The opioid crisis continues to devastate the lives of countless people and communities across the United States. For individuals with moderate to severe opioid use disorder (OUD), medication-assisted treatments (MATs) such as oral methadone and extended-release naltrexone (XR-NTX) are the gold standard in initiating and maintaining long-term recovery. Still, many patients struggle with persistent sleep disturbance and stress reactivity in the early stages of recovery, which drive relapse behaviors. Research on sleep disturbance and the circadian rhythms of stress in the human experience of OUD recovery is scarce. This proposal constitutes a novel mechanistic approach to understanding the role of the orexin system in sleep disturbance and circadian rhythms of stress in OUD patients who are maintained on either oral methadone or XR-NTX and are early in recovery. The scientific premise of this study is based on a rich preclinical literature demonstrating that increased orexin signaling disrupts sleep, increases stress via the hypothalamic-pituitary-adrenal axis (HPA- axis), and drives drug seeking behaviors in rodent models. The proposed study will determine whether the FDA-approved sleep medication, suvorexant (SUVO)—a dual orexin-receptor antagonist—improves sleep continuity and decreases diurnal measures of stress, and whether improvement of sleep/stress processes translates to improved OUD treatment outcomes including reduced opioid relapse. To execute this study, we have assembled an exceptional team of experts in OUD, MATs, sleep, stress, and ambulatory monitoring. This study will recruit persons with OUD who have been abstinent from illicit opioids for 3-6 weeks, report sleep disturbance, and are utilizing a stable dose of oral methadone (n=100) or XR-NTX (n=100). The study will consist of baseline measurements for 7 days (week 0) followed by randomization to either 20mg SUVO or placebo for an 8-week, double-blind randomized-controlled trial. Participants will undergo daily ambulatory monitoring of sleep and daytime activity throughout the study using wrist-worn actigraphy and electronic sleep diaries (weeks 0-8). Moreover, participants will undergo more intensive Data Bursts during study weeks 0 (baseline), 1, 4, and 8, which consist of four-times-daily ecological momentary assessments (EMA) of self- reported stress, craving, and affect, and diurnal salivary cortisol. Primary analyses 1 and 2 examine the effect of SUVO on total sleep time (TST), wake after sleep onset (WASO), and diurnal self-reported stress and separately in patients on oral methadone or XR-NTX, respectively. Primary analysis 3 examines the effect of TST, WASO, and diurnal self-reported stress and salivary cortisol on opioid relapse, across MATs. Exploratory analyses include the effect of SUVO on opioid relapse and treatment retention, and the effect of MAT status on TST, WASO, and diurnal self-reported stress and salivary cortisol within the placebo condition. The proposed study will fill critical gaps in our understanding of the role of the orexin system in sleep disturbance and circadian rhythms of stress that impact OUD recovery.

NARRATIVE One of the consequences of opioid use disorder (OUD) is a disruption of the daily patterns of sleep and stress. Medication-assisted treatments such as methadone and extended-release naltrexone are the front-line treatment for moderate to severe OUD, however there is little understanding of how persistent disruptions of the daily patterns of sleep and stress might impact patients on these medications. This study will use a dual- orexin receptor antagonist to better understand the role of the orexin system in daily patterns of sleep and stress, and whether improving sleep and reducing stress also improves OUD treatment outcomes for persons utilizing methadone or extended-release naltrexone.