Sodium Channel Blockers

A novel generation of pain medications has arrived. The drugs, known as peripheral sodium channel blockers, mark the first time in over four decades that doctors have a new therapeutic that can reduce pain without the uncomfortable side effects and potential for addiction that come with opioids.

“I used to say that I was optimistic that there will likely be a new class of nonaddictive nonsedating pain medications,” says Stephen Waxman, MD, PhD, Bridget M. Flaherty Professor of Neurology and of neuroscience and pharmacology at Yale School of Medicine (YSM). “Now I can say they’re here.”

The U.S. Food and Drug Administration approved a sodium channel blocker called suzetrigine in January 2025, the first of this new class of pain medication to receive approval. This new class of drugs targets specific types of sodium channels—which act like molecular batteries that enable neurons to fire signals—in peripheral nerve cells. Their development is based on decades of research led by Waxman. “One of the exciting things about the development of this drug is that it really embodies the arc of science,” Waxman says.

Waxman’s laboratory has been studying the role of sodium channels in pain since the 1980s. “Sodium channels are one of the crown jewels of neuroscience,” he says. Researchers once thought that there was only one sodium channel. But findings emerging in the 1980s revealed that there are multiple types.

Sodium channel blockers in general are not new; but those that are already commonly used are nonspecific, meaning that they block all sodium channels. When you go to the dentist, for example, you might receive a shot of Novocaine^®, which blocks all sodium channels on nerve cells near the injection site. However, nonspecific sodium channel blockers have a major downside. “If you took a drug like Novocaine and put it in a pill, it would affect sodium channels in the brain,” Waxman explains. “This can cause loss of balance, double vision, sleepiness, and confusion.”

Thus the researchers began searching for peripheral sodium channels—those found only in the peripheral nervous system—the portion of the nervous system outside the brain and spinal cord. Blocking these channels would bypass the debilitating side effects associated with nonspecific drugs.

Scientists eventually found three peripheral sodium channels—Nav1.7, Nav1.8, and Nav1.9. At first, they focused on Nav1.7 due to compelling genetic evidence. Gain-of-function mutations—in which mutations in the gene that encodes for Nav1.7 enhance the channel’s activity—can cause sensory cells known as dorsal root ganglion neurons to become hyperactive. These mutations are affiliated with chronic pain conditions like inherited erythromelalgia, also known as man-on-fire syndrome due to the severe burning sensation it causes in the hands and feet. “People with inherited erythromelalgia describe the pain as feeling as if they have been burned by a blowtorch,” Waxman says.

In contrast, loss-of-function mutations in Nav1.7 can eliminate pain perception. These mutations can lead to a condition called congenital insensitivity to pain. “People with this condition can feel absolutely no pain—painless fractures, painless burns, painless tooth extractions,” Waxman says. Waxman spent about a decade collaborating with Pfizer on a Nav1.7 blocker. A clinical trial on a small number of patients, each studied in great detail, showed that the drug reduced pain. In a larger study, however, Pfizer did not find significant benefit.

Interestingly, investigations in Waxman’s lab had revealed that Nav1.8 was as promising a target as Nav1.7. “In a mechanistic sense, we knew back in 1997 that Nav1.8 was as important as Nav1.7, and in some ways more important, in driving the firing of pain-signaling peripheral neurons,” he says. In the beginning of 2024, Vertex Pharmaceuticals announced findings that its selective Nav1.8 inhibitor, now known as suzetrigine, was effective in reducing pain following abdominoplasty (“tummy tuck”) or bunionectomy (bunion removal) surgeries.

“It showed statistically significant but modest efficacy in acute pain,” says Waxman. “But even though the pain relief was only modest, the important point is that this study established proof-of-concept that you can reduce pain in humans by blocking Nav1.8.”

While Waxman’s work in this area began in the 1980s, it built upon discoveries made by Alan Hodgkin and Andrew Huxley at the University of Cambridge in 1949. After measuring electrical currents inside the giant nerve fibers of squid, the two developed a theoretical framework to explain how the nerves work, proposing that charged atoms are able to flow through the permeable membranes of the nerves. John Eccles took a different tack, studying synapses in the 1950s while at the Australian National University, and together the three won the Nobel Prize in Physiology or Medicine in 1963.

What Hodgkin and Huxley described would turn out to be sodium channels—Waxman and his team “picked up the baton” a couple of decades later, as he says, investigating how these channels contribute to pain. When asked what motivated his research, Waxman speaks of his father, who spent the last two years of his life in a near-coma from all the opiates he was prescribed in an unsuccessful attempt to dull the severe pain caused by diabetic neuropathy. “There he was, crying from pain, and not only did the opiates not work very well, but they also took away his capacity to think,” Waxman says.

Many debilitating chronic pain conditions can be unresponsive to existing therapies, including peripheral neuropathy—a form of nerve damage that manifests as uncomfortable or sometimes debilitating symptoms, including pain, numbness, or tingling. Peripheral neuropathy can be caused by such conditions as diabetes, cancer, shingles, or autoimmune disease. Neuropathic pain also occurs in trigeminal neuralgia, a disorder that causes pain so severe that its nickname is the “suicide disease.”

In many patients, neuropathic pain does not respond to current treatments, including nonsteroidal anti-inflammatory drugs like ibuprofen, physical therapy, antidepressants, or highly addictive opioids. “So we now are building on the current progress with Nav1.8 blockers, trying to make the leap from acute pain to chronic pain,” Waxman says.

Waxman is hopeful that this new class of drug will only get better. “If you think of the history of statin drugs, the first ones in retrospect were not all that good,” he explains. “But they encouraged research that led to the second and third generation of drugs that really delivered the bang for the buck.” Currently, about a half-dozen pharmaceutical companies are striving to develop their own Nav1.8 inhibitors, he adds.

In ongoing studies, Sulayman Dib-Hajj, PhD, professor of neurology at YSM and a collaborator of Waxman’s, is investigating whether gene therapy approaches could modify the genes for these peripheral sodium channels, to mute them to prevent the cells from firing inappropriately. Waxman has also uncovered a genetic mutation linked to pain resilience. His team is working to understand how this mutation eases pain and also looking for others that could offer further insights into how to induce resilience to pain therapeutically.

While there is still much work to be done, Waxman is optimistic that future pain medications will fill today’s glaring gaps. “It’s not going to happen tomorrow, or next month, or next year. But I expect sometime in the next three to eight years, there will be a series of additional drugs,” he says. “Each one will be better than the last, and sometime within the next 10 years, we will win the battle against pain."