Acute Intoxications and Fatalities Associated With Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review

Background: Synthetic benzimidazole opioids (BOs) are highly potent µ-opioid receptor agonists with heroin-like effects. Isotonitazene was first available in 2019 in the drug market, although new analogs have multiplied recently. The authors aimed to identify BO use trends and gather toxicological data from BO-related cases to assist in clinical and forensic investigations. Methods: A systematic literature search was conducted according to the PRISMA guidelines. PubMed and Scopus databases were accessed in October 2021 to identify scientific reports of BO-related intoxication and fatalities. Publication dates, case descriptions, symptoms, autopsy findings, and concentrations of BOs and metabolites in biological matrices were compiled. Results: Data from 8 case reports with 93 fatalities involving isotonitazene ( n = 65), metonitazene ( n = 20), etonitazepyne ( N -pyrrolidino etonitazene) ( n = 8), flunitazene ( n = 4), and/or butonitazene ( n = 1), and 1 acute intoxication involving etonitazepyne were collected. Autopsy findings included pulmonary congestion/high lung weight (66%), cardiomegaly/high cardiac weight (39%), cerebral edema (22%), gastric contents in the airways (22%), and organ congestion (22%). Median peripheral blood concentrations were 1.7 ng/mL for isotonitazene (0.4–9.5 ng/mL, n = 13), 5.4 ng/mL for metonitazene (0.52–33 ng/mL, n = 17), 5.4 ng/mL for etonitazepyne (2.4–8.3 ng/mL, n = 2), 1.3 ng/mL for flunitazene (0.58–2.1 ng/mL, n = 2), and 3.2 ng/mL for butonitazene ( n = 1). Central nervous system depressants were almost always coadministered. Conclusions: Isotonitazene was predominant in cases from 2019 to mid-2020 and was replaced by metonitazene after scheduling in the United States. Typical findings on opioid overdoses have been reported. Peripheral blood concentrations were consistent with a potency similar to that of fentanyl. These results must be interpreted carefully, considering the scarcity of reports on BO-related cases and drug co-exposures.