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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.

摘要前庭痛（VBD）是一种慢性盆腔疼痛，影响1/6的育龄妇女，但仍然存在用标准的试错法无效地处理。我们的小组已经确定了两种不同的VBD亚型可能受益于不同类型的治疗：1）VBD外周（VBD-p）亚型，其特征在于局部外阴前庭特异性疼痛，和2）VBD中枢（VBD-c）亚型，特征为两侧阴道疼痛和远程身体区域。初步数据进一步表明，VBD-p和VBD-c亚型与关于患者报告的结果（例如，身体和精神健康）、细胞因子（细胞内调节疼痛神经和炎症过程的活性的蛋白质）和microRNA的表达（调节基因表达的小的非编码RNA分子）。患有VBD-p的女性心理特征;平衡的循环促炎和抗炎细胞因子;以及调节雌激素途径中基因表达的microRNA。相比之下，患有VBD-c的女性报告说，功能状态下降和躯体化增加;促炎性增加但非抗炎性细胞因子;以及调节与肌肉、神经和神经系统相关的基因表达的microRNA的失调。免疫细胞功能基于这些数据，我们假设两种VBD-p和VBD-c亚型将在优先响应外周、中枢或联合治疗，并可通过细胞因子和微小RNA谱。这些假设将在评估不同治疗的III期临床试验中进行测试 VBD-p和VBD-c妇女的战略。参与者将被随机分配到四个平行组之一： 5%利多卡因+0.5mg/ml雌二醇复方乳膏外周治疗; 2）中心治疗三环类抗抑郁药去甲替林，3）外周和中枢联合治疗，或4）安慰剂。治疗阶段将持续4个月（治疗开始时为6周滴定期，4个月时为2周逐渐减量期），在4个时间点（0、2、4和6个月）评估结果测量和生物标志物。首先，我们将比较使用标准化的VBD-p和VBD-c治疗减轻女性疼痛的疗效在麦吉尔疼痛问卷中插入数字评级量表和自我报告的疼痛。接下来我们就比较治疗在改善女性身体、心理和性健康方面的疗效 VBD-p和VBD-c使用标准化问卷。最后，我们将测量细胞因子和microRNA 使用多重检测和RNA测序，在患有VBD-p和VBD-c的女性中，这些生物标志物来预测治疗反应。成功完成拟议的工作将提供新的深入了解两种不同VBD亚型中驱动疼痛感知和治疗反应的机制，以及确定外周、中枢和联合治疗逆转这种疼痛的疗效。这样的发现，转化为改善患者护理，使数百万患有VBD的女性，她们的伴侣和临床医生能够更明智的决定疼痛管理。