Mark ở vũ trụ khác · Another Universe Genes and Rare Diseases #8 · Pain · The SCN9A gene

Feeling no pain

Cox et al. · Nature · 2006 · and the non-opioid painkiller approved by the FDA on 30 January 2025

The storya boy in Pakistan who never felt pain, and his family
GeneSCN9A, which makes the Nav1.7 sodium channel on pain-sensing nerves
TodayNav1.7 blockers have not succeeded; a "sibling" channel, Nav1.8, now has a drug
LabelSolid on the gene, Caution on the drug route

Source: Cox et al. (2006), Nature 444: 894–898; FDA announcement 30/1/2025 (read via trade press).

For reading and understanding, not a substitute for medical advice.

Re-read in 1 minute

Essence

Never feeling painSome children in Pakistan were born unable to feel pain, though they sense touch, warmth and cold normally.
A broken gateIn 2006 the gene SCN9A was found: it makes the Nav1.7 channel, a gate that amplifies pain signals.
Not a superpowerYoung children bit their own lips and tongues; injuries went unnoticed. Pain is a protective signal.
Smell is lost tooThe same channel sits in smell cells, so many affected people cannot smell either.
Drugs: a detourNav1.7 blockers have not worked out. In 2025 the FDA approved a blocker of the "sibling" channel Nav1.8.

Source: Cox et al. (2006), Nature 444; OMIM #243000 (remaining senses, lip and tongue injuries); Weiss et al. (2011), Nature 472 (smell); FDA 30/1/2025 (suzetrigine).

Part 1

The question

If you never felt pain, would life be easier or more dangerous? And what did a family who could not feel pain teach scientists about how the body raises the alarm?

The question is Mark's, based on the paper by Cox et al. (2006).

Before 2006A boy in LahoreWalked on hot coals, put knives through his arm, felt no pain.
→
2006The gene is foundBroken SCN9A means the Nav1.7 "gate" cannot open.
→
2015 to 2025Hunting for painkillersNav1.7 proved hard; Nav1.8 got a drug in 2025.
Part 2

The story

Who, where, when: from a street performance to a lab in Cambridge.

Before 2006 · Lahore, PakistanA boy performed in the street: he pushed knives through his arms and walked on burning coals, feeling no pain. He often came to hospital to have his wounds patched up after a show. Doctors took notice.
About age 14 · An accidentHe died after a fall from a roof, before the research team could examine him. Not feeling pain does not mean not getting hurt.
The years after · Three familiesThe team of geneticist Geoffrey Woods (Cambridge Institute for Medical Research, UK) found relatives of the boy, aged 4 to 14, who had also never felt pain. They belonged to three families in northern Pakistan where relatives had married each other.
What the children could still feelTouch, warmth, cold, tickle, pressure and limb position were all normal. Parents and teachers judged their intelligence normal. But in their first 4 years they bit their lips and tongues until injured; one needed plastic surgery on the lip.
14/12/2006 · The Nature paperCox, Woods and colleagues showed that each family carried a different mutation, but all three broke the same gene, SCN9A. Conclusion: this gene is "essential and non-redundant" for pain in humans.

Source: Cox et al. (2006), Nature 444: 894–898 (three families in northern Pakistan, three mutations, conclusion); OMIM #243000 summarising the paper (remaining senses, intelligence, lip and tongue injuries in the first 4 years); Nature News 13/12/2006, HealthDay, The Naked Scientists (the boy in Lahore, his age at death, relatives aged 4–14, Woods's team; secondary sources).

Why did marriage between relatives help find the gene?

The condition is recessive: a child must inherit a broken copy from both parents to be affected. When parents are related, a child's two copies are more likely to be identical in the same stretch of DNA. The team searched for that shared stretch in the affected children and narrowed it to a region on chromosome 2 that contains SCN9A.

This is about how genes are inherited, not a judgement on any community's customs.

Source: Cox et al. (2006) (recessive, region 2q24.3).

Part 3

How the gene works, in 3 sentences

1. The SCN9A gene makes the Nav1.7 sodium channel, a small "gate" in the membrane of pain-sensing nerves.

2. When skin is burned or cut, Nav1.7 amplifies a small signal enough for the nerve to fire up to the spinal cord and brain, and we feel "pain".

3. With both copies broken the gate cannot open: the signal dies at the start. Mutations that make the gate open too easily do the opposite: severe burning pain.

Two rows. Top, normal: a flame touches skin, the signal passes an open Nav1.7 gate, is amplified, travels to the spinal cord and brain, and the brain signals pain. Bottom, SCN9A lost: no Nav1.7 gate, the signal fades, the brain stays quiet; touch, warmth and cold still travel another way. normal burn, cut Nav1.7 open signal amplified spinal cord → brain "ouch!" → pull away both SCN9A copies lost no gate signal dies at the start brain stays quiet touch, warmth, cold stilltravel another way
The brain is not "unable to feel pain"; the alarm is never sent. The three families carried three different mutations, all stopping the gene early ("nonsense" mutations); channels made from the broken gene carried no current. Simplified diagram.Source: Cox et al. (2006), Nature 444: 894–898 (S459X, I767X, W897X; current no greater than background); Dib-Hajj et al. (2013), Nature Reviews Neuroscience (Nav1.7 amplifies small signals at nerve endings); OMIM #243000 (remaining senses).
Three volume knobs for the same gene SCN9A. Off: loss of function, no pain and usually no smell (Cox 2006; Weiss 2011). Normal: pain when injured. Too loud: gain of function, erythromelalgia (2004) and paroxysmal extreme pain disorder (2006). off (loss of function) no painusually no smellCox 2006; Weiss 2011 normal pain when injuredalarm at the right time too loud (gain of function) severe burning painerythromelalgia; PEPDYang 2004; Fertleman 2006
One gene, three outcomes. The fact that one gene causes both "no pain" and "too much pain" is why researchers saw Nav1.7 as a great painkiller target. The volume knob is Mark's metaphor.Source: Cox et al. (2006); Weiss et al. (2011), Nature 472: 186–190; Yang et al. (2004), J Med Genet 41(3): 171–174; Fertleman et al. (2006), Neuron 52(5): 767–774.
Part 4

Fact check: what is true and what is rumour

13 things often said about people who feel no pain, checked against original sources. Tap a row to see why.

SOLIDA broken SCN9A gene means no pain from birth

Three families, three different mutations, the same gene (Cox et al. 2006).

SOLIDThey still sense touch, warmth, cold and pressure

Only pain is missing; other sensations are normal (OMIM #243000, summarising Cox 2006).

SOLIDMany also lose their sense of smell

Nav1.7 is also in smell cells; people with loss-of-function SCN9A cannot smell (Weiss et al. 2011; MedlinePlus Genetics).

SOLID"Turned-up" mutations in the same gene cause severe burning pain

Erythromelalgia (Yang et al. 2004) and paroxysmal extreme pain disorder (Fertleman et al. 2006).

SOLIDFeeling no pain leads to more injuries and may shorten life

Lips and tongues bitten in early years (OMIM); repeated injuries, possibly shorter life expectancy (MedlinePlus Genetics).

SOLIDIn 2025 the FDA approved a new class of non-opioid painkiller

Suzetrigine, 30/1/2025, for moderate-to-severe acute pain in adults (FDA, via trade press).

CAUTION"The boy who walked on coals was the one studied"

He died before the team could examine him. The paper studied his relatives (Nature News 2006, secondary source).

CAUTION"Finding SCN9A would quickly give us new painkillers"

Nearly 20 years on, no Nav1.7 blocker has been approved. A major candidate stopped in 2015 after a failed phase 2 trial (Nature Reviews Drug Discovery 2019); a 2025 review shows mouse experiments differ sharply from human trials (Pain 2025).

CAUTION"Blocking Nav1.7 in adults would mimic being born without it"

People born without the channel lack it for life, and the body may adapt differently. One study (peer-reviewed preprint, eLife 2025) found pain-sensing cells can use other sodium channels instead.

FALSE"Feeling no pain is lucky, a superpower"

Pain is an alarm. Without it, children hurt themselves without knowing; the boy in Lahore died after a fall (OMIM; MedlinePlus; Nature News 2006).

FALSE"The new 2025 painkiller targets Nav1.7 itself"

Suzetrigine blocks Nav1.8, a different sodium channel on pain-sensing nerves (FDA 2025).

FALSE"Everyone who feels no pain has an SCN9A mutation"

Insensitivity to pain with inability to sweat (CIPA) is caused by the NTRK1 gene (MedlinePlus Genetics). A woman in Scotland feels little pain because of changes in FAAH and FAAH-OUT (British Journal of Anaesthesia 2019, read via news).

FALSE"Feeling no pain comes with intellectual disability"

With SCN9A, parents and teachers judged the children's intelligence normal (OMIM, summarising Cox 2006). Intellectual disability is common in CIPA, a different disease.

Source: as given in each row; full list in Part 9.

Part 5

Where things stand today

From one gene to the hunt for non-addictive painkillers.

2011 · Smell is lost tooPeople with loss-of-function SCN9A cannot smell; Nav1.7 is needed for smell cells to "talk" to the brain.
2015 · Nav1.7 blockers stumbleThe first selective Nav1.7 blocker to reach large trials was stopped after phase 2 in painful diabetic neuropathy. Many other programmes stopped too.
2019 · Another gene, another storyA woman in Scotland feels little pain because of a change in FAAH-OUT. Pain has several "switches".
2021 · Switching the gene down in miceA form of CRISPR that does not cut DNA (dCas9) temporarily silenced the Nav1.7 gene in mouse spinal nerves: pain relief lasting weeks to months. Mice only.
30/1/2025 · A drug via the "sibling channel"The FDA approved suzetrigine, a Nav1.8 blocker, for moderate-to-severe acute pain in adults, based on two phase 3 trials after surgery. The FDA called it the first drug in a new class of non-opioid painkillers.
2025–2027 · Still being testedSuzetrigine is in phase 3 trials for painful diabetic neuropathy, expected to finish in 2027. No results yet (checked 16/10/2026).
Two sodium channels on the same pain-sensing nerve. Nav1.7, gene SCN9A: the strongest genetic evidence, but no approved blocker. Nav1.8: suzetrigine approved by the FDA on 30/1/2025 for acute pain. pain-sensing nerve Nav1.7 (gene SCN9A)strongest genetic evidenceblockers: none approved Nav1.8the "sibling" channelblocker: FDA-approved 2025
The gene points the way, but the drug may take a detour. The Nav1.7 finding pushed a whole field to hunt for sodium-channel blockers; the first target to succeed was the channel next door.Source: Nature Reviews Drug Discovery (2019) (stopped in 2015, secondary source); FDA 30/1/2025, via Practical Neurology and Patient Care (suzetrigine, Nav1.8, two phase 3 trials); ClinicalTrials.gov NCT06628908.

Source: Weiss et al. (2011), Nature 472: 186–190; Yang et al. (2025), Pain (PubMed 39928833); Habib et al. (2019), British Journal of Anaesthesia (via news, secondary source); Moreno et al. (2021), Science Translational Medicine (mice; duration of relief per UC San Diego and GEN News, secondary sources); FDA 30/1/2025; ClinicalTrials.gov NCT06628908, NCT07231419.

Part 6

Rating

Scores are Mark's assessment based on the sources in Part 9, not figures from a study.

Strength of the gene finding
5/5
Understanding of how pain works
4/5
Drugs from this very gene
1/5
Lesson for readers
5/5
Strengths
  • Three families, three mutations, one gene
  • The same gene causes "no pain" and "too much pain"
  • Launched a whole field of painkiller research
Weaknesses
  • Very few patients, hard to study in depth
  • Nav1.7 blockers have not succeeded
  • Mouse results have not carried over to people

Label: SOLID on the gene, CAUTION on the drug route. A family who could not feel pain showed the world how precious pain is.

More: why is the gene clear but the drug hard?

People born without Nav1.7 lack it in every cell, all their lives. A pill blocks only part of it, for a few hours, and must avoid very similar sodium channels in the heart and brain. Mouse experiments often use young male mice, inflammatory pain and a single dose; human trials are usually in nerve pain with daily doses.

Source: Yang et al. (2025), Pain (mouse vs human mismatch); eLife preprint 2025 (other channels compensate). The comments are Mark's.

Part 7

Takeaway: pain is a signal, don't just try to switch it off

People who feel no pain show that pain is an alarm system. Knowing how to read the alarm helps you ask your doctor better questions.

For reading and understanding, not a substitute for medical advice.

Four habits: note down the pain; ask for the cause, not just a drug; when reading news of a new painkiller, check which pain it was approved for; be sceptical of "instant pain relief" ads. 1 · note the painwhere, whenhow strong out of 10 2 · ask "why"cause firstdrug second 3 · read drug newsapproved for which pain?acute or chronic 4 · doubt the ads"instant relief"silences the alarm, not the fire People who feel no pain get hurt without noticing. What is your pain telling you?
Each habit is based on something real in the SCN9A story. The 2025 drug was approved for acute pain, tested after surgery; for chronic pain it is still being tested.Source: Cox et al. (2006); OMIM #243000; FDA 30/1/2025; ClinicalTrials.gov NCT06628908. The habits are Mark's suggestions.
Note down the painWhere, since when, how strong on a 0–10 scale, what makes it worse. That is exactly what a doctor needs.
Ask "why", not only "what to take"Lasting or unusual pain is a signal worth tracing to its cause. Don't silence it with medicine on your own.
Read "new painkiller" news closelyApproved for which pain, in whom, tested after what surgery? Don't extend it to every kind of pain.
Doubt "instant pain relief"A product that promises to stop pain at once without naming a cause is promising to switch off the fire alarm.
Self-check: your most recent pain

1. Think of the last pain that lasted more than a few days.

2. Could you say where it was, since when, how strong out of 10, and what made it worse?

3. Did you ask (or learn) the cause, or only ask for a medicine?

4. Missing two or more: next time, write it down before the appointment.

The self-check is Mark's suggestion, not a procedure from a study.

Part 8

Read next

Cox et al. (2006), NatureThe original paper. The abstract is short and readable.
MedlinePlus Genetics, "Congenital insensitivity to pain"A plain-language page from the US National Library of Medicine.
Genes and Rare Diseases #7: Progeria, the child who ages fastOne changed letter in a gene, and a family that started a research foundation. Read
Genes and Rare Diseases #9: CRISPR, scissors borrowed from bacteriaWhere the tool the 2021 team used to silence Nav1.7 in mice came from. Read
Part 9

Sources

Main sources are the original paper, the FDA decision and medical databases. The working environment blocks NCBI and the FDA, so figures were checked against excerpts of those same pages in search results (16/10/2026), without opening full texts. Secondary sources are labelled.

  1. Cox JJ et al. (2006), "An SCN9A channelopathy causes congenital inability to experience pain", Nature 444: 894–898. PubMed
  2. OMIM #243000, "Indifference to pain, congenital, autosomal recessive" (summary of Cox 2006). omim.org
  3. Weiss J et al. (2011), "Loss-of-function mutations in sodium channel Nav1.7 cause anosmia", Nature 472: 186–190, doi 10.1038/nature09975.
  4. Yang Y et al. (2004), SCN9A mutations in primary erythermalgia, Journal of Medical Genetics 41(3): 171–174.
  5. Fertleman CR et al. (2006), "SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes", Neuron 52(5): 767–774.
  6. Dib-Hajj SD, Yang Y, Black JA, Waxman SG (2013), "The NaV1.7 sodium channel: from molecule to man", Nature Reviews Neuroscience.
  7. MedlinePlus Genetics, "Congenital insensitivity to pain" and "Congenital insensitivity to pain with anhidrosis". medlineplus.gov
  8. Yang et al. (2025), "Discordance between preclinical and clinical testing of NaV1.7-selective inhibitors for pain", Pain. PubMed
  9. FDA (30/1/2025), approval of suzetrigine (Journavx) for moderate-to-severe acute pain in adults (read via Practical Neurology, Patient Care).
  10. ClinicalTrials.gov NCT06628908, NCT07231419, NCT06696443 (suzetrigine, painful diabetic neuropathy).
  11. Moreno AM et al. (2021), "Long-lasting analgesia via targeted in situ repression of NaV1.7 in mice", Science Translational Medicine.
  12. Habib AM et al. (2019), British Journal of Anaesthesia (the FAAH-OUT case).
  13. Secondary sources: Nature News 13/12/2006, HealthDay, The Naked Scientists (the boy in Lahore, Woods's team, relatives aged 4–14); Nature Reviews Drug Discovery 2019 (Nav1.7 blocker stopped in 2015); eLife peer-reviewed preprint 2025 (other channels compensate); NBC News, Practical Neurology, Patient Care (details of the 2025 FDA decision); UC San Diego, GEN News (Moreno 2021); PET, Technology Networks (the Jo Cameron case).