Drug-Drug Interactions Involving Methadone and Buprenorphine

美国应对阿片类药物流行的一个关键组成部分是扩大药物辅助治疗的使用， 最常用的是美沙酮或丁丙诺啡，用于阿片类药物使用障碍。许多有阿片类药物使用障碍的人 需要使用其他急性和长期使用的药物治疗的合并症，这一比例是 预计将随着阿片类药物流行人口结构的变化而上升。美沙酮和丁丙诺啡有药理作用- 动力学和药效学特性，使其极有可能与许多其他药物产生不利作用，其中一些 其中一些是非常常用的。此外，过去的经验表明，现有的药理学知识是 不足以预测所有临床上重要的药物-药物相互作用。尽管有很高的潜力和严重的 无论是可预见的还是不可预见的药物-药物相互作用的后果，几乎没有研究检验过现实世界 与美沙酮或丁丙诺啡合用的药物对健康的影响。这就形成了一个惊人的知识鸿沟。 对临床和公共卫生造成巨大的和不断增长的后果。 该项目的广泛目标是产生临床上可操作的和生物学上相关的知识 药物与美沙酮和/或丁丙诺啡相互作用。我们的工作将进一步阐明以下方面的相互作用 药物起始顺序、剂量-反应效应、持续-反应效应和易感人群。我们将实现 这些目标通过：a)执行高通量的基于生理的药代动力学筛查以预测程度 包括美沙酮或丁丙诺啡在内的两种药物和三种药物组合会增加生物接触 这些药物；b)对两种药物和三种药物组合进行高通量药物流行病学筛选 包括美沙酮或丁丙诺啡在急诊科就诊或住院率方面 阿片类药物过量和中毒、阿片类药物不良反应和心脏骤停；c)召开独立的多学科会议 审查筛查结果并确定潜在的毒品相互作用对和三合会的优先次序以供进一步调查的专家小组； 和d)进行一系列严格的药物流行病学研究，以提供因果推论，从而产生 美沙酮和丁丙诺啡药物相互作用优先顺序的临床可操作证据。这个严谨的， 创新研究将产生可操作的结果，指导在不断增长的人口中选择药物治疗 使用美沙酮或丁丙诺啡的人，患有需要治疗的合并症。

A crucial component of the US response to the opioid epidemic is expanding the use of medication assisted treatment, most commonly using methadone or buprenorphine, for opioid use disorder. Many persons with opioid use disorder have comorbidities that necessitate treatment with other acutely and chronically used medications, and this proportion is expected to rise with the evolving demographics of the opioid epidemic. Methadone and buprenorphine have pharmaco- kinetic and pharmacodynamic properties that make them highly likely to interact adversely with many other drugs, some of which are very commonly used. Further, past experience demonstrates that existing pharmacologic knowledge is insufficient to predict all clinically important drug-drug interactions. Despite the high potential for and serious consequences of both predicted and unanticipated drug-drug interactions, almost no research has examined the real-world health effects of drugs given concomitantly with methadone or buprenorphine. This presents a striking knowledge gap with large and growing clinical and public health consequences. This project's broad objective is to produce clinically-actionable and biologically-relevant knowledge about which medications interact with methadone and/or buprenorphine. Our work will further elucidate interactions with regard to order of drug initiation, dose-response effects, duration-response effects, and susceptible populations. We will achieve these objectives by: a) performing high-throughput physiologically-based pharmacokinetic screening to predict the degree to which two-drug and three-drug combinations that include methadone or buprenorphine increase biological exposure to those agents; b) performing high-throughput pharmacoepidemiologic screening of two-drug and three-drug combinations that include methadone or buprenorphine with regard to rate of emergency department presentation or hospitalization for opioid overdose and poisoning, opioid adverse effects, and cardiac arrest; c) convening an independent multidisciplinary Expert Panel to review screening results and prioritize potential drug interaction pairs and triads for further investigation; and d) conduct a series of rigorous pharmacoepidemiologic studies to inform causal inferences and thereby generate clinically-actionable evidence on prioritized methadone and buprenorphine drug-drug interactions. This rigorous, innovative study will produce actionable results that will guide the selection of drug therapy in the growing population of persons using methadone or buprenorphine who have comorbidities necessitating treatment.