6-Methoxyflavone antagonizes chronic constriction injury and diabetes associated neuropathic nociception expression.

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.

Vestibulodynia: Clinical characteristics, first-line treatments, and factors associated with escalation of treatment with EMG-guided injections of botulinum toxin in a retrospective french cohort study.

BACKGROUND: Vestibulodynia is a highly prevalent chronic pain disorder affecting the vulva having a major impact on women's physical, psychological, and sexual well-being. It remains an underrecognized disease that responds insufficiently to therapies such as physiotherapy and medication. AIM: To assess the global efficacy of first-line therapies and factors associated with treatment escalation in women with vestibulodynia. PATIENTS AND METHODS: This retrospective cohort study was conducted at the dermatology outpatient clinic of the University Hospital in Besancon (France) between 2013 and 2017 and follow-up until 2021. RESULTS: Among 132 patients, the mean [standard deviation] age at diagnosis was 27.2 [±9.45] years, with an average duration of symptoms of 42.3 [±37.92] months. Most cases comprised provoked (75.0%) or secondary (72.7%) vestibulodynia. At least one comorbid pain or psychologic condition was identified respectively in 63 (47.7%) and 23 patients (54.5%). Vulvar hyperesthesia associated with pelvic floor muscle dysfunction was present in 121 patients (91.6%) and vulvar erethism was noted in 94 patients (71.2%). First-line treatments consisted of pelvic floor physiotherapy with biofeedback in 85% of patients, associated with amitriptyline in 36% of cases, and of additional lidocaine cream in 17%. Fifty-two patients (39%) presented at least a good response to first-line treatment, with only 21 (15%) being in complete remission, irrespective of therapeutic strategy (p = 0.25). Botulinum toxin injections were performed in 54 patients. Patients with either primary vestibulodynia (p = 0.04) or spontaneous vestibulodynia (p = 0.03) were more likely to receive this treatment. CONCLUSION: Our study highlights the current lack of efficacy of first-line treatments in vestibulodynia. Considering the high prevalence of muscular dysfunction, botulinum toxin injections are of particular interest despite a lack of randomized controlled trials in this indication.

Changes in pelvic floor electrical activity and vulvar pain after botulinum toxin treatment of vestibulodynia: are clinical and electrophysiological outcomes related?

Vestibulodynia is a gynecological condition with different treatment options available, including botulinum neurotoxin type A (BoNT/A) injections into the vulvar vestibule. Unlike other treatments, no studies have assessed changes in the myoelectrical activity of the pelvic floor muscles (PFM) after BoNT/A treatment. The aim of this study was thus to evaluate these changes and to correlate them with changes in vulvar pain sensitivity. To do this, 35 patients with vestibulodynia were recruited, the myoelectrical activity of their left and right PFM was recorded with surface electromyography (sEMG), and their vulvar pain sensitivity was monitored according to Visual Analogue Scale (VAS) and an algometer, both before and after BoNT/A treatment. According to our results, patients' signals during PFM relaxation showed a significantly higher power than those of healthy women at baseline, as shown by their root mean square values (RMS), but became similar at follow-up. Patients' mean vulvar pain VAS scores significantly decreased after treatment. Furthermore, baseline-to-follow-up differences of RMS at PFM rest vs. mean VAS were significantly correlated (CC=0.48, p<0.01) so that higher reductions in the PFM activity power were associated with higher decreases in vulvar pain.Clinical Relevance- Altered PFM electrophysiological condition of patients with vestibulodynia becomes similar to healthy women's after BoNT/A treatment. This study also points to a relationship between the evolution of clinical and PFM electrophysiological conditions.

Treatment of Vestibulodynia with Submucosal Injections of IncobotulinumtoxinA into Targeted Painful Points: An Open-Label Exploratory Study.

The studies carried out to date on vulvodynia treatment with botulinum neurotoxin type A (BoNT/A) have followed generic injection protocols and reported contradictory outcomes on its effects. The aim of the present study was thus to propose a protocol for injecting BoNT/A into targeted painful points, to comprehensively assess the clinical effect of BoNT/A treatment and identify the risk/protective factors for successful treatment. Thirty-five vestibulodynia patients were treated with submucosal injections of incobotulinumtoxinA and assessed 8, 12 and 24 weeks after their treatment. Their clinical and pelvic statuses were assessed from self-reported questionnaires (Visual Analogue Scale (VAS), Female Sexual Function Index (FSFI), Marinoff's Dyspareunia Scale (MDS), Hospital Anxiety and Depression Scale (HADS), Catastrophizing Scale (CS)), physical examinations and surface electromyography (sEMG). The patients reported a reduction in provoked vestibulodynia (FSFI, p < 0.01;

Botulinum Toxin Injections as a Treatment of Refractory Vulvodynia in Adolescents: A Case Series.

BACKGROUND: Vulvodynia involves vulvar discomfort that occurs in the absence of an identifiable cause. Because vulvodynia is often accompanied by myofascial pain and pelvic floor tension, transvaginal botulinum toxin (BT) injection into the pelvic floor has been proposed as a possible treatment. METHODS: Retrospective case series RESULTS: Three adolescents with vulvodynia had a suboptimal response to treatment with several interventions, including neuromodulators (oral and topical), tricyclic antidepressants (oral and topical), and pelvic floor physical therapy. Subsequently, these patients underwent BT injections to the pelvic floor as treatment with varying responses. CONCLUSION: In select adolescent patients with vulvodynia, transvaginal BT injection into the pelvic floor can be an effective treatment. Further studies are needed to assess the optimal dosing, frequency, and sites of BT injections in the treatment of vulvodynia in pediatric and adolescent patients.

New Topical Therapy for Provoked Vestibulodynia: Improvement of Psychological and Sexual Well-Being.

Vulvodynia is a vulvar discomfort that occurs in the absence of any specific, clinically identifiable disorder. Few therapies have shown to be effective for the treatment of vulvodynia. In our recently published study, we tested a drug-free gel in women affected by vulvar vestibulitis. It is a cosmetic gel which acts locally without any metabolic, pharmacological or immunological effect. In order to further promote the validity of this new product, in this manuscript we analyzed the results obtained from the administration of four questionnaires in the same two groups of women affected by PVD and treated with a placebo and the new product. The questionnaires used: Female Sexual Function Index Scoring (FSFI), Female Sexual Distress Scale (FSDS), Hospital Anxiety and Depression Scale (HADS), and health-related quality of life measured by SF-36 (SF-36). The results obtained by this current analysis showed that the new gel has also proven benefits on women's quality of life and sexual function, including improvements in arousal, desire, orgasm and satisfaction.

Exclusive manual perineal rehabilitation with lidocaine 2% gel in the treatment of provoked vestibulodynia: results from a single-arm interventional study.

As of now, there is no adequate therapeutic strategy for provoked vestibulodynia (PVD). Pelvic Floor Muscle Therapy (PFMT) is a widely used technique in general pelvic floor rehabilitation. The objective of this study is to examine the effects of exclusive manual perineal rehabilitation with lidocaine 2% gel on PVD. During the first session, recruited patients (n = 68; mean age 31 ± 8.6; range: 18-52) received a questionnaire (Q1) on general well-being and health, pain of the genital area, sexual function, and symptoms during vaginal penetration. This questionnaire was based on a generalised questionnaire on the quality of life, the Medical Outcomes Study 36-item (SF-36), the Female Sexual Function Index (FSFI), and the Visual Analogue Scale (VAS). A second identical questionnaire with an additional set of open-ended questions concerning the assessment of the treatment was collected after treatment (Q2). A total of 45 questionnaires were completed. Statistical results showed a significant improvement of all items before and after treatment (p < 0.001): perceived general well-being and health, perceived vulvar pain, perceived sexual function, and perceived vaginal penetration. In conclusion, exclusive manual perineal rehabilitation using lidocaine 2% gel seems to be a safe and effective treatment option for vulvodynia in women.

Vestibular hyaluronic acid injection in provoked vestibulodynia patients and its effect on pain and sexual function: A preliminary report.

OBJECTIVE: Provoked vestibulodynia (PVD) is a challenging and distressing problem for women. The aim of this study was to examine the effect of hyaluronic acid (HA) in the management of this condition. METHOD: This is a retrospective review of 12 women diagnosed with PVD and treated with HA (19 mg/mL) applied, point-by-point, to the vestibular region at 2 mm intervals and at a depth of 0.5 mm. Women completed a pain VAS and a Female Sexual Function Index (FSFI) before and 45 days after treatment. RESULTS: An improvement was observed both in mean FSFI scores (17.8 to 23.3; p = 0.003) and mean VAS scores (7.2 to 4.1; p = 0.002) after HA application respectively. However, on a telephone interview 3 months post treatment, five women (41.7 %) complained of recurrence of their dyspareunia. CONCLUSION: HA is a promising management option in provoked vestibulodynia. However, further larger studies with possible alternative regimens and longer follow-up are required.

Rationale and design of a multicenter randomized clinical trial of vestibulodynia: understanding pathophysiology and determining appropriate treatments (vestibulodynia: UPDATe).

BACKGROUND: Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c. METHODS: Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response. CONCLUSION: This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. ADMINISTRATIVE INFORMATION: Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.

Behavioral sex therapy and medications associated in the treatment of provoked vulvodynia: efficacy on pain and sexuality in three illustrative cases.

This paper tests the hypothesis that medications combined with behavioral sex therapy might lessen pain and restore sexuality in women with provoked vulvodynia. Three women affected by vulvodynia, otherwise healthy, in heterosexual relationship were treated at the Department of Obstetrics and Gynecology in a university hospital. In consecutive sessions of behavioral sex therapy, oral tricyclic antidepressants and vulvar applications of estrogen and hydrocortisone creams were prescribed in association with vaginal dilators and sensate focus exercises. The outcome supports the hypothesis that combined medications and sexual behavior interventions may be effective in lessening pain and restoring sexuality in women with provoked vulvodynia. The different dyadic balances observed in this small case series suggest how to best use this protocol. The positive results appear to be mostly due to behavioral sex therapy that was the new element added to the combination of pharmacological agents commonly used to treat provoked vulvodynia.

Efficacy of ganglion impar block on vulvodynia: Case series and results of mid- and long-term follow-up.

RATIONALE: Vulvodynia is a common chronic gynecological disease that affects approximately 16% of women, although it is rarely diagnosed. However, no known effective treatment exists. The etiology of vulvodynia is unknown and may be heterogeneous and multifactorial, so it is difficult-if not impossible-to improve this condition using 1 treatment method. Reports have shown that vulvodynia has an element of neuropathic pain. Although the role of the sympathetic nervous system in neuropathic pain is controversial, sympathetic nerve blocks have long been used to treat patients with chronic pain giving good results. A ganglion impar block (GIB), a sympathetic nerve block technique, may effectively manage pain and discomfort in patients with vulvodynia. PATIENT CONCERNS: Four patients suffering from chronic vulvar pain for 6 months-10 years were referred by gynecologists. The gynecologists could not identify the cause of the chronic vulvar pain, and symptoms were not improving by conservative therapy with medication. Patients complained of various chronic vulvar pain or discomfort. The initial visual analog scale (VAS) scores were 8 or 9 out of 10, and Leeds assessment of neuropathic symptoms and signs pain scale score was more than 12 out of 24. The review of gynecological medical records confirmed whether they showed allodynia during the cotton swab test and hyperalgesia to pin-prick test. DIAGNOSES: All patients were diagnosed with vulvodynia. INTERVENTIONS: All patients were treated with a GIB, once in 2 patients, 3 times in 1 patient, and 4 times (1 alcoholic neurolysis) in the other patient, under fluoroscopic guidance. OUTCOMES: After the procedures, the VAS score and the leeds assessment of neuropathic symptoms and signs (LANSS) pain scale score were decreased to less than 2 and 5, respectively, in all patients. Follow-up observations for 6 months-2 years revealed that 2 patients' symptoms entirely or nearly entirely improved and did not require further treatment. The pain of the remaining patients were well controlled with medications only. LESSONS: GIB is a good treatment option for patients suffering from chronic pain and discomfort caused by vulvodynia.

Health seeking behaviours and treatments received by Australian women with vulvodynia: A cross-sectional survey.

BACKGROUND: Vulvodynia is a condition characterised by pain in the vulva lasting more than three months and for which no obvious aetiology can be found. It affects around 8% of women and has significant negative impacts on quality of life. There is a paucity of research on healthcare management pathways and the use of evidence-based treatments in an Australian community setting. AIMS: To explore which healthcare professionals Australian women with vulvodynia seek treatment from, and which treatments are recommended, provided, or prescribed by these healthcare professionals. MATERIALS AND METHODS: A cross-sectional online survey was conducted from May 2019 to August 2019. Women were eligible to participate if they had been diagnosed with vulvodynia by a healthcare professional, were currently living in Australia, and were over 18 years old. RESULTS: Fifty respondents meet the inclusion criteria, with a mean age of 30.5 years. On average, respondents reported seeing four different types of healthcare professionals in the management of their vulvodynia, with general practitioners (GPs) (98%), medical specialists (96%), and physiotherapists (80%) being the three most commonly consulted. Most respondents reported seeing multiple GPs (>87%), multiple medical specialists (>77%), and multiple physiotherapists (50%). The most commonly prescribed interventions were pelvic floor down-training exercises (76%), topical (70%) and oral (70%) medication, and vulvodynia information (56%). CONCLUSIONS: Australian women with vulvodynia seek help from several professionals and receive a variety of treatments for their pain. Of concern is many treatments that are being offered clinically have very little peer-reviewed evidence of effectiveness in vulvodynia.

Comparing Vestibule Examination Techniques: Light Touch, Serial Forces, and the Lidocaine Test.

OBJECTIVE: The purpose of this study was to compare techniques and pain scales that assess tenderness in the vulvar vestibule in provoked vestibulodynia, using the cotton swab test and a vulvalgesiometer, and assess topical lidocaine solution with each. MATERIALS AND METHODS: This randomized study at a specialty vulvar clinic evaluated tender vestibules of reproductive-aged women with vestibulodynia using light rolling cotton swab touch at 6 sites and evaluated the vulvalgesiometer at 2 sites, randomizing the order of the initial tool. Participants reported pain using the Numerical Rating Scale 0-10 and the Verbal Pain Scale 0-3. With the vulvalgesiometer, the pain tolerance threshold was measured using forces of 10, 25, 50, 100, 200, and 300 g. After both initial tests, lidocaine 4% topical solution was applied for 3 minutes, and the swab test and vulvalgesiometer were repeated in the order initially performed, constituting the lidocaine test. Data analysis used t tests, Fisher exact tests, Wilcoxon signed rank tests, and Spearman rank correlation. RESULTS: Sixteen patients completed the study, 8 starting with each instrument. Light swab touch evoked significant pain, and lidocaine reduced pain to zero or mild levels. The pain threshold was 25 g, and only 38% could tolerate testing past 100 g without lidocaine. The Verbal Pain Scale correlated well with the Numerical Rating Scale. CONCLUSIONS: Light rolling cotton swab touch using the 4-item verbal scale can map vestibulodynia tenderness that can be extinguished by lidocaine, consistent with distinguishing a mucosal condition. Forces by vulvalgesiometer of greater than 100-200 g may evoke pain other than mucosal allodynia.

Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia.

Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia in premenopausal women, characterized by pain with light touch to the vulvar vestibule surrounding the vaginal opening. The devastating impact of LPV includes sexual dysfunction, infertility, depression, and even suicide. Yet, its etiology is unclear. No effective medical therapy exists; surgical removal of the painful vestibule is the last resort. In LPV, the vestibule expresses a unique inflammatory profile with elevated levels of pro-nociceptive proinflammatory mediators prostaglandin E2 (PGE2) and interleukin-6 (IL-6), which are linked to lower mechanical sensitivity thresholds. Specialized pro-resolving mediators (SPMs), lipids produced endogenously within the body, hold promise as an LPV treatment by resolving inflammation without impairing host defense. Ten of 13 commercially available SPMs reduced IL-6 and PGE2 production by vulvar fibroblasts, administered either before or after inflammatory stimulation. Using a murine vulvar pain model, coupling proinflammatory mediator quantification with mechanical sensitivity threshold determination, topical treatment with the SPM, maresin 1, decreased sensitivity and suppressed PGE2 levels. Docosahexaenoic acid, a precursor of maresin 1, was also effective in reducing PGE2 in vulvar fibroblasts and rapidly restored mouse sensitivity thresholds. Overall, SPMs and their precursors may be a safe and efficacious for LPV. Perspective: Vulvodynia, like many pain conditions, is difficult to treat because disease origins are incompletely understood. Here, we applied our knowledge of more recently discovered vulvodynia disease mechanisms to screen novel therapeutics. We identified several specialized pro-resolving mediators as likely potent and safe for treating LPV with potential for broader application.

Topical treatment of vulvodynia, dyspareunia and pudendal neuralgia: A single clinic audit of amitriptyline and oestriol in organogel.

BACKGROUND: Vulvodynia and pudendal neuralgia comprise significant contributors to vulvar-related pain and its impact on daily life. AIM: A retrospective clinical audit was conducted at the Women's Health & Research Institute of Australia, Sydney, to determine the pattern of use and the efficacy of the application of topical amitriptyline 0.5% plus oestriol 0.03% in organogel (AOO), to the vulvar vestibule in reducing the impact of pain on daily life. MATERIALS AND METHODS: There were 1174 patients who received a script from May 2017 until February 2020: 1054 patients agreed to be contacted and had a valid email address. RESULTS: There were 376 (35.7%) patients who replied. Pain with intercourse was the main indication for use. Treatment was rated effective by 51.2% (95% CI: 35.4-66.8%) of patients less than 30 years of age, 66.7% (95% CI: 57.3-74.9%) of patients 30-50 years of age, and 58.3% (95% CI: 50.9-65.4%) in patients over 50. Stinging at the site of application was the most commonly reported side effect. CONCLUSION: Topical AOO is an effective and well-tolerated treatment for vulvar pain.

Clodronate Treatment Prevents Vaginal Hypersensitivity in a Mouse Model of Vestibulodynia.

INTRODUCTION: Improved understanding of vestibulodynia pathophysiology is required to develop appropriately targeted treatments. Established features include vulvovaginal hyperinnervation, increased nociceptive signalling and hypersensitivity. Emerging evidence indicates macrophage-neuron signalling contributes to chronic pain pathophysiology. Macrophages are broadly classified as M1 or M2, demonstrating pro-nociceptive or anti-nociceptive effects respectively. This study investigates the impact of clodronate liposomes, a macrophage depleting agent, on nociceptive signalling in a mouse model of vestibulodynia. METHODS: Microinjection of complete Freund's adjuvant (CFA) at the vaginal introitus induced mild chronic inflammation in C57Bl/6J mice. A subgroup was treated with the macrophage depleting agent clodronate. Control mice received saline. After 7 days, immunolabelling for PGP9.5, F4/80+CD11c+ and F4/80+CD206+ was used to compare innervation density and presence of M1 and M2 macrophages respectively in experimental groups. Nociceptive signalling evoked by vaginal distension was assessed using immunolabelling for phosphorylated MAP extracellular signal-related kinase (pERK) in spinal cord sections. Hyperalgesia was assessed by visceromotor response to graded vaginal distension. RESULTS: CFA led to increased vaginal innervation (p < 0.05), increased pERK-immunoreactive spinal cord dorsal horn neurons evoked by vaginal-distension (p < 0.01) and enhanced visceromotor responses compared control mice (p < 0.01). Clodronate did not reduce vaginal hyperinnervation but significantly reduced the abundance of M1 and M2 vaginal macrophages and restored vaginal nociceptive signalling and vaginal sensitivity to that of healthy control animals. CONCLUSIONS: We have developed a robust mouse model of vestibulodynia that demonstrates vaginal hyperinnervation, enhanced nociceptive signalling, hyperalgesia and allodynia. Macrophages contribute to hypersensitivity in this model. Macrophage-sensory neuron signalling pathways may present useful pathophysiological targets.

Botulinum Toxin A as a Treatment for Provoked Vestibulodynia: A Randomized Controlled Trial.

OBJECTIVE: To evaluate pain reduction after two injections of 50 units botulinum toxin A compared with placebo for provoked vestibulodynia. METHODS: We conducted a double-blinded, placebo-controlled randomized trial of 50 units botulinum toxin A or placebo injected in the bulbocavernosus muscles twice, 3 months apart, in women with provoked vestibulodynia. Primary outcome was self-reported dyspareunia or pain at tampon use on a visual analog scale (VAS, 0-100). Secondary outcomes were pain at weekly tampon insertion (VAS score), reduction of pelvic floor hypertonicity (measured with a vaginal manometer), adverse events, and sexual function and distress. A sample size of 38 participants for each group was calculated to achieve a statistical power of 80% based on an effect size of 20 VAS units (0-100) (mean score range 56-76±31 SD). RESULTS: Between May 2016 and June 2018, 124 women with provoked vestibulodynia were assessed, and 88 were randomized to botulinum toxin A (BTA group, n=44) or placebo (placebo group, n=44). Primary outcome showed a lower but statistically nonsignificant pain rating by 7 VAS units (95% CI -15.0 to 0.4) in the BTA group compared with the placebo group. Secondary results showed a significant decrease in pain at weekly tampon insertion by 11 VAS units (95% CI -16.6 to 6.0) with botulinum toxin A injection. The vaginal manometer measured lower maximum contraction strength by 7 mm Hg (95% CI -12.7 to -2.4) and lower 10-second endurance strength by 4 mm Hg (95% CI -7.72 to -1.16) in the BTA group compared with the placebo group. No changes were observed for sexual function and distress, but there was a significant increase in women attempting vaginal intercourse in the BTA group (0.27, 95% CI 0.06-0.48). No severe adverse events were reported. CONCLUSION: Twice-repeated injections of 50 units of botulinum toxin A in women with provoked vestibulodynia did not reduce dyspareunia or pain at tampon use, but secondary outcomes suggested positive effects of the treatment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02773641.

Clinical outcomes and adherence to topical corticosteroid therapy in women with vulvar lichen sclerosus: A retrospective cohort study.

BACKGROUND: Vulvar lichen sclerosus is a progressive dermatitis with significant itching, pain, and sexual dysfunction. OBJECTIVE: To investigate topical steroid use and clinical improvement across multiple specialties. METHODS: Retrospective cohort study at dermatology, gynecology, and vulvovaginal specialty clinics from 2012 to 2017. Descriptive statistics and panel logistic regression were performed. RESULTS: A total of 333 women attended 1525 visits (median 6/patient; range, 1-24 visits). Patients used steroids exactly as prescribed at 66% of visits, less than prescribed at 26%, and not at all at 8%. Versus no use, exact use improved symptoms (odds ratio [OR], 4.6; 95% confidence interval [CI], 2.2-9.6) and physical examination findings (OR, 6.9; 95% CI, 2.7-17.6) more than infrequent steroid use (symptoms: OR, 2.5; 95% CI, 1.2-5.4; physical examination findings: OR, 4.2; 95% CI, 1.6-11.0). Sexual activity status was noted in 93% of vulvovaginal, 29% of gynecology, and 0% of dermatology visits. At intake, 42% of women were sexually inactive because of pain; of these, 37% became sexually active after steroid treatment. Steroid adherence was not associated with change in sexual activity. CONCLUSIONS: Women with vulvar lichen sclerosus improve more when topical steroids are used exactly as prescribed, although some improvement occurs with imperfect use. Sexual activity documentation is inconsistent, limiting quality of life follow-up.

Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia.

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8+CD103+ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ9-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.