Influence of Orexin Antagonism on Opioid and Methamphetamine Demand

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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.