¹Idorsia Pharmaceuticals US Inc, Global Medical Affairs, Radnor, United States, ²Medical College of Georgia at Augusta University, Psychiatry and Health Behavior, Augusta, United States, ³Johns Hopkins University School of Medicine, Psychiatry and Behavioral Sciences, Baltimore, United States, ⁴Idorsia Pharmaceuticals Ltd, Drug Safety, Allschwil, Switzerland, ⁵Idorsia Pharmaceuticals Ltd, Biometry, Allschwil, Switzerland, ⁶Idorsia Pharmaceuticals Ltd, Global Clinical Development, Allschwil, Switzerland, ⁷Idorsia Pharmaceuticals Ltd, Global Medical Affairs, Allschwil, Switzerland

Background: Insomnia disorder is a chronic medical condition that is estimated to affect 12% of adults. Although CBTi is recognized as an important first line therapy it can be challenging to access and implement, resulting in problems with compliance. As a result many individuals with insomnia disorder receive medication treatment, often for prolonged periods of time. The potential for abuse of hypnotics can prevent patients from accessing necessary medications to effectively treat insomnia as a chronic condition.

Aims & Objectives: This study examined the real-world abuse potential of approved and off-label medications used for the treatment of insomnia, employing data from the FDA Adverse Event Reporting System (FAERS) database.

Method: Data from 1 January 2014 to 31 March 2024 were retrieved from the FAERS database. We compared the occurrence of unsolicited reported drug abuse events defined via Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries SMQ). Drugs of interest included Schedule IV drugs (benzodiazepines, Z-drugs, dual orexin receptor antagonists [DORAs]) and non-scheduled drugs (trazodone, doxepin, ramelteon). Trazodone was selected for comparison as it is one of the most widely prescribed medications for insomnia in the US, despite it not being approved for this condition. Relevant reported adverse events denoting drug abuse were identified if they contained an event with any preferred terms (PTs) from the SMQ categories: drug abuse, dependence, and withdrawal (MedDRA v26.1), with a modified SMQ applied to exclude cases with PTs associated with overdose or suicidal behaviors. Only PT's with a frequency threshold > 1% in any drug group are reported. Trazodone and zolpidem were used as reference drugs for disproportionality as they are the most widely prescribed drugs for insomnia in the US. Reporting odds ratios (ROR) and proportional reporting ratios (PRR) were used as disproportionality measures.

Results: Rates of adverse event cases of abuse, dependence, and withdrawal retrieved were highest for benzodiazepines approved for any indication (27.7%), followed by benzodiazepines approved for insomnia (23.0%), trazodone (22.7%), doxepin (22.3%), Z-drugs (15.3%), ramelteon (8.0%), and DORAs (2.6%). DORAs were associated with a low ROR value relative to Z-drugs (ROR = 0.150; 95% CI [0.131, 0.171]), and to trazodone (ROR = 0.092; 95% CI [0.081, 0.105]). Similar results were obtained using the PRR to measure disproportionality.

Discussion & Conclusions: This study identified significantly fewer reported cases of abuse, misuse, overdose, dependence and withdrawal for DORAs compared with drugs typically prescribed long term for insomnia treatment. This included benzodiazepines (both indicated for and used off label) as well as z-drugs. The DORA class had significantly lower odds of reporting for adverse events denoting drug abuse when compared with both the scheduled drug zolpidem and the non-scheduled drug trazodone. This suggests that categorization of DORAs as Schedule IV drugs may overstate their abuse potential.