Summary: Researchers have discovered a “holy grail” in pain management: a high-potency opioid that provides powerful relief without the deadly side effects of addiction and respiratory depression. The study focused on a sidelined class of 1950s synthetic compounds called nitazenes.
While the parent drug (FNZ) was dangerous, its metabolite, DFNZ, acts as a “superagonist” that provides hours of pain relief but fails to trigger the rapid dopamine bursts that cause addiction. This discovery challenges the long-held belief that “stronger” opioids are inherently more dangerous.
Key Facts
- The Nitazene Revival: Nitazenes were abandoned in the 1950s for being “too potent.” Modern engineering allowed the NIH team to isolate DFNZ, which targets the mu-opioid receptor with extreme efficacy but high safety.
- No Breathing Suppression: Unlike fentanyl or morphine, which depress the respiratory system (the leading cause of overdose deaths), DFNZ actually produced a moderate increase in brain oxygen levels in animal models.
- Addiction Resistance: In self-administration tests, rats stopped seeking DFNZ immediately once it was replaced with saline. This is the opposite of heroin or fentanyl, where animals continue compulsive drug-seeking behavior.
- Dopamine Dynamics: DFNZ increases slow-acting dopamine (providing relief/reward) but avoids the “rapid bursts” that create the intense drug-cue associations responsible for cravings and relapse.
Source: NIH
Researchers at the National Institutes of Health (NIH) have identified a novel, highly potent opioid that shows potential as a therapy for both pain and opioid use disorder.
In a study published in Nature, the team observed the new drug’s effect in laboratory animals. They showed that it has high pain-relieving effects without causing respiratory depression, tolerance or other indicators of potential for addiction in humans.
“Opioid pain medications are essential for medical purposes, but can lead to addiction and overdose,” said Nora D. Volkow, M.D., director of NIH’s National Institute on Drug Abuse (NIDA). “Developing a highly effective pain medication without these drawbacks would have enormous public health benefits.”
The team investigated formulations of an understudied class of synthetic opioid compounds, known as nitazenes. Nitazenes selectively engage mu-opioid receptors, primary targets for opioid drugs in the brain and peripheral nervous system.
However, nitazenes had been shelved in the 1950s due to their excessive potency. The scientific team revisited this class of compounds with a focus on harnessing their selectivity for the mu opioid receptor and engineering new nitazenes with a safer pharmacological profile.
“Our goal was to study the profile, or pharmacology, of these drugs,” said Michael Michaelides, Ph.D., senior author and NIDA investigator. “We wanted to decrease the potency and create a potential therapeutic. What we discovered exceeded our expectations.”
The team focused initially on a chemical formulation called FNZ that could be administered to rats and tagged with a radioisotope for positron emission tomography (PET). PET imaging enables tracking of the drug in real time throughout the rat brain. The team discovered that FNZ entered the brain only briefly, for approximately five to 10 minutes.
Yet pain relief, known as analgesia, persisted for at least two hours. Knowing that nitazenes can have active metabolites, or by-products, the team investigated whether an FNZ metabolite might be responsible for the prolonged effect. That investigation revealed DFNZ, another opioid dubbed a “superagonist” for its extremely high efficacy at the mu opioid receptor.
Whereas FNZ carries serious risks, including depressed breathing and high potential for addiction, DFNZ appears to sidestep these liabilities.
At preclinical therapeutic doses, DFNZ produced a moderate and sustained increase in brain oxygen rather than depressing respiration. Repeated doses of the drug did not result in tolerance, drug dependency, or meaningful withdrawal effects. Among 14 classic opioid withdrawal symptoms, the researchers only observed irritability, as measured by vocalization, when handling DFNZ-treated rats.
To test the drug’s rewarding effects, an important component of their addictive potential, the team studied its effects in rats who had been trained to press a lever for a dose of the pain-relieving drug. They found that animals readily self-administered DFNZ, indicating that it does produce some rewarding effect. However, when the drug was replaced with saline, animals stopped the drug-seeking behavior.
The immediate behavior change is in contrast with what researchers see with other opioids such as heroin, morphine, and fentanyl. In those cases, animals typically persist in seeking the drug even after it is removed.
Further investigation revealed a likely neurochemical explanation. While DFNZ increases slow-acting dopamine release in the brain’s reward circuitry, it does not trigger the rapid dopamine bursts associated with the formation of strong drug-cue associations, the conditioned responses that drive craving and relapse in addiction.
“DFNZ has an unprecedented pharmacology for an opioid,” Michaelides said. “It is a potent and high-efficacy analgesic, but in certain contexts it resembles partial agonists, drugs that activate the receptor with low efficacy, which is what scientists think is needed for safety. Its capacity to be administered at therapeutic doses without producing respiratory depression is very important.”
The teams’ findings challenge the prevailing view that high-efficacy mu-opioid receptor drugs are unsuitable for development as safe analgesics. In fact, the authors of the paper maintain that DFNZ should be explored for use in treatment for opioid use disorder and may be preferable to current opioid agonist medications, which have an associated risk of causing respiratory depression.
The research team will pursue additional preclinical studies to support an application for regulatory approval to conduct studies of DFNZ in humans. They believe several patient populations may benefit from DFNZ, including those in surgical settings and with cancer-related or chronic pain who have a particularly high need for effective pain treatment.
Funding: This research was supported in part by the NIH Intramural Research Program and by NIH/NIDA grant DA056354.
Key Questions Answered:
A: Addictive potential isn’t just about strength; it’s about speed. Most opioids hit the brain’s reward system with a massive, rapid spike of dopamine that “rewires” the brain to crave more. DFNZ provides a slow, steady release of dopamine. It satisfies the pain but doesn’t create the “high” that leads to compulsive seeking.
A: This is the most unprecedented part of the study. Standard opioids “shut down” the brain’s signal to breathe. DFNZ appears to have a unique pharmacological profile that engages the pain-killing receptors (mu-opioid) without triggering the secondary pathways that suppress the respiratory center in the brainstem.
A: The study is currently in the preclinical (animal) stage. Because the results are so “unprecedented,” the team is fast-tracking additional studies to apply for human clinical trials. It could eventually replace methadone or buprenorphine for treating opioid use disorder, as it’s safer and more effective.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuropharmacology research news
Author: NIH Office of Communications
Source: NIH
Contact: NIH Office of Communications – NIH
Image: The image is credited to Neuroscience News
Original Research: Open access.
“A μ opioid receptor superagonist analgesic with minimal adverse effects” by Juan L. Gomez, Emilya N. Ventriglia, Zachary J. Frangos, Agnieszka Sulima, Michael J. Robertson, Michael D. Sacco, Reece C. Budinich, Ilinca M. Giosan, Tongzhen Xie, Oscar Solis, Anna E. Tischer, Jennifer M. Bossert, Kiera E. Caldwell, Hannah Bonbrest, Amelie Essmann, Zelai M. Garçon-Poca, Shinbe Choi, Michael R. Noya, Feonil Limiac, Ali Arce, Grant C. Glatfelter, Margaret Robinson, Li Chen, Angelina A. Mullarkey, Dain R. Brademan, Garrett Enten, William Dunne, César Quiroz, Ingrid Schoenborn, Chae Bin Lee, Rana Rais, Daniel P. Holt, Robert F. Dannals, Lei Shi, Ruth Hüttenhain, Sergi Ferré, Eugene Kiyatkin, Jordi Bonaventura, Yavin Shaham, Venetia Zachariou, Michael H. Baumann, Georgios Skiniotis, Kenner C. Rice & Michael Michaelides. Nature
DOI:10.1038/s41586-026-10299-9
Abstract
A μ opioid receptor superagonist analgesic with minimal adverse effects
Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction.
Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling.
Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes.
DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR–galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure.
Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure.
These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents.
