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.
Woods’s and Waxman’s work suggested a potential target for a novel painkiller. Opioids target the parts of the brain that receive pain signals. A drug acting on sodium channels might mitigate the sending of pain signals.
“We know that, in radios and computers, electricity is carried by electrons through wires,” Chris Miller, a professor emeritus of biochemistry at Brandeis University, explained to me. “In biological systems, it’s carried by ions via ion channels.” Miller has spent decades studying how the channels work. “I don’t really care what these molecules do for human health—I just find them such fascinating entities. A nerve spike will zoom down an axon to the tune of one hundred metres per second.” He compared that with other bodily systems, like hormones, which effect changes over minutes to hours. It is only relatively recently that we began to understand in much detail how the channels in our nerves work. In August, 1939, the British physiologist Alan Hodgkin and his student Andrew Huxley (Aldous’s half brother) examined squid giant axons, which are up to a thousand times thicker than typical human nerve fibres and thus easier to study. Hodgkin and Huxley used fine electrodes to look for voltage differences across axons, and within a few weeks had exciting preliminary results—but then Hitler invaded Poland. Their work was put on hold for about seven years. (Hodgkin went into radar development.) In 1946, before modern computers or microelectrodes, Hodgkin and Huxley designed clever experiments from a few basic measurements that allowed them to conclude that the nerve cells must have ion channels embedded in them, regulating the flow of current. (We now know that there are channels specific to five kinds of ions—sodium, calcium, potassium, chloride, and hydrogen ions—that generate electrical signals in nerves and other cells.) “They couldn’t see the channels,” Waxman said, with admiration. “They had no idea of their structure. Yet they predicted their presence and their properties with great prescience.”
A decade earlier, an anesthetizing compound that acted on sodium channels had been found—though it wasn’t understood that it was sodium channels it was acting on. Researching a mutated strain of barley, scientists at Stockholm University tried synthesizing substances that lent the plant pest resistance. The testing method was of its time. “One of them tests a compound on his tongue, and his tongue goes numb,” John Wood, a professor of molecular neurobiology at University College London, whom Woods describes as “the doyen of sodium channels,” told me. During the war, the Swedish anesthesiologist Torsten Gordh ran a small trial using his medical students as subjects. As compensation, he offered them a choice of a copy of his Ph.D. dissertation or a pack of cigarettes. Half the students were given the compound, half were given the placebo, and most took the cigarettes. The results were conclusive: the substance killed pain. “That’s the origin of lidocaine,” Wood told me. “It’s a Swedish fairy tale.”
When applied locally, lidocaine was a marvellous anesthetic. It worked especially well for dental procedures. But, if you took enough of it to knock out pain in your whole body, it could kill you. Postwar anesthesiologists and dentists knew not to give the drug systemically, but they didn’t yet fully understand that it worked by acting on sodium channels, which are found in pain-sensing neurons, as well as in muscles in the heart, and in the brain. Lidocaine blocks all the sodium channels, everywhere in the body. Your heart muscles fail to contract, your brain goes quiet. Researchers realized that if you want to design a painkiller that you can administer systemically and safely, it needs to block only some kinds of channels, and only in specific locations.
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. Well, actually, that would be very difficult, but still. “The genetic validation for NaV1.7 was knock-your-socks-off strong,” Waxman said. NaV1.7 was the perfect target. “But there’s a catch in the story,” Wood said.
Cartoon by Natalie Horberg
Waxman’s lab started with a small trial of a drug that targeted the NaV1.7 sodium channels. Five people with inherited erythromelalgia participated. “We saw an encouraging response,” Waxman recalled. The drug advanced to a trial involving dozens of patients with other conditions at multiple sites. But, in the large trial, researchers “did not see a signal of efficacy,” Waxman said. It could be that the drug did block NaV1.7 channels, but that the dose was insufficient; or that the drug didn’t distribute to the right locations in the body; or that NaV1.7 blocking worked on some forms of pain but not others. And there was yet another possibility. “Pain is important for survival, so it makes sense that the mechanism of pain signalling has redundancy at the molecular level to make it robust,” Bruce Bean, a sodium-channel researcher at Harvard, told me. NaV1.7 was out of favor.
But it wasn’t the only promising sodium channel. A toxin found in the puffer fish, that marine creature that resembles a devilish massage-therapy ball, affects six of the nine known sodium channels. During their research into pain, Wood and his team discovered that mice in which they had disabled the gene for NaV1.8—a channel that the puffer-fish toxin does not block—felt much less pain. The researchers were thrilled. They formed a company and quickly raised eight million British pounds in support.
But they, too, encountered difficulties. Wood said, “We were all set to go into toxicity studies”—and then they ran out of money, then merged with another company, which also ran out of money. A further discouragement: by 2015, it became known that some people with Brugada syndrome, in which the heart may abruptly stop, had mutations in the gene that encodes NaV1.8. It wasn’t clear whether a substance that blocked NaV1.8 would precipitate such a problem, but it was a serious concern. “We thought, Oh, that’s no good,” Wood said. Many researchers put NaV1.8 behind them. But the cell biologist Paul Negulescu, who had started looking into it in 1998, continued working.
In college, at Berkeley, Negulescu had initially studied history. “Then, as a junior, I took a physiology class where a professor explained how the kidney worked,” he told me. “It was all about keeping sodium ions and chloride ions and potassium ions in balance.” The kidney, a tremendously under-celebrated organ, basically does four-dimensional sudoku with ions. “I was just in awe of the genius of nature. It just clicked in my head—this is amazing.” He volunteered in an ion-channel lab as an undergrad, and later, as a Ph.D. student in physiology, collaborated with the professor on research; when the professor started a company, Negulescu joined it, and in 2001 it was bought by Vertex Pharmaceuticals, where he is now a senior vice-president. In 2019, Negulescu’s team received F.D.A. approval for Trikafta, a drug for cystic fibrosis which works on the faulty chloride channels responsible for the disease. A patient who starts taking the drug as a teen-ager has a life expectancy of more than eighty years—nearly twice the span of someone whose disease is managed with supportive-care treatments only. “We like ion channels,” Negulescu said. “We think they’re really good drug targets. They just require a lot of care and attention to how you measure them.”
The papers that Wood’s team published on the role of the NaV1.8 channel in pain signalling were a major inspiration for Negulescu to turn his attention to sodium channels and pain. “Each sodium-channel type has its own personality,” he said. “They open at different voltages. They remain open for different lengths of time. They evolved to perform in certain ways in certain tissues.” NaV1.8 channels open and close up to twenty times a second. “So we had to catch them in the act,” he said.
In trying to find a molecule that would inhibit NaV1.8, one might surmise that likely compounds would have shapes similar to those of lidocaine or of other anesthetics. But, Negulescu said, “We didn’t want to rely only on our intuition about what chemical classes might work.” His team aimed to be “agnostic,” remaining open to unforeseen possibilities. This approach would not have been feasible even a few years earlier, because of limits on how many lab tests could be done in a reasonable window of time. But Negulescu’s team had developed a new technology that allowed them to screen compounds much more quickly; it was like buying tens of thousands of lottery tickets, instead of a few hundred. Eventually, they discovered a previously undescribed class of molecules that looked promising—a process that took about ten years.
Ideally, one wants a drug that is highly selective—like Cinderella’s glass slipper, it fits the intended target and not a whole range of feet—and potent. An early version of an NaV1.8 blocker developed by Negulescu’s team was selective and fairly potent. But, in drug development, adverbs like “fairly” won’t do. Years of “optimization” followed. When I asked Negulescu to explain what optimization was like, day by day, he said, “Painful. It’s iterative learning. There’s the hypothesis: this is what we think would improve the potency of the molecule, or the selectivity of it.” Synthetic chemists then make the compounds they think might improve efficacy, and the lab team tests them quickly—“within hours”—then sends the data back to the synthetic chemists. I asked Negulescu how many compounds his team screened. “Hundreds of thousands,” he said. Then he said it again. “Hundreds of thousands.” Millions were screened to find the class of molecules, and then there were another ten thousand or so screenings done in the optimization process. Negulescu recalled encountering one of the chemists holding a tray in the hallway outside a lab: “I asked him, ‘Are there some important compounds in there?’ He looked at me and said, ‘Paul, they’re all important.’ ” After more than twenty years, they had a potent and extremely selective compound, called suzetrigine. And it wasn’t making people sick. The time had come to bring it to a large-scale clinical trial.
Establishing a painkiller’s efficacy is trickier than, for example, seeing whether a blood-pressure drug is effective. There’s a reason that the McGill Pain Questionnaire had seventy-eight words. Todd Bertoch ran the Phase III clinical trials for suzetrigine. “It’s a very high bar in pain research, to show effectiveness,” Bertoch said. “Some of the drugs don’t reach that bar, not because they’re not great drugs but because the models are imperfect and our statistical approaches are imperfect.” Terms like “moderate” and “uncomfortable” don’t offer the precision of, say, 135 and 150. As Negulescu put it, “There’s no pain-o-meter.”
Two large-scale Phase III clinical trials on suzetrigine have been completed so far. One looked at 1,118 patients following an abdominoplasty, and another at 1,073 patients following a bunionectomy; both are procedures after which people experience acute pain. Participants were given either suzetrigine, Vicodin, or a placebo, and were monitored for forty-eight hours. A smaller trial looked at suzetrigine versus a placebo in two hundred and two patients with sciatica, a nerve pain. In the sciatica study, suzetrigine worked about the same as the placebo. However, for the abdominoplasty and bunionectomy patients, suzetrigine worked as well as Vicodin and better than a placebo. And more patients reported side effects on the placebo than on suzetrigine. In January, suzetrigine, under the name Journavx, became the first new non-opioid painkiller in more than twenty years to receive F.D.A. approval for acute-pain treatment.
This has occasioned enormous celebration, which can at first glance be difficult to understand, since the results seem modest: the comparison is to a relatively weak opioid, and it remains unclear if Journavx will be helpful with chronic pain, cancer pain, or neuropathic pain. Additionally, the drug costs fifteen dollars a pill. Insurance plans and assistance programs can lower the price, but it is still much more expensive than the pennies-per-pill option of a generic opioid.
Yet scientists working in pain research described the underlying scientific achievement as “a magisterial first step,” “just marvellous,” and “the holy grail.” “This proves the concept,” Waxman told me. “My expectation is that there may be next-generation medications that work even better.” Painkillers that alleviate chronic and neuropathic pain are especially needed. A Phase III clinical trial of suzetrigine for diabetic peripheral neuropathy is under way, and the F.D.A. granted the drug a Breakthrough Therapy designation for the treatment of such pain, which should speed the drug’s potential approval.
“I don’t think there’s a miracle drug that’s going to replace opioids—and suzetrigine isn’t that drug—but what we’re doing is chipping away,” Bertoch said. “Before suzetrigine, if acetaminophen and an NSAID were insufficient, my next step was a mild to moderate-strength opioid. Now I can kick the opioid can down the road.” Bertoch said that early in his career a mentor told him, about opioids, that, “as long as someone had real pain, they can’t become addicted. Obviously, that’s been proven completely wrong.” And the correction on opioid prescribing has precipitated a new problem—pain going undertreated or untreated. “We need something else to fill that gap,” Bertoch said. “We’re not just talking about addiction—we’re talking about people who are suffering and can’t get the pain medicine they need.” He went on, “Ultimately, I think we are going to be able to find a place where, if opioids are needed, it’s going to be rare.”
In the laboratory, more compounds continue to be screened. “We keep mining,” Negulescu told me. “It’s never over—there’s always more to learn.” He, too, sees suzetrigine as a kind of first step, and believes that “our future NaV1.8 molecules will probably be even more potent.” He and others are looking both at blocking NaV1.7 and at combining the blocking of NaV1.7 and NaV1.8.
Waxman has continued to follow his Man on Fire patients. He noticed something curious, which later proved revelatory. There were two mother-son pairs in which both mother and son had the same pain-causing NaV1.7 genetic mutation but the mother experienced much less pain than expected. The “pain-resilient” mothers, it turned out, had a further mutation, one that affected not a sodium channel but a potassium channel. This new channel was involved in dampening pain signals. The mothers have one mutation that makes the neuron hyperactive and another that mutes it. “So, in addition to sodium channels, which are the batteries that produce the signalling, we’re looking at potassium channels, which are the brakes,” Waxman said.
“Pain is not our enemy,” Negulescu told me. “We’re not trying to get rid of pain. But we’re trying to get rid of needless suffering.” Woods had made a similar point, in reflecting on his work with patients who can’t feel pain: “Pain has this great function. It allows you to understand what your body can and can’t do. It allows you to learn how to modulate your activities and become graceful.” Melzack, of the McGill Pain Questionnaire, considered pain “one of the most fascinating problems in psychology.” In his book “The Puzzle of Pain,” he thinks through mechanisms by which the mind might be doing its magical work of modulating pain signals. He gives the example of a football player who injures his shin while playing, but doesn’t feel pain until later, when he takes off his sock in the locker room and sees blood. It’s not mind over matter—it’s mind and matter.
And not all pain arrives as a message received from peripheral pain-sensing nerves. “More Die of Heartbreak” is one of the few novels by Saul Bellow whose title doesn’t include the main character’s name or role, making it seem as if the central character is heartbreak itself. “The only pain they ever suffer is emotional pain, which is interesting,” Woods said to me, of his patients who feel no physical pain. That’s one of the reasons he finds the diagnosis of congenital insensitivity to pain to be a bit misleading. “They know what pain is. They just don’t know what it is physically,” he said. When Woods made this observation, it at first confused me. Emotional pain and physical pain appear so categorically different that it seems odd that we use the same word to describe them. And yet the extent of the common language for emotional and physical pain is itself remarkable: crushing sadness, pangs of guilt, wrenching news, the need for something to kill the pain. In thinking about why any given person becomes addicted to opioids, we aren’t thinking only about pains for which we might first try extra-strength Tylenol. Edward Kessler writes in his poem “Pain”:
There are days when you wish your pain
Would hunker down on a toe or finger,
Some extremity you could do without,
Instead of wandering around the universe,
Calling itself fancy names like Angst. ♦