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ORIGINAL ARTICLE

Benzodiazepine Co-Exposure Among Patients Presenting to the Emergency Department With a Confirmed Opioid Overdose

Adrienne Hughes

Corresponding Author

Adrienne Hughes

Oregon Health and Science University, Portland, Oregon, USA

Correspondence:

Adrienne Hughes ([email protected])

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Hannah Spungen

Hannah Spungen

University of California, Los Angeles, California, USA

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Rachel Culbreth

Rachel Culbreth

American College of Medical Toxicology, Phoenix, Arizona, USA

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Kim Aldy

Kim Aldy

American College of Medical Toxicology, Phoenix, Arizona, USA

Baylor University Medical Center, Dallas, Texas, USA

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Alex Krotulski

Alex Krotulski

Center for Forensic Science Research and Education, Fredric Rieders Family Foundation, Horsham, Pennsylvania, USA

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Robert G. Hendrickson

Robert G. Hendrickson

Oregon Health and Science University, Portland, Oregon, USA

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Alexandra Amaducci

Alexandra Amaducci

Lehigh Valley Health Network/USF Morsani College of Medicine, Allentown, Pennsylvania, USA

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Bryan Judge

Bryan Judge

Corewell Health, Michigan State University, Grand Rapids, Michigan, USA

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Christopher Meaden

Christopher Meaden

Rutgers New Jersey Medical School, Newark, New Jersey, USA

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Diane P. Calello

Diane P. Calello

Rutgers New Jersey Medical School, Newark, New Jersey, USA

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Jennie Buchanan

Jennie Buchanan

Denver Health and Hospital Authority, Denver, Colorado, USA

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Joseph Carpenter

Joseph Carpenter

Emory University School of Medicine, Atlanta, Georgia, USA

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Joshua Shulman

Joshua Shulman

University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

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Jeffrey Brent

Jeffrey Brent

University of Colorado School of Medicine, Aurora, Colorado, USA

Toxicology Associates, Littleton, Colorado, USA

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Paul Wax

Paul Wax

American College of Medical Toxicology, Phoenix, Arizona, USA

University of Texas Southwestern Medical Center, Dallas, Texas, USA

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Sharan Campleman

Sharan Campleman

American College of Medical Toxicology, Phoenix, Arizona, USA

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Michael Levine

Michael Levine

University of California, Los Angeles, California, USA

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Evan Schwarz

Evan Schwarz

University of California, Los Angeles, California, USA

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Alex F. Manini

Alex F. Manini

Icahn School of Medicine at Mount Sinai, Center for Research on Emerging Substances, Poisoning, Overdose, and New Discoveries (RESPOND), NYC Health + Hospitals/Elmhurst, New York, New York, USA

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First published: 15 July 2025

Funding: This work was supported by National Institute on Drug Abuse, R01DA048009.

Supervising Editor: Steven Bradley Bird

ABSTRACT

Background

Simultaneous exposure to both benzodiazepines and opioids can lead to synergistic respiratory depression, complicating overdose management. Our objective was to report on the detection of prescription and novel benzodiazepine co-exposures among patients treated in emergency departments (EDs) with suspected opioid overdoses. We aimed to describe novel benzodiazepine exposures in this population and to compare the clinical severity of co-exposure to benzodiazepines and opioids versus opioids alone.

Methods

This study utilized data from the Toxicology Investigators Consortium (ToxIC) Fentalog Study, an observational study at 10 ED sites (Sept 2020–Dec 2023). Waste serum samples were analyzed using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) for the presence of over 1200 novel psychoactive substances (NPS), drugs, therapeutics, and metabolites. Analyses included demographics, clinical severity, and outcomes among those with prescription benzodiazepines, novel benzodiazepines, or no benzodiazepines.

Results

Among the patients with opioids present (n = 1427), 29.0% of patients had detectable benzodiazepines. 20.5% of patients had detectable prescription benzodiazepines, and 8.5% of patients had detectable novel benzodiazepines. The most commonly detected prescription benzodiazepine was alprazolam (39.3%); the most common novel benzodiazepine was bromazolam (46.3% of novel benzodiazepines). The median age of those with novel benzodiazepines was 34, which was younger than those without benzodiazepines (40) and those with prescription benzodiazepines (41; p = 0.001). Patients without benzodiazepines received naloxone more frequently (p = 0.02), while novel benzodiazepine co-exposure was associated with higher naloxone nonresponse rates (p = 0.03). Patients with novel benzodiazepines (compared to the opioid-only group) had increased odds of requiring mechanical ventilation (aOR: 2.14; 95% CI: 1.07, 4.05) after adjusting for age, gender, race and ethnicity, and the presence of prescription benzodiazepines and/or fentanyl.

Conclusions

Nearly a third of patients with confirmed opioid overdose presenting to the ED also had concomitant benzodiazepine exposures. Those with novel benzodiazepines had significantly higher odds of intubation, suggesting greater severity of overdose.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Research data are not shared.

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