Taking A New Look At Pain

There are moments in medical history when science morphs into magic. Few are as vivid as Oct. 16, 1846, the day Gilbert Abbott, a Boston printer, walked into Massachusetts General Hospital, lay down on a surgical table and, after breathing in a mysterious chemical called ether, became the first human being to go under the knife without feeling a shred of pain. As doctors and medical students looked on from narrow wooden seats in the operating theater, surgeon John Collins Warren sliced into Abbott's jaw and removed a tumor. Abbott slept through it all. "Gentlemen," Warren said to his audience, "this is no humbug." In an instant, anesthesia was born, and surgery entered a new era. Said the People's Journal of London: "We have conquered pain."

If only it were that simple. Surgery may not hurt the way it used to, but pain remains a blight on countless lives. In its many guises--migraine, arthritis, back pain--it causes more disability than cancer and heart disease combined. The psychological effects can be devastating, ranging from depression to anxiety and sleeplessness. And the annual cost, including treatment and lost workdays, now hovers around $100 billion in the United States. No wonder the medical world is so keen on the problem. Patients are demanding that pain be seen as a condition unto itself, not just a byproduct of injury or illness. Congress, for its part, recently declared this the "Decade of Pain Control and Research."

Thanks to advances in brain science and medical technology, the research is exploding. Harnessing high-tech imaging equipment and stunning advances in genomics, scientists are detangling the pain system at its molecular level. Researchers are isolating genes associated with pain and uncovering the influences of emotion and gender. Specialists are devising more targeted treatments. And engineers are creating more efficient drug-delivery systems. Scientists envision a day when a simple test will help diagnose pain and medications will be tailored to individuals. "It's a heady time," says Dr. Michael Salter, head of the University of Toronto Center for the Study of Pain. "We're in the middle of a revolution."

In its most basic and acute form, pain can be a force for good. Sip a cup of burning coffee, and your tongue fires off a message to your brain; you wince, then slow down, sparing your cells further damage. You may think it would be nice to never feel pain again. But consider the fate of people with the rare condition called congenital analgesia. Born with no innate pain sensors, they spend their lives struggling to survive cuts, burns and even latent bouts of appendicitis. Most die young, from injuries or infections that flourish in joint tissue destroyed by repetitive damage. By enduring brief bouts of misery, the rest of us are spared the real danger: feeling no pain at all.

But chronic pain, which can linger for months, years, even a lifetime, is a very different matter. This is the torment of rheumatoid arthritis, cancer and mysterious nerve damage, which may have no identifiable cause at all. Nobody can describe the agony better than those who bear it. After Cynthia Toussaint, now 42, tore her hamstring 21 years ago, she developed a body wide pain disorder called reflex sympathetic dystrophy syndrome, which left her bedridden for almost a decade. "It feels like I've been doused with gasoline and lit on fire," she says. Lisa Scott, 41, says the migraines she's battled for 20 years are like "a glowing, hot railroad spike in my head."

How does the body create such excruciating sensations? Twenty-five years ago, medical students were taught that chemical messengers traveled on a one-way "pain pathway" starting at the spinal cord and dead-ending at the brain. Today's experts bristle at that simplicity. Dr. Scott Fishman, chief of the division of pain medicine at the University of California, Davis, describes pain as "a symphony"--a complex dynamic involving not only pain sensors but emotions, memory and hormones.

The sensation starts in cells called nociceptors, which respond to injury by sending electrical messages to an area in the spinal cord called the dorsal horn. Here, in this gateway for pain, neurotransmitters and other chemicals relay a signal to the brain--the immediate "ouch." The brain interprets the message and then responds by unleashing an army of painkilling suppressors called endorphins or endogenous opioids, as well as other chemicals such as norepinephrine, to damp down the hurt. Scientists are only now beginning to appreciate the vast array of players involved in both of these processes. When the peptide substance P was isolated as a pain transmitter 30 years ago, it was treated as an only child. It's now known to be one in a cast of hundreds, including chemicals involved in memory and depression as well.

Just how these players interact depends on a host of factors: how serious the pain is, whether there's some sort of imminent threat, even what kind of a mood you're in that day. If, for example, you're hurt while being chased by wild animals or playing professional football, your brain will pump out higher levels of painkilling chemicals, softening the agony so you can make it out of danger or into the end zone.

The very system that works on your behalf, however, can also break down, which is why people like Cynthia Toussaint end up in chronic pain. What exactly goes wrong is a multilayered mystery, but scientists have teased out several important mishaps. After an injury, your spinal cord maps out the location, then recruits healthy cells in the same neighborhood to help their injured friends. Eventually, as the damage heals, the neighbors can go back to normal life. But problems arise when those healthy cells get stuck.

There can be trouble, too, back in the dorsal horn, where our body's two sensory nervous systems meet. One, our high-threshold system, registers cuts and burns; the other logs everyday sensations, like the way this paper feels on your fingers. Normally, the two systems live in separate dorsal quarters. But after nerve injury they --commingle, confusing the high-threshold pain with the low. That's why those who suffer from shingles can't bear the touch of light clothing--a mild sensation gets ratcheted up to an abnormal frequency. "This is where the symptom of pain becomes the disease of pain," says Fishman.

We all come equipped with the same basic nerve fibers, neurotransmitters and brain structures, but our pain systems can behave in radically different ways, depending on circumstance, gender and heredity. It is no revelation that people have different thresholds for pain. You might be able to keep your hand submerged in ice water for a few minutes, while your friend will be out in seconds. Using sophisticated brain-imaging equipment, scientists can now see those variances in action. Dr. Jon-Kar Zubieta and colleagues at the University of Michigan injected small amounts of salt water into the jaw muscles of a group of healthy volunteers, simulating temporo-mandibular joint pain, or TMJ. As the participants rated their pain, researchers watched their brains activate painkilling chemicals on positron emission tomography (PET) scans. The images confirmed not only the relationship between how much pain a person feels and his brain's response, but also the dramatic disparity from one person to the next.

An individual's own reaction to pain can also change enormously, depending on concentration or mood. A parent who kisses a child's boo-boo and offers an ice-cream cone knows intuitively that distraction will melt the tears away. Now scientists are seeing that process come alive on brain scans. At McGill University in Montreal, Dr. Catherine Bushnell has found that when volunteers are subjected to heat probes, their brains duly register pain. But when the same people are distracted by digital sounds, the signals are dampened and the two brain images--one bright, one dim--look nothing alike. Now Bushnell is testing the effect of odors--good ones, like perfume and cookie dough, and not-so-good ones. She's found that when volunteers smell something they like, their mood improves and their pain becomes less unpleasant, even though the intensity of the thermal probe hasn't changed. "Your psychological state can clearly change the way pain is processed in the brain," says Bushnell. "We can have some control over our pain in a way that we don't necessarily realize."

Anyone who has accused the other sex of being wimpy about pain won't be surprised to learn that gender and hormones appear to play a critical role, too. In general, women tend to report more severe and persistent pain than men. So Zubieta's team compared women's response to pain early on in their menstrual cycles, when hormone levels are low, and then again with the boost of an estrogen patch. Their findings: women's painkilling systems were much more active on estrogen and their response to pain less pronounced. The genders differ when it comes to treatment, too, at least in the case of a class of painkillers called kappa opioids, which appear to be more effective in women than in men. Jeffrey Mogil, a pain expert at McGill, recently reported that he'd found a culprit--a gene --called melanocortin-1, which somehow increases sensitivity to kappa opioids and, interestingly, is also responsible for red hair and fair skin. In a pain test, men and women of all hair colors felt similar distress. But female redheads did a lot better on the drugs. "The data suggest that males and females use different circuitry to modulate pain," says Mogil.

The isolation of genes linked to pain brings a vast new understanding of how individual responses are triggered. Zubieta's team discovered that a small variation in a gene called COMT, which helps regulate the brain chemicals dopamine and noradrenaline, separates the sensitive from the steadfast when it comes to putting up with pain. Among the gene's many amino acids are two called valine (or "val") and methionine ("met"). People who had two copies of val dealt with jaw pain far better than those with two copies of met. And brain scans confirmed that their painkilling systems were more active in getting rid of the anguish.

The discovery of pain-related genes opens up a new frontier for drug development. Last year Toronto's Salter found that genetically engineered mice that lacked a gene called DREAM were far less sensitive to pain than mice who had the gene. Biotech companies are, of course, eager to exploit such discoveries. The goal is to develop new drugs that attack specific chemical processes in pain, instead of launching a full-body assault. Researchers believe that one day treatments will vary by individual. "About 10 years from now," says Dr. Christian Stohler, a collaborator of Zubieta's and dean of the University of Maryland's dental school, "your physician will examine your genomic makeup and then prescribe a drug that will work for you." And that pill, says Mogil, will "likely be blue or pink," depending on your sex.

The focus today is on enhancing current treatments. Doctors now use antiseizure drugs to calm overactive nerves in conditions like shingles. Opioids such as morphine and fentanyl are still the most powerful antidotes to the severe pain of cancer, but they have serious side effects, like constipation, nausea and physical dependence. New delivery systems carry the promise of making them less burdensome. Fentanyl now comes in a "lollipop" form called Actiq. Endo Pharmaceuticals is testing a matchstick-size capsule that could provide three months' relief when implanted under the skin. Pain Therapeutics is testing opioids that contain minute amounts of naltrexone, a drug that blocks addiction. And Aradigm has devised an opioid inhaler with a magnetic lock, opened only by a bracelet or set of keys prescribed to the patient.

Even the giddiest scientist knows that the journey from lab to clinic is long and unpredictable. But experimental techniques are chipping away at pain. Not far from Mass General's now silent "Ether Dome," patients like Lee Hartford, 48, receive a promising new treatment for intractable spinal-disc pain. In less than an hour, doctors snake a coil around Hartford's irksome disc and heat it to almost 200 degrees Fahrenheit to strengthen tissue and destroy the nerve fibers shooting pain messages to the brain. The procedure's long-term benefits are still unknown, but after 15 years of knee-buckling back pain, Hartford is optimistic. Within weeks of the operation, he utters the words that every pain sufferer lives for. "I feel good," he says.

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