David C. Foster

The vulvodynia guideline

Objective. To provide a review of the literature and make known expert opinion regarding the treatment of vulvodynia. Materials and Methods. Experts reviewed the existing literature to provide new definitions for vulvar pain and to describe treatments for this condition. Results. Vulvodynia has been redefined by the International Society for the Study of Vulvovaginal Disease as vulvar discomfort in the absence of gross anatomic or neurologic findings. Classification is based further on whether the pain is generalized or localized and whether it is provoked, unprovoked, or both. Treatments described include general vulvar care, topical medications, oral medications, injectables, biofeedback and physical therapy, dietary changes with supplementations, acupuncture, hypnotherapy, and surgery. No one treatment is clearly the best for an individual patient. Conclusions. Vulvodynia has many possible treatments, but very few controlled trials have been performed to verify efficacy of these treatments. Provided are guidelines based largely on expert opinion to assist the patient and practitioner in dealing with this condition.

Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled trial.

OBJECTIVE: To estimate the efficacy of common treatments for vulvodynia: topical lidocaine monotherapy, oral desipramine monotherapy, and lidocaine-desipramine combined therapy. METHODS: A 12-week randomized, double-blinded, placebo-controlled trial was conducted on 133 vulvodynia-afflicted women assigned to four treatment arms: placebo tablets–placebo cream, desipramine tablets–placebo cream, placebo tablets–lidocaine cream, and desipramine tablets–lidocaine cream. The tampon test was selected as primary end point using a modified intention-to-treat analysis. Twelve secondary end points were also examined. At completion of the 12-week randomized phase, women were examined “open label” through 52 weeks postrandomization. RESULTS: All treatment arms reported substantial tampon-test pain reduction: 33% reduction placebo cream–placebo tablet, 20% reduction lidocaine cream–placebo tablet, 24% reduction placebo cream–desipramine tablet, and 36% reduction lidocaine cream–desipramine tablet. Compared with placebo, we found no significant difference in tampon-test pain reduction with desipramine (t=0.90; P=.37) or lidocaine (t=1.27; P=.21). Of the remaining 12 outcome measures, only the Index of Sexual Satisfaction, improved with desipramine compared with placebo (t=-2.81; P=.006). During the open-label phase, women undergoing vestibulectomy surgery reported significantly improved pain as measured by cotton swab test and the McGill Pain Scale compared with nonsurgical alternatives. CONCLUSION: Oral desipramine and topical lidocaine, as monotherapy or in combination, failed to reduce vulvodynia pain more than placebo. Placebo or placebo-independent effects are behind the substantial pain improvement seen in all treatment allocations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00276068. LEVEL OF EVIDENCE: I

Effects of intradermal foot and forearm capsaicin injections in normal and vulvodynia-afflicted women

&NA; Cutaneous response to capsaicin has been used to assess central sensitization in pain research. This study compared the response to intradermal capsaicin in the forearm and foot of vulvar vestibulitis (vestibulodynia)‐afflicted cases and controls. We hypothesized that cases will experience greater spontaneous pain, larger cutaneous areas of punctate hyperalgesia and dynamic allodynia, and greater vascular flow than controls. We also hypothesized enhanced post‐injection pain in the foot compared to the forearm based on dermatome proximity of the foot and vulva. Methods. Ten vulvar vestibulitis syndrome (VVS) cases and 10 age and ethnically matched controls underwent two randomized, cross‐over trials with intra‐dermal injections of capsaicin or a saline placebo in the forearm and foot. Outcome measures included spontaneous pain level, surface area of punctate hyperalgesia, surface area of dynamic allodynia, cutaneous blood flow, regional skin temperature and vital signs. Results. VVS cases experienced greater spontaneous pain, punctate hyperalgesia and dynamic allodynia than pain‐free controls. Within the VVS group, post‐capsaicin spontaneous pain, punctate hyperalgesia and dynamic allodynia were similar in the forearm and foot. Post‐capsaicin blood flow did not differ between cases and controls by anatomic site. Measures of depression and anxiety correlated with spontaneous pain intensity but did not correlate with measures of hyperalgesia, allodynia, or blood flow. VVS cases had higher resting pulse rates and lower resting systolic blood pressures than in controls. Conclusion. VVS patients show enhancement of post‐capsaicin pain response extending far beyond the anatomic location of the primary complaint.

Urethral pressure variation in women with vulvar vestibulitis syndrome

OBJECTIVES It is hypothesized that patients with vulvar vestibulitis syndrome will demonstrate increased urethral pressure variability. STUDY DESIGN Twelve patients with confirmed vulvar vestibulitis syndrome were compared with two groups: 13 patients with chronic pelvic pain matched for age and race and 23 asymptomatic unmatched patients. Urodynamic variables studied included maximum urethral pressure, functional urethral length, bladder capacity, and urethral pressure variability. During urethral pressure measurement each patient was given a standard mental exercise. RESULTS Urethral pressure variability was significantly greater in patients with vulvar vestibulitis than in those with chronic pain or in asymptomatic controls (Wilcoxon test, p < 0.001). Use of a multiple regression model that controlled for age, race, and parity showed that diagnostic group predicted a significant degree of urethral pressure variability (F = 8.18, p < 0.001). CONCLUSIONS Vulvar vestibulitis syndrome is associated with increased urethral pressure variability, and variation in muscular tone of the urethra is the probable source of this variability. However, the possible relationship with the pathogenesis of vulvar vestibulitis syndrome is unknown at present.

Effect of vulvovaginal estrogen on sensorimotor response of the lower genital tract : A randomized controlled trial

OBJECTIVE To assess the effect of vulvovaginal estrogen on mucocutaneous sensory threshold and circumvaginal motor strength. METHODS Thirty-nine postmenopausal, hypoestrogenic women with mixed lower-genitourinary-tract complaints were placed in four masked treatment arms by permuted-block randomization for 6 weeks. One group received topical estradiol (E2) cream and pelvic muscle biofeedback training, the second received topical E2 cream and sham biofeedback, the third received placebo cream and pelvic muscle biofeedback training, and the fourth received placebo cream and sham biofeedback. Circumvaginal muscle strength was measured by averaging maximum intravaginal pressure (mmHg) generated over a set of four pelvic muscle contractions. Absolute changes in von Frey threshold (mN) and maximum intravaginal pressure (mmHg) over 4 and 6 weeks were reported as summary measures. Of 39 subjects, 30 completed the study. RESULTS Topical estradiol cream significantly improved mechanical sensitivity of the vulvar vestibule to von Frey hairs, a -1.2-mN threshold decrease at 4 weeks (F = 10.29; P = .004), and a -1.6-mN threshold decrease at 6 weeks (F = 8.24; P = .009) compared with placebo cream. Stratification by age showed significantly greater improvement in mechanical sensitivity in the older (70-79 years) age group randomized to estrogen cream and a -5.49-mN threshold reduction (F = 17.65; P = .002). Maximum intravaginal pressures during circumvaginal muscle contraction did not differ between estrogen and placebo cream users (F = 0.00; P = .99). CONCLUSION Improved sensation to mechanical stimuli can result from a rapidly acting, direct effect of topical E2 cream on the vulvar vestibule.

Age at menopause in women participating in the postmenopausal estrogen/progestins interventions (PEPI) trial: An example of bias introduced by selection criteria

Our objective is to illustrate the bias introduced in assessing factors associated with age at menopause when the population sample has been selected using restricted criteria, i.e. number of years since menopause, by using a cross-sectional analysis of baseline data from a population-based randomized clinical trial. The participants were women who participated in the Postmenopausal Estrogen/Progestins Intervention (PEPI) trial, had not had a hysterectomy, were between 45 and 64 years old, and were menopausal for at least 1 but not greater than 10 years. The outcome measures were self-reported age at menopause and factors thought to be associated with it, including smoking, alcohol use, oral contraceptive use, number of pregnancies, education, income, body mass index, waist-hip ratio, thigh girth, and systolic and diastolic blood pressures. At entry, the mean age of the 601 women was 56.2 years. Mean age at menopause was 51.0 years. Chronologic (current) age was strongly correlated with age at menopause (r = 0.74, p = 0.0001). In bivariate analyses, factors associated with younger age at menopause were ever-use of cigarettes, former oral contraceptive use, and higher thigh girth; factors associated with later age at menopause were greater number of pregnancies, higher waist-hip ratio, and higher systolic blood pressure. After stratification by 5-year age intervals, these associations were no longer statistically significant. Because of restricted sampling, an artificial association was observed between chronologic age and age at time of menopause. This artifact made it difficult to distinguish between factors associated with chronologic age and those that may be independently associated with menopause. Failure to recognize this bias could lead to erroneous conclusions.

Site-specific mesenchymal control of inflammatory pain to yeast challenge in vulvodynia-afflicted and pain-free women.

Abstract Fibroblast strains were derived from 2 regions of the lower genital tract of localized provoked vulvodynia (LPV) cases and pain-free controls. Sixteen strains were derived from 4 cases and 4 controls, age and race matched, after presampling mechanical pain threshold assessments. Strains were challenged with 6 separate stimuli: live yeast species (Candida albicans, Candida glabrata, Candida tropicalis, and Saccharomyces cerevisiae), yeast extract (zymosan), or inactive vehicle. Production of prostaglandin E2 (PGE2) and interleukin 6 (IL-6) were proinflammatory response measures. Highest IL-6 and PGE2 occurred with vestibular strains after C albicans, C glabrata, and zymosan challenges, resulting in the ability to significantly predict IL-6 and PGE2 production by genital tract location. After C albicans and C glabrata challenge of all 16 fibroblast strains, adjusting for dual sampling of subjects, PGE2 and IL-6 production significantly predicted the presampling pain threshold from the genital tract site of sampling. At the same location of pain assessment and fibroblast sampling, in situ immunohistochemical (IHC)(+) fibroblasts for IL-6 and Cox-2 were quantified microscopically. The correlation between IL-6 production and IL-6 IHC(+) was statistically significant; however, biological significance is unknown because of the small number of IHC(+) IL-6 fibroblasts identified. A low fibroblast IL-6 IHC(+) count may result from most IL-6 produced by fibroblasts existing in a secreted extracellular state. Enhanced, site-specific, innate immune responsiveness to yeast pathogens by fibroblasts may be an early step in LPV pathogenesis. Fibroblast strain testing may offer an attractive and objective marker of LPV pathology in women with vulvodynia of inflammatory origin.

Polymorphism in the SCN9A Voltage-Gated Sodium Channel Gene Associated With Interstitial Cystitis/Bladder Pain Syndrome

OBJECTIVE To determine whether an association exists between interstitial cystitis/bladder pain syndrome (IC/BPS) and a nonsynonymous single nucleotide polymorphism in the SCN9A voltage-gated sodium channel gene previously associated with other chronic pain syndromes. MATERIALS AND METHODS Germline deoxyribonucleic acid was sampled from archived bladder biopsy specimens from patients with a documented diagnosis of IC/BPS. Deoxyribonucleic acid from hysterectomy specimens was obtained as a control population. The genotype of single nucleotide polymorphism rs6746030 was determined by deoxyribonucleic acid sequencing after polymerase chain reaction amplification. Contingency analysis of genotypes was performed using Pearsons chi-square test and Fishers exact test. RESULTS Polymerase chain reaction product was obtained from 26 of 31 control specimens and from 53 of 57 IC/BPS biopsy specimens. Of the 26 control subjects, 3 (11.5%) were genotype AG and 23 were GG. In contrast, AA or AG genotypes were present in 21 of 53 (39.6%) patients with IC/BPS, a statistically significant difference compared with the controls (Pearsons chi-square, P=.036). Similarly, the A allele was at a greater frequency in the IC/BPS group using Fishers exact test (P=.009). CONCLUSION These data strongly suggest that pain perception in at least a subset of patients with IC/BPS is influenced by this polymorphism in the SCN9A voltage-gated sodium channel.

Rationale and design of a multicenter randomized clinical trial of extended release gabapentin in provoked vestibulodynia and biological correlates of response

INTRODUCTION Few randomized controlled trials (RCTs) have been conducted to establish evidence-based management protocols for provoked vestibulodynia (PVD), a chronic vulvar pain condition affecting approximately 14 million women in the U.S. We describe the rationale and design of an NIH funded multicenter clinical trial utilizing an extended release formulation of gabapentin (G-ER), an intervention that preliminary data suggest may be efficacious for this condition. OBJECTIVES 1) to determine if pain from tampon insertion (primary outcome measure) is lower in PVD patients when treated with G-ER compared to when treated with placebo and 2) to determine if G-ER reduces vulvar mechanical hyperalgesia, vaginal muscle pain to palpation, the number and intensity of somatic tenderpoints, spontaneous and provoked pain to intradermal capsaicin with an accompanying increase in cardiac beat-to-beat variability and to identify mechanistically-based PVD subtypes. Additional outcomes include subject reported intercourse pain and summative 24-hour pain. METHODS This 16-week, randomized, double-blind, placebo-controlled, crossover study will enroll 120 women 18 years and older 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 G-ER (up to 3000 mg/d) compared to when treated with placebo. Psychophysiological measures will be obtained at baseline and after 2 weeks at the maximum tolerated dose. CONCLUSION We will conduct the first multicenter RCT to confirm efficacy of an agent that is currently used in clinical practice for treating PVD.

A review of the available clinical therapies for vulvodynia management and new data implicating proinflammatory mediators in pain elicitation

Localised provoked vulvodynia (LPV) is a common, chronic, and disabling condition: patients experience profound pain and a diminished quality of life. The aetiologic origins of vulvodynia are poorly understood, yet recent evidence suggests a link to site‐specific inflammatory responses. Fibroblasts isolated from the vestibule of LPV patients are sensitive to proinflammatory stimuli and copiously produce pain‐associated proinflammatory mediators (IL‐6 and PGE2). Although LPV is a multifactorial disorder, understanding vulvar inflammation and targeting the inflammatory response should lead to treatment advances, especially for patients exhibiting signs of inflammation. NFκB (already targeted clinically) or other inflammatory components may be suitable therapeutic targets.