Researchers find new approach to reversing chronic pain

Chronic pain affects more than 50 million Americans, yet for decades, treatment options for pain that persists in the absence of inflammation have been limited. Seventy-five percent of these patients, disproportionately women, experience pain that is inadequately managed by current therapeutics.

Now, scientists at Virginia Tech have found a way to switch it off in female mice by blocking a single pathway using compounds developed at the National Institutes of Health’s National Center for Advancing Translational Sciences.

In a new study published in PAIN, neuroscientist Ann Gregus and her team erased well-established pain behaviors by shutting down an enzyme system that produces molecules known to amplify pain signals. This finding could open the door to the first new class of non-opioid chronic pain treatments in years — a potential lifeline for patients whose symptoms defy standard drugs.

“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 who works alongside her partner, lab co-director and co-author Matthew Buczynski, an associate professor, both of the Virginia Tech College of Science’s School of Neuroscience. “It provides hope for people living with daily, persistent pain that does not respond to conventional treatments.”

A stubborn pain type — and a new target

The study zeroed in on nociplastic pain, a poorly understood category that includes fibromyalgia, chronic low back pain, and some migraines. Unlike pain caused by injury or ongoing inflammation, nociplastic pain arises from changes in how the nervous system processes signals, often leaving no visible damage to treat.

These conditions are famously resistant to treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) and are only partially relieved by anticonvulsants and antidepressants. Opioids are a last resort and generally are avoided due to risks of dependence and addiction. While NSAIDs block certain inflammatory pathways, the Gregus lab’s approach targets a different biochemical route that those drugs leave untouched.

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

From early clues to a breakthrough

Gregus’s lab had a lead. In 2018, she and her colleagues showed in rats that activating an immune receptor in the spinal cord set off enzymes that released molecules capable of intensifying pain.

When pandemic supply shortages limited their usual research models, the team turned to a different strain of female mice — almost by chance. It turned out to be a pivotal decision: these mice developed persistent, long-lasting pain behaviors, cold sensitivities, and grip force deficits typical of arthritis, while another commonly used strain barely responded.

“It was serendipity,” Gregus said. “We were working with whatever limited resources were accessible, and we ended up with a model that gave us clues about how pain transitions from acute to becoming chronic that we may not have discovered otherwise.”

Switching off pain after it’s entrenched

To mimic nociplastic pain, the researchers used an immune challenge that activates this receptor and ramps up pain pathways in the spinal cord. Once the mice developed clear pain behaviors, they treated them with highly selective compounds that block parts of the enzyme system.

The results were striking: tissue analysis confirmed that the immune challenge had ramped up production of pain-driving molecules, but upon treatment administration, tactile and cold pain hypersensitivity vanished, and grip strength returned. Administering those molecules alone also reproduced the pain state, confirming their role.

One of the compounds tested is currently in Phase II clinical trials for another disease by Veralox Therapeutics. Because it already has human safety data, it could shorten the path to clinical trials for chronic pain.

“It’s rare to see a drug work in reversing so many different pain models in multiple species,” Gregus said. “That makes it especially exciting to think about what it could do for patients.”

Personal stakes in the search for relief

For Gregus, the pursuit isn’t only scientific. She has lived with migraines and peripheral neuropathy herself, giving her an unfiltered view of how current treatments fall short.

“I know what it’s like to live with pain every day and be told there’s nothing else that can be done,” she said. “That’s why I’m driven to continue doing research even though at times it seems improbable — to bring new solutions to the people who need them the most.”

From the lab toward the clinic

The lab’s next step is to see whether the same enzyme-blocking strategy works in models that mirror the complexity of human disease: for example, conditions such as chemotherapy-induced peripheral neuropathy, which can linger for years after cancer treatment, and diabetic neuropathy, a leading cause of disability worldwide.

“If we can reverse chronic pain in those settings without the abuse liability of opioids,” Gregus said, “that’s when we know we’re ready to think about clinical trials.”

A therapy that could block and reverse the underlying cause — rather than simply mask symptoms — would mark a rare breakthrough in chronic pain care. For Gregus, that potential makes the path forward clear: translate the discovery into a treatment that delivers what patients almost never get — lasting relief.

The study was led by co-first authors Cristina Miliano, research scientist; Irene Chen, technician and now a graduate student at Johns Hopkins University; and Brieann Brown, graduate student in the School of Neuroscience. Additional contributors included Liwu Li, professor, and Shuo Geng, research assistant professor, both in the Department of Biology at Virginia Tech; Michael Burton, associate professor at the University of Texas at Dallas; and Tony Yaksh, professor at the University of California, San Diego.

Original study: DOI 10.1097/j.pain.0000000000003711