Each type has problems — and one looks more dangerous
STUDY: Gao S et al, Front Pharmacol 2026;17:1788736
STUDY TYPE: Pharmacovigilance study (FAERS database analysis)
FUNDING: Independent
Background
There are three generations of sleep meds that are still in use:
- Benzodiazepines: More dangerous with tolerance, dependence, falls, and cognitive problems
- Z-drugs (zolpidem/Ambien, zaleplon/Sonata, and eszopiclone/Lunesta): This are marketed as safer, and likely are, but act in similar ways to benzos and carry similar risks.
- Dual orexin receptor antagonists (DORAs) like suvorexant/Belsomra, lemborexant/Dayvigo, and daridorexant/Quviviq: First released in 2015, these are lower risk, with safety confirmed in populations where sleep meds are more dangerous, like in sleep apnea and older adults. They also improve next-day functioning, something other sleep meds do not.
This new study expands looks at these risks in a real-world database.
The Study
Researchers mined the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2025, identifying 5,447 adverse event reports in patients 65 and older where a Z-drug or DORA was the primary suspect. They used multiple statistical methods to detect disproportionate reporting signals for specific adverse events.
Z-drugs — especially eszopiclone — generated strong signals for therapeutic failure (“drug ineffective,” “insomnia”). Eszopiclone also caused a unique side effect of metallic or bitter taste. DORAs, by contrast, showed strong and mechanistically expected signals for nightmares, abnormal dreams, and hallucinations — consistent with their orexin-blocking mechanism which disrupts sleep-wake boundaries.
Neither class generated a significant signal for falls in this dataset, which likely reflects underreporting rather than true absence of risk (other studies show a lower fall risk with DORAs).
Practice Implications
- A surpise to see more treatment failure with z-hypnotics. Why? Maybe these are cases of tolerance that stood out, prompting FDA reports. It reminds me of other recent trials where DORAs worked after people developed tolerance to benzos and z-hypnotics.
- For patients, DORAs may not feel as strong as z-hypnotics at first, but their real strength is is better next-day functioning and lower risk of tolerance.
- Watch out for nightmares and hallucinations on DORAs (usually hypnogogic hallucinations while falling asleep)
- To relieve the bitter taste on eszopiclone, take it with a citrus drink
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- Are you seeing side effects on DORAs? Tolerance on z-hypnotics?
