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TOPLINE:

Nearly one third of patients with confirmed opioid overdose in the emergency department (ED) also had benzodiazepine coexposures; novel benzodiazepines were linked to a greater risk for intubation, indicating greater severity of overdose.

METHODOLOGY:

• Researchers conducted a multicenter, prospective, observational study from 2020 to 2023, analyzing data of 1427 adults (median age, 40 years; 72.1% men) with suspected acute opioid overdose who had residual blood samples from routine clinical care.
• The samples were screened using liquid chromatography quadrupole time-of-flight mass spectrometry for the presence of over 1200 novel psychoactive substances, drugs, therapeutics, and metabolites.
• Patients were categorized based on toxicology results into three groups: those with confirmed opioid exposure without benzodiazepine exposure (n = 1013; median age, 40 years), those with confirmed opioid exposure and prescription benzodiazepine coexposure (n = 293; median age, 41 years), and those with confirmed opioid exposure and novel benzodiazepine coexposure (n = 121; median age, 34 years).
• Researchers assessed the association between benzodiazepine coexposure and opioid overdose severity, as measured by the need for intubation/mechanical ventilation.
• Secondary outcomes included the need for cardiopulmonary resuscitation (CPR) and naloxone-related outcomes (dose, response, and infusion requirement).

TAKEAWAY:

• Patients in the novel benzodiazepine coexposure group were more than twice as likely to require mechanical ventilation (10.7%) as patients in the no benzodiazepine exposure group (4.8%; P = .02) and the prescription benzodiazepine coexposure group (4.4%; adjusted odds ratio [aOR], 2.14).
• The novel benzodiazepine group also had a higher prevalence of naloxone nonresponse than the prescription benzodiazepine coexposure and no benzodiazepine exposure groups, both after the initial dose (28.3% vs 20.5% and 17.2%, respectively; P = .03) and after all doses (30.4% vs 25.6% and 20.3%, respectively; P = .03).
• The presence of a novel benzodiazepine was associated with reduced odds of receiving a naloxone infusion (aOR, 0.29; 95% CI, 0.09-0.73); fentanyl coexposure increased total naloxone bolus requirements by 38% (adjusted rate ratio, 1.38; 95% CI, 1.14-1.66).
• Coma/central nervous system depression within the first hour was more likely in the novel benzodiazepine group (52.9%) than in the prescription benzodiazepine coexposure group (40.3%) or the no benzodiazepine exposure group (40.6%; P = .03). CPR requirements were similar across groups (6.6% in the novel benzodiazepine group vs 6.5% in the prescription benzodiazepine coexposure only group vs 8.4% in the no benzodiazepine exposure group; P = .49).

IN PRACTICE:

"In this large multicenter study of ED patients with confirmed mixed benzodiazepine-fentanyl overdose, novel benzodiazepine detection was rare but was an independent predictor of high overdose severity. Patients with novel synthetic opioids detected were more likely to have novel benzodiazepines co-detected," the authors wrote.

SOURCE:

The study was led by Adrienne Hughes, Oregon Health and Science University, Portland, Oregon. It was published online on July 15, 2025, in Academic Emergency Medicine.

LIMITATIONS:

Though the study was multicentric, its generalizability may have been limited by regional variation in illicit drug supplies, its observational design, reliance on discarded blood samples from select academic centers, and potential selection bias from excluding patients without available specimens. Benzodiazepine detection in serum reflects exposure but does not necessarily indicate clinical intoxication. Technical constraints, particularly limited blood sample volumes and analysis restricted only to qualitative testing, prevented more advanced quantitative toxicology that could have better identified substances implicated in overdoses. Finally, although intubation was the primary outcome, it may not have fully reflected all patient-centric outcomes.

DISCLOSURES:

The study was funded by the National Institute on Drug Abuse. The authors reported having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.