Researchers have discovered a novel synthetic opioid that provided potent pain relief in preclinical models without many of the dangerous side effects that limit current opioid therapies.

The compound, N-desethyl-fluornitrazene (DFNZ), produced strong analgesia in rodents without causing respiratory depression, tolerance, or other indicators of potential addiction, reported the researchers, led by Michael Michaelides, PhD, with the National Institute on Drug Abuse (NIDA).

“Opioid pain medications are essential for medical purposes, but can lead to addiction and overdose. Developing a highly effective pain medication without these drawbacks would have enormous public health benefits,” NIDA Director Nora D. Volkow, MD, said in a news release. 

The study was published online April 1 in Nature. 

Surprising Discovery 

The researchers discovered DFNZ by revisiting a class of synthetic opioids known as nitazenes, which were originally developed in the 1950s but abandoned due to excess potency and overdose risk. 

“Our goal was to study the profile, or pharmacology, of these drugs. We wanted to decrease the potency and create a potential therapeutic. What we discovered exceeded our expectation,” Michaelides said in the statement. 

The compound they discovered, DFNZ, acts on the mu-opioid receptor — the same target as morphine and fentanyl. However, DFNZ is a novel mu-opioid receptor agonist in that it displays “supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects,” the researchers explained. 

DFNZ showed “an unexpectedly strong” safety profile for a nitazene mu-opioid receptor superagonist, they said. 

In rodents, DFNZ produced robust analgesia for both acute and inflammatory pain syndromes, with a markedly improved safety profile compared with traditional opioids. 

The compound did not produce significant respiratory depression at analgesic doses and did not cause brain hypoxia. And repeated doses of DFNZ did not result in measurable tolerance, drug dependency, or meaningful withdrawal effects. Among 14 classic opioid withdrawal symptoms, the researchers only observed irritability in DFNZ-treated rats. 

Mechanistic analyses showed that DFNZ produced smaller and slower increases in dopamine signaling in reward-related brain regions and lacked the rapid “phasic” dopamine bursts associated with addiction-related learning.

“DFNZ has an unprecedented pharmacology for an opioid,” Michaelides said. 

“It is a potent and high-efficacy analgesic, but in certain contexts it resembles partial agonists, drugs that activate the receptor with low efficacy, which is what scientists think is needed for safety. Its capacity to be administered at therapeutic doses without producing respiratory depression is very important,” Michaelides added. 

On to Clinical Trials?

The researchers said their results “challenge” the prevailing view that high-efficacy mu-opioid receptor agonists are unsuitable for development as safe analgesics. 

“Our results indicate that DFNZ, and potentially other nitazenes with similar safety profiles, warrant further investigation as potential therapeutic agents for pain,” the researchers wrote.

DFNZ may also have applications beyond pain management, including as a treatment for opioid use disorder, given its demonstrated ability to reduce heroin self-administration in animal models.

“DFNZ may offer therapeutic benefits comparable to those of the full [mu-opioid receptor] agonist methadone, but without the associated risk of respiratory depression,” investigators noted.

Additional preclinical studies are planned to support an application for regulatory approval to conduct studies of DFNZ in humans. 

Support for this research was provided by the National Institutes of Health and NIDA. Disclosures for the authors are available in the original publication.