Pain is body language trying to warn us. But there are people in the world who live their own lives and have never felt pain. Could their “problem” open up a new way to manage chronic pain? At the Institute for Human Genetics in Aachen, Germany, Dr. Ingo Kurt is preparing for a rather unusual appointment. She collects blood samples from Stefan Betz, a 21-year-old university student who suffers from a genetic disorder so rare that only a few hundred people worldwide have it.
Betz has a congenital insensitivity to pain (CIP). This means that he can stick his hand in boiling water or undergo surgery without pain relief, while not feeling any discomfort. Otherwise, his sensory perception is normal. He sweats when the room is too hot and shudders in the cold wind. But like everyone who suffers from CIP, Betz considers his condition a curse, not a blessing.
"People think it's cool not to feel pain, you're practically superhuman," Betz says. “But for people with CIP, it's exactly the opposite. We would love to know what pain is and what it feels like to feel pain. Life is full of problems without her."
In Betz's early childhood, his parents believed he was mentally retarded. “We couldn't understand why he was so clumsy,” his father Dominic recalls. "He was constantly bumping into corners and walking around with cuts and bruises."
Neither his parents nor his brothers and sisters have this problem. The diagnosis became known when, at the age of five, Betz bit off the tip of his tongue without any pain. Shortly thereafter, he broke the metatarsal bone in his right leg when he jumped down a ladder.
From an evolutionary perspective, one of the reasons the diagnosis of CIP is so rare is that few people survive to adulthood with it. “We are afraid of pain, but in terms of development from child to adult, pain is very important for learning the right physical activity so as not to damage our body and identify risks,” explains Kurt.
Without a natural warning mechanism, many people with CIP exhibit self-destructive behavior during childhood or early adolescence. Kurt tells the story of a young Pakistani man who has attracted the attention of academics for his reputation as a street performer. He walked over hot coals and thrust knives into his hands, showing no signs of pain. He later died in his early teens, jumping from the roof of a house.
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“Of all the CIP patients I have worked with in the UK, many died by the age of 20 because they were unrestrained in pain and were doing very scary things,” says Jeff Woods, pain researcher at Cambridge Medical Institute. "Or they damaged their joints so badly that they ended up in a wheelchair and later committed suicide, not wanting to live that kind of life."
Betz has been to the hospital more times than he can remember. He has a slight limp in his left leg due to an osteomyelitis infection that appeared after breaking his tibia while skateboarding. “You have to pretend to be in pain so you don't be reckless,” he says. “It's not easy when you don't know what it is. I have to control myself so that my body will not fail one day."
But the very mechanisms that led to the Betz problem could one day improve the lives of millions of people around the world.
The CIP was first discovered in 1932 when New York physician George Dearborn described the case of a 54-year-old ticket salesman. He claimed that he did not remember any pain, although as a child he was pierced by a sharpened ax. Together with him, he ran home.
For the next 70 years, scientists paid little attention to this strange condition, which appeared from time to time in medical journals around the world. But with the advent of social media to make it easier to find groups with CIP, scientists have begun to realize that studying this rare disease could provide new insights into pain itself and how to turn it off for many people with chronic conditions.
The main incentive is, of course, finances. Pain is a global industry on a staggering scale. The world's population consumes 14 billion doses of pain medications every day, and each year one in ten adults is diagnosed with chronic pain that lasts seven consecutive years. The reason we feel pain is due to the actions of proteins that live on the surface of our pain neurons, cells that run from the skin to the spinal cord. There are six types of pain neurons, and when they are activated by stimuli like high temperatures, lemon acid or others, they send a signal to the spinal cord, where it perceives it as pain in the central nervous system. The brain can turn off the pain signaling network if it wants to, producing endorphins in situations of high stress or adrenaline.
The world of pain relievers is dominated by opiates such as morphine, heroin, and tramadol. They work in the same way as endorphins and are addictive. The consequences are dire. In the United States, 91 people die daily from opioid overdoses. Alternatives like aspirin are not effective for severe pain and can cause serious gastrointestinal side effects over long periods of time. But while the demand for breakthroughs in pain research has been colossal, little has been achieved. Until recently.
In the early 2000s, a small Canadian biotech company, Xenon Pharmaceuticals, heard of a Newfoundland family in which several family members were congenitally insensitive to pain. “The boys in the family often broke their legs, and one even stepped on a nail without visible pain,” said Simon Pimstone, president and CEO of Xenon.
The company began examining the globe for similar cases to try and sequence the correct DNA. The study identified a common mutation in a gene called SCNP9A, which regulates the Nav1.7 sodium channel pathway in the body. The mutation clogged this channel and at the same time the ability to feel pain.
This was the breakthrough that the pharmaceutical industry has been waiting for.
Over the past decade, Nav1.7 has intensified a pain race between biotech companies and pharmaceutical giants. They are all trying to create a whole new class of pain relievers as one.
But developing sodium channel blockers that act on the peripheral nervous system is not easy. While the promise is there, it will take another five years to fully understand whether inhibition of Nav1.7 could be the key to modulating pain signals in humans. Xenon is betting on this. They now have three products in clinical trials in partnership with Teva and Genentech.
“Nav1.7 is a complex and challenging drug target because it is one of nine sodium channels that are very similar,” Sherrington says. “And these channels are active in the brain, heart, nervous system. Therefore, you need to design something that will fall into this particular channel and will only work on the fabrics you need. Great care is required."
Meanwhile, new ways of dealing with pain are emerging in the CIP research process. One of the most interesting is the PRDM12 gene, which acts as a master switch that turns on and off a series of genes associated with pain neurons.
But while the world of pain reliever research benefits from the uniqueness of those who were born with congenital insensitivity to pain, the benefits of their lives remain dubious.
Gene therapy has not yet reached the stage where scientists could think about repairing the missing channel and possibly returning pain to those who have never had it. For such a small percentage, there is simply no financial motivation.
But Betz says he doesn't give up hope. “I would like to contribute and help the world learn more about pain. Perhaps one day scientists will be able to use this knowledge that we gave them to help us too."
ILYA KHEL