When doctors ask Sara Gehrig to describe her pain, she often says it is indescribable. Stabbing, burning, aching—those words frequently fail to depict sensations that have persisted for so long they are now a part of her, like her bones and skin. “My pain is like an extra limb that comes along with me every day.”
Gehrig, a former yoga instructor and personal trainer who lives in Wisconsin, is 44 years old. At the age of 17 she discovered she had spinal stenosis, a narrowing of the spinal cord that puts pressure on the nerves there. She experienced bursts of excruciating pain in her back and buttocks and running down her legs. That pain has spread over the years, despite attempts to fend it off with physical therapy, anti-inflammatory injections and multiple surgeries. Over-the-counter medications such as ibuprofen (Advil) provide little relief. And she is allergic to the most potent painkillers—prescription opioids—which can induce violent vomiting.
Today her agony typically hovers at a 7 out of 10 on the standard numerical scale used to rate pain, where 0 is no pain and 10 is the most severe imaginable. Occasionally her pain flares to a 9 or 10. At one point, before her doctor convinced her to take antidepressants, Gehrig struggled with thoughts of suicide. “For many with chronic pain, it’s always in their back pocket,” she says. “It’s not that we want to die. We want the pain to go away.”
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Gehrig says she would be willing to try another type of painkiller, but only if she knew it was safe. She keeps up with the latest research, so she was interested to hear earlier this year that Vertex Pharmaceuticals was testing a new drug that works differently than opioids and other pain medications.
That drug, a pill called VX-548, blocks pain signals before they can reach the brain. It gums up sodium channels in peripheral nerve cells, and obstructed channels make it hard for those cells to transmit pain sensations. Because the drug acts only on the peripheral nerves, it does not carry the potential for addiction associated with opioids—oxycodone (OxyContin) and similar drugs exert their effects on the brain and spinal cord and thus can trigger the brain’s reward centers and an addiction cycle.
In January Vertex announced promising results of clinical trials of VX-548, which it is calling suzetrigine, showing that it dampened acute pain levels by about one half on that 0-to-10 scale. The company is applying for U.S. Food and Drug Administration approval for the drug this year.
Other pain drugs that target sodium channels are now being developed, some by firms motivated by Vertex’s success. Navega Therapeutics, led by biomedical engineer Ana Moreno, is even using molecular-editing tools such as CRISPR to suppress genes involved in chronic pain. “We are definitely hopeful that we can replace opioids, and that’s the goal here,” she says.
One in five U.S. adults—51.6 million people as of 2021—is living with chronic pain. New cases arise more often than other common conditions, such as diabetes, depression and high blood pressure. Yet pain treatments have not kept pace with the need. There are over-the-counter pills such as aspirin, acetaminophen (Tylenol) and nonsteroidal anti-inflammatories (NSAIDs) such as Advil. And there are opioids. The glaring inadequacy of existing medications to alleviate human suffering has fueled the ongoing opioid epidemic, which has led to more than 730,000 overdose deaths since its start.
VX-548 does have limits. It left some patients in significant discomfort, and so far it has been tested mostly in those with acute pain, not the much larger problem of chronic pain. Gehrig says she wants more assurances that the drug won’t cause nasty side effects before she takes it.
But the compound has shown that a new mechanism of pain relief is possible, says Stephen Waxman, a neurologist at Yale University who studies pain signals—and who is not involved in the Vertex clinical trials. Future drugs using that mechanism are likely to be even more effective, he notes. Waxman used to tell patients that a new means of managing their pain was on the way but that it may not happen for many years. “Now I can relax the caveat and say I think things are going to happen fairly quickly,” he says.
A young Pakistani firewalker had a genetic mutation affecting pain-signaling neurons, letting the boy walk on burning coals without feeling pain.
The pain medications that exist today are, in large part, derivatives of natural products that have been around for thousands of years. Aspirin originally came from willow bark. Morphine and codeine were derived from the opium poppy plant. Prescriptions for what evolved into the two major classes of pain drugs—NSAIDs and opioids—were etched on clay tablets by ancient Sumerians 4,000 years ago.
Modern research on the molecular mechanisms underlying pain, conducted during the past two decades, makes a different approach possible. Scientists know that our body is home to large numbers of pain-signaling nerve cells that innervate our skin, muscle and visceral tissues. These cells act like an alarm system, detecting threatening stimuli such as extreme temperatures, sharp objects or noxious chemicals. In response to these cues, they create impulses that carry pain signals along nerve fibers to clusters of cells known as dorsal root ganglia, which are tucked beside the spinal cord. From there, the signals continue their journey upward to the brain, where pain becomes reality. “This is the axis of pain,” says Rajesh Khanna, a pharmacologist and pain researcher at the University of Florida.
Central to this pathway are sodium channels, cellular gates scattered throughout the membranes of nerve cells. Whenever there is a shift in membrane potential, these gates open to allow the influx of sodium ions that generate the electric currents responsible for nerve impulses. Normally those pain signals serve a protective purpose—alerting someone to pull their hand away from a hot stove or noting inflammation or injury that needs to be addressed. But in chronic pain, those protective mechanisms can go awry.
A voltage-gated sodium channel (or NaV, Na standing for sodium and V for voltage) seems like the ideal target for treating pain; after all, if you can stop it, you can stop pain signals from being transmitted. Yet because these channels control electrical impulses that power the heart and brain, blocking them willy-nilly would impair vital functions. That’s why novocaine and lidocaine—which are sodium-channel blockers—are used as local numbing agents but can cause serious side effects if administered systemically. So scientists trying to block these pain pathways searched for channels that act more often in the peripheral sensory nerves, eventually identifying three: NaV1.7, NaV1.8 and NaV1.9.
NaV1.7 and NaV1.8 are the pivotal players in pain signaling. “They work in tandem, like dominoes,” Waxman says. “NaV1.7 initiates the electrical signal, and NaV1.8 takes off, producing 80 percent of the current underlying the action potential.” (NaV1.9 plays a more niche role in setting the pain-signaling neurons’ threshold potential.)
Beginning about 20 years ago, a series of reports linked these channels to pain disorders in humans. A mutation in the SCN9A gene, which encodes NaV1.7, was discovered in a family in China who suffered from a rare condition called erythromelalgia, or “man on fire” syndrome. In people with this condition, mild warmth can trigger attacks of searing pain that feels like a blowtorch. Waxman found that mutations in patients with erythromelalgia made the NaV1.7 channel overactive, causing pain-signaling neurons “to scream when they should be whispering.” Elsewhere, researchers found a mutation with the opposite effect in a young Pakistani firewalker. That mutation extinguished the flow of pain-signaling ions through the NaV1.7 channel. As a result, the boy could walk on burning coals without feeling pain.
The discovery of the genetic basis of his condition—known as congenital insensitivity to pain—set off a race in the pharmaceutical industry to identify molecules that could block NaV1.7. The goal was to provide a similar pain-free existence to the rest of the population. “This was the holy grail. You have a protein, you mutate it, you have no pain—it’s got to be the target,” Khanna says. “A lot of pharma companies put a lot of money into this effort, but none of those compounds have been successful.”
Many compounds targeting NaV1.7 looked promising in the laboratory, only to fail in clinical trials. Pharma companies AstraZeneca and Genentech both developed candidates that stalled after phase 1 trials. Pfizer’s PF-05089771 failed to perform in a battery of tests evoking pain in healthy volunteers. Biogen scrapped development of its NaV1.7 inhibitor, vixotrigine, after lackluster results from a string of phase 2 trials in several types of neuropathic pain. After more than a decade of false starts, investment dwindled, and drug candidates disappeared from development pipelines.
“For many with chronic pain, it’s always in their back pocket. It’s not that we want to die. We want the pain to go away.” —Sara Gehrig pain patient
In 2017 the White House declared a public health emergency for the opioid crisis, which was killing 91 people every day. That same year Francis Collins, then director of the National Institutes of Health, gathered industry leaders as well as basic scientists and clinicians to discuss strategies to combat the crisis. Sean Harper, who led R&D at biopharmaceutical giant Amgen at the time, remembers the meeting had representatives from about 20 of the world’s top pharma companies, and Collins asked what they had in the works. “It was sad,” Harper recalled. “There were very few companies that were working on anything other than tamper-proof, crush-proof opioid pills.”
Across the industry, novel pain-drug research stagnated. Amgen, which had identified a number of potential NaV1.7 inhibitors, eventually shuttered not only its pain research but also the bulk of its neuroscience program. In general, “I think what happened is people sort of felt that it was just too hard,” Harper says.
One big reason for the difficulty had to do with the nature of the targets themselves. The NaV channel family contains nine closely related members that share more than 50 percent of their genetic sequence. Because of this similarity, the sodium channel inhibitors developed in the 2000s were often unable to target one subtype without hitting others. “The selectivity was terrible, frankly,” says John Mulcahy, a chemist and CEO of the San Francisco–based biotech firm SiteOne Therapeutics. “It’s taken a long time to overcome that.”
At Vertex, researchers believed that the compounds that had been tested before were simply not selective enough or didn’t attach to a channel for enough time and that to find molecules that worked they just needed to keep searching. To speed up their hunt, they had been working on a technology that could measure the effect of massive numbers of molecules, at various concentrations, on the opening and closing of several types of sodium channels. Traditionally, researchers have studied sodium channels using a laborious method called patch-clamp electrophysiology. The technique involves isolating part of a cell’s membrane, applying voltage to trigger its channels to open, adding one single potential drug, and then recording the oscillating waves of electrical activity.
In the early 2000s Vertex scientists Jesús González and Michael Maher designed a system called E -VIPR (for electrical stimulation voltage ion probe reader) to test many compounds against one channel very quickly.
