静脉途径误用时的药代动力学和药效学。本申请通过进行一系列研究来收集有关阿片类药物的新数据，扩展了这些发现，这些阿片类药物据称滥用倾向较低，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，招募散发性阿片类药物滥用者和阿片类药物依赖者，以检查曲马多、丁丙诺啡和丁丙诺啡/纳洛酮通过各种给药途径滥用时的相对滥用潜力和强化疗效。这些研究包括仔细的双盲、随机、安慰剂对照、交叉设计，并将创新的方法学添加到标准滥用倾向方法中，包括1）使用人类自我给药程序同时评价这些化合物的直接增强功效，以评估"金标准"方法与直接检查药物服用行为的模型之间的结果一致性，2）多种相关的比较剂，和3）安全性、主观报告、自我评价和心理表现的多维结局沿着。三项拟议的住院研究将检查1）口服曲马多在一定剂量范围内与羟考酮相比的滥用倾向和强化疗效（一种高效激动剂），可待因2）鼻内丁丙诺啡和丁丙诺啡/纳洛酮在一定剂量范围内相互比较以及与羟考酮比较，可待因和安慰剂在非依赖性阿片类药物滥用者中，和3）鼻内丁丙诺啡和丁丙诺啡/纳洛酮在一定剂量范围内相互比较，以及与羟考酮、纳洛酮和安慰剂在维持短效药物阿片类药物的阿片类药物依赖受试者中比较。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被重新安排到更严格状态的风险。疼痛患者和阿片类药物依赖者寻求基于办公室的药物依赖治疗），同时保护公众安全。这些研究将提供关于这些药物在相关人群中的相对滥用倾向的经验数据，并可为循证监管决策提供信息和支持。 公共卫生相关性：处方阿片类药物滥用在美国急剧增加，是一个重大的公共卫生问题。必须了解处方类阿片的药理作用，以便预测和控制其滥用和其他负面健康后果。这些研究将提供关于曲马多（用于疼痛）和丁丙诺啡单独使用以及与纳洛酮（用于治疗阿片类药物依赖）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).