New Non-Opioid Compound Provides Innovative Pain Relief

Researchers are closer to developing a safe and effective non-opioid pain reliever after a study showed that a new compound they created reduces the sensation of pain by regulating a biological channel linked to pain.

The National Institutes of Health estimates 100 million people in the U.S. suffer from chronic pain. Approximately 21-29% of patients prescribed opioids for chronic pain misuse them and 8-12% of people using an opioid for chronic pain develop an opioid use disorder, according to the National Institute on Drug Abuse. In 2019, nearly 50,000 people in the U.S. died from opioid-involved overdoses.

“Drug discovery for chronic pain is at the forefront of this research, and it's being amplified by the intersection of the COVID-19 pandemic and the opioid epidemic,” said Rajesh Khanna, PhD, who will join NYU College of Dentistry in January as a professor in the Department of Molecular Pathobiology. He is currently the associate director of the UArizona Health Sciences Comprehensive Pain and Addiction Center, professor of pharmacology in the UArizona College of Medicine – Tucson and a member of the BIO5 Institute.

“Drug discovery is a very arduous process. Our lab looked at a fundamental mechanism of pain, came up with a way to differentiate it from those before us and found a compound that has potential as a new non-opioid treatment for pain,” added Dr. Khanna.

The paper, “Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents,” was published in Science Translational Medicine.

The biological mechanism at the heart of the research is NaV1.7, a sodium ion channel that previously was linked to the sensation of pain through genetic studies of people with rare pain disorders.

Nerve cells, or neurons, use electrical currents to send signals to the brain and throughout the body, and sodium ion channels are vital to a cell's ability to generate those electrical currents. When a neuron is stimulated, the NaV1.7 channel opens and allows positively charged sodium ions to cross the cell membrane and enter the previously negatively charged cell. The change in charge across the cell membrane generates an electrical current, which increases the excitability of the neuron and sets in motion a cascade of events that leads to pain.

Because NaV1.7 is a human-validated target for pain, multiple attempts have tried to stop pain by using sodium ion channel inhibitors to block NaV1.7. None have been successful. Dr. Khanna and his team took a different approach – rather than block NaV1.7, they wanted to indirectly regulate it.

Using a compound they designed and dubbed 194, the team successfully regulated NaV1.7 activation in the laboratory using nerve cells from four different species, including humans. In animal models, 194 was effective in reversing pain in six different pain models in both sexes.

Researchers also found that 194 may promote pain relief by activating the body’s endogenous, or naturally occurring, opioid system. Once produced, endogenous opioids activate receptors that produce physiological changes such as pain relief. And 194 did so without causing motor performance issues, depressive behaviors or addiction.

Finally, Dr. Khanna and the team observed a synergistic effect when 194 was combined with morphine and gabapentin. This is a promising sign that 194 could be used in a dose-reduction strategy for painkillers that have negative side effects, including opioids, while maintaining high levels of pain relief.

Read more about the NIH-funded research from the University of Arizona Health Sciences website.