Nitazenes: review of comparative pharmacology and antagonist action.

Abstract

Introduction: Nitazenes are a class of potent synthetic opioids that have emerged in illicit drug markets and have been identified in combination with other opioids in cases of poisoning and fatalities. Originally developed in the 1950s, these compounds were abandoned due to their high toxicity and unfavourable therapeutic index. Recent reports indicate that nitazenes exhibit a wide range of potencies, with some exceeding that of fentanyl. Understanding the pharmacological and toxicological profiles of nitazenes is critical for public health and clinical management. This review synthesizes literature on the pharmacology, toxicity, and antagonist action of nitazenes, particularly their response to naloxone.

Methods: A comprehensive literature review was conducted using EMBASE, Ovid MEDLINE(R), APA PsycInfo, Scopus, and Web of Science up to 26 July 2024. The main search terms used were: "nitazen*", "2-benzylbenzimidazole", "aminoisotonitazene" OR "butonitazeneor clonitazene" OR "desnitazene" OR "etodesnitazene" OR "etonitazene" OR "flunitazene" OR "isotonitazene" OR "metodesnitazene" OR "metonitazene" OR "protonitazene". Inclusion criteria encompassed in vitro and animal studies, post-mortem toxicology, clinical trials, and case reports on nitazene poisoning. Data regarding naloxone dosing in confirmed cases of nitazene poisoning were also analyzed.

Results: We identified 1,383 studies, and after removing duplicates, 557 abstracts were screened. Based on the eligibility criteria, 78 articles underwent full-text screening, and 35 were included in the final review. Nitazenes exhibit variability in potency and toxicity. In vitro studies suggest that their receptor affinity and potency often surpass those of both morphine and fentanyl. Real-world data indicate that in vivo potency is often lower than experimental findings. Case reports and clinical series indicate that naloxone remains an effective antidote for nitazene poisoning. A median dose of parenteral naloxone 1.20 mg effectively reversed poisoning, with a median dose of 0.8 mg in the pre-hospital setting. However, a subset of patients received prolonged naloxone infusions due to the persistence of opioid effects. Six out of 30 patients were treated with naloxone infusions. This ratio is higher than that reflected in current clinical guidelines, in which shorter observation time is deemed sufficient. Post-mortem toxicological analyses reveal highly variable nitazene concentrations, with overlap with those concentrations found in patients. This complicates the establishment of lethal thresholds. In several cases, nitazene metabolites were detected in isolation, suggesting independent pharmacological activity or alternative routes of administration. Additionally, nitazene poisoning often involves polysubstance use, further complicating diagnosis and management.

Discussion: Data on nitazene potency in humans are scarce. Nitazenes are a heterogeneous group with very high experimental potency compared to morphine. The potency in in vivo outcome studies in humans is far lower than that in in vitro studies. Post-mortem concentrations of many nitazenes are similar to the post-mortem concentrations of fentanyl and indicate a similar potency. Treatment of nitazene poisoning should follow the guidelines for opioid poisoning, that is, instituting airway management and administering naloxone. All cases reviewed had several opioids and other sedating drugs in addition to nitazenes in their analytical workup. The median parenteral dose for successful reversal of features was 1.20 mg. This finding provides reassurance that naloxone is effective for the treatment of poisoning due to nitazene as well as other potent opioids.

Conclusions: Nitazenes represent an emerging public health challenge due to their high potency, unknown pharmacokinetics, and increasing presence in illicit drug supplies. While naloxone is effective in reversing nitazene poisoning, cases of prolonged toxicity suggest the need for extended monitoring and repeated naloxone dosing. The findings of this review highlight the importance of enhanced drug surveillance, improved clinical awareness, and the development of targeted harm reduction strategies, including the potential for novel opioid antagonists with prolonged efficacy. Future research should focus on defining nitazene receptor kinetics, post-mortem redistribution effects, and optimizing naloxone administration protocols for these emerging synthetic opioids.