Nitazenes

Media reports frequently refer to nitazene class opioids simply as "nitazene",^[2] but nitazene itself is only around the same potency as morphine and has only rarely been identified as having been sold as a recreational drug. References to "nitazene" in the context of drug overdoses or police seizures almost invariably refer instead to one of the more potent analogues, but these are generally regarded as broadly interchangeable, and initial reports often do not identify the particular compound involved. Most cases of abuse and overdose are linked to potent derivatives such as metonitazene, protonitazene, isotonitazene, etonitazepyne, and etodesnitazene.

In the mid-1950s, the pharmaceutical research department of Ciba AG discovered the (low) analgesic effect of 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene).^[3] Systematic derivatization of this parent compound in the course of structure-activity relationship investigations revealed an enhancement of activity by nitration of the 5-position. 4'-Methoxylated and ethoxylated compounds achieved potencies in the hot plate test that were previously unattained.^[4] The thus discovered etonitazene is the most potent nitazene opioid known to date. The morphine-like mechanism of action was elucidated from the antagonizability of analgesia with allylnormorphine. In a human clinical trial two nitazenes (etonitazene and clonitazene) were investigated in 363 patients and the results were published in 1958.^[5]

The early 21st century marked the beginning of the spread of nitazene opioids in the drug scene and in the early 2020s the substances were recognized as emerging drugs of abuse.^[6][7] Isotonitazene was first identified in samples of illicit drugs, and implicated in opioid overdose deaths in Europe, Canada, and the United States in March and April 2019.^[8] Previously known nitazene analogs such as metonitazene and butonitazene, as well as novel nitazenes not previously described in the scientific or patent literature, have since been discovered in toxicologic samples during forensic investigations.^[7] Nitazenes have been found in pills missold as other drugs, such as benzodiazepines, in the United Kingdom^[9] and New Zealand.^[10]

Nitazenes have fueled a drug crisis in the United Kingdom and Baltic States, with the British government reporting more than 400 overdose deaths from the drugs in the 18-month period through January 2025.^[11] In the UK, abuse of nitazene analogues first emerged in 2023 as an important cause of drug-overdose death, with it being linked to 54 deaths over a six-month period. Most of the deaths have occurred outside London, the source of supply is thought to be by post from laboratories in China, and some of the deaths have been associated by the mislabeling of nitazenes as fentanyl.^[12]

The class of nitazene opioids is defined chemically by the presence of the benzimidazole core structure and pharmacologically by μ opioid agonism.

Nitazenes are benzimidazoles that are substituted with a dialkylaminoethyl group at the 1-position, in the 2-position with a substituted benzyl group and often in the 5-position, usually with a nitro group but sometimes with other substitutions. Compounds substituted in the 6-position are less effective, while the 4- or 7-substituted compounds are not analgesically active. Analgesically active nitazenes are also usually substituted in the para-position of the benzyl group, and only rarely in the ortho or meta positions. At the methylene linker, a methyl or an amide group is tolerated stereospecifically by the target receptor, and this carbon can also be replaced by CH₂CH₂, S, or NCH₃ with reduced but in some cases still significant activity.^[13][14] Nitazenes are structurally unrelated to most other opioids, but have structural similarity to benzimidazole derivatives from the orphine group, as well as to viminol and its analogues.

The compounds are derived from the historical prototype 1-(β-diethylaminoethyl)-2-benzylbenzimidazole (desnitazene). The replacement of the N,N-dialkylamino unit by pyrrolidinyl or piperidinyl, which is found in nitazepyne and nitazepipne compounds, falls into the spectrum of designer drugs. Substitution of the benzyl for thienylmethyl, pyridylmethyl, α-napthylmethyl or styryl has a potency-reducing effect.^[15][16] Substitution in position 4 of the benzyl affects analgesic potency in the following order: ethoxy > isopropyloxy > n-propyloxy > methoxy > methylthio > H/Cl/F > hydroxy. The most potent of the known compounds contain a nitro group in position 5.^[16][17] The replacement of benzimidazole with an indole has been known from studies conducted by Ciba AG since 1963.^[18]

Since 2024, an immunoassay-based point-of-care testing in the form of test strips is available for the detection of nitazenes.^[19] The drug sample is added to water and requires sufficient solubility for the test to be successful. The detection limit of the highly potent isotonitazene is given as 2000-3000 ng/mL. The test is of limited general applicability for non-nitazene benzimidazole opioids. Desnitazenes, for example, which are not substituted at the benzo structure portion, cannot be successfully tested by this method. According to the manufacturer, there is no cross-reactivity with frequently used adulterants such as acetaminophen, caffeine, diphenhydramine, other non-benzimidazole opioids (heroin, methadone, fentanyl) and common non-opioid drugs (xylazine, MDMA, cocaine, ketamine).^[20]

• Benzimidazole opioids