by Atul Gawande
Other studies along these lines have shown that extroverts have greater pain tolerance than introverts, that drug abusers have low pain tolerance and thresholds, and that, with training, one can diminish one’s sensitivity to pain. There is also striking evidence that very simple kinds of mental suggestion can have powerful effects on pain. In one study of five hundred patients undergoing dental procedures, those who were given a placebo injection and reassured that it would relieve their pain had the least discomfort—not only less than the patients who got a placebo and were told nothing but also less than the patients who got a real anesthetic without any reassuring comment that it would work. Today, it is abundantly evident that the brain is actively involved in the experience of pain, and is no mere bell on a string. Today, every medical textbook teaches the Gate-Control Theory as fact. There’s a problem with it, though. It doesn’t explain people like Roland Scott Quinlan.
Gate-Control Theory accepts Descartes’s view that what you feel as pain is a signal from tissue injury transmitted by nerves to the brain, and it adds the notion that the brain controls a gateway for such an injury signal. But in the case of Quinlan’s chronic back pain, where is the injury? Or take something like phantom-limb pain. After amputation of a limb, most people suffer a period of constant, intractable burning or cramping that feels exactly as if the limb were still there. Without a limb, however, there are no nerve impulses for the gate to control. So where does the pain come from? The rope and clapper are gone, but the bell can still ring.
One spring day in 1994, Dr. Frederick Lenz, a neurosurgeon at the Johns Hopkins Hospital, brought to his operating table a patient suffering from severe hand tremors. The patient, whom I’ll call Mark Taylor, was only thirty-six, but over the years his hands had come to shake so violently that the simplest of tasks—writing, buttoning his shirt, drinking from a glass, or typing on his keyboard at his job as a purchasing agent—grew absurdly difficult. Medications failed, and he lost jobs more than once because of his difficulties. Desperate for a return to a normal life, he agreed to a delicate procedure: brain surgery that would destroy cells in a small structure called the thalamus, which was already known to contribute to such excessive stimulation of the hands.
Taylor had another big problem, though: for seventeen years, he had struggled with a severe panic disorder. At least once a week, while he was working at his computer terminal or was at home in the kitchen feeding a child, he would suddenly be overcome by severe chest pains, as if he were having a heart attack. His heart would pound, his ears would ring; he would grow short of breath and would have an overwhelming urge to escape. Nevertheless, a psychologist Lenz consulted assured him that the disorder was unlikely to hinder the operation.
Initially, Lenz says, everything went as he had expected. He injected a local anesthetic—the operation is done with the patient awake—and burred a small opening in the top of Taylor’s skull. Then he cautiously inserted a long, thin electrical probe deep inside, right down into the thalamus. Lenz talked to Taylor the whole time, asking him to stick out his tongue, to move a hand, to do any of a dozen other tasks that showed he was all right. The danger in this type of surgery is that it might destroy the wrong cells: the thalamic cells involved in tremor lie just fractions of a millimeter away from cells that are essential for sensation and motor activity. So before cauterizing with a second, larger probe, the surgeon had to find the right cells by stimulating them with a gentle electric pulse. The probe was in a portion of Taylor’s thalamus that Lenz labeled Site 19, and he zapped it with low voltage. He had been here a thousand times before, and typically, he told me, zapping the site makes people feel a prickle in the forearm. Sure enough, this is what Taylor felt. Lenz then zapped an adjacent area he labeled Site 23, where stimulation generally produces a mild and very ordinary tingling in the chest. This time, however, Taylor felt an unexpectedly far more harsh pain—in fact, the exact chest pain of his panic attacks, along with the suffocation and instant sense of doom that always accompanied them. It made him cry out and nearly leap off the table. When Lenz stopped the stimulation, however, the sensation disappeared, and Taylor became instantly calm again. Puzzled, Lenz zapped Site 23 once more, and found that doing so produced the same effect again. He stopped, apologized to Taylor for the discomfort, and went on to locate the cells controlling his tremor and to cauterize them. The operation was a success.
Yet even as Lenz completed the procedure, his mind was racing. Only once before had he seen anything like this kind of effect. It was in a sixty-nine-year-old woman with a long history of difficult-to-manage anginal pain that came on not only with strenuous activity but even with mild physical exertion that wouldn’t be expected to stress her heart. Performing a similar operation on her, Lenz found that stimulating the microscopic section of her brain that usually triggered mild chest tingling had instead, as with Taylor, brought on her more severe and familiar chest pain—a sensation she described as “deep, frightful, squeezing.” The implications might have easily been lost, but Lenz had spent many years researching pain and realized that he had witnessed an important and telling effect. As he later noted in a report published in the journal Nature Medicine, the response in these two patients was wildly out of proportion to the stimulus. What in most people produces no more than a tingle was torture to them. Areas of the brain governing ordinary sensations appeared to have become abnormally sensitized—set to fire in response to perfectly harmless stimuli. In the woman’s case, her chest pain had begun as a signal of her heart disease but now appeared in circumstances that did not reflect anything like an impending heart attack. Even more oddly, in Taylor’s case, the pain had not begun with any such bodily damage, but with his panic disorder, which is understood to be a psychological condition. Lenz’s findings suggest that, in fact, all pain is “in the head”—and further that sometimes, as with Mark Taylor or perhaps Roland Scott Quinlan, no physical injury of any kind is needed to make the pain system go haywire.
This is the newest theory of pain. Its leading proponent is, once again, Melzack, who abandoned Gate-Control Theory in the late 1980s and began telling incredulous audiences to revise their understanding of pain once again. Given the evidence, he now says, we should stop thinking that pain or any other sensation is a signal passively “felt” in the brain. Yes, injury produces nerve signals that travel through a spinal-cord gate, but it is the brain that generates the pain experience, and it can do so even in the absence of external stimuli. If a mad scientist reduced you to nothing but a brain in a jar, Melzack says, you could still feel pain—indeed, you could have the full range of sensory experience.
According to the new theory, pain and other sensations are conceived as “neuromodules” in the brain—something akin to individual computer programs on a hard drive, or to tracks on a compact disc. When you feel pain, it’s your brain running a neuromodule that produces the pain experience, as if someone pressed the PLAY button on a CD player. And a great many things can press the button (besides a neurosurgeon zapping the right neuron with low DC voltage). The way Melzack explains it, a pain neuromodule is not a discrete anatomical entity but a network, linking components from virtually every region of the brain. Input is gathered from sensory nerves, memory, mood, and other centers, like members of some committee in charge of whether the music will play. If the signals reach a certain threshold, they trigger the neuromodule. And then what plays is no one-note melody. Pain is a symphony—a complex response that includes not just a distinct sensation but also motor activity, a change in emotion, a focusing of attention, a brand-new memory.
Suddenly, a simple toe-stubbing no longer seems so simple. In this view, the signal from the toe still has to make it through the spinal-cord gate, but thereafter it joins a lot of other signals in the brain—from memories, anticipation, mood, distractions. Altogether, they may combine to activate a toe-pain neuromodule. In some people, however, the physical stimulus may be canceled out and the stubbed toe hardly noticed. There’s nothing s
urprising here so far. But now we can imagine—and this is the most radical implication of Melzack’s ideas—that the same neuromodule can go off, generating genuine toe pain, without a toe’s having been stubbed at all. The neuromodule could—like Site 23 in Mark Taylor’s brain—become primed like a hair trigger. Then virtually anything could set it off: a touch, a stab of fear, a sudden frustration, a mere memory.
The new theory about the psychology of pain has, almost perversely, helped give direction to the pharmacology of pain. For pharmacologists, the Holy Grail of chronic-pain treatment is a pill that would be more effective than morphine but lack its side effects, such as dependence, sedation, and motor impairment. If an overactive neuronal system is the problem, then what one needs is a drug that will damp it down. That’s why, in what a decade ago might have seemed a strange development, pain specialists increasingly prescribe anti-epileptic drugs, like carbamazepine and gabapentin, for their most difficult-to-treat patients. After all, that’s what these drugs do: they tune brain cells to modulate their excitability. So far, these kinds of drugs work only for some people—Quinlan has been on gabapentin for more than six months without much effect—but drug companies are hard at work on a new generation of similar “neuro-stabilizing” compounds.
Neurex, for example, a small Silicon Valley biotechnology company (now called Elan Pharmaceuticals), not long ago designed a pain drug from the venom of the Conus sea snail following such thinking. Venoms are, needless to say, biologically potent, and, unlike most of the proteins from nature that scientists have tried to use as drugs, they evade the body’s mechanisms for breaking proteins down. The trick is to tame the venom, to modify it so it is medically useful. The Conus venom was known to kill by blocking specific pathways in the brain that are necessary in order for neurons to fire. With a few alterations, however, Neurex scientists created Ziconotide, a drug that only slightly inhibits those pathways. Instead of shutting brain cells down, it seems to merely mute their excitability. In initial clinical trials, Ziconotide effectively controlled chronic pain from cancer and from AIDS. Another new generation analgesic in development is Abbott Laboratories’ ABT-594, a compound related to a poison secreted by an Ecuadorian frog, Epibpedobates tricolor. In animal experiments that were published in the journal Science, ABT-594 proved to be as much as fifty times as potent as morphine in relieving pain. Companies have other pain drugs in the pipeline, too, including a class of drugs known as NMDA antagonists, which also work by reducing neuronal excitability. One of these could turn out to be the painkiller that Quinlan and patients like him are looking for.
At best, however, these drugs represent only a halfway solution. The fundamental problem for research is how to stop the pain system in such patients from going haywire in the first place. The stories that people tell of their chronic pain typically start with an initial injury. So, historically, we have tried to prevent chronic pain by preventing acute strains. A whole ergonomics industry has developed around this idea. Yet the lesson from Ross’s pain clinic and Lenz’s operating table is that the antecedents of pain lie elsewhere than in the muscle and bone of patients. In fact, some forms of chronic pain behave astonishingly like social epidemics.
In Australia during the early 1980s, workers—particularly keyboard operators—experienced a sudden outbreak of disabling arm pain, which doctors labeled “repetition strain injury,” or RSI. This was not a mild case of writer’s cramp but a matter of severe pain, which started with minor discomfort during typing or other repetitive work and progressed to invalidism. The average time that a sufferer lost from work was seventy-four days. As with chronic back pain, no consistent physical abnormalities or effective treatment could be found, yet the arm pain spread like a contagion. It had hardly existed before 1981, but by its peak, in 1985, enormous numbers of workers were affected. In two Australian states, RSI disabled as much as 30 percent of the workforce in some industries; at the same time there were pockets of workers who were almost entirely unaffected. Clusters appeared even within a single organization. At Telecom Australia, for example, the incidence of RSI among telephone operators in a single city varied widely between departments. Nor could investigators find any connection between RSI and the physical circumstances of the workers—the actual repetitiveness of their jobs or the ergonomics of their equipment. Then, as suddenly as it had begun, the epidemic crashed. By 1987, it was essentially over. In the late 1990s, Australian researchers were complaining that they couldn’t find enough RSI patients to study.
Chronic back pain has been with us for so long that it is hard conceptually—and even politically—to step back and recognize its social etiology, let alone figure out how cultural factors make an individual’s pain system go awry. The Australian pain epidemic demonstrates the power of those factors to cause genuine, disabling pain on a national scale, and yet our knowledge of these causes and how to control them is meager. We know from a variety of studies that social-support networks—a happy marriage and satisfying employment, say—protect against disabling back pain. We know, statistically speaking, that being given certain diagnostic labels and being provided disability pay (and thus a kind of official recognition and validation) can perpetuate chronic pain. In Australia, for example, many researchers believe that two major factors that sparked the epidemic were the coining of RSI as a diagnostic label and early action by the government to insure compensation for the syndrome as a work-related disability. When the diagnosis fell out of favor with physicians, and disability coverage became harder to get, the incidence of the symptoms associated with the disorder plummeted. It also appeared that initial publicity about the possible portents of arm pain and concerted campaigns in some places to increase the reporting of arm pains or to institute ergonomic changes only contributed to the epidemic. More recently, in the United States, a debate has erupted over the origins of a similar workplace epidemic, called, variously, repetitive-stress injury, repetitive-motion disorder, and—in the currently favored nomenclature—cumulative-trauma disorder. Once again, the salient risk factors seem to be social rather than physical.
Back and arm pain are not unique in having nonphysical causes. Studies have shown that social conditions play a dominant role in many chronic-pain syndromes, including chronic pelvic pain, temporomandibular-joint disorder, and chronic tension headache, to name just a few. Again, none of this should be taken to mean that people are faking it. As Melzack’s account suggests, pain that doesn’t arise from physical injury is no less real than pain that does—in the brain it is precisely the same. And so a compassionate approach toward chronic pain means investigating its social coordinates, not just its physical ones. For the solution to chronic pain may lie more in what goes on around us than in what is going on inside us. Of all the implications of the new theory of pain, this one seems to be the oddest and the most far-reaching: it has made pain political.
A Queasy Feeling
In the beginning, the nausea didn’t seem anything to worry about. Amy Fitzpatrick was eight weeks pregnant—with twins, as an ultrasound had revealed—and, having watched her sister and her friends go through their pregnancies, she understood that nausea was simply part of the deal. Her first episode was certainly inconvenient, though. She was on New York City’s F.D.R. Drive, piloting her Honda Civic to work through the frantic rush of morning traffic. Speeding along at fifty miles per hour, she realized that she was about to throw up.
Fitzpatrick was twenty-nine years old, tall, with long, thick black hair set against pale Irish skin and a dimpled, almost teenage face that sometimes made it hard for people to take her seriously, despite her Wharton M.B.A. She lived in Manhattan, where her husband was an investment banker, and she commuted to Manhasset, on Long Island, where she worked as a management consultant for the North Shore Health System. It was a brisk March morning, and she needed to find somewhere to pull over fast.
As she got off the F.D.R. onto the ramp to the Triborough Bridge, her head was swimming and her stomach was roiling. She w
as in what scientists call the “prodromal phase of emesis.” Salivation increases, sometimes torrentially. The pupils dilate. The heart begins to race. The blood vessels in the skin constrict, increasing pallor—NASA scientists have even used skin sensors to detect space sickness in astronauts, who are sometimes reluctant to admit experiencing nausea. People break out in a cold sweat. Fatigue and often drowsiness occur in minutes. Attention, reflexes, and concentration wane.
While all this is going on, the stomach develops abnormal electrical activity, which prevents it from emptying and causes it to relax. The esophagus contracts, pulling the upper portion of the stomach from the abdomen, through the diaphragm, and into the chest, forming a kind of funnel from stomach to esophagus. Then, in a single movement, known as the “retrograde giant contraction,” the upper small intestine evacuates its contents backward into the stomach in preparation for vomiting. In the lower small intestine, smaller rhythmic contractions push the contents into the colon.