Vagus Nerve Stimulation in Fibromyalgia

描述（由申请人提供）：纤维肌痛综合征（FMS）是一种原因不明的慢性疼痛疾病，其特征为弥漫性身体疼痛和压痛。越来越多的证据表明，FMS的发病机制可能与疼痛调节系统的中枢失调有关，表现为异常高的疼痛敏感性和不耐受阈值。基于来自动物的生理数据和来自人类的心理物理数据，发现VNS疗法可以降低实验室疼痛的强度，特别是当诱导中枢疼痛调节系统（称为发条）致敏时。缠绕被认为是FMS慢性疼痛的基础。因此，VNS治疗可能是FMS患者可行的连续治疗选择。随着时间的推移，传统的药物和行为疗法在缓解FMS疼痛方面已被证明在很大程度上不成功。虽然阿片类药物维持治疗是目前对患有严重，持续疼痛的FMS患者的“最后手段”治疗选择是有效的，但由于担心成瘾，通常会避免使用。因此，未缓解的FMS疼痛导致生活质量差、残疾、经济劣势和过度利用医疗保健系统。VNS有可能成为一种突破性的非药物治疗方式，以缓解FMS疼痛并停止这一过程。残疾和抑郁的FMS患者通常被认为预后最差。 拟定的初步研究将是一项开放标签、非随机、单组、纵向、单中心VNS研究。我们计划植入并研究30例代表难治性FMS患者的FMS患者。所有患者均对常规四级药物FMS疼痛管理方案的至少两个级别具有治疗抗性。根据最近的患病率估计，我们选择的FMS样本中有三分之一将是工作残疾，三分之二不会。同样，三分之一的FMS患者不会并发抑郁症，而三分之二的患者会并发抑郁症。这项初步研究的主要目的是确定VNS在难治性FMS患者中的安全性和耐受性限度。本研究将提供在3个月、急性和9个月随访研究期内耐受VNS器械植入、VNS输出电流激活和斜升以及刺激的FMS患者比例的数据。此外，我们还将估计可耐受的VNS输出电流范围，并确定FMS中任何不良事件的发生率是否高于癫痫或抑郁样本。这些数据将为III期试验的设计提供关于这些患者可能的最大刺激强度和最短试验持续时间的信息。本研究的次要目的（假设VNS耐受）是评估VNS治疗对FMS症状的影响（包括疼痛强度、身体功能、患者对变化的总体印象[FM 20]、情绪和生活质量，以及疼痛敏感性的实验室指标）。

DESCRIPTION (provided by applicant): Fibromyalgia Syndrome (FMS) is a chronic pain disorder of unknown origin, characterized by diffuse body pain and tenderness. Evidence is accumulating that the pathogenesis of FMS may be associated with central dysregulation of pain regulatory systems manifesting itself psychophysically in abnormally high pain sensitivity and intolerance thresholds. Based on physiological data derived from animals and psychophysical data derived from humans, VNS therapy was found to reduce the intensity of laboratory pain, especially when sensitization of the central pain regulatory system, known as wind-up, was induced. Wind-up is thought to underlie chronic pain in FMS. Thus, VNS therapy may be a viable adjunctive treatment option for FMS patients. Conventional drug and behavioral therapies have proven to be largely unsuccessful in relieving FMS pain over time. While opioid maintenance therapy, the current 'last resort' treatment option for FMS patients with severe, unrelenting pain, is efficacious, it is often avoided for fear of addiction. Thus, unrelieved FMS pain leads to poor quality of life, disability, economic disadvantage, and over utilization of the health care system. VNS has the potential to be a break-through non-pharmacological treatment modality to relieve FMS pain and halt this process. FMS patients who are disabled and depressed are usually considered to have the poorest prognosis. The proposed pilot study will be an open label, non-randomized single-arm, longitudinal, single-center study of VNS. We plan to implant and study 30 FMS patients representative of the spectrum of refractory FMS patients. All patients will have been treatment resistant to at least two levels of a conventional four level pharmacological FMS pain management protocol. In line with recent prevalence estimates, one-third of our selected FMS sample will be work disabled and two-thirds will not be. Likewise, one-third of FMS patients studied will not have a concurrent depressive disorder, while two-thirds will. The primary aim of this pilot study is to define the limits of VNS safety and tolerability in patients with refractory FMS. This study will provide data regarding the proportion of FMS patients tolerating implantation of the VNS device, activation, and ramp up of VNS output current, as well as stimulation over a 3-months, acute, and a 9 months follow-up study period. In addition, we will estimate the range of VNS output current tolerated and determine whether the rates of any adverse events are higher in FMS than epilepsy or depression samples. These data will inform the design of a Phase HI trial about maximal stimulation intensities and the minimum duration of a trial that is possible in these patients. The secondary aim of this study, assuming VNS is tolerated, is to assess the impact of VNS therapy on symptoms of FMS (including pain intensity, physical function, patient's global impression of change [FM20], mood, and quality of life, as well as laboratory measures of pain sensitivity).