Opioid use disorder (OUD) is a leading cause of death, with disparities in morbidity and mortality widening by race, ethnicity, sex and gender. Medications for OUD are life-saving; increasing their access, utilization and retention is the most effective pathway forward to combat this public health crisis. Comorbid conditions com- mon among people with OUD, such as insomnia, hinder OUD treatment benefit, rendering patients at persis- tent overdose risk. Insomnia is prevalent in the majority of patients receiving buprenorphine for OUD, regard- less of a patient’s stage in recovery, representing an ideal target for adjunctive relapse prevention treatments. Using the innovative NIDA Phenotyping Battery (PhAB), our group has identified a multidimensional profile, or ‘phenotype’, among individuals with OUD and SUD that encompasses both sleep and co-occurring neurofunc- tional domains (i.e., reward, negative emotionality, metacognition). We hypothesize that symptoms related to this constellation of neurofunctional domains in OUD are associated with the brain’s orexin system, which reg- ulates homeostasis, playing roles in sleep, reward and the stress response. This hypothesis is consistent with preclinical studies highlighting how targeting the orexin system reduces opioid self-administration in animal models. Identifying the full constellation of neurofunctional mechanisms underlying how the orexin system im- pacts OUD could illuminate multiple targets to advance treatments and medication development. We propose a mechanistic study to investigate how targeting the orexin system affects symptoms related to the neurofunc- tional domains identified in our prior phenotyping work through a clinical trial of participants with OUD on bu- prenorphine. Deep phenotyping, such as with the NIDA PhAB, has been touted as a method to achieve preci- sion medicine in addictions via tailoring treatments to individuals’ biopsychosocial profiles. This comprehensive approach, especially when coupled with health equity assessments, is warranted for this investigation at the intersection of sleep and addictions given the interplay between socioecological contexts and individual-level factors that shapes these conditions’ trajectories. We will utilize lemborexant, an FDA-approved dual orexin receptor antagonist, building upon our group’s phase 1 study indicating its safety and tolerability among outpa- tients with OUD receiving buprenorphine. We will examine the detailed effects of pharmacologically antagoniz- ing the orexin system with lemborexant on the NIDA PhAB pre-specified four neurofunctional domains we hy- pothesize are underlying OUD treatment benefit over a 2-month follow-up: sleep (Aim 1), reward, negative emotionality, and metacognition (Aim 2). In line with precision medicine, a health equity lens and the Trans-NIH Strategic plan for Women’s Health Research, we will harness our team’s complementary expertise to also ex- plore associations of intervention responses by sex, behavioral, and select biopsychosocial variables using our established deep phenotyping procedures (Aim 3). Results will advance our understanding of the neurofunc- tional mechanisms engaged by orexin targets underlying OUD treatment response.

Project Narrative The proposed research is relevant for public health as it evaluates the mechanisms underlying opioid use dis- order treatment benefit while also testing a novel pharmacological treatment for insomnia, a common comor- bidity among individuals receiving addiction treatment. The goal of this project is to take critical initial steps to uncover the neurofunctional mechanisms engaged by the orexin system in the brain that regulates sleep, re- ward and stress responses. Project findings will advance the development of novel therapeutics in the ongoing overdose crisis for individuals seeking recovery from opioid use disorder.