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 anaesthetic wore off, she called out for something to ease the pain and was pleasantly surprised. The drug she received — a new kind of analgesic administered as part of a clinical trial — eased her discomfort without the grogginess or nausea of an opioid.
“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 — a drug called suzetrigine that works by selectively blocking sodium channels on pain-sensing nerve cells and delivers 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 are responsible for a wave of overdoses and deaths in the United States and beyond. Drug developers, meanwhile, see the approval as validation that targeting sodium channels — a strategy that has long defied the pharmaceutical industry’s best efforts — can yield success.
“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 given the brandname Journavx, is not the first sodium channel-targeting drug to be used for pain management. Compounds such as procaine (Novocain) and lidocaine have provided reliable anaesthesia for over a century. However, sodium channels come in nine flavours, or subtypes, and these older drugs block all nine indiscriminately, so they must be administered locally — via injections or skin creams and gels — to avoid widespread side effects.
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The hunt for more selective drugs began following the discovery, in the 1990s, that three of the sodium channels appear primarily on pain-sensing neurons — meaning that they have little activity in the heart or brain, and thus a much lower risk of toxicity or addiction potential.
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 target drugs at these channels focused largely 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 fire 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 channel, NaV1.9, then modulates the signal’s intensity and duration further.
Genetics studies from the mid-2000s, first in people with a chronic-pain condition called ‘man on fire’ syndrome1 and later in people with complete insensitivity to pain2, had implicated NaV1.7 as a master regulator of pain perception. These were “knock your socks off” findings that, according to Waxman, led “the majority of the money and attention” to pour into targeting this channel subtype. 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 of 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. ”
