We all do our best to avoid pain. But Dr Monty Lyman, a clinical fellow at Oxford University who is studying brain inflammation, is enthralled by it.
In a new book investigating the mysterious world of pain, he also meets the people who are blessed — or lethally cursed — by the fact that they never actually feel it.
And reveals how their unusual condition might help scientists identify new treatments that could help the rest of us.
Ask anyone who has given birth what the experience feels like, and prepare to be entertained and/or terrified by descriptions such as: ‘A bowling ball landing on my spine,’ and ‘My pelvis felt as if it was being ripped apart like tectonic plates’.
That is, unless you are Candice. ‘For my first birth I was really nervous and thought it was going to hurt like hell,’ the teaching assistant from Northamptonshire told me, recalling when her first labour started.
‘I was Christmas shopping at Tesco one day, when I felt a sharp sensation across my abdomen. It was strange, but not really painful.’
She thought that this was a false labour, or Braxton Hicks contraction, a tightening sensation across the womb that can happen during the final weeks of pregnancy, as it was a week before her due date and she’d previously experienced a few of these false contractions.
Candice finished her shopping and went home. A friend from antenatal classes then popped over for a coffee.
We all do our best to avoid pain. But Dr Monty Lyman, a clinical fellow at Oxford University who is studying brain inflammation, is enthralled by it
Because this woman was extremely anxious about giving birth, she had brought a community midwife with her.
During coffee and cake, Candice felt another odd tightening of her abdomen.
‘I think I’m having contractions,’ she told them. The midwife doubted that the relaxed and chatty Candice was going into labour, but suggested she go to the nearby hospital anyway.
ONE IN 100 WOMEN HAVE ‘NATURAL EPIDURAL’ GENE
When Candice arrived at the hospital her cervix was 3cm dilated, but after only about ten minutes she had dilated to 10cm — in other words fully dilated, and at the stage where midwives normally encourage women to start pushing.
What happened next was so unremarkable it is utterly remarkable: ‘I had about two contractions and then I just pushed my son out. He popped out like a rugby ball.’
Candice knows what it’s like to feel pain, but her suspicions that she had a higher pain threshold than her friends were confirmed after she had required no pain relief whatsoever for any of her three labours.
Professor Geoff Woods is a Cambridge geneticist who studies how genes influence pain.
In 2020 his team reported in the journal Cell Reports that Candice’s condition is likely caused by a ‘natural epidural’ gene.
The study identified around 1,000 women across the UK who had not needed any pain relief during their first labour.
The women experienced a number of types of experimental pain: their forearms were subjected to both burning and freezing sensations, and mechanical pressure was applied with a blood-pressure cuff.
They then rated their pain using a pain- scale questionnaire.
These women had higher pain thresholds than a control group of women, and, importantly, the researchers found no differing cognitive or emotional abilities between the groups that could explain the difference in pain thresholds.
Miracle: Jo Cameron’s gene anomaly means she never feels pain
The team then sequenced the genomes of both groups, and found that in the painless-labour group there was a much higher prevalence of a mutation in the KCNG4 gene.
This gene effectively regulates the gateway to danger-detecting receptors in nerves, either allowing danger signals to be sent to the brain or blocking them.
The mutation does not render the gateway completely useless — so these people can still feel pain — but it means they require a much greater stimulus (such as very strong contractions during labour) to send a nerve impulse from the site of the body that’s being hurt to the brain, and for the patient to feel pain.
Surprisingly, these mutations are relatively common. Roughly one in 100 women carries this variant.
The discovery isn’t just a medical curiosity: if a new painkiller that specifically targets this gateway mechanism is developed, it could present a revolutionary way to provide labour-pain relief with no side-effects on the mother or baby — something we do not yet have.
Candice also shows how genetic variations influence how each of us feels pain. There are likely many genetic variations that influence pain thresholds and pain experience that we do not yet know about.
At my school, during the inescapable playground fights, the boy to avoid was Duncan, a large, red-haired Scot.
As well as being at least a foot taller than the rest of us, he claimed that his terrifying strength lay in the fact that ‘Scottish people don’t feel pain!’
Fascinatingly, research published in the Scandinavian Journal of Pain in 2011 by Aalborg University, in Denmark, suggests that red-haired people may indeed be more resistant to a number of types of pain, including electrical shocks, but are more sensitive to thermal pain.
The study suggested that this could be due to little-explored effects of a mutation in the melanocortin 1 receptor (MC1R) gene, which produces their red hair pigment.
Other people can be pain-proofed in other ways. Jo Cameron, a Scottish septuagenarian and retired teacher told me: ‘I honestly don’t know what pain is.’
Jo has a genetic mutation that means she never feels pain.
‘I have such a happy disposition that I’m positively irritating sometimes,’ she chirped.
Jo’s energy is infectious. Not only does she not feel pain, but she also doesn’t feel anxiety or fear. None whatsoever.
She felt no rush of adrenaline when her car veered off the road and overturned a few years ago, nor when she was left dangling over a ravine on a zip wire in Montenegro a week before our interview.
‘I guess the only downside to the mutation is that it affects my short-term memory’ she told me.
‘I’m always forgetting where I leave my keys. But, then again, that doesn’t bother me very much, either.’
Jo has a mutation in a pseudogene (a largely inactive copy of another gene) called FAAH-OUT.
This was long assumed to be a piece of ‘junk’ DNA, genes that don’t seem actually to do anything.
But it turns out that it plays a crucial role in regulating the FAAH (fatty acid amide hydrolase) gene.
The enzyme this gene produces normally breaks down anandamide — this is an endocannabinoid, a molecule that carries nerve signals that binds to cannabinoid receptors in the brain and body.
These receptors play roles in regulating mood, memory and pain. The most famous cannabinoid is tetrahydrocannabinol (THC), the most potent psychoactive ingredient in cannabis.
In Jo’s case, the mutation means that her anandamide is not broken down. And as a result, to some extent, Jo is permanently high.
‘I think the scientists who named the FAAH-OUT gene were having a bit of a laugh, as the high levels of cannabinoids in my blood make me relaxed, carefree and a bit forgetful,’ she says.
‘Essentially I’m lifelong stoner. Far out, dude.’
What is just as remarkable as her condition is the way in which it was discovered. Jo didn’t realise she was any different until the age of 65.
Over a four-year period, her hip would occasionally give way when she walked, although doctors thought little of it as she felt no pain and it hardly bothered her.
DIDN’T NEED PAIN RELIEF AFTER SURGERY
Eventually an X-ray revealed that the joint was severely damaged by osteoarthritis, a disease normally accompanied by agonising discomfort.
When she had her hip replaced, the surgeons noted that — unbeknown to her — both of her thumbs were also grossly damaged by osteoarthritis.
Her anaesthetist was already flummoxed by Jo’s incredible pain threshold in relation to post-surgical pain — she didn’t need any painkillers.
But when, some months after the hip replacement, Jo felt nothing following notoriously painful thumb surgery (a trapeziectomy, which involves removing a small bone in the wrist) he contacted James Cox, a geneticist at University College London.
Cox had long been studying remarkable painless individuals; he was Professor Woods’s postdoctoral student in Cambridge, and he went to analyse Jo’s genes to discover the cause of her condition.
Jo says: ‘After I was told about the genetic mutation, in hindsight things started to make sense.
‘As a child, I didn’t know that I’d broken my arm until the bone started healing at a strange angle, and I only realise that my hand has been on the cooker too long when I smell burning flesh.’
(And, like Candice, she didn’t need any pain relief for the birth of her — two — children.) Jo nonchalantly continued: ‘Actually, right now there’s a square-shaped bruise on the top of my foot. I have no idea how it got there.
‘I must have dropped something on it.’
What I couldn’t understand was how she had lived into her 70s, especially without losing any limbs, if she doesn’t feel any pain at all.
The secret to Jo’s survival, compared with others who are insensitive to pain, and are frequently maimed or killed as a consequence, may be due to another mysterious quirk of the FAAH-OUT mutation.
The many wounds she sustained throughout her life healed remarkably quickly, often without scarring.
Studies of mice with mutations in the FAAH gene support the accelerated skin-wound healing theory including a 2016 study by Italian and American researchers published in the journal Proceedings of the National Academy of Sciences.
This could be because one of the fatty acids usually broken down by FAAH stimulates the proliferation of skin cells.
Jo is not just an oddity. She is a miracle. Pain and fear are our teachers and guide through this dangerous life, and they have long been assumed to be necessary for survival. Jo has neither of these.
It also seems to make sense that a life without pain would be a bit dull, with no pain to motivate us or make pleasure rewarding. But Jo’s long life appears to be a perennially satisfied one. Throughout 2021 she is undergoing experiments intended to make her feel pain for the first time, and she’s looking forward even to that.
AND FEELS NO FEAR OR ANXIETY EITHER
This lack of concern is one reason why Jo is so different from other individuals who don’t feel pain, none of whom has demonstrated significantly low anxiety levels.
This could well be due to the fact that Jo’s body also shows unusually active CB1 receptors.
These cannabinoid receptors are activated both by the anandamide found naturally in the body, and the THC in cannabis.
Increased activation of these receptors reduces anxiety and helps the mind and body cope with stressful situations, researchers at Vanderbilt University, Nashville, reported in the journal Nature Communications in 2017.
Jo is a living, talking demonstration of how pain and mood are intertwined.
Jo’s single mutation reveals that pain is controlled and modulated in very different ways.
Her FAAH-OUT mutation increases the amount of painkillers found naturally in the body.
Jo’s confirmation of the analgesic power of anandamide provides hope for new painkillers that might work with the body’s endocannabinoid system.
It is also tempting to wonder whether these could also recreate Jo’s happy-go-lucky disposition, and might treat anxiety and depression as well.
Sadly, we have known about FAAH for some time, and not one of the many FAAH inhibitors developed have progressed to become medications.
Tragically, in this race to find the miracle painkiller, some have paid the ultimate price.
In a clinical trial in France in 2016, a new ‘FAAH-inhibitor’ drug that targeted the endocannabinoid system (as a potential painkiller and mood enhancer, among other functions) had numerous unintended effects on the human nervous system, leading to the death of one study participant and permanent brain damage in four others.
Blocking an enzyme that breaks down different substances in different tissues of the body is fiendishly difficult.
But hopefully the discovery of incredible people like Jo will be a catalyst for new research into treatments for persistent pain.
It is very much a field in its early days, no doubt, in part, because very often, sadly, people who are insensitive to pain live only short lives with bad endings.
When Professor Woods was researching neurological diseases in Pakistan, a local doctor asked him to assess Naveed.
Thirteen-year-old Naveed was something of a celebrity in his village in the north of Pakistan.
Crowds of curious shoppers would throng around the trail of hot coals laid out at the side of the street as he nonchalantly walked barefoot over them.
Once sufficiently remunerated by the awestruck onlookers, the boy would then theatrically brandish a knife. Without so much as a wince, he would slowly drive the blade into his arms.
This boy had seemingly gained complete mastery over what should be indescribable pain.
Naveed’s condition, known as congenital analgesia, was first medically documented in 1932, by the American neuropsychiatrist George Van Ness Dearborn.
He had assessed a mystifying middle-aged man who was, to all intents and purposes, a distinctly average individual, apart from the fact that he had managed to sustain a number of injuries (including accidentally shooting off his left index finger with a pistol) without experiencing pain.
Dearborn admitted that, ‘in short, we know as yet far too little about the nervous system to warrant a single guess as to the neuropathology of such a case as this’.
It was 70 years between Dearborn’s case report and Woods receiving news of the painless boy in Pakistan, but little had changed: knowledge was still scant.
Meeting Naveed would be an incredible opportunity for Woods, not to see a medical curiosity but to look through a living window into the mechanisms of pain and — potentially — its treatment.
Around the time of Naveed’s 14th birthday in 2006 — just as Professor Woods was preparing to set out to meet him — the boy was showing off to his friends by jumping off the high roof of his family home.
After hitting the ground, Naveed stood up, dusted himself off and walked away, seemingly unscathed.
Soon afterwards, and with little warning, he rapidly lost consciousness and died. It later turned out that he’d hit his head so hard in the fall that it had caused a catastrophic bleed in his brain, but he hadn’t felt even a bump.
Members of Geoff Woods’s team at Cambridge and a group of doctors in Pakistan contacted Naveed’s family.
It transpired that numerous family members — as well as two other families within the same clan in northern Pakistan — also had congenital analgesia.
DISCOMFORT IS BODY’S WARNING SYSTEM
Many had scars and broken bones, and had bitten off the front portions of their tongues.
Fascinatingly, although they felt no pain, their senses of touch, pressure and temperature were preserved.
Such people are increasingly the subject of intense pharmaceutical interest. They are rapidly expanding our understanding of pain, and reveal tantalising mechanisms for future pain-relieving drugs.
But they also do something simple yet astounding: they demonstrate pain’s key role as a protector.
Without pain, we would live lives of unprotected injury and early death.
The first step to understanding and living with pain — even persistent, chronic pain — is knowing that pain is a protector, and it wants to look after us.
Adapted from The Painful Truth: The New Science Of Why We Hurt And How We Can Heal, by Monty Lyman is published by Bantam, £20. © Monty Lyman 2021.
To order a copy for £17, go to mailshop.co.uk/books or call 020 3308 9193. Free UK delivery on orders over £20. Offer price valid until July 6, 2021.