New class of opioids that may be more potent than fentanyl emerges globally

A new class of potentially deadly synthetic opioids is suddenly appearing around the globe, including in the US, and scientists are rushing to figure out how to detect it in the drug supply.

Within the last month, nitazenes were implicated in four overdose deaths in Manchester, England; they were detected in over 2,500 counterfeit oxycodone pills in Hamilton, Canada; and they were found for the first time in the Netherlands. The US Drug Enforcement Administration has warned about their appearance in Washington DC.

Nitazenes are a class of synthetic opioid first developed in the 1950s but never approved to go to market.

Claire Zagorski, a translational science PhD student at the University of Texas, Austin, who specializes in drug checking, said that after drug companies scrapped nitazenes, “they filed the patent, they filed the synthesis and stuck it away on a shelf, and then they were unearthed by people in the illicit market”.

Nitazenes were first detected in the US in 2019, and appear to have proliferated rapidly in the last year.

Christophe Stove, a professor who works in the laboratory of toxicology at Ghent University in Belgium, said that all the “ingredients are in place” for nitazenes to create a new drug crisis. The Taliban recently banned poppy production in Afghanistan, which has led to a heroin shortage in the illicit drug market, especially in Europe, where heroin is still more popular than fentanyl. For illicit drug suppliers, nitazenes could be a cheap and easy way to fill that gap.

Zagorski studied how isotonitazene, one of the more commonly detected nitazenes, is synthesized in order to understand its viability in the synthetic drug market. She found that it is cheap to produce with legally available ingredients.

Nitazenes are also a cheap option because some of them are much more potent than fentanyl, which is already roughly 100 times more potent than morphine. According to Stove, whose lab has studied most known nitazenes as well as some that may emerge in the near future, animal studies confirm that the strongest known nitazene, etonitazene, is “roughly 40 times more active than fentanyl”.

He said other nitazenes have a range of strengths depending on the precise chemical structure, from slightly weaker than fentanyl to much more potent.

That high potency level raises a number of challenges. Richard Bade, a senior research fellow in environmental sciences at the University of Queensland in Australia, conducted a study to determine if nitazenes could be detected in wastewater – this method is also used to determine community levels of Covid-19.

Bade said that nitazenes “are quite challenging” because their potency means “the concentrations seen in wastewater can be very low, even if they are known to be in a community”. His study found that it is possible to detect nitazenes in wastewater, but they require more sensitive methods than other substances.

The high potency of some nitazenes also makes them more dangerous for people using them. Stove said some pills might end up containing a lot of nitazene powder if illicit manufacturers don’t mix them properly: “If you’re unlucky enough to get the ones that have a bit more, you may overdose,” he said.

Nitazenes are especially dangerous when people don’t know they’re taking them. Stove said that until recently, most nitazene consumers were specifically seeking them out online. But these days, nitazenes are showing up in street drugs marketed as other things, like Xanax or oxycodone. Someone who has not developed a tolerance for opioids and thinks they’re taking a different drug is more likely to overdose when exposed to high-potency opioids like nitazenes.

Test strips are an inexpensive method that allows people to see if their drug supply contains undisclosed substances.

“It’s really simple. It’s a little strip that you dip in the liquid that you prepared to inject or smoke your drug or whatever,” said Zagorski. After you dip the strip, you wait to see if a line appears indicating a positive result – the same concept as a Covid test or a pregnancy test.

Harm-reduction organizations often distribute fentanyl test strips to help prevent overdoses, but fentanyl test strips do not detect nitazenes. While the two drug types have similar effects, nitazenes are chemically different enough from fentanyl that they don’t show up on fentanyl test strips.

One company already manufactures and sells nitazene test strips, although they have yet to be widely distributed. Stove and his colleagues worked at an urgent pace to publish a study this month on whether the strips are functional enough to be helpful.

“I had my PhD students really prioritize this project, because we really felt that this information had to be sent out to the users of these strips,” said Stove. The study found that the test strips were generally effective, although they might not detect every type of nitazene. “If you don’t get a positive result, it doesn’t mean that the drug is safe, but that holds true for any drug-checking using test strips,” Stove said, emphasizing that the strips can only test for one substance at a time.

The gold standard for drug checking involves expensive, sophisticated instruments, like gas chromatography/mass spectrometry machines, according to Zagorski. But, she said, these machines are expensive to operate and “there isn’t a lot of money for harm reduction”. In Texas, where Zagorski’s lab is based, drug-checking tools, including GC/MS machines and drug test strips, are illegal.

Zagorski is glad that European researchers, like Stove, are also working to better understand and detect nitazenes.

“Europe has much more progressive laws with this kind of thing, and they’re able to do testing a lot more quickly,” she said. In the US, “even if we kind of objectively see the utility in studying the drug supply, it very much has this kind of suspicious patina over it, kind of like, ‘Why are you studying this?’” she added.