A new synthetic opioid designed to relieve pain could hold promise for replacing addictive painkillers like morphine or fentanyl in patients, a study in lab rats suggests.

The research hints that the new opioid carries a lower risk of addiction — though it's likely not completely risk-free.

In the 1950s, a class of highly potent opioids called nitazenes was developed and offered 1,000 times more relief than morphine, but they carried a much higher risk of overdose. Michael Michaelides, a pharmacologist at the National Institute on Drug Abuse, told Live Science in an email that "research using nitazenes was stopped and they were largely forgotten until they re-emerged as street drugs a few years ago."

But now, in a study published April 1 in the journal Nature, Michaelides and his colleagues developed a new patented nitazene called DFNZ that offers pain relief without slowing down breathing as sharply as other nitazenes do. That makes it much less likely to cause an overdose.

Additionally, while many opioids cause euphoria by flooding the brain with the neurotransmitter dopamine, DFNZ did not trigger a large surge of the chemical. That suggests it might not cause euphoria and thus may carry a lower risk of addiction.

Measuring addiction risk

To demonstrate that DFNZ could be less addictive than other opioids, the team allowed rats to self-administer the drug and use it as much as they liked. To do so, they inserted a catheter tube into the rodents' jugular veins and hooked up the tube to a lever that the rats could press to get a hit of DFNZ. They also ran the same experiment with morphine.

Regardless of whether the rats were hooked up to a morphine lever or a DFNZ lever, they would repeatedly self-administer the drug, which suggests both drugs have the potential to cause addiction.

Next, the researchers halted drug administration via the lever to assess whether the rats experienced withdrawal symptoms. Looking for signs like teeth chattering, jumping or paw tremors, they found that rats cut off from morphine experienced worse withdrawal than rats denied DFNZ. They also found that rats coping without morphine would futilely press the defunct lever over and over in hope of a fix, whereas rats discontinuing DFNZ were quicker to give up this behavior. That suggests DFNZ might be less addictive than morphine.

"The studies are good at suggesting that it has a weaker addictive potential than some of the other drugs out there," said Natashia Swalve, an assistant professor of behavioral neuroscience who studies drug addiction at Grand Valley State University and was not involved with the work. However, she cautioned that the self-administration test "still leads me to believe that there is a potential for an addictive profile."

In another experiment, the researchers wanted to see whether DFNZ might be useful for treating heroin addiction. They administered heroin to rats, provided them with a lever to self-administer more heroin, and then treated them with either DFNZ, fentanyl or a placebo drug. Rats receiving the placebo pressed the lever significantly more times than rats treated with either fentanyl or DFNZ, suggesting these opioids tempered the urge to use heroin.

Based on these results, "DFNZ could potentially be used for the treatment of opioid use disorder similar to how methadone or buprenorphine are used," Michaelides suggested. "But rigorous multi-phase clinical trials would have to first demonstrate its safety and efficacy, and it would need to receive regulatory approval."

In their paper, the researchers noted that they didn't study the impact pain could have on the addictive potential of DFNZ. In other words, there's a worry that the pain relief provided by the drug could pose a higher risk of addiction, even in the absence of euphoria.

With aspirations that the new opioid may one day be used to treat chronic conditions such as cancer or post-surgical pain, it's important to determine whether rodents in constant pain are more likely to repeatedly press the lever even when DFNZ is withdrawn.

Swalve added that the researchers only tested the addictive potential of a pain-relieving dose of the drug. They should also assess higher doses, she said, because people could potentially take larger volumes than prescribed.

With multiple safety tests and clinical trials still to run, Swalve expects it would take at least a decade before DFNZ reaches the hospital.

Kamal Nahas is a freelance contributor based in Oxford, U.K. His work has appeared in New Scientist, Science and The Scientist, among other outlets, and he mainly covers research on evolution, health and technology. He holds a PhD in pathology from the University of Cambridge and a master's degree in immunology from the University of Oxford. He currently works as a microscopist at the Diamond Light Source, the U.K.'s synchrotron. When he's not writing, you can find him hunting for fossils on the Jurassic Coast.

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