A mechanistic study of the role of the orexin system and insomnia within a buprenorphine opioid use disorder treatment sample - Opioid use disorder (OUD) is a leading cause of death, demanding improvements in OUD treatments. Medica- tions for OUD are life-saving; increasing their consistent utilization is the most effective pathway forward to combat this public health crisis. However, after treatment engagement, multiple factors can hinder outcomes, such as sleep problems and neurofunctional impairment that can leave patients at persistent overdose risk. NIDA has promoted targeting the mechanisms underlying each individual patient's addiction as an avenue to advance precision medicine and improve treatment quality. Targeting the orexin system is one mechanism that could ultimately lead to improved treatments. The orexin system is hypothesized to be a predominant mecha- nism linking poor OUD outcomes with disturbances in sleep/wake cycles and with other orexin-activity effects on reward-related neurofunctional domains known to underlie OUD. Consistent with this advancing science, our group has identified how insomnia exists as part of a constellation of symptoms related to neurofunctional dysfunctions among buprenorphine-treatment patients. Thus, we propose that targeting insomnia by way of orexin perturbation shows high potential to advance OUD medication development, such as via identifying tar- gets for adjunctive relapse prevention therapeutics to medications for OUD. However, how the orexin system and insomnia engage neurobiological mechanisms in humans with OUD has not been investigated. Using in- novative dynamic causal modeling, our group has identified a neurocircuit connectivity (Anterior cingulate cor- tex (ACC) to Hippocampus) that is associated with drug cue driven attentional bias in individuals with OUD, making this a promising marker in the evaluation of potential relapse prevention therapeutics. We propose herein a mechanistic study where we will recruit OUD treatment patients receiving buprenorphine with and without clinically significant insomnia (N=100). We will experimentally manipulate the orexin system using lem- borexant, a dual orexin receptor antagonist, which our group has found to be safe and tolerable with buprenor- phine in our Phase 1 clinical trial. We will rigorously measure sleep (actigraphy) and fMRI-based brain connec- tivity before and after randomization to 14 days of placebo or lemborexant added to their ongoing buprenor- phine treatment. Building from our group's extensive preliminary data, we propose that the effective (direc- tional) connectivity of the ACC to Hippocampus pathway, with its overlapping system involvements related to orexin, drug use, and sleep, represents an optimal primary outcome for this mechanistic trial in response to RFA-DA-25-044. In Aim 1, we will identify differences in this baseline drug cue-elicited brain connectivity be- tween insomnia groups. In Aim 2, we will determine whether pharmacologic orexin antagonism attenuates this connectivity, regardless of insomnia status. These mechanistic findings will characterize the interplay between insomnia, orexin and OUD in a buprenorphine treatment sample to advance the development of personalized relapse prevention therapeutics which are urgently needed in the ongoing overdose crisis.
