Idorsia presented compelling real-world evidence at World Sleep 2025 demonstrating that dual orexin receptor antagonists (DORAs) exhibit remarkably low abuse potential compared to other insomnia medications. The comprehensive analysis of FDA Adverse Event Reporting System (FAERS) data spanning over a decade reveals significant safety advantages for this newer class of sleep medications.
FAERS Analysis Reveals Striking Differences in Abuse Rates
The study, conducted in collaboration with the Medical College of Georgia and Johns Hopkins University, examined adverse event reports from January 1, 2014, to March 31, 2024. The analysis focused on abuse-related adverse events across various insomnia treatments, revealing stark differences in safety profiles.
DORAs demonstrated the lowest rate of abuse-related adverse events at just 2.6% of all reported adverse events. This contrasts dramatically with benzodiazepines approved for any indication, which showed the highest rate at 27.7%, followed by benzodiazepines specifically approved for insomnia at 23.0%. Notably, trazodone—the most prescribed insomnia medication in the US despite lacking FDA approval for this indication—showed a 22.7% rate of abuse-related events.
The complete hierarchy of abuse potential based on FAERS data showed: benzodiazepines for any indication (27.7%), benzodiazepines for insomnia (23.0%), trazodone (22.7%), doxepin (22.3%), Z-drugs (15.3%), ramelteon (8.0%), and DORAs (2.6%).
Statistical Significance Supports Safety Profile
The researchers employed rigorous statistical measures to quantify the differences in abuse potential. DORAs showed significantly lower reporting odds ratios (ROR) compared to Z-drugs (ROR = 0.150; 95% CI [0.131, 0.171]) and trazodone (ROR = 0.092; 95% CI [0.081, 0.105]). Similar results were obtained using proportional reporting ratios (PRR), reinforcing the statistical robustness of the findings.
Professor William V. McCall, MD, Professor Emeritus of the Department of Psychiatry and Health Behavior at the Medical College of Georgia, emphasized the clinical significance: "Abuse potential has long shaped the regulation of insomnia medications, with benzodiazepines and z-drugs carrying well-known risks. This study identified a very low rate of reported cases of abuse, misuse, overdose, dependence and withdrawal for the DORA class. This rate was much lower compared with other drugs for insomnia treatment."
Implications for Current Drug Scheduling
The findings raise important questions about current regulatory classifications. Professor David Neubauer, MD, Associate Professor of Psychiatry at Johns Hopkins University School of Medicine, noted: "The DORA class had significantly lower odds of reporting for adverse events denoting drug abuse when compared with the scheduled drug zolpidem and the non-scheduled drug trazodone, both used as a reference. This suggests that categorization of DORAs as Schedule IV drugs may overstate their abuse potential."
This observation is particularly significant given that insomnia disorder affects approximately 12% of adults in the US, with many requiring long-term medication management. Concerns about abuse potential can limit access to effective treatments for this chronic condition.
Comprehensive Methodology Strengthens Findings
The researchers employed a sophisticated approach using Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries to identify relevant adverse events. The study included both Schedule IV drugs (benzodiazepines, Z-drugs, DORAs) and non-scheduled medications (trazodone, doxepin, ramelteon) to provide comprehensive comparisons.
The analysis specifically focused on adverse events related to drug abuse, dependence, and withdrawal, with modifications to exclude cases associated with overdose or suicidal behaviors. Only preferred terms with frequency thresholds greater than 1% in any drug group were included, ensuring statistical relevance.
Clinical Context and Treatment Landscape
The study's selection of trazodone as a primary comparator reflects current prescribing patterns, as it remains one of the most widely prescribed medications for insomnia in the US despite lacking specific approval for this indication. The comparison with zolpidem, another frequently prescribed sleep medication, provides additional context for the superior safety profile of DORAs.
These findings reinforce the favorable safety profile of DORAs such as daridorexant (QUVIVIQ), supporting their role as modern treatment options with minimal abuse potential for patients requiring long-term insomnia management. The data suggests that current regulatory frameworks may need reassessment to ensure appropriate access to these safer therapeutic alternatives.
