The Woman Who Can’t Feel Pain Thanks to Her Endocannabinoid System
Following a normally painful operation on her hand to help with severe arthritis, a 66-year-old woman shocked medical staff by reporting experiencing no pain or discomfort following the operation.
Jo Cameron, who was receiving treatment at her Raigmore Hospital in Inverness, Scotland, received a standard general anesthetic prior to the hand operation, a trapeziectomy with ligament reconstruction and tendon interposition and extensor pollicis longus realignment. Extraordinarily, she required no other postoperative painkillers than a dose of paracetamol on the same day as the surgery. She was discharged from the hospital the day after the operation, after repeatedly rating her pain intensity as a 0 out of 10 on a 10-point scale, despite the recovery following an operation of this sort typically being a painful experience.
All this was unsurprising to Cameron, who has had a long history of pain insensitivity. The year before, she sought treatment for an issue with her hip, which she reported as painless but was discovered to be a case of osteoarthritis with a severe degree of joint degeneration. Following her hip replacement, Cameron took some paracetamol but noted that she never asked for any analgesics and simply took what the doctors recommended. A single dose of morphine was originally given following the surgery, but it caused episodes of vomiting for two days, and so no further doses were given.
“Pain is there for a reason, it warns you, you hear alarm bells,” explained Cameron to BBC News. "It would be nice to have warning when something's wrong. I didn't know my hip was gone until it was really gone; I physically couldn't walk with my arthritis."
Cameron’s insensitivity also leads her to sustain cuts, burns, and bruises all without pain. She can even eat several of the famously spicy Scotch Bonnet chili peppers without any discomfort. But Cameron’s freedom from pain may also have its side effects. She often suffers from long-standing memory lapses and claims she rarely experiences panic; she scored a zero on health questionnaires for anxiety and depression. Recounting a recent car accident to the BBC, Cameron claimed she was completely unfazed in the moments after the accident, whereas the driver was “shaking like anything”.
“I don't have adrenalin. You should have that warning, it's part of being human, but I wouldn't change it.”
After her hearing this pain-free history, Dr Devjit Srivastava, a hospital consultant in anesthesia and pain medicine at the Raigmore Hospital, referred Cameron to pain geneticists at University College London (UCL) and Oxford University for examination with her consent.
Mutation in previously-unknown gene found by researchers
The findings of the UCL and Oxford University researchers have recently been published in the British Journal of Anaesthesia.
It was noted that Cameron’s mother, husband, and daughter do not experience any sort of pain insensitivity, but her does. With their consent, researchers took blood samples from the family for genomic DNA analysis.
From Cameron’s genome, the researchers identified an -8 kb microdeletion in a pseudogene which had until now been near-unknown in medical literature, here dubbed FAAH-OUT, and a mutation in neighboring gene that controls the FAAH enzyme. Her son also seemed to carry this microdeletion FAAH-OUT, but didn’t have the same accompanying FAAH hypomorphic single nucleotide-polymorphism (SNP) that was seen in his mother.
Fatty-acid amide hydrolase (FAAH) is the major catabolic enzyme for the fatty-acid amides (FAAs), which are bioactive lipids in the body. These FAAs include the N-acyl ethanolamines, which act as a ligands for the cannabinoid receptors in the endocannabinoid system, the same receptors that are activated by cannabis consumption. Anandamide (AEA), one of these N-acyl ethanolamines, has been linked previously to roles in nociception, fear-extinction memory, anxiety, and depression. Other important substrates of FAAH are the N-acyl ethanolamines palmitoylethanolamide (PEA) and oleoylethanolamine (OEA).
Animal studies have also indicated that FAAH inhibition might be an attractive approach to treating pain disorders, though recent attempts to recreate these pain-suppressant effects in human clinical trials have yet to be successful. Given that FAAH inhibition in mice was shown to result in pain insensitivity, memory lapses, and reduced anxiety and depression — all effects that were reported or observed in Cameron — it was proposed that the microdeletion could be responsible for her extraordinary pain insensitivity by negating the normal function of FAAH in some way.
Further studies by a team at the University of Calgary, Canada identified elevated levels of three neurotransmitters in Cameron’s blood. These N-acyl ethanolamines and cannabinoid receptors would ordinarily be degraded by the FAAH enzyme confirming suspicions that the mutations were indeed inhibiting ordinary FAAH function.
The endocannabinoid system and pain
The paper concludes that this case has given new insight into the role of the endocannabinoid system, specifically the FAAH genomic locus, in analgesia and pain sensitivity. The observed effects of the previously uncharacterized FAAH-OUT gene could be key to understanding why previous efforts at treating pain relief though FAAH-inhibition have failed, and how to more effectively create an FAAH-related analgesic.
“The implications for these findings are immense,” said Dr Srivastava in the press release accompanying the research paper. “One out of two patients after surgery today still experiences moderate to severe pain, despite all advances in pain killer medications and techniques … we hope the FAAH-OUT gene could change things particularly for post-surgical pain, it remains to be seen if any new treatments could be developed based on our findings.”
Dr James Cox, a fellow author of the paper, added, “People with rare insensitivity to pain can be valuable to medical research as we learn how their genetic mutations impact how they experience pain, so we would encourage anyone who does not experience pain to come forward.”
“We hope that with time, our findings might contribute to clinical research for post-operative pain and anxiety, and potentially chronic pain, PTSD and wound healing, perhaps involving gene therapy techniques.”
In the meantime, the researchers are continuing the work with Cameron to better understand her condition. They also urge others who experience similar symptoms to make themselves known, as Cameron’s pain insensitivity was not diagnosed until her late-60s despite a history of painless incidents would suggest that the condition is likely to be under-reported.
