Wednesday, April 1, 2026
Optimistic security profile of novel drug compound is shock for class of artificial opioids shelved years in the past.
Researchers on the Nationwide Institutes of Well being (NIH) have recognized a novel, extremely potent opioid that exhibits potential as a remedy for each ache and opioid use dysfunction. In a research printed in Nature, the crew noticed the brand new drug’s impact in laboratory animals. They confirmed that it has excessive pain-relieving results with out inflicting respiratory despair, tolerance or different indicators of potential for habit in people.
“Opioid ache medicines are important for medical functions, however can result in habit and overdose,” mentioned Nora D. Volkow, M.D., director of NIH’s Nationwide Institute on Drug Abuse (NIDA). “Growing a extremely efficient ache remedy with out these drawbacks would have monumental public well being advantages.”
The crew investigated formulations of an understudied class of artificial opioid compounds, often known as nitazenes. Nitazenes selectively have interaction mu-opioid receptors, major targets for opioid medication within the mind and peripheral nervous system. Nonetheless, nitazenes had been shelved within the Fifties as a result of their extreme efficiency. The scientific crew revisited this class of compounds with a deal with harnessing their selectivity for the mu opioid receptor and engineering new nitazenes with a safer pharmacological profile.
“Our objective was to review the profile, or pharmacology, of those medication,” mentioned Michael Michaelides, Ph.D., senior creator and NIDA investigator. “We wished to lower the efficiency and create a possible therapeutic. What we found exceeded our expectations.”
The crew centered initially on a chemical formulation known as FNZ that could possibly be administered to rats and tagged with a radioisotope for positron emission tomography (PET). PET imaging permits monitoring of the drug in actual time all through the rat mind. The crew found that FNZ entered the mind solely briefly, for about 5 to 10 minutes. But ache reduction, often known as analgesia, endured for a minimum of two hours. Realizing that nitazenes can have energetic metabolites, or by-products, the crew investigated whether or not an FNZ metabolite is perhaps liable for the extended impact. That investigation revealed DFNZ, one other opioid dubbed a “superagonist” for its extraordinarily excessive efficacy on the mu opioid receptor.
Whereas FNZ carries critical dangers, together with depressed respiratory and excessive potential for habit, DFNZ seems to sidestep these liabilities.
At preclinical therapeutic doses, DFNZ produced a average and sustained enhance in mind oxygen reasonably than miserable respiration. Repeated doses of the drug didn’t lead to tolerance, drug dependency, or significant withdrawal results. Amongst 14 traditional opioid withdrawal signs, the researchers solely noticed irritability, as measured by vocalization, when dealing with DFNZ-treated rats.
To check the drug’s rewarding results, an essential part of their addictive potential, the crew studied its results in rats who had been skilled to press a lever for a dose of the pain-relieving drug. They discovered that animals readily self-administered DFNZ, indicating that it does produce some rewarding impact. Nonetheless, when the drug was changed with saline, animals stopped the drug-seeking habits. The speedy habits change is in distinction with what researchers see with different opioids reminiscent of heroin, morphine, and fentanyl. In these instances, animals usually persist in in search of the drug even after it’s eliminated.
Additional investigation revealed a probable neurochemical clarification. Whereas DFNZ will increase slow-acting dopamine launch within the mind’s reward circuitry, it doesn’t set off the speedy dopamine bursts related to the formation of sturdy drug-cue associations, the conditioned responses that drive craving and relapse in habit.
“DFNZ has an unprecedented pharmacology for an opioid,” Michaelides mentioned. “It’s a potent and high-efficacy analgesic, however in sure contexts it resembles partial agonists, medication that activate the receptor with low efficacy, which is what scientists assume is required for security. Its capability to be administered at therapeutic doses with out producing respiratory despair is essential.”
The groups’ findings problem the prevailing view that high-efficacy mu-opioid receptor medication are unsuitable for improvement as secure analgesics. In actual fact, the authors of the paper keep that DFNZ needs to be explored to be used in remedy for opioid use dysfunction and could also be preferable to present opioid agonist medicines, which have an related danger of inflicting respiratory despair.
The analysis crew will pursue further preclinical research to assist an utility for regulatory approval to conduct research of DFNZ in people. They imagine a number of affected person populations might profit from DFNZ, together with these in surgical settings and with cancer-related or persistent ache who’ve a very excessive want for efficient ache remedy.
This analysis was supported partly by the NIH Intramural Analysis Program and by NIH/NIDA grant DA056354.
Concerning the Nationwide Institute on Drug Abuse (NIDA): NIDA is a part of the Nationwide Institutes of Well being, U.S. Division of Well being and Human Companies. NIDA helps many of the world’s analysis on the well being facets of drug use and habit. The Institute carries out a big number of packages to tell coverage, enhance follow, and advance habit science. For extra details about NIDA and its packages, go to www.nida.nih.gov.
Concerning the Nationwide Institutes of Well being (NIH): NIH, the nation’s medical analysis company, consists of 27 Institutes and Facilities and is a part of the U.S. Division of Well being and Human Companies. NIH is the first federal company conducting and supporting primary, medical, and translational medical analysis, and is investigating the causes, remedies, and cures for each frequent and uncommon illnesses. For extra details about NIH and its packages, go to www.nih.gov.
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Reference
Michaelides M., Rice Ok., Skiniotis G., et al. A μ opioid receptor superagonist analgesic with minimal adversarial results. Nature. 2026. DOI: 10.1038/s41586-026-10299-9.
