Emerging and upcoming therapies in insomnia

Insomnia, commonly treated with benzodiazepine (BZD) receptor agonists, presents challenges due to associated serious side effects such as abuse and dependence. To address these concerns, many researches have been conducted to develop and advance both pharmacological and non-pharmacological interventions. Dual orexin receptor antagonists (DORAs), which include suvorexant, daridorexant and lemborexant, have recently been approved by United States Food and Drug Administration (US FDA) as a novel pharmacotherapeutic alternative. Unlike BZD receptor agonists that act as positive allosteric modulators of the gamma-aminobutyric acid type A subunit alpha 1 receptor, DORAs function by binding to both orexin receptor types 1 and 2, and inhibiting the action of the wake-promoting orexin neuropeptide. These drugs induce normal sleep without sleep stage change, do not impair attention and memory performance, and facilitate easier awakening. However, more real-world safety information is needed. Selective orexin-2 receptor antagonists (2-SORAs) is under clinical developments. This review provides an overview of the mechanism of action in relation to insomnia, pharmacokinetics, efficacy and safety information of DORAs and SORA. According to insomnia management guidelines, the first-line treatment for chronic insomnia is cognitive behavioral therapy for insomnia (CBT-I). Although it has proven effective in improving sleep-related quality of life, it has several restrictions limitations due to a face-to-face format. Recently, prescription digital therapy such as Somryst® was approved by US FDA. Somryst®, a smartphone app-based CBT-I, demonstrated meaningful responses in patients. However, digital limitations may impact scalability. Overall, these developments offer promising alternatives for insomnia treatment, emphasizing safety, efficacy, and accessibility.