Orexin Receptor Antagonism for the Treatment of Alcohol Use Disorder and Stress-Related Drinking

Ohio State University, Columbus OH

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Alcohol use disorder (AUD) affects millions and is one of the leading causes of preventable death worldwide. Existing pharmacotherapies for AUD have limited efficacy and variable treatment response. There is an urgent need to expand pharmacologic treatment options for AUD and to better understand how and for whom new medications exert their therapeutic effects. Suvorexant – a dual receptor antagonist of the orexin system, FDA- approved for insomnia- has been identified as promising novel addiction pharmacotherapy that may target stress-related drinking and the negative reinforcement cycle of AUD. The MPIs have recently completed two studies designed to advance the translation of suvorexant (SUV) for AUD including a randomized, double-blind, placebo-controlled clinical trial (RCT) with repeat lab assessments in non-treatment seeking individuals with current AUD (R21AA030097; NCT05656534). The R21 study demonstrated that 10mg of nightly SUV was well- tolerated and associated with acute and sustained reductions in well-defined laboratory assays of exaggerated stress reactivity: i.e., startle eyeblink potentiation to unpredictable threat. Preliminary data also revealed that SUV was associated with changes in subjective stress levels and heavy drinking days. There is now mounting animal and human evidence that suggests that the orexin system is critically involved in stress-related alcohol use. The overarching goal of the current R01 proposal is to further test whether SUV can be used as a novel therapeutic for AUD and stress-related drinking. We will conduct a double-blind, placebo-controlled, between- subjects RCT with 250 treatment-seeking individuals with current AUD. To optimize clinical translation, this study will simultaneously assess treatment: 1) efficacy; 2) mechanisms; and 3) prediction. Participants will be randomized to either 8-weeks of 10mg of SUV (nightly oral capsules) or placebo (PBO) and complete baseline, mid-point, and end-point laboratory assessments of stress reactivity and other competing mechanisms of interest (e.g., alcohol cue reactivity). Throughout the RCT, daily reports of stress, alcohol craving and consumption, sleep, and medication compliance will be captured via smartphones. Wrist-worn sensors will measure objective sleep metrics and real-time alcohol consumption, while blood plasma will yield biomarkers of recent alcohol use and SUV concentration. This innovative, comprehensive design will allow for a well-controlled test of whether nightly SUV decreases the proportion of heavy drinking days (PHDD; primary) and a variety of secondary subjective and objective measures of alcohol consumption compared with PBO (Aim 1). We will also investigate how SUV works by testing whether SUV decreases objective and subjective indices of stress and stress-related alcohol craving and consumption (Aim 2). Lastly, we will identify whom SUV works for best and whether multimodal markers of heightened baseline stress reactivity can be used to create a predictive tool for future SUV treatment assignment (Aim 3). Findings from this study will provide critical knowledge on a novel therapeutic for AUD and help to develop a prospective SUV treatment assignment strategy for optimizing AUD outcomes.