Opioid overdoses are a major public health issue in the U.S., killing tens of thousands of people every year. The medicine naloxone, which is available as an over-the-counter nasal spray or given by injection, has saved countless lives by rapidly reversing opioid overdoses. But in blocking opioid receptors in the brain, naloxone causes severe withdrawal symptoms, including pain, vomiting and agitation.

A research team from the Moron-Concepcion Lab at WashU Medicine has discovered a promising new way to treat opioid overdoses without triggering severe withdrawal symptoms. Their study, titled “Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior,” is published in eLife.

The work shows that targeting opioid receptors outside the brain can effectively reverse overdose effects without causing the intense discomfort typical of current treatments.

Led by Jose Moron-Concepcion, Ph.D., and Brian Ruyle, Ph.D., the researchers tested a drug called naloxone-methiodide, which is similar to naloxone but does not cross the blood-brain barrier and instead focuses on the body. In the study, they found that naloxone-methiodide could effectively reverse fentanyl-induced respiratory depression without triggering the severe withdrawal symptoms associated with naloxone.

“These findings have significant potential impact given that fentanyl is still the major driver for opioid-related deaths in this country,” said Moron-Concepcion. “Our new therapeutic approach shows promise in reducing the adverse effects typically seen with naloxone, offering a safer way to reverse overdoses.”

This discovery opens up the possibility of safer and more humane overdose treatments, helping to reduce the fear and stigma that often prevent people from seeking life-saving care.