NIH Funding

The National Institutes of Health (NIH) began funding vulvodynia research in 2000. The NIH recently announced a new opportunity for vulvodynia research funding. More information on this funding opportunity can be viewed here. There are also a few program announcements related to pain research into which vulvodynia research could fit, please visit: PA-14-243, PA-14-244, PA-15-188 and PA-16-102. A summary of current NIH vulvodynia research priorities can be viewed here.

Information on NIH-funded studies conducted to date follows.

Gloria_Bachmann

Gloria Bachmann, MDAssociate Dean for Women’s Health UMDNJ-Robert Wood Johnson Medical SchoolVulvodynia Prevalence And Efficacy Of 4 Interventions (2000 – 2005)

Abstract: Vulvodynia is a complex, multi-factorial chronic pain syndrome which is associated with significant distress and interpersonal. Vulvar vestibulitis and dyspareunia are two common, although not well-understood clinical components or sub-types of vulvodynia. Chronic vulvar pain is experienced by, according to recent surveys, about 10-15% of the female population between 18 and 80. Pathophysiologic findings have not been convincing for the role of any specific antibody or etiological mechanism, although several have been proposed including aberrant somatosensory processing in the peripheral or central inflammatory process. The epidemiology and predictors of vulvodynia have similarly not been well- articulated in the literature. One study suggested that the disorder may be largely limited to white, middle-aged women, although sampling and data gathering limitations cloud the assessment of these findings. Thirdly, many centers have begun emphasizing surgical treatments for vulvar vestibulitis, although these approach is rejected by about 1/3 of women at the outset. The vestibulectomy procedure also leads to definite worsening of the condition in about 10% of cases. This grant will propose to examine efficacy, outcomes and cost-effectiveness associated with four non-surgical interventions for vulvodynia. In general, the women’s Health Research Section of RWJMS is committed to offering minimally- invasive services and treatments to a broad diversity of women in the central northeast region. Our previous experience and that of our Co-PI’s make our site uniquely well-prepared to offer a broad range of dissemination and educational experiences, both locally and nationally, in the final years of the grant cycle. We plan to arrange and host an international consensus conference (something we have done twice recently in other areas of relevance), and to disseminate findings obtained from this and similar conferences broadly. We will also disseminate any questionnaires and treatment manuals developed in the context of this grant via website or other appropriate electronic or non-electronic form. We will develop patient education and public information materials, which will also be distributed in the most accessible and least costly form. Our ultimate goal is to share findings from this and related research with the broadest cross-spectrum of women that we can.

A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response (2011-2016)

Abstract: Approximately 14 million U.S. women have provoked vestibulodynia (PVD), a type of localized vulvar pain which causes major disruption in the everyday lives of up to 60% of affected women and negatively impacts sexual function in 45%. The financial burden imposed on the health care system is also significant, as these women visit multiple clinicians and specialists, and try numerous, unproven treatments. To date, few randomized controlled trials (RCTs) have been conducted to establish evidence based protocols for PVD management. The first immediate goal is to conduct a multicenter RCT of gabapentin treatment for PVD. Gabapentin was selected because of its efficacy in treating other neuropathic pain conditions and the promising, preliminary data on its use in PVD. This is a significant research project because PVD is a highly prevalent, chronic pain condition that is costly to the health care system and that currently has limited management options available to affected women. The second immediate goal is to define psychophysiologic measures of gabapentin response and to define mechanistically-based PVD subtypes, which may be related to abnormalities in central sensitization, muscle hypertonicity, and autonomic dysregulation. Identifying predictors of treatment response in PVD would have clinical applicability to other chronic pain syndromes, and is consistent with NIH’s mission to investigate coexisting pain conditions in order to identify common etiological pathways and develop therapeutic targets. The specific aims are (1): to test the prediction that pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with gabapentin compared to when treated with placebo. Additional outcome measures include reported intercourse pain and 24-hour pain, and (2) to test the prediction that gabapentin treatment will reduce mechanical allodynia, reduce area and duration of hypersensitivity induced by intradermal capsaicin, reduce vaginal muscle pain to palpation, decrease the number and intensity of somatic tender points, and increase cardiac beat-to-beat variability. This 16-week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 women between 18-50 years of age who report tenderness localized to the vulvar vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects when treated with gabapentin (up to 3600 mg/d) compared to when treated with placebo. The approach is innovative because it focuses on an understudied condition, in a multicenter setting, using a novel outcome measure (the tampon test), and a newly developed web-based recruitment and patient-reporting tool. Data management will include a mechanism-based analysis of drug effectiveness. These study outcomes will ultimately lead to our long-range goal of identifying underlying pathophysiologic mechanisms of PVD in order to create evidence-based differential diagnoses of subtypes of PVD for more effective and cost-effective management options. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because we will determine the efficacy of gabapentin in women with provoked vestibulodynia, a highly prevalent and distressful condition that causes severe pain in the outer vagina, and which consumes large amounts of health care resources and has few treatment options. We will also identify predictors of treatment response that will have clinical applicability to other chronic pain syndromes, and is relevant to NIH’s mission to investigate coexisting pain conditions in order to identify common etiological pathways for developing therapeutic targets.
c_brown
Candace Brown, PharmD, MSNProfessor, Departments of OB-GYN, Pharmacy & Psychiatry
University of Tennessee
A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response (2011-2016)

Abstract: Approximately 14 million U.S. women have provoked vestibulodynia (PVD), a type of localized vulvar pain which causes major disruption in the everyday lives of up to 60% of affected women and negatively impacts sexual function in 45%. The financial burden imposed on the health care system is also significant, as these women visit multiple clinicians and specialists, and try numerous, unproven treatments. To date, few randomized controlled trials (RCTs) have been conducted to establish evidence based protocols for PVD management. The first immediate goal is to conduct a multicenter RCT of gabapentin treatment for PVD. Gabapentin was selected because of its efficacy in treating other neuropathic pain conditions and the promising, preliminary data on its use in PVD. This is a significant research project because PVD is a highly prevalent, chronic pain condition that is costly to the health care system and that currently has limited management options available to affected women. The second immediate goal is to define psychophysiologic measures of gabapentin response and to define mechanistically-based PVD subtypes, which may be related to abnormalities in central sensitization, muscle hypertonicity, and autonomic dysregulation. Identifying predictors of treatment response in PVD would have clinical applicability to other chronic pain syndromes, and is consistent with NIH’s mission to investigate coexisting pain conditions in order to identify common etiological pathways and develop therapeutic targets. The specific aims are (1): to test the prediction that pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with gabapentin compared to when treated with placebo. Additional outcome measures include reported intercourse pain and 24-hour pain, and (2) to test the prediction that gabapentin treatment will reduce mechanical allodynia, reduce area and duration of hypersensitivity induced by intradermal capsaicin, reduce vaginal muscle pain to palpation, decrease the number and intensity of somatic tender points, and increase cardiac beat-to-beat variability. This 16-week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 women between 18-50 years of age who report tenderness localized to the vulvar vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects when treated with gabapentin (up to 3600 mg/d) compared to when treated with placebo. The approach is innovative because it focuses on an understudied condition, in a multicenter setting, using a novel outcome measure (the tampon test), and a newly developed web-based recruitment and patient-reporting tool. Data management will include a mechanism-based analysis of drug effectiveness. These study outcomes will ultimately lead to our long-range goal of identifying underlying pathophysiologic mechanisms of PVD in order to create evidence-based differential diagnoses of subtypes of PVD for more effective and cost-effective management options. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because we will determine the efficacy of gabapentin in women with provoked vestibulodynia, a highly prevalent and distressful condition that causes severe pain in the outer vagina, and which consumes large amounts of health care resources and has few treatment options. We will also identify predictors of treatment response that will have clinical applicability to other chronic pain syndromes, and is relevant to NIH’s mission to investigate coexisting pain conditions in order to identify common etiological pathways for developing therapeutic targets.
nih_funding_clip_image002
Thomas Chelimsky, MDAdjunct Professor of Neurology
Case Western Reserve University School of Medicine
IC/BPS Evaluation of Psychophysiologic and Autonomic Characteristics (2012-2013)

Abstract: Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) is a chronic idiopathic visceral pain syndrome that occurs commonly (about 2.5% of the population), produces severe pain, and disables young women in the prime of their lives. Although IC/PBS has historically been conceptualized from a urologic perspective, the finding of bladder wall abnormalities has not led to effective treatment. Further, the symptoms of IC/PBS suggest impairment of bladder innervation, both sensory afferent and autonomic efferent. The large number of autonomic disorders epidemiologically and clinically associated with IC/PBS, support this reconceptualization and suggest a more widespread and remote core defect. Our long-term aim is to define the broad neural, psychological, and endocrine phenotypes that characterize IC/PBS. We hypothesize that IC/PBS actually is a member of a larger family of disorders (of which vulvodynia may also be a part) that share a common (familial) predisposition to aberrant central autonomic and sensory responses to stress, pain or threat, usually first manifested following an acute traumatic event (infection, injury). This hypothesis predicts that careful investigation of patients with IC/PBS and their family members will reveal specific neural defects that are not present in healthy controls. Special emphasis will also be placed on distinguishing findings that are specifically associated with IC/PBS, in contrast to non-specific chronic pelvic pain, by comparing the findings to those in patients with myofascial pelvic pain without IC/PBS. We propose to test this innovative hypothesis by investigating neuro-urologic, gynecologic, autonomic, gastrointestinal, and psychological function, exposure to early adverse experience, and function of the stress response system in each of these four groups. This research is important because it will provide, for the first time, a detailed clinical investigation of central, peripheral, afferent and efferent nervous system function in many systems in addition to the bladder in patients with IC/PBS. The comparison with not only healthy subjects, but also subjects who have chronic pelvic pain without IC/PBS will be crucial to sort between findings related simply to the presence of pain, and those truly related to IC/PBS. This expanded view is designed to lead to a better understanding of causal factors that contribute to the disease process, and to suggest novel treatment or prevention strategies.
j_christianson
Julie Carlsten Christianson, PhDAssistant Professor, Department of Anatomy and Cell Biology
University of Kansas
Impact of Early Experience on Vulvovaginal Sensitivity in Adult Mice (2011-2013)

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject’s principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Early life experience has been shown to have a profound impact on the prevalence of chronic pain. Prematurely born infants are exposed to numerous stressors, including repeated invasive procedures and prolonged periods of maternal separation, and often later develop adverse behavioral and physiological responses to painful events, as well as have a higher incidence of some functional pain disorders. Newborn rats that undergo stress or repeated painful procedures similarly develop chronic pain as adults. This study is designed to 1) determine how neonatal stress or irritation affects the sensitivity and sensory innervation of the vulva and vagina, and 2) employ a method to selectively remove the nerves responsible for pain sensations as a preclinical test for treating vulvodynia in humans. Vulvodynia affects an estimated 15% of women and is clinically defined as chronic discomfort or pain of the vulva, often occurring as burning, stinging or soreness. Little is known regarding potential changes in the nerves that supply this region and no animal models exist in the current literature. Successful completion of these studies will not only provide the first published model of vulvodynia, but is also the first step in developing a new class of compounds that alleviates chronic pelvic pain without affecting normal sensations. Considering the high degree of comorbidity between vulvodynia and other chronic pelvic pain syndromes, e.g. endometriosis, irritable bowel syndrome and interstitial cystitis, chemical ablation of this population of nociceptors could also alleviate symptoms of these syndromes, as well.
d_clauw
Daniel Clauw, MDProfessor of Internal Medicine
University of Michigan Health System
Sensory Sensitivity and Urinary Symptoms in the Female Population (2011 – 2013)

Abstract: 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), vulvodynia, 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, vulvodynia 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), nonbladder pain (vulvodynia, irritable bowel symptoms, fibromyalgia) 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: Pelvic 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, additional studies can be done to examine the etiology of these symptoms and design novel treatments that are focused on central, rather than peripheral pathophysiology.
clemens
J. Quentin Clemens, MDAssociate Professor of Urology
University of Michigan Health System
Sensory Sensitivity and Urinary Symptoms in the Female Population (2011 – 2013)

Abstract: 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), vulvodynia, 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, vulvodynia 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), nonbladder pain (vulvodynia, irritable bowel symptoms, fibromyalgia) 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: Pelvic 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, additional studies can be done to examine the etiology of these symptoms and design novel treatments that are focused on central, rather than peripheral pathophysiology.
Gregory Essick, DDS, PhD

Gregory Essick, DDS, PhDProfessor, School of DentistryUniversity of North Carolina – Chapel HillPhenotyping Core of Complex Persistent Pain Conditions (2011-2016)

The purpose of the Phenotyping Core is to identify and implement a set of efficient and expedient assessment tools that will elucidate common physiological and psychological abnormalities associated with a number of painful syndromes, which based on the diversity of bodily systems affected, have largely been considered in isolation. These complex persistent pain conditions (CPPCs) include episodic migraine (Subproject 1), vulvar vestibulitis (Subproject 2), fibromyalgia (Subproject 3), irritable bowel syndrome and temporo-mandibular disorders. To accomplish this goal, the Core has the following Specific Aims: 1. To develop and administer a package of advanced phenotyping procedures to four groups of pafient participants referred from the clinics associated with Subprojects 1-3 and the UNC Center for Functional Gl & Motility Disorders that will adequately and efficienfiy capture the important elements of physiological and psychological processes that are hypothesized to be involved in mechanisms that initiate and maintain the patients’ pain condition. 2. To serve as the clinical administrative unit for the enrollment and management of patients with episodic migraine, vulvar vestibulitis, fibromyalgia, irritable bowel syndrome and the recruitment, screening, and enrollment of healthy non-CPPC control subjects for the psychophysical and psychosocial assessments that will used to study the four patients groups of Subprojects 1-3.
MelissaFarmer

Melissa Farmer, BA, PhDcMcGill UniversityMouse model of vestibulodynia using recurrent vulvovaginal Candidiasis (2008 – 2010)

Abstract: Vestibulodynia is the most prevalent form of vulvar pain in North American women, with approximately 10% of women suffering from this debilitating pain condition. The objective of the proposed research is to develop a mouse model of vestibulodynia in order to elucidate the physiological mechanisms underlying this pain condition. The research will empirically evaluate a leading hypothesis about the etiology of vestibulodynia, which posits that prolonged vulvovaginal inflammation initiates a chronic state of vulvar allodynia. The specific research aims are fourfold: (a) to conduct a longitudinal assessment of whether the frequency of vulvovaginal candidiasis is associated with changes in vulvar mechanical sensitivity testing; (b) to evaluate sensory fiber expression following chronic vulvovaginal inflammation, including nerve fiber density (via Pgp 9.5 immunohistochemistry) and markers of nociception (via calcitonin gene related peptide and the vanilloid receptor TRPV1); (c) to examine the immunological profile of vulvar tissue following chronic inflammation to reveal potential pain mechanisms, including an assessment of cytokine levels (IL-6 and IL- 8), and mast cell count in vulvovaginal tissue; and, (d) to evaluate the importance of the MC1R gene in the development of vulvar pain by applying the methodology to MC1R-deficient mutant mice. These aims will be accomplished with a novel method of mechanical sensitivity testing whereby von Frey filaments are applied to the mouse vulva, located ventrally from the anogential ridge. This method has produced highly reliable findings in preliminary work. Mouse vulvar sensitivity will be assessed across four separate infections with C. albicans to mimic the human condition of recurrent vulvovaginal candidiasis (with treatment), with each post-infection vulvar sensitivity measurement taking place three weeks after negative cultures are obtained. Following the final behavioral testing session, mouse vulvar tissue will be assessed for nerve fiber density, and expression of pain fiber activation. This work aims to examine peripheral mechanisms of chronic vulvar pain and to evaluate a potential genetic risk factor for vulvar pain, thereby elucidating a way by which inflammation can initiate and sustain pathological pain. Importantly, the development of a successful model for provoked genital pain can enable a comprehensive investigation into the genetic and neurochemical mechanisms of vulvar pain to evaluate the efficacy of, and mechanisms underlying, current treatments for vulvar pain (e.g., topical capsaicin) and to stimulate the development of new pharmacological interventions.
ColleenFitzgerald
Colleen Fitzgerald, MDAssociate Professor of Physical Medicine and Rehabilitation
Loyola University Chicago
Mechanistic Distinctions in Female Chronic Pelvic Pain Subtypes (2013-2016)

Abstract: Chronic pain is a significant and highly prevalent health condition and women comprise a majority of all chronic pain populations, particularly persistent pelvic pain. Female chronic pelvic pain (CPP) is a rapidly growing and costly health concern, and may reflect a number of underlying pain diagnoses including endometriosis, interstitial cystitis,vulvodynia and pregnancy-related pelvic pain. The frequent comorbidities shared by these pain conditions have been attributed to the complex interplay of somatic (cutaneous and musculoskeletal), visceral, and viscero-visceral crosstalk that shapes peripheral pain transmission within the pelvic girdle. Unfortunately, many previous attempts to understand normal and pathological variants of pelvic pain have primarily focused on these types of pain in isolation rather than considering system interactions. Our long term goal is to delineate the differences between pelvic pain mechanisms critical to the understanding, classification, and treatment of these myriad pain conditions. An examination of subtypes that are predominated by prototypical somatic features compared to visceral features will be undertaken. The short term goal of this application is to examine the sensory and functional characteristics of women with postpartum pelvic pain (somatic-musculoskeletal pain) and interstitial cystitis/IC/CPP (visceral pain), compared with women without CPP. Additionally, we will initiate preliminary investigation in the central brain imaging of these CPP subtypes. Our central hypothesis is that women with varying types of CPP will demonstrate unique peripheral (sensory and functional) and central characteristics specific to their diagnoses and their underlying mechanisms. The expected outcome of this study is the delineation of the clinical and scientific assessment methods that most accurately reflect the underlying peripheral and possible central mechanisms driving CPP subtypes. The public health impact of this proposed work will be to enable clinicians to provide more timely and targeted interventions to improve the quality of life of women with CPP.
David_foster
David Foster, MD, MPHAssociate Professor of Obstetrics and Gynecology
University of Rochester School of Medicine
Vulvar Vestibulitis Trial: Desipramine-Lidocaine (2002 – 2007)

Abstract: DESCRIPTION (provided by applicant): This application is submitted in response to RFA:HD-00-008 entitled Pathophysiology, Epidemiology and Treatment of Vulvodynia. Studies are proposed for the subtype of vulvodynia known as vulvar vestibulitis. The first major aim of this application is to conduct a randomized, placebo-controlled, double-blinded clinical trial to study the clinical efficacy of four medical regimens: topical lidocaine, oral desipramine, topical lidocaine combined with oral desipramine and placebo. The efficacy of standard treatments for vulvar vestibulitis proven by randomized, placebo-controlled, blinded clinical trials has not been assessed. The tricyclic class of antidepressants, represented by desipramine, have gained empiric acceptance for the treatment of vulvar vestibulitis, although favorable therapeutic results have been reported by only a few retrospective studies or uncontrolled clinical trials. Although the precise mechanism of action remains undefined for tricyclic antidepressants, a “central” action through the dorsal horn and brain stem has been suggested. In contrast to oral desipramine, the long-term, topical application of lidocaine may act through a “local” mechanism. This randomized, placebo-controlled, double-blinded clinical trial is designed to determine whether “local” or “centrally-acting” treatments alone, or in combination are efficacious in treating vulvar vestibulitis. Outcome measures of success will include reduced overall pain, reduced pain to touch, reduced pain to standardized mechanical stimuli, increased pain-free intercourse, improved sexual function, improved quality-of-life as measured by psychometric tests, and adherence to active drug regimens. The second major aim of this application is to study the relationship among genetic polymorphisms of the IL-1 Receptor Antagonist locus, tissue levels of pro-inflammatory cytokines, and response to treatment of vulvar vestibulitis. Pro-inflammatory cytokines, such as interleukin-I beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha), are secreted from a local cellular source and accumulate above normal levels in the region of the hymeneal ring. Recent genetic analysis finds a 53% homozygosity for allele 2 IL-1 Receptor Antagonist (IL-1 RA*2) in cases of vulvar vestibulitis, in contrast to 8.5% homozygosity in asymptomatic women. Furthermore, the IL-1 RA*2 allele has been linked to increased production of IL-1 beta in vitro. In our second aim, we will determine whether these in vitro results can be extrapolated to clinical cases of vulvar vestibulitis. Using samples from our clinical trial, we will assess the relationship between homozygosity for IL-1 RA*2, tissue levels of IL-1 beta, and TNF-alpha, and response to treatment. In summary, this project will allow us to answer several important questions about vulvar vestibulitis. Is medical treatment effective? Is centrally-acting or locally-acting treatment equally effective or is one superior to the other? Is there any benefit from combined local and systemic treatments? And finally, do genetic characteristics and tissue cytokine concentrations influence treatment response? The results of the study can be found at: http://www.ncbi.nlm.nih.gov/pubmed/20733439 and https://www.ncbi.nlm.nih.gov/pubmed/19305326.

A Controlled Trial of Gabapentin in Vulvodynia: Biological Correlates of Response (2011-2016)

Abstract: Approximately 14 million U.S. women have provoked vestibulodynia (PVD), a type of localized vulvar pain which causes major disruption in the everyday lives of up to 60% of affected women and negatively impacts sexual function in 45%. The financial burden imposed on the health care system is also significant, as these women visit multiple clinicians and specialists, and try numerous, unproven treatments. To date, few randomized controlled trials (RCTs) have been conducted to establish evidence based protocols for PVD management. The first immediate goal is to conduct a multicenter RCT of gabapentin treatment for PVD. Gabapentin was selected because of its efficacy in treating other neuropathic pain conditions and the promising, preliminary data on its use in PVD. This is a significant research project because PVD is a highly prevalent, chronic pain condition that is costly to the health care system and that currently has limited management options available to affected women. The second immediate goal is to define psychophysiologic measures of gabapentin response and to define mechanistically-based PVD subtypes, which may be related to abnormalities in central sensitization, muscle hypertonicity, and autonomic dysregulation. Identifying predictors of treatment response in PVD would have clinical applicability to other chronic pain syndromes, and is consistent with NIH’s mission to investigate coexisting pain conditions in order to identify common etiological pathways and develop therapeutic targets. The specific aims are (1): to test the prediction that pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with gabapentin compared to when treated with placebo. Additional outcome measures include reported intercourse pain and 24-hour pain, and (2) to test the prediction that gabapentin treatment will reduce mechanical allodynia, reduce area and duration of hypersensitivity induced by intradermal capsaicin, reduce vaginal muscle pain to palpation, decrease the number and intensity of somatic tender points, and increase cardiac beat-to-beat variability. This 16-week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 women between 18-50 years of age who report tenderness localized to the vulvar vestibule, pain with tampon insertion, and, when sexually active, insertional dyspareunia. Electronically entered daily diaries will be used to determine if pain is lower in PVD subjects when treated with gabapentin (up to 3600 mg/d) compared to when treated with placebo. The approach is innovative because it focuses on an understudied condition, in a multicenter setting, using a novel outcome measure (the tampon test), and a newly developed web-based recruitment and patient-reporting tool. Data management will include a mechanism-based analysis of drug effectiveness. These study outcomes will ultimately lead to our long-range goal of identifying underlying pathophysiologic mechanisms of PVD in order to create evidence-based differential diagnoses of subtypes of PVD for more effective and cost-effective management options. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because we will determine the efficacy of gabapentin in women with provoked vestibulodynia, a highly prevalent and distressful condition that causes severe pain in the outer vagina, and which consumes large amounts of health care resources and has few treatment options. We will also identify predictors of treatment response that will have clinical applicability to other chronic pain syndromes, and is relevant to NIH’s mission to investigate coexisting pain conditions in order to identify common etiological pathways for developing therapeutic targets.

Localized Vulvodynia Pathogenesis: Fibroblast, Yeast and Melanocortin (2012-2017)

Abstract: Our long-term goal is to develop an understanding of the vulvodynia pain mechanism leading to a mechanism-based disease classification and ultimately to a mechanism-based therapy. Our research team has reported a mechanistic connection between yeast products, regional fibroblast activation, pro-opiomelanocortins, and localized provoked vulvodynia (LPV). Fibroblasts are now recognized as more than structural cells as they not only respond to signals but can prodigiously produce many different biologic mediators, including those that promote pain. Fibroblasts also exhibit considerable regional specialization. We discovered that fibroblasts from the vulvar vestibule produce markedly elevated levels of pro-inflammatory, pro-pain mediators following activation with yeast cell wall products. In particular, heightened pro-inflammatory mediator responses are generated by fibroblasts from the vulvar vestibule of LPV-afflicted women. This may be related to single nucleotide polymorphisms (SNP) in the melanocortin-1 receptor (MC1R) that enhance inflammatory mediator production. We propose that the vulvar vestibule of all women possesses a unique inflammatory/pain-inducing responsiveness and that vulvodynia pain reflects an extreme but natural inflammatory phenomenon. We hypothesize that vulvodynia arises 1) in a region of the genital tract predisposed to inflammation, 2) in the presence of specific irritants such as yeast, that are 3) exacerbated by genetic predisposition. To significantly advance and impact the field, we have assembled a multidisciplinary team, experienced in LPV, fibroblast biology, and inflammation to achieve the following three aims. Specific Aim 1: To determine whether pro-inflammatory fibroblasts segregate to painful areas of the vulva. Using lower genital tract pain mapping, we will discover whether pro-inflammatory fibroblasts localize to painful anatomic regions in situ. Fibroblast strains will be developed from painful and non-painful areas of the vulva and their biosynthetic capabilities for pro-inflammatory and other mediators determined after exposure to key fibroblast activating cytokines. Specific Aim 2: To determine whether yeast or yeast products activate fibroblasts via Toll-like receptors (TLR) and whether specific MC1R SNPs modify that response. We will determine whether the LPV-afflicted patients carry a different pattern of yeast species and yeast load, and whether yeast cell wall products initiate, through toll-like receptors, a pro-inflammatory, pain-inducing response from fibroblasts derived from painful regions. Specific Aim 3: To determine whether pro-opiomelanocortin “loss-of-function” promotes vulvodynia. We will investigate whether “loss-of-function” melanocortin-1 receptor SNPs enhance site-specific fibroblast activation, and can be identified with a simple clinical measure, skin colorimetry. We will assess an anti-inflammatory melanocortin derivative with therapeutic potential for vulvodynia and investigate the underlying molecular mechanism(s). PUBLIC HEALTH RELEVANCE: Our research goal is to identify a target cell residing in painful regions of the vulva that responds with a heightened pro-inflammatory, pain-generating response to common environmental stimuli. Through this goal we wish to develop an understanding of the vulvodynia pain mechanism, leading to a mechanism-based classification of disease, and ultimately leading to mechanism-based therapeutics and prevention. Results to date can be found at: http://www.ncbi.nlm.nih.gov/pubmed/25683963, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378529/, and http://www.ncbi.nlm.nih.gov/pubmed/24858303.
Richard_Gracely

Richard Gracely, PhDA Necessary Multi-Parametric Evaluation of Vulvodynia (2012-2017)

Abstract: Vulvodynia is a poorly understood and treated chronic pain disorder that affects an estimated 14 million women and is characterized by significant variation in location, temporal characteristics and clinical course. The contribution of multiple known and unknown components hinders adequate diagnosis and consequently rational choice of treatment. Identification and assessment of these underlying mechanisms would greatly advance the phenotyping of this prevalent disorder, which is a necessary step towards efficacious treatment. The proposed methods contain three necessary components. The first provides a systemic clinical exam of vulvar mucosa and muscle that is broadened greatly to include consideration of pain processes that are initiated by persistent pain. These include spinally-mediated C-fiber temporal summation, central sensitization and altered pain regulatory mechanisms that include decreased descending inhibition and increased descending facilitation. The methods will also evaluate a general pain amplification mechanism that has been observed in vulvodynia, fibromyalgia and low back pain, and that is likely distinct from spinally-mediated central sensitization. The second component recognizes the influence of psychological variables that determine distinct subgroups in other disorders and that can influence pain through physiological mechanisms ranging from increased muscle tension to increased sympathetic outflow. The proposal will use our previous experience and current results from a large-scale multi-center study (n=3500) and from an ongoing program project (n=1500) to evaluate important dimensions of psychological distress and cognitive style. The third component recognizes that adequate analysis of multiple evaluation procedures requires considerable knowledge and expertise in advance statistical methods. The research team includes a statistician, Dr. Eric Bair, who is especially knowledgeable about these types of analyses and experiences including the multi-center study and the program project cited above. The research team is particularly well prepared to conduct the proposed investigation because of significant experience and expertise in the proposed methods including clinical assessment and treatment of vulvodynia, psychophysical and neurophysiological assessment of pain and sensory function and sophisticated statistical analysis of data from pain assessments. The proposed work is supported by a significant amount of pertinent preliminary data that includes advanced clinical and psychophysical methodology. PUBLIC HEALTH RELEVANCE: Vulvodynia is a disabling chronic pain condition that affects 14 million women in the USA at some point in their lifetime. Little is known about the underlying mechanism and effective treatment of women with vulvodynia. Our team is very experienced in the analysis of complex pain mechanisms and is developing novel tools and classification algorithms to identify the relative contribution of multiple pain mechanisms in individual patients to enhance diagnosis and choice of tailored, mechanistic-based treatments.
Bernard_harlow
Bernard L. Harlow, PhDProfessor and Head
Division of Epidemiology and Community Health
University of Minnesota School of Public Health
Prevalence And Etiological Predictors Of Vulvodynia (2000 – 2005)

Abstract: DESCRIPTION (Adapted from the applicant’s description): Vulvodynia is a syndrome of unexplained vulvar itching, burning, and/or pain that causes major physical and psychological distress. It is a diagnosis of exclusion when vulvar discomfort becomes chronic over many months and the presence of any other remediable cause, such as infection or dermatitis, is ruled out. The two major subtypes of vulvodynia — generalized vulvar dysesthesia and vestibulodynia — are often misclassified. Few descriptive or etiologic epidemiological studies have been performed. Thus, the prevalence and incidence in the general population is unknown and no preventable exposures have been identified. A recent NIH sponsored consensus conference stressed the need to determine the prevalence of vulvodynia and conduct population-based observational studies to identify modifiable risk factors. The applicant has conducted a population-based prevalence survey in more than 400 women that achieved a 70% response rate and found that 18% of women reported a lifetime history of chronic vulvar symptoms that lasted three months or longer. Approximately 8% of all women surveyed were currently experiencing these symptoms. In addition, the applicant conducted a pilot case-control study of 31 women diagnosed with either dysesthetic vulvodynia or vestibulodynia, or a combination of the two within the last five years and compared them to 31 similarly aged healthy women identified from the general population. Cases were, on average, three times more likely to report medical treatments or surgical procedures for conditions that may have influenced perineal pain, or a greater frequency of condom use and use of talcum powder in the genital area that may have lead to mucosal abrasion and inflammation. The applicant now proposes to survey 16,000 women 20-59 years of age from the general population to estimate the age-specific prevalence of vulvodynia. From this sample, the applicant will identify 400 cases of vulvodynia, verified through a two-step screening process, and a sample of 400 frequency matched age and county of residence controls. Structured interviews will assess a wide spectrum of exposures related to trauma. A subsample of 80 cases and 80 controls will receive a clinical examination to confirm the presence or absense of vulvodynia, and also will provide a vaginal lavage and vulvar swab specimen for the assessment of cytokines and the culturing of microbiological organisms. The applicant hypothesizes that various types of vulvar trauma may precede the spontaneous and evoked vulvar pain experienced by women with vulvodynia and that vulvodynia may be a variant of a specific type of Complex Regional Pain Syndrome that is consistent with sensory disturbances such as mechanical allodynia.

Immunological Factors and Risk of Vulvodynia (2009 – 2012)

Vulvodynia (VVD) is debilitating chronic vulvar pain that occurs in the absence of visible findings or clinically identifiable neurological disease. Between 2000 and 2005, we estimated the prevalence of vulvodynia and examined factors associated with its largely unknown etiology (NIH-ROI-HD38428). We learned that nearly 16% of reproductive aged women self-report current or past history of vulvar pain lasting >3 months (an estimated 14 million U.S. women annually), less than 50% seek treatment, few receive an adequate diagnosis, and Hispanic women are more likely to report vulvar pain. Regarding etiology, we learned that women with VVD compared to controls have a) higher levels of neurogenic inflammation markers, b) more psychological trauma and psychiatric morbidity antecedent to vulvar pain symptoms, c) a more prevalent history of environmental exposures that act on immuno-inflammatory response (IIR), and d) significant abnormalities in the characteristics of their vaginal microflora. Furthermore, recent studies have suggested that women with VVD may have an alteration in genes that regulate cytokine expression. Collectively, these findings suggest that VVD is the result or an altered IIR mechanism that occurs as a consequence or reproductive, gynecologic, environmental, or psychological exposures, with abnormal vaginal microflora and genetic polymorphisms as potential modifiers of the effects of interest. To test this etiological hypothesis we propose to screen a multiracial sample of approximately 24,000 women from the administrative databases of 4 community health clinics that closely resembles the surrounding general population. Through screening procedures, we expect to identify 325 women with VVD who may or may not have been previously diagnosed. After clinical confirmation, these cases will be frequency-matched to 325 randomly-sampled controls. Data collection and analyses will determine I) whether reproductive, gynecological and environmental exposures influence the odds of VVD, 2) whether psychological trauma and psychiatric morbidity influence the odds of VVD, and 3) whether markers of immuno-inflammation and nerve fiber proliferation are directly associated with the odds of VVD, and the extent to which genetic and microbiological markers modify associations in I and 2 above. A recent congressional report has cited the need for new educational initiatives to create more awareness of VVD, but the report also indicates that the ability to implement improved treatment and prevention strategies hinges on our understanding of VVD etiology. Our proposed study is unique in that it uses an epidemiological approach with adequate statistical power to confirm specific antecedent risk factors among a diverse sample of women at risk of VVD (who may or may not have sought care for their condition), while also measuring biological markers and related psychological processes that inform the plausibility of potential etiological pathways. We have also built into our study sophisticated analytical techniques to address the extent to which biases inherent in observational case-control studies could potentially influence our associations. Three important enhanced research goals have been added to be accomplished during the first 2 years of this study. We will determine I) whether demographic characteristics of women identified through community clinic-based administrative databases are comparable to that of census data drawn from the general population surrounding the community clinic, 2) whether the prevalence of vulvar pain symptoms in a sample of women derived from community clinic-based administrative databases that includes insured and uninsured subjects is comparable to that of similarly aged women sampled through a true population-based assessment done in the Boston Metropolitan Area, and 3) what factors contribute toward women choosing to or not choosing to participate in studies that involved stigmatizing conditions such as vulvodynia. These enhanced research aims have enormous impact on all scientists involved in population-based studies that previously used approaches such as random digit dialing and motor vehicle registration directories that are now no longer viable for identifying population-based subjects. It will also help determine what factors contribute toward successful recruitment of subjects for important studies of stigmatizing conditions which can be extremely prevalent among women.
Colleen Kennedy MD
Colleen Kennedy, MDAssistant Professor of Obstetrics and Gynecology
University of Iowa Carver College of Medicine
Vulvar Disease and Bladder and Bowel Symptoms (2004 – 2008)

Abstract: DESCRIPTION (provided by applicant): Patient-oriented research in vulvar and vaginal disorders has primarily been descriptive. In addition to lack of formal training and education of clinical researchers in this field, pelvic disorders are divided among various specialties. Each pelvic organ is compartmentalized and treated without regard to global or systemic effect. Despite identification of various pelvic and vulvar disease entities such as vulvodynia, little is known about their etiology, treatment, or prevention. Case-series have noted the presence of painful bladder syndrome in women who have vulvodynia and vestibulitis. We propose an epidemiologic study to determine the extent to which painful bladder syndrome and functional bowel disorders overlap with specific vulvar diseases and to determine whether the rate of painful bladder syndrome and functional bowel disorders differ between women with vulvar disease and controls. This will establish whether the association noted in the case-series is significant. In addition to expanding current knowledge regarding the epidemiology of vulvodynia and vestibulitis, this will provide a foundation for global evaluation of pelvic disorders in general. This in turn may encourage a more effective multi-disciplinary approach to the management of pelvic floor disorders including vulvodynia. Dr. Colleen Kennedy is committed to a career as a productive academic clinical researcher studying vulvar and vaginal diseases. This award would allow Kennedy to pursue a clinical investigation foundation through didactic training, mentoring, and research development. Further training in research methodology and advanced statistical techniques will increase her potential to make significant contributions to the field of vulvar and vaginal diseases. The overarching aim of this research program is to significantly improve the quality of care of women with vulvar and vaginal diseases. Dr. Kennedy’s immediate goals during the award period include: 1) further didactic training in patient-oriented research methods, and enhance ongoing mentoring relationships, 2) gain further experience in the area of vulvar and vaginal disease, by working with experts in vulvar disease, by reviewing current literature, and by attending professional meetings, 3) conduct research to further the knowledge of vulvar vaginal disease manifestation, treatment, and outcomes, and 4) further pursue an academic career through clinical research, teaching, and mentoring. Her long-term career objectives include: 1) advance the state of the science in vulvar vaginal diseases, 2) improve quality and outcomes of care for women with these disorders, and 3) serve as a role model, and train new clinical scientists who are interested in vulvar vaginal and pelvic floor disorders.
JenniferLabus
Jennifer Labus, PhDAdjunct Assistant Professor
Semel Institute for Neuroscience & Human Behavior
University of California, Los Angeles
Profiling Vulvodynia Based on the Neurobiological and Behavioral Endophenotypes (2013-2018)

Abstract: Vulvodynia (VD) is a chronic pain disorder affecting up to 15% of women and resulting in substantial impairment in health-related quality-of-life. The treatment of the disorder is hampered by a lack of knowledge regarding its neurobiological basis. The proposed study is based on the general hypothesis that like other persistent pain conditions, VD clinical phenotypes are composed of multiple biological endophenotypes, and that meaningful subgroups can be identified. In the current proposal, we plan to extensively phenotype a large sample of VD patients using functional and structural brain imaging together with genetic, physiological, and biological parameters. We hypothesize that central mechanisms (including alterations in the processing/modulation of interoceptive signals from the external genitals) are important determinants of the clinical presentation, and that differences in these brain signatures could play an important role in treatment responsiveness. Such phenotyping has considerable implications for future drug development. We propose to test this hypothesis by accomplishing three specific aims. Aim 1 will characterize alterations in multimodal structural brain and connectivity indices in VD. This will be accomplished by applying complex network analysis and machine learning algorithms to compare resting state [RS] functional and structural (grey and white matter) brain imaging in VD patients to 200 age-matched female healthy controls (HC), 200 patients with irritable bowel syndrome (IBS) and 100 patients with interstitial cystitis/painful bladder syndrome which are available from a large brain scan repository at UCLA. Aim 2 will characterize the connectivity indices in VD and identify the association between structural (grey and white matter) and RS alterations with clinical, behavioral and genetic parameters. This will be accomplished by associating structural and RS functional abnormalities identified in Aim 1 with relevant parameters including: clinical (symptom severity, disease duration, co-morbid pain or psychiatric diagnosis), behavioral (pressure pain thresholds), and biological (candidate gene polymorphisms belonging to clusters of genes related to hypothalamic-pituitary-adrenal [HPA] axis function, pain, inflammatory, catecholamine, and serotonin signaling systems). Aim 3 will identify VD patient subgroups based on endophenotype clusters by applying advanced mathematical classification techniques to brain, biological, behavioral and clinical endophenotypes. This will be accomplished by combining imaging and other phenotyping data using unsupervised machine learning algorithms and will yield distinct mechanistic subgroups of VD.
William_Maixner
William Maixner, DDS, PhDDirector of the Center for Neurosensory Disorders
University of North Carolina – Chapel Hill
Complex Persistent Pain Conditions: Unique and Shared Pathways of Vulnerability (2011-2016)

Complex persistent pain conditions (CPPCs) such as headache conditions, fibromyalgia, temporomandibular disorders, irritable bowel syndrome, and vulvar vestibulitis are high prevalent and shared or comorbid chronic pain conditions. There are two features of CPPCs that are fundamental to the aims and goals of this proposal: 1) the etiology of CPPCs is multifactorial and 2) the clinical manifestations of CPPCs are diverse. In this Program Project, we expect to identify a mosaic of risk factors for each of five CPPCs: fibromyalgia (FM), episodic migraine (EM), vulvar vestibulitis (VVS), irritable bowel syndrome (IBS), and temporomandibular joint disorders (TMD). Furthermore, we expect to characterize clusters of patients within each CPPC that vary significantly according to manifestations of their condition in addition to its painful characteristics (e.g., fatigue, dysfunction, sleep loss). Importantly, we expect some clusters of patients to be more alike across CPPCs than within any single CPPC, consistent with our view that there is some overlap in the manifestations of CPPCs. A unifying hypothesis integrating this Program is that multiple genetic factors, when coupled with environmental exposures (e.g. injury, infections, physical and psychological stress), increase the susceptibility to highly prevalent CPPCs by enhancing pain sensitivity and/or increasing psychological distress. To address the aims and goals of the subprojects and cores described in this application, a group of accomplished pain clinicians, pain researchers, psychophysiologists, molecular and cellular geneticists, biostatisticians and epidemiologists have been brought together to form this Program. Studies proposed in this Program Project application seek to identify the psychological and physiological risk factors, clusters, and associated genetic polymorphisms, that influence pain amplification and psychological profiles in enrollees who have established CPPDs. Additionally, the proposed studies seek to characterize the biological pathways through which these genetic variations causally influence CPPCs.
Robin_masheb
Robin Masheb, PhDAssistant Professor of Psychiatry
Yale University School of Medicine
Cognitive-Behavioral Therapy For Vulvodynia (2000 – 2003)

Abstract: DESCRIPTION (adapted from the investigator’s abstract): The proposed study aims to benefit women with vulvodynia. This newly identified women health problem may affect as many as 15 percent of women who seek gynecological care, yet little attention is given to this condition and it is frequently dismissed as psychosomatic. In 1998, the National Institute of Health called for systematic epidemiologic, etiologic, and therapeutic studies of vulvodynia. The purpose of the present study is to address the need identified by the NIH, and assess the efficacy of a psychosocial treatment for vulvodynia. The primary aim of the present study is to evaluate the efficacy of a well-established psychosocial intervention, i.e. cognitive-behavioral therapy that has been shown to decrease pain severity, disability, and affective distress for various chronic pain conditions. The study will test the hypothesis that cognitive-behavioral therapy, relative to supportive psychotherapy, will result in substantial improvement in pain, severity, disability, and affective distress. The proposed study is a randomized two-treatment condition CBT versus supportive psychotherapy by three evaluation period (pretreatment, post-treatment, and six-month follow-up), repeated measures, and factorial design. Sixty participants with vulvodynia will be randomly assigned to either CBT or Support for 10 weeks. Empirically supported outcome measures will be used to assess pain severity, disability, and affective distress. Medication and healthcare use, global improvement, and sexual activity will also be measured. Research findings from this study, in particular with the use of empirically supported treatment outcome measures, may serve as background for the planning of larger comparative studies. Clinically, results from this study may provide a justified treatment option for women with vulvodynia.
Mokha
Sukhbir Mokha, PhDProfessor of Neurobiology and Neurotoxicology,
Meharry Medical College
Control of Nociception in the Spinal Cord (2007-2015)

Abstract: Many pain syndromes/disorders observed below the head region, such as irritable bowel syndrome (IBS), fibromyalgia, vulvodynia, endometriosis and pelvic pain, have a greater prevalence in women or are female-specific. The long-term goal of our research is to understand biological mechanisms that make women more susceptible to the development of pain syndromes and to enhance our understanding of the sex-related differences in the regulation of pain throughout the life span. Our postulate that estrogen-induced negative regulation of the function of many G protein coupled receptors (GPCRs) such as the opioid receptor like1 (ORL1) and 12-adrenoceptors makes women more susceptible to the development of pain syndromes is both novel and provocative. We will test the hypothesis that estrogen differentially regulates the antinociceptive function of KOR and ORL1 receptors via both genomic mechanisms, involving transcription of receptors and signaling machinery, as well as non-genomic mechanisms, via membrane-associated estrogen receptors. Aim 1 uses behavioral techniques to determine whether estrogen differentially regulates the antinociceptive function of KOR and ORL1 via genomic as well membrane estrogen receptor (GPR30, ER1, ER2)-mediated non-genomic mechanisms. Aim 2 uses biochemical techniques to determine estrogen-induced changes in the temporal expression of the KOR and ORL1 genes, affinity of KOR and ORL1 receptors, and coupling to G proteins (Gi/Go). Aim 3 uses neuroanatomical techniques to determine whether estrogen receptors co-localize with KOR and ORL1 receptors in projection neurons and/or in interneurons in the dorsal horn of the spinal cord. The proposed studies will provide fundamental new knowledge regarding the estrogen-induced differential regulation of the role of KOR and ORL1 in pain suppression in the spinal cord, and a new perspective in the treatment of pain, particularly in women at different phases of their life (pre-puberty, reproductive years, pregnancy, and menopause) and aging men. KOR agonists will be effective analgesics during the reproductive years in women whereas ORL1 agonists will be more effective in postmenopausal women. ORL1 agonists will be effective in adult men but their effectiveness may diminish in aging men as the levels of testosterone decline. Further, antinociception produced by activation of KOR and ORL1 is not linked to addictive side- effects characteristic of other opioid receptor subpopulations. PUBLIC HEALTH RELEVANCE: The goal of our research is to understand biological mechanisms that make women more vulnerable to the development of pain syndromes and enhance our understanding of the sex-related differences in the regulation of pain throughout the life span. This will lead to better pain treatment strategies.
Andrea_nackly
Andrea Nackley Neely, PhDAssistant Professor of Pharmacology, Center for Neurosensory Disorders
University of North Carolina
Molecular Profiling Core of Complex Persistent Pain Conditions (2011-2016)

Fibromyalgia (FM), irritable bowel syndrome (IBS), vulvar vestibulitis syndrome (WS), and episodic migraine (EM) are prevalent complex persistent pain conditions (CPPCs). CPPCs commonly aggregate as comorbid conditions and are characterized by a report of pain greater than expected upon physical examination. Because we do not understand the efiology of CPPCs, patients receive inadequate treatment and suffer severe physiologic, psychologic, and socioeconomic consequences. Recent studies suggest that CPPCs are mediated in large part by genefic variability which can produce functional consequences on the amount and/or activity of proteins, which regulate downstream signaling events that impact pain-relevant processes. However, little is known about the specific nature of the relationship between genotype and biologic activity and their relevance to clinical phenotype. Thus, the objective of the Molecular Profiling Core is to identify biologic mediators that contribute to CPPCs. This goal will be achieved through execution of three specific aims. In Aim I, FM, IBS, WS, and EM cases and pain free controls (N = 300 per group) will be genotyped using the Pain Research Panel developed by our investigative team to measure neariy 3,000 polymorphisms in 350 genes whose protein products are linked to biologic pathways that influence pain transmission, inflammatory response, or psychological state. In Aim II, changes in the expression of proteins corresponding to the 350 genes represented on the Pain Research Panel will be measured in plasma and leukocytes from cases and controls using custom protein microarray technology. Results of these studies will allow us to evaluate changes in protein expression patterns that direcfiy result from functional polymorphisms. Moreover, they will inform the design of studies associated with Aim III, which is to create a lymphoblast repository that will provide an in vivo system within which to model cell signaling processes based on genefic and protein analyses. Elucidating the pathophysiologic mechanisms that underlie CPPCs will facilitate the long-term goal of our program which is to provide more accurate subdiagnoses as well as individualized therapeutic regimens to individuals who suffer from these conditions.

Complex Persistent Pain Conditions: Unique and Shared Pathways of Vulnerability

Complex persistent pain conditions (CPPCs) such as headache conditions, fibromyalgia, temporomandibular disorders, irritable bowel syndrome, and vulvar vestibulitis are high prevalent and shared or comorbid chronic pain conditions. There are two features of CPPCs that are fundamental to the aims and goals of this proposal: 1) the etiology of CPPCs is multifactorial and 2) the clinical manifestations of CPPCs are diverse. In this Program Project, we expect to identify a mosaic of risk factors for each of five CPPCs: fibromyalgia (FM), episodic migraine (EM), vulvar vestibulitis (VVS), irritable bowel syndrome (IBS), and temporomandibular joint disorders (TMD). Furthermore, we expect to characterize clusters of patients within each CPPC that vary significantly according to manifestations of their condition in addition to its painful characteristics (e.g., fatigue, dysfunction, sleep loss). Importantly, we expect some clusters of patients to be more alike across CPPCs than within any single CPPC, consistent with our view that there is some overlap in the manifestations of CPPCs. A unifying hypothesis integrating this Program is that multiple genetic factors, when coupled with environmental exposures (e.g. injury, infections, physical and psychological stress), increase the susceptibility to highly prevalent CPPCs by enhancing pain sensitivity and/or increasing psychological distress. To address the aims and goals of the subprojects and cores described in this application, a group of accomplished pain clinicians, pain researchers, psychophysiologists, molecular and cellular geneticists, biostatisticians and epidemiologists have been brought together to form this Program. Studies proposed in this Program Project application seek to identify the psychological and physiological risk factors, clusters, and associated genetic polymorphisms, that influence pain amplification and psychological profiles in enrollees who have established CPPDs. Additionally, the proposed studies seek to characterize the biological pathways through which these genetic variations causally influence CPPCs.
Andrea_rapkin
Andrea Rapkin, MDProfessor of Obstetrics and Gynecology
University of California, Los Angeles
Profiling Vulvodynia Based on the Neurobiological and Behavioral Endophenotypes (2013-2018)

Abstract: Vulvodynia (VD) is a chronic pain disorder affecting up to 15% of women and resulting in substantial impairment in health-related quality-of-life. The treatment of the disorder is hampered by a lack of knowledge regarding its neurobiological basis. The proposed study is based on the general hypothesis that like other persistent pain conditions, VD clinical phenotypes are composed of multiple biological endophenotypes, and that meaningful subgroups can be identified. In the current proposal, we plan to extensively phenotype a large sample of VD patients using functional and structural brain imaging together with genetic, physiological, and biological parameters. We hypothesize that central mechanisms (including alterations in the processing/modulation of interoceptive signals from the external genitals) are important determinants of the clinical presentation, and that differences in these brain signatures could play an important role in treatment responsiveness. Such phenotyping has considerable implications for future drug development. We propose to test this hypothesis by accomplishing three specific aims. Aim 1 will characterize alterations in multimodal structural brain and connectivity indices in VD. This will be accomplished by applying complex network analysis and machine learning algorithms to compare resting state [RS] functional and structural (grey and white matter) brain imaging in VD patients to 200 age-matched female healthy controls (HC), 200 patients with irritable bowel syndrome (IBS) and 100 patients with interstitial cystitis/painful bladder syndrome which are available from a large brain scan repository at UCLA. Aim 2 will characterize the connectivity indices in VD and identify the association between structural (grey and white matter) and RS alterations with clinical, behavioral and genetic parameters. This will be accomplished by associating structural and RS functional abnormalities identified in Aim 1 with relevant parameters including: clinical (symptom severity, disease duration, co-morbid pain or psychiatric diagnosis), behavioral (pressure pain thresholds), and biological (candidate gene polymorphisms belonging to clusters of genes related to hypothalamic-pituitary-adrenal [HPA] axis function, pain, inflammatory, catecholamine, and serotonin signaling systems). Aim 3 will identify VD patient subgroups based on endophenotype clusters by applying advanced mathematical classification techniques to brain, biological, behavioral and clinical endophenotypes. This will be accomplished by combining imaging and other phenotyping data using unsupervised machine learning algorithms and will yield distinct mechanistic subgroups of VD.
Barbara_reed
Barbara Reed, MDProfessor of Family Medicine
University of Michigan Medical School
Neuroimmunology/Cytokine Alterations In Vulvodynia (2000 – 2003)

Abstract: Hundreds of thousands of women in the United States suffer from vulvodynia a chronic burning vulvar pain of unknown cause. Millions of health care dollars are spent annually for this disorder in the United States alone, not only on management, but also on the large proportion of cases that are misdiagnosed and inadequately treated. This pain, associated with allodynia and hyperpathia, has a strong genetic predelection, with African-American women rarely being affected. The broad, long-term objectives of this proposal are to assess the differences in specific neuroimmunological characteristics between women with vulvodynia and asymptomatic controls. The specific aims include: evaluation of l) the individual cytokine/neurokine production response to stimulation of peripheral blood; 2) local changes in nerve fiber, mast cell, Substance P and serotonin density in vulvar tissue; 3) the interactions of the systemic and local immunologic systems assessed in l) and 2); and 4) the multivariable assessment of these laboratory factors with historical risk factors for vulvodynia to explore potential pathophysiologic mechanisms accounting for the historical risk factors identified. The research design involves a case-control evaluation of 100 women with vulvodynia, 100 controls matched for ethnicity, and 100 African-American control women, using questionnaires, physical examinations, clinical laboratory data, cytokine/neurokine levels in stimulated peripheral blood, and neuroimmunohistological assessment of vulvar biopsy specimens for nerve fiber density, mast cells, Substance P and serotonin. Results from this study will lead to improved understanding of neuroimmunologic alterations in women with vulvodynia which will direct future therapeutic strategies for this disorder.

Midcareer Vulvodynia Research and Mentoring Project (2003 – 2008)

Abstract: This application is in response to the K24 Midcareer Investigator Award in Patient-Oriented Research Program Announcement (PA-00-005), which is designed to provide support for clinicians for protected time to increase their expertise and activities in patient-oriented research and to serve as mentors for beginning clinical investigators. Barbara D. Reed, M.D., M.S.P.H. has developed a research career that focuses on gynecologic disorders of women, with an emphasis on neuroimmunological factors associated with vulvar dysesthesia (vulvodynia). This award would allow her to become increasingly involved with state-of-the-art immunological/neurological technology, to increase multicenter collaborations among vulvodynia researchers, and to further her investigations on the pathogenesis and epidemiology of vulvodynia. Mentoring is also a vital aspect of this award. The award will allow Dr. Reed to augment her own mentoring activities with more junior researchers, while simultaneously developing a program to improve the consistency and accountability of the mentoring of each of the junior investigators throughout her department. Dr. Reed is currently conducting a three-year NICHD-funded project on “Neuroimmunology/cytokine alterations in vulvodynia.” This patient-centered case control project assesses specific cytokine/neurokine responses to lymphocyte stimulation and their association with neurohistochemical changes found in vulvar tissue. Further studies on other aspects of the neuroimmune interactions that clarify differences among women with and without vulvodynia are at various stages of development, including assessing the relationship of cytokine production to local and peripheral psychophysical sensory responses of women with vulvodynia and controls, assessment of the immediate and delayed hypersensitivity reactions and cytokine correlates, evaluation of neuroimmunological changes following treatment, and the use of proteomics for immunological assessment of these women. Support from this award would allow further development, pursuit of funding, and implementation of these projects. Dr. Reed’s research experience, ongoing investigations, and mentoring experience provide the context for this expanded program of study, vulvodynia research, and personal and departmental mentoring.

Longitudinal Population-Based Study of Vulvodynia (2008 – 2013)

Abstract:Vulvodynia is a chronic, painful disorder of the vulvar region that affects 3-18 percent of women in the United States. Most research on this disease has been cross-sectional in design, and has focused on women referred to vulvodynia specialty clinics. Hence, little is known about the natural history of this disorder or the risk factors associated with its occurrence, persistence, or resolution in a general population. A number of genetic characteristics have been found to be associated with chronic pain syndromes in general [Catechol-O-Methyltransferase (COMT) and Nerve Growth Factor receptors (NGF-r)], and vulvodynia in particular [Interleukin-1 receptor antagonist (IL1RN) and melanocortin-1 receptor (MC1R)]. Similarly, hormonal exposures of women have been associated with the presence of vulvodynia and with pain sensitivity of the vulva, but results have been inconsistent. Assessment of genetic susceptibility in conjunction with hormonal factors, in order to assess gene-environment interaction, is imperative to further clarify the impact of these factors on the incidence, persistence, and remission of this morbid disorder. We hypothesize that an increased prevalence of one or more of the pain-associated genetic polymorphisms mentioned above will be present in women with vulvodynia, and that the risk of the onset, persistence, and remission of vulvodynia in these women will be influenced by previous and current exogenous hormone use, such as oral contraceptive and hormone therapy. Using a longitudinal prospective population-based study design, we propose to evaluate the prevalence, incidence, persistence, and remission rates of vulvodynia among a population-based, geographically defined group of 2500 women. Our specific aims are 1) to assess the prevalence, incidence, persistence, and remission rates of vulvodynia among these women, with clinical confirmation and DNA analysis in all women reporting current or past vulvodynia, in a representative subset of asymptomatic controls, and in all women reporting new or resolved vulvar symptoms during the study, and 2) to determine the association between pain-related genetic polymorphisms and exogenous hormone use, singly and in combination, with the incidence, persistence, and remission of vulvodynia via 2a) determining the prevalence of specific polymorphisms of candidate genes related to neuropathic pain (COMT, NGF-r, IL1RN, and MC1R) among these groups of women, 2b) assessing the associations between exogenous hormone use and the natural history of vulvodynia, and 2c) assessing gene-environment interactions between hormone exposure and genetic polymorphisms and their impact on the incidence, persistence, and remission of vulvodynia. Results from this study will substantially augment our understanding of the combined role of genetics and hormone exposure in the onset, maintenance, and remission of vulvodynia, facilitating future studies on pathophysiology, treatment, and prevention. PUBLIC HEALTH RELEVANCE: Results from this study will substantially augment our understanding of the combined role of genetics and hormone exposure in the onset, maintenance, and remission of vulvodynia, and will further direct our studies on pathophysiology, treatment, and prevention.

Characterization of Pain Processing in Vulvodynia (2005 – 2007)

Abstract: Vulvodynia is a chronic pain disorder, consisting of vulvar pain (burning, stabbing, irritation) for three months or longer, and lack of an infectious or dermatologic diagnosis consistent with the pain. The clinical characteristics of vulvodynia, and response to pharmacological therapy, are consistent with those of neuropathic pain. However, previous data from our group indicate increased sensitivity to pressure not only at the vulva, but also in the periphery (thumb, deltoid, and shin), suggesting that central mechanisms may be playing a role in women with vulvodynia. Further clarification of central and peripheral pain processing in women with and without vulvodynia has the potential to dramatically increase our understanding of this disorder, and will direct further study of pathophysiologic mechanisms and treatment options in vulvodynia.The specific aims of this study are: 1) to assess multi-modal sensory profiles at the vulva and in the periphery of 100 women with vulvodynia and 50 women without vulvar pain, and to use principal component and cluster analyses to identify novel subgroupings within the groups, and, 2) to further identify underlying mechanisms of vulvar pain in the established subgroupings by identifying, via fMRI, the qualitative and quantitative differences in location and character of supraspinal activity evoked by non-painful and painful sensory provocation at both vulvar and peripheral sites. We expect to find significant differences among the validated groups, and to then be able to use the known functional role of specific activated neural structures in the central nervous system to further refine hypotheses about the mechanisms that initiate and maintain painful vulvar disorders.Information from this research is anticipated to further define vulvodynia and its variants, to define subgroups based on underlying mechanisms, and to further our understanding of the pathophysiology of women with this disorder.

Sensory Sensitivity and Urinary Symptoms in the Female Population (2011 – 2013)

Abstract: 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), vulvodynia, 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, vulvodynia 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), nonbladder pain (vulvodynia, irritable bowel symptoms, fibromyalgia) 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: Pelvic 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, additional studies can be done to examine the etiology of these symptoms and design novel treatments that are focused on central, rather than peripheral pathophysiology.
Peter_smith
Peter Smith, PhDDirector, Department of Molecular & Integrative Physiology
The University of Kansas Medical Center
Female Pelvic Pain, Hormones and Neuroplasticity (2006 – 2011)

Abstract: DESCRIPTION (provided by applicant): Hormonal status and vaginal function are closely linked. Diminished reproductive hormones at menopause lead to vaginal atrophy and dryness. Menopause is often accompanied by dysesthetic vulvodynia, a pain syndrome consisting of burning and itching. Together with vulvar vestibulitis, an allodynia-like syndrome linked to early oral contraceptive use, vulvodynia represents an under-recognized but significant health problem, afflicting some 16% of the adult US female population. The etiology of these syndromes is poorly understood, although vulvar vestibulitis is associated with increased numbers of pain-sensing fibers. No animal models have been available to provide a better framework of understanding. Recently, we showed that estrogen regulates vaginal innervation in rats. Ovariectomy, which approximates human menopause, dramatically increases numbers of vaginal sensory nociceptors, as well as sympathetic and parasympathetic axons. We hypothesize that this is due to modulation of trophic factor release from vaginal tissues, and that altered innervation will influence key aspects of vaginal function, including blood flow, vascular permeability, and pain sensitivity. In aim 1 we propose to characterize the relationship between hormonal status and vaginal innervation in rats during the estrous cycle, pregnancy, and adult and juvenile hormone administration. We also determine if human vaginal innervation varies with hormonal state. Aim 2 assesses cellular mechanisms underlying axonal remodeling by determining effects of reproductive hormones on vaginal target tissue and on sensory and autonomic neurons. Aim 3 examines molecular mechanisms mediating vaginal remodeling by investigating expression and functional relevance of potential trophic factors. In aim 4, we assess the functional significance of vaginal nerve remodeling on blood flow, neurogenic inflammation and behavioral avoidance of painful stimuli. These studies are conducted using methods in cell biology, tissue culture, molecular biology, physiology, pharmacology and behavior. The findings of these experiments will provide insight into mechanisms underlying hormone-dependent remodeling of vaginal innervation, and whether altered innervation may contribute to vaginal dysfunction. Moreover, these studies will provide a better understanding of the relationship between vaginal nerve plasticity and vulvodynia, and potentially lead to new therapeutics aimed at reversing vaginal sensory hyperinnervation.

Identifying Therapeutic Targets for Vulvodynia (2012-2017)

Abstract: An estimated 6 million women in the US suffer from vulvodynia. Provoked vestibulodynia occurs most often in premenopausal women. This chronic pain syndrome is characterized by increased numbers of nociceptor axons usually localized to the posterior vestibule. Clinical evidence suggests that reproductive hormones influence the development and severity of vulvar vestibulitis syndrome (VVS). Aside from surgical excision of the hyperinnervated tissue, there are no effective therapies. This application proposes preclinical studies designed to characterize an animal model of VVS, and to use it to assess biological mechanisms that may be amenable to therapeutic targeting. We developed a rat model of VVS that replicates many clinical findings in humans. Small-volume injections of complete Freund’s adjuvant into the rat posterior vestibule evoke persistent hypersensitivity and hyperinnervation. In Aim1, we use this model to investigate neural consequences of vestibular inflammation, including sprouting and phenotype alterations. We will investigate the persistence of hyperinnervation and its correlation to mechanical vestibular sensitivity, and determine if our model shows behavior consistent with dyspareunia. We will assess whether estrogen, which alters normal patterns of nociceptor innervation, also affects development of hyperinnervation. We will build on preliminary findings that progesterone administered to juvenile rats causes persistent increases in sensory innervation density, and determine whether this augments development of vestibular hyperinnervation. We will assess the extent to which our model simulates human cytological changes by comparing findings in rats with tissue excised from patients with VVS. In Aim 2, we test the hypothesis that activation of the angiotensin II receptor type 2 (AT2) mediates hyperinnervation and hypersensitivity in VVS. In preliminary studies, we show that AT2 blockade abrogates hyperinnervation and hypersensitivity in our model. We hypothesize that inflammatory cells create a local renin-angiotensin system that synthesizes angiotensin II, which initiates sensory axon sprouting. We will determine if angiotensin II is synthesized by rat and human vestibular tissue, and using explant cultures, that it elicits sprouting. We will determine if AT2 activation in the absence of inflammation elicits sprouting and hypersensitivity in our rat model. We will determine if AT2 antagonism not only prevents, but also reverses hyperinnervation and hypersensitivity. We will determine if AT2 blockade is overcomes hyperinnervation and mechanical sensitivity augmented by the actions of reproductive hormones. This application will provide fundamental information on mechanisms that regulate innervation in normal and inflamed vestibular tissue. It employs a novel rat model to identify the biological underpinnings of vestibular inflammatory hypersensitivity with the intention of manipulating a key signaling pathway in order to identify new therapeutic targets in VVS. Information obtained in these studies has strong potential to substantively change our thinking and clinical approach to the management of some forms of vulvodynia. PUBLIC HEALTH RELEVANCE: Vulvodynia affects approximately 16% of the adult US female population, but is poorly understood and there are limited treatments. This project uses both a rat model and tissues from affected patients to investigate a novel mechanism that may explain one of the key features of this disorder: an abnormally high number of pain-sensing nerves. We also investigate a potential therapeutic target which we have found to reduce nerve numbers and hypersensitivity.
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Mark Tommerdahl, PhDProfessor of Biomedical Engineering
University of North Carolina – Chapel Hill
Sensory Based CNS Diagnostics for the Clinic (2011-2013)

Abstract: There is currently a significant gap that exists between fundamental neuroscience research and translation of the findings of that research into everyday practice. Experimental findings at the genetic, cellular, molecular and systems level often take a fairly long and frequently circuitous route to make an impact on a particular neurological disease or disorder. The goal of our work is to bridge the neuroscientific gap at the systems level of study by developing standardized sensory measures that can be not only utilized in clinical or clinical research settings, but can be directly correlated with the observations obtained directly from sensory cortex in non-human primates via high resolution imaging and extracellular recording. Successful development of an experimental model that iteratively evaluates the relationship of clinical measures and systemic CNS responses to specific mechanistic alterations will be quite significant. Such an evaluation of an individual’s CNS status could be directly linked to systemic mechanistic deficiencies or alterations observed in animal experimentation. Towards that goal, we have successfully designed and fabricated a tactile sensory diagnostic device. In parallel with that development, we designed a number of protocols – based on experimental neurophysiological findings from both our non human primate research and that of others – that could be rapidly and efficiently delivered (1-3 minutes) to a number of subject populations. The tactile diagnostic system that we have developed was conceptually designed to investigate differences in cortical information processing strategies between people with autism and people without. In this proposal we ask whether or not the strategy that we have devised for investigating a population with a neurodevelopmental disorder could be broadly applied to a number of neurological disorders. In other words, we consider the changes manifested by the neurodevelpmental disorder autism to be systemic, and if systemic cortical alterations occur in other neurological disorders, could they also be detected in the same manner? Proof-of-concept studies in a number of clinical research areas demonstrated that these newly developed metrics were sensitive to systemic cortical alterations. One question that emerges from this data is that most of these neurological disorders result in some type of altered central sensitization, no matter what the cause – whether it be neurodevelopmental, neurodegenerative, pharmacological or trauma induced – in which there is a significant change in the balance between excitation and inhibition. This application proposes to determine if sensory perceptual metrics, similar to those that were used to successfully distinguish subjects with autism from healthy control populations (with 90% accuracy using SVM to assess the results of a 25 minute battery of 9 protocols), could be used to reliably distinguish – on an individual basis – subjects with neurological disorders that are not neurodevelopmental in nature. Towards this goal, we target subjects from one broad category of neurological disorders – chronic pain. More specifically, we will examine the differences and commonalities from observations of pain patients diagnosed with one of the following: fibromyalgia, vulvodynia, TMJD, IBS and migraine. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed work is to investigate the utility of novel sensory-based methodologies that are currently being used in both basic and clinical research. Recently, utilizing state-of-the-art technology, we built a multi-site tactile stimulator that allows for investigation of central nervous system (CNS) health and advanced methods in sensory perceptual metrics. These metrics have been demonstrated to be sensitive to changes in centrally mediated mechanisms; and systemic alterations of cortical health (via neurodegenerational, neurodevelopmental, pharmacological or trauma induced changes) robustly change the measures. It is anticipated that clinicians will be able to utilize these measures to improve diagnostic performance and enable assessment of efficacy of treatment. The study itself will serve to validate the utility of a number of these measures in several types of pain, specifically fibromyalgia, TMJD, IBS, vulvodynia and migraine. The information from this study could aid in understanding centrally mediated mechanisms that undergo significant alterations with chronic pain
Frank_tu
Frank Tu, MD, MPHDirector, Division of Endoscopic Surgery and Chronic Pelvic Pain
North Shore University Health System
Novel Pelvic Floor Pain Measures to Enhance Female Pelvic Pain Evaluation (2008 – 2013)

Abstract: DESCRIPTION (Adapted from the applicant’s description): A major shortcoming in the present diagnostic framework for painful bladder syndrome (PBS) and related pelvic pain disorders is the failure to incorporate objective measures of pain sensitivity. As a gynecologist, the applicant’s long-term research goal is to define modifiable disease mechanisms in urogenital pain syndromes. Through the present application, he seeks training in the physiological assessment of pain in order to mechanistically subtype pelvic pain patients. At present, failure to systematically diagnose heterogeneous etiologies in pelvic pain hinders the rational use of specific interventions. A two part-program is proposed. First, under a structured program of mentorship (drawn from gynecology, urology, gastroenterology, psychology, physiology, and neurology) he will study relevant pain physiology and pertinent correlates of the human pain experience. The candidate will engage in both formal didactic and experiential training in design of multi-site clinical trials, assessment of pain physiology in diseased states, and characterization of psychological determinants of pain experience. Simultaneously, he will gain practical experience while conducting a prospective observational study of one important but understudied aspect of PBS and related pelvic pain syndromes: pelvic floor pain dysfunction. The central hypothesis is that women suffering from PBS have increased pelvic floor pain sensitivity (i.e., worse pain when the muscles are examined by a clinician) compared to healthy controls. This hypothesis will be tested using three specific aims: 1) Determine whether pelvic floor (somatic) pain sensitivity is enhanced in PBS; 2) Determine correlates of enhanced bladder (visceral) pain sensitivity; and 3) To correlate urogenital distress among PBS patients and pain-free controls with pelvic muscle pain sensitivity, visceral pain sensitivity, and psychological factors. The approach is innovative, by employing accepted pain assessment tools to an important, understudied area: the pelvic floor musculature. The research proposed in this application is significant for improving diagnosis of PBS and other pelvic pain syndromes in both women and men. Objective, valid measures of pelvic floor pain dysfunction will allow rational application of mechanism-specific treatments, such as physical therapy, neuropathic pain medications, cognitive-behavioral therapy, or botulinum toxin injections. Public Narrative: The outcomes of this study will likely enhance our approach to the assessment of pain symptomatology not only in PBS, but in all pelvic pain syndromes associated with pelvic floor sensitivity or irritative voiding symptoms.
Ursula_wesselmann
Ursula Wesselmann, MD, PhDProfessor of Anesthesiology
University of Alabama at Birmingham
Mechanisms of Vulvodynia (2001 – 2006)

Abstract: DESCRIPTION: (provided by applicant) The long range objective of this research is to elucidate the pathophysiological mechanisms of vulvodynia, a chronic pain syndrome of the vaginal and vulvar area, in order to develop improved treatment strategies for alleviating chronic pain in these women, targeted at the underlying pathophysiological mechanisms. Vulvodynia is a major challenge for women who suffer from this chronic pain syndrome, and has a detrimental impact on their sexual lives. Treatment strategies, including medical and surgical approaches, are empirical only and are often unsuccessful. We propose two approaches to gain a better understanding of the pathophysiological mechanisms of vulvodynia: (1) We will develop an animal model in the rat, that will allow to study the spinal cord pathways involved in the processing of noxious input from the vagina. The specific goals of this animal research project are (a) to obtain detailed information about the spinal cord pathways that process nociceptive afferent input from the vaginal area, (b) to determine the influence of the estrous cycle on the spinal cord processing of noxious vaginal stimulation, (c) to assess the effects of pharmacological agents on the spinal cord processing of noxious vaginal stimulation, (d) to study the influence of previous vaginal/vulvar trauma on the response to noxious vaginal stimulation. (2) We propose to characterize pain in patients with vulvodynia in detail. Our hypothesis is that patients with vulvodynia can be differentiated into distinct groups based on their pain characteristics, and that treatment of pain in vulvodynia will be more effective, if based on recognition of the underlying neurophysiological mechanisms. The specific goals of this clinical research project are to (a) to assess the response to non-noxious and noxious stimuli in the vulvar and vaginal area in women suffering from vulvodynia in comparison to healthy controls using quantitative sensory testing, (b) to determine the influence of the gonadal hormonal milieu on pain in patients with vulvodynia. These studies will provide fundamental new insights into the pathophysiological mechanisms of vulvodynia. The results of these studies may rapidly contribute to the design of new treatment strategies specifically targeted at the underlying neural mechanisms of chronic pain in women with vulvodynia.
Jackie D. Wood
Jackie Wood, PhDProfessor of Physiology and Cell Biology
Ohio State University College of Medicine
Function of the Enteric Nervous System (2011-2016)

This 5-year project is a study of interactive signaling between the enteric nervous system (ENS), spinal sensory afferent nerves and enteric mast cells, with the guinea pig small intestine as the experimental model. The project tests a hypothesis, supported by preliminary data, that a positive feed-back signaling loop connecting spinal afferents, ENS neurons and enteric mast cells amplifies nociceptive and other forms of sensory input from the gut to the central nervous system. The information to be gained from this neurophysiological investigation of interactions between spinal afferents, ENS and enteric mast cells is basic for translational understanding of visceral hypersensitivity and the emerging recognition that functional abdominal pain can involve comorbidity of gut hypersensitivity with other pain syndromes elsewhere in the body (e.g., interstitial cystitis, prostatitis, vulvodynia, vulvar vestibulitis and fibromyalgia).
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Denniz Zolnoun, MDAssistant Professor of Obstetrics and Gynecology
University of North Carolina – Chapel Hill
Refining Diagnostic Criteria of a Pain Disorder: Vulvar Vestibulitis Syndrome (2006 – 2011)

Abstract: Vulvar Vestibulitis Syndrome (VVS), the most common type of chronic vulvo-vaginal pain, negatively impacts the psychological, physical, and reproductive health of approximately 10% of women at some point in their life. Despite decades of research, the etiology and pathophysiology of VVS remain unknown. Current treatments are largely empiric and guided more by an individual clinician’s prior experience and comfort level than objective data on therapeutic efficacy. Recent evidence suggests that the etiology of VVS involves impairment of biological and psychological processes, similar to those of other chronic pain disorders. Although women diagnosed with VVS present with a spectrum of mucosal sensitivity, pelvic muscle dysfunction, and psychological distress, the actual diagnosis of VVS continues to rely on relatively crude measures of mucosal sensitivity (cotton swab palpation and patient report of pain) on clinical exam. A lack of strict criteria for evaluation, and dependence on highly subjective measures by both clinician and patient, suggests that this diagnosis is currently poorly circumscribed. As such, it is likely to encompass a heterogeneous, potentially divergent group of women with the sole common feature of frustration with persistent vulvar pain and dyspareunia. Refinement of therapeutic interventions and insight into the underlying pathophysiology of VVS are critically impaired by lack of methods to reliably and reproducibly assess key features of VVS, as well as by the lack of a classification system based on pathophysiological processes. Our long-term goal is to understand the pathogenesis of VVS, so that optimal treatment strategies can be developed. The primary goal of this proposal is to establish the reliability and reproducibility of our recently developed quantitative assessment tools to determine the spectrum of mucosal and pelvic muscle pain sensitivity (Aims 1-2). We will also assess central dysregulation (via experimental pain sensitivity procedures) and psychological factors to provide a solid evidence-based framework for a comprehensive, multiaxial assessment of VVS as a true pain disorder (Aims 3-4). Our rationale is that advances in treatment and potential for prevention of VVS can only be realized in the context of a conceptual framework informed by comprehensive multiaxial assessment of VVS, similar to that of other pain disorders (e.g., temporomandibular disorder, TMD). The public health relevance of this research is that its successful completion will positively impact the physical, psychological and reproductive health of millions of women

VVS: Subproject 2 of Complex Persistent Pain Conditions (2011-2016)

Vulvar Vestibulitis Syndrome (VVS), the most common type of chronic vulvo-vaginal pain, negatively impacts the psychological, physical, and reproductive health of approximately 10% of women at some point in their life. Despite decades of research, the etiology and pathophysiology of VVS remain unknown. Current treatments are largely empiric and guided more by an individual clinician’s prior experience and comfort level than objective data on therapeutic efficacy. Recent evidence suggests that the etiology of WS involves impairment of biological and psychological processes, similar to those of other chronic pain disorders. Although women diagnosed with VVS present with a spectrum of mucosal sensitivity, pelvic muscle dysfunction, and psychological distress, the actual diagnosis of WS continues to rely on relatively crude measures of mucosal sensitivity (cotton swab palpation and patient report of pain) on clinical exam. A lack of strict criteria for evaluation, and dependence on highly subjective measures by both clinician and patient, suggests that this diagnosis is currently poorly circumscribed. As such, it is likely to encompass a heterogeneous, potentially divergent group of women with the sole common feature of frustration with persistent vulvar pain and dyspareunia.