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#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

David Daien November 28, 2022

Helpful review on relatively new med

Andrew Affleck November 28, 2022

8.3% somnolence could be an issue

Robin Bustin November 29, 2022

These drugs may not be very useful

Maxwell Meyer December 7, 2022

good new data

Shahnaz Sadiq December 13, 2022

Non pharmacological treatment should be emphasized .
One of my pts felt adverse effects and self stopped this medication .
This information has been helpful

Nilanga Abeysinghe January 14, 2023

going thru this, its difficult to decide whether such small benefits outweighs the risks of getting side effects

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

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.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.