Pain-Relieving Drug with Minimal Addictive Properties Discovered

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 without causing respiratory depression, tolerance or other indicators of potential for addiction in humans.

In the study, the researchers investigated formulations of an understudied class of synthetic opioid compounds, known as nitazenes (shelved in the 1950s due to excessive potency), which selectively engage mu-opioid receptors, primary targets for opioid drugs in the brain and peripheral nervous system. “Our goal was to study the profile, or pharmacology, of these drugs,” said Michael Michaelides, PhD, senior author and NIH’s National Institute on Drug Abuse investigator. “We wanted to decrease the potency and create a potential therapeutic. What we discovered exceeded our expectations.”

Initially, research focused on a chemical formulation called FNZ that could be administered to rats and tagged with a radioisotope for positron emission tomography, which enables tracking of the drug in real time throughout the rat brain. They 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 byproducts, an investigation of whether an FNZ metabolite might be responsible for the prolonged effect 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 doesn’t cause these effects.

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. They also found that while it does produce some rewarding effect, when the drug was replaced with saline, animals stopped the drug-seeking behavior, which is in contrast with other opioids.

According to the researchers, findings challenge the prevailing view that high-efficacy mu-opioid receptor drugs are unsuitable for development as safe analgesics, and 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 is planning to pursue additional preclinical studies to support an application for regulatory approval to conduct studies of DFNZ in humans.