By Stacy Pigott, University of Arkansas Office of Research and Partnerships, and Neile Jones, National Center for Wellness & Recovery
TULSA, Okla. — As synthetic opioids such as fentanyl continue to claim tens of thousands of American lives each year, researchers at the National Center for Wellness and Recovery (NCWR) in Tulsa, Oklahoma and the University of Arizona 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, NCWR-10, that could reshape how opioid overdoses are treated.
“The compound we are currently testing is a long-acting opioid antagonist that could potentially save lives with a single dose,” said Todd Vanderah, Ph.D., 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 amounts as small as two milligrams can be fatal.
“There is an urgent need to combat fentanyl overdose on the frontlines of the crisis,” said Don Kyle, Ph.D., chief executive officer of the NCWR. “In our partnership we are designing, synthesizing and testing new molecules, including NCWR-10, in preclinical models. By combining our capabilities and experience, we hope to accelerate the translation of new research into useful clinical solutions.”
“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 said. “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.”
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 slightly 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 potentially deadly doses as of August 24.
“It may be surprising to learn that after receiving naloxone, people often experience a sudden, often severe, precipitated withdrawal,” explained Kyle. “To alleviate these unpleasant symptoms, many use opioids again shortly after being rescued with naloxone and this is especially dangerous.”
EMS and emergency department data show that many overdose-rescued patients refuse transport so they can relieve the withdrawal by using again. Some community overdose programs report that the majority of revived individuals use again within 24 hours.
“NCWR-10 has a unique pharmacological feature that may turn out to be very significant,” Kyle said.
“It is blocking the receptors, but it may have a little bit of agonist activity,” Vanderah explained. “That always sounds like a bad thing, but in some cases, it could reduce the amount of withdrawal. 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.”
Kyle has been collaborating with Frank Porreca, professor of pharmacology at the College of Medicine – Tucson, and Vanderah since 2021 on several projects, including this one, aimed at developing a new class of fentanyl reversal agents with an extended duration of action, high potency and no reliance on opium for preparation.
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.
The team is also preparing to test the compound against the newest synthetic opioid threats including carfentanil and isotonitazine. Carfentanil, a synthetic opioid, 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 DEA.
“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 overdose antagonist, and we think NCWR-10 could be the answer.”
The team is currently running additional studies that will elevate NCWR-10 from a promising molecule into a potential drug. The project has a checklist of FDA requirements to meet before a human clinical trial could begin, but the team is committed to 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.”
“Our motivation is to save lives and we feel that NCWR-10 is a significant step in the right direction,” said Kyle.
Todd Vanderah
Director, Comprehensive Center for Pain and Addiction
Head and Regents Professor, Department of Pharmacology, College of Medicine – Tucson
Co-Director, MD/PhD Dual Degree Program, College of Medicine – Tucson
Professor, Department of Anesthesiology, College of Medicine – Tucson
Professor, Department of Neurology, College of Medicine – Tucson
Member, BIO5 Institute
Frank Porreca
Research Director, Comprehensive Center for Pain and Addiction
Associate Head and Professor, Department of Pharmacology, College of Medicine – Tucson
Co-Principal Investigator, Center of Excellence in Addiction Studies
Professor, Department of Anesthesiology, College of Medicine – Tucson
Don Kyle
CEO, National Center for Wellness and Recovery