Dual Orexin Receptor Agonists Show Lower Real-World Abuse Potential Than Traditional Insomnia Treatments

William V. McCall, MD

A real-world study using data from the FDA Adverse Event Reporting System (FAERS) database revealed that among several different classes of medications for insomnia, dual orexin receptor agonists (DORA) had the lowest reported cases of abuse, misuse, overdose, and other safety risks. Overall, the case reports for abuse related features were far less than approved benzodiazepine (BZ) and z-drugs as well as the non-approved and unscheduled drug, tradozone.^1,2

Presented at the World Sleep Congress (WSC), the rates of abuse, dependence, and withdrawal were highest for BZs approved for any indication (27.7%), followed by BZs approved for insomnia (23.0%), trazodone (22.7%), doxepin (22.3%), z-drugs (15.3%), ramelteon (8.0%), and DORAs (2.6%). The analysis included the 3 approved DORAs–suvorexant, Lemborexant, and daridorexant–which came into the market in 2014, 2019, and 2022, respectively.

"Abuse potential has long shaped the regulation of insomnia medications, with benzodiazepines and z-drugs carrying well-known risks,” William V. McCall, MD, professor Emeritus of the Department of Psychiatry and Health Behavior, Medical College of Georgia, said in a statement.¹ "This study identified a very low rate of reported cases of abuse, misuse, overdose, dependence and withdrawal for the DORA class. This rate was much lower compared with other drugs for insomnia treatment. This observation included schedule IV drugs, but also and surprisingly non-scheduled drugs.”

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The analysis included data from January 2014 to March 2024 to specifically capture the market presence of the DORA class and to provide a decade worth of pharmacovigilance experience. Investigators queried for adverse events (AEs) associated with terms like drug abuse, drug withdrawal, and drug dependence, but excluded cases if the same patient reported overdose or suicidal behaviors to avoid misclassifying overdoses as drug abuse. Overall, this was represented as a modified Standardized MedDRA Query (SMQ) term.

BZs, even restricted to those approved for insomnia, were associated with the highest reported odds, which was consistent with a previously conducted post-marketing study wherein BZs were associated with the greatest risk for abuse. That study, conducted in 2004, tested 12 different drugs, including 5 BZs, 3 anti-depressants, 2 non-BZ hypnotics and 2 histamines. Three of the BZs (diazepam, nitrazepam, temazepam) emerged as having substantially more abuse liability than any of the drugs tested, as revealed by higher scores on abuse liability items.³

"The DORA class had significantly lower odds of reporting for adverse events denoting drug abuse when compared with the scheduled drug zolpidem and the non-scheduled drug trazodone, both used as a reference,” study author David Neubauer, MD, associate professor of psychiatry at the Johns Hopkins University School of Medicine, said in a statement.¹ "This suggests that categorization of DORAs as Schedule IV drugs may overstate their abuse potential."

Suvorexant set the standard as the first approved DORA in 2014, pioneering the drug class for future therapies. Lemborexant, which followed, is also considered a DORA, but with a somewhat different receptor binding profile and stronger affinity for orexin receptor 2 (OX2R) than suvorexant. Daridorexant, the most recently approved DORA, carries a relatively short half-life, and is designed to minimize residual morning sedation while maintaining efficacy overnight. All 3 of these therapies carry the same boxed warning for “complex sleep behaviors” such as sleepwalking, sleep driving, and engaging in other activities while not fully awake.

REFERENCES
1. Idorsia highlights very low real-world abuse potential of DORA class for insomnia treatment at WSC 2025. News release. Idorsia. September 8, 2025. Accessed September 10, 2025. https://www.globenewswire.com/news-release/2025/09/08/3146311/0/en/Idorsia-highlights-very-low-real-world-abuse-potential-of-DORA-class-for-insomnia-treatment-at-WSC-2025.html
2. Saskin P, McCall WV, Neubauer D, et al. Real-world data on the abuse potential of medications for the treatment of insomnia. Presented at: World Sleep Congress 2025; Abstract 167.
3. Jaffe JH, Bloor R, Crome I, et al. A postmarketing study of relative abuse liability of hypnotic sedative drugs. Penn State. doi:10.1111/j.1360-0443.2003.00631.x