Tools for Practice

#328 RXs for Orexins? The efficacy and safety of orexin antagonists for insomnia

Are orexin antagonists safe and effective for primary insomnia?

Orexin antagonists help people fall asleep ~9 minutes faster and increase total sleep time by ~19 minutes versus placebo over 1-3 months. About 8% of people taking orexin antagonists will experience next-day somnolence compared to 2% placebo.

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  • 7 systematic reviews of randomized, controlled trials (RCTs).1-7 Focusing on the most recent and comprehensive. Results statistically significant unless indicated.
  • Systematic review1 (13 RCTs, 7875 patients, mean age ~55 years) over ~1-3 months:
    • Sleep diary outcomes; compared to placebo, orexin antagonists changed:
      • Sleep onset: ~9 minutes faster [example: Baseline 65 minutes, 47 minutes with orexins versus 56 minutes (placebo)].
      • Total sleep time: Increased ~19 minutes.
      • Time awake after falling asleep: ~9 minutes less.
      • Sleep quality: Improved ~5% (example improved 0.2 points on a 4-point scale, not likely clinically meaningful).8
      • No clinical difference: Awakenings or feeling refreshed on awakening.
      • Other reviews2-6 found similar.
        • Response on insomnia score:6 55% versus 42% (placebo), NNT=8.
    • One RCT with 12 months follow-up found similar.9
    • Adverse events:
      • Stopping due to adverse effects: No difference.2,3,7
      • Most common adverse events:1
        • Somnolence 8.3% versus 2.2% (placebo), number needed to harm (NNH)=16.
        • Fatigue, dry mouth, abnormal dreams each ~2-3% versus 1% placebo.
      • Effects on falls unclear (4 small observational studies in hospitals): Range from associated with increased fall risk to decreased.10-13
        • One observational study suggests fracture risk similar between suvorexant and z-drugs.14
  • RCT comparing 5 and 10mg Lemborexant to Zolpidem ER:15
    • Sleep onset: Lemborexant ~6 minutes better.
    • Time awake after falling asleep: Range from no difference to zolpidem ~15 minutes better.
    • Proportion of time asleep: No difference
    • Dropout due to adverse events: 0.9% versus 2.7% zolpidem.
  • Limitations
    • RCTs industry sponsored, use of run-ins, incomplete outcome reporting.
  • Similar efficacy16 in those >65.
  • Limited evidence suggests minimal withdrawal symptoms.2,13,15,17
    • Abuse potential not formally assessed in insomnia RCTs.
  • Orexin inhibitors have been associated with sleep paralysis/complex sleep behaviors (example “sleep-driving”).18
  • Non-pharmacologic sleep restriction therapy is effective.19
  • Lemborexant (available in Canada) price: $48/30 tablets.20

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  • Adrienne J Lindblad BSP ACPR PharmD
  • Erin Lee PharmD candidate
  • Jamie Falk BSP PharmD
  • Jennifer Young MD CCFP-EM

1. Xue T, Wu X, Chen S, et al. Sleep Med Rev. 2022 Feb; 61:101573.. Epub 2021 Nov 26.

2. McElroy H, O'Leary B, Adena M, et al. J Manag Care Spec Pharm. 2021 Sep; 27(9):1296-1308. Epub 2021 Jun 12.

3. Kuriyama A, Tabata H. Sleep Med Rev. 2017 Oct; 35:1-7. Epub 2016 Oct 28.

4. Chiu HY, Lee HC, Liu JW, et al. Sleep. 2021 May 14; 44(5):zsaa260.

5. Wang L, Pan Y, Ye C, et al. Neurosci Biobehav Rev. 2021 Dec; 131:489-496. Epub 2021 Sep 21.

6. Wilt TJ, MacDonald R, Brasure M, et al. Ann Intern Med. 2016 Jul 19; 165(2):103-12. Epub 2016 May 3.

7. Kishi T, Nomura I, Matsuda Y, et al. J Psychiatr Res. 2020 Sep; 128:68-74. Epub 2020 May 28.

8. Herring WJ, Connor KM, Ivgy-May N, et al. Biol Psychiatry. 2016 Jan 15; 79(2):136-48. Epub 2014 Oct 23.

9. Michelson D, Snyder E, Paradis E, et al. Lancet Neurol. 2014 May; 13(5):461-71. Epub 2014 Mar 27.

10. Ishibashi Y, Nishitani R, Shimura A. et al. PLoS One. 2020 Sep 11; 15(9):e0238723. Erratum in: PLoS One. 2021 Oct 27; 16(10):e0259430.

11. Ishigo T, Takada R, Kondo F, et al. Yakugaku Zasshi. 2020; 140(8):1041-1049.

12. Sogawa R, Emoto A, Monji A, et al. J Clin Pharm Ther. 2022 Jun; 47(6):809-813. Epub 2022 Mar 1.

13. Torii H, Ando M, Tomita H, et al. Biol Pharm Bull. 2020; 43(6):925-931.

14. Adomi M, Maeda M, Murata, et al. J Am Geriatr Soc. 2022 Oct 2; 1-12. Online ahead of print.

15. Rosenberg R, Murphy P, Zammit G, et al. JAMA Netw Open. 2019 Dec 2; 2(12):e1918254. Erratum in: JAMA Netw Open. 2020 Apr 1; 3(4):e206497. Erratum in: JAMA Netw Open. 2021 Aug 2;4(8):e2127643.

16. De Crescenzo F, D'Alò GL, Ostinelli EG, et al. Lancet. 2022 Jul 16;400(10347):170-184.

17. Herring WJ, Connor KM, Snyder E, et al. Am J Geriatr Psychiatry. 2017 Jul; 25(7):791-802. Epub 2017 Mar 8.

18. Dayvigo [product monograph]. Mississauga (ON): Eisai Ltd; November 3, 2020. Available from: /media/Files/CanadaEisai/DAYVIGOProductMonograph-English.pdf?hash=26a10d38-baa9-40b7-8bee-c50313bc3a3e Accessed September 28, 2022.

19. Allan GM, Lindblad AJ, Varughese J. Can Fam Physician. 2017; 63(8):613

20. McKesson Pharmaclik. Accessed Aug 7, 2022.

Authors do not have any conflicts of interest to declare.