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04. Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety

Published on August 5, 2026 Certification expiration date: August 5, 2029

Bhanu Prakash Kolla, M.D.

Professor of Psychiatry - Mayo Clinic

Key Points

When prescribing DORAs, favor medium-to-high doses for better sleep outcomes. Side effects appear dose-independent, with low-to-medium doses comparable to placebo.
Post-marketing surveillance indicates DORAs carry lower abuse potential. This makes them preferable for patients with comorbid substance use disorders.
Limited evidence suggests that no single DORA is superior to another; treatment choice usually depends on insurance coverage.

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Slides and Transcript

Slide 1 of 10

In this section, we will talk about DORAs or dual orexin receptor antagonists for insomnia, which include suvorexant, lemborexant and daridorexant.

Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety Slide 1 of 10

Slide 2 of 10

The dual orexin receptor antagonists work through the orexin system. Orexins or hypocretins, as they were previously known, are thought to be primarily excitatory neurotransmitters and likely have important roles in various central nervous system functions such as vigilance, attention, learning and memory. Antagonism at both orexin receptors appears to have greater sedative effects. Studies have examined antagonism at either receptor alone but compared to that when there is dual orexin receptor antagonism, patients experience more sedation.

References:

Ten-Blanco, M., Flores, Á., Cristino, L., Pereda-Perez, I., & Berrendero, F. (2023). Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: from animal to clinical studies. Frontiers in Neuroendocrinology, 69, 101066. https://doi.org/10.1016/j.yfrne.2023.101066
Sears, R. M., Fink, A. E., Wigestrand, M. B., Farb, C. R., de Lecea, L., & Ledoux, J. E. (2013). Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. *Proceedings of the National Academy of Sciences of the United States of America*, *110*(50), 20260–20265. https://doi.org/10.1073/pnas.1320325110

Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety Slide 2 of 10

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Slide 3 of 10

In this figure, we can see how the prepro-orexin breaks down into orexin-A and orexin-B, which act on the different orexin receptors and these are spread all over the brain with multiple functions, including promoting wakefulness and antagonizing both of these receptors helps promote sedation.

References:

Ten-Blanco, M., Flores, Á., Cristino, L., Pereda-Perez, I., & Berrendero, F. (2023). Targeting the orexin/hypocretin system for the treatment of neuropsychiatric and neurodegenerative diseases: from animal to clinical studies. Frontiers in Neuroendocrinology, 69, 101066. https://doi.org/10.1016/j.yfrne.2023.101066

Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety Slide 3 of 10

Slide 4 of 10

Choosing among the dual orexin receptor antagonists. There actually is little data to indicate superiority of a single DORA over others. Treatment choice usually depends on insurance coverage. All DORAs remain on patent without any generic options currently available. Because of the expense involved, most insurance companies require prior authorization including trial of other medications before DORAs are covered.

References:

Xue, T., Wu, X., Chen, S., Yang, Y., Yan, Z., Song, Z., Zhang, W., Zhang, J., Chen, Z., & Wang, Z. (2021). The efficacy and safety of dual orexin receptor antagonists in primary insomnia: A systematic review and network meta-analysis. Sleep Medicine Reviews, 61, 101573. https://doi.org/10.1016/j.smrv.2021.101573

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Slide 5 of 10

In this table, you can look at the dosing of the three currently available DORAs, the half-lives. While lemborexant does have a long half-life, this does not translate to substantial daytime somnolence in clinical practice. And these are the side effect profiles with the common side effects for all DORAs including the three that are currently available being daytime sedation, hypnogogic hallucinations, sleep paralysis and occasionally suicidal thoughts.

References:

Kishi, T., Ikuta, T., Citrome, L., Sakuma, K., Hatano, M., Hamanaka, S., Nishii, Y., & Iwata, N. (2025). Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis. Translational Psychiatry, 15(1), 211. https://doi.org/10.1038/s41398-025-03439-8
Żełabowski, K., Petrov, W., Wojtysiak, K., Ratka, Z., Biedka, K., Wesołowski, M., Fus, K., Ślebioda, D., Rusinek, M., Sterkowicz, M., Radzka, I., & Chłopaś-Konowałek, A. (2025). Targeting the orexin system in the pharmacological management of insomnia and other diseases: Suvorexant, lemborexant, daridorexant, and novel experimental agents. International Journal of Molecular Sciences, 26(17), 8700. https://doi.org/10.3390/ijms26178700

Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety Slide 5 of 10

Slide 6 of 10

How to work with patients with DORAs. While these medications are new, there are no convincing data to indicate superiority to existing hypnotics. Usually, a trial of one to two weeks can determine whether these medications are efficacious. Overall, side effect profile for these medications is safer compared to most other hypnotics.

References:

Kishi, T., Ikuta, T., Citrome, L., Sakuma, K., Hatano, M., Hamanaka, S., Nishii, Y., & Iwata, N. (2025). Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis. Translational Psychiatry, 15(1), 211. https://doi.org/10.1038/s41398-025-03439-8
Álamo, C., Sáiz Ruiz, J., & Zaragozá Arnáez, C. (2024). Orexinergic receptor antagonists as a new therapeutic target to overcome limitations of current pharmacological treatment of insomnia disorder. Actas Españolas de Psiquiatría, 52(2), 172–182. https://doi.org/10.62641/aep.v52i2.1659

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Slide 7 of 10

Efficacy of these DORAs. All three improve total sleep time, wake after sleep onset and lead to improvements in the insomnia severity index scores. Medium to high dose of DORAs showed significantly better efficacy while low to medium doses of DORAs showed similar safety compared with placebo. Side effects appear to be independent of the DORA dose.

References:

Clark, J. W., Brian, M. L., Drummond, S. P. A., Hoyer, D., & Jacobson, L. H. (2020). Effects of orexin receptor antagonism on human sleep architecture: A systematic review. Sleep Medicine Reviews, 53, 101332. https://doi.org/10.1016/j.smrv.2020.101332
Kishi, T., Ikuta, T., Citrome, L., Sakuma, K., Hatano, M., Hamanaka, S., Nishii, Y., & Iwata, N. (2025). Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis. Translational Psychiatry, 15(1), 211. https://doi.org/10.1038/s41398-025-03439-8

Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety Slide 7 of 10

Slide 8 of 10

In terms of the impact of DORAs on sleep architecture, there appears to be very little impact overall. There could be a slight increase in the amount of REM sleep and how quickly people go into REM but overall, there does not appear to be much impact on sleep architecture. There could be a slight increase in REM sleep without significant changes to the non-REM sleep amounts that are obtained.

References:

Clark, J. W., Brian, M. L., Drummond, S. P. A., Hoyer, D., & Jacobson, L. H. (2020). Effects of orexin receptor antagonism on human sleep architecture: A systematic review. Sleep Medicine Reviews, 53, 101332. https://doi.org/10.1016/j.smrv.2020.101332

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Slide 9 of 10

In terms of safety considerations, DORAs are classified as Schedule IV by the DEA and this is similar to the Z-drugs and benzodiazepines. However, real-world post marketing surveillance data suggest that DORAs are of lower abuse potential and this makes them more suitable for patients with comorbid substance use disorders.

References:

Kishi, T., Ikuta, T., Citrome, L., Sakuma, K., Hatano, M., Hamanaka, S., Nishii, Y., & Iwata, N. (2025). Comparative efficacy and safety of daridorexant, lemborexant, and suvorexant for insomnia: a systematic review and network meta-analysis. Translational Psychiatry, 15(1), 211. https://doi.org/10.1038/s41398-025-03439-8

Dual Orexin Receptor Antagonists: Efficacy, Dosing, and Safety Slide 9 of 10

Slide 10 of 10

The key points in this section are: Orexins are excitatory neurotransmitters that promote wakefulness, attention and vigilance. Dual orexin antagonism appears to have greater sedative effects. Medium to high dose of DORAs improve total sleep time and subjective insomnia symptoms. Side effect profile of DORAs is relatively benign. Current practice of DORAs in clinical practice is mainly determined by insurance coverage and cost issues. DORAs have lower abuse potential, making them more suitable for patients with comorbid substance use disorders.

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Next Section

05. Z-Drugs and Benzodiazepines for Insomnia

Learning Objectives:

Describe the diagnostic criteria for chronic insomnia disorder and apply the Insomnia Severity Index to screen patients and monitor treatment response.
Compare the efficacy, dosing, and safety profiles of FDA-approved and off-label agents for insomnia, including dual orexin receptor antagonists, Z-drugs, benzodiazepines, melatonin agonists, and sedating antidepressants.
Select appropriate pharmacotherapy for insomnia in special populations, including pregnancy, older adults, patients receiving opioids or with comorbid substance use disorder, and patients requiring long-term treatment.

Original Release Date: August 05, 2026
Expiration Date: August 05, 2029

Faculty: Bhanu Kolla, M.D.
Medical Editor: Tomás Abudarham, M.D.

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None of the faculty, planners, and reviewers for this educational activity has relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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