About one third of Americans, an estimated 100 million people, suffer from chronic pain, making it one of the most common reasons people visit the doctor. Pain can be the side effect of serious medical problems like cancer and rheumatoid arthritis, but it also exists independently of any other medical condition. Despite decades of research and millions of dollars devoted to studying the problem, current therapies provide only marginal relief for many sufferers. But there are glimmers of hope. Among other developments, researchers today are working on novel approaches that focus on controlling activity in the brain's pain centers and on cells previously thought to play only a supporting role in the central nervous system.
Success can't come any too soon. Prescription drugs like Oxycontin, Percocet, and Vicodin, while effective weapons against chronic pain, are under increasing scrutiny because they can be addictive for patients and have also been abused by others who simply take them, without prescriptions, for their euphoria-producing effects. To relieve the widespread overdependence on painkillers, researchers are investigating new ways to attack this most primitive sensation and not merely mask it, as opioid drugs do. But researchers have to tread carefully, as pain can help keep "us out of trouble," as in a warning to draw back from a hot stove, says Sean Mackey, chief of the pain management division at Stanford University School of Medicine. The goal is to lessen or eliminate chronic pain that serves no useful purpose.
Often, pain starts with a physical injury such as a burn or scrape. When tissue is damaged, sensory receptors in the skin or elsewhere in the body send signals in the form of electrical impulses along nerves, or neurons, to the spinal cord. In the spinal cord, chemical neurotransmitters are released that activate other nerves, sending an electrical signal to the brain, where it is processed and interpreted as pain.
Until recently, researchers have focused on the nerves at the site where the pain occurs, like an aching knee joint, and on the spinal cord. But pain is dependent on perception, which occurs in the brain. The sensation is a complex bodily experience incorporating the physical feeling ("That hurts!"), the emotional reaction ("Why did I grab the hot pan?"), and the intellectual response ("I need to be more careful.") "Without perception there is no pain," notes Kenneth Follett, professor and chief of neurosurgery at the University of Nebraska Medical Center. Some soldiers wounded in battle, for example, have said they didn't know they were hurt until after the danger had passed. The reasons for this are unclear, says Follett, but attention likely plays a role. When it is focused elsewhere, the brain may not perceive pain.
At the Stanford Systems Neuroscience & Pain Laboratory, Mackey is trying to better understand the mechanisms involved. In one study, he and colleagues performed brain scans on subjects' anterior cingulate cortices, one of the areas responsible for perceiving and controlling pain. The subjects, whose hands were intermittently heated by a probe, could watch on a screen as their brain activity increased or decreased, depending on the intensity of the pain they were feeling. Researchers suggested ways subjects could control the sensation, such as by focusing on something else or attempting to change their perception of the pain from something frightening and damaging to something neutral. After four 13-minute sessions, healthy subjects, who were included in the study, reduced their sensation of pain by 23 percent. Chronic pain patients, who learned to control their body's own pain sensations, reported an even more dramatic average reduction of 64 percent.
"We thought, maybe we can help people control their own brain activity," Mackey explains. He says researchers hope that, with increased training, patients can "reshape" the circuits responsible for pain. Mackey and his colleagues were recently awarded a $9 million grant from the National Center for Complementary and Alternative Medicine, part of the National Institutes of Health, to study the effectiveness of this neurofeedback technique and other mind-body approaches to treating chronic low back pain.
Rewiring the brain. Researchers at Stanford and the Medical University of South Carolina, among others, are investigating another way to reduce pain, called transcranial magnetic stimulation, which is currently used to treat people with major depression. In this procedure, an 8-inch coil is placed on the head and an electrical current is run through it, creating a magnetic field that causes electrical changes in the brain. According to Kevin Johnson, a research associate at the Stanford pain lab, early experiments suggest that by using a high frequency electrical current to stimulate the primary motor cortex (involved in planning and executing bodily movement), the pain pathways can be disrupted.
Researchers are still puzzling over why this occurs, but it may hinge on the fact that the actions of the motor cortex are closely linked to parts of the central nervous system that control sensory perception, says Johnson. When you move your arm, for example, you can sense its motion even though your eyes may be closed. Pain also has a sensory component. "My best guess is that by stimulating the motor cortex, you're [somehow] overriding sensory perception," including the ability to sense pain, Johnson says. Mackey believes that repeated use of this kind of electrical stimulation can teach the central nervous system to develop alternative sensory pathways that ultimately reduce a patient's sensation of chronic pain.
Researchers at the University of Colorado–Boulder are leading another promising area of study, involving the body's glial cells. In the past, scientists believed that glia existed primarily to support nerve cells. Derived from the Greek word for "glue," glia wrap around the neurons, holding them in place, and perform housekeeping functions such as removing debris, dead neurons, and the like.
But in the past 20 years, researchers have discovered an entirely different role for glial cells in revving up a person's protective pain response. When you have the flu, for example, that muscle soreness you feel is your body's way of encouraging you to remain still and quiet until you heal. When the immune system is activated, glial cells release neuroactive substances that increase the excitability of the spinal cord neurons responsible for relaying pain messages to the brain. They also increase the release of pain-related neurotransmitters from sensory nerve endings. Once activated, glial cells produce proteins called proinflammatory cytokines that exaggerate, or amplify, the body's pain response like the volume knob on a radio, says Linda Watkins, a professor in the department of psychology and neuroscience at UC–Boulder. Under certain conditions, if someone has nerve damage, perhaps, or a virus like HIV that homes in on the central nervous system, glia can become activated and cause a strong pain response that doesn't serve a protective purpose. It's just pain. Researchers are working to develop drugs that block the glia's harmful effects while leaving their housekeeping functions intact.
"All the current pain drugs target neurons," Watkins explains. "We started looking at how you could target these glial cells very specifically." The team has a grant from NIH to move toward human trials in the next few years of XT-101, a drug that Watkins describes as "Valium for glia," halting the release of proinflammatory cytokines and calming them down to their normal state. In animal trials, the drug blocked neuropathic pain from nerve injury for three months in rats. "The rats say this will work," Watkins says, adding that early trials with dogs also look promising.
At Stanford, researchers looking at glial cells have reported some success in a small study using a drug called naltrexone to inhibit the activity of the cells. (Currently, the drug is approved to treat addiction by blocking the effect of opioids and alcohol on the body.) When researchers gave 10 women with fibromyalgia a very low dose of the drug, their pain symptoms improved more than 30 percent compared with a placebo. "The early information looks very promising," says Mackey. The next step is to move toward larger clinical trials, he says.
Currently, "pain treatment occupies about 10 percent of all healthcare expenditures but receives about 1 percent of research funding," says Roger Fillingim, a professor at the University of Florida College of Dentistry and president of the American Pain Society, a professional group. Transformational change in diagnosis and treatment of pain will require a greater national commitment, the experts say. In the end, the financial investment could pay off in major savings across the healthcare system if researchers resolve one of the most intractable and pervasive problems that still challenge doctors and their patients.