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Published Online: 26 April 2021

The Risk of Overdose With Concomitant Use of Z-Drugs and Prescription Opioids: A Population-Based Cohort Study

Abstract

Objective:

The Z-drugs (zolpidem, zopiclone, zaleplon) are widely used to treat insomnia in patients receiving prescription opioids, and the risk of overdose resulting from this coprescription has not been explored. The authors compared the rates of overdose among patients using opioids plus Z-drugs and patients using opioids alone.

Methods:

All individuals 15 to 85 years of age receiving prescription opioids, regardless of underlying indication and without evidence of cancer, were identified in the IBM MarketScan database (2004–2017). Patients with concomitant exposure to Z-drugs were matched 1:1 to patients with exposure to prescription opioids alone based on opioid prescribed, morphine equivalents, number of days’ supply, and hospitalization within the past 30 days. The primary outcome was any hospitalization or emergency department visit due to an overdose within 30 days, using an intention-to-treat approach. Fine stratification on the propensity score was used to control for confounding.

Results:

A total of 510,529 exposed patients and an equal number of matched reference patients were analyzed. There were 217 overdose events among the exposed patients (52.5 events per 10,000 person-years) and 57 events among the reference patients (14.4 events per 10,000 person-years), corresponding to an unadjusted hazard ratio of 3.67 (95% CI=2.75, 4.90). Using fine stratification on the propensity score (c-statistic: 0.66), the adjusted hazard ratio was 2.29 (95% CI=1.79, 2.91). Results were consistent across sensitivity analyses.

Conclusions:

Among patients receiving prescription opioids, after controlling for all confounding factors, concomitant treatment with Z-drugs was associated with a substantial relative increase in the risk of overdose. The potential implications are significant given the large number of opioid-treated patients receiving Z-drugs.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 643 - 650
PubMed: 33900810

History

Received: 14 July 2020
Accepted: 7 December 2020
Published online: 26 April 2021
Published in print: July 2021

Keywords

  1. Substance-Related and Addictive Disorders
  2. Opioids
  3. Sedatives
  4. Overdose
  5. Insomnia

Authors

Details

Alejandro Szmulewicz, M.D., M.P.H. [email protected]
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Szmulewicz, Huybrechts); Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (Bateman, Levin, Huybrechts), and Department of Anesthesiology, Perioperative and Pain Medicine (Bateman), Brigham and Women’s Hospital and Harvard Medical School, Boston
Brian T. Bateman, M.D., M.Sc.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Szmulewicz, Huybrechts); Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (Bateman, Levin, Huybrechts), and Department of Anesthesiology, Perioperative and Pain Medicine (Bateman), Brigham and Women’s Hospital and Harvard Medical School, Boston
Raisa Levin, M.S.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Szmulewicz, Huybrechts); Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (Bateman, Levin, Huybrechts), and Department of Anesthesiology, Perioperative and Pain Medicine (Bateman), Brigham and Women’s Hospital and Harvard Medical School, Boston
Krista F. Huybrechts, M.Sc., Ph.D.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Szmulewicz, Huybrechts); Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (Bateman, Levin, Huybrechts), and Department of Anesthesiology, Perioperative and Pain Medicine (Bateman), Brigham and Women’s Hospital and Harvard Medical School, Boston

Notes

Send correspondence to Dr. Szmulewicz ([email protected]).

Funding Information

Dr. Bateman receives research support through his institution from Baxalta, Eli Lilly, GlaxoSmithKline, and Pacira. Dr. Huybrechts is an investigator on research grants from Eli Lilly to Brigham and Women’s Hospital. The other authors report no financial relationships with commercial interests.

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