Researchers at the National Institutes of Health (NIH) have identified a novel, highly potent opioid that shows potential as a treatment for both pain and opioid use disorder. In a study published in natureThe research team observed the effects of the new drug in experimental animals. They demonstrated high analgesic efficacy in humans without causing respiratory depression, tolerance, or other indicators of potential addiction.
Opioid painkillers are essential for medical purposes, but can lead to addiction and overdose. Developing highly effective painkillers that do not have these drawbacks would greatly benefit public health. ”
Nora D. Volkow, MD, Director, NIH National Institute on Drug Abuse (NIDA)
The research team investigated formulations of an understudied class of synthetic opioid compounds known as nitazene. Nitazen selectively engages the mu-opioid receptor, the main target of opioid drugs in the brain and peripheral nervous system. However, Nitazen was shelved in the 1950s due to its excessive potency. The scientific team re-examined this class of compounds, focusing on exploiting their selectivity for mu-opioid receptors and developing new nitazenes with safer pharmacological profiles.
“Our goal was to study the profile, or pharmacology, of these drugs,” said senior author and NIDA researcher Dr. Michael Michaelides. “We wanted to reduce its potency and create a potential therapeutic agent. What we discovered exceeded our expectations.”
The research team initially focused on a chemical formulation called FNZ that can be administered to rats and tagged with a radioactive isotope for positron emission tomography (PET). PET imaging allows real-time tracking of drugs throughout the rat brain. The researchers found that FNZ only entered the brain for a short time, about 5 to 10 minutes. However, the pain relief, known as analgesia, lasted at least two hours. Knowing that nitazene may have active metabolites or byproducts, the research team investigated whether FNZ metabolites were responsible for its long-lasting effects. That investigation revealed another opioid, DFNZ, called a “superagonist” because of its extremely high efficacy at mu-opioid receptors.
FNZ carries serious risks, including respiratory depression and a high potential for addiction, but DFNZ appears to be shirking these responsibilities.
At preclinical therapeutic doses, DFNZ moderately and persistently increased brain oxygen rather than suppressing breathing. Repeated administration of the drug did not result in tolerance, drug dependence, or significant withdrawal effects. Of the 14 classic opioid withdrawal symptoms, researchers only observed irritability, as measured by vocalizations, when handling DFNZ-treated rats.
To test the drug’s beneficial effects, which are a key factor in its addictive properties, the research team studied its effects in rats trained to press a lever to deliver a single dose of pain medication. They found that animals readily self-administered DFNZ and showed that it produced some beneficial effects. However, when the drug was replaced with saline, the animals stopped seeking the drug. This immediate behavioral change is in contrast to what researchers have observed with other opioids such as heroin, morphine, and fentanyl. In these cases, the animal typically continues to seek the drug even after it has been removed.
Further investigation revealed a likely neurochemical explanation. DFNZ increases slow-acting dopamine release in the brain’s reward circuits, but does not produce the rapid dopamine bursts associated with the formation of strong drug cue associations, the conditioned responses that cause addictive craving and relapse.
“DFNZ has unprecedented pharmacology with respect to opioids,” Mr Michaelides said. “It is a powerful and highly effective analgesic drug, but in certain circumstances it resembles a partial agonist, a drug that activates less effective receptors, which scientists believe is necessary for safety. Its ability to be administered at therapeutic doses without causing respiratory depression is critical.”
The research team’s findings challenge the commonly held view that highly effective mu-opioid receptor drugs are not suitable for development as safe analgesics. Indeed, the authors argue that DFNZ should be considered for use in the treatment of opioid use disorder and may be preferable to current opioid agonists, which carry the risk of causing respiratory depression.
The research team plans to pursue further preclinical studies to support the application for regulatory approval to conduct studies of DFNZ in humans. They believe that several patient populations may benefit from DFNZ, including surgical patients with cancer-related pain and chronic pain, where the need for effective pain treatment is particularly high.
This research was supported in part by the NIH Intramural Research Program and NIH/NIDA grant DA056354.
sauce:
National Institutes of Health (NIH)
Reference magazines:
Michaelides, M., et al. (2026) μ-opioid receptor superagonist analgesic with minimal side effects. nature. DOI: 10.1038/s41586-026-10299-9. https://www.nature.com/articles/s41586-026-10299-9
