US drug agency approves potent painkiller — the first non-opioid in decades
The FDA’s nod for suzetrigine bolsters confidence in the pharmaceutical industry’s strategy to target sodium channels
Elie Dolgin
Researchers have long sought potent, but non-addictive, painkillers as alternatives to opioids.Credit: Getty
When Terp Vairin awoke from a 2023 surgery that straightened a bend in her nasal passage, she felt like she’d taken a hard punch to the nose. As the anaesthesia wore off, she called out for something to ease the pain, and was pleasantly surprised. The drug she received — a new kind of analgesic being tested in a clinical trial — eased her discomfort, without the grogginess or nausea of opioids.
“I felt very lucid,” says Vairin, an artist from Decatur, Georgia.
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Now, millions more people will soon have access to this painkiller — suzetrigine. It works by selectively blocking sodium channels on pain-sensing nerve cells, providing opioid-level pain suppression without the risks of addiction, sedation or overdose. On Thursday, the US Food and Drug Administration approved suzetrigine for short-term pain management, making it the first pain drug given a regulatory nod in more than 20 years that works through a brand-new mechanism.
Pain-medicine specialists hailed the arrival of a potent but safer alternative to opioids, which have fuelled a wave of overdoses and deaths in the United States and beyond. For drug developers, meanwhile, suzetrigine proves that targeting sodium channels — a strategy that has long stymied the pharmaceutical industry — can succeed.
“This is a big step forward,” says Stephen Waxman, a neuroscientist at the Yale School of Medicine in New Haven, Connecticut.
“Anything we can add to the toolbox that will allow us to reduce opioid dependency is a significant positive,” says Paul White, an anaesthesiologist at the Cedars-Sinai Medical Center in Los Angeles, California, who was involved in suzetrigine’s development.
The hunt for selectivity
Suzetrigine, now marketed as Journavx, is not the first sodium-channel-targeting drug for pain management. Compounds such as procaine (Novocain) have provided reliable anaesthesia for more than a century. However, sodium channels come in nine flavours, or subtypes, and older drugs block all of them indiscriminately, so they must be administered locally — through injections or skin creams and gels — to avoid widespread side effects.
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The hunt for more selective drugs began in the 1990s, following the discovery that three of the channel subtypes are found mainly on pain-sensing neurons — meaning that they have little activity in the heart and brain, minimizing the risk of toxicity or addiction.
Sodium channels operate like gates, opening and closing in response to electrical signals flowing through nerve cells to let sodium ions pass through. This initiates a cascade of nerve impulses that transmit pain signals to the brain.
Early efforts to design drugs targeting these channels focused mainly on one subtype, called NaV1.7. Waxman likens it to the fuse in a firecracker, which amplifies the initial spark of a pain signal. This in turn ignites NaV1.8, another channel subtype that acts like a propellant, intensifying the signal further and relaying it, in the form of repetitive impulses, down nerves to the spinal cord and ultimately to the brain. A third subtype, NaV1.9, further modulates the signal’s intensity and duration.
Genetics studies in the mid-2000s, first in people with a chronic-pain condition called ‘man on fire’ syndrome1 and later in those with complete insensitivity to pain2, had implicated NaV1.7 as a master regulator of pain perception. These “knock your socks off” findings led “the majority of the money and attention” to pour into targeting this channel subtype, says Waxman. Yet, the drug industry’s initial efforts to inhibit NaV1.7 yielded disappointing clinical results.
NaV1.9 proved challenging to study and target in the laboratory, so attention shifted to NaV1.8, with Vertex Pharmaceuticals in Boston, Massachusetts, leading the way. After first trialling two other selective NaV1.8 inhibitors, the company leaned into suzetrigine (previously known as VX-548) — finding that it blocks its target more than 30,000 times more potently than other sodium channels3.
“VX-548 didn’t come out of nowhere,” says Marc Rogers, a drug-discovery consultant in Cambridge, UK. “It’s a story of long, hard work. ”
