Response to Morphine in Children with SC Disease

描述(申请人提供)：镰状细胞病(SCD)是一种遗传性疾病，以慢性溶血性贫血为特征，有急性和慢性并发症。由于血管闭塞导致的组织缺血引起的疼痛发作是SCD儿童入院的最常见原因。痛苦的血管闭塞发作(VOE)占急诊科和医院入院人数的很大一部分。通过病人自控镇痛的吗啡在医院中被广泛用于治疗SCD的剧烈疼痛。然而，在每个疼痛发作中，实现疼痛缓解所需的阿片类药物剂量有很大差异，从一个发作到另一个发作，以及不同患者之间，一些患者没有得到足够的缓解。我们的假设是，患有镰状细胞病的儿童无法达到治疗水平的吗啡血浆浓度。我们建议研究对吗啡缺乏反应是否与治疗下的吗啡浓度或其他因素有关。吗啡的药代动力学参数将与急性疼痛状态下的已知人群值进行比较。其中一份血液样本将用于对可能影响对吗啡反应的基因(UGT2B7、MOR1、COMT)进行基因分型。对吗啡的反应将使用疼痛强度和疼痛缓解评分、疼痛部位和疼痛质量以及副作用，如镇静/嗜睡、恶心、瘙痒、换气不足(血氧饱和度、呼吸频率)或低血压(血压)进行评估。来自这一职业发展奖K23的数据将被用于设计最佳的疼痛管理策略和临床方案，旨在将患有镰状细胞疾病的儿童在急性血管闭塞发作期间未得到治疗或管理不当的疼痛造成的短期和长期后果降至最低。疼痛管理方面的这些进步将引导雅各布博士实现她作为一名独立临床研究员的长期职业目标。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is an inherited disease characterized by chronic hemolytic anemia with acute and chronic complications. The painful episode that results from tissue ischemia due to vaso-occlusion is the most common reason for admission in children with SCD. Painful vaso-occlusive episodes (VOE) account for a significant number of emergency department and hospital admissions. Morphine via patient controlled analgesia is widely used in hospital settings to manage severe pain in SCD. However, the opioid dose required to achieve pain relief varies considerably within each painful episode, from one episode to another, and between individual patients, and some patients do not receive adequate relief. Our hypothesis is that children with sickle cell disease do not achieve plasma concentrations of morphine at therapeutic levels. We propose to examine whether the lack of response to morphine is related to subtherapeutic morphine concentrations or other factors. Pharmacokinetic parameters of morphine will be compared with known population values during acute painful states. One of the blood samples will be used for genotyping genes (UGT2B7, MOR1, COMT) that may affect response to morphine. Response to morphine will be assessed using pain intensity and pain relief scores, pain location and pain quality, and side effects such as sedation/drowsiness, nausea, itching, hypoventilation (oxygen saturation, respiratory rate), or hypotension (blood pressure). Data from this career development award K23 will be used to design optimal pain management strategies and clinical protocols that aim to minimize the short and long term consequences resulting from untreated or inadequately managed pain during acute vaso-occlusive episodes in children with sickle cell disease. These advancements in pain management will lead Dr. Jacob to her long term career goal as an independent clinical researcher.