In January 2025, the US Food and Drug administration approved suzetrigine (Journavx), the first of a new class of non-opioid analgesics, for the treatment of acute pain. This approval marks the first new class of pain medication in over two decades and the first non-opioid painkiller since the 1980s.
Years of Crisis
Opioids are associated with a high risk of addiction and overdose, and are responsible for the devastating opioid crisis which has swept through North America in the last two decades and is thought to be responsible for over half a million deaths in the US alone. Opioids act through binding opioid receptors present throughout the central nervous system leading to widespread side effects including slowed breathing and heartrate. They also trigger the release of endorphins, leading to addiction and dependence even with short-term use.
However, these potent painkillers are often the only option for the treatment of moderate to severe pain. There is clearly a need for painkillers which can treat moderate to severe pain through an alternative mechanism without the potential for addiction.
A Solution in Selectivity
Sodium channels, which control the passage of sodium ions across cell membranes, have long been known to play a role in the transmission of pain signals to the brain. There are nine sodium channel subtypes (Nav1.1-Nav1.9) found in various tissue types throughout the body including in the heart, muscle tissues and throughout the central nervous system. Drugs which indiscriminately target multiple sodium channels, such as procaine and lidocaine, are widely used as local anaesthetics. However, these non-selective drugs are not appropriate for systemic administration due to the potential for serious side effects.
The discovery in the 1990s that three specific sodium channels: Nav1.7, NaV1.8 and NaV1.9, are found primarily on pain-sensing neurons sparked a widespread search for selective sodium channel inhibitors. Inhibition of these specific sodium channels can prevent pain signals from reaching the brain with minimal side effects. Suzetrigine, developed by Vertex Pharmaceuticals, selectively inhibits the NaV1.8 sodium channel and is the first approved drug to result from these efforts.
In clinical trials involving over 1000 patients, suzetrigine demonstrated significant efficacy in treating moderate-to-severe acute pain post-surgery and was well-tolerated. Patients reported pain reductions comparable to those achieved with an opioid-based regimen of hydrocodone/acetaminophen, with a lower occurrence of side effects. Suzetrigine also does not carry the risk of addiction or dependence, thanks to its highly selective mechanism of action.
The Beginning of the End?
While suzetrigine has shown excellent results for the treatment of acute pain, there is still more research to be done into its potential for use in chronic pain management, where the need for non-opioid treatments is arguably the most pressing. In phase II clinical trials in patients with painful lumbosacral radiculopathy experienced clinically significant reduction in pain over 12 weeks. However, a similar pain reduction was reported by patients in a placebo group, making the true efficacy of suzetrigine unclear.
Vertex Pharmaceuticals have set out plans for a further Phase III clinical trial taking place over the course of a year in patients with painful diabetic peripheral neuropathy. Results from this are not expected for some time, but will no doubt be eagerly anticipated.
Suzetrigine leads the way for a wave of sodium channel inhibitors, and it is estimated that over 25 other Nav1.8 inhibitors are currently in various stages of clinical development. In March 2025, the FDA granted fast-track approval to the Nav1.8 blocker LTG-001 (Latigo Therapeutics) as a possible best in class drug after favourable clinical trial results which indicated faster absorption than suzetrigine.
A breakthrough in pain management certainly appears to be on the horizon - could this be the beginning of the end of the opioid era?
