Abstract
BACKGROUND: Fentanyl concentrations are typically interpreted in forensic contexts using postmortem and driving under the influence data, both of which have important limitations. This study describes fentanyl and norfentanyl concentrations measured in an acute, clinical setting among patients presenting to the emergency department with a suspected opioid overdose. METHODS: A prospective observational study was performed utilizing the Toxicology Investigators Consortium (ToxIC) Drug Overdose Toxico-Surveillance (DOTS) Reporting Program enrolling patients ≥ 13 years old from April 2023 to July 2024 following a life-threatening overdose treated at 17 EDs within the United States. Fentanyl and norfentanyl concentrations were determined by liquid chromatography tandem quadrupole mass spectrometry (lower limit of quantification (LLOQ) 1 ng/mL). Fentanyl and norfentanyl concentrations were summarized using descriptive statistics and stratified by time of ED presentation to blood collection. Fentanyl concentrations were also stratified by norfentanyl concentrations. RESULTS: Three hundred and thirty-one patients presented with a clinical presentation consistent with an opioid overdose and were included in the study. Of these, 248 (74.9%) had fentanyl concentrations above the LLOQ. The median concentration of fentanyl and norfentanyl was 4.5 ng/mL (IQR: 2.4, 8.8) and 2.7 ng/mL (IQR:1.6, 5.3), respectively. The median time to blood draw was 165 min. The median fentanyl/norfentanyl (F/NF) ratio was 0.5 (IQR: 0.4, 1.0). CONCLUSIONS: Quantitative fentanyl and norfentanyl concentrations in the acute emergency department setting among patients with a suspected opioid overdose were lower than those in the postmortem literature with significant toxicity observed at levels below the LLOQ. Use of an arbitrary F/NF ratio of 1 did not delineate acute exposure. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13181-026-01132-w.