The emergence of nitazenes: a new chapter in the synthetic opioid crisis

As reported by United Nation Office on Drugs and Crime (UNODC), opioids are the first class of psychotropic substances worldwide in terms of overdose deaths and the second most widely used. In North America, particularly the United States, what was a dramatic decade-long opioid dependence has now escalated to persistent health emergency. Here, the number of overdose deaths has risen markedly since the appearance of several more and more potent synthetic opioids, in particular fentanyl and its structural analogs. The restrictions applied to the fentanyl class have effectively produced a progressive decrease in UNODC reports of new derivatives, but illegal markets have been able to adapt quickly by turning to a new class of synthetic opioid receptor agonists, the nitazenes, characterized by potent side effects that prevented any safe use as sedative and analgesic drugs. Since the appearance of isotonitazene in 2019, the scientific community has been challenged in the identification and characterization of new structural analogs, the study of their pharmacodynamics and pharmacokinetics, the identification of corresponding metabolites, and the development of analytical methods able to identify and quantify these compounds even at the near or sub ng/mL concentrations at which they are present in biological samples. The purpose of this review, 6 years after the emergence of the phenomenon, is therefore to present an updated overview of the knowledge gained and the progress made in enhancing the tools available to forensic toxicologists, ultimately supporting efforts to fight the spread of this dangerous class of abused substances.