Central Sensitization in Vulvodynia and Endometriosis: What Have We Been Overlooking So Far?

Importance: Women experience more frequent and greater pain than men, although they receive less adequate treatment and are perceived as more anxious than males. Recent clinical research has lead to hypothesize a common etiology for overlapping chronic pain conditions and mood disorders, namely, central sensitization, which originates from an alteration of pain processing pathways in the central nervous system. Objective: The aim of this review was to collect all available evidence regarding the potential role of central sensitization in vulvodynia and endometriosis. Evidence Acquisition: A systematic literature search was performed between July and August 2022 using the electronic database PubMed. The extracted data were summarized using a narrative approach. Results: Ten articles were chosen for the review. Participants' mean age was 39.2 years (SD = 5.1). Among serum markers of central sensitization, nitric oxide levels were greater in women with endometriosis than in controls, whereas brain-derived neurotrophic factor and S100B levels differed among pain conditions with structural anomalies and those without. Functional magnetic resonance imaging showed different resting state networks between patients with endometriosis and controls. In neurophysiology studies, cases had reduced pain thresholds, compared with healthy controls. Lastly, self-reported questionnaires suggested a central component of pain in women with endometriosis-related dyspareunia and associated bladder/pelvic floor tenderness. Conclusions and Relevance: The management of vulvodynia and endometriosis may benefit from a new perspective, which considers their possible central etiology. It is compelling that treatment of pain starts to be considered a therapeutic goal in its own right.

Neuroproliferative dyspareunia in endometriosis and vestibulodynia.

INTRODUCTION: Endometriosis is a common cause of deep dyspareunia, while provoked vestibulodynia is a common cause of superficial dyspareunia. The etiology of dyspareunia in both conditions is multifactorial and may include the role of local nerve growth (neurogenesis or neuroproliferation) that sensitizes pelvic structures and leads to pain with contact. OBJECTIVES: To review the evidence for neuroproliferative dyspareunia in endometriosis and provoked vestibulodynia. METHODS: Narrative review. RESULTS: The pelvic peritoneum and vulvar vestibule receive somatic and autonomic innervation. Various markers have been utilized for nerve subtypes, including pan-neuronal markers and those specific for sensory and autonomic nerve fibers. The nerve growth factor family includes neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, and their receptors. Studies of endometriosis and provoked vestibulodynia have demonstrated the presence of nerve fibers around endometriosis epithelium/stroma in the pelvic peritoneum and within the vulvar vestibule. The number of nerve fibers is higher in these pain conditions as compared with control tissue. Nerve growth factor expression by endometriosis stroma and by immune cells in the vulvar vestibule may be involved in local neuroproliferation. Local inflammation is implicated in this neuroproliferation, with potential roles of interleukin 1ß and mast cells in both conditions. Several studies have shown a correlation between nerve fibers around endometriosis and dyspareunia severity, but studies are lacking in provoked vestibulodynia. There are several possible clinical ramifications of neuroproliferative dyspareunia in endometriosis and provoked vestibulodynia, in terms of history, examination, biopsy, and surgical and medical treatment. CONCLUSIONS: A neuroproliferative subtype of dyspareunia may be implicated in endometriosis and provoked vestibulodynia. Additional research is needed to validate this concept and to integrate it into clinical studies. Neuroproliferative pathways could serve as novel therapeutic targets for the treatment of dyspareunia in endometriosis and provoked vestibulodynia.

The Association Between Immune-Related Conditions Across the Life-Course and Provoked Vulvodynia.

Vulvodynia, impacts up to 8% of women by age 40, and is hypothesized to manifest through an altered immune-inflammatory response. To test this hypothesis, we identified all women born in Sweden between 1973 and 1996 diagnosed with localized provoked vulvodynia (N76.3) and/or vaginismus (N94.2 or F52.5) between 2001 and 2018. We matched each case to two women from the same birth year with no vulvar pain ICD codes. As a proxy for immune dysfunction, we used Swedish Registry data to capture 1) immunodeficiencies, 2) single organ and multiorgan autoimmune conditions, 3) allergy and atopies, and 4) malignancies involving immune cells across the life course. Women with vulvodynia, vaginismus or both were more likely to experience immune deficiencies (OR 1.8, 95% CI, 1.2-2.8), single organ (OR 1.4, 95% CI, 1.2-1.6) and/or multi-organ (OR 1.6, 95% CI, 1.3-1.9) immune disorders, and allergy/atopy conditions (OR 1.7, 95% CI, 1.6-1.8) compared to controls. We observed greater risk with increasing numbers of unique immune related conditions (1 code: OR = 1.6, 95% CI, 1.5-1.7; 2 codes: OR = 2.4, 95% CI, 2.1-2.9; 3 or more codes: OR = 2.9, 1.6-5.4). These findings suggest that women with vulvodynia may have a more compromised immune system either at birth or at points across the life course than women with no vulvar pain history. PERSPECTIVE: Women with vulvodynia are substantially more likely to experience a spectrum of immune related conditions across the life course. These findings lend support to the hypothesis that chronic inflammation initiates the hyperinnervation that causes the debilitating pain in women with vulvodynia.

Pelvic mapping to explore patterns of chronic pelvic pain.

PURPOSE: Chronic pelvic pain syndromes (CPPS) are commonly encountered by urologists and urogynecologists and pose diagnostic and therapeutic challenges. Body maps have been helpful adjuncts to verbal descriptions of pain and may serve a role in phenotyping what is known to be a heterogeneous patient population. The aim of this study was to assess whether patterns of pain as marked on a body map of the pelvis exist among common CPPS diagnoses. The secondary aim was to investigate the association between the total number of pain locations marked on the map and clinical indices in patients with 1 to 3 CPPS diagnoses. MATERIALS AND METHODS: Data was collected on patients who visited the Northwell Health Pelvic Pain Treatment Center (PPTC) from January to May 2022 and were diagnosed with at least one of four major CPPS diagnoses: interstitial cystitis/bladder pain syndrome (IC/BPS), pelvic floor myalgia (PFM), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and vulvodynia. Demographic data as well as survey data from pelvic pain maps, Genitourinary Pain Index (GUPI) forms, and the short form-6 of the Pain Catastrophizing Scale (PCS-6) were recorded. Descriptive statistics among CPPS groups and Pearson correlations among the number of CPPS diagnoses were computed. RESULTS: One hundred seventy females and 125 males with CPPS were included in the study. Significant cross-over in mapping patterns was notable between IC/BPS and PFM groups, both most commonly marking "abdomen" and "genital" regions. The most distinct pattern of pain was seen in patients with CP/CPPS and in patients with vulvodynia. Among the total sample, as the mean number of pain locations marked within the pelvis increased, GUPI and PCS scores increased (p < 0.05). As the number of CPPS diagnoses increased, the strength of the relationship independently increased. CONCLUSIONS: Pelvic body mapping demonstrated that different forms of CPPS displayed different distributions of pain, but mapping was not predictive of any diagnostic group. Nevertheless, the pelvic body map proved useful in identifying precise locations of pain and may help uncover regions of pain that cannot be easily communicated. The total number of pain sites marked appeared to correlate with worse clinical features.

A longitudinal case-control analysis of pain symptoms, fear of childbirth, and psychological well-being during pregnancy and postpartum among individuals with vulvodynia.

OBJECTIVE: Little research has examined changes in chronic vulvar pain (vulvodynia) symptoms with pregnancy and childbirth, nor fear as it relates to pregnancy/delivery amongst individuals with vulvodynia. The purpose of this study was to examine change in pain symptoms from pregnancy to postpartum amongst women with vulvodynia, as well as pain anxiety, fear of childbirth, and anxiety and depressive symptoms. DESIGN: Prospective Case-Control Study. SETTING: Online survey. PARTICIPANTS: Fifty-Seven pregnant individuals with a diagnosis of vulvodynia, and 41 pregnant control participants who reported being free of vulvar pain. Participants were recruited from the community and from hospital-based clinics for this study. MEASUREMENTS AND FINDINGS: Online surveys were administered to women diagnosed with vulvodynia and pain-free control participants during pregnancy and at three and six months postpartum. The survey contained both investigator-developed items and validated questionnaires, including the Pain Anxiety Symptoms Scale (PASS-20), the Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ) to assess fear of childbirth, the Generalized Anxiety Disorder-7 (GAD-7) measure to assess symptoms of anxiety, and the Patient Health Questionnaire (PHQ-9) to assess symptoms of depression. Linear mixed models with random intercepts for longitudinal analyses indicated statistical improvements for most of the vulvar pain outcomes in the postpartum period amongst women with vulvodynia, including reduced pain intensity at three (p = 0.005) and six months (p = 0.013) postpartum for those women who delivered vaginally. The mean change in pain intensity corresponded though to only a minimal clinical change. Compared to controls, women with vulvodynia reported higher levels of fear of childbirth on the W-DEQ (p = 0.024). In both groups, increases in general anxiety on the GAD-7 were found from pregnancy to three (p = 0.005) and six months (p = 0.033) postpartum. Mode of birth moderated the findings for pain-related anxiety as measured by the PASS-20: only individuals who delivered via caesarean section reported increases in pain anxiety between pregnancy and six months postpartum (p < 0.001). KEY CONCLUSIONS: Pregnant women with vulvodynia experienced postpartum improvements in vulvar pain symptoms. Mode of birth may play a role in symptom trajectory. IMPLICATIONS FOR PRACTICE: Individuals with vulvodynia often have concerns about how pregnancy and childbirth will impact their symptoms. The current findings can be used to help such individuals make reproductive decisions knowing there may be improvements in vulvar pain and increases in anxiety that can occur postpartum. The statistical versus clinical significance of the pain intensity results also highlight the importance of asking each individual what changes in pain symptoms they experience and the meaning of such changes for that person.

Examining vaginal and vulvar health and sexual dysfunction in patients with interstitial cystitis (UNICORN-1 study).

INTRODUCTION AND HYPOTHESIS: The Vaginal Health Index Score (VHIS) and vulvodynia swab tests are used to assess vaginal health and vulvodynia. However, few studies have used these tests in patients with interstitial cystitis/bladder pain syndrome (IC/BPS). IC/BPS is a chronic, debilitating disorder, characterised by urinary frequency, urinary urgency and pelvic pain. It adversely affects organs adjacent to the urinary system, leading to complications of sexual dysfunction. This study was aimed at understanding sexual dysfunction in patients with IC/BPS, as well as deterioration of vaginal health and vulvodynia. METHODS: This study compared the vaginal health of IC/BPS patients with that of asymptomatic control individuals. The Pain Urgency Frequency (PUF) score, Female Sexual Function Index (FSFI), VHIS, and vulvodynia swab tests, were used as tools. The PUF and FSFI are questionnaire-based surveys of bladder symptoms and sexual function respectively. VHIS evaluation and vulvodynia swab tests are performed by physicians. The PUF was used to assess baseline IC/BPS symptoms to validate the patient population, and FSFI, vulvodynia swab tests and VHIS were used to determine between-group differences. RESULTS: Thirty-seven patients were recruited in each group. The IC/BPS group had a higher PUF score (18.19±3.51 vs 3.56±2.35; p<0.05), worse total FSFI (15.72±4.46 vs 26.3±4.93; p<0.05), and worse vulvodynia swab test and total VHIS (11.59±2.87 vs 22.05±3.05; p<0.05) scores than those of the control group. CONCLUSIONS: Asian women with IC/BPS experienced greater sexual dysfunction, worsened vaginal health and increased vulvodynia compared with control individuals. Information on vaginal and vulva health is very useful in evaluating IC/BPS patients.

Persistent genital arousal disorder - the present knowledge. / Zespól przetrwalego pobudzenia genitalnego ­ aktualny stan wiedzy.

Persistent genital arousal disorder (PGAD) is a relatively recently described sexual disorder, characterized by symptoms of spontaneous genital arousal which persist in the absence of sexual desire and may affect women and men. Epidemiological studies conducted so far indicate that the prevalence of PGAD in the population may reach 1-4%. The etiology of PGAD remains unclear and complex, hypothesized causes include vascular, neurological, hormonal, psychological, pharmacologic, dietary, mechanical factors or a combination of these factors. Proposed methods of treatment include pharmacotherapy, psychotherapy, electroconvulsive therapy, hypnotherapy, injection of botulinum toxin, pelvic floor physical therapy, application of anesthetizing agents, reduction of identifiable factors exacerbating the symptoms, and transcutaneous electrical nerve stimulation. There is no standardized treatment algorithm for PGAD due to lack of clinical trials (evidence-based medicine). The classification of PGAD is under discussion: it could be classified as a separate sexual disorder, a subtype of vulvodynia or a disorder with pathogenesis similar to overactive bladder (OAB) and restless legs syndrome (RLS). Due to specificity of symptoms, patients may feel shame and discomfort during the examination or even delay reporting symptoms to the specialist. Thus, it is crucial to spread knowledge about this disorder, which would allow doctors to diagnose and help PGAD patients sooner.

Predictors of Mucosal and Muscle Pain in Vulvodynia: A Cross-Sectional Analysis From the National Vulvodynia Registry.

Diagnostic criteria for provoked vestibulodynia (PVD) rely on mucosal pain in the vulvar vestibule, with less emphasis on pain from pelvic floor muscles. It is unknown how psychosocial variables associated with PVD are differentially associated with mucosal versus muscle pain. Analysis of data from the National Vulvodynia Registry (n = 202) revealed several factors associated with increased mucosal pain: pain duration (P = .043), the McGill sensory subscore (P = .0086) and the Gracely pain scale (P< .001). Increased mucosal pain was also associated with decreased arousal (P = .036). On the other hand, factors significantly associated with greater muscle pain included number of comorbid pain conditions (P = .001), decreased intercourse frequency post PVD onset (P = .02) and higher scores on the McGill sensory (P = .0001) and affective (P = .0002) subscores, the Gracely pain scale (P = .0012), and state anxiety (P < .001). Sexual function was also significantly impacted by high pelvic floor muscular pain, with lower scores for arousal (P = .046), orgasm (P = .0014) and satisfaction (P = .013), and higher pain (P = .01). Significant differences in the relationship between muscle and mucosal pain for pain duration (P = .005), McGill affective score (P = .001), orgasm (P = .049), change in intercourse frequency (P = .027), and state anxiety (P = .030) suggest the possibility of mucosal or muscle pain predominant PVD subtypes. PERSPECTIVE: Patients with higher pelvic floor muscle pain scores than mucosal pain scores may represent different subgroups or characteristics of patients with provoked vestibulodynia. This research highlights the importance of assessment of the pelvic floor muscles in addition to the cotton swab test of the vestibule.

Pain, Anxiety, Depression, and Quality of Life in Patients with Vulvodynia.

BACKGROUND/AIMS: The term vulvodynia refers to vulvar pain of unknown origin lasting at least 3 months. Psychiatric comorbidities are a common feature and, along with pain, may severely affect patients' wellbeing. We aimed to determine the characteristics of pain in vulvodynia, to correlate characteristics with symptoms of anxiety and depression, and to analyse the impact of these factors on patients' quality of life. METHODS: This cross-sectional observational study analysed pain, anxiety, and depression and the effects of these factors on quality of life. Pain, anxiety, and depression were assessed using validated tools in 110 women. RESULTS: Statistical analyses found correlations between pain and anxiety and between anxiety and worsened quality of life. Patients often reported stinging, burning, pain, itching, and dyspareunia, pointing to the importance of temporal, localisation, punctate pressure, thermal, tactile sensitivity, and emotional tension characteristics. Most patients had severe pain related to psychiatric comorbidities and decreased quality of life. CONCLUSION: Using descriptors of pain quality and assessing anxiety and depression might help to define subgroups of patients that may benefit from different therapeutic approaches and thus enable treatments to be tailored to individual patients.

The association of vulvar pain and urological urgency and frequency: findings from a community-based case-control study.

INTRODUCTION AND HYPOTHESIS: Vulvodynia is chronic debilitating burning vulvar pain or pain on contact. Although women who suffer from vulvodynia are more likely than others to experience co-morbid interstitial cystitis (IC) and urinary tract infections (UTIs), few studies have explored whether women with vulvodynia experience adverse urinary symptoms (lower urinary tract symptoms [LUTS]) in the absence of urological pain. METHODS: Two hundred and eleven participants with and 226 participants without clinically confirmed vulvodynia completed the Pelvic Pain and Urgency/Frequency (PUF) questionnaire and were scored using all questions, and then a subset of questions relating only to their current frequency and bother of urination during day and night, and the frequency, severity and bother of urgency after voiding. Total, symptom, and bother scores were compared in women with and without vulvodynia, and regression models estimated adjusted odds ratios and 95% confidence intervals for the various LUTS symptoms. RESULTS: As expected, 40% of women with vulvodynia met the criteria for IC (PUF > 12) compared with 2% without vulvodynia. After excluding questions related to bladder or vulvovaginal pain, women with vulvodynia, compared with those without, were skewed toward higher PUF scores, including being 2.4 times more likely to report usually or always bothered by night-time voiding (95% CI 1.22-4.74), and 18 times more likely to report moderate/severe urgency after urination (95% CI 5.48-64.12). CONCLUSIONS: Women with vulvodynia are substantially more likely to report voiding dysfunction and symptoms of urgency than women with no history of vulvar pain. These findings are independent of comorbid interstitial cystitis or history of UTIs.

Systematic review and meta-analysis of the effects of treatment modalities for vestibulodynia in women.

Objective: To quantify the effects of available treatments of vestibulodynia. Methods: Systematic review of randomised controlled trials (RCTs) in six search engines until December 2018, comparing any intervention vs. placebo or sham in women with vestibulodynia. Primary outcome was dyspareunia assessed with visual analogue (VAS) or numeric rating (NRS) scales. Secondary outcomes were daily vestibular symptoms (DVS), McGill Pain Questionnaire (MPQ) and Index of Sexual Satisfaction (ISS). Effects were described as mean differences (MDs) with their 95% confidence intervals (CIs). Traditional and frequentist network meta-analyses (NMA) were performed using random effect models. Results: Four RCTs (n = 275) were included evaluating vaginal cream of conjugated oestrogens, oral desipramine with or without topical lidocaine, topical lidocaine, laser therapy and transcranial direct current. In traditional MA, interventions did not reduce dyspareunia (MD = 0.08; 95%CI = -0.49 to 0.64), DVS (MD = -0.04; 95%CI = -0.31 to 0.24; 4 interventions), or MPQ (MD = -0.17; 95%CI = -2.16 to 1.81; 4 interventions). ISS was significantly improved (MD = -5.14; 95%CI = -9.52 to -0.75). In NMA, oral desipramine with or without lidocaine significantly improved ISS vs. other treatments. Conclusions: Several existing interventions were not associated with improvements in vestibulodynia. There only was improvement of sexual function with oral desipramine with or without lidocaine.

Environmental Exposure History and Vulvodynia Risk: A Population-Based Study.

BACKGROUND: Risk factors for vulvodynia continue to be elusive. We evaluated the association between past environmental exposures and the presence of vulvodynia. MATERIALS AND METHODS: The history of 28 lifetime environmental exposures was queried in the longitudinal population-based Woman-to-Woman Health Study on the 24-month follow-up survey. Relationships between these and vulvodynia case status were assessed using multinomial logistic regression. RESULTS: Overall, 1585 women completed the 24-month survey, the required covariate responses, and questions required for case status assessment. Screening positive as a vulvodynia case was associated with history of exposures to home-sprayed chemicals (insecticides, fungicides, herbicides-odds ratio [OR] 2.47, 95% confidence interval [CI] 1.71-3.58, p < 0.0001), home rodent poison and mothballs (OR 1.62, 95% CI 1.25-2.09, p < 0.001), working with solvents and paints (OR 2.49, 95% CI 1.68-3.70, p < 0.0001), working as a housekeeper/maid (OR 2.07, 95% CI 1.42-3.00, p < 0.0001), working as a manicurist/hairdresser (OR 2.00, 95% CI 1.14-3.53, p < 0.05), and working at a dry cleaning facility (OR 2.13, 95% CI 1.08-4.19, p < 0.05). When classified into nine individual environmental exposure categories and all included in the same model, significant associations remained for four categories (home-sprayed chemicals, home rodent poison or mothballs, paints and solvents, and working as a housekeeper). CONCLUSIONS: This preliminary evaluation suggests a positive association between vulvodynia and the reported history of exposures to a number of household and work-related environmental toxins. Further investigation of timing and dose of environmental exposures, relationship to clinical course, and treatment outcomes is warranted.

The Relationship Between Vulvovaginal Candidiasis and Provoked Vulvodynia: A Systematic Review.

BACKGROUND: Provoked vulvodynia (PVD) is a chronic vulvar pain condition affecting up to 8.3% of the female population. Despite many years of research, no clear cause for PVD has been identified. Several risk factors have been studied, including vulvovaginal candidiasis (VVC). However, to date, the role of Candida infections in PVD has remained unclear. VVC and PVD have an overlap of symptoms that may contribute to diagnostic inaccuracy and mistreatment. AIM: To systematically review the literature on the relationship between VVC and PVD. METHODS: Cohort and case-control studies were included that compared women with PVD with healthy controls with respect to the presence of a history of Candida vulvovaginitis. PVD had to be diagnosed by Friedrich's criteria or the International Society for the Study of Vulvovaginal Disease criteria. The inclusion process as well as the quality appraisal of the studies, using the Newcastle-Ottawa Quality Assessment Scale, were performed independently by 2 authors. MAIN OUTCOME MEASURE: Outcomes of the population-based case-control studies were listed as odds ratio. Outcomes of the pathophysiological studies were based on local pro-inflammatory responses on Candida in vitro. RESULTS: We included a total of 14 studies, both population and clinic-based case-control, and pathophysiological research. 7 studies were of low methodological quality, and 7 studies were of medium methodological quality. The population-based case-control studies showed a significantly increased odds ratio for self-reported VVC in PVD cases compared with controls. The pathophysiological studies revealed a tendency for an increased local proinflammatory response on Candida in vitro in patients with PVD. Owing to the substantial heterogeneity of the studies, meta-analysis was not performed. CLINICAL IMPLICATIONS: Health care providers may consider a diagnosis of PVD in women with self-reported VVC, and to act on this properly. Reiteration of antifungal prescriptions by physicians without a decent diagnosis, will lead to mistreatment. Women should be informed by their health care provider that intercourse during (or shortly after) the treatment of VVC might worsen the vulnerability of the vulvar skin. STRENGTH AND LIMITATIONS: This is the first systematic review performed to describe the relation between VVC and PVD. An independently performed in- and exclusion process and quality appraisal, ensured optimal internal validity. However, there were important methodological limitations and the size of heterogeneity prevented establishing a meta-analysis. CONCLUSION: This systematic review is unable to draw conclusions regarding a relationship between actual VVC and PVD because studies were based on self-reported VVC. Until new evidence becomes available, we advocate that PVD should be considered as an unexplained chronic pain condition. In women with recurrent or persistent VVC-like complaints, physicians should consider a diagnosis of PVD. Leusink P, van de Pasch S, Teunissen D, et al. The Relationship Between Vulvovaginal Candidiasis and Provoked Vulvodynia: A Systematic Review. J Sex Med 2018;15:1310-1321.

Communal motivation in couples coping with vulvodynia: Sexual distress mediates associations with pain, depression, and anxiety.

OBJECTIVE: To examine the role of a novel motivational perspective-sexual communal motivation-in women's pain during intercourse and both partners' distress in couples coping with vulvodynia, a prevalent gynecological pain condition. Our goal was to test whether sexual communal strength (i.e., motivation to meet a partner's sexual needs) and unmitigated sexual communion (i.e., prioritization of a partner's sexual needs in neglect of one's own needs) were indirectly associated with pain, depression, and anxiety via sexual distress. METHODS: Couples (N=101) completed daily surveys about their sexual communal motivation, sexual distress, anxiety, depression, and women reported on their pain during intercourse. Using multilevel modeling, we examined how daily fluctuations in sexual communal motivation were directly and indirectly (via sexual distress) associated with pain and psychological distress. RESULTS: On days when women with vulvodynia reported higher sexual communal strength, they reported less pain and anxiety, and on days when they reported higher unmitigated sexual communion, they reported more pain, more anxiety, and both partners reported more depressive symptoms. Daily associations between women's unmitigated sexual communion and greater pain, depression and anxiety were mediated by sexual distress. CONCLUSIONS: Being motivated to meet a partner's sexual needs was associated with less pain and anxiety for women with vulvodynia, but when this motivation excluded a focus on one's own needs, there were detrimental consequences for women's pain and both partners' depressive symptoms. Interventions for improving women's pain and the psychological well-being of affected couples should target motivational factors and sexual distress.

Vulvar vestibular effects of ospemifene: a pilot study.

The study aimed to assess the effects of ospemifene on vulvar vestibule in postmenopausal women with vulvar pain and dyspareunia. Fifty-five postmenopausal women used oral ospemifene 60 mg/d for 60 d. Symptoms of dryness, burning, and dyspareunia were evaluated on a 10 cm visual analog scale. Visual examination of the vulvar vestibule was also conducted. Patients also underwent current perception threshold (CPT) testing obtained from the vulvar vestibule. Fifty-five patients (94.6%) completed the treatment. Hot flashes were the most frequent adverse effects, but this led to a discontinuation of therapy in three patients (5.4%). After therapy, there was a statistically significant decrease from the baseline in the mean scores for dryness, burning, and dyspareunia and reduction of vestibular trophic score (baseline value of 11.2-4.2 after the therapy, p ≤ 002) and cotton swab test scores (2.81 compared with 1.25, p = .001). There was a difference in CPT values for all nerve fibers and more consistent for C fibers (-38% of sensitivity). These results confirm the efficacy of ospemifene on postmenopausal vestibular symptoms and signs; moreover, the drug was effective in normalizing vestibular innervation sensitivity.

Inflammatory Renin-Angiotensin System Disruption Attenuates Sensory Hyperinnervation and Mechanical Hypersensitivity in a Rat Model of Provoked Vestibulodynia.

Vestibulodynia is characterized by perivaginal mechanical hypersensitivity, hyperinnervation, and abundant inflammatory cells expressing renin-angiotensin system proteins. We developed a tractable rat model of vestibulodynia to further assess the contributions of the renin-angiotensin system. Complete Freund's adjuvant injected into the posterior vestibule induced marked vestibular hypersensitivity throughout a 7-day test period. Numbers of axons immunoreactive for PGP9.5, calcitonin gene-related peptide, and GFRα2 were increased. Numbers of macrophages and T cells were also increased whereas B cells were not. Renin-angiotensin-associated proteins were abundant, with T cells as well as macrophages contributing to increased renin and angiotensinogen. Media conditioned with inflamed vestibular tissue promoted neurite sprouting by rat dorsal root ganglion neurons in vitro, and this was blocked by the angiotensin II receptor type 2 receptor antagonist PD123319 or by an angiotensin II function blocking antibody. Sensory axon sprouting induced by inflamed tissue was dependent on activity of angiotensin-converting enzyme or chymase, but not cathepsin G. Thus, vestibular Complete Freund's adjuvant injection substantially recapitulates changes seen in patients with provoked vestibulodynia, and shows that manipulation of the local inflammatory renin-angiotensin system may be a useful therapeutic strategy. PERSPECTIVE: This study provides evidence that inflammation of the rat vestibule induces a phenotype recapitulating behavioral and cytological features of human vestibulodynia. The model confirms a crucial role of the local inflammatory renin-angiotensin system in hypersensitivity and hyperinnervation. Targeting this system holds promise for developing new nonopioid analgesic treatment strategies.

Alpha Lipoic Acid Plus Omega-3 Fatty Acids for Vestibulodynia Associated With Painful Bladder Syndrome.

OBJECTIVE: This study assessed the effectiveness of alpha lipoic acid (ALA) plus omega-3 polyunsaturated fatty acids (n-3 PUFAs) in combination with amitriptyline therapy in patients with vestibulodynia/painful bladder syndrome (VBD/PBS). METHODS: Women with VBD/PBS were randomly assigned to receive amitriptyline or amitriptyline plus a commercially available preparation (ALAnerv Age; Alfa Wassermann, Bologna, Italy) containing, in 2 capsules, ALA 600 mg plus docosahexaenoic acid 250 mg and eicosapentaenoic acid 16.67 mg. Symptoms of burning and pain were assessed using a 10-cm visual analog scale and the short form of the McGill-Melzack Pain Questionnaire. RESULTS: Among 84 women who were randomized, the mean ± standard deviation dose of amitriptyline was 21.7 ± 6.6 mg/day, without statistical difference between the two groups. Pain, as assessed using both the pain rating index of the visual analog scale and the short-form McGill Pain Questionnaire, decreased significantly in both trial groups, with a greater effect seen with the addition of ALA and n-3 PUFAs. The addition of ALA/n-3 PUFAs to amitriptyline treatment was also associated with improvements in dyspareunia and pelvic floor muscle tone. The overall incidence of adverse events was low, and none led to treatment discontinuation. CONCLUSIONS: The addition of ALA/n-3 PUFAs to amitriptyline treatment in patients with VBD/PBS appears to improve outcomes and may allow for a lower dosage of amitriptyline, which may lead to fewer adverse effects.

A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia.

Vestibulodynia is a form of provoked vulvodynia characterized by profound tenderness, hyperinnervation, and frequently inflammation within well-defined areas of the human vestibule. Previous experiments in animal models show that inflammatory hypersensitivity and hyperinnervation occur in concert with establishment of a local renin-angiotensin system (RAS). Moreover, mechanical hypersensitivity and sensory axon sprouting are prevented by blocking effects of angiotensin II on angiotensin II receptor type 2 (AT2) receptors. This case-control study assessed whether a RAS contributes to hyperinnervation observed in human vestibulodynia. Vestibular biopsies from asymptomatic controls or patients' nontender areas showed moderate innervation and small numbers of inflammatory cells. In women with vestibulodynia, tender areas contained increased numbers of mechanoreceptive nociceptor axons, T-cells, macrophages, and B-cells, whereas mast cells were unchanged. RAS proteins were increased because of greater numbers of T cells and B cells expressing angiotensinogen, and increased renin-expressing T cells and macrophages. Chymase, which converts angiotensin I to angiotensin II, was present in constant numbers of mast cells. To determine if tender vestibular tissue generates angiotensin II that promotes axon sprouting, we conditioned culture medium with vestibular tissue. Rat sensory neurons cultured in control-conditioned medium showed normal axon outgrowth, whereas those in tender tissue-conditioned medium showed enhanced sprouting that was prevented by adding an AT2 antagonist or angiotensin II neutralizing antibody. Hypersensitivity in provoked vestibulodynia is therefore characterized by abnormal mechanonociceptor axon proliferation, which is attributable to inflammatory cell-derived angiotensin II (or a closely related peptide) acting on neuronal AT2 receptors. Accordingly, reducing inflammation or blocking AT2 represent rational strategies to mitigate this common pain syndrome. PERSPECTIVE: This study provides evidence that local inflammation leads to angiotensin II formation, which acts on the AT2 to induce nociceptor axon sprouting in vulvodynia. Preventing inflammation and blocking AT2 therefore present potential pharmacological strategies for reducing vestibular pain.