DORA The Explorer: Exploring Dual Orexin Receptor Antagonists for Insomnia in Hospice and Palliative Medicine

Key Message: Dual orexin antagonists offer a new avenue for the treatment of insomnia. Integration of these agents in the palliative care and hospice space has been largely limited to lack of familiarity and cost. Additional discussion of these agents is warranted as clinicians strive to integrate safe and effective medication regimens.

Abstract: Dual Orexin Receptor Antagonists (DORAs) are rapidly being adopted for the treatment of insomnia in medical practice (1). This class of medications targets orexin neurons in the brain to reduce arousal and induce sleep. Because these medications avoid traditional pathways used by traditional hypnotics (i.e. GABA-ergic and antihistaminergic pathways) they carry a unique, largely favorable safety profile (2-3). Further, a growing body of evidence indicates these drugs may have protective effects against delirium and dementia, likely due to enhancing REM sleep (4).

However, despite these benefits, DORAs remain underutilized in Hospice and Palliative Medicine (HPM) likely due to lack of familiarity and cost. This presentation will aim to address this gap by providing guidance from members an interdisciplinary team (physician and pharmacist) with extensive experience in use of DORAs in both inpatient and outpatient palliative care settings who have led implementation in their medical centers.

This presentation aims to provide a review of the larger DORA class as well as a discussion of the pharmacokinetic and dynamic properties of the three agents currently approved by the FDA (suvorexant, lemborexant, and daridorexant). Further discussion of practical issues (accessibility, use in medically complex patients, how to discontinue, etc.) will also be provided.

Additionally, the presentation will educate attendees on upcoming developments for the medication class, most notably ongoing clinical trials of orexin-2-selective receptor antagonists (2-SORAs)(5). Finally, in effort to expand use and access, this presentation will be accompanied by a virtual guide on the use of DORAs (in both English and Spanish) created by the presentation authors.

References: 1. Sateia MJ, et al. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guidelines. J Clin Sleep Med. 2017; 13 (2): 307-50
2. Michelson D, et al. Safety and Efficacy of Suvorexant during 1-year treatment of Insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomized, double-blind, placebo-controlled trial. Lancet Neuro. 2014; 13 (5); 461-71
3. McElroy H, et al. Comparative Efficacy of Lemborexant and other insomnia treatments. J Manag Car Spec Pharm. 2021; 27 (9): 1296-308
4. De Oliveira HM, et al. Efficacy of Ramelteon, Suvorexant, and Lemborexant for Delirium Prevention in Hospitalized Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2025
5. Revell, V.L., et al. Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial. Neuropsychopharmacol. 47, 719–727 (2022).