Nitazenes are potent mu‐opioid receptor agonists with profound respiratory depression

Nitazene opioids (2-benzylbenzimidazole opioids) were first identified in multiple overdose fatalities a few years ago. It has been shown that nitazene drugs are highly active at the mu-opioid receptor, with potency and efficacy exceeding fentanyl. Because of this, isotonitazene was added to Schedule I of the controlled substance list in August 2020 by the Drug Enforcement Agency. Further studies have shown the high potency of the N-desethyl-isotonitazene metabolite, which was similar in potency of isotonitazene itself. The objective of this study was to compare the pharmacokinetics with regards to respiratory depression between N-desethyl-isotonitazene and fentanyl in vivo rabbit model.The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4kg) were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the c5 rootlet. Phrenic neural activity, respiratory rate, arterial blood pressure, and airway carbon dioxide concentration were recorded on a computerized chart recorder (Powerlab/16SP; ADInstrumentes, Australia). We determined the magnitude and time course of respiratory rate depression from 1mcg/kg N-desethyl-isotonitazene and fentanyl and subsequently the dose required to achieve apnea. Data were collected using LabChart data and exported to SigmaPlot 11 (Systat Software, USA) for data processing, data plotting and statistical analysis. Using the phrenic neurogram, we determined the respiratory rate and peak phrenic activity. We plotted the average respiratory rate for each minute normalized to control frequency, removed artefacts, and determined the best fitting curve for each plot. Plots were averaged for each dose and displayed as mean± standard error.Fentanyl (1mcg/kg) depressed respiratory rate by 25±5% from baseline (n=3) while N-desethyl-isotonitazene caused a 38±2% depression (n=6). Recovery to baseline was 150±15 minutes for N-desethyl-isotonitazene and 46±8 minutes for fentanyl. N-desethyl-isotonitazene caused apnea at 4mcg/kg (n=6), and complete recovery to baseline respiratory rate was 201±33 min minutes. Fentanyl caused apnea at 8mcg/kg (n=4), and 64±7 minutes were needed to recovery.Nitazenes are potent synthetic opioids. At equal doses, they cause more profound and longer lasting respiratory rate depression than fentanyl.