Meta-Analysis Reveals Safety Concerns With FDA-Approved Dual Orexin Receptor Antagonists for Insomnia


A meta-analysis on studies assessing FDA-approved dual orexin receptor antagonists for insomnia treatment highlighted a greater risk of adverse events, particularly for narcolepsy-like symptoms.

In-hwan Baek, PhD, professor of pharmacy at Kyungsung University

In-hwan Baek, PhD

Credit: Kyungsung University

In a new meta-analysis of randomized controlled trials, treatment with FDA-approved dual orexin receptor antagonists (DORAs) for insomnia showed a higher risk of adverse event (AE)-related narcolepsy-like symptoms compared with the placebo.1 These findings provide valuable insights into the potential safety concerns associated with the use of these treatments in insomnia, highlighting the need to develop alternative DORAs with a lower risk of these adverse events.

Among 11 randomized controlled trials with 7703 patients, investigators observed an association between DORAs and a higher risk of treatment-emergent AEs (TEAEs)(risk ratio [RR], 1.09; 95% CI, 1.03-1.15; P = .002) and treatment-related TEAEs (RR, 1.69; 95% CI, 1.49-1.92, P <.00001) when compared with placebo. However, authors noted no significant difference in incidence of TEAEs leading to discontinuation (RR, 1.00; 95% CI, 0.78-1.27; P = .36) and serious AEs (RR, 0.70; 95% CI, 0.41-1.21; P = .26) between DORAs and placebo.

Top Clinical Takeaways

  • The meta-analysis revealed a higher risk of adverse events, particularly narcolepsy-like symptoms, associated with FDA-approved dual orexin receptor antagonists (DORAs) for insomnia compared with placebo.
  • Daridorexant showed the highest risk ratio for treatment-emergent adverse events (TEAEs), while lemborexant exhibited the highest risk ratio for treatment-related TEAEs among the FDA-approved DORAs.
  • The study underscored the importance of considering longer treatment periods in future trials to obtain more comprehensive insights into the tolerability profiles of insomnia treatments.

Conducted by senior author In-hwan Baek, PhD, professor of pharmacy at Kyungsung University, and colleagues, 5 databases were searched to identify trials that assessed the safety of FDA-approved DORAs including suvorexant (Belsomra; Merck), lemborexant (Dayvigo; Eisai), and daridorexant (Quviviq; Idorsia), with a focus on narcolepsy-like symptoms associated with these treatments. The primary safety outcomes included TEAEs, treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Additional outcomes for safety such as excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were characterized as AEs-related narcolepsy-like symptoms.

READ MORE: Narcolepsy Agent TAK-861 Moves to Phase 3 Studies Following Positive Phase 2b Data

Among the FDA-approved DORAs, daridorexant showed the highest risk of TEAEs compared with placebo (RR, 1.17; 95% CI, 1.03-1.32; P = .01) and lemborexant had the highest risk of treatment-related TEAEs compared with placebo (RR, 1.90; 95% CI, 1.50-2.40; P <.00001). The analysis also revealed that DORAs were associated with a higher risk of EDS (RR, 2.15; 95% CI, 1.02-4.52; P = .04), and sleep paralysis (RR, 3.40; 95% CI, 1.18-9.80; P = .02), than the placebo group. Notably, suvorexant demonstrated the highest risk of EDS occurrence compared to placebo (RR, 3.44; 95% CI, 1.19-9.91; P = .02).

All told, limitations of the study included the variability in the amount of studies associated with each treatment and the few events reported in some trials which might have limited the robustness of specific outcomes. In some of cases in the analysis, data were based on only 1 trial which might hinder making a definitive conclusion. Additionally, authors noted that the duration of the double-blind period varied among the included trials, ranging between 2 days and 6 months. Thus, researchers noted that longer treatment periods in trials should be considered in future research as they may yield different tolerability profiles. Although the limited amount of trials in this analysis might impact the generalizability of the result, authors noted the importance of them as they all were of high quality, being double-blinded, randomized, and placebo- controlled studies.

A previous meta-analysis of randomized controlled trials on suvorexant and lemborexant for insomnia showed that both medications were significantly superior in efficacy compared with placebo.2 Published in Frontiers in Psychiatry, investigators conducted a comprehensive search on 3 databases up until August 14, 2021, without any restrictions on the retrieve of relevant articles. The search presented 8 articles with 5 studies on suvorexant and 3 studies on lemborexant. Authors noted that although all efficacy outcome measures favored and significantly differed with suvorexant compared with placebo, the safety profile did not differ significantly. Additionally, all the efficacy outcomes significantly differed between lemborexant 5mg and lemborexant 10mg compared with placebo. Notably, somnolence rate for lemborexant 5mg and lemborexant 10mg and nightmare for lemborexant 10mg were significantly higher in comparison with the placebo.

1. Na HJ, Jeon N, Staatz CE, Han N, Baek IH. Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis. Sleep. 2024;47(2):zsad293. doi:10.1093/sleep/zsad293
2. Khazaie H, Sadeghi M, Khazaie S, Hirshkowitz M, Sharafkhaneh A. Dual orexin receptor antagonists for treatment of insomnia: A systematic review and meta-analysis on randomized, double-blind, placebo-controlled trials of suvorexant and lemborexant. Front Psychiatry. 2022;13:1070522. Published 2022 Dec 12. doi:10.3389/fpsyt.2022.1070522
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