Unlike traditional medications, a prodrug is engineered to remain inactive until it encounters specific conditions in the body that trigger its activation. This unique feature offers a significant advantage, as it allows for targeted delivery of medication precisely where it is needed. This is particularly crucial for pain relief treatments.
Recently, a group of international researchers has harnessed a well-established chemical reaction to develop a groundbreaking medication that delivers localized pain relief, especially for those suffering from chronic pain. This remarkable, nonaddictive painkiller stays dormant until it reaches the sites of discomfort.
Rather than merely masking pain signals like conventional analgesics, this new medication directly tackles the root cause of the pain. Its developers are actively progressing toward human trials, bringing hope for a more effective solution to chronic pain management.
“Our team has created a targeted prodrug (a compound which metabolizes inside the body into a pharmacologically active drug) and found it to be capable of relieving chronic pain during preclinical trials,” said Professor Andrew Abell of the Department of Chemistry and the ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP), Institute for Photonics and Advanced Sensing (IPAS) at the University of Adelaide. “We believe we were the first people to come up with the idea of using this particular chemical reaction in a biological sense, and we already see potential for its use in other settings.”
The innovative mechanism of action for this targeted prodrug harnesses the body’s natural processes, activating the active drug through a chemical reaction with reactive oxygen species like hydrogen peroxide—substances that are significantly elevated at pain sites compared to other areas of the body.
Developed in Professor Abell’s cutting-edge laboratory, this prodrug circulates throughout the body in its inactive form, becoming activated specifically at pain sites, where it transforms into a therapeutic agent. Extensive testing in both chemical and preclinical models has demonstrated that this prodrug effectively provides targeted relief for sciatic nerve injuries and various chronic pain conditions characterized by oxidative stress, including osteoarthritis, chemotherapy-induced peripheral neuropathy, and diabetic neuropathy.
Results showed that administering the compound orally for several days, even six months post-injury, restored sensitivity to touch and cold; additional testing revealed that the drug’s effects were dose-dependent, with consistent pain relief achieved through repeated doses.
“This showed us that the compound did not induce a tolerance, which is a major limiting factor to powerful painkillers like morphine,” said Mr Turner. “Chronic pain remains a large unmet medical need, and nonaddictive treatments like this would revolutionize the field, which is currently dominated by addictive opioids.”
The researchers received funding from the US National Institutes of Health (NIH) Helping to End Addiction Long-term (HEAL) Initiative and will now undergo more preclinical trials to determine effectiveness and safety.
“The few drugs available to treat chronic pain are only effective for about one in six people, and they simply reduce the activity of nerves that send pain signals,” said Associate Professor Grace. “Our new prodrug addresses an underlying problem by reducing the molecules that are responsible for sending the pain signals. This has potential for a new approach to chronic pain treatment.”
Team members have participated in establishing a company called Immunologic, which is in the process of securing funding to finalize the preclinical phase work and advance this prodrug toward human clinical trials.
“This project is capitalizing on the promise of resolving oxidative stress and inflammation to effectively treat pain,” said Immunologic Executive Chairman and CEO Stephen Collins MD PhD. “There are no other companies doing something quite like this.”
Journal reference:
- Thomas D. Avery, Jiahe Li, Dion J. L. Turner, Mohd S. U. Rasheed, Fisher R. Cherry, Damian L. Stachura, Fátima Rivera-Escalera, David M. Ruiz, Michael J. Lacagnina, Caitlyn M. Gaffney, Clarissa Aguilar, Jingxian Yu, Yang Wang, Huan Xie, Dong Liang, Andrew J. Shepherd, Andrew D. Abell & Peter M. Grace. Site-specific drug release of monomethyl fumarate to treat oxidative stress disorders. Nature Biotechnology, 2024; DOI: 10.1038/s41587-024-02460-4
