Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments (Vestibulodynia: UPDATe)

前庭痛：了解病理生理学并确定适当的治疗方法（前庭痛：UPDATe）

基本信息

批准号：
10649404
负责人：
Andrea G Nackley
金额：
$ 73.87万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-11 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649404
关键词：
Affect Anti-Inflammatory Agents Biological Markers Blood Body Regions Caring Cell physiology Chronic Clinic Visits Clinical Combined Modality Therapy Complex Controlled Clinical Trials Cream Data Double-Blind Method Equilibrium Estradiol Estrogens Etiology Exhibits Functional disorder Gene Expression Health Immune Impairment Inflammation Mediators Inflammatory Lidocaine McGill Pain Scale Measures Mediating Mental Health MicroRNAs Muscle Nerve Nerve Pain Newly Diagnosed Nortriptyline Numeric Rating Scale Outcome Measure Pain Pain management Participant Pathology Pathway interactions Patient Care Patient Outcomes Assessments Patient Self-Report Peripheral Phase Phase III Clinical Trials Placebo Control Placebos Prediction of Response to Therapy Process Production Proteins Questionnaires Randomized Reporting Research Design Resort Sampling Sexual Health Site Small RNA Standardization Tampons Testing Time Titrations Translating Treatment Efficacy Treatment Protocols Tricyclic Antidepressive Agents United States Untranslated RNA Update Vagina Vestibule Vestibulodynia Vulva Woman Work aged arm chronic painful condition chronic pelvic pain comparative efficacy cytokine efficacy evaluation functional status improved insight microRNA biomarkers multidisciplinary multiplex assay pain perception physical conditioning psychologic recruit reproductive response transcriptome sequencing treatment choice treatment response treatment strategy vulvar pain

项目摘要

ABSTRACT 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. Our group has 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, we 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 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, we 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, we 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, we 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.

抽象的前庭型（VBD）是一种慢性骨盆疼痛疾病，影响6个生殖老年女性，但仍然存在通过标准试验方法无效治疗。我们的小组已经确定了两个不同的VBD亚型可能受益于不同类型的治疗：1）以局部化为特征的VBD外围（VBD-P）亚型特定于外阴前庭的疼痛，以及2）VBD中央（VBD-C）亚型，其特征是在两种阴道上疼痛和偏远的身体区域。初步数据进一步表明，VBD-P和VBD-C子类型的不同尊重患者报告的结果（例如身体和心理健康），细胞因子的产生（细胞内调节疼痛神经和炎症过程活性的蛋白质）和microRNAS的表达（调节基因表达的小非编码RNA分子）。 VBD-P妇女表现正常心理概况；平衡循环促和抗炎细胞因子；和失调调节雌激素途径基因表达的microRNA。相反，有VBD-C报告的妇女功能状态降低和躯体化增加；促炎性但没有增加抗炎细胞因子；在microRNA中调节基因表达与肌肉，神经和免疫细胞功能。基于这些数据，我们假设两个VBD-P和VBD-C子类型将优先对外围，中心或联合治疗的反应，可以通过细胞因子和 microRNA轮廓。这些假设将在评估多种处理的III期临床试验中进行检验 VBD-P和VBD-C女性的策略。参与者将被随机分配到四个平行臂之一： 5％利多卡因 + 0.5 mg/ml雌二醇化合物奶油，2）中心处理与5％利多卡因的外围处理三环抗抑郁剂北替林，3）联合外围和中央处理，或4）安慰剂。治疗阶段将持续4个月（在治疗开始时进行6周的滴定和4个月的2周锥度），其中2周）在4个时间点（0、2、4和6个月）评估的结果度量和生物标志物。首先，我们将比较使用标准化的卫生棉条，治疗方法可以减轻VBD-P和VBD-C女性疼痛的功效插入数字评级量表和麦吉尔疼痛问卷上的自我报告的疼痛。接下来，我们会的比较治疗方法在改善女性感知到的身体，心理和性健康方面的功效使用标准化问卷使用VBD-P和VBD-C。最后，我们将测量细胞因子和microRNA 在使用多重测定和RNA测序的VBD-P与VBD-C的女性中，并确定这些生物标志物可以预测治疗反应。成功完成拟议的工作将提供新的对两个不同VBD亚型的疼痛感知和治疗反应的机制的见解，以及确定外围，中心和联合疗法在逆转这种疼痛方面的功效。这样的发现很容易转化为改善的患者护理，允许数百万与VBD，其伴侣和临床医生的女性成为关于疼痛管理的更明智的决定。