NIH Identifies Novel Opioid DFNZ for Pain and Opioid Use Disorder Treatment

Researchers at the National Institutes of Health (NIH) have identified a novel opioid compound, DFNZ, which demonstrated potential for treating both pain and opioid use disorder in laboratory animal studies. Published in Nature, the research indicates DFNZ provides pain relief without inducing respiratory depression, tolerance, or typical indicators of addiction potential observed with conventional opioids.

Introduction

The findings from the study, published in Nature, indicate DFNZ's potential as a therapy for both pain and opioid use disorder in laboratory animal models. The drug was observed to provide pain relief without causing respiratory depression, tolerance, or other signs typically associated with addiction potential in humans.

"Opioid pain medications, while medically essential, carry risks of addiction and overdose," noted Nora D. Volkow, M.D., director of NIH's National Institute on Drug Abuse (NIDA), highlighting the public health need for effective pain medication without these drawbacks.

Research Background

The research team investigated nitazenes, a class of synthetic opioid compounds that selectively engage mu-opioid receptors. These compounds were originally set aside in the 1950s due to their excessive potency.

The current research aimed to engineer new nitazenes with a safer pharmacological profile by leveraging their selectivity for the mu opioid receptor while decreasing potency. Michael Michaelides, Ph.D., senior author and NIDA investigator, stated the objective was to study the pharmacology of these drugs to create a potential therapeutic.

Discovery and Mechanism of DFNZ

The initial focus of the research was on FNZ, a chemical formulation tracked using positron emission tomography (PET) in rat brains. FNZ was observed to enter the brain briefly, for approximately 5 to 10 minutes, yet its pain-relieving effects lasted for at least two hours.

Further investigation identified DFNZ as a metabolite of FNZ, responsible for the prolonged effect. DFNZ was characterized as a "superagonist" due to its high efficacy at the mu opioid receptor. While FNZ carries risks, including depressed breathing and high addiction potential, DFNZ appeared to mitigate these liabilities.

Safety Profile and Addiction Potential

In preclinical therapeutic doses, DFNZ produced a moderate and sustained increase in brain oxygen rather than depressing respiration. Repeated administration of DFNZ did not result in tolerance, drug dependency, or significant withdrawal effects. Researchers observed only irritability in DFNZ-treated rats, measured by vocalization, among 14 classic opioid withdrawal indicators.

To assess addiction potential, rats trained to self-administer a pain-relieving drug were used. Animals readily self-administered DFNZ. However, when the drug was replaced with saline, drug-seeking behavior ceased immediately. This contrasted with the persistent seeking behavior observed with opioids such as heroin, morphine, and fentanyl.

Neurochemical analysis suggested that DFNZ increases slow-acting dopamine release in the brain's reward circuitry but does not trigger the rapid dopamine bursts linked to strong drug-cue associations that are associated with craving and relapse.

Michaelides noted DFNZ's pharmacology as distinct for an opioid, describing it as a potent and high-efficacy analgesic that, in certain contexts, resembles partial agonists—drugs that activate receptors with low efficacy, a trait considered relevant for safety. The ability to administer DFNZ at therapeutic doses without causing respiratory depression was highlighted.

Future Implications

These findings suggest a reevaluation of the view that high-efficacy mu-opioid receptor drugs are unsuitable as safe analgesics. The authors propose DFNZ for exploration in opioid use disorder treatment, suggesting it may offer an advantage over current opioid agonist medications that carry respiratory depression risks.

The research team plans additional preclinical studies to support regulatory approval for human trials. Potential beneficiaries include patients in surgical settings and individuals with cancer-related or chronic pain. Partial support for this research was provided by the NIH Intramural Research Program and NIH/NIDA grant DA056354.