Effect of discontinuation of lemborexant following long‐term treatment of insomnia disorder: Secondary analysis of a randomized clinical trial

Discontinuing long‐term pharmacotherapy for insomnia can result in rebound insomnia or withdrawal symptoms and suboptimal treatment. Post hoc analyses evaluated rebound insomnia and withdrawal symptoms among the subset of subjects from a phase III, 12‐month, global, multicenter, randomized, double‐blind, parallel‐group study who completed 12 or 6 months of active treatment and follow‐up period. Study E2006‐G000‐303 (Study 303) included adults (N = 655) with subjective sleep‐onset latency ≥30 min and/or subjective wake‐after‐sleep onset ≥60 min at least three times weekly during the 4 weeks before enrollment. Subjects were randomized 1:1:1 to lemborexant 5 mg (LEM5) or 10 mg (LEM10) or placebo for 6 months. Thereafter, for an additional 6 months, LEM5‐ and LEM10‐treated subjects continued lemborexant and the placebo group was rerandomized 1:1 to LEM5 or LEM10. Month 12 was followed by abrupt discontinuation and a 2‐week end‐of‐study follow‐up. Using daily electronic sleep diaries, patients reported (subjective) sleep end points (sleep‐onset latency, wake‐after‐sleep onset, sleep efficiency, and total sleep time). Withdrawal symptoms were assessed using the Tyrer Benzodiazepine Withdrawal Symptoms Questionnaire (T‐BWSQ). Sleep outcome improvements with lemborexant at month 12 were generally maintained throughout the 2‐week off‐treatment period wherein <20% of subjects experienced significant worsening of insomnia symptoms versus screening. There was no evidence of withdrawal symptoms by T‐BWSQ following lemborexant discontinuation. This analysis demonstrates rebound insomnia is unlikely to occur with lemborexant, and its effectiveness is maintained after abrupt discontinuation without placebo replacement following 6–12 months of treatment.