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

血管闭合性发作（VOE；痛苦危机）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遭遇的原因。这些患者出现急性疼痛的频率存在显著的异质性。SCD患者还会因并发症（如缺血性坏死和腿部溃疡）而经历慢性疼痛。虽然这种异质性可以用众所周知的基因修饰因子（如血红蛋白F）来解释，但仍有大量患者缺乏对这种变异的明确解释。阿片类药物是SCD患者急性和慢性疼痛管理的重要组成部分。慢性阿片类药物使用，有时与一部分患者的依赖和成瘾有关，可能造成困难的管理问题。再加上普遍缺乏足够的疼痛管理知识和对成瘾的恐惧，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镇痛药的主要作用位点。最近的数据表明，OPRM1基因的多态性以及其他基因（COMT, PTGS1, PTGS2, SLC6A4, SCN9A）与此相关

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.