Genetic Mutation Results in Inability to Feel Pain

The sensation of pain is a subjective phenomenon. It can be unpredictable, striking without warning, and can take many forms: emotional pain, acute pain, chronic pain, breakthrough pain, and even phantom pain.

It's safe to say that for most people, pain is rarely welcomed, and often has us reaching for a box of painkillers so that we can try to proceed with our daily lives. A headache can interrupt our working day, stubbing your toe results in a rant of cursing, and chronic pain conditions can prove highly debilitating for the 50 million Americans estimated to suffer.

What if we felt no pain whatsoever? Interestingly, this is the reality for some individuals – and, no, we're not discussing characters in a Marvel comic book. A Scottish woman in her 60s has been identified as possessing a previously undiscovered mutation that means she can feel virtually no pain. A research paper published today in the British Journal of Anaesthesia documents the findings from a genetics case study of the woman, co-led by UCL.

A life without pain

At 65, the woman was experiencing an issue with her hip that led to a visit to the doctors. It was revealed that, despite not reporting feeling any pain, she was suffering from severe joint degeneration. Later, she underwent surgery on her hand, a procedure that is typically very painful, and yet – alas – she reported no pain sensation after the surgery. Devjit Srivastava, Consultant in Anaesthesia and Pain Medicine at an NHS hospital in the north of Scotland, diagnosed pain insensitivity. Interestingly, the patient also reported feeling very little anxiety and fear in her lifetime thus far, even in a recent automobile incident.

The woman was referred to pain geneticists at University College London and the University of Oxford where she underwent a series of genetic analyses. Two notable mutations were identified in her genotype: a microdeletion in a pseudogene (previously only briefly discussed in the literature) that researchers have dubbed FAAH-OUT, and a mutation in the neighbouring gene responsible for controlling the FAAH enzyme. 

Researchers in the field are acquainted with the FAAH gene as it plays a part with endocannabinoid signalling, associated with pain sensation, mood and memory function. The FAAH-OUT gene was previously disregarded as "junk" DNA that was not functional; however, animal model studies suggest otherwise. Mice lacking the FAAH gene present with reduced pain sensation, accelerated wound healing and enhanced fear-extinction memory.

The patient self-reports similar traits, noting that in her medical history there were times where she has suffered burns that went unnoticed until the smell of burning flesh caught her attention, and that her injuries typically heal rapidly. Blood tests also revealed elevated blood serum levels of neurotransmitters that are typically degraded by FAAH, suggesting further evidence for a loss of function of the FAAH gene.

"We found this woman has a particular genotype that reduces activity of a gene already considered to be a possible target for pain and anxiety treatments," says one of the study's lead researchers, James Cox, M.D. at UCL Medicine. "Now that we are uncovering how this newly-identified gene works, we hope to make further progress on new treatment targets."

Cox suggests the fact this lady was unaware of her condition until reaching her mid 60's could mean that there are people out there with the same mutation. "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," adds Cox.

Creating solutions for different types of pain?

The researchers are continuing to work alongside the female patient, conducting further testing in cell samples to gain understanding of the pseudogene's function. "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," said Cox.

Pain following surgery can majorly impact not only an individual's physical recovery, but also their mental attitude towards recovery.

"The findings point towards a novel pain killer discovery that could potentially offer post-surgical pain relief and accelerate wound healing. We hope this could help the 330 million patients who undergo surgery globally every year," Srivastava remarks. "One out of two patients after surgery today still experiences moderate to severe pain, despite all advances in painkiller medications and techniques since the use of ether in 1846 to first 'annul' the pain of surgery. There have already been unsuccessful clinical trials targeting the FAAH protein - while 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."