New preclinical research has identified a gene therapy that directly targets areas of the brain that process pain, while avoiding the addiction risks associated with opiates. The findings could bring new hope to the more than 50 million Americans living with chronic pain.
Living with chronic pain is often likened to a radio stuck at maximum volume and no matter what you try, the noise won’t go away. Opioids such as morphine can reduce that amount, but they also act on other parts of the brain, which can cause serious side effects and a high risk of addiction.
Researchers say the new gene therapy works like a precise volume control that suppresses pain signals without affecting other parts of the brain. The works published in naturewas conducted by scientists from the Perelman School of Medicine and Nursing at the University of Pennsylvania and collaborators from Carnegie Mellon University and Stanford University.
“The goal was to reduce pain while reducing or eliminating the risk of addiction and dangerous side effects,” said Dr. Gregory Corder, co-senior author and assistant professor of psychiatry and neuroscience at the University of Pennsylvania. “By targeting the precise brain circuits that morphine acts on, we believe this is the first step in providing new relief to people whose lives are being upended by chronic pain.”
AI helps map pain circuits for safer treatment
Morphine, an opium-derived drug, is widely used for pain relief but has a high potential for misuse. Over time, patients often develop resistance. This means that increasingly higher doses are required to achieve the same level of relief.
To better understand how morphine works, researchers studied brain cells involved in tracking pain signals. Using these insights, they built a system that leverages artificial intelligence (AI) in mice. This system helps monitor natural behavior, estimate pain levels, and determine how much treatment is needed.
This system served as a guide to design a targeted gene therapy that reproduces the analgesic effects of morphine without causing addiction. This therapy introduces a unique pain “off switch” in the brain. Once activated, it provides sustained pain relief without interfering with normal sensation or activating reward pathways associated with addiction.
“To our knowledge, this is the world’s first central nervous system-targeted gene therapy for pain and a concrete blueprint for non-addictive, circuit-specific analgesics,” Corder said.
Addressing chronic pain without fueling the opioid crisis
The study reflects more than six years of research supported by the National Institutes of Health’s New Innovators Award, which allowed the team to investigate how chronic pain develops and persists.
It is clear that safer treatments are urgently needed. In 2019, drug use was linked to 600,000 deaths, 80% of which involved opioids. A 2025 Pew study found that nearly half of Philadelphians know someone with opioid use disorder (OUD) and one-third know someone who has died from an overdose.
At the same time, chronic pain remains a prevalent and costly condition, often described as a “silent epidemic.” Approximately 50 million Americans are affected, resulting in more than $635 million in annual costs, including medical costs and lost productivity due to missed work and lost income. If future studies confirm these findings, this new approach could help reduce that burden by providing effective pain relief without the risks associated with opioids.
Next steps towards clinical trials
The research team is currently collaborating with Dr. Michael Platt, James S. Riepe University Professor, Professor of Neuroscience, and Professor of Psychology, to advance the study toward potential clinical trials.
“The road from discovery to implementation is long, but this is a strong first step,” Pratt said. “Speaking as a scientist and as a family member of people who suffer from chronic pain, the possibility of relieving suffering without fueling the opioid crisis is exciting.”
This research was supported by the National Institutes of Health (NIGMS DP2GM140923, NIDA R00DA043609, NIDA R01DA054374, NINDS R01NS130044, NIDA R01DA056599, NIDA R21DA055846, NIDA F31DA062445, NINDS). F31NS143421, NIDA F32DA053099, NIDA F32DA055458, NIDA F31DA057795, NINDS F31NS125927, NIDA T32DA028874, NINDS RF1NS126073), Howard Hughes Medical Institute, Whitehall Foundation, and Tito’s Love Research Fund.
Several of the authors are inventors who have filed provisional patent applications through the University of Pennsylvania and Stanford University for the development of synthetic opioid promoters and custom sequences used in their applications (patent application number: 63/383,462 “Human and Murine Oprm1 Promoters and Uses Thereof”).
