Naloxone Use in Novel Potent Opioid and Fentanyl Overdoses in Emergency Department Patients

Nmaducci A, Aldy K, Campleman SL, Li S, Meyn A, Abston S, Culbreth, Krotulski AJ, Logan BK, Wax P, Brent J, Manini AF, for the Toxicology Investigators Consortium Fentalog Study Group

Question  What are the naloxone requirements and clinical sequelae of emergency department patients with novel potent opioid (NPO) overdose exposures?

Findings  In this cohort study of 537 patients, all patients with NPO overdose presented with opioid overdose symptoms and received multiple doses of naloxone. Compared with fentanyl overdose, patients with NPO overdose had a higher number of naloxone doses administered in-hospital; metonitazene overdose was associated with cardiac arrest and more naloxone doses overall.

Meaning  These findings suggest that NPOs may have a higher potency than fentanyl due to the observed naloxone administration in the clinical setting of overdose.

Importance  Synthetic opioids, such as the fentanyl analogue and nitazene drug class, are among the fastest growing types of opioids being detected in patients in the emergency department (ED) with illicit opioid overdose (OD). However, clinical outcomes from OD of novel potent opioids (NPOs), specifically nitazenes, are unknown aside from small case series.

Objective  To determine naloxone administration and clinical sequelae of patients who were in the ED with NPO overdose compared with fentanyl OD.

Design, Setting, and Participants  This is a cohort study subgroup analysis of adults admitted to the ED and tested positive for NPOs among in the ongoing nationwide ToxIC Fentalog cohort study from 2020 to 2022. Patients who were in the ED with a presumed acute opioid OD and residual blood samples were included, and those testing positive for NPOs were analyzed. Patients were included in this analysis if their confirmatory testing was positive for an NPO analyte, such as brorphine, isotonitazene, metonitazene, and/or N-piperidinyl etonitazene. A comparison group included patients that were positive for fentanyl and devoid of any other analytes on toxicologic analysis.

Exposures  Patients were exposed to NPOs, including brorphine, isotonitazene, metonitazene and/or N-piperidinyl etonitazene.

Main Outcomes and Measures  The primary outcome was the total number of naloxone doses and total cumulative naloxone dose administered as part of routine clinical care following the OD. Naloxone requirements and clinical sequelae of NPO-positive patients were compared with those testing positive for fentanyl only.

Results  During the study period, 2298 patients were screened, of whom 717 met inclusion criteria, 537 had complete laboratory testing data, with 11 (2.0%) positive for only fentanyl and 9 (1.7%) positive for NPOs (brorphine, isotonitazene, metonitazene, or N-piperidinyl etonitazene). The age range of patients was aged 20 to 57 years (4 males [44.4%] and 5 females [55.6%]). The NPO group received a statistically significantly higher mean (SD) number of naloxone boluses in-hospital (1.33 [1.50]) compared with the fentanyl group (0.36 [0.92]) (P = .02), which corresponded to a moderately large effect size (Cohen d = 0.78). Metonitazene overdose was associated with cardiac arrest and more naloxone doses overall. Metonitazene cases had a mean (SD) number of 3.0 (0) naloxone doses, and 2 of 2 patients (100%) with metonitazene overdoses were administered cardiopulmonary resuscitation.

Conclusions and Relevance  In this cohort study of patients admitted to the ED with confirmed opioid overdose testing positive for NPOs, in-hospital naloxone dosing was high compared with patients who tested positive for fentanyl alone. Further study is warranted to confirm these preliminary associations.