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J Gen Intern Med. 2015 Aug;30(8):1081-96. doi: 10.1007/s11606-015-3199-4. Epub 2015 Feb 4.

Drug Overdose in a Retrospective Cohort with Non-Cancer Pain Treated with Opioids, Antidepressants, and/or Sedative-Hypnotics: Interactions with Mental Health Disorders.

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Division of General Internal Medicine, Department of Medicine, University of Texas Health Science Center San Antonio (UTHSCSA), 7411 John Smith Rd. Suite 1050, San Antonio, TX, 78229, USA,



Opioid analgesics and other psychoactive drugs may pose an even greater risk for drug overdose in persons with mental health disorders.


The purpose of this study was to examine interactions of filled prescriptions for opioids, benzodiazepines, antidepressants, and zolpidem with mental health disorders in regard to drug overdose.


The study was a retrospective cohort review.


Subjects were national HMO beneficiaries aged 18-64 years, enrolled at least 1 year (01/2009 to 07/2012), who filled at least two prescriptions for Schedule II or III opioids for non-cancer pain.


The outcome was the first inpatient or outpatient drug overdose after the first filled opioid prescription. Predictors were calculated in 6-month intervals and exactly 6 months before a drug overdose: opioid use (mean daily morphine-equivalent dose), benzodiazepine use (days' supply), antidepressant use (days' supply), zolpidem use (days' supply), mental health disorders (depression, anxiety/PTSD, psychosis), pain-related conditions, and substance use disorders (alcohol, other drug).


A total of 1,385 (0.67%) subjects experienced a drug overdose (incidence rate 421/100,000 person-years). The adjusted odds ratios (AOR) for overdose among all subjects rose monotonically with daily opioid dose, but highest (AOR = 7.06) for persons with depression and a high opioid dose (≥100 mg) versus no depression or opioid use. Longer-term antidepressants (91-180 days) were protective for persons with depression, with 20% lower AORs for overdose versus short-term (1-30 days) or none. For persons without depression, the AORs of overdose were increased for antidepressant use, but greatest (AOR = 1.98) for short-term use versus none. The AORs of overdose increased with the duration of benzodiazepine therapy among all subjects, with over 2.5-fold higher AORs for 91-180 days versus none.


Opioids and longer-duration benzodiazepines were associated with drug overdose among all subjects, but opioid risk was greatest for persons with depression. Antidepressant use > 90 days reduced the odds of overdose for persons with depression, but all antidepressant use increased the risk for persons without depression.

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