Old Drugs and New Challenges: A Narrative Review of Nitazenes

National Library of Medicine ^ | Cureus. 2023 Jun; 15(6): | National Library of Medicine

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Abstract

Nitazenes are a group of compounds developed in the 1950s as opioid analgesics, but they were never approved to market. As such, they are not well known outside of academic research laboratories. A characteristic of nitazenes is their high potency (e.g., hundreds to thousands fold more potent than morphine and other opioids and tenfold more potent than fentanyl). In the past few years, several nitazenes, including “designer analogs,” have been detected in the illicit drug supply and have been implicated in overdose mortality, primarily due to their exceptionally high potency. In the street drug supply, nitazenes are often found mixed with fentanyl or other agents but their presence is not always disclosed to drug buyers, who may not even be familiar with nitazenes. These drugs pose a particular challenge since there is little experience in how to reverse a nitazene overdose or potential drug-drug or drug-alcohol interactions. Public health efforts are needed to better inform street drug consumers, first responders, healthcare professionals, and the general public about these “new old drugs” that are infiltrating the recreational drug supply.

Keywords: designer drugs, addiction, opioid use disorder, opioids, street drugs, nitazenes

Introduction and background

In the late 1950s, the synthesis of 2-benzylbenzimidazole opioids led to the creation of several compounds now known collectively as nitazenes - although they do not technically meet the current United States Adopted Name (USAN) definition of an “azene.” They were of particular interest because their chemical structures are distinct from the typical morphine-like phenanthrene motif and meperidine analogs like fentanyl. The nitazenes were intended to be developed as analgesics but they were never approved for any therapeutic purpose [1,2] Their potency and street appeal caused them to be compared frequently to fentanyl, although they are structurally unrelated. As the Drug Enforcement Administration (DEA) and the Food and Drug Administration (FDA) have been better able to identify and schedule numerous fentanyl analogs [3], it appears that chemists in clandestine labs have gone back through historical pharmacology research literature for early attempts at developing synthetic opioids [4]. Novel psychoactive substances (NPS), including “novel” synthetic opioid analogs such as the re-emergence of the older nitazene drugs, are considered the driver in the recent upward trends in overdose mortality in the United States [5]. Despite the fact that nitazenes have been identified in the illicit recreational drug supply, few clinicians are aware of them or their implications for emergency medicine.

NPS are defined as synthetic agents possessing actual or alleged morphine-like or other psychoactive pharmacological properties that are not currently regulated by national or international law. The murky legal status of these substances combined with their potent psychoactivity and relatively inexpensive manufacturing costs makes them valuable street drugs [6]. Drug laws are based on specific agents, so the rapid and consistent emergence of novel drugs that enter the street market every year poses challenges to law enforcement [7,8]. While the DEA has recently introduced scheduling that makes many nitazenes illegal, the creation of new analogs can circumvent those rulings [9]. The aim of this narrative review is to describe nitazene drugs and to discuss the implications these dangerous new substances may have on clinical practice and society at large.

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