As synthetic opioids such as fentanyl continue to claim tens of thousands of American lives each year, researchers at the University of Arizona and the National Center for Wellness and Recovery in Tulsa, Oklahoma, have joined forces and are racing to bring a new kind of rescue therapy into reality. By combining their research experiences and synergies, they’ve identified a promising molecule that could reshape how opioid overdoses are treated.

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“The compound we are currently testing is a long-acting opioid antagonist that could potentially save lives with a single dose,” said Todd Vanderah, director of the University of Arizona’s Comprehensive Center for Pain and Addiction and a Regents Professor at the College of Medicine – Tucson.

Fentanyl, originally developed for surgical and cancer-related pain relief, is a synthetic opioid that is up to 100 times more potent than morphine. Its potency makes it incredibly dangerous outside medical settings, where even small amounts as little as two milligrams can be fatal.

The Drug Enforcement Administration reports that nearly 70% of all drug poisonings and overdose deaths in 2023 involved synthetic opioids, primarily fentanyl. More than 50,000 Americans died of opioid overdoses in 2024, according to the Centers for Disease Control and Prevention, and while that figure is down from the previous year, the opioid epidemic remains a significant public health threat. In 2024, the DEA seized more than 60 million fentanyl-laced fake pills and nearly 8,000 pounds of fentanyl powder. The 2024 seizures are equivalent to more than 380 million lethal doses of fentanyl. The 2025 fentanyl seizures represent over 232 million deadly doses as of August 24. 

Current treatments to reverse opioid overdoses, including naloxone, are effective but often require multiple doses and are short-lived.

“Naloxone will push fentanyl off the opioid receptor, stopping the drug’s effect on the body and therefore stopping the overdose. But fentanyl is very potent and exhibits very high binding activity to the opioid receptors. Fentanyl and its analogs don’t just bind strongly, they come back,” Vanderah explained. “Even after naloxone kicks them off the receptors, they can reattach and cause respiratory failure again. That’s why a longer-acting antagonist like NCWR-10 could be so important.”

NCWR-10 is the most promising molecule identified by the team, which is led by Vanderah, Frank Porreca, professor of pharmacology at the College of Medicine – Tucson, and Don Kyle, CEO of the National Center for Wellness and Recovery. It offers a potential breakthrough: a fast-acting, longer-lasting opioid overdose antagonist that may require only one dose to prevent overdose deaths from respiratory depression.

From a molecule to a drug

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NCWR-10 was originally designed and synthesized by Kyle, a chemist and one of the nation’s leading experts in drug design and development. Kyle, Porreca and Vanderah have been collaborating since 2021 to develop a class of fentanyl reversal agents with an extended duration of action and high potency.

“There is an urgent need to combat fentanyl overdose on the frontlines of the crisis,” Kyle said. “Our unique partnership takes molecules developed at the National Center for Wellness and Recovery and rigorously tests them in preclinical models at the University of Arizona. By combining our capabilities and experience, we hope to accelerate the transition of new research into useful clinical solutions. Ultimately, this project offers hope for a more efficient and effective means of preventing fentanyl overdoses.” 

Early research results for NCWR-10 are promising. In mouse models, it worked as quickly as naloxone in returning respiratory rates to normal, and it lasted longer. Early testing also revealed a surprising twist –it could be mildly activating opioid receptors while also blocking fentanyl.

“It is blocking the receptors, but it may have a little bit of agonist activity,” Vanderah said. “That always sounds like a bad thing, but in some cases, it could reduce the amount of withdrawal activity. So that’s what we are testing next. While unexpected, this might reduce the severe withdrawal symptoms often triggered by opioid reversal, making NCWR-10 more tolerable for people in crisis.”

The team is also preparing to test the compound against the newest synthetic opioid threats, including carfentanil and isotonitazine.

Carfentanil was originally developed for veterinary use, including to tranquilize extremely large animals such as elephants. It is estimated to be 10,000 times more potent than morphine and 100 times stronger than fentanyl. A nearly microscopic amount of carfentanil, just .02 milligrams, can be fatal for humans. Isotonitazine, or ISO, has never been approved for medical use and is also much more potent than heroin and morphine, according to the Drus Enforcement Administration.

“Carfentanil is one of the deadliest fentanyl analogs,” Vanderah said. “While naloxone might reverse a carfentanil overdose, the effects would be extremely short-acting due to carfentanil’s potency. There is a huge need for a longer lasting opioid overdoes antagonist, and we think NCWR-10 could be the answer.”

The team is currently running toxicology studies that will elevate NCWR-10 from a promising molecule into a potential drug. The project has a checklist of Food and Drug Administration requirements to meet before a human clinical trial could begin, but the team is committed to doing whatever is necessary to advance life-saving tools like NCWR-10.

“We’re continuing to work closely together to develop these compounds,” Vanderah said. “This is about saving lives. And this molecule could be the difference between tragedy and survival.”