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Unpacking the Hurt
What is pain? Defining something as varied and complex as pain continues to be a challenge for doctors, even as they try to improve their ability to treat it. While most experts agree it is a phenomenon of the nervous system, only in recent years have they accepted that pain isn't always traceable to a physical source. Patients with amputated limbs who still feel discomfort in the missing appendage are still hurting, for example, since their brain is registering signals, however distorted, of the sensation. The subjective experience of pain is also nearly unlimited in its variety. Pain can come and go, a bothersome reminder of a past injury; it can be dull and achy or sharp and shooting; it can be concentrated in one joint or muscle or seem to radiate throughout the body. With chronic pain, the problem is compounded, since in most cases there's no proximate cause or injury to treat. What do you do about a surgical site that healed long ago yet still causes agony? What do you do about whole-body pain that has never stopped since a round of chemo far in the past?
Part of the answer may lie in the chemicals that bathe the brain and promote communication among nerve cells. Most studies of chronic pain involve people with fibromyalgia, a condition involving abnormal pain responses that generally affects women. Chronic fatigue syndrome and back disorders can also cause constant pain, and studies of patients with all these conditions have found these individuals have more-active nerve responses, which amplify pain receptors throughout the body. This can set off the pain cascade with hair-trigger sensitivity.
Fibromyalgia patients are a case in point. They often report deep aches as well as shooting discomfort from their joints, even if they don't show signs of inflammation there. What they frequently do have, however, are lower levels of endorphins compared with those who don't suffer from the condition. This may make them more sensitive to pain. Endorphins are the body's natural morphine, and they dull pain by binding to nerve-cell receptors reserved for opiates. Also linked to mood, endorphins can contribute to feelings of euphoria and satisfaction, another mechanism by which they may divert the brain from pain.
And it's not just chemical compounds but neural circuits that may be altered in chronic-pain sufferers. For example, an adaptive mechanism in which severe pain in one area of the body inhibits pain in another is impaired among women with fibromyalgia. Normally, this system works as a check on the amount of pain the brain can handle; if your arm is sore and someone steps hard on your toe, your arm will temporarily feel better as all of your brain's pain attention is focused on the new insult. In chronic-pain patients, this mechanism is faulty or nonexistent.
Genes, too, almost certainly play a role in the response to pain. Inherited differences in the number, density and type of receptors that detect pain, as well as in the body's ability to control it, could help explain why some people feel pain more acutely than others do, as well as why one patient recovers from a knee operation without lasting effects while another never does.
But unraveling the DNA-based component of pain takes more than simply comparing the genomes of chronic-pain sufferers with those of other people and isolating the differences in their genes. That would yield an overwhelming number of potential leads mixed with a good dose of genetic red herrings. So Woolf, for one, has started small, isolating some intriguing possibilities in a species that's easier to study: the fruit fly. He has already found some painregulating genes in that simple model, and if they work the same way in humans, those genes could be manipulated with new drugs to tackle pain in a personalized, targeted way.
Such strategies may be novel and in many cases purely theoretical, but they build on a very basic understanding of human anatomy and function. The body's natural painkilling system the opioids and analgesics we all produce are the basis for our most powerful painkillers, including nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen. All of them, natural and synthetic, work by stopping pain signals from speeding along neural highways into the spinal cord and brain. But there may be a more direct way to exploit this pain-dampening system than with drugs that diffuse throughout the entire body.