Peripheral and Central Mechanism of Pain in Patients with Fibromyalgia

描述（由申请方提供）：本申请的目的是表征与纤维肌痛综合征（FM）受试者临床疼痛相关的外周和中枢疼痛机制。由于强直性伤害性肌肉输入可能在FM和其他肌肉骨骼疼痛综合征的慢性疼痛和痛觉过敏中发挥重要作用，因此FM受试者对肌肉操作的反应的仔细心理物理表征可以为这一假设提供关键支持。本申请的第一个特定目的将表征FM和NC受试者与仔细控制的肌肉强直性疼痛操作相关的机械和热痛觉过敏。我们认为FM中的局部自发性疼痛强烈提示局部和广泛的热和机械痛觉过敏。此外，我们将测试的作用，实验操作的外周紧张性伤害性输入的临床疼痛和局部/广泛的痛觉过敏的FM受试者施加持续的机械压力，以招标肌肉（紧张性伤害性输入）。我们认为，与NC受试者相比，FM受试者的临床疼痛和皮肤/肌肉疼痛敏感性在强直性肌肉刺激后将更显著地增加，并且这些效应在FM受试者中将特别延长。我们将比较基线测试期间获得的机械和热测试刺激的结果与肌肉刺激后获得的结果。相对于操作的肌肉区域，邻近和可能的远端继发性痛觉过敏的增加将支持强直性肌肉伤害性输入对FM受试者的痛觉过敏和临床疼痛的作用。在第二个具体目标中，我们将研究FM受试者与将利多卡因或生理盐水安慰剂注射到疼痛性肌痛（TrapM）压痛点（镇痛）相关的镇痛机制。我们认为，局部利多卡因/生理盐水安慰剂注射到一个TrapM压痛点将具有几种效果; a）它将减少肌肉痛觉过敏（原发性）和注射后的局部疼痛; B）它将减少FM受试者在邻近和远处身体区域内的继发性皮肤痛觉过敏; c）它将减少一般临床FM疼痛。我们将比较基线测试期间获得的热和机械测试刺激的反应与肌肉注射后获得的反应。我们将通过比较紧张性疼痛肌肉刺激期间的自然史（无镇痛干预）与生理盐水安慰剂和利多卡因注射，仔细估计安慰剂效应的贡献。重要的是，研究设计将提供外周镇痛机制（即痛觉输入外周来源的麻醉）和安慰剂镇痛机制对FM疼痛局部和全身减轻的相对贡献的临床相关信息。我们承诺：a）与生理盐水安慰剂注射相比，肌内注射利多卡因将产生更大的局部和全身疼痛减轻，和B）安慰剂反应的方差将与预期疼痛强度和减轻疼痛的愿望的评级强烈相关，与我们先前的工作一致。虽然可能仅安慰剂因素就足以减少临床疼痛和痛觉过敏，并可能解释肌肉注射治疗效果的部分、大部分甚至全部差异，但我们的初步数据显示利多卡因注射的上级有效性。因此，这些发现将具有相当大的临床和机制意义，因为它们将证实先前的工作，显示利多卡因对痛觉过敏状态的显著影响，并提供其幅度的估计。在第三个具体目标中，我们将评估镇痛操作（利多卡因或生理盐水安慰剂）对实验和临床疼痛的安慰剂效应。我们认为：a）旨在增加安慰剂效应的操作（口头建议）将增强利多卡因和生理盐水注射的镇痛效果; B）安慰剂效应的大小由疼痛缓解的预期和愿望预测。安慰剂效应的表征将提供与肌肉注射相关的镇痛机制的重要信息。因此，我们的应用程序将不仅提供强有力的证据支持或反对的作用，强直性伤害性输入肌肉作为临床疼痛和FM患者痛觉过敏的相关机制，但也描绘了镇痛机制（中央，外周，或两者），是在注射疼痛的肌肉操作。无论哪种方式，我们都将提供证据来描述局部麻醉、安慰剂镇痛或两者的作用。因此，患有FM和其他类似疼痛综合征的患者可能会从我们的研究结果中获益。

DESCRIPTION (provided by applicant): The Aim of this application is to characterize peripheral and central pain mechanisms relevant for clinical pain in subjects with fibromyalgia syndrome (FM). Because tonic nociceptive muscle input may play an important role for chronic pain and hyperalgesia in FM and other musculoskeletal pain syndromes, a careful psychophysical characterization of the response of FM subjects to muscle manipulations could provide crucial support of this hypothesis. The first Specific Aim of this application will characterize the mechanical and thermal hyperalgesia of FM and NC subjects in relation to carefully controlled tonic pain manipulation of muscles. We posit that local spontaneous pain in FM is strongly indicative of local and widespread thermal and mechanical hyperalgesia. In addition, we will test the role of experimental manipulations of peripheral tonic nociceptive input on clinical pain and local/widespread hyperalgesia of FM subjects by applying sustained mechanical pressure to tender muscles (tonic nociceptive input). We posit that clinical pain and cutaneous/muscle pain sensitivity will more markedly increase following tonic muscle stimulation in FM compared to NC subjects, and these effects will be particularly prolonged for FM subjects. We will compare the results of mechanical and thermal test stimuli obtained during baseline testing with those obtained after the muscle stimulation, An increase of adjacent and possibly of distant secondary hyperalgesia relative to the manipulated muscle area would support the role of tonic muscle nociceptive input for hyperalgesia and clinical pain of FM subjects. In the second Specific Aim we will study the analgesic mechanisms of FM subjects related to injections of lidocaine or saline placebo into painful trapezius muscle (TrapM) tender points (analgesia). We posit that local lidocaine/saline placebo injection into one TrapM tender point will have several effects; a) it will reduce muscle hyperalgesia (primary) and local pain after injection; b) it will reduce the secondary cutaneous hyperalgesia of FM subjects within adjacent and distant body areas; c) it will reduce general clinical FM pain. We will compare the response to thermal and mechanical test stimuli obtained during baseline testing with those obtained after the muscle injections. We will carefully estimate the contribution of the placebo effect by comparing the natural history (no analgesic intervention) to saline placebo and lidocaine injections during tonic painful muscle stimuli. Importantly, the study design will provide clinically relevant information about the relative contribution of peripheral analgesic mechanisms (i.e. anesthesia of peripheral sources of algesic input) and placebo analgesic mechanisms to local and general reductions in FM pain. We posit: a) Intramuscular lidocaine injections will produce larger reductions in local and generalized pain than will saline placebo injections and b) the variance in placebo responses will be strongly associated with ratings of expected pain intensities and desire for pain reduction, consistent with our previous work. Although it is possible that placebo factors alone are sufficient to produce reductions in both clinical pain and hyperalgesia and may account for some, most, or even all of the variance in therapeutic effects from muscle injections, our preliminary data showed superior effectiveness of lidocaine injections. Thus, such findings would be of considerable clinical and mechanistic significance, because they would corroborate previous work showing considerable effects of lidocaine on hyperalgesic states and provide estimates of their magnitude. In the third Specific Aim we will evaluate the placebo effects of analgesic manipulations (lidocaine or saline placebo) on experimental and clinical pain. We posit that a) manipulations designed to increase the placebo effect (verbal suggestions) will enhance the analgesic efficacy of lidocaine and saline injections; b) the magnitude of the placebo effect is predicted by expectations and desire for pain relief. Characterization of the placebo effect will provide important information on analgesic mechanisms related to muscle injections. Thus our application will not only provide strong evidence for or against the role of tonic nociceptive input from muscles as a relevant mechanism for clinical pain and hyperalgesia of FM patients but also delineate the analgesic mechanisms (central, peripheral, or both) that are operant during injections of painful muscles. Either way, we will provide evidence that will characterize the role of local anesthesia, placebo analgesia, or both. Thus patients with FM and other similar pain syndromes may strongly benefit from the results of our study.