Protonitazene Overdose: Naloxone Dosing in Emergency Department Patients with Confirmed Exposure

Protonitazene is a novel synthetic opioid in the nitazene family. The nitazenes are structurally distinct from fentanyl and its analogs, and from in vitro studies, can be 10-fold more potent than fentanyl and 1,000-fold more potent than morphine.1,2 Nitazenes are increasingly prevalent in recent opioid overdoses, and prior studies and case reports have cited longer lengths of stay and higher naloxone-dose administration for patients with overdose due to isotonitazene, etonitazene, and metonitazene.3,4 Data specific to outcomes with protonitazene overdose are limited, and it is unclear if protonitazene overdose is associated with higher naloxone-dose administration or more severe clinical outcomes. This study seeks to fill this gap in knowledge by examining prehospital and in-hospital naloxone dosing, clinical outcomes and resource utilization in emergency department (ED) patients with protonitazene overdose in comparison to ED patients with overdose due to fentanyl alone. The authors conducted a secondary analysis of the ToxIC Fentalog study database. The ToxIC Fentalog study is a national prospective cohort of ED patients with suspected opioid overdose, with over 2,500 patients enrolled at 10 clinical sites across the United States from 2020 to 2025.3 All patients enrolled in the ToxIC Fentalog study have waste blood sent to a centralized lab, the Center for Forensic Science Research and Education (CSFRE), with qualitative analysis of serum drug analytes. The CSFRE employs liquid chromatography quadrupole time-of-flight mass spectrometry, with a library of over 1,200 analytes. Analyte data were paired with clinical data by the authors for comprehensive analysis. In this study, the authors used lab analyte data to identify patients with opioid overdose due to protonitazene (exposure group) and patients with opioid overdose due to fentanyl alone (control group). The study's primary outcome was naloxone dosing, which was defined by the authors in three ways: (1) total number of prehospital naloxone bolus doses, (2) total prehospital naloxone dose in milligrams, and (3) total in-hospital naloxone dose in milligrams. The study's secondary outcomes were clinical outcomes (the occurrence of cardiac arrest and respiratory failure) and resource-utilization outcomes (occurrence of floor and ICU admission, and total length of stay). Of 7,417 patients screened for the ToxIC fentalog study, 2,074 were included in the parent study. From these included patients, 45 patients had only fentanyl present on serum analysis and 9 had protonitazene present. Patients in the fentanyl-only and protonitazene groups were similar with regard to age, race/ethnicity, and gender. Patients with protonitazene overdose received a significantly higher number of prehospital naloxone bolus doses (2.3 versus 1.3, P = .02). Patients with protonitazene overdose were also found to receive a higher total prehospital dose of naloxone (6.6 versus 4.1 mg), although this did not reach statistical significance. There were no significant differences in clinical outcomes, admission rates, or lengths of stay. Table 1 - Comparison of prehospital and in-hospital naloxone-dose administration in ED patients with opioid overdose due to protonitazene and fentanyl alone Variable Protonitazene Fentanyl-only P value Total prehospital dose (mean, SD) 6.6 mg (SD: 6.5) 4.1 mg (SD: 2.8) NS Total in-hospital dose (mean, SD) 1.6 mg (SD: 2.0) 1.7 mg (SD: 1.7) NS Number of prehospital boluses (mean, SD) 2.3 (SD: 1.3) 1.3 (SD: 0.8) .02 Number of in-hospital boluses (mean, SD) 0.6 (SD: 1.1) 0.8 (SD: 1.3) NS Total overall bolus dose (mean, SD) 7.0 mg (SD: 6.3) 4.4 mg (SD: 2.8) NS Abbreviations: ED, emergency department; NS, not significant. The authors findings suggest that protonitazene overdose may have a more severe initial presentation that is more refractory to naloxone. These findings may be mediated by greater opioid-receptor potency, increased duration of action, or partial reversibility to naloxone. Patients with protonitazene overdose in this study had overall low rates of cardiac arrest and respiratory failure when compared to prior studies looking at overdose due to other nitazenes.3 Patients with protonitazene overdose in this study also had a shorter length of stay when compared to studies of other nitazenes.4 This study suggests that reassessment of current prehospital naloxone dosing protocols and EMS opioid-overdose field-response algorithms is warranted. Nitazenes, including protonitazene, are becoming increasingly prevalent in the national drug supply. Given the potentially uniquely severe initial presentation in protonitazene overdose, prehospital providers should receive targeted education and preparation for optimal management, including the potential need for more aggressive prehospital reversal. The authors also noted that despite the increased prehospital dose requirements noted above, there was an overall low rate of adverse clinical outcomes and shorter lengths of stay in protonitazene overdose. These findings suggest that early aggressive reversal may mitigate downstream morbidity once adequate antagonism is achieved. These results may have practice implications with regard to monitoring and disposition in areas with high local prevalence of nitazenes, but larger studies are needed for validation and to fully understand potential implications for clinical care and prognostication. This study was limited by a small sample size, selection bias given that only patients with waste blood available were included, lack of granular exposure data with regard to route, timing, etc, and potential uncontrolled confounders. Future larger studies that allow for multivariable analysis are needed to validate this study's findings. Future studies should also include quantitative serum analysis of protonitazene concentrations to more fully characterize implications of protonitazene overdose. The authors ultimately conclude that patients presenting to the ED with overdose due to protonitazene received a significantly higher number of prehospital naloxone bolus doses when compared to patients with overdose due to fentanyl alone, suggesting the need for revision of prehospital care protocols. Further studies are needed to fully elucidate clinical and hospital resource-utilization implications of protonitazene overdose.