Can a sleep med improve next-day cognition and prevents falls?
STUDY: Winter Y & Arnaldi D, Expert Rev Neurother 2026;
STUDY TYPE: Narrative review
FUNDING: Industry
This narrative review from Germany synthesizes the clinical trials for daridorexant, a dual orexin receptor antagonist (DORA) approved in the US in 2022 as Quviviq and now available across Europe, Canada, Japan, and China.
While most sleep meds boost sedative signals in the brain, the orexin antagonists block the chemical that keeps people awake. Daridorexant blocks both orexin receptors, with half-life of roughly 8 hours.
The Trials
In the Phase 3 trials (involving 1,854 subjects), patients on daridorexant 50 mg fell asleep about 30 minutes faster and spent 30 fewer minutes awake after sleep onset, while also gaining roughly an hour of total sleep. Daridorexant’s effects on sleep held through 48 weeks with no tolerance, no rebound, and no withdrawal on discontinuation.
How Orexin Antagonists Differ from Older Hypnotics
Daytime functioning improved on daridorexant, with significant reductions in fatigue, sleepiness, and cognitive fog. These benefits are seen with other orexin antagonists but not with z-hypnotics or benzos.
Surprisingly, falls were lower on daridorexant than on placebo. That has been seen with other orexin antagonists, though the effect is usually not statistically significant. Perhaps the improvements in next-day cognition help prevent falls. Daridorexant has safety data in the elderly and sleep apnea, populations where sleep meds are riskier (other orexin antagonists have this too).
Drug-liking studies suggest a potential for misuse, though less than benzodiazepines and Z-drugs like zolpidem (Ambien).
Switching Meds
We have a few studies on switching from benzodiazepines, Z-drugs, trazodone, or antipsychotics to orexin antagonists. When the older meds were not working, the switch helped, although these are observational studies. Cross-taper from one to the other gradually over about a month.
Implications for Practice
- With these unique benefits, the orexin antagonists are first-line options for insomnia, particularly for older adults and in sleep apnea
- It’s not clear which of the three orexin antagonists is ideal — daridorexant, lemborexant, or suvorexant? Although we lack head-to-head trials, meta-analyses suggest greater efficacy with daridorexant and lemborexant.
- In my experience, the efficacy depends on the patient. They can try each for a week to see which is best, using coupons or samples to reduce the cost.
- These hypnotics don’t alter consciousness like older sleep meds, and some patients miss that. Suggest they focus on how they function the next day, rather than how “knocked out” they feel at night.
- For daridorexant, 50 mg is usually the ideal dose, but stay at 25 mg with moderate CYP3A4 inhibitors or moderate hepatic impairment, and avoid with strong CYP3A4 inhibitors.
- Watch out for nightmares and hypnogogic hallucinations on orexins
- Insurance, unfortunately, prefers generic options.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
Share Your Input in Comments
- Which orexin antagonist have you had most success with?
- How are you getting them approved?
