Vulvar vestibulitis trial: Desipramine-Lidocaine

描述(由申请人提供)：建议对外阴前庭炎的外阴疼痛亚型进行研究。这项应用的第一个主要目的是进行一项随机、安慰剂对照的双盲临床试验，以研究四种药物方案的临床疗效：外用利多卡因、口服地昔帕明、外用利多卡因联合口服地昔帕明和安慰剂。通过随机、安慰剂对照、盲法临床试验证实的标准治疗外阴前庭炎的疗效尚未得到评估。以地西帕明为代表的三环类抗抑郁药在治疗外阴前庭炎方面已经获得了经验性的接受，尽管只有少数回顾研究或非对照临床试验报道了良好的治疗效果。虽然三环类抗抑郁药的确切作用机制尚不明确，但已经提出了通过背角和脑干的“中枢”作用。与口服地塞帕明不同，长期局部应用利多卡因可能通过“局部”机制起作用。这项随机、安慰剂对照、双盲的临床试验旨在确定“局部”或“中枢作用”疗法单独或联合治疗外阴前庭炎是否有效。衡量成功的结果将包括减少总体疼痛，减少触摸疼痛，将疼痛减少到标准化的机械刺激，增加无痛性行为，改善性功能，通过心理测量测试改善生活质量，以及坚持积极的药物治疗方案。这项应用的第二个主要目的是研究IL-1受体拮抗剂基因座遗传多态、组织促炎细胞因子水平和外阴前庭炎治疗反应之间的关系。促炎细胞因子，如白介素Iβ(IL-1β)和肿瘤坏死因子α(TNF-α)，从局部细胞来源分泌，并在处女膜环区域积累高于正常水平。最近的遗传分析发现，在外阴前庭炎患者中，等位基因2 IL-1受体拮抗剂(IL-1RA*2)的纯合率为53%，而在没有症状的女性中，这一比例为8.5%。此外，IL-1RA*2等位基因在体外与IL-1β的产生增加有关。在我们的第二个目标中，我们将确定这些体外结果是否可以外推到外阴前庭炎的临床病例。使用我们临床试验的样本，我们将评估IL-1RA*2纯合性、组织中IL-1β和肿瘤坏死因子-α水平与治疗反应之间的关系。总而言之，这个项目将使我们能够回答几个关于外阴前庭炎的重要问题。内科治疗有效吗？集中作用疗法和局部作用疗法是同等有效的，还是一种优于另一种？局部和全身联合治疗是否有任何益处？最后，遗传特征和组织细胞因子浓度是否会影响治疗反应？

DESCRIPTION (provided by applicant): Studies are proposed for the subtype of vulvodynia known as vulvar vestibulitis. The first major aim of this application is to conduct a randomized, placebo-controlled, double-blinded clinical trial to study the clinical efficacy of four medical regimens: topical lidocaine, oral desipramine, topical lidocaine combined with oral desipramine and placebo. The efficacy of standard treatments for vulvar vestibulitis proven by randomized, placebo-controlled, blinded clinical trials has not been assessed. The tricyclic class of antidepressants, represented by desipramine, have gained empiric acceptance for the treatment of vulvar vestibulitis, although favorable therapeutic results have been reported by only a few retrospective studies or uncontrolled clinical trials. Although the precise mechanism of action remains undefined for tricyclic antidepressants, a "central" action through the dorsal horn and brain stem has been suggested. In contrast to oral desipramine, the long-term, topical application of lidocaine may act through a "local" mechanism. This randomized, placebo-controlled, double-blinded clinical trial is designed to determine whether "local" or "centrally-acting" treatments alone, or in combination are efficacious in treating vulvar vestibulitis. Outcome measures of success will include reduced overall pain, reduced pain to touch, reduced pain to standardized mechanical stimuli, increased pain-free intercourse, improved sexual function, improved quality-of-life as measured by psychometric tests, and adherence to active drug regimens. The second major aim of this application is to study the relationship among genetic polymorphisms of the IL-1 Receptor Antagonist locus, tissue levels of pro-inflammatory cytokines, and response to treatment of vulvar vestibulitis. Pro-inflammatory cytokines, such as interleukin-I beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha), are secreted from a local cellular source and accumulate above normal levels in the region of the hymeneal ring. Recent genetic analysis finds a 53% homozygosity for allele 2 IL-1 Receptor Antagonist (IL-1 RA*2) in cases of vulvar vestibulitis, in contrast to 8.5% homozygosity in asymptomatic women. Furthermore, the IL-1 RA*2 allele has been linked to increased production of IL-1 beta in vitro. In our second aim, we will determine whether these in vitro results can be extrapolated to clinical cases of vulvar vestibulitis. Using samples from our clinical trial, we will assess the relationship between homozygosity for IL-1 RA*2, tissue levels of IL-1 beta, and TNF-alpha, and response to treatment. In summary, this project will allow us to answer several important questions about vulvar vestibulitis. Is medical treatment effective? Is centrally-acting or locally-acting treatment equally effective or is one superior to the other? Is there any benefit from combined local and systemic treatments? And finally, do genetic characteristics and tissue cytokine concentrations influence treatment response?