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.

University Hospital, Ghent
Lipofilling as a Treatment for Vestibulodynia (2018 — 2023)
The investigators would like to investigate if lipofilling with its adipose derived stem cells (ADSC) could be a new, less invasive but equally or more effective therapeutic option for women with vestibulodynia than vestibulectomy. The investigators expect the study to be successful because of the anti-inflammatory effects of the ADSC and its effectiveness -although not thoroughly studied- in some neuropathic pain disorder like pudendal neuralgia or post mastectomy pain syndrome.)
Method: A controlled intervention study: one group receiving golden standard therapy 'vestibulectomy' and one group receiving vestibular lipofilling. PRIMARY OUTCOME MEASURES: Outcome Measures: Q-tip scores (Cotton swab assessment of vaginal pain) 3 months after surgery Measure Description: Very light pressure along specific points in the area of the vulvar vestibule and where there is tenderness, asking the patient to characterize the tenderness on a scale of 0-10, whether it's no pain or exquisite pain and then plotting that on a diagram. Most physicians will find that in women with vestibulitis, the tenderness is most pronounced just below the hymenal margin and around the orifices of the so-called "Bartholin" gland ducts. Time Frame: 3 months after surgery Study Record | ClinicalTrials.gov

Liverpool University Hospitals NHS Foundation Trust
A Patient Reported Outcome Measure for Vulval Conditions (2021 — 2022)
In order to create the proposed vulval specific patient reported outcome measure we will use semi structured questionnaires and a focus group interview. Methods: Participating patients will be recruited through their attendance at a specialist vulval dermatology clinic across two secondary care centres, by the direct patient care team. Written consent will be obtained at every stage and each patient will receive written information in the form of a patient information leaflet as to why the research is being conducted. Patients will be reassured that declining involvement in the research will have no impact upon the quality of their care and that their involvement is entirely voluntary. Initially fifty (50) follow up/new patients attending the specialist vulval clinic across two sites will be invited to answer questionnaires on their attendance at clinic, which will ask a number of open-ended questions about aspects of their vulval condition that may have affected them. These questions have been devised by the research team based on professional experience and the results of previous research, which have identified common themes to life impairment to include symptoms, sexual function, personal relationships, emotions, daily activities and social/leisure activities.4,7 Based upon the findings we will develop a preliminary questionnaire (patient reported outcome measure) in conjunction with an expert panel compromising of a consultant dermatologist and speciality doctor in gynaecology, both of which have a specialist interest in vulval medicine. This questionnaire will be subsequently piloted on a focus group of fifteen (15) patients with a variety of vulval conditions. The research team feels that a small focus group would be preferential over individual interviews as we hope a group discussion in which people can share their experiences will stimulate discussion, generate new ideas and help reach a consensus opinion on the newly created patient reported outcome measure. Furthermore, focus groups have been successfully used in other studies of patients suffering with vulval disease. 8,9 Individual diagnoses will not be discussed in the patient group setting and It will be attended by the full patient care team and directed by the Chief Investigator. Based upon their comments and professional consensus the questionnaire will be further refined. Patients will be consented for their involvement and the justification of the research explained. These patients may or may not have been asked to complete the original questionnaire which was used to help develop the subsequent patient reported outcome measure. In order to authenticate the newly created patient outcome measure, one hundred (100) patients attending the specialist vulval dermatology clinic on an opportunistic basis across two centres (both new and follow up) will be invited to participate in completing the newly created questionnaire. These patients may be previously been part of the pilot group and/or been asked to contribute to the initial questionnaire which led to the development of the patient reported outcome measure. All patients will be given the questionnaire fifteen (15) minutes prior to their clinic appointment and given the opportunity to ask questions in their clinic appointment should they wish. A second duplicate questionnaire will be given to all the participating women in a self-addressed envelope, with instructions to complete it after two weeks and return it in the post. If the second questionnaire is not received within three weeks, two reminder calls will be made. Through repeating the questionnaire at 2 weeks, its reliability can be determined using statistical methods. At the same clinic visit patients will also be asked to complete the dermatology life quality index (DLQI), which is a questionnaire that is routinely used in clinical practice to assess the impact of a patient's skin condition on their quality of life. This is done so comparisons can be made between the DLQI and new questionnaire. Statistical methods will be used analyse the results and interpret the authenticity of the new questionnaire. Data analysis The validation of the vulval specific patient reported outcome measure will be addressed in a number of ways: The test retest reliability will be assessed by asking the women to fill out the same questionnaire two weeks after their initial recruitment into the study. The second questionnaire will be given to the women with a self-addressed envelope after their initial recruitment into the study, with instructions to complete it after two weeks and return it in the post. This time period was chosen in order to avoid recall bias. If a second questionnaire is not received in three weeks, two reminder calls will be places. Test-retest reliability will be measured for individual questions using the kappa coefficient for individual questions. The test retest reliability for the sum of the different scales will be measured by intra class coefficients. Cronbach's alpha will be used to measure internal consistency. Confirmatory factor analysis will be used to verify the five a priori scales of the vulval specific patient reported outcome measure. (These are assumed to be sexual function, emotions, symptoms, daily activities and social functioning) This will be used to address construct validity. Construct validity will be also be determined through testing against the Dermatology Quality Life Index. There is currently no gold standard quality of life measure used in vulval conditions, but the DLQI is used routinely in dermatology practice, including patients who present to the specialist vulval clinic. All patients (n=100) will be given a DLQI form to complete at the same time as the piloted questionnaire.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
questionnaire development questionnaire development 1 year
Study Record | ClinicalTrials.gov

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.

Marcela Bardin, PT University of Campinas, Brazil
Physical Therapy as Adjuvant Treatment of Vulvodynia: a Randomized Controled Trial (2016 — 2017)
Detailed Description:
GOALS
  1. General Check the effectiveness of physical therapy applied to the pelvic floor muscles used as an adjunct to standard treatment (amitriptyline hydrochloride) on the improvement of symptoms of vulvodynia.
  2. Specific
Check and compare in women with vulvodynia before and after being randomly assigned to three treatment arms (drug only drug associated with therapeutic exercise or medication associated with electrotherapy with CI):
  • Pain during intercourse and during the swab test obtained by Visual Analogue Scale (VAS);
  • The scores obtained in the questionnaire Female Sexual Function Index (FSFI);
  • The change in the volume of puborectal, pubococcygeus and iliococcygeal muscles accessed through Tridimensional Ultrasound (US3D);
  • The variation of the perfusion of the pelvic floor muscles by pudendal artery obtained by 3D ultrasound;
  • The effectiveness of therapeutic exercise in the improvement of vulvar pain to test swab and sexual intercourse by penetration in women diagnosed with vulvodynia;
  • The effectiveness of electrical therapy with interferential current in the improvement of vulvar pain to test swab and sexual intercourse by penetration of women diagnosed with vulvodynia;
  • Compare the effectiveness of electrical therapy and kinesiotherapy in the improvement of vulvar pain;
  • Compare the effectiveness of physical therapy as an adjunct to standard against standard treatment alone.
SUBJECTS AND METHODS:
  1. Study design:clinical trial randomized controlled single-blind. Designed according to the CONSORT standards, pending completion of the project after approval by Brazil Platform for final implementation, scheduled for July 2016.
  2. Sample size:To calculate the sample size, we sought in literature studies addressing the main variables to be analyzed in this study (FSFI score after physical therapy intervention and medication versus medication, change in visual analog pain scale before and after the intervention).The study whose design and statistical analysis were closer than we propose in this project was used to calculate the sample, and its purpose was to compare in women with vulvodynia, the improvement in pain using the VAS pain and sexual function index using the FSFI after undergoing sessions of transcutaneous electrical stimulation (TENS) (65).Assuming type II alpha error probability equal to 0.05 and study of power equal to 80%, and considering the average VAS score of 8 (± 3.4) and 2.2 (± 6.1), the sample size calculation estimated using the Small software Stata 13.1 was n = 16 for each group, totaling n = 48. However, as a study with follow-up two months and assuming loss of follow-up of 20% of the total number of the sample, we assume a sampling size n = 58.
  3. Variables and concepts:
3.1 Independent Variables Vulvodynia Characterized by present or absent, it is diagnosed by the presence of vulvar pain sexual penetration or touch gynecological self-reported, burning to light touch in the lobby (swab test [13]) and erythema. It can be classified as localized or generalized. 3.2 Dependent Variables Muscle thickness - Measure cross the levator ani muscle given in millimeters, obtained by 3D US in three situations: rest, maximum voluntary contraction and Valsalva; Perfusion pudendal artery - blood flow of the pudendal artery, given in millimeters per square centimeters (mm / cm2) obtained by 3D US. Pain referred to the swab test - referred pain to perform the swab test, playing with a swab certain points of the vulvar vestibule, pointed using the visual analog scale (VAS) ranging from zero to 10, where ten is the highest grade concerning the higher pain threshold. Pain said the vaginal penetration - mean referred pain during sexual intercourse with vaginal penetration, pointed using the visual analog scale (VAS) ranging from zero to 10, where ten is the maximum note to higher pain threshold. FSFI - female sexual function index, as measured by the score obtained by the self-administered questionnaire FSFI (Female Sexual Function Index), which proposes to evaluate women's sexual response in the areas: desire, arousal, vaginal lubrication, orgasm, sexual satisfaction and pain. Assesses the relative strength of each field of female sexual response and transform subjective measures in objective, quantifiable and analyzable data. Applied in therapeutic exercise before and after the program applied to the pelvic floor. 3.3 Control variables BMI: body mass index, obtained by dividing weight in kilograms by height in meters squared. Categorized to assess the degree of obesity of an individual, it is considered underweight when BMI <20; ideal weight BMI = 20 to 25; overweight BMI = 26 to 30; moderate obesity BMI = 31 to 35; severe obesity BMI = 36 to 40; Morbid obesity BMI = 41 to 50; super obesity BMI> 50. Gestation: number of times the respondent became pregnant, including abortions until the day of the interview (self reported); Delivery type: delivery route number taken by the respondent to the day of the interview, self reported, classified as: C-section; Forceps, vaginal; Frequency of sex: number of sexual contacts per month in the last six months (self reported); Number of sexual partners: number of partners in the last six months (self reported); Frequency of physical activity: number of times a week practicing physical activity on average in the last six months (self reported); Type of physical activity: type of physical activity carried out in the last six months (self reported) classified as: (I) strengthening (weight training, pilates class, functional training), (II) aerobic (walking, running, swimming, cycling, wrestling) and / or (III) stretching (stretching classes, yoga); (IV) sedentary. Symptoms or pelvic floor dysfunction signs: self reported complaint by the patient in relation to the perineum such as dyspareunia, dysuria, redness, cracking, itching, vaginal flatus, urinary incontinence, fecal incontinence. Treatment for vulvodynia used before kinesiotherapy: techniques and previously tested therapies to reduce the nuisance caused by vulvodynia. Drug name, time and amount of drugs administered during the period of participation in the survey. 3.4 Descriptive Variables Age: elapsed time in years from the date of birth and date of the first interview, said the participant. Given in ordinal numbers; Education: number of years of study referred to by the subject. Given in ordinal numbers; Marital status: marital status of the subject at the time of the study. Categorized in (I) with a steady partner and (II) without a professional occupation; Skin color: skin color referred to by the subject. Categorized into (I) White and (II) not white; Smoking: current smoking habit, self reported by the interviewee, considering the options (I) yes or (II) not; Contraceptive methods that are used by women in order to prevent conception, informed by the participant, categorized into (I) male or female condom, (II) oral hormonal pill, (III) injectable hormonal contraceptive (IV) ligation of the fallopian tubes (V) or levonorgestrel copper intrauterine device (VI) rhythm, (VII) withdrawal, (VIII) and vasectomy (IX) other; Subject Selection Women who attend the outpatient genital infections and sexuality and are diagnosed with vulvodynia will be invited to participate in this study. Will also be distributed informative pamphlets on chronic vulvar pain and the methodology of this research in specialized clinics vulvodynia, vulvodynia groups on the Internet and clinics where researchers involved in this study attend. Women who agree to participate in the study aged over 18 years old will be interviewed in order to meet the criteria for inclusion in the study (Appendix I). The evaluation will be scheduled in the center of comprehensive care to women's health of Unicamp (CAISM) in physiotherapy clinic to perform the steps of the research participation. The volunteers will be randomized through a computer program in www.randomizer.org obtained in three treatment arms: only amitriptyline, amitriptyline combined with kinesiotherapy applied to the pelvic floor and electrical therapy associated with the amitriptyline.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Pain Scale Measurement Effectiveness of the treatment for vulvodynia will be accessed through pain score scale from zero to ten, compared from day zero of treatment to day eight Eight weeks
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Female Sexual Index Function Improvement Will be accessed through FSIF (Female Sexual Index Function questionnaire) score that goes from 2 to 36, compared from day zero of treatment to day eight, which indicates sexual disfunction pointed by scores below 26,55. Eight weeks
3D Ultrasound measurement of Pelvic Floor Muscle thickness and pudendal artery flow A 3D Ultrassound will be used to access these outcomes and compare changes from day zero to day eight of treatment Eight weeks
OTHER OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Interleukin 1-B Vaginal Inflammatory response Vaginal fluid collected will be analysed in laboratory to access possible inflammatory response of vulva and vagina of women with vulvodynia obtained by comparing quantitatively interleukin 1-B presente before and after treatment Eight weeks
Study Record | ClinicalTrials.gov

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.
Study Record | ClinicalTrials.gov

Ewa Baszak-Radomańska, MD, PhD Medical University of Lublin
Effectiveness of Low-dose Naltrexone in Patients With Different Types of Vulvodynia (2023 — 2026)
Vulvodynia (Vd) is chronic functional vulvar pain, with prevalence of 3-16% and unclear etiopathology. Although Vd significantly deteriorates quality of life, the problem is marginalized, no pharmacologic treatment standards exist. Naltrexone hydrochloride is a specific opioid antagonist with slight agonist activity. There is growing body of evidence supporting the effectiveness of low-dose naltrexone (LDN) in different types of chronic pain. The main goal of this trial is to test the effect of LDN on pain perception and quality of life in women with different types of Vd. Half of the study population receives LDN and the remaining patients take placebo, according to randomization list. This RTC is quadruplet blinded.
In this Randomized Controlled Trial the effectiveness of LDN in reducing chronic pain and improvement of quality of life in women with provoked, spontaneous or mixed vulvodynia is assessed on the basis of the test results recommended according to IMMPACT protocol, compared to the placebo arm. Patients remain in the study for 6 months (4 months of treatment with LDN or placebo). There are 5 visits by a gynecologist (diagnosis of vulvodynia, inclusion and exclusion criteria, randomization), nurse, psychologist and physiotherapist: screening, randomization, control telephone visit, final visit and telephone summary visit. Pain perception and quality of life estimation is reported by the patient in e-diary, validated psychology questionnaires are fulfilled and physical examination acc. Fascial Manipulation (CFMS) L. Stecco method is performed. Tolerability of LDN therapy will also be assessed.
PRIMARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Treatment effectiveness - change in pain intensity measured by 11-point NRS scale based on spontaneously experienced vulvar and vaginal pain and during vaginal penetration from pre-treatment values (VISIT 2) to end of treatment values (VISIT 4) assessed for 4 months
Treatment effectiveness - change in type and severity of pain measured by McGill Questionnaire (SF-MPQ) from pre-treatment values (VISIT 2) to end of treatment values (VISIT 4) assessed for 4 months
Treatment effectiveness - change in emotional functioning Beck Depression Inventory (BDI-II) from pre-treatment values (VISIT 2) to end of treatment values (VISIT 4) assessed for 4 months
Patient's satisfaction measured by 11-point Lickert scale from pre-treatment values (VISIT 2) to end of treatment values (VISIT 4) assessed for 4 months
SECONDARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Treatment tolerability Assessment of the tolerability of LDN therapy based on the assessment of side effects and adverse events throughout the treatment period (from VISIT 2 to VISIT 4) assessed for 4 months
Study Record | ClinicalTrials.gov

Sophie Bergeron, PhD Professor Université de Montréal
Study to Compare the Efficacy of Cognitive-behavioral Couple Therapy and Lidocaine for Provoked Vestibulodynia (CBCT-RCT) (2014 — 2018)
Background: Chronic pain problems involving the female reproductive system are major health concerns in women of all ages. As conditions which are poorly understood and often misdiagnosed or ignored, they entail a great personal cost to patients and a significant financial cost to society. One such condition is vulvodynia, or chronic unexplained vulvar pain. A recent population-based study suggests that the lifetime cumulative incidence of vulvodynia is 16%, indicating that approximately 2.5 million Canadian women may experience idiopathic vulvar pain during their lifetimes. Provoked vestibulodynia (PVD) - an acute recurrent pain localized within the vulvar vestibule and experienced primarily during sexual intercourse - is suspected to be the most frequent cause of vulvodynia in premenopausal women, with prevalence estimates of 12% in community samples. Despite its high prevalence and negative impact on psychosexual functioning, there has been a paucity of controlled research to provide empirically validated treatments for afflicted couples. The present proposal draws on our previous cross-sectional and prospective CIHR funded research on the dyadic determinants of pain and psychosexual impairment in women with PVD and their partners, as well as on our past randomized trials evaluating the efficacy of group cognitive-behavioral therapy for this condition. Specifically, the goal of our study is to evaluate the efficacy of a targeted cognitive-behavioral couple therapy (CBCT) intervention that we developed for the treatment of PVD. Objectives: The proposed two-centre randomized clinical trial aims to evaluate the efficacy of a novel 12-week targeted couple therapy intervention (CBCT) for women with PVD in comparison to one of the most frequently prescribed first line medical interventions, topical lidocaine, shown to be effective and safe in the management of PVD. The primary research question focuses on whether there is a significant difference between the two treatments on women's pain during intercourse post-treatment. Secondary research questions focus on whether there are significant differences between the two treatments post-treatment and at 6-month follow-up on (a) the multidimensional aspects of women's pain on the McGill Pain Questionnaire and (b) women and partners' sexuality (sexual function and satisfaction, frequency of intercourse), psychological adjustment (anxiety, depression, catastrophizing, self-efficacy, pain attributions, quality of life, acceptance of pain, compassionate love for partner, self-compassion, emotion regulation and thoughts and feelings related to pain experience), relationship factors (partner responses, dyadic adjustment, attachment, and communication) and self-reported improvement and treatment satisfaction. We will also examine whether childhood trauma and co-morbid pain conditions moderate treatment response. Finally, a third research question is to evaluate the role of hormonal contraceptive use and the risk of PVD. Research plan/methodology: The proposed research is a 3.5-year, two-centre parallel randomized controlled trial for PVD using an intent-to-treat analysis strategy, with pain during intercourse as the primary outcome. The main research questions will be addressed by: 1) recruiting 224 premenopausal women and their partners with medically diagnosed PVD; 2) performing comprehensive gynecological and psychosexual pre-treatment evaluations focusing on our outcome measures; 3) randomly assigning women to one of the two 12-week treatment arms: CBCT or lidocaine, and 4) evaluating pain during intercourse, as well as sexual, psychological and relationship outcomes, in addition to self-reported improvement and treatment satisfaction, post-treatment and at 6-month follow-up. These procedures will take place in two different university centers: Université de Montréal in Montréal, Québec, and Dalhousie University in Halifax, Nova Scotia, and their affiliated hospitals. Both university centres will store data securely, adhering to the protocols outlined by the ethics review boards at each site. Statistical Analyses: Analyses will be conducted based on intention to treat. Descriptive statistics will be used to define and compare the participants in both intervention groups. More specifically, we will calculate means, medians, deviations and interquartile ranges and T-tests will be used to determine the differences between groups for socio-demographic variables. Chi-square tests and observed differences between groups will be used for categorical variables. If differences are observed between groups, these variables will be controlled for in subsequent analyses. We will verify that variables are normally distributed. If variables are not normally distributed, non-parametric tests will be employed. A repeated measures analysis of variance will permit the assessment of efficacy of the two treatments at post-treatment and at 6-month follow-up. The analyses will focus on the changes in pain experienced during intercourse from pre-treatment assessment to post-treatment and 6-months follow-up. To do this, time will be the intra-subject variable, and the experimental condition will be the inter-subject variable. For secondary analysis, multiple analyses will be conducted in multiple steps, with multivariate analyses being conducted first for repeated measures (MANOVA). Correlated measures will be grouped based on conceptual domain (e.g., pain, dyadic adjustment, catastrophizing). Univariate analyses will be conducted if the multivariate results are significant (ANOVA). This will be followed by orthogonal contrasts to examine changes between different measurements. Moreover, we will use exploratory analyses for participants who completed the experimental protocol to determine the effect protocol adherence has on treatment efficacy. Multiple regression analyses will be used to examine the link between socio-demographic variables, pre-treatment dependent variables and pain at post-treatment and 6-months follow-up to identify factors associated with therapeutic success. These latter analyses will be conducted for each treatment group separately. Bonferroni corrections will be used during analyses for multiple comparison adjustments. In the case of missing data, we will explore the effects of withdrawal on sensitivity analyses, replace the missing data with data from the most recent assessment or with averaged or aggregate values. Significance of study: Results of the proposed research may improve the health and quality of life of Canadians afflicted with a highly prevalent and neglected women's health problem - vulvodynia - by providing a rigorous test of the efficacy of a novel targeted couple therapy intervention.
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).
Study Record | ClinicalTrials.gov

Nina Bohm-Starke, MD, PhD Karolinska Institutet Danderyd Hospital
Botulinum Toxin A as a Treatment for Provoked Vestibulodynia (2016 — 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
Study Record | ClinicalTrials.gov

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.
Study Record | ClinicalTrials.gov

Jacob Bornstein, MD, MPA, Professor Department of Obstetrics & Gynecology Western Galilee Hospital-Nahariya
A Search for Helicobacter Pylori in Localized Vulvodynia (2004 — 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. Study Record | ClinicalTrials.gov

Efficacy Study of Topical Application of Nifedipine Cream to Treat Vulvar Vestibulitis (2006 — 2008)
30 women aged 18-45 diagnosed with Provoked localized Vulvodynia will be included. 10 women will use topical Nifedipine cream 0.2% 4 times a day for 6 weeks (except for menstrual period). 10 other women will use topical Nifedipine cream 0.4% 4 times a day for 6 weeks (except for menstrual period). 10 women will be a control group and will use a placebo cream. The study will be randomized and double blind. Participants will be examined before starting the treatment, at the end of the treatment and 3 months after completion the treatment. A special detailed questionnaire has been prepared in three languages and will be used to compare dyspareunia and associate variables between the groups. The Q-tip tests will be performed and findings will be drawn in each examination. Differences between the groups will be examined, and uni- and multi-variate analysis will be performed.
Primary Outcome Measures:
  1. Complete resolution of vestibulitis. [ Time Frame: Participants will be examined before starting the treatment, at the end of the treatment and 3 months after completion the treatment, using the questionnaire and the Q-tip applicator for detection of vestibular sensitivity. ]
Secondary Outcome Measures:
  1. Safety of the Nifedipine treatment. [ Time Frame: Participants will be examined before starting the treatment, at the end of the treatment and 3 months after completion the treatment, using the questionnaire. ]
Study Record | ClinicalTrials.gov

Enoxaparin as Treatment for Vulvodynia (2009 — 2011)
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
Study Record | ClinicalTrials.gov

Search for Genetic Basis of Vulvodynia (2008 — 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).
Study Record | ClinicalTrials.gov

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]
Study Record | ClinicalTrials.gov

Dysbiosis in Localized Provoked Vulvodynia (LPV) (DMLPV) (2015 — 2017)
Vulvodynia - vulvar pain. The exact etiology has not been elucidated yet, and therapy is often unsatisfactory. Two main types of Vulvodynia exist, with the far more common type being Localized provoked vulvodynia (LPV), also known as Vestibulodynia, and in the past - Vestibulitis. This study will concentrate on this common disorder which affects young women, whose quality of life deteriorate significantly by the inability to experience vaginal sex. The vaginal microbiome The new field of microbiome research focuses on the composition of overall microorganisms in the human body and their impacts on our human health. Amazingly, the number of microbial cells within our body is 10 times greater than the sum of all our human somatic and germ cells, and they carry 150 times more genetic information than our own. Changes in the composition of the vaginal microbiota (dysbiosis) have been linked with different health and disease states. The vagina is colonized with around 108-109 bacteria/mL vaginal fluid which is comparable to the small intestine. Recently, the NIH Human Microbiome Project characterized the bacterial communities across the human body and found that the vagina harbors low complexity bacterial communities. These communities had the lowest alpha diversity (within sample diversity) among the different body sites and low beta diversity (between sample diversity) at the genus level. This diversity was high at the species level due to distinct Lactobacillus spp. The communities were sampled at the sub sites that included the posterior fornix, mid vagina and the vaginal introitus. There was little distinction between the three sites hence we will focus on posterior fornix. The vaginal communities of healthy women, have also been repeatedly observed to occupy one of five states, four dominated by Lactobacillus spp. and one by higher overall microbial diversity. Shifts between the community structures within individuals (dysbiosis) are associated with disease states so it would be interesting to study whether women with LPV belong to a different enterotype than healthy women. The vaginal microbial communities have been shown to change during different stages in a woman's life and to influence pregnancy. As early as 1930, Cruickshank and Baird described changes in the vaginal bacterial communities that occurred between the 5th and 7th month of pregnancy. In 2010 a study was undertaken among Amerindian women to examine the microbial vaginal signature at term in relation to delivery mode (n=9). Variability in vaginal taxa was noted between subjects particularly for Lactobacillus species. Metagenomic analysis of the vaginal microbiome in a cross-sectional study of 24 healthy pregnant women and 60 non-pregnant controls at three vaginal sites (introitus, posterior fornix and midvagina) found the richness and diversity of the vaginal microbiome to be reduced in pregnancy in ways that did not appear to be driven by BMI, race or ethnicity . As pregnancy progressed and as proximity to the uterus increased, less diversity and richness were noted. Lactobacillus species were enriched in pregnancy, which the authors postulated may be biologically significant as lactic acid bacteria produce bacteriocins that may reduce the risk of ascending infections. It has also been proposed that the vaginal microbiota has the potential to influence the conception process by influencing the local production of proinflammatory cytokines which in turn impact the survival rate and motility of sperm cells. The vaginal microbiome and Vulvodynia Several microorganisms have been discussed for presumed role in LPV development: LPV is frequently associated with preceding chronic recurrent candidiasis, LPV may be produced in a mouse model by repeated vulvovaginal fungal infection, the difficulty in treating women with concomitant LPV and candidiasis (complicated LPV), the reports of the beneficial effect of treatment with combined antibiotics, aimed at eradicating H. pylori peptic condition (although H. pylori has not been detected in LPV tissues). Indirect evidence of the role of the microbiome with the development of LPV may be deduced from the beneficial effect (14.3 - 50%), reported by some authors, of a diet avoiding oxalate and rich in Calcium citrate, on LPV. As women with LPV consume more oxalate - although not significantly, we suspect that the variability in response rate may be due to the indirect effect of the diet - through changes in the microbiome, which may be affecting LPV severity. In addition, the adverse effect of oral contraceptive pills (OCP) in increasing LPV symptoms; OCP tend to change the composition of the vaginal microbiota, consequent to their effect of thinning and dehydrating the vaginal mucosa. These finding prompt us to further inquire the possible association of vaginal microbiome dysbiosis and the development of LPV. Objective: The proposed study will first compare the vaginal microbiome of women with severe LPV, not treated by diet and otherwise healthy, to women without LPV (we will also compare our results to the NIH HMP data). At the second stage we will characterize the effect of a three-month low oxalate diet on the vaginal microbiota of women with LPV and on the outcome compared to a group of patients with LPV not treated by diet. Vaginal pH and date of menstrual cycle will be checked. We propose that dysbiosis in the vaginal microbiota may trigger the development of LPV. Vulvodynia subtype:
  • The research will study women with localized provoked Vulvodynia
  • Only secondary type of LPV will be included.
  • LPV diagnosis will be based on documenting first two Friedrich's criteria for vulva vestibulits syndrome: patient's complaint of entry dyspareunia, a positive Q-tip test.
  • Only women suffering from levels II or III dyspareunia according to Marinoff : Level II is where the pain prevents intercourse from taking place on most occasions; and Level III where pain results in total apareunia.
Methods/Protocol This will be a double blind, prospective study comparing the microbiome of women with severe LPV to women without LPV, and to compare the effect of consuming the low oxalate diet with calcium citrate supplements for one month on the microbiome of women with LPV. The local Institutional Review Board approval has been requested. Every woman participating in the study will sign an informed consent prior to enrollment. Study group The study group will consist of 35 women:
  • Meeting first two Friedrich's criteria for vulva vestibulitis syndrome
  • Diagnosed by a gynecological examination with Localized Provoked Vulvodynia
  • Diagnosed with a Level II or III degree of the syndrome according to Marinoff Control group
  • The control group will consist of 35 consecutive women who are referred to the departments of the co-investigators. Presentation of LPV is an exclusion criterion.
Materials and Methods: Prior to enrollment, the women will be questioned about possible inclusion and exclusion criteria, and fill in the ISSVD Vulvodynia questionnaire. Women found suitable for the study will undergo a Q-tip test to confirm the diagnosis of Vestibulodynia. Women of the LPV group will be instructed to consume a "low oxalate diet" with calcium citrate supplements, as recommended by Solomons et al for the duration of at least one month, to assess its impact on the vaginal microbiome. Clinical pain scores and vulvar sensitivity by Q-tip test will be repeated after one month and compared to the clinical pain scores at the beginning of the study. Subjective evaluation will be carried out by comparing personal data from questionnaires filled in at enrollment and one month later. Clinical evaluation will be performed by an experienced vulvar expert, using the pain intensity scale (The 11 points (0-10) pain intensity numerical rating scale-PI-NRS), in seven foci throughout the vestibule (the Q-tip test) and by comparing patients' responses to questionnaires evaluating pain during intercourse or other activities (riding a bicycle/horse), before and after diet.
PRIMARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Change in vaginal microbiome composition of women with localized provoked vulvodynia following three months of low oxalate diet The microbiome components will be examined before and after the diet by characterization of the genomic components of the bacterial communities Within one week after three months of low oxalate diet
SECONDARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Level of dyspareunia following three months of low oxalate diet in women with localized provoked vulvodynia The level of vestibular tenderness will be examined before and after the diet Within one week after three months of low oxalate diet
Study Record | ClinicalTrials.gov

Is Localized Provoked Vulvodynia Caused by Laxity of the Utero-Sacral Ligaments? (2017 — 2018)
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).
Study Record | ClinicalTrials.gov

Lori Brotto, PhD Professor of Obstetrics and Gynecology University of British Columbia
"Vestibulitis Educational Seminar Trial" Study (2006 — 2009)
The purpose of this study is to investigate the efficacy of an educational seminar series for women with vulvar vestibulitis syndrome (VVS).
HYPOTHESIS: It is hypothesized that this educational seminar series might be effective in reducing the pain experienced and improving sexual response and quality of life of women with Vulvar Vestibulitis Syndrome (VVS) by providing an open forum for discussion of the pathology, etiological theories, treatment plans as well as the impact of sexual pain on sexual relationships and ways to cope with VVS. At Vancouver Hospital, the current waitlist for women with distressing, unremitting genital pain is approximately 10 months. Once accepted for management, the diagnosis of VVS is given, where applicable, by Dr. Sadownik. Only women with pure VVS and without a compounding skin condition are then referred on to the 3-session educational seminars given by Dr. Thomson. By the end of the educational series, women have an understanding of current scientific literature on etiology and treatment of VVS, and it's interaction with sexual health factors. At this point they are referred for individualized treatment of the VVS either by Dr. Thomson, Dr. Sadownik or back to their referring physician. This study aims to explore the existing VVS Educational Seminars by measuring sexual function, sexual distress, pain levels (general pain, genital pain and pain upon sexual activity), psychological well-being (depression and anxiety), relationship satisfaction, sexual knowledge and overall quality of life at pre- and post seminar. An age-matched control group of women diagnosed with VVS, but unable to attend the Seminar series, will complete the measures at the same intervals as the treatment group. The use of the control group allows us to accurately evaluate the efficacy of the Educational seminars, above and beyond non-specific factors. Vulvar Vestibulitis Syndrome Educational Seminars have been run through the Vulvar Disease Clinic at Vancouver Hospital since 2001, however no data has been collected to determine the effects of this program. By collecting pre- & post seminar and follow up data, this study will allow us to assess the efficacy of the VVS Educational Seminars when compared to a group of women suffering from VVS but unable to attend the information seminars. Given that a large proportion of the women cannot be treated at Vancouver Hospital and are instead referred back to their family physician, the VVS Educational Seminar is a necessary first step in the treatment process for ensuring that women receive accurate and timely treatment. It will also help treatment providers improve and expand their current treatment practices Study Record | ClinicalTrials.gov

Pregnancy, Childbirth Intentions and Outcomes Under Sexual Pain (PRECIOUS) (2012 — 2016)
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.
Study Record | ClinicalTrials.gov

Integrated Mindfulness-based Cognitive Behaviour Therapy Versus Cognitive Behaviour Therapy for Provoked Vestibulodynia (COMFORT) (2012 — 2017)
PURPOSE: The purpose of this study is to determine whether an 8-session MBCT intervention for PVD is no worse than an 8-session CBT intervention for improving women's pain intensity and reducing their sexual distress, catastrophizing and hypervigilance towards pain. The investigators will also examine whether pain improvements at follow-up are mediated by changes in self-compassion and mindfulness (in the MBCT arm only) and moderated by pre-treatment credibility, personality, and anxiety sensitivity. HYPOTHESES:
  1. At follow-up (4 weeks, 6 months and 12 months post-treatment), women in the MBCT arm will experience a greater decline (vs. pre-treatment) in vestibular pain intensity compared to women in the CBT arm.
  2. At follow-up (4 weeks, 6 months and 12 months post-treatment), women in the MBCT arm will experience a greater decline (vs. pre-treatment) in sex-related distress, pain catastrophizing, hypervigilance, and self-reported pain during intercourse/other penetrative sex compared to women in the CBT arm.
  3. The investigators hypothesize that improvements in pain intensity during vestibular touch will be mediated by changes in self-compassion and mindfulness in the MBCT arm only at 6 and 12 months follow-up.
  4. The investigators hypothesize that pre-treatment credibility, personality, and anxiety sensitivity will significantly moderate improvements in pain intensity during vestibular touch at 6 and 12 months follow-up.
  5. The investigators hypothesize improvements in both arms on the "Patient Global Impression of Change Scale" and significantly greater improvements in the MBCT arm relative to the CBT arm at follow-up (4 weeks, 6 months and 12 months post-treatment).
Primary Outcome Measures:
  1. Change in Vulvslgesiometer Pain Rating From Baseline to One Month Post-treatment to 6 Months Post-treatment [ Time Frame: Pre-treatment, one month post-treatment and 6 months post-treatment. ]
    The investigators have selected pain intensity during a controlled examination as the primary endpoint in this study. Specifically, pain intensity at the vulvar vestibule will be assessed using a vulvalgesiometer. The vulvalgesiometer is an instrument that provides a measure of pain/sensitivity that can be standardized across time points. The vulvalgesiometer is calibrated to exert a fixed amount of pressure. In this study, 30 grams of pressure at the 1, 3, 4, 6, 8, 9, and 11 o'clock positions (randomly) around the vestibule will be applied using the vulvalgestiometer. Women will also report their pain at each site using a numeric rating scale from 0 (no pain) to 10 (worst pain ever).
Secondary Outcome Measures:
  1. Self-reported Pain During Penetration [ Time Frame: Pre-treatment,one month post-treatment, and 6 months follow-up. ]
    The investigators will measure self-report of pain during attempted or completed intercourse (or dildo entry for non-heterosexual women). Numeric Rating Scale that asked participants to rate the "intensity of pain during vaginal penetration attempts with sexual intercourse or penetration over the past 4 weeks" This question was rated on a 0 to 10 scale from no pain (0) to worst possible pain (10).
  2. Sexual Function [ Time Frame: Pre-treatment, one month post-treatment, and 6 months post-treatment. ]
    The investigators will examine women's self-reported sexual function by administering the Female Sexual Function Index (FSFI). The Female Sexual Function Index (FSFI) is a 19-item self-report questionnaire which assesses sexual function in women. It covers six sexual domains: lubrication, arousal, desire, pain, orgasm and satisfaction. Scores range from 7.2 - 36 where increase in sexual dysfunction is represented by lower scores. Subscales: Desire- 2, 3 [Subscale scores Range: 1.2 - 6] Arousal- 5,6,7,8 [Subscale Scores Range: 1.2 - 6] Lubrication- 9,10,11,12 [Subscale Scores Range: 1.2 - 6] Orgasm- 13, 14, 15 [Subscale Scores Range: 1.2 - 6] Satisfaction- 1, 16, 17 [Subscale Scores Range: 1.2 - 6] Pain- 18, 19, 20 [Subscale Scores Range: 1.2 - 6] Extra item: (4) have you been sexually active in past 4 weeks? (yes/no) [Scores Range 0 (no) - 1 (yes)] Note: Ranges applicable only if question 4 was answered "yes".
  3. Sexual Distress [ Time Frame: Pre-treatment, one month post-treatment, and 6 months post-treatment. ]
    The investigators will examine women's self-reported sexual distress by administering the Female Sexual Distress Scale-Revised. This is a 12-item self-report questionnaire assessing for sexuality related personal distress. Scores on the scale range from 0 - 48, where higher scores represent higher levels of distress.
  4. Pain Catastrophizing [ Time Frame: Pre-treatment, one month post-treatment, and 6 months post-treatment.. ]
    The investigators will examine women's self-reported pain catastrophizing by administering the Pain Catastrophizing Scale. The Pain Catastrophizing Scale (PCS) is a self-report questionnaire that asks participants to think about past painful experiences, or a specific experience of pain, and to indicate the degree to which they have any of the presented thoughts or feelings when they are experiencing pain. Each one of the 13-items is rated on a Likert scale from 0 (not at all) to 4 (all the time), where a higher total score indicates higher pain catastrophizing. Subscales: Rumination- (4 items) 8, 9, 10, and 11 [Scores Range: 0 - 16] Magnification- (3 items) 6, 7, and 13 [Scores Range: 0 - 12] Helplessness- (6 items) 1, 2, 3, 4, 5, and 12 [Scores Range: 0 - 24] Sum of all items [Overall Range: 0 - 52]
  5. Pain Hypervigilance [ Time Frame: Pre-treatment, one month post-treatment, and 6 months post treatment. ]
    The investigators will examine women's self-reported hypervigilance about pain by administering the Pain Vigilance and Awareness Questionnaire. The Pain Vigilance and Awareness Questionnaire (PVAQ) is a 16 item self-report measure to assess the awareness, vigilance, preoccupation and observation of pain. Sum total score [Scores Range: 0 - 80].
  6. Chronic Pain Acceptance, Activities Engagement [ Time Frame: Pre-treatment, one month post-treatment, and 6 months post-treatment. ]
    The investigators will examine women's self-reported pain acceptance, activities engagement, by administering the CPAQ chronic pain acceptance questionnaire. The Chronic Pain Acceptance Questionnaire (CPAQ) measures the degree of acceptance of pain by chronic pain patients. It consists of 20 items measuring two domains, Activities Engagement and Pain Willingness. Total score range is from 0 - 120, with higher scores indicating higher levels of pain acceptance. Subscales: Activities engagement (11 items)- Q 1, 2, 3, 5, 6, 8, 9, 10, 12, 15, 19 [Scores Range: 0 - 66] Pain willingness (9 items)- Q 4, 7, 11, 13, 14, 16, 17, 18, 20 [Scores Range: 0 - 54]
  7. Chronic Pain Acceptance, CPAQ Pain Willingness [ Time Frame: Pre-treatment, one month post-treatment, and 6 months post treatment. ]
    The investigators will examine women's self-reported pain acceptance, activities engagement, by administering the CPAQ chronic pain acceptance questionnaire. The Chronic Pain Acceptance Questionnaire (CPAQ) measures the degree of acceptance of pain by chronic pain patients. It consists of 20 items measuring two domains: Activities Engagement and Pain Willingness. Total score range is from 0 - 120, with higher scores indicating higher levels of pain acceptance. Subscales: Activities engagement (11 items)- Q 1, 2, 3, 5, 6, 8, 9, 10, 12, 15, 19 [Scores Range: 0 - 66] Pain willingness (9 items)- Q 4, 7, 11, 13, 14, 16, 17, 18, 20 [Scores Range: 0 - 54] Study Record | ClinicalTrials.gov

Integrated Mindfulness for Provoked Vestibulodynia (IMPROVED) (2008 — 2017)
This study aims to test the efficacy of a 4-session intervention (Group psychoeducational treatment) using a randomized study design. Participants will be randomized in to 'immediate treatment' or 'waitlist control'. Women in the wait-list condition will receive the 4-session IMPROVED treatment, just as women randomized to the experimental group, after the end of their wait-list period.  
Primary Outcome Measures:
  1. Pain intensity [ Time Frame: one week pre-treatment to one week post treatment ]
    Pain intensity will be measured with the Q-tip test- a standard method of diagnosing vestibulodynia and assessing the pain associated with the diagnosis. The Q-tip test involves the physician lightly touching a Q-tip to specific areas around the vulvar vestibule while the patient indicates how much pain they feel on a scale from 0-10 in response to this provoked touch.
  2. Long-term pain intensity [ Time Frame: One week pre-treatment to 6 months post preatment ]
    Pain intensity will be measured with the Q-tip test- a standard method of diagnosing vestibulodynia and assessing the pain associated with the diagnosis. The Q-tip test involves the physician lightly touching a Q-tip to specific areas around the vulvar vestibule while the patient indicates how much pain they feel on a scale from 0-10 in response to this provoked touch
Secondary Outcome Measures:
  1. Sexual Distress [ Time Frame: One week pre-treatment, one week post treatment and 6-months follow up ]
    The investigators will examine women's self-reported sexual distress by administering the Female Sexual Distress Scale-Revised (Derogatis et al, 2008)
Other Outcome Measures:
  1. Pain Catastrophising [ Time Frame: one week pre-treatment, one week post treatment and 6-months follow-up ]
    The investigators will examine women's self-reported pain catastrophising by administering the Pain Catastrophizing Scale (Sullivan, Bishop & Pivik, 1995).
  2. Pain hypervigilance [ Time Frame: one week pre-treatment, one week post treatment and 6-months follow-up ]
    The investigators will examine women's self-report hypervigilance about pain by administering the Pain Vigilance and Awareness Questionnaire, McCracken, 1997)
Study Record | ClinicalTrials.gov

Candace Brown, PharmD, MSN Professor, Departments of OB-GYN, Pharmacy & Psychiatry University of Tennessee
Savella in Treatment for Provoked Vestibulodynia (2010 — 2012)
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.
Study Record | ClinicalTrials.gov

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. Study Record | ClinicalTrials.gov

Monica Buhrman, PhD Senior Lecturer/Associate Professor Department of Psychology Uppsala University
Internet-based Treatment for Provoked Vestibulodynia (2019 — 2021)
Provoked vestibulodynia is a pain condition, which is associated with lower quality of life and discomfort. Furthermore, it is underdiagnosed and undertreated. Provoked vestibulodynia is defined as vulvar pain with no known cause. Provoked vestibulodynia can be generalized and involve several areas of the vulva. It can also be localized and involve only one area of the vulva. Pain is often provoked by touch or pressure but it can also be spontaneous or both. The life prevalence for vestibulodynia varies between 3-28 percent in different populations. Persons with vestibulodynia report more frequently anxiety-, depression- and stress- symptoms than the normal population.
The aim of the present study is to evaluate an internet-based treatment for vestibulodynia. The intervention will be based on Acceptance and commitment therapy (ACT) and cognitive behavior therapy with focus on exposure and acceptance.
Patients suffering from vestibulodynia often experience psychological distress. Acceptance and commitment therapy (ACT) has been shown to be effective in treating psychological distress and pain. However delivering relevant treatment can be difficult due to logistics, cost and lack of personnel with required competence. Delivering ACT though the internet (iACT) is a novel approach, sidestepping logistical issues while lowering costs. There is however, a need to research this kind of treatment for persons with vestibulodynia. This study will primarily investigate whether an ACT-treatment administered through the internet can be beneficial for patients suffering from provoked vestibulodynia. The treatment will be 10 weeks long. Participants will be randomized to the treatment program or a waiting-list control group. Analysis of possible mediating variables will be able to give insight into the internal workings of the treatment itself, further elucidating efficacy of specific interventions, data which will be useful in future developments of treatment design. The treatment will consist of a 10-week period where participants would get access to a series of treatment modules, each addressing a separate problem area using ACT techniques. The treatment includes modules focuses on acceptance and exposure techniques. The participants will receive every week different exposure assignments. The platform used is an existing platform employed by the Pain Center at Uppsala university hospital for delivering internet based treatments. The study will be conducted using a randomized controlled trial with a between-group design. Participants will be randomized to two groups, were one group will gain access to iACT treatment while the second group will be a wait-list control, and will gain access to the program once treatment of the active group is finished. A licensed psychologist will assess participants. In addition to online ACT modules, consisting of information, exercises and homework assignments, all participants will have regular contact by secure email-channel with a licensed psychologists or last-year psychology student under supervision. This contact will guide treatment, providing support, feedback on homework, and if necessary clarify treatment content and help with IT-related problems interfering with treatment adherence. After a year, participants will be invited to take part in a follow-up module, consisting of limited treatment recapitulation and evaluation.
PRIMARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Female sexual function index It measures sexual dysfunction with 19 items. The answers are rated in a likert scale ranging from 0-5 regarding sexual activity. The results are presented in one total scale Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Female sexual distress-scale It measures distress related to sexual function with 13 items and an additional question. The answers are rated from Always, Often, Sometimes, Rarely and Never. The results are presented in one total scale Baseline-, post-(at 10 weeks) and follow up- measure (6months)
 
SECONDARY OUTCOME MEASURES: 
Outcome Measure Measure Description Time Frame
Brunnsviken Brief Quality of Life Inventory (BBQ) BBQ has a total of 12 items covering six life areas: Leisure, View on life, Creativity, Learning, Friends and Friendship, and View on self. All items are scored using the same response format, consisting of a five-step Likert rating scale, visually scored 0-4 with written anchor points at 0 (Strongly disagree) and 4 (Strongly agree). The BBQ total score is computed by summing the weighted satisfaction ratings, i.e. by multiplying the Satisfaction and Importance items for each life area and summing the six products for a total score (possible score range 0-96). Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Pain severity scale in Multidimensional Pain Inventory (MPI) The pain severity scale contains three items ranging from 0 to 6 (seven points) and measures pain intensity. The score is calculated by adding the score for each item divided by the number of items (scores range from 0-6). Higher scores indicate greater pain intensity. Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Montgomery Åsberg Depression Rating Scale (MADRS-S) The Montgomery Åsberg Depression Rating Scale measures depression symptom with 9 items.The respondents rate their symptoms on a scale that ranges from 0 to 6, where a higher value indicates a higher level of depressive symptoms. The score can range from 0-54, higher scores indicate more severe depressive symptoms e.g. a score >35 indicates a severe depression. The questionnaire includes questions on the following symptoms 1. Apparent sadness 2. Reported sadness 3. Inner tension 4. Reduced sleep 5. Reduced appetite 6. Concentration difficulties 7. Lassitude 8. Inability to feel 9. Pessimistic thoughts 10. Suicidal thoughts Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Generalised Anxiety Disorder 7-item scale (GAD-7) Generalized Anxiety Disorder 7-item scale /GAD-7) measures anxiety with 7 items. The GAD-7 score is calculated by assigning scores of 0, 1, 2, and 3, to the response categories of "not at all," "several days," "more than half the days," and "nearly every day," respectively, and then adding together the scores for the seven questions. GAD-7 total score for the seven items ranges from 0 to 21. Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Vaginal penetration cognition questionnaire (VPCQ) The Vaginal penetration cognition questionnaire (VPCQ) measures cognitions regarding vaginal penetration are assessed where the participant score in a likert scale ranging from 0-6 in 22 statements. Possible answers range from "0 = not at all applicable" to "6 = very strongly applicable." The VPCQ consists of 5 subscales: Control Beliefs (4 items), Catastrophic and Pain Beliefs (5 items), Self-Image Beliefs (6 items), Positive Beliefs (5 items), and Genital Incompatibility Beliefs (2 items). Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Chronic pain acceptance questionnaire (CPAQ) Chronic pain acceptance questionnaire (CPAQ) measures with 20 items acceptance related to pain and an aspect of psychological flexibility. It is a process variable and consists of two subscales, Willingness and Engagement. Items are rated on a scale from 0 (never true) to 6 (always true).Higher scores denote greater activity engagement and pain willingness.The total score is also reported, higher scores is associated with higher levels of acceptance. Baseline-, mid-(week 5), post-(at 10 weeks) and follow up- measure (6months)
Committed Action Questionnaire-8 (CAQ-8) Committed Action Questionnaire (CAQ-8) measures commitment, an aspect of psychological flexibility. It is a process variable and consists of 8 items. lease rate the truth of each statement as it applies to you by circling a number. The rating scale ranges from 0(never true)to 6 (always true). The total score represents an individual's general propensity to persist in goal-directed behaviour, capturing both positive and negative aspects of the construct. Higher values indicating higher levels of committed action. Baseline-, mid-(week 5), post-(at 10 weeks) and follow up- measure (6months)
Mindful Attention Awareness Scale (MAAS) The Mindful Attention Awareness Scale (MAAS) is a 15-item scale designed to assess a core characteristic of dispositional mindfulness, namely, open or receptive awareness of and attention to what is taking place in the present. Mindful attention awareness, an aspect of psychological flexibility. It is a process variable. The responder mark their response in a 1-6 scale and indicate how frequently or infrequently the person currently have each experience. To score the scale, the mean of the 15 items is calculated. Higher scores reflect higher levels of dispositional mindfulness. Baseline-, mid-(week 5), post-(at 10 weeks) and follow up- measure (6months)
Treatment credibility scale (TCS) The treatment credibility scale (TCS) measures how credible the treatment is perceived by the participant where the participant rates five statements. Every item i rated on a scale from 1 to 10, the last question is rated from 0% to 100%. The score is calculated by adding the score for each item.Higher values are associated with higher expectancy and credibility. After the first treatment week
CHAMP Sexual Pain Coping Scale (CSPCS), Sexual Pain Coping Scale (CSPCS) measure avoidance and endurance coping behaviors during penetration with 12-item. This measure consists of three sub-scales: avoidance, endurance and alternative strategies. Respondents rate their agreement of each statement between 1 ("Never true") and 7 ("Always true"). Total scores range from 4-28 on each sub-scale.12 items that measures cognitions and emotions related to sex and sexual pain Baseline-, post-(at 10 weeks) and follow up- measure (6months)
Quality of dyadic relationship (QDR-36) Measures 5 dimensions (Dyadic Consensus, Dyadic Satisfaction, Dyadic Sensuality, Dyadic Cohesion and Dyadic Sexuality)of a relationship with 36 items. Answers are rated in a scale that ranges from 1-6, an average score is calculated for every dimension. The average in every dimension is summed and an index is calculated which ranges from 5-30. The quota for the total questionnaire ranges from 6 to 1. Higher scores indicate good perceived quality in the relationship while lower scores indicate lower quality in the relationship.
Study Record | ClinicalTrials.gov

An Investigation of Nomothetic Versus Idiographic Assessment in Chronic Pain (2022 — 2023)
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
Study Record | ClinicalTrials.gov

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].
Study Record | ClinicalTrials.gov

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].
Study Record | ClinicalTrials.gov

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.

Christina Damsted Petersen, MD Department of Obstetrics and Gynecology Rigshospitalet University Hospital
Botox on Vulvar Vestibulitis (2005 — 2008)
The study seeks to evaluate the effect of botulinum toxin on vulvar vestibulitis (VVS) after local injection with Botox, a potential treatment to relieve patients of vulvar pain, reducing the need for painkillers, and improving the sexual quality of life of the patients.
Vulvar vestibulitis (VVS) is characterized by pain confined to the vulvar vestibule that occurs upon touch and attempted introitus entry ( e.g. intercourse, tampon insertion), with minimal associated clinical findings. The aetiology of VVS is not well established and many variables have been associated with the condition, e.g. neuropathy secondary to inflammation. Injection of Botulinum Toxin is tested as a therapeutic option for this condition. A temporary paralytic effect on the surrounding skeletal muscle hypertonicity is seen and earlier in cases described as a successful treatment of pelvic floor dysfunction, dyspareunia and interstitial cystitis.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Reduce vulvar pain on a visual analogue scale (VAS).
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Investigate the effect on sexuality, quality of life, marital relationship, depression and need of analgesics
Study Record | ClinicalTrials.gov

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. Study Record | ClinicalTrials.gov

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.

Cemal Tamer Erel Istanbul University
Therapeutic Efficacy of Erbium:YAG Laser in Postpartum Patients With Episiotomy Scars (2022 — 2024)
Episiotomy is a planned surgical incision to the perineum and posterior wall of the vagina during the second stage of labor. The fibrotic and sclerotic scar tissue formed as part of the healing process of episiotomies may cause pain. Therefore, episiotomy is associated with sexual dysfunction due to the painful sexual intercourse, chronic pain and infections and scarring in long term. 40% of the patients complain about persisted dyspareunia after 6 months of delivery. Genital pelvic pain/penetration disorders disturb the quality of sexual life of the couple and affect the psychology and wellbeing of the partners. Since, vulva is rich in afferent nerve endings, episiotomy scar healing is associated with pain. Er:YAG laser is a safe option for the treatment of vulvar pain. Er:YAG laser is a non-invasive and non-ablative procedure that strengthens the connective tissue in the vaginal wall. It provides controlled thermal energy and causes shrinkage of the collagen fibrils in the vaginal epithelium and lamina propria. It also induces neocollagenesis, elastogenesis and neoangiogenesis by temperature change. With minimum damage to the peripheral tissue, the viable cells in the target tissue react to this temperature change by expressing heat shock proteins (HSP). Then, HSP increases the levels of transforming growth factor-beta, fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, vascular epithelial growth factor which induce neocollagenesis and neoangiogenesis. Therefore, the thermal energy stored in the vaginal wall induces proliferation of the epithelium which is rich in glycogen, neovascularization and collagen production in the lamina propria. Er:YAG laser is also an effective modality to treat the scar tissue formed after the mediolateral episiotomy since it is a matter of functionality and esthetics. By tissue remodeling effect Er:YAG laser will improve the scar tissue of episiotomy and ameliorate the vulvar pain. In this study, the therapeutic effect of Er:YAG laser on the tissue healing of the episiotomy scars and the reduction of vulvar pain. PRIMARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Efficacy: Rate of change of pain Change of vulvar pain in patients with mediolateral episiotomy measured by visual analogue scale (0-10) 6 months
Efficacy: Rate of scar tissue healing Evaluation of the efficacy and safety of scar tissue healing by USG Elastography for fibrosis 6 months
SECONDARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Efficacy: Rate of improvement in sexual function Evaluation of the change of Genital Pelvic Pain by Female Sexual Function Index 6 months
Safety: Incidence and severity of device related Adverse Events Incidence and severity of device related Adverse Events (i.e., infections, edema, superficial burns, wound dehiscence) 6 months
Study Record | ClinicalTrials.gov

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 — 2021)
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/

Bradford Fenton, MD, PhD Summa Health System
Effect of Repetitive Transcranial Direct Current Stimulation (tDCS) on Chronic Pelvic Pain (2009 — 2009)
We will rigorously test whether modulation of the motor cortex by transcranial direct current stimulation (tDCS) is an effective treatment for patients with chronic pelvic pain through the following specific aims: A) The primary aim of this study is to determine whether transcranial direct current stimulation applied to the motor cortex in patients with chronic pelvic pain induces a significant decrease in the pain or symptoms as compared with sham tDCS. We will also measure changes in the clinical symptom scores of multiple pelvic organs, drug intake (narcotic), anxiety, depression, traumatic stress, as well as overall improvement in the quality of life to assess the effects of this treatment. B) Determine the duration of the clinical effects of tDCS. We will therefore compare the amelioration of pain and related symptoms between active and sham tDCS for one year following treatment. C) Determine whether tDCS changes the threshold for pain detection as compared with sham tDCS. Patients with chronic pelvic pain have a lower threshold for pain as compared to healthy subjects and we hypothesized that this threshold will increase after stimulation with tDCS. D) Finally, we will examine whether 5 days of tDCS treatment is safe for use in chronic pelvic pain patients. Safety will be assessed through neuropsychological tests and adverse event reporting.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Patient Global Assessment (PGA): 2 weeks
Visual analog scale (VAS) for pain: 2 weeks
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Interstitial cystitis symptom index: 2 weeks
Study Record | ClinicalTrials.gov

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.

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? Study Record | ClinicalTrials.gov 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 (2011 — 2013)
The purpose of this protocol is to determine whether pain with sexual intercourse can be reduced in menopausal, breast cancer survivors and to evaluate the effectiveness of a non-hormonal therapy (Lidocaine Liquid) vs. a placebo liquid in reducing pain. The investigators hypothesize that the pain arises in the vulvar vestibule. The investigators predict that the localized use of lidocaine will be more efficacious than use of placebo liquid.
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.

IIan Gruenwald Rambam Medical Center
The Use of Low Intensity Shock Wave Therapy for the Treatment of Provoked Vestibulodynia Disorder (PVD) (2018 — 2020)
Provoked vestibulodynia (PVD) is an exhausting pain syndrome that immensely affects quality of sexual life, and consequently negatively affects quality of life. Low intensity shock wave therapy produces physical forces that lead to pain relief. Aim: To evaluate the feasibility, safety and efficacy of low-intensity shockwave therapy in patients with provoked vestibulodynia. Methods: A double-blinded, randomized, sham-controlled, prospective study of 32 women. The treatment protocol included a series of treatments, performed twice a week for 6 weeks. Each treatment consisted of 500 pulses of low intensity shockwaves (0.09 mJ/〖mm〗^2 ) using the "Medispec ED-1000®" shock wave generator or sham. The study was a single center, double-blinded, randomized, sham-controlled, prospective study. Study eligibility criteria were treatment at the Neuro-urology Unit in Rambam Medical Center, during January 2018 - January 2020 and a diagnosis of PVD. PVD diagnosis was based on description of the pain and on a positive cotton swab test15. Women were randomized at a 2:1 ratio to treatment or sham groups. The treatment protocol included a series of treatments, performed twice a week for 6 weeks, for a total of 12 sessions. Each treatment consisted of 500 pulses of low intensity shockwaves (0.09 millijoul/〖mm〗^2 ) using the "Medispec ED-1000®" shock wave generator. The sham protocol included the same treatment protocol without shock wave generator activation. The patients were evaluated three times throughout the trial by an investigator blinded to the group allocation: before the first treatment, and one and three months after the twelfth treatment. Pain was assessed by both subjective and objective measures. The primary outcome measure was a change in dyspareunia, as assessed by scores on the 10-point visual analogue scale (VAS) (range 0-10 ). Secondary outcome measures for evaluating pain were increases in pain threshold and tolerance, assessed by a quantitative validated algometer test16, 17, the Wong-Baker pain FACES scale (range 0-10)18, the Female Sexual Function Index (FSFI) (range 2-38)19 and the Patients' Global Impression of Change scale (PGIC) (first component range 0-7; 0=no change, 7=a great deal better; second component range 0-10; 0=much better and 10=much worse)20. The PGIC assessed the self-reported impression of a general change due to the intervention. The algometer applied was a very basic and simple device that was assembled and used at our unit after validating its safety, accuracy, and adequacy in evaluating introitus pain vs control (doctorate dissertation). For assessing the pain threshold with the algometer, radial pressure (mmHg) was applied by progressively inflating a cylindrical balloon inserted in the introitus. The participant was required to report the first painful sensation, and this pressure, defined as the threshold pressure, was registered. The measurement was performed sequentially 4 times and the average of the measured pressures was considered the first pain threshold). Finally, for pain tolerance measurement, the participant was again asked to report when she had reached her pain limit (1-10 on the verbal scale ) upon continuous pressure.  
Primary Outcome Measures:
  1. Visual Analog Scale (VAS) [ Time Frame: 1 year ]
    The primary outcome was a change in dyspareunia, as assessed by scores on the 10-point Visual Analogue Scale where 1 is the minimum score meaning painless and 10 is the maximum score meaning excruciating pain
Secondary Outcome Measures:
  1. Algometer testing [ Time Frame: 1 year ]
    measures threshold of pain in mmHg, where any threshold below 100 mmHg is considered pathological
  2. Wong-Baker pain FACES scale [ Time Frame: 1 year ]
    from a scale of 1 to five showing sad face for score 1 and very happy face for score 5
  3. Female Sexual Function Index (FSFI) [ Time Frame: 1 year ]
    A validated questionnaire assessing female sexual dysfunction, any score above 22.5 is pathological
  4. Patients' Global Impression of Change scale. [ Time Frame: 1 year ]
    one question with a scale from -3 to+3 where 0 is not better nor worse, -3 is much worse and +3 is much better
Study Record | ClinicalTrials.gov

Yaron Hamani, MD Hadassah Medical Organization
The Use of Acupuncture for the Treatment of Vulvar Vestibulitis (2006 — 2007)
Randomized controlled trial designed to determine whether acupuncture is an effective treatment for vestibulitis.
Detailed Description:
Patients were randomized to five acupuncture sessions designed to treat pain in the vulvar area (study group), or five acupuncture sessions designed for tranquility (controls). Participants and evaluating gynecologists were blinded to randomization. Participants were examined clinically before treatment and one month after completion of assigned treatment; at both visits they completed the Female Sexual Function Index (FSFI) questionnaire. FSFI scores for pain during intercourse and total score were used to evaluate change. The examining gynecologist evaluated the degree of sensitivity to touch and the degree of local erythema. Response to treatment was evaluated for each group before and after treatment, and for study group compared to the control group.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Female Sexual Function Index (FSFI) questionnaire 1 month after completion of the assigned treatment
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Clinical examination Visual presence or absence of vestibular erythema 1 month after completion of the assigned treatment
Study Record | Beta ClinicalTrials.gov

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/.

Women's Health Study: Immunological Factors and Risk of Vulvodynia (2009 — 2014)
Women aged 18-40 years who were seen for any reason within a 2-year period at one of the Twin Cities metro-area's Fairview Health Services outpatient clinics will be send a confidential self-administered questionnaire, and given the option to return it by mail, or complete it via phone or via a secure online server. This questionnaire will serve to determine any history of unexplained vulvar pain. Those with a history of past or current vulvar pain likely to represent vulvodynia, will be asked to come to one of four study clinic locations to confirm the diagnosis of vulvodynia. If confirmed, they will be asked to provide venous blood and vulvovaginal specimens. In addition, they will be asked to complete a medical history and psychosocial survey, along with an interviewer-administered Structured Clinical Interview for the Diagnostic and Statistical Manual-IV (SCID-IV). A random sample of women with no history of vulvar pain will be asked to serve as controls. Those confirmed as controls will also be asked to provide the same biological specimens and complete the same questionnaires/interview. The long-term objective of this research is to provide etiological information that may prove critical to the treatment and prevention of vulvodynia, an under-recognized and extremely debilitating condition that we and others have shown may affect up to 10% of the adult female population.  
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Reproductive, gynecological and environmental exposures and their association with vulvodynia & immuno-inflammatory response Determine whether reproductive, gynecological and environmental exposures influence the odds of vulvodynia, and whether the effect is associated with immuno-inflammatory response Baseline
Past psychological trauma and psychiatric morbidity and their association with vulvodynia & immuno-inflammatory response Determine whether psychological trauma and psychiatric morbidity influence the odds of vulvodynia and whether the effect is associated with immuno-inflammatory response 6 month post baseline visit
immuno-inflammation and nerve fiber proliferation and vulvodynia. Determine whether markers of immuno-inflammation and nerve fiber proliferation are directly associated with the odds of vulvodynia, and, whether genetic and microbiological markers modify associations, as well as associations evaluated in aims 1 and 2 above. Baseline
 

Vesna Harni, MD Obstetrician-Gynecologist Ginekološka Poliklinika, Zagreb
Diagnostic Accuracy of "Three Rings Vulvoscopy" for Detection of Vulvar Dermatosis (DATRIV) (2011 — 2016)
The objective of the study was to determine sensitivity, specificity and diagnostic accuracy of "Three Rings Vulvoscopy" for detection of vulvar dermatosis using histopathology as the reference standard. "Three Rings Vulvoscopy" (TRIV) is a new, and original technique for performing colposcopy of the vulva, taking into account three different skin types and zones as well as morphological evaluation of vulvar lesions according to their specificity (non-specific and lesions specific for dermatosis). To evaluate the clinical value of TRIV, we designed two index tests, a quantitative test called "Vulvoscopy Index" and a semi-quantitative test marked as "N-S-P scheme." The sensitivity, specificity and diagnostic accuracy of both index tests were estimated in comparison with histopathology as the reference test in two groups of 164 consecutive patients with vulvar discomfort (82 patients with vulvar dermatosis and 82 patients with vulvodynia ) and 164 consecutive patients without vulvar discomfort (82 patients with "normal vulva" and 82 patients with "impaired vulvar skin"). The study was performed stratified, on three levels, whereby the first two levels were pre-assignments. The first level of the study was an evaluation of vulvar discomfort during the routine gynecological care in the clinic "Poliklinika Harni" Zagreb, Croatia, where we searched for symptomatic patients; and in the esthetic gynecological unit of the same clinic, where we searched for asymptomatic patients. Vulvar discomfort was evaluated anamnestically by the "International Society for the Study of Vulvovaginal Disease (ISSVD) Vulvodynia Pattern Questionnaire." On the second level, we performed detailed clinical examination (inspection and Cotton-Swab test), searching for non-specific and lesions specific for skin (vulvar) dermatosis, and patients with vulvodynia who fulfilled Friedrich's criteria. Patients with vulvar infection or pre/malignancy were excluded from the study. Vulvar lesions in patients with vulvodynia were not relevant to the diagnosis of vulvodynia. Among women without vulvar discomfort, we described those without any clinical findings ("normal vulva") and those with some non-specific findings on the vulva. We called this group "impaired vulvar skin." The results of the clinical examination were collected using "TRIV Form Data." On this way, we identified four groups of patients during the recruitment: vulvar dermatosis, vulvodynia, impaired vulvar skin, and normal vulva. For each patient with vulvar dermatosis (82 patients), the first consecutive patient with vulvodynia (82), impaired vulvar skin (82) and normal vulva (82) were taken for comparison. The third level of the study presents the investigation and included diagnostic interventions "Three Rings Vulvoscopy" and vulvar biopsy with histopathology. The results of vulvoscopy were collected using "TRIV Form Data" and then assessed by "Vulvoscopy Index" and the "N-S-P Scheme." Biopsy of the vulva from the symptomatic patients was taken to confirm/exclude vulvar dermatosis. Asymptomatic patients, who were recruited from patients undergoing planned labiaplasty, granted vulvar samples to further investigation. The statistical tests were made on a personal computer (PC) in the Statistical Package 12.0. All qualitative variables are shown in the tables with the absolute number and percentage. Quantitative variables are presented with arithmetic mean and standard deviation (if normal distribution), and by the median and range (if not a normal distribution). A chi-squared test was used to test the difference between qualitative variables among the two groups. A chi-squared test with Yates correction was used for 2x2 size tables, and Fisher's exact test was used for small values. T-test proportions were used for the evaluation of the differences between the two percentages. Variance analysis (ANOVA) and post hoc Tukey HSD were used to test quantitative variables with normal distribution between multiple groups. Differences between the arithmetic mean of the two groups were tested by t-test. Variables that did not have normal distribution were tested by nonparametric tests. The differences between several groups were tested by Kruskal-Wallis ANOVA and the differences between the two groups Mann-Whitney U test.
Primary Outcome Measures:
  1. Diagnostic Accuracy of "Three Rings Vulvoscopy" by the "Vulvoscopy Index" for Detection of Vulvar Dermatosis [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the distribution of patients with and without vulvar dermatosis diagnosed by "Three Rings Vulvoscopy" (TRIV) using the "Vulvoscopy Index" and histopathology as a reference test. The Vulvoscopy Index as an outcome measure of TRIV is designed as a quantitative test based on five characteristics: vulvar complaints, Marinoff index, Cotton-Swab test, vulvar lesions according to the three vulvar rings and specificity of lesions; with following results: "Normal Vulva" (0-2 points), "Impaired Vulvar Skin" (3-11 points), "Vulvodynia" (12-18 points), and "Vulvar Dermatosis" (19-32 points). Since histopathology distinguishes only patients with and without vulvar dermatosis, the clinical value the Vulvoscopy Index had been estimated according to these two groups of patients. Patients with vulvoscopy diagnoses: "Normal Vulva," "Impaired Vulvar Skin" and "Vulvodynia" were classified into the group "Absent Vulvar Dermatosis."
  2. Distribution of Patients With Vulvar Dermatosis Diagnosed by Vulvoscopy (TRIV) and Histopathology According to Single Categories of the "Vulvoscopy Index" [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the distribution of patients with "Vulvar Dermatosis" diagnosed by "Three Rings Vulvoscopy" and histopathology according to single categories of the "Vulvoscopy Index." We described five categories within the Vulvoscopy Index:
    1. Vulvar complaints (present vs. absent),
    2. Marinoff index (positive vs. negative),
    3. Cotton-Swab test (positive vs. negative),
    4. Vulvar lesions according to the vulvar rings (Outer, Middle, and Inner Vulvar Ring Lesion) and
    5. Specificity of lesions (Non-specific and Specific Lesions).
  3. Distribution of Patients With "Absent Vulvar Dermatosis" Diagnosed by Vulvoscopy (TRIV) and Histopathology According to Single Categories of the "Vulvoscopy Index" [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the distribution of patients with "Absent Vulvar Dermatosis" diagnosed by "Three Rings Vulvoscopy" (patients with vulvoscopical diagnoses "Normal Vulva," Impaired Vulvar Skin "and" Vulvodynia") and histopathology, according to single categories of the "Vulvoscopy Index." The five categories within the Vulvoscopy Index are:
    1. Vulvar complaints (present vs. absent),
    2. Marinoff index (positive vs. negative),
    3. Cotton-Swab test (positive vs. negative),
    4. Vulvar lesions according to the vulvar rings (Outer, Middle, and Inner Vulvar Ring Lesion) and
    5. Specificity of lesions (Non-specific and Specific Lesions).
  4. "Vulvoscopy Index" (Mean ± SD) in Patients With "Vulvar Dermatosis" Diagnosed by Vulvoscopy (TRIV) and Histopathology [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the results of "Three Rings Vulvoscopy" (TRIV) by single categories of the "Vulvoscopy Index" (mean ± SD) in patients with "Vulvar Dermatosis" diagnosed by TRIV and histopathology. The Vulvoscopy Index is based on five characteristics:
    1. Vulvar complaints (negative=0; positive=4 points),
    2. Marinoff index (negative=0; positive=3 points),
    3. Cotton-Swab test (negative=0; positive=2 points),
    4. Vulvar lesions according to the vulvar rings (Outer Vulvar Ring Lesions=4 points; Middle Vulvar Ring Lesions=2 points and Inner Vulvar Ring Lesions=1 point) and
    5. Specificity of lesions (Non-Specific Lesions=2 points; Specific Lesions=14 points).
    According to the Vulvoscopy Index, we have set the diagnoses: "Normal Vulva" (0-2 points), "Impaired Vulvar Skin" (3-11 points), "Vulvodynia" (12-18 points), and "Vulvar Dermatosis" (19-32 points). The likelihood of the diagnosis of "Vulvar Dermatosis" was higher as the value of the Vulvoscopy index was higher.
  5. "Vulvoscopy Index" (Mean ± SD) in Patients With "Absent Vulvar Dermatosis" Diagnosed by Vulvoscopy (TRIV) and Histopathology [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the results of "Three Rings Vulvoscopy" (TRIV) by single categories of the "Vulvoscopy Index" (mean± SD) in patients with "Absent Vulvar Dermatosis" diagnosed by TRIV and histopathology. According to the Vulvoscopy Index, we have set the diagnoses: "Normal Vulva" (0-2 points), "Impaired Vulvar Skin" (3-11 points), "Vulvodynia" (12-18 points), and "Vulvar Dermatosis" (19-32 points). Since histopathology can distinguish only patients with and without vulvar dermatosis, the distribution was estimated according to these two groups of patients. Hence, patients with vulvoscopical diagnoses "Normal Vulva," Impaired Vulvar Skin "and" Vulvodynia" were classified into the one group called "Absent Vulvar Dermatosis." The likelihood of the diagnosis of "Absent Vulvar Dermatosis" was higher as the value of the Vulvoscopy index was lower.
  6. "Vulvoscopy Index" (Median | Range) in Patients With "Vulvar Dermatosis" Diagnosed by Vulvoscopy (TRIV) and Histopathology [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the results of "Three Rings Vulvoscopy" (TRIV) by single categories of the "Vulvoscopy Index" (median ± SD) in patients with "Vulvar Dermatosis" diagnosed by TRIV and histopathology. The Vulvoscopy Index is based on five characteristics:
    1. Vulvar complaints (negative=0; positive=4 points),
    2. Marinoff index (negative=0; positive=3 points),
    3. Cotton-Swab test (negative=0; positive=2 points),
    4. Vulvar lesions according to the vulvar rings (Outer Vulvar Ring Lesions=4 points; Middle Vulvar Ring Lesions=2 points and Inner Vulvar Ring Lesions=1 point) and
    5. Specificity of lesions (Non-specific Lesions=2 points; Specific Lesions=14 points).
    According to the Vulvoscopy Index, we have set the diagnoses: "Normal Vulva" (0-2 points), "Impaired Vulvar Skin" (3-11 points), "Vulvodynia" (12-18 points), and "Vulvar Dermatosis" (19-32 points). The likelihood of the diagnosis of "Vulvar Dermatosis" was higher as the value of the Vulvoscopy index was higher.
  7. "Vulvoscopy Index" (Median | Range) in Patients With "Absent Vulvar Dermatosis" Diagnosed by Vulvoscopy (TRIV) and Histopathology [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the results of "Three Rings Vulvoscopy" (TRIV) by single categories of the "Vulvoscopy Index" (median ± SD) in patients with "Absent Vulvar Dermatosis" diagnosed by TRIV (patients with vulvoscopical diagnoses "Normal Vulva," Impaired Vulvar Skin "and" Vulvodynia") and histopathology. According to the Vulvoscopy Index, we have set the diagnoses: "Normal Vulva" (0-2 points), "Impaired Vulvar Skin" (3-11 points), "Vulvodynia" (12-18 points), and "Vulvar Dermatosis" (19-32 points). The likelihood of the diagnosis of "Absent Vulvar Dermatosis" was higher as the value of the Vulvoscopy index was lower.
  8. Diagnostic Accuracy of "Three Rings Vulvoscopy" by the "N-S-P Scheme" for Detection of Vulvar Dermatosis [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The distribution of patients with and without vulvar dermatosis diagnosed by vulvoscopy ("N-S-P Scheme") and histopathology. According to the specificity of lesions, vulvoscopy results were classified as normal "N" (absence of any lesion), suspect "S" (non-specific lesions) and pathologic "P" results (lesion specific to dermatosis); and each of the three vulvar rings is represented by a single result. The final vulvoscopy result is presented in the form of a three-letter formula, where the first letter indicates the vulvoscopy result in the Outer Vulvar Ring, the mean initial indicates the vulvoscopy result of the Middle Vulvar Ring and the last letter denotes the vulvoscopy result of the Inner Vulvar Ring. "N-S-P Scheme" divides the results of the vulvoscopy into three groups: "Normal Vulvoscopy," "Suspect Vulvoscopy" and "Pathological Vulvoscopy." Diagnosis of vulvar dermatosis was established if one or more vulvar rings showed pathological results ("Pathological Vulvoscopy").
  9. Distribution of Vulvar Lesions According to the "N-S-P Scheme" in Patients With Vulvar Dermatosis Diagnosed by Vulvoscopy (TRIV) and Histopathology [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the distribution of vulvoscopy lesions in relation to the vulvar rings and their specificity according to the "N-S-P Scheme," in patients with vulvar dermatosis diagnosed by vulvoscopy (TRIV) and histopathology. Vulvoscopy findings of each of the three vulvar rings: Outer (first letter in the formula), Middle (second letter), and Inner Vulvar Ring (third letter) were evaluated as normal "N" (absence of any lesions), suspect "S" (non-specific lesions), or pathological "P" (lesions specific for dermatosis). "Normal vulvoscopy" indicated the absence of any lesion in all three vulvar rings ("N-N-N"). "Suspect vulvoscopy" was used to mark findings of non-specific lesions ("S-#*-#"; "S-S-#"; "S-S-S"; "S-N-S" etc.). "Pathological vulvoscopy" spelled out the finding of lesions specific for dermatosis in any of the three vulvar rings ("P-#-#"; "P-P-"; "P-P-P"; "P-N-S" etc.).
    • is the label for any of the three possibilities: N or S or P.
  10. Distribution of Vulvar Lesions According to the "N-S-P Scheme" in Patients With Absent Vulvar Dermatosis Diagnosed by Vulvoscopy (TRIV) and Histopathology [ Time Frame: ISSVD Questionnaire and TRIV, up to 75 minutes for each participant. ]
    The table shows the distribution of lesions according to their specificity and vulvar rings in patients without vulvar dermatosis diagnosed by vulvoscopy (TRIV) and histopathology, as a reference test. According to the "N-S-P scheme," we have set the diagnoses: "Normal result" (no lesion), "Suspect result" (non-specific lesion in any of the vulvar rings), and "Pathological result" (specific for dermatosis in any of the vulvar rings). Since histopathology can distinguish only patients with and without dermatosis, the distribution was estimated according to these two groups of patients. Hence, patients with normal and suspect vulvoscopic results were classified into one group called "Absent Vulvar Dermatosis."
Secondary Outcome Measures  :
  1. Baseline Characteristics: Age [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the age in four groups of patients with and without vulvar discomfort.
  2. Baseline Characteristics: Weight [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the weight in four groups of patients with and without vulvar discomfort.
  3. Baseline Characteristics: Height [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the height in four groups of patients with and without vulvar discomfort.
  4. Baseline Characteristics: BMI [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the body mass index (Mean ± SD) in four groups of patients with and without vulvar discomfort.
  5. Demographic Data in Patients With and Without Vulvar Discomfort [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows demographic data - age: more or less than 65 years, reproductive age, menopause, domicile country as a country of birth, the degree of education (more and less than 12 years), marital status, births, abortions, and using of contraception among four groups of patient.
  6. Various Characteristics and Duration of Vulvar Discomfort in Patients With Vulvar Dermatosis and Vulvodynia [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows various characteristics of vulvar pain (complaints) in patients with vulvar dermatosis or vulvodynia. Generally, we can differentiate between two categories of pain - the dull pain vs. the sharp pain depending on the nerve fibers in the skin, which are involved in the provocation of the pain. The symptoms of the dull pain are burning, stinging, soreness, irritation, itching, feeling of inflammation and aching. The symptoms of the sharp pain are a knife-like pain, paper-cuts pain, stabbing and sticking. We do not know, are there some symptoms characteristic for vulvar dermatosis or vulvodynia.
  7. Sexual Activity and Abstinence in Patients With and Without Vulvar Discomfort [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows sexual activity and sexual abstinence due to dyspareunia or lack of a sexual partner in four groups of patients.
  8. Dyspareunia and Marinoff Index in Patients With and Without Vulvar Discomfort [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the degree of dyspareunia in sexually active patients with and without vulvar discomfort. We used Marinoff Index as a measure of the degree of dyspareunia. Negative Marinoff Index (0) is a sign of the absence of dyspareunia. Four grades of Marionoff Index are: Marinoff Index 0 = no dyspareunia; Marinoff Index 1= discomfort/pain with intercourse that doesn't interfere with the frequency of sex; Marinoff Index 2= pain with intercourse which sometimes prevents intercourse and Marinoff Index 3= pain with intercourse preventing any intercourse.
  9. Aggravation Of Vulvar Complaints Depending On Sexual Intercourse In Patients With Vulvar Dermatosis And Vulvodynia [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The relationship between sexual vulvar discomfort and sexual intercourse (provocation and aggravation) in patients with vulvar dermatosis and vulvodynia, as recommended in the ISSVD Questionnaire.
  10. Aggravation of Vulvar Discomfort Through Various Triggers in Patients With Vulvar Dermatosis and Vulvodynia [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the relationship among worsening of vulvar discomfort by using tampons, cycling, wearing tight clothes, menstruation, and urination in patients with vulvar dermatosis and vulvodynia.
  11. Problems Associated With Urination and Defecation in Patients With and Without Vulvar Discomfort [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the incidence of the problems with urination and defecation in four groups of patients with and without vulvar discomfort.
  12. Other Associated Symptoms and Diseases in Patients With and Without Vulvar Discomfort [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the incidence of the other associated symptoms and diseases in four groups of patients, as recommended in the ISSVD Questionnaire.
  13. Previous Treatment of Patients With Vulvar Dermatosis and Vulvodynia [ Time Frame: ISSVD Questionnaire, up to 30 minutes for each participant. ]
    The table shows the incidence of the previous treatment in patients with vulvar dermatosis and vulvodynia.
  14. Cotton Swab Test (Q-Tip) in Patients With and Without Vulvar Discomfort [ Time Frame: Cotton Swab Test, up to 10 minutes for each participant. ]
    The table shows the results of Cotton-Swab Test in four groups of patients. Cotton-Swab Test or Q-Tip Testing is part of a multidisciplinary approach to the assessment of sexual pain, especially, vulvodynia or vestibulodynia, in women. ISSVD recommended the Cotton-Swab test for the differential diagnosis of vulvodynia. The test consists of using a cotton-swab to palpate multiple vulvar and vestibular site while recording the woman's pain. We performed Cotton-Swab Test by touching the vulva at 6 points (each vulvar ring), organized into locations based on a clock face and marked like the hours on the clock: 2h, 4h, 6h, 8h, 10h, and 12 h.
  15. Distribution of Non-Specific and Specific Vulvar Lesions in Relation to The Three Vulvar Rings (TRIV) [ Time Frame: Three Rings Vulvoscopy, up to 45 minutes for each participant. ]
    The table shows the distribution of non-specific and specific vulvar lesions in relation to the three vulvar rings (TRIV). The "OUTER Vulvar Ring" includes vulvar skin, the "MIDDLE Vulvar Ring" encompasses the modified mucosa, and the "INNER Vulvar Ring" is presented with glicogenized mucosa. "Non-Specific Lesions" include non-specific erythema, punctuations, papillae, paleness and smoothness, fissures or sores in the absence of infection and pre/malignancy in any part of the vulva. "Specific Lesions" comprise eczematous inflammation with thickened, excoriated skin within chronic lichen simplex; hypopigmented or white lesions, fusion or resorption of the labia minora and clitoral hood, loss of vulvar architecture and sclerotic changes in lichen sclerosis; white reticular pattern to extensive erosion with agglutination or resorption of the labia within lichen planus and psoriatic erythematous papules with silver, scaly plaques.
  16. Distribution of Non-Specific and Specific Lesions of the Outer Vulvar Ring According to the "Three Rings Vulvoscopy" [ Time Frame: Three Rings Vulvoscopy, up to 45 minutes for each participant. ]
    The table shows the distribution of the non-specific and specific lesions of the vulva according to individual structures of the Outer Vulvar Ring according to the TRIV. The "OUTER Vulvar Ring" includes vulvar skin with the following structures: mons pubis, labia majora, and the perineum. "Non-Specific Lesions" include non-specific erythema, punctuations, papillae, paleness and smoothness, fissures or sores in the absence of infection and pre/malignancy in any part of the vulva. "Specific Lesions" (lesions specific for vulvar dermatosis) comprise eczematous inflammation with thickened, excoriated skin within chronic lichen simplex; hypopigmented or white lesions, fusion or resorption of the labia minora and clitoral hood, loss of vulvar architecture and sclerotic changes in lichen sclerosis; white reticular pattern to extensive erosion with agglutination or resorption of the labia within lichen planus and psoriatic erythematous papules with silver, scaly plaques.
  17. Distribution of Non-Specific and Specific Lesions of the Middle Vulvar Ring According to the "Three Rings Vulvoscopy" [ Time Frame: Three Rings Vulvoscopy, up to 45 minutes for each participant. ]
    The table shows the distribution of non-specific and specific lesions of the vulva in relation to the individual structures of the Middle vulvar ring according to the "Three Rings Vulvoscopy." The "MIDDLE vulvar ring" includes the anterior commissure with the prepuce of the clitoris, interlabial sulci, labia minora, and the posterior commissure. "Non-Specific Lesions" include non-specific erythema, punctuations, papillae, paleness and smoothness, fissures or sores in the absence of infection and pre/malignancy in any part of the vulva. "Specific Lesions" comprise eczematous inflammation with thickened, excoriated skin within chronic lichen simplex; hypopigmented or white lesions, fusion or resorption of the labia minora and clitoral hood, loss of vulvar architecture and sclerotic changes in lichen sclerosis; white reticular pattern to extensive erosion with agglutination or resorption of the labia within lichen planus and psoriatic erythematous papules with silver, scaly plaques.
  18. Distribution of Non-Specific and Specific Lesions of the Inner Vulvar Ring According to the "Three Rings Vulvoscopy" [ Time Frame: Three Rings Vulvoscopy, up to 45 minutes for each participant. ]
    The table shows the distribution of non-specific and specific lesions of the vulva in relation to the individual structures of the Inner vulvar ring according to the "Three Rings Vulvoscopy." The "INNER vulvar ring" includes clitoris, Hart's line, urethral sulcus, urethral meatus, hymenal remnants, Bartholin's gland opening, and the vestibule. "Non-Specific Lesions" include non-specific erythema, punctuations, papillae, paleness and smoothness, fissures or sores in the absence of infection and pre/malignancy in any part of the vulva. "Specific Lesions" comprise eczematous inflammation with thickened, excoriated skin within chronic lichen simplex; hypopigmented or white lesions, fusion or resorption of the labia minora and clitoral hood, loss of vulvar architecture and sclerotic changes in lichen sclerosis; white reticular pattern to extensive erosion with agglutination or resorption of the labia within lichen planus and psoriatic erythematous papules with silver, scaly plaques.
  19. Aceto-Whitening Reaction (AWR) in Relation to the Three Vulvar Rings [ Time Frame: Aceto-Whitening Test, up to 10 minutes for each participant. ]
    The table shows the presence, the quality, and the distribution of the aceto-whitening reaction after 5% acetic acid application (Aceto-Whitening Test), in relation to the three vulvar rings. The "OUTER Vulvar Ring" includes vulvar skin, the "MIDDLE Vulvar Ring" encompasses the modified mucosa, and the "INNER Vulvar Ring" is presented with glicogenized mucosa. Acetic acid is thought to cause swelling of the epithelial tissue through reversible coagulation or precipitation of the nuclear proteins and cytokeratins. Areas of pre-/malignant lesions turn densely white and opaque immediately after application of acetic acid, due to the presence of large numbers of dysplastic cells in the superficial layers of the epithelium. The acetowhite appearance is not unique to pre-/malignancy; it is also seen in other conditions with increased nuclear protein. The acetowhite reaction varies in intensity, within and between patients.
  20. Velocity of the Aceto-Whitening Reaction (Mean ± SD) [ Time Frame: Aceto-Whitening Test, up to 10 minutes for each participant. ]
    The table shows the velocity (Mean ± SD) of the aceto-whitening occurrence after 5% acetic acid application (AWR - aceto-whitening reaction) in patients with positive AWR classified into four groups based on anamnestic data and clinical examination. Acetic acid is thought to cause swelling of the epithelial tissue through reversible coagulation or precipitation of the nuclear proteins and cytokeratins. Areas of pre-/malignant lesions turn densely white and opaque immediately after application of acetic acid, due to their higher concentration of abnormal nuclear protein and the presence of large numbers of dysplastic cells in the superficial layers of the epithelium. The acetowhite appearance is not unique to pre-/malignancy; it is also seen in other conditions with increased nuclear protein like immature squamous metaplasia, regeneration, inflammation, HPV-infection, hyperkeratosis, etc. The acetowhite reaction varies in intensity, within and between patients.
  21. Velocity of Aceto-Whitening Reaction (Median | Range) [ Time Frame: Aceto-Whitening Test, up to 10 minutes for each participant. ]
    The table shows the velocity (Median | Range) of the aceto-whitening occurrence after 5% acetic acid application (AWR - aceto-whitening reaction) in patients with positive AWR classified into four groups based on anamnestic data and clinical examination. Acetic acid is thought to cause swelling of the epithelial tissue through reversible coagulation or precipitation of the nuclear proteins and cytokeratins. Areas of pre-/malignant lesions turn densely white and opaque immediately after application of acetic acid, due to their higher concentration of abnormal nuclear protein and the presence of large numbers of dysplastic cells in the superficial layers of the epithelium. The acetowhite appearance is not unique to pre-/malignancy; it is also seen in other conditions with increased nuclear protein like immature squamous metaplasia, regeneration, inflammation, HPV-infection, hyperkeratosis, etc. The acetowhite reaction varies in intensity, within and between patients.
  22. Distribution of Aceto-Whitening Reaction in Relation to the Structures of the Outer Vulvar Ring [ Time Frame: Aceto-Whitening Test, up to 10 minutes for each participant. ]
    The table shows the distribution of aceto-whitening occurrence (AWR) after 5% acetic acid application in relation to the structures of the Outer Vulvar Ring. The "OUTER Vulvar Ring" is presented with the following structures: Mons Pubis, Labia Majora, and the Perineum. Acetic acid is thought to cause swelling of the epithelial tissue through reversible coagulation or precipitation of the nuclear proteins and cytokeratins. Areas of pre-/malignant lesions turn densely white and opaque immediately after application of acetic acid, due to the presence of large numbers of dysplastic cells in the superficial layers of the epithelium. The acetowhite appearance is not unique to pre-/malignancy; it is also seen in other conditions with increased nuclear protein. The acetowhite reaction varies in intensity, within and between patients.
  23. Distribution of Aceto-Whitening Reaction in Relation to the Structures of the Middle Vulvar Ring [ Time Frame: Aceto-Whitening Test, up to 10 minutes for each participant. ]
    The distribution of aceto-whitening occurrence after 5% acetic acid application (AWR - aceto-whitening reaction) in relation to the structures of the Middle Vulvar Ring. The "MIDDLE vulvar ring" encompasses the following structures: the anterior commissure with the prepuce of the clitoris, interlabial sulci, labia minora, and the posterior commissure.
  24. Distribution of Aceto-Whitening Reaction in Relation to the Structures of the Inner Vulvar Ring [ Time Frame: Aceto-Whitening Test, up to 10 minutes for each participant. ]
    The table shows the distribution of aceto-whitening reaction (AWR) after 5% acetic acid application (AWR - aceto-whitening reaction) in relation to the structures of the Inner Vulvar Ring. The "INNER Vulvar Ring" is presented with the following structures: the clitoris, Hart's line, the urethral sulcus, the urethral meatus, hymenal remnants, Bartholin's gland opening, and the vestibule. Acetic acid is thought to cause swelling of the epithelial tissue through reversible coagulation or precipitation of the nuclear proteins and cytokeratins. Areas of pre-/malignant lesions turn densely white and opaque immediately after application of acetic acid, due to the presence of large numbers of dysplastic cells in the superficial layers of the epithelium. The acetowhite appearance is not unique to pre-/malignancy; it is also seen in other conditions with increased nuclear protein. The acetowhite reaction varies in intensity, within and between patients.
  25. Histopathological Characteristics of Vulvar Specimens in Patients With And Without Vulvar Discomfort [ Time Frame: Histopathological Examination, up to 30 minutes for each vulvar sample. ]
    The table shows the distribution of histopathological findings of vulvar epidermis among patients with and without vulvar discomfort, classified into four groups based on anamnestic data, clinical examination and "Three Rings Vulvoscopy." Histopathological characteristics of vulvar epidermis included hyperkeratosis, parakeratosis, acanthosis, and epidermal atrophy. In the vulvar dermis, there were evaluated presence of inflammatory infiltrates (monocytes, lymphocytes, mastocytes), collagen fibers, hyalinization, hyperpigmentation, elongated dermal papillae, blood vessels, sebaceous glands, and nerve fibers.
  26. Histopathological Features of the Vulvar Epidermis and Vulvar Discomfort in Patients With Vulvar Dermatosis [ Time Frame: Histopathological Examination, up to 30 minutes for each vulvar sample. ]
    The table shows the relationship between histopathological features of the vulvar epidermis (normal versus abnormal) and single vulvar symptoms from the categories of the dull ("slow") and sharp ("fast") pain of the vulva in 82 patients with vulvar dermatosis. The dull pain comprises sensations of burning, stinging, soreness, irritation,itching, inflammation and aching. The fast pain includes sensations like sticking and stabbing, paper-cut or knife-like pain.
  27. Histopathological Features of the Vulvar Epidermis and Vulvar Complaints in Patients With Vulvodynia [ Time Frame: Histopathological Examination, up to 30 minutes for each vulvar sample. ]
    The table shows the relationship between histopathological features of the vulvar epidermis (normal versus abnormal), and single vulvar symptoms from the categories of the dull ("slow") and sharp ("fast") pain of the vulva in 82 patients with vulvodynia diagnosed anamnestically and clinically following Friedrich's criteria. The "dull" pain comprises sensations of burning, stinging, soreness, irritation, itching, inflammation and aching. The "fast" pain includes sensations like sticking and stabbing, paper-cut or knife-like pain.
  28. Histopathological Features of Vulvar Dermis in Patients With Vulvar Dermatosis Depending On The Duration of Vulvar Discomfort [ Time Frame: Histopathological Examination, up to 30 minutes for each vulvar sample. ]
    The table shows the relationship between histopathological features of the vulvar dermis depending on the duration of vulvar discomfort (less or more than 24 months) in 82 consecutive patients with vulvar dermatosis. Histopathological characteristics of vulvar dermis included inflammatory infiltrates (mononuclear, lymphocytes, mastocytes), collagen fibers, hyalinization, hyperpigmentation, elongated dermal papillae, blood vessels, sebaceous glands, and nerve fibers.
  29. Histopathological Features of the Vulvar Dermis in Patients With Vulvodynia Depending on The Duration of Vulvar Discomfort [ Time Frame: Histopathological Examination, up to 30 minutes for each vulvar sample. ]
    The table shows the relationship between histopathological features of the vulvar dermis depending on the duration of vulvar discomfort (less or more than 24 months) in 82 patients with vulvodynia, diagnosed anamnestically and clinically following Friedrich's criteria. Histopathological characteristics of vulvar dermis included inflammatory infiltrates (mononuclear, lymphocytes, mastocytes), collagen fibers, hyalinization, hyperpigmentation, elongated dermal papillae, blood vessels, sebaceous glands, and nerve fibers. Study Record | ClinicalTrials.gov

Lumara Health Inc.
Safety and Efficacy of Two Vaginal Products Versus Placebo in Patients With Vaginal Discomfort (2007 — 2009)
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 ]
Study Record | ClinicalTrials.gov

Lee Hullender Rubin, DAOM, LAc Oregon College of Oriental Medicine
Provoked, Localized Vulvodynia Treatment With Acupuncture and Lidocaine Pilot Study (2013 — 2016)
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).
Study Record | ClinicalTrials.gov

Chery Iglesia, MD Professor MedStar Health
Clobetasol Propionate Versus Fractionated Carbon Dioxide Laser for the Treatment of Lichen Sclerosus (CuRLS) (2015 — 2019)
This study is being done to compare the effects, good and bad, of fractionated CO2 laser treatment and clobetasol propionate .05% ointment on vulvar lichen sclerosus.
Vulvar lichen sclerosus (LS) is a well-characterized dermatosis resulting in labial atrophy, synechiae and introital narrowing and can often cause dyspareunia, itching and co-existent vulvar pain. Biopsy is necessary to confirm the clinical diagnosis and the mainstay of treatment usually consists of topical steroid therapy (Chi). Clobetasol propionate and mometasone furoate are potent topical steroids that have long been considered gold-standard treatment for vulvar lichen sclerosus and work through anti-inflammatory, anti-mitotic, and immunosuppressive effects. One of the complications of long-term steroid use, however, is potential thinning of the vulvar skin, therefore limiting long-term use. Clobetasol propionate has a range of efficacy from 61-91% depending on the selected outcome criteria. The vulvovaginal SmartXide -V2-LR laser system by DEKA (Calezano, Italy) is a fractionated C02 laser with maximum 40 Watt power and laser energy emission at 10,600 nanometer wavelength which is mainly absorbed by water in the underlying tissue (Salvatore). The SmartXide-V2-LR system was first introduced in 2009 with DOT therapy distributing fractioned CO2 laser in small spots of 200 microns to the vulvar skin or vaginal epithelium, resulting in a portion of the skin remaining intact with less tissue destruction and faster healing (Salvatore). The device is cleared by the US Food and Drug Administration (FDA) for incision, excision, ablation, and coagulation of gynecologic soft tissues. The fractioned therapy has been shown to stimulate fibroblastic growth through activation and biosynthesis of collagen and restoration of the extracellular matrix with collagen fibers. Very little is known about long-term effects of fractionated C02 laser therapy use in the vulva or vagina, although the treatment is widely accepted in plastic and cosmetic surgery and dermatology. Increased marketing for laser vaginal rejuvenation has spawned a proprietary female genital cosmetic surgery industry in the US with very limited published outcome data. SmartXide -V2-LR has some established outcome data for treatment of genitourinary syndrome of menopause (GSM), also known as vulvovaginal atrophy (Salvatore). The purpose of this study is to compare the safety and efficacy of clobetasol propionate .05% ointment to fractionated CO2 laser procedure for the treatment of vulvar lichen sclerosus. Women presenting to the urogynecology clinic will be screened for lichen sclerosus. Vulvar biopsy will be performed for confirmation, and, if eligible, the patient will be consented to undergo baseline questionnaires, photodocumentation of vulvar lesions and randomization. A minimum of 2 weeks are required from the time of biopsy to treatment. Patient will be randomized to monthly LASER treatment for 3 months or topical STEROID therapy (clobetasol propionate .05% ointment nightly for one month then three times weekly for 2 additional months) in a 1:1 ratio using a computer generated randomization schedule. Because of the nature of the treatment, it will not be possible to blind patients but the assessor will be blinded to the intervention. Patients may have used clobetasol propionate in past, but must complete 8 week wash out period. Patient questionnaires include multiple validated scales and surveys to provided reproducible measures of vulvar symptoms as primary and secondary outcomes. Questionnaires will be completed at the intake visit, repeated at 6 month and one year follow up. The investigators expect improved subjective and objective results in the LASER group at 6 months compared with the STEROID group. At 6 months, participants are giving the option to crossover to receive the other treatment arm if desired due to continued symptoms. All groups are followed to 12 months for comparison. Sample size calculations were conducted using the absolute change in the Skindex 29 as the primary end point. Out study will reach 80% power to detect a mean difference of 16 points on the Skindex 29 (sd=22 for both groups) between the study groups with 25 patients in each group, or 50 in total based on a one-sided two-sample t-test with alpha=0.05 (He). By accounting for 10% attrition, the investigators propose to recruit 56 patients to the study to be randomized with a 1:1 ratio to each group, with a blocked component for those who used tropical clobetasol in the past. Data will be entered into a secure RedCAPS Database which provides complete auditing for data management processes. De-identified backup data will be kept in locked files at the participating site. Plans for publication will be handled by the investigators at MedStar Washington Hospital Center and will adhere to publication policies. All personnel with access to data collected have completed the Program for Ethics Education in Research training with the appropriate HIPAA certification. Patients will not be compensated for travel and may be accountable for some medical bills for office visits. Study location is Medstar Lafayette Office 1133 21st St NW, Washington, DC 20036.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Change in SkinDEX-29 Score The Skindex-29 is a validated questionnaire for assessing acute dermatologic symptoms over a 4-week period. The Skindex-29 is a 29 question version of the original SkinDEX questionnaire. Total numeric score is reported ranging from 0-100. Scores reported as a change between six months and baseline with more negative scores indicating greater improvement in symptoms (better outcome). Change from baseline score to score at six months
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Change in Subjective Vulvovaginal Symptoms Questionnaire (VSQ) Subjective measure of vulvar symptoms of itching, burning, dyspareunia of Lichen Sclerosus. VSQ is a 21-item instrument and scores range from 0 to 20 with increased scores indicating increased vulvovaginal symptom bother. The change in VSQ is reported with more negative scores indicating greater improvement. Baseline to six months
Change in Subjective Vulvovaginal Symptoms Questionnaire (VSQ) Subjective measure of vulvar symptoms of itching, burning, dyspareunia of Lichen Sclerosus. VSQ is a 21-item instrument and scores range from 0 to 20 with increased scores indicating increased vulvovaginal symptom bother. The change in VSQ is reported with more negative scores indicating greater improvement. Six month to one year after treatment
Number of Participants Considered Satisfied as Assessed by Health Related Quality of Life (HRQOL) Score Patient global impression of satisfaction total score on visual analog scale (very satisfied or satisfied) ranging from 1-5 with higher scores indicating greater satisfaction. Six months from treatment
Number of Participants Considered Satisfied as Assessed by Health Related Quality of Life (HRQOL) Score Patient global impression of satisfaction total score on visual analog scale (very satisfied or satisfied) ranging from 1-5 with higher scores indicating greater satisfaction. 1 year from treatment
Change Vaginal Health Index (VHI) Score The Vaginal Health Index is a five item scale with scores ranging from 5-25 with lower scores indicating greater urogenital atrophy. The change in VHI is express with more negative scores indicating greater improvement between study time points. Baseline to 6 months after treatment
Change Vaginal Health Index (VHI) Score The Vaginal Health Index is a five item scale with scores ranging from 5-25 with lower scores indicating greater urogenital atrophy. The change in VHI is express with more negative scores indicating greater improvement between study time points. Six month to one year after treatment
Change Vulvar Symptom Visual Analog Scale (VAS) Score Patient subjective scale of symptoms of Lichen Sclerosus. Each item scaled 0-10 with greater severity of symptoms indicated by higher score. Results expressed as change with more negative values indicating greater improvement. Baseline to 6 months after treatment
Change Vulvar Symptom Visual Analog Scale (VAS) Score Patient subjective scale of symptoms of Lichen Sclerosus. Each item scaled 0-10 with greater severity of symptoms indicated by higher score. Results expressed as change with more negative values indicating greater improvement in symptoms (better outcome). Six months to one year after treatment
Change SkinDEX-29 Score The Skindex-29 is a validated questionnaire for assessing acute dermatologic symptoms over a 4-week period. The Skindex-29 is a 29 question version of the original SkinDEX questionnaire. Total numeric score is reported ranging from 0-100. Scores reported as a change between six months and baseline with more negative scores indicating greater improvement. Six months to one year from treatment
Change Objective Provider VAS Visual Analog Scale Provider scored objective appearance of vulvar Lichen Sclerosus. Each item scaled 0-10 with greater severity of appearance indicated by higher score. Results expressed as change with more negative values indicating greater improvement. Baseline to Six months from treatment
Change Objective Provider VAS Visual Analog Scale Provider scored objective appearance of vulvar Lichen Sclerosus. Each item scaled 0-10 with greater severity of appearance indicated by higher score. Results expressed as change with more negative values indicating greater improvement. Six months to One Year from treatment
Number of Patients With Adverse Outcomes Total number for adverse outcomes (of any severity) to include description of pain, infection, de novo or worsening dyspareunia, contact dermatitis and burns from treatment Six Month to One Year from treatment
Number of Patients With Adverse Outcomes Total number for adverse outcomes (of any severity) to include description of pain, infection, de novo or worsening dyspareunia, contact dermatitis and burns from treatment. 12 Weeks to Six months from treatment
Number of Patients With Adverse Outcomes Total number for adverse outcomes (of any severity) to include description of pain, infection, de novo or worsening dyspareunia, contact dermatitis and burns from treatment. 12 Weeks from treatment
Study Record | ClinicalTrials.gov

Michael Ingber, MD Morristown Medical Center
CO2 Laser vs Lidocaine for Vestibulodynia in Premenopausal Women (2019 — 2021)
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
Study Record | ClinicalTrials.gov

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.

To Evaluate if the Medication Gabapentin Lessens Vulvar Pain (2007 — 2008)
There is not a "best" treatment plan for vulvar pain including vulvodynia (chronic vulvar pain) and vulvar vestibulitis syndrome (VVS, chronic vulvar pain localized to the vaginal opening). We propose that vulvodynia is a neuropathic pain (pain that effects the nervous system) as characterized by pain from stimuli that is not usually painful, stimuli that would not usually be painful causing significant pain, and burning pain. Gabapentin has been shown to be effective in treating chronic pain.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Change From Baseline in Vulvar Pain change in vulvar pain following gabapentin compared to placebo - will evaluate the efficacy of gabapentin to decrease vulvar pain compared to placebo. end of 1st treatment (after 8 weeks) and end of 2nd treatment (after 19 weeks). Pain was assessed using ordinal scale (0-10): 0 = no pain, 10 = most severe pain. 19 weeks

Linda LaBorde, BS PT, ProHealth Care, Inc
Cold Laser: A Modality to Promote Vulvar Healing and Pain Relief (2014 — 2015)
The objectives of this pilot study are to demonstrate effectiveness of application of the Erchonia Laser (manufactured by Erchonia Corporation),a non-invasive, non-significant risk low level laser red diode light therapy device, in providing relief of pain symptoms in patients with provoked and non- provoked vulvar vestibulitis; to reduce the frequency of use of oral medications to manage pain symptoms; and to reduce the debilitating affect vulvar vestibulitis has on the patient's daily activities, relationships and emotional well-being.
In the current proposed pilot study, application of a low level laser light device, manufactured by Erchonia Corporation, to reduce the pain of vulvar vestibulitis will be evaluated. The Erchonia Laser device will emit three independent 7 milliWatt, 635 nanometer red light diodes in a hand-held device and is a variable frequency pulsed wave device. Erchonia low level lasers have been determined safe and effective and non-significant risk (NSR) by the Food and Drug Administration (FDA) for application for numerous and various pain reduction indications, providing justification for the anticipated safety and effectiveness of application of the Erchonia Laser to reduce pain in patients with vulvar vestibulitis. The FDA has granted 510(k) clearances for Erchonia low level laser devices for five pain reduction indications, all cleared under Product Code 'NHN', defined as: "A light based non-laser device that emits energy in infrared or other wavelengths, provides non-heating and non-thermal effect, and is indicated for adjunctive use in pain therapy or related indication. It does not provide therapeutic topical heating." The research will be conducted at ProHealth Care; Inc. across four campuses. Patients will be seen in private rooms in the therapy departments. All study staff are licensed in the field of either Occupational Therapy or Physical therapy (2 in each) with the advanced continuing education necessary to call them a "specialist" in the treatment of pelvic floor disorders. All investigators will complete CITI training for research. Subjects will be referred into the ProHealth Care system via a prescription for pelvic floor therapy signed by a licensed medical professional with the expertise to diagnose Vulvar vestibulitis. Written information regarding the study and proposed treatment will also be mailed to a larger group of pelvic floor therapists in the greater Milwaukee Wisconsin region through a "Pelvic Floor Study Group" list informing them of the need for subjects with this diagnosis so that they may inform their clients of the availability of such research. These clients may then request a referral from their private health care provider. The pilot study will be completed in twelve months following the commitment of ProHealth Care, Inc. Institutional Review Board as well as procurement of initial funding through grants applied for during 2013. There will be 10 patients enrolled in the pilot study. Patients will be screened after they are referred by their physician for physical therapy.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Percent Improvement Change in Visual Analogue Pain Scale (VAS) Calculated With Q-tip Palpation Over 6 Sites From Baseline Visit to Follow up at Two Week From Last Visit III. Q-tip testing: . Q-tip pressure will be applied at the following areas, in the exact order listed: 2:00, 10:00, 5:00, 7:00, 12:00, and 6:00. An average VAS report of pain taken overall and compared from first baseline visit to end of study re-assessment two weeks following last treatment. • Pain intensity marked an a line with a point between 0-100 on the Visual Analogue Scale (VAS). A separate rating is recorded for each of the 6 numbered areas (see box 1 for reference). 100 is maximum pain level and 0 is no pain measured in centimeters per FDA guidelines for pain calculation on the VAS Average of all sites Compared from baseline visit and at 8 week (from start) follow up
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Change in Patient Specific Functional Scale Questionnaire Questionnaire that measures on a 0-10 scale (0= No function, and 10= normal function) one function that most impacts the patient's present symptoms (vaginal penetration/intercourse chosen as most important and pertinent) Measured amount of point change on the scale. Baseline, and two weeks following last treatment at Week 8
OTHER OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Change in the Vulvar Pain Functional Scale Questionnaire Questionnaire of eleven questions involving specific functions that may impart pain in the vulvar region and patient response to present tolerance level. Questions have 4-5 answer choices weighted on a 0-3 scale of impairment, with 3 being worst. Worst reported score of functional impact =33. No functional impact = 0 Baseline, and after last treatment visit at Week 8
Study Record | ClinicalTrials.gov

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. Study Record | ClinicalTrials.gov

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 (2015 — 2017)
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.
Study Record | ClinicalTrials.gov

Remote Mindfulness Education PLV (2018 — 2024)
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.
Study Record | ClinicalTrials.gov

Vestibulectomy Surgical Techniques Comparison Study (2022 — 2025)
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.
Study Record | ClinicalTrials.gov

Cherie LeFevre, MD St. Louis University
Vulvodynia: Identification of Potential Relevant Biomarkers (2019 — 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
Outcomes of Delivery in Patients With Dyspareunia (2013 — 2016)
The focus of this pilot study is to determine if a woman who experiences pain during sexual intercourse has a higher risk of complications during labor and delivery secondary to pelvic floor dysfunction, anxiety and intolerance towards pelvic examinations. Furthermore, it is unclear whether women with prepartum dyspareunia experience an improvement following vaginal delivery. While physicians may expect that vaginal birth improves dyspareunia due to the stretching effect on pelvic floor, to date, there is insufficient evidence to support this claim. The Investigators plan to prospectively study 200 patients at our Institution, collect information regarding birth and follow them, via questionnaires, regarding their dyspareunia postpartum.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Obstetrical outcome of women with a history of dyspareunia The Investigators will record the mode of delivery (vaginal, instrumental or cesarean section), length of the second stage of labor, use of anesthetics, perineal tears and\or episiotomies, and newborn's birth weight. The evaluation will be done prospectively, comparing data with matched controls without a history of dyspareunia. 3 months -1 year
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Rate of alleviation of dyspareunia following vaginal delivery as assessed through patient questionnaires. 2 years
Study Record | ClinicalTrials.gov

The Reciprocal Relations Between Psychosocial Characteristics and the Progression of Vestibulodynia (2016 — 2021)
Provoked vestibulodynia (PVD) is the term describing a syndrome of provoked, localized allodynia of the vestibule of the vulva, not explained by another condition, and lasting more than 3 months. PVD is not a defined disease but rather a symptom. It is thought that PVD represent a group of distinct disorders that have been classified together because they produce pain in the same anatomic location. Studies found that different factors such as genetic, inflammation, recurrent vaginitis, allergy, trauma, emotional and neural may be involved in the development of PVD. Treatment of PVD is generally predicated on a trial and error basis, because the pathogenesis is not defined. The result is that many forms of therapeutic interventions have been used, yet the evidence remains largely inconclusive, the response rates varies considerably, and many women do not respond to any of the treatments. It is therefore important to recognize which factors mediate the syndrome's severity, and influence the effectiveness of treatments. The proposed study will evaluate how different patients' characteristics (personality, cognitive) and responses (emotional and behavioral) influence the natural history of the syndrome and the response to treatment. The study is based on the bio-psycho-social model and the adult attachment theory, which integrates psychosocial factors to define susceptibility to acquire pain disorders and predict response to therapy. According to this model, choosing effective coping strategy during a crisis and receiving support from a spouse are vital for recovery. The study aim to:
  1. Characterize interactions between attachment patterns, personality types, cognitive factors (catastrophization, coherence, and partner's support), emotional factors (coping strategies, emotional stress and satisfaction from intimate relationship) to pain levels, pelvic floor hypertonicity, sexual function and patient's emotional health.
  2. Examine whether treatments' results are influenced by personality, relationship, cognitive, emotional and behavioral characteristics of the patient.
  3. Recognize factors that influence the extent of adherence to treatment.
  4. Characterize patients' profile in regard to successful outcome.
Methods Patients will be recruited from the clinic for vulvovaginal disorders in Clalit Healthcare services in Jerusalem. The diagnostic procedures, patients' sub-classification and the proposed treatments in the current protocol are identical to those currently used in the clinic. Each patient will undergo a standard evaluation which includes: detailed history intake, vulvar and vaginal examination, evaluation of vestibular tenderness (Q tip test), pelvic floor musculature tenderness examination, vaginal pH measurement, saline and 10% potassium hydroxide microscopy, yeast and bacterial cultures and STD screening. Patients who fulfill diagnostic criteria of PVD and who will be willing to participate in the study will be asked to sign an informed consent and complete the following self-administered intake questionnaires:
  • Socio-demographic questionnaire (age, marital status, religios, PVD onset, health status, education etc.)
  • Close Relations Experiences questionnaire
  • Five Factor Inventory -NEO-FFI
  • Pain catastrophizing questionnaire
  • Sense of Coherence Scale
  • Ways of giving support questionnaire
  • COPE -Multidimensional Coping Inventory
  • Semantic Differential Measure of Marital Satisfaction
  • PSS-10 - Perceived Stress Scale
  • FSFI-Female Sexual Function Index
Instructions for treatment will be given in regards to the diagnosis. Patients will be instructed to schedule follow-up appointments at 3,6,9, and 12 months. During follow-up appointments they will be assessed in regard to vestibular tenderness (using various parameters), as well as by the same questionnaires. Additional treatment will be recommended according to medical status, in an identical way to this routinely used in the clinic. 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. ]
Study Record | ClinicalTrials.gov

Subtypes of Provoked Vestibulodynia (2016 — 2021)
Background: Provoked vestibulodynia (PVD) is the term describing a syndrome of provoked, localized allodynia of the vestibule of the vulva, not explained by another condition, and lasting more than 3 months. PVD is not a defined disease but rather a symptom. It is thought that PVD represent a group of distinct disorders that have been classified together because they produce pain in the same anatomic location. Causes of these disorders include hormonal imbalance, mainly caused by hormonal contraception, nerve fiber proliferation in the vestibular mucosa and hypertonic pelvic floor dysfunction. PVD may appear with sexual debut or first attempts to insert a tampon (primary PVD) or can be a new onset of pain with activities that did not previously illicit pain (secondary PVD). Studies found that different factors such as genetic, inflammatory mediators, recurrent vaginitis, allergy and trauma may be involved in the development of PVD. A high percentage of patients with vulvar pain report an antecedent history of vulvovaginal candida infection, although it is unknown if this represents a true increase in incidence or a misdiagnosis. It has been suggested that repeated vulvovaginal infections are a triggering event for some women leading to chronic vulvar pain. This observation has led to hypothesis that in patients with neurogenic vulnerability, an initiating event or series of events may lead to chronic vulvar pain. Treatment of vulvodynia is generally predicated on a trial and error basis, because the pathogenesis is not defined. The result is that many forms of therapeutic interventions have been used, yet the evidence remains largely inconclusive, the response rate varies between 40-85%, and many women do not respond to any of the treatments. Unfavorable outcomes to therapy can be explained by grouping patients with different conditions under one diagnosis, and then studying an intervention that might only help one subset of the conditions. This can lead to an apparent lack of effect, due to dilution of the patient subpopulations. A different approach to diagnosis and treatment of PVD was suggested by Dr. Andrew Goldstein. He classifies PVD into groups, based on history and examination findings:
  1. Hormonally mediated PVD - The pain began while taking hormonal contraceptive or other medications that affect hormones, after removal of ovaries, breastfeeding or menopause. Typically, patients have a low calculated free testosterone and complain of dryness and decreased libido. The entire vestibule is tender and vestibular mucosa is often dry and thin. Treatment includes stopping hormonal contraception and application of topical estradiol with testosterone to the vestibule.
  2. Hypertonic pelvic muscle dysfunction - In this subgroup, pelvic floor (PF) muscles become tight and tender. Patients often have other symptoms suggesting hypertonicity (urinary frequency, urgency and hesitancy, constipation, hemorrhoids and anal fissures), and predisposing factors, such as musculoskeletal disorders or anxiety may coexist. Typically, the pain is much worse at 4-8 o'clock position of the vestibule with minimal or no pain in the upper vestibule. Treatment includes PF physiotherapy, with an optional addition of muscle relaxants (valium suppositories and Botulinum toxin injections).
  3. Neuroproliferative PVD- In this condition, women have an increased number of nociceptors in the vestibular mucosa. This group is further subdivided into congenital and acquired forms. In the congenital subgroup, vestibular pain has always been present, and there may be sensitivity to palpation of the belly button (which is an evidence of a congenital neuronal hyperplasia within the tissue derived from the urogenital sinus). With acquired neuroproliferative PVD, the pain may begin after a severe allergic reaction or vaginitis. There is tenderness of the entire vestibule. Treatments include topical anaesthetics, antidepressants, antiseizure drugs, capsaicin cream and vulvar vestibulectomy.
Goldstein's diagnostic algorithm is claimed to allow differentiation between different causes of PVD. In doing so, appropriate treatments to each subgroup can be selected, and their success rate should exceed the reported success rate in PVD treatment studies. Although investigators have a good personal experience with this method, the algorithm is not evidence based. Objectives: The proposed study is a prospective, cohort-based study, which will evaluate the characteristics of PVD-subgroups according to Goldstein's algorithm, patients' response to treatment and their outcome. General aims: Define whether women that have been diagnosed according to Goldstein's algorithm experience higher rates of favorable outcome in comparison to those reported in the literature. This will allow us to study the effectiveness of this classification and to better define the subgroups. Specific aims:
  1. Describe the population of women with PVD attending the clinic, the distribution of criteria and the characteristics of women in each category.
  2. Follow women diagnosed according to algorithm for one year and define treatment success.
Methods: The proposed study is a prospective, cohort-based study. Patients will be recruited from the clinic for vulvovaginal disorders in Clalit Healthcare services in Jerusalem. The diagnostic procedures, patients' sub-classification and the proposed treatments in the current protocol are identical to those currently used in the clinic. Patients who fulfill diagnostic criteria of PVD and who will be willing to participate in the study will be asked to sign an informed consent and complete self-administered intake questionnaires requesting data about their PVD condition and its severity, various parameters of quality of life (QOL), general health, Ob\Gyn history, sexual function, psychometric characteristics (anxiety, depression etc) and demographics. After completing the questionnaires, each patient will undergo a standard evaluation, and will be diagnosed according to Goldstein's algorithm. Instructions for treatment will be given in regards to the diagnosis. Patients will be instructed to schedule follow-up appointments at 3,6,9, and 12 months. During follow-up appointments they will be assessed in regard to vestibular tenderness using various parameters, as well as by questionnaires of QOL and sexual function.
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 ]
Study Record | ClinicalTrials.gov

Mark Lumley, PhD Professor Wayne State University
Life-Stress Interview for Women With Chronic Urogenital Pain Conditions (2014 — 2016)
The goal of this study is to test the efficacy, feasibility, and acceptability of providing an experiential assessment interview that targets health, and emotional and stressful experiences in a tertiary care setting specializing in women's urology.
In this randomized, controlled trial, the investigators will compare an interview condition to a wait-list control condition. The investigators hypothesize that helping individuals identify the links between their stress, emotions, and physical symptoms will likely increase their awareness and endorsement of the link between stress and physical symptoms, including a willingness to engage in stress management techniques. It is also expected that helping raise an individual's awareness about their symptoms, followed by an experience and expression of unexpressed emotion is likely to influence their physical and psychological well-being.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Symptom Interpretation Questionnaire (SIQ) Change from baseline symptom attribution at 6-weeks
Brief Pain Inventory (BPI) Change from baseline pain at 6-weeks
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Patient Health Questionnaire-15 (PHQ-15) Change from baseline in symptom severity at 6 weeks
Brief Symptom Inventory (BSI) Change from baseline symptoms at 6-weeks
Satisfaction With Life Scale (SWLS) Change from baseline life satisfaction at 6-weeks
Pelvic Floor Distress Inventory -20 (PFDI-20) Change from baseline pelvic symptoms at 6-weeks
Global Assessment Response (GRA) Change from baseline overall symptoms at 6-weeks
Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) Change from baseline pain at 6-weeks
Emotional Approach Coping (EAC) Change from baseline emotional approach coping at 6-weeks
Emotional Processing Scale-25 (EPS-25) Change from baseline emotional processing at 6-weeks
Inventory of Interpersonal Problems-32 (IIP-32) Change from baseline interpersonal problems at 6-weeks
Pain Catastrophizing Scale Change from baseline pain catastrophizing at 6-weeks
Change Assessment Questionnaire Change from baseline stage of change at 6-weeks
Study Record | ClinicalTrials.gov

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 (2000 — 2005)
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) (2011 — 2015)
The structural/RSN study involves Structural and Resting State Neuroimaging. The purpose of Structural Neuroimaging is to use MRI technology to identify cortical and white matter morphometric differences between patients with chronic pain conditions and healthy control subjects. The purpose of the Resting State Neuroimaging study is to use functional MRI to identify possible disease related differences in various resting state networks in the brain. In addition we are looking at the effect gut microbiota on brain function in healthy and IBS participants. The overall goal is to identify structural and functional brain differences in persons with chronic pain conditions such as Irritable Bowel Syndrome (IBS, Cyclical Vomiting Syndrome(CVS) and vestibulodynia/vulvodynia. We are also looking at Inflammatory Bowel Disease(ulcerative colitis and Crohn's disease. We will be comparing differences between these conditions and matched healthy control subjects. 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.
Study Record | ClinicalTrials.gov

Linda McLean, PhD Professor University of Ottawa
Is Low Level Laser Therapy (LLLT) Effective for Reducing Pain Experienced by Women With Provoked Vestibulodynia? (2021 — 2023)
Vulvar pain affects the psychological and sexual health of more than one in five Canadian women, yet its pathophysiology is poorly understood. Provoked vestibulodynia (PVD) is one major subtype of vulvodynia, affecting close one in ten women and resulting in sharp, burning pain during attempts at vaginal intercourse and/or attempts to insert a digit, device or tampon into the vagina. Hypersensitivity of the vulvar vestibule is one of the key defining characteristics of PVD and, while its pathogenesis is unknown, it has been primarily attributed to inflammatory processes and hyperinnervation. Pelvic floor muscle (PFM) dysfunction has also been implicated in many forms of dyspareunia, yet the nature of this involvement also remains largely unknown. Low Level Laser Therapy (LLLT), or photobiomodulation, is a therapeutic resource involving irradiation of injured or diseased tissue with a combination of red and infrared light. This laser is thought to initiate a series of physiological reactions within the cells exposed to light at these wavelengths, leading to the restoration of normal cell structure and function. The purpose of this randomized controlled trial is to assess the feasibility of using a comprehensive LLLT intervention for the management of PVD in women with PVD alone (PVD) or with concurrent vaginismus (PVD+VAG). True and sham LLLT will be delivered by the BioFlexTM laser system (Health Canada License No. 7931). The aim is to determine whether there is evidence of a positive effect of LLLT delivered using a semi-standardized protocol delivered by the BioFlexTM laser in terms of primary outcomes including pain, sexual functioning and overall symptoms and secondary outcomes including changes in physiological responses to pressure applied at the vulvar vestibule, corticomotor excitability to the PFMs, and tonic activation and motor control of the PFMs. Women will be recruited from among eighty women participating in a cross sectional study investigating pelvic floor muscle involvement in PVD. Women will therefore already have been recruited through local physiotherapists and gynecologists who have specific expertise in genital pain disorders and a diagnosis of PVD and PVD+VAG will have been confirmed through screening (Friedrich's Criteria as well as digital palpation assessment) by a gynaecologist, gynaecology resident or pelvic health physiotherapist, all with specific training on the assessment of vulvar pain. Other causes of vulvar pain, including generalized vulvodynia, infection, lichen sclerosis etc. will have been ruled out. Potential participants will be approached by the study protocol officer after they have participated in the cross sectional study and asked if they are interested in participating in this intervention study. If so, they will be asked to consent to having their data from the cross sectional study passed on to the current study. Women will be evaluated before and after the 12-week intervention on all outcome measures, while primary outcome measures will be also evaluated after 3 weeks of intervention in both groups. The physical assessment will be conducted by an experienced pelvic floor physiotherapist. The evaluations will include the completion of five online questionnaires (The Vulvar Pain Assessment Questionnaire (VPAQ), Female Sexual Functioning Index, Pain Catastrophising Scale, Depression Anxiety Stress Scales, the Central Sensitization Index) and the physical assessment. The physical assessment will involve:
  1. Tampon test: participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. The participant will be instructed to report the level of pain induced through the entire insertion/removal experience on a 0-10 numeric rating scale for pain (0 meaning no pain and 10 meaning the worst pain imaginable).
  2. Pressure pain threshold (PPT) will be determined involving three trials using a custom vulvalgesiometer, and will be defined as the median pressure at which women first report pain when a cotton swab tip is applied at the posterior fourchette of the vaginal introitus.
  3. Temporal summation (TS) of pain: The vulvalgesiometer will again be used. A consistent pressure equivalent to the pressure that induced a pain rating of 4/10 will be applied to the posterior vaginal fourchette ten times at a rate of approximately one per second. Participants will rate their pain level on the initial and final application of this pressure using the numeric rating scale (0-10). TS will be defined as the difference in pain rating between the final and first application of the pressure.
  4. Responses of the pelvic floor muscles to pressure applied at the vulvar vestibule: Women will be instrumented with electromyography (EMG) electrodes over four muscles. The superficial (bulbocavernosus and external anal sphincter) layer will be instrumented with rectangular self-adhesive gelled electrodes placed in a differential configuration on the participant's right side. The deep (pubovisceralis) PFMs will be instrumented using one custom differential suction electrode (DSE) configuration with one electrode (pole) placed on the vaginal wall overlying the muscle on the right side and the other electrode (pole) located on the anterior vaginal wall superficial to the PFMs (i.e. approx. 1.5 cm from the introitus). A common reference gelled electrode will be adhered to the skin overlying the anterior superior iliac spine on the right side. Additionally, Delsys D.E. 2.1 differential electrodes will be located over the upper trapezius muscle and over the adductor longus muscle on the right side. All EMG electrodes will be interfaced with Delsys Bagnoli-16 amplifiers (overall gain X1000, common mode rejection ratio -120dB at 60Hz; bandpass 20Hz-450Hz) and all EMG data will be sampled at 2000Hz through a 32-bit National Instruments Analog to Digital Converter (NIDAQ USB3086) and stored on a PC using Powerlab Labchart 8 Pro software. Two separate, custom vulvalgesiometers will be instrumented such that a switch that is activated when a low (25 g) or moderate (232 g) pressure is delivered. The switch (on-off) data will be recorded alongside the EMG data through the PowerLab™ software in order to separate out anticipatory activation (i.e. the EMG signal onset is before the switch is activated) from response activation (i.e. the EMG signal onset is after the switch is activated). The vulvalgesiometers will be used at the posterior vaginal fourchette and at the posterior aspect of the thigh. The order of the pressure application sites (vaginal fourchette vs posterior thigh) and the intensity of the pressure stimulus (low vs moderate) will be randomized using a computer generated randomization scheme. Five repetitions will be performed for each location/pressure intensity combination using a consistent inter-stimulus interval of 120 seconds. For each pressure level and site, an anticipatory response will be considered to be present on an EMG channel if, at that site, EMG activity rises two standard deviations above the noise before the pressure is applied on at least two of ten trials; while a behavioral response will be considered to be present on any EMG channel if, at that site, the EMG activity rises two standard deviations above the noise after the pressure is applied on all ten trials. For each pressure level and site, EMG response amplitudes will be recorded based on smoothed (full-wave rectified and low pass filtered using a 4th order dual-pass Butterworth filter with 3dB cut-off of 5Hz).
  5. Tonic, phasic and reflex activation of the PFMs: After five minutes of rest, tonic EMG activation will be recorded from all EMG channels for a period of one minute while women are instructed to relax their PFMs as much as possible, then EMG data will be recorded throughout three trials of maximum effort PFM contractions. Next, women will be instructed on a bearing down maneuver (Valsalva) whereby they will use their diaphragm and abdominal muscles to generate an increase in intra-abdominal pressure. EMG data will be recorded from one second before the command to inhale and until 20 seconds after the command to bear down is given; three separate trials will be performed. A rest of two minutes will be given between trials and tasks to minimize the effect of fatigue, activation induced by the tasks, and/or vasovagal symptoms. Raw EMG data will be smoothed (full-wave rectified and low pass filtered using a 4th order dual-pass Butterworth filter with 3dB cut-off of 5Hz) before EMG amplitudes are determined. For tonic activation and activation during the Valsalva, mean smoothed EMG amplitude will be computed across the length over which the task is sustained. For voluntary activation, the peak smoothed EMG amplitude will be retained.
  6. Corticomotor excitability of the projections to the PFMs - A Magstim® 200 system coupled with a double cone coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs using transcranial magnetic stimulation (TMS). Participants will be fitted with a Waveguard TMS compatible cap (ANT North America Inc, WI 53719) and the vertex location will be marked at the intersection between the sagittal and coronal bisections of the head. An additional EMG channel will be added to the others already instrumented; a D.E. 2.1 electrode will be placed over the tibialis anterior muscle on the right side. With the coil at a point 2cm ventral to the vertex, magnetic stimulation intensity will be systematically increased until MEPs (50µv) are reliably evoked from the tibialis anterior muscle. The resting motor threshold (rMT) will be established using a software tool (Motor Threshold Assessment Tool 2.0) which allows fast and reliable estimation with 14 to 17 stimulations. After rMT determination, 12-20 MEPs will be recorded with participants at rest and using an intensity equivalent to 1.3 rMT. The intensity will be set at 100% maximum stimulator output in cases where the 1.3 rMT is greater than 90 % maximum stimulator output. Next the cortical silent period (cSP) will be assessed by asking participants to perform 5-10 moderate contractions of their PFMs while the TMS pulse is delivered at the same intensity (1.3 rMT) as above during the contraction. During this contraction. This will conclude the pre-intervention assessment.
After the initial assessment is complete, using concealed allocation, women will be randomized to receive either the LLLT protocol or a sham protocol, for a twelve- week intervention period using a permuted block computer-generated randomization scheme (block size 4) stratified by condition (PVD vs PVD+VAG). The participant, the protocol officer, the physiotherapists delivering the treatment and the PI will remain blinded to participant group assignment throughout the treatments and the follow-up assessment. The intervention protocol will consist of 15 sessions provided over a 12- week period, applied by two experienced pelvic floor physiotherapists (>5 years) who have received specialized training on the application of LLLT using the Bioflex Laser system. The intervention protocol was developed in collaboration with the Clinical Director of Meditech International Rehabilitation Centers, who is also a scientific advisor to BioFlexTM Laser. Each treatment will last approximately 45 minutes and will be scheduled at the participant's convenience. During the 12- week treatment period, each participant will progress through 5 stages of treatment parameters at their own rate. The sham group will follow the same treatment steps, but the output of the laser will be at a sub-clinical intensity of 1% power. All of the steps will first include laser arrays (red and infrared light) applied to the skin overlying the sacral spine in both a horizontal and oblique placement bilaterally and the laser probe applied over the base of the spine (red and infrared light). Next, the array will be applied to the surface of the perineum (red and infrared light) followed by red light delivered by the probe at specific sites along the perineum, including the vulvar vestibule. Finally, infrared light will be applied using the probe applied to the skin overlying the branches of the pudendal nerve. Women will progress through treatment stages whereby at each stage, the same array positions and probe placement will be used but the dosage of light will be increased according to the BioFlex protocol. The laser arrays and probes will be protected with a low density polyethylene plastic cover that is compliant with the Food and Drug Administration (FDA) and United States Department of Health and Human Services (USDA) regulations. Each cover will be discarded after a single use. A mindfulness-based meditation will be provided during each assessment through noise cancelling headphones interfaced to a PC playing an audio CD. To ensure that the physiotherapists delivering the treatment remain blinded to the treatment being delivered, the real and sham (A and B) protocols have been entered into the Bioflex Laser system by the supplier and verified by a physiotherapist who is not involved in the study to ensure that they are correct. In this way none of the investigators will know which protocol (A or B) is the real treatment, and black towels will be used to cover the arrays while the treatment is delivered such that any differences in light intensity will not be visible. Three weeks after initiating the intervention, women will repeat the five on-line questionnaires, the tampon test, PPT testing, TS testing as well as Global Perception of Improvement and Global satisfaction with treatment questionnaires, reporting to a research assistant who will remain blinded to treatment assignment. After the final treatment session (12 weeks), women will repeat these on-line questionnaires as well as the tampon test, PPT testing, TS testing, tonic and voluntary activation, anticipatory and behavioural responses, and the TMS protocol, administered by the same, blinded physiotherapist who performed the initial assessment. After all follow-up visits are complete, women, and the research assistants, will learn whether they received the real or sham LLLT therapy, and those who received sham therapy will be invited to begin the real intervention. If follow-on funding becomes available, all women will be re-evaluated at 12 weeks following the initial therapy on all outcomes. All outcomes will first be tested for normality using the Shapiro-Wilks test. If all outcomes are normally distributed, they will be compared between the using repeated measures (RM) ANOVA models. The Global perception of improvement will be compared between group (intervention vs control) and time (3 weeks after beginning the intervention, 12 weeks after beginning the intervention, 12 weeks after completing the intervention if available) using a three-way RM ANOVA and including condition (PVD, PVD+VAG) as a nested effect. The other outcomes will be compared between groups using three-way RM ANOVAs including group (intervention, control) and time (pre-intervention, post-intervention, 12 weeks later if available) as main effects, and including condition (PVD, PVD+VAG) as a nested effect. Alpha=0.05 will be used for all tests and effect sizes will be computed based on group means and standard deviations. Adherence rates will be recorded and intent to treat analyses are planned for participants who drop out or are lost to follow-up. For outcomes that are not normally distributed, equivalent non-parametric tests will be used wherever possible. The sample size is based on the only pilot study that tested the therapeutic effect of LLLT on women with PVD, this study reported a significant, positive effect on pain reported during attempts at sexual intercourse among women with PVD (n=18) treated using LLLT when compared to controls (n=16) who received sham LLLT. They found that participants who received the treatment were more likely than controls to report significant or complete improvement in their pain (p=0.042) on verbal report at follow-up, a scale similar to the "Global Perception of Improvement" scale as described in this proposal. Using this result, a post-hoc power analysis (Minitab, V. 18) suggested that a sample size of 16 per group will be adequate to see a significant difference in treatment outcomes between women who receive the LLLT intervention and those who receive the sham intervention. The results of the pilot study did not demonstrate a significant treatment effect in any of their objective parameters. For example, post-hoc power analysis (MinitabTM v. 18) estimates that 154 participants per group would be required to detect a difference between treatment and control using the tampon test as the primary outcome. Given that the LLLT intervention proposed here is far more comprehensive than that used in the only pilot study published so far, there may be a greater effect associated with the proposed protocol as compared to the effect seen in the published pilot study.
Primary Outcome Measures:
  1. Global perception of improvement [ Time Frame: 3 weeks (during intervention) ]
    The Global perception of improvement is a single question through which participants provide a ordinal rating based on their overall perception of improvement attributed to the intervention. Much Better, Better, About the same, Worse, Much worse. Higher ratings is associated with better outcomes.
  2. Global perception of improvement [ Time Frame: 12 weeks (following intervention) ]
    The Global perception of improvement is a single question through which participants provide a ordinal rating based on their overall perception of improvement attributed to the intervention. Much Better, Better, About the same, Worse, Much worse. Higher ratings is associated with better outcomes.
  3. Global perception of improvement [ Time Frame: 12 weeks after intervention (if funding becomes available) ]
    The Global perception of improvement is a single question through which participants provide a ordinal rating based on their overall perception of improvement attributed to the intervention. Much Better, Better, About the same, Worse, Much worse. Higher ratings is associated with better outcomes.
  4. The Vulvar Pain Assessment Questionnaire (VPAQ)Inventory:COMPREHENSIVE (FULL) VERSION [ Time Frame: Baseline ]
    Designed to assess: pain quality, the temporal nature of the pain, associated symptoms, pain intensity, emotional/cognitive functioning, physical functioning, coping strategies, and interpersonal functioning. Core Domains: Consists of 63 items:8 questions assessing the onset, location, temporal pattern, degree of burning pain, and associated symptoms of vulvar pain, along with six subscales. Subscales are composed of 55 items rated on 5-point scales with anchors tailored to the nature of the questions being asked:
    1. Pain severity
    2. Emotional response
    3. Cognitive response
    4. Life interference
    5. Sexual function interference
    6. Self-stimulation/penetration interference
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  5. The Vulvar Pain Assessment Questionnaire (VPAQ)Inventory:COMPREHENSIVE (FULL) VERSION [ Time Frame: 3 weeks (during intervention) ]
    Designed to assess: pain quality, the temporal nature of the pain, associated symptoms, pain intensity, emotional/cognitive functioning, physical functioning, coping strategies, and interpersonal functioning. Core Domains: Consists of 63 items:8 questions assessing the onset, location, temporal pattern, degree of burning pain, and associated symptoms of vulvar pain, along with six subscales. Subscales are composed of 55 items rated on 5-point scales with anchors tailored to the nature of the questions being asked:
    1. Pain severity
    2. Emotional response
    3. Cognitive response
    4. Life interference
    5. Sexual function interference
    6. Self-stimulation/penetration interference
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  6. The Vulvar Pain Assessment Questionnaire (VPAQ)Inventory:COMPREHENSIVE (FULL) VERSION [ Time Frame: 12 weeks (following intervention) ]
    Designed to assess: pain quality, the temporal nature of the pain, associated symptoms, pain intensity, emotional/cognitive functioning, physical functioning, coping strategies, and interpersonal functioning. Core Domains: Consists of 63 items:8 questions assessing the onset, location, temporal pattern, degree of burning pain, and associated symptoms of vulvar pain, along with six subscales. Subscales are composed of 55 items rated on 5-point scales with anchors tailored to the nature of the questions being asked:
    1. Pain severity
    2. Emotional response
    3. Cognitive response
    4. Life interference
    5. Sexual function interference
    6. Self-stimulation/penetration interference
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  7. The Vulvar Pain Assessment Questionnaire (VPAQ) Inventory:COMPREHENSIVE (FULL) VERSION [ Time Frame: 12 weeks after intervention (if funding becomes available) ]
    Designed to assess: pain quality, the temporal nature of the pain, associated symptoms, pain intensity, emotional/cognitive functioning, physical functioning, coping strategies, and interpersonal functioning. Core Domains: Consists of 63 items:8 questions assessing the onset, location, temporal pattern, degree of burning pain, and associated symptoms of vulvar pain, along with six subscales. Subscales are composed of 55 items rated on 5-point scales with anchors tailored to the nature of the questions being asked:
    1. Pain severity
    2. Emotional response
    3. Cognitive response
    4. Life interference
    5. Sexual function interference
    6. Self-stimulation/penetration interference
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  8. Pain rating during the tampon test [ Time Frame: Baseline ]
    The participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. After, they will be asked to record the degree of pain during the entire insertion/removal experience in a 11-point numerical rating scale (NRS) with anchors of 0 (no pain at all) to 10 (worst pain imaginable).
  9. Pain rating during the tampon test [ Time Frame: 3 weeks (during the intervention) ]
    The participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. After, they will be asked to record the degree of pain during the entire insertion/removal experience in a 11-point numerical rating scale (NRS) with anchors of 0 (no pain at all) to 10 (worst pain imaginable).
  10. Pain rating during the tampon test [ Time Frame: 12 weeks (immediately after the intervention) ]
    The participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. After, they will be asked to record the degree of pain during the entire insertion/removal experience in a 11-point numerical rating scale (NRS) with anchors of 0 (no pain at all) to 10 (worst pain imaginable).
  11. Pain rating during the tampon test [ Time Frame: 12 weeks later (if funding becomes available) ]
    The participants will be provided with Original Regular Tampax Tampon and will be instructed to insert and then remove it. After, they will be asked to record the degree of pain during the entire insertion/removal experience in a 11-point numerical rating scale (NRS) with anchors of 0 (no pain at all) to 10 (worst pain imaginable)..
  12. Pressure pain threshold (PPT) at the posterior vaginal fourchette [ Time Frame: Baseline ]
    PPT will be determined using a custom vulvalgesiometer and will be defined as the average pressure at which women first report pain when the cotton swab tip is applied at 6 o' clock position of the vaginal introitus. The vulvalgesiometer will also be used to evaluate TS of pain when the pressure measured before will be applied ten times at a rate of approximately one per second at the same location on the vestibule. Participants will rate their pain level on the initial and final application of this pressure using the same numeric rating scale (0-10).
  13. Pressure pain threshold (PPT) at the posterior vaginal fourchette [ Time Frame: 3 weeks (during the intervention) ]
    PPT will be determined using a custom vulvalgesiometer and will be defined as the average pressure at which women first report pain when the cotton swab tip is applied at 6 o' clock position of the vaginal introitus. The vulvalgesiometer will also be used to evaluate TS of pain when the pressure measured before will be applied ten times at a rate of approximately one per second at the same location on the vestibule. Participants will rate their pain level on the initial and final application of this pressure using the same numeric rating scale (0-10).
  14. Pressure pain threshold (PPT) at the posterior vaginal fourchette [ Time Frame: 12 weeks (following intervention) ]
    PPT will be determined using a custom vulvalgesiometer and will be defined as the average pressure at which women first report pain when the cotton swab tip is applied at 6 o' clock position of the vaginal introitus. The vulvalgesiometer will also be used to evaluate TS of pain when the pressure measured before will be applied ten times at a rate of approximately one per second at the same location on the vestibule. Participants will rate their pain level on the initial and final application of this pressure using the same numeric rating scale (0-10).
  15. Pressure pain threshold (PPT) at the posterior vaginal fourchette [ Time Frame: 12 weeks after intervention (if funding becomes available) ]
    PPT will be determined using a custom vulvalgesiometer and will be defined as the average pressure at which women first report pain when the cotton swab tip is applied at 6 o' clock position of the vaginal introitus. The vulvalgesiometer will also be used to evaluate TS of pain when the pressure measured before will be applied ten times at a rate of approximately one per second at the same location on the vestibule. Participants will rate their pain level on the initial and final application of this pressure using the same numeric rating scale (0-10).
  16. Temporal summation of pain [ Time Frame: Baseline ]
    Difference between pain reported on first application of pressure at the vulvar vestibule, delivered through a vulvalgesiometer, and the pain reported after the tenth application of that same pressure
  17. Temporal summation of pain [ Time Frame: 3 weeks (during the intervention) ]
    Difference between pain reported on first application of pressure at the vulvar vestibule, delivered through a vulvalgesiometer, and the pain reported after the tenth application of that same pressure
  18. Temporal summation of pain [ Time Frame: 12 weeks (after the intervention) ]
    Difference between pain reported on first application of pressure at the vulvar vestibule, delivered through a vulvalgesiometer, and the pain reported after the tenth application of that same pressure
  19. Temporal summation of pain [ Time Frame: 12 weeks later (if funding becomes available) ]
    Difference between pain reported on first application of pressure at the vulvar vestibule, delivered through a vulvalgesiometer, and the pain reported after the tenth application of that same pressure
Secondary Outcome Measures:
  1. Global Patient satisfaction with treatment [ Time Frame: 3 weeks (during intervention) ]
    Global patient satisfaction with treatment is a single question through which participants provide a ordinal rating based on their satisfaction with the intervention. Completely, Somewhat, Not at all. Higher ratings is associated with better outcomes.
  2. Global Patient satisfaction with treatment [ Time Frame: 12 weeks (following intervention) ]
    Global patient satisfaction with treatment is a single question through which participants provide a ordinal rating based on their satisfaction with the intervention. Completely, Somewhat, Not at all. Higher ratings is associated with better outcomes.
  3. Global Patient satisfaction with treatment [ Time Frame: 12 weeks after intervention (if funding becomes available) ]
    Global patient satisfaction with treatment is a single question through which participants provide a ordinal rating based on their satisfaction with the intervention. Completely, Somewhat, Not at all. Higher ratings is associated with better outcomes.
  4. Female Sexual Function Index (FSFI) [ Time Frame: Baseline ]
    This is a 19-item validated questionnaire for assessing the key dimension of sexual function in women, considered a gold standard for evaluation of sexual function. It assesses six domains: desire, arousal , lubrification, orgasm, satisfaction, and pain. All scores are totaled for a maximum of 36. Higher scores represents better sexual function. A score ≤26.55 has been set as a cutoff to identify those at risk for sexual dysfunction.
  5. Female Sexual Function Index (FSFI) [ Time Frame: 12 weeks (following intervention) ]
    This is a 19-item validated questionnaire for assessing the key dimension of sexual function in women, considered a gold standard for evaluation of sexual function. It assesses six domains: desire, arousal , lubrification, orgasm, satisfaction, and pain. All scores are totaled for a maximum of 36. Higher scores represents better sexual function. A score ≤26.55 has been set as a cutoff to identify those at risk for sexual dysfunction.
  6. Female Sexual Function Index (FSFI) [ Time Frame: 12 weeks after intervention (if funding becomes available) ]
    This is a 19-item validated questionnaire for assessing the key dimension of sexual function in women, considered a gold standard for evaluation of sexual function. It assesses six domains: desire, arousal , lubrification, orgasm, satisfaction, and pain. All scores are totaled for a maximum of 36. Higher scores represents better sexual function. A score ≤26.55 has been set as a cutoff to identify those at risk for sexual dysfunction.
  7. Motor evoked potential (MEP) peak to peak amplitude (µV) [ Time Frame: Baseline ]
    Transcranial magnetic stimulation outcome will be determined for all participants and compared among groups. A Magstim® 200 system coupled with a double coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs. MEPs will be ensemble averaged to generate estimates of MEP peak to peak amplitude (µV).
  8. Motor evoked potential (MEP) peak to peak amplitude (µV) [ Time Frame: 12 weeks (immediately after the intervention) ]
    Transcranial magnetic stimulation outcome will be determined for all participants and compared among groups. A Magstim® 200 system coupled with a double coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs. MEPs will be ensemble averaged to generate estimates of MEP peak to peak amplitude (µV).
  9. Motor evoked potential (MEP) peak to peak amplitude (µV) [ Time Frame: 12 weeks later (if funding becomes available) ]
    Transcranial magnetic stimulation outcome will be determined for all participants and compared among groups. A Magstim® 200 system coupled with a double coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs. MEPs will be ensemble averaged to generate estimates of MEP peak to peak amplitude (µV).
  10. Cortical silent period (ms) [ Time Frame: Baseline ]
    Transcranial magnetic stimulation outcome will be determined for all participants and compared among groups. A Magstim® 200 system coupled with a double coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs. MEP cortical silent period (cSP) will be measured from individual trials and then averaged.
  11. Cortical silent period (ms) [ Time Frame: 12 weeks (immediately after the intervention) ]
    Transcranial magnetic stimulation outcome will be determined for all participants and compared among groups. A Magstim® 200 system coupled with a double coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs. MEP cortical silent period (cSP) will be measured from individual trials and then averaged.
  12. Cortical silent period (ms) [ Time Frame: 12 weeks later (if funding becomes available) ]
    Transcranial magnetic stimulation outcome will be determined for all participants and compared among groups. A Magstim® 200 system coupled with a double coil (96 mm loops, P/N 9902) will be used to probe the corticospinal projections to PFMs. MEP cortical silent period (cSP) will be measured from individual trials and then averaged.
  13. Pain Catastrophizing Scale [ Time Frame: Baseline ]
    This is a reliable and valid scale to measure of catastrophizing. The scores from this questionnaire is predictors of intensity of physical and emotional distress. It is a self-report measure, consisting of 13 items scored from 0 to 4, resulting in a total possible score of 52. The higher the score, the more catastrophizing thoughts are present.
  14. Pain Catastrophizing Scale [ Time Frame: 12 weeks (after the intervention) ]
    This is a reliable and valid scale to measure of catastrophizing. The scores from this questionnaire is predictors of intensity of physical and emotional distress. It is a self-report measure, consisting of 13 items scored from 0 to 4, resulting in a total possible score of 52. The higher the score, the more catastrophizing thoughts are present.
  15. Pain Catastrophizing Scale [ Time Frame: 12 weeks later (if funding becomes available) ]
    This is a reliable and valid scale to measure of catastrophizing. The scores from this questionnaire is predictors of intensity of physical and emotional distress. It is a self-report measure, consisting of 13 items scored from 0 to 4, resulting in a total possible score of 52. The higher the score, the more catastrophizing thoughts are present.
  16. Depression Anxiety Stress Scale (DASS) [ Time Frame: Baseline ]
    This is a 42-item self report instrument designed to measure the three related negative emotional states of depression, anxiety and tension/stress. Each one contains 14 items, divided into subscales of 2-5 items with similar content. The DASS have been shown to have high internal consistency and to yield meaningful discriminations in a variety of settings. A higher score on the DASS indicates greater severity or frequency of these negative emotional symptoms. The maximum score is 126.
  17. Depression Anxiety Stress Scale (DASS) [ Time Frame: 3 weeks (during the intervention) ]
    This is a 42-item self report instrument designed to measure the three related negative emotional states of depression, anxiety and tension/stress. Each one contains 14 items, divided into subscales of 2-5 items with similar content. The DASS have been shown to have high internal consistency and to yield meaningful discriminations in a variety of settings. A higher score on the DASS indicates greater severity or frequency of these negative emotional symptoms. The maximum score is 126.
  18. Depression Anxiety Stress Scale (DASS) [ Time Frame: 12 weeks (after the intervention) ]
    This is a 42-item self report instrument designed to measure the three related negative emotional states of depression, anxiety and tension/stress. Each one contains 14 items, divided into subscales of 2-5 items with similar content. The DASS have been shown to have high internal consistency and to yield meaningful discriminations in a variety of settings. A higher score on the DASS indicates greater severity or frequency of these negative emotional symptoms. The maximum score is 126.
  19. Depression Anxiety Stress Scale (DASS) [ Time Frame: 12 weeks later (if funding becomes available) ]
    This is a 42-item self report instrument designed to measure the three related negative emotional states of depression, anxiety and tension/stress. Each one contains 14 items, divided into subscales of 2-5 items with similar content. The DASS have been shown to have high internal consistency and to yield meaningful discriminations in a variety of settings. A higher score on the DASS indicates greater severity or frequency of these negative emotional symptoms. The maximum score is 126.
  20. Central sensitization index [ Time Frame: Baseline ]
    The Central Sensitisation Inventory (CSI) is a self-report outcome measure designed to identify patients who have symptoms that may be related to central sensitisation (CS) or central sensitivity syndromes (CSS). Part A includes 25 questions related to common CSS symptoms. Part B determines if the patient has been diagnosed with certain CSS disorders or related disorders, such as anxiety and depression. CSI severity levels have been established for part A: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100.
  21. Central sensitization index [ Time Frame: 12 weeks (after the intervention) ]
    The Central Sensitisation Inventory (CSI) is a self-report outcome measure designed to identify patients who have symptoms that may be related to central sensitisation (CS) or central sensitivity syndromes (CSS). Part A includes 25 questions related to common CSS symptoms. Part B determines if the patient has been diagnosed with certain CSS disorders or related disorders, such as anxiety and depression. CSI severity levels have been established for part A: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100.
  22. Central sensitization index [ Time Frame: 12 weeks later (if funding becomes available) ]
    The Central Sensitisation Inventory (CSI) is a self-report outcome measure designed to identify patients who have symptoms that may be related to central sensitisation (CS) or central sensitivity syndromes (CSS). Part A includes 25 questions related to common CSS symptoms. Part B determines if the patient has been diagnosed with certain CSS disorders or related disorders, such as anxiety and depression. CSI severity levels have been established for part A: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100.
  23. The Vulvar Pain Assessment Questionnaire - Supplemental Domains [ Time Frame: Baseline ]
    Supplemental Domains Pain Descriptors (VPAQdesc). This pain descriptor scale contains the most common words used to describe chronic vulvar pain.
    1. Burning/stinging pain
    2. Incisive pain
    3. Sensitivity
    Coping Strategies (VPAQcope). This scale addresses some common coping strategies that are utilized by women with vulvar pain.
    1. Distraction/relaxation strategies
    2. Problem-solving strategies
    Partner Factors (VPAQpartner). This 24-item scale encompasses how romantic partners/spouses may be impacted by/respond to vulvar pain experienced by one partner.
    1. Negative response
    2. Support seeking
    3. Impact on relationship
    4. Sexual communication
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  24. The Vulvar Pain Assessment Questionnaire - Supplemental Domains [ Time Frame: 3 weeks (during intervention) ]
    Supplemental Domains Pain Descriptors (VPAQdesc). This pain descriptor scale contains the most common words used to describe chronic vulvar pain.
    1. Burning/stinging pain
    2. Incisive pain
    3. Sensitivity
    Coping Strategies (VPAQcope). This scale addresses some common coping strategies that are utilized by women with vulvar pain.
    1. Distraction/relaxation strategies
    2. Problem-solving strategies
    Partner Factors (VPAQpartner). This 24-item scale encompasses how romantic partners/spouses may be impacted by/respond to vulvar pain experienced by one partner.
    1. Negative response
    2. Support seeking
    3. Impact on relationship
    4. Sexual communication Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  25. The Vulvar Pain Assessment Questionnaire - Supplemental Domains [ Time Frame: 12 weeks (following intervention) ]
    Supplemental Domains Pain Descriptors (VPAQdesc). This pain descriptor scale contains the most common words used to describe chronic vulvar pain.
    1. Burning/stinging pain
    2. Incisive pain
    3. Sensitivity
    Coping Strategies (VPAQcope). This scale addresses some common coping strategies that are utilized by women with vulvar pain.
    1. Distraction/relaxation strategies
    2. Problem-solving strategies
    Partner Factors (VPAQpartner). This 24-item scale encompasses how romantic partners/spouses may be impacted by/respond to vulvar pain experienced by one partner.
    1. Negative response
    2. Support seeking
    3. Impact on relationship
    4. Sexual communication
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
  26. The Vulvar Pain Assessment Questionnaire - Supplemental Domains [ Time Frame: 12 weeks after intervention (if funding becomes available) ]
    Supplemental Domains Pain Descriptors (VPAQdesc). This pain descriptor scale contains the most common words used to describe chronic vulvar pain.
    1. Burning/stinging pain
    2. Incisive pain
    3. Sensitivity
    Coping Strategies (VPAQcope). This scale addresses some common coping strategies that are utilized by women with vulvar pain.
    1. Distraction/relaxation strategies
    2. Problem-solving strategies
    Partner Factors (VPAQpartner). This 24-item scale encompasses how romantic partners/spouses may be impacted by/respond to vulvar pain experienced by one partner.
    1. Negative response
    2. Support seeking
    3. Impact on relationship
    4. Sexual communication
    Each subscale is scored separately and is the average of the items. The lowest possible score is 0 (Not at all) and the highest is 4 (very much). Higher score means worse symptoms
 
Other Outcome Measures:
  1. Tonic activation of the pelvic floor muscles (PFMs) [ Time Frame: Baseline ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while the muscles remain at rest.
  2. Tonic activation of the pelvic floor muscles (PFMs) [ Time Frame: 12 weeks (after intervention) ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while the muscles remain at rest.
  3. Tonic activation of the pelvic floor muscles (PFMs) [ Time Frame: 12 weeks later (if funding becomes available) ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while the muscles remain at rest.
  4. Maximum voluntary activation of the pelvic floor muscles (PFMs) [ Time Frame: Baseline ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while participants attempt a maximum voluntary activation of their PFMs
  5. Maximum voluntary activation of the pelvic floor muscles (PFMs) [ Time Frame: 12 weeks (after intervention) ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while participants attempt a maximum voluntary activation of their PFMs
  6. Maximum voluntary activation of the pelvic floor muscles (PFMs) [ Time Frame: 12 weeks later (if funding becomes available) ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while participants attempt a maximum voluntary activation of their PFMs
  7. Activation of the pelvic floor muscles (PFMs) during a bearing down maneuver [ Time Frame: Baseline ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while participants perform a bearing down maneuver
  8. Activation of the pelvic floor muscles (PFMs) during a bearing down maneuver [ Time Frame: 12 weeks (after intervention) ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while participants perform a bearing down maneuver
  9. Activation of the pelvic floor muscles (PFMs) during a bearing down maneuver [ Time Frame: 12 weeks later (if funding becomes available) ]
    Mean smoothed, rectified activation amplitude of the PFMs recorded through electromyography while participants perform a bearing down maneuver
  10. Anticipatory responses (ms) to pressure applied at the vulvar vestibule [ Time Frame: Baseline ]
    The proportion of women in each group who demonstrate anticipatory responses of the PFMs to impeding pressure applied at the vulvar vestibule will be determined for each group. Participants will be deemed to have anticipatory responses if electromyiographic signals recorded from the PFMs precede the application of pressure. A vulvagesiometer will be employed using a response-dependent methodology. The vulvagesiometer will be used to apply low (25g) and moderate (232g) pressure to the posterior vaginal fourchette or to the posterior thigh.
  11. Anticipatory responses (ms) to pressure applied at the vulvar vestibule [ Time Frame: 12 weeks (after the intervention) ]
    The proportion of women in each group who demonstrate anticipatory responses of the PFMs to impeding pressure applied at the vulvar vestibule will be determined for each group. Participants will be deemed to have anticipatory responses if electromyiographic signals recorded from the PFMs precede the application of pressure. A vulvagesiometer will be employed using a response-dependent methodology. The vulvagesiometer will be used to apply low (25g) and moderate (232g) pressure to the posterior vaginal fourchette or to the posterior thigh.
  12. Anticipatory responses (ms) to pressure applied at the vulvar vestibule [ Time Frame: 12 weeks later (if funding becomes available) ]
    The proportion of women in each group who demonstrate anticipatory responses of the PFMs to impeding pressure applied at the vulvar vestibule will be determined for each group. Participants will be deemed to have anticipatory responses if electromyiographic signals recorded from the PFMs precede the application of pressure. A vulvagesiometer will be employed using a response-dependent methodology. The vulvagesiometer will be used to apply low (25g) and moderate (232g) pressure to the posterior vaginal fourchette or to the posterior thigh.
  13. Behavioural responses (µV) to pressure applied at the vulvar vestibule [ Time Frame: Baseline ]
    The proportion of women in each group who demonstrate behavioural responses of the PFMs to pressure applied at the vulvar vestibule will be determined for each group. Participants will be deemed to have behavioural responses if the activation of the PFMs (or other muscles) occurs after the pressure is applied. A vulvagesiometer will be employed using a response-dependent methodology. The vulvagesiometer will be used to apply low (25g) and moderate (232g) pressure to the posterior vaginal fourchette or to the posterior thigh.
  14. Behavioural responses (µV) to pressure applied at the vulvar vestibule [ Time Frame: 12 weeks (after the intervention) ]
    The proportion of women in each group who demonstrate behavioural responses of the PFMs to pressure applied at the vulvar vestibule will be determined for each group. Participants will be deemed to have behavioural responses if the activation of the PFMs (or other muscles) occurs after the pressure is applied. A vulvagesiometer will be employed using a response-dependent methodology. The vulvagesiometer will be used to apply low (25g) and moderate (232g) pressure to the posterior vaginal fourchette or to the posterior thigh.
  15. Behavioural responses (µV) to pressure applied at the vulvar vestibule [ Time Frame: 12 weeks later (if funding becomes available) ]
    The proportion of women in each group who demonstrate behavioural responses of the PFMs to pressure applied at the vulvar vestibule will be determined for each group. Participants will be deemed to have behavioural responses if the activation of the PFMs (or other muscles) occurs after the pressure is applied. A vulvagesiometer will be employed using a response-dependent methodology. The vulvagesiometer will be used to apply low (25g) and moderate (232g) pressure to the posterior vaginal fourchette or to the posterior thigh.
  16. Adherence to the intervention protocol [ Time Frame: 12 weeks (after the intervention) ]
    Attendance of laser treatment visits will be tracked.
Study Record | ClinicalTrials.gov

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 (2019 — 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. Study Record | ClinicalTrials.gov

Dysport in Vulvodynia Phase II Study (DYVINIA) (2018 — 2021)
This study is designed to define optimal doses of Dysport and evaluate its efficacy and safety compared with placebo for the treatment of vulvodynia. The study will consist of a dose escalation stage (Stage 1) and a dose expansion stage (Stage 2). Both Stage 1 and Stage 2 will consist of a double-blind period (with treatment cycle 1; Dysport or placebo) followed by an open label treatment period. One or two optimally safe and effective doses of Dysport selected from Stage 1 will be further investigated in the Stage 2.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the DB Treatment Period (Stage 1) For Stage 1, the primary endpoint was safety during the DB treatment period as assessed by the incidence of adverse events (AEs). An AE was the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An undesirable medical condition could have been symptoms, signs or abnormal results of an investigation. A TEAE was an event with start date on or after the date of the first investigational medicinal product (IMP). Relatedness to treatment was assessed by the investigator. TEAEs of special interest included events suggesting a possible remote spread of effect of the toxin, events related to urinary incontinence or faecal incontinence and events assessed as a potential hypersensitivity reaction. Results for this outcome are reported as the number of participants experiencing at least one TEAE in each specified category. From Baseline (Cycle 1 Day 1) to Cycle 1 Week 12 (DB treatment period, Stage 1)
Mean Change From Baseline in Vaginal Dilator Induced Pain During the DB Treatment Period at Week 6 (Stage 2) Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 (DB treatment period, Stage 2)
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Mean Change From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point Numeric Rating Scale (NRS) During the DB Treatment Period at Week 6 and Week 12 (Stage 1) For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as change from Baseline during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Number of Participants Who Reported at Least a 50% Decrease From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥50% decrease from Baseline during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Number of Participants Who Reported at Least a 30% Decrease From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥30% decrease from Baseline during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Number of Participants Who Reported at Least a 2-point Decrease From Baseline in Vaginal Dilator Induced Pain as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) For the dilator test, a vaginal dilator was used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The dilator test was used to assess the change from Baseline in the vaginal dilator induced pain (using the DMTS reported at Baseline). Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥2-point decrease from Baseline during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Mean Change From Baseline in the DTMS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) For the dilator test, a set of 8 vaginal dilators of increasing diameter (#1 being the smallest and #8 being the largest) were used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. Based on the subjective pain threshold, the largest sized dilator that the participant accepted/tolerated for the test, was defined as the DMTS. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as change from Baseline in the DTMS during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Mean Change From Baseline in the Composite Score for the Vaginal Dilator Induced Pain and Dilator Size During the DB Treatment Period at Week 6 and Week 12 (Stage 1) For the dilator test, a set of 8 vaginal dilators of increasing diameter (#1 being the smallest and #8 being the largest) were used by the investigator to provoke pain to allow assessment of vestibular pain intensity in each participant. The composite score for the vaginal dilator induced pain and dilator size was the sum of all pain measurements across the full range of dilator sizes. For any dilator size that was beyond the DMTS, the pain score was 10. There was to be at least 6 pain scores (recorded by the investigator) to calculate the composite score. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as change from Baseline in the composite score for the dilator test during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Mean Change From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) From 2 weeks prior to the next planned visit, all participants rated in the electronic diary (eDiary) once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the change from Baseline in participant reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Number of Participants Who Reported at Least a 50% Decrease From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) From 2 weeks prior to the next planned visit, all participants rated in the eDiary once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥50% decrease from Baseline in participant reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Number of Participants Who Reported at Least a 30% Decrease From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) From 2 weeks prior to the next planned visit, all participants rated in the eDiary once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a ≥30% decrease from Baseline in participants reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Number of Participants Who Reported at Least a 2-point Decrease From Baseline in Pain During Insertion of Vaginal Dilator Number 6 Size as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) From 2 weeks prior to the next planned visit, all participants rated in the eDiary once a week the level of the corresponding pain following insertion of the number 6 vaginal dilator into the vagina. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the number of participants who had a 2-point decrease from Baseline in participant reported pain score for the number 6 dilator test during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Mean Change From Baseline in Pain During Intercourse as Reported on an 11-point NRS During the DB Treatment Period at Week 6 and Week 12 (Stage 1) From the Screening visit, and then 2 weeks prior to the next planned visit, participants recorded on a daily basis in the eDiary if they had intercourse and if yes, the level of the corresponding pain during each intercourse instance. Participants rated their pain using an 11-point NRS ranging from 0 to 10, where 0 was no pain and 10 was the worst possible pain. Higher scores indicate a worse outcome. The 2-week average was used, which was calculated as the average of the score over the last 2 weeks (14 days) prior to the visit. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the change from Baseline in participant reported pain score during intercourse (over the last 2 weeks prior to each visit) during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Mean Change From Baseline in the Number of Intercourse Instances in Participants With Partners During the DB Treatment Period at Week 6 and Week 12 (Stage 1) From the Screening visit, and then 2 weeks prior to the next planned visit, participants recorded on a daily basis in the eDiary if they had intercourse and if yes, the number of intercourse instances in the previous 24-hour period. The number of intercourse instances over the 2 weeks preceding the visit was calculated as the total recorded number of intercourse instances over 14 days prior to the visit. Baseline was defined as the last value available prior to the first study IMP treatment administration. Results for this outcome are reported as the change from Baseline in number of intercourse instances (over the last 2 weeks prior to each visit) during the DB treatment period at Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Use of Pain Rescue Medication Associated With Intercourse During the DB Treatment Period at Week 6 and Week 12 From the Screening visit, and then 2 weeks prior to the next planned visit, participants recorded on a daily basis in the eDiary if they had intercourse and also details of any pain rescue medication consumed for each intercourse instance to prevent or treat the vestibular pain. If a participant used the rescue medication associated with at least one instance during the 2-week prior to a visit, the participant was considered as having used the rescue medication for that visit. Results for this outcome are reported as the number of participants using pain rescue medication associated with intercourse (over the last 2 weeks prior to each visit) during the DB treatment period at Baseline, Week 6 and Week 12. Baseline (Cycle 1 Day 1) and Cycle 1 Week 6 and Week 12 (DB treatment period, Stage 1)
Study Record | ClinicalTrials.gov

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
Efficacy of a Physiotherapy Treatment in Women Suffering From Provoked Vestibulodynia (2011 — 2015)
Chronic gynaecological pain is a major medical problem that affects 20-30% of women at different moments of their life. This largely neglected issue has a significant impact on the sexual and conjugal life of women suffering from it as well as on their psychological health. Furthermore, this kind of pain is not well understood, often misdiagnosed or even totally ignored. Also, treatment is limited and not extensively studied. This study aims at better understanding and treating gynaecological pain. The focus of the study will be provoked vestibulodynia, pain at the entry of the vagina. The efficacy of specialized pelvic floor physiotherapy will be compared to a topical cream (lidocaine) applied to the vulva. The treatment efficacy will be assessed in 234 women (aged from 18-45 years old) suffering from provoked vestibulodynia recruited in 4 hospitals (CHUS, Jewish General Hospital, Royal-Victoria Hospital, CHUM St-Luc).
This is a randomised controlled trial comparing the impact of multimodal physiotherapy treatments to topical lidocaine in women suffering from provoked vestibulodyina. The first treatment consists of 10 sixty minutes weekly physiotherapy treatments including relaxation techniques, stretching and pelvic floor muscle control exercises. The second treatment is a night time application of lidocaine to the vulva for 10 weeks. Physiotherapists will then evaluate women's pain and sexual function right after the treatment and 6 months later.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Change in pain during intercourse evaluated with a visual analog scale before treatment, after treatment, 6 months after treatment
Change in global sexual function evaluated with the female sexual function index (FSFI) before treatment, after treatment, 6 months after treatment
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Change in pain catastrophizing evaluated using the pain catastrophizing scale before treatment, after treatment, 6 months after treatment
Change in psychologic distress evaluated using the State-trait Anxiety Inventory (STAI) before treatment, after treatment, 6 months after treatment
Change in fear of pain evaluated using the Pain Anxiety Symptoms Scale (PASS-20) before treatment, after treatment, 6 months after treatment
Change in vulvar blood circulation evaluated using a doppler laser before treatment, after treatment, 6 months after treatment
Change in pelvic floor muscles function evaluated using transperineal ultrasound and dynamometry before treatment, after treatment, 6 months after treatment
Change in pain sensitivity (pressure pain) evaluated using a vulvagesiometer before treatment, after treatment, 6 months after treatment
Study Record | ClinicalTrials.gov

Efficacy of Transcranial Direct-Current Stimulation (tDCS) for Provoked Vestibulodynia : a Triple Blind Randomized Controlled Trial (PVD/tDCS) (2014 — 2016)
Provoked vestibulodynia (PVD) is the most common form of vulvodynia and despite its high prevalence and important sexual, conjugal and psychological deleterious repercussions, effective evidence-based interventions remain limited. For a high proportion of women, significant pain persists despite the currently available treatments. Transcranial direct-current stimulation (tDCS) was shown to be effective in various chronic pain conditions. So far, only one case report study has shown significant pain reduction in women with vulvodynia. The main goal of this randomized controlled trial is to evaluate the efficacy of tDCS in women with PVD compared to sham tDCS. Forty women diagnosed with PVD, by a gynecologist following a standardized protocol will be randomized to either active or sham tDCS for ten 20 minute sessions of 2 mA stimulation over a 2-week period. Outcome measures will be collected at baseline, after treatment and at 3-month follow-up. The primary outcome is pain during intercourse assessed with a numerical rating scale (NRS). Secondary measurements focus on sexual function, vestibular pain sensitivity, psychological distress, treatment satisfaction and Patient Global Impression of Change (PGIC). The investigators expect that active tDCS treatment will significantly reduce pain during intercourse (post-treatment and 3-month follow-up compared to pre-treatment assessment). This trial will provide important information for determining the efficacy of a novel and promising intervention for women with PVD.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Pain during intercourse (Numeric rating scale) Pain during intercourse will be assessed using a numeric rating scale (NRS) ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain ever. This method for measuring pain has been shown to detect significant treatment effects in women with PVD 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 (Bergeron et al., 2008; Bergeron et al., 2001; Morin et al., 2010; Morin et al., 2011). Change in the NRS scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Pain (McGill-Melzack questionnaire) The McGill-Melzack questionnaire allows the assessment of sensory, affective and evaluative components of pain. This world-renowned questionnaire, studied for its validity, reliability and responsiveness to change, is commonly used in RCTs (Bergeron et al., 2001; Melzack, 1975; Davidoff et al., 1987; Hays et al., 1994; Bansal et al., 2009; Moy et al., 2011; Foster et al., 2010). Change in the McGill-Melzack scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Vestibular sensitivity (algometer) A gradual pressure (1 to 1000 g) will be applied to three distinct points of the vestibule at the 3, 6 and 9 o'clock positions (Cyr et al., 2014). Each of these pressure points will be applied randomly (e.g. 3,6,9 or 3,9,6 or 6,9,3.). During this procedure, each participant will be asked to indicate when they start to feel pain (pain threshold) and subsequently the maximal pressure that can be tolerated (pain tolerance). Pain intensity is assessed throughout the test using a Computerized Visual analog scale (CoVas). This assessment has shown good reliability and validity (Cyr et al., 2014). Change in the pain threshold and pain tolerance scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Female Sexual Function Index (FSFI) The Female Sexual Function Index (FSFI) is a multidimensional measure of sexual function evaluating desire, arousal, lubrication, orgasm, satisfaction and pain. In addition to good psychometric properties (reliability, internal consistency and responsiveness to change (Rosen et al., 2000; Goldfinger et al, 2009), normative data are available for this questionnaire suggesting clinical level of dysfunctions (Wiegel et al., 2005). Change in the FSFI scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Pain Catastrophizing Scale (PCS) Pain catastrophizing will be assessed using the Pain Catastrophizing Scale (Sullivan, Bishop, & Pivik, 1995), which consists of 13 items measuring exaggerated negative thoughts and feelings about the meaning of pain. Items are scored on a 5-point scale with the end points (0) not at all and (4) all the time. The PCS is a reliable and valid measure that has demonstrated a stable factorial structure across clinical and general populations, including a French population (French et al., 2005; Osman et al., 2000; Sullivan, et al., 1995). Change in the PCS scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Spielberg State-Trait Anxiety Inventory (IASTA) Anxiety will be assessed using the Spielberger State-Trait Anxiety Inventory (STAI - (Spielberger, Gorsuch, & Lushene, 1970); ASTA - (Gauthier & Bouchard, 1993)). The STAI is a 40-item, well-known and widely used measure of state and trait anxiety that has demonstrated very good psychometric properties (Cronbach's alpha State = .93, Trait = .97) in various clinical and non-clinical samples including pain populations (Gauthier & Bouchard, 1993; Greenberg & Burns, 2003; Rule & Traver, 1983; Tanaka-Masumi & Kameoka, 1986). Change in the IASTA state and IASTA trait scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Beck Depression Inventory questionnaire (BDI-II) Depression or depression symptoms will be measured with the Beck Depression Inventory-II (BDI-II). The BDI-II is comprised of 21 items, with scores for most items ranging from 0 (low intensity) to 3 (high intensity) (Beck, Steer & Brown, 1996; Beck, Steer & Garvin, 1988). This measure of depression has been validated for use in chronic pain populations (Turner & Romano, 1984). Change in the BDI scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Pain Anxiety Symptoms Scale (PASS-20) The Pain Anxiety Symptoms Scale (PASS-20), evaluating fear of pain, also shows good psychometric properties (Coons, Hadjistavropoulos & Asmundson, 2004; McCracken & Dhingra, 2002). Change in the PASS-20 scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment
Patient's global impression of change (PGIC) Patient self-reported improvement [scale of 0 (completely dissatisfied) to 10 (completely satisfied)] and treatment satisfaction [scale of 0 (worse) to 10 (complete cure)] will be measured at the 2-week post-treatment and 3-month post-treatment structured interview in order to assess the clinical significance of results. Change in the PGIC scores from 2-week post-treatment to 3-month post-treatment
Global Measure of Sexual Satisfaction scale (GMSS) 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) (Lawrance & Byers, 1998). Change in the GMSS scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment

High-level Laser for Provoked Vestibulodynia (2020 — 2021)
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).
Study Record | ClinicalTrials.gov

Pelvic Floor Myofascia: A New Player Involved in Vulvodynia (2022 — 2023)
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.
Study Record | ClinicalTrials.gov

Feasibility Study for Provoked Vestibulodynia (2022 — 2023)
The feasibility and acceptability of a somatosensory rehabilitation program and an educational pain management program will be investigated in women with provoked vestibulodynia. Forty-four women will be randomized into the two groups. The secondary objective is to explore the effects of the somatosensory rehabilitation program compared to the pain management program. Each participant will receive 12 weekly sessions with a physiotherapist. The somatosensory rehabilitation program includes minimizing contact with the painful zone of the vulva and uses repeated tactile stimulation at a tolerated distance, proximal to the vulva. The pain management program includes teaching participants about vulvar hygiene, chronic pain mechanisms, relaxation techniques, and approaches to reduce skin irritations in painful regions. Participants in both groups will also receive advice on sexual function and steps toward resuming sexual activities with vaginal penetration. Feasibility and acceptability outcomes will be assessed and analyzed using descriptive statistics for the adherence rates to treatment sessions and home exercises, the recruitment rate, retention rate, satisfaction, and adverse effects. The results will be compared to predetermined thresholds to determine the feasibility and acceptability of a future clinical trial. Secondary measures will be assessed at baseline, two weeks after the treatment, and at three months follow-up. These outcomes will be assessed using validated questionnaires (pain, sexual function, global impression of change, psychological variables, quality of life) as well as evaluations of tactile and pressure sensitivity in vulvar regions using monofilaments, a 2-point aesthesiometer and an algometer. Linear mixed models for repeated measurements (2 groups, 3 measurement times) will be used to explore the treatment effects and will contribute to determining the feasibility of a future clinical trial. Hypothesis and expected results: It is expected that both programs will meet the pre-determined criteria for acceptability and feasibility in women with provoked vestibulodynia. This study will provide guidance for a future randomized clinical trial.  
Primary Outcome Measures:
  1. Adherence rate to home exercises [ Time Frame: From first to last session (baseline to 12th week) ]
    The adherence rate to home exercises for each treatment group will be assessed using a daily diary. The participants will record the frequency and duration of the exercises completed.
  2. Patients' adherence rate to treatment sessions [ Time Frame: From first to last session (baseline to 12th week) ]
    The patients' adherence to treatment sessions will be recorded in the participants' treatment files (present vs absent).
  3. Adherence rate to assessment sessions [ Time Frame: Baseline to 3 months post-treatment evaluation ]
    The adherence to assessment sessions (present vs absent) will be recorded in the participants' assessment files. The reasons for absences will be documented.
  4. Retention rate [ Time Frame: Baseline to 3 months post-treatment evaluation ]
    The retention rate will be assessed by calculating the ratio of participants who stay in the study until the post-intervention and 3-month follow-up assessments. Reasons for dropouts will be collected.
  5. Recruitment rate [ Time Frame: At baseline only (during the recruitement period) ]
    The recruitment rate will be recorded as the average number of participants recruited per month as well as the participant accrual rate (participants enrolled / participants screened for diagnosis). Reasons for refusing to participate will be documented if the participant consents to inform the study's research team.
  6. Therapists treatment adherence [ Time Frame: From first to last session (baseline to 12th week) ]
    The therapists' treatment adherence will be assessed within the therapists' files to verify that all the interventions' key components were applied and respected.
Secondary Outcome Measures:
  1. Intervention Acceptability Questionnaire [ Time Frame: At 2-week post-treatment and at 3 months post-treatment ]
    The Intervention Acceptability Questionnaire explores the participants' acceptability of the interventions. This questionnaire consists of 4 items measured on a VAS scale (Minimum value: 0; Maximum Value: 10). Each item is analyzed separately, with a greater score meaning higher acceptability of the intervention. This outcome measure will contribute to identifying factors limiting the acceptability of each program.
  2. Credibility and Expectancy Questionnaire [ Time Frame: At baseline only (before the initiation of the treatment) ]
    The Credibility and Acceptability Questionnaire explores the credibility and the participants' expectancy for the interventions. This questionnaire consists of 3 items: two items are measured on a 9-point Likert scale (Minimum value: 1; Maximum Value: 9) and one item is measured in percentages (Minimum: 0, Maximum: 100%). Each item is analyzed separately, with a greater score meaning higher credibility.
  3. Patients' Global Impression of Change and Satisfaction [ Time Frame: At 2-week post-treatment and 3 months post-treatment ]
    These two items will determine patient self-reported improvement and satisfaction regarding the effects of the intervention on pain (Patient's Global Impression of Change and Satisfaction). The Patient's Global Impression of Change contains two items that address change in pain and quality of sexual life. It is assessed on a 7-point scale ranging from "very much worse" to "very much improvement". The Satisfaction will be assessed with a single item on an 11-point Likert scale (Minimum: 0, Maximum: 10). A greater score means higher satisfaction. This outcome measure explores the acceptability of the interventions by assessing the extent to which the intervention is perceived as likely to achieve its purpose.
  4. Self-Efficacy Question [ Time Frame: At baseline, 6 week after the initiation of treatment, and at the last treatment (12th week) ]
    A single item included in the participant's diary will assess at which point the participant feels she is confident and self-sufficient in being able to apply the exercises and advice. This item is measured on a VAS scale (Minimum: 0, Maximum: 10) with a greater score meaning higher confidence in being self-sufficient in applying the exercises and advice. This outcome measure will explore self-efficacy regarding the interventions.
  5. Adverse events [ Time Frame: 2-week and 3 months post-treatment ]
    The adverse events will be noted in the participant's daily diary and in the treatment files.
  6. Pain intensity during intercourse (Numerical Rating Scale) [ Time Frame: Changes from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    Pain during intercourse will be assessed using a numeric rating scale (NRS) ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain ever.
  7. Pain quality (McGill-Melzack questionnaire-short form) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    The McGill-Melzack questionnaire- short form consists of 15 items that assess the sensory, affective and evaluative components of pain. Items are scored on a 4-point scale with the endpoints (0) no pain at all and (3) severe pain. Minimum value: 0, Maximum value: 45, with more elevated scores meaning higher pain.
  8. Vulvar sensitivity [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    Gradual pressure (1 to 1000 g) will be applied to three distinct points of the vestibule at the 3, 6 and 9 o'clock positions. Each of these pressure points will be applied randomly (e.g. 3,6,9 or 3,9,6 or 6,9,3.). During this procedure, each participant will be asked to indicate when they start to feel pain (pain threshold) and subsequently the maximal pressure that can be tolerated (pain tolerance). A higher result means a more elevated pain threshold and a higher pain tolerance.
  9. Vulvar tactile allodynia area [ Time Frame: Change in the surface from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    A force of 15g will be applied using a monofilament in the vulvar region in order to outline the borders of the allodynia (hypersensitivity to tactile stimuli) surface. The width and length of the surface will be measured with a graduated cotton swab (ruler). The surface will be computed by multiplying its width by its length (squared centimeters). This method of assessing allodynia severity is described within the Somatosensory Rehabilitation Method Handbook. A higher value indicates a greater area with tactile allodynia.
  10. Vulvar tactile alllodynia severity [ Time Frame: Change in the surface from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    A series of seven monofilaments (0.02g, 0.4g, 0.7g, 1.5g, 4.0g, 8.0g, 15.0g) will be applied to the outside border of the vulvar vestibule to find the smallest force that causes an increase in pain. This method of assessing allodynia severity is described within the Somatosensory Rehabilitation Method Handbook. A lower result indicates more severe allodynia.
  11. Vulvar tactile sensibility [ Time Frame: Change in the surface from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    Once the allodynia has resolved, the smallest perceived force will be measured by applying monofilaments in a decreasing order (force) to the outside border of the vulvar vestibule (Max: 29g; Min: 0.005g). A lower force value indicates better tactile sensibility.
  12. Two-point discrimination test [ Time Frame: Change in the surface from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    The two-point discrimination test assesses an integrative aspect of tactile sensibility. Once the allodynia has resolved, a 2-point stainless steel aesthesiometer will be applied with one point on the vulvar vestibule border and the other point outside this area. It will be applied at variable and decreasing distances. The result is the smallest distance between the two points at which the person can discriminate if one or two points are being applied (Minimum: 1mm, Maximum: 100mm). A smaller value suggests tactile perception of a higher quality.
  13. Female Sexual Function Index (FSFI) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    The Female Sexual Function Index (FSFI) is a multidimensional measure of sexual function evaluating desire, arousal, lubrication, orgasm, satisfaction and pain. This 19-item questionnaire explores changes in sexual function with a Likert scale ranging from 0 (or 1) to 5. The overall score has a minimum value of 2 and a maximum value of 36. Lower scores mean worse outcomes (low sexual function).
  14. Female Sexual Distress Scale (FSDS) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    The FSDS 13-item questionnaire explores sexually related personal distress in women. Each item is assessed on a 5-point Likert scale from 0 (never) to 5 (always). The total score ranges from a minimum value of 0 to a maximum value of 100. Higher scores mean worse outcomes (greater sexually related distress).
  15. Pain Anxiety Symptoms Scale (PASS-20) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    The PASS-20 is a 20-item questionnaire that explores fear and anxiety responses specific to pain. Each item is assessed on a 6-point Likert scale from 0 (never) to 4 (always). The total score ranges from a minimum value of 0 to a maximum value of 52. Higher scores mean worse outcomes (greater fear of pain).
  16. Pain Catastrophizing Scale (PCS) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    Pain catastrophizing will be assessed using the PCS, which consists of 13 items measuring exaggerated negative thoughts and feelings about the meaning of pain. Items are scored on a 5-point scale with the endpoints (0) not at all and (4) all the time. Minimum value: 0, Maximum value: 52, higher scores mean worse outcomes (greater pain catastrophizing).
  17. Beck Depression Inventory questionnaire (BDI-II) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    Depression or depression symptoms will be measured with the Beck Depression Inventory-II (BDI-II). The BDI-II is comprised of 21 items, with scores for most items ranging from 0 (low intensity) to 3 (high intensity). The maximum total score is 63. Scores above 10 meet the threshold for depression. Higher scores mean more severe depression.
  18. Vaginal Penetration Cognition Questionnaire (VPCQ) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, and from pre-treatment to 3-month post-treatment ]
    The VPCQ is a 40-item questionnaire that assesses cognitions regarding vaginal penetration in women. Items are scored on a 6-point scale with the end points (0) never and (6) always. Five aspects of vaginal penetration cognition are assessed: control cognitions, catastrophic and pain cognitions, self-image cognitions, positive cognitions, and genital incompatibility cognitions. Higher scores show higher levels of perceived penetration control.
  19. 12-item Short Form Survey (SF-12 v2) [ Time Frame: Change in the scores from pre- to 2-week post-treatment, from 2-week post-treatment to 3-month post-treatment, and from pre-treatment to 3-month post-treatment ]
    The SF-12 questionnaire assesses the impact of health on an individual's everyday life and quality of life. The second version of the SF-12 will be used. Scores range from 0 (minimum) to 100 (maximum). Higher scores indicate better physical and mental health.
Other Outcome Measures:
  1. Short-Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS) [ Time Frame: At baseline only (before the initiation of the treatment) ]
    The S-LANSS 7-item questionnaire assesses the presence of neuropathic symptoms and signs. The dichotomous answers have different weights in the total score with the absence of the sign/symptom valued at 0 and the presence of the sign/symptom valued between 1 and 5 points. Scores range from 0 (minimum) to 24 (maximum). Scores of 12 or greater suggest pain of a predominantly neuropathic origin. The proportion of neuropathic symptoms and signs in each group will be documented.
Study Record | ClinicalTrials.gov

Dry Needling for Provoked Vestibulodynia (2023 — 2024)
This is a randomized and controlled study investigating the feasibility and acceptability of a dry needling treatment for women suffering from provoked vestibulodynia. Following their enrollment in the study, participants will undergo a gynecological examination for confirmation of their diagnoses of provoked vestibulodynia. Women diagnosed with provoked vestibulodynia will be randomized into the dry needling group or the sham-needle group. The dry needling group will receive 6 sessions of real dry needling for 6 consecutive weeks. The sham group will receive 6 sessions of sham needling for 6 consecutive weeks, using a validated sham-needle. Outcomes measures will be assessed at baseline and at post-treatment and will include: feasibility and acceptability variables, pain intensity and quality, pain during palpation and pressure pain threshold, psychosexual variables, perceived improvement and satisfaction after the treatment as well as pelvic floor muscle stiffness and function.
Up to 18% of reproductive-aged women experience chronic pain in the vulvar region during sexual intercourse. This chronic pain condition is called vulvodynia. The main subtype of this pain condition is provoked vestibulodynia (PVD), which is characterized by a sharp or burning pain at the vaginal opening when there is a pressure applied to the vulvar vestibule or attempting vaginal penetration. Women suffering from PVD suffer from sexual dysfunctions, psychological distress and worsened quality of life. The treatment options currently available are still quite limited and some women still experience pain despite undertaking all options available. We, therefore, proposed a randomized and controlled study to investigate the feasibility and acceptability of a dry needling treatment for women suffering from PVD. Women diagnosed with provoked vestibulodynia will be randomized into the dry needling group or the sham-needle group. Participants and evaluators will be blinded. The dry needling group will receive 6 sessions of real dry needling for 6 consecutive weeks. For the first three sessions, the dry needling/or sham techniques will be aimed at the muscles of the trunk, lower back, hips and SI joints. For the last 3 treatment sessions, the dry needling/or sham techniques will aimed at the pelvic floor muscles. The sham group will receive the same 6 sessions of sham needling for 6 consecutive weeks, using a validated sham-needle. Outcomes measures will be assessed at baseline and 2 weeks post-treatment and will include: feasibility (adherence to treatment, retention rates, adverse effects, recruitment rates and data on dry needling (needles, # of insertions, pain related) and acceptability variables. Secondary outcomes will include pain intensity during intercourse (numeric scale) and quality (McGill pain questionnaire), pain during palpation and pressure pain threshold (Pressure algometer), psychosexual variables (sexual distress and sexual function), change in pain catastrophizing, change in quality of life in domains associated with chronic pelvic pain (Pelvic Pain Impact questionnaire, severity of symptoms related to central sensitization), perceived improvement and satisfaction after the treatment as well as pelvic floor muscle stiffness (shearwave elastography and dynamometric speculum)and function (dynamometric speculum), blinding efficacy.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Adherence to treatment sessions a. To determine feasibility, the patients' adherence to treatment sessions will be recorded (present vs absent) as well as reasons for non-attendance. Through treatment completion (session 1 to 6; 6 weeks of treatment)
Adherence to treatment protocol a. To determine feasibility by assessing adherence to treatment sessions. Through treatment completion (session 1 to 6; 6 weeks of treatment)
Retention rate a. To determine feasibility by assessing the percentage of participants completing the post-treatment assessment. Reason for dropouts will be compiled Baseline to Post-treatment assessment (2-week post-treatment)
Adverse effects a. Adverse effects observed and reported will be documented at each treatment session and at the post-treatment assessment. Through treatment completion (session 1 to 6; 6 weeks of treatment)
Adverse effects a. Adverse effects observed and reported will be documented at each treatment session and at the post-treatment assessment. Post-treatment assessment (2-week post-treatment)
Recruitment rate a. To determine feasibility by assessing the percentage of participants included versus the participants screened. The barriers and reasons for refusing to participate as well as the reasons for exclusion will be documented Baseline
Intervention Acceptability Questionnaire a. The Intervention Acceptability Questionnaire will be used to assess the participants' acceptability of the interventions. This questionnaire consists of 6 items measured on a VAS scale (Minimum value: 0; Maximum Value: 10). Each item is analyzed separately, with a greater score meaning higher acceptability of the intervention. Baseline
Intervention Acceptability Questionnaire a. The Intervention Acceptability Questionnaire will be used to assess the participants' acceptability of the interventions. This questionnaire consists of 6 items measured on a VAS scale (Minimum value: 0; Maximum Value: 10). Each item is analyzed separately, with a greater score meaning higher acceptability of the intervention. After treatment session 3 (week 3)
Intervention Acceptability Questionnaire a. The Intervention Acceptability Questionnaire will be used to assess the participants' acceptability of the interventions. This questionnaire consists of 6 items measured on a VAS scale (Minimum value: 0; Maximum Value: 10). Each item is analyzed separately, with a greater score meaning higher acceptability of the intervention. Post-treatment assessment (2-week post-treatment)
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Change in pain intensity during intercourse 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. Baseline to Post-treatment assessment (2-week post-treatment)
Change in pain quality To explore changes on the sensory, affective, and evaluative components of pain (McGill-Melzack Questionnaire). Ranging from 0 to 78, higher scores mean worst outcome (higher pain). Baseline to Post-treatment assessment (2-week post-treatment)
Change in pain catastrophizing To explore changes on pain catastrophizing (Pain catastrophizing scale (PCS)). Ranging from 0 to 52, higher scores mean worse outcome (higher pain catastrophizing). Baseline to Post-treatment assessment (2-week post-treatment)
Change in fear of pain To explore changes in fear of pain (Pain anxiety Symptoms Scale (PASS-20). Ranging from 0 to 100, higher scores mean worse outcome (higher fear of pain). Baseline to Post-treatment assessment (2-week post-treatment)
Change in sexual function To explore changes in sexual function (Female Sexual Function Index - FSFI). Ranging from 2 to 36, lower scores mean wort outcome (low sexual function). Baseline to Post-treatment assessment (2-week post-treatment)
Change in sexual distress To explore changes in sexual distress (Female Sexual Distress Scale - FSDS). Ranging from 0 to 52, higher scores mean worse outcome (higher sexually related distress). Baseline to Post-treatment assessment (2-week post-treatment)
Change in quality of life in the domains associated with chronic pelvic pain To explore changes in quality of life Pelvic Pain Impact Questionnaire (PPIQ). Ranging from 0 to 32, higher scores mean worse outcome (less quality of life associated with pelvic pain). Baseline to Post-treatment assessment (2-week post-treatment)
Severity of symptoms related with central sensitization To explore changes in symptoms related to central sensitization (Central Sensitization Inventory). Ranging from 0 to 100, a higher scores indicates higher central sensitivity. Baseline to Post-treatment assessement (2-week post-treatment)
Satisfaction with treatment To determine acceptability by measuring the participants' satisfaction with the treatment on a Numeric Rating Scale (NRS) ranging from 0 (completely dissatisfied) to 10 (complete satisfied). Post-treatment assessment (2-week post-treatment)
Patient's global impression of change 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. Post-treatment assessment (2-week post-treatment)
Blinding effectiveness To assess the feasibility of maintaining blinding to group allocation for the participants. Evaluated by asking the question: ''What treatment do you think you have received? '' Post-treatment assessment (2-week post-treatment)
Changes in pelvic floor muscle stiffness To explore changes in pelvic floor muscle stiffness (Shearwave elastography) Baseline to Post-treatment assessment (2-week post-treatment)
Changes in pelvic floor muscle function To explore changes in pelvic floor muscle function (Dynamometric speculum) Baseline to Post-treatment assessment (2-week post-treatment)
Changes in pain at palpation To explore changes at intravaginal palpation of the internal obturators and the levator ani muscles following a standardized procedure (Numerical Rating Scale). Ranging from 0 to 10, where 0 is no pain at all, and 10 is the worst pain ever. Baseline to Post-treatment assessment (2-week post-treatment)
Changes in pressure pain threshold To explore changes in pressure pain threshold if predetermined areas of the pelvis (Wagner algometer) Baseline to Post-treatment assessment (2-week post-treatment)
Study Record | ClinicalTrials.gov

Efficacy of High Intensity Laser for Provoked Vestibulodynia (Laser_RCT) (2022 — 2025)
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.
Study Record | ClinicalTrials.gov

Filippo Murina, MD
Ultrasound Evaluation and Vestibular Perception Thresholds Changes in Women Affected by Vestibulodynia (VBD) After One Cycle of Pixel CO2-Alma Fractionated Laser (2022 — 2022)
Vestibulodynia (VBD), term revised by Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia in 2015, is a vulvar pain of at least 3 months' duration, without clear identifiable cause and localized at vestibuli. Women affected by this disease report localized hypersensitivity and pain of the vulvar vestibule to the touch (eg, during sexual intercourse or tampon use). This pattern of responses is suggestive of sensory abnormalities in the form of evoked pain (eg, hyperalgesia or allodynia). Research biopsy studies have demonstrated increased innervation of the vulvar vestibule and increased subepithelial heparinase activity and cytokines that have been associated with neuroinflammatory processes. In addition, the discomfort inherent in VBD is always associated with pelvic floor muscle overactivity, with the development of myofascial trigger points, resulting in localized or radiating pain and/or severe tenderness. A rich nerve plexus was identified within the vaginal submucosa, which was only composed of sympathetic and parasympathetic axons, with contributions of smaller sensory fibers. The sensory nerve endings of the vulvar vestibule are dense and shallow, making this region more physiologically sensitive. Several works suggest that a thinner vestibular mucosa is more sensitive to nociception because nerve endings become more superficial, thus altering the transduction of mechanical pressure to facilitate nociception. The CO2 fractionated laser, has been used to safely and effectively treat symptomatic vaginal atrophy. This tool has also been found to be useful in the treatment of vestibulodynia. In this open pilot study, 30 female subjects aged more 18 years old at inclusion, having symptoms of VBD from at least 6 months, have given her informed consent and meet all the eligibility criteria, will be enrolled. The subjects will be treated with CO2 Fractionated Laser into vestibule, for 3 sessions at monthly intervals with a follow up of 4 months. Subjects will come to a total of 6 visits over a period of 3 months. The primary objectives of the study are to evaluate the performance and safety of Pixel CO2-Alma Fractionated Laser in women affected by VBD by the assessment of vestibular mucosa thickness by ultrasound evaluation and vestibular perception thresholds changes at day 84 and 120 and by searching the adverse event during all the study. The secondary objectives are the assessment of VAS for burning/pain, and dyspareunia, evaluation of pain and hypersensitivity to the touch by Swab test, Female Sexual Function Index (FSFI) and by Vulval Pain Functional Questionnaire (VQ) at the visits.
Primary Outcome Measures:
  1. Vestibular mucosa thickness measured in µm by B-scan ultrasonography (DermaScan C, Cortex Technology, Denmark) [ Time Frame: 120 days ]
    The Investigator will use B-scan ultrasonography with a 20-MHz validated system. The changing was evaluated from baseline to day 84 (visit 5), and 120 (final visit).
  2. Vestibular perception thresholds measured with values from 1 to 25 by Neurometer CPT (Neurotron, Inc, Baltimore, MD) [ Time Frame: 120 days ]
    In Vestibular perception thresholds (VPT) a value ranging from 6 to 13 is classified as normal, while a value ranging from 1 to 5 show hyperesthesia. A value between 14 and 25 shows hypoesthesia. The changing was evaluated from baseline to day 84 (visit 5), and 120 (final visit).
Secondary Outcome Measures:
  1. Dyspareunia by Visual Analogue Scale [ Time Frame: 120 days ]
    The changing will be measured by Visual Analogue Scale (VAS) mean value from baseline to day 84 (visit 5), and 120 (final visit). The minimum score is 0 and the maximum score is 10, where 0 represents no symptoms and 10 represents severe symptoms.
  2. Burning/pain by Visual Analogue Scale [ Time Frame: 120 days ]
    The changing will be measured by Visual Analogue Scale (VAS) mean value from baseline to day 84 (visit 5), and 120 (final visit). The minimum score is 0 and the maximum score is 10, where 0 represents no symptoms and 10 represents severe symptoms.
  3. Pain/hypersensitivity to the touch at Swab test measured by Visual Analogue Scale. [ Time Frame: 120 days ]
    The changing from baseline to day 84 (visit 5), and 120 (final visit) will be reported in a Visual Analogue Scale (VAS). The minimum score is 0 and the maximum score is 10, where 0 represents no symptoms and 10 represents severe symptoms.
  4. Sexual Function by Female Sexual Function Index [ Time Frame: 120 days ]
    Sexual function will be evaluated at baseline and after 84 and 120 days by the Italian validated translation of the Female Sexual Function Index (FSFI), a self-report instrument consisting of 19 items that assess sexual function over the past 4 weeks in six areas: sexual desire, arousal, lubrication, orgasm, satisfaction, and pain. Mean value in each group separately and in the two groups in comparison will be analyzed.
  5. Vulval pain by Vulval Pain Functional Questionnaire (VQ) [ Time Frame: 120 days ]
    In the Vulval Pain Functional Questionnaire (VQ) a numerical value is assigned to each response. The higher the score the greater the functional limitation. A diminishing score represents improvement.
  6. Vestibular trophism by the Vestibular Health Score [ Time Frame: 120 days ]
    Vestibular Health Score (VHS) will be used by the Investigator evaluating 5 parameters (Petechiae, Pallor, Fragility, Dryness, Erythema) which lead to obtain a final score defining the degree of atrophy. Each item is scored on a Likert scale between 0 =absent and 3 =severe. Total scores range from 0 to 15.
  7. Incidence of Treatment-Emergent Adverse Events/ Adverse Device Events/ Serious Adverse Events/ Serious Adverse Device Events [Safety and Tolerability] [ Time Frame: up to 120 days ]
    The incidence will be calculated by searching for Adverse Event (AE), Adverse Device Event ADE, Serious Adverse Event (SAE), Serious Adverse Device Event (SADE) at each visit
Study Record | ClinicalTrials.gov

Lila Nachtigall, MD
Sexual Penetration Pain in Postmenopausal Women: A Topical Botanical Drug Treatment (2018 — 2021)
This study will evaluate the use of topical 5 or 10% sinecatechins, a botanical drug derived from green tea for the alleviation of sexual pain in the area around the vaginal opening (the vulvar vestibule), that is a main source of pain during sexual contact or dyspareunia, in postmenopausal women, with vulvovaginal atrophy. Women may or may not be using estrogens. Half of the women will receive the study drug, 5 or 10% sinecatechins and half will receive placebo. In addition to the reduction or elimination of pain upon penetration, women may also experience increase in lubrication, arousal and intensity of orgasm.
Topical Veregen (15% sinecatechins) is an FDA approved botanical drug derived from green tea and is approved to be used as multiple doses, three times a day to treat all visible external genital warts. Topical green tea ointment has been shown to alleviate pain and improve wound healing in the vulvar vestibule for women who have had a recent episiotomy in the medical literature. In private clinical practice, dilute Veregen, sinecatechins ointment, has been effective in alleviating , sexual pain, vulvar vestibular pain, dyspareunia, in postmenopausal women as well as improving overall sexual satisfaction,( increasing lubrication, arousal and quality of orgasm). In this study, dilute Veregen, (5 or 10% sinecatechins) or placebo is being applied, as a single dose, topically, three times/week up to once a day, to alleviate pain in the vulvar vestibule, penetration pain, upon sexual contact or other manipulation of this area in postmenopausal women. Women are eligible whether or not they are currently using any form of estrogen or other hormonal treatments (eg. DHEA). Please note that women not using estrogen or who maybe taking aromatase inhibitors, tamoxifen, SERMS, are also eligible to be included.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Numerical Rating Scale for Pain Scale Title: Numerical Pain Scale to measure overall pain perceived from vulvar vestibule. Minimum value of scale: 0; Maximum value of scale: 10. Subjects were asked to rate from 0 to 10 pain perceived from their vulvar vestibule. The mean (standard error) for Numerical Pain Scale at each visit was calculated. A higher Numerical Rating Score means worse outcome and lower Numerical Rating Score means a better outcome. The following Numerical Rating Scale categories for Pain definition were utilized: 0=no pain, 1-3=mild pain, 4-6=moderate pain; 7-9=significant pain and 10=severe pain. Numerical Rating Scale for pain was assessed at Visit 1 (initial visit); Visit 2 (at 2 weeks), and Visit 3 (at 4 weeks).
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Q-tip Test Test for Pain on the Vulvar Vestibule Scale Title: Q-tip test of vulvar vestibular pain. Minimum value of scale: 0; Maximum value of scale: 10. Subjects were asked to rate from 0 to 10 pain perceived from their vulvar vestibule. The mean (standard error) for Q-tip test at each visit was calculated. A higher Q-tip score means worse outcome and lower Numerical Rating Score means a better outcome. The following Q-tip test categories for Pain definition were utilized: 0=no pain, 1-3=mild pain, 4-6=moderate pain; 7-9=significant pain and 10=severe pain. Q-tip test score for pain was assessed at Visit 1 (initial visit); Visit 2 (at 2 weeks), and Visit 3 (at 4 weeks).
Study Record | ClinicalTrials.gov

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.

Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments (2019 — 2023)
Vestibulodynia (VBD) is a chronic pelvic pain condition that affects 1 in 6 reproductive aged women, yet remains ineffectively treated by standard trial-and-error approaches. The investigators have identified two distinct VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p) subtype characterized by localized pain specific to the vulvar vestibule, and 2) VBD central (VBD-c) subtype characterized by pain at both vaginal and remote body regions. Preliminary data further demonstrate that VBD-p and VBD-c subtypes differ with respect to patient reported outcomes (e.g., physical and mental health), production of cytokines (intracellular proteins that regulate the activity of pain nerves and inflammatory processes), and expression of microRNAs (small non-coding RNA molecules that regulate gene expression). Women with VBD-p exhibit normal psychological profiles; balanced circulating pro- and anti-inflammatory cytokines; and dysregulation in microRNAs that regulate the expression of genes in estrogen pathways. In contrast, women with VBD-c report decreased functional status and increased somatization; increased pro-inflammatory but not anti-inflammatory cytokines; and dysregulation in microRNAs that regulate the expression of genes relevant to muscle, nerve, and immune cell function. Based on these data, the investigators hypothesize that two VBD-p and VBD-c subtypes will preferentially respond to peripheral, central, or combined treatments and can be distinguished by cytokine and microRNA profiles. These hypotheses will be tested in a phase III clinical trial that evaluates diverse treatment strategies in women with VBD-p and VBD-c. Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% estradiol compound cream, 2) central treatment with the tricyclic antidepressant nortriptyline, 3) combined peripheral and central treatments, or 4) placebo. The treatment phase will last 4 months (with a 6-week titration at treatment initiation and 2-week taper period at 4 months), with outcome measures and biomarkers assessed at 4 time points (0, 2, 4, and 6 months). First, the investigators will compare the efficacy of treatments in alleviating pain among women with VBD-p and VBD-c using standardized tampon insertion with a numeric rating scale and self-reported pain on the McGill Pain Questionnaire. Next, the investigators will compare the efficacy of treatments in improving perceived physical, mental, and sexual health among women with VBD-p and VBD-c using standardized questionnaires. Finally, investigators will measure cytokines and microRNAs in women with VBD-p versus VBD-c using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. Successful completion of the proposed work will provide new insights into the mechanisms that drive pain perception and treatment response in two distinct VBD subtypes, and determine the efficacy of peripheral, central, and combined therapies in reversing this pain. Such findings will readily translate to improved patient care, permitting the millions of women with VBD, their partners, and clinicians to make more informed decisions about pain management.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Change in pain score during the tampon test The Tampon Test will provide a self-reported numeric rating scale of pain with self-tampon insertion, performed by the patient and reported to the research nurse. Participants will be asked to verbally rate the pain on a scale of 0-10, with 0 meaning no pain and 10 meaning the worst possible pain. Baseline, 16 weeks
Change in self-reported pain via the Short Form- McGill Pain Questionnaire (SF-MPQ) The SF-MPQ will be used to create a summary score. The SF-MPQ measures perceived sensory qualities of pain using 11 describers and affective qualities related to pain using 5 describers. Responses on 4-point scales are summed to compute scores for each section. Baseline, 16 weeks
Change in self-reported physical/mental health via SF-12 Health Survey (SF12v2) The SF-12 assesses 6 domains: global health, physical functioning, physical roles, emotional functioning, emotional roles and pain interference using an algorithm based on answers to 12 physical and mental health-related questions. Baseline, 16 weeks
Change in sexual health via Patient-Reported Outcomes Measurement Information System (PROMIS) The PROMIS score is based on a 96-item form developed by the NIH that measures 11 domains of biopsychosocial function and includes an assessment of sexual function measures (e.g., desire, frequency, fear, and pain) related to sexual intercourse. Baseline, 16 weeks
Change in inflammation as measured by cytokine expression levels Cytokine expression levels will be measured via mesoscale discovery assays. Baseline, 16 weeks
Change in regulators of pro-pain and pro-inflammatory genes, as measured by microRNA expression levels MicroRNA expression levels will be measured via sequencing read. Baseline, 16 weeks
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Change in pain level as measured by Vaginal Vestibule Pressure Pain Intensities (PPI) Vaginal Vestibule PPIs will be determined using a cotton swab applied to 6 externally-accessed sites (at 12, 10, 7, 6, 5, 2 o'clock on the vestibule) for 1-2 seconds. Upon application of cotton swab at each site, participants will rate their pain intensity on a scale from 0-10. Baseline, 8 weeks, 16 weeks, and 24 weeks
Levator Muscle Complex Pressure Pain Thresholds (PPTs) Levator Muscle Complex PPTs will be determined using a digital vestibular algometer applied internally to the right, midline, and left puborectalis levator muscles sites (5, 6, and 7 o'clock) just lateral to the perineum. Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in pain level as measured by Remote Bodily PPTs Remote Bodily PPTs will be determined by applying the algometer to 3 'neutral' non-pelvic body sites (deltoid, shin, and trapezius), right and left, beginning at 1N and increasing until the participant's first sensation of pain. A composite score will be calculated. Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in degree of overlapping pain, as measured by COPC follow-up survey The COPC survey consists of 2 questions used to determine the change in degree of overlapping pain. Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in mood as measured by the Symptom Checklist-27 (SCL-27) Symptom Check List 27 (SCL-27) questionnaire will be used to measure a broad range of psychological symptoms (e.g., anxiety and depression). Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in somatic awareness via Pennebaker Index of Limbic Languidness (PILL) Pennebaker Index of Limbic Languidness (PILL) is used to create a summary score of somatic symptoms (e.g., itchy eyes, dizziness). Symptom frequency is recorded on a five-point Likert scale ranging from "never" to "more than once a week". Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in perceived stress via Perceived Stress Scale (PSS) The Perceived stress scale (PSS) is a 10-item scale that measures the impact of personal stress on thoughts and feelings. Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in sleep as measured by the sleep scale The sleep scale is a 12-item scale that measures amount of sleep and ease/difficulty of initiating and maintaining sleep. Baseline, 8 weeks, 16 weeks, and 24 weeks
Change in in pain score during the tampon test at other time points Change in pain score during the tampon test will be measured as described above. 8 weeks and 24 weeks
Change in in pain score via the SF-MPQ at other time points Change in pain score via the SF-MPQ will be measured as described above. 8 weeks and 24 weeks
Change in self-reported health on the SF12v2 at other time points Change in self-reported health on the SF12v2 will be measured as described above. 8 weeks and 24 weeks
Change in self-reported health on the PROMIS at other time points Change in self-reported outcomes on the PROMIS will be measured. The PROMIS score is based on a 96-item form developed by the NIH that measures 11 domains of biopsychosocial function and includes an assessment of sexual function measures (e.g., desire, frequency, fear, and pain) related to sexual intercourse. 8 weeks and 24 weeks
Change in cytokine biomarkers at other time points Change in cytokine levels will be measured as described above. 8 weeks and 24 weeks
Change in microRNA biomarkers at other time points Change in microRNA levels will be measured as described above. 8 weeks and 24 weeks
Study Record | ClinicalTrials.gov

Patricia Nelson, PT, ScD, FNAP, OCS Professor University of Mary Hardin-Baylor
Effect of Spinal Manipulation on Vulvar Pain (SpManipPP) (2019 — 2021)
The purpose of the study is to determine the effect of thoracic spine manipulation on vestibule pain as determined by sensory testing (q-tip and pressure algometry) in a group of women with provoked vestibulodynia (PVD). The objective is to compare the immediate effect of manipulation and sham manipulation on the results of sensory testing of the external vulva, or vestibule.
PRE-SCREENING: Participants expressing interest in this study will be interviewed to determine if eligibility criteria to participate in this study are met. If that is the case, the participant will then be invited to attend the familiarization and study session and informed of the need to refrain from alcohol use and keep medication regiment consistent in the 24 hours prior to the study appointment. FAMILIARIZATION and CONSENT: During this session, the study protocol will be described and a written explanation of the study provided to the participant. After any questions have been addressed, the participant will sign the informed consent statement. Next, the participant will complete demographic and health questionnaires, which will be reviewed by the investigators to ensure eligibility criteria are met. If qualified,the participant will complete additional questionnaires that ask about pain, other symptoms of the pelvis and perineum and about feelings of anxiety and depression. Along with the questionnaires, a pelvic and lower extremity secondary screening examination will be performed as described below. SECONDARY SCREEN and BASELINE TESTING: During the lower extremity screening examination, the participant will be asked to bend and straighten their spine, stretch in specific ways with the spine and legs and report if these motions provoked discomfort or pain. The pelvic exam and baseline testing is to ensure that the participant has pain in the perineum (area that is wiped after toileting). This will be tested in 2 ways, one using a sterile cotton tipped swab (q-tip test) and the other with a pressure sensing device called an algometer. One trained pelvic floor Physical Therapist (PT1) investigator will perform these tests. While investigator PT1 waits outside, the participant will undress from the waist down then lay under a sheet. PT1 will enter and perform the sensory tests during which the participant's pelvic floor and vestibule will be exposed in a similar manner to receiving a gynecologic exam. PT1 will use a q-tip to touch specific points around the vaginal opening (vestibule) and ask the participant to report any pain on a scale of 0 (none)-10 (worst). Next, a pressure algometer will be used to measure the amount of pressure tolerated on the most painful q-tip spot. This algometer has a flat disc, the size of a pencil eraser, that is covered to ensure cleanliness. Then the participant's lower body will be draped. Participant's with provoked pain are eligible to continue; those without are not eligible to continue in the study and will be done. INTERVENTION and REPEAT BASELINE TESTING: The eligible participants are randomly assigned, by participant number, into one of the two testing groups. One group will receive a sham thoracic spine manipulation (ThS) and the other, a thoracic spine manipulation (ThM). During the thoracic intervention, the participant will lay on their back with arms crossed. The second PT (PT2), who is blinded to the results of the pain testing, will position one hand along the participant's thoracic spine and the other on the participant's crossed arms to apply a posterior motion to the participant's spine. This will be small motion that may be done quickly or slowly. After the technique, the participant will continue to rest on their back, while PT1 returns to repeat testing of the vestibule with the q-tip and algometer in the same manner as previously described. Then participation is finished. PRIMARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Change in Numeric Pain Rating Scale (NPRS) (0=none to 10=worst) report to cotton swab test in clock pattern Participant report on NPRS Pre and immediately post thoracic intervention. No longer term follow-up is planned.
SECONDARY OUTCOME MEASURES:
Outcome Measure Measure Description Time Frame
Change in peak pressure algometer Nm2 pressure reading of provoked pain on most painful point Pre and immediately post thoracic intervention. No longer term follow-up is planned
Study Record | ClinicalTrials.gov

Elisabet Nylander, MD Umeå University
Treatment and Mapping of Impostor Phenomenon (2023 — 2024)
The aim of this study is to evaluate persons/patients with different skin diseases or pain to evaluate whether unhealthy perfectionism, stress, anxiety, impostor phenomenon (inability to realistically assess your competence and skills) and lack of self-compassion (a positive attitude towards ourselves), have impact on symptoms, handling, and treatment regarding some dermatological diseases/pain.
The investigators have noticed that these conditions are common among patients attending the clinic. The investigators therefore want to do mapping of the occurrence and make an intervention to be able to change and evaluate handling of these patients. The hypothesis is that there is a connection between these conditions and that they are all part of the patients´ disease. The study will be done by using validated questionnaires which are answered anonymously using a code, that is known only by the participant, and with exercises/interventions for five or ten weeks. The questionnaires and interventions are formerly used in several international studies and by the investigators in populations of healthy persons with different professions. Examples of diseases:
  • Localised provoked vulvodynia (former vulvar vestibulitis) is a state of pain that mainly affects young women. The symptoms are localized to the vulvar vestibulum and provoked by touch and experienced by the patient as pain or burning. The aetiology is not clearly known but probably due to both physical and psychological factors. Treatment is due to several strategies like treating the pain, rehabilitation of the perineum, and psychosocial support. Persons with this type of pain will also answer a short questionnaire regarding their symptoms.
  • Hyperhidrosis is excessive sweating without known cause. Hyperhidrosis may be primary focal or multifocal with debut in childhood. Secondary hyperhidrosis is often due to another disease. Hyperhidrosis often means big stress on mental health but may also affect physical functions.
Persons with hyperhidrosis estimate their quality of life equal with those affected by severe acne or psoriasis. The investigators´ ongoing research with mapping of these different traits of character shows that the occurrence is increasing, but no treatment has so far been available in Sweden. The investigators therefore want to evaluate whether treatment by intervention with one or two exercises each week may diminish the occurrence of impostor phenomenon and to be able to influence the disease. The questionnaires that will be used are "Self-Compassion scale short version" (SCS-SF), "Clance Impostor Phenomenon scale" (CIPS), "Perceived Stress scale 4" (PSS-4), "Generalized Anxiety Disorder-2" (GAD-2), and "Clinical Perfectionism Questionnaire short form" (CPQ-SF). These questionnaires are validated by other investigators and used in several international research studies. The questionnaires have already been translated from English to Swedish, except CIPS that has been translated and back-translated. There will also be questions on gender, age, and term. The software for statistical analyses is Statistical Package for the Social Sciences (SPSS) version 27 from International Business Machines Corporation (IBM). Before starting treatment, the participants will get a web-based survey including twenty questions about impostor phenomenon (CIPS), six questions about stress and anxiety (PSS-4 and GAD-2), twelve questions about self-compassion (SCS-SF) and six questions about perfectionism (CPQ-SF). The questionnaires are repeated week twelve and 24 after intervention. After inclusion and answering the first questionnaire the persons are asked to participate in a series of one or two interventions, 30 minutes each, every week for ten or five weeks respectively.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Signs of impostor Questionnaire regarding impostor At the beginning, after 12 and 24 weeks
Signs of disease/pain Questionnaire regarding symptoms At the beginning, after 12 and 24 weeks
Study Record | ClinicalTrials.gov

Suzanne O'Sullivan, MD Cork Womens Clinic
Trans-perineal Trigger Point Dry Needling for Chronic Pelvic Pain (2016 — 2018)
Chronic Pelvic Pain (CPP) are around 10% of gynaecology referrals.Non-relaxing pelvic floor dysfunction (NRPFD) is an under-appreciated cause for CPP with dyspareunia where no other pathology exists. The effectiveness of manual therapy in studies have shown statistically significant pre and post treatment differences.However no study has reviewed the efficacy of inclusion of trans- perineal trigger point dry needling used with manual therapy for NRPFD. This study will investigate the effectiveness of trans-perineal trigger point dry needling used with manual therapy techniques for CPP.
This study will investigate the effectiveness of inclusion of trans-perineal trigger point dry needling with manual therapy treatment for chronic pelvic pain with dyspareunia and associated pelvic floor dysfunctions.The use of trigger point dry needling (TrptDN) for chronic low back pain has proved beneficial.This study will evaluate the treatment outcomes of trans-perineal trigger point dry needling and manual therapy to only manual therapy for CPP. The outcomes will evaluate the number of treatment requirements between the dry needling with manual therapy group and the manual therapy group and review which group has faster resolution in pain and other associated pelvic floor symptoms.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Pain reduction or resolution within 10 treatment sessions, evaluated with the 0-10 Numeric Pain Rating Scale (0-10NPRS) Participants will be asked to fill the 0-10NPRS at base line, 4th, 8th and 10th session or earlier on resolution of symptoms and to review which arm has faster resolution with lesser treatment sessions. 10 weeks or earlier on resolution
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Resolution in dyspareunia Evaluated with the Female Sexual Functional Index questionnaire (FSFI) at baseline and the 10th session or earlier on resolution 10 weeks or earlier on resolution
Resolution in bladder, bowel and sexual dysfunction Evaluated with the abbreviated International Pelvic Pain Questionnaire (IPPQ) concentrating on dyspareunia and painful bladder and bowel symptoms. This is done at baseline and at 10th session or earlier as per resolution. 10 weeks or earlier on resolution
Patient treatment satisfaction in each group Evaluated with Pain Treatment Satisfaction Scale (PTSS) at 10th session or earlier on resolution 10 weeks or earlier on resolution
Study Record | ClinicalTrials.gov

Mary Ojo-Carons, MD
Effects of Flourish HEC on Localized Provoked Vulvodynia (2022 — 2024)
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.
Study Record | ClinicalTrials.gov

Fabien Pelletier, MD
Long-Term Assessment of Quality of Life and Effectiveness of Onabotulinumtoxina Injections in Provoked Vestibulodynia (QUALVESTO) (2013 — 2013)
The study aims to assess and compare the pain in women suffering from provoked vestibulodynia, before treatment with botulinum injections, 3 months after treatment and 18 months after treatment.
Primary Outcome Measures:
  1. Long-term pain improvement after botulinum toxin injections [ Time Frame: 18 months ]
    Assessment and comparison of pain using Visual Analogic Scale values before treatment,3 months after treatment and 18 months after treatment.
Study Record | ClinicalTrials.gov

A Pilot Study of the Effects of Botulinum Toxin in the Treatment of Provoked Vestibulodynia (VESTIBULE) (2010 — 2019)
The main objective of this study is to compare the efficacy of botulinum toxin injections on vestibulodynia pain compared to a group treated with a placebo.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Pain improvement Significant improvement of pain on contact in the treated group, compared to placebo group, measured with Visual Analogic Scale 3 months

Kenneth Peters, MD William Beaumont Hospitals
CC-10004 For The Treatment Of Vulvodynia (2008 — 2011)
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. Study Record | ClinicalTrials.gov

The Women's Urology Center/​WISH Database Project (2006 — 2015)
Comprehensive database from the Women's Urology Center/WISH (Women's Initiative for Pelvic Pain and Sexual Health) program at Beaumont.
This women's health database will help us to identify health issues/concerns, useful therapies and interventions, and identify areas for improvement or further research specific for women's health. It will allow evaluation of outcomes of clinical interventions to enhance the care and treatment of women with pelvic pain and sexual health concerns.

Caroline Pukall, MD Professor Queens University
Effectiveness of Cognitive Behavioural Therapy and Physical Therapy for Provoked Vestibulodynia (2009 — 2012)
The purpose of the study was to compare the effectiveness of cognitive behavioural therapy (CBT) and physical therapy (PT) on pain and psychosexual outcomes in women with provoked vestibulodynia (PVD).
Provoked vestibulodynia (PVD) is the most common condition leading to painful intercourse and is currently best understood within a biopsychosocial framework. Although the usefulness of non-medical treatment options for vulvar pain is recognized by many, there is limited research investigating the effectiveness of these treatments using a biopsychosocial approach to outcome measurement. Furthermore, there is little evidence to support the mechanisms by which these treatments lead to pain reduction. This study aimed to address these gaps by investigating two non-medical treatment options: individual cognitive-behavioural therapy (CBT) and physical therapy (PT).
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
change from baseline in pain with sexual intercourse at 12 weeks measured on an 11-point numerical rating scale Baseline, 12 weeks

Investigating the Effectiveness of PelvicSense(R) on Pain and Sexual Outcomes in Provoked Vestibulodynia (2023 — 2025)
This study will examine the effectiveness of the PelvicSense 3-month online program on pain and other outcomes in those with provoked vestibulodynia. This study is prospective in nature and will involve several assessment points: baseline, immediately post-treatment (at the end of the 3 month program), and 3-month follow up. All aspects of the study will be conducted remotely (e.g., online, email, video calls), and participants will be at least 18 years of age, fluent in English, and experience pain due to provoked vestibulodynia for at least 3 months with a physician diagnosis. Participants are expected to continue their treatment as usual and this information will be documented throughout the study.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Pain intensity Pain Intensity Numerical Rating Scale (NRS). Participants will be asked to report their pain intensity on an 11-point numerical scale of 0 (no pain) to 10 (worst pain ever felt). Baseline
Pain intensity Pain Intensity Numerical Rating Scale (NRS). Participants will be asked to report their pain intensity on an 11-point numerical scale of 0 (no pain) to 10 (worst pain ever felt). At the end of the 3 month program
Pain intensity Pain Intensity Numerical Rating Scale (NRS). Participants will be asked to report their pain intensity on an 11-point numerical scale of 0 (no pain) to 10 (worst pain ever felt). 3 months after the end of the program
SECONDARY OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Pain catastrophizing Pain Catastrophizing Scale (PCS). 13 items rated on 5 point scales from 0 (not at all) to 4 (all the time). Total scores range from 0-52. Higher scores are worse. Baseline
Pain catastrophizing Pain Catastrophizing Scale (PCS). 13 items rated on 5 point scales from 0 (not at all) to 4 (all the time). Total scores range from 0-52. Higher scores are worse. At the end of the 3 month program
Pain catastrophizing Pain Catastrophizing Scale (PCS). 13 items rated on 5 point scales from 0 (not at all) to 4 (all the time). Total scores range from 0-52. Higher scores are worse. 3 months after the end of the program
OTHER OUTCOME MEASURES
Outcome Measure Measure Description Time Frame
Sexual distress Sexual Distress Scale, Short Form (SDS-SF). 5 items rated on 5 point scales from 0 (never) to 4 (always). Total scores range from 0-20. Higher scores are worse. Baseline
Sexual distress Sexual Distress Scale, Short Form (SDS-SF). 5 items rated on 5 point scales from 0 (never) to 4 (always). Total scores range from 0-20. Higher scores are worse. At the end of the 3 month program
Sexual distress Sexual Distress Scale, Short Form (SDS-SF). 5 items rated on 5 point scales from 0 (never) to 4 (always). Total scores range from 0-20. Higher scores are worse. 3 months after the end of the program
Pain self-efficacy Pain Self-Efficacy Questionnaire (PSEQ). 10 items rated on 7 point scales from 0 (not at all confident) to 6 (completely confident). Total scores range from 0-60. Higher scores are better. Baseline
Pain self-efficacy Pain Self-Efficacy Questionnaire (PSEQ). 10 items rated on 7 point scales from 0 (not at all confident) to 6 (completely confident). Total scores range from 0-60. At the end of the 3 month program
Pain self-efficacy Pain Self-Efficacy Questionnaire (PSEQ). 10 items rated on 7 point scales from 0 (not at all confident) to 6 (completely confident). Total scores range from 0-60. 3 months after the end of the program
Study Record | ClinicalTrials.gov

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.

Beri Ridgeway, MD Chief of Staff Cleveland Clinic
Pregabalin for the Treatment of Vulvodynia (2009 — 2013)
The purpose of this study is to determine whether pregabalin is effective in the treatment of vulvodynia.
Vulvodynia is a condition exclusive to women and involves mostly burning, rawness, and itching of the external genitourinary tract that often results in painful intercourse. Vulvodynia rarely results in severe morbidity or mortality; rather it causes symptoms of the lower genital, urinary, and gastrointestinal tracts that can impact a woman's daily activities and negatively affect her quality of life. Despite the fact that chronic vulvovaginal symptoms are one of the most common reasons for visits to a gynecology clinic, epidemiologic studies of the incidence and prevalence of these conditions are rare and available population-based studies are limited. Approximately 16% of women will experience chronic vulvar pain at some point in their lifetime; with 5% experiencing this condition before age 25. Treatment approaches include behavioral changes, medical management, and surgery, specifically vulvar vestibulectomy. Prior to considering surgical intervention, all medical treatment options should be exhausted. Although vulvodynia is quite prevalent and can be a debilitating disease, there are few studies that critically evaluate the medical management of vulvodynia. Pregabalin is an anticonvulsant that has proven efficacy in the treatment of diabetic neuropathy, post-herpetic neuralgia, and fibromyalgia. Anecdotal data and one case report provide hope that this medication may also be effective in the treatment of vulvodynia.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Reduction in Average Pain Over the Last 7 Days of Each Arm Using an 11-point Scale (0-10) The primary objective of this protocol is to compare the reduction in pain using an 11-point scale (0-10) at four weeks of treatment. A responder will be defined as a subject noting a ≥50% reduction in pain using this scale. The NRS is an 11-point scale comprising a number from 0 through 10; 0 indicates "no pain", and 10 indicates the "worst imaginable pain". Outcomes measure not assessed due to early discontinuation because of poor recruitment. As such, the study was terminated prior to the designated follow up interval. Therefore, no outcomes data was collected. 4 weeks
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Effect on Anxiety and Depression in Women With Vulvodynia Based on the Kessler Psychological Distress Scale (K10) Subjects will complete the Kessler Psychological Distress Scale (K10). It is a measure of psychological distress. Scores will range from 10 to 50, with the higher the score, the higher the mental distress Data not measured due to early discontinuation of the study prior to the designated follow up time frame.
Study Record | ClinicalTrials.gov

Berit Schei Norwegian University of Science
Multidisciplinary Treatment of Chronic Vulvar Pain (2018 — 2024)
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
Study Record | ClinicalTrials.gov

Judith Schlaeger, PhD, CNM, LAc University of Illinois at Chicago
Acupuncture for the Treatment of Vulvodynia (2012 — 2012)
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
Study Record | ClinicalTrials.gov

Acupuncture for Vulvodynia: A Pre-pilot Study (2015 — 2016)
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
Study Record | ClinicalTrials.gov

Double-Blind Phase 2 RCT: Effect of Acupuncture on Patient Vulvodynia Outcomes (2018 — 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. Study Record | ClinicalTrials.gov

Bethanee Schlosser, MD, PhD Northwestern University
Vulvar Mucosal Specialty Clinic Chart Review (2016 — 2020)
This study aims to develop a clinical database of patients presenting with vulvar complaints in order to comprehensively assess the presentation and current trends in management of vulvar disease.
Vulvar disorders are common, but their frequency and importance are often under-recognized. The spectrum of vulvar disease is vast and includes congenital malformations, inflammatory mucocutaneous diseases, blistering and erosive diseases, benign and malignant tumors, autoimmune disorders, infectious diseases, and various idiopathic conditions. Evaluation and management of genital complaints and dermatoses are complicated by the frequent multifactorial nature of vulvar symptoms and variable clinical expressions of disease on the vulva. In many cases, empiric treatment is instituted in the absence of a definitive diagnosis. Of note, expertise in the diagnosis and management of vulvar disorders is often lacking on the parts of gynecology, dermatology and primary care physicians. The investigators seek to analyze the data on this patient population at Northwestern Memorial Hospital (NMH) and the outpatient clinics of the Northwestern Memorial Faculty Foundation (NMFF) to better define the clinical spectrum of vulvar disease. The investigators will also assess approaches to the diagnosis and management of patients with vulvar disease with attention given to clinical outcome and the impact on quality of life. This information with help the investigators to better understand the scope of care these patients currently receive, to identify deficits in current practice, and to advance potential new standards of care.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Clinical database of patients presenting with vulvar complaints in order to comprehensively assess the presentation and current trends in the management of vulvar disease Through study completion, an average of 1 year
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Potential prognostic indicators in various vulvar conditions Through study completion, an average of 1 yea
Study Record | ClinicalTrials.gov

Alkistis Skalkidou, MD, PhD Department of Women's and Children's Health Uppsala University
An Internet-based Information Platform for Vulvodynia Patients (EMBLA) (2016 — 2020)
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.
Study Record | ClinicalTrials.gov

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
Lasertherapy for Vulvodynia (Lydia) (2021 — 2024)
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".
Study Record | ClinicalTrials.gov

Acupuncture in a Multidisciplinary Approach for Vulvodynia and Chronic Pelvic Pain (AMALIA) (2022 — 2025)
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.
Study Record | ClinicalTrials.gov

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.

Gary Ventolini, MD Professor of Obstetrics and Gynecology Texas Tech University Health Sciences Center
Prospective Data Bank Creation to Study Vaginal Conditions (CRIPB-13-002) (2013 — 2027)
The purpose of this study is to identify and elucidate the pattern and perhaps role of atypical proteins, cytokines and vaginal microbial flora in the pathogenic mechanisms involved in the development of vulvodynia, recurrent fungal and bacterial vaginosis and preterm labor.
Our approach specifically targets the evaluation of the proteins and cytokines present and the bacteriological analysis of the microflora in the vaginal milieu. Conjectures:
  • An initial insult in the vagina (possibly involving a bacterial, viral or fungal organism or their products) causes modifications in the vaginal milieu
  • The vaginal milieu responds to the insult by developing an inflammatory reaction characterized by cytokine and protein production
  • Long lasting or repetitive insults maintain biochemical changes in the vaginal milieu producing a reaction, chemical irritation or micro flora alteration by changes in proteins and/or abnormal protein production
  • Those changes eventually result in hypersensitivity, irritation, burning, and pain manifested in patients with vulvodynia. And those changes may also result in the recurrence of fungal or bacterial infections
  • Those changes may also contribute to initiate the cascade of premature events conducting to cervical effacement and dilation observed in preterm labor
The conjectures will be investigated by using a multidisciplinary approach including: microbiology, proteomics and cytokines evaluation of the vaginal milieu. Specifically we will be comparing an asymptomatic female population to serve as a baseline to patients affected by vulvodynia, recurrent fungal or bacterial vaginosis and/or pregnancy. This is a prospective, descriptive study of about 550 women age 12 to 75 years. There will be four groups: 1) Asymptomatic healthy women, 2) Women being seen for any gynecological vulvovaginal condition, and 3) Pregnant women who are asymptomatic and healthy, and 4) Pregnant women have any gynecological vulvovaginal condition. We will evaluate the following:
  • Types of cytokines normally present in women and in patients with vulvodynia, recurrent fungal and bacterial vaginosis and preterm labor
  • Normal microbiology flora in women and variations present in the vaginal milieu in these patients
  • The presence of normal and atypical proteins in the vaginal milieu of healthy women and patients with vulvodynia, recurrent fungal and bacterial vaginosis and preterm labor
  • Informed consent will be obtained and documented for participation in the study
  • Comprehensive history assessment of environmental factors, topical vulvovaginal issues and co morbid conditions as defined in the exclusion criteria.
  • Pelvic examination to obtain two samples via cotton swabs for proteomics, cytokines, vaginal lactobacillus from vaginal secretions.
A. Swab procedure: The cotton swabs (2) will be introduced only in the middle vagina, one at the time, no other areas will be sampled. B. Swab processing One swab will be placed in a special room temperature solution. This de-identified swab will be mailed for Lactobacillus. The second de-identified swab is to be place in 2 separated micro-containers in Liquid Nitrogen Containers (one for cytokines and one for Proteomics). When 50 samples are completed they will be processed at TTUHSC Permian Basin campus, with the Proteomics testing being done in Lubbock. Therefore, there are 3 samples, each processed differently. Data will be recorded in a confidential manner with no personal identifiers, only an assigned study subject number. As such, the de-identified data may serve as a database for additional studies. The computer used will belong to TTUHSC and be password protected, access limited to only authorized personnel. Consent forms will be stored separately from the study data in the research office.
Primary Outcome Measures:
  1. Cytokines Determination [ Time Frame: one time for all except pregnant patients 4 times 12 months ]
    To determine types of cytokines normally present in women's vagina and in patients with vulvodynia, recurrent fungal and bacterial vaginosis and preterm labor
Secondary Outcome Measures:
  1. Proteins Determination [ Time Frame: one time for all except pregnant patients 4 times 12 months ]
    The vaginal milieu will respond to the insult by developing an inflammatory reaction characterized by protein production (in terms of increased protein concentration according to the Bradford protein assay).
  2. Lactobacillus determination [ Time Frame: one time for all except pregnant patients 4 times 12 months ]
    Long lasting or repetitive insults maintain biochemical changes in the vaginal milieu producing lactobacillus microflora alteration.
Study Record | ClinicalTrials.gov

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) (2013 — 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.
Study Record | ClinicalTrials.gov

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.

Kristene Whitmore, MD Urologist
Clinical Efficacy of Changing the InterStim® Parameters in Patients With Interstitial Cystitis/​Painful Bladder Syndrome (2011 — 2018)
Purpose:
  1. Primary: to demonstrate better symptoms control (pain, urinary urgency and frequency) with sacral neuromodulation (SNM) in patients with interstitial cystitis /painful bladder syndrome (IC/PBS) using a stimulation frequency of 40 hertz (experimental) compared to a frequency of 14 hertz (standard).
  2. Secondary: The evaluate the efficacy of the two frequency settings on the other associated conditions that often coexist in patients with IC/PBS, such as female sexual dysfunction (FSD), bowel dysfunction, high tone pelvic floor dysfunction (HTPFD, painful spasm of the pelvic floor muscles), Vulvodynia (pain at the opening of the vagina).
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Improvement in Urinary symptoms and Bladder pain/discomfort To demonstrate better symptoms control (pain, urinary urgency and frequency) with sacral neuromodulation (SNM) in patients with interstitial cystitis /painful bladder syndrome (IC/PBS) using a stimulation frequency of 40 hertz (experimental) compared to a frequency of 14 hertz (standard). 1 year
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Improvement in Bowel symptoms and Sexual Function The evaluate the efficacy of the two frequency settings on the other associated conditions that often coexist in patients with IC/PBS, such as female sexual dysfunction (FSD), bowel dysfunction, high tone pelvic floor dysfunction (HTPFD, painful spasm of the pelvic floor muscles), Vulvodynia (pain at the opening of the vagina). 1 year
Study Record | ClinicalTrials.gov

Slawomir Wojniusz, PhD Oslo Metropolitan University
Somatocognitive Therapy in Treatment of Provoked Vestibulodynia - a Feasibility Study (ProLoVe) (2019 — 2020)
This study examines feasibility of R&D activities in the planned randomized controlled trial where effectiveness of somatocognitive therapy intervention will be compared to treatment as usual in provoked vestibulodynia. Provoked vestibulodynia is a multifactorial, persistent pain condition, affecting young women. It represents the most common cause of pain during sexual intercourse. Existing treatment approaches are predominantly based on clinical experience, observational studies, or reports of expert committees. Although, physiotherapy is one of the most commonly recommended treatments, high quality randomized controlled trials are needed to assess its effectiveness. This is a phase I, feasibility study with the purpose of testing R&D activities for a planned full size RCT. Additionally, patients experiences with the somatocognitive therapy intervention, assessment measures and condition itself will be collected using qualitative interviews. The results will be applied to adjust time-line of the treatment, outcome measures and therapeutic approach before commencing full scale RCT.
Primary Outcome Measures:
  1. Recruitment rate [ Time Frame: 5 months ]
    Number of eligible patients and number of recruited participants per week
  2. Follow-up rate [ Time Frame: 8 months ]
    The follow-up rate is measured by the percentage of participants who were followed up successfully until the 8 months follow-up
  3. Adherence [ Time Frame: 8 months ]
    Adherence is defined as the number of participants who fully complete the battery of self-report questionnaires, 14-day diary, biweekly forms about the received treatment and perform Tampon tests.
  4. Evaluation of Tampon test as a primary outcome measure - score variance [ Time Frame: 8 months ]
    Participants perform Tampon test 3 times in course of 14 days (day1, 7 and 14) at each of the 3 time points (baseline, post-treatment, 8 months after baseline), 9 scores in total. Numerical rating scale (0-10) will be used to score pain intensity. Intra-individual score variance will be estimated as difference between the min and max score at each time point for every participant. Lower variability is better.
  5. Adverse events [ Time Frame: 8 months ]
    If participant is pulled out of the study because somatocognitive therapy is deemed as a non-appropriate treatment (e.g. participant is instead referred to psychological counselling), such event is recorded as adverse.
  6. Evaluation of Tampon test as a primary outcome measure - qualitative interviews [ Time Frame: 8 months ]
    All participants are asked in individual qualitative interviews if they experience a Tampon test as a relevant instrument for assessing pain sensitivity experienced during intercourse.
Secondary Outcome Measures:
  1. Implementation and acceptability of the somatocogntive therapy intervention [ Time Frame: 8 months ]
    Participants will be asked in qualitative interviews about their experiences with somatocogntitve therapy intervention. Global Rating of Change scale will be used to provide quantitative estimation of participants' satisfaction with the treatment effect directly after treatment and at 8 months follow-up. The scale ranges from 1 to 6. Score of 1 means that treatment helped a lot and the score of 6 means that the treatment made the condition much worse.
  2. Evaluation of somatocognitive therapy intervention's potential to reduce pain [ Time Frame: 8 months ]
    Changes in individual mean scores (0-10, the lower score the better) of pain experienced during tampon test between 3 measurements time points.
  3. Evaluation of somatocognitive therapy intervention's potential to improve sexual functioning [ Time Frame: 8 months ]
    Changes in individual scores on Female Sexual Function Index between 3 measurements time points. Scale ranges 0-36, higher score means better sexual functioning.
  4. Evaluation of somatocognitive therapy intervention's potential to reduce psychological distress [ Time Frame: 8 months ]
    Changes in individual scores on Hopkins Symptom Check List - 25 questions version between 3 measurements time points. Scale ranges 1-4, lower score indicates less psychological distress.
  5. Evaluation of somatocognitive therapy intervention's potential to reduce pain catastrophizing [ Time Frame: 8 months ]
    Changes in individual scores on Pain Catastrophizing Scale between 3 different time points. Scale ranges 0-52, the lower score represents less pain catastrophizing
Study Record | ClinicalTrials.gov

Somatocognitive Therapy in Treatment of Provoked (Localized) Vestibulodynia - Randomized Clinical Trial (ProLoVe Study) (ProLoVe) (2021 — 2025)
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.
Study Record | ClinicalTrials.gov

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). Enteric Nervous System: Neuropathic Gastrointestinal Motility | SpringerLink

Denniz Zolnoun, MD Assistant Professor of Obstetrics and Gynecology University of North Carolina – Chapel Hill
5% Lidocaine Ointment in the Treatment of Vulvar Vestibulitis (2006 — 2009)
  • Study Hypothesis: Use of 5% topical lidocaine ointment will result in improved ability to have sexual intercourse and decreased pain scores in women with vestibulitis when compared to placebo.
  • This is a study to assess if topical lidocaine will improve symptoms in women with vulvar vestibulitis. It compares use of nightly 5% topical lidocaine ointment to placebo ointment. The duration of the study is 8 weeks. 28 women will be in each arm for a total of 56 women in the study.
  • After consent is obtained patients will undergo the following treatment plan: randomization to treatment with 5% lidocaine ointment or placebo for vestibulitis. There will be 56 women total (28 in each arm).The placebo used will be hydrophilic petrolatum. Randomization will be performed using computer generated permuted blocks. A standard history and physical exam incorporating assessment of skin allodynia (testing with q-tip swab) on the vestibule and pressure measurements of the pelvic floor muscles (how much tenderness there is on perineal muscles with palpation) will be performed. Baseline questionnaires that will evaluate sexual frequency, sexual function survey (Female sexual function index), the modified Gracely pain scale of intercourse related pain, and psychometric evaluation including evaluation of anxiety, somatization (State-Trait Anxiety Inventory and Brief Symptom Inventory). Depression can also be evaluated with the Brief Symptom Inventory. Lastly, overall quality of health can be assessed with the SF-12. There is a baseline, 2 week and 6 week visit. Women will abstain from intercourse during these 6 weeks. Women will have a physical exam evaluation of the vestibule at each visit. They will then be able to have intercourse and will repeat surveys of sexual frequency, function, pain scale of intercourse related pain and the SF-12 at 8 weeks.
  • Aim 1: To assess if lidocaine ointment produces a superior treatment response to placebo.
  • Hypothesis 1: Use of topical lidocaine, compared with placebo, will result in improved sexual function and self-reported pain scores. This is to be measured as the ability to have successful intercourse. Secondarily, sexual function, quality of life and scores for intercourse related pain will be evaluated.
  • Aim 2: To assess if there are predictors of response to treatment such as demographics, duration of disease, primary or secondary vulvar vestibulitis, or psychometric assessments (anxiety and somatization).
  • Hypothesis 2: There are predictors of response to treatment of vulvar vestibulitis based upon patient characteristics, characteristics of the disease and psychometric assessments.
PRIMARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
Number of Participants Who Report the Ability to Have Intercourse Participants' response upon inquiry. baseline, week 8
Change in Visual Analog Scale (VAS) Scores With Intercourse From Baseline to Week 8 Visual Analog Scale (VAS) scores (range 0-100 mm; 0 = none, 100 = worst pain) were recorded for pain during intercourse during baseline and week 8 of the study, for lidocaine treated subjects and controls. The "mean" listed for each group is average week 8 score subtracted from the average baseline score. baseline, week 8
SECONDARY OUTCOME MEASURES 
Outcome Measure Measure Description Time Frame
SF-12 Quality of Life Scores The SF-12 is a subset of 12 items from the Medical Outcomes Study 36-Item Short Form Survey (SF-36) and was collected at the bi-weekly office visits. Each score ranges from 0-100. The components measure physical and mental health, respectively. Higher scores are indicative of better function. ANCOVA Model with dependent variable being change from baseline scores and independent variables being treatment, baseline, and age. baseline, week 8
Modified Gracely Pain Scale The Modified Gracely Pain Scale consists of two components: 1) three numerical scales scored 0-100 for lowest, average, and highest pain level during during the preceding week, and 2) two word choice scales measuring affective and intensity levels. Each word in the word choice scales has an assigned number. Change scores on each subscale can thus be calculated over time (baseline v. week 8). baseline, week 8
Study Record | ClinicalTrials.gov

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. Refining Diagnostic Criteria of a Pain Disorder: Vulvar Vestibulitis Syndrome | UNC Pelvic Pain Research Center

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.