Why some people don't feel pain

By Geoff Woods, Ya-Chun Chen

It's estimated that the prevalence of congenital analgesia is about one in a million people worldwide.Photo / Creative Commons
It's estimated that the prevalence of congenital analgesia is about one in a million people worldwide.Photo / Creative Commons

For many years physicians and scientists have been studying people with congenital analgesia, a rare genetic disorder that means they don't feel pain. People with the condition may have a sense of touch but their lack of a sense of pain means they often injure themselves, for example by biting their tongue or being scalded with hot water without noticing as you and I would do.

Now a team of researchers have identified a mutation in a gene called SCN11A by comparing the gene sequence of a girl with the condition with that of her parents (who were able to feel pain). The mutation disrupts how people with the condition perceive pain and was also found in another individual in the study.

We already know something of the genetic causes that lead to no sense of pain. But the newly identified mutation gives us some surprising new insights into their role and could help in the development of new painkillers.

Living without pain

To feel no pain anywhere in your body at any time during your life is very rare. It's estimated that the prevalence of congenital analgesia is about one in a million people worldwide.

Such people show just how essential a sense pain is for us. As babies they chew their lips, tongue, toes and fingers - and often lose the tips of their tongue and fingers. They have no fear of fires or cookers, knives and sharp edges, of walking into doors or falling rather than sitting down - behaviour we learn through experiencing pain.

Because of the collection of bruises, burns and fractures they accumulate, their exasperated parents are often accused of child abuse. And childhood can be marred by three problems: being thought of as "slow" because they bump into things, are clumsy and have so many accidents; having to learn what pain is and pretend to experience it (so they don't stand out); and trying to avoid serious accidents - which is far more of a problem for males than females, to which the lack of affected males older than 20 is testimony.

All adults with no sense of pain tend to have significant orthopaedic injuries that won't heal properly because a lack of pain stops people restricting activities. All of this shows two fundamental roles that pain has in humans: protecting us so we live longer and helping our development as we learn how to use our bodies and the limits to which we can stress our body before causing damage.

Genetic causes

The genetic causes of the condition can be split into two groups: neuropathies, where the pain-sensing nervous system fails to develop altogether, and congenital analgesia (from birth) where the pain sensing nervous system develops but does not work.

People with complete analgesia can't feel temperatures (and as a result some have died of heat stroke) and may have learning difficulties. The best example of this is Hereditary Sensory and Autonomic Neuropathy Type 4, or HSAN4.

With congenital analgesia, the pain-sensing nervous system develops well but their neurons (known as nociceptors), which pass on information through chemical signals, are unable to function. They fail to generate nerve impulses after painful/tissue damaging stimuli. People with congenital analgesia are of normal intelligence and until now, the only proven condition in this group was Congenital Insensitivity to Pain (CIP) - discovered in 2006.

Excessive sweat and smelling things

CIP is caused by mutations in the SCN9A gene that encodes a protein called Nav1.7, which is essential for initiating pain signals between neurons. Interestingly this mutation means people with CIP also have no sense of smell.

Neurons transmit pain signals using a battery-like system - using a more negative pole on their inside and a more positive pole on their outside. Activating the Nav1.7 protein results in an electrical signal transmitting along a neuron and relaying the signal on to the next neuron, before finally reaching the brain where it generates a feeling of pain.

But the new research identifies a second congenital analgesia condition, one that is caused by mutations of a different gene: SCN11A.

SCN11A programmes another protein called Nav1.9, which maintains a difference in voltage between the inside and outside of the pain-signalling cell, which enables a pain signal to travel.

A small surprise was that people with this condition in the study sweating excessively for no obvious reason (something not seen in SCN9A-CIP) and had a normal sense of smell.

But there were two large surprises: that both individuals in the study had the same mutation in their SCN11A gene and that the mutation made their protein more active than normal, affecting the balance of voltage in the cell.

We thought that painlessness resulted from a mutation that stopped the cells from generating painful signals. From the new research, we now also know that it can also result from keeping these cells balanced in a resting state.

Peculiar side effects

So why is a finding about only two people so exciting? Because we now have two new targets for pain killers: either molecules that inhibit the gene SCN9A and the protein Nav1.7 (to stop pain signals), or that activate SCN11A and the protein Nav1.9 (to keep neurons in that resting state).

But targeting these molecules would mimic the clinical features of people with analgesia and new pain killing drugs might have some unusual side-effects.

We can reasonably extrapolate that a SCN9A/Nav1.7 painkiller could also cause a temporary loss of smell, and a SCN11A/Nav1.9 painkiller could cause excess sweating. But these will probably be minor prices to pay when you're in a lot of pain.


Geoff Woods receives funding from Medical Research Council. One of these grants is an Industrial Collaborative grant involving Neusentis, a company owned by Pfizer.

Ya- Chun Chen has received funding from the Wellcome Trust

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