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

Abstract

ImportanceSynthetic 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.ObjectiveTo determine naloxone administration and clinical sequelae of patients who were in the ED with NPO overdose compared with fentanyl OD.Design, Setting, and ParticipantsThis 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.ExposuresPatients were exposed to NPOs, including brorphine, isotonitazene, metonitazene and/or N-piperidinyl etonitazene.Main Outcomes and MeasuresThe 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.ResultsDuring 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 RelevanceIn 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.

Potency, dissociation kinetics and reversibility of fentanyls and nitazenes by naloxone at the μ opioid receptor

“…A second important finding of this study was that slowly dissociating agonists such as carfentanil were more resistant to antagonism by naloxone. There have been numerous reports of more naloxone, in the form of multiple or higher doses, being required to reverse overdoses involving fentanyls and nitazenes compared with heroin overdoses (Moe, Godwin et al ., 2020; Irvine, Oller et al, 2022; Amaducci, Aldy et al ., 2023). What may be occurring with the fentanyls may in fact be ‘over’ overdose, i.e.…”

“…For agonists and antagonists interacting at the same orthosteric binding site on a receptor a competitive antagonist such as naloxone would be expected to reverse all agonists equally given that the antagonist binds to the unbound receptor and prevents agonist binding rather than physically displacing the agonist from the receptor (Ritter, Flower et al ., 2024). However there have been numerous reports of more naloxone, in the form of multiple or higher doses, being required to reverse overdoses involving fentanyls and nitazenes compared with heroin overdoses (Moe, Godwin et al ., 2020; Irvine, Oller et al, 2022; Amaducci, Aldy et al ., 2023). Reduced sensitivity to naloxone has also been observed in animal studies using sub lethal doses of fentanyls (Hill, Santhakumar et al ., 2020; Elder, Varshneya et al ., 2023)…”

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids

“…In a cohort study of adults admitted to emergency departments with a presumed OIRD it was found that those patients ( n = 9) who tested positive for brorphine [a potent, non-fentanyl–derived synthetic opioid ( 62 )] or various nitazenes required in-hospital doses of naloxone with a cumulative dose of 4.4 mg compared to those in the fentanyl-only group ( n = 11) with a cumulative dose of 6.41 mg. However, the non-fentanyl group was administered a statistically significantly higher number of in-hospital naloxone boluses compared with the fentanyl group, which suggests that brorphine and nitazenes may be more potent than fentanyl ( 63 ). As with synthetic opioids in general, better evidence is needed about the optimal naloxone doses, the delay between doses, and how many doses are ideally needed for treating nitazene overdoses ( 24 , 27 , 28 ).…”

Nalmefene Hydrochloride: Potential Implications for Treating Alcohol and Opioid Use Disorder

“… 5 , 6 The highest rate of fatality from NPS was from synthetic opioids, which may require many times the dose of naloxone available in emergency departments with limited resources. 7 , 8 The numbers for OUD and opioid overdose deaths justify the term “opioid epidemic” used by both scientific and popular outlets and constitute a social and public health crisis that needs to be prioritized by implementing new prevention, treatment, and mitigation approaches, among them pharmacotherapy.…”