Synthetic Opioids

Loren Bonner

Nitazenes, a group of powerful illicit synthetic opioids derived from 2-benzylbenzimidazole, are increasingly turning up in overdose deaths across the country.

Among the drugs in this class are isotonitazene, protonitazene, and etonitazene. Those analogs can exceed the potency of fentanyl. Another nitazene analog, metonitazene, has similar potency to fentanyl.

In 2022, researchers reported in CDC’s Morbidity and Mortality Weekly Report that nitazine-involved fatal drug overdoses in Tennessee rose from 0 in 2019 to 10 in 2020, jumping to 42 in 2021. They noted that this number is likely an underestimate because of low testing frequency.

“Given their potency, raising awareness about nitazenes and implementing strategies to reduce harm through increased testing, surveillance, and linkage to treatment for substance use disorders are of vital importance,” wrote researchers.

In February 2024, The Lancet published a research report titled “Nitazenes—heralding a second wave for the UK drug-related death crisis.” In that report, researchers cited 54 deaths in a recent 6-month period, reported by the UK National Crime Agency, in which nitazenes were detected in postmortem toxicology.

“This is likely the tip of the iceberg, as many tests are still in process and emerging drugs are not routinely tested for,” researchers wrote. “Other European countries, particularly the Baltic states, have also reported increasing numbers of deaths related to nitazenes.”

Potent synthetic drugs such as nitazenes offer clear benefits for producers. They can be manufactured rapidly and inexpensively, said the researchers in The Lancet.

Scheduling laws

Nitazenes were originally developed in the 1950s as an alternative to morphine. But they were never pursued commercially and are not FDA-approved.

In 2020, DEA announced a temporary placement of isotonitazene as a Schedule I controlled substance. That same year, isotonitazene was detected in autopsy reports in more than 180 cases in 18 states, with clusters in Illinois, Indiana, Michigan, Wisconsin, Minnesota, and Tennessee, according to a 2020 paper published in the International Journal of Drug Policy, based on research by Krotulski and colleagues in the Journal of Analytical Toxicology published in 2020.

In 2021, the United Nations Commission on Narcotic Drugs added isotonitazene to its Schedule I classification in 2021. After this change, other nitazenes—specifically protonitazene and metonitazene—began appearing on the streets.

“The context of isotonitazene’s rapid ascent demonstrates that scheduling laws are ineffective at reducing drug-related harms, illustrating the so-called ‘balloon effect’ of drug prohibition diverting production to other, often more harmful substances,” wrote researchers in the International Journal of Drug Policy article. “Clinicians, people working in harm reduction, and researchers must be alert to this rapidly changing risk environment.”

Naloxone doses

Researchers in a JAMA Network Open paper from August 29, 2023, said that the exact motivations to produce nitazenes 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. This change in chemical precursors may have led to these newer and more potent opioids,” they wrote.

That research team looked into the question of the effectiveness of naloxone in reviving patients in the emergency department with novel potent opioids compared with fentanyl overdose. Researchers noted that synthetic opioids, such as fentanyl and nitazenes, are among the fastest-growing types of opioids being detected in patients in the emergency department with illicit opioid overdose.

In the study cohort of 537 patients, all patients coming in with novel potent opioid overdose presented with opioid overdose symptoms and received multiple doses of naloxone. Compared to patients coming in with fentanyl overdose, patients with novel potent opioid overdose had a higher number of naloxone doses administered to them in the hospital. They also found that metonitazene overdoses were associated with cardiac arrest and more naloxone doses overall. ■