PHILADELPHIA—A groundbreaking preclinical study has revealed a new gene therapy that targets pain centers in the brain while eliminating the addiction risks associated with narcotics. This breakthrough could provide significant relief for over 50 million Americans suffering from chronic pain.
Chronic pain can be likened to an incessant, blaring radio with no volume control. Opioid medications, such as morphine, attempt to turn down this volume but often affect other brain areas, leading to severe side effects or addiction. The new gene therapy, however, acts like a precise volume knob, reducing only the “pain station” without disturbing other brain functions. This research, conducted by teams at the University of Pennsylvania Perelman School of Medicine, School of Nursing, Carnegie Mellon University, and Stanford University, was published today in Nature.
“The goal was to reduce pain while lessening or eliminating the risk of addiction and dangerous side effects,” said Gregory Corder, PhD, co-senior author and assistant professor of Psychiatry and Neuroscience at Penn. “By targeting the precise brain circuits that morphine acts on, we believe this is a first step in offering new relief for people whose lives are upended by chronic pain.”
An AI-Driven Approach to Pain Management
Morphine, a narcotic derived from opium, has a high potential for abuse as patients often develop a tolerance, necessitating higher doses for the same pain relief. By imaging brain cells that act as pain trackers, the research team gained new insights into how morphine alleviates suffering.
Utilizing these insights, they developed a mouse-model behavioral platform powered by artificial intelligence (AI). This platform tracks natural behaviors, creates a readout of pain levels, and helps determine the necessary treatment to alleviate pain. This readout served as a map, allowing the team to design a targeted gene therapy that mimics morphine’s beneficial effects while avoiding its addictive properties, delivering an “off switch” specifically for brain pain. When activated, this switch provides durable pain relief without affecting normal sensation or triggering reward pathways that can lead to addiction.
“To our knowledge, this represents the world’s first CNS-targeted gene therapy for pain, and a concrete blueprint for non-addictive, circuit-specific pain medicine,” Corder stated.
Addressing the Opioid Crisis
The results of this study are the culmination of over six years of research, supported by a National Institutes of Health New Innovator Award. This funding enabled Corder and his colleagues to delve into the mechanisms of chronic pain.
In 2019, drug use was attributed to 600,000 deaths, with 80 percent related to opioids. A 2025 Pew survey found that nearly half of Philadelphians knew someone with opioid use disorder (OUD), and one-third knew someone who had died from an overdose.
Chronic pain, often referred to as a ‘silent epidemic,’ affects approximately 50 million Americans, costing upwards of $635 million annually in direct medical expenses and indirect costs from lost productivity, including missed work and reduced earning capacity. These findings have the potential to ease that pain—turning down the noise—should the science hold through additional testing and into clinical trials.
Next Steps Toward Clinical Trials
The research team is advancing to the next phase of work with Michael Platt, PhD, the James S. Riepe University Professor of Neuroscience and Psychology, aiming to bridge the gap toward future clinical trials.
“The journey from discovery to implementation is long, and this represents a strong first step,” Platt said. “Speaking both as a scientist and as a family member of people affected by chronic pain, the potential to relieve suffering without fueling the opioid crisis is exciting.”
This work was supported by the National Institutes of Health, the Howard Hughes Medical Institute, the Whitehall Foundation, and the Tito’s Love Research Fund. Some authors are inventors on a provisional patent application through the University of Pennsylvania and Stanford University regarding the custom sequences used to develop, and the applications of, synthetic opioid promoters.
As the research progresses, the hope is that this innovative approach to pain management will provide a viable alternative to opioids, offering relief without the risk of addiction.
