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The Neuroscience and Endocrinology of Fibromyalgia

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By National Institute of Arthritis and Musculoskeletal and Skin Diseases • • December 1, 1996

A scientific workshop on the Neuroscience and Endocrinology of Fibromyalgia was held at the National Institutes of Health (NIH), in Bethesda, Maryland, on July 16 and 17, 1996. The workshop, organized by Dr. Stanley Pillemer and Dr. Susana-Serrate Sztein of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, focused on the basic science of chronic pain, neuroendocrinology, circadian rhythms, and sleep disorders.
In his introductory remarks at the workshop, Dr. Stephen I. Katz, Director of the NIAMS, said: "This is NIH at its best: Investigators from diverse groups have been brought together to share perspectives, research advances, and research problems so that collective wisdom can be focused on particular areas of research."

A chronic disorder, fibromyalgia is characterized by widespread musculoskeletal pain, fatigue, and multiple tender points. People with this syndrome may also experience sleep disturbances, morning stiffness, irritable bowel syndrome, anxiety, and other symptoms. Fibromyalgia affects 3 to 6 million Americans, and occurs primarily in women of childbearing age. However, children, the elderly, and men can also be affected.

The Chronic Pain segment of the workshop was chaired by Dr. Laurence A. Bradley, Professor of Medicine at the University of Alabama at Birmingham. Researchers discussed their studies in this area outlining the current state-of-the-art and the relationship of the findings of pain studies to fibromyalgia.

Dr. Kenneth L. Casey, Professor of Neurology at the University of Michigan in Ann Arbor, said that fibromyalgia may be related to abnormalities of central pain processing, or processing of nociceptive (nerve endings or pathways concerned with pain) information in the central nervous system (CNS). There are specialized nociceptors (receptors for pain) in skin and in muscle that are activated by mechanical stimuli. Diseases or injuries to the CNS can produce pain and can profoundly alter the perception of pain in animals and in humans. Dr. Casey mentioned that a PET (positron emission tomography ) scan can measure regional blood flow changes in individuals experiencing pain. "Ultimately," said Dr. Casey, "we will be able to identify those areas of the brain that are responsive to different forms of noxious (harmful) stimulation and identify the pathological pathways that may take place in disorders of the central nervous system."

Dr. Ronald Dubner, Chairman of the Department of Oral, Cranial, Facial, and Biological Sciences, University of Maryland at Baltimore, said that persistent pain lasting for hours or days may lead to changes in the central nervous system and the peripheral nervous system, which consists of all the nerves that carry signals between the CNS and the rest of the body. He added that if the balance is altered between these two systems, this could lead to a further increase and spread of pain. Chemical changes may take place at the site of tissue damage and after nerve injury. There is increased activity of the nerves in the tissues of the body that causes changes (plasticity) in CNS functioning. It is this hyperactivity that may play a role in the amplification and the increased duration of pain.

Dr. Bradley said that chronic pain is pain that persists despite medical or surgical interventions. "When you follow patients with fibromyalgia, you find changes in pain intensity and changes in severity of symptoms. Even after a 10-year period, the majority of patients continue to have some pain and some symptoms." Dr. Bradley found that compared to healthy people, fibromyalgia patients have decreased cerebral (brain) blood flow and higher levels of substance P in their system. Substance P is a chemical involved in the transmission of pain signals via the nervous system.

Dr. I. Jon Russell, Professor of Medicine and Clinical Immunology at the University of Texas Health Science Center at San Antonio, said that substance P levels are substantially elevated in spinal fluid of people with fibromyalgia compared to normal people. He found that in fibromyalgia patients, the pain threshold was much lower, stiffness was greater, physical function was more impaired, and anxiety and depression were greater. Dr. Russell also noted that since other researchers had found a decreased blood flow to the brain in fibromyalgia patients, "It suggests very strongly that there is a relationship between the substance P level and the decrease in blood flow in the brain among fibromyalgia patients."

Dr. Wendy Sternberg, Professor in the Department of Psychology at Haverford College in Pennsylvania, found that female rodents, like their human counterparts, are more sensitive to certain painful stimuli than are males. She said that this sensitivity may be related to the estrogen cycle in females, since researchers have found that when estrogen levels are at their peak pain sensitivity is highest. "Considering the hormonal effects on pain sensitivity, some striking differences exist between the sexes in the chemistry of the brain for pain inhibition in lower animal species, such as rodents, and may provide a possible physiological explanation for the sex differences in chronic pain conditions," she added.

Dr. Francis J. Keefe, Director of the Pain Management Program and Professor of Medical Psychology at Duke University Medical center in Durham, North Carolina, said, "We need not only to focus on the underlying biological processes in fibromyalgia, but also to understand the different levels, the cognitive processes--such things as an individual's beliefs, expectations, memories, the way they appraise the phenomena that are occurring to them, and how they cope." He added that the notion of self-efficacy, the belief that one's actions can attain a desired outcome, is very important to explain how fibromyalgia patients cope with pain. Researchers have conducted treatment outcome studies looking at whether exercise training or combined biofeedback and exercise training or just biofeedback alone could increase self-efficacy in individuals with fibromyalgia. They found that exercise training intervention or combined biofeedback and exercise training resulted in significant increases in patients' sense of confidence that they could control the limitations of their disease. Dr. Keefe said that a new study, supported by NIAMS, will look at cognitive behavior in patients with fibromyalgia.

Dr. Richard H. Gracely, a Research Psychologist in the Neurobiology and Anesthesiology Branch at the National Institute of Dental Research, NIH, discussed issues involved in conducting pain research. He said that these include the psychological predisposition of patients, the methods of measuring pain thresholds, the lack of experimental controls, and the problems in measuring the entire experience.

The Neuroendocrine segment was chaired by Dr. Leslie J. Crofford, Assistant Professor of Internal Medicine, Division of Rheumatology, at the University of Michigan at Ann Arbor. Neuroendocrinology refers to the study of the interactions between the nervous system and the endocrine (hormonal) system. Scientists discussed their studies pertaining to the stress system and its relationship to altered sleep, mood, pain perception, and biological rhythms. The parallels between what is known about fibromyalgia and the implications for future research were mentioned.

Dr. George P. Chrousos, Chief of the Section on Developmental Endocrinology in the Developmental Endocrinology Branch at the National Institute of Child Health and Human Development, NIH, said that human beings and all living things try to maintain equilibrium. Every time you disturb this equilibrium, you disturb homeostasis (the natural state of balance) and cause stress. To give a little background, Dr. Chrousos said that the stress system consists of two components, a central nervous system component and a peripheral component. "Normally the system is quite benign. When it is activated, it helps us and then goes back to its normal state." If the stress system is constantly either hyperactivated or underactivated you have problems, he added. Dr. Chrousos said that researchers at NIH have studied seasonal depression and found that people who suffer from this disorder have an underactive stress response. He added that patients with chronic fatigue syndrome and fibromyalgia also may belong in this group.

Dr. Eve Van Cauter, Research Associate Professor in the Department of Medicine, Section of Endocrinology, at the University of Chicago in Illinois, demonstrated that sleep disturbances can go hand in hand with neuroendocrine disturbances. She emphasized that various hormones are secreted in rhythmic patterns and that single measurements of individual hormones have little value, because the body has different hormonal states of functioning at different times of the day. Dr. Van Cauter explained that the timing, duration, and quality of sleep are controlled by two major components of bodily functioning involved in sleep called the homeostatic and circadian components. The homeostatic component reflects the time that has elapsed since sleeping. The longer the time that has elapsed the greater is the tendency to sleep. On the other hand, the circadian component, which is related to the time of day, appears to be important in waking. With increasing age, the balance between the homeostatic and circadian components appears to shift. This may explain why a forty year old person who has had an unduly late night may be unable to sleep all day to make up the deficit, whereas a teenager may be able to do so. Dr. Van Cauter speculated that fibromyalgia also may be associated with an alteration in the balance between the homeostatic and circadian components of sleep.

Sleep is important in controlling the release of growth hormone. The hypothalamic pituitary adrenal (HPA) axis, a complex body system that modulates the production of the hormone cortisol and is involved in the body's response to stress, is primarily influenced by the circadian rhythm, but cortisol itself influences sleep. Waking suppresses the secretion of growth hormone but stimulates the release of cortisol. Fragmentation of sleep would tend to cause low levels of growth hormone and higher levels of cortisol. Dr. Van Cauter suggested that fibromyalgia patients may demonstrate hormonal profiles similar to those seen in people with fragmented sleep, but research is needed to test this.

She described preliminary sleep studies showing that a drug called gamma hydroxybutyrate may stimulate slow wave (deep, non-dreaming) sleep. She found that the amount of growth hormone secreted at the beginning of the sleep period increased threefold, and there was a progressive increase in the amount of slow wave sleep, but only during the first 2 hours of sleep. "In fibromyalgia patients, slow-wave sleep is disturbed. You may want to try and overcome the alpha suppression by stimulating the slow-wave sleep, and see if it has a beneficial effect," she said.

Dr. Paul Plotsky, Professor in the Department of Psychiatry and Behavioral Sciences at Emory University in Atlanta, Georgia, said that for several months, studies were conducted in his laboratory on rat pups focusing on the effects of not handling newborn rat pups and separating them from their mothers. When compared to normal rats, deprived rats showed high degrees of fear and anxiety. Dr. Plotsky said that researchers can program an animal to have an overactive or underactive stress response to pain stimulation. He added that these changes seem to last the lifetime of the animal. "Early experience is really important since it can bias the behavior of these animals for a lifetime," he said.

Dr. Sarah L. Berga, Associate Professor of Obstetrics, Gynecology, and Reproducitve Sciences and Psychiatry, Division of Reproductive Endocrinology, at the University of Pittsburgh School of Medicine in Pennsylvania, discussed the impact of stress on ovulation. She said that ovulation and menstrual cycles are initiated by the hypothalamic pituitary gonadal axis. The hypothalamus, a part of the brain, produces hormones that stimulate the pituitary gland, which lies under the hypothalamus, to release other hormones that affect the female gonads (ovaries). She added that most women have a sufficient number of hormone pulses that cause them to ovulate when normal levels of progesterone are present. Others have very few pulses and don't ovulate. "We found any behavior or reaction that activates the hypothalamic pituitary adrenal axis has the potential to disrupt the reproductive system and compromise gonadal function," Dr. Berga said.
Dr. David S. Goldstein, a Senior Investigator in the Clinical Neuroscience Branch of the National Institute of Mental Health, NIH, said that stress is neither a stimulus nor a response, but a condition where there is a discrepancy between the state that the organism is programmed to maintain and the state that is sensed. He discussed how the sympathetic nervous system (a part of the nervous system that controls many of the involuntary activities of the glands, organs, and other parts of the body) responds differently to particular stressors. Dr. Goldstein said that the closer you look at the sympathetic nervous system, the more complex it appears and the more difficult it is to precisely define it.

Dr. Crofford said that a number of clinicians have observed that fibromyalgia can be precipitated by acute stress or psychological stress that might activate either the HPA axis or the sympathetic nervous system. "Researchers believe that stress response systems might be different in fibromyalgia patients. Stressors such as a psychological or emotional disturbance, metabolic or physiologic disturbance, and infection or inflammatory change can disturb homeostasis and cause the HPA axis and the sympathetic nervous system to try and re-establish homeostasis," she said. Dr. Crofford discussed fibromyalgia studies at the National Institutes of Health where she collaborated with Drs. Stanley Pillemer, George Chrousos, and Ronald Wilder. They found that patients with fibromyalgia had lower levels of cortisol (a steroid stress hormone), in their urine than did healthy people. She noted that cortisol is very important for all metabolic systems (physical and chemical processes) in the body. Fibromyalgia sufferers also showed increases in ACTH (a hormone secreted by the pituitary gland) secretion compared with healthy normal subjects when they were given corticotropin-releasing hormone (a hormone that triggers ACTH secretion).

The Sleep Disorders segment was chaired by Dr. Harvey Moldofsky, Director and Professor of Psychiatry and Medicine at the Centre for Sleep and Chronobiology at the Toronto Hospital in Ontario, Canada. Researchers discussed their studies in the following areas: sleep control mechanisms; animal models of sleep; sleep deprivation influences on behavior and immune function in animals; regulation of body temperature and sleep-wake physiology; and fibromyalgia as a model for certain sleep disorders.

Dr. Robert W. McCarley, Professor and Head, Harvard Medical School Department of Psychiatry, and Deputy Chief of Staff for Mental Health Services at the Brockton/West Roxbury Veterans Administration Medical Center, in Brockton, Massachusetts, discussed all aspects of sleep. He began by saying that a rapid increase in the knowledge of basic mechanisms during the past 5 to 10 years has revolutionized our understanding of sleep. Dr. McCarley said that we start out awake and then gradually progress to the deeper stages of sleep, which include slow wave, delta, restorative, and thenREM (rapid eye movement). REM sleep is the phase that is associated with dreaming, and is promoted by cholinergic neurons (nerve cells that produce a substance called acetylcholine). These neurons turn on before and during the onset of REM sleep. He said that as you go to sleep, your cholinergic neurons are quiet. Then they become active, and at a certain threshold REM sleep occurs. The cycle repeats itself all through the night. "It has been a mystery whether REM sleep and slow wave sleep are linked together or arepart of the same process," Dr. McCarley said. He outlined recent research that demonstrated that nerve cells in the hypothalamus may control sleeping and waking states. Dr. McCarley said that ongoing studies of the structure of the brain show exciting possibilities that these nerve cells may also coordinate other systems including those controlling stress responses and the endocrine glands.
Dr. Carol Everson, Assistant Professor of Physiology and Biophysics at the University of Tennessee at Memphis, presented Dr. James M. Krueger's paper, which focused on immune and neuroendocrine functions. She said that there is much evidence that implicates interleukin-1 (IL-1) in sleep regulation. IL-1 is a molecule that is produced by certain cells of the immune system and occurs naturally in the brain. Studies have shown that IL-1 induces excess sleep in rabbits, cats, rats, and monkeys. IL-1 antibodies, which block the action of IL-1, inhibit normal sleep and restorative sleep after sleep deprivation.

Dr. Everson said that in sleep-deprived people psychiatric changes are marked and these include mood and dispositional changes, hallucinations, unusual body sensations, tremors, losses of equilibrium, slurred speech, and changes in brain waves. In addition, there are physiological changes such as a decrease in body temperature and in blood levels of cortisol. She said that sleep-deprivation is a risk factor in disease. Dr. Everson cited studies comparing sleep-deprived rats to rats that slept normally. She said that researchers demonstrated that sleep-deprived rats had a decline in blood levels of thyroid hormones that is consistent with central hypothyroidism in humans and experimental animals. She also found that the animals had depressed immune systems and bacteria appeared in their blood, indicating an increased susceptibility to infections.
Dr. Evelyn Satinoff, Chair of the Psychology Department at the University of Delaware in Newark, discussed the importance of thermal or temperature factors on sleep. In young female rats, she demonstrated that sleep and body temperature are interdependent. She said, "Animal studies in my laboratory demonstrated how REM sleep could be affected by temperatures above and below normal." Experiments in female rats demonstrated that aging is also associated with thermal and sleep rhythm disturbances. However, when old rats that were no longer ovulating were compared to young female rats that had their ovaries removed, the animals without ovaries did not show a deterioration in their sleep or body temperature rhythms. The rhythms were actually more precise. Similar studies in males also excluded a role for sex hormones. Further investigation showed that the instability of temperature and sleep rhythms with aging occur independently of one another.

Dr. Moldofsky said that fibromyalgia may be a model for sleep dysregulation. "The theoretical model is that the diffuse pain, the unrefreshing sleep, the fatigue, and psychological disturbance are the result of disturbances in the biological rhythms...," he added. Dr. Moldofsky cited studies on normal healthy people who participated in a sleep study. "When their sleep was disturbed they became tired and achy, and some had gastrointestinal symptoms."

After each segment, the panel discussed specific aspects of the research and how they might apply to fibromyalgia. At the completion of the talks, the chairmen summarized the results of the workshop. A lively discussion with comments from all attendees ensued.

At the conclusion of the meeting, Director Dr. Stephen I. Katz said, "This workshop will help to provide NIAMS with directions for future research and assist in planning efforts in this area." He also expressed hope that the workshop will stimulate scientists to submit grant applications for research on this disorder.

The meeting was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Nursing Research; National Center for Sleep Disorders of the National Heart, Lung, and Blood Institute; Office of Research on Women's Health, NIH Office of the Director; and Office of Behavioral and Social Sciences Research, NIH Office of the Director.

The voluntary organizations that were represented at the meeting included the American Fibromyalgia Syndrome Association, Inc.; the Fibromyalgia Alliance of America; the Fibromyalgia Association of Houston, Inc.; the Fibromyalgia Association of Greater Washington; the Fibromyalgia Association of Texas; the Fibromyalgia Network; the Fibromyalgia Resources Group; the Fibromyalgia Support Group of Frederick County, Maryland; the National Fibromyalgia Research Association; the Seattle Fibromyalgia International Team, Inc.; the Arthritis Foundation; and the Lupus Foundation of America.

Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases Scientific Workshop Summary. 12/96. BW.

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