Prescription Medications for the Treatment of Insomnia and Risk of Suicide Attempt: a Comparative Safety Study
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Guidelines for the pharmacological treatment of chronic insomnia in adults recognize that trazodone and other off-label medications are commonly prescribed despite poor evidence. The Department of Veterans Health Affairs (VA) fills high volumes of inexpensive, over-the-counter sedating antihistamines and older antidepressants in addition to benzodiazepines and zolpidem. Yet little is known about the comparative safety of these agents with regard to suicidal behavior.
To assess the comparative effectiveness of the safety of medications routinely used to treat insomnia in VA.
Comparative effectiveness using propensity score-matched samples.
VA patients without any history of suicidal ideation or behavior 12 months prior to first exposure.
VA formularies and data were used to identify prescriptions for insomnia. Agents accounting for at least 1% of total insomnia fill volume were < 200 mg trazodone, hydroxyzine, diphenhydramine, zolpidem, lorazepam, diazepam, and temazepam. Exposure was defined as an incident monotherapy exposure preceded by 12 months without any insomnia medications. Subjects with insomnia polypharmacy or cross-overs in the 12 months following first exposure were excluded.
Main Outcomes and Measures
Suicide attempts within 12 months of first exposure.
Three hundred forty-eight thousand four hundred forty-nine subjects met criteria and three well-balanced cohorts by drug class matched to zolpidem were created. After adjusting for days’ supply, mental health history, and pain and central nervous system medication history, hazard ratios (compared to zolpidem) were as follows: (< 200 mg) trazodone (HR = 1.61, 95% CI 1.07–2.43); sedating antihistamines (HR = 1.37, 95% CI 0.90–2.07); and benzodiazepines (HR = 1.31, 95% CI 0.85–2.08).
Conclusions and Relevance
Compared to zolpidem, hazard of suicide attempt was 61% higher with trazodone (< 200 mg). No significant differences in suicide attempt risk were identified between benzodiazepines or sedating antihistamines and zolpidem, respectively. These findings provide the first comparative effectiveness evidence against the use of trazodone for insomnia.
KEY WORDSsuicide suicide attempt suicidal behavior insomnia comparative safety pharmacotherapy medication drug antihistamines benzodiazepines zolpidem hypnotics trazodone Veteran
Jill E. Lavigne, Ph.D.,1,9 drafted the manuscript and led the study, including identification of monotherapies and concomitant medications, interpretation of results, and drafting of the manuscript. Kwan Hur, Ph.D.,2 designed the statistical analysis, guided the interpretation of results, and participated in the writing of the manuscript. Cathleen Kane, M.S.,9 led the data management and implementation of the analyses and contributed to the interpretation of results. Anthony Au, Pharm.D.,2 advised on the use of medications commonly used in VA to treat insomnia and central nervous system medications. Todd M. Bishop, Ph.D.,3,9 contributed to the literature review and discussion. Wilfred R. Pigeon, Ph.D.,3,9 contributed to the discussion section of the manuscript, participated in manuscript preparation, and supported acquisition of funding and other resources.
This work was supported by the Department of Veterans Affairs Office of Mental Health and Suicide Prevention with in-kind support provided by the Center of Excellence for Suicide Prevention at the VISN 2 Canandaigua VAMC.
Compliance with Ethical Standards
This study was approved by the VA VISN2 (Syracuse VA) Institutional Review Board.
Conflict of Interest
Dr. Pigeon received speaker fees from Merck in 2015. All other authors have no conflicts of interest to report.
The authors’ views or opinions do not necessarily represent those of the Department of Veterans Affairs or the United States Government.
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