Poster Number-77 - When an Old Drug Brings New Challenges: Nitazenes

In the late 1950s, the synthesis of 2-benzylbenzimidazole opioids led the development of several new synthetic opioid analgesics, none of which were cleared or market release. These nitazenes were extremely potent agents and older medical literature documented their chemistry.  Recently, toxicology reports have documented the emergence of nitazenes in the recreational drug stream. Illicit nitazenes, manufactured in clandestine labs, have entered the street drug trade with alarming consequences. 

The public health crisis of opioid use disorder has caused considerable financial impact to the healthcare system and our society at large. This cost is so large it is difficult to estimate fairly. In 2017-2018, the U.S > spent $2 billion just on treating opioid overdoses. An out-of-hospital successful opioid rescue cost an estimated $3000 per event.¹  Over dose deaths are a main cause of death for Americans aged 25 to 64 years,² ( and nonfatal overdoses can be associated with prolonged and costly opioid-related morbidity.  The emergence of new and highly potent synthetic opioids is alarming.

 


Our aim was to report on nitazenes as the latest new synthetic opioid family and the clinical implications of their arrival on the recreational drug scene.


Methods: This is a narrative review and was based on recent literature about the re-emergence of nitazenes. Medline and Google Scholar databases were used along with authoritative websites, particularly government-run sites reporting on this as news. There is very little recent material available about nitazenes.

Results: N

itazenes are potent mu-opioid receptor agonists with psychoactive effects similar to heroin. There are several of these agents, the best known of which is isotonitazene (street name Iso or Tony), which was first identified in Europe in 2019. Metonitazene was identified in North America in 2020. The creation of numerous analogs is possible and technically not an obstacle. Some, but not all, nitazenes are as potent or more potent than fentanyl. Metonitazene was confirmed to be present in 20 forensic autopsies and in most cases was used in combination with other drugs.³  A 2021 analysis in Tennessee found metonitazene and fentanyl as a combination occurred in 26 overdose deaths.⁴

Nitazenes are sometimes mixed with other drugs to add potency, and consumers are not necessarily aware of nitazene additives. Counterfeit pharmaceutical products such as counterfeit hydromorphone tablets have been identified. In this case, inert material is mixed with nitazenes and formed to resemble a pharmaceutical product using a pill press.⁵ (Pill presses are available for sale on Google.)

Some of these “new, old” nitazenes fall outside the Drug Enforcement Administration’s schedule of controlled substances, giving them a murky legal status. Their manufacture in clandestine labs assures that there are no purity, quality, or manufacturing standards. Each new agent brings with it its own toxicity and specific challenges.

The clinical implications are profound because first responders and many emergency clinicians are not aware of nitazenes and many drug users take them without knowing it. Most labs do not routinely test for nitazenes so their presence in the recreational drug stream may be underreported.



Conclusion: Nitazenes are infiltrating the recreational drug market with potentially devastating consequences. These potent synthetic opioids may be mixed in with other drugs or taken in polysubstance abuse and have been associated with overdose mortality. Greater awareness of nitazenes are needed in both the clinical and first-responder communities. The mechanics of nitazene-induced respiratory depression are not elucidated, and rescue protocols should be developed. Nitazene-associated respiratory depression and distress can be challenging to treat.

References: 1. LaPointe J. Opioid overdose care totals $1.94B in annual hospital costs. Revcycle intelligence. Practice management news Web site. https://revcycleintelligence.com/news/opioid-overdose-care-totals-1.94b-in-annual-hospital-costs. Published 2019. Accessed June 6, 2022.
2. Dezfulian C, Orkin AM, Maron BA, et al. Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association. Circulation. 2021;143(16):e836-e870.
3. Krotulski AJ, Papsun DM, Walton SE, Logan BK. Metonitazene in the United States—Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry. Drug testing and analysis, 2021-10, Vol13 (10), p1697-1711. 2021.
4. Trecki J, Gerona RR, Ellison R, Thomas C, Mileusnic-Polchan D. Notes from the Field: Increased Incidence of Fentanyl-Related Deaths Involving Para-fluorofentanyl or Metonitazene - Knox County, Tennessee, November 2020-August 2021. MMWR Morb Mortal Wkly Rep. 2022;71(4):153-155.
5. Ujváry In, Christie R, Evans-Brown M, et al. DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles. ACS chemical neuroscience, 2021-04-07, Vol12 (7), p1072-1092. 2021.