Robert R. Edwards - US grants

[unreadable] DESCRIPTION (provided by applicant): Pain is a critical yet poorly-understood and under-treated problem in the management of breast cancer. Recent studies have estimated that approximately 50% of women who undergo lumpectomies will experience persistent pain, which is associated with impaired quality of life, significant disability, and, in some studies, cancer-related mortality. To date, studies of women undergoing breast surgery have identified few consistent or strong predictors of who reports long-term treatment-related pain, and to what degree. Though not previously studied in the context of breast cancer treatment, emerging evidence suggests that individual differences in how the central nervous system processes pain may be a powerful contributor to the extent of pain experienced after surgery. The proposed project is a prospective cohort study of women undergoing lumpectomy followed by radiation therapy for treatment of early-stage breast cancer. Pain responses will be evaluated pre-surgically by assessing responses to brief, standardized stimuli (i.e, heat, cold, pressure). Patients will be followed during their acute recovery periods using a combination of electronic diaries and automated telephone calls to assess treatment-related pain, analgesic usage, and pain-related sequelae. This study will determine: (1) whether pre-operative psychophysical testing to evaluate pain responses is useful in predicting acute and longer-term pain outcomes after lumpectomy, and (2) what are the most effective measures of experimental pain responses in predicting treatment-related pain outcomes. We hypothesize that the individuals who show the greatest degree of pain sensitivity and the lowest degree of endogenous pain inhibition will report the most acute pain, require the most analgesics, and report the highest levels of long-term pain and pain-related disability. This work will provide important information on mechanisms and risk factors contributing to the experience of pain following treatment for breast cancer. In addition, the findings may enhance future pain-treatment studies by allowing investigators to target high-risk individuals for clinical trials of analgesics. Finally, results from this research would have general implications for post-surgical pain management; those who showed the most high-risk profiles might benefit from additional pre-emptive or post-operative analgesic interventions, or more intense follow-up for a longer period. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Painful musculoskeletal diseases affect millions of Americans, and are associated with profound consequences such as disability and mortality. Increasing evidence suggests that part of the deleterious impact of pain may be mediated by inflammation, that pain and inflammatory processes engage in a dynamic, reciprocally-interacting relationship, and that cognitive and emotional factors are intimately involved in the experience of pain and its consequences. The present proposal will provide the necessary foundation to build a clinical research program elucidating the mechanisms by which psychosocial processes such as pain-related catastrophizing exert deleterious effects on pain-related outcomes in arthritis, fibromyalgia, and other painful musculoskeletal conditions. Catastrophizing has been identified as a set of negative cognitive and emotional processes in response to pain, and has been linked to central sensitization, reduced quality of life, and enhanced disease activity in the context of rheumatic pain. The PI for this proposal has a NIAMS Mentored Career Development Award to study rheumatoid arthritis;the present application would provide the necessary resources to investigate pro-inflammatory immune system responses to acute pain (and catastrophizing's impact on inflammatory responses to acute pain) not only in RA, but in other rheumatic disease groups as well. Participants will undergo sessions of quantitative sensory testing, during which painful mechanical and cold stimuli will be administered;individual and group differences in the magnitude and time course of neuroendocrine (i.e., cortisol) and pro-inflammatory cytokine (i.e., IL-6 and TNF-1) responses to acute pain will be studied. To our knowledge, this would be the first controlled study to evaluate catastrophizing's impact on inflammatory responses to acute noxious stimulation across multiple samples of patients with persistent pain. The need for further research into catastrophizing's mechanisms of action is increasingly important in the context of an epidemic of chronic pain. Epidemiological studies have identified catastrophizing as a risk factor for the development and persistence of pain, and reduction of pain-related catastrophizing represents an important goal for multidisciplinary pain treatment. The applicant's goal for the proposed project is to understand the pathways by which catastrophizing impacts pain-related outcomes in order to refine biopsychosocial models of pain and facilitate the enhancement of psychosocial interventions for chronic musculoskeletal pain. PUBLIC HEALTH RELEVANCE: Painful musculoskeletal diseases affect millions of Americans, and are associated with profound consequences such as disability and mortality. Increasing evidence suggests that part of the deleterious impact of pain may be mediated by inflammation, that pain and inflammatory processes engage in a dynamic, reciprocally-interacting relationship, and that cognitive and emotional factors are intimately involved in the experience of pain and its consequences. Epidemiological studies have identified catastrophizing as a risk factor for the development and persistence of pain, and reduction of pain-related catastrophizing represents an important goal for multidisciplinary pain treatment. The applicant's goal for the proposed project is to understand the pathways by which catastrophizing impacts pain-related outcomes in order to refine biopsychosocial models of pain and facilitate the enhancement of psychosocial interventions for chronic musculoskeletal pain.

DESCRIPTION (provided by applicant): Degenerative joint disease, particularly knee osteoarthritis (OA), is one of the most prevalent and disabling chronic pain conditions and is projected to increase sharply as the U.S. population ages. Projections also indicate that the annual number of total knee replacements, the treatment of choice for end-stage knee OA, will increase five- to ten-fold in the U.S. over the next several decades. While the outcomes following total knee arthroplasty are generally good, a substantial minority of patients continue to experience significant long-term pain and disability after surgery. These individual differences in the trajectory of pain and function after knee replacement are minimally related to findings from physical examination and imaging procedures. Our group has identified several potentially important variables that are likely to play a role in shaping long-term pain outcomes, though there are few published studies in patients with knee OA. The proposed 2-site prospective cohort project will carefully evaluate and follow a sample of patients undergoing total knee replacement. Knee OA patients will be assessed pre-surgically with a battery of psychophysical pain testing procedures, multimodal evaluation of sleep quality, continuity, and architecture, questionnaires regarding psychological function, and physiological sampling (e.g., blood and saliva samples). Outcomes such as pain, functioning, and analgesic usage will be evaluated through 12-month follow-up. These data will allow us to model the unique and combined impact of these classes of "risk factor" variables. Collectively, the identification of factors associated with the development and maintenance of persistent pain and pain-related disability following joint replacement has important practical implications for selection of surgical patients and for management of post-operative pain, as well as theoretical importance in understanding the sources of individual differences in pain-related outcomes. PUBLIC HEALTH RELEVANCE: Chronic pain is a critical national and international health problem, making the identification of groups at high risk for the development or persistence of chronic pain an increasingly important area of investigation. This project seeks to identify risk factors for persistent pain and physical disability following total knee replacement, a surgical procedure projected to increase five- to ten-fold in the U.S. over the next several decades. Collectively, the identification of factors associated with the development and maintenance of persistent pain and pain-related disability following joint replacement has important practical implications for the selection of surgical patients, for the management of post-operative pain, and for understanding the sources of individual differences in pain-related outcomes.

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 knowledge about pain and to transform public policy and clinical practice in order 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. The annual meeting integrates basic, experimental and clinical pain research, and encourages cross-fertilization among the participants. This bidirectional translational interchange between clinicians who diagnose and manage clinical pain and pre-clinical scientists who are elucidating pain mechanisms is the cornerstone of improved pain therapy and advances in pain management. 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. Collectively, the APS Young Investigator Travel Awards program is designed to facilitate the mentoring and nurturing of the next generation of pain researchers.

DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the change in clinical and experimental pain in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT) and compare them with men with PCa not receiving ADT (non-ADT). The use of ADT is associated with a significant decrease in quality of life (QOL).This decrease is evident in both physical and mental composites of SF-36 QOL questionnaire. One of the aspects of the physical composite is the perception of pain. Preliminary cross-sectional studies have shown that men undergoing ADT report more clinical pain when compared with men in the non-ADT group and with age-matched healthy controls. As this increased pain perception is seen even in those androgen-deprived men without any metastatic disease, these findings implicate profound hypogonadism as the main etiology for these symptoms. Male hypogonadism is an inflammatory state associated with an increase in pro-inflammatory cytokines like IL-6 and TNF-¿, both of which have been associated with clinical and experimental pain. Androgen deprivation therapy is also associated with metabolic abnormalities such as insulin resistance and hyperglycemia. Hence, it is unclear whether the increased prevalence/severity of pain in men on ADT is due to direct effects of hypogonadism or secondary to these metabolic abnormalities. We propose a prospective study in which: 1) we will compare changes in clinical pain reports and psychophysical pain responses between men undergoing ADT vs. non-ADT over a 6-month time period, and 2) We will assess the associations of various metabolic and inflammatory markers with pain perception and pain threshold in men undergoing ADT. The proposed study, in addition to advancing our understanding of the mechanism of pain development in men on ADT, is likely to have a significant clinical impact on the overall health-management of patients on ADT. The results of this study will guide physicians to use ADT for appropriate indications and to screen these patients for incident pain during ADT. Since androgen replacement is contraindicated in men with PCa, this study will lay the groundwork for prospective trials assessing the role of novel anti-inflammatory agents, insulin- sensitizing agents or SARMS (selective androgen receptor modulators) in the prevention and treatment of pain during ADT.

DESCRIPTION (provided by applicant): Chronic pain is a widespread international health problem that imposes costs of over 600 billion dollars per year. This application focuses on fibromyalgia (FM), which is characterized by persistent, widespread body pain, with significant evidence of altered brain function. One of the few effective treatments for FM is cognitive-behavioral therapy (CBT), which has been shown to reduce pain intensity and pain-related disability, potentially via reductions in catastrophizing, an important psychosocial factor that plays a crucial role in shaping individual differences in pain- related outcomes. It is likely that brain mechanisms underpin the beneficial effects of lowered catastrophizing and reduced pain in FM, and CBT-produced decrements in catastrophizing may act to normalize dysfunctional central nervous system pain processing. Our previous study in FM patients confirms that patients who are high in catastrophizing show enhanced pain-related activation in brain areas that process emotional aspects of pain (e.g., anterior insula and medial thalamus). In addition, catastrophizing was associated with altered pain-evoked functional connectivity between thalamus, anterior insula, and default mode network (DMN) structures such as medial prefrontal cortex. The DMN is a constellation of brain regions that mediate self- focused cognitive processing; our prior work has implicated altered resting-state functional connectivity between DMN and insula as a biomarker for clinical pain in FM. In our pilot study, a subset of FM patients was randomized to CBT or an active educational control condition. We found that CBT reduced catastrophizing and produced corresponding changes in brain activation and DMN connectivity. In the present proposal, we hypothesize that CBT-produced improvements in pain will be anticipated and mediated by reductions in catastrophizing and their associated effects on pain-related brain functioning. Participants with FM will be randomized to 8 weekly treatments with CBT or an education/attention control, and followed up for 6 months. Functional MRI data, including functional connectivity during both a resting and evoked deep- tissue pain state, will be collected at baseline, mid-treatment, and after the final treatment visit. We hypothesize that CBT will reduce catastrophizing early in treatment, resulting in adaptive changes in the brain's responses to an externally-applied noxious stimulus. These changes will then predict subsequent changes in patients' resting state connectivity in DMN and pain- relevant brain regions, which will underlie long-term improvements in clinical pain. Our overarching goal is to understand the neurobiological pathways by which CBT and reduced catastrophizing facilitate improvements in chronic pain; such information will help to refine biopsychosocial models of pain, identify potential non-responders early in treatment, and facilitate the enhancement of psychosocial interventions for chronic musculoskeletal pain.

? DESCRIPTION (provided by applicant): Chronic low back pain (CLBP) afflicts up to 50 million US adults and is a primary cause of disability. Currently, opioid analgesics are a cornerstone of pain management, and are among the most common medications prescribed by physicians for CLBP. Despite their potential benefits, major concerns have been raised regarding opioids due to their potential iatrogenic consequences, such as the development of opioid-induced hyperalgesia (OIH) and prescription opioid misuse (POM), both of which have the potential to impair treatment benefits. It is clear that not all patients taking long-term opioids will experiene these maladaptive effects. Our preliminary data indicate that specific subgroups of pain patients might be more prone to developing OIH, as well as deleterious shifts in central nervous system (CNS) pain-modulatory processes. Furthermore, our preliminary data suggest that OIH and opioid-induced changes in pain modulation might increase patients' propensity to misuse opioids. Given the current opioid prescribing rates in the U.S., there is an urgent need to better understand effects of opioids on CNS pain processing and, in turn, the effects of those sensory changes on risk for opioid misuse or addiction. In this study, we propose to conduct a 4-month randomized, controlled trial of oral opioids among patients with CLBP. In this trial, each participant will undergo quantitative sensory testing (QST) at baseline, before being randomized to receive either extended-release oral morphine or matched placebo. Patients will then undergo repeat QST at 1, 2, 3, and 4 months. At each of these follow-up time points, we will assess changes in pain sensitivity and modulation, and prescription opioid misuse. Treatment efficacy will be assessed using daily electronic dairy entries We hypothesize that an identifiable subgroup of patients, characterized by high levels of negative affect and pain catastrophizing, will be at the greatest risk for experiencing maladaptive opioid-induced changes in pain sensitivity (i.e., OIH) and pain modulation, as well as an increased likelihood of prescription opioid misuse. Collectively, there is a very strong animal literature on OIH (which seems to be a highly robust phenomenon in rats), but there is currently a paucity of prospective human data. We hope that findings from this research would be novel, timely, and would have direct implications for the field of opioid pain management. Identifying subgroups of patients who are at elevated risk for OIH and POM should facilitate more effective tailoring of treatment regimens to individual patients, and aid in reducing the potentially severe iatrogenic impacts of long-term opioid therapy in patients with chronic pain.

Project Summary The objective of the Early Phase Pain Investigation Clinical Network (EPPIC-Net) and EPPIC- Net initiatives is to rapidly and efficiently translate advances in the neurobiology of pain into treatments for people with chronic and acute pain, conditions associated with a significant burden to both patients and society. Challenges to the successful and efficient development of novel treatments for people with pain include inefficiencies in regulatory and institutional submissions and approvals, a variety of barriers to recruitment of subjects that slow down clinical research, inadequate quality assurance of trials, and a shortage of individuals trained and prepared to participate in and lead multicenter trials. The primary goal of the Clinical Coordinating Center (CCC) for EPPIC-Net is to promote and facilitate, from initial conception through final analysis, clinical trials in adult and pediatric populations with acute or chronic pain by providing efficient methodological, organizational and logistical support. The EPPIC-Net-CCC will adopt and establish processes aimed at dramatically increasing the efficiency of multicenter clinical trials, improving the overall quality of clinical trials, promoting patient recruitment and retention as well as increasing the number of clinical investigators and research staff well trained and passionate about leading and conducting multicenter clinical trials. The Specific Aim 1 of our proposal is to harness through a collaborative Clinical Coordinating Center multidisciplinary clinical research and data management expertise to provide the scientific leadership and infrastructure required to design and conduct multi-site Phase 2 clinical trials, biomarker validation studies, and deep phenotyping of patient populations to understand the biologic basis of a specific pain condition and its response to treatment. The Specific Aim 2 of our proposal is to expand the pool of experienced clinical Investigators and research staff to be participants and leaders of multicenter clinical research trials by providing education, training, resources and professional mentorship. Finally, the Specific Aim 3 of our proposal is to engage and mobilize federal, industry, foundations and patient partners by working with the EPPIC-Net Steering Committee (EPPIC-Net-SC), EPPIC-Net-DCC and Project Team Principal Investigators to conduct multi-site Phase 2 clinical trials, biomarker validation studies, and deep phenotyping of patient populations to understand the biologic basis of a specific pain condition and its response to treatment.

Chronic pain affects over 100 million American adults and >40% of older adults age ?65, with estimated costs of >$500 billion to $1 trillion annually. Older adults are at increased risk of having multiple painful conditions and are living longer with the negative impacts of chronic pain. Chronic pain, regardless of anatomy or diagnosis involved (e.g., back pain, migraine), is the leading cause of disability worldwide. Limited insights into whether common mechanisms underlie all pain conditions, regardless of diagnosis, has contributed to inadequate pain management options, and in turn, to the opioid epidemic. Health care providers who treat one pain condition (e.g., joint pain) typically do not manage symptoms in other parts of the body (e.g., abdominal pain), and patients are often referred from one specialist to another. Studying commonalities of various chronic overlapping pain conditions (COPC) in community-based cohorts unselected for pain conditions can provide novel insights into causes and consequences of chronic pain as a disease itself. For example, neurophysiologic alterations in pain processing such as pain sensitization (assessing ascending pain pathways) and conditioned pain modulation (CPM) (assessing descending pain modulation) may be common mechanisms underlying all chronic pain. Such knowledge would spur development of novel pain management approaches for all types of pain regardless of anatomy or diagnosis involved. Despite the substantial public health burden of chronic pain, little is known about the epidemiology and evolution of COPC in older adults, nor of the impact of COPC on physical function, risk of nursing home admission, and mortality in older adults. We propose to evaluate chronic pain in the upcoming study visit of a thoroughly-characterized community-based older adult cohort unselected for any pain complaints, the Framingham Heart Study (FHS) (N~1874, mean age 76, 84% ?age 70). We aim to understand the epidemiology of COPC, regardless of anatomy or diagnosis involved, the evolution of COPC over time, neurophysiologic alterations in pain processing as risk factors for COPC and its evolution, and consequences of COPC and altered pain processing in older adults. We propose acquiring objective quantitative sensory testing (QST) measures of pain sensitization and CPM, which are associated with pain severity and response to treatment in experimental settings of subjects selected for particular pain conditions. However, whether QST- assessed neurophysiologic alterations may be common underlying risk factors for all forms of chronic pain, and for functional limitations, institutionalization, and mortality in a community-based cohort of older adults unselected for pain is unknown. We will collect data regarding a multitude of chronic pain conditions, QST, self-report and performance-based physical function, and nursing home admissions during the next planned study visit, as well as two follow-up assessments to obtain longitudinal data, and leverage the ongoing FHS surveillance of mortality. Our work will address several knowledge gaps, and insights gained may ultimately facilitate new preventive and therapeutic approaches to relieving chronic pain and its consequences, regardless of underlying diagnosis.

Chronic pain affects over 100 million American adults, with an estimated cost of $560-635 billion annually, yet this major burden is relatively understudied in African Americans (AAs). Older adults are at increased risk of having multiple painful conditions and are living longer with the negative impacts of chronic pain. Chronic pain, regardless of anatomy or diagnosis involved (e.g., back pain, migraine), is the leading cause of disability worldwide. Limited insights into whether common mechanisms underlie all pain conditions, regardless of diagnosis, has contributed to inadequate pain management options. Health care providers who treat one pain condition (e.g., joint pain) typically do not manage symptoms in other parts of the body (e.g., abdominal pain), and patients are often referred from one specialist to another. Studying commonalities of various chronic overlapping pain conditions (COPC) in community-based cohorts unselected for pain conditions can provide novel insights into causes and consequences of chronic pain as a disease itself. For example, neurophysiologic alterations in pain processing such as pain sensitization (assessing ascending pain pathways) and conditioned pain modulation (CPM) (assessing descending pain modulation) may be common mechanisms underlying all chronic pain. Such knowledge would spur development of novel pain management approaches for all types of pain regardless of anatomy or diagnosis involved. Despite the substantial public health burden of chronic pain, little is known about the epidemiology and evolution of COPC in older AA adults, nor of the impact of COPC on physical or psychosocial function, risk of nursing home admission, and mortality in older AAs. We propose to evaluate chronic pain in the upcoming study visit of a thoroughly-characterized community-based older AA cohort unselected for any pain complaints, the Jackson Heart Study (JHS) (N~2540, two-thirds ?age 65). We aim to understand the epidemiology of COPC, regardless of anatomy or diagnosis involved, the evolution of COPC over time, neurophysiologic alterations in pain processing, healthy lifestyle factors and psychosocial factors as risk factors for COPC, and consequences of COPC and altered pain processing in older adults. We propose acquiring objective quantitative sensory testing (QST) measures of pain sensitization and CPM, which are associated with pain severity in experimental settings. Whether QST-assessed neurophysiologic alterations may be common underlying risk factors for all forms of chronic pain, and for poor physical and psychosocial functioning, institutionalization, and mortality in a community-based cohort of older AAs unselected for pain is unknown. We will collect data regarding a multitude of chronic pain conditions, QST, healthy lifestyle factors, physical and psychosocial function, and nursing home admissions during the next planned study visit, as well as two follow-up assessments to obtain longitudinal data, and leverage the ongoing JHS surveillance of mortality. Our work will address several knowledge gaps, and insights gained may ultimately facilitate new preventive and therapeutic approaches to relieving chronic pain and its consequences, regardless of underlying diagnosis.

PROJECT SUMMARY There is abundant evidence that women and men do not experience pain equally. Compared to men, women are overrepresented in the majority of clinical pain conditions and also exhibit greater sensitivity to experimental pain. Similarly, use of analgesics is twice as common in women, compared to men, for conditions of comparable severities. These data suggest that testosterone has anti-nociceptive properties. However; this analgesic cushion provided by testosterone is lost when men are prescribed opioid-analgesics as opioids potently suppress testosterone production. Indeed, ~70-100% of men on chronic opioids are hypogonadal. In recent years, the use of sustained-action opioids in the management of chronic non-cancer pain has grown with many men taking multiple opioid analgesics. The development of opioid-induced hypogonadism deprives these men of the anti-nociceptive properties of testosterone and leads to a vicious cycle resulting in perpetuation of chronic pain despite being on opioids, subjecting patients to long-term requirement of even higher doses of opiates. Preliminary trials of testosterone replacement in men with opioid-induced hypogonadism have shown improvement in both clinical and experimental pain, and also improvement in certain aspects of QOL. However, the efficacy of testosterone replacement on pain perception has not been studied in adequately-powered trials. The overall goal of this proposal is to evaluate the efficacy of physiologic testosterone replacement therapy in improving clinical and experimental pain in a double-blind, randomized, placebo-controlled trial in men with chronic back pain who are being treated with opioid- analgesics for at least 6 months and have opioid-induced hypogonadism. We also plan to perform fMRI during quantitative sensory testing to characterize the central mechanisms underpinning the changes in pain processing that occur over the course of testosterone replacement in these hypogonadal men. We will also assess the efficacy of testosterone replacement on QOL, mood and depression. We propose a large, double- blind, randomized, placebo-controlled, 6-month trial in which we will compare the efficacy of physiologic testosterone replacement with weekly intramuscular injections (the most reliable form of testosterone replacement) versus placebo injections in men age 18 and older with chronic back pain and opioid-induced hypogonadism. The following outcomes will be measured: 1) clinical pain, 2) quantitative sensory testing along with fMRI, and 3) QOL, mood and depression. Because chronic pain is a major public health problem for which existing therapies are suboptimal and only provide partial relief, if this trial confirms benefits of testosterone therapy, patients will have an inexpensive, relatively safe and easy to administer medication available that has the potential to transform the care of these patients.

Chronic pain affects >100 million American adults with estimated costs of up to $1 trillion annually. Older adults are at increased risk of having multiple painful conditions and are living longer with the negative impacts of chronic pain. Chronic pain, regardless of anatomy or diagnosis involved (e.g., back pain, migraine), is the leading cause of disability worldwide. Limited insights into whether common mechanisms underlie all pain conditions, regardless of diagnosis, has contributed to inadequate pain management options, and in turn, to the opioid epidemic. Health care providers who treat one pain condition (e.g., joint pain) typically do not manage symptoms in other parts of the body (e.g., abdominal pain), and patients are often referred from one specialist to another. Studying commonalities of various chronic overlapping pain conditions (COPC) in community-based cohorts unselected for pain conditions can provide novel insights into causes of chronic pain as a disease itself, and into shared risk factors that may be promising targets to help ameliorate chronic pain regardless of diagnosis. Alterations in nociceptive signaling such as pain sensitization assessed by quantitative sensory testing (QST) may commonly underlie chronic pain, but why such alterations occur is not known, and whether such nociceptive signaling changes are heritable is also not known. Beyond nociception, there may be broader nervous system dysfunction underlying chronic pain. Generalized heightened sensitivity to external stimuli (e.g., light, sound) and impaired autonomic nervous system functioning, reflected by diminished heart rate variability (HRV), are associated with chronic pain, but it is unclear if they contribute to COPC, QST-assessed abnormalities, or development of chronic pain. Treatments targeting these potential risk factors could represent new avenues for pain management. Another untapped potential is in understanding whether positive factors such as resilience, sleep quality, and physical activity can be harnessed to alter risk of COPC or QST abnormalities. We propose evaluating COPC in the upcoming study visit of a community-based middle age and older adult cohort unselected for any pain complaints, the 3rd Generation of the Framingham Heart Study (FHS) (N~3374, mean age 60). We aim to understand the relation of multisensory sensitivity, autonomic function, resilience, sleep, and physical activity to COPC, QST-assessed pain processing and evolution of chronic pain over time; and to study heritability of QST abnormalities. Understanding the relation of these novel factors to COPC and QST would spur development of novel pain management approaches for all types of pain regardless of diagnosis involved. We will collect data regarding common chronic pain complaints, QST (to assess pain sensitization), and proposed risk factors, and conduct two follow-up assessments to obtain longitudinal data. We will leverage the ongoing FHS Offspring (2nd Generation) Exam in which we are collecting the same QST measures to assess heritability of pain processing abnormalities. Our work will address several knowledge gaps, and insights gained may facilitate new approaches to relieving chronic pain and its consequences, regardless of underlying diagnosis.

Abstract The Early Phase Pain Investigation Clinical Network (EPPIC-Net) is designed to rapidly and efficiently translate advances in the neurobiology of pain into treatments for people with chronic and acute pain, conditions associated with a significant burden to both patients and society. Dr. Edwards is one of the Principal Investigators of EPPIC-Net?s Clinical Coordinating Center (CCC); the primary goal of the CCC for EPPIC-Net is to promote and facilitate, from initial conception through final analysis, clinical trials in adult and pediatric populations with acute or chronic pain by providing efficient methodological, organizational and logistical support. One of the CCC?s Specific Aims is to expand the pool of experienced clinical Investigators and research staff to be participants and leaders of multicenter clinical research trials by providing education, training, resources and professional mentorship. This K24 would allow Dr. Edwards to increase the amount of time he spends mentoring junior pain scientists. Much of this mentoring will involve work on precision pain medicine, including biomarker validation studies, and deep phenotyping of patient populations to understand the biologic basis of a specific pain condition and its response to treatment. Collectively, there is an urgent need for more research to establish best practices in clinical pain management, and a limited workforce pipeline of clinical pain researchers to meet NIH?s long-term goals of providing effective non-opioid options for the treatment of pain conditions. Increasing the supply and availability of mentors in the field with the goal of mentoring a new generation of diverse and highly skilled clinical pain researchers is a critically-important goal addressed by this K24. This project would efficiently leverage current HEAL funding (for the EPPIC-Net CCC) to encourage an interest in the field of clinical pain management, generate innovative research projects, and increase the number of clinical researchers, especially research from diverse background, trained in high-quality clinical pain research.