Daniel J. Clauw, MD - US grants

Fibromyalgia is the second most common rheumatic disorder, affecting approximately 8 - 10 million persons in the U.S. This condition is characterized by the presence of widespread musculoskeletal pain, and of soft tissue tenderness on examination. Although there are several therapeutic modalities that have been demonstrated to be somewhat effective in relieving the symptoms of fibromyalgia, despite these treatments most persons with this illness continue to be quite debilitated. Acupuncture, although considered an alternative therapy in the West, has been demonstrated to be effective in treating several conditions, and a growing data base suggests that acupuncture may be a particularly effective and safe intervention for a variety of pain syndromes. Since the cardinal manifestation of fibromyalgia is pain, and current treatments are frequently ineffective, fibromyalgia is an ideal disorder to examine for efficacy with this treatment modality. Although there have been anecdotal reports of the efficacy of fibromyalgia, there has only been one randomized controlled trial, and there are numerous methodological problems with this study that limit the interpretation of these data. This pilot study will examine numerous issues regarding the use of acupuncture as a therapeutic modality in fibromyalgia, so that a full scale randomized controlled trial (RCT) could be performed in this condition. The issues which will be examined include: 1) the optimal duration and frequency of treatment, 2) the independent and synergistic effects of needle placement and needle stimulation on efficacy, and 3) appropriate control strategies. The present proposal utilizes a randomized, blinded, sham-controlled design that incorporates several unique aspects to accomplish these aims. A 2 X 2 factorial design will be used examine the individual and synergistic effects of both needle placement and of needle stimulation on the efficacy of acupuncture. The four arms of the trial will include: 1) active site, with stimulation, 2) active site, without stimulation, 3) sham site, with stimulation, and 4) sham site, without stimulation. In each of the four arms of the trial, subjects will receive acupuncture in escalating frequency, beginning at once weekly and culminating in three times weekly. This "forced-titration" design is commonly used in the preliminary phases of drug (development, to examine the optimal dose of a medication for each person in a trial. In this manner, we will be able to determine the "dose-effect" for the analgesic effect of acupuncture in each person, and in each group. This design allows the detection of inter-patient differences in responsiveness to acupuncture, as well as the factors which may predict responsiveness (or a lack thereof). Secondary goals of the study are to collect pilot data on the mechanism, safety, and cost-effectiveness of acupuncture in fibromyalgia, and to determine the optimal outcome measures, for a full-scale RCT.

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.

Clinical; Health; Institutes; Michigan; Research

NIH Roadmap Initiative tag

The University of Michigan Clinical and Translational Sciences Award (UM CTSA) will focus the formidable strengths of one of the world's finest research institutions on supporting and facilitating clinical and translational "team science". The UM CTSA will be housed in the newly created Michigan Institute of Clinical and Health Research (MICHR). MICHR was created by the University to maximize the potential of an institution that is extremely supportive of interdisciplinary research and has tremendous strengths in the health sciences. MICHR creates a partnership between relevant unit of the University, the NIH, external industry partners, and the community. The overwhelming majority of UM schools, colleges, and institutes are participating, including the top-ranked Schools of Business, Dentistry, Medicine, Nursing, Social Work, and Public Health, the Colleges of Engineering, Pharmacy, and Literature, Science and Arts, the Division of Kinesiology, the Institute of Social Research, and the Life Sciences Institute. The University-owned Health System, which includes integrated outpatient and inpatient facilities, is contributing significantly to a strong partnership with the UM CTSA. The Director of MICHR is the PI of the UM CTSA grant, and reports to a University Executive Vice President, who also oversees the Medical School and Health System. In addition to the grant resources, the institution is contributing nearly $11 million/vr of in-kind support, cost-sharing, support of pilot and recruitment programs, and renovation costs, a more than 1:1 match of NIH dollars. Blue Cross Blue Shield of Michigan and Pfizer are also making sizable investments. Departments are also contributing more than 100 FTE in potential faculty effort, so that MICHR can grant effort for pilot studies, K- 12, and new "mini-K programs". These aggregate resources are used to create robust infrastructure and support based on strong existing units and programs, as well as academic programs in key clinical and translational disciplines, to provide faculty leadership, expertise, and consultation as well as high quality services. These Programs are in Biomedical Informatics, Biostatistics, Clinical Translation, Novel Methods, Technical Cores, Community Engagement, Ethics, Health Disparities, Pediatrics, and Regulatory Support. A radically reconfigured Participant and Clinical Interactions Resource is also described. These programs are all united by an Education Program that reaches a wide spectrum of audiences: from undergraduates to mid-career faculty, from basic scientists to population researchers, from staff to community members. Both accelerated options and intensive programs are available. Finally, a robust pilot program will disburse up to $8 million/yr in pilot funds, focusing on stimulating translational and interdisciplinary studies.

DESCRIPTION, OVERALL (provided by applicant): The University of Michigan is ideally poised to house a MAPP Discovery Site. The faculty of the Chronic Pain and Fatigue Research Center (CPFRC) are internationally known for translational research in fibromyalgia (FM) and related illnesses, including interstitial cystitis/painful bladder syndrome (IC/PBS). The Center has begun collaborating with a strong group of colleagues from the DM Urology Department. These investigators have expertise that spans the translational bench to community continuum of IC and chronic pelvic pain. All of our projects will pursue a unifying hypothesis that we feel has been supported in related pain conditions and may underlie IC/PBS: A subset of women with IC/PBS has a central problem in pain or sensory processing, as occurs in FM, rather than a disorder confined to the bladder. Project one extends the ongoing NIH-funded RICE study (a cross-sectional epidemiological study that queries individuals in the U.S. regarding their current symptoms). This study will 1) examine the natural history of IC/PBS in the general population, 2) show that IC/PBS patients in tertiary care clinical samples have higher rates of co-morbid conditions, including psychological co-morbidities, than IC/PBS patients in the population, and will also identify a population-based cohort of IC/PBS patients in the Michigan region that can be recruited for studies at our discovery site. Project two will perform experimental sensory testing and functional neuroimaging in women with IC/PBS, healthy controls, and FM patients. We hypothesize that IC/PBS patients are diffusely sensitive to pain and other sensory stimuli, similar to FM patients. Project three will further explore the precise reason(s) for the augmented pain and sensory processing seen in IC/PBS. A specific molecular probe will test whether a subset of IC/PBS patients has attenuated descending analgesic activity that is restored via administration of a selective noradrenergic/serotonergic reuptake inhibitor (NSRI), milnacipran. We hypothesize that we will show via experimental pain testing and functional neuroimaging that there is attenuated descending analgesic activity in some IC/PBS patients, and that improvements in these experimental parameters will be accompanied by improvement in pain and urinary urgency/frequency. We also hypothesize that certain genetic polymorphisms in COMT and beta-2 and-3 adrenoreceptors will predict the magnitude of the descending analgesic response, and response to a NSRI.

1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-; 1-Propanamine, 3-(10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5-ylidene)-N,N-dimethyl-; 3-(2-Aminoethyl)-1H-indol-5-ol; 5-HT; 5-Hydroxytryptamine; 5HT; Acetylcholine Agents; Adverse drug effect; Adverse effects; Affect; Amitriptyline; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; Attenuated; Binding; Binding (Molecular Function); Biologic Marker; Biological; Biological Markers; Bladder; Blood Pressure, High; Cholinergic Agents; Cholinergic Drugs; Cholinergic Receptors; Cholinergics; Cholinoceptive Sites; Cholinoceptors; Clinical; Clinical Trials; Clinical Trials, Unspecified; Cognitive; Complex; Condition; Count; Cyclopropanecarboxamide, 2-(aminomethyl)-N,N-diethyl-1-phenyl-, cis-(+-)-; Data; Diffuse Myofascial Pain Syndrome; Disease; Disorder; Drug Side Effects; Drug usage; Drugs; ENPT; End Point; EndPointCode; Endpoints; Enteramine; Fatigue; Fibromyalgia; Fibromyositis-Fibromyalgia Syndrome; Fibrositis; Functional Magnetic Resonance Imaging; Future; Genetic; Genetic Polymorphism; Hippophaine; Hypertension; Individual; Ion Channels, Sodium; Knowledge; Lack of Energy; Levarterenol; Levonorepinephrine; MPD syndrome; MRI, Functional; Magnetic Resonance Imaging, Functional; Measures; Medication; Medicine; Methodology, Research; Methods; Methods and Techniques; Methods, Other; Michigan; Molecular; Molecular Interaction; Molecular Marker; Molecular Probes; Multicenter Studies; Nature; Noradrenaline; Norepinephrine; Numbers; Outcome; Outcome Measure; Pain; Pain Threshold; Pain Tolerance Level; Painful; Pathway interactions; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Polymorphism (Genetics); Polymorphism, Genetic; Pressure; Pressure- physical agent; Process; Process Measure; Property; Property, LOINC Axis 2; Range; Rate; Receptors, ACh; Receptors, Acetylcholine; Research; Research Methodology; Research Methods; Rheumatism, Muscular; Role; SSRI; Science of Medicine; Selective Serotonin Reuptake Inhibitor; Selective serotonin re-uptake inhibitor; Sensory Process; Serotonin; Signature Molecule; Site; Sodium Channel; Symptoms; Techniques; Testing; Toxic effect; Toxicities; Treatment Side Effects; Urinary System, Bladder; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Woman; Work; amitryptiline; analgesia; biomarker; central pain; cholinergic; chronic pain; chronic painful condition; clinical effect; clinical investigation; cohort; concept; cortical pain; design; designing; disease/disorder; drug efficacy; drug use; drug/agent; fMRI; fibromyalgia syndrome; hyperpiesia; hyperpiesis; hypertensive disease; improved; inhibitor; inhibitor/antagonist; midalcipran; milnacipran; myofascial pain dysfunction syndrome; neuroimaging; noradrenergic; pain tolerance; pathway; polymorphism; pressure; psychologic; psychological; restoration; reuptake; serotonin reuptake inhibitor; side effect; social role; therapy adverse effect; treatment adverse effect; urinary bladder

Infrastructure; Pediatric Research; Research Infrastructure

Clinical Trials; Clinical Trials, Unspecified; Infrastructure; Research Infrastructure; clinical investigation

Infrastructure; Research; Research Infrastructure

DESCRIPTION (provided by applicant): There have been tremendous advances in our understanding of the basic science of pain within the past few decades, and this information needs to be translated into clinical practice so that our diagnostic and treatment paradigms match our current knowledge. Even though pain is the presenting complaint for most individuals with musculoskeletal pain, very few clinicians seeing these patients have training in either pain assessment or management. Even fewer clinicians perform research related to pain. This situation puts large groups of investigators and clinicians at a disadvantage if they do not understand modern pain translational research as they study, evaluate, and treat individuals with rheumatic diseases. By gathering together leaders in pain and musculoskeletal disorders we will be taking a significant step toward narrowing the gap between translational research in pain and pain management. The proposed conference will represent the first of its kind. In a single conference it will bring together internationally recognized experts in a broad range of domains in the pain field, as well as similarly esteemed faculty that broadly represent the rheumatology field. The didactic seminars, breakout sessions, and networking opportunities are all designed to bring two worlds of investigators together to stimulate interdisciplinary research between individuals who study musculoskeletal disorders, and those who study pain and other sensory symptoms. The specific aims of the conference are: 1) To examine the aggregate state-of-the-art knowledge in the pain field, especially regarding the role that neural factors play in affecting individual pain sensitivity. 2) To discuss the latest research techniques in the pain field, as well as the strengths and weaknesses of each technique. 3) To stimulate new interdisciplinary relationships, including mentor-mentee relationships, between individuals in pain research and those studying musculoskeletal diseases. 4) To disseminate the knowledge gained from this conference. Over a period of one and a half days, the group of experts will engage in a concentrated exchange of ideas during general discussions that follow formal presentations and in separate break-out sessions. These interactions will be summarized in a statement reviewing of all the topics covered and incorporating review articles submitted by speakers. The conference will ultimately lead to a durable publication in a monograph, as well as one or more position papers presenting group findings and recommendations to be published in a peer reviewed journal (such as Arthritis and Rheumatism). The collaborative and interactive nature of the proposed workshop will ensure that the recommendations generated will have a broad impact on the scientific community, and will generate collaborative, interactive research amongst scientists and clinicians with an interest in rheumatic illnesses.

DESCRIPTION (provided by applicant): Bladder pain and discomfort, as well as urinary urgency and frequency, are common and bothersome symptoms seen in the general population. Clinical diagnostic terms used to describe these symptoms include interstitial cystitis (IC), painful bladder syndrome (PBS), chronic prostatitis, and overactive bladder (OAB), but there is tremendous overlap between these entities, and the distinction between them is based more on imminence than evidence. Pain and/or sensory sensitivity have been suspected to play a role in the pathogenesis of both bladder pain and urinary urgency/frequency. However, there has never been a study to determine whether entities such as IC/PBS and OAB might merely represent different points in a continuum of bladder sensory sensitivity. Moreover, we know of no studies that have directly compared whether sensory sensitivity in the bladder is related to global (i.e. CNS-mediated) sensory sensitivity. In the proposed study, a team of investigators with complementary expertise will perform a population-based study assessing bladder and overall sensory sensitivity, in a cohort of women chosen to be representative of the general population with respect to the entire continuum of bladder pain (from none to severe), and symptoms of urgency/frequency. These individuals will undergo urodynamics to measure sensory sensitivity in the bladder, as well as pressure pain and auditory loudness thresholds. Our Specific Aims are to demonstrate that in the population, 1) sensory sensitivity in the bladder is related to sensory sensitivity elsewhere in the body, suggesting that this is a CNS-driven mechanism, and 2) those individuals in the population that have more pronounced global sensory sensitivity will display: a) more bladder pain, b) more urgency/frequency, and c) more other symptoms of centrally-mediated pain states, such as pain elsewhere, fatigue, and insomnia. We feel that these studies are crucial to better understand the relationship between sensory sensitivity and urinary symptoms, and to add to the evidence necessary to appropriately diagnose and treat these symptoms and individuals. PUBLIC HEALTH RELEVANCE: Bladder symptoms such as pain and urgency are very common, and treatments are poorly effective. These studies will examine for clinical evidence of global pain hypersensitivity in these patients. If a global pain abnormality is identified, additioal studies can be done to examine the etiology of these symptoms and design novel treatments that are focused on central, rather than peripheral, pathophysiology.

DESCRIPTION (provided by applicant): Recent studies suggest the lifetime risk for symptomatic knee OA (KOA) is 45%1. An aging population and increasing rates of obesity contribute to dramatic increases in the prevalence of this condition. Historically, the disease of OA is viewed primarily as damage to the cartilage and bone. As such, the magnitude of damage or inflammation of these structures should predict symptoms. Population-based studies suggest otherwise; 30- 50% of individuals with moderate to severe radiographic changes of OA are asymptomatic, and approximately 10% with moderate to severe knee pain have normal radiographs2,3. Psychological factors do account for some 4,5 of this variance in pain and other symptoms, but only to a small degree . This failure of peripheral damage, inflammation, or even psychological factors to explain the presence, absence, or severity of chronic pain should not be surprising. To date, no chronic pain state involves a strong relationship between peripheral factors and the level of pain reported. We hypothesize that, although peripheral nociceptive input and to a lesser extent psychological factors are important in leading to pain and symptom expression in KOA, some patients possess varying degrees of non-psychological central nervous system (CNS) factors which play an equally or even more prominent role in the expression of pain and co-morbid symptoms 6-8. Broadly within chronic pain states, subsets of patients have been identified that have prominent CNS mechanisms (as opposed or in addition to, peripheral damage) playing important roles in pain perception. Such factors include diffuse hyperalgesia or allodynia, and/or a lack of endogenous descending analgesic activity 6,8, 9 . The exploration of these CNS factors has been somewhat limited to date in OA, but evidence is emerging that supports the hypothesis that subsets of OA patients do indeed have these mechanisms operative 10-12. Our hypothesis is further strengthened by studies that have identified co-morbid somatic symptoms known to be associated with central pain conditions (e.g., fatigue, sleep problems) to be commonly present in OA 13, 14. Finally, recent RCTs have demonstrated that compounds that alter pain neurotransmitters centrally such as 15,16 serotonin and norepinephrine (e.g., duloxetine, tricyclics) are efficacious in OA . We will identify the role that CNS factors are playing in KOA by first showing that subsets of patients have symptom patterns and experimental sensory testing abnormalities consistent with having a central component to their pain. We will then demonstrate the utility of these measures by showing that individuals with KOA with central pain will respond poorly to knee arthroplasty. Such a study possesses 17 high public health impact given the high failure rate of knee arthroplasty . If the status quo in practice for KOA is maintained, demand for knee arthroplasty will increase by an expected 700% in the next 20 years 18. Thus, in addition to this study providing a potential paradigm shift in our thinking regarding the disease of OA, this study also develops practical clinical tools for identifying the presence of centrally-enhanced pain in OA.

DESCRIPTION (provided by applicant): The spectrum of conditions known as Temporomandibular Joint Disorders and Orofacial Pain (TMJD/OP) are difficult to diagnose and manage because their etiologies and pathogeneses are poorly understood. Progress towards definitive therapies and rational diagnoses has been slow due to the complex nature of the disorders and the lack of scholars working in this field, many of whom utilize a very narrow silo approach to investigating these disorders. We propose training four high caliber clinician scientists and basic scientists per year to enhance the number and quality of interdisciplinary researchers that can appropriately unravel the mechanisms underlying TMJD/OP and identify the most effective treatments. Towards this objective, we will engage Scholars for interdisciplinary mentorship in TMJD/OP, with the goal of bridging bench to bedside and back, to better understand these conditions in three main areas of inquiry: (1) pain mechanisms and therapies; (2) TMJ pathogenesis; and (3) developmental biology, regeneration and tissue engineering of joint, muscle and ligaments. Where appropriate, embedded within each of these areas will be research and didactic experiences in contemporary methodologies, including bioinformatics, genomics, imaging and biomarkers. The Scholars will have a minimum of 75 percent protected time for research and research career development. An individualized career development plan will be customized with each scholar and their interdisciplinary research mentors and mentorship team. Each plan will include an intensive supervised research experience, didactic training including instruction and assistance in grant writing/submission and scientific writing, ongoing mentor feedback, formal annual evaluation, and instruction in the responsible conduct of research. The Scholars' mentoring teams, didactic coursework, and experiential learning will highlight the need to understand the entire translational continuum and the complex interplay between peripheral and central factors that contribute to complex chronic pain states. The training of interdisciplinary scholars under the mentorship of established investigators, including those working in related areas outside the field, will likely lead to novel discoveries and provide the needed momentum for innovations in the diagnostics and therapeutics for TMJD/OP. These include: 1) the ability to better phenotype these patients to identify sub-sets of individuals (i.e. endophenotypes) that respond to specific therapies; 2) th identification and use of local or systemic biomarkers to diagnose disease or monitor improvements in therapy; 3) the use of both peripheral and central nervous system, joint and muscle imaging technologies for earlier and more sensitive diagnostics; and 4) the use of biomedicine, biomimetics, and imaging to design and manufacture bioengineered joints. Collectively, this application offers a comprehensive and systems-based approach to training researchers in the TMJD/OP field.

DESCRIPTION (provided by applicant): The University of Michigan (UM) is one of the largest and most highly ranked public universities in the country, and a major center for graduate and post-graduate research training. The Ann Arbor campus is home to 19 schools and colleges, and UM faculty and students embrace inter- and multi-disciplinary training and research. Because of this, UM typically ranks in the top five universities in total research expenditures nationally, totaling $1.24B in 2010-2011. This proposed new NIGMS T32 Postdoctoral Training Program in Anesthesiology will provide support to post-doctoral trainees interested in careers in academic anesthesiology, and who embrace the interdisciplinary nature of of our institution. This T32 will heavily borrow from the UM Clinical and Translational Sciences Award (CTSA), which has been very successful at creating a number of innovative post-doctoral training programs for translational biomedical researchers. A unique aspect of this T32 program is that our mentoring teams, curricula, and research projects emphasize that successful anesthesiology researchers need to be competent in performing (and leading) inter-disciplinary research. We envision this process involving teams of individuals who include scientists that can successfully bi-directionally translate scientific knowledge from bench to bedside to practice - and back. Thus, all of our trainees will have a program designed that will provide them a necessarily deep understanding (i.e., walk the walk) of a particular scientific discipline combined with a broad understanding (i.e., talk the talk) of the terminology and issues facing their colleagues in other disciplines and/or related to points along the translational continuum.

? DESCRIPTION (provided by applicant): Moderate to severe pain following surgery is common, even after surgeries thought of as minor. Opioids are the mainstay for acute postoperative pain care despite their known side effects and related adverse events. Most research to date has focused on the anesthetic and surgical factors associated with higher acute pain, thereby largely ignoring the inter-patient variability in pain sensitivity. As such, pharmacological adjuncts to opioids and regional anesthetics have been broadly applied in an all or none fashion rather than personalized based on patient characteristics. There is a growing appreciation of the importance of altered central nervous system (CNS) processing of pain and other symptoms in chronic pain states. The widespread body pain, hyperalgesia and comorbid symptomatology of centralized pain states has been best studied in fibromyalgia. Rather than being present or absent, fibromyalgia symptoms occur on a continuum that has been termed fibromyalgianess and can serve as a crude surrogate of the degree of centralization. Opioids are thought to be less effective in centralized pain patients. Our primary hypothesis is that although peripheral nociceptive input is important in the acute pain response, some patients possess varying degrees of CNS amplification (higher fibromyalgianess) that plays an equally or even more prominent role in the expression of pain and opioid consumption. Thus, we hypothesize that the patients with pain that is more centralized in that the degree of pain centralization as measured on a simple self-report measure strongly predicts acute opioid pain responsiveness by providing a surrogate measure of endogenous opioid tone. To test our hypothesis, we will conduct a prospective assessment of pain, opioid consumption and adverse acute postoperative period in patients undergoing total knee arthroplasty (n=200). These data will be used to assess whether fibromyalgianess predicts higher acute pain, more opioid consumption, and a lesser response of pain for the opioids administered. To assess the mechanistic underpinnings of these clinical findings, we will conduct preoperative functional imaging (fMRI and PET scanning) in 60 of the 200 knee arthroplasty patients across the continuum of fibromyalgianess to determine preoperative opioid tone and previously described brain imaging findings of hyperalgesia. The opioid consumption and pain reports will then be analyzed with the brain imaging findings. Consistent with our long term goal of personalized pain medicine, the proposed research could have a major impact on clinical practice because a subset of individuals could be easily identified who would be strong candidates for non- or reduced opioid acute analgesic regimens.

PROJECT SUMMARY / ABSTRACT RESEARCH PROJECT Chronic musculoskeletal pain is extremely common, and pain is the most common symptom in nearly all rheumatic disorders. However, in all chronic pain conditions there is a tremendous disparity between identifiable damage/inflammation in the periphery ? and pain, and classic psychological factors, such as mood or catastrophizing, explain very little of the variance between pain and objective findings. Many individuals with chronic pain have surgery and have continued pain despite excellent surgical results, just as many patients with autoimmune disorders continue to have pain after inflammation is well controlled with biologics. Our CORT Research Project, ?MiCAPP ? Mechanisms of the CentrAlized Pain Phenotype? will have three cohorts with different forms of chronic musculoskeletal pain, one cohort with an autoimmune disorder and inflammatory pain (rheumatoid arthritis), one condition generally considered to be non-inflammatory pain conditions (osteoarthritis), and another considered to be neuropathic (carpal tunnel syndrome). We will demonstrate that in all of these individuals, higher degrees of pain centralization as measured by the 2011 Fibromyalgia (FM) Survey Criteria, will predict non-responsiveness to peripherally-directed analgesic therapies, and will have a common neurobiological signature identifiable on experimental pain testing and functional neuroimaging. Our overall hypothesis is that the current 2011 FM Survey Criteria can identify a subset of individuals across chronic musculoskeletal pain disorders with centralized pain, where the central nervous system (CNS) plays a prominent role in symptom expression, and thus these individuals will be less responsive to interventions aimed at the periphery. Furthermore, we will demonstrate that this centralized pain phenotype has stereotypical underlying neurobiological features across cohorts of individuals with chronic musculoskeletal pain. The Overall Specific Aims that are specifically addressed in this study are: 1) To demonstrate that the current 2011 FM Criteria predict non-responsiveness to peripherally-directed therapies, including a) surgery meant to relieve pain, b) administration of a biologic agent to an individual with an autoimmune disorder, and c) acute and sub-acute administration of opioids; 2) To demonstrate that in all three cohorts, individuals with the highest FM Survey Criteria scores will have the most pronounced neurobiological findings associated with pain centralization, including abnormal QST findings and aberrant findings on functional, chemical and structural neuroimaging; 3) To use the data from the above aims as well as other ongoing studies to develop and pilot test a more efficient and predictive self-report measure of centralization than the 2011 FM Criteria, which we will refer to as a Centralized Pain Index (CPI); and 4) To explore the clinical and mechanistic features of subsets of centralized pain patients that show improvement in centralization following reduction of peripheral nociceptive input (i.e. the central centralization or bottom-up subset) versus those that do not improve (the top down form).

PROJECT SUMMARY / ABSTRACT OVERALL COMPONENT Chronic musculoskeletal pain is extremely common, and pain is the most common symptom in nearly all rheumatic disorders. However, in all chronic pain conditions there is a tremendous disparity between identifiable damage/inflammation in the periphery ? and pain, and classic psychological factors such as mood or catastrophizing explain very little of the variance between pain and objective findings. Many individuals with chronic pain have surgery for this problem and have continued pain despite excellent surgical results, just as many patients with autoimmune disorders continue to have pain after inflammation is well controlled with biologics. We hypothesize that the reason there is such a disparity between pain and other symptoms - and the degree of damage/inflammation in the periphery - is that individuals with chronic musculoskeletal pain display variable degrees of fibromyalgia. The University of Michigan Fibromyalgia CORT proposes that the current 2011 FM Survey Criteria is a surrogate measure of centralized pain, and that higher scores on this measure will be predictive of more pain and other symptoms originating from the central nervous system (CNS). Thus higher scores on this measure will render individuals less responsive to analgesic therapies aimed at peripheral/nociceptive pain (surgery, biologics, opioids). We will demonstrate that this centralized pain phenotype has stereotypical clinical and neurobiological features to FM even when it is co-morbid with other musculoskeletal pain conditions with disparate underlying pain mechanisms: osteoarthritis, rheumatoid arthritis, and carpal tunnel syndrome. Our specific aims are: 1) To demonstrate that the current 2011 FM Survey Criteria serve as a strong surrogate of pain centralization and strongly predict non-responsiveness to therapies generally effective for treating peripherally-based pain, including a) surgery intended to relieve pain (hip arthroplasty, carpal tunnel release), b) administration of a biologic agent to treat an autoimmune disorder (rheumatoid arthritis), and c) acute perioperative administration of opioids; 2) To demonstrate that in all three cohorts individuals with the highest FM scores will have similar neurobiological findings of pain centralization on quantitative sensory testing (QST) and neuroimaging; 3) To develop and pilot test a shorter and more predictive self-report measure of pain centralization; 4) To explore the clinical and mechanistic features of two important subsets of centralized pain: top-down (i.e. previously termed primary FM) vs. bottom-up (i.e. previously termed secondary FM); and 5) To serve as a core national resource for training both researchers and clinicians in contemporary musculoskeletal pain research and care.

ABSTRACT Chronic Pelvic Pain (CPP) is a debilitating problem that afflicts 15-20% of women in the United States. Although over 200,000 hysterectomies are performed annually for the treatment of CPP, 1 in 4 women under- go the discomfort and morbidity of hysterectomy without relief of pain. Factors that predict treatment failure re- main poorly characterized. While the pathogenesis of CPP is not fully understood, the best-supported hypothe- sis is that CPP is a heterogeneous condition that results from a complex interaction between pathology in pe- ripheral tissues (e.g. endometriosis), the peripheral nervous system (PNS), and the central nervous system (CNS), each with variable contribution in any given patient with CPP. Preliminary data presented in this appli- cation confirms that a subset of women with CPP exhibit evidence of peripheral and central sensitization. What remains unclear is how peripheral and central factors interact to maintain CPP, and whether measures of pe- ripheral and central sensitization prior to hysterectomy can be used to guide clinical care in these women. The long-term goal is to understand the interplay between peripheral pathology and peripheral and central neurobi- ological dysfunction in women with CPP so that personalized treatment strategies can be developed for indi- vidual patients. The objective of this study is to characterize role of peripheral and central sensitization among women undergoing hysterectomy for CPP and to explore the utility of preoperative measures of PNS and CNS factors to predict the likelihood of persistent post-hysterectomy pain. This prospective observational study will recruit 250 women over 4 years who are scheduled to undergo hysterectomy, 200 for the treatment of CPP, 50 pain-free controls. Preoperative measures of central sensitization (self-report measures, quantitative sensory testing, neuroimaging), peripheral sensitization (endometrial nerve fiber density, neurotrophins and proinflam- matory cytokines), and psychosocial factors will be assessed. Patients will be followed at regular intervals for 6 months to assess pain symptoms and related surgical outcomes. Our central hypothesis is that preoperative factors associated with central sensitization predict failure of hysterectomy to relieve pain, whereas findings associated with peripheral sensitization predict a higher likelihood of pain relief from hysterectomy, since hys- terectomy is likely to remove the peripheral pathology that maintains peripheral sensitization. The approach is innovative because it will use state-of-the-art methods to simultaneously determine the relative contributions of both peripheral and central factors that maintain CPP and failure of hysterectomy to cure pain. These results will have a significant positive impact in women's health because they will have broad implications for the de- velopment of a personalized, mechanism-based treatment strategy for CPP, which may also be applicable to other chronic pain states. Not only will we be able to identify which individuals with CPP are not likely to benefit from surgery, these results will help develop algorithms for choosing the correct combinations of peripherally- and centrally-directed treatments for individual patients with chronic pain.

The Michigan Institute for Clinical & Health Research (MICHR) recognizes the need for a highly skilled, diverse workforce that can conduct impactful clinical and translational research that improves health. Since the inception of MICHR, the development of a diverse translational workforce has been a consistent priority. This priority includes engaging pre-doctoral trainees within their first few years of training and providing direct experience partnered with specific didactic training. Developed over the course of a decade, our current TL1- supported training programs include a short-term component (Summer Immersion Program) and a long-term component (the Master of Science in Clinical Research Program [MSCR]). This proposal requests support for 10 short-term trainees and 10 long-term trainees (an increase of one trainee) each year. Trainees will comprise a mixture of pre-professional doctoral students (e.g., medical student) and post-professional degree trainees. Other goals include: 1. Providing more opportunities for TL1 trainees to participate in community based research. 2. Supporting trainee career development by formally educating faculty mentors on mentoring skills using the curricula from the National Research Mentoring Network. 3. Expanding the network supporting the development of MSCR trainees. 4. Providing more intern/externship experiences for TL1 trainees. 5. Developing, demonstrating, and disseminating competency-based assessments for all TL1 trainees to improve the measurement of translational research skills. These five key goals will allow the MICHR TL1 programs to effectively train the next generation of translational scientists. The goal is that, upon program completion, these trainees will be highly engaged and motivated to continue work in clinical and translational research, competent in the skills necessary for clinical-translational research, experienced members of multidisciplinary or interprofessional teams led by highly skilled and engaged mentors, and nuanced in their capability to successfully participate in community based research.

PROJECT SUMMARY / ABSTRACT ADMINISTRATIVE CORE One of the advantages of the University of Michigan (UM) Fibromyalgia CORT Administrative Core is that all of the necessary leadership skills, faculty, staff, and procedures are already in place and have been for many years. The leadership team proposing this CORT has a successful track record of working together, coordinating large groups of investigators, conducting multiple projects simultaneously, and disseminating research findings. The Chronic Pain and Fatigue Research Center (CPFRC) at UM is acknowledged as one of the most successful pain research groups in the world due not only to the personnel but also to the strong institutional support provided to the group by the University of Michigan in the form of administrative infrastructure. This same institutional support will enable the success of the CORT. Another advantage we bring to our proposed CORT is that the Director, Dr. Clauw, was the first PI of the University of Michigan CTSA award and rejoined the leadership team as Associate Director. He founded the Michigan Institute for Clinical and Health Research, the unit that provides all necessary infrastructure for clinical and translational research at UM, and that houses the UM CTSA award. In the context of leading the UM CTSA programs, Dr. Clauw created innovative mentoring and training, and pilot grant programs, and the structure of these programs will be emulated in several of the new functions proposed in this regard for the CORT. Dr. Brummett, the Director of Pain Research for the Department of Anesthesiology and Associate Director for the proposed CORT, possesses the complementary leadership skills and areas of scientific strength that have allowed he and Dr. Clauw to work productively together for many years on their current R01s. The Specific Aims of the Administrative Core are: 1) To be responsible for the planning, development, coordination and overall administration of the UM CORT; 2) To develop and maintain a vibrant pilot grant program for the UM CORT; 3) To help train and mentor the next generation of individuals who wish to incorporate contemporary pain research techniques into musculoskeletal research, and; 4) To disseminate information regarding the UM CORT findings to a broad constituency, from scientists to clinicians to patients.

PROJECT SUMMARY / ABSTRACT Chronic post-surgical pain (CPSP) is a major cause of new chronic pain, occurring between 10 - 40% after common surgical procedures. Thoracic surgery procedures have among the highest rates of chronic post- surgical pain (CPSP), with roughly 30 - 47% of patients developing new chronic pain within 6 months of surgery. While the high incidence of CPSP following thoracic surgery is well-described, the patient- and care- factors associated with the development of CPSP are still not clear. Some factors such as anxiety have been described; however, most cohorts lack the sample size to assess potentially important factors, including neuroimaging, quantitative sensory testing, and blood samples for genomics, metabolomics and proteomics. We believe that thoracic surgery is an ideal second surgical population to add to the Acute to Chronic Pain Signatures (A2CPS) program, complementing the first MCC population of knee arthroplasty, which has much lower rates of new CPSP but is a better cohort to identify risk factors for failure to resolve chronic pain. Our inter-disciplinary team from the proposed University of Michigan A2CP Multisite Clinical Center (MCC) has unparalleled expertise to examine the phenotypic and genotypic risk factors for the development of CPSP among patients undergoing thoracic surgery. Our co-PIs include an anesthesiologist, two surgeons, and a rheumatologist that have successfully collaborated in ongoing work, and partner within a statewide network of hospitals performing thoracotomy procedures, the Michigan Society of Thoracic and Cardiovascular Surgeons (MSTCVS) Quality Collaborative. Collaborative quality improvement programs including MSTCVS are funded by Blue Cross Blue Shield of Michigan to conduct participatory, provider-driven quality improvement initiatives, and our team has heavily leveraged these to study postoperative pain- and opioid-related outcomes and generate best practices. The implementation and dissemination of these best practices has dramatically reduced perioperative prescribing of opioids in the state of Michigan, and this strong partnership will enable us to recruit thoracotomy patients from a population-based sample across diverse healthcare systems. We will recruit 1800 patients from seven hospitals in Michigan undergoing surgery via a thoracic approach (lung resection, esophageal resection/reconstruction, and other general thoracic surgery). We will capture patient-reported health status alongside QST and functional neuroimaging at baseline and 6 months using a novel smart phone- and web-enabled application. At baseline and 6 months, biological samples will also be collected. From the 1800 participants recruited, we will identify 200 cases and 200 controls of CPSP at 6 months after surgery for repeated neuroimaging, quantitative sensory testing and blood sample collection. The successful completion of the proposed study would provide an unparalleled resource for the understanding the factors associated with CPSP and will allow for more efficient and personalized trials to prevent the development of chronic pain after thoracotomy and other thoracic surgeries.

Project Summary / Abstract Chronic Overlapping Pain Conditions (COPCs) represent up to 50% of all chronic pain cases, occur more commonly in women, and can be more debilitating than other forms of chronic pain. These conditions include but are not limited to the following: temporomandibular disorders (TMD), fibromyalgia (FM), irritable bowel syndrome (IBS), vulvodynia (VVD), interstitial cystitis/painful bladder syndrome (IC/PBS), painful endometriosis (ENDO), chronic tension type headache (cTTH), migraine headache (MI), chronic low back pain (cLBP), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common neurobiological substrates (e.g., central sensitization) have been suspected to account for the overlap; but until recently, it has been difficult to efficiently classify each of these conditions within individuals. A digital, logic driven classification tool has been developed for this purpose but access to the tool remains limited. Here we propose converting this COPC classification tool into the REDCap format so that it will be more broadly accessible by academic researchers including those involved in the HEAL initiative. Following the REDCap conversion of the COPC screener, a small validation study will help to assure that the new format retains its construct validity, usability, and equivalence to existing versions of the instrument.