Comprehensive understanding of the treatment of insomnia with lemborexant

Benzodiazepine derivatives and Z-drugs have traditionally been the cornerstone of pharmacological insomnia treatment. However, concerns regarding increased risks of falls, next-morning residual effects, dose tolerance, dependence, and withdrawal symptoms have prompted growing interest in alternative therapies.

This review critically assesses the effectiveness and challenges of lemborexant, a dual orexin receptor antagonist (DORA), in treating insomnia. It draws on current pharmacokinetic and clinical pharmacodynamic evidence, including data from phase 3 trials and meta-analyses.

Lemborexant, with relative selectivity for the orexin receptor type 2, offers robust efficacy for both sleep initiation and maintenance. Its pharmacokinetic profile yields a quick onset and steep decline in plasma levels, helping minimize next-morning residual effects despite a long terminal half-life. Network meta-analyses demonstrate improvements in subjective and objective sleep measures, with lemborexant often ranking highest among hypnotics. Somnolence is the most common adverse event, while withdrawal symptoms, dependence, falls, cognitive impairment, and driving deficits are uncommon or comparable to placebo. Nightmares and sleep paralysis occur infrequently. Evidence supports its safe use in older adults and patients with obstructive sleep apnea or chronic obstructive pulmonary disease. Further research should address its role in psychiatric and medical comorbidities, and substance use disorders.