Influence of Orexin Antagonism on Opioid and Methamphetamine Demand

项目摘要 被认为是“孪生流行病”或“第四波”，流行病学证据强调， 使用阿片类药物的人使用甲基苯丙胺的健康危害。这些数据尤其令人担忧 鉴于没有FDA批准的甲基苯丙胺使用药物疗法或既定的治疗方法， 甲基苯丙胺/阿片类药物合用。调节兴奋剂和阿片类药物动机的一个有希望的目标是 增食欲素系统临床前和早期临床研究结果表明，食欲素系统拮抗作用是临床上可行的。 有选择地减少阿片类药物和兴奋剂的动机的方法。需要人类实验室数据来 研究这种机制并将其扩展到共同使用环境。本项目将通过使用 行为经济需求框架，以评估使用阿片类药物，甲基苯丙胺及其 阿片类药物使用障碍患者的联合用药。需求分析将直接指导后续的 治疗研究，确定阿片类药物和甲基苯丙胺共同使用的动机， 药物作为替代物（即，当一个消费减少时，另一个消费增加）， 将需要靶向两种药物的治疗以避免突破性使用，或作为补充（即，作为 一种消耗减少，另一种消耗减少），这将支持靶向 一种药物同时减少另一种药物的使用。这是一种最佳方法， 迅速开展治疗试验，并通过查明不正确的 目标的我们将在阿片类药物非寻求治疗的受试者中进行一项住宅人体实验室研究 使用障碍。参与者将完成口服甲基苯丙胺的盲法给药， 羟考酮、它们的组合和安慰剂。经验证的对药理学敏感的需求指标 操纵将决定自身价格需求（单独商品）和交叉商品需求（同时 商品）。受试者将在整个住院期间随机接受口服苏沃雷生或安慰剂。 留下吧我们假设食欲素拮抗作用将导致更高的需求弹性（更低的药物使用动机） 甲基苯丙胺羟考酮及其混合物我们还假设大多数参与者 将显示甲基苯丙胺作为羟考酮使用的替代品的需求反应，这表明 需要针对这两种药物进行治疗，以避免突破性使用。次要分析将评价 非治疗日和研究药物（甲基苯丙胺、羟考酮或其 联合给药），我们假设在苏沃雷生条件下睡眠障碍较少。这 工作将使用转化实验室方法来评估药理学和行为机制 潜在的阿片类药物、兴奋剂和共同使用动机，为共同使用提供见解和治疗指导 公共卫生危害呈上升趋势。

PROJECT SUMMARY ABSTRACT Deemed a “Twin Epidemic” or “Fourth Wave”, epidemiological evidence emphasizes rapidly increasing public health harms of methamphetamine use among people who use opioids. These data are particularly worrisome given there are no FDA approved pharmacotherapies for methamphetamine use or established treatments for methamphetamine/opioid co-use. A promising target for the regulation of stimulant and opioid motivation is the orexin system. Preclinical and early clinical findings suggest that orexin system antagonism is a clinically viable approach to selectively reduce motivation for both opioids and stimulants. Human laboratory data are needed to investigate this mechanism and extend it to a co-use setting. This project will address this gap by using a behavioral economic demand framework to evaluate motivation for use of opioids, methamphetamine, and their combination in people with opioid use disorder. Demand analyses will directly inform the direction of subsequent treatment studies by identifying motives for opioid-methamphetamine co-use and determining whether these drugs act as substitutes (i.e., as consumption of one decreases, consumption of the other increases), which would necessitate treatments that target both drugs to avoid breakthrough use, or as complements (i.e., as consumption of one decreases, consumption of the other decreases), which would support treatments that target one drug to concomitantly decrease use of the other. This is an optimal approach that will inform more expeditious development of treatment trials and reduce risk of inducing harm with identification of incorrect targets. We will conduct a residential human laboratory study with non-treatment seeking participants with opioid use disorder. Participants will complete sessions with blinded administration of oral methamphetamine, oxycodone, their combination, and placebo. Validated demand measures sensitive to pharmacological manipulation will determine own-price demand (commodity alone) and cross-commodity demand (concurrent commodities). Participants will be randomized to receive oral suvorexant or placebo throughout the residential stay. We hypothesize that orexin antagonism will result in higher demand elasticity (lower drug use motivation) for methamphetamine, oxycodone, and their combination. We also hypothesize that the majority of participants will show a demand response in which methamphetamine serves as a substitute for oxycodone use, suggesting that treatments will be needed to target both drugs to avoid breakthrough use. Secondary analyses will evaluate sleep disturbances on non-session days and days in which study drug (methamphetamine, oxycodone, or their combination) is administered and we hypothesize fewer sleep disturbances in the suvorexant condition. This work will use translational laboratory methods to evaluate pharmacological and behavioral mechanisms underlying opioid, stimulant, and co-use motivation, providing insight into and treatment directives for a co-use trend of increasing public health harm.