A Virginia Commonwealth University researcher’s new project focusing on medications for combating synthetic opioid use disorder has earned recognition – and funding – from the National Institutes of Health as a highly innovative and “bold research project with unusually broad scientific impact.”

Piyusha Pagare, Ph.D., a research assistant professor in the Department of Medicinal Chemistry at VCU School of Pharmacy, has been awarded a $2.1 million five-year grant from the NIH’s National Institute on Drug Abuse to lead a study on developing new drug therapies to prevent fatal overdoses stemming from ultra potent synthetic opioids like fentanyl and provide treatment for those in recovery.

The new project, “Novel Mu Opioid Receptor Modulators to Counteract Synthetic Opioids,” earned an NIH Director's Pioneer Award, which, the NIH states, “supports highly innovative researchers at any career stage who propose bold research projects with unusually broad scientific impact. To be considered ‘pioneering,’ the proposed research must reflect ideas that are substantially different from those being pursued in the investigator’s research program or elsewhere.”

In 2022, opioid-related overdose became the No. 1 cause of death for individuals in the U.S. between the ages of 25 and 64 years of age. “Because of the introduction of highly potent synthetic opioids (e.g., fentanyl) to the illicit drug market,” Pagare described in a 2023 Pharmacological Research paper, “there is an urgent need for therapeutics that successfully reduce the number of overdoses and can help opioid use disorder patients maintain sobriety.”

Several medications are currently approved to aid in detoxification and relapse prevention, to reverse overdose or to serve as longer-term treatments, Pagare said, but these medications can also carry negative side effects or abuse potential. Her project will focus on developing new drug therapies to counteract the lethal effect of fentanyl and other opioids.

“The U.S. is confronting an escalating opioid crisis, with new synthetic opioids emerging faster than public health and regulatory systems can respond,” Pagare said. “While fentanyl and its derivatives have long dominated the illicit drug supply, stricter controls have fueled a surge in novel non-fentanyl opioids — many of which are even more potent, longer-acting, and harder to treat in overdose situations. Their extreme potency often renders standard reversal drugs like naloxone less effective, and treatment options for opioid use disorder remain limited by low engagement and retention rates. 

“This growing challenge underscores the urgent need for innovative medications and approaches. With this project, we are aiming to develop new molecular tools that help us untangle how opioids activate the brain’s receptors — separating the pathways that drive pain relief from those that cause addiction. By doing so, we hope to lay the groundwork for safer overdose reversal strategies, more effective treatments for opioid use disorder, and non-addictive options for pain management.”

Pagare’s project is one of just three projects nationally in 2025 that has earned the Avenir Award in Chemistry and Pharmacology of Substance Use Disorders, a subset of the NIH Director’s Pioneer Award that supports bold, innovative research by early-stage investigators. This marks the first Director’s Pioneer Award for VCU School of Pharmacy — and also the first across VCU.

NIDA's Avenir Award Program looks toward the future by supporting early-stage investigators proposing highly innovative research in the area of chemistry and pharmacology of substance use disorders and addiction. The purpose of this award is to support those in an early stage of their career who propose high-impact research and who show promise of being tomorrow's leaders in the field.

The Avenir Award for Chemistry and Pharmacology of Substance Use Disorders program supports early-stage investigators proposing transformative studies that open new avenues of research in the area of chemistry and pharmacology of addictive substances, substance use disorders and addiction.

A graduate of VCU’s Ph.D. in pharmaceutical sciences program with a concentration in medicinal chemistry in 2018 who subsequently served as a postdoctoral fellow in the lab of Yan Zhang, Ph.D., Pagare will be the project’s principal investigator. Her research has spanned cancer and sickle cell disease but, in the last five years, has focused more on identifying treatments for opioid use disorder.