Pain might flicker, flash, prickle, drill, lancinate, pinch, cramp, tug, scald, sear, or itch. It might be blinding, or gruelling, or annoying, and it might, additionally, radiate, squeeze, or tear with an intensity that is mild, distressing, or excruciating. Yet understanding someone else's pain is like understanding another person's dream. The dreamer searches out the right words to communicate it; the words are always insufficient and imprecise. In 1971, the psychologist Ronald Melzack developed a vocabulary for pain, to make communication less cloudy. His McGill Pain Questionnaire, versions of which are still in use today, comprises seventy-eight words, divided into twenty groups, with an additional five words to describe intensity and nine to describe pain's relationship to time, from transient to intermittent to constant. Not included in the M.P.Q. is the language that Friedrich Nietzsche used in describing the migraines that afflicted him: "I have given a name to my pain and call it 'dog.' It is just as faithful, just as obtrusive and shameless, just as entertaining, just as clever as any other dog."
Specific words for pain can correlate with the underlying causes of it -- and different causes point to different approaches to relief. A steroid injection might help with a slipped disk, Tylenol with injuries from a fall, a dark room with a migraine, and a hot-water bottle with a stomach ache, unless the stomach ache is caused by appendicitis, which calls for a more radical remedy. The ancients had as wondrous and occasionally questionable a mixture of notions as we have, and also knew, as we do, that not all pains respond to the same remedies. Dioscorides of Anazarbus, a first-century Greek physician, recommended treating hip pain with mountain-goat droppings on oil-soaked wool; for anesthesia, he suggested boiled mandrake root or Memphitic stone, and for migraines an unguent of roses, applied to the temples and forehead. Pliny reported the use of a mole's tooth as an aid for human toothache. Some eighteen hundred years later, Nietzsche had his migraines treated with leeches applied to his ears.
These remedies were imperfect, and the path to finding them was uncertain. In the nineteenth century, pain and fever were treated with sodium salicylate, but the drug could cause nausea and a ringing in the ears, so a chemist for Friedrich Bayer & Co. thought it would be worth trying variants on salicylic acid. He concocted the acetylsalicylic acid that we call aspirin. Other painkillers followed more zigzagging paths. In 1886, two German physicians decided to try naphthalene as a treatment for a patient with worms and a fever; the worms were unfazed, but the fever dropped. The physicians discovered that the pharmacist had accidentally given them the wrong substance, the later identification of which led to the development of acetaminophen, or Tylenol. The common epilepsy drug carbamazepine was developed to treat the shooting nerve pain of trigeminal neuralgia, which is described as feeling like a hatchet to the head and is often called the suicide pain.
Physicians today have a number of ways of categorizing pain and its causes, and the categories often overlap. Rheumatoid arthritis is an example of inflammatory pain, and also of chronic pain. Nerve damage or malfunction -- like sciatica -- is neuropathic pain, whereas the pain you appropriately feel when you close a door on your thumb is nociceptive pain. Surgery, broken bones, burns -- that's acute pain. The pain associated with cancer, and with cancer treatment, is another category. It tends not to be sufficiently ameliorated by any available drugs -- though the standard of care is to treat it with opioids.
We have tended to get in trouble when we mismatch pains and painkillers. Opioids and opiates have been particularly vexed. Historians disagree about how long humans have been using opium. One relatively early data point comes from the tenth-century Persian polymath al-Razi: "I have heard amazing accounts, amongst which is the following: the physician . . . prescribed for gout a potion prepared with two mithqals of colchicum, half a dirham of opium, and three dirhams of sugar. This drug is said to be effective within the hour, but I need to verify this." Thomas De Quincey, the nineteenth-century English essayist, famously offered a firsthand account of his laudanum addiction in "Confessions of an English Opium-Eater." One chapter is titled "The Pleasures of Opium," and another "The Pains of Opium"; he goes into the pains more extensively, the pleasures more seductively. Today, the opioids Percocet and Vicodin are often prescribed for acute pain, which they are very good at alleviating. They are also prescribed for chronic pain, which is estimated to affect around fifty million Americans. This is trickier: a meta-study has concluded that they aren't particularly helpful for such pain. They're also not much good for neuropathic pain. The not inconsequential effectiveness of placebos should be considered, too, when thinking about how best to treat pain. Patients in clinical trials are sometimes asked to keep a pain diary, and it turns out that the keeping of the diary itself can diminish the intensity of pain and improve one's mood.
The risks of addiction and overdose make prescribing opioids not unlike sending someone home with a gun. More than two million people in the United States are believed to have an opioid-use disorder, and last year more than fifty thousand died from overdoses. The risk of addiction for any particular person can't be confidently predicted, but studies show that some seven per cent of people who are prescribed opioids after an operation are still refilling their prescriptions three months later. Opioids are miserable in other ways: they leave users sleepy, confused, and constipated. But what else is there to give? "The last twenty years have been quite depressing to be a pain researcher," Todd Bertoch, an anesthesiologist who has overseen more than a hundred and fifty clinical trials, told me. "Everybody was waiting for a magic non-opioid opioid -- something that wasn't an opioid, but behaved just like one." Now, at last, there is something substantially new.
Geoff Woods, a clinical geneticist working at St. James's University Hospital, in Leeds, wasn't thinking about pain. It was the late nineteen-nineties, and he kept seeing a rare form of microcephaly -- undersized heads -- in Yorkshire's Pakistani-immigrant community, most of whom came from Mirpur. (Woods is now at Cambridge.) "They were always saying, 'Oh, we've got a cousin back in Pakistan with the same condition,' " Woods told me. Woods knew that this suggested a genetic basis. If he could see the cousins -- take their medical histories, speak with multiple family members, obtain blood samples -- he would have a better chance of identifying the underlying genes.
Woods started to spend a few weeks every year working in clinics in and around Mirpur and meeting with the extended families of his patients from Yorkshire. 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.
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.
"I assigned a team of skilled Ph.D. physiologists who worked around the clock," trying to figure out what changes the mutation produced, Waxman recalled. The neuroscientist Sulayman Dib-Hajj, also at Yale, inserted the mutant SCN9A gene into neurons. The neurons "were firing like a machine gun when they should have been silent," Waxman said. The sodium channels were too easily activated. "And suddenly we knew why these people were on fire when they should be feeling mildly warm," Waxman said. The genetic mutation associated with inherited erythromelalgia is what is called a "gain of function" mutation. There can also be "loss of function" mutations -- that's what the people who felt no pain had.