Nitazenes

"Highly potent synthetic opioids have not played such a prominent role in rising deaths among people who use drugs in the UK. Global drug markets are, however, rapidly evolving. Of particular concern is the emergence of nitazenes: a class of synthetic opioids developed by the pharmaceutical industry in the 1950s but never approved as medicines.³ Like other opioids, nitazenes can cause fatal respiratory depression, and some are hundreds of times more potent than heroin (table).³ In the UK, nitazenes have been detected in substances sold as other opioids, benzodiazepines, and cannabis products.⁴ This means many consumers are using nitazenes inadvertently, unaware of the risks they face."

"The current trend towards the use of high potent synthetic opioids, especially fentanyl, has caused an extreme increase in the prevalence of non-fatal and fatal overdose events [13, 14]. However, the trend towards higher opioid potency is still ongoing, with several analogues and novel opioids becoming increasingly available. Particularly carfentanil, an analgesic used in veterinary medicine to anesthetise elephants, provides reason for concern. It is estimated to be around 10’000 times more potent than morphine. In 2021, 8% of all illicit drug toxicity deaths in British Columbia (BC) Canada involved this agent [14, 15]. Furthermore, benzimidazole opioids or “nitazenes” emerged in North America and have since gained a foothold in its drug street markets [16, 17]. Nitazenes and their analogues can exceed the potency of fentanyl by a factor of ten and their availability is steadily increasing [18]. For example, isotonitazene was identified in Canadian drug seizures 12 times in 2019, a number that increased to 288 times in 2021 [19]."

"Novel potent opioids (NPOs) are novel nonfentanyl opioids in the illicit opioid supply. Synthetic opioids are one of the fastest growing classes of opioids being detected in patients in the emergency department (ED) with opioid overdose (OD).¹

"A subclass of synthetic opioids referred to as nitazenes contain a 2-benzylbenzimidazole structure that has μ-opioid agonism. Isotonitazene, metonitazene, and N-piperidinyl etonitazene are NPOs with a piperidine benzimidazolone structure. Brorphine is a nonnitazene NPO that is a full μ-opioid receptor agonist with a structure similar to fentanyl. NPOs possess high potency at the μ-opioid receptor and an understudied propensity for adverse health effects. Nitazenes are structurally unrelated to fentanyl, but have been found to be up to 1000-fold more potent than morphine.¹

"The exact motivation to produce nitazenes and brorphine are unclear. The increased regulation of fentanyl and fentanyl analogues throughout the last decade may have led to a change in the chemical precursors required for clandestine laboratory production that were not yet regulated.¹ This change in chemical precursors may have led to these newer and more potent opioids."

"This study is the first, to our knowledge, to document the clinical sequelae and naloxone administration for patients who were in the ED following confirmed NPO drug OD. The NPO group was administered a statistically significantly higher number of in-hospital naloxone boluses compared with the fentanyl group, which corresponded to a moderately large effect size. While these findings were based on limited sample sizes, we detected a large effect size for the association between increased naloxone doses and NPO overdose. The majority of patients with ODs that involved NPO received 2 or more doses of naloxone, whereas most of the patients who OD from fentanyl only received 1 dose of naloxone. While this study was statistically underpowered to detect differences in naloxone administration in total cumulative dosage and clinical sequelae between patients with NPO and fentanyl only OD, this study provides important preliminary data on NPOs to inform clinicians and patients of the severity of ODs involving NPOs. Furthermore, this preliminary data underscores the urgent need to study NPOs in a larger, future cohort. These data suggest that NPOs may have higher potency than fentanyl and by extension heroin.

"NPOs, such as nitazenes and brorphine, are relatively new to the illicit opioid supply but may have significant clinical implications based on the findings of the present study. The nitazene drug class is structurally unrelated to fentanyl but has been found to be up to 1000-fold more potent than morphine.¹ Isotonitazene and brorphine are 2 of the NPOs that emerged as novel psychoactive substances (NPS) in 2019 and 2020, respectively. Brorphine was initially created in 2018 and first noted on the recreational drug market in 2019.⁸ Nitazenes and brorphine have consistently demonstrated stronger in vitro μ-opioid receptor activation than fentanyl¹ but until now translation of these findings to the clinical setting has been difficult.

"In general, naloxone dosing was high in both groups studied, which may have been influenced by the prehospital administration of 2 mg naloxone intranasally in most regions studied. In the present study, most patients in the NPO group required multiple doses of naloxone. However, the fentanyl only group received almost 50% more naloxone than the NPO groups. Thus, while the present study was underpowered to calculate statistically significant differences in cumulative naloxone administration, true population differences may exist and require further study.

"NPOs have higher μ-opioid receptor activation than morphine and fentanyl, which has previously been demonstrated by an in vitro study which pharmacologically evaluated 10 nitazenes using 2 cell-based β-arrestin2/mini-Gi recruitment assays monitoring μ-opioid receptor activation.¹ In addition, there appear to be differences within each drug in the nitazene class. In the present study, metonitazene appears to have the most severe clinical toxicity given that both patients in which metonitazene was detected presented in cardiac arrest, and 1 patient died."

"During the 1950s, nitazenes were developed by commercial pharmaceutical companies as synthetic opioid candidates and they were described in medical and pharmaceutical literature of the era. Thus, clandestine labs needed only to turn to the historic pharmacological literature to learn about the nitazene family. The European Monitoring Center for Drugs and Drug Addiction was first notified about the presence of isotonitazene in a biological sample obtained in July 2019 [15]. Since that time, isotonitazene has been implicated in over 200 drug-related overdose deaths in Europe and North America [7], but its presence likely is under-detected because many testing facilities are not set up to test for isotonitazene, or any other nitazenes, for that matter [8].

"Metonitazene was first identified in the street drug supply during the COVID-19 pandemic (early 2020) [13]. Metonitazene has been confirmed in 20 authentic forensic autopsies with an average serum concentration level of 6.3 ± 7.5 ng/mL (median 3.8 ng/mL, range 0.5 to 33 ng/mL) and urine concentrations of 15 ± 13 ng/mL (median 11 ng/mL, range 6-46 ng/mL) [13]. In those 20 cases, metonitazene was the sole opioid found in 30% of the decedents, but metonitazene was more often used in combination with other drugs such as fentanyl, benzodiazepines, hallucinogens, and other opioids. Medical examiners listed metonitazene as the drug contributing to the death and the manner of death was determined to be accidental in all cases [13]. A 2021 analysis of unintentional drug overdose deaths that occurred in Knox County, Tennessee, United States, found that 26 of the 218 overdoses (12%) involved metonitazene combined with fentanyl [2].

"Nitazenes are available in powders, counterfeit tablets, or liquids and may be mixed with inert substances and/or combined with other drugs, such as heroin, fentanyl, and benzodiazepines [7]. Their inclusion in other drug products is not detectable by consumers and may not be disclosed to them by sellers. When the new clandestine nitazenes entered the illicit market, they were not scheduled as controlled substances. In December of 2021, the DEA temporarily put numerous nitazenes on its Schedule I [9]. Since there are few validated methods to search for these substances and little is known about the network of clandestine labs and chemists who manufacture these drugs, the geographical distribution of these drugs is not known [7]."

"Following the core scheduling of fentanyl analogues (first temporarily in 2018 and then permanently in 2023), the illicit recreational drug market started switching to alternatives that were not registered as Schedule I Substances [12]. Interestingly, researchers predicted the misuse of nitazenes as early as 1975 due to the relatively easy manufacturing process and extreme potency [13]. According to the United Nations Office on Drugs and Crime (UNODC), the number of nitazene analogues is now quickly rising, with the European Union Drugs Agency (EUDA) now monitoring 81 new opioids, 16 of which are nitazenes [14, 15]. As of 2024, the UNODC has listed a total of seven of these nitazenes as Schedule I Substances: etonitazene and clonitazene (added in 1961) and butonitazene, protonitazene, etonitazepyne, metonitazene and isotonitazene (all five added between 2021 and 2024) [16]. These last five nitazenes were added in recent years due to the sudden increase in sales and usage of these substances, mostly in North America (United States and Canada), Australia and Europe (United Kingdom, Slovenia, Estonia, Latvia, Belgium and the Netherlands) [14, 17].

"Due to the potency of nitazenes in combination with often unknowing buyers and users of the substances, the UNODC, the World Health Organization (WHO) and the EUDA have warned and alerted agencies and health professionals of the emergence of these substances [14, 17, 18, 19]. The UNODC reports that synthetic opioids account for the largest burden of disease attributed to drug use disorders, as the high potency of these substances, including fentanyl and nitazenes, can cause overdoses with only minimal quantities of drug ingested [14]."

"Naloxone appears to be effective in treating PNZ [Protonitazene] intoxications, with most patients who received naloxone recovering completely, but the exact efficacy of naloxone and the effective dosage amounts are unknown due to the complicated nature of the currently reported intoxications. In the reviewed case reports, naloxone was administered through intranasal, intramuscular and intravenous routes [29, 30, 32]. The efficacy of naloxone in these cases cannot be properly assessed due to the coingestants, on which naloxone has no effect, such as alcohol or benzodiazepines. As the in vivo half‐life of PNZ is not known, there are insufficient data to determine whether repeat naloxone dosing is required to combat PNZ intoxications, as it is with several other opioids with long half‐life times. If they present themselves, cases concerning monointoxications with only PNZ ought to be reported to learn more about these aspects of the substance. Furthermore, the statement made by Partridge et al. [29] regarding the requirement of higher doses of naloxone for nitazene intoxications must be nuanced by noting that case reports can only retrospectively document how much naloxone was given and, as such, cannot state that the naloxone ‘was required’. To do this, further study is necessary."

"This study presents an independent, laboratory-based assessment of the potential of the first commercially available NTS for drug checking applications. The NTS displayed limited lot-to-lot variability, with an experimental limit of detection for isotonitazene of 2000 or 3000 ng/mL. Twenty-four of the 33 evaluated nitazene analogues cross-reacted with the NTS at concentrations at or below 9000 ng/mL. The test strips consistently detected the presence of a nitazene analogue in 6 authentic drug samples. Based on our cross-reactivity data, most of the currently circulating nitazene analogues, except for ‘desnitazenes’, are likely detectable with the BTNX NTS, while analogues with a lengthened linker between the aromatic groups may not be detectable. Altogether, taking into account limitations that hold true for test strip-based testing in general, and taking into account the cross-reactivity data presented here, the findings from this study indicate that the BTNX nitazene immunoassay test strips show potential to recognize the presence of nitazene analogues in drug preparations in real-life settings."

"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."

"The trend towards higher potency is likely most indicative of what to expect from future illicit substance market developments. According to Canadian drug seizure statistics heroin is no longer among the top ten recovered illegal substances [32, 40]. Fentanyl is currently the most-seized opioid but likely in the process of being replaced with even more potent synthetic opioids [10, 11]. This trend is exemplified by the fact that carfentanil is now being found more frequently than heroin during drug seizures [40]. Fentanyl’s evolutions to the drug of choice demonstrates how the market supply itself can define and change drug use patterns [10]. Although there is currently no clear indication of individuals specifically seeking and prioritising nitazenes or fentanyl-analogues over fentanyl, these substances have the potential of becoming the drug of choice in the near future. The transition to ultra-potent synthetic opioids could resemble the one that happened 5 years ago with fentanyl. That is, individuals who use opioids will be gradually exposed to these drugs, as the fentanyl sold will be cut, knowingly or unknowingly to the individuals using it [11, 45]. The exposure to these substances will likely lead to increased tolerance, and fentanyl alone may no longer provide the sought after physical and psychological effect it once did. This allows agents that are initially perceived to be contaminants to become to the drug of choice. Notably, a shift towards less potent and less dangerous substances has to date not been observed either in opioid markets or in other substance classes, making this development seem unidirectional and irreversible."

"Nitazenes are a series of highly potent, fully synthetic opioids that have recently emerged into the illicit drug supply and has led to many deaths throughout the world.¹⁷ Nitazenes are usually added to counterfeit tablets (i.e., benzodiazepines) or combined with heroin, where numerous incidences of overdose have been reported due to unintentional consumption.¹⁷⁻¹⁹ Recent media reports are also emerging of e-cigarettes spiked with nitazenes, in addition to a WEDINOS submission from November 2022.^14,20,21 An overdose death from opioid toxicity associated with the use of a nitazene-containing e-cigarette has also been reported in Australia.²²"

"On 9 November 2023, the Health Service Executive Ireland (HSE) was notified of an unusually high pattern of opioid overdoses occurring in Dublin city centre among people attending homeless services. This represented the very early signs of drug market changes and the emergence of N-pyrrolidino protonitazene in Ireland. During the following 5 days there were 57 overdoses among people who use heroin in Dublin city centre, followed by a second outbreak over 6 days in the Cork region in December (n = 20) [1]. Rapid responses helped to protect people who use drugs through an urgent analytical review of samples, mobilization of frontline services to deliver tailored harm reduction measures and ‘Red Alert’ risk communications issued for these regions.

"Two additional alerts have since been issued in 2024 following the seizure in Dublin of another nitazene powder (protonitazene) and the identification of N-pyrrolidino protonitazene in a Dublin prison setting leading to a small number of overdoses (< 5) [1]. It is too early to speculate on the long-term impact of nitazenes in Ireland, but this is an area requiring intensive monitoring. Nitazenes sold as falsified medicines and as other drugs in the United Kingdom and Europe [2, 3] as well as the use of these substances by non-opioid using populations with no tolerance or access to naloxone, is a particular concern."