Nitazenes: An Old Drug Class Causing New Problems

Abstract

The illicit opioid supply is increasingly adulterated with novel synthetic opioids such as nitazenes. Nitazenes are very potent opioids and are increasingly associated with opioid overdoses and deaths. Despite their potency, nitazenes are reversed by naloxone. Given the high risk of overdose associated with these agents, improvements in the delivery of addiction care and naloxone distribution are needed to prevent morbidity and mortality from nitazenes and other novel opioids.

The Evolution of the Opioid Crisis

More than 107,000 drug overdose deaths occurred in 2022 with an age-adjusted rate of 32.6 deaths per 100,000 of the standard population.¹ Since 2002, the age-adjusted rate of drug overdose deaths increased for both men and women, although from 2021 to 2022 the rate decreased by one percent for women. In 2021 and 2022, drug overdose death rates were highest for adults aged 35–44 years old; people over the age of 65 had the largest percent increase from 12.0 to 13.2%. Regarding overdoses involving synthetic opioids, including fentanyl and fentanyl analogs, rates increased from 2013 to 2022 (1.0 to 22.7%), while rates from heroin overdoses decreased from 2.8 to 1.8% from 2021 to 2022.

This is all consistent with the changing phases of the opioid crisis from mainly heroin-based to more potent synthetic opioids such as fentanyl and fentanyl analogs. The increase in morbidity and mortality was not only due to this change from heroin to fentanyl but also due to adulteration of the drug supply, including non-opioid adulterants such as designer benzodiazepines and other sedatives.^2–4

Additionally, more novel synthetic opioids were also added to the drug supply including fentanyl analogs such as carfentanil, and non-fentanyl analogs such as U-4700 and AH-7921.⁵ Nitazenes are one of the latest classes of novel synthetic opioids to be found in the illicit drug supply.⁶

What Are Nitazenes?

2-Benzylbenzimidazole opioid agonists, otherwise known as nitazenes, are an older class of opioids developed by a Swiss pharmaceutical research laboratory in the 1950s.⁷ Interestingly, members of this class that lack opioid agonism are also used as fungicides to treat nematode infections.⁸ Carbendazim is a well-known antifungal benzimidazole. Other members of the nitazene family were demonstrated to have opioid-like effects but were determined to be very potent with a high risk of addiction. As such, further development was halted, and they were never released for human use.⁹ This class of opioids all contain a benzimidazole ring (a benzene ring attached to an imidazole ring) with substitutions creating analogs with potentially unique properties (Figure 1). Their chemical structures are distinct from morphine so will not be identified by standard drug screens.⁸ Nitazenes can be consumed similar to any other opioid, including intranasally, intravenously, and by inhalation.

Figure 1.

Nitazene Structure

Reproduced from : https://picryl.com/media/nitazene-structure-f88d10

According to the Drug Enforcement Agency’s (DEA) National Forensic Laboratory Information System (NFLIS) Drug database, clonitazene and etonitazene were initially identified in the drug supply between 1999- 2004 before reemerging in 2019.⁷ Isotonitazene was identified in street drugs in Europe in 2019, and since then, has been implicated in more than 200 deaths in Europe and North America.^10,11 Another analog, metonitazene, was first detected in the drug supply during COVID-19 in early 2020.¹² The NFLIS-Drug database has identified more than 4,300 reports of nitazenes since 2019.⁷ As of January 2024, forensic and toxicology reports identified 20 unique nitazenes, although there are likely substantially more in the drug supply now. Clonitazene and etonitazene were both scheduled in the 1960s.¹³ Isotonitazene was made a schedule I substance in 2020, and other nitazene opioids have since followed. However, many still fall outside the Controlled Substances Act and so may be legal, and none are approved for medical use in the United States.¹⁴

Are They Really That Potent?

Nitazenes are very potent opioids, demonstrating a potency up to 500 times that of morphine¹³ (Table 1). Their metabolites may also have activity at the mu receptor, contributing to further respiratory depressant effects.¹⁵ In one animal study, the respiratory depressive effect was greater and the time to recovery of baseline respiratory rate was longer for an isotonitazene metabolite compared to an equivalent amount of fentanyl. Nitazenes are also metabolized in the liver by the P450 system.¹³ As such, polymorphisms including deficiencies or dysfunction of certain CYP enzymes may also impact their clinical effects, similar to other opioids.

Table 1.

Relative Potency of Nitazenes

Drug	Relative Potency to Heroin
Fentanyl	50
Metonitazene	50
Protonitazene	100
Isotonitazene	250
Etonitazene	500

Table reproduced from Holland et al.²¹

Their potency has garnered much attention, both due to the possibility of greater adverse effects (e.g., respiratory depression) and because of misconceptions or misunderstandings regarding the term potency and what it means from a clinical perspective.^5,16,17 Potency is the ability of a substance to exert a chemical effect. Put simply, substances with high potencies need smaller amounts to obtain the same effect comparted to a less potent substance. Clinically, we see this with other opioids that we commonly administer in the hospital. Fentanyl is more potent than morphine. This is partially reflected in the fact that fentanyl is dosed in micrograms and morphine in milligrams when administered in the hospital. However, if enough morphine is administered, a similar magnitude of effect (analgesia and respiratory depression) can be obtained. This means nitazenes may have smaller therapeutic windows compared to other opioids, which is likely part of the reason that development for medicinal use was halted. In essence, very small amounts may mean the difference between therapeutic effects (e.g., analgesia) versus over sedation and respiratory depression (i.e., an overdose). Their greater potency, therefore, implies that it may be easier to overdose on nitazenes compared to other opioids, especially in consideration of the lack of control and precision when they are added in illicitly obtained drugs.

Importantly, potency is independent from a substance’s ability to bind to a receptor (binding affinity), remain on a receptor (dissociation), or its duration of effect. This means that very potent substances may bind poorly (have a low affinity) to a receptor or come off the receptor (dissociate) very easily. As an example, methadone is more potent than morphine but equivalent, small doses of naloxone can knock both of them off the mu-opioid receptor and reverse their effects.^18,19

Another example of these pharmacologic properties is with buprenorphine. Buprenorphine has a very high binding affinity at the opioid receptor, meaning that it binds more avidly to the receptor than most other opioids. In addition to its ceiling effects for (or limit on its ability to cause) respiratory depression, its high binding affinity is another reason it is used to treat patients with opioid use disorder. Once someone is on buprenorphine, even if a very potent illicit opioid is then used, the buprenorphine will remain on the opioid receptors due to its higher binding affinity, thereby competitively inhibiting the binding ability of the more potent opioid. These examples are intended to illustrate the difference between potency and other pharmacologic properties of opioids. This concept will become important in the following discussion of how to manage patients following a nitazene overdose.

Nitazenes in the Drug Supply

Nitazenes are increasingly being detected in the drug supply in the United States and Europe, both in heroin and fentanyl, but also in illicitly obtained alprazolam, oxycodone, and other drugs.²⁰ They can be manufactured rapidly and are inexpensive to produce making them attractive to illicit drug manufacturers.^8,21 Additionally, they do not require crops to produce, which is important because certain countries are prohibiting the cultivation of the poppy plant and production of opium from it. Etonitazene or etodesnitazene was the first nitazene detected in the illicit drug supply.¹⁴ It was first detected in Italy in the late 1960s, Germany in the 1980s, Russia in the 1990s, and the United States in 2003.

Welsh Emerging Drugs and Identification of Novel Substances (WEDINOS) is a drug surveillance programming monitoring trends across Wales and the United Kingdom.²² Nitazenes were first detected by WEDINOS on April 14, 2021. From April 2022 to March 2023, WEDINOS detected 36 samples containing nitazenes. None were originally thought to contain nitazenes with eight (22%) thought to only contain benzodiazepines (alprazolam and diazepam).

In another report, nitazenes were identified in what was thought to be counterfeit hydromorphone.¹¹ The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) received reports from multiple countries of counterfeit oxycodone tablets containing metonitazene and etonitazepyne, as well as brorphine, from 2021–2022.²³ Brorphine is a benzimidazolone, which is structurally similar to nitazenes and fentanyl.¹⁴ It was first known to be synthesized in 2018, and like the nitazenes, is also an agonist at opioid (mu) receptors. Its identification and detection coincided with the declining production and distribution of isotonitazene due to the latter being made a controlled substance. Similar to other novel opioids, brorphine was detected in forensic samples from fatal overdoses.²⁴

The Tennessee State Unintentional Drug Overdose Reporting System (TN SUDORS) was searched for reports of nitazenes from January 2019 to December 2021.²⁵ SUDORS collects information associated with overdose deaths. During this interval, 52 nitazene-involved fatal drug overdoses were identified. The implicated nitazenes were isotonitazene, metonitazene, etonitazene, and protonitazene. Four times as many nitazene-involved overdoses were identified in 2021 than in 2020. Additionally, tablets packaged as health supplements were seized from an international mail facility in the United States from December 2021 to May 2022.²⁶ Etonitazene, etodesnitazene, and isotonitazene were all identified in the tablets.

Implications for Treatment

Nitazenes produce clinical effects similar to those of any other opioid including sedation and respiratory depression. Morbidity and mortality from nitazenes are therefore due to hypoxia following hypoventilation and apnea. Resuscitation should be directed at restoring respiration and oxygenation, which includes rescue breathing and naloxone.

Nitazenes should respond to naloxone. As of this writing, there is not an opioid that naloxone has failed to reverse. There is speculation that due to the potency of some nitazenes and other novel opioids, that larger amounts of naloxone or longer acting opioid antagonists are required.^14,16,17 It is true that some patients are receiving larger doses of naloxone following suspected or confirmed opioid overdoses.

However, there are several plausible explanations for this that do not implicate nitazenes as requiring higher doses of naloxone for reversal. First, more naloxone is being administered prior to arriving at the hospital either by the lay public or first responders due to using the standard 4 mg intranasal (IN) devices, which is the lowest amount that they can administer. As such, doses will be larger when compared to historical data from patients that only received naloxone in the hospital and thus generally received smaller amounts of naloxone, initially. Second, as many patients are hypoventilating or apneic prior to receiving naloxone, they may have very high amounts of carbon dioxide in their system causing respiratory issues or altered mental status even if all the opioid was already reversed. In this situation, someone may continue giving them naloxone as they are still altered or not breathing well. Finally, the persistent respiratory depression or altered mental status may be due to other non-opioid sedatives such as xylazine and benzodiazepines in the illicit opioid supply. Clearly, naloxone or any opioid antagonist will not reverse effects of non-opioid substances.

As previously discussed, potency is independent of other pharmacologic properties so it is not necessarily correct that highly potent opioids require large amounts of naloxone. The use of naloxone was investigated in patients presenting to the emergency department following suspected nonfatal opioid overdoses.²⁷ Data was abstracted from the electronic health record and waste blood samples were sent for analysis. Patients were included if their samples tested positive for nitazenes or brorphine. From September 2020 to September 2022, nine patients met inclusion criteria. Of the six with known naloxone doses and not in cardiac arrest, two patients received 2 mg or less, one received 4 mg IN followed by 0.2 mg intravenous [IV], one received multiple doses for a total of 0.36 mg followed by a naloxone infusion, and one received 2 mg IN followed by two doses of 0.04 mg IV. The remaining patient received 8 mg IN. As such, the authors believe it is reasonable to start resuscitation with standard doses of naloxone (either 0.04 or 0.4 mg of IV naloxone or the 2 or 4 mg IN naloxone devices in the prehospital setting) and titrate up to the improvement of respiratory status.

Conclusion

These incredibly potent opioids with an increased risk of overdose indicate that increasing and improving addiction care and offering harm reduction are even more important. This includes low barrier access to medications for opioid use disorder and increasing access to buprenorphine and methadone especially in more rural areas. From a harm reduction perspective, naloxone distribution is even more important. The public should be trained to administer it and patients at risk should leave the emergency department or hospital with naloxone in hand as opposed to just with a prescription.