The new opioid painkiller has surprisingly few side effects

Using the long-abandoned class of opioids as a starting point, scientists have discovered opioid painkillers that do not have the typical side effects of this class of drugs (nature 2026, DOI: 10.1038/s41586-026-10299-9). In tests with mice, the molecule – known as N— desethyl-fluornitrazene, or DFNZ — had less potential for addiction and did not cause respiratory depression, which is what causes many opioid overdose deaths. Although this compound has many hurdles to becoming an approved drug, it could be used as an analgesic and as an alternative to methadone in the treatment of opioid-use disorder.

DFNZ is a member of the nitazine family of opioids. Because of their high potency and overdose risk, nitazines were discontinued long after they were first reported in the 1950s. Etonitazene, the most potent member of the nitazene family, is 1000 times stronger than morphine.

Researchers led by Michael Michaelides and Kenner C. Rice at the US National Institute on Drug Abuse at St. Jude Children’s Research Hospital wanted to develop a radiolabeled version of etonitazine so they could use positron emission tomography (PET) to study its ability to enter the brain. They removed the fluorine atom from the ethoxy group of atonitazine, which also reduced the compound’s potency, and created a version of fluorine-18.

The researchers gave the rats a radiolabeled compound and used PET to observe brain penetration, but they were in for a surprise. “We thought it would stay in the brain longer and cause more negative effects,” Michaelides says. Instead, the team observed that the radiolabeled compound goes in and then quickly comes out of the brain.

This “led us to speculate which metabolites would not be present in the brain,” Michaelides says. The primary metabolite became DFNZ.

Researchers used medicinal chemistry, structural biology, pharmacology, and animal studies to study DFNZ. They describe the compound as a μ-opioid receptor superagonist—a molecule that exerts a greater effect than a full agonist such as morphine.

DFNZ “has an overall very interesting profile that seems to be different from other existing opioids,” Michaelides says. It can treat pain while it doesn’t seem to enter the brain, and it seems to affect the release of dopamine in the brain in a way that’s different from other opioids — meaning it’s less likely to be abused. It also does not produce the tolerance or withdrawal symptoms associated with other opioids. Michaelides says researchers are now pursuing a new drug application for DFNZ.

Victor Mathis and Emmanuel Darque, who study neurological disorders at the University of Strasbourg, write in a commentary accompanying the article that this work is “a promising approach to opioid analgesics that separates pain relief from side effects such as tolerance, hyperalgesia, respiratory depression and potential abuse.”nature 2026, DOI: 10.1038/d41586-026-00806-3).

But Mathis and Dark noted that there are important limitations to address to avoid repeating the mistakes that led to the opioid crisis. Premature and overly optimistic calls for safe analog formulations of oxycodone “stand as a stark reminder that early claims of responsibility for reducing abuse require rigorous, independent, and long-term evaluation,” they write.

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