A novel opioid developed by National Institutes of Health researchers has shown early potential to deliver powerful pain relief without the addiction and respiratory risks tied to conventional opioids, according to a study published in the science journal Nature.
The compound known as DFNZ — formally N-desethyl-fluornitrazene — relieved pain in lab rodents in preclinical testing while not resulting in drug dependency or meaningful withdrawal effects, according to the study.
The discovery emerged as National Institute on Drug Abuse researchers revisited nitazenes, a potent class of synthetic opioids abandoned in the 1950s because of their high potency.
In modifying the compounds to target opioid receptors while reducing potency more selectively, researchers uncovered DFNZ, a “superagonist” compound.
Researchers believe DFNZ eventually could be used to treat surgical, cancer-related and chronic pain. The compound has so far been tested only in rodents. With an uncertain timeline, the NIDA team is pursuing additional preclinical studies to bolster an application for approval to test in humans.
Dr. Ajay Wasan is a pain medicine specialist and psychiatrist as well as a professor of anesthesiology and the co-director of the Center for Innovation in Pain Care at the University of Pittsburgh School of Medicine. He called the discovery a “breakthrough chemical” and “the equivalent of hitting a grand slam at your first time at-bat.”
But he also urged caution.
“Often it takes about a decade to get it to humans, if it makes it that far,” Wasan said. “A lot of times, the doses used in animals are much higher than what you would use in a human. When you use lower doses in humans, you may not see any benefits. That’s unlikely to be true here because this is a very powerful opioid.
“And then the other thing is side effects. You really don’t know if humans can tolerate those things. So it’s exciting and promising, but it really has to be tested, and it’s just the first study.”
Recalibration mode
The dangers of conventional opioids are well known.
In 2017, the U.S. government declared the opioid epidemic a public health emergency. By 2023, opioids were linked to roughly 80,000 deaths annually from prescription and illicit substances, according to the National Center for Drug Abuse Statistics, and were involved in 7 in 10 overdose deaths.
Nearly 9 million people misuse prescription opioids in a year, according to the National Center for Drug Abuse Statistics. Since 2021, opioid manufacturers, distributors and retailers have agreed to pay out more than $57 billion in settlement funds to state, local and tribal governments.
Dr. Michael Patterson, a pain medicine specialist with more than 15 years at Allegheny Health Network, said DFNZ’s potential speaks to a longstanding challenge: treating a subjective pain problem without relying heavily on highly addictive drugs.
“We had this addiction issue that developed, and when I started my training, the pendulum had swung too far in one direction, and we actually were making things worse,” Patterson said. “Right now, we’re kind of in a recalibration, and I think we’re trying to figure out a soft landing.”
He said if DFNZs emerge from testing as early indications speculate and if the compound is implemented slowly with care, it could contribute to pain specialists returning to a more balanced prescribing model.
“We’ve seen where people have committed suicide or harmed themselves because they can’t access treatment,” Patterson said. “And so there’s got to be a balance where certainly there’s people who respond and benefit.”
What the study revealed
In the study, rats experiencing pain and trained to press a lever for doses of DFNZ self-administered the drug but quickly stopped seeking it once researchers substituted saline. The animals later showed just one of the 14 common signs of opioid withdrawal — irritability marked by vocalization.
That differed from behavior typically seen with opioids such as heroin, morphine and fentanyl, where drug-seeking behavior often persists after the drug is removed.
Researchers suggested the difference may stem from how DFNZ affects dopamine in the brain’s reward center, triggering slower dopamine release while avoiding the rapid surges associated with addictive behavior.
Wasan and Patterson said DFNZ is more likely to become another “tool in the toolbox” for clinicians alongside other pain-management approaches rather than a standalone breakthrough solution.
“It’s not going to replace everything and be this blockbuster,” Wasan said. “At the same time, the field (of pain management) has been evolving. There are more and more non-opioid treatments being done … and there are new non-opioid medications that have come out and are FDA approved.
“So by the time this, in theory, might become FDA approved, you might have a whole range of non-opioid medications where your need for opioids would be less and less and less.”
Potential applications
Surgical settings, oncology and treating individual flare-ups from chronic pain outside the emergency room were among the potential applications for DFNZ that Wasan and Patterson highlighted.
“There will always be a need for some opioid analgesics. Think about major traumas, major surgery. There’s going to be some role at some point,” Wasan said. “If there’s a better opioid out there that you know produces good pain relief but has very few side effects and few … negative consequences, then it certainly will have a role.”
Patterson calledthecompoundpotentiallya“significantgamechanger”forthosedealingwithcancer-relatedpain.
“One of the concerns is that those patients, particularly at the end of life, you’re titrating that dose. You are concerned not with addiction aspects, but the respiratory aspects. Is there a way of providing pain relief without that concern?” Patterson said.
Both noted that, even absent the withdrawal side effects, long-term opioid use still can lead to issues like metabolism changes, osteoporosis, endocrine system abnormalities, immunosuppression and constipation. Those issues, they said, would render DFNZs incompatible with managing chronic pain.
“The Holy Grail is something that gives you pain relief without the side effects,” Patterson said.
More rigorous and purposefully focused testing, they said, would be needed to assess DFNZs viability for treating opioid use disorder.