Dual orexin receptor antagonists for the treatment of insomnia disorder: Real-world safety evidence analysis and comparison with established therapeutic options

Insomnia disorder (ID) is a widespread and debilitating condition characterised by persistent difficulty initiating or maintaining sleep, often resulting in impaired daytime functioning and marked distress. Dual orexin receptor antagonists (DORAs) have recently emerged as a promising therapeutic option. By modulating the orexin system (a key regulator of wakefulness) they reduce the drive to remain awake, facilitating both the onset and maintenance of sleep. However, much of the current safety evidence for DORAs is derived from pre-marketing clinical trials, typically constrained by highly controlled environments and relatively small participant cohorts. These limitations highlight the need for robust real-world safety evaluations. This dissertation presents two studies that leverage two of the largest international pharmacovigilance databases to examine the post-marketing safety profiles of DORAs. The first study focuses on daridorexant, the most recently introduced DORA, drawing on data from the U.S. Food and Drug Administration Adverse Event Reporting System and comparing its safety characteristics against previously marketed DORAs. The second study explores the overall safety of the DORA class and contrasts it with that of Z-drugs, utilising data from the World Health Organization’s database. Together, these investigations aim to provide a more comprehensive and clinically relevant understanding of the real-world safety landscape for DORAs.