ABSTRACT Opioid use disorder has reached epidemic proportions in the US causing substantial mortality and morbidity. While medication treatment for opioid use disorder (MOUD) can improve clinical outcomes, relapse rates remain high. In addition, common medications used for MOUD such as methadone and buprenorphine have been found to cause central sleep apnea (CSA) in as many as 30% of patients receiving treatment. Given the high prevalence of sleep complaints in patients on MOUD and evidence that CSA causes sleep fragmentation and intermittent hypoxemia that have been associated with adverse clinical consequences in other forms of sleep- disordered breathing, there is an urgent need to better understand whether CSA caused by MOUD has an adverse effect on clinical outcomes and the mechanistic pathways implicated. Preliminary data suggest CSA may lead to sympathetic activation and nocturnal arousal which in turn exacerbate emotional distress and drug craving that can then increase risk of drug relapse and reduce treatment retention. In this proposal, we will use home sleep apnea testing to identify a cohort of patients receiving MOUD therapy with CSA and a control population without any sleep-disordered breathing, confirm CSA status with polysomnography, and assess differences in sleep, autonomic nervous system function, nocturnal arousal, anxiety, depression, and drug craving. We will also assess longitudinally the risk of drug lapses and treatment retention rates over six months in the two groups. This work will establish whether CSA is associated with worse outcomes among patients receiving MOUD therapy and the extent to which sympathetic activation and nocturnal arousal play roles in mediating this effect. In addition, we will conduct a short-term randomized trial of acetazolamide versus placebo in 40 patients receiving MOUD therapy with CSA to evaluate the impact of treating CSA on improving sleep quality, restoring autonomic balance, and reducing nocturnal arousal, emotional distress, and drug craving. Results from this proposal will advance understanding of the impact of CSA among patients receiving MOUD therapy and help establish the role of sympathetic activation and nocturnal arousal in mediating the adverse effects of this increasingly common form of sleep-disordered breathing. Our findings will advance understanding of the potential importance of identifying and treating CSA in patients receiving MOUD as a means to improve clinical outcomes. Our work will also help identify potential interventions to limit the adverse impact of CSA in this population.

PROJECT NARRATIVE Central sleep apnea, a condition where people stop breathing in their sleep, can be caused by medications used to treat opioid use disorder. This project will evaluate whether central sleep apnea, by worsening sleep and causing low blood oxygen levels, may lead to nighttime arousal and emotional distress, which in turn may increase risk of drug relapse in patients receiving treatment for opioid use disorder.