Analgesic technique on pain and biomarkers during sickle pain crisis

描述（由申请人提供）：尽管对患有镰状细胞病的儿童进行了广泛的研究，但对患有该疾病的成人的研究很少。许多患有镰状细胞病（SCD）的成年患者每天都会经历疼痛。虽然镰状细胞相关疼痛的病理生理学是复杂的，但认为涉及微循环闭塞与组织缺血和炎症级联反应的激活。急性血管闭塞性危象是大多数镰状细胞相关医疗就诊的原因。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性危象的发生和维持中起作用，但尚未鉴定出与急性危象的强度或持续时间相关的特异性血清生物标志物。一个有效的镇痛治疗模式，可以评估血清生物标志物和改进尚未系统地研究SCD疼痛危机。因此，本R21提案的目的是检验以下假设：镇痛的质量和方法影响特定血液生物标志物的水平，并可能与疼痛水平相关。因此，这项研究将提供一个独特的机会，了解镰状细胞危象对疼痛的治疗效果，并为未来的干预措施和临床使用特定的血清生物标志物提供基础。第一个目的是检验这一假设，即镇痛技术的模式影响疼痛危象的结果，由疼痛评分，止痛药的消耗和住院率在SCD疼痛危象。SCD受试者将在常规医院访视期间入组（总目标为75例受试者），并在急性疼痛危象的急诊访视期间接受随访。将使用胃肠外和口服阿片类药物治疗的标准镇痛技术。目的是评估镇痛治疗对急性镰状疼痛危象期间和之后的急性和亚急性疼痛水平的影响，并确定血清炎症/疼痛分子作为SCD疼痛危象中疼痛严重程度的生物标志物，并检验血清生物标志物可用于预测SCD患者入院需求、镇痛药需求增加以及可能的疾病并发症发生率的假设。此外，确定镇痛治疗是否影响血清生物标志物，并可用作镇痛疗效的预测因子。将在定期医院访视期间测定所有入组受试者的血浆IL-12、TNF-1、P物质（SP）、热休克蛋白70（HSP 70）、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。将在急性疼痛危象急诊访视期间和出院前测量这些血浆标志物的水平。将在急性疼痛危象后2 - 4周的计划访视期间进行生物标志物的最终分析。最后，本研究将产生两组基本的初步数据，这两组数据都将允许更深入地评估SCD疼痛综合征和其他治疗方案的机制。 公共卫生相关性：该R21计划公告的目标之一是开发转化研究计划，将基于实验室的科学发现应用于疼痛状况的实际/临床环境。因此，本提案的目的是评价镰状细胞病（SCD）疼痛危象期间的标准镇痛治疗选择，并确定预测疼痛危象期间发生率和治疗结局的血清生物标志物。因此，该提案完全属于PA-06-542的范围，作为一项探索性提案，试图了解镇痛治疗的疗效，以及是否可以将新型血清生物标志物确定为SCD疼痛危象未来研究的有用工具。

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.