When I was an undergraduate, while walking across a grassy field, I stepped into a hidden hole and fell forward. As I did so, I flung out my left arm to break the fall and that jerky motion was sufficient to dislocate my shoulder. I recall being in excruciating pain and was taken to the campus health center where the person who treated me was very familiar with sports injuries such as dislocation and he simply straightened my elbow, gave my arm a twist, and pushed it back into the socket. Like magic, the pain ceased immediately and its sudden disappearance made me feel euphoric. But now, although I recall the incident vividly, I cannot remember what the pain actually felt like. I remember that I was in great pain, but I cannot recall the feeling of pain.

This is not uncommon. Sufferers of pain find it hard to communicate to others what they are actually experiencing, however acute it might feel to them. This unfortunately means that pain sufferers might get less sympathy and consideration from those around them. This feature also makes treatment of pain difficult because we have no pain-o-meters to measure it and see how effective any treatment might be. Despite that limitation, there have been tremendous strides in the categorization and treatment of pain in the last century, depending on the type of pain being experienced, such as inflammatory and chronic pain from things like rheumatoid arthritis that is caused by nerve damage, acute pain from things like broken bones, and pain from cancers.

Opioids are potent painkillers but they are known to be highly addictive. It used to be the conventional wisdom that if you took opioids because you had real pain, you would not get addicted and that once the source of the pain went way, so would your desire for the painkiller. Hence opioids were prescribed quite freely. But now that view has changed and it is known that you can get addicted and remain so even after the cause of the pain has disappeared. The scandal over abusive over-prescribing of them, led by people like the Sackler family, the companies that distribute them, and physicians who received incentives for encouraging patients to use them, has led to doctors being much more circumspect about prescribing opioids, which has resulted in less relief for some people who really suffer from acute pain.

So the search is on for painkillers that can address the pain problem without harmful side effects. In a recent article in the June 2, 2025 issue of The New Yorker, Rivka Galchen looked at the history of pain and looked at recent developments in its treatment. There was one aspect that grabbed my attention and that is that some people have a mutation in their SCN9A gene that makes them impervious to pain while others have a different mutation of the same gene that makes them feel pain much more acutely. The former case is actually more dangerous since it is the fear of pain that prevents people from doing many things that might harm them. Pain is an important survival mechanism.

She describes what Geoff Woods, a researcher in the UK, who visited Mirpur in Pakistan to investigate family members of his UK patients who all had a different genetically transmitted ailment, heard about a boy who seemed to feel no pain at all.

On one visit, doctors told him about a child who worried them. They suspected that he had a genetic condition, and they were curious to get Woods’s opinion. The boy was well known as a street performer. He would stab his arms with a knife, or walk on hot coals. “And then he would come to casualty, and they would patch him up,” Woods recalled being told. He was usually brought in by his overwhelmed mother, who wished that she could talk some sense into him. The boy said that he couldn’t feel pain. Woods agreed to see him on his next visit to Pakistan.

Woods knew of cases of people who didn’t feel pain, but those cases were marked by excessive sweating and increased infections—they seemed clinically different. He told me that, at the time, few researchers really believed that some people were simply born unable to feel pain. It would have sounded like a fable, or like the Grimms’ fairy tale about the boy who didn’t know fear. When Woods returned to Pakistan, the clinicians told him that the boy, on his fourteenth birthday, had jumped from the roof of a house to show off for his friends. He had been brought to the hospital unconscious and died a short time later. “I think it was at that stage that it stopped being a mythical disease for me,” Woods said. “I hadn’t got it—that, if you feel pain, well, there are some things you would normally not do because you know it’s going to hurt.” Now we know that there is a condition known as congenital insensitivity to pain. Woods met other people in the region who had experiences similar to those of the child who died. “The boys, about half of them end up killing themselves by their early twenties, just doing the craziest things that normally pain would have taught you not to do,” he said. “The girls are sensible. They are hypervigilant. They know they’re at great risk of terrible problems and are very careful.” Woods eventually discovered that all these people had mutations in the SCN9A gene, which is involved in the production of tiny passageways, found in cell membranes, which regulate the flow of sodium ions into and out of cells, and are thus crucial in sending electrical signals. Nerves use such signals to communicate pain to your brain.

The difference in behaviors of boys and girls to the same condition of feeling no pain, the former taking much greater risks while the latter becoming more careful, is startling. It gives support for the ‘young men are crazy’ trope, that they do dangerous things to show off to their peers. That is the basis of the joke that the most common last words of young men are “Hey guys! Watch this!” It is possible to construct an evolutionary tale to explain it, such as that in prehistoric times the men who were hunters were obliged to be risk takers while the women as gatherers did not feel the same pressure. But such an explanation seems somewhat facile and a form of just-so story and should not be accepted without more rigorous justifications.

There is another mutation of the SCN9A gene that causes more sensitivity to pain and is also intriguing. Galchen describes a study of people in the US.

Around the same time, Stephen Waxman, a professor of neurology, neuroscience, and pharmacology at Yale’s medical school, received a phone call about a neighborhood in Alabama where many people preferred to walk barefoot, or wore open-toed sandals and liked stepping in cold puddles. Some of them said that their hands and feet felt like they were on fire, and that this was true of family members going back at least five generations. “These people feel excruciating, burning, scalding pain in response to mild warmth—wearing a sweater, wearing shoes, going outside when it’s seventy-two degrees Fahrenheit,” Waxman told me. Their condition is known as inherited erythromelalgia or “Man on Fire” syndrome. Waxman sent a team from his lab to Alabama to meet both affected and unaffected family members, and to collect DNA samples. All the affected members, and none of the unaffected ones, had the same mutation of the SCN9A gene—the gene that Woods had identified as altered in the Pakistanis who couldn’t feel pain.

The researchers identified the cause as due the sodium channels in the pain pathways. In those who feel no pain, these channels were muted while those who felt greater pain had those channels hypercharged. This has led to ideas for a new way to treat pain. While opioids target the parts of the brain that receive pain signals, you might be able to reduce pain by mitigating the sending of pain signals, by finding a drug that acts on the sodium channels.

The genetic mutations that the patients of both Waxman and Woods had affect a sodium channel called NaV1.7, which is predominantly found in peripheral pain-sensing neurons. A drug interrupting pain signalling before it ever reached the brain would likely lack the addictiveness of opioids. “We all went crazy, because people without NaV1.7 were pain-free but otherwise normal,” Wood, the doyen of sodium channels, told me. “It was unbelievably exciting.” All that researchers had to do was to make a compound that affected only that sodium channel.

But that early promise faded. Another drug called suzetrigine that targeted another gene NaV1.8 showed positive but modest results and is also very expensive. It is now undergoing Phase III clinical trials.

There is as yet no drug that blocks the pain channels that reduces pain as effectively as opioids, so for the foreseeable future that is going to be dominant. But there is hope. Unless of course the cuts in scientific research by RFK Jr., Elon Musk, and Trump stall such research.