Imagine a life without ever feeling any pain. It may be hard to envision, but for patients with the rare condition called congenital insensitivity to pain (CIP) this is exactly the case. In the past decade, several different genetic mutations have been discovered that cause CIP, most of which produce dysfunction in the nerve cells that contribute to pain processing.
Now, researchers led by Devjit Srivastava from Raigmore Hospital, Inverness, UK and James Cox, from University College London, UK, have identified a new case of CIP in a woman in her 60s who has genetic alterations in a key enzyme known as fatty acid amide hydrolase (FAAH); enzymes are molecules that quicken the pace of chemical reactions. FAAH is part of the body’s endocannabinoid system, which regulates hunger, mood and pain sensation.
“This is an absolutely fascinating case report of a woman who doesn’t feel pain,” said David Finn, a scientist from the National University of Ireland, Galway, who studies the role of the endocannabinoid system in pain, anxiety and stress but was not involved in the current study. Finn said that the newly discovered case of CIP builds upon years of work in the lab on the role of the endocannabinoid system in pain and is consistent with what researchers have learned from animal studies.
The woman initially came to the attention of Srivastava, a surgeon, when she was referred to him for a notoriously painful hand surgery to help treat arthritis.
“The first thing she said to me was that she doesn’t feel pain, doesn’t need an anesthetic, and doesn’t take painkillers,” Srivastava said. “As you can imagine, I was a little taken aback by this, but as an anesthetist you’re supposed to make sure that the patient feels no pain during and after surgery. I took no risk and gave her the normal anesthetic protocol, but what she had said stayed with me.”
Following up with the patient the next day, he discovered that she had only taken one gram of acetaminophen after the surgery and no other pain-relieving drugs. This was highly unusual and made Srivastava suspect he had a unique case on his hands.
Srivastava then contacted James Cox, who is well known for studying the genetic mutations that cause CIP. Cox, along with the first author of the current study, Abdella Habib, had previously discovered genetic alterations that produced different forms of CIP in a Pakistani family and in an Italian family.
Cox and Habib set about trying to find the cause of the woman’s inability to feel any pain. After an extensive search for genetic abnormalities in her DNA, they discovered two mutations that caused CIP in this patient.
The first was a mutation known as a single nucleotide polymorphism, or SNP. A SNP is a genetic mutation in a single DNA building block (known as a nucleotide) and is the most common type of genetic variation in people. In this case, the SNP causes the FAAH enzyme to lack its normal function.
That is, normally FAAH is responsible for the breakdown of anandamide, a key neurotransmitter in the endocannabinoid system. In animal studies, blocking the activity of FAAH increases anandamide levels and reduces pain.
The other mutation was a novel, rare mutation in a piece of DNA. The researchers called this mutation FAAH-OUT.
“The FAAH SNP is quite frequent in the general population, estimated to be at around 25 percent,” said Cox. “The FAAH-OUT [mutation] is much rarer. The patient’s son has it, as does as an anonymous male from Colombia, but neither have the FAAH SNP. This patient is the first person we are aware of to carry both mutations,” explained Cox. (The son had some reduced pain sensitivity, but not to the same extent as his mother).
FAAH SNP mutations are associated with a reduced need for pain relievers following surgery, in some cases. But, as Habib explained it, “it’s clear that both genetic mutations are required” for the current instance of CIP.
When the researchers measured levels of anandamide in the patient’s blood, they discovered that compared to individuals without these mutations in FAAH, her levels were 70% higher. This is likely to be a major factor contributing to this patient’s insensitivity to pain.
Other symptoms that this individual experiences, apart from pain insensitivity, include low levels of fear and anxiety, a permanently cheerful outlook on life, as well as being quite forgetful. All of these are consistent with previous studies of FAAH and anandamide in laboratory experiments in cells and animals.
The new findings have a number of potential implications for the treatment of pain. For instance, it could build interest in the development of FAAH inhibitors as pain-relieving drugs.
Interestingly, although the new study involved only one patient, it is likely that there are others like her yet to be discovered who also have both of the mutations. That’s because the FAAH-OUT mutation is flanked by specific sequences of DNA that are very similar to each other. Such repeated stretches of DNA often cause mutations in other genetic disorders.
Another reason to think that there are others with both mutations is because the patient in the current study only came to the attention of the medical community when she was already in her 60s.
“There are people out there who are pain free and who are not going to the doctor, and pain is such a common reason for initially visiting a doctor, so it’s difficult to find these people,” said Cox.
Finally, new reports like the current one spark great interest in the scientific and broader non-scientific communities, which could help overcome one of the challenges of studying CIP patients: They are exceedingly rare.
“In the last decade we have been working with only a handful of CIP patients,” said Cox, “but every time a new report like this comes out it helps us to recruit more. We now have upwards of 80 individuals who have emerged after this paper was released who have very similar phenotypes [observable characteristics], and we are currently investigating them. We are very thankful for this particular patient. She has been really kind to work with us over these past few years and has shown great patience with us; we are really grateful.”
This story first appeared on the Pain Research Forum and has been adapted for RELIEF.
Dara Bree is a postdoctoral research fellow at Beth Israel Deaconess Medical Center and Harvard Medical School.