Fibromyalgia Research: Challenges and Opportunities.

Background on Fibromyalgia 

Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, and tenderness in localized areas of the neck, spine, shoulders, and hips called "tender points." People with this syndrome may also experience sleep disturbances, morning stiffness, irritable bowel syndrome, anxiety, and other symptoms. Available data suggest that the number of persons aged 18 and older in the United States with fibromyalgia is approximately 3.7 million. It primarily occurs in women of childbearing age, but children, the elderly, and men may also be affected.

Although the cause of fibromyalgia is unknown, researchers have several theories about the causes or triggers of fibromyalgia. Some scientists believe that the syndrome may be caused by an injury or trauma. This injury may affect the central nervous system. Fibromyalgia may be associated with changes in muscle metabolism, such as decreased blood flow, causing fatigue and decreased strength. Others believe the syndrome may be triggered by an infectious agent such as a virus in susceptible people, but no such agent has been identified.

Fibromyalgia is difficult to diagnose because many of the symptoms mimic those of other diseases. The American College of Rheumatology (ACR) has developed criteria for fibromyalgia that physicians can use in diagnosing the disease. According to ACR criteria, a person is considered to have fibromyalgia if he or she has widespread pain for at least 3 months in combination with tenderness in at least 11 of 18 specific tender point sites.

Treatment of fibromyalgia requires a comprehensive approach. The physician, physical therapist, and others in the medical support system, as well as the patient may all play an active role in the management of fibromyalgia. Studies have shown that aerobic exercise, such as swimming and walking, improves muscle fitness and reduces muscle pain and tenderness. Heat and massage may also give short-term relief. Antidepressant medications may help elevate mood, improve quality of sleep, and relax muscles. Fibromyalgia patients may benefit from a combination of exercise, medication, physical therapy, and relaxation.

Research on Fibromyalgia

Support of fundamental research is extremely important in fibromyalgia as well as in many disorders characterized by pain and sleep abnormalities, and many disciplines of medical research contribute to the knowledge base in understanding these symptoms. Since it is impossible to know with certainty which area will produce the next important discovery, the community of science, of which the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is a part, has to be open to all ideas. Discoveries can come from research funded in a variety of areas. For example, the National Institutes of Health (NIH) supports pain research at different levels--from the gene, molecule, cell, and organ to the human organism itself. NIH spends more than $70 million on pain research, which is conducted and supported by 15 institutes, centers, and offices. However, while this figure would not be reported as funding for fibromyalgia research specifically, certain aspects of pain research are applicable to understanding fibromyalgia.

The research on fibromyalgia supported by NIAMS covers a broad spectrum from basic research to behavioral interventions. For example, NIAMS investigators are examining the interactions between the nervous system and the endocrine (hormonal) system and regulation of adrenal function in fibromyalgia patients. Studies have shown that abnormally low levels of the hormone cortisol may be associated with fibromyalgia. Researchers are studying regulation of the function of the adrenal glands (which make cortisol) in fibromyalgia. People whose bodies make inadequate amounts of cortisol experience many of the same symptoms as people with fibromyalgia. It is hoped that these studies will increase understanding about fibromyalgia and may suggest new ways to treat the disorder.

Basic research studies to advance our understanding of the molecular and genetic basis of sleep and sleep disorders are also included in the NIAMS research portfolio. One specific study on mice focuses on identifying genetic factors that underlie molecular events involved in the regulation of sleep. A wealth of information on the neuroanatomy, neurochemistry, and neurophysiology of sleep provides a firm foundation for a genetic approach to studies of sleep. This study will use genetics to screen for single gene mutations that affect sleep patterns in the mouse. Understanding this in the mouse will advance understanding of how this translates to humans. Other basic research studies using animal models are investigating the link between sleep and long-term memory.

In addition, NIAMS is currently funding research projects related to understanding the role of behavioral factors in fibromyalgia. Investigators are evaluating the effects of two of the most promising nonpharmacologic interventions for fibromyalgia: cognitive behavioral therapy for pain management, and physical exercise training. This study is designed to test the hypothesis that combining cognitive behavioral therapy and physical training will be more effective than cognitive behavioral therapy or exercise alone. If the cognitive and exercise interventions have synergistic effects in fibromyalgia patients, future studies could evaluate this combination in patients with other rheumatic diseases, or in stroke or burn injury patients who are having pain during exercise/rehabilitation regimens.

Providing social support and education about one's disease or disorder has been shown to be an effective means for improving the health care status of individuals with chronic diseases. Studies are currently underway focusing on patients with fibromyalgia to advance understanding of how social support and education interventions may be helpful to these patients as well.

Why Is Basic Research Important to Understanding Fibromyalgia?

The research mission of NIAMS is broad and diverse. Progress in one area of the Institute provides important clues for research in other areas. Similarly, progress in areas supported by other NIH institutes can and does provide valuable information for diseases within the NIAMS research portfolio. That is why it is essential to support studies across the research spectrum and to encourage cross-fertilization of experts from many disciplines. Studies on the neuroendocrine system, pain and sleep disorders, and rheumatic and autoimmune diseases all may lead to a better understanding of fibromyalgia.

Since not all the outcomes can be anticipated, and it is hard to know where all advances will come from, NIAMS strives to support and maintain a diverse research portfolio. This is especially important in the area of fibromyalgia, where many areas are being developed simultaneously. Advancing understanding about fibromyalgia requires both basic and clinical research projects. Because basic research appears so far removed from actual patients suffering from the disease, the benefits derived from this type of research may not be so obvious.

For many diseases and conditions, including fibromyalgia, basic research must be done in order to obtain fundamental clues that direct research in humans. Basic research is usually done in systems that are simpler than the human system, so that the experimental variables can be manipulated to observe changes in structure and function. This provides a general understanding of biological events that may affect humans. Simpler organisms used include bacteria, yeast, fruit flies (drosophila), and mice. For example, researchers study the fruit fly because it is more complex than a bacterium, but can easily be maintained in a laboratory. In addition, fruit flies have been studied for many years, and a great deal is known about their genetics, biochemistry, and behavior. For example, scientists recently discovered that mutations in the human version of a gene that controls fruit fly growth and development are the likely cause of both the basal cell nevus syndrome, a rare inherited disorder, and sporadic basal cell carcinoma of the skin, the most common human cancer. In terms of fibromyalgia research, studies in fruit flies may tell us what the molecules are that link sleep and consolidation of long-term memory. Understanding this relationship in flies may provide clues and research tools that will enable investigators to learn why people with chronic sleep disturbances experience problems with memory.

Why Is Behavioral Research Important to Understanding Fibromyalgia?

Behavioral and social sciences research is an important area of investigation at NIH and cuts across a wide range of research topics. NIAMS has long supported behavioral research related to many arthritic and musculoskeletal conditions. Behavioral and social factors are important contributors to health and illness, frequently interact with biological factors to influence health outcomes, and represent critical avenues for treatment and prevention.

Behavioral and social sciences research encompasses a wide array of disciplines. The field employs a variety of methodological approaches including surveys and questionnaires, interviews, randomized clinical trials, direct observation, physiological manipulation and recording, descriptive methods, laboratory and field experiments, standardized tests, economic analyses, statistical modeling, ethnography, and evaluation. In addition, several key crosscutting themes are characteristic of social and behavioral sciences research. These include an emphasis on theory-driven research; the search for general principles of behavioral and social functioning; the importance ascribed to a developmental, life-span perspective; emphasis on individual variation and variation across sociodemographic categories such as gender, age, and sociocultural status; and a focus on both the social and biological context of behavior.

Behavioral and social sciences research is important to understanding how to better treat some of the clinically challenging symptoms that are experienced by fibromyalgia patients. Research opportunities include behavioral research on all aspects of fibromyalgia, including the relationships among disturbed sleep, inactivity, pain, and depression that are often observed in some patients with fibromyalgia, and the development of innovative approaches for treatment. development of innovative approaches for treatment.

How Are Fibromyalgia Grants Selected for Funding by NIAMS?

NIAMS currently supports research on fibromyalgia through two mechanisms: investigator-initiated research projects and Multipurpose Arthritis and Musculoskeletal Diseases Research Centers. Applications for funding may be solicited by the Institute (as with a request for applications [RFA]) or initiated by investigators. In general, most of the research projects funded by NIH are unsolicited research projects, known as investigator-initiated grants. NIAMS has made awards in the area of fibromyalgia for projects resulting both from solicited and unsolicited applications.

Applications submitted to NIH go through a two-step peer review system. The design of this system is that applications from researchers are reviewed first by study sections for their scientific merit. Applications for research on fibromyalgia may be reviewed by the Chronic Fatigue Syndrome Special Emphasis Panel or by other relevant panels depending on the expertise required. The second level of review is each institute's advisory council, which assesses the relevance and priority of proposed projects, and may make recommendations on funding particular meritorious applications.

Primary consideration for funding is scientific merit. This is determined during the review process and is reflective of the soundness of the approach, the innovativeness of the approach, the qualifications of the investigators, the potential significance of the work, and the overall research environment. This process is used throughout NIH for applications in all diseases and areas of science. The reviewers are asked to evaluate the significance of the research proposal in terms of improving understanding of an area of research or disease, advancing scientific knowledge, learning about the mechanisms that cause symptoms and signs of disease, or developing new treatments or prevention strategies.

Recent Research Initiatives

New Directions in Pain Research-Program Announcement. In September 1998, NIAMS joined 10 other NIH components in issuing a program announcement (PA) entitled "New Directions in Pain Research." The purpose of the PA is to inform the scientific community of broad, shared interests in pain research across the various components of the NIH, and to stimulate and encourage a wide range of basic, translational, and patient-oriented clinical studies on pain. Applications are encouraged to study pain throughout the lifespan from the perspectives of molecular genetics; transcriptional controls; signal transduction, including cellular/molecular mechanisms; innovative imaging technologies; plasticity; and hormonal or gender influences. The goal of the PA is to advance the development of novel pain interventions, treatments, and management strategies.

Basic and Clinical Research on Fibromyalgia--Request for Applications. In March 1998, NIAMS issued an RFA to promote investigator-initiated research projects and exploratory/developmental projects that will advance understanding of fibromyalgia and related disorders and provide critical new knowledge needed for the treatment and prevention of the syndrome. Several NIH institutes and offices have joined NIAMS in issuing this RFA. These include the National Institute of Dental Research (NIDR), which has an interest in pain and the relationship between temporomandibular disorders and fibromyalgia; the National Institute of Neurological Disorders and Stroke (NINDS), which has an interest in pain research; and three offices within the NIH Office of the Director: the Office of Alternative Medicine, the Office of Research on Women's Health, and the Office of Behavioral and Social Sciences Research.

In addition to the announcement being listed in the usual manner on the World Wide Web in the NIH Guide to Grants and Contracts, NIAMS distributed over 1,600 copies of the announcement to individual Guide to Grants and Contracts, NIAMS distributed over 1,600 copies of the announcement to individual investigators and organizations to stimulate an interest in fibromyalgia research. NIAMS grantees in fibromyalgia, arthritis, and muscle diseases, as well as in the centers program, received copies as did grantees NIH-wide in the fields of chronic pain, chronic fatigue syndrome, sleep, neuroendocrinology, and other related fields.

Acupuncture Clinical Trials-Program Announcement. In February 1998, the NIH Office of Alternative Medicine, along with six NIH institutes, including NIAMS and NINDS, and the Agency for Health Care Policy and Research, issued a PA entitled "Acupuncture Clinical Trial Pilot Grants." The objective of the PA is to increase the quality of clinical research evaluating the efficacy of acupuncture for the treatment or prevention of disease and accompanying symptoms. Back pain, cancer, fibromyalgia, temporomandibular disorders, HIV/AIDS, and reflex sympathetic dystrophy are among the diseases and conditions identified in the PA.

NIH Pain Research Consortium-Conferences. The NIH-wide Pain Research Consortium encourages information sharing and collaborative research efforts, provides coordination of pain research across all NIH components, and ensures that results of NIH-sponsored pain research are widely communicated. A major goal of the Consortium is to coordinate efforts across 21 NIH components to develop a better understanding of what causes pain, so better treatments are available to people with painful disorders such as fibromyalgia. The Consortium sponsored a symposium entitled "New Directions in Pain Research," on November 20-21, 1997, and a second conference entitled "Gender and Pain" on April 7-8, 1998.

Molecular Biology and Genetics of Sleep and Sleep Disorders-Request for Applications. In fiscal year 1997, NIAMS awarded two grants submitted in response to a request for applications issued by the National Heart, Lung, and Blood Institute, NIAMS, and several other NIH institutes. The NIAMS grants are basic research studies and will focus on rest and long-term memory consolidation in drosophila and on the genetics of sleep and rest behavior in the mouse.

Scientific Workshop: The Neuroscience and Endocrinology of Fibromyalgia. In July 1996, NIAMS sponsored a scientific workshop that explored recent advances in the neuroscience and endocrinology of fibromyalgia. The workshop focused on chronic pain, neuroendocrinology, and sleep disorders associated with fibromyalgia. What made this workshop so unusual and effective was its design, which brought together researchers in the basic sciences of chronic pain, neuroendocrinology, circadian rhythms, and sleep disorders--all challenges for patients with fibromyalgia. These experts in basic research were joined by clinicians who treat patients with fibromyalgia and by a significant number of patients themselves. This multidisciplinary workshop helped to identify research needs and opportunities, and the gaps in understanding of this clinically challenging condition.

The summary report of the presentations and discussion was recently published in Arthritis and Rheumatism, Vol. 40, No. 11, November 1997. Publication of the summary of the workshop in this peer-reviewed journal provides for wide distribution of the discussion of research opportunities to the scientific community with interest in this disorder. The workshop also led to the March 1998 RFA mentioned previously.

Fibromyalgia Advocate Appointed to Institute Advisory Council. A leading advocate for fibromyalgia, Ms. Tamara Liller, President of the Fibromyalgia Association of Greater Washington, Inc., recently joined the National Arthritis and Musculoskeletal and Skin Diseases Advisory Council. The Advisory Council, which includes both scientific and public members, meets three times a year and provides valuable input to the Institute's priority-setting process.

E-text updated: October 1998