NIH Researchers Develop New Opioid with Reduced Addiction Risks

Researchers at the National Institutes of Health (NIH) have identified a novel opioid compound, DFNZ, which shows promise in treating pain without the significant risks of addiction and respiratory depression associated with traditional opioids. This discovery, detailed in a study published in *Nature*, revisits the nitazene class of synthetic opioids, previously abandoned due to their extreme potency. The study's lead investigator, Michael Michaelides, Ph.D., emphasized the potential of DFNZ to provide effective pain relief while minimizing adverse effects.

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DFNZ operates by targeting mu opioid receptors in the brain, similar to other opioids, but with a distinct pharmacological profile. In laboratory tests, DFNZ demonstrated strong analgesic effects lasting at least two hours, despite its brief presence in the brain. The compound was found to increase brain oxygen levels steadily, contrasting with the respiratory suppression typical of existing opioids. Notably, repeated dosing of DFNZ did not lead to tolerance or significant withdrawal symptoms, with only minor irritability observed in test subjects.

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To assess DFNZ's addictive potential, researchers conducted experiments with rats trained to self-administer the drug. While the animals did exhibit some rewarding effects, they quickly ceased seeking DFNZ when it was replaced with saline, a behavior that differs significantly from the persistent seeking seen with drugs like heroin and fentanyl. This suggests that DFNZ may not produce the strong drug-related cues that often drive cravings and relapse, a significant finding in opioid research.

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The findings challenge the prevailing notion that highly active mu opioid receptor drugs cannot be safely developed for pain management. DFNZ could serve not only as a pain reliever but also as a potential treatment for opioid use disorder, offering advantages over current therapies that still pose risks of respiratory depression. The research team plans to continue preclinical studies to support regulatory approval for human trials, aiming to benefit patients requiring effective pain relief in surgical and chronic pain contexts.

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Nora D. Volkow, M.D., director of NIH’s National Institute on Drug Abuse, remarked on the significance of developing a highly effective pain medication without the drawbacks of addiction and overdose, stating, “Developing a highly effective pain medication without these drawbacks would have enormous public health benefits.”

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The NIH research team is focused on advancing the preclinical work necessary for regulatory approval, with the goal of initiating human studies to further evaluate DFNZ's safety and efficacy in pain management and opioid use disorder treatment.

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• “DFNZ has an unprecedented pharmacology for an opioid,” — Michael Michaelides, Ph.D., Senior Author, NIH

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• “Our goal was to study the profile, or pharmacology, of these drugs,” — Michael Michaelides, Ph.D., Senior Author, NIH

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This research represents a significant step forward in the quest for safer pain management solutions amidst the ongoing opioid crisis.

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