Risk of Overdose with Exposure to Prescription Opioids, Benzodiazepines, and Non-benzodiazepine Sedative-Hypnotics in Adults: a Retrospective Cohort Study

  • Joanne ChoEmail author
  • Michele M. Spence
  • Fang Niu
  • Rita L. Hui
  • Patricia Gray
  • Steven Steinberg
Original Research



Concurrent use of benzodiazepines in opioid users has been linked to a higher risk of an emergency room visit or inpatient admission for opioid overdose and death from drug overdose. Further research is needed to confirm the findings and analyze contributing risk factors for opioid overdoses in a large commercially insured population.


To estimate the risk of opioid overdose associated with opioid users exposed to various combinations of opioid, benzodiazepine, and non-benzodiazepine sedative-hypnotic therapy. To identify other factors that are associated with increased risk for opioid overdose.


Retrospective cohort study.


New start adult users of opioids, defined as naïve to opioids for 6 months, in Kaiser Permanente California regions from January 2013 through September 2017.

Main Measures

Inpatient or emergency department admissions due to opioid-related overdose.

Key Results

A total of 2,241,530 patients were included in this study. Patients exposed to opioids, benzodiazepines, and non-benzodiazepine sedative-hypnotics at any point during their follow-up were 60% more likely to overdose than those who were only exposed to opioids (p < 0.0001). Those exposed to opioids and benzodiazepines were 20% more likely to have an opioid-related overdose than those exposed to opioids only (p < 0.0001). Significant risk factors for opioid overdose included exposure to all three medication classes, higher opioid dosage strengths, elderly age (age ≥ 65 years), history of previous overdose, and substance use disorder.


Results from this study demonstrate a significant increase in risk of opioid overdose in patients exposed to combinations of sedative-hypnotics with opioids compared to those only taking opioids. Findings from this study provide evidence that opioids should be avoided in combination with benzodiazepines and non-benzodiazepine sedative-hypnotics, used at the lowest dose possible, and used with caution in the elderly, those with previous history of overdose, and those with substance use disorder at baseline.


patient centered outcomes research medical safety risk assessment pain 



Contributors: The authors would like to thank Carol Havens, MD, Doris J. Kao, PharmD, BCPS, FCSHP, Jane Takagi, PharmD, FCSHP, FASHP, Maisha Draves, MD, and Sameer Awsare, MD for their support.

Compliance with Ethical Standards

Conflict of Interest

Dr. Steven G. Steinberg is currently employed by Southern California Permanente Medical Group. All remaining authors declare that they do not have a conflict of interest.

Supplementary material

11606_2019_5545_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 34 kb)


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Copyright information

© Society of General Internal Medicine 2020

Authors and Affiliations

  • Joanne Cho
    • 1
    Email author
  • Michele M. Spence
    • 2
  • Fang Niu
    • 2
  • Rita L. Hui
    • 2
    • 3
  • Patricia Gray
    • 4
  • Steven Steinberg
    • 5
  1. 1.Pharmacy Services Kaiser PermanenteBakersfieldUSA
  2. 2.Pharmacy Outcomes Research GroupDowneyUSA
  3. 3.Pharmacy Outcomes Research GroupOaklandUSA
  4. 4.Pharmacy ServicesKaiser PermanenteRiversideUSA
  5. 5.Southern California Permanente Medical GroupPasadenaUSA

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