NEUROENDOCRINE FUNCTION IN FIBROMYALGIA

Grant Number: 5K24AR002139-02
PI Name: CROFFORD, LESLIE J.
PI Title: ASSOCIATE PROFESSOR
Project Title: NEUROENDOCRINE FUNCTION IN FIBROMYALGIA

Abstract: The etiology of fibromyalgia (FM) and other chronic musculoskeletal pain syndromes remains unclear. Treatment options are limited and often ineffective. Our group considers FM to be one of a spectrum of disorders characterized by dysregulated hypothalamic-pituitary-adrenal (HPA) axis function spanning both somatic and psychiatric syndromes. The HPA axis is a principal component of the coordinate stree-response system that is activated in response to both physical and psychological stimuli. There are interactions between the HPA axis and other systems contributing to linkage between the central nervous system and peripheral structures. Evidence of functional interaction between stress response systems and descending pain modulatory pathways exists. These findings suggest a role for the central nervous system in chronic musculoskeletal pain syndromes such as FM. Our research program is a multidisciplinary effort focused on basal and stimulated HPA axis function of patients with FM that is directed by the applicant. Our program has strong institutional support from units within the institution, including the general clinical research, psychology and the Institute for Social Research, psychiatry, neurology, and internal medicine. We have developed a database of patients with FM from which patients to participate in our research efforts are recruited. There is an ongoing effort to recruit appropriate patients to participate in our programs. There is a tremendous need for clinical research in the area of musculoskeletal pain. The applicant's efforts in this area have stimulated a programmatic effort at this institution that did not previously exist. Funding from the applicants research efforts have been secured, and trainees have been recruited to participate in the research program. This award will allow for continuing high quality patient-oriented research in central and peripheral neuroendocrine function in FM and other syndromes of chronic musculoskeletal pain.

Thesaurus Terms: education evaluation /planning, fibromyalgia, health science research potential, hypothalamic pituitary adrenal axis, science education curriculum, medical outreach /case finding clinical research

Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2001
Department: INTERNAL MEDICINE
Project Start: 01-JUL-2000
Project End: 31-MAY-2005
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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NEUROENDOCRINE ALTERATIONS IN FIBROMYALGIA AND IBS

Grant Number: 5R01AR046122-02
PI Name: CHANG, LIN
PI Title:
Project Title: NEUROENDOCRINE ALTERATIONS IN FIBROMYALGIA AND IBS

Abstract: The long-range goal of this proposal is to develop an understanding of the etiology of chronic functional pain syndromes, such as fibromyalgia (FM) and irritable bowel syndrome (IBS). The constellation of symptoms in the FM and IBS suggest a failure to appropriately activate pain modulatory mechanisms, a failure to activate neuroendocrine stress mechanisms, and an alteration in the autonomic response. Our general hypothesis is that a neurobiological model exists in patients with FM and IBS, which includes as its primary components alterations in the following CNS responses to stressors: inadequate antinociceptive response, blunted hypothalamic-pituitary-adrenal (HPA) axis response and altered autonomic balance and responsiveness. By applying similar methodologies across two functional pain syndromes (FM, IBS, and IBS plus FM), we will elucidate if altered CNS circuits are shared by these functional disorders or are site-specific and may explain the differences in symptom expression in the somatic or visceral domains. The first aim is compare the visceral and somatic pain thresholds before and after a noxious conditioning stimulus in three female patient populations (IBS, FM and IBS plus FM) with female controls, which would allow us to determine if altered perceptual responses are due to hypersensitive afferent pathways, or to a failure to activate antinociceptive systems. To further characterize alterations in the activation of specific antinociceptive pathways in response to conditioning stimuli, we will assess the effect of pharmacological manipulations of the opioid system (fentanyl, naloxone), and the noradrenergic system (corticotropin-releasing hormone (CRH), dexamethasone) on pain thresholds. Finally, we will compare brain activation in regions known to play central roles in antinociception in the 4 study populations with H215O PET brain imaging during visceral and somatic stimuli before and after the conditioning stimulus. In the second aim, we will test the responsiveness of the HPA axis, which has been shown to be altered in patients with FM, in the 4 study populations and address the potential mechanisms to explain these HPA axis alterations. To characterize these alterations, we will obtain serial measurements of plasma cortisol and ACTH over a 24-hour period to assess baseline alterations in the diurnal pulsatile rhythm and synchrony of ACTH and cortisol. We will also assess HPA axis responsiveness to acute stress by comparing ACTH and cortisol levels before and after a visceral or somatic conditioning stimulus. Finally, in our third aim, we will compare autonomic responses to visceral and somatic stimuli during visceral and somatic conditioning paradigms. In order to determine if the response of central autonomic networks to visceral or somatic stimulation differ between the study groups, regional brain activation will be correlated to autonomic responses during the visceral and somatic stimuli in the PET studies using covariate analysis. The combination of experimental approaches should improve our understanding of the CNS mechanisms underlying functional pain syndromes.

Thesaurus Terms: disease /disorder etiology, fibromyalgia, irritable bowel syndrome, neuroendocrine system adrenocorticotropic hormone, afferent nerve, central nervous system, cortisol, hypothalamic pituitary adrenal axis, neuropharmacology, pain, pain threshold, stress, stressor brain visualization, clinical research, female, human subject

Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2000
Department: MEDICINE
Project Start: 13-SEP-1999
Project End: 31-AUG-2004
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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REGULATION OF ADRENAL FUNCTION IN FIBROMYALGIA

Grant Number: 5M01RR002635-170504
PI Name: ADLER, GAIL K.
PI Title:
Project Title: REGULATION OF ADRENAL FUNCTION IN FIBROMYALGIA

Abstract: The purpose of this study is to characterize the regulation of adrenal steroid hormone production in individuals with fibromyalgia and Chronic Fatigue Syndrome versus healthy individuals.

Thesaurus Terms: adrenal gland, corticosteroid, fibromyalgia, hormone regulation /control mechanism chronic fatigue syndrome clinical research, human subject

Institution: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG:

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ADAPTATION TO PAIN AND STRESS IN FIBROMYALGIA

Grant Number: 1R01AR046034-01A2
PI Name: ZAUTRA, ALEX J.
PI Title: PROFESSOR AND PROGRAM DIRECTOR
Project Title: Adaptation To Pain And Stress In Fibromyalgia

Abstract: APPLICANT'S DESCRIPTION: This grant focuses on individual differences in the stress response as significant factors determining who develops a chronic pain syndrome characterized by widespread pain, and who is unable to recover from it. Maladaptive responses to pain and withdrawal from positive social interactions are studied as key factors that underlie the affective distress and persistence of fibromyalgia symptoms. To test this model three well established methods of inquiry are used: 1. Field assessments of responses to stress, developed in prior research on arthritis patients, and 2. Laboratory tests of stress reactivity under controlled experimental conditions. 3. Longitudinal follow-up of patient status 2 years after pre-tests. Two groups of Osteoarthritis participants are studied: (1) 150 OA participants who meet criteria for Fibromyalgia (FM), and (2) 200 participants with osteoarthritis (OA) who report levels of pain comparable to the FM group, but who do not display the classic tender point symptoms found among those with FM. Longitudinal assessments on all subjects as well as thorough initial testing will permit three types of comparisons. 1.The examination of case-control differences between groups of FM respondents and those with OA only. 2.The examination of variables predictive of recovery among those with FM. 3. The examination of those factors predictive of the onset of widespread pain among the OA sample that displayed only regional pain at the initial assessment.

Thesaurus Terms: chronic pain, female, fibromyalgia, longitudinal human study, osteoarthritis, pain threshold, pathologic process, physiologic stressor, psychological adaptation comorbidity, coping, functional ability, human middle age (35-64), interpersonal relations, mental health, social adjustment, social support network, women's health behavioral /social science research tag, electromyography, field study, human subject, interview, patient oriented research, questionnaire, statistics /biometry

Institution: ARIZONA STATE UNIVERSITY
Fiscal Year: 2001
Department: PSYCHOLOGY
Project Start: 08-MAY-2001
Project End: 28-FEB-2006
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZRG1

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BIOBEHAVIORAL ETIOLOGY OF CHRONIC TEMPOROMANDIBULAR DISORDERS

Grant Number: 5R01DE011252-05
PI Name: FRICTON, JAMES R.
PI Title: PROFESSOR
Project Title: BIOBEHAVIORAL ETIOLOGY OF CHRONIC TEMPOROMANDIBULAR DISORDERS

Abstract: This research proposal is designed to determine which central and peripheral factors are involved in the etiology of chronic dysfunctional TMS. This study is a prospective observational cohort study in which baseline jaw dysfunction, oral habits, depression, and fibromyalgia are the primary risk factors to be evaluated for their prognostic importance in the development of chronic dysfunctional pain in temporomandibular disorders. The study design is a 3-year cohort study of 500 non-chronic TMD pain patients who will be followed at 18 and 36 months to determine which subjects develop chronic pain and the influence that these factors have in predicting development. These patients will meet Research Diagnostic Criteria (RDC) axis II Chronic Pain Grading system I or II and have a physical diagnosis of myofacial pain and/or temporomandibular joint (TMJ) disc displacement. Examination data will include the standardized exam of the RDC/TMD axis I, Craniomandibular Index, an occlusal index, and a tender point exam to screen for possible fibromyalgia. Questionnaires will include RDC/TMD axis I and II, coping strategies questionnaire, a self report fibromyalgia screening form, and IMPATH.

Thesaurus Terms: central nervous system, chronic disease /disorder, disease /disorder etiology, oral facial pain, oral pharyngeal disorder, pathologic process, peripheral nervous system, temporomandibular joint syndrome analgesic, coping, depression, disease /disorder proneness /risk, fibromyalgia, longitudinal human study, oral pharyngeal surgery, psychological model, psychometrics clinical research, human subject, oral pharyngeal disorder diagnosis, questionnaire, statistics /biometry

Institution: UNIVERSITY OF MINNESOTA TWIN CITIES Fiscal Year: 2001 Department: DIAGNOSTIC/SURGICAL SCIS Project Start: 01-SEP-1997 Project End: 30-JUN-2002 ICD: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH IRG: BEM

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OUTCOMES IN YOUNG WOMEN WITH FIBROMYALGIA

Grant Number: 5R21AR046084-02
PI Name: BURCKHARDT, CAROL S.
PI Title: PROFESSOR
Project Title: OUTCOMES IN YOUNG WOMEN WITH FIBROMYALGIA

Abstract: The prospect of becoming unable to function in a satisfying manner as a result of fibromyalgia is of great concern to newly diagnosed woman as well as health care providers, policy makers, and payers. The goal of this pilot project is to gain information that can be used to support the development of new and innovative early intervention strategies to prevent long-term negative outcomes and promote the health and quality of life of young women with fibromyalgia. Perspectives from newly diagnosed young women in two countries with different approaches to social welfare (United States and Sweden) will be described. The specific aims are to: (1) describe the perceived difficulties and limitations encountered by young women with fibromyalgia; and, (2) develop a model that can be used to assist health care providers in planning early intervention treatment strategies that minimize dysfunction and maximize health status and quality of life. The study will use a descriptive, correlational design in which data will be collected 3 times at 6-month intervals from 100 newly diagnosed women between the ages of 18 and 39 recruited from two specialty care settings. Data concerning symptoms, physical and psychological function, work status, leisure activity, medical regimens, self-management activities, social support demographic risk factors, health status and quality of life will be obtained through semi-structured interviews, standardized questionnaires, and physical fitness testing.

Thesaurus Terms: adolescence (12-18), adult human (19+), disabling disease, female, fibromyalgia, human population study, person with disability, quality of life Scandinavian country, United States, data collection methodology /evaluation, disease /disorder prevention /control, employment of women, health care model, longitudinal human study, outcomes research, patient care planning, psychological adaptation, self care, social adjustment, social service, women's health clinical research, human subject, interview, questionnaire

Institution: OREGON HEALTH SCIENCES UNIVERSITY
Fiscal Year: 2000
Department: PRIMARY HEALTH CARE
Project Start: 01-MAY-1999
Project End: 30-APR-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

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PAIN PERCEPTION AND HEALTH CARE SEEKING BEHAVIOR IN FIBROMYALGIA

Grant Number: 5M01RR000032-410582
PI Name: BRADLEY, LAURENCE A.
PI Title:
Project Title: PAIN PERCEPTION AND HEALTH CARE SEEKING BEHAVIOR IN FIBROMYALGIA

Abstract: The initial purpose of this project was to examine abnormal pain perception and health care seeking behavior among persons with fibromyalgia (FM). Our initial subject groups consisted of 66 rheumatology clinic patients with FM, 39 community residents with FM who had not obtained medical care for their painful FM symmptoms in the past 10 years (i.e., nonpatients), and 39 healthy controls recruited from the community. We found that both patients and nonpatients with FM show significantly lower pain threshold levels and produce significantly higher scores on an index of sensory discrimination than healthy controls. These findings were replicated at 1- and 2-year followup assessments. These findings indicated that abnormal pain perception is associated with FM independently of health care seeking behavior. Moreover, it was found that lifetime history of psychiatric disorders was the best psycho-social predictor of obtaining health care at a tertiary care, rheumatology clinic for FM symptoms, i.e., greater psychiatric morbidity was associated with health care seeking. This indicated that the high levels of psychiatric morbidity seen in tertiary care clinic patients with FM is more strongly related to health care seeking than to the disorder itself. This project has been renewed by the NIH for another four years. The purpose of the second cycle of the project is to examine functional brain activity in three groups of subjects during resting conditions and during exposure to an acute painful stimuluus. These groups are 30 patients with fibromyalgia, 30 patients with chronic fatigue syndrome, and 30 healthy controls. Functional brain activity is assessed by single photon emission computed tomographic imaging. Four subject protocols have been completed at present. It is anticipated that patients with fibromyalgia will show inhibited funtional brain activity, relative to patients with chronic fatigue syndrome and controls, in the thalamus and caudate nucleus during resting conditions and during painful stimulation. However, it also is expected that the fibromyalgia patients, compared to the other subject groups, will show higher levels of functional brain activity in the anterior cingulate cortex during painful stimulation.

Thesaurus Terms: fibromyalgia, health behavior, health care service utilization, pain, perception epidemiology, longitudinal human study, social psychology behavioral /social science research tag, clinical research, health services research tag, human subject, psychometrics

Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG:

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MECHANISM OF PAIN IN PATIENTS WITH FIBROMYALGIA SYNDROME

Grant Number: 5R01NS038767-03
PI Name: STAUD, ROLAND M.
PI Title: ASSOCIATE PROFESSOR
Project Title: MECHANISM OF PAIN IN PATIENTS WITH FIBROMYALGIA SYNDROME

Abstract: Fibromyalgia Syndrome (FMS) is characterized by chronic widespread pain associated with allodynia. Our preliminary experiments with FMS subjects have indicated abnormalities of second pain in these patients which are related to central N-methyl-D-aspartate (NMDA) receptor processing. Our basic hypothesis is that abnormal central pain processing of second pain in FMS subjects is one of the fundamental abnormalities in this syndrome. Second pain results from impulse conduction in peripheral C (unmyelinated) afferent axons and is particularly sensitive to inhibition by opioid compounds. Second pain also increases in intensity when stimuli are applied more often than once every three seconds and this summation has been hypothesized to result from a central NMDA receptor mechanism. First pain is related to stimulation of A-Delta (myelinated) nociceptors and has been utilized almost exclusively to evaluate pain sensitivity. In order to compare directly abnormal processing of A-Delta and C-Fiber input in FMS subjects, we will utilize forms of brief experimental pain stimuli that can reliably evoke perceptions of first and second pain when applied to the hand or foot of human subjects. We will test the hypothesis that oral doses of dextromethorphan, a common cough suppressant and NMDA receptor antagonist, will selectively reduce temporal summation of second pain for normal male and female subjects. The purpose of another experiment is to examine the effects of graded doses of naloxone and fentanyl on first and second pain and temporal summation of second pain for normal male and female subjects, This analysis is designed to answer questions about opioid mechanisms of pain reduction and about the possible existence of a tonic endogenous pain modulatory system. These psychophysical tests of NMDA receptor mechanisms, opioid responsiveness, and level of tonic pain inhibitory mechanisms will then be compared across pain-free control subjects and fibromyalgia patients in order to ascertain the extent to which abnormalities of these mechanisms contribute to these pain states. Potential sex differences in pain sensitivity and effects of pharmacological manipulations will be evaluated in normal subjects and pain patients, with attention to the impact of psychosocial variables. Also, relevant to the greater risk factor for females to present with fibromyalgia, ovarian hormone states will be monitored in female subjects. Because fibromyalgia is a generalized muscular pain disorder which characteristically worsens with physical activity, the effects of exercise on different forms of pain sensitivity will be compared for fibromyalgia patients and matched normal controls.

Thesaurus Terms: NMDA receptor, chronic pain, fibromyalgia, pain, pain threshold C fiber, dextromethorphan, drug screening /evaluation, exercise, fentanyl, gender difference, myelin, naloxone, opioid, psychopharmacology, psychophysics, sex hormone, somatic afferent nerve clinical research, human subject, oral administration

Institution: UNIVERSITY OF FLORIDA
Fiscal Year: 2001
Department: MEDICINE
Project Start: 10-JUN-1999
Project End: 31-MAY-2002
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZRG1

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EFFECTIVENESS OF STATIC MAGNETIC FIELDS IN FIBROMYALGIA

Grant Number: 5F31AT000058-02
PI Name: BOYDEN, KATHLEEN M.
PI Title:
Project Title: EFFECTIVENESS OF STATIC MAGNETIC FIELDS IN FIBROMYALGIA

Abstract: Fibromyalgia affects up to an estimate 10 percent of the population, primarily women. The syndrome is characterized as both a musculoskeletal and a subtle neurological disorder, and is associated with widespread muscle pain and tender points, along with fatigue, muscle weakness, and stiffness. Conventional medical approaches have limited success in treating fibromyalgia, leading patients to seek complementary therapies, including the use of magnetic therapies, in the hope of finding more effective pain relief. However, the efficacy and safety of magnetic therapy has not been definitively established through rigorously controlled trials. This double-blind randomized placebo-controlled study is the second in a series investigating the efficacy of static magnetic field (SMF) therapies in alleviating symptoms associated with fibromyalgia. Chronic conditions are frequently associated with poor quality of life; and fibromyalgia is associated with even poorer quality of life than a variety of other chronic conditions such as rheumatoid arthritis, osteoarthritis, permanent ostomies, chronic obstructive pulmonary disease, and insulin dependent diabetes. Successful management of pain, the primary symptom of fibromyalgia, may result in improved quality of life. The study tests the primary hypotheses that locally applied quadripolar SMF devices, which have been shown to suppress the firing of action potentials of sensory neurons, will provide pain reduction and other therapeutic benefits. It is further proposed that treatment with SMF devices will lead to improved functional status and improved quality of life. The specific aims of the research are to compare the effects of quadripolar SMF devices externally applied to tender points and the effects of magnetic placebo devices. The proposed study will include a 6-month treatment period and a 9 month follow-up assessment to determine long-term effectiveness.

Thesaurus Terms: fibromyalgia, human therapy evaluation, magnetic field, musculoskeletal disorder therapy alternative medicine, clinical research, human subject

Institution: UNIVERSITY OF VIRGINIA CHARLOTTESVILLE
Fiscal Year: 2001
Department: NURSING
Project Start: 01-JUN-2000
Project End:
ICD: NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
IRG: NRRC

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REGULATION OF ADRENAL FUNCTION IN FIBROMYALGIA

Grant Number: 5R01AR043130-07
PI Name: ADLER, GAIL K.
PI Title: ASSISTANT PROFESSOR
Project Title: REGULATION OF ADRENAL FUNCTION IN FIBROMYALGIA

Abstract: DESCRIPTION: (Adapted From Applicant's Abstract) This competitive renewal project proposes to extend studies of the hypothalamic-pituitary-adrenal axis in fibromyalgia syndrome previously undertaken by the PI. Her initial data suggested reduced adrenocorticotropin (ACTH) and epinephrine responses to graded hypoglycemic challenge, and blunting of the normal diurnal cortisol rhythm in patients with fibromyalgia when compared to normal controls. The PI postulates that the decreased ACTH response to hypoglycemic challenge is the result of impaired CRH release, this also results in decreased sympathoadrenal response to hypoglycemia. The PI further proposes that the diurnal cortisol rhythm in patients with fibromyalgia is abnormal due to a shift in the circadian phase. In Specific Aim 1, the PI and her colleagues propose to assess hypothalamic CRH-pituitary ACTH activity at baseline and in response to three stimuli: hypoglycemia, metapyrone-induced glucocorticoid administration, and an immune stimulus with tetanus toxoid vaccine. In Specific Aim 2, sypathoadrenal responses to hypoglycemia, the cold pressor test, metapyrone vs. placebo will be compared in patients with fibromyalgia and controls. In Specific Aim 3, the circadian phase (measured by core body temperature and melatonin levels) will be compared in women with fibromyalgia and healthy controls. Additional studies of the relationship between disrupted sleep pattern and night-time secretion of ACTH and cortisol and cytokines are planned if the circadian phase is not shifted.

Thesaurus Terms: corticotropin releasing factor, cortisol, fibromyalgia, hormone regulation /control mechanism, hypothalamic pituitary adrenal axis, pituitary adrenal axis adrenal gland, body temperature, circadian rhythm, glucocorticoid, hypoglycemia, melatonin, sleep, tetanus toxoid clinical research, female, human subject, placebo

Institution: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2000
Department:
Project Start: 25-SEP-1994
Project End: 31-JUL-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZRG5

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