In the past decade, as opioids claimed nearly half a million lives across the United States, surgeons, dentists, and other clinicians have pined for pain relievers that work as well as hydrocodone or oxycodone but without the high risk of addiction and overdose. Last year, the U.S. Food and Drug Administration (FDA) approved suzetrigine, the first in a new class of drugs that promised pain relief approaching that of opioid pills without those concerns.
Many expected to see even more powerful drugs emerge from this class of agents, known as Nav1.8 inhibitors, which block sodium channels on pain-sensing neurons to quell their activity. But efforts to improve on suzetrigine—which has been shown to offer consistent but moderate effects on acute pain—have not produced stronger relief. Recent research has aimed to explain what seems to be a ceiling to the drugs’ benefits, and to get a better handle on their real-world limits.
Nav1.8 inhibitors are a needed advance, pain researchers agree, as federal guidance has sought to curb use of opioid painkillers. “Almost everyone you talk to either has a friend or family member that’s been affected by the opioid crisis,” says independent pharmacologist Paul Desjardins, who designed some of the widely used surgical protocols for testing pain drugs and consults for companies developing Nav1.8 inhibitors. But “the data to this point don’t convince me that any of the sodium channel blockers that I’ve seen are better than ibuprofen or naproxen or acetaminophen when they are combined.”
The origin story of the drug class led to high hopes. Starting in the late 1990s, genetic studies of people with rare syndromes marked by chronic or excessive pain flagged mutations that caused peripheral sensory neurons, which relay pain signals to the brain, to become hyperactive. The syndromes were linked to changes in the function of two proteins, Nav1.7 and Nav1.8, that regulate neuronal activity by allowing sodium to flow into the cells. Blocking these channels offered a more precise painkilling strategy compared with drugs such as lidocaine, which blocks sodium channels more broadly and has too many toxic effects to be given systemically.
Although both Nav1.7 and Nav1.8 showed promise as drug targets in lab studies, clinical research has pointed to the latter as the stronger bet. Suzetrigine won approval based on studies measuring pain relief after bunionectomy, a foot surgery commonly used to test pain drugs, and abdominoplasty, or tummy tuck. The pills reduced pain comparably to hydrocodone and acetaminophen combined.
Nearly 1 million suzetrigine prescriptions were written in the first half of this year, according to a report by its manufacturer, Vertex Pharmaceuticals, but the evidence for it remains limited. Developers of pain drugs tend to first test for short-term relief after surgeries to win initial FDA approvals for acute pain, leaving a lot of unknowns about how they perform in other settings. “Bunionectomy and tummy tucks are not giant societal needs,” says Yale University pain researcher Stephen Waxman. “The big societal need is chronic pain. The question is, can we make the leap?”
Vertex is testing suzetrigine in people with diabetic neuropathy, a pain type that can be chronic, and those who follow the field say the drug is already being used off label for this and other pain conditions. The company’s phase 2 trial in people with sciatica, another pain condition that can be chronic, did not show better results than placebo.
At the Hospital for Special Surgery, pain researchers Faye Rim and Alexandra Sidaris are exploring suzetregine’s limits in acute pain by testing it in hip replacement, a more complex and painful procedure than those used in the manufacturers’ trials. Their clinical trial, scheduled to run through next spring, will help determine whether giving suzetrigine before surgery keeps patients from experiencing sudden pain when their anesthesia wears off, Sideris says—and whether it also reduces their need for opioid treatment during recovery. “This is above and beyond what current literature has shown,” she says.
To date, no Nav1.8 blocker has performed better than opioids, though it was hoped that newer candidates in the pipeline might. In a trial last year run by Vertex, a different Nav1.8 drug did not meaningfully reduce pain in people undergoing bunionectomy compared with placebo. And just last month researchers at Latigo Biotherapeutics reported in The New England Journal of Medicine that another experimental Nav1.8 blocker, selected for its better penetration of peripheral nerves, performed about as well against a placebo as suzetrigine among people having abdominoplasty.
With the offerings bringing only modest relief, “the reflex answer is often ‘let’s design a better [version],’” Waxman says. But last year, his team and a group led by pain researcher Bruce Bean at Harvard Medical School independently identified a deeper issue with the drug class. Lab-dish studies of their electrical activity revealed that some pain-relaying populations of dorsal root ganglion (DRG) neurons in the spine resist suppression of their firing by Nav1.8 blockers, no matter how high the dose. Up to 40% of DRG neurons fall into this category, says Waxman, who argued in a 2025 paper that therapies selectively targeting Nav1.8 had “intrinsic limits” to their effectiveness.
At least a half-dozen inhibitors of either Nav1.7 or Nav1.8 are still in clinical development. But some groups are looking to develop agents that target the two channels in combination. Three such drug candidates are currently in human trials, including one, developed by Dogwood Therapeutics, that uses a purified form of tetrodotoxin, or pufferfish poison.
Waxman and Bean think this dual approach may help raise the ceiling on pain relief nonopioids can offer. “Pain-sensing neurons have strong expression of Nav1.7 sodium channels in addition to Nav1.8,” Bean says, “so an obvious strategy is to try to inhibit both.”