Scientists Reverse Chronic Pain in Breakthrough Study—Without Opioids

Scientists at Virginia Tech have achieved something remarkable: they successfully reversed chronic pain in laboratory mice without using opioids. The breakthrough study, published in PAIN, targeted a specific enzyme system that amplifies pain signals, potentially opening the door to the first new class of non-opioid chronic pain treatments in years.

This discovery is particularly significant because chronic pain affects more than 50 million Americans, with 75% of patients—disproportionately women—experiencing inadequate pain relief from current treatments. The research focused on nociplastic pain, a poorly understood category that includes fibromyalgia, chronic low back pain, and some migraines.

How Did Researchers Reverse Established Pain?

The Virginia Tech team, led by neuroscientist Ann Gregus and her partner Matthew Buczynski, took a different approach than previous studies. Instead of trying to prevent pain from developing, they worked to reverse pain that was already well-established—which more closely mirrors what human patients experience.

The researchers used female mice that developed persistent pain behaviors, cold sensitivities, and grip force deficits typical of arthritis. Once these pain behaviors were clearly established, they treated the mice with highly selective compounds that block specific parts of an enzyme system responsible for producing pain-amplifying molecules.

The results were striking. The treatment approach targeted several key areas:

• Tactile sensitivity: Pain hypersensitivity to touch completely vanished after treatment
• Cold sensitivity: Mice no longer showed heightened responses to cold temperatures
• Physical function: Grip strength returned to normal levels

What Makes This Treatment Different?

Unlike traditional pain medications, this approach targets a biochemical pathway that nonsteroidal anti-inflammatory drugs (NSAIDs) leave untouched. While NSAIDs block certain inflammatory pathways, the new treatment focuses on an immune receptor in the spinal cord that triggers enzymes releasing pain-intensifying molecules.

"Earlier studies have focused largely on preventing development of pain—so the key finding here is the reversal of an established pain state and associated functional deficits, which more closely mimics the human experience," said Gregus, an assistant professor in Virginia Tech's School of Neuroscience.

The discovery happened somewhat by chance. When pandemic supply shortages limited their usual research models, the team switched to a different strain of female mice. This strain developed the persistent, long-lasting pain behaviors the researchers needed to study, while commonly used strains barely responded.

Could This Help Human Patients Soon?

One of the compounds tested is already in Phase II clinical trials for another disease, which could significantly shorten the path to clinical trials for chronic pain since it already has human safety data. The research team confirmed their findings by showing that administering the pain-driving molecules alone could reproduce the pain state, proving their central role in chronic pain.

"Chronic pain patients are often told pain is all in their heads and they just have to learn how to tolerate it," Gregus explained. "But what we're showing is that there is a clear biological mechanism—and one we can target."

For Gregus, this research is deeply personal. She lives with migraines and peripheral neuropathy herself, giving her firsthand experience with how current treatments fall short. The lab's next steps include testing whether the same enzyme-blocking strategy works in models of chemotherapy-induced peripheral neuropathy and diabetic neuropathy—conditions that can cause years of persistent pain.

The study was conducted by a team including co-first authors Cristina Miliano, Irene Chen, and Brieann Brown, along with additional contributors from Virginia Tech, the University of Texas at Dallas, and the University of California, San Diego.