Researchers at Washington University (WashU) School of Medicine in St. Louis and Stanford University have developed a promising compound that could serve as a nonaddictive alternative to opioids for the treatment of chronic pain. In their mouse study, published in Nature, the investigators showed that the new compound mimics the pain-relieving properties of a natural molecule found in cannabis, without causing addiction or mind-altering effects.
“There is an urgent need to develop nonaddictive treatments for chronic pain, and that’s been a major focus of my lab for the past 15 years,” said senior study author Susruta Majumdar, PhD, a professor of anesthesiology at WashU Medicine. “The custom-designed compound we created attaches to pain-reducing receptors in the body but, by design, it can’t reach the brain. This means the compound avoids psychoactive side effects such as mood changes and isn’t addictive because it doesn’t act on the brain’s reward center.”
Opioids, which are commonly prescribed for pain, can be highly addictive and potentially deadly. In 2022, opioid-related overdoses led to more than 82,000 deaths in the United States. Development of this new compound could provide an alternative to prescription opioids and significantly reduce the number of people who become addicted to their use to manage chronic pain. It is estimated that in the United States alone, more than 50 million people suffer from chronic pain.
The compound was developed by modifying a synthetic cannabinoid, a molecule derived from cannabis, to prevent it from crossing the blood-brain barrier. Typically, cannabis-based compounds activate cannabinoid receptor type 1 (CB1) in the brain, which is what produces its psychoactive effects. The modified version, however, selectively targets CB1 receptors on pain-sensing nerve cells outside the brain, allowing it to provide pain relief without altering brain function.
“For millennia, people have turned to marijuana as a treatment for pain,” Robert W. Gereau, PhD, a corresponding author of the study and director of the WashU Medicine Pain Center. “Clinical trials also have evaluated whether cannabis provides long-term pain relief. But inevitably the psychoactive side effects of cannabis have been problematic, preventing cannabis from being considered as a viable treatment option for pain. However, we were able to overcome that issue.”
To test their compound, the research team used mouse models of nerve injury pain and migraine headaches and measured hypersensitivity to touch as a proxy for pain. They found that the compound successfully eliminated hypersensitivity to touch and the compound provided prolonged pain relief, with no signs of the mice developing tolerance despite administration of the compound over nine days.
The compound’s ability to prevent the development of tolerance was an important part of its design. Working with researchers at Stanford, the WashU team performed molecular dynamics simulations to identify a previously unknown pocket on the CB1 receptor, which they theorized could provide an additional binding site for cannabinoids. This pocket, when utilized, reduces the cellular activity that leads to tolerance, a major issue with many pain medications.
“Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects,” wrote the researchers in the study’s abstract. “VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance.” This finding indicates that VIP36 could be a viable target for chronic pain relief without the usual risks associated with opioid use.
“Designing molecules that relieve pain with minimal side effects is challenging to accomplish,” Majumdar said. “We hope that with further refinement, this compound can be tested in clinical trials to evaluate its potential for treating chronic pain in humans.”