A novel generation of pain medications could be on the horizon. The drugs, known as peripheral sodium channel blockers, would mark the first time in over four decades that doctors have a new therapeutic to offer the millions of Americans living with neuropathy, or nerve pain. Neuropathy, a form of nerve damage that manifests as uncomfortable or sometimes debilitating symptoms including pain, numbness, or tingling, can be caused by a number of conditions such as diabetes, cancer, shingles, or autoimmune disease. The new approach is meant to treat chronic pain that has not responded to current treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, physical therapy, antidepressants, or highly addictive opioids.
This experimental class of drugs targets specific types of sodium channels—which act like molecular batteries that enable neurons to fire signals—in peripheral nerve cells. Now, in a new study, researchers focused specifically on therapeutically blocking a subtype known as sodium voltage-gated channel alpha subunit 10 [Nav1.8]. They discovered that partially blocking Nav1.8 reduced the firing of pain-signaling neurons in a model of chronic neuropathic pain. These findings highlight the promise of drugs that block Nav1.8, which could offer much needed medicine for neuropathic pain that doesn’t respond to existing therapies. The study, led by first author Dmytro Vasylyev, PhD, research scientist in neurology, was recently published in the Journal of General Physiology.
“If you block a little bit of Nav1.8, there is a dramatic effect in which neuronal hyperexcitability returns to normal,” Vasylyev says.
“I used to say that I was optimistic that there will likely be a new class of non-addictive, non-sedating pain medications,” says Stephen Waxman, MD, PhD, Bridget M. Flaherty Professor of Neurology and of neuroscience, and the study’s principal investigator. “Now, I’m telling patients and their families confidently that there will be new medications.”
Targeting peripheral sodium channel blockers to treat pain
Waxman’s laboratory has been studying sodium channel blockers since the 1990s. “It’s part of the crown jewel of neuroscience,” he says. Researchers used to believe that there was only one sodium channel. But in the 1980s, emerging science revealed that there were multiple kinds of these channels.
Today’s available sodium channel blockers are nonspecific, meaning they block all channels. When we go to the dentist, for example, we sometimes receive a shot of Novocain or Bupivacaine, which blocks all sodium channels on nerve cells near the injection site. However, nonspecific sodium channel blockers have a major downfall: “If you took a drug like Novocain 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, researchers began searching for peripheral sodium channels. These would be channels found only in the peripheral nervous system—the portion outside of 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 very 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 nerve cells known as dorsal root ganglion (DRG) neurons to become hyperactive. “If they become hyperexcitable, they start to fire spontaneously, which creates pain,” says Vasylyev.
These mutations are affiliated with chronic pain conditions such as inherited erythromelalgia, also known as “man-on-fire syndrome” due to the severe burning it causes in the hands and feet. “People with IEM 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. However, in a larger study, Pfizer did not find a significant benefit. Other pharmaceutical companies, including Merck and Genentech, have also been studying Nav1.7 blockers. “On the one hand, we’ve had encouraging results,” says Waxman. “But on the other hand, the work is still ongoing, and there has not been a demonstration in a large study of efficacy.”
Investigations in Waxman’s lab also 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 in driving the firing of pain-signaling peripheral neurons,” he says.
Finally, earlier this year, Vertex Pharmaceuticals announced findings that its selective Nav1.8 inhibitor, VX-548, was effective in reducing pain following abdominoplasty [“tummy tuck”] or bunionectomy [bunion removal] surgeries. “It showed modest efficacy in acute pain,” says Waxman. “But even though the pain relief was only modest, it established a proof-of-concept that you can reduce pain in humans blocked by Nav1.8.”
Blocking Nav1.8 reduces neuron hyperactivity
Based on their past work with these two subtypes, Vasylyev and Waxman wondered if studying the interactions between Nav1.7 and Nav1.8 could offer clues for treating chronic pain. They hypothesized that blocking Nav1.8 could help not just acute pain, but potentially chronic neuropathic pain. They also questioned if only partially blocking Nav1.8 would be effective in reducing pain.
To investigate, the researchers decided to explore Nav1.7 and Nav1.8 interactions in a chronic neuropathic pain setting. The team took pain-signaling DRG neurons from rats and used a technique called dynamic clamp to make these neurons hyperactive. Dynamic clamp is a method that scientists use—by administering precisely calibrated amounts of simulated currents—to study how nerve cells communicate with each other through electrical signals. The team used this technique to simulate the mutation that causes inherited erythromelalgia. They replaced the normal Nav1.7 current with a “mutated” hyperactive current, which in turn caused the animal neurons to become hyperactive. “They’re shrieking when they should be whispering,” Waxman says of the mutated cells.
Then, using dynamic clamp, the team explored how much Nav1.8 they needed to counteract the hyperactivity. They found that reducing the Nav1.8 current by 25% normalized the excessive firing of the neurons. “In this paper, we show that when we induce inherited erythromelalgia in these cells, they give off spontaneous oscillations [electrical activity] that drive pain-signaling,” says Vasylyev. “And then removing Nav1.8 decreases the amplitudes of these oscillations.”
“That encourages me to believe that Nav1.8 blockers are going to be useful in any chronic nerve condition—diabetic neuropathy and conditions of that sort,” Waxman says.
New approach could revolutionize medicine for neuropathic pain
The study is the first time that researchers have visualized how Nav1.7 and Nav1.8 interact with each other at a very high resolution, Waxman says, offering new insights into how therapeutically blocking these sites could reduce the hyperactive pain signaling in chronic conditions that are unresponsive to available treatments.
When asked why this research is important, Waxman spoke 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 his 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” he says.
There are many debilitating chronic conditions that are often unresponsive to existing therapies, such as chemotherapy-induced neuropathy, post-shingles neuropathy, and trigeminal neuralgia—which causes pain so severe that its nickname is the “suicide disease.” “There are all these forms of neuropathic pain for which we have basically very little,” Waxman says.
While Vertex’s Nav1.8 inhibitor has shown only modest efficacy, the researchers are hopeful. “If you think of the history of statin drugs, the first ones, in retrospect, were not all that good,” Waxman says. “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 diving in and striving to develop their own Nav1.8 inhibitors, he adds.
In ongoing studies, Waxman’s lab is investigating whether gene therapy approaches could modify the genes for these peripheral sodium channels—so as to mute them so the cells do not inappropriately fire. His lab has also uncovered a genetic mutation linked to pain resilience. They are working to understand how this mutation eases pain and if there are others, which could offer further insights into therapeutically inducing resilience to pain. Furthermore, Vasylyev is interested in exploring how Nav1.7 and Nav1.8 inhibitors could work together to reduce pain. “There could be an additive or synergetic effect,” he hypothesizes. “We want to explore that avenue a little bit more.”
While there is still much work to be done, Waxman is confident 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 totally change pain management.”