Analgesic technique on pain and biomarkers during sickle pain crisis

描述(申请人提供)：虽然已经对患有镰状细胞疾病的儿童进行了广泛的研究，但对患有这种疾病的成年人的研究很少。许多患有镰状细胞病(SCD)的成年患者每天都会感到疼痛。尽管镰状细胞相关疼痛的病理生理学机制很复杂，但微循环闭塞与组织缺血和炎症级联反应的激活被认为是有关的。大多数镰状细胞相关的就诊是由急性血管闭塞危象引起的。尽管有强有力的证据表明组织和血管炎症在急性血管闭塞危象的启动和维持中起作用，但尚未发现与急性危象的强度或持续时间相关的特定血清生物标志物。在SCD疼痛危象中，一种可以通过血清生物标志物进行评估并加以改进的有效止痛治疗模式尚未得到系统的研究。因此，R21建议的目的是检验这样一个假设，即止痛的质量和方法影响特定血液生物标记物的水平，并与疼痛程度相关。因此，这项研究将为了解镰状细胞危机对疼痛的治疗效果提供一个独特的机会，并为未来的干预和特定血清生物标志物的临床应用提供基础。第一个目的是验证以下假设：在SCD疼痛危机中，疼痛评分、止痛药用量和住院率决定了止痛技术的模式影响疼痛危机的结局。SCD受试者将在常规医院就诊期间登记(总目标为75名受试者)，并在急性疼痛危象的紧急就诊期间进行跟踪。将使用标准的非肠道和口服阿片类药物治疗的止痛技术。其目的是评估在急性镰刀痛危机期间和之后止痛治疗对急性和亚急性疼痛水平的影响，确定血清炎性/疼痛分子作为SCD疼痛危象疼痛严重程度的生物标记物，并检验血清生物标记物可用于预测SCD的入院需求、对止痛剂的需求增加以及可能的疾病并发症发生率的假设。此外，为了确定止痛治疗是否影响血清生物标志物，并可作为预测止痛疗效的指标。所有入选受试者的血浆IL-12、肿瘤坏死因子-1、P物质(SP)、热休克蛋白70(HSP70)、亚硝酸盐水平(一氧化氮合酶活性的测量)和胍丁胺的基线水平将在定期医院就诊期间进行测定。这些血浆标志物的水平将在急性疼痛危象的急诊期间和出院前进行测量。生物标志物的最终分析将在急性疼痛危机后2至4周的预定访问期间进行。最后，这项研究将产生两组基本的初步数据，这两组数据都将使我们能够更深入地评估SCD疼痛综合征的机制和其他治疗方案。 公共卫生相关性：R21计划公告的目标之一是开发转化性研究计划，在该计划中，基于实验室的科学发现被应用到疼痛条件下的实际/临床环境中。因此，这项建议的目的是评估镰状细胞病(SCD)疼痛危机期间的标准止痛治疗方案，并确定在疼痛危机期间预测其发生和治疗结果的血清生物标志物。因此，这项建议完全在PA-06-542的范围内，作为一项探索性建议，试图了解止痛治疗的有效性，以及新的血清生物标志物是否可以被确定为未来SCD疼痛危机研究的有用工具。

DESCRIPTION (provided by applicant): Although extensive research has been conducted with children who have sickle cell disease, there is a paucity of studies on adults with the disease. Many adult patients with sickle cell disease (SCD) experience daily pain. Although the pathophysiology of sickle cell related pain is complex, microcirculatory occlusion with tissue ischemia and activation of inflammatory cascades are believed to be involved. Acute vasoocclusive crises are responsible for most sickle cell related medical visits. Despite strong evidence for a role of tissue and vascular inflammation in the initiation and maintenance of acute vasoocclusive crises, no specific serum biomarkers have been identified which correlate with the intensity or duration of the acute crisis. An effective mode of analgesic treatment that can be assessed by serum biomarker and improved has not been methodically investigated in SCD pain crisis. Therefore, the objective of this R21 proposal is to test the hypothesis that quality and method of analgesia affect the level of specific blood biomarkers and can be correlated with pain levels. Thus, this study would provide a unique opportunity to understand the treatment effects of sickle cell crisis on pain and provide a basis for future interventions and clinical use of specific serum biomarkers. The first aim is to test the hypothesis that the mode of analgesia technique affects the outcome of pain crisis as determined by pain scores, analgesic consumption and hospital admission rates in SCD pain crisis. The SCD subjects will be enrolled during a regular hospital visit (total target of 75 subjects) and followed up during the emergency visit for the acute pain crisis. The standard analgesic technique of parenteral and oral opiate treatment will used. The aim is to assess the effect of analgesic treatment on acute and subacute pain levels during and after an acute sickle pain crisis and to identify serum inflammatory/pain molecules as biomarkers for pain severity in SCD pain crisis and to test the hypothesis that serum biomarkers can be used to predict need for admission, increased need for analgesics, and possibly disease complication rates in SCD. Furthermore, to determine if the analgesic treatment influence serum biomarkers and can be used as a predictor of analgesic efficacy. The baseline levels of plasma IL-12, TNF-1, Substance P (SP), heat shock protein 70 (HSP70), nitrite levels (measure of nitric oxide synthase activity) and agmatine will be determined in all enrolled subjects during the regular hospital visit. The levels of these plasma markers will be measured during the emergency visit for acute pain crisis and before discharge. The final analysis of the biomarkers will be made during the scheduled visit at 2 to 4 weeks after the acute pain crisis. At the conclusion, this study will produce two basic sets of preliminary data both of which will allow a more in-depth evaluation of the mechanisms of SCD pain syndrome and other treatment options. PUBLIC HEALTH RELEVANCE: One of the objectives of this R21 program announcement is to develop translational research program where laboratory-based scientific discoveries are applied into practical/clinical settings in pain conditions. Accordingly, the objective of this Proposal is to evaluate the standard analgesic treatment option during sickle cell disease (SCD) pain crisis and to identify serum biomarkers that will predict the occurrences and for treatment outcome during pain crisis. Thus, this Proposal is well under the scope of the PA-06-542 as an exploratory proposal in attempting to understand the efficacy of analgesic treatment and whether novel serum biomarkers can be identified as useful tools for future studies in SCD pain crisis.