When pain pills and a heating pad couldn't help mask the severe pains searing through her lower back, Sandra Coulter would climb into her bathtub.

    "I would sit in a hot tub for hours. It was the only way I could relieve the pain," recalls Coulter. "It was excruciating."

    For three years, Coulter dealt with her debilitating, monthly torment until shortly after work one day, she fainted. In the hospital she learned the source of her pain--a disease of the uterus called endometriosis. Abnormal growth of uterine tissue was making the days before her menstrual cycle a living hell.

    Surgery eventually cured Coulter's problem, which affects between 10 and 20 percent of all women between the ages of 25 and 49. She was lucky. Some women afflicted with the disease never get properly diagnosed or treated and spend the better part of their child-bearing years in morbid fear of monthly torment. And even after surgery, some women continue to have pain for years.

    Coulter is among tens of thousands of women--and as many men--who encounter the phenomenon of chronic pain--deep-seated hurting that seemingly lasts forever and that in many cases has no discernible cause. In Coulter's case, doctors were able to pinpoint the source of her distress, an all-too-common category of chronic pain associated with the female reproduction system. Endometriosis is only one of a variety of painful conditions that only target women in child-bearing years.

    But chronic pain is hardly a respecter of gender, says Dr. Karen Berkley (Ph.D. Washington) a neuroscientist who has made pain the focus of 30 years of research and teaching at FSU. Both men and women are subject to real, unrelenting pain that may or may not be traceable to organic disorders such as cancer, arthritis, gastrointestinal disease or to bodily injury.

    In all her areas of research, Berkley, a McKenzie Professor in FSU's Program in Neuroscience, is guided by the curious paradox of pain.

    "Pain is always a motivator," she said. "It's extremely important--it alerts us that we need to take care of an injury that may have taken place. Without pain, we don't survive very well."

    But constant, wracking pain also is a motivational force millions would like to live without. The National Institutes of Health estimates that up to 90 million Americans are chronic pain sufferers. In fact, chronic pain is the costliest health problem in the nation, totaling upwards of $100 billion annually in treatment costs, lost time from work, insurance pay-outs and legal bills.

    Berkley is a member of a small international network of scientists who regard the phenomenon of chronic pain as one of the most challenging issues in the field of neurobiology, the science given over to the study of how the nervous system works. In the past 25 years, research into the cause and treatment of chronic pain has made extraordinary progress that has given hope to millions of sufferers worldwide.

    Such strides include a host of therapies that range from the development of better and more economical pain-killing drugs to very expensive, high-tech treatments such as brain-implanted electrodes. Researchers have now found ways that the old stand-by morphine, for example, can be used safely and more often than ever before.

    Some of the most exciting research surrounds the discovery of a class of pain-reducing proteins--called endorphins--produced by the body itself. These natural compounds come in a variety of strengths, researchers have found, and one of the latest discovered, called dynorphin, is reportedly 10 times more potent than morphine.

    But despite the promise that both new and old treatments hold, for many victims of chronic pain nothing seems to work. Sufferers who have "tried it all" often are those whose conditions seem to defy all scientific and medical knowledge about the root causes of chronic pain and how to alleviate it. These unfortunates often make life hard for their families, and are ripe candidates for drug dependence, rip-offs from frauds selling miracle cures, despondency and depression. Often such sufferers are ultimately written off as "head cases," a label that can be as socially debilitating as the condition itself.

    Berkley says the mysterious nature of chronic pain--how it so obviously differs from the normal "ouch" variety--makes it one of the most interesting and important candidates for continued research. Unlike everyday scrapes, bumps and bruises that an aspirin can take care of, by its clinical definition chronic pain lasts at least six months and often has no obvious cause. But what clinicians and scientists call "acute" pain from traumatic injuries or common maladies can trigger chronic anguish long after an injury has healed or a painful disease has been cured.

    Berkley's research is focussed on improving our understanding of how such unnecessary and often useless pain develops. This fall, she was in London finishing up a year-long sabbatical from FSU as a visiting professor at University College and at the National Hospital for Neurology and Neurosurgery. Her stay has afforded her opportunities to extend the medical applications of her research at FSU. Her sphere of research interests now includes colleagues working in Japan, Italy, Sweden and Canada, as well as in Britain, all of whom have visited her FSU lab at one time or another.

The Panoply of Pain

    A consensus is emerging among Berkley's group that researchers who study chronic pain need to begin rethink the way the body's whole system of pain works. To Berkley and her colleagues, the often inexplicable manifestations and behavior of chronic pain suggest that the conventional theories of how the entire nervous system--the brain, spinal cord and all the peripheral nerves--create the perception of pain need to be changed.

    Med schools generally teach that pain is a fairly straightforward response to injury. Abnormal amounts of pressure, heat and certain chemicals in injured tissue trigger a response in surrounding nerve fibers that are expressly designed to handle so-called "pain signals." These fibers are said to fire "pain messages" toward the brain through a network in the spinal cord.

    Before the brain receives these messages, a type of "gating" mechanism in a specific region of the spinal cord controls the duration and intensity of "pain signals" ultimately passed on to special parts of the brain. This gate is itself thought to be controlled by nerve impulses from all of the body's five senses. Whatever "pain messages" the gate passes on become the raw material the brain uses to create the sensation of pain. Under the right circumstances, the gate can completely shut off all signals, resulting in no pain.

    This interpretation of the so-called "spinal cord gate theory" is still the predominant concept of how pain works among many researchers and most physicians, and treatments of all pain are largely based on it.

    However, Berkley and her colleagues--including Prof. P.D. Wall of London's St. Thomas's Hospital, one of the theory's originators--argue that the gate theory has been grossly misrepresented. Wall has been a frequent visitor to Berkley's group at FSU in recent years.

    As Berkley explains it, the original gate theory refuted the idea that nerve fibers from the body handle so-called "pain messages." What these fibers really do, she says, is deliver messages to the spinal cord--not about pain, but merely about stimulating events occurring to the body.

    Once such information arrives at the spinal cord, it is subject to modification ("gating") by interactions within the spinal cord itself and by information coming down from the brain, says Berkley. This modified information is then relayed to many parts of the brain where it gets modified even more by information arriving from other sensory organs. The final result may or may not be the perception of pain.

    What this means, somewhat ironically, is that pain is a perceptual creation that is in fact always "in the head," so to speak. What's important, says Berkley, is that this means that injury or disease does not necessarily produce pain. And, conversely, pain can occur without any injury or threatening stimulus--ergo, an explanation for chronic pain that defies all efforts by physicians to pinpoint a cause.

    Work by Berkley and her students at FSU, along with Wall and other colleagues in France and England, has extended the concept of how the brain creates the sensation of pain. Traditionally, neuroscientists thought that a particular nervous pathway identified years ago ferried information about gentle pressure on the skin to the brain. Berkley and her colleagues found that in fact this so-called "touch pathway" also carries information about both gentle and damaging events happening in internal organs.

    This breakthrough discovery, published in the journal Nature Medicine in 1995, has considerably expanded scientists' appreciation of the varied parts of the brain involved in creating the sensation of pain, says Berkley.

    Because the brain is constantly receiving information from other organs, the picture it processes of what's happening in the body is constantly changing as well, says Berkley. The upshot is that how the brain ultimately creates pain involves different "ensembles" of brain regions in different individuals at different times in their lives, she said.
 

Hope Through Multi-Therapy

    Thinking of pain as being the synthesis of activity occurring simultaneously in more than one part of the brain constitutes the basis of the ensemble theory of pain, which Berkley staunchly advocates. The concept embraces the individual genetic, molecular, physiological, emotional and sociocultural factors that make every person unique, and prescribes treatment accordingly, she says.

    Therefore, the ensemble concept encourages a more active cooperation between patients and their care-givers, allowing the gathering of more complete information about the patient's life so that doctors and chronic pain sufferers can develop a strategy of deliberate multi-therapy--using two or more treatment methods at once.

    Even though the ensemble approach isn't very common among scientists or lay people, wise doctors and clinicians have been following some of the theory's basic tenets for years and not even realizing it, says Berkley.

    "Good cardiologists advise their heart patients to change their eating habits, get more exercise, perhaps undergo bypass surgery and take medications," she says. "This is multi-therapy, a simultaneous combination of several treatment modalities that is tailored for a particular person."

    Ensemble theory, says Berkley, holds that in treating chronic pain, no single treatment may work well or at all in any given patient. "But all of them may work together," she says.

    Because pain can be, and usually is, such an individualized phenomenon (a bee sting can put some people to their knees, for example, and be a mere nuisance to others) Berkley insists that a rational approach to treating chronic pain must embrace individual differences, which in many cases may require a multi-therapeutic approach to be successful.

    Berkley believes that the main reason why more clinicians don't rely on multi-therapy in treating chronic pain is because they still cling to outmoded views of how the gate-control theory of pain works. Most still believe that "real pain" must be derived from obvious injuries or diseases that trigger "pain signals" to the brain. Treatment, therefore, is typically prescribed in serial fashion, trying one therapy first, then another, and another, and so forth until something finally works.

    Or doesn't. In such cases, after hopping from one treatment to another in futility, patients often wind up being referred to a psychologist, a demeaning predicament to many who suddenly realize their doctors think they've simply invented their pain from nothing.

    Fortunately, says Berkley, attitudes in the western medical profession are changing. Spurred on by professional scientist-clinician organizations such as the International Association for the Study of Pain and the American Pain Society, doctors who specialize in the treatment of chronic pain are learning that multi-therapeutic treatment approaches are much more effective than single, either-or ones, says Berkley.

Considering Sex

    Other than a patient's age, mood, or overall emotional well-being, whether they are male or female can say a great deal about how they perceive and handle chronic pain, say researchers. Berkley has written extensively on the topic.

    Sex and gender differences associated with pain was the major theme of a national conference of leading pain researchers held in Washington last April and sponsored by the National Institutes of Health. Dozens of researchers reported the results of experiments aimed at understanding why and under what circumstances men and women differ in their perception and handling of pain.

    Although the scientists cautioned about over-generalizing about gender differences in response to pain, evidence was presented by a number of researchers that suggested women tend to be more vulnerable and sensitive to pain than males but are better able to cope with it.

    Berkley, who led off the conference, says that research shows, overall, that women are more ready than men to acknowledge the presence of pain.     Furthermore, women suffer from more chronically painful diseases than do men, such as rheumatoid arthritis, irritable bowel disease, fibromyalgia and interstitial cystitis. Researchers at the University of Washington reported that women also are more likely to suffer pain in the head, neck, face, abdomen, joints and shoulder than men, while older men complain more about pains of the chest and back than older women.

    Possibly because of their increased vulnerability, says Berkley, women are better prepared to deal with pain and generally cope with it better than men. For example, Ohio University psychologist Dr. Francis Keefe reported "striking differences" in the incidence of arthritic pain between the sexes. In one study, Keefe said arthritic women reported 40 percent more pain in their joints than men, but handled the emotions accompanying their discomfort better than men.

    "Men have lessons to learn from women in coping with pain," Keefe was quoted as saying. "While women may experience more intense pain, they may be better able to limit its emotional consequences than men."

    Several studies at the conference showed evidence that the hormone estrogen plays a fundamental role in pain among women. In studies with mice, Dr. Jeffrey Mogil, a psychologist at the University of Illinois at Urbana-Champaign, believes that estrogen may serve as a switch that turns on a mechanism in females that produces analgesia, an inability to feel pain. What's more, he said his research suggests that females, in fact, may be able to inhibit pain by activating different brain circuitry than do males.

    Research by Berkley with her colleagues in Italy has shown that pain sensitivity is greater for men than women in certain regions of their bodies (the lower abdomen). Some painful diseases are more prevalent in males than in females (cluster headache, for example).

    Interestingly, research by Dr. Dennis Turk at the University of Washington showed that when diseases become life-threatening, such as terminal cancer, all sex and gender differences disappear. This finding underscores Berkley's contention that when it comes to trying to figure out the nature of pain "it all comes back to differences inherent in individuals, with sex and gender being only one component."

The Role of Menstruation

    Berkley has an intimate personal as well as professional appreciation for a type of chronic pain men will never know--severe, recurring menstrual pain. As a teenager, she was a victim of severe dysmennorrhea, extremely painful menstruation that can be temporarily crippling. Over the years, Berkley has become an expert on the topic which afflicts between 10 and 40 percent of all women at some time in their child-bearing lives.

    Dysmennorrhea can be caused by readily diagnosable disorders, such as endometriosis, but also occurs in a large proportion in otherwise perfectly healthy women, says Berkley. Women cope with it in a variety of ways, including drugs, massage, heat therapy, acupuncture and biofeedback. Another modern treatment is transcutaneous electrical stimulation, better known by the acronym TENS. In too many cases, none of the treatments work.

    But abnormal menstrual pain aside, even the onset of a woman's monthly cycle can make everyday aches and pains--to say nothing of serious injury or disease--feel much worse. Berkley and her colleagues working in Italy found that women suffering from kidney stones are most likely to show up in the emergency room complaining of severe pain just before or during their periods.

    This and other research by Berkley and her students at FSU have led them to conclude that the large hormonal increases and decreases that occur across the menstrual cycle can sometimes act like systemically administered drugs, with some acting to reduce the painful consequences of diseases, others acting to enhance them.

    "If we can understand these actions," she says, "it may lead to the development of new therapeutic avenues that could benefit men as well as women." Some of these ideas were published in the journal Pain in 1997.

    But even though many of the worst types of chronic pain women suffer are clearly related to their reproduction systems, Berkley says that sex differences represent only a small part of the vast array of other factors that impact on pain. Approaches to pain therapy aren't ever likely to be grounded in sexual differences, she feels.

    "It will never be that absolute," she told reporters at the NIH conference. "But we will be able to factor in sexual differences as a way of individually designing better treatment procedures."

Toward Alternatives

    Evidence that the multi-therapeutic approach to treating chronic pain is gaining strength in mainstream medicine can be found in the astonishing variety of treatments now available (see below)

    "There is now a vast, hopeful and ever-increasing array of medical, somatic and situational therapies that can be applied to people in pain," Berkley said.

    The range of therapies embraces a large number of different types of drugs and ways they can be administered; different types of surgery; multiple ways of manipulating the body including massage, exercise, nerve blocks and acupuncture; options in social and environmental changes; counseling options and even an endorsement of the therapeutic values of art, music, poetry and religion.

    She hopes her work will help change things so that at the start of treatment of chronic pain for which no organic cause is found, both physician and patient will consider and select from such therapies, with a mutual understanding that any single treatment may not be the answer.

    Meanwhile, Berkley looks forward to continuing her investigation into the intriguing mysteries of chronic pain, which she and others regard as an unnecessary, even dangerous, anomaly of human biology.

    "This pain isn't helping anymore. It doesn't protect the individual and it doesn't help us live a better life."