One of the most common general surgeries is a technique for hernia repair that involves severing the ilioinguinal nerve in the groin. The surgeon does the procedure and declares it a success; the patient goes home, and the surgeon never sees him or her again. But a large-scale Danish survey of prior scientific studies found that 10 percent of the patients developed moderate to severe chronic pain subsequent to the operation, and up to a quarter of the patients said that the pain restricted their daily activity. A British study found that 30 percent of the men reported chronic pain persisting more than three months after the operation. There are alternative surgical techniques that preserve the nerve, but doctors don’t understand the importance of using them, and patients don’t know to demand them.
THE CELLULAR SECRET OF THE CHRONIC PAIN CYCLE
The gap between what’s going on in the lab and among practitioners is enormous,” Dr. Clifford Woolf commented, in his soft-spoken way. “Pain management now is on the level that treatment of TB once occupied—driven by desperation on the part of the patient and the clinician.” A South African emigrant who trained as a neurologist, he is a tall, fine-boned man with a shaved head, a gentle manner, and a vaguely melancholic air. He gives the impression of being attuned to suffering. Although he does no clinical work, when he talks about pain patients, he conveys a sense of deep feeling. He hunched his shoulders against the rain in his black leather jacket as we walked toward the neuroplasticity lab he directs at Massachusetts General Hospital, curiously located in the Charlestown Navy Yard.
“This is the new frontier of medicine. What we’re learning is that chronic pain is not just a sensory or affective or cognitive state. It’s a biologic disease afflicting millions of people. We’re not on the verge of curing cancer or heart disease, but we are closing in on pain. Very soon, I believe, there will be effective treatment for pain because, for the first time in history, the tools are coming together to understand and treat it.”
In the harbor, hulking relics of yesterday’s battles still float, but inside the lab is a vast landscape of test tubes containing rat DNA, and delicate machinery with which to interpret it. The critical tools of modern pain research are the increasing sophistication of functional imaging techniques in recording pictures of brain activity (fMRIs), the completion of the human genome project, and new “gene chip” technology derived from the computer world—plastic detectors coded with an array of DNA sequences that can detect which genes become active when neurons respond to pain-causing stimuli. “In the past thirty years of pain research, we’ve looked for pain-related genes, one at a time, and come up with sixty,” Dr. Woolf said. “In the past year, using gene-chip technology, we’ve come up with fifteen hundred.” He looked more cheerful. “We’re drowning in new information. All we have to do is read it all—to prioritize, to find the key gene, the master switch that drives others.
“The psychological element to pain clinics”—teaching people how to cope with their pain—“is an admission of how poor the treatment options are. Although we know chronic pain is a disease, there’s no diagnosis or treatment protocol for it as a disease now.” Among practitioners, he added, “there’s this amorphous notion that pain is one thing and can be treated as one glob of problem.” With most problems, such as lower-back pain, it is not possible to say whether the pain is neuropathic, arthritic, or muscular-skeletal in nature. “Is the pain 25 percent peripheral, 25 percent central, 25 percent inflammatory, and 25 percent muscular? Or are the joints diseased but the nerves normal? There is only symptomatic rather than mechanistic treatment, yet the symptoms all overlay.”
He mentioned a grim truism in analgesia research known as the “30 rule”—that the existing pain drugs generally reduce pain by 30 percent in 30 percent of people—“and before we start treating them, we have no idea who is going to respond or not.” His aim is to “push the idea that there are distinct pain generators, and what we need to do is to identify them in each patient—to find the fingerprint of the underlying neurogenetic mechanism in each patient and see which one is actually operating. What is the damage to the central nervous system and how can it be repaired? What are the nervous pathways? What genes are switched on and off?”
Descriptions of the quality of the pain, such as “burning” or “aching,” do not actually reveal neuropathology: burning pain in one patient appears not to have the same mechanism as burning pain in another and does not necessarily respond to the same treatment. “Right now we can only deduce backwards who is suffering from what by how they respond to the treatment,” he said, “if they find a treatment they respond to.” Pain patients typically have to try many drugs to find one thing that works—if they find anything.
Much of the lab’s work uses rats to try to identify the cellular mechanisms of neuropathic pain. On the table the day that I visited, a graduate student was measuring pain responses in a plump white creature. First an electric shock was applied to the sensory fibers of a rat’s paw, and the firing response in the neurons of the spinal cord was measured. Then a burn injury was made elsewhere on the paw. When the same electrical stimulus was applied to the original sensory nerves, there was a much greater neural response. Moreover, the rat’s other paw became more responsive to the pain stimuli as well. The rat’s nervous system had undergone what Dr. Woolf termed a central sensitization. The nerves in the spinal cord became hyperexcitable and began spontaneously firing. This state of hyperexcitability causes the neurons to die—a phenomenon called excitotoxicity. It turned out that after a major injury to a peripheral nerve, a quarter of the cells in the spinal cord died from excitotoxicity: not only the injured neurons die, but the adjacent ones as well. Dr. Woolf believes that excitotoxicity is a critical feature of neuropathic pain because—bad luck—many of the neurons that die are inhibitory ones, whose function is to dampen pain.
“The loss of the normal brakes in the nervous system that inhibit pain signals creates disinhibition—a persistent amplification of pain,” he said. “If we could identify the missing inhibitory signals, perhaps we could introduce them as a drug.”
Terrifyingly, it is not only the spinal cord but also the brain that can be pathologically reordered by pain. Dr. Woolf bred a particular strain of rat to be prone to pain sensitivity. Then he injured the rats’ sciatic nerves. Ten days later, when he cut open the rats’ brains, he could discern the imprint of the nerve injury: corresponding maladaptive changes in the way the rats’ brains process and generate pain. “In animal models, anytime there is an injury to a major nerve branch, this nasty cortical reorganization occurs,” he said.
What about humans? Work done by Dr. A. Vania Apkarian at Northwestern University found that chronic pain causes degeneration in parts of the human brain in a way that he speculates is due to “overuse atrophy”—death of neurons owing to excitotoxicity and inflammatory agents (as had been previously found in the spinal cord). He also found that chronic pain appears to diminish cognitive abilities and interfere with parts of the brain (specifically areas of the prefrontal cortex) that are involved in making emotional assessments, including decision making, and in controlling social behavior.
One of Dr. Apkarian’s studies contrasted brain images of normal subjects with those of twenty-six patients who had suffered from unrelenting chronic back pain for more than a year (with the typical pain patient having had pain for five years). Back pain is the most common pain syndrome next to headache: a quarter or more of Americans report suffering from back pain in the prior three months, and for a quarter of those, the pain becomes severe and chronic. The scans revealed that chronic pain had dramatically reduced the gray matter of the patients’ brains. (The amount of gray matter in certain areas of the brain is correlated with intelligence; it contains neurons that process information and store memory.) While normal aging causes gray matter to atrophy by half a percent a year, the gray matter of chronic pain patients atrophies dramatically faster: the pain patients showed losses amounting to between 5 and 11 percent, the equ
ivalent often to twenty years of aging.
Normal aging processes differ from the process associated with chronic pain, in a particularly disturbing way. Where aging causes atrophy in many regions of the brain, chronic pain specifically atrophies those parts of the brain whose job is to modulate pain (the thalamus and parts of the prefrontal cortex). Both neuropathic and inflammatory pain were associated with decreases in gray matter density, but neuropathic pain had a distinct and much greater impact on the brain. The loss in brain density seemed related to pain duration, with 1.3 cubic centimeters of gray matter being lost for every year of chronic pain. When asked, Dr. Apkarian estimated that the chronic pain patients would lose roughly twice as much gray matter per year as the normal subjects.
Here, finally, I realized, is the secret of the chronic pain cycle, why it worsens over time without new nerve or tissue damage: pain causes changes in the brain that diminish the parts of the brain charged with modulating pain, which results in an increase in pain, which further atrophies the brain . . . and so forth. “As atrophy of elements of the circuitry [of the brain] progresses, the pain condition becomes more irreversible and less responsive to therapy,” the study ominously concluded.
If my own brain had lost 1.3 cubic centimeters of its gray matter for each year I had pain, then it would have lost . . . what percent by now? How many extra years had pain aged my brain? The thalamus and prefrontal cortex—the parts of my brain that were supposed to modulate pain, the parts of my brain with which I was trying to understand pain . . .
I couldn’t bear to complete the calculation.
THE WONDERFUL DREAM THAT PAIN HAS BEEN TAKEN AWAY FROM US
How can such a syndrome be prevented? Dr. Woolf has some ideas about molecular agents he believes may be critically involved in inciting or sustaining neuropathic pain. For example, he said, in animal models there are certain abnormal sodium ion channels that appear and become activated only in the damaged sensory neurons. There are also sodium channels involved in inflammatory pain that help determine the excitability of nerve fibers or pain fibers in the vicinity of the damaged tissue. If the critical molecular components in different types of chronic pain could be identified, then an antagonist might be found and introduced as a drug.
Would “the wonderful dream that pain has been taken away from us,” which was trumpeted at the invention of anesthesia, finally, then, be true? Would such a drug help all the people who already have this pain—or only prevent others from developing it? Can the cortical reorganization be reorganized, the gray matter un-atrophied, the damage to the central nervous system repaired? After all, neuroprotective drugs can’t protect neurons that have already died, and neurons cannot regenerate. What about Lee Burke, and the babies circumcised without anesthesia? What about me?
Dr. Woolf looked at me and hesitated, as if wondering just how unwelcome the news would be. “We don’t really know,” he said tactfully. Another pause. “Not in the present state, no.” But even if the damage cannot be undone, he pointed out, treatment might still help suppress the abnormal sensitivity. “But obviously it’s going to be much easier to prevent the establishment of abnormal channels than to treat the ones already there.” He rested his head against his hand. “Obviously.”
I glanced out the window and tried to make out the shapes of the ships in the harbor through the rain. But just then pain radiated down my shoulder and into my hand, so swiftly I dropped my pen on the tabletop. I thought of the Righteous Sufferer.
Head pain has surged up upon me from the breast of hell . . .
A demon has clothed himself in my body for a garment . . .
I asked about pain’s relationship to meaning.
Dr. Woolf blinked, surprised, and then scrunched up his face as he recalled a lecture given to the Harvard Medical School by Divinity School faculty on the religious meanings of pain.
“Imagine how foreign that point of view was to me,” he said, shaking his head disapprovingly at the memory.
“But pain feels meaningful,” I suggested timidly, “like a riddle or a dream.”
“That’s crazy,” he said forcefully. “That’s like the myths about TB we were talking about. Chronic pain is not some”—he searched for the right word—“code. It is a terrible, abnormal sensory experience, pathological activity in the nervous system.”
Could these science terms, still so foreign in my mouth, become mine? Could the demon that clothed itself in my body turn into excitotoxicity and overuse atrophy? Cervical spondylosis and spinal stenosis and impingement syndrome—if I truly believed that’s what it was and that’s all it was—would be far less alarming than a curse, a punishment, a private sorrow, a symptom of aloneness, an inexplicable blight, or any of the myriad unhappy ways I understood and experienced and expressed my condition.
Would it also be less painful?
Seven years later, Dr. Woolf—newly appointed director of the neurobiology program at Children’s Hospital in Boston—was replete with good news. His group had recently discovered a drug combination they are working on to develop into a pain-specific local anesthetic—an anesthetic, that is, that would act only on pain nerves and not affect the motor and autonomic nerves the way the current ones do. Such an anesthetic could potentially allow a person, for example, to go to the dentist and eat a pastry afterward, because the mouth muscles would be unaffected, or enable a woman to feel no pain during labor yet still register other sensations in her uterus and retain command of the muscles needed to focus her pushing.
The common local anesthetic lidocaine works by generally depressing the activity of all neurons. But by combining a derivative of lidocaine with capsaicin (the substance that makes chili peppers burn your mouth by binding to the pain receptors that detect burning), Dr. Woolf was able to target the lidocaine derivative into the pain neurons through the channel opened by capsaicin while leaving the other neurons unaffected. His work has been done on rodents, but he has licensed the idea to a pharmaceutical company that is preparing to begin human trials.
Most of Dr. Woolf’s lab’s work of recent years, however, has focused on decoding the genetics of neuropathic pain. “It is clear that pain is a complex disease, involving lots of different genes. We’ve been able to identify several key players,” he said, sounding—in his low-key way—distinctly pleased. “It looks like about 50 percent of variation in neuropathic pain sensitivity is heritable,” he told me.
Some pain research has focused on obscure pain-related genes, looking at interrelated families in Saudi Arabia or Pakistan. Such work has led to the identification of the genetic mutations responsible for the rare, bizarre disease congenital insensitivity to pain, which is marked by the inability to feel physical pain. Dr. Woolf’s group has focused instead on the common genes found in different variants throughout the population. He recently identified a gene that produces an enzyme called GCH1 (GTP cyclohydrolase), which is a key modulator of pain sensitivity; one variant of this gene is significantly protective against the development of neuropathic pain.
Can the action of the pain-protective gene variant be copied and introduced as a drug for those who lack it? (Enroll me in that trial!) The gene variant inhibits excessive production of a substance called BH4 (tetrahydrobiopterin), which plays a critical role in pain sensitivity and persistence, with greater amounts of BH4 causing greater sensitivity to pain. Fifteen percent of the population has the lucky gene variant that most strongly limits BH4 production and makes people less susceptible to developing persistent neuropathic pain—and makes healthy humans significantly less sensitive to acute pain in lab experiments.
Dr. Woolf has identified a gene substitute—an agent that inhibits the production of BH4—which he is attempting to develop into a drug. Of course, there can be a long road between discovering a substance that does the job molecularly, so to speak, and turning it into a drug (the substance may be unstable or toxic, or it may dissolve too quickly in the body, or someone else might own the intellectual property!). But the
first step has been taken.
Pain Diary:
I Try to Understand Science
BAD NEWS
nociception
pain-sensitivity gene
hyperalgesia, allodynia
central sensitization, peripheral centralization
excitotoxicity, overuse atrophy
cellular pain memory
cortical reorganization
gray matter shrinkage, neuronal loss, atrophy of the circuitry
the pain that pain spawns is ever more malign
GOOD NEWS
developing pain-nerve-specific analgesia
pain-protective gene
agent that mimics pain-protective gene action
hope agent can be turned into drug
the wonderful dream that pain has been taken away from us
IV
FINDING A VOICE:
Pain as Narrative
FINDING A VOICE
Physical pain has no voice, but when it at last finds a voice it begins to tell a story,” Scarry writes, expressing the paradox of the relation between disease and the narrative it inevitably becomes. Pain has no voice. Why, then, does it seem to speak?
When Hippocrates instructed physicians to treat the patient rather than the disease, it was because physicians did not understand disease. Now that science has shown that pain is a biological disease, to treat it otherwise would seem to do the sufferer a disservice: to personalize it, to see it as a state of being (which is what it feels like) rather than a state of the nervous system.
Yet, as lived experience, the disease of pain turns into the individual suffering of illness, an understanding of which requires studying the patient as well as the disease. Recall Foucault’s neat formulation that modern medicine began when the doctor switched from soliciting an illness narrative—“What is the matter with you?”—to asking the medical question “Where does it hurt?” Alas, that insight does not finally or perfectly illuminate pain. For better and for worse, the nature of the person in pain bears on the nature of the pain itself.
The Pain Chronicles Page 19