Raising the Threshold of Pain Research

Managing chronic pain is not only essential to quality of life, but also to good health. Duke researchers are working to understand the causes of pain and to develop new treatments.

Before she showed up at Duke's Morreene Road Pain Clinic last year, Christy Anderson had suffered through intense migraines for more than three decades. They hunkered down in her forehead for days at a time, making her feel as if someone had planted a suction machine behind her eyebrows. During the worst attacks, all the forty-six-year-old Anderson could do was lie in the dark, motionless, hoping not to throw up. Raising her two children became an exhausting burden. "When they wanted to play tennis or kick the soccer ball, or they wanted me to go to a school play, it was very difficult for me to drive a car," she says. The most workaday tasks, such as showering, became challenges. "Even the water hitting your head hurts," she says.

"It makes you so sad, because you want to enjoy your life and you can't participate."

Anything could trigger a migraine for Anderson: certain smells, not enough sleep, changes in barometric pressure, the approach of menstruation. Nothing seemed to help. Anderson tried the painkiller Vicodin and the injectable migraine medication Imitrex. They provided some respite, she says, "but I didn't find any long-term relief."

Illustration by Polly Becker

 Illustration by Polly Becker

By the time she arrived at Duke, Anderson was in good company. According to the American Medical Association, 75 million people in the United States suffer from chronic pain, often severe enough to warrant medical attention. Many travel from doctor to doctor, never getting complete relief. The result is what some experts call an "epidemic" of untreated pain, similar to other noninfectious disease epidemics.

"Chronic pain is a medical problem—like diabetes, like heart failure, like chronic obstructive lung disease—and it needs to be managed," says Christine Miaskowski, a past president of the American Pain Society. "We don't have a health-care system that's equipped for that. If a person doesn't get better after two Vicodin, most primary-care doctors don't know how to deal with it."

The results of this inattention can be disastrous. Left to fester, pain can lead to obesity, depression, insomnia, even immunosuppression. Research suggests that chronic pain triggers abnormalities in the brain and spinal cord and worsens the prognoses of cancer patients. "Treating pain is not just a compassionate exercise for quality of life. It's essential for health," says Scott Fishman, past president of the American Academy of Pain Medicine.

In recent years, the medical profession has turned its attention to understanding pain on a deeper level and to developing innovative therapies for patients like Anderson. Across Duke's campus, from the anaesthesiology department to the Divinity School, physicians are crossing disciplines in search of new approaches to pain management. Some of the research involves biological fixes such as concentrated salt injections and topical creams. The most interesting work, however, acknowledges that pain is more than a one-dimensional condition—it also involves the mind, the spirit, and the social context.

That's why some doctors are experimenting with stress-reduction techniques such as relaxation skills and guided imagery; probing the links between pain and seemingly unconnected issues like parental substance abuse; and exploring the role of faith communities in increasing access to pain care. "We are on the verge of unprecedented research that will put Duke on the forefront, in ways we have never seen before," says Winston Parris, chief of Duke's Division of Pain Management, under whose umbrella some of the researchers work.

What remains to be seen, though, is whether the medical profession as a whole will start treating pain as seriously as it treats other diseases—particularly in a regulatory climate that sometimes punishes doctors for practicing aggressive medicine.

Until recently, when it came to pain, many physicians adhered to a rather simplistic scientific model. "The way pain has been traditionally understood has been using the notion of a simple ‘pain pathway,'" says Duke psychiatry professor Frank Keefe, a world-renowned pain expert. In this model, signals travel from the injury site along a series of nerve fibers until they reach the brain. "This is a model that, back to Descartes, has been used to explain pain," Keefe says. "The problem is that it often doesn't work."

During World War II, seriously injured soldiers on Italy's Anzio beachhead reported far less pain than civilians who had undergone surgery in U.S. hospitals. Harvard anaesthesiologist Henry Knowles Beecher, who observed this as an Army medical consultant, concluded that the joy of survival and the prospect of leaving the battlefield often masked the pain of the injury itself. Pain, Beecher later wrote, was "complex, subjective, and different for each individual."

"You don't have to go to Anzio to see this," Keefe says. Subsequent studies have shown that doctors can rarely predict the intensity of a patient's suffering from the severity of the injury. Keefe, like many of his colleagues, now believes pain is mediated by both thoughts and emotions, which can actually close "gates" in the neural pathways, blocking unpleasant sensations. His own work focuses on using the brain to control pain. In one experiment, he taught a group of osteoarthritis patients coping skills such as relaxation, imagery, and calming self-statements—and discovered significant drops in both pain and psychological disability. "We believe these treatments alter how the brain processes pain signals," says Keefe, who is now studying patients with non-cardiac chest pain, various cancers, and chronic low-back pain.

Keefe doesn't work in a vacuum. Over the past twenty years, researchers have become more sophisticated in examining the neurobiological mechanisms underlying different types of pain. Likewise, clinicians have developed bolder and more-nuanced treatment strategies. Many of the nation's top-ranked hospitals have opened facilities devoted specifically to pain management—including Duke, which in 2000 pulled together neurologists, anaesthesiologists, psychiatrists, psychologists, physical therapists, and neurosurgeons to create the multidisciplinary clinic on Morreene Road near the hospital.

In this changing national climate, pioneers like Keefe have paved the way for the next generation of researchers, including assistant clinical professor of psychiatry and hematology Christopher L. Edwards A.H.C. '97, who is exploring the complex ways pain interconnects with brain chemistry, social networks, emotions, money, diet, genetics, and even faith.

Mind control: Keefe focuses on the brain’s ability to control pain

Mind control: Keefe focuses on the brain's ability to control pain. Les Todd

When Edwards was an undergraduate at Winston-Salem State University, his mentor, psychologist Nelson Adams, handed out a stack of materials for his students to read. Overwhelmed by the sheer volume, Edwards skimmed the articles quickly—until one in particular caught his eye. Culled from the popular press, it discussed how hormones can influence memories, either by sharpening them or by making them blurrier. Scientists have long known that the body protects itself from physical discomfort by releasing hormones—think of how endorphins serve as natural painkillers. Intuitively, it makes sense for the body to have a similar mechanism for blunting psychological discomfort by helping us forget pain. By the time Edwards had entered college in the 1980s, researchers had conducted some animal studies on this question. But "there was not a lot of human work," he says.

Edwards became fascinated by the intersection of hormones, pain, and cognition. His interest persisted as he entered graduate school at the University of Kentucky. For his dissertation, Edwards subjected a group of female volunteers to a pain-making device that used weights to compress their fingers. Afterwards, half the women took a placebo; the others took the drug naltrexone, which blocks the effects of endorphins in the body. He then administered the California Verbal Learning Test, a standard instrument that measures memory.

The women who took naltrexone aced the tests; they had no changes in memory. But the ones who took the placebo—that is, whose bodies were allowed to react to endorphins normally—had a dramatic deterioration in how much they could recall. This suggested the endorphins reduce the amount of information trauma victims can store—perhaps to protect them from the distress of remembered pain. "If you're hit by a car," Edwards asks, "how productive is it to remember the first sound of crushing or the feeling of a rear wheel breaking an arm and a leg?" Likewise, he says, there's an evolutionary advantage for women to forget the agony of childbirth: It makes them more willing to endure another pregnancy and pass on their genes.

In 1996, Edwards came to Duke for a dual fellowship in psychiatry and endocrinology. There, he met Elaine Whitworth, director of education at Duke's Comprehensive Sickle Cell Center. At the time, Edwards knew little about sickle cell disease, a painful genetic disorder marked by misshapen red blood cells. Over time, he came to learn that the condition, which, in the United States, primarily strikes African Americans, was seriously understudied. "There was almost no research into psychosocial factors in sickle cell disease," he says. "Almost anything I contributed would be significant."

Administering lengthy questionnaires to Duke's sickle-cell patients, Edwards looked at three survival skills common among African Americans: prayer, hostility, and the single-minded determination known as "John Henryism." Only one of those strategies had an unambiguous impact, he found: Hostility significantly increased depression and anxiety, making it harder for patients to cope with pain.

The effect of John Henryism, a term often defined as "prolonged, high-effort coping with difficult psychological stressors," was somewhat more complex. Coined by Sherman James, a social epidemiologist at Duke's Terry Sanford Institute of Public Policy, the term derives from the tale of the mythical African-American railroad worker who defeats a steam-powered drill in a steel-driving contest and dies afterward. Edwards learned that the success or failure of patients who scored high on the John Henryism scale varied based on whether they also had money, strong family and community ties, and ready access to medical care. "With adequate resources, these patients shine," Edwards says. For patients lacking these resources, though, "John Henryism is a predictor of depression and anxiety." It can also be a predictor of physical pain: If a sickle-cell patient has a fierce determination to succeed but lacks the workplace support to take sick leave, he or she might try to work through an intensive period of pain. This, in turn, can lead to more pain.

Prayer also yielded complicated results. Pain patients who prayed several times a week and who attended church with some frequency tended to suffer less than others from depression and anxiety. "It absolutely surprised me," Edwards says. But, upon reflection, he realized that prayer serves a similar purpose to the calming techniques used by Keefe's research subjects. Edwards says health professionals should work with these findings: Rather than teaching some religious patients yoga or guided imagery, clinicians could encourage these patients to keep praying. "If you're getting deep relaxation from your prayer, and getting medical benefit, why would you teach the patient another skill?" he asks.

But this benefit disappeared with the most religious patients, the ones who prayed at least once a day and attended church with the most frequency. They actually suffered the highest levels of depression, anxiety, and psychosomatic symptoms, along with kinesiophobia, the fear of movement and reinjury. "In essence, prayer appears to be a very effective pain-coping skill until it is used exclusively and to the exclusion of other active coping strategies," Edwards says. "There is a time for prayer and there is a time for action."

In his clinical practice, Edwards has found that some very religious patients are resistant to taking their medications. "Many patients view their pain as coming from God and are less likely to want to do something about their pain," Edwards says. "They think it's punishment for something they did earlier in their lives." Faced with such noncompliance, "we often can match a patient with a clinician of a similar orientation. If a patient believes this is from God, we assist them in broadening their thinking: Possibly God is empowering you to overcome this obstacle."

Psychosocial interventions like these are a long way from simply prescribing painkillers. But, Edwards says, "narcotics only attend to biology," while a patient's pain is often a mélange of physical, psychological, and social factors. "It's not a single piece of tissue" involved in an injury, he says. "The treatment needs to be equally comprehensive."

Interconnected networks: Edwards explores pain management at the nexus of psychiatry and neurobiology

Interconnected networks: Edwards explores pain management at the nexus of psychiatry and neurobiology. Les Todd

The types of available treatments for pain are varied and abundant. They range from massage to physical therapy to acupuncture and acupressure. They include spinal-cord stimulators and steroid injections. There are psychological interventions like the biofeedback and the calming statements advocated by Keefe. And of course there are opioid (narcotic) medications like morphine and oxycodone. This arsenal reflects the recognition that pain is a complex syndrome that comes from a variety of sources and triggers significant ripple effects.

Still, for all the attention focused on pain these days, many patients remain underserved by the medical system. In 2003, a research team that included Duke anaesthesiologist Tong Joo Gan reported that almost 70 percent of surgery patients suffer from moderate, severe, or extreme pain after their operations—and one-third never have a conversation with a professional about relieving their symptoms. The following year, a survey by Roper Public Affairs and Media revealed that nearly half of all chronic-pain sufferers could not get their symptoms under control.

In part that's because, psychosocial interventions notwithstanding, opioid medications remain the core treatment for both chronic and acute pain. "For improving desperate people's quality of life, the benefits are enormous," says Clifford Woolf, a professor of anaesthesia research at Harvard Medical School. "It takes the edge off their pain, so they can move on with their lives." But given Rush Limbaugh's widely publicized struggle with OxyContin in 2003, along with news reports of OxyContin abuse in the rural South, it's hard to convince patients that opioids carry almost no risk of addiction when used as prescribed. Even some doctors remain unconvinced, despite voluminous studies debunking any link between proper opioid use and addiction. "If you look at the armamentarium of drugs, the ones we tend to shy away from—the opiates—are probably the safest of the lot," says Miaskowski of the American Pain Society.

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Illustration by Polly Becker

Pain may be a medical and social problem, but it's a legal one as well. Even more than addiction, many physicians worry about prosecution. Over the past few years, the U.S. Drug Enforcement Administration (DEA) has become more aggressive in going after physicians who prescribe painkillers in large quantities. In some cases, the DEA's targets have been well-regarded specialists who inherit the toughest patients: those requiring opioids in very large doses.

"Doctors aren't perfect," says David Brushwood, a professor of pharmacy-health-care administration at the University of Florida. "They make mistakes. In every successful medical practice, there will be some chance of giving these drugs to fakers and liars, because the only way to avoid that is denying the drugs to patients who are suffering." In the past, Brushwood says, the DEA collaborated with health professionals to keep opioids away from troublemakers. Now, he says, "regulators wait and watch until a small problem becomes a big one. Then they sweep in with a SWAT team of police, helmeted, in riot gear, with automatic weapons, and they arrest the doctor or pharmacist, charging them with crimes that could have been prevented with an early consult." Last year, for example, Virginia pain physician William Hurwitz was sentenced to twenty-five years in prison on charges of drug trafficking, after some of the opioids he prescribed were diverted to the street.

DEA officials would not comment on these prosecutions or their chilling effect. But physicians say it's hard to watch respected colleagues get arrested without getting spooked themselves. "The DEA sometimes doesn't appreciate what I call the ‘state-trooper effect,' " says Richard Payne, director of the Duke Institute for Care at the End of Life. "You can be cruising along the highway, not even speeding, but when you see the state trooper, you get nervous." As a result, many doctors won't prescribe opioids at all or do so at levels that don't provide sufficient relief. For some patients, this inaction can be devastating. "We get daily e-mails—every day—where people tell us they're planning their suicides," says Siobhan Reynolds, president of the Pain Relief Network, a national patient-advocacy group.

According to Duke pain specialists, the university has not been exempt from this nationwide under-treatment trend. Physician Billy Huh says the Morreene Road clinic, where he works, receives a fair number of patients whose primary-care doctors failed to treat their pain. "They may start opioids, but they won't keep writing the prescription," Huh says. "To put it bluntly, they're dumping these patients they don't want to keep." Christopher Edwards says he has experienced this, too, but is quick to add that the university isn't unique in this regard. "It is not just the Duke family physicians, but the general national medical community that is reluctant to aggressively treat pain," he says. "There are so many perceived consequences of aggressive narcotic management, in particular, that many docs refer to clinics like ours and/or ignore the problems. Even worse, for many, is that they just don't ask about pain."

Christy Anderson, the headache patient, arrived at the Duke clinic in 2005. She was assigned to Edwards, who prescribed a combination of Imitrex and the migraine-prevention drug Topamax. But Edwards also believed there were other factors causing Anderson's headaches besides pain pathways, and he decided to incorporate psychotherapy into the regimen. The two began exploring the reasons Anderson tended to neglect her own well-being, eating unhealthily and foregoing regular exercise. "I have in the past allowed people I care about to take center stage," she realized, "instead of taking care of myself." They discussed how Anderson could redirect some of her energies to her own care. "Knowing that you're empowered, that you're in the driver's seat, helps with pain management," she says. "When you manage your life, you're better able to manage your pain."

The headaches have not disappeared entirely. But Anderson says she feels better equipped to cope when they do return. She knows the healing process will be gradual and will take effort on her part. "I'm not saying I'm there yet," she says. "It's a work in progress. Dr. Edwards has given me the prescription. Now I have to follow it."



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