This post draws on Dr. Hannah Thomasy's TheScientist article “Man on Fire” Syndrome, Ion Channels, and the Quest for Safer Pain Treatments.
Stephen Waxman, a neuroscientist at Yale School of Medicine, has dedicated his career to studying ion channels—proteins that regulate the flow of charged molecules (ions) across cell membranes—and their role in neuropathic pain.
Neuropathic pain is chronic pain arising from damage or dysfunction in the somatosensory nervous system, including peripheral nerves, spinal cord, or brain. Unlike nociceptive pain, which results from direct injury to tissues (e.g., cuts and burns), neuropathic pain is caused by abnormal neural processing, leading to persistent pain even without ongoing tissue damage (Jensen et al., 2021). Neuropathic pain is difficult to treat with conventional painkillers.
Nav1.7 and Nav1.8 Sodium Channels
Two sodium channels, Nav1.7 and Nav1.8, are particularly important in pain signaling. Nav1.7 acts as a "fuse," amplifying small depolarizations in sensory neurons, while Nav1.8 serves as a "firecracker," generating the majority of the electrical current needed for neurons to fire an action potential. Dysfunction in these channels can lead to extreme pain or, conversely, an inability to feel pain. Sodium channel graphic © Juan Gaertner/Shutterstock.com.
Research into these channels gained momentum in the early 2000s when mutations in the Nav1.7 gene were linked to inherited erythromelalgia (Man on Fire Syndrome), which causes intense burning pain in response to mild warmth. Conversely, individuals with loss-of-function mutations in Nav1.7 experience a complete lack of pain perception. These discoveries suggested that targeting Nav1.7 with drugs might help manage pain. However, clinical trials of Nav1.7 blockers have shown inconsistent results.
Waxman’s recent research has highlighted the importance of Nav1.8 in neuropathic pain. Even in cases where Nav1.7 is overactive, Nav1.8 plays a critical role in maintaining neuronal hyperexcitability. Reducing Nav1.8 activity by 25-50% appears sufficient to normalize sensory neuron activity, suggesting it may be a better therapeutic target.
Journavx Selectively Inhibits Nav1.8 Sodium Channels
This idea led to the development of suzetrigine, a selective Nav1.8 inhibitor, which the FDA approved in 2025 as Journavx (jor-na-vix) for treating moderate to severe acute pain. Suzetrigine's clinical efficacy has been evaluated in two randomized, double-blind, placebo- and active-controlled trials involving patients undergoing abdominoplasty and bunionectomy procedures. Abdominoplasty, commonly referred to as a tummy tuck, is a surgical procedure that removes excess skin and fat from the abdomen while tightening the abdominal muscles. It is often performed for cosmetic reasons or to repair muscle separation after pregnancy. Bunionectomy is a surgical procedure to remove a bunion, a bony deformity that forms at the base of the big toe due to misalignment of the foot’s bones. This surgery relieves pain and corrects the toe’s position.
In both trials, suzetrigine significantly reduced pain intensity compared to placebo, as measured by the time-weighted sum of the pain intensity difference over 48 hours (SPID48).
Clinical Significance
These findings suggest that suzetrigine represents a promising alternative to opioid analgesics for managing acute postoperative pain. By targeting peripheral sodium channels without engaging opioid receptors, it may reduce the risks of opioid-related adverse effects and dependence while providing effective pain relief in surgical and other acute pain settings. Further research is needed to assess its long-term safety and efficacy across broader patient populations.
Vertex Pharmaceuticals plans to advance suzetrigine into pivotal Phase 3 development for painful lumbosacral radiculopathy, which is a neurological condition characterized by pain, weakness, numbness, or tingling in the lower back and legs due to compression, inflammation, or irritation of nerve roots in the lumbosacral spine (L1–S5). Researchers aim to refine trial designs to better control placebo effects. Additionally, suzetrigine is being evaluated in a pivotal program for painful diabetic peripheral neuropathy, another chronic neuropathic pain condition.
Key Takeaways
Role of sodium channels in pain: Nav1.7 amplifies small depolarizations, acting as a "fuse," while Nav1.8 generates the electrical current needed for neurons to fire, acting as a "firecracker."
Nav1.7 and extreme pain conditions: Mutations in the Nav1.7 sodium channel gene are linked to inherited erythromelalgia (Man on Fire Syndrome), which causes intense burning pain. Conversely, loss-of-function mutations in Nav1.7 result in an inability to feel pain, highlighting its critical role in pain perception.
Nav1.8 as a therapeutic target: Recent research has identified Nav1.8 as a key player in maintaining neuronal hyperexcitability in neuropathic pain. Reducing Nav1.8 activity by 25-50% appears sufficient to normalize sensory neuron activity, suggesting that Nav1.8 may be a more promising therapeutic target than Nav1.7.
Development and approval of suzetrigine: Based on the potential of targeting Nav1.8, the selective Nav1.8 inhibitor suzetrigine (Journavx) was developed and approved by the FDA in 2025 for treating moderate to severe acute pain. Clinical trials demonstrated significant pain reduction compared to placebo in patients undergoing abdominoplasty and bunionectomy procedures.
Potential as a non-opioid analgesic: Suzetrigine offers a promising non-opioid alternative for managing acute pain, potentially reducing the risk of opioid-related side effects and dependence. Ongoing research aims to evaluate its efficacy in chronic neuropathic pain conditions such as lumbosacral radiculopathy and painful diabetic peripheral neuropathy.
Glossary
abdominoplasty: a surgical procedure that removes excess skin and fat from the abdomen while tightening the abdominal muscles.
action potential: the rapid electrical signal that transmits information along neurons.
bunionectomy: a surgical procedure to remove a bunion, a bony deformity that forms at the base of the big toe due to misalignment of the foot’s bones.
chronic pain: pain that persists for three months or longer despite the resolution of the initial injury or underlying cause. It can result from ongoing tissue damage, nerve dysfunction, or abnormal pain processing in the nervous system.
depolarization: the process of making the neuron’s interior less negative, leading to increased excitability.
gain-of-function mutation: a genetic mutation that increases the activity of a protein, often leading to heightened sensitivity or abnormal function.
inherited erythromelalgia (Man on Fire Syndrome): a rare condition caused by mutations in Nav1.7, leading to severe burning pain in response to mild heat.
ion channels: proteins embedded in cell membranes that allow ions (e.g., sodium, potassium) to pass in and out, regulating nerve signals.
loss-of-function mutation: a mutation that reduces or eliminates protein activity, such as Nav1.7 mutations that cause an inability to feel pain.
lumbosacral radiculopathy: a neurological condition characterized by pain, weakness, numbness, or tingling in the lower back and legs
Nav1.7: a sodium channel that acts as a "fuse," amplifying small nerve signals but not triggering full action potentials.
Nav1.8: a sodium channel that functions as a "firecracker," generating most of the electrical current needed for neuronal firing.
neuropathic pain: chronic pain caused by nerve damage rather than physical injury, often resistant to standard treatments.
potassium channel: ion channels that regulate neuron excitability by counteracting sodium influx, acting as "brakes" to reduce nerve firing.
suzetrigine (Journavx): a Nav1.8 inhibitor approved for treating moderate to severe acute pain without opioid-related side effects.
Reference
Jensen, T. S., Finnerup, N. B., & Fuglsang-Frederiksen, A. (2021). Diagnosis and management of neuropathic pain. BMJ, 374, n2265. https://doi.org/10.1136/bmj.n2265
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