Kathleen A. Sluka - US grants

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.

DESCRIPTION (Taken from the applicant's abstract): The long-term goals are to gain a better understanding of pain associated with the musculoskeletal system and the analgesia produced by physical therapy treatments. The award will allow more research-related time to expand current and develop new collaborative efforts. These collaborative efforts will be aimed at developing new techniques (isolated primary afferent recording and push-pull perfusion), new ideas (mechanisms of analgesia produced by joint mobilization) and expanding current ideas (TENS, microdialysis, muscle hyperalgesia). Interactions with scientists from multiple basic science (Anatomy, Neurosciences, Pharmacology, Chemistry, Molecular Biology) and clinical disciplines (Physical Therapy, Internal Medicine, Anesthesia, Pathology, Chiropractic) provide an interdisciplinary perspective to the examination of musculoskeletal pain and physical therapy pain treatments. Group journal clubs and laboratory meetings are held weekly with several laboratories (Gebhart, Brennan, Hammond, Proudfit, Sluka) investigating pain. The research proposal in this application is designed to characterize a newly developed animal model of chronic pain induced by two unilateral injections of low pH saline into the gastrocnemius muscle. In the work proposed they hypothesize that the development of the long lasting bilateral hyperalgesia is dependent initially on activation of acid sensing ion channels (ASIC) from the site of injection. Activation of acid sensing ion channels results in long lasting, widespread hyperalgesia that is sustained by activation of central mechanisms in the spinal cord. These proposed studies are intended to help in the understanding and thus potential treatment of chronic muscle pain including such conditions as fibromyalgia, myofascial pain and low back pain.

DESCRIPTION (provided by applicant): Joint manipulation is a non-pharmacological treatment approach that has been utilized for many years, for the treatment of musculoskeletal disorders. Although there is increasing evidence to support the use of manipulative therapy in the management of painful musculoskeletal conditions, the neurophysiological mechanisms of the analgesia remain largely unknown. The current proposal is designed to establish an animal model of manipulation-induced analgesia that can be utilized to test the hypothesis that central inhibitory mechanisms are involved in mediating manipulation-induced analgesia. Specific Aim #1 will establish and characterize the analgesic effects of joint manipulation in animal models of articular pain. Specific Aim #2 will establish the spinal pharmacological receptors involved in the analgesic effects of joint manipulation. Specific Aim #3 will establish the effects of joint manipulation on hyperalgesia and pain in human subjects with clinical disorders that parallel the animal models utilized in Specific Aim #1 The current proposal is designed to gain preliminary data that can form the basis for more extensive studies using a variety of neuroanatomical, pharmacological and physiological approaches. These results are significant because they are expected to demonstrate involvement of central inhibitory mechanisms in the pain relief produced by joint manipulation and thus, provide a scientific rationale for its use. This information will further assist the clinician in determining the treatment of choice for a particular patient and potentially guide future clinical research.

DESCRIPTION (provided by applicant): Although 10-15% of the United States population suffers from chronic widespread musculoskeletal pain (CWP), the etiology of these conditions is virtually unknown. CWP syndromes, such as fibromyalgia, are disabling and difficult to treat. To more fully characterize the mechanisms that initiate and drive CWP, we developed an animal model with widespread mechanical hyperalgesia that mimics CWP. Repeated intramuscular injections of acid into one gastrocnemius muscle is a unique model since there is bilateral mechanical hyperalgesia without peripheral tissue damage, and the contralateral hyperalgesia is not maintained by peripheral afferent activity. In parallel to the bilateral hyperalgesia, 1) there are bilateral increases in the spinal cord for the phosphorylation of the transcription factor, CREB (cAMP responsive element binding protein);24 h following induction of long-lasting muscle pain with acid, and 2) ipsilateral dorsal horn neurons show an expansion of their receptive fields to include the contralateral limb. We posit that these bilateral events distant from the site of insult reflect increased facilitatory influences from the brainstem. In support, descending facilitator/ pathways from the rostroventral medial medulla (RVM) mediate or maintain secondary hyperalgesia produced by intra-articular carrageenan, and the hyperalgesia associated with neuropathic pain and visceral inflammation. The spinal projections from these nuclei are bilateral, and receptive fields of these medullary neurons are widespread and include the contralateral hind limb. The Specific Aims will determine if local anesthetic or receptor blockade of the RVM during the first or second injection of acidic saline prevents, or after induction of hyperalgesia reverses the bilateral mechanical hyperalgesia and spinal increases in p-CREB produced by repeated intramuscular acid injection, a model of non-inflammatory widespread muscle pain. We will also determine if there is an increased release of glutamate in the RVM in response to the second injection of acidic saline. These studies will be the first to examine the role of Q descending facilitation following muscle insult and will further determine if descending facilitatory influences drive the spinal cord changes. We expert that the bilateral hyperalgesia and bilateral spinal increases in p-CREB that occur after muscle insult will be prevented by supraspinal blockade of input at the time of insult, and reversed by supraspinal blockade after development of hyperalgesia. These studies will also be the first to determine the release pattern for glutamate in the RVM in response to tissue injury. We expect an increase in glutamate in response to the second injection of acidic saline that parallels the hyperalgesia. If so, these data would suggest that supraspinal influences in the RVM utilizing glutamate are critical for the generation and the maintenance of bilateral hyperalgesia and spinal cord changes. A better understanding of the pathobiological mechanisms underlying musculoskeletal pain conditions may lead to the development of novel therapeutic approaches for its treatment.

Approximately 10-15% of the US population has chronic widespread pain (CWP);while 20-25% of the population has chronic regional muscle pain. The etiology and pathogenesis of painful musculoskeletal conditions are poorly understood. Most of our knowledge about mechanisms of pain has been obtained from studies using cutaneous pain models. Further, peripheral initiators of muscle pain are virtually unknown, but likely key to the development of chronic pain after muscle insult. Recently, we showed that mechanical hyperalgesia induced by muscle insult do not develop in mice with a null mutation of the acid-sensing ion channel, ASICS. However, it is not clear from these experiments whether the absence of ASICS in the DRG innervating muscle (where insult occurs) or in the skin (where testing occurs) is critical for development of mechanical hyperalgesia, and if ASICS is involved in both the early acute phase as well as the later maintenance phase of muscle-induced hyperalgesia. Since models of cutaneous pain are unaffected in mice without ASICS, the data also suggest that expression of ASICS in sensory dorsal root ganglion (DRG) neurons innervating muscle is unique relative to skin. Therefore, these aims will test the hypotheses that 1) ASIC3 in the muscle is a key factor for full development of cutaneous mechanical hyperalgesia induced by muscle insult, 2) ASIC3 mRNA, protein expression in muscle and/or DRG neurons, and ASIC currents in DRG innervating muscle increases in a time-dependent manner after muscle insult. The specific aims are designed to determine if site specific (muscle vs. skin) expression of ASICS in knockout mice, downregulation of ASICS in wild-type mice, or pharmacological blockade of ASICs in muscle mediates the mechanical hyperalgesia induced by muscle insult. They will also determine will determine ASICS expression - mRNA, protein, and function - at selected times for two weeks after muscle insult. We will analyze TRPV1 simultaneously as a comparison. It is expected that ASICS in muscle, but not skin, will be important for development of secondary cutaneous mechanical hyperalgesia. We further expect that changes in the expression of ASICS in DRG neurons innervating muscle will correlate with the development and duration of mechanical hyperalgesia after muscle insult. Understanding the mediators and molecules that initiate development of chronic muscle pain is critical to development of new treatment strategies aimed at treating musculoskeletal pain. These studies could lead to peripherally based therapeutic approaches to control pain without undesirable CMS (central nervous system) side effects, including gene therapy.

[unreadable] DESCRIPTION (provided by applicant): The American Pain Society is a multidisciplinary community that brings together a diverse group of scientists, clinicians and other professionals to increase the knowledge of pain and transform public policy to reduce pain-related suffering (APS Mission Statement, October 2005). The integration of science and care is further depicted in the APS Vision Statement - APS envisions a world where pain prevention and relief are available to all people. There are multiple goals of the Annual Scientific Meeting of APS. We wish to promote discussion and interactions between basic science researchers and clinical researchers to advance the science of pain in a high quality, relaxed and relatively small meeting that promotes open discussion. Equally important is for APS members of disciplines related to patient care to meet and share advances in the treatment and management of pain. What makes this meeting valuable to attendees is the cross fertilization of ideas and concepts which arise formally in symposia and informally in poster sessions between members of disparate specialties. The meeting creates a milieu where scientists and clinicians can share relevant information from their different perspectives to enable us to tackle important research questions in an innovative and productive manner frequently leading to advances in clinical care. The objective of this application is to secure funds to be used for travel awards for trainees to attend the 2007 Annual Scientific Meeting of the American Pain Society. The 2007 meeting will be held at the Washington Convention Center, May 2-5, 2007, in Washington, D.C. These funds will allow trainees to attend and interact with both clinicians and researchers from multiple disciplines including medicine, nursing, psychology, and physical therapy. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Fibromyalgia is a chronic pain condition that is characterized by widespread pain. Pain associated with fibromyalgia interferes with daily function, work, and social activities resulting in a decreased quality of life. In addition people with fibromyalgia have a significant amount fatigue and a fear of movement. The cause of fibromyalgia is unknown, but people with fibromyalgia show enhanced excitability of pain neurons in central nervous system and reduced pain inhibition. One of the main treatments for patients with fibromyalgia must, therefore, focus on pain relief to allow the person to function more independently both at home and at work. Transcutaneous electrical nerve stimulation (TENS) is a modality used by health professionals that delivers electrical stimulation through the skin for pain control. Basic science studies, from the PIs laboratory, show that TENS activates descending pain inhibitory pathways to inhibit excitability of pain neurons. Thus, the ideal patient population for the treatment of TENS would be one in which there is enhanced central excitability and reduced inhibition;fibromyalgia is such a condition. Although TENS is effective for several pain conditions such as osteoarthritis, chronic musculoskeletal pain, and postoperative pain [5;20;39], its effectiveness in treatment of people with fibromyalgia is virtually unknown. Furthermore, there is a general thought among clinicians that since fibromyalgia pain is widespread, TENS would be ineffective in this population. Thus, TENS may decrease pain associated with fibromyalgia by increasing central inhibition and decreasing central excitability. This decrease in pain is expected to increase function and improve quality of life. We hypothesize that application of TENS to patients with fibromyalgia will reduce resting and movement-related pain and reduce central excitability by restoring diffuse noxious inhibitory controls (DNIC), and that this decrease in pain and/or central excitability will reduce fatigue and fear of movement, thereby improving function and quality of life. We will test this hypothesis through 3 Specific Aims. Aim #1: The primary aim of the study is to test the effectiveness of the long-term use of TENS on resting and movement-related pain in people with fibromyalgia with random assignment to three treatments: no treatment control, placebo TENS and active TENS. Aim #2: A secondary aim will test if pain reduction by TENS results in a concomitant decrease in fatigue and fear of movement, and an increase in function and quality of life. Aim #3 will determine if active TENS alters pain processing in people with fibromyalgia and if improvement in clinical symptoms correlates with normalization of pain processing physiology. This innovative study will be the first to examine the effectiveness of TENS in people with fibromyalgia using multiple outcomes including pain at rest and during movement, as well as function, fatigue, and quality of life in individuals with fibromyalgia. Using multiple measures will give us a better understanding of appropriate measures for future clinical trials of non-pharmacological treatments, and for treatment of pain in people with fibromyalgia.

DESCRIPTION (provided by applicant): We are requesting support for travel stipends to encourage the participation of young investigators at the annual meeting of the American Pain Society (APS). These young investigators are beginning their careers in basic and clinical research in pain. The APS is a multidisciplinary community that brings together a diverse group of scientists, clinicians and other professionals to increase the knowledge of pain and transform public policy and clinical practice to reduce pain-related suffering. The annual APS meeting provides a unique forum for disseminating cutting edge advances in evidence-based pain research and treatment in a setting that optimizes the interactions between scientists and clinicians. This bidirectional translational interchange between clinicians who diagnose and manage clinical pain and pre-clinical scientists who are defining the mechanisms of and treatments for pain is the cornerstone of improved pain therapy. We seek funds solely for the purpose of providing travel awards for young investigators who have submitted an abstract which has been accepted by our peer review process and therefore are engaged in research. These young investigators may be from any research training background (basic or clinical science, psychology, medicine, or biostatistics) and may be at any level in training, including students, residents, pre-doctoral trainees, postdoctoral fellows, or those who have completed their postdoctoral training within the last 3 years. All applicants must be APS members. The APS Young Investigator Travel Awards program is designed to mentor and nurture the next generation of pain researchers.

DESCRIPTION (provided by applicant): Regular physical activity (exercise) can reduce pain in people with chronic musculoskeletal pain; whereas, unaccustomed exercise can exacerbate pain. This apparent dichotomy in pain response to physical activity is poorly understood, making exercise prescription for individuals with pain challenging. In sedentary mice, a single bout of exercise enhances the nociceptive response to subthreshold muscle stimuli (pH 5.0 saline); this enhancement is prevented by 5 days of voluntary running wheel activity. Further, in mice the development of chronic muscle pain, induced by repeated intramuscular acid (pH 4.0) injections, is prevented by 8 weeks of voluntary running wheel activity. Regular exercise is believed to activate central inhibitory pathways that produce an opioid-mediated analgesia; the rostral ventromedial medulla (RVM) is a key central nucleus in opioid-induced analgesia. However, little data is available to support a role for central opioid mechanisms in exercise-induced analgesia, particularly in conditions of chronic pain. Our preliminary data show that the analgesic effect of 8 weeks of running wheel activity (i.e. regular exercise) is reversed by systemic blockade of opioid receptors, establishing that opioids are important in regular exercise-induced analgesia. Our preliminary data show that there is increased p-NR1 (NMDA receptor) in the RVM in sedentary animals after a single-bout of exercise or induction chronic muscle pain. These increases in p-NR1 in the RVM, however, are prevented by regular exercise, suggesting that p-NR1 is modulated by mechanisms activated by exercise. These data led to our central hypothesis that regular exercise enhances activation of central inhibitory pathways that utilize endogenous opioids to modulate p-NR1 in the RVM. We will address our central aim through the following specific aims. Aim 1 will determine if regular physical activity (running wheel exercise) prevents the development of chronic muscle pain, and if such an effect is associated with motor and autonomic responses that might occur in response to exercise training and activation of the RVM. Aim 2 will determine if regular physical activity prevents the development of hyperalgesia by activation of opioid receptors. We will test this by pharmacological and genetic manipulation of opioid receptors. Aim 3 will explore the neural circuitry involved in the enhanced nociception to unaccustomed physical activity and the analgesia produced by regular physical activity. We will establish if NMDA receptors are located on and modulate pain facilitatory ON cells through m- opioid receptors (MOR), and if these cells project to the spinal cord. These studies will be the first to evaluate the effects of regula exercise on hyperalgesia and the underlying mechanisms that mediate these effects. Understanding these interactions will give us a better understanding of the underlying neurobiology to improve the overall management of people with chronic musculoskeletal pain, and prevention of development of chronic pain. PUBLIC HEALTH RELEVANCE: Regular physical activity (exercise) can reduce pain in people with chronic musculoskeletal pain; whereas, unaccustomed exercise can exacerbate pain. This proposal aims to examine the central mechanisms underlying the effects of exercise on pain using recently developed animal models of exercise-induced pain, and exercise-induced analgesia. Understanding these interactions will give us a better understanding of the underlying neurobiology to improve the overall management of people with chronic musculoskeletal pain, and prevention of development of chronic pain.

DESCRIPTION (provided by applicant): Pain associated with fibromyalgia interferes with daily function, work, and social activities resulting in a decreased quality of life. People with fibromyalgia also have a significant amount fatigue and a fear of movement. People with fibromyalgia show enhanced excitability of pain neurons in the central nervous system and reduced pain inhibition. Therefore, one of the main treatments for patients with fibromyalgia must focus on pain relief to allow the person to function more independently both at home and at work. Transcutaneous electrical nerve stimulation (TENS) is used by health professionals to deliver electrical stimulation through the skin for pain control. Basic science studies, from the PIs laboratory, show that TENS activates descending pain inhibitory pathways to inhibit excitability of pain neurons. Thus, the ideal patient population for the treatment of TENS would be one in which there is enhanced central excitability and reduced inhibition; fibromyalgia is such a condition. We hypothesize that application of TENS to patients with fibromyalgia will reduce movement-related pain and reduce central excitability by restoring central inhibition, and that this decrease in pain and/or central excitability will reduce fatigue and fear of movement, thereby improving function and quality of life. We will test this hypothesis through 4 Specific Aims. Aim 1: test the effectiveness of repeated use of TENS on movement-related pain in people with fibromyalgia with random assignment to three treatments: standard care, placebo TENS and active TENS. Aim 2: test if pain reduction by TENS results in a concomitant decrease in fatigue and fear of movement, and an increase in function and quality of life. Outcome measures will include physical function by directly assessing daily activity with an accelerometer, as well as performing specific functional tasks. Aim 3: determine if active TENS alters pain processing in people with fibromyalgia and if improvement in clinical symptoms correlates with normalization of pain processing physiology. We will evaluate change in these physiologic parameters in responders versus non-responders as assessed clinically. Aim 4: determine if PROMIS is a useful outcome for fibromyalgia by comparing to the revised version of the fibromyalgia impact questionnaire (FIQ-R).

PROJECT SUMMARY/ABSTRACT The transition from acute to chronic pain has eluded researchers for years, likely due to its complex nature and the inherent individual variability. The ability to identify individuals at risk, and those with reduced risk, for the transition to chronic pain using biomarkers will advance personalized acute pain treatment strategies, reduce reliance on opioid pharmacotherapy, and help identify novel therapeutic targets, thereby transforming the management of acute pain events. The Acute to Chronic Pain Signatures (A2CPS) Program aims to identify biomarkers and their collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain after an acute pain event through the development of a large consortium. The advantage of multisite observational studies is their ability to comprehensively phenotype large population cohorts across multiple biopsychosocial domains in a relatively short time. This application describes a partnership between a strong group of pain scientists (Sluka, Frey Law) and the Clinical Trials Statistical and Data Management Center (Coffey, Ecklund) at the University of Iowa. The proposed CCC applies thorough and well-organized principles to facilitate, support and enhance the scientific rigor and effectiveness of key stakeholders for the identification of critical biomarkers for the acute to chronic pain transition, using the following task-based specific aims: 1) Lead the development and implementation of clinical protocols. 2) Provide oversight and management of collaborative activities across the consortium to support the overall goals of A2CPS. And 3) Facilitate transparent and effective communication between consortium members. The CCC will support study design, bringing expertise in pain and adaptive designs to help identify biomarkers for study inclusion; promote efficiency and quality through development of milestones, Standard Operating Procedures (SOPs), individualized recruitment plans, and staff training protocols. The CCC will be responsible for regulatory procedures including: standardizing the electronic health record; coordinating a central Institutional Review Board (cIRB); and convening a Data Safety and Monitoring Board (DSMB). The CCC will track protocol quality control procedures and safety monitoring; perform central monitoring and on-site monitoring visits; and monitor progress towards A2CPS milestones, particularly site- specific enrollment and retention targets, a critical component in the success of the A2CPS initiative. The success of the A2CPS Program is dependent on effective management and coordination of activities across the Consortium. We have assembled a team with expertise spanning pain science, clinical trials in patients with pain and other conditions, and successful large multi-site trial coordination. The University of Iowa has a highly collaborative environment with strong pain science researchers, making us well prepared to successfully perform the many needed roles of the A2CPS Clinical Coordination Center.

Project Summary/ Abstract Regular physical activity is associated with reduced incidence of chronic pain in epidemiological studies; yet, an acute bout of exercise can exacerbate pain in those with chronic pain. Analogously in animal models, we show a single bout of exercise enhances the nociceptive response to muscle insult in physically inactive mice, and that regular physical activity prevents the development of chronic muscle hyperalgesia. The mechanisms driving this apparent dichotomy in pain response to physical activity are poorly understood. We propose this dichotomy may in large part be explained by the plasticity of local muscle macrophages. Macrophages release inflammatory or anti-inflammatory cytokines depending on two relevant phenotypes: classically-activated (M1) macrophages release inflammatory cytokines and regulatory (M2) macrophages release anti-inflammatory cytokines. The relative proportion of macrophage phenotype dictates the immune response, and we propose that regular physical activity shifts the balance between M1 and M2 macrophages to result in greater release of anti-inflammatory cytokines. Fatigue metabolites, adenosine triphosphate (ATP) and protons, produce pain in humans and hyperalgesia in inactive animals, and activate surface receptors, P2X7 and ASIC3, on macrophages. Our preliminary data support a role for macrophages in both activity-induced pain and activity- induced analgesia and show a greater proportion of M2s after regular exercise. Specific Aim 1 will investigate the role of macrophages in activity-induced hyperalgesia in physically inactive mice. We hypothesize that activation of P2X7 or ASIC3 on muscle macrophages releases IL-1? in physically inactive animals to produce hyperalgesia. Specific Aim 2 will characterize the role of macrophages in prevention of chronic muscle pain by regular physical activity. We hypothesize that activation of P2X7 or ASCI3 on muscle macrophages releases IL-10 in physically active animals to produce analgesia. Specific Aim 3 will investigate if ATP, protons, or their combination produces a phenotypic switch in cultured macrophages from M1 to M2. We hypothesize that the combination of ATP and protons is necessary to induce the phenotypic switch from M1 to M2 macrophages. These studies will examine the interactions between muscle, macrophages, and nociceptors and thus will be the first to determine the role of the innate immune system in activity-induced hyperalgesia and analgesia. Understanding these mechanisms is critically important to understanding the development and prevention of chronic pain, and the consequences of physical activity in individuals with pain. Treatments aimed at reducing pain during an initial exercise program could lead to better adherence in maintaining regular physical activity for people with chronic pain. Further determining factors activated by regular physical activity, which activates endogenous resolution mechanisms, is a critical component to preventing the transition from acute to chronic pain.

Project Summary Fibromyalgia (FM) is a complex condition characterized by widespread pain and fatigue that is associated with sleep dysfunction and reduced function that affects 2-4% of the population (Heidari et al., 2017). Current 2016 diagnostic criteria are by symptomology only, as there are no validated chronic pain biomarkers to assist with diagnosis, or treatment evaluation endpoints (Wolfe et al., 2016). Diagnosing FM often takes years with patients seeing multiple physicians, which delays treatment (Choy, 2010). This delayed diagnosis and treatment initiation would be dramatically reduced with the identification of FM biomarkers. The long-term goal of this line of research is to identify unique biomarkers for FM to improve the diagnosis and/or develop therapeutic targets for individuals with widespread pain. Using a semi-targeted metabolomics approach, our preliminary data from women with FM (n=59), compared to healthy controls (n=38), show 18 potential candidates that differ significantly between cohorts with several metabolites showing good-excellent sensitivity (>90%) and specificity (>90%). The primary goal of this proposed research is to assess and validate candidate metabolic biomarkers in a new, larger cohort of individuals and compared to other chronic pain populations. The proposed study will use a multi-site, cross-sectional design to identify and characterize metabolic biomarkers, biosignatures, and their associations with multiple symptomology domains to address the following two specific aims: Aim 1: We will characterize diagnostic test metrics for candidate biomarkers using receiver operating curves (ROCs), i.e. sensitivity and specificity, and test-retest reliability, to correctly identify individuals with FM from healthy controls and other chronic pain conditions: osteoarthritis, carpal tunnel syndrome, and rheumatoid arthritis. Aim 2: We will determine associations between putative metabolic biomarkers and multiple self-reported symptom domains in those with FM: a) pain; b) fatigue; c) sleep; d) physical function; e) psychological factors, and f) disease impact/disability. We have identified several promising metabolic biomarkers that may serve as diagnostic or within-disease phenotype identifiers. Once completed, we will examine potential mechanistic and therapeutic targets for the candidate biomarkers in subsequent studies. These novel studies have the potential to identify a diagnostic, and potentially a therapeutic, biomarker of FM associated with cell metabolism. To accomplish this study, we have developed a strong multidisciplinary and multi-site team, leveraging blood samples and phenotype data collected as part of an on-going funded study, as well as additional data collection for repeatability analyses. The study team has the necessary expertise in human, basic science and metabolomics investigations to successfully complete these aims.