Mu Opioid Polymorphisms as Genetic Modifiers of Pain and Opioid Use in

血管闭塞性发作(VOE；痛苦的危象)是镰状细胞病(SCD)的一个众所周知的标志，是绝大多数医疗保健接触的原因。在这些患者中，VOE(急性疼痛)的频率存在显著的异质性。SCD患者还会因并发症而经历慢性疼痛，如缺血性坏死和腿部溃疡。虽然一些这种异质性可以用众所周知的遗传修饰物来解释，比如血红蛋白F，但有大量的患者对这种变异缺乏明确的解释。阿片类药物是治疗SCD患者急性和慢性疼痛的重要组成部分。慢性阿片类药物的使用，有时与一部分患者的依赖和成瘾有关，可能会带来困难的管理问题。这一点，再加上普遍缺乏对疼痛管理的充分知识，以及对上瘾的恐惧，往往导致对疼痛状况的治疗不足。Mu阿片受体(OPRM1)是内源性阿片肽和阿片类镇痛剂的主要作用部位。最近的数据表明，OPRM1基因以及其他基因(COMT、PTGS1、Ptgs2、SLC6A4、SCN9A)的多态与 痛阈值和麻醉剂需求量的差异。这项研究将检验这一假设，即这些基因的变异作为遗传修饰物影响疼痛频率、强度、阈值、阿片类药物的使用和剂量需求，以及阿片类药物依赖。这将通过1)VOE频率、疼痛日记和总阿片类药物使用的前瞻性分析，2)由VOE住院频率、住院VOE期间的麻醉药物使用、疼痛评分的演变和住院时间以及这些数据与上述基因遗传变异的相关性组成的前瞻性数据收集，以及3)使用压力痛痛计测试痛阈值的实验部分。预计将确定疼痛频率和阿片类药物剂量需求的遗传相关性，并将导致SCD患者疼痛管理的个体化。

Vasoocclusive episodes (VOE; painful crises) are a well-known hallmark of sickle cell disease (SCD) and are responsible for the vast majority of health care encounters. There is significant heterogeneity in the frequency of VOE (acute pain) among these patients. SCD patients also experience chronic pain due to complications such as avascular necrosis and leg ulcers. While some of this heterogeneity can be explained by well known genetic modifiers, such as the hemoglobin F, there is a large number of patients in whom there is a lack of a clear-cut explanation for this variation. Opioids form an important component of the management of acute and chronic pain in patients with SCD. Chronic opioid use, sometimes associated with dependence and addiction in a subset of patients, may pose difficult management problems. This coupled with a general lack of adequate knowledge of the management of pain and the fear of addiction often results in under-treatment of painful conditions. The Mu opioid receptor (OPRM1) is the primary site of action of endogenous opioid peptides and opioid analgesics. Recent data indicate that polymorphisms in the OPRM1 gene as well as other genes (COMT, PTGS1, PTGS2, SLC6A4, SCN9A) are associated with differences in pain threshold and narcotic requirements. This study will test the hypothesis that variations in these genes act as genetic modifiers influencing pain frequency, intensity, threshold, opioid usage and dose requirement, as well as opioid dependency. This will be achieved by 1) a prospective analysis of frequency of VOE, pain diaries, and total opioid usage, 2) a prospective data collection consisting of frequency of hospitalizations with VOE, narcotic usage during a hospitalized VOE, evolution of pain scores, and length of hospital stay and correlation of these data with genetic variation in the aforementioned genes, and 3) an experimental component of testing pain threshold with a pressure pain algometer. It is anticipated that genetic correlates of pain frequency and opioid dose requirements will be determined and will lead to individualization of the management of pain in patients with SCD.