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Biomedicine

The Brain in Chronic Pain

Sophisticated brain-imaging studies suggest new ways to treat chronic pain.

Anyone who suffers from chronic pain knows that the experience is fundamentally different from enduring a scratch or a broken toe. Growing evidence from brain-imaging studies supports this notion: people with chronic pain show fundamental differences in both the structure and function of their brain. Scientists are now using these findings to develop and test new drugs created specifically for chronic pain.

Pain relief: Imaging studies have indentified brain areas gone awry in people with chronic pain.

“It should eventually be possible to identify patterns of brain activity involved in perpetuating chronic pain, and then to introduce interventions that we know from published evidence can block or compete with those patterns,” says Richard Chapman, director of the Pain Research Center at the University of Utah, in Salt Lake City.

Chronic pain is one of the biggest medical health issues in the Western world; it costs the United States about $150 billion a year. Unlike with acute pain, the causes of chronic pain are often unclear–for example, doctors can identify a physical source in only about 10 percent of those with chronic back pain. A growing number of studies suggest that chronic pain should be viewed as a progressive disease, likely triggered by aberrant but potentially permanent changes in the brain.

The painkillers that help headaches and broken bones do little for chronic pain, leaving a huge need for new treatments. But developing them has been difficult. Perception of pain depends strongly on our level of attention and our emotional state–two factors that are difficult to study in animal models. “We don’t have one drug developed from preclinical models of pain that works for chronic pain,” says Irene Tracey, a scientist at the University of Oxford, in England, who studies pain.

Now scientists are aiming to develop and test new drugs using human brain imaging. A. Vania Apkarian and his colleagues at Northwestern University have found a series of abnormalities in the brains of chronic pain sufferers: the part of the prefrontal cortex linked to decision making appears to have shrunk in chronic pain patients. And another part of the prefrontal cortex linked to emotion is hyperactive. In fact, a unique study assessing background pain in chronic back-pain patients suggests that the constant pain these people experience is linked to activity almost entirely in emotion-regulating parts of the brain.

Researchers used functional magnetic resonance imaging (fMRI), which measures brain activity, to study background pain. They asked back-pain patients to continually rate their pain while lying in the scanner, and then the researchers compared brain activity patterns during periods of constant pain with those during periods of worsening pain.

While activity patterns during flare-ups resembled those previously linked to acute pain, the pattern associated with constant background pain was distinct: it centered on the medial prefrontal cortex, a brain area involved in emotion and sense of self. “It almost seems like they’ve turned off the sensory part and are suffering entirely from the emotional aspect,” Apkarian says.

Given these findings, the scientists are beginning human tests of a compound called d-cycloserine, an FDA-approved antibiotic that also blocks certain receptors in the brain. (It is currently being tested for treating post-traumatic stress disorder and other conditions.) “We think it increases transmission within the prefrontal cortex to better control the emotional component of pain,” says Apkarian. “This will be the first hypothesis-driven test for a pain drug driven by human-imaging studies.”

Another hot target for chronic pain is the modulatory system that humans have evolved to suppress pain when necessary–so that they can run from a predator while wounded, for example. Preliminary evidence suggests that chronic pain sufferers aren’t good at recruiting this inhibitory system. Indeed, ongoing studies suggest that people with chronic pain may be hyperactive in the opposite direction: they amplify pain signals on their way to the brain. Sean Mackey, a physician and researcher at Stanford University, and his colleagues are now studying the brain stem and spinal cord, two crucial components of this modulatory system that have traditionally been very difficult to assess with fMRI. These parts of the nervous system move with every breath and heartbeat, so the researchers had to develop new analysis methods to generate clean images.

Identifying the neural signatures linked with chronic pain may also provide a new way to screen experimental drugs for human testing. A small study of pain patients given gabapentin–an epilepsy drug also used to treat nerve pain–showed significant activity changes in the parts of the brain that respond to pain. Drug developers could use this measure as a quick way to assess which experimental compounds to send for further testing, says Tracey, who is developing the technique. “We are getting to the point where we can test novel compounds.”

In the absence of effective drugs, many chronic pain patients have turned to behavioral therapies to try to control their pain. Tracey’s studies have shown that people who are better at distracting themselves from pain show more activity in a specific part of the pain modulating system. “Maybe we could use brain imaging as a screening tool to determine who would do well on cognitive behavioral therapy,” she says.

One of the newest experimental approaches to controlling pain is real-time fMRI, in which patients watch their brain activity in real time as they try to consciously control brain areas involved in pain. (See “Seeing Your Pain.”) Mackey and his collaborators have shown that chronic pain patients could reduce their pain in the short term using this method–essentially, a more precisely targeted form of biofeedback–and the researchers are now assessing long-term effects. Mackey says that brain-imaging studies of these patients are shedding light on how people learn to control their pain, and which parts of the brain are the most effective targets.

Scientists don’t yet know why some people develop chronic pain and others don’t. “There seems to be cortical reorganization at a high level because of the injury itself, but whether that’s a coping mechanism or just a consequence, we don’t know,” says Apkarian. “Some people might be predisposed to chronic pain. But it still seems to get worse as they live with the pain.”

He and others say that one of the biggest benefits to brain-imaging studies of chronic pain is that they convince both patients and doctors that it really exists. “It’s been revolutionary in providing validation to people that pain is something with a real neurological basis,” says Mackey. “We can point to areas of the brain and say, That’s part of the brain that’s dysfunctional.”

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