Text version
Hello. I am Dr. Carlos H. Schenck, MD, professor of psychiatry at the University of Minnesota Medical School in Minneapolis. I practice sleep medicine and also outpatient psychiatry.
The focus of this Quick Take is on the “Use of Daridorexant Among Patients with Chronic Insomnia: A Retrospective Observational Analysis” published recently in the Journal of Clinical Sleep Medicine. Daridorexant is the latest, and the third, of the so-called DORAs—dual orexin receptor antagonists—for treating insomnia. You may wonder why this is important. It represents a new class of medication that turns off wakefulness, contrasting with other hypnotic medications like benzodiazepines and benzodiazepine receptor agonists, which enhance inhibitory neurotransmitters and sleep. DORAs turn off wakefulness, offering a novel mechanism of action with great promise in treating insomnia.
For me, as a sleep physician and researcher, the fascinating aspect is that orexin, also called hypocretin, is a neurotransmitter produced only in a specific area of the hypothalamus. Discovered in 1998, its deficiency causes narcolepsy, characterized by sleep attacks, excessive daytime sleepiness, cataplexy, and hypnagogic or hypnopompic hallucinations. Interestingly, the identification of hypocretin and orexin deficiency as the cause of narcolepsy led to the development of medication for insomnia. The treatment of insomnia with these medications produces an artificial narcolepsy at bedtime, which physicians should be aware of due to potential side effects, like hypnagogic hallucinations and sleep paralysis.
The daridorexant study was meticulous and demonstrated that 78% of the 86-patient cohort showed clinically meaningful improvement, as defined by at least a 6-point drop in a specific insomnia severity index score. This indicates efficacy in switching patients from various other medications to daridorexant. The data suggest that for patients with an incomplete response to current therapy, switching to daridorexant is a safe and effective alternative.
The first 2 DORAs were suvorexant, introduced in 2014, and lemborexant, followed by daridorexant, which has the shortest terminal half-life and a favorable side-effect profile, potentially minimizing morning oversedation and improving sleep parameters over existing medication.
The study also noted substantial benefits in treating insomnia with daridorexant after switching from other ineffective medications, including GABA-A medications, trazodone, atypical antipsychotics, and tricyclic antidepressants. After 30 nights of daridorexant treatment, 79% of patients reported improvement in daytime symptoms, with one-third nearly or entirely resolving their symptoms and experiencing increased daytime alertness.
The authors highlight the significance of “turning off wake” via the orexin pathway as opposed to “turning on sleep” via the GABA pathway, underscoring the move towards a more personalized approach in treating insomnia. Long-term data for 59 out of the 86 patients showed a consistent and durable response, with only 2 patients discontinuing daridorexant between 1 and 3 months. The study also revealed remarkable responses in patients suffering from fragmented sleep and chronic insomnia for many years. The authors emphasized the need for future studies on the use of DORA medication in patients with severe obstructive sleep apnea.
Abstract
Use of Daridorexant among Patients with Chronic Insomnia: A Retrospective Observational Analysis
Scott G Williams, Domingo Rodriguez-Cué
Insomnia is the most prevalent sleep disorder, affecting millions worldwide and taking a heavy toll on patient health with significant social and economic impact. Even though there are multiple different types of insomnia medications and behavioral therapies, there are still many individuals for whom treatment remains ineffective. The objective of this retrospective study was to analyze the effectiveness of daridorexant in a cohort of chronic insomnia patients largely transitioned from GABA-A positive allosteric modulators (benzodiazepines, zolpidem or eszopiclone) or other frequently prescribed insomnia medications (including trazodone, atypical antipsychotics or tricyclic antidepressants). A total of 86 patients were treated in the course of ordinary practice and the primary analytic endpoint was the change in Insomnia Severity Index (ISI) score following ≥ 30 nights of treatment with daridorexant. Results from 80 of the 86 patients with full data (65% female, mean age 53.5 years, 18.8% with comorbid obstructive sleep apnea, 91.3% transitioned from a different medication) showed a mean improvement in ISI score of 7.0 ± 0.54 points (SEM) (p < 0.0001) from 18.0 to 11.0. Overall, 78% of the cohort demonstrated a clinically meaningful improvement as defined by at least a six-point drop in ISI. Total sleep time increased by 54 ± 1.0 min (SEM) (p < 0.0001) from 6.0 h to 6.9 h. Mean sleep latency decreased by 23.9 ± 2.4 min (SEM) (p < 0.0001) from 58.8 min to 34.9 min. Wake after sleep onset decreased by 31.6 ± 3.2 min (SEM) (p < 0.001) from 42.8 min to 11.3 min. Sleep efficiency improved by 10.5 ± 1.1% (SEM) (p < 0.0001) from 79.3% to 89.8%. No significant adverse events were noted during the study duration. Keeping in mind this study's limitations, these data suggest that for insomnia patients with an incomplete response to current therapy, switching to daridorexant is safe and may be an effective alternative treatment.
Download PDF and other files
Reference
Williams, S. G., & Rodriguez-Cué, D. (2023). Use of daridorexant among patients with chronic insomnia: A retrospective observational analysis. Journal of Clinical Medicine, 12(9), 3240.
