Introduction for FF #496: Guidelines recommend sleep hygiene and cognitive behavioral therapy as first-line treatment for insomnia. Pharmacologic treatments may be considered when symptoms are refractory and largely revolve around sedating antidepressants or antipsychotics, melatonin receptor agonists, and sedative-hypnotics such as benzodiazepines and zolpidem. These medications have been associated with limited long-term effectiveness and many are associated with loss of deep sleep involving rapid eye movements and/or other significant adverse effects such as elevated fall risk and abuse potential (1,2). Dual orexin receptor antagonists (DORAs) are a new class of medications for insomnia, and they will be reviewed in this Fast Fact (2).

Mechanism of action: The orexin signaling system plays a crucial role in maintaining arousal and wakefulness. DORAs act as antagonists at both orexin receptors (OX1R and OX2R) within the orexin cascade in the sleep-wake cycle. This is thought to promote sleep induction and maintenance in a more localized and targeted effect than other common medications for insomnia (3,4). DORAs primarily enhance the duration of rapid eye movement (REM) sleep and leave non-REM sleep unchanged or reduced (5).

Pharmacology: DORAs are scheduled IV substances. Post-marketing surveillance data suggests low abuse and overdose potential and no evidence of physical dependence (6). Concurrent administration with potent CYP3A4 inducers and inhibitors is discouraged (4,5). No dose adjustments are required for patients with mild hepatic impairment or mild to severe renal impairment, but increased somnolence is a risk in patients with severe renal impairment (5,7). Research on the optimal duration of treatment is limited. Much of the current evidence for the efficacy and safety of DORAs is based on industry-sponsored (e.g., references 2,3,6) studies conducted over a maximum period of 12 months compared to placebo (2,4). Only a few studies compared DORAs with both placebo and zolpidem as an active control drug (4,8,9). 

Utility in symptom management: In a systematic review of 20 medications for primary insomnia in adults, DORAs had the highest values in terms of sleep latency, awake time after sleep onset (total minutes awake after initially falling asleep), total sleep time, and sleep efficiency (10). DORAs also had the second-best safety profile behind placebo (10). However, trials directly comparing DORAs with traditional sedatives and hypnotics are still lacking (10). Patients with Alzheimer’s dementia (AD) have been found to have elevated levels of orexin in the cerebrospinal fluid, which has been linked to cognitive decline, reduced sleep efficiency, and reduced REM sleep (11). Suvorexant has been approved for sleep disturbances in mild to moderate AD (12) since it was associated with a statistically significant improvement in total sleep time and awake time after sleep onset compared to placebo (13). It was well-tolerated and did not impair next‐day cognitive or psychomotor performance nor worsen the underlying cognitive impairment (12,13); this is somewhat unique in that most hypnotics can be cognitively harmful in patients with AD. Early research suggests that suvorexant and lemborexant may treat and/or prevent delirium by reducing sleep disruptions which could alleviate delirium (14-16).

Side effects: Dose-dependent somnolence, nasopharyngitis, and headache are most common (17). Abnormal dreams, fatigue, and dry mouth have also been reported (4,10,17). Use of DORAs is contraindicated in patients with narcolepsy (3). They are not recommended in patients with severe hepatic dysfunction (5,7).  Additional warnings include worsening of depression and worsening of complex sleep behaviors, such as sleepwalking and sleep paralysis (18-20).

Pediatrics: Suvorexant specifically has been shown to be safe and effective in adolescents with insomnia in a limited study involving 30 participants aged 10 to 20 years (21). Additionally, it has shown good tolerability (other than occasional irritability) and effectiveness in managing circadian rhythm disorders in children aged 2 to 22, particularly among those with neurodevelopmental disorders (21,22).

Cost: DORAs are generally more expensive than other insomnia treatments (e.g., usual cost of $13-20 per tablet) and are not always covered by insurance (23). Therefore, cost can limit their availability.

Summary: DORAs demonstrate promise to treat insomnia with fewer side effects (10).  However, further head-to-head trials by independent investigators are necessary to determine if DORAs are cost-effective.

References: 

1. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13:307-349.
2. Waters K. Review of the Efficacy and Safety of Lemborexant, a Dual Receptor Orexin Antagonist (DORA), in the Treatment of Adults With Insomnia Disorder. Ann Pharmacother. 2022;56(2):213-221. doi:10.1177/10600280211008492.
3. Kishi T, Nishida M, Koebis M, et al. Evidence-based insomnia treatment strategy using novel orexin antagonists: A review. Neuropsychopharmacol Rep. 2021;41(4):450-458. doi:10.1002/npr2.12205.
4. Rocha RB, Bomtempo FF, Nager GB, et al. Dual orexin receptor antagonists for the treatment of insomnia: systematic review and network meta-analysis. Arq Neuropsiquiatr. 2023;81(5):475-483. doi:10.1055/s-0043-1768667.
5. Alger SE, Stekl E, Allotey-Addo S, et al. The role of pharmacological interventions for sleep deprivation and restriction. In: Kushida CA, ed. Encyclopedia of Sleep and Circadian Rhythms. 2nd ed. Academic Press; 2023:506-517. ISBN 9780323910941. doi:10.1016/B978-0-12-822963-7.00009-8.
6. Moline M, Asakura S, Beuckman C, et al. The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act. Psychopharmacology (Berl). 2023;240(4):699-711. doi:10.1007/s00213-023-06320-y.
7. Chakraborty DS, Choudhury S, Lahiry S. Daridorexant, a recently approved dual orexin receptor antagonist (DORA) in the treatment of insomnia. Sleep Sci. 2023;16(2):256-264. doi:10.1055/s-0043-1770805.
8. Rosenberg R, Murphy P, Zammit G, et al. Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open. 2019;2(12). doi:10.1001/jamanetworkopen.2019.18254.
9. Dauvilliers Y, Zammit G, Fietze I, et al. A novel dual orexin receptor antagonist (ACT-541468) to treat insomnia: a randomized, double-blind, placebo-controlled, active-reference phase 2 study. Sleep. 2019;42–A153. doi:10.1093/sleep/zsz067.374.
10. Yue JL, Chang XW, Zheng JW, et al. Efficacy and tolerability of pharmacological treatments for insomnia in adults: a systematic review and network meta-analysis. Sleep Med Rev. 2023;68:101746.
11. Gao F, Liu T, Tuo M, et al. The role of orexin in Alzheimer disease: from sleep-wake disturbance to therapeutic target. Neurosci Lett. 2021;765:136247. doi:10.1016/j.neulet.2021.136247.
12. Merck receives approval for BELSOMRA® (suvorexant) C-IV label update to include findings from study of insomnia in patients with mild-to-moderate Alzheimer’s disease. Available from: https://www.merck.com/news/merck-receives-approval-for-belsomra-suvorexant-c-iv-label-update-to-include-findings-from-study-of-insomnia-in-patients-with-mild-to-moderate-alzheimers-disease. Accessed April 8, 2024.
13. Herring WJ, Ceesay P, Snyder E, et al. Polysomnographic assessment of suvorexant in patients with probable Alzheimer’s disease dementia and insomnia: a randomized trial. Alzheimers Dement. 2020;16(3):541–551.
14. Hatta K, Kishi Y, Wada K, et al; DELIRIA-J Group. Preventive effects of suvorexant on delirium: a randomized placebo-controlled trial. J Clin Psychiatry. 2017;78(8). doi:10.4088/JCP.16m11226.
15. Matsuoka A, Tobita S, Sogawa R, et al. Evaluation of suvorexant and lemborexant for the prevention of delirium in adult critically ill patients at an advanced critical care center: a single-center, retrospective, observational study. J Clin Psychiatry. 2023;84(1):22m14471.
16. Hatta K, Kishi Y, Wada K, et al. Suvorexant for Reduction of Delirium in Older Adults After Hospitalization: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(8):e2427691. doi:10.1001/jamanetworkopen.2024.27691
17. Xue T, Wu X, Chen S, et al. The efficacy and safety of dual orexin receptor antagonists in primary insomnia: a systematic review and network meta-analysis. Sleep Med Rev. 2022;61.
18. Merck. Belsomra [package insert]. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204569s008lbl.pdf#page=23. Accessed April 27, 2024.
19. Eisai Co., Ltd. DaVigo [package insert]. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212028s000lbl.pdf. Accessed April 27, 2024.
20. Idorsia Pharmaceuticals. Quviviq [package insert]. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf. Accessed April 27, 2024.
21. Kawabe K, Horiuchi F, Ochi M, et al. Suvorexant for the treatment of insomnia in adolescents. J Child Adolesc Psychopharmacol. 2017;27(9):792-795. doi:10.1089/cap.2017.0078.
22. Witt RM, Byars KC, Decker K, et al. Current considerations in the diagnosis and treatment of circadian rhythm sleep-wake disorders in children. Semin Pediatr Neurol. 2023;48:101091. doi:10.1016/j.spen.2023.101091.
23. Lexicomp Online. Lexi.com. 2024. Available at: https://online.lexi.com/lco/action/home. Accessed April 3, 2024.

Author Affiliations: Kaiser Permanente Los Angeles Medical Center
Conflicts of Interest: none
Version History:  First electronically published in December 2024; originally edited by Sean Marks MD