Suzetrigine and the Shift Toward Non-Opioid Pain Management
by Emma Crowley-Dolen
figures by Salvador Balkus
Modern pain treatment in the U.S.: opioids, opioids, and opioids
If you have ever had surgery, you have likely been prescribed an opioid for post-surgical pain. After knee surgery, for example, patients are often prescribed hydromorphone. For egg retrieval during in vitro fertilization procedures, fentanyl is administered. At sixteen years old, when I had my wisdom teeth removed, I was given OxyContin. For centuries, opioids have been the standard of care for severe pain. When it comes to treating pain, they are highly effective. However, as you likely already know, they are also extremely addictive. In fact, in the United States, 85,000 people per year become addicted to opioids after taking opioids they were prescribed by their doctors. Yet even with the high risk of addiction, opioids have still been the standard of care to treat severe and even chronic pain, as safe and effective alternatives have been limited. This year, the opioid status quo has finally been challenged with the arrival of a new pain drug to the market. Suzetrigine (brand name Journavx), developed by Vertex Pharmaceuticals, is a newly approved non-opioid pain reliever shown to reduce postoperative pain and, unlike opioids, has not shown signs of potential abuse. So, what makes suzetrigine different? And is it as effective at relieving pain as opioids?
What exactly is pain and why do we use opioids to treat it?
To address this question, we first need to talk about pain. When you experience pain, a signal is sent from the site of pain, up your spinal cord, and into your brain, where the “ow!” feeling is registered (Figure 1a). Opioids work by telling your brain to dial down the sensation of pain, even when your body might be experiencing something that should feel painful. To do this, opioids bind to opioid receptors on the outside of cells in the spinal cord and brain. When opioids bind to their receptors, they send a message to neighboring cells to tell them to “turn off” the pain signaling (Figure 1c). For decreasing pain, opioids are very effective! However, the brain gets desensitized to opioids and starts to require more and more opioids to decrease pain signaling by the same amount. Furthermore, opioids hijack the brain’s natural reward system, leading to dopamine release and feelings of euphoria. The brain’s natural reward system becomes so dysregulated that the brain does not signal feelings of pleasure from naturally rewarding activities (think: the joy you feel from getting a hug from a friend or eating a delicious meal). The brain starts to require opioids just to experience baseline feelings of pleasure. The combination of needing more and more opioids to block pain and the dependence on opioids to experience natural feelings of pleasure often leads to addiction. Recent data from the FDA show that approximately 22.5% of patients prescribed extended-release, long-acting opioids developed an addiction to opioids within a year.
Other drugs to treat pain, like ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) do not function by binding to opioid receptors in the brain and spinal cord. Rather, NSAIDs block inflammation at the source of the injury (Figure 1b). This mechanism of pain treatment can be effective, but often not effective enough for severe pain, like the pain you may experience immediately following surgery. If opioids are too risky because they act on the brain’s pain and reward circuits, and NSAIDs are not strong enough for severe pain, perhaps there is a middle ground: can we block pain signals directly at the injury site without affecting the brain? Can we make a non-addictive drug for severe pain? Enter, suzetrigine.
The role of sodium channels in pain signaling
Suzetrigine was approved by the FDA for the treatment of moderate-to-severe acute (short-term) pain in early 2025. It is not an opioid, meaning it does not act on opioid receptors in the brain and spinal cord. Instead, it works by blocking other receptors outside of the brain known as sodium channels. Sodium channels are like tunnels that allow sodium ions to travel from the outside of a cell to the inside. They play a role in brain activity, heart rhythm, muscle contraction, and pain signaling. Back in the 1990s, when Dr. Stephen Waxman of Yale University was studying nerve cell signaling, it was already known that inhibiting sodium channels could numb pain. Under normal conditions without pain, sodium channels on sensory neurons are closed, like a tunnel with a closed gate blocking entry. When there is a pain stimulus, these sodium channels open, allowing sodium ions to flow through the tunnel and into the sensory neuron, causing the cell to begin signaling. This finding was taken advantage of in the setting of anesthetics. For example, if you have ever had a cavity filled or a root canal, the dentist likely administered a local anesthetic like lidocaine to your mouth. To prevent the feeling of pain, lidocaine inhibits sodium channels, blocking the movement of sodium ions into sensory neurons, thereby blocking pain. However, lidocaine does not only block pain signaling. In addition to inhibiting sodium channels in sensory neurons, lidocaine also inhibits sodium channels in other types of cells. Have you ever left the dentist after a root canal and found yourself drooling because you did not realize your mouth was hanging open? That is a side effect of the lidocaine inactivating sodium channels in motor neurons, in addition to the targeted sensory neurons.
Dr. Waxman was interested in the many types of sodium channels and how they could be different from one another. He discovered two sodium channels that are only found on sensory neurons outside of the brain. The first channel, Nav1.7, was deemed “the firecracker fuse” by Dr. Waxman. This channel is the first one that activates upon a painful stimulus, allowing sodium ions to enter the cell. This in turn activates another channel, Nav1.8, “the amplifier”, which allows even more sodium ions to enter the cell. Together, these sodium ions entering the cell cause an electrical “pain” signal to be sent to the spinal cord and brain (Figure 2).
The role of sodium channels in pain treatment
Pharmaceutical companies took note of this academic research, aiming to develop a drug to specifically inactivate only Nav1.7 or Nav1.8 and not other sodium channels in the brain, heart, and skeletal muscle. Because sodium channels all look similar, however, scientists were not sure it would be possible to develop a sodium channel inhibitor that was specific to just one type of sodium channel. After years of study and testing many compounds for either specific Nav1.7 or Nav1.8 inhibition, Vertex discovered suzetrigine, a compound that inhibits Nav1.8, but no other sodium channels. In clinical trials, Vertex administered suzetrigine to patients after surgeries that normally receive an opioid prescription. The trial results were striking: suzetrigine eased pain by the same amount as the opioids.
Following successful clinical trials, suzetrigine was approved by the FDA in early 2025 for acute pain, like pain from surgery. Although there remains a need for non-opioid treatments for chronic pain – suzetrigine is currently being tested for this – its approval for acute pain marks a significant milestone toward the development of pain medications with low addiction risk. While it is still too early to tell, suzetrigine and future Nav1.7 and Nav1.8 inhibitors have the potential to change the way pain is treated and could reduce the number of patients that become addicted to opioids. For the first time in decades, we have a real alternative to opioids that can relieve severe pain without acting on the brain’s reward system, signaling a new chapter in modern pain management.
Emma Crowley-Dolen is a PhD candidate in the Chemical Biology program at Harvard University.
Salvador Balkus is a PhD candidate in Biostatistics at the Harvard T.H. Chan School of Public Health.