New opioid reduces pain without causing hard-to-beat addiction in early studies

A new synthetic opioid designed to reduce pain could replace addictive painkillers such as morphine and fentanyl in patients, a study in laboratory rats suggests.

This study suggests that newer opioids have a lower risk of addiction, but they may not be completely risk-free.

Opioids are highly effective in treating severe pain associated with surgery, physical trauma, or illness. However, they can also cause euphoria, increasing the likelihood that patients will become addicted and abuse these drugs outside of a medical setting. When using opioids regularly, users often develop a tolerance and increase their dosage to compensate. Ingesting high doses can slow breathing and lead to a fatal overdose.

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In the 1950s, a type of extremely powerful opioid called nitazene was developed that provided 1,000 times more pain relief than morphine, but the risk of overdose was much higher. “Research using nitazene was discontinued and nitazene was largely forgotten until it re-emerged as a street drug a few years ago,” Michael Michaelides, a pharmacologist at the National Institute on Drug Abuse, told Live Science in an email.

But now, in a study published April 1 in Nature, Michaelides and his colleagues have developed a new patented nitazen, called DFNZ, that reduces pain without slowing breathing as drastically as other nitazenes. This makes it much less likely to cause an overdose.

Additionally, many opioids cause euphoria by flooding the brain with the neurotransmitter dopamine, but DFNZ did not cause a significant surge of the chemical. This suggests that it may not cause euphoria and may have a low risk of addiction.

Measuring addiction risk

To demonstrate that DFNZ may be less addictive than other opioids, the researchers self-administered the drug to rats and allowed them to use it as much as they wanted. To do so, they inserted a catheter tube into the rodent’s jugular vein and connected the tube to a lever that the rat could press to attack the DFNZ. They also performed the same experiment using morphine.

Regardless of whether the rats were connected to the morphine or DFNZ lever, they repeatedly self-administered the drug, suggesting that both drugs can cause addiction.

The researchers then stopped administering the drug via the lever to assess whether the rats experienced withdrawal symptoms. The researchers found that rats deprived of morphine had worse withdrawal symptoms than rats that refused DFNZ, looking for signs such as chattering teeth, jumping, and shaking legs. They also found that rats coping without morphine repeatedly pressed the dysfunctional lever in the hope of recovery, whereas rats that stopped DFNZ abandoned this behavior more quickly. This suggests that DFNZ may be less addictive than morphine.

“This study does a good job of suggesting that it’s less addictive than other drugs,” said Natasia Swalb, an assistant professor of behavioral neuroscience at Grand Valley State University who studies drug addiction and was not involved in the study. However, she warned that self-administered tests “still lead us to believe that there is a possibility of an addictive profile”.

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In a separate experiment, researchers wanted to see if DFNZ could help treat heroin addiction. They administered heroin to rats, provided the rats with a lever to self-administer more heroin, and treated them with either DFNZ, fentanyl, or a placebo drug. Rats given placebo pressed the lever significantly more than rats treated with either fentanyl or DFNZ. This suggests that these opioids reduce the urge to use heroin.

Based on these results, Michaelides suggested that “DFNZ could be used to treat opioid use disorder, similar to how methadone and buprenorphine are used.” “However, safety and efficacy will first need to be demonstrated in rigorous multiphase clinical trials and regulatory approval will need to be obtained.”

The researchers noted in their paper that they did not study the effect of pain on DFNZ’s addictive potential. In other words, there are concerns that the pain relief provided by drugs, even in the absence of euphoria, may increase the risk of addiction.

Given the hope that new opioids may one day be used to treat chronic diseases such as cancer and postoperative pain, it is important to determine whether rodents exposed to continuous pain are more likely to repeatedly press the lever even when DFNZ is discontinued.

Swalb added that the researchers were only testing the addictive potential of the drug at an analgesic dose. She said higher doses also need to be evaluated because people may take more than prescribed.

Swalve expects it will be at least 10 years before DFNZ reaches hospitals, as multiple safety tests and clinical trials are still pending.