Researchers at the National Institutes of Health (NIH) have identified a powerful synthetic opioid that provides effective pain relief while minimizing risks of addiction and respiratory depression, according to a study published in Nature.
The team focused on a class of synthetic opioids called nitazenes, originally shelved in the 1950s due to their extreme potency. These compounds selectively target mu-opioid receptors, which mediate pain relief but are also linked to opioid addiction and overdose risks.
By modifying these compounds, researchers developed a drug called FNZ and tracked its behavior in laboratory rats using positron emission tomography (PET). FNZ had a brief brain presence but prolonged analgesic effect lasting at least two hours. Further investigation revealed that its metabolite, DFNZ, acts as a “superagonist” at mu-opioid receptors, exhibiting both high efficacy and a safer profile.
Unlike traditional opioids, DFNZ did not cause respiratory depression in rats at therapeutic doses, instead producing sustained increases in brain oxygen levels. Repeated dosing did not lead to tolerance, dependency, or significant withdrawal symptoms. While DFNZ induced some reward-driven drug-seeking behavior, rats quickly ceased this behavior when the drug was replaced with saline, contrasting with persistent seeking seen with heroin or fentanyl.
The researchers suggest this reduced addictive potential may be due to DFNZ triggering slow dopamine release in the brain’s reward centers, without rapid dopamine bursts responsible for strong drug-cue associations and relapse. According to senior author Michael Michaelides, Ph.D., the drug’s unique pharmacology resembles safer partial agonists, yet retains potent analgesic properties.
Why it matters
Current opioid medications, while effective for pain, carry high risks of addiction, tolerance, respiratory depression, and overdose. The discovery of DFNZ’s potent analgesic effects combined with a lower safety risk profile addresses an urgent public health need for safer opioid therapies, especially for patients with acute or chronic pain.
The research team plans additional preclinical studies to support applications for human clinical trials. They highlight potential benefits for surgical patients and those with cancer-related or chronic pain who require effective pain management but face high addiction risks with existing opioids.
Background
The NIH’s National Institute on Drug Abuse (NIDA) led the study, reflecting its mission to advance addiction science and develop safer treatments. Nitazenes had largely been overlooked since the mid-20th century despite their receptor selectivity and potency. This study is among the first to engineer and evaluate these compounds with a focus on reducing adverse effects while maintaining analgesia.
NIH and NIDA support most U.S.-based research on drug addiction and treatment, providing context for the significance of this discovery in both pain medicine and substance use disorder therapy.
Sources
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