Influence of Orexin Antagonism on Opioid and Methamphetamine Demand

项目总结摘要 被认为是“双胞胎流行”或“第四波”，流行病学证据强调公众人数迅速增加 在使用阿片类药物的人中使用甲基苯丙胺对健康的危害。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确定的治疗方法 甲基苯丙胺/阿片类药物联合使用。对兴奋剂和阿片类药物的动机进行调控的一个有希望的目标是 食欲素系统。临床前和早期临床研究表明，食欲素系统拮抗剂在临床上是可行的。 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才能 研究这一机制，并将其扩展到共同使用环境。该项目将通过使用 评估阿片类药物、甲基苯丙胺及其药物使用动机的行为经济需求框架 阿片类药物使用障碍患者的联合用药。需求分析将直接为后续工作提供方向 通过确定阿片类药物和甲基苯丙胺共同使用的动机并确定这些 药物充当替代品(即，随着一种药物的消费减少，另一种药物的消费增加)，它 将需要针对两种药物的治疗，以避免突破性使用，或作为补充(即 一个的消费减少，另一个的消费减少)，这将支持针对 一种药物同时减少另一种药物的使用。这是一种最佳方法，将向您提供更多信息 加快治疗试验的开发，通过识别错误降低诱发伤害的风险 目标。我们将对没有寻求阿片类药物治疗的参与者进行一项住宅人体实验室研究 使用无序。参与者将在盲目口服冰毒的情况下完成治疗， 羟考酮、它们的组合和安慰剂。对药理学敏感的有效需求衡量标准 操纵将决定自有价格需求(仅限于商品)和跨商品需求(并发 大宗商品)。参与者将在住院期间随机接受口服Suvorexant或安慰剂 留下来。我们假设食欲素拮抗会导致较高的需求弹性(较低的用药动机) 甲基苯丙胺、羟考酮以及它们的组合。我们还假设大多数参与者 将显示需求响应，其中甲基苯丙胺作为羟考酮使用的替代品，建议 需要针对这两种药物进行治疗，以避免突破性使用。二次分析将评估 非会议日和研究药物(甲基苯丙胺、羟考酮或其 联合应用)，我们假设在超复氧条件下睡眠干扰较少。这 这项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、兴奋剂和联合使用动机，为联合使用提供洞察和治疗指导 公共卫生危害性加大的趋势。

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.