“Man on Fire” Syndrome, Ion Channels, and the Quest for Safer Pain Treatments

Neuroscientist and clinician Stephen Waxman explores new strategies to break the circuit of neuropathic pain.

Hannah Thomasy, PhD headshot
| 5 min read
An artist’s rendering of glowing red and yellow neurons against a dark background.

When sensory neurons are damaged, they can become hyper-excitable, sometimes producing a feeling of burning or shooting pain.

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Note: On January 30, 2025 the FDA approved the first-in-class non-opioid analgesic Journavx (suzetrigine) for the treatment of moderate to severe acute pain in adults. The novel drug reduces pain by targeting Nav1.8 sodium channels.

Astubbed toe, a burned finger, a scraped knee: these are all familiar pains that we experience on a day-to-day basis with plainly observable causes. Sometimes, however, the mechanism is far more covert, whereby subtle changes in gene expression or the genetic code itself alter how sensory neurons transmit information.

Stephen Waxman, a molecular neuroscientist at the Yale School of Medicine, has spent decades studying this latter type of pain. In particular, he is interested in how ion channels, which let molecules like sodium or potassium flow in or out of cells, regulate the activity of sensory neurons and mediate pain signaling.

Ion channels are not a recent discovery—cell physiologists Erwin Neher and Bert Sakmann won the Nobel Prize for experiments they carried out in the 1970s on ion channel function—but Waxman said that scientific understanding is far from complete. “What I love [about this field] is that—as much as we've learned already—each month, you learn something new, and you generate three new questions,” he said.

Earlier in his career, Waxman focused on sodium channels in the context of nerve injury, but soon became interested in how these channels contributed to neuropathic pain—shooting or burning pain caused by damage or disease in sensory neurons which is difficult to treat with traditional painkillers.1 In the late 1990s, multiple research groups discovered and characterized two new types of sodium channels, Nav1.7 and Nav1.8, that are present in peripheral nerves and seem to play critical yet distinct roles in pain signaling.2

“I have likened [Nav1.7 and Nav1.8] to a fuse and a firecracker,” said Waxman. “1.7 is like a fuse: It amplifies small, slow depolarizations.” At rest, the inside of a neuron is negatively charged compared to its surroundings; depolarizations reduce the difference between inside and outside as positively charged molecules flow into the cell. “Then 1.8—the firecracker—takes over and produces 70 to 80 percent of the current needed for the explosive all-or-none action potential.”

If both channels were important, how could researchers decide which one to target in the long and arduous drug development process? Around the turn of the century, said Waxman, genetic validation was a popular approach in the biopharma space to identify therapeutic targets to prioritize.3 This process often involved studying individuals with rare inherited disorders and identifying the underlying gene mutations, enabling researchers to link symptoms, like high cholesterol or excessive pain, with specific molecular drivers. Fortunately, researchers didn’t have to wait very long for human genetic research to direct them towards one of these two potential sodium channel targets: “In the early 2000s, genetic validation not only arrived, but it arrived in Technicolor [for Nav1.7],” said Waxman.

In 2004, a research group at Peking University First Hospital discovered a mutation in the gene coding for a sodium-channel subunit in individuals with a rare and serious disorder called inherited erythromelalgia, also known as “Man on Fire” Syndrome.4

“These patients have strong gain-of-function mutations of Nav1.7,” said Waxman. “Patients describe the attacks, which are triggered by mild warmth, as feeling as if their body is filled with hot lava.”

Two years later, researchers at the Cambridge Institute for Medical Research identified individuals with genetic mutations that caused a loss of function in Nav1.7.5 “These families are full of people with painless fractures, painless burns, painless childbirth, painless tooth extractions,” said Waxman. “So, this was genetic validation, as strong as it gets.”

This evidence was enough to tip the scales in favor of Nav1.7. In 2007, Waxman began working with Pfizer to study pharmacological targeting of this channel, and after several years, they finally had a drug that was ready for human trials. Initial results seemed promising: In a group of five patients with inherited erythromelalgia, the Nav1.7 blocker reduced average pain scores relative to placebo, although some patients appeared to benefit less than others.6 Larger trials, however, which examined pain in diabetic neuropathy patients and in healthy participants, did not find statistically significant effects on pain.7,8

“The bottom line is that genetics has taught us a lot about Nav1.7 and pain, but whether you can target Nav1.7 to relieve pain in the clinical domain is still not clear,” said Waxman.

Undaunted, Waxman has continued his explorations of ion channels, neuronal excitability, and pain. In his more recent work, Waxman has examined how different types of sodium channels work together to change sensory neuron activity. Last year, Waxman and his research team used a cellular model of neuropathic pain to show that even when Nav1.7 was overactive—as seen in patients with inherited erythromelalgia—Nav1.8 still plays an important role in mediating the excitability of sensory neurons, and therefore potentially in pain signaling.9 Moreover, said Waxman, “We found that removing as little as 25 to 50 percent of the Nav1.8 current would normalize the behavior of these hyperactive cells.” This suggests that even partial blockade of Nav1.8 could potentially reduce pain; however, as emphasized by the clinical trials of Nav1.7 blockers, further research is needed.

While Nav1.8 works with Nav1.7 to increase the likelihood of neuronal firing, Waxman has also explored how other channel types work against Nav1.7. During their study of families with inherited erythromelalgia, Waxman and his team identified two people with the Nav1.7 gain-of-function mutation who experienced only moderate pain. Genomic analysis of these individuals revealed that they also carried another gain-of-function mutation, this one in a potassium channel.10

“If you think of sodium channels as the molecular batteries that enable nerve cells to produce nerve impulses, then potassium channels are the molecular brakes that end the nerve impulse,” explained Waxman. Sure enough, in vitro experiments in human sensory neurons showed that activating specific potassium channels could reduce excitability. Waxman and his team are pursuing this avenue further, investigating whether compounds that activate certain potassium channels might be useful for treating pain.

  1. Waxman SG, et al. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol. 1994;72(1):466-470.
  2. Vijayaragavan K, et al. Gating properties of Nav1.7 and Nav1.8 peripheral nerve sodium channels.J Neurosci. 2001;21(20):7909-7918.
  3. Plenge RM, et al. Validating therapeutic targets through human genetics.Nat Rev Drug Discov. 2013;12(8):581-594.
  4. Yang Y, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004;41(3):171-174.
  5. Cox JJ, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894-898.
  6. Cao L, et al. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia. Sci Transl Med. 2016;8(335):335ra56.
  7. McDonnell A, et al. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain. 2018;159(8):1465-1476.
  8. Siebenga P, et al. Lack of detection of the analgesic properties of PF‐05089771, a selective Nav1.7 inhibitor, using a battery of pain models in healthy subjects.Clin Transl Sci. 2020;13(2):318-324.
  9. Vasylyev DV, et al. Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain. J Gen Physiol. 2024;156(11):e202413596.
  10. Estacion M, et al. Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability. Front Pharmacol. 2023;14:1138556.

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Meet the Author

  • Hannah Thomasy, PhD headshot

    Hannah Thomasy, PhD

    Hannah joined The Scientist as an assistant editor in 2023. She earned her PhD in neuroscience from the University of Washington in 2017 and completed the Dalla Lana Fellowship in Global Journalism in 2020.
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