"This study is the first, to our knowledge, to document the clinical sequelae and naloxone administration for patients who were in the ED following confirmed NPO drug OD. The NPO group was administered a statistically significantly higher number of in-hospital naloxone boluses compared with the fentanyl group, which corresponded to a moderately large effect size. While these findings were based on limited sample sizes, we detected a large effect size for the association between increased naloxone doses and NPO overdose. The majority of patients with ODs that involved NPO received 2 or more doses of naloxone, whereas most of the patients who OD from fentanyl only received 1 dose of naloxone. While this study was statistically underpowered to detect differences in naloxone administration in total cumulative dosage and clinical sequelae between patients with NPO and fentanyl only OD, this study provides important preliminary data on NPOs to inform clinicians and patients of the severity of ODs involving NPOs. Furthermore, this preliminary data underscores the urgent need to study NPOs in a larger, future cohort. These data suggest that NPOs may have higher potency than fentanyl and by extension heroin.

"NPOs, such as nitazenes and brorphine, are relatively new to the illicit opioid supply but may have significant clinical implications based on the findings of the present study. The nitazene drug class is structurally unrelated to fentanyl but has been found to be up to 1000-fold more potent than morphine.1 Isotonitazene and brorphine are 2 of the NPOs that emerged as novel psychoactive substances (NPS) in 2019 and 2020, respectively. Brorphine was initially created in 2018 and first noted on the recreational drug market in 2019.8 Nitazenes and brorphine have consistently demonstrated stronger in vitro μ-opioid receptor activation than fentanyl1 but until now translation of these findings to the clinical setting has been difficult.

"In general, naloxone dosing was high in both groups studied, which may have been influenced by the prehospital administration of 2 mg naloxone intranasally in most regions studied. In the present study, most patients in the NPO group required multiple doses of naloxone. However, the fentanyl only group received almost 50% more naloxone than the NPO groups. Thus, while the present study was underpowered to calculate statistically significant differences in cumulative naloxone administration, true population differences may exist and require further study.

"NPOs have higher μ-opioid receptor activation than morphine and fentanyl, which has previously been demonstrated by an in vitro study which pharmacologically evaluated 10 nitazenes using 2 cell-based β-arrestin2/mini-Gi recruitment assays monitoring μ-opioid receptor activation.1 In addition, there appear to be differences within each drug in the nitazene class. In the present study, metonitazene appears to have the most severe clinical toxicity given that both patients in which metonitazene was detected presented in cardiac arrest, and 1 patient died."


Amaducci A, Aldy K, Campleman SL, et al. Naloxone Use in Novel Potent Opioid and Fentanyl Overdoses in Emergency Department Patients. JAMA Netw Open. 2023;6(8):e2331264. Published 2023 Aug 1. doi:10.1001/jamanetworkopen.2023.31264