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

摘要 前庭疼痛(VBD)是一种慢性盆腔疼痛，每6名育龄妇女中就有1人受到影响，但仍 用标准的反复试验的方法治疗效果不佳。我们的小组已经确定了两种不同的VBD亚型 这可能受益于不同类型的治疗：1)以局限性为特征的VBD外周(VBD-p)亚型 外阴前庭特有的疼痛；2)VBD中心型(VBD-c)，特征为双侧阴道疼痛 和偏远的身体区域。初步数据进一步表明vbd-p和vbd-c亚型不同于 关于患者报告的结果(例如，身体和精神健康)、细胞因子的产生(细胞内 调节疼痛神经活动和炎症过程的蛋白质)，以及microRNAs的表达 (调节基因表达的非编码小RNA分子)。患有VBD-P的女性表现正常 心理特征；平衡循环中的促炎和抗炎细胞因子；以及 调节雌激素途径中基因表达的microRNAs。相比之下，患有VBD-C的女性报告说 功能状态降低，躯体化程度增加；促炎作用增强，而非抗炎作用增强 细胞因子；以及调节肌肉、神经和神经相关基因表达的microRNA中的失调。 免疫细胞功能。基于这些数据，我们假设两个vbd-p和vbd-c亚型 优先对外周、中枢或联合治疗有反应，并可通过细胞因子和 MicroRNA图谱。这些假说将在评估不同治疗方法的III期临床试验中得到验证。 患有vbd-p和vbd-c的妇女的策略。参与者将被随机分配到四个平行手臂中的一个： 外用5%利多卡因+0.5 mg/ml复方雌二醇乳膏，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。治疗方法 阶段将持续4个月(治疗开始时滴定6周，4个月减少2周)， 在4个时间点(0、2、4和6个月)评估结果测量和生物标记物。首先，我们将比较 标准化卫生棉条治疗女性VBD-p和VBD-c疼痛的疗效观察 在麦吉尔疼痛问卷上插入数字分级量表和自我报告的疼痛。接下来，我们将 比较治疗在改善女性的生理、心理和性健康方面的效果 使用标准化问卷对VBD-p和VBD-c进行调查。最后，我们将测量细胞因子和microRNA 在患有VBD-p和VBD-c的女性中，使用多重分析和RNA测序，并确定 这些生物标志物可以预测治疗反应。拟议工作的成功完成将提供新的 洞察两种不同的VBD亚型中驱动疼痛感知和治疗反应的机制，以及 确定外周、中枢和综合疗法在逆转这种疼痛方面的效果。这样的发现将很容易 转化为改善患者护理，允许数百万患有VBD的女性、她们的伴侣和临床医生 关于疼痛管理的更明智的决定。

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.