// Twitter Cards // Prexisting Head The Biologist Is In: Pain

Tuesday, December 15, 2015


You think you know pain. You've experienced pain all your life. You just might have probably broken a bone, or given birth, or been [mildly] electrocuted...  some of the more physically painful events that a person might think of experiencing.  If you're really unlucky, you may even now be living through the intractable, unending, pain that can be caused by cancer or some other disorders.

Some rare few people have no comprehension of your experience. They have a disorder called Congenital Insensitivity to Pain, or CIP. The disorder interferes with their ability to feel any pain. Not having to feel pain might sound like a nice idea, but pain is your body's way of telling you that something is wrong. Pain can get out of hand at times, but without it...  life gets difficult.

You learned a hot pan from the stove was not to be touched, because it hurt. You learned to take care while running, because it hurt when you fell. When you accidentally bite your tongue or cheek, it hurts and you [try to] avoid it again. Without pain, you would never learn any of those lessons. You would be severely burned, or break bones, or bite through your cheek and tongue. Pain is important, because it helps you learn to keep from damaging yourself as you go through life. People with CIP have very difficult childhoods, with their bodies experiencing damage at levels a typical person could never imagine.

Geneticists have studied families with high rates of CIP and have identified several mutations in the gene SCN9A. This gene encodes the voltage-gated sodium channel Nav1.7, critical for the normal transmission of signals along pain-responsive nerves. The same ion channel is responsible for the transmission of signals along olfactory nerves (Ahn et al 2011; ), so patients with the disorder also have an impaired sense of smell.

Researchers recently replicated one of these mutations in the laboratory mouse (Minnett et al, 2015). The resulting mice had no reaction to stimuli that should have caused a great deal of pain, without causing actual physical damage, like electro-stimulation. The mouse showed increased endogenous opiod activity. The introduction of the opiod antagonist Naloxone resulted in restoration of the mouse's ability to feel pain. A human subject with a similar mutation of SCN9A also showed a restoration of the ability to feel pain when treated with Naloxone, for the first time in their 39 years of life. The researchers are using their new knowledge to develop a treatment for intractable, chronic pain. The treatment would mimic the effects of the SCN9A mutation, by using a low dose of opiods paired with an Nav1.7 antagonist. This should allow for the effective management of pain with low doses of opiods, so avoiding the potentially-lethal side-effects associated with high-dose opiod pain-management therapy.

Not all cases of congenital insensitivity to pain are due to mutations in SCN9A. I found a paper (Manfredi et al, 1981) which describes a patient who had no pain response, but did not have an impaired sense of smell. This ability to smell indicates the patient had a functional SCN9A gene. The patient was also described as not showing a restoration of pain sensation upon treatment with Naloxone. My reading of the 2015 paper suggests the authors didn't realize that Naloxone would restore pain sensation in their patient. It looks like they missed this critical knowledge that was known in the 1981 paper when they were doing their literature research for the project. The 1981 patient may have a mutated NTRK1 gene, another known cause of congenital insensitivity. The state of research in 1981 didn't involve the intensive genome sequencing needed to identify mutant genes, so it remains unclear.

Did you catch the problem in this story?

The 2015 paper indicated the patient had never experienced pain until the researchers realized that Naloxone might be a treatment for their disorder. The 1981 paper described an interesting patient with congenital insensitivity to pain who, surprisingly, didn't respond to Naloxone. Naloxone has been known as the treatment for this disorder for more than thirty years.

The patient described in the 2015 study has lived through 39 years without a medical professional giving them the known treatment for the disorder that resulted in them experiencing the extreme physical damage that the disorder leads to. The treatment could have normalized their pain responses and prevented the damage. Because of the diversity of underlying biological causes to different cases of CIP, Naloxone treatment may not work, but it is readily tested and has minimal side-effects.

This disorder impacts maybe 100 people on the planet. It receives very little research attention, even though it is a relatively charismatic disorder, so it is understandable that critical knowledge might occasionally be forgotten or not communicated to those who should know it. That the re-found knowledge of the 2015 paper is being used to develop a treatment for the intractable pain experienced by many people across the world is a wonderful thing. It really could improve the lives of millions of people by removing their chronic pain without needing powerful and dangerous drugs. However, It still makes me very angry that the patient in the 2015 paper wasn't given appropriate treatment for most of their life with the disorder.


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