Phase 1b/2a safety study of lemborexant as an adjunctive treatment for insomnia to buprenorphine-naloxone for opioid use disorder: A randomized controlled trial.

Background: Evidence supports the common incidence of sleep disturbance in opioid use disorder (OUD) as a potential marker of disrupted orexin system functioning. This study evaluated the initial safety and tolerability of a challenge dose of lemborexant, a dual orexin antagonist, as an adjunct to buprenorphine/naloxone. Methods: Patients (18-65 years old) with OUD receiving sublingual buprenorphine/naloxone, with a Pittsburgh Sleep Quality Index total score of 6 or higher, were recruited from outpatient clinics. After randomization, while being monitored on an inpatient research unit over two 10-hour daytime periods, participants received a placebo or lemborexant (5 mg on day one and 10 mg on day two) along with buprenorphine/naloxone. Primary outcomes included safety and tolerability: adverse events, physiologic measures, sedation level assessments. Generalized linear mixed model analysis assessed the effect of study drug and time on outcomes. Results: N=18 (14=male, 4=female) were randomized to lemborexant (n=12) or placebo (n=6). No unanticipated problems occurred; five adverse events occurred in the lemborexant group and two in the placebo group with no serious adverse events. None of the physiologic measures showed a significant interaction of time and placebo vs. lemborexant (5 or 10 mg): Pulse oximetry (F=0.6; p=0.84), End-tidal CO2 (F=0.5; p=0.91), Heart rate (F=0.6; p=0.82), Systolic blood pressure (F=0.7; p=0.73), Diastolic blood pressure (F=2.0; p=0.06). At 9 hours after study drug administration, all participants returned to baseline sedation levels and were discharged. Conclusions: Findings support the initial safety and tolerability of lemborexant as an adjunctive treatment for insomnia in humans receiving buprenorphine for OUD. Future longitudinal work is warranted with larger samples.