1) Patient Behavioral Insomnia Therapy for Fibromyalgia:
Funded by NIAMS - $107,321
Jack D. Edinger, PhD. - Duke University Medical Center, Durham, NC

This prospective randomized clinical trial will test whether cognitive behavioral therapy will improve insomnia in patients with fibromyalgia.

BEHAVIORAL INSOMNIA THERAPY FOR FIBROMYALGIA PATIENT

    Grant Number: 5R21AR046094-03
    PI Name: EDINGER, JACK D.
    PI Title: ASSOCIATE CLINICAL PROFESSOR
    Project Title: BEHAVIORAL INSOMNIA THERAPY FOR FIBROMYALGIA PATIENTS

Abstract: Fibromyalgia (FM) is a prevalent and debilitating condition which contributes to impaired occupational/social functioning and increased disability among affected individuals. The vast majority of FM patients present with persistent sleep disturbances (e.g. onset difficulty; repeated or extended awakenings; nonrestorative sleep) which worsen other FM-related symptoms (e.g. chronic pain, fatigue) and sustain their general dysfunction. Pharmacologic treatments (e.g. antidepressants, hypnotics) may produce symptom reduction for some FM patients but many FM patients display little enduring improvement in their sleep and other FM-related symptoms in response to such agents. Our clinical observations and initial pilot work have suggested that factors common among other insomnia subtypes such as conditioned bedtime arousal, erratic sleep/wake scheduling and spending too much time in bed likely perpetuate the sleep problems of these medication-refractory FM patients. Over the past decade, we have developed, refined, and repeatedly tested a cognitive-behavioral therapy (CBT) which has proven effective for reducing sleep disturbances perpetuated by such underlying cognitive/behavioral mechanisms. Moreover, as suggested by the case study reported herein, this treatment holds promise for addressing medication-refractory FM-related sleep disturbance. The proposed project's Specific Aims/Major Objectives entail conducting a prospective randomized clinical trial to confirm these preliminary findings and to determine the efficacy of CBT insomnia treatment for interrupting the disturbed nocturnal sleep/daytime pain, fatigue and distress symptom complex which defines FM. One arm of this study's 3 x 4 factorial design will compare CBT with both a contact control treatment and standard care. The other arm in the design is a repeated-measures factor consisting of 4 time points (i.e. baseline, mid-treatment, post-treatment, and 6 month follow-up periods) at which outcome is assessed. Subjects will be assessed at all 4 time points with objective (wrist actigraphy) and subjective (sleep logs, Insomnia Symptom Questionnaire) measures of sleep improvements, measures of subjective pain, and questionnaires which assess mood (State-Trait Anxiety and Beck Depression Scales) and general quality of life (SF-36). Multivariate statistics and tests of clinical significance will be conducted with these various measures. Exploratory analyses will also be conducted to determine if polysomnographically-derived sleep measures obtained prior to treatment correlate with initial levels of pain/distress or eventual treatment outcome. Results should provide information about the usefulness of CBT for treating FM-related sleep difficulties. Results should also improve understanding of the FM syndrome in general and provide new information about the potential role of behavioral therapy in the overall management of this disorder.

Thesaurus Terms: cognitive behavior therapy, fibromyalgia, human therapy evaluation, sleep disorder clinical trial, emotion, pain, personal log /diary, quality of life, wakefulness behavioral /social science research tag, clinical research, human subject, outcomes research, polysomnography, questionnaire

Institution: DUKE UNIVERSITY
Fiscal Year: 2001
Department: PSYCHIATRY AND BEHAVIORAL SCIS
Project Start: 01-JUL-1999
Project End: 30-JUN-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

Purpose

MedlinePlus related topics:  Fibromyalgia;   Sleep Disorders
 

Study Type: Interventional
Study Design: Treatment, Randomized, Single Blind, Active Control, Parallel Assignment, Efficacy Study

Official Title: Behavioral Insomnia Therapy for Fibromyalgia Patients

Study start: July 1999;  Study completion: June 2003
 

Eligibility

Location Information

More Information

Publications

Krystal AD, Edinger J, Wohlgemuth W, Marsh GR. Sleep in peri-menopausal and post-menopausal women. Sleep Med Rev. 1998 Nov;2(4):243-53.

Publications that report results of this study

Edinger JD, Wohlgemuth WK, Krystal AD, Rice JR. Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial. Arch Intern Med. 2005 Nov 28;165(21):2527-35.

2) Autonomic Stress-Reactivity in Fibromyalgia:
Funded by NIAMS - $98,297
Akiko Okifuji, PhD - University of Washington School of Medicine, Seattle

The relationship between stress-reactivity and pain sensitivity in fibromyalgia patients will be examined and compared to that of patients with temporomandibular disorder (who have localized pain) and pain-free people.

AUTONOMIC'STRESS REACTIVITY IN FIBROMYALGIA

    Grant Number: 1R21AR46077-01
    PI Name: OKIFUJI, AKIKO
    PI Title:
    Project Title: AUTONOMIC STRESS REACTIVITY IN FIBROMYALGIA

Abstract: This is an R21 application proposing to conduct a preliminary study on the relationship between autonomic stress-reactivity and pain sensitivity in patients with fibromyalgia syndrome (FMS). Although the exact pathphysiologic mechanisms of FMS are yet to be determined, FMS is generally considered as a disorder involving dysregulated central pain modulation. In addition, FMS seems to be associated with dysfunctional stress adaptation. Many FMS patients report that stress exacerbates their pain and symptoms. Research has suggested that autonomic dysregulation exists in FMS. FMS patients tend to exhibited blunted autonomic reactivity to noise, cold, and physical stressors. Research in cardiovascular and headache disorders, as well as animal/human laboratory studies, have demonstrated the antinociceptive effects of increased arousal, particularly baroreflex and occulosympathetic reactivity. These previous reports suggest that dysregulated autonomic functions in response to stressors play an important role in elevated pain sensitivity and other FMS symptoms.
In the proposed study, we hypothesize that

1) FMS is associated with blunted sympathetic reactivity,

2) FMS is related to increased susceptibility to develop orthostatic intolerance, and

3) stress-induced analgesics are minimized in FMS.

30 FMS patients, 30 patients with temporomandibular disorder (TMD: localized pain control), and pain-free healthy subjects will undergo various stress tasks, orthostatic tolerance test, and pain sensitivity test while blood pressure and pupil size are continuously measured. The levels of stress associated with tasks are relatively moderate (mental arithmetic, discussion of stressful experience), thereby allowing us to determine the importance of daily stressors patients report as an aggravating factor. Results from this study thus should provide initial evidence regarding the effects of stress-induced dysautonomia in FMS symptoms. Furthermore, the results of the study may provide an important avenue for improving those symptoms secondary to autonomic dysfunction.

Thesaurus Terms: autonomic reflex, fibromyalgia, pain threshold, stress, temporomandibular joint syndrome, analgesia, baroreflex, blood pressure, pathologic process, postural hypotension, clinical research, female, human subject

Institution: UNIVERSITY OF WASHINGTON
3935 UNIVERSITY WAY NE
SEATTLE, WA 98195
Fiscal Year: 1999
Department: ANESTHESIOLOGY
Project Start: 01-JUL-99
Project End: 30-JUN-02
ICD: NAT INST OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

3) Employment and Health Status Among Women With Fibromyalgia:
Funded by NIAMS - $264,115
Susan Reisine, PhD - University of Connecticut School of Medicine, Center, Farmington

This project will explore the relationship among paid work, family work, daily stress and psychological health among women with fibromyalgia.
 

EMPLOYMENT AND HEALTH STATUS IN WOMEN WITH FIBROMYALGIA

    Grant Number: 5R01AR046041-03
    PI Name: REISINE, SUSAN T.
    PI Title: PROFESSOR AND HEAD
    Project Title: EMPLOYMENT AND HEALTH STATUS IN WOMEN WITH FIBROMYALGIA

Abstract: Preliminary data on women with rheumatoid arthritis (RA) indicate that those who are able to enter and leave the work force experience the best health outcomes; homemakers report the worst health. These findings raise several new questions about the dynamic relationship among paid work, unpaid family work and health status among women with rheumatic diseases and whether these results hold for other musculoskeletal conditions. We propose to study women with primary fibromyalgia syndrome (FMS) and to describe prospectively the simultaneous evolution of health status, paid work status, unpaid family work, and daily stressors. Women with MS will be compared to a control group similar in age, race, and employment status. Finding from the study will shed light on the relationships among paid and unpaid family work and physical and psychological health status. We will recruit a sample of 245 women diagnosed with FMS and 250 healthy women from the community similar in age, race, and employment status. The total sample will consist of equal groups of those who are employed outside the home and those who are not currently employed. Patients will be recruited from a national sample of rheumatologists who are fellows in the ACR. Annual interviews will be conducted with participants from a national sample of rheumatologists who are fellows in the ACR. Annual interviews will be conducted with participants to collect detailed data on family and employment structure and functional status. Participants to collect detailed data on family and employment structure and functional status. Participants also will complete a daily diary for one week at the time of the baseline and annual interviews each year to collect detailed data on daily stressors as possible mediator of work and family structure on functional status. The proposed study will provide data describing the natural course of paid and unpaid family work and health status among FMS patients and control subjects and will address questions about the relationship between paid work, unpaid family work structure and the physical and psychological health status of women with FMS and controls. The data will be analyzed first, using descriptive statistics in order to describe the experiences of the patients and controls in the study; second, MANOVA and MANCOVA techniques will be used to assess differences in health status between groups at baseline and to assess changes over time in health status between groups adjusting for covariates.

Thesaurus Terms: employment of women, fibromyalgia, quality of life, women's health family, functional ability, health behavior, occupational psychology, personal log /diary, psychological stressor, rheumatoid arthritis behavioral /social science research tag, clinical research, female, human subject, interview

Institution: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
Fiscal Year: 2001
Department: BEHAV SCIS & COMMUNITY HEALTH
Project Start: 01-JUL-1999
Project End: 30-JUN-2004
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

4) Noradrenergic Dysfunction: A Model of Fibromyalgia Pain:
Funded by NIAMS - $107,167
Luc Jasmine, MD, PhD - Georgetown University, Washington DC

The goal of this project is to develop a rat model of fibromyalgia pain by manipulating the release of substance P, a chemical involved in the transmission of pain signals via the nervous system.

NORADRENERGIC DYSFUNCTION--A MODEL OF FIBROMYALGIA PAIN

    Grant Number: 5R21AR046085-03
    PI Name: JASMIN, LUC
    PI Title:
    Project Title: NORADRENERGIC DYSFUNCTION--A MODEL OF FIBROMYALGIA PAIN

Abstract: The goal of this project is to develop a rat model of fibromyalgia pain which could provide the basis for future research into this complex disease. The difficulty in finding an etiology for this painful condition is in part because fibromyalgia is not a discrete or unique disease, but patients also a display number of different symptoms in addition to the widespread tenderness, including fatigue, sleep disturbances, headaches, gastrointestinal symptoms, etc. As such, fibromyalgia overlaps conditions such as Chronic Fatigue Syndrome, Irritable Bowel Syndrome, tension and migraine headaches. These conditions share several features, including a female predominance, initiation or exacerbation in response to several different types of "stressors", and response to similar types of pharmacologic and non-pharmacologic modalities (e.g. tricyclic drugs, aerobic exercise). A dysfunction of the noradrenergic system, the basis for the proposed model, presents a unifying explanation for many seemingly disparate findings in fibromyalgia by accounting for the neuroendocrine and autonomic abnormalities, in addition to the chronic pain. Our guiding hypothesis is that in fibromyalgia, chronically decreased noradrenergic input to the spinal cord facilitates substance P release and subsequent hyperalgesia (decreased threshold for pain). This hypothesis is based on both clinical evidence of decreased noradrenaline and increased substance P in the spinal cord of fibromyalgia patients, as well as evidence from basic research demonstrating that acute decreases in spinal noradrenaline allow for greater release of substance P and sustained hyperalgesic effects of this neurotransmitter. These alterations in turn result in greater expression and redistribution of the substance P receptor in the spinal cord, contributing to the chronicity of the hyperalgesia. In the female rat, we will apply a novel technique of selective immunolesion of brainstem noradrenergic input to nociceptive areas of the spinal cord. The first aim will test the hypothesis that lowered nociceptive thresholds in rats with decreased spinal noradrenaline depend on substance P neurotransmission. This hypothesis will be tested by determining the contribution of spinal SP neurotransmission in alterations of nociceptive behavioral and neuronal responses to noxious and innocuous stimuli. The second aim will test the hypothesis that chronically decreased spinal noradrenaline chronically increases basal levels, and facilitates evoked release of substance P, by measuring levels of substance P in the CSF, primary afferent neurons, and spinal cord, both basal and following noxious and innocuous stimulation. In the third aim, we will test the hypothesis that decreased spinal noradrenaline facilitates stimulus-induced increased expression and redistribution of the substance P receptor (NK1 receptor) in the spinal cord by measuring basal and noxious stimulus-induced alterations in the expression of this receptor.

Thesaurus Terms: disease /disorder model, fibromyalgia, model design /development, norepinephrine, pain threshold cerebrospinal fluid, chronic pain, endocrine disorder, hyperalgesia, neuroendocrine system, neuropeptide receptor, receptor expression, spinal cord, substance P female, laboratory rat

Institution: UNIVERSITY OF CALIFORNIA SAN FRANCISCO
Fiscal Year: 2001
Department: NEUROLOGICAL SURGERY
Project Start: 01-JUL-1999
Project End: 30-JUN-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

5) Chronic Low Back Pain as a Model of Fibromyalgia:
Funded by NIAMS - $258,300
Daniel Clauw, MD - Georgetown Medical Center, Washington DC

This study will examine the relationship of pain sensitivity to clinical outcome and physiological and psychosocial factors in both fibromyalgia and low back pain.

    Grant Number: 5R01AR046049-04
    PI Name: CLAUW, DANIEL J.
    PI Email: clauwd@gunet.georgetown.edu
    PI Title: ASSOCIATE PROFESSOR
    Project Title: CHRONIC LOW BACK PAIN AS A MODEL OF FIBROMYALGIA

Abstract: Fibromyalgia (FM) is defined by a history of widespread pain, and the finding of tender points on examination. Arguably the two most discriminating features of FM are: 1) a generalized disturbance in pain perception, and 2) elevated levels of pro-nociceptive neuropeptides in the cerebrospinal fluid. The first feature, pain induced by a normally non-painful stimuli, is not surprising since this is a defining feature of FM. But it is not certain how tenderness relates to pain, since population based studies have demonstrated that not all persons who are tender have pain, and vice versa. And it has recently become clear that tender points are a poor measure of a person's inherent tenderness. The meaning of these elevated levels of CSF neuropeptides is likewise unclear. These findings may not be specific for FM, and may be the cause of pain and/or tenderness, or may be the result of pain, tenderness, or some other process. Chronic lower back pain (CLBP) is among the most common medical problems in industrial societies. Despite this, little is actually known about the precise cause for most cases of CLBP. Anatomic and psychosocial factors have been demonstrated to predict only a small portion of the variance in the degree of pain or disability in CLBP. In preliminary studies in CLBP, we have demonstrated that tenderness predicts a significant percentage of the variance in both functional status and pain, more than either the severity of path-anatomical abnormality (i.e., X-ray/MRI),or by psychosocial factors. In a small pilot study of a subset of these patients tenderness was correlated with CSF levels of pro-nociceptive neuropeptides. There are 3 specific aims in the proposed study: 1) To confirm in a cross-sectional study of 200 CLBP patients that pain sensitivity predicts more variance in clinical outcome (e.g. functional status, pain level, Roland index) than either anatomic or psychological factors. Furthermore, we will demonstrate that pain sensitivity is an independent trait, and not a surrogate for psychological factors such as depression, anxiety, or work-related stressors. 2) To demonstrate that an individual's global pain sensitivity is determined primarily by physiologic factors (e.g. neurotransmitters in cerebrospinal fluid) and modified by psychosocial factors (e.g. cognitive and behavior influences on pain perception). We will measure the CSF concentrations of pro-nociceptive peptides such as Substance P and Nerve Growth Factor, and hypothesize that the levels of these substances largely determine an individual's global pain sensitivity. This testing will be done in patients with CLBP and FM, as well as sedentary and non-healthcare-seeking controls. 3) To use alternative methods of pain assessment that are much less influenced by psychological factors (e.g., scaling methods, Multiple Random Staircase), using both pressure and thermal stimuli, to examine the true meaning of tender points, and the relationship between these results, and the results of the above noted physiologic and psychologic parameters in individuals with FM and CLBP.

Thesaurus Terms: backache, chronic pain, disease /disorder model, fibromyalgia, hyperalgesia, neural information processing, pain threshold, psychophysiology
cerebrospinal fluid, cognition, comorbidity, heat stimulus, neuropeptide, neurotrophic factor, prognosis, sensory discrimination, sensory mechanism, substance P, clinical research, human subject, lumbar puncture, personality test, questionnaire

Institution: GEORGETOWN UNIVERSITY
WASHINGTON, DC 20057
Fiscal Year: 2002
Department: MEDICINE
Project Start: 15-JUN-1999
Project End: 31-MAY-2004
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

6) Exercise-Induced Changes in HPA Activity in FMS:
Funded by NIAMS - $180,937
Patricia Deuster, PhD, MPH - Henry Jackson Foundation, Rockland, Maryland

This clinical project will attempt to determine whether aerobic exercise benefits patients with fibromyalgia by enhancing the hypothalamic stimulus of pituitary and adrenal gland function.

EXERCISE INDUCED CHANGES IN HPA ACTIVITY IN FIBROMYALGIA

    Grant Number: 5R01AR046016-02
    PI Name: DEUSTER, PATRICIA A.
    PI Title:
    Project Title: EXERCISE INDUCED CHANGES IN HPA ACTIVITY IN FIBROMYALGIA

Abstract: Five to 10 percent of patients entering general practice centers report symptoms of fibromyalgia syndrome (FMS), a painful and debilitating condition of the musculoskeletal system. Although the cause(s) and pathophysiology of this disorder are poorly understood, FMS has been referred to as a syndrome of physical deconditioning and involves dysregulation of the hypothalamic- pituitary-adrenal (HPA) axis. Interestingly, regular exercise has been shown to confer benefit for some patients with FMS, as well as rheumatoid arthritis and depression. Importantly these health conditions all have the common element of reduced hypothalamic drive for pituitary adrenal function. Thus, exercise may confer benefit in FMS by upregulating hypothalamic drive to the pituitary and adrenal glands. The overall objective of this proposal is to determine whether aerobic training benefits FMS by inducing alternations in HPA axis regulation. The central hypothesis is that aerobic training serves to enhance hypothalamic drive, and thus pituitary-adrenal function. Specifically, 20 patients with FMS and 20 age-, gender-, weight-matched controls will be challenged at baseline; after 12 weeks with no intervention (control), and after 12 weeks of aerobic conditioning to evaluate whether aerobic training results in: (1) An increase in hypothalamic drive as evidenced by augmented adrenocorticotropin (ACTH) responses to a standardized exercise test (SET); (2) An increase in tonic and stimulated hypothalamic drive as evidenced by augmented ACTH responses following administration of metyrapone and dexamethasone (DEX) coupled with SET; (3) An increase in hypothalamic-pituitary responsiveness as evidenced by augmented ACTH responses stimulated by a bolus of ovine corticotropin releasing hormone (o-CRH) after pretreatment with DEX; and (4) Improved clinical and psychological profiles in FMS. Plasma ACTH will be used to assess hypothalamic drive during four challenge tests: (a) SET for control stimulation; (b) SET during enhancement of glucocorticoid negative feedback by DEX; (c) tonic and SET during attenuation of glucocorticoid negative feedback by metyrapone; and (d) responsivity of pituitary corticotropes following a bolus of o-CRH during enhancement of glucocorticoid negative feedback by DEX. Finally, disease activity (tender point index, tender point score, and myalgic score), and self-reported physical measures of function, depression and self efficacy will be used to assess clinical and psychological profiles over the course of the study. The information gained will provide an understanding of the pathology of FMS and the mechanisms by which exercise confers benefit in FMS. Given the important role exercise serves in the prevention of disease, this information will also contribute to our basic knowledge regarding how exercise modulates HPA axis reactivity in health and, in so doing suggest, mechanisms for HPA dysregulation in disease.

Thesaurus Terms: adrenocorticotropic hormone, aerobic exercise, fibromyalgia, hormone regulation /control mechanism, hypothalamic pituitary adrenal axis arginine vasopressin, corticotropin releasing factor, depression, dexamethasone, emotion, metyrapone, pain, self concept clinical research, human subject, human tissue, questionnaire, urinalysis

Institution: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
Fiscal Year: 2000
Department:
Project Start: 15-SEP-1999
Project End: 31-AUG-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1

7) Outcomes in Young Women With Fibromyalgia:
Funded by NIAMS - $95,929
Carol Burckhardt, PhD - Oregon Health Sciences University, Portland

This pilot project will develop a model to plan early intervention strategies that minimize disabilities and maximize health status in young women with fibromyalgia.

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

8) A controlled Family Study in Patients With Fibromyalgia:
Funded by NIAMS - $212,615
Lesley Arnold, MD - University of Cincinnati, College of Medicine

This study will determine the prevalence of irritable bowel syndrome, migraines, chronic fatigue syndrome and mood disorders in first-degree relatives of patients with fibromyalgia. It will explore whether a common risk factor or pathophysiologic mechanism exists among affected family members. The study will compare the results with those obtained in families of people with rheumatoid arthritis.

CONTROLLED FAMILY STUDY IN PATIENTS WITH FIBROMYALGIA

Grant Number: 5R01AR046054-03
PI Name: ARNOLD, LESLEY M.
PI Title: ASSOCIATE PROFESSOR
Project Title: CONTROLLED FAMILY STUDY IN PATIENTS WITH FIBROMYALGIA

Abstract: Fibromyalgia, a chronic musculoskeletal pain disorder of unknown etiology, is a significant public health problem. Evidence from studies of phenomenology, comorbidity, family history, and pharmacologic treatment response suggest that fibromyalgia may be associated with major mood disorder, and possibly to a proposed group of conditions known as affective spectrum disorders. Prior psychiatric research has demonstrated that major mood disorder is highly familial. Family history studies provide a method by which to assess how medical disorders co-aggregate in families and, therefore may share a common risk factor or pathophysiologic mechanism. To date, few studies have explored the morbid risk of major mood disorder (and other proposed affective spectrum disorders) in probands with fibromyalgia and their first- degree relatives. All of these studies have used the family history method, which entails interviewing probands regarding their knowledge of psychiatric illness in relatives. Although most of these studies have provided important preliminary data suggesting an association between fibromyalgia and major mood disorder, this method has been demonstrated to be less sensitive in detecting illness in relatives than direct interview (the family interview method). In order to provide further evidence of a relationship between fibromyalgia and major mood disorder, we propose to study the prevalence of psychiatric and rheumatologic disorders in probands with fibromyalgia and their first-degree relatives as compared to probands with rheumatoid arthritis and their relatives using the family interview method. In addition to assessing the degree of co-aggregation of these disorders within families, we will also study the occurrence of other conditions within the proposed group of affective spectrum disorders in relation to fibromyalgia, and the association between the severity of fibromyalgia symptoms and the presence of major mood disorder within families.

Thesaurus Terms: comorbidity, family genetics, fibromyalgia, mood disorder, rheumatoid arthritis anxiety disorder, bipolar depression, chronic fatigue syndrome, interview, irritable bowel syndrome, major depression, mental health epidemiology, migraine clinical research, human subject

Institution: UNIVERSITY OF CINCINNATI
Fiscal Year: 2001
Department: PSYCHIATRY
Project Start: 01-JUL-1999
Project End: 30-JUN-2002
ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1





9) FMS, Depression, and Myofacial Pain:

Funded by NIDCR - $485,341

Karen Raphael, PhD - University of Medicine and Dentistry of New Jersey, Newark



This project explores the cause and nature of the association of fibromyalgia and temporomandibular disorders with myofacial pain syndrome. Temporomandibular disorders are associated with chronic pain in the temporomandibular (jaw) joint and the muscles of mastication (chewing).



FIBROMYALGIA, DEPRESSION AND MYOFASCIAL TMD
Grant Number: 1R01DE13486-03
PI Name: RAPHAEL, KAREN G.
PI Title:
Project Title: FIBROMYALGIA, DEPRESSION AND MYOFASCIAL TMD

Abstract:
DESCRIPTION (taken from the application): The well-established comorbidity of fibromyalgia (FMS) and major depression (MDD) has motivated speculations about the direction of the relationship.
Three principal hypotheses to be tested here are:

(l)that FMS is a variant of depression;

(2) that MDD in FMS sufferers is a reaction to FMS; and

(3) that high rates of MDD in FMS patients are an artifact of studying treatment-seekers.

The proposed study's first aim is to support one and refute other hypotheses, by conducting a family study. Community women meeting criteria for FMS (n= 120) will be stratified so that half (n=60) have a lifetime history of MDD. Demographically-matched non-FMS controls (n= 120) from the same sampling frame will also be stratified on MDD status. Direct psychiatric interviews and physical examinations will be conducted with probands and all their available adult first degree relatives.

To support the first hypothesis, familial MDD rates should be elevated in FMS probands, even among probands with no personal depression histories; to support the second, probands with FMS and MDD should have low familial depression rates, as their depression should be more likely reactive to FMS; to support the last, familial MDD should be elevated in probands with MDD histories themselves, regardless of FMS status.

A second aim, prompted by the comorbidity of FMS and myofascial temporomandibular disorder (M/TMD), is test (1) whether M/TMD is a regional manifestation of FMS or (2) whether M/TMD comorbid with FMS is different from M/TMD expressed as a regional disorder.

To accomplish this aim, we will first reconfirm that FMS is familial, utilizing data gathered to satisfy the first aim. Second, we will reconstitute the groups from Aim 1, according to both FMS and M/TMD status. Rates of familial M/TMD in FMS and control probands, broken down by proband M/TMD status, will be examined. If M/TMD is found in the family of FMS probands, regardless of proband M/TMD status, this will support the first hypothesis. If only FMS probands have familial M/TMD but M/TMD probands do not, this will support the 2nd hypothesis and indicate that the two disorders are provoked through different pathogenic processes.



Thesaurus Terms: comorbidity, fibromyalgia, major depression, temporomandibular joint syndrome disease /disorder etiology, family genetics, mental health epidemiology clinical research, female, human subject, interview, statistics /biometry

Institution: UNIV OF MED/DENT NJ NEWARK
Fiscal Year: 2001
Department: PSYCHIATRY
Project Start: 01-JUL-1999
Project End: 30-JUN-2003
ICD: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
IRG: ZAR1





10) Neurotrophins and Animal Model of FMS:

Co-Funded by NIAMS and NINDS - $249,602

Alice Larson, PhD - University of Minnesota, St. Paul

To better understand the neurochemistry behind FMS. An experimental study of molecular mediators involved in stimulating nerve fibers, producing substance P (a pain receptor stimulator) and regulating pain in rats.

NEUROTROPHINS AND AN ANIMAL MODEL OF FIBROMYALGIA
Grant Number: 5R01NS039740-03
PI Name: LARSON, ALICE A.
PI Title: PROFESSOR
Project Title: NEUROTROPHINS AND AN ANIMAL MODEL OF FIBROMYALGIA

Abstract: DESCRIPTION (taken from the application): Fibromyalgia syndrome (FMS) is characterized by pain throughout the body (multifocal) with specific areas that are particularly sensitive to pressure. Primary afferent C-fibers are believed to be important in pain transmission. Some C-fibers contain substance P (SP) and are regulated by nerve growth factor (NGF), while others are characterized by the enzyme thiamine monophosphatase (TMPase) and are supported by glial derived neurotrophic factor (GDNF). Consistent with the hypothesis that C-fibers are involved in FMS, the concentrations of SP and NGF in the CSF of these patients are elevated. What initiates this is not known. C-fibers are depolarized by kainic acid, an excitatory amino acid analog. A single i.p. injection of kainic acid increases TMPase stain in the dorsal spinal cord, suggesting sprouting, and produces a persistent (> 12 weeks) decrease in the intensity of mechanical stimulation required to evoke withdrawal responses in rats similar to the lowered threshold of pressure required to produce pain in patients with FMS. Whether kainic acid produces these effects by increasing GDNF or NGF activity along nociceptive pathways is not known. We will test the hypotheses that the mechanical hyperalgesia produced by kainic acid is caused by enhancement of neurotrophic activity that supports C-fibers (NGF and GDNF) which, in turn, enhances proteins associated with these nociceptive pathways. To accomplish this, we will use a rat model (1) to characterize the effect of kainic acid on mechanical nociception using von Frey fibers and grip force; (2) determine whether the content of NGF and GDNF (immunoreactivity) or its receptors (binding) are affected by treatment with kainic acid; (3) to determine whether the application of exogenous NGF or GDNF is sufficient to increase mechanical nociception; (4) to determine whether there is a change in the density of SP- or NkiR immunoreactivity and/or the density of TMPase in the spinal cord or DRG after injection of NGF or GDNF; and (5) to determine whether injection of kainic acid alters either the density of SP- or NKiR-immunoreactivity in the spinal cord or DRG, in a fashion that correlates with its ability to induce mechanical hyperalgesia. These studies will determine whether kainic acid alters neurotrophic activity and nociceptive responses in the rat in a fashion that is consistent with the biochemical and sensory characteristics of FMS. If kainic acid activity proves to be a useful model of FMS, therapeutic options may be more readily developed for this disease.

Thesaurus Terms: disease /disorder model, fibromyalgia, hyperalgesia, model design /development, neurotrophic factor C fiber, growth factor receptor, kainate, phosphomonoesterase, spinal ganglion, substance P, thiamine injection /infusion, laboratory rat

Institution:
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:





11) Combining N-of-1 Trials to Assess FMS Therapies:

Co-Funded by NIAMS and ORWH - $308,928

Deborah Zucker, MD, PhD - New England Medical Center, Boston, MA

This trial of antidepressant therapy in fibromyalgia uses new effectiveness-testing method that combines individual treatment results to obtain population-wide estimates of treatment effectiveness.

COMBINING N OF 1 TRIALS TO ASSESS FIBROMYALGIA THERAPIES

Grant Number: 1R01AR45416-01A1
PI Name: ZUCKER, DEBORAH R.
PI Title:
Project Title: COMBINING N OF 1 TRIALS TO ASSESS FIBROMYALGIA THERAPIES

Abstract:
Fibromyalgia (FM) is a very common rheumatologic condition yet providing an effective treatment for an individual patient remains a challenge. To improve clinical treatment, better understanding of the effectiveness of new drug regimens and the factors effecting patients' responses to these treatments is needed. Anti-depressant medications have been used to treat patients with FM. However, most studies have reported that only about one third of patients show significant improvement with these treatments. A recent study reported that a combination therapy of amitriptyline and fluoxetine (AM + FL) resulted in significantly greater improvement in patients' symptoms as compared with either drug alone. As part of medical practice, physicians and patients often try new, potentially beneficial therapies to assess their effectiveness for the individual. If these studies could be carried out in a scientifically rigorous manner, the collective information could contribute greatly to our understanding of patients' responses to medical treatments. We have developed a method for effectiveness research which uses patient-focused N- of-1 trials and then combines these trials' results to obtain population estimates of treatment effectiveness and to aid in treatment decision-making for an individual patient. This proposal aims to prospectively apply this methodology to compare the effectiveness of the combination therapy AM + FL versus AM alone in the treatment of patients with FM. We propose to carry out N-of-1 trials to compare the effectiveness of AM vs. AM + FL for patients with FM using individual patient (N-of-1) trials. We will analyze the resulting data using the combined N-of-1 methodology to assess overall treatment effectiveness and compare this to results from a prior standard center-based trial. We propose to extend the use of N-of-1 trials into community practices to enable comparison of center-based and practice-based results. Through this broader patient inclusion we will attempt to identify potential patient characteristics which may affect treatment response variation. The results and feedback from both patients and physicians participating in this study will help to develop a framework that will allow transportability of this approach to effectiveness research to the study of other diagnoses and treatments.
Thesaurus Terms:
amitriptyline, antiarthritic agent, arthritis therapy, combination chemotherapy, fibromyalgia, fluoxetine, human therapy evaluation, clinical trial, data collection methodology /evaluation, health care professional practice, longitudinal human study, medical education, outcomes research, patient care management, clinical research, human subject

Institution: NEW ENGLAND MEDICAL CENTER HOSPITALS
750 WASHINGTON ST
BOSTON, MA 02111
Fiscal Year: 1999
Department:
Project Start: 09-SEP-99
Project End: 31-AUG-02
ICD: NAT INST OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG: ZAR1





12) Mapping of Genes for Fibromyalgia Syndrome:

Funded by NIAMS - $490,223

Jane Olson, PhD - Case Western Reserve University, Cleveland, OH

The primary goal of this study is to identify genes that predispose a person to FMS so that in the long term, the causes and biological mechanisms of this illness can be better understood. This study will carry out a genetic linkage analysis in 120 families with fibromyalgia and a genome-wide scan of 160 families with the disorder. (Dr. Yunus of AFFTER’s Medical Advisory Committee is involved in this study and is looking for participants. See page 13 for details.)

MAPPING GENES FOR FIBROMYALGIA SYNDROME
Grant Number: 3N01AR092235-002
PI Name: OLSON, JANE
PI Title:
Project Title: MAPPING GENES FOR FIBROMYALGIA SYNDROME

Abstract: The purpose of the contract is to support a core facility dedicated to the collection and characterization of Fibromyalgia syndrome (FMS) families, uni and multiplex for FMS. The facility will operate two simultaneous activities. It will serve as a Registry of FMS pedigrees by collecting, validating and updating clinical, demographic and laboratory data on families with two or more members affected with FMS. Individuals will be considered to be affected with FMS if they meet the American College of Rheumatology criteria for primary FMS, including 11 of 18 tender points on examination and a history of widespread pain for at least three months, and absence of other heumatologic disease, chronic infection, or other concomitant disease, as evidenced by patient history, examination and routine Chemistry blood panel. Phenotype information collected will also include measurement of platelet serotonin level and the presence or absence and/or degree of FMS-related symptoms, including morning stiffness, sleep difficulty, fatigue, gastrointestinal symptoms, headache, depression, and stress. The facility will also operate as a repository of DNA and will store and manage genotyping data of the families enrolled. In addition, the investigators will also conduct genetic linkage analysis. The contents of the database, DNA samples and genotypes will be made available to basic and clinical researchers. The NIAMS expects that the availability of these resources will encourage and accelerate research in the genetic bases of FMS. The contract includes an option to extend the period of performance from 9/29/2000 to 9/29/2003

Thesaurus Terms: family genetics, fibromyalgia, genetic mapping, genetic registry /resource /referral center, patient /disease registry blood chemistry, case history, linkage mapping clinical research, human subject

Institution: CASE WESTERN RESERVE UNIVERSITY Fiscal Year: 2000 Department: EPIDEMIOLOGY AND BIOSTATISTICS Project Start: 30-SEP-1999 Project End: 29-SEP-2003 ICD: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES IRG:





13) Fibromyalgia and TMD in Young Women - a Multiracial Study:

Co-Funded by NIDCR and ORWH - $316,014

Octavia Plesh, DDS - University of California, San Francisco

Study of risk factors associated with TMD (temporomandibular disease) and fibromyalgia in young women participating in the National Heart, Lung and Blood Institute (NHLBI) growth and health study.

FIBROMYALGIA AND TMD IN YOUNG WOMEN - A MULTIRACIAL STUDY
Grant Number: 5R01DE013487-02
PI Name: PLESH, OCTAVIA
PI Title: PROFESSOR
Project Title: FIBROMYALGIA AND TMD IN YOUNG WOMEN-A MULTIRACIAL STUDY

Abstract: This investigation will determine the relationship of temporomandibular disorders (TMDs) with fibromyalgia (FM) and factors associated with the two conditions in an established, populations-based cohort (51% black, 49% white) women; and assess racial differences regarding prevalence and the factors explaining this difference. This cohort has been participating for 10 years in the longitudinal National Heart Lung and Blood Institute Growth and Health Study (NGHS) conducted by the University of California, Berkeley and the University of Cincinnati The specific aims are: 1) to assess the prevalence of self-reported, common chronic pains (including TMD and FM) based on questionnaires and to identify potential TMD, FM, and regional chronic pain (RCP) cases and controls; 2) to clinically determine combined body pain and TMD status based on palpating tender points and the distribution of TMD diagnostic types; 3) to compare potential explanatory risk factors (predictors) for these groups and determine the temporal relationship between NGHS-collected factors and diagnostic group status; 4) to analyze factors responsible for racial differences. The cohort consists of 1573 women currently 18-19 years old, recruited from west Contra Costa County, CA and the greater Cincinnati area. Longitudinal data collected over 10 years in the NGHS study regarding physical development, (e.g. growth, sexual development, and reproductive health history) and psychosocial development (e.g. coping strategies inventory and family environmental scale) will be assessed as potential risk factors for combined body pain and TMD group status. These longitudinal data collected during the development of this cohort offer a unique opportunity to study multiple risk factors thought to be associated with different types of chronic pain such as FM and TMDs, as they enter the most vulnerable period of life for developing such conditions. Our proposed study will be able to examine the interconnectedness of the longitudinal psychosocial and physiological measures with cross-sectional FM and TMD status, enabling a case-control design to draw conclusions like a longitudinal study.

Thesaurus Terms: chronic pain, female, fibromyalgia, racial /ethnic difference, social psychology, temporomandibular joint syndrome comorbidity, epidemiology, hyperalgesia, longitudinal human study, psychometrics, socioeconomics behavioral /social science research tag, clinical research, human subject

Institution: UNIVERSITY OF CALIFORNIA SAN FRANCISCO
Fiscal Year: 2000
Department: RESTORATIVE DENTISTRY
Project Start: 25-SEP-1999
Project End: 31-AUG-2002
ICD: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
IRG: ZAR1





14) Neurobiology of chronic muscle pain:

Co-Funded by NIAMS and NINDS - $184,039

Kathleen Sluka, PhD - University of Iowa, College of Medicine, Iowa City

Develop a new model of pain that is both chronic and widespread, then determine if the mechanisms responsible involve the peripheral or Central Nervous System will be identified.

NEUROBIOLOGY OF CHRONIC MUSCLE PAIN
Grant Number: 5R01NS039734-03
PI Name: SLUKA, KATHLEEN A.
PI Title:
Project Title: NEUROBIOLOGY OF CHRONIC MUSCLE PAIN

Abstract: DESCRIPTION (taken from the application): Although 14% of the United States population suffers from chronic musculoskeletal pain, most of our knowledge about pain has been obtained from studies on cutaneous pain. The current models of musculoskeletal pain typically produce short term hyperalgesia (resolved in 24 h or less). However, clinically, chronic muscle pain, as experienced by people with fibromyalgia, is long lasting (months to years). In preliminary studies, I determined that a long lasting bilateral hyperalgesia can be induced by two injections of low pH saline, five days apart, into one gastrocnemius muscle. In the work proposed I hypothesize that the development of the long lasting bilateral hyperalgesia is dependent initially on input from the site of injection following both the first and second injection. I further propose that once the long lasting hyperalgesia develops plastic changes in the central nervous system occur that maintain the hyperalgesia through increased activity in spinal neurons. The specific aims will establish and characterize a new model of muscle pain that is chronic and widespread. The proposed studies will establish if the neural mechanisms involved in the development and maintenance of chronic pain, induced by stimulation of muscle nociceptors, involve peripheral or central nervous system processes. These proposed studies will help in the understanding and thus potential treatment of chronic muscle pain, including such conditions as fibromyalgia, myofascial pain and low back pain.

Thesaurus Terms: chronic disease /disorder, disease /disorder model, fibromyalgia, model design /development, neurobiology acidity /alkalinity, dorsal horn, glutamate receptor, heat injury, hyperalgesia, neuron injection /infusion, laboratory rat

Institution:
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:





15) Neuroendocrine Alterations in Fibromyalgia and Irritable Bowel Syndrome:

Funded by NIAMS - $263,599

Lin Chang, MD - University of California, Los Angeles

This is a study to identify the mechanism and areas of the brain that mediate responses to visceral and peripheral stimuli in patients with fibromyalgia and irritable bowel syndrome.

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

UPDATE SOURCES
Abstract Database from CRISP
Computer Retrieval of Information on Scientific Projects

http://crisp.cit.nih.gov/