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Purpose <p>This review synthesizes evidence on FDA-approved (Suvorexant, Lemborexant, daridorexant) and emerging Orexin receptor antagonists (ORAs), emphasizing mechanistic insights, head-to-head comparisons, and gaps in long-term safety data. While dual ORAs improve sleep maintenance (WASO reduction: 30–50%), selective agents like seltorexant show promise for comorbid depression but lack phase 3 validation. Future trials must address chronic use (&gt; 12&#xa0;months) and high-risk populations (OSA, elderly).</p> Methods <p>A structured narrative review was conducted using PubMed, Cochrane Library, and clinicaltrials.gov databases. The review included 38 studies meeting predefined criteria: randomized controlled trials on ORA efficacy and safety in both healthy individuals and those with insomnia or comorbid insomnia. Studies excluded were non-original data studies, case reports, retrospective analyses, and other review articles. The analysis focused on ORAs effects on total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) through a qualitative synthesis.</p> Results <p>This review highlights three FDA-approved ORAs: suvorexant, daridorexant, and lemborexant, which demonstrate significant improvements in WASO, SE, and TST in patients with primary and comorbid insomnia. Suvorexant is especially validated in cases with comorbidities, while daridorexant and lemborexant show efficacy in primary insomnia. Emerging agents like almorexant and filorexant require further validation, and selective agents like seltorexant have not yet reached phase 3 trials.</p> Conclusion <p>FDA-approved ORAs—suvorexant, daridorexant, and lemborexant—significantly improve sleep metrics in insomnia and comorbid insomnia, with a positive safety profile. However, additional high-quality clinical trials are essential to explore the potential of non-FDA-approved ORAs in treating insomnia and related sleep disorders.</p>

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Orexin Receptor Antagonists and Insomnia

  • 期刊论文

  • 发表日期：

    2025年10月1日

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  • Jayaram Saibaba,
  • Ramkumar Sugumaran

摘要

Purpose

This review synthesizes evidence on FDA-approved (Suvorexant, Lemborexant, daridorexant) and emerging Orexin receptor antagonists (ORAs), emphasizing mechanistic insights, head-to-head comparisons, and gaps in long-term safety data. While dual ORAs improve sleep maintenance (WASO reduction: 30–50%), selective agents like seltorexant show promise for comorbid depression but lack phase 3 validation. Future trials must address chronic use (> 12 months) and high-risk populations (OSA, elderly).

Methods

A structured narrative review was conducted using PubMed, Cochrane Library, and clinicaltrials.gov databases. The review included 38 studies meeting predefined criteria: randomized controlled trials on ORA efficacy and safety in both healthy individuals and those with insomnia or comorbid insomnia. Studies excluded were non-original data studies, case reports, retrospective analyses, and other review articles. The analysis focused on ORAs effects on total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) through a qualitative synthesis.

Results

This review highlights three FDA-approved ORAs: suvorexant, daridorexant, and lemborexant, which demonstrate significant improvements in WASO, SE, and TST in patients with primary and comorbid insomnia. Suvorexant is especially validated in cases with comorbidities, while daridorexant and lemborexant show efficacy in primary insomnia. Emerging agents like almorexant and filorexant require further validation, and selective agents like seltorexant have not yet reached phase 3 trials.

Conclusion

FDA-approved ORAs—suvorexant, daridorexant, and lemborexant—significantly improve sleep metrics in insomnia and comorbid insomnia, with a positive safety profile. However, additional high-quality clinical trials are essential to explore the potential of non-FDA-approved ORAs in treating insomnia and related sleep disorders.