The Pain Chronicles (20 page)

A 2001 study led by Dr. Robert R. Edwards of Johns Hopkins School of Medicine tested pain tolerance in a chronic pain population of blacks and whites. His team tested 337 patients with a painful arm tourniquet procedure. African Americans showed dramatically less arm pain tolerance (whites tolerated the pain for an average of nearly nine minutes, and African Americans lasted five)
and
their increased sensitivity was found to correlate with their reports of higher levels of chronic pain as well as greater pain-related disability.

Why? Another study found that a subgroup of African Americans had significantly lower beta-endorphin levels in response to stress, which would lessen the ability to modulate pain. An alternative explanation may involve differences between black and white Americans in their central nervous systems in relation to cardiovascular and hormonal responses to stress. Pain causes the release of the stress hormone adrenaline (epinephrine), which has a variety of effects, increasing heart rate and blood pressure and intensifying the experience of pain; African Americans have been shown to have greater vascular and hormonal responses to stress than do whites, which might create more pain. Moreover, African Americans suffer from greater levels of daily stress, which may lead to greater levels of daily pain. A 2005 study at the University of North Carolina at Chapel Hill found changes in African Americans in pain-regulatory mechanisms involving blood pressure and the stress hormones cortisol and noradrenaline.

The pharmacological implications of genetic differences among ethnic groups is an emergent area of research, as drugs have traditionally been tested exclusively on Western populations. Research done on genetic samples from Tel Aviv University, for example, recently discovered that many Ethiopian Jews have a gene variation that makes them metabolize opioids and some other common drugs more quickly than other Jews, thereby putting them at risk for greater side effects.

Although the Victorians were wrong more often than they were right about the
sequence
of the links in their great chain—and Anarcha, the slave on whom J. Marion Sims honed his surgical techniques, may have been more sensitive to pain than he—the concept of a continuum of pain sensitivity turns out not to be entirely specious. But the social and moral implications of the metaphor of the chain and the algorithm employed in the calculus of suffering certainly were: while the difference in pain sensitivity between a fair maiden and a wild beast is significant, beasts nevertheless feel pain and suffer from it, and among humans, the differences are modest. With respect to pain, humans are more alike than different—and in need of treatment.

INDIVIDUAL PAIN SENSITIVITY

If certain groups are more likely to develop chronic pain, what about certain individuals? Most pain does not become chronic pain—why does some of it? Are some people genetically at risk for pain in the same way others are at risk for cancer or obesity? If so, how can we identify them and try to prevent the development of a chronic pain syndrome?

An article by Dr. Robert R. Edwards hypothesizes that individual differences in pain sensitivity and pain modulation place individuals at varying risks of suffering severe acute pain following an injury and also of suffering chronic pain. Although most studies focus on pain sensitivity, another important factor is how well an individual’s nervous system modulates pain. When repeated painful stimuli are administered close together in time, their effects become additive: each successive shock hurts more than the last as the nervous system becomes increasingly sensitive. But this effect is checked by the body’s own pain-modulatory capacities—the robustness of its descending analgesia (the brain’s ability to temporarily switch on pain-inhibiting mechanisms). In chronic pain patients, those capacities are reduced. In fibromyalgia patients, for example, the pain caused by successive noxious stimuli increases much more rapidly than in normal individuals. And while both high pain sensitivity and low pain-modulatory capacities increase an individual’s risk of developing acute and chronic pain, pain modulation seems to be the more significant factor.

Innate pain sensitivity not only makes the development of pain syndromes more likely, it also reduces the efficacy of opioid analgesics to ameliorate the syndromes (in mice as well as humans). Patients who suffer from postherpetic neuralgia (recurrent herpes that causes itchy, burning pain) also have low pain thresholds in areas of their bodies unaffected by the neuralgia, and they have been found to derive less analgesic relief from opioids than those with normal pain thresholds. Moreover, treatments that do not involve drugs (physical therapy, talk therapy, meditation, and so forth) have also been found to be less successful on pain-sensitive people.

Pain sensitivity may reflect the influence of countless factors, ranging from cultural training to personal history. Brain imaging has shown that the psychological tendency to “catastrophize”—to embroider pain with fear and anxiety—results in enhanced central nervous system activity and more pain and anxiety. Early exposure to pain has been shown to lower pain thresholds by damaging the undeveloped nervous system. Emotional trauma has also been shown to affect pain sensitivity: victims of childhood sexual abuse, for example, have higher rates of chronic pelvic pain as adults because the trauma seems to alter the way they process pelvic sensation.

There also appears to be an important—if largely unknown—genetic basis for variations in pain sensitivity. In addition to the opioid-receptor genes, there is promising research on a lesser-known gene that encodes an enzyme (catecholamine-O-methyltransferase, or COMT) that appears to modulate pain. A 2005 study published in
Human Molecular Genetics
identified three variants of the COMT gene associated with differing degrees of pain sensitivity in the laboratory, which turn out to be predictive of the chance of healthy women developing myogenous temporomandibular joint disorder (a common musculoskeletal condition involving pain and inflammation of the joint that connects the lower jaw to the skull, often called TMJ or TMD).

Another recent study concerned a gene called SCN9A that is involved in the functioning of nociceptive neurons. Severe mutations of SCN9A are known to produce both extreme pain syndromes (when they increase neuronal activity) or, in other cases, complete congenital analgesia (when they block it), but the new study showed that much smaller, more common mutations were predictive of pain scores among patients with osteoarthritis, sciatica pain, and phantom limb pain, and even affected the pain sensitivity of healthy women to a heat stimulus in a lab setting.

If individuals at high risk for chronic pain could be identified through genetic tests, many pain syndromes could be prevented through aggressive early intervention. For example, pain-sensitive individuals are more likely to experience severe pain during an initial outbreak of herpes zoster. And higher pain ratings, in turn, have been shown to be predictive of the development of postherpetic neuralgia many years later. Yet an immediate antiviral drug treatment for herpes zoster can prevent the development of the syndrome.

Knowledge of genetic vulnerability to chronic pain might influence choices about surgery. With certain surgeries, nerve-sparing techniques are available, although not always practiced. With other surgeries, such as plastic surgery, knowing the likelihood of chronic pain might make the risks outweigh the benefits. Greater pre- or postoperative analgesia might be employed, or more intense follow-up conducted.

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 equivalent 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.