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, MD Associate Dean for Women’s Health UMDNJ-Robert Wood Johnson Medical School
Vulvodynia 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.

Vanessa Barnabei, MD, PhD UBMD Obstetrics and Gynecology State University of New York at Buffalo
Vulvodynia Pain Thresholds (2020 — 2022)
The investigators will develop annotated pain maps showing region and size of areas sensitive to mechanical stimulus. The pain maps will be created by combining IR images, photographs, and clinical input, and will be correlated with patient co-morbidities. The IR images will assess for areas of inflammation and increased skin temperature. Pain maps will be created with patient response to mechanical stimulation with a cotton swab and will be overlaid on the thermographic images. Through this combination of measurements, the investigators plan to expand the diagnostic tools used in patient care as well as on the classification of this heterogeneous disorder.
Primary Outcome Measures:  
  1. Annotated Pain Mapping [Time Frame: 2 years.] Develop annotated pain maps showing region and size of area sensitive to mechanical stimulus.
Secondary Outcome Measures:
  1. Change in pain map after clinical intervention [Time Frame: 3 years.] Determine changes in the location and size of sensitive regions following various conventional clinical interventions for vulvodynia.
  2. Database Development [Time Frame: 3 years.] Develop a large, information-rich database of annotated pain maps from patients, and use Artificial Intelligence to identify patterns and trends.

Sophie Bergeron, PhD Professor Université de Montréal
Study to Compare the Efficacy of Cognitive-behavioral Couple Therapy and Lidocaine for Provoked Vestibulodynia (CBCT-RCT) (2013 — 2019)
Chronic pain problems involving the female reproductive system are major health concerns for all women. Poorly understood, they entail great personal and financial cost. One such condition is vulvodynia, or chronic unexplained vulvar pain, which has a prevalence of 16%. Despite its negative impact on psychosexual and relationship satisfaction, there is little research examining empirically-tested treatments for afflicted couples. The proposed research builds on findings from our work focusing on the impact of relational factors on vulvodynia, and our previous research evaluating the efficacy of group cognitive-behavioral therapy for this problem. This two-centre randomized clinical trial aims to assess the efficacy of a novel, 12-week targeted couple therapy (CBCT) for women with vulvodynia in comparison to one of the most commonly prescribed first line medical interventions, topical lidocaine. Primary research question: Is there a significant difference between the two treatments on women's pain during intercourse post-treatment? Secondary research questions will assess for significant differences between the two treatments post-treatment and at 6-month follow-up on multidimensional aspects of pain using the McGill Pain Questionnaire, women and partners' sexuality (sexual function and satisfaction), psychological adjustment (anxiety, depression, catastrophizing, self-efficacy, attributions, and quality of life), relationship factors (partner responses, couple satisfaction, attachment, and communication styles), and self-reported improvement and treatment satisfaction. Results of this study will improve the health and quality of life of patients with vulvodynia by rigorously testing the efficacy of a novel couples treatment. Primary Outcome Measures:
  1. Change in pain during intercourse / sexual activity from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ] Pain during intercourse will be assessed using a visual analog scale (VAS) ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain ever, as recommended by the IMMPACT guidelines for chronic pain clinical trials (Dworkin et al., 2005). Participants will report on pain experienced in the preceding month. The main outcome will be the change in the VAS scores from pre- to post-treatment. This measure has been shown to detect significant treatment effects in women with PVD (Bergeron et al., 2001) and demonstrates a significant positive correlation with other pain intensity measures. Pain during intercourse is the main symptom of PVD and the one that most interferes with quality of life, hence the most relevant measure of functional outcome.
Secondary Outcome Measures:
  1. Change in qualitative components of pain from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ] Qualitative components of pain will also be assessed using the Short-Form McGill Pain Questionnaire (MPQ; Melzack, 1985), a measure of the sensory, affective and evaluative components of pain. The MPQ is a widely used adjective 15-item checklist which assesses both qualitative and quantitative aspects of pain (Grafton, Foster, & Wright, 2005; Melzack & Katz, 2001). We will use the Pain Rating Index (PRI) scale.
  2. Changes in partner responses to pain from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ] Partner responses from the point of view of the women with PVD and their partners will be measured with the West Haven-Yale Multidimensional Pain Inventory - Significant Other Response Scale (MPI; Kerns, Turk, & Rudy, 1985), and the Spouse Response Inventory - Facilitative subscale (SRI; Schwartz, Jensen, & Romano, 2005) which have been adapted to our PVD population and their partners.
  3. Change in dyadic adjustment from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ].Dyadic adjustment will be assessed using the Couple Satisfaction Index (CSI; Funk & Rogge, 2007), a 32-item measure of relationship satisfaction. Compared to other well-known relationship satisfaction measures (e.g., Dyadic Adjustment Scale; Spanier, 1976) it demonstrates strong convergent validity, and a higher precision and power for detecting distinctions in satisfaction levels (Funk & Rogge, 2007). Moreover, unlike similar relationship satisfaction scales, the CSI has been tested with a sample of participants spanning the relationship spectrum (e.g., dating, engaged, married).
  4. Change in pain catastrophizing for both women and partners from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Pain catastrophizing will be assessed using the Pain Catastrophizing Scale (PCS; Sullivan, Bishop, & Pivik, 1995), which consists of 13 items scored on a 5-point scale with the end points (0) not at all and (4) all the time. The PCS is divided into three subscales: rumination, magnification and helplessness. It is a reliable and valid measure that has demonstrated a stable factorial structure across clinical and general populations, including a French population (Sullivan, Bishop, & Pivik, 1995; Osman et al., 2000; French et al., 2005). Cano et al. (Cano, Leonard, & Franz, 2005) recently validated a partner version and found excellent psychometric properties.
  5. Changes in pain attributions from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Pain attributions will be measured with the Extended Attributional Style Questionnaire (EASQ; Metalsky, Halberstadt, & Abramson, 1987), adapted for use with women who experience genital pain, and their partners. The adapted EASQ consists of 12 hypothetical negative situations that occur within a genital pain context, and participants are asked to indicate the major cause of the situation (open-ended), and then rate the cause on the following dimensions: internal, global, and stable on a 7-point Likert scale. The EASQ adapted for genital pain demonstrates good internal consistency (alpha=0.84-0.86) for subscales and total score, as well as a similar factor structure to the original EASQ (Jodoin et al., 2011). We have used both the woman and partner version successfully in previous studies (Jodoin et al., 2008; 2011).
  6. Change in anxiety from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete the Trait Anxiety subscale of the Spielberger State-Trait Anxiety Inventory (STAI - (Spielberger, Gorsuch, & Lushene, 1970). This 20-item, well-known, and widely used measure has demonstrated very good psychometric properties in clinical and non-clinical populations, including in chronic pain (Gauthier & Bouchard, 1993; Greenberg & Burns, 2003; Rule & Traver, 1983; Tanaka-Masumi & Kameoka, 1986).
  7. Change in depression symptoms to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete the Beck Depression Inventory-Fast Screen (BDI-FS; Beck, Steer, & Brown, 1996; Beck, Steer, & Garvin, 1988), an adapted 7-item version of the widely-used 21-item measure. Specifically, the BDI-FS assesses sadness, loss of pleasure (anhedonia), suicide ideation, pessimism, past failure, self-dislike and self criticalness with scores for items ranging from 0 (low intensity) to 3 (high intensity). This measure has been used with chronic pain populations (Poole, Bramwell, & Murphy, 2008).
  8. Change in pain self-efficacy of women with PVD from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Pain self-efficacy will be assessed using the Painful Intercourse Self-Efficacy Scale (PISES; Desrochers et al., 2009), which was adapted from the Arthritis Self-Efficacy Scale (Lorig et al., 1989). The PISES consists of 20 items with three subscales: self-efficacy for controlling pain during intercourse, for sexual function, and for other symptoms. Participants indicate their perceived ability to carry out sexual activity or to achieve outcomes in pain management by responding on a scale from 10 (very uncertain) to 100 (very certain). Higher scores indicate greater self-efficacy. The reliability and validity of the original version have been established (Lorig et al., 1989) and the factor structure of the adapted version has been shown to be identical to that of the original (Desrochers, 2009). In our previous samples, Cronbach's alphas ranged from .79 to .89 for women and .74 to .91 for partners.
  9. Self-reported improvement following treatment (duration of treatment is 12 weeks) [ Time Frame: Post-treatment, and 6-months post-treatment ]. Woman and partner self-reported improvement [scale of 0 (worse) to 5 (complete cure)] and treatment satisfaction [scale of 0 (completely dissatisfied) to 10 (completely satisfied)] will be measured post-treatment and at 6-month follow-up to assess the clinical significance of results.
  10. Change in sexual satisfaction for both partners from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Sexual satisfaction will be assessed using the Global Measure of Sexual Satisfaction scale, which consists of 5 items assessing global sexual satisfaction. Internal consistency of this scale is high (alpha = 0.90), as is test-retest reliability (r = 0.84; Lawrence & Byers, 1998).
  11. Changes in sexual function from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Sexual function for both women and their partners will be assessed using the Derogatis Interview for Sexual Functioning - Self-Report (DISF-SR), a 25-item self-report measure of sexual function for men and women (Derogatis, 1997). It covers five dimensions of sexuality: sexual cognition/fantasy, arousal, sexual behaviour/experience, orgasm, and sexual drive/relationship. Scores can be calculated for each dimension and for global sexual functioning. The DISF-SR boasts good internal consistency and reliability (Derogatis, 1997; Meston & Derogatis, 2002; Daker-White, 2002).
  12. Changes in quality of life from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete the Quality Metric™ Short Form 12-question Health Survey (SF-12). This reliable and valid survey was adapted from the widely-used SF-36 health survey and assesses physical and mental health and wellness across 8 scales: physical function, bodily pain, vitality, general health, emotional and physical roles, social functioning, and mental health (Cheak-Zamora, Wyrwich, & McBride, 2009; Ware, Kosinski, Keller, 1996). The SF-36 has been used previously in PVD samples (Sutton, Pukall, & Chamberlain, 2009).
  13. Changes in attachment, or experiences in close relationships from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Attachment will be measured using the Experiences in Close Relationships Scale-Revised (ECR-RS; Wei, Russel, Mallinckrodt, & Vogel, 2007). The ECR-RS is a 12-item scale that assesses components of adult attachment (e.g., secure, anxious, avoidant attachment). Both members of the couple will complete this measure.
  14. Change in interpersonal sexual goals from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Approach and avoidance interpersonal sexual goals will be assessed with a 15-item measure adapted from Cooper et al. (1998) (Impett, Peplau, & Gable, 2005; Impett et al., 2008; Impett, Gordon, & Strachman, 2008). Participants rate the importance of 9 approach and 6 avoidance interpersonal goals in influencing their decision to engage in sex on a 7-point scale. This measure has demonstrated high internal consistency (Impett et al., 2005; Impett et al., 2008).
  15. Changes in communication patterns from baseline, and over the course of treatment [ Time Frame: Baseline, Weeks 1, 4, 8, and 12 of treatment ]. At the pre-treatment, post-treatment, and follow-up evaluation sessions, both partners will complete the Communication Patterns Questionnaire - Short Form (Christensen & Heavey, 1990), an 11-item measure of communication patterns during couples' discussions of problems. This measure examines three overall patterns of communication: conflict avoiding, conflict engaging, and positive interaction (Futris et al., 2010). This measure has demonstrated good psychometric properties (Futris, Campbell, Nielsen, & Burwell, 2010). We will also collect 12 additional items from the full measure to assess the subscales of mutual avoidance, mutually constructive communication, and other communication patterns during and after periods of conflict (Christensen & Shenk, 1991).
  16. Change in intimacy ratings from baseline, and over the course of treatment [ Time Frame: Baseline, Weeks 1, 4, 8, and 12 of treatment ]. Both partners will complete measures of general relationship intimacy (8-items; Laurenceau et al., 2005) and sexual intimacy (12-items; Bois et al., 2013). These measures assess self-disclosure, partner disclosure, and partner responsiveness in the context of the interpersonal exchanges and sexual activity. They have demonstrated high internal consistency in our previous PVD research (Bois et al., 2013).
  17. Changes in Fear of Pain from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Fear of pain will be measured using the Pain Anxiety Symptoms Scale (PASS-20; McCracken & Dhinga, 2002), a 20-item, self-report measure of fear of pain designed for individuals with chronic pain problems and has been adapted for use in a sexual context (i.e. the word sexual has been added before the word activity for several items). Subscales include: Cognitive Anxiety, Escape/Avoidance, Fearful appraisal, and Physiological Anxiety. Only women with PVD will complete this measure.
  18. Changes in Hypervigilance to Pain from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Hypervigilance to pain during intercourse will be assessed with the Pain and Vigilance Awareness Questionnaire (PVAQ); McCracken, 1997), a 16-item measure of attention to pain that has been used to evaluate awareness, consciousness and vigilance to pain in various clinical and non-clinical populations. It shows good test-retest reliability and internal consistency (Roelofs et al., 2003). Only women with PVD will complete this measure.
  19. Changes in Acceptance of Chronic Pain from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete an adapted version of the Chronic Pain Acceptance Questionnaire (McCracken, Vowles, &Eccleston, 2004) for use with women experiencing vulvovaginal pain and their partners. This 20-item scale measures acceptance and openness to experiencing pain sensations, and the pursuit of a satisfying life in spite of pain. The partner version references their own acceptance of their partner's pain. A recent systematic review of measures of acceptance of chronic pain indicated that, based on psychometric properties, there is the most support for use of the CPAQ to measure acceptance of pain in chronic pain patients, as compared to other questionnaires (Reneman et al., 2010). Studies using the CPAQ have found Cronbach's alpha of the sum score that ranges from 0.78-0.85.
  20. Changes in female sexual function from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Only women with PVD will complete the Female Sexual Function Inventory (FSFI), a self-report 19-item measure assessing sexual functioning in women such as sexual arousal, orgasm, sexual satisfaction and discomfort experienced during sexual activity and intercourse with high internal consistency (i.e., high inter-item correlation for the six domains) and validity among several samples of women with sexual difficulties (Rosen et al., 2000; Meston, 2003; Wiegel, Meston & Rosen, 2005).
  21. Changes in sexual distress from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete the Female Sexual Distress Scale, a 12-item measure designed to assess sexually related personal distress. Although designed for women, items are gender non-specific and could pertain to both women and men. Thus, no adaptations are required for use with male partners. This measure has demonstrated high internal consistency, test-retest reliability, discriminate validity, and construct validity (Derogatis et al., 2002).
  22. Changes in Ambivalence over Emotional Expression from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete the Ambivalence over Emotional Expression Questionnaire (AEQ; King & Emmons, 1990). This measure assesses various aspects of ambivalence over expressing emotions (e.g., wanting to express but being unable to, expressing but not wanting to, or expressing and then regretting the decision). This self-report measure consists of 28 items. The AEQ has been shown to have good psychometric properties, including good internal stability, test-retest reliability and convergent validity (King & Emmons, 1990).
  23. Changes in Dyadic Sexual Communication from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Dyadic sexual communication will be measured using the Dyadic Sexual Communication Scale (Catania, 1986). This measure is a 13-item scale that assesses partners' perceptions of their communication processes around sexual problems. Both members of the couple will complete this measure, which has demonstrated good reliability and a uni-factorial structure (Catania, Pollack, McDermott, Qualls, & Cole, 1990).
  24. Changes in male sexual function from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Male partners will complete the International Index of Erectile Function (IIEF; Rosen, Riley, Wagner, Osterloh, Kirkpatrick & Mishra, 1997). The IIEF is a well-known instrument for assessing erectile function in men. It is comprised of 15 items, and 3 items to assess pelvic pain in men have been added to this measure, and these items are complimentary to those that appear in the FSFI.
  25. Changes in self-compassion from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both women and partners will complete the Self-Compassion Scale (Neff, 2003), a 26-item self-report inventory that assesses three different aspects of self-compassion.
  26. Changes in experience of genito-pelvic pain from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. The Experience of Genito-Pelvic Pain Scale is comprised of 24 items focusing on the thoughts and feelings associated with pain during sexual activity. These include how the pain is experienced in relation to a romantic/sexual partner, how it affects one's sense of being a woman, and how it may generate negative emotions such as guilt and shame. This self-report measure is in the initial stages of development and will be partially validated during the course of the study. We expect that it will be sensitive to treatment changes. This measure will be completed by women only, given it focuses on pain during sexual activity.
  27. Changes in experience of emotion regulation from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Emotion regulation will be measured in both partners using the Difficulties in Emotion Regulation Scale (DERS). The DERS is a brief, 36-item, self-report questionnaire designed to assess multiple aspects of emotion dysregulation. The DERS has been shown to have good psychometric properties, including good internal stability (α =0.93) and test-retest reliability. (Gratz & Roemer, 2004).
  28. Changes in experience of compassionate love for partner from baseline to post-treatment, and 6-months post-treatment [ Time Frame: Baseline, Post-treatment (12 weeks), and 6-months post-treatment (9 months from baseline) ]. Both partners will complete a Compassionate love for partner scale, the specific close other version of the Compassionate Love scale (Sprecher & Fehr, 2005). Compassionate love is an attitude "containing feelings, cognitions, and behaviors that are focused on caring, concern, tenderness, and an orientation toward supporting, helping, and understanding the other, particularly when the other is perceived to be suffering or in need." The 21 items of this self-report inventory are rated on a scale from 1 (not at all true) to 7 (very true). Higher score indicates more compassionate love for the partner. Cronbach's alpha for this version of the scale was .94 (Sprecher & Fehr, 2005).

Nina Bohm-Starke, MD, PhD Karolinska Institutet Danderyd Hospital
Botulinum Toxin A as a Treatment for Provoked Vestibulodynia (2019 — 2019)
Rationale Dyspareunia is a common pain problem among women. The prevalence has been estimated to be 10-15%. The most common type of dyspareunia among premenopausal women is provoked vestibulodynia (PVD). PVD is characterized by pain upon touch, pressure and stretch of the vestibular tissue in spite of the absence of other gynecological or dermatological disease [4]. The pain and its associated sexual consequences have a severe negative impact on the quality of life of affected women. Currently the etiology, although still not completely clarified, is considered to be multi-factorial involving biomedical and psychosexual causes. Two sub-categories of PVD has been identified; primary PVD, where pain occurs at the first attempt of vaginal entry (intercourse or tampon use) and secondary PVD, where pain occurs after a period of normal functioning. There is evidence of patho-physiological changes in three interdependent systems; the vestibular tissue, the pelvic floor muscles and the pain regulatory pathways of the central nervous system. Signs of a neurogenic inflammation in the vestibular mucosa, with neural hyperplasia of CGRP and Substance P positive C-fibers have been found. Furthermore, recent evidence supports the importance of a pelvic floor muscle (PFM) dysfunction to the etiology of PVD. Women with PVD have been shown to have elevated resting activity, lower maximal strength and poorer control of the PFM compared to healthy controls. Evidence suggests that this hyperactivity, although possibly originating as a protective defense mechanism provoked by pain, is chronic and thus contributes to maintaining and exacerbating the neurogenic inflammation and pain. A circular model has been suggested in which pain during intercourse and fear of pain may decrease sexual arousal and increase PFM tonus, whereby the PFM hyperactivity might act as an initiator of vestibular sensory changes and inflammation. However there is a lack of longitudinal studies to answer the question whether the PFM dysfunction is antecedent to the pain or a result of the pain. Gentilcore-Saulnier et al. proposed that superficial and deep layers of the PFM may differ in their involvement in PVD as assessed with EMG external surface electrodes and an intravaginal probe, respectively. They found that women with PVD have significantly higher resting activity in the superficial muscle (bulbocaverneous) in comparison with controls. The difference was not significant for the deep layer (puborectalis, pubococcygeus, ileococcygeus and ischiococcygeus muscles). The treatment guidelines today recommend a multi-modal treatment including topical anesthetic agents, cognitive behavioral therapy and PFM rehabilitation based on physiotherapy. As a second line treatment injections with botulinum toxin A (BTA) in the bulbocavernous muscles bilaterally has been suggested and to a limited extent tested. The main target for BTA is a transient paretic effect on skeletal muscular fibers and it also blocks the release of neuropeptides and neurotransmitters involved in the neuropathic pain and could therefore have additional effect in the treatment of PVD. Previously published reports on the effects of BTA for PVD are few and the methods of injection (different injection sites, use or non-use of an EMG needle for direction of injection sites) and doses used (20, 35, 100 IU) differ as well as methods of measuring treatment outcome. Only one double blind RCT has been published so far where no additional effect of BTA compared to saline could be detected, however the BTA dose used was low (20 IU) and only one treatment was performed. Using BTA in the PFM seems to be safe and only tenderness at the injection site and mild influenza like symptoms have been reported side effects so far. Hypothesis Our hypothesis is that two treatments (three months apart) of injections with 50 Allergan-units of BTA in the bulbocavernosus muscles in women with PVD will reduce the hyperactivity in the PFM and thus significantly decrease the pain during intercourse. Primary Outcome Measures:
  1. Change in self-reported dyspareunia last month measured by VAS 0-100 [ Time Frame: At baseline up to 6 months ]
    VAS 0 (no pain) to 100 (worst pain imaginable).
Secondary Outcome Measures:
  1. Change in pain at tampon insertion last week, measured by VAS 0-100 [ Time Frame: At baseline and up to 12 months ]
    VAS 0 (no pain) to 100 (worst pain imaginable).
  2. Change in pelvic floor hyperactivity/tonus, [ Time Frame: At baseline and up to 12 months ]
    Measured with a vaginal manometer in mmHg
  3. Safety aspects regarding adverse events of BTA [ Time Frame: The complete study, 12 months ]
    Monitoring possible adverse events
  4. Change in quality of Life (WHOQOL-BREF) [ Time Frame: At baseline and up to 12 months ]
    The validated questionnaires WHO Quality of Life-BREF (WHOQOL-BREF) will be used
  5. Change in quality of Life (EQ5D) [ Time Frame: At baseline and up to 12 months ]
    Health-related quality of life as assessed using the EuroQOL five dimensions
  6. Change in sexual function [ Time Frame: At baseline and up to 12 months ]
    The validated questionnaire Female Sexual Function Index (FSFI) will be used
  7. Change in sexual distress [ Time Frame: At baseline and up to 12 months ]
    The validated questionnaire Female Sexual Distress Scale (FSDS) will be used
  8. Change in level of stress [ Time Frame: At baseline and up to 12 months ]
    The validated questionnaire PSS (Percieved stress scale) will be used
  9. Change in level of anxiety [ Time Frame: At baseline and up to 12 months ]
    A validated questionnaire Adult Anxiety Scale will be used

Placebo-controlled RCT of Botulinum Toxin A as a Treatment for Provoked Vestibulodynia (2016 — 2019)
Design and methodology General outline The study is an investigator- initiated phase III study to determine the effect of botulinum toxin A injections in the bulbocavernosus muscles in women with provoked vestibulodynia for reduction of the level of dyspareunia. The study will be a double blind, placebo-controlled RCT analyzed according to the intention to treat. The study will be carried out according the trial protocol, current regulations (LVFS 2011:19, ICH GCP) and to the latest version of the Helsinki declaration. Ethical approval from the Stockholm regional ethic committee will also be obtained before the study begins. No financial support from the manufacturer of the active drug is obtained. Women with PVD, age 18-40 years, will be informed about the study by their gynecologist or via advertisement with information on how to contact the research nurse or the responsible gynecologists for more information. If the diagnosis of PVD needs to be clarified, a screening appointment will be scheduled. It is estimated that the project will require 4 years for recruitment and treatment of all participants, follow-ups, data analyses and report of results. During the recruitment, the patients with PVD will be asked to participate in an epigenetic study analyzing the grade of methylation of certain candidate genes associated to pain and anxiety before and after treatment and a "genome wide association study" with the aim to find possible genetic markers of PVD. If they accept, a venous blood sample will be taken during Visit 1 and Visit 5. These studies are otherwise separated from the RCT and have ethical approval. The blood samples will be registered in Stockholms Medicinska Biobank (registreringsnummer 941 hos IVO) and stored for later analyses at the research department of Dept. of Obstetrics and Gynecology, 182 88 Danderyd, Sweden. Visit 1(recruitment and baseline) If the patient is willing to participate and fulfill inclusion and exclusion criteria she will sign informed consent in the presence of the gynecologist in charge of the injections of BTA or placebo. Evaluation of psycho-sexual health and quality of life (QoL) The following validated (including the Swedish language) questionnaires will be filled in;
  • Data on general and reproductive health including current medication and anti-conception method
  • Female Sexual Function Index (FSFI)
  • Female Sexual Distress Scale (FSDS)
  • Quality of life (WHOQOL-BRIEF, Swedish version
  • EQ-5
  • PSS (perceived stress scale)
  • Anxiety questionnaire (Spence, Swedish version).
Evaluation of coital pain/dyspareunia
  • The level of dyspareunia the last month will be reported at baseline using VAS 0 (no pain) to 100 (worst pain imaginable)
  • Functional measure of coital impairment (Never pain, Occasional or mild pain - not preventing intercourse, Moderate pain - sometimes preventing intercourse, Severe pain - most times preventing intercourse). In addition the
  • Pain at insertion of a normal size tampon will also be reported according to VAS 0-100.
Vaginal pressure measurement Measurement of vaginal pressure will be performed by the use of a thin plastic catheter with a small pressure transducer at the top (4 mm), connected to a manometer. The catheter is placed in the vagina, 3 -4 cm from the vaginal opening. Vaginal resting pressure in mm Hg (VRP), pelvic floor muscle (PFM) strength, PFM endurance for 10s will be measured. Venous blood sample of 20 ml to separate genetic studies.Randomization The research nurse will perform the randomization according to a computerized block-randomization and prepare sealed envelopes containing data of randomized treatment for each participant. She will also prepare a randomization list with name, personal number and randomization number that will be kept locked away in the research department. Blinding and masking The research nurse who opens the randomization envelope will prepare the syringe with active drug or placebo according to the randomization number. The syringe will be marked with the patient's name, personal number and randomization number and left on a tray at an assigned place where it will be collected by the insertion provider (responsible investigator). Thus, a double blind procedure is obtained. Participation in the study and the patient's randomization number will be noted and kept in each patient's Clinical Research Format (CRF). Copies of the randomization envelopes will be kept locked away in the research department of the Dept. of Obstetrics and Gynecology, Danderyd Hospital. In case of emergency the individual envelopes can be obtained at all times and can then be accessed by all investigators involved in the study. Thereby the blinding of the study is not jeopardized in case of emergency. Drug administration A total amount of 50 Allergan-units BTA, diluted in sterile NaCl solution 9 mg/ml to 0, 5 ml or 0, 5 ml of the sterile NaCl solution 9 mg/ml will be injected at two occasions (tree months apart) at 4 sites (2 at each side) in m. bulbocavernosus approximately 3-4 cm from the vaginal opening by EMG guidance and the use of an EMG needle (37mm x 27G, Natus Manufacturing Limited, Ireland). Participants without a highly effective anti-conception method will undergo a pregnancy test before randomization and treatment. Highly anti-conception methods are defined as; combined hormonal method containing estrogen and progesterone (oral, intravaginal, transdermal), progesterone only (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tube occlusion, vasectomized partner, sexual abstinence. In between visits, a web-based diary will be kept for reporting of adverse events, pain during sexual activity and the result of the tampon test performed once a week at home. The research nurse will send e-mails with the questionnaires to be filled in before each follow-up visit and check that all questionnaires have been completed. She will also remind the participants via e-mail to report adverse events and perform the tampon test as required. Visit 2, 4-6 weeks after baseline. Evaluation of reported adverse events Vaginal pressure measurement. Visit 3, 12 weeks after baseline Evaluation of reported adverse events Questionnaires for psycho-sexual health and QoL - same as Visit 1. Coital pain and the tampon test (VAS 0-100) and functional measure of coital impairment Vaginal pressure measurement Pregnancy test of participants without highly effective anti-conception method The patients will be treated with the same treatment as they were randomized for at baseline (either 50 Allergan-units BTA (0.5 ml) or 0.5 ml placebo) injected in the same manner. Visit 4, 16-18 weeks after baseline Evaluation of reported adverse events Vaginal pressure measurement. Visit 5, 24 weeks after baseline Evaluation of reported adverse events Questionnaires for psycho-sexual health and QoL - same as Visit 1. Coital pain and the tampon test (VAS 0-100) and functional measure of coital impairment. Vaginal pressure measurement Venous blood sample of 20 ml to separate genetic studies At this point patients will be offered, if needed, information on conventional treatment of PVD with exercises for desensitizing the vestibular mucosa and exercises pelvic floor muscles rehabilitation. Visit 6, 12 months from baseline Questionnaires for psycho-sexual health and QoL - same as Visit 1. Coital pain and the tampon test (VAS 0-100), and functional measure of coital impairment. Vaginal pressure measurement. End of Trial. The trial is completed when the last patients has come for her Visit 6. After the trial is completed, participants who have received placebo will be offered treatment with Botox injections, administered the same way as in the study, if the results show that Botox is more effective than placebo for PVD and that no serious adverse events have occurred during the trial. For the post-trial treatment, the patients have to pay for the medication. The treatment is otherwise free of charge. No other treatment for PVD is planned to be carried out and the participants will resume contact with their ordinary open care gynecologist if needed when the trial is completed.
Primary Outcome Measures:
  1. Self-reported dyspareunia measured by VAS [ Time Frame: Baseline to 6 months after baseline ]
    VAS 0 (no pain) to 100 (worst pain imaginable).
Secondary Outcome Measures:
  1. Pain at tampon insertion measured by VAS 0-100 [ Time Frame: Baseline to 6 months after baseline ]
    VAS 0 (no pain) to 100 (worst pain imaginable).
  2. Reduction of pelvic floor hyperactivity/tonus, [ Time Frame: Baseline to 6 months after baseline ]
    Measured with a vaginal manometer.
  3. Quality of Life (questionnaires) [ Time Frame: Baseline to 6 months after baseline ]
    Use of validated questionnaires.
  4. Psychosexual evaluations (questionnaires) [ Time Frame: Baseline to 6 months after baseline ]
    Use of validated questionnaires.
  5. Registrations of adverse events [ Time Frame: 1 year ]
    Adverse events will be registered according to the protocool.

Jacob Bornstein, MD, MPA, Professor Department of Obstetrics & Gynecology Western Galilee Hospital-Nahariya
A Search for Helicobacter Pylori in Localized Vulvodynia (2007 — 2007)
Subsequent sections from the paraffin blocks were prepared and stained by modified Giemsa. Immunostaining for H. pylori was done as described. In short, tissue sections were deparaffinized in xylene, rehydrated through decreasing concentrations of alcohol ending in phosphate-buffered saline (PBS), and subjected to pretreatment with Proteinase K (8 minutes). The sections were quenched with 3% hydrogen peroxidase, incubated with protein block for 15 minutes at room temperature, and washed in PBS. Tissues then were incubated with polyclonal rabbit anti-H pylori antibody (dilution, 1:10; clone ch-20 429, DAKO, Carpinteria, CA). Finally, sections were washed in 0.05% polysorbate 20 in PBS, pH 7.4, and the bound antibody was detected using streptavidin and biotinylated secondary antibody with diaminobenzidine as the chromogen. Sections were counterstained with hematoxylin, dehydrated, and mounted. Negative controls were sections treated as above, but instead of incubation with the primary antibody, they were incubated with 1% bovine serum albumin in PBS. Vulvar biopsies of seven other women without localized vulvodynia served as healthy controls. The positive and negative control gastric tissues for the immunohistochemical stain of the H. pylori microorganisms were obtained from the archives of the Department of Pathology.

Search for Genetic Basis of Vulvodynia (2012 — 2012)
The short-term goal proposed for the current study was to investigate the possibility of an association between Localized Provoked Vulvodynia (LPV) that is both severe and primary and polymorphic markers/single nucleotide polymorphisms (SNPs) in and around the genes encoding heparanase (HSPE-1), Vanilloid Receptor VR1 (TRPV1), and Nerve Growth Factor (NGF). Eight polymorphic SNPs in the three different genes suspected to be involved in LPV has been examined as follow:
  1. HSPE gene: Four polymorphic SNPs: rs4693608, rs11099592, rs6856901 and rs4364254 that were found to be informative in the Ashkenazi Jewish population
  2. TRPV1 gene: Two polymorphic SNPs: rs222747 and rs8065080.
  3. NGF gene: A novel T to C SNP in the promoter region at position -198 (rs11102930) and rs6330 which was found to be associated with anxiety-related personality traits and has been suggested to may affect intracellular processing and secretion of NGF.
Primary Outcome Measures:
  1. Genetic association of Vulvodynia [Time Frame: four years]
    the possibility of an association between Localized Provoked Vulvodynia (LPV) that is both severe and primary and polymorphic markers/single nucleotide polymorphisms (SNPs) in and around the genes encoding heparanase (HSPE-1), Vanilloid Receptor VR1 (TRPV1), and Nerve Growth Factor (NGF).

The Effectiveness of Vestibulectomy (2009 — 2012)
Women with vulvodynia will fill out a questionnaire and undergo a gynecological examination before and 6 months after vestibulectomy. The investigators hypothesize that pain will decrease.
Primary Outcome Measures:
  • pain [Time Frame: 6 months following surgery]
 
Secondary Outcome Measures:
  • sexual function [Time Frame: 6 months afater surgery]

Is Localized Provoked Vulvodynia Caused by Laxity of the Utero-Sacral Ligaments? (2017 — 2019)
Patients with LPV who sign an informed consent form will first undergo the cotton-swab test during which they will rate the pain elicited on a scale of 1 to 10. This score will be used as the patient's baseline level of pain for data analysis later. Then, each patient will be randomized into one of two groups: One group which will first undergo the control manipulation and then the study manipulation, or the second group in which the study manipulation will precede the control manipulation. This is done to neutralize a possible effect of the order of the manipulations on the trial's results when the data will be analyzed. The control manipulation: Inserting a speculum into the vagina without applying pressure. The study manipulation: First inserting a speculum, then inserting through it a large-sized applicator reaching the posterior fornix, then retrieving the speculum while keeping the applicator in place, and then applying significant pressure to the posterior fornix. During each of the manipulations, the cotton-swab test will be performed again, and each patient will be asked to rate the level of pain elicited by the test. All data will be recorded, and we will later analyze if there was a significant difference between the pain elicited by the cotton-swab test during the study manipulation compared with the control manipulation, or compared with the baseline test. Primary Outcome Measures:
  • Level of pain [Time Frame: Immediate result]. Patients will rate the level of pain elicited each time the cotton-swab test will be performed, using a 1-10 scale (1 - not painful, 10 - worst pain imaginable).

Enoxaparin as Treatment for Vulvodynia (2009 — 2020)
The investigators hypothesize that injections of Low molecular weight heparin (LMWH) [enoxaparin] will reduce pain in women with vulvodynia. Primary Outcome Measures: 1. vestibular pain [Time Frame: one year].
Arm  Intervention/treatment 
Experimental: 1 Drug: Clexane (enoxaparin)
One arm receives enoxoparin, second arm receives saline
Placebo Comparator: 2 Drug: Clexane (enoxaparin)
One arm receives enoxoparin, second arm receives saline
 

Lori Brotto, PhD Professor of Obstetrics and Gynecology University of British Columbia
Pregnancy, Childbirth Intentions and Outcomes Under Sexual Pain (PRECIOUS) (2012 — 2017)
The main purpose of this study is to assess conception, pregnancy, childbirth, and pain experiences among women who have been diagnosed with vulvodynia. Specifically, this study aims to examine the following among women who have been diagnosed with vulvodynia: 1) rates of pregnancy/childbirth and desire for children; 2) fear of pregnancy and childbirth; 3) potential difficulties experienced while attempting to become pregnant and during pregnancy/childbirth; 4) methods used to become pregnant and deliver; 5) methods used to manage vulvodynia symptoms during pregnancy; and 6) pain outcomes associated with pregnancy. Very little research has examined pregnancy/childbirth experiences among women with vulvodynia, or the natural history of vulvodynia. As such this is a preliminary investigation that will provide descriptive information regarding many of the proposed research questions. Based on the clinical experience of the investigators, it is expected that women with vulvodynia will report lower rates of pregnancy and higher levels of fear about pregnancy and childbirth in comparison to women without such pain. It is also expected that women with vulvodynia will report more difficulties becoming pregnant as compared to women without such pain, and that women with vulvodynia will report more elective nonvaginal births in comparison to vaginal births.
Primary Outcome Measures:
  1. Pregnancy Rates [ Time Frame: data is collected at a single time point ]
    We will assess if women with vulvodynia experience different rates of pregnancy in comparison to women without such pain
  2. Intentions to have children [ Time Frame: data is collected at a single time point ]
    We will assess how many women with vulvodynia wish to have children in their lifetime.
  3. Fear of pregnancy/childbirth [ Time Frame: data is collected at a single time point ]
    We will assess if women with vulvodynia report higher levels of fear about pregnancy and childbirth in comparison to women without such pain.
  4. Difficulties becoming pregnant [ Time Frame: data is collected at a single time point ]
    We will assess if women with vulvodynia experience more difficulties becoming pregnant in comparison to women without such pain.
  5. Pregnancy/delivery complications [ Time Frame: data is collected at a single time point. ]
    We will assess if women with vulvodynia experience more complications during pregnancy and delivery in comparison to women without such pain.
  6. Pregnancy/delivery methods [ Time Frame: data is collected at a single time point ]
    We will assess what methods women with vulvodynia use to become pregnant and deliver.
  7. Symptom management during pregnancy [ Time Frame: data is collected at a single time point ]
    We will assess how women manage their vulvodynia symptoms during pregnancy.
  8. Change of pain symptoms during and after pregnancy [ Time Frame: data is collected at a single time point ]
    We will assess if vulvodynia-related pain symptoms change during and after pregnancy.
Secondary Outcome Measures:
  1. Course of vulvodynia [ Time Frame: data is collected at a single time point ]
    We will assess the course of vulvodynia after treatment is received from health care workers specializing in vulvar pain.

Candace Brown, PharmD, MSN Professor, Departments of OB-GYN, Pharmacy & Psychiatry University of Tennessee
Savella in Treatment for Provoked Vestibulodynia (2011 — 2014)
This is an 18-week, open-label, flexible-dose "proof of concept" trial where women with a diagnosis of vestibulodynia will be evaluated at baseline for eligibility. Eligible patients will be openly treated with 200 mg/d milnacipran (or the maximum tolerated dose) for a total of 12 weeks. The study design involves 4 phases: screening and washout, baseline assessment, dose escalation, and stable-dose phase (Figure 1). After completing a 2-week washout of prohibited medications, patients will enter a 2-week baseline period, where they will be trained in the use of daily diaries and the tampon test, and baseline safety and efficacy data will be recorded. Patients who continue to meet the eligibility criteria at the end of the baseline period will begin a 6-week period of dose escalation. All patients will be scheduled to receive a total of 12 weeks of stable dose treatment after the 6-week dose-escalation period for a total of 18 weeks of drug exposure.
Primary Outcome Measures:
  1. Pain Rating Index [ Time Frame: 18 weeks ]
    The Pain Rating Index is a component of the McGill Pain Questionnaire which measures sensory and affective components of pain. "0" equals no pain to "45" equals severe pain. This measure was used to measure mean values at baseline and at 18 weeks post-treatment.
Secondary Outcome Measures:
  1. Tampon Pain [ Time Frame: 18 weeks ]
    "0" equals no pain with tampon insertion to "10" equals worse pain imaginable with tampon insertion. This measure was used to measure mean values at baseline and at 18 weeks post-treatment.
  2. Coital Pain [ Time Frame: 18 weeks ]
    "0" equals no pain with intercourse to "10" equals worse imaginable pain with intercourse. This measure was used to measure mean values at baseline and at 18 weeks post-treatment.
  3. 24-hour Vulvar Pain [ Time Frame: 18 weeks ]
    "0" equals no vulvar pain within the last 24 hours to "10" equals worse imaginable vulvar pain within the last 24 hours. This measure was used to measure mean values at baseline and at 18 weeks post-treatment.

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. Results to date can be found at: https://www.ncbi.nlm.nih.gov/pubmed/29742655.

Monica Buhrman, PhD Senior Lecturer/Associate Professor Department of Psychology Uppsala University
An Investigation of Nomothetic Versus Idiographic Assessment in Chronic Pain (2022 — 2022)
Endometriosis, vulvodynia, and fibromyalgia are chronic pain conditions that cause great suffering. The pain conditions are associated with suffering both psychologically and physically. However, knowledge about these conditions is scarce.
The present study aims to investigate the relationship between pain intensity, psychological flexibility, pain functioning, catastrophizing, and depressive symptoms in people with endometriosis, vulvodynia, and fibromyalgia. The investigators want to investigate how these factors relate to each other over time, but also whether there is a difference between people who are in contact with health care for these conditions and those who are not, and whether there is a difference depending on which of the included pain conditions one has. Another aim of the project is to investigate whether the variables the investigators intend to measure meet the criteria for group-to-individual generalizability, meaning that group means and correlation coefficients based on aggregated group data also apply to individuals and that it is reasonable to draw conclusions about individuals from group data. Many psychological variables do not meet the criteria for this type of generalizability. By examining whether the results from variables can be generalized from a group level to an individual level, the investigators will gain clues about how much individualization is required in future research, assessments, and treatments for the pain conditions included in the current project. In order to investigate group-to-individual generalizability, the project requires a large sample of participants to obtain group averages but also a large number of repeated measurements over a longer period of time for each participant. Repeated measurements from each individual are planned to be carried out to obtain individual mean values, in order to compare this with the group data. A diary will be created which is intended to be used daily, and a further aim of this study is to evaluate whether this diary is valid to use for future studies in these pain conditions. On the first day of the study, participants will complete forms collecting demographic and background information, including information about the participants' pain. On the first as well as the last day, information will also be collected from standardized questionnaires, including the Multidimensional Psychological Flexibility Inventory (MPFI), Patient Health Questionnaire-9 (PHQ-9), Brief Pain Inventory (BPI), and Pain Catastrophizing Scale (PCS). On the second day of the study, participants will start to fill in twice daily measures at fixed times, and with a 12-hour interval between these two daily measurements. These are based on an ecological momentary assessment approach (EMA), where frequently repeated measurements are taken in the natural environment of the research subjects and where the time that participants have to think back on when answering is kept short. Using EMA, the within-individual variation can be easily monitored over time. The daily measurements will be collected for 42 days. The measurements consist of items from MPFI, BPI, PHQ-2, and PCS. In addition, two items are developed by the research team to assess sexual functioning and energy levels. Participants will also fill out a weekly diary administered six times in total. The weekly diary consists of three items asking the participant to rate the previous week, and indicate whether something out of the ordinary has happened. Primary Outcome Measures:
  1. Multidimensional Psychological Flexibility Inventory (MPFI) - Psychological Inflexibility subscale [ Time Frame: Measured immediately following participant consent to undertake survey ]
    A 30-item measure reflecting all facets of psychological inflexibility, namely: experiential avoidance, lack of contact with the present moment, self as content, fusion, lack of contact with values, and inaction. The minimum score is an average of 1 across the 30 items, and the maximum score is 6 across the 30 items. It can also be scored on a facet level with a minimum score of 1 and a maximum score of 6 for the individual facet scored. A higher average score indicates higher psychological inflexibility.
  2. Multidimensional Psychological Flexibility Inventory (MPFI) - Psychological Inflexibility subscale [ Time Frame: Six weeks after participant consent ]
    A 30-item measure reflecting all facets of psychological inflexibility, namely: experiential avoidance, lack of contact with the present moment, self as content, fusion, lack of contact with values, and inaction. The minimum score is an average of 1 across the 30 items, and the maximum score is 6 across the 30 items. It can also be scored on a facet level with a minimum score of 1 and a maximum score of 6 for the individual facet scored. A higher average score indicates higher psychological inflexibility.
  3. Psy-Flex [ Time Frame: Measured immediately following participant consent to undertake survey ]
    A 6-item measure assessing all facets of psychological flexibility using one item per facet. The minimum score is 6 and the maximum score is 30. Higher scores indicate higher psychological flexibility.
  4. Psy-Flex [ Time Frame: Six weeks after participant consent ]
    A 6-item measure assessing all facets of psychological flexibility using one item per facet. The minimum score is 6 and the maximum score is 30. Higher scores indicate higher psychological flexibility.
  5. Patient Health Questionnaire-9 (PHQ-9) [ Time Frame: Measured immediately following participant consent to undertake survey ]
    A nine-item measure on symptoms of depression, with a minimum score of 0 and a maximum score of 27. Higher scores indicate higher levels of depression. The scale also includes an additional item regarding how the depressive symptoms have interfered with everyday functioning. Higher scores indicate higher levels of everyday interference.
  6. Patient Health Questionnaire-9 (PHQ-9) [ Time Frame: Six weeks after participant consent ]
    A nine-item measure on symptoms of depression, with a minimum score of 0 and a maximum score of 27. Higher scores indicate higher levels of depression. The scale also includes an additional item regarding how the depressive symptoms have interfered with everyday functioning. Higher scores indicate higher levels of everyday interference.
  7. Pain Catastrophizing Scale (PCS) [ Time Frame: Measured immediately following participant consent to undertake survey ]
    A 13-item measure assessing the level of catastrophizing when in pain. Includes three main factors; rumination, magnification, and helplessness. The minimum score is 0 and the maximum score is 52. Higher scores indicate higher levels of pain catastrophizing.
  8. Pain Catastrophizing Scale (PCS) [ Time Frame: Six weeks after participant consent ]
    A 13-item measure assessing the level of catastrophizing when in pain. Includes three main factors; rumination, magnification, and helplessness. The minimum score is 0 and the maximum score is 52. Higher scores indicate higher levels of pain catastrophizing.
  9. Brief Pain inventory - short form (BPI-SF) [ Time Frame: Measured immediately following participant consent to undertake survey ]
    For this study, two items on pain severity (one regarding average pain severity during the last week and one regarding pain severity at the current moment) and ten items on pain interference will be used. Three out of the ten pain interference items, exploring how pain interferes with sexual activities, enjoyment of sex, and feelings of being rested, have been created and added by the research team. The two pain severity items are each scored from 0 to 10, with 0 indicating the least amount of pain and 10 indicating the highest amount of pain. The original seven pain interference items are each scored in the same way, but can also together generate an average score, with the minimum average score then being 0 and the maximum average score being 10. A higher score indicates a higher level of pain interference. The three pain interference items created by the research team are scored in the same way.
  10. Brief Pain inventory - short form (BPI-SF) [ Time Frame: Six weeks after participant consent ]
    For this study, two items on pain severity (one regarding average pain severity during the last week and one regarding pain severity at the current moment) and ten items on pain interference will be used. Three out of the ten pain interference items, exploring how pain interferes with sexual activities, enjoyment of sex, and feelings of being rested, have been created and added by the research team. The two pain severity items are each scored from 0 to 10, with 0 indicating the least amount of pain and 10 indicating the highest amount of pain. The original seven pain interference items are each scored in the same way, but can also together generate an average score, with the minimum average score then being 0 and the maximum average score being 10. A higher score indicates a higher level of pain interference. The three pain interference items created by the research team are scored in the same way.
  11. Endometriosis Health Profile - 5 (EHP-5) [ Time Frame: Measured immediately following participant consent to undertake survey ]
    A five-item measure assessing quality of life in people with endometriosis. Each item is scored on a four-point scale. The minimum score is 0, and the maximum score is 100. A higher score indicates worse health status. The measure is only administered to participants responding that they suffer from endometriosis.
  12. Endometriosis Health Profile - 5 (EHP-5) [ Time Frame: Six weeks after participant consent ]
    A five-item measure assessing quality of life in people with endometriosis. Each item is scored on a four-point scale. The minimum score is 0, and the maximum score is 100. A higher score indicates worse health status. The measure is only administered to participants responding that they suffer from endometriosis.
  13. Brief Pain inventory - short form (BPI-SF) [ Time Frame: Six weeks ]
    An eight-item questionnaire. One item measuring current pain intensity and seven items measuring pain interference on general activity, mood, sleep, feeling of being rested, relations with other people, enjoyment of life, and enjoyment of sex. The two items measuring pain interference on feelings of being rested and enjoyment of sex are developed by the research team. Item assessing sleep is administered once per day in the morning, and the item assessing feelings of being rested is administered once per day in the evening. Pain intensity is scored from 0 to 10, with 0 indicating the least amount of pain and 10 indicating the highest amount of pain. The pain interference items are each scored in the same way, but can also together generate an average score, with the minimum average score then being 0 and the maximum average score being 10. A higher score indicates a higher level of pain interference. Administered twice daily for 42 days.
  14. Patient Health Questionnaire-2 (PHQ-2) [ Time Frame: Six weeks ]
    A two-item version of the PHQ-9 made for assessing the level of interest and pleasure of doing things and, depression and hopelessness. The items are scored from 0 to 10. The minimum score is 0 and the maximum score is 20. Higher scores indicate higher levels of depression. Administered twice daily for 42 days.
  15. Multidimensional Psychological Flexibility Inventory (MPFI) - Psychological Inflexibility [ Time Frame: Six weeks ]
    Six items from the MPFI measuring psychological inflexibility. Assessing the domains; experiential avoidance, lack of contact with the present moment, self as content, fusion, lack of contact with values, and inaction. The items are scored from 0 to 10. The minimum score is 0 and the maximum score is 10. A higher average score indicates higher psychological inflexibility. Administered twice daily for 42 days.
  16. Pain Catastrophizing Scale (PCS) [ Time Frame: Six weeks ]
    Three items from the PCS measuring the level of catastrophizing when in pain. The items are scored from 0 to 10. The minimum score is 0 and the maximum score is 30. Higher scores indicate higher levels of pain catastrophizing. Administered twice daily for 42 days.
  17. Weekly events [ Time Frame: Six weeks ]
    A three-item measure developed by the research team to measure how the week has been in general, if something out of the ordinary has happened, and what this event was related to. The first item is from -10 to 10, with a higher score indicating a good week. The second item has five options and the third item has eight options for the participant to choose from. No summary score will be calculated, items are scored individually. Administered once a week for six weeks.
  18. End of study questionnaire [ Time Frame: Once approximately six weeks after intake ]
    An eight-item questionnaire developed by the research team assessing whether participants have begun any new treatment for their chronic pain condition, whether something out of the ordinary has happened during their study participation, and six items providing an opportunity for participants to give feedback on the study procedure, questionnaires, and platforms used in the current study

Donna Carrico, NP William Beaumont Hospitals
Relationship: Interstitial Cystitis & Vulvodynia-Part 2 (2008 — 2008)
In a mailed survey (Part 1 of this study), 127 women with a documented diagnosis of IC agreed to be contacted for an in-office examination. The mailed survey was internally developed specifically for this project and included items related to demographics, adolescent and adult history related to genital pain and current health. The last section allowed the subject to include contact information if they would also like to participate in Part 2 (additional questionnaires and examination) of the study.The study coordinator will review those surveys containing contact information and all women at least 18 years of age will be invited to the WISH program (Beaumont Women's Initiative for Pelvic Pain and Sexual Health) to be examined by a certified Nurse Practitioner (NP) who will be blinded to their survey responses.Questionnaires will be completed by the subject. These questionnaires relate to one's history, pain symptoms, quality of life, bladder symptoms and sexual function and will be completed prior to the examination. The NP will perform all the clinical evaluations. A vaginal pH and wet mount slide will be done first. Testing for vulvodynia will be done utilizing an algesiometer q-tip followed by Neurometer® surface CPT testing for pain threshold (not tolerance) to quantify pain levels in the distribution of the pudendal nerve on the perineum and vulva will be done. The Neurometer® current perception threshold (CPT) is a device for evaluating and measuring sensation It is a battery-operated stimulator which delivers painless electrical stimulation via surface electrodes at frequencies of 5 Hz, 250 Hz, and 2000 Hz and at a current of 0.01 to 99mAmps. Primary Outcome Measures:  
  • The objective of our study is to identify and clinically confirm the presence of vulvodynia in women diagnosed with Interstitial Cystitis (IC) based on mailed survey results (Part 1, HIC #2007-183) and confirmed with a clinical assessment. [Time Frame: Visit 1].

Relationship of Interstitial Cystitis to Vulvodynia (2007 — 2009)
This study is important in urologic nursing since many patients have interstitial cystitis (IC), a condition of frequency, urgency and pain affecting more than 1 million women in the United States. The vulva may actually be the site of some of the reported pain in women with IC, not the urethra or bladder. IC and vulvodynia can impact one's sexual functioning and diminish one's quality of life. The purpose of this two-part study is to identify and clinically confirm the presence of vulvodynia in women diagnosed with Interstitial Cystitis (IC). Primary Outcome Measures:
  • The purpose of this two-part study is to identify and clinically confirm the presence of vulvodynia in women diagnosed with Interstitial Cystitis (IC). [Time Frame: Prospective].
 

Devavani Chatterjea Macalester College
Contributions of Mast Cells to Intersections of Allergy and Pain Pathways (2015 — 2018)
DESCRIPTION (provided by applicant): Chronic pain and allergic diseases are two widespread global health challenges lacking clear preventive measures or satisfactory therapeutic solutions. Approximately 30-40% of the world's population suffers from at least one allergic disease while one out of every 10 adults is newly diagnosed with chronic pain each year. Tissue mast cells orchestrate allergic pathologies. An emerging body of evidence also places them as critical mediators of both protective and maladaptive pain. Mast cells have been clinically associated with migraines, inflammatory bowel disease, fibromyalgia, and bladder pain. In both migraine and chronic vulvar pain, a history of allergies is known to increase the risk of developing the pain condition. While the roles of mast cells in allergies and pain have been separately studied, the interaction of these pathways has not been investigated. Here we propose to dissect mast cell regulation of allergy- driven pain via two closely connected specific aims: (1) Characterize contributions of mast cell activation, by different IgE antibody clones against the same antigen, to hind paw thermal and mechanical sensitivity in a mouse model of IgE-mediated passive cutaneous anaphylaxis and (2) Identify mast cell-regulated pathways at the intersection of allergic and chronic vulvar pain pathologies in vulvar pain provoked by chronic labiar contact hypersensitivity. We will use thermal and mechanical pain measurements, semi-quantitative single/multiplexed PCR, immuno-fluorescent, confocal, and transmission electron microscopy, and protein assays (ELISA, western blot, flow cytometry). We build on groundwork laid in our previous NIH- supported work (R15 NS067536-01A; 2010-2013) on contributions of mast cells to acute, inflammatory pain. Preliminary findings indicate that acute allergic reactions mediated by different IgE antibodies against the same antigen can provoke different pain outcomes, and chronic allergic reactions can change the long-term pain sensitivity of affected tissue even after overt allergic inflammation has resolved. Mast cells and nerves reside in close proximity in many tissues and regulate each other through networked signals of neurotransmitters, cytokines and adhesion molecules. Identification of key mediators of nerve-mast cell interactions in allergy- associated pain will provide novel mechanistic insights applicable beyond any single allergy or pain disorder and lead to novel therapeutics and strategic interventions that enhance progress toward improved health and quality of life.

Thomas Chelimsky, MD Adjunct 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.

Julie Carlsten Christianson, PhD Assistant Professor, Department of Anatomy and Cell Biology University of Kansas
Impact of Early Experience on Vulvovaginal Sensitivity in Adult Mice (2011 — 2018)
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.

Effect of Neonatal and Adult Stress on Pelvic Pain Disorders and Comorbidity (2014 — 2019)
DESCRIPTION (provided by applicant): An estimated 20% of the US population suffers from chronic pelvic pain, which encompasses a number of debilitating disorders including interstitial cystitis, irritable bowel syndrome, vulvodynia, chronic prostatitis and endometriosis, and costs more than $30 billion in direct medical and indirect costs annually. Up to 50% of women with chronic pelvic pain experience symptoms from more than one disorder, creating a greater negative impact on quality of life and complicating already less-than-optimal treatment strategies. Early life stress or trauma is a significant risk factor for developing functional pain disorders and is due, in part, to altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response and influences the perception of pain. Proper feedback within the hypothalamus, as well as regulatory input from higher limbic structures, influences the response to stress and subsequent return to homeostasis. Several key molecules are involved in this process, including corticotropin releasing factor (CRF), the principal initiator of the stress response through the CRF1 receptor; the related urocortins (Ucn), which can inhibit stress response through the CRF2 receptor; and glucocorticoids, which mediate downstream stress responses, as well as influence both positive and negative feedback onto the HPA axis. Rodent models of neonatal stress display disruption of proper feedback onto the HPA axis, resulting in visceral hyperalgesia, permanent changes in central and peripheral pain processing, and increased peripheral expression of inflammatory mediators. The goal of the current proposal is to understand how early life stress predisposes an individual to developing pelvic pain syndromes during adulthood. Our central hypothesis is that neonatal maternal separation (NMS) disrupts proper functioning of CRF-responsive brain regions and peripheral targets, resulting in altered bladder function and sensitivity, as well as enhanced susceptibility to stress-induced symptomology and comorbidity. We have designed three specific aims (SAs) to test this hypothesis. SA1 will determine the effect of neonatal and adult stress on limbic regulation of the HPA axis and downstream neurogenic inflammation of the bladder. SA2 will examine how neonatal and adult stress affects central and peripheral CRF/Ucn2-dependent control of micturition. SA3 will evaluate the efficacy of CRF antagonism for attenuating neonatal and adult stress-induced bladder dysfunction, hypersensitivity and neurogenic inflammation, as well as comorbid vaginal hypersensitivity. At the completion of this project, we will have gained new information about how early life stress drives neuronal plasticity, primes the nervous system for future insult, and increases the susceptibility for developing comorbid functional pain disorders. By focusing on stress-induced changes in visceral sensitivity, we will gain insight as to how best treat a specific subpopulation of patients suffering from IC, vulvodynia, and potentially a number of other comorbid stress-induced functional pain disorders.

J. Quentin Clemens, MD Associate 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.

Marcy Dayan, BSR, MHA Clinician Specialist, Women's Health Dayan Physiotherapy
Physiotherapy Intervention for Provoked Vulvar Vestibulodynia (2012 — 2020)
Hypothesis:
  1. Specific physiotherapy interventions will decrease pain, improve pelvic floor motor control, increase self efficacy, improve sexual function and decrease pain catastrophizing behaviour in women with provoked vulvar vestibulodynia.This study will look at specific physiotherapy treatment interventions to see if they decrease pain, improve pelvic floor motor control, increase self efficacy, improve sexual function and decrease pain catastophizing behaviour. Participants will fill out a questionnaire on their pain symptoms and complete standardized scales prior to starting treatment and after 4 sessions to determine change due to interventions.
  2. A combination of physiotherapy, group educational sessions and group cognitive behavioural therapy will have better outcomes than physiotherapy alone.
Results of physiotherapy intervention alone will be compared to results of those treated with physiotherapy, group educational sessions and group cognitive behavioural therapy at a separate treatment centre. Physiotherapy interventions and outcome measures are the same between both groups. Justification: Standard treatment is hard to identify as many approaches are taken, none with any evidence to support them. This study aims to look at specific techniques (pelvic floor coordination and relaxation exercises, education on female sexual response and pain pathophysiology education) to see if there is a benefit. Primary Outcome Measures: Upon completion of data analysis, establishment of the efficacy of pelvic floor physiotherapy for the treatment of Provoked Vulvar Vestibulodynia will be determined [ Time Frame: 2 years ]. Time frame: Following completion of data collection.

Valerie Dernetz University of Maryland Baltimore
Neurophysiological and Psychological Correlates of Vulvodynia (2014 — 2018)
DESCRIPTION (provided by applicant): vulvodynia is a multifaceted, chronic, female urogenital pain syndrome that is understudied and carries a substantial psychological and economic burden for women and their families, the healthcare system, and society. Similar to other chronic pain syndromes, the development and maintenance of vulvodynia symptomatology is most likely a complex combination of biological and psychological factors; however, these mechanisms are not well-described or understood and effective treatment remains elusive. An increased understanding of the respective contribution of each of these elements will impart critical information about vulvodynia and provide the crucial first steps for the development of mechanistic-based interventions. In recent years, studies have suggested the underlying mechanisms may vary amongst the multifarious clinical presentations of vulvodynia. Therefore, the purpose of this descriptive study is to thoroughly elucidate the physiological and psychological factors associated with vulvodynia in comparison to women without and test the hypothesis that these mechanisms differ in women with distinct patterns of disease onset, specifically primary (i.e., has always experienced vulvar pain) and secondary (i.e., development of pain following a pain free period) vulvodynia. First, the applicant will assess the neurosensory processing using a comprehensive battery of quantitative sensory testing (QST) methods in 20 women with primary vulvodynia, 20 women with secondary vulvodynia, and 20 age and race matched women without vulvodynia. Training will focus on increasing knowledge in neurophysiology and learning experimental methods in pain research. Second, the applicant will assess psychological factors using self-report measures of fear of pain and catastrophizing (i.e., negative cognitive-affective response to anticipated or actual pain) in the three groups of women. Training will focus on learning methods to accurately assess these psychological factors in a chronic vulvar pain population. A team of senior mentors with expertise in the experimental investigation of neurosensory processing of chronic pain and the neurobiology of urogenital pain disorders will guide the applicant in the proposed research project and throughout her doctoral training. The proposed research aligns well with the NINR's mission to examine the underlying biological mechanisms of symptoms (e.g., pain) associated with disease. Ultimately, findings from this study will inform our knowledge about vulvodynia and will provide direction for future research with regard to development of novel targeted therapies for treatment of vulvodynia.

Gregory Essick, DDS, PhD Professor, School of Dentistry University of North Carolina – Chapel Hill
Phenotyping 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 patient participants referred from the clinics associated with Subprojects 1-3 and the UNC Center for Functional Gl & Motility Disorders that will adequately and efficiently 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.

Arthur Fan, MD(CHN), PhD McLean Center for Complementary and Alternative Medicine
Effect of Two Acupuncture Protocols on Vulvodynia (Acu/Vul-pain) (2018 — 2020)
Aims of this study:
  • Get preliminary data for future larger, randomized- controlled trials.
  • See whether acupuncture is better than no-acupuncture treatments (where participations are following standard care for this condition), or at least have probable better outcomes than no acupuncture treatment (there may not be significance in statistics, given the small sample in current proposed trial);
  • See if acupuncture group 1a (with focus on the points in pudendal nerve distribution near the pain area) has better results(at least, a trend) than acupuncture group 1b (traditional acupuncture focus on meridian or distal points).
The basic design and interventions:
  • Diagnosis: Vulvodynia/Vulval pain by gynecologist or pain specialist/doctor, who will adopt International diagnose criteria.
  • Patient sample (estimated): 17 in each acupuncture group (34 total), and 17 patients in the no-acupuncture group or standard care waiting list . Total 51 patients;
  • Groups: Group 1a (17 cases): acupuncture, using the local points in pudendal nerve distribution area (tender points, and up to two other set of acupuncture points); Group 1b (17 cases): traditional acupuncture, using common meridian or distal points; Group 2 (17 cases): standard care, waiting list. This group will receive no acupuncture treatment.
  • Randomized method: If the patient feels comfortable with acupuncture, they will be randomly assigned to either Group 1a or Group1b using randomization numbers generated by computer; if the patients still are under the treatments of routine conventional treatments, such as using pain medications, local injections, and physical therapies, or other non-surgical procedure, they will serve as participants in the standard care group, the waiting list.
  • Blind Method: Patients will be blind as to the purpose of the study as well as to the groups that they are assigned too. Each participant in either group 1a or 1b will receive actual, real acupuncture treatment but, depending on their group assignment, the strategy and points used will vary.
  • Treatments: Group 1a: acupuncture: needling focus on Hui yang, pudendal nerve points and local point(s) near the pain location with needling manipulation (such as twisting 200/min for 2-5 minutes at pudendal nerve points); Group 1b: acupuncture: using meridian points, focus on Xue Hai (SP9), San Yin Jiao (SP6), Zu San Li (ST36); Both groups also use: Shen Ting (GV24), Tou Wei (ST 8), Yin Tang (EX2) for helping to release stress and create calm. Both group 1(a/b) and group 2 patients are all allowed to use pain medications (in which the medications' name and how many pills used during 6 weeks' observation period will be carefully document); the standard care group actually is a waiting list, without acupuncture intervention. Follow up: 6 weeks. Acupuncture time and frequency: 45 min per session, once or twice per week, for 6-12 sessions (in 6 weeks).
  • Main observation:
(1) Objective pain score(tested using cotton swab); (2) Patient self reported pain score (subjective, before Cotton swab test); Others: Pain duration and pain score during intercourse.
  • Statistics: student t-test.
Sample calculation: The expected difference (ECSD) between two means is 3, and the common within group standard deviation is 3. Giving an 80 chance that an 0.05 level test of significance will find a statistically significant difference between two sample means are compared, the sample size is approximately 17 per group. Comparisons:
  • At the end point (end of 6 weeks), make comparisons between acupuncture (1a+1b) group and group 2, acupuncture 1a and group 2, acupuncture 1b and group 2; between acupuncture 1a and acupuncture 1b; respectively.
  • At the end point (end of 6 weeks), make comparisons in each group self (before and after).
Primary Outcome Measures: 1. Pain Score (objective) [Time Frame: at the end of 6 weeks]. Figure out the pain score using Visual Analog pain scale(VAS) using cotton swab , [score 0-no pain, 10-strongest (unbearable) pain]. Expected clinical significant difference (ECSD): 3.
Secondary Outcome Measures: 1. Pain Score (Subjective) [Time Frame: at the end of 6 weeks]. Figure out the pain score using Visual Analog pain scale(VAS) before use of cotton swab to to test pain , [score 0-no pain, 10-strongest (unbearable) pain]. Expected clinical significant difference (ECSD): 3.    2. Pain duration [ Time Frame: at the end of 6 weeks ]. Monitor the hours of pain per day. 3. Intercourse pain [ Time Frame: at the end of 6 weeks ]. Record how much pain during intercourse using Visual Analog pain scale(VAS) [score 0-no pain, 10-strongest].

Melissa Farmer, BA, PhDc McGill University
Mouse 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 anogenital 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. Results to date can be found at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996207/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243907/

Colleen Fitzgerald, MD Associate 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.

Siri Forsmo, Professor Norwegian University of Science and Technology
Multidisciplinary Treatment of Chronic Vulvar Pain (2018 — 2022)
Patients with chronic vulvar pain constitute a heterogeneous group with regards to causes and moderators of pain. Multidisciplinary teams simultaneously assess contributing factors such as infections and dermatoses and treat known mediators of pain, namely mucosal hypersensitivity, pelvic muscle floor dysfunction and general pain management. Treatment as usual, on the other hand, is primarily based on a sequential model applying one type of treatment at a time. The investigator's aim is to compare multidisciplinary treatment including multimodal physiotherapy (intervention group) with standard treatment (control group) in reducing pain, sexual dysfunction and related symptoms in women with vulvodynia. The study sample will be allocated randomly 1:1 to multidisciplinary treatment by a vulva team or to standard treatment by a specialist in gynaecology. The intervention will include a joint consultation by a gynaecologist and a dermatologist, tailored multimodal physiotherapy by a physiotherapist and guided imagery (mindfulness and relaxation) by use of a sound track during home sessions. The controls will receive standard care by a gynaecologist, who is free to offer any kind of non-standardized treatment. Treatment effect will be measured at 3 months, 6 months and 12 months after inclusion.
Primary Outcome Measures  :
  1. Pain intensity with Brief pain inventory (BPI) [ Time Frame: Baseline, 3 months and 6 months (change) ]
    Intensity of pain measured with BPI using the mean of the 4 subscales (current, averaged, maximum and minimum pain during the last week) on a 0-10 numerical rating scale (0 minimum and 10 maximum pain)
Secondary Outcome Measures  :
  1. Pain intensity with Brief pain inventory (BPI) [ Time Frame: Baseline, 3 months, 6 months and 12 months (change) ]
    Intensity of pain measured with BPI using the mean of the 4 subscales (current, averaged, maximum and minimum pain during the last week) on a 0-10 numerical rating scale (0 minimum and 10 maximum pain)
  2. Pain intensity with tampon test [ Time Frame: Baseline and 6 months (change) ]
    Intensity of pain with tampon insertion and removal (tampon test) measured on a 0-10 numerical rating scale (0 minimum and 10 maximum pain)
  3. Pain intensity with tampon test [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Intensity of pain with tampon insertion and removal (tampon test) measured on a 0-10 numerical rating scale (0 minimum and 10 maximum pain)
  4. Vulvar pressure pain threshold with vulvalgesiometer [ Time Frame: Baseline and 6 months (change) ]
    Vulvar pressure pain threshold in Newton measured with a cotton tipped vulvalgesiometer
  5. Vulvar pressure pain threshold with vulvalgesiometer [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Vulvar pressure pain threshold in Newton measured with a cotton tipped vulvalgesiometer
  6. Pain intensity with Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) [ Time Frame: Baseline and 6 months (change) ]
    Pain intensity measured by a 22-Item NRS-based (0-10) questionnaire (SF-MPQ-2). Both total and subscale (continuous, intermittent, neuropathic, and affective pain) mean scores.
  7. Pain intensity with Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Pain intensity measured by a 22-Item NRS-based (0-10) questionnaire (SF-MPQ-2). Both total and subscale (continuous, intermittent, neuropathic, and affective pain) mean scores.
  8. Sexual distress with Female Sexual Distress Scale - revised (FSDS) [ Time Frame: Baseline and 6 months (change) ]
    Sexual distress measured with a 13-item Likert scale-based (0-4) questionnaire (FSDS). Mean score.
  9. Sexual distress with Female Sexual Distress Scale - revised (FSDS) [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Sexual distress measured with a 13-item Likert scale-based (0-4) questionnaire (FSDS). Mean score.
  10. Affective symptoms with Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline and 6 months (change) ]
    Affective symptoms measured with a 14-item Likert scale-based (0-3) questionnaire (HADS). Both total and subscale (depression and anxiety) scores.
  11. Affective symptoms with Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Affective symptoms measured with a 14-item Likert scale-based (0-3) questionnaire (HADS). Both total and subscale (depression and anxiety) scores.
  12. Illness perception with Brief Illness Perception Questionnaire (BIPQ) [ Time Frame: Baseline and 6 months (change) ]
    Illness perception measured with a 8-Item NRS-based (0-10) questionnaire. Mean score of total scale.
  13. Illness perception with Brief Illness Perception Questionnaire (BIPQ) [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Illness perception measured with a 8-Item NRS-based (0-10) questionnaire. Mean score of total scale.
  14. Pain catastrophizing with Pain Catastrophizing Scale (PCS) [ Time Frame: Baseline and 6 months (change) ]
    Pain catastrophizing measured with a 13-Item Likert scale-based (0-4) questionnaire (PCS). Total score.
  15. Pain catastrophizing with Pain Catastrophizing Scale (PCS) [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Pain catastrophizing measured with a 13-Item Likert scale-based (0-4) questionnaire (PCS). Total score.
  16. Levator hiatal area [ Time Frame: Baseline and 6 months (change) ]
    Ultrasound-measured difference in levator hiatal area (cm^2) between rest and contraction and between rest and valsalva maneuver
  17. Levator hiatal area [ Time Frame: Baseline, 6 months and 12 months (change) ]
    Ultrasound-measured difference in levator hiatal area (cm^2) between rest and contraction and between rest and valsalva maneuver

David Foster, MD, MPH Associate 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: https://journals.lww.com/greenjournal/fulltext/2010/09000/Oral_Desipramine_and_Topical_Lidocaine_for.6.aspx and https://www.ncbi.nlm.nih.gov/pubmed/19305326.

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/ http://www.ncbi.nlm.nih.gov/pubmed/24858303.

Martha Goetsch, MD OHSU Knight Cancer Institute
Therapy to Prevent Sexual Pain in Breast Cancer Survivors (2012 — 2017)
For this study there will be three visits over a 3 month period. Subjects will undergo a gynecological exam at the screening visit to determine the severity of pain associated with uncomfortable intercourse. A touch test using Q-tips will be used during screening exam so subjects can report pain during application of both study drug and placebo. Subjects will also report pain during tampon test. A sample of vaginal cells and liquid will be obtained at screening visit so that PI can rule out possible infection, disease, or disorders. PI will also show subject the area of the vestibule in a mirror so that subject can apply study drug at home properly. Subjects will fill out 4 questionnaires about medical and health history, cancer history, pain, and distress and sexual activity. Subject will be given a supply of either study drug or placebo to take home. The first visit will last approximately 2 hours.
Subjects will return for a second visit after 4 weeks and a third visit after 8 weeks for diary review, questionnaires, and examination. The second and third visit examinations will be repeats of the examination done at the first visit, but there will be no comparison with placebo, the PI will use only study drug during the touch test. The second and third visits will last approximately 1 hour. Subjects will fill out questionnaires throughout study participation. Topics include; medical and health history, cancer history, pain, distress and sexual activity. Subjects will also fill out a diary that charts tampon test completed from home, sexual activity performed, pain levels and study drug application days.
Primary Outcome Measures:
  1. Prevention of Entry Dyspareunia With Non-hormonal Therapy [ Time Frame: During Phase II (0-4 weeks) and during Phase III (5-12 weeks) ]
    Mean intercourse pain reported by subjects using the Numerical Rating Scale pain ratings (range 0-10, 0 being "no pain" and 10 being "worst possible pain"). Testing was during weeks 0-4 (Phase II) (with blinded randomization for placebo vs active intervention medication) and testing was during weeks 5-12 (Phase III) (with open-label active medication for 8 weeks after completing the blinded 4 weeks). Subjects agreed to try penetration twice per week and score their pain using the Numerical Rating Scale pain ratings.The scores were averaged during each phase.
  2. Location of Pain in Postmenopausal Dyspareunia [ Time Frame: Enrollment visit ]
    To determine the specific site of vulvovaginal tenderness in menopausal breast cancer survivors who have entry dyspareunia. Examine the vulvar vestibule with a swab test to determine locations and severity of touch tenderness. Eight sites were evaluated around the vaginal opening and there location was in reference to a clock face. Measured using the Numerical Rating Scale, a scale which measures pain from 0 to 10 with 0="no pain" and 10="the worst pain you have ever felt".
Secondary Outcome Measures:
  1. Improvement of Quality of Sexual Life - Visit 1 [ Time Frame: Visit 1 (Enrollment) ]
    To determine whether women's quality of sexual life is improved by use of this local therapy to prevent pain with intercourse. Measured by average scores on the Sexual Function Questionnaire. There are 8 domains measured in the Sexual Function Questionnaire each asking for a score for the prior 30 days: Desire (score range 5-31; ≥23 considered normal function), Arousal-sensation (score range 4-20; ≥14 considered normal function), Arousal-lubrication (score ranges 2-10; ≥8 considered normal function), Arousal-cognitive (score range 2-10; ≥8 considered normal function), Orgasm (score range 1-15; ≥12 considered normal function), Pain (2-15; ≥12 considered normal function), Enjoyment (score range 6-30; ≥23 considered normal function) and Partner (score range 2-10; ≥8 considered normal function).
  2. Improvement of Quality of Sexual Life - Visit 2 [ Time Frame: Visit 2 (Week 4) ]
    To determine whether women's quality of sexual life is improved by use of this local therapy to prevent pain with intercourse. Measured by averaged scores on the Sexual Function Questionnaire. There are 8 domains measured in the Sexual Function Questionnaire each asking for a score for the prior 30 days: Desire (score range 5-31; ≥23 considered normal function), Arousal-sensation (score range 4-20; ≥14 considered normal function), Arousal-lubrication (score ranges 2-10; ≥8 considered normal function), Arousal-cognitive (score range 2-10; ≥8 considered normal function), Orgasm (score range 1-15; ≥12 considered normal function), Pain (2-15; ≥12 considered normal function), Enjoyment (score range 6-30; ≥23 considered normal function) and Partner (score range 2-10; ≥8 considered normal function).
  3. Improvement of Quality of Sexual Life - Visit 3 [ Time Frame: Visit 3 (End of Study) ]
    To determine whether women's quality of sexual life is improved by use of this local therapy to prevent pain with intercourse. Measured by average scores on the Sexual Function Questionnaire. There are 8 domains measured in the Sexual Function Questionnaire each asking for a score for the prior 30 days: Desire (score range 5-31; ≥23 considered normal function), Arousal-sensation (score range 4-20; ≥14 considered normal function), Arousal-lubrication (score ranges 2-10; ≥8 considered normal function), Arousal-cognitive (score range 2-10; ≥8 considered normal function), Orgasm (score range 1-15; ≥12 considered normal function), Pain (2-15; ≥12 considered normal function), Enjoyment (score range 6-30; ≥23 considered normal function) and Partner (score range 2-10; ≥8 considered normal function).

Richard Gracely, PhD
A 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 L. Harlow, PhD Professor 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 led 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 sub-sample of 80 cases and 80 controls will receive a clinical examination to confirm the presence or absence 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. Results to date can be found at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326349/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241190/, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885163/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036065/.

Lumara Health Inc.
Safety and Efficacy of Two Vaginal Products Versus Placebo in Patients With Vaginal Discomfort (2011 — 2012)
This study will evaluate the efficacy and safety of two vaginal products compared with that of placebo to determine if the two products are better than placebo in the relief of vaginal discomfort.
Primary Outcome Measures:
  1. Mean Marinoff Dyspareunia Scale Score (MDSS) at End of Treatment (12 Weeks) [ Time Frame: 12 weeks ]
    The MDSS consists of a participant rating of their dyspareunia (painful sexual intercourse) on a 0- to 3-point scale. Each numerical value on the scale coincides with a level of pain experienced during sexual intercourse; 0 = no dyspareunia (no pain with intercourse) and 3 = completely prevents intercourse
Secondary Outcome Measures:
  1. Change From Baseline in Marinoff Dyspareunia Scale Score at End of Treatment (12 Weeks) [ Time Frame: Baseline -12 Weeks ]
    0-3 scale with 0=no dyspareunia and 3= completely prevents intercourse
  2. Change From Baseline in Overall Vulvar Vestibulitis Syndrome (VVS)-Related Discomfort Visual Analog Scale (VAS) Score at End of Treatment (12 Weeks) [0 = No Discomfort and 100 = Most Severe Discomfort] [ Time Frame: 12 Weeks ]
  3. Change From Baseline in Overall Intercourse-Related Pain Visual Analog Scale (VAS) Score at End of Treatment (12 Weeks) [0 = No Pain and 100 = Most Severe Pain] [ Time Frame: 12 weeks ]
  4. Change From Baseline in Overall Vulvar Vestibulitis Symptoms Visual Analog Scale (VAS) Score at End of Treatment (12 Weeks) [0 = No Symptoms and 100 = As Bad as They Can be] [ Time Frame: 12 Weeks ]
  5. Change From Baseline in Tenderness (on a 0- to 3-point Scale) on Palpation at End of Treatment (12 Weeks) [Scale Rates the Severity of Pain; 0 =Absent and 3 = Severe] [ Time Frame: 12 Weeks ]

Lee Hullender Rubin, DAOM, LAc Oregon College of Oriental Medicine
Provoked, Localized Vulvodynia Treatment With Acupuncture and Lidocaine Pilot Study (2013 — 2017)
This is a randomized, controlled, single-blinded, pilot trial to study the feasibility and acceptability of acupuncture and 5% lidocaine. Patients will be recruited from the patient population of the Oregon Health & Science University Vulvar Health Clinic. Thirty (30) patients with PLV will be enrolled as study participants into the study. Fifteen (15) will be allocated in the treatment (classical) acupuncture + 5% lidocaine group and fifteen (15) will be allocated in the control (non-classical) acupuncture + 5% lidocaine group via a computer generated randomization program to balance allocation based on four variables: pain intensity, smoking status, body mass index, and pain duration. The acupuncturist will interview each patient and perform an exam of the pulse and tongue. A standardized acupuncture treatment will be assigned, and both groups will receive 18 acupuncture treatments that follow a standardized protocol on classical or non-classical acupuncture points, with or without mild electrical stimulation. All study participants will self-apply lidocaine cream to their genital region four times daily during the study.
Primary Outcome Measures:
  1. Tampon Test [ Time Frame: Weeks 1 and 12 study period ]
    Primary outcome variable will be to measure the change in the reported pain of the "Tampon Test" (mean at Week 1) to the reported pain of "Tampon Test" (mean of Week 12); Every week, study participants will be asked to fully insert and remove a tampon and rate the level of pain with insertion on a 10-point Visual Analog Scale (0 indicating no pain, 10 indication worst possible pain).
Secondary Outcome Measures:
  1. Cotton Swab test [ Time Frame: Weeks -4, -3, -2, -1, 0, 1, 12 or 13 and 24. ]
    Secondary outcome variable will compare the "Cotton Swab Test" with a blinded assessor reported pain at three timepoints. 1) change in reported pain at (mean at Weeks -2, -1, 0, and 1) to the reported pain (mean at Weeks 12 and 13; 2) change in reported pain (means Weeks -2, -1, 0, and 1) to the reported pain (mean at Week 24); 3) change in reported pain (mean at Week 12) to (mean at Week 24). Vestibular tenderness will be assessed by light touch with a cotton swab by a blinded assessor to the study participant's: 1) vestibule (cotton swab test) at four defined points (1:00, 5:00, 7:00, and 11:00); 2) the perineum; 3) labia majora (2:00 and 8:00), and 4) labia minora (4:00 and 10:00). Tenderness at each location will be rated by the Study Participant on a 10-point scale (0 indicating no pain, 10 indicating worst possible pain).
  2. Patient Reported Outcomes Measurement Information System (PROMIS) Scales [ Time Frame: At baseline visit, 6 weeks, 12 weeks, and 24 weeks ]
    Assess changes in scores quality of life, vaginal discomfort, pain intensity, pain interference and behavior, anxiety, and depression at 6 weeks, 12 weeks, and 24 weeks compared to baseline.
  3. Satisfaction [ Time Frame: Weeks 12 and 24 ]
    Using 5-point scales (Very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, Very dissatisfied), Study participants will be asked how satisfied they are with the study interventions and how satisfied they are with their pain relief.
  4. Expectation [ Time Frame: Week 1 ]
    Study participants will be asked about how much they 'expect' the study interventions will or will not help, how much they 'think' the intervention will or will not help, and how much they 'feel' about the intervention will or will not help via 10-point scales.
  5. Feasibility [ Time Frame: Weeks 12 and 24 ]
    Assess feasibility by the number of study participants enrolled.
  6. Acceptability [ Time Frame: Weeks 12 and 24 ]
    Assess acceptability by the number of study visits attended by participants enrolled.
  7. Tampon Test [ Time Frame: Weeks 1 and 6; Weeks 1 and 24 ]
    Secondary outcome variables will be to:
    1. measure the change in reported pain of the "Tampon Test" (mean at Week 1) to the reported pain of "Tampon Test" (mean of Week 6);
    2. measure the change in reported pain of the "Tampon Test" (mean at Week 1) to the reported pain of "Tampon Test" (mean of Week 24);
    3. measure the change in reported pain of the "Tampon Test" (mean at Week 12) to the reported pain of "Tampon Test" (mean of Week 24).
    Every week, study participants will be asked to fully insert and remove a tampon and rate the level of pain with insertion on a 10-point Visual Analog Scale (0 indicating no pain, 10 indication worst possible pain).
Other Outcome Measures:
  1. Traditional Chinese Medicine (TCM) Diagnosis Category [ Time Frame: Week 1 ]
    TCM Diagnosis Category will be recorded and tracked by the primary investigator to determine if it may be a potential predictor of treatment response.
  2. 24-hour mean pain score [ Time Frame: Baseline, Weeks 6, 12, and 24 ]
    In a daily pain diary, study participants will be asked to record the level of pain they are experiencing based via the 10-point VAS scale (0 indicates no pain, 10 indicates worst possible pain).
  3. Frequency of intercourse [ Time Frame: Baseline, Weeks 6, 12, and 24 ]
    In a daily pain diary, study participants will be asked to record if they engaged in intercourse within the last 24 hours.
  4. Intensity of Intercourse pain [ Time Frame: Baseline, Weeks 6, 12, and 24 ]
    In a daily pain diary, study participants will be asked to record the level of pain they are experienced with intercourse based via the 10-point VAS scale (0 indicates no pain, 10 indicates worst possible pain).

Michael Ingber, MD Morristown Medical Center
CO2 Laser vs Lidocaine for Vestibulodynia in Premenopausal Women (2022 — 2022)
The purpose of this study is to see if vaginal laser therapy with MonaLisa Touch® will be more effective in treating vestibulodynia than current treatment with a topical lidocaine ointment. Vestibulodynia is a common bothersome condition and is more likely to occur in women on hormonal contraceptive treatment. To date, there are no effective treatments that address the underlying causes of the disease. MonaLisa Touch® is a laser procedure that delivers CO2 laser energy to the vaginal wall tissue. This energy causes the patient's own body to regenerate collagen and blood vessels, changing the tissue to make it healthier. The MonaLisa Touch® technology may help vestibulodynia by potentially fixing the underlying cause. This may be more effective than using the topical lidocaine which makes the tissue numb.
Primary Outcome Measures:
  1. VAS [ Time Frame: 3 months ]
    visual analog pain scale to q-tip palpation
Secondary Outcome Measures:
  1. PFDI [ Time Frame: 3 months ]
    pelvic floor distress inventory

Colleen Kennedy, MD Assistant 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.

Jennifer Labus, PhD Adjunct 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.

Deriving Novel Biomarkers of Localized Provoked Vulvodynia Through Metabolomics: A Biological System Based Approach (2016 — 2018)
PROJECT SUMMARY Vulvodynia is a chronic pain disorder affecting up to 15% of women and resulting in substantial impairment in health related quality of life. Provoked Vestibulodynia (PVD), a form of localized provoked vulvodynia (formerly called vulvar vestibulitis syndrome) consists of severe pain upon vaginal penetration and objective findings of vulvar burning pain when touching the vulvar vestibule with a cotton swab in the absence of detectable infectious, neurological or immunological explanation The treatment of the disorder is hampered by a lack of knowledge regarding the biological mechanism underlying symptoms. The human vaginal microbiota play a key role in preventing a number of urogenital diseases. Research on the association between altered composition of the vaginal microbiome in vulvodynia is sparse, but provides tentative support for the involvement of microbiota. Discovering an association between microbiome and PVD has great implications for personalized prevention, practical, targeted diagnostic testing, and personalized therapy for girls and women with PVD. Research indicates brain regions involved in the processing/modulation of signals from the external genitals are altered in vulvodynia subjects and that these alterations correlate with subjective reports of pain and vaginal muscle tenderness. There is growing preclinical and emerging clinical evidence that the microbiota and their metabolites may play a significant role in the modulation of brain activity and central signaling systems, and a potential role in the etiology and pathophysiology of pain and psychiatric disorders. In the current proposal, we will assess the vaginal microbiota and plasma and vaginal metabolites of 50 female healthy controls and 50 PVD subjects. The PVD subjects will have also been enrolled in our extensive phenotyping study (Labus/Rapkin R01 HD076756) where we use brain imaging to assess the structure and function of the brain along with clinical, genetic, physiological, and biological parameters. This study will test the hypotheses that 1) Microbiota composition and/or metabolite profiles discriminate PVD patients from HCs as well as within PVD subjects, 2) Microbiota composition and/or metabolite profiles are correlated with PVD symptom severity, pressure pain sensitivity, perceived stress and trauma history, and 3) Microbiota composition and/or metabolite profiles are correlated with brain regions altered in PVD, suggesting a possible interaction between the microbiota and the brain structure/function.

Catherine Leclair, MD Professor of Obstetrics and Gynecology, School of Medicine Oregon Health and Science University
M-gCBT for Women With Provoked Localized Vulvodynia (2016 — 2019)
M-gCBT is a type of counseling that teaches women to have more control over their pain. Educational seminars teach women about the different aspects of PLV that affect emotional and physical health. Both groups will be given a binder containing course material at the first session and homework at each session that you will be asked to complete. The group education seminars will include an informational video clip reviewing an aspect of PLV and sexuality and will be followed by a group discussion facilitated by an instructor. Each session will involve a teacher and a small group of 6 to 12 women with PLV. Additionally, women in both groups will be asked to perform a weekly test to measure pain and to complete a daily diary.
Primary Outcome Measures: 
  1. Tampon Test [Time Frame: Change from time of enrollment until 6 months after study]. The change from baseline in pain measured by the Tampon Test at 6 months. The tampon test is a validated tool used to measure (vulva) vestibular skin pain by having participants insert and remove a tampon. Participants will be asked to rate their pain along a 100 mm Visual Analog Scale on a scale of 0 (No pain) to 10 (Pain as bad as you can imagine). This test will occur at baseline and 6 months follow up.
Secondary Outcome Measures:
  1. Sexual Distress Survey Response [Time Frame: Change from time of enrollment until 6 months after study]. Change from baseline in sexual distress at 6 months. Participants will complete a Female Sexual Distress Scale (FSDS) survey to rate their feelings associated with sexual activities; range 0 (better outcome) - 52 (worse outcome). The FSDS surveys will be completed at baseline and 6 months follow up. A negative change in FSDS score from baseline indicates less sexual distress over time (better outcome) and a positive change in FSDS score from baseline indicates more sexual distress over time (worse outcome).
  2. Sexual Function Questionnaire Response [Time Frame: Change from time of enrollment until 6 months after study]. Change from baseline in sexual function at 6 months. Participants will complete a Female Sexual Function Index (FSFI) survey which asks questions about participants sexual feelings over the past 4 weeks; range 2 (worse outcome) - 95 (better outcome). The FSFI surveys will be completed at baseline and 6 months follow up. A negative change in FSFI score from baseline indicates less sexual function over time (worse outcome) and a positive change in FSFI score from baseline indicates more sexual function over time (better outcome).
  3. Depression Questionnaire Response [Time Frame: Change from time of enrollment until 6 months after study]. Change from baseline in depression at 6 months. Participants will complete the Beck Depression Inventory (BDI-PC) questionnaire, which consists of 21 groups of statements where participants selects which statement best describes how they have been feeling during the past 2 weeks. Total score = sum of 21 statement subscales; range 0 (better outcome) - 63 (worse outcome). The BDI-PC surveys will be completed at baseline and 6 months follow up. A negative change in BDI-PC score from baseline indicates less depression over time (better outcome) and a positive change in BDI-PC score from baseline indicates more depression over time (worse outcome).
  4. Anxiety Questionnaire Response [Time Frame: Change from time of enrollment until 6 months after study]. Change from baseline in anxiety at 6 months. Participants will complete the General Anxiety Disorder-7 (GAD-7) scale questionnaire. The GAD-7 consists of 7 problems where participants rate how often they have been bothered by those problems during the past 2 weeks. Total score = sum of 7 subscales; range 0 (better outcome) - 21 (worse outcome). The GAD-7 surveys will be completed at baseline and 6 months follow up. A negative change in GAD-7 score from baseline indicates less anxiety over time (better outcome) and a positive change in GAD-7 score from baseline indicates more anxiety over time (worse outcome).
  5. Pain Catastrophizing Scale Response [Time Frame: Change from time of enrollment until 6 months after study]. Change from baseline in pain catastrophizing at 6 months. Participants will complete the Pain Catastrophizing Scale survey. The survey consists of thirteen statements describing different thoughts and feelings that may be associated with pain. Total score = sum of 13 statement subscales; range 0 (better outcome) - 52 (worse outcome). The pain catastrophizing surveys will be completed at baseline and 6 months follow up. A negative change in score from baseline indicates less pain catastrophizing over time (better outcome) and a positive change in score from baseline indicates more pain catastrophizing over time (worse outcome).
  6. Quality of Life Questionnaire Response [Time Frame: Change from end of study until 6 months after study]. Perceived treatment improvement and satisfaction in quality of life questionnaire. Questionnaires for quality of life at end of group intervention and at 3 months and 6 months follow up.

Remote Mindfulness Education PLV (2018 — 2022)
The purpose of study is to evaluate the effectiveness of a remotely delivered mindfulness intervention combined with education for the treatment of the pain and distress associated with Provoked Localized Vulvodynia (PLV). Women with PLV will be randomized to either an app- based mindfulness program (Headspace®) with online education or online education only. Pain and sexual distress with be evaluated through a number of measures. The primary outcome of the study will be the change in distress relating to sexual activity over the 8-week intervention period, which will be measured by a change (reduction) in the Female Sexual Distress Scale (FSDS). Participants will additionally perform a weekly Tampon Test and fill out a weekly survey regarding their perceived pain as well as the frequency of use and completion of the weekly education materials.
Primary Outcome Measures:
  • Change in Female Sexual Distress Scale (FSDS) at 8 weeks [Time Frame: Baseline & 8 weeks]. The change in distress relating to sexual activity, measured by a change in the FSDS from baseline (study enrollment) survey. Participants will complete a Female Sexual Distress Scale (FSDS) survey to rate their feelings associated with sexual activities. Survey questions are on a number scale of 0 (Never) to 4 (Always). The FSDS surveys will be completed at baseline and 8 weeks after study enrollment.
Secondary Outcome Measures:
  • Change in Tampon Test Pain Scores at 8 weeks [Time Frame: Baseline & 8 weeks]. The change in tampon test pain scores (a validated tool that measures introital pain). The tampon test is a validated tool used to measure (vulva) vestibular skin pain by having participants insert and remove a tampon. Participants will be asked to rate their pain along a 100 mm Visual Analog Scale on a scale of 0 (No pain) to 10 (pain as bad as you can imagine). This test will occur at baseline and 8 weeks after enrollment.

Vestibulectomy Surgical Techniques Comparison Study (2022 — 2022)
Vestibulectomy: A Prospective Comparison of Two Surgical Techniques for the treatment of Provoked Localized Vulvodynia (PVD). Primary Outcome Measures:
  1. Change in Tampon Test pain scores from baseline to 3 months [ Time Frame: Baseline visit to 3 months after surgery ]
    The change from baseline in pain measured by the Tampon Test at 3 months after surgery. The tampon test is a validated tool used to measure (vulva) vestibular skin pain by having participants insert and remove a tampon. Participants will be asked to rate their pain along a 100 mm Visual Analog Scale on a scale of 0 (No pain) to 10 (Pain as bad as you can imagine). This test will occur at baseline and 3 months follow up.
  2. Change in pain scores from baseline to 6 months [ Time Frame: Baseline visit to 6 months after surgery ]
    The change from baseline in pain measured by the Tampon Test at 6 months after surgery. The tampon test is a validated tool used to measure (vulva) vestibular skin pain by having participants insert and remove a tampon. Participants will be asked to rate their pain along a 100 mm Visual Analog Scale on a scale of 0 (No pain) to 10 (Pain as bad as you can imagine). This test will occur at baseline and 6 months follow up.
  3. Change in pain scores from baseline to 12 months [ Time Frame: Baseline visit to 12 months after surgery ]
    The change from baseline in pain measured by the Tampon Test at 12 months after surgery. The tampon test is a validated tool used to measure (vulva) vestibular skin pain by having participants insert and remove a tampon. Participants will be asked to rate their pain along a 100 mm Visual Analog Scale on a scale of 0 (No pain) to 10 (Pain as bad as you can imagine). This test will occur at baseline and 12 months follow up.

Cherie LeFevre, MD St. Louis University
Vulvodynia: Identification of Potential Relevant Biomarkers (2016 — 2020)
Sphingosine-1-phosphate (S1P) is a potent anti-apoptotic sphingolipid with potent pro-inflammatory actions which are driven in most part by activation of the S1P receptor subtype S1PR158. Biologically active S1P is generated by the phosphorylation of sphingosine, catalyzed by two sphingosine kinases (SphK1, SphK2). S1P levels are further regulated by its dephosphorylation by two phosphatases (SGPP1 and SGPP2) and through degradation by one lyase (SGPL1). Once released S1P initiates signaling through a family of five cognate G protein-coupled receptors (S1PR1-5), leading to various cellular responses9. S1P signaling has important roles in inflammation and cancer. S1P acting via the S1PR1 has been implicated in the development of pain of several etiologies as discovered by Salvemini and coworkers and subsequently extended by others. FTY720 (fingolimod/Gilenya®) is the first orally available agent approved by the FDA for the treatment of relapsing-remitting multiple sclerosis (MS). The work by Salvemini's group in providing a mechanistic basis for understanding chronic pain through the S1P/S1PR1 axis, provides a promising therapeutic target for the use of agents like FTY720 as a novel treatment for pain. Ongoing work by the Salvemini's lab suggests that increased expression of S1PR1 in circulating peripheral blood leukocytes (PBLs) may provide a relevant biomarker to predict severity and pain induction outcomes as well as predict patient responses to anti-S1PR1 approaches.
Primary Outcome Measures: 1. S1PR1 elevation [Time Frame: up to one year.] S1PR1 is elevated in the peripheral blood leukocytes (PBLs) of patients with vulvodyna-related pain.
Biospecimen Retention:   Samples Without DNA
Peripheral blood leukocytes (PBLs) may provide a relevant biomarker to predict severity and pain induction outcomes as well as predict patient responses to anti-S1PR1 approaches.

Ahinoam Lev-Sagie, MD
The Reciprocal Relations Between Psychosocial Characteristics and the Progression of Vestibulodynia (2016 — 2022)
The proposed study will evaluate how personality characteristics, cognitive factors and the emotional and behavioral responses of patients with provoked vestibulodynia (localized provoked vulvodynia) influence the natural history of the syndrome, patients' adherence to therapeutic interventions, provoked pain levels, pelvic floor rehabilitation, emotional health and sexual functioning. Primary Outcome Measures:
  1. Change of measure of Q tip test assessing pain intensity [ Time Frame: Change in measure between recruitment to 3 months, 6 months , 9 months and 12 months ]
    The exam is performed by touching the vestibule with a cotton-tip applicator in 6 defined points (2,5,6,7, 10 and 12),while the patient is being asked to rate the intensity of pain verbally from 0 to 10 at each point.
Secondary Outcome Measures:
  1. Measurement of vestibular tenderness using a vulvar algesiometer [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months. ]
  2. Change of pain using Visual analog scale [ Time Frame: Change in VAS between recruitment to 3 months, 6 months , 9 months and 12 months ]
  3. Adherence to therapy [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months. ]
    Adherence to therapy will be assessed by calculating attendance to planed appointments (physical therapy, medical appointments and LLL treatments)
  4. Female sexual function index questionnaire [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months. ]
  5. Pelvic floor hypertonicity measurements [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months. ]
    Pelvic floor muscle tonicity will be evaluated using manual palpation of the muscles by the physician.
  6. Brief Symptom Inventory-18 questionnaire (evaluating emotional symptoms) [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months. ]

Subtypes of Provoked Vestibulodynia (2016 — 2022)
The proposed study will evaluate a clinical algorithm for the diagnosis and treatment of provoked vestibulodynia (PVD). The algorithm, distinguishes between four subtypes of PVD: hormonally mediated PVD, hypertonic pelvic floor dysfunction, congenital neuroproliferative PVD and acquired neuroproliferative PVD, based on a patient's history and physical exam. The study will follow patients diagnosed with PVD, for one year, and evaluate the treatment outcome in the different subgroups. Investigators hope that conducting a prospective study, showing clinical benefit and improved outcome for patients classified according to this method may change the common practice of "trial and error" based treatment, and will improve clinical results.
Primary Outcome Measures:
  1. Change of measure of Q tip test assesing pain intensity [ Time Frame: Change in measure between recruitment to 3 months, 6 months 6 months, 9 months and 12 months ]
    The exam is performed by touching the vestibule with a cotton-tip applicator in 6 defined points (2,5,6,7, 10 and 12),while the patient is being asked to rate the intensity of pain verbally from 0 to 10 at each point.
Secondary Outcome Measures:
  1. Visual analog scale (VAS) [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months ]
  2. Measurement of vestibular tenderness using a vulvar algesiometer [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months ]
  3. QOL parameters (questionnaire) [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months ]
  4. Improvement in condition using a verbal report [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months ]
    in the follow-up appointments, patients will be asked to estimate the change in their condition, using percentage scaling: no or little improvement (<30%), moderate improvement (30-80%), much improvement (>80%) and total improvement (100%).
  5. Tampon test [ Time Frame: Every month for one year ]
    Patients will be provided with original Regular Tampax Tampons and will be instructed to deposit the tampon fully into the vagina above the level of the hymeneal ring with the applicator, remove the applicator from the vagina, and finally remove the tampon from the vagina by traction on the tampon string, immediately after vaginal insertion, without any lubrication. Patients will record the degree of pain during the entire insertion- removal experience, on a 0-10 pain numeric scale, with 0 meaning no pain, and 10 meaning the worst possible pain.
  6. Female sexual function index [ Time Frame: Every 3 months for 1 year- 0, 3 months, 6 months, 9 months and 12 months ]

William Maixner, DDS, PhD Director 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, PhD Assistant 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.

A Randomized Clinical Trial for Women With Vulvodynia (2008 — 2016)
Many treatments used for women with vulvodynia are based solely upon expert opinion. This randomized trial aimed to test the relative efficacy of cognitive-behavioral therapy (CBT) and supportive psychotherapy (SPT) in women with vulvodynia. Of the 50 participants, 42 (84%) completed 10-week treatments and 47 (94%) completed one-year follow-up. Mixed effects modeling was used to make use of all available data. Participants had statistically significant decreases in pain severity (p's<.001) with 42% of the overall sample achieving clinical improvement. CBT, relative to SPT, resulted in significantly greater improvement in pain severity during physician examination (p=.014), and greater improvement in sexual function (p=.034), from pre- to post-treatment. Treatment effects were well maintained at one-year follow-up in both groups. Participants in the CBT condition reported significantly greater treatment improvement, satisfaction and credibility than participants in the SPT condition (p's<.05). Findings from the present study suggest that psychosocial treatments for vulvodynia are effective. CBT, a directed treatment approach that involves learning and practice of specific pain-relevant coping and self-management skills, yielded better outcomes and greater patient satisfaction than a less directive approach. Primary Outcome Measures: 1. Pain Severity [Time Frame: Measured at 1-year follow-up.]
Secondary Outcome Measures: 1. Sexual Functioning [Time Frame: Measured at 1-year follow-up.] 2. Emotional Functioning [Time Frame: Measured at 1-year follow-up.]

Emeran Mayer, MD Professor of Psychology and Physiology, Director University of California, Los Angeles
Multi Modal Imaging: An MRI Study to Investigate Differences in the Structure and the Function of the Brain at Rest. (MMI) (2012 — 2016)
The study involves 2 visits. The screening visit is about 90 minutes and involves signing the consent, completing questionnaires, a medical history, modified physical exam and psychological interview to identify stressors, anxiety, depression and other conditions. The second visit is the MRI visit (both functional and structural) and also will take about 90 minutes, with the scanning lasting about 45 minutes. There are questionnaires and a measure of skin conductance also. We have added a single stool sample for microbiota analysis and a food frequency questionnaire in the healthy control and IBS populations.
Primary Outcome Measures:
  1. Resting state networks [ Time Frame: within 1 week of scanning visit ]
    The resting state functional MRI scan will be done to assess differences in the resting state networks in subjects with chronic pain conditions in comparison to healthy controls.

Ipsen Medical Director San Diego, Sexual Medicine; Center for Vulvovaginal Disorders; Omaha OB-GYN Associates, PC; The Center for Vulvovaginal Disorders
Validation of Patient Reported Outcome Measures for Use in Vulvodynia (2018 — 2019)
The overall aim of this project is to demonstrate content validity and usability of the modified Vulvar Pain Assessment Questionnaire (mVPAQ), the modified Female Sexual Function Index (mFSFI), and pain on intercourse Numeric Rating Scale (NRS) for adult patients with Vulvodynia.
Primary Outcome Measures:
  1. Validation of mVPAQ [Time Frame: 1 week]. Cognitive debrief and usability through interviews and completion of an electronic diary.
  2. Validation of mFSFI [Time Frame: 1 week]. Cognitive debrief and usability through interviews and completion of an electronic diary.
  3. Validation of Pain on Intercourse Numeric Rating Scale (NRS) [Time Frame: 1 week]. Cognitive debrief and usability through interviews and completion of an electronic diary. Pain on Intercourse NRS that describes pain experienced during this sexual intercourse episode by number. The higher is the number the worse is pain.
Secondary Outcome Measures: Vulvar pain NRS [Time Frame: 1 week]. Assess understanding of the appropriateness of the vulvar pain NRS through interview and completion of an electronic diary.

Sukhbir Mokha, PhD Professor 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.

Mélanie Morin, PT, PhD Université de Sherbrooke
Pelvic Floor Myofascia: A New Player Involved in Vulvodynia (2022 — 2022)
Vulvodynia, chronic vulvar pain, is identified as a neglected condition by the World Health Organization and the National Institutes of Health. This is explained by a poor understanding of the pathology and compromised diagnosis, leading to poor therapeutic management and a lack of effective treatment options. Provoked vestibulodynia, characterized by pain at the entry of the vagina elicited by pressure and penetration, is the leading subtype of vulvodynia. Recent scientific advances have highlighted the importance of the pelvic floor muscles and the potential role of the surrounding connective tissues (the fascias). Therefore, a new potential contributor is emerging in the etiology of provoked vestibulodynia, namely the pelvic myofascial tissues. The first objective of this study is to develop transperineal ultrasound evaluation techniques (B-mode and ultrasound elastography/shearwave) to assess the morphometry (thickness) and viscoelasticity (shear strain and shear elastic modulus) of the pelvic myofascial tissues and to examine the intra- and inter-rater reliability in asymptomatic controls. The second objective of this study is to examine the potential contribution of the pelvic myofascial tissues to the etiology of provoked vestibulodynia. To do this, morphometric (thickness) and viscoelastic (shear strain and shear elastic modulus) ultrasound imaging features of the pelvic myofascial structures will be compared in women with provoked vestibulodynia and asymptomatic controls. The association between ultrasound data and clinical characteristics will also be investigated. The clinical characteristics will include self-administered psychosexual questionnaires.
Primary Outcome Measures:
  1. Morphometry - muscle thickness [Time Frame: Baseline evaluation]
    Muscle thickness will be measured by transperineal ultrasound in B-mode.
  2. Viscoelasticity - shear strain [ Time Frame: Baseline evaluation ]
    Shear strain will be measured by transperineal ultrasound with elastography.
  3. Viscoelasticity - shear elastic modulus [ Time Frame: Baseline evaluation ]
    Shear elastic modulus be measured by transperineal ultrasound with elastography/shearwave.
 
Secondary Outcome Measures:
  1. Pain intensity [ Time Frame: Baseline evaluation ]
    To assess pain intensity during intercourse (Numerical Rating Scale (NRS), ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain possible).
  2. Pain quality [ Time Frame: Baseline evaluation ]
    To assess pain quality including its sensory, affective and evaluative components using the McGill-Melzack pain questionnaire (MPQ). Minimum value: 0, Maximum value: 78, higher scores indicate worse pain.
  3. Depression symptoms [ Time Frame: Baseline evaluation ]
    To address depressive symptoms according to the Beck Depression Inventory (BDI-II). Minimum value: 0, Maximum value: 63, higher scores indicate more severe depression symptoms.
  4. Sexual function [ Time Frame: Baseline evaluation ]
    To assess sexual function using the Female Sexual Function Index (FSFI). Minimum value: 2, Maximum value: 36, Inferior scores indicate lower sexual function.
  5. Sexual distress [ Time Frame: Baseline evaluation ]
    To assess sexual distress (Female Sexual Distress Scale - FSDS). Minimum value: 0, Maximum value: 52, Superior scores indicate higher sexually related distress.
  6. Pain catastrophizing [ Time Frame: Baseline evaluation ]
    Pain catastrophizing assessed with the Pain Catastrophizing Scale (PCS). Minimum value: 0, Maximum value: 52, Superior scores indicate higher pain catastrophizing.
  7. Fear of pain [ Time Frame: Baseline evaluation ]
    Fear of pain according to the Pain Anxiety Symptoms Scale (PASS-20). Minimum value: 0, Maximum value: 100, Superior scores indicate higher fear of pain.

Efficacy of High Intensity Laser for Provoked Vestibulodynia (Laser_RCT) (2022 — 2022)
Vulvodynia, a chronic vulvar pain condition, affects between 8 and 18% of reproductive-aged women. The main subtype of vulvodynia is provoked vestibulodynia (PVD), which is characterized by a sharp or burning pain at the vaginal opening while applying pressure to the vulvar vestibule or attempting vaginal penetration. Women suffering from PVD experience greater psychological distress, a worsened quality of life and overall well-being as well as sexual dysfunctions for both the women and their intimate partners. Women suffering from PVD have limited treatment options, and some women have persistent pain despite the available treatment options. Therefore, a new therapeutic avenue needs to be explored. High intensity laser therapy (HILT), a non-invasive and non-ablative laser technique, was found to be effective in several chronic pain conditions. Our randomized pilot study confirmed that HILT is feasible for treating PVD. The promising findings obtained provided support for conducting this large multicenter randomized controlled trial.
Primary Outcome Measures:
  1. Change in pain intensity during intercourse [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore changes in pain intensity during intercourse (Numerical Rating Scale (NRS), ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain ever)
Secondary Outcome Measures  :
  1. Change in pain quality [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore changes in the sensory, affective, and evaluative components of pain (McGill-Melzack Questionnaire). Minimum value: 0, Maximum value: 78, higher scores indicate a worse outcome (higher pain).
  2. Change in sexual function [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore changes in sexual function (Female Sexual Function Index - FSFI). Minimum value: 2, Maximum value: 36, lower scores indicate a worse outcome (low sexual function).
  3. Change in sexual distress [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore changes in sexual distress (Female Sexual Distress Scale - FSDS). Minimum value: 0, Maximum value: 52, higher scores indicate a worse outcome (higher sexually-related distress).
  4. Change in pain catastrophizing [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore changes in pain catastrophizing (Pain Catastrophizing Scale - PCS). Minimum value: 0, Maximum value: 52, higher scores indicate a worse outcome (higher pain catastrophizing).
  5. Change in fear of pain [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore changes in fear of pain (Pain Anxiety Symptoms Scale - PASS-20). Minimum value: 0, Maximum value: 100, higher scores indicate a worse outcome (higher fear of pain).
  6. Change in cognitions regarding vaginal penetration [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore the cognitions of women towards vaginal penetration (Vaginal penetration cognition questionnaire (VPCQ)). Minimum value: 0, Maximum value: 240, higher scores show higher levels of perceived penetration control.
  7. Change in the life impact of pelvic pain [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore the change in the life impact of pelvic pain (Pelvic Pain Impact Questionnaire). Minimum value: 0, Maximum value: 32, higher scores indicate that the pelvic pain of the participants has a strong impact on their life.
  8. Change in intercourse self-efficacy [ Time Frame: Baseline, 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To explore the change self-efficacy regarding painful intercourse (Painful Intercourse Self-Efficacy Scale). Minimum value: 20, Maximum value: 100, higher scores indicate higher self-efficacy.
  9. Level of satisfaction with treatment [ Time Frame: 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To determine acceptability by measuring the participants' satisfaction with the treatment on a Numeric Rating Scale (NRS) ranging from 0 (completely dissatisfied) to 10 (completely satisfied).
  10. Patient's global impression of change [ Time Frame: 2-week post-treatment evaluation, 6-months follow-up assessment ]
    To examine patient self-reported improvement (Patient's Global Impression of Change - PGIC) ranging from "very much worse" to "very much improved" on a 7-point scale.

High-level Laser for Provoked Vestibulodynia (2020 — 2022)
This is a randomized feasibility and acceptability study investigating the effects of laser treatment in women suffering from provoked vestibulodynia compared to a sham-laser treatment. Participants will be randomized into the laser group or sham-laser group. The laser group will receive 12 sessions of real high-level laser therapy (HILT) (30-minutes biweekly for 6 consecutive weeks). The sham-laser group will receive 12 sessions (30-minutes biweekly for 6 consecutive weeks) of laser therapy using a deactivated probe. Outcomes measures will be assessed at baseline and at post-treatment and will include: feasibility and acceptability variables, pain, sexual function, sexual distress, psychological variables and perceived improvement after the treatment.
Primary Outcome Measures:
  1. Adherence rate [Time Frame: 2-week post-treatment evaluation]
    To determine acceptability by assessing adherence to treatment sessions
  2. Level of satisfaction with the treatment [Time Frame: 2-week post-treatment evaluation]
    To determine acceptability by measuring the participants' satisfaction with the treatment on a numeric rating scale ranging from 0 (completely dissatisfied) to 10 (completely satisfied)
  3. Willingness to recommend the treatment [Time Frame: 2-week post-treatment evaluation]
    To determine acceptability by assessing whether the participant would recommend the treatment.
  4. Rate of adverse events [Time Frame: 2-week post-treatment evaluation]
    To document any adverse events.
  5. Blinding effectiveness [Time Frame: 2-week post-treatment evaluation]
    To assess the feasibility of maintaining blinding to group allocation for the therapists, assessors and therapists. Evaluated by asking the question: ''What treatment do you think you have received / given? ''
  6. Recruitment rate [Time Frame: Baseline to 2-week post-treatment evaluation]
    To assess the recruitment rate including the barriers and reasons for refusing to participate as well as the reasons for exclusion
  7. Completion and dropout rates [Time Frame: 2-week post-treatment evaluation]
    To evaluate completion and dropout rates based on the completion of the post-treatment evaluation.
  8. Completeness of data [Time Frame: Baseline to 2-week post-treatment evaluation]
    To examine the percentage of completed outcome measures.
Secondary Outcome Measures:
  1. Change in pain intensity during intercourse [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in pain intensity during intercourse (Numerical Rating Scale, ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain ever)
  2. Change in sexual function [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in sexual function (Female Sexual Function Index). Minimum value: 2, Maximum value: 36 and lower scores mean worst outcome (low sexual function).
  3. Change in sexual distress [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in sexual distress (Female Sexual Distress Scale ). Minimum value: 0, Maximum value: 52, higher scores mean worst outcome (higher sexually related distress).
  4. Change in pain quality [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes on the sensory, affective and evaluative components of pain (McGill-Melzack Questionnaire). Minimum value: 0, Maximum value: 78, higher scores mean worst outcome (higher pain).
  5. Patient's global impression of change [Time Frame: Baseline to 2-week post-treatment evaluation]
    To examine patient self-reported improvement (Patient's Global Impression of Change ranging from "very much worse" to "very much improved" on a 7-point scale.
  6. Change in fear of pain [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in fear of pain (Pain Anxiety Symptoms Scale (PASS-20)). Minimum value: 0, Maximum value: 100, higher scores mean worst outcome (higher fear of pain).
  7. Change in pain catastrophization [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in pain catastrophization (Pain Catastrophizing Scale (PCS)). Minimum value: 0, Maximum value: 52, higher scores mean worse outcome (higher pain catastrophization)
  8. Change in vulvar pain sensitivity [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in vulvar pain sensitivity (algometer)
  9. Change in vulvar blood circulation [Time Frame: Baseline to 2-week post-treatment evaluation]
    To explore changes in vulvar blood circulation using the laser speckle. Vulvar vestibule blood perfusion is expressed in arbitrary perfusion units (APUs).

Andrea Nackley Neely, PhD Assistant 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 etiology 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 genetic 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 nearly 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 directly 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 genetic 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.

Mary Ojo-Carons, MD
Effects of Flourish HEC on Localized Provoked Vulvodynia (2022 — 2022)
Vulvodynia is a chronic pain condition affecting the tissues of the external genitalia in women. Localized provoked vulvodynia (LPV) is a specific subset of vulvodynia in which pain occurs upon touching specific sites on the vestibule (or, less commonly, another defined area), and which has been present for more than three months without a known cause. LPV is characterized both by allodynia (pain in response to a normally non-painful stimulus) and hyperalgesia (excessive pain response), leading to pain with sex, tampon use, and even with activities of daily life, such as sitting or wearing tight clothing. It is becoming accepted that LPV occurs as a type of hypersensitivity to Candida and other antigens which occurs in susceptible women. LPV is an inflammatory condition with increased levels of B-cells, T-cells, and macrophages in tender areas vs. non-tender areas. The inflammatory process sparks neuroproliferation - growth of new nerve endings - which increases the density of nerve fibers in tender spots, especially in areas of lymphoid aggregates. The vulvar and vaginal microbiomes are connected to each other; species found in one are often found in the other. In fact, Jayaram et al. showed that all vaginal species were also found on the vestibule, and the dominant vaginal species is also the dominant vestibular species, suggesting that vaginal secretions are a major contributor to the vestibular/vulvar microbiome. Three recent studies have examined the link between vulvodynia and the vaginal microbiome. Results vary by study, with one showing differences in the present vaginal microbiomes between women with vulvodynia and healthy women, and others not showing differences. These may be explainable by inclusion/exclusion criteria (two studies excluded women with active yeast infection; one study specified studying generalized, not localized, vulvodynia; while the others did not specify). But it is agreed that past alterations in the microbiome primed women for excessive pain in response to gentle stimuli. Vaginal microbiome composition is known to affect immune activation in the vagina and vulva. Campisciano and colleagues showed that vaginal dysbiosis is associated with elevated levels of interleukin (IL)-1ra and IL-2, and lower levels of fibroblast growth factor (FGF)-beta and granulocyte-macrophage colony stimulating factor (GM-CSF) than observed in healthy vaginas. Another study by the same group reported associations between vaginal microbiome composition and IL-1alpha and IL-18. Doerflinger showed activation of the innate immune response by Lactobacillus iners (intermediate flora) and Fannyhessea vaginae (associated with bacterial vaginosis), but not L. crispatus (healthy flora). Of greatest relevance, Falsetta and colleagues investigated expression and activation of the toll-like receptor family and found seven of them to be expressed at higher levels in tissue biospies from tender spots in LPV than in control tissue, and that exposure to HIV increased expression of TLR7 expression and the downstream inflammatory molecule IL-6. Notably, no studies have examined whether improving the vaginal microbiome might lead to reductions in immune signaling in vulvodynia. Taken together, it is reasonable to hypothesize that the constitution of the vaginal microbiome may influence the hypersensitivity to allergens that comprises the cause of LPV. It is also possible that improving the vaginal microbiome may reduce immune cell recruitment and activation, reducing pain. It is predicted that using sequencing-based technology, differences between the vaginal microbiomes of women with LPV and those without will be detectable. Furthermore, its is predicted that using an over-the-counter feminine hygiene system designed to support a healthy vulvovaginal microbiome will reduce pain in women with LPV over and above any reductions observed with standard-of-care treatment. The investigators recently conducted an 11-week pilot study of similar design. Women with recurrent bacterial vaginosis (BV) were recruited to use the Flourish Vaginal Care System® for 11 weeks. Primary outcomes were vaginal fluid pH and whether or not women had BV recurrence. By the end of the study, the average vaginal fluid pH had fallen from mean (SD) of 4.54 (0.53) at week 0 to 4.08 (0.40) at week 11. At baseline, 30% of women had active BV. (These women were treated with standard of care oral metronidazole). The number of BV-positive women steadily declined until 5 weeks, at which point no woman had BV. There was no recurrence of BV in any woman through the end of the study. Women reported fewer vulvovaginal symptoms throughout the study. An ad hoc follow-up phone survey a year later showed that only one participant had a recurrence of BV since the end of the study. This study shows that the system we propose to use in the present study is able to effect positive changes in the vaginal microbiome. A follow-up trial at the same center examining the vaginal microbiome using the same system for 6 months has shown very low recurrence rates, based on preliminary analysis, less than 20% in 6 months, compared with other studies showing 3-month recurrence rates of 43% or 62%. This study, which has completed data collection but has not yet been published, also showed that the vaginal microbiome was in a healthy or intermediate community state type (CST; not BV) during use of the system, though it took over 5 weeks of usage for one woman to move from a BV-like CST to a healthy CST. A similar study is underway using the "Flourish HEC" system - a nearly identical kit with a different vaginal moisturizing gel, gentler for those with sensitivities. To date, five participants are enrolled, and only the initial microbiome tests are available. However, study subjects are reporting that they are feeling good while using the system. It is this Flourish HEC system that will be tested in the present study. We emphasize that the vaginal care system is not intended to modify the body; it has no active drug components. Instead, it is a hygiene system that mimics the proper vaginal environment for a healthy microbiome to develop and thrive. The investigators hypothesize that regular use of the Flourish HEC Vaginal Care System by women with LPV for three months will colonize the vagina and vulva with healthy bacteria, and that this will reduce inflammation, immune system activation, and neuroproliferation, ultimately reducing pain.
Primary Outcome Measures:
  1. Vaginal microbiome in women with localized provoked vulvodynia (LPV) [Time Frame: Baseline]
    Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance.
  2. Changes in the vaginal microbiome in women with localized provoked vulvodynia (LPV) with and without Flourish HEC [Time Frame: Baseline to 6 weeks.]
    Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance. Changes in these values from baseline to 6 weeks will be compared in women using or not using the Flourish HEC system.
  3. Changes in the vaginal microbiome in women with localized provoked vulvodynia (LPV) with and without Flourish HEC [Time Frame: Baseline to 3 months.]
    Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance. Changes in these values from baseline to 3 months will be compared in women using or not using the Flourish HEC system.
  4. Changes in the vaginal microbiome in women with localized provoked vulvodynia (LPV) with and without Flourish HEC [Time Frame: 6 weeks to 3 months.]
    Using whole-genome sequencing, all microbes present in the vaginal microbiome will be identified and reported for relative abundance. Changes in these values from 6 weeks to 3 months will be compared in women using or not using the Flourish HEC system.
  5. Pain intensity by cotton swab test [Time Frame: Baseline to 2 weeks to 6 weeks to 3 months.]
    The PI will gently palpate the study participant at selected vulvar and extra-vulvar sites using a cotton swab; the participant will report pain on a scale of 0 (no pain) to 10 (most intense pain imaginable). Changes in pain intensity per location from baseline to 2 weeks, 6 weeks, and 3 months will be compared between women using and not using the Flourish HEC system.
  6. Vulvovaginal symptoms questionnaire (VSQ) and addendum [Time Frame: Baseline to 2 weeks to 6 weeks to 3 months.]
    Study participants responses to questions on the previously-validated VSQ and not-yet-validated additional questions will be collected on a 4-point Likert scale (0=not at all, 3 = all the time), except when questions are binary by nature. Change in question scores between timepoints will be compared between women who use and women who do not use the Flourish HEC system.
Secondary Outcome Measures:
  1. Treatment escalation [Time Frame: Baseline to 2 weeks to 6 weeks to 3 months.]
    A typical vulvodynia patient is started on a mild treatment, then escalated over time if symptoms do not improve. Treatment escalation will be compared between women who use and women who do not use the Flourish HEC system.

Kenneth Peters, MD William Beaumont Hospitals
CC-10004 For The Treatment Of Vulvodynia (2008 — 2014)
CC-10004 is a well-tolerated, selective PDE4 inhibitor with a demonstrated inhibitory effect on inflammatory mediators and is under development for the treatment of inflammatory and immune mediated conditions. This is an open-label, one arm, phase II study at William Beaumont Hospital. Twenty female subjects aged 18 or older meeting criteria for diagnosis of vulvodynia or vulvar vestibulitis (vestibulodynia) will be treated with CC-10004 at 20mg orally twice a day for 12 weeks.The patient will be seen for a total of ten visits by the study coordinator. The primary efficacy measure was a Global Response Assessment (GRA), a subject completed questionnaire that measures improvement in overall symptoms. The GRA is a 7-point scale the allows the subject to respond to the question: "As compared to when you started the study, overall how do you feel? The responses are: Markedly Improved - 7, Moderately Improved - 6, Mildly Improved - 5, Same - 4, Mildly Worse - 3, Moderately Worse - 2, Markedly Worse - 1. The primary outcome showing response to treatment was the number of subjects that were moderately or markedly improved on the GRA scale.

Barbara Reed, MD Professor 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.

Characterization of Pain Processing in Vulvodynia (2005 — 2011)
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.

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.

Judith Schlaeger, PhD, CNM, LAc University of Illinois at Chicago
Acupuncture for the Treatment of Vulvodynia (2014 — 2014)
A randomized controlled pilot study was conducted to evaluate the effect of an acupuncture protocol for the treatment of vulvodynia. Hypotheses:
  1. Acupuncture reduces vulvar pain and dyspareunia in women with vulvodynia.
  2. Acupuncture increases sexual function in women with vulvodynia.
Primary Outcome Measures:
  1. vulvar pain [ Time Frame: Baseline and 5 weeks ]
    Change from baseline in The Short Form McGill Pain Questionnaire at 5 weeks
Secondary Outcome Measures:
  1. Dyspareunia [ Time Frame: Baseline and 5 weeks ]
    Change from baseline in the pain subscale of the Female Sexual Function Index at 5 weeks
Other Outcome Measures:
  1. Female sexual function [ Time Frame: Baseline and 5 weeks ]
    Change from baseline in the total score of the Female Sexual Function Index at 5 weeks

Acupuncture for Vulvodynia: A Pre-pilot Study (2016 — 2017)
Vulvodynia is a women's pain condition. Women have pain in their vulva, the area in their genitals between the vagina and labia (lips of the vagina). They also have pain when they have sexual intercourse or insert anything in the vagina. Sometimes they have so much pain, that they cannot have sex. This research is being done for two reasons. The first reason is to test a set of special needles called double-blinded acupuncture needles to give acupuncture treatments (one is a real needle and the other is a fake needle). The second reason is to develop a protocol (checklist) that will be used in this and future studies, and to identify and resolve any procedural problems. The protocol will be first tested by the principal investigator who is also an acupuncturist. The investigator will perform acupuncture using the protocol, if necessary change the protocol, and then teach a second acupuncturist using the modified protocol how to use the double-blinded acupuncture needles. The real needle called the penetrating needle penetrates the skin. The fake needle called the non-penetrating placebo touch needle does not penetrate the skin but it touches the skin so it feels like a needle is being inserted. It has a blunt tip. Participants can't see which needle they are getting acupuncture with because the needles are housed in a double-blinded needle device which has two tubes (an inner and an outer) that neither the acupuncturists nor the participants can see through. If a fake acupuncture needle can be used in acupuncture research like a sugar pill is used for drug studies to see how well the real medicine works, the investigators can see how effective acupuncture is. The investigators will be testing these needles to treat participants with vulvodynia.
Primary Outcome Measures:
  1. Change in Vulvar Pain Scale [ Time Frame: baseline and twice weekly for 5 weeks ]
    PainReportIt, the computerized McGill Pain Questionnaire
  2. Change in Dyspareunia Questionnaire [ Time Frame: baseline and once per week for 5 weeks ]
    Female Sexual Function Index
Secondary Outcome Measures:
  1. Vulvar Function Status Questionnaire [ Time Frame: at baseline and 5 weeks ]
    Assesses vulvar function
Other Outcome Measures:
  1. Sleep Quality Scale [ Time Frame: at baseline and 5 weeks ]
    Pittsburgh Sleep Quality Index
  2. The Protocol Acceptability Scale for Treating Vulvodynia with Acupuncture [ Time Frame: 5 weeks ]
    Acceptability of the acupuncture protocol for the participant
  3. Double-Blinded Needle Questionnaires for the Acupuncturist and for the Participant [ Time Frame: 5 weeks ]
    Assesses the Ability of the Acupuncturist and Subject to Remain Blind

Double-Blind Phase 2 RCT: Effect of Acupuncture on Patient Vulvodynia Outcomes (2017 — 2022)
Abstract: Our long-term goal is to demonstrate the effects of acupuncture for the treatment of vulvodynia. Up to 14 million American women have vulvodynia, a debilitating pain syndrome characterized by vulvar pain and dyspareunia that renders sexual intercourse virtually impossible. Although no therapies have been proven efficacious and rapid pain relief is unpredictable and rarely possible, there have been no sham control studies of acupuncture as a treatment for vulvodynia, a high priority population for several NIH institutes. In our recently published randomized wait-list controlled pilot study of 36 women with vulvodynia, we found a statistically and clinically significant reduction in vulvar pain and dyspareunia and an increase in overall sexual function after a 13-needle, 10-session acupuncture protocol. We have also demonstrated in a small pilot study that it is feasible to use double-blind needles in the same 13-needle, 10- session acupuncture protocol for the treatment of vulvodynia. We now propose a pretest/posttest randomized controlled, double- blind design to determine efficacy of this acupuncture treatment protocol. Subjects will be randomized 1:1 to either a penetrating needle group or a skin touch placebo needle group. The acupuncturist will be observed for fidelity in use of both types of needles, which are designed to blind both the acupuncturist and subject to the type of needle. Eighty subjects with vulvodynia will insert and remove a tampon as a standardized stimulus and complete measures of vulvar pain (average pain intensity from pain now, least and worst pain in the past 24 hours [PAINReportIt®]); and dyspareunia (Female Sexual Function Index, FSFI dyspareunia subscale score) and sexual function (FSFI total score) at pretest (pretreatment baseline) and at posttest after the 10th acupuncture session. Specific aims are to: Aim 1. Compare the penetrating needle group and the skin touch placebo needle group for effects on the (a) primary outcome of vulvar pain (PAINReportIt® average pain intensity), and (b) secondary outcomes of dyspareunia (FSFI dyspareunia) and sexual function (FSFI total). Hypothesis: Controlling for baseline values, at posttest there will be statistically significant less vulvar pain and dyspareunia and more sexual function over the five weeks in the penetrating needle group compared to the skin touch placebo group. Aim 2. In subjects with a clinically meaningful reduction in pain intensity (at least 1.5 points) at posttest compared to pretest, describe the duration of the acupuncture treatment and placebo effects weekly until pain returns to pretest or up to 12 weeks after posttest. We will describe the variability over time in vulvar pain intensity (0-10) after a tampon insertion-removal stimulus and thereby explore the duration of the effect by intervention group, vulvodynia subgroups, and demographic subgroups (age, race, occupation). These findings will provide important insights to guide future research on initial and maintenance acupuncture treatment protocols for control of vulvodynia pain.

Alkistis Skalkidou, MD, PhD Department of Women's and Children's Health Uppsala University
An Internet-based Information Platform for Vulvodynia Patients (EMBLA) (2016 — 2021)
Vulvodynia is a very common but vastly under-diagnosed and under-treated gynaecological condition that leads to extreme suffering for both the women involved but also their partners. It has also been shown to be associated with poor quality of life, leading to depression and anxiety states. When left untreated, the condition takes a very long time to resolve, with a substantial associated disability and suffering. Both psycho-education and internet-based interventions have been shown to be highly successful while they can be quite affordable. This makes them highly cost-effective. The present study aims at evaluating the effectiveness of such an intervention among a vulvodynia patient population from the clinics of Uppsala, Falun, Orebro and Gävle. The patients will be recruited by treating physicians and given access to the internet-based platform, where they will fill out questionnaires during four different time-points, after randomization to the control or the intervention group. The intervention group will also have access to multiple activities and information material uploaded in the internet-based platform. Differences in pain, quality of life and mental health parameter outcomes will be assessed at the end of the study. Should this intervention prove effective, it will be implemented in clinical praxis in the four regions.
Primary Outcome Measures: 1. 
  1. Unprovoked pain change, post-intervention [Time Frame: Baseline to post-intervention (6 weeks)]. Change in self-reported unprovoked pain assessment, assessed by Visual Analogue Scale (VAS), between baseline and post-intervention (6 weeks).
  2. Unprovoked pain change, end of clinical treatment [Time Frame: Baseline to end of clinical treatment (typically 10-12 months) or 1 year following inclusion]. Change in self-reported unprovoked pain assessment, assessed by Visual Analogue Scale (VAS), between baseline and after completion of clinical treatment or 1 year following inclusion.
  3. Unprovoked pain change, one year post-treatment [Time Frame: 1 year after end of clinical treatment]. Change in self-reported unprovoked pain assessment, assessed by Visual Analogue Scale (VAS), between baseline and 1 year after completion of clinical treatment.
  4. Provoked pain change, post-intervention [Time Frame: post-intervention (6 weeks)]. Change in self-reported provoked pain assessment, assessed by Visual Analogue Scale (VAS), between baseline and post-intervention (6 weeks).
  5. Provoked pain change, end of clinical treatment [Time Frame: after clinical treatment (typically 10-12 months) or 1 year following inclusion]. Change in self-reported provoked pain assessment, assessed by Visual Analogue Scale (VAS), between baseline and after completion of clinical treatment or 1 year following inclusion.
  6. Provoked pain change, one year post-treatment [Time Frame: 1 year after ending of clinical treatment]. Change in self-reported unprovoked pain assessment, assessed by Visual Analogue Scale (VAS), between baseline and 1 year after completion of clinical treatment.
Secondary Outcome Measures:
  1. Satisfaction with Life change [Time Frame: Baseline to post-intervention (6 weeks)]. Change in satisfaction with Life, assessed with Satisfaction with Life Scale, between baseline and post-intervention (6 weeks)
  2. Sexuality [Time Frame: Baseline to post-intervention (6 weeks)]. Change in sexuality measures, assessed by Female Sexual Function Index (FSFI).
  3. Number of visits for clinical treatment [Time Frame: One year after the end of clinical treatment]. Number of visits for clinical treatment.
  4. Cost-effectiveness, assessed with the EQ-5D scale [Time Frame: Baseline to one year after completion of clinical treatment]. Cost-effectiveness, assessed with the EQ-5D scale, from baseline to one year after completion of clinica treatment.
  5. Sexual function parameters [Time Frame: Baseline to end of clinical treatment]. Change in sexual function parameters, assessed by the Female Sexual Dysfunction Scale (SFDS), between baseline and completion of clinical treatment.
  6. Number of days off work [Time Frame: Baseline to end of clinical treatment].
  7. Satisfaction with Life change, one year post-treatment [Time Frame: Baseline to one year post-treatment]. Change in satisfaction with Life, assessed with Satisfaction with Life Scale, between baseline and one year after completion of clinical treatment.

Peter Smith, PhD Director, 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.

Mark Tommerdahl, PhD Professor 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 neurodevelopmental 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.

Gerda Trutnovsky, MD Department of Obstetrics and Gynecology Medical University of Graz, Austria
Acupuncture in a Multidisciplinary Approach for Vulvodynia and Chronic Pelvic Pain (AMALIA) (2022 — 2022)
Background: Vulvodynia and chronic pelvic pain (CPP) are common and challenging gynecologic pain syndromes. A multidisciplinary approach is recommended. Study aim: To study the effectiveness of acupuncture as part of a multimodal treatment for women with vulvodynia and CPP. Design: Randomised controlled clinical study. Study Population: Recruitment from a University outpatient clinic Study groups: Participants will be randomised (1:1) Acupuncture group and Waiting list control group. Sample size: 68 patients.  Study outcome: Subjective Pain Perception (VAS) and Health-related quality of life (questionnaires).Experimental: Acupuncture Group-Acupuncture treatment will be performed according to a defined protocol, and includes body and ear acupuncture. The needles will be stimulated manually and will remain for 20 minutes. Body acupuncture needles (diameter 0.3mm, length 30 mm) will be placed on the following positions: On the lower abdomen and back within Th11 and L1
  • Kidney 13 and 14; alternately unilaterally
  • Ren2 and 3 (midline) On classical acupuncture points on the extremities and the head
  • Stomach 36, Spleen 6; bilaterally
  • Large intestine 4, Liver 3; Bladder 60 bilaterally
  • Du 20 (midline)
Ear acupuncture: Ear acupuncture needles (diameter 0,2 mm, length 20mm) will be used: Veg. I (Sympathetic), lower pelvis, hypogastric plexus, Heart,Thalamus, genital system (combining Chinese and French ear acupuncture). For point detection an electric potentiometer will be used. Ear points are punctured according to their generally accepted positions. No Intervention: Waiting list Group-Participants allocated to the waiting list control group may continue previously initiated standard therapy, but must not initiate any new treatment. They will be asked not to undergo acupuncture treatment for any condition within the next 3 months. After this period they are offered 10 acupuncture treatments over a period of 3 months. Primary Outcome Measures: 1.
  1. Change of Subjective Pain Perception [Time Frame: evaluation at 3 and 6 months]. Numeric Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain). Secondary Outcome Measures: 1. Change of Health-related quality of life - DSF [Time Frame: evaluation at 3 and 6 months]. Questionnaire,German Pain Assessment (Deutscher Schmerzfragebogen/DSF). The modules on pain assessment (e.g. pain characteristics, relieving and aggravating factors) and on demographic information will be used.
  2. Change of Health-related quality of life - PHQ-D [Time Frame: evaluation at 3 and 6 months]. Questionnaire Patient Health Questionnaire (PHQ-D) 9 is a sensitive screening tool for detecting depressive symptoms in a general patient population.
  3. Change of Health-related quality of life - PSQ [Time Frame: evaluation at 3 and 6 months]. Questionnaire Pain sensitivity questionnaire (PSQ) is an instrument for the assessment of pain sensitivity based on pain intensity self ratings of daily life situations.
  4. Change of Health-related quality of life - EHP-30 [Time Frame: evaluation at 3 and 6 months]. Questionnaire Endometriosis Health Profile (EHP-30) contains a total of 30 items. The modular part consists of six scales (work, relationship with children, sexual intercourse, infertility, medical profession, and treatment) and contains a total of 23 items. Items within scales are summed to create a raw score, and then each scale is translated into a score ranging from 0 (best health status) to 100 (worst health status).
  5. Change of Subjective improvement [Time Frame: evaluation at 3 and 6 months]. Patient Global Impression of Improvement (PGI-I) scale is a ), a single item instrument with a 7-step Likert type response scale to assess subjective improvement after treatment.
  6. Patient treatment satisfaction [Time Frame: evaluation at 3 months]."Fragebogen zur Patientenzufriedenheit - ZUF8" is an 8-item tool for measuring global patient satisfaction.

Lasertherapy for Vulvodynia (Lydia) (2021 — Present)
Detailed Description:
  • Randomized double blinded sham-controlled clinical study
Main hypothesis:
  • Laser therapy will be more effective than sham laser therapy in vulvar pain reduction measured by Q-tip test and tampon test
Secondary study hypotheses Laser therapy, in comparison to sham laser therapy
  • will lead to more improvement of Sexual Health and HrQoL
  • will have similar rates of side effects
Primary Outcome Measures  : 1. Change of Vestibular pain index [ Time Frame: Baseline and final assessment (3 months). ] The Vestibular pain index is derived from the Q-tip test and the tampon test. A standardized Q-Tip test (MRC Systems GmbH, Heidelberg, Germany), developed for quantitative sensoric testing, will be used. Pain on six defined anatomical regions of the vulvar vestibule (at 2 ,5,6,7,10 and 12 o clock) will be assessed. Patients will be asked to rate the level of vulvar pain on a numeric rating scale (NRS) of 0 "none at all" to 10 "worst imaginable". The tampon test is a standardized tampon insertion and removal test. The vestibular pain index will be calculated as follows: (mean NRS score of the standardized Q-tip test (6 sites) + NRS score during the tampon test) / 2. Secondary Outcome Measures  :
  1. Change of pelvic floor muscle (PFM) function- PFM contraction strength [ Time Frame: Baseline and final assessment (3 months). ] The Modified Oxford Scale (MOS) will be used to score maximal PFM contraction strength, ranging from 0 (no contraction) to 5 (strong contraction and lift).
  2. Change of pelvic floor muscle (PFM) function- PFM tone [ Time Frame: Baseline and final assessment (3 months). ] PFM tone will be scored on a 7-point PFM tone scale ranging from -3 (very hypotonic) to +3 (very hypertonic), with 0 representing a "normal" pelvic muscle tone.
  3. Change of levator hiatal dimensions at rest [ Time Frame: Baseline and final assessment (3 months). ] 3D perineal ultrasound will be used to measure levator hiatal dimensions at rest.
  4. Change of levator hiatal dimensions at maximal voluntary contraction [ Time Frame: Baseline and final assessment (3 months). ] 3D perineal ultrasound will be used to measure levator hiatal dimensions at maximal voluntary contraction.
  5. Change of levator hiatal dimensions at maximal Valsalva maneuver [ Time Frame: Baseline and final assessment (3 months). ] 3D perineal ultrasound will be used to measure levator hiatal dimensions at maximal Valsalva maneuver.
  6. Change of Vaginal health score index (VHSI) [ Time Frame: Baseline and final assessment (3 months). ] In postmenopausal women the VHSI will be performed to assess elasticity, fluid volume, pH, epithelial integrity and a moisture on a scale from 1 (none) to 5 (excellent) each. The sum score will be recorded.
  7. Change of Sexual activity [ Time Frame: Baseline and final assessment (3 months). ] Participants will be asked to complete a study diary and record whether they experienced sexual intercourse. Possible answers are: #1-"No, too painful" indicating that the woman could not accept an approach to physical intimacy because of pain, #2 -"No, not interested", indicating that the subject was not in the mood for sexual intimacy, #3-"No,no opportunity", indicating that her partner was not available, #4-"Yes" meaning that an attempt at sexual intercourse was made. If intercourse was attempted the level of pain during intercourse should be rated on a 0 - 10 NRS pain scale.
  8. Change of Sexual Function [ Time Frame: Baseline and final assessment (3 months). ] The German version of the Female Sexual Function Index (FSFI-d) will be used to assess women´s sexuality. The validated 19-item questionnaire examines several aspects of female sexuality, i.e. sexual arousal, orgasm and dyspareunia.
  9. Change in Endometriosis Health Profile (EHP-30) [ Time Frame: Baseline and final assessment (3 months). ] The EHP-30 consists of five scales -pain, control and powerlessness, emotional well-being, social support, and self-image (30 items) and a module with 23 items. The modular part consists of six scales - work, relationship with children, sexual intercourse, infertility, medical profession, and treatment.
  10. Change in German Pain Assessment (assessed by Deutscher Schmerzfragebogen/DSF) [ Time Frame: Baseline and final assessment (3 months). ] The DSF was developed for the comprehensive assessment and therapy planning of patients with chronic pain conditions. The modules on pain assessment (e.g. pain characteristics, relieving and aggravating factors) and on demographic information will be used.
  11. Change in Patient Health Questionnaire (PHQ-D) [ Time Frame: Baseline and final assessment (3 months). ] The PHQ-D is a sensitive screening tool for detecting depressive symptoms in a general patient population. The 9-item tool assesses the degree and severity of depression, and has been found to be a valid and useful tool for therapy evaluation.
  12. Change in Pain sensitivity questionnaire (PSQ) [ Time Frame: Baseline and final assessment (3 months). ] The PSQ is an instrument for the assessment of pain sensitivity based on pain intensity self ratings of daily life situations.
  13. Change in Patient Global Impression of Improvement (PGI-I) [ Time Frame: Baseline and final assessment (3 months). ] The Patient Global Impression of Improvement (PGI-I), a valid instrument with a 7-step Likert type response scale, will be used to assess subjective improvement after treatment. After three months, i.e. one month after the second laser therapy, women will be asked to rate the change in vulvar pain.
  14. Change in Patient treatment satisfaction [ Time Frame: Baseline and final assessment (3 months). ] Treatment satisfaction will be assessed using an adopted version of the "Fragebogen zur Patientenzufriedenheit - ZUF8". The questionnaire, the German version of the original "Client Satisfaction Questionnaire-CSQ8", is a tool for measuring global patient satisfaction at the end of inpatient treatment.
  15. Change in Treatment discomfort [ Time Frame: Twice after treatment, one and two months after baseline. ] At the end of each treatment session patients are asked to indicate the degree of discomfort during laser therapy on a NRS ranging from 0 "no discomfort" to 10 "worst possible discomfort."
  16. Change in Treatment pain [ Time Frame: Twice after treatment, one and two months after baseline. ] At the end of each treatment session patients are asked to indicate the degree of pain during laser therapy on a NRS ranging from 0 "no pain" to 10 "worst possible pain".

Frank Tu, MD, MPH Director, 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.

Hans Verstraelen, MD, MPH, PhD Associate Professor University Hospital, Ghent
Infiltration of the Vestibulum Vaginae With Botulin Toxin in Patients With Localized Provoked Vulvodynia (VVS-01) (2012 — 2018)
In this study we will investigate the efficacy and safety of infiltration of the vestibulum vaginae with botulin toxin in women who were diagnosed with localized provoked vulvodynia. In literature covering this subject we find that the prevalence of this condition is between 10 and 15%. Especially young, sexually active women suffer from this problem and some of them are not capable of having sexual relations with their partner because of this burning pain. The most probable explanation for the physiopathological mechanism is an increase of nerve endings in the epithelium of the vestibulum, with an increase and activation of pain receptors in the vestibular mucosa. It also seems that patients with vestibulodynia have a higher tonus of the pelvic floor muscles, a greater muscle contraction in response to pain and a lower capacity of relaxation. Botulin toxin (Botox) is a neurotoxin that causes a temporary paralysis of the muscle cells. That way it can decrease the increased tension of the pelvic floor muscles Botox also inhibits the pain receptors in the vestibulum. Patients will be recruited through the gynecology consultations. Every patient with localized provoked vulvodynia that has tried previous treatments (pelvic floor muscle therapy, antidepressants, anti-epileptics, local anesthetics) will undergo Q-tip testing. If positive and there are no underlying diseases, the patient will be invited to participate in the study and after oral and written informed consent, will be included in the study population. Every 6 weeks there will be given injections with 50 units of botulin toxin, on 6 different spots in the vestibulum. 50 % of the subjects will receive physiological water instead of Botox (control population). After 3 sessions, we will assess if there is any difference in provoked pain in treated patients vs. placebos through Q-tip testing. Primary Outcome Measures:
  • to evaluate the efficacy and safety of botulin toxin in alleviating dyspareunia associated with localized provoked vulvodynia. [Time Frame: every 6 weeks up to week 18]. Before each session (every 6 weeks) and after the last session the patients will have to fill in a FSFI questionnaire. This way we can evaluate the influence of the therapy on the patients' sexual wellbeing. (efficacy). Before each sessions and 6 weeks after the last injection, patients will undergo Q-tip testing. This way we can objectively evaluate the pain score over the vestibulum. (efficacy). Recording of self-reported side-effects.

Ursula Wesselmann, MD, PhD Professor 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.

Slawomir Wojniusz, PhD Oslo Metropolitan University
Somatocognitive Therapy in Treatment of Provoked (Localized) Vestibulodynia - Randomized Clinical Trial (ProLoVe Study) (ProLoVe) (2022 — 2022)
This is a two-arm randomized clinical trial assessing effectiveness of somatocognitive therapy versus treatment as usual for provoked vestibulodynia (PVD). PVD is a common, but under-treated persistent pain condition, mostly affecting young women in their late teens and early 20s. It is the most frequent cause of pain during sexual intercourse affecting around 10% of women in the general population. There are no generally accepted evidence-based guidelines for the medical management of PVD. The most commonly used treatments are topical (85%), physiotherapy (52%), and oral medications (45%). High quality randomized clinical trials testing effectiveness of various therapy approaches are urgently needed. Somatocognitive therapy SCT is a multi-modal physiotherapy approach developed for alleviating musculoskeletal persistent pain conditions. SCT has been previously evaluated in the treatment of women with chronic pelvic pain. In the current study, 128 women with PVD will be randomized into SCT and treatment as usual (TAU) group. Participants will be assessed at baseline, after 6 months and after 12 months. The main outcome will be changes in female sexual function index scored at 12 months follow up. Secondary outcomes include pain intensity as assessed by a tampon test as well as a number of questionnaires recording different aspects of emotional and cognitive functioning. In addition cost-effectiveness analysis of SCT versus TAU will be performed. Participants in the SCT group will receive up to 15 therapy sessions and will additionally be offered one booster session at 6 months after treatment ending. TAU group will follow treatment options of their own choice based on recommendations from the Vulva clinic at Oslo University Hospital, a center that is specialized in treating women with vulvar pain conditions.
Primary Outcome Measures:
  1. Change in female sexual function index (FSFI) (Rosen et al. 2000) [ Time Frame: Baseline, 6 and 12 months follow up ]
    A multidimensional scale assessing key dimensions of female sexual function. The FSFI is a 19-item self-report questionnaire designed to measure sexual functioning in women. It assesses six domains of sexual function: sexual desire, sexual arousal, lubrication, orgasm, satisfaction, and pain (i.e., pain associated with vaginal penetration). Higher scores indicate better sexual functioning.
Secondary Outcome Measures:
  1. Change in Participant Perceived Improvement (PGIC) (Dworkin et al. 2005) [ Time Frame: 6 and 12 months follow up ]
    Participants are asked to rate on a 7-points Likert scale how much their condition has changed since baseline measurement. Answering alternatives: very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse
  2. Change in the tampon test (Foster et al. 2009) [ Time Frame: Baseline, 6 and 12 months follow up ]
    The tampon test measures vulvar pain intensity during insertion and removal of a standard sanitary tampon. At each assessment time (baseline, 6 and 12 months follow up), the test will be performed three times at home during a 7-day period, on days 1, 4 and 7. A mean value of these 3 measurements will be used as a measure of pain sensitivity. Pain intensity is recorded on the Numeric Rating Scale (0-10) where 0 is no pain and 10 is the worst pain imaginable.
  3. Change in recalled pain intensity during intercourse [ Time Frame: Baseline, 6 and 12 months follow up ]
    Participant is asked to score on a Numeric Rating Scale (0-10) how intense was the pain during last intercourse, where 0 is no pain and 10 is the worst pain imaginable.
  4. Change in Vulvar Pain Assessment Questionnaire (VPAQ) (Dargie et al. 2017) - life interference [ Time Frame: Baseline, 6 and 12 months follow up ]
    VPAQ is developed to assist in the assessment and diagnosis of vulvodynia. Life interference sub-scale describes impact of vulvodynia on daily living. It consists of 11 questions addressing different domains of daily functioning. Each question is scored on a 6-points Likert scale with a higher score indicating higher negative impact of vulvodynia on daily activities
  5. Change in Vulvar Pain Assessment Questionnaire (VPAQ) (Dargie et al. 2017) - coping strategies [ Time Frame: Baseline, 6 and 12 months follow up ]
    VPAQ - coping strategies sub-scale consists of 12 statements describing different pain-coping strategies. Each statement is scored on a 5-points Likert scale referring to how often a specific strategy is used. A higher score indicate more frequent use of a given strategy.
  6. Change in vulvodynia related self-efficacy [ Time Frame: Baseline, 6 and 12 months follow up ]
    The scale will be assessed to record participant's belief in her ability to cope with the vulvodynia symptoms on her own. The scale is based on one question scored on 5-points Likert scale with higher scores indicating higher belief in woman's ability to cope with her symptoms.
  7. Change in pain catastrophizing scale (Fernandes et al. 2012) [ Time Frame: Baseline, 6 and 12 months follow up ]
    The pain catastrophizing scale is a self-report measure consisting of 13 items scored from 0 to 4. The higher the score, the more catastrophizing thoughts are present. It assesses an impact of negative cognition's and catastrophizing on pain experience. This version of the scale has been specifically adapted for pain related to vulvodynia.
  8. Change in Rumination Response Scale (RRS-10) (Parola et al. 2017) [ Time Frame: Baseline, 6 and 12 months follow up ]
    Rumination and worry express a method of coping with negative emotions and feelings that is characterized by self-focused attention, repetitive focus on negative emotions and self-reflection. RSS-10 includes 10 questions scored on a 4-points Likert scale. The higher scores indicate more worry and rumination.
  9. Change in Hopkins Symptoms Check List (HSCL-25) (Derogatis et al.1974) [ Time Frame: Baseline, 6 and 12 months follow up ]
    HSCL-25 evaluates psychological distress related to the anxiety and depression symptoms. It consists of 25 questions scored on a 4-points Likert scale. Higher scores indicate higher levels of psychological distress.
  10. Change in EQ-5D-5L (Herdman et al. 2011) [ Time Frame: Baseline, 6 and 12 months follow up ]
    EQ-5D-5L is used to assess health related quality of life and/or cost-effectiveness of assessed interventions. It consists of 5 domains scored on 5-points Likert scale with higher scores indicating lower quality of life. Additionally 100 points NRS scale is used for evaluation of current health status with higher score indicating better health.

Jackie Wood, PhD Professor 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).

Denniz Zolnoun, MD Assistant 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.