By Paul McClure
November 12, 2024
A non-addictive painkiller remains inactive in the body until it encounters areas of chronic pain
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Researchers have developed a non-addictive painkiller that remains inactive until it reaches sites of chronic pain. Instead of dulling the nerves that send the pain signals like other analgesics, this new pain pill directly addresses the underlying cause. Its makers are currently working towards testing the compound in human trials.
Different from other medications, a prodrug remains inactive until it encounters a specific circumstance in the body that activates it. One of the major benefits of using a prodrug is that it delivers medication directly to where it’s needed in the body. For something like a pain-relieving medication, that’s important.
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Now, a team of international researchers has capitalized on a well-known chemical reaction to create a medication that provides localized pain relief, especially for chronic pain.
“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 Center of Excellence for Nanoscale BioPhotonics (CNBP) at the University of Adelaide, and the study’s co-corresponding author. “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 researchers’ prodrug is activated by a chemical reaction with reactive oxygen species (ROS), like hydrogen peroxide and peroxynitrite, which are found in higher concentrations at persistent pain sites than at other sites. What that means is that the prodrug circulates around the body, inactive, until it reaches these pain sites, where it exerts its effects.
The prodrug reduces the molecules responsible for producing chronic pain in conditions like osteoarthritis
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“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 Peter Grace from the University of Texas MD Anderson Cancer Center, the other of the study’s corresponding authors. “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.”
The researchers tested the prodrug’s effectiveness in mouse models of chronic pain that feature localized sites of oxidative stress caused by the accumulation of ROS. When an oral, multi-day preparation of the prodrug was tested on models of diabetic neuropathy, osteoarthritis, and chemotherapy-induced peripheral neuropathy, it reversed hypersensitivity to touch and cold six months after injury. While testing showed that the prodrug’s effects were dose-dependent, the researchers observed that repeated dosing maintained its analgesic effects.
“This showed us that the compound did not induce a tolerance, which is the major limiting factor to powerful painkillers like morphine,” said PhD candidate Dion Turner, a study co-author. “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 continue with preclinical trials to determine the prodrug’s effectiveness and safety before moving on to human trials.
For those who are interested, the chemical reaction capitalized on by the researchers is called Baeyer-Villiger oxidation (BVO). It’s too complicated to discuss in detail here, but if you’re organic-chemistry-minded and want to know more about BVO, YouTube’s Chad gives a good explanation of it in the video below.
19.8 Baeyer Villiger Oxidation | Organic Chemistry
The study was published in the journal Nature Biotechnology.
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