Pharmacogenetics of Oxycodone, Personalized Care and Persistent Surgical Pain

项目简介：在美国，每年有600万儿童和3500万成人接受痛苦的手术。 虽然阿片类药物是减少手术疼痛的首选镇痛剂，但有几人死亡和严重的不良反应 例如，阿片类药物会出现呼吸抑制，特别是在儿童中。此外，这些外科手术中高达50% 患者围手术期阿片类药物的疼痛缓解不足和/或严重不良反应，原因是 他们狭窄的治疗指数和不可预测的遗传不同个体之间的差异 病人。它花了20年的时间才认识到与可待因相关的危及生命的并发症和死亡 接受扁桃体切除手术的儿童和母乳喂养的婴儿中的CYP2D6基因变异。作为替代方案 与可待因相比，羟考酮更常用于扁桃体摘除手术的儿童，这已经被证明。 对于婴儿和哺乳母亲来说，它不是可待因的安全替代品。目前，没有证据表明 证明羟考酮在接受手术的儿童中比可待因更安全。此外，两个潜在的 可预防的长期并发症与大手术和阿片类药物有关：慢性持续性手术 疼痛(CPSP)和阿片依赖/成瘾(OD)。所有这些可预防的公共卫生危机都赋予了 不可持续的社会经济负担和生产生活损失。这些不利的后果目前 由于患者之间在疼痛感知和阿片类药物方面的差异存在严重的知识差距，因此难以避免 回应。我们的长期目标是提高阿片类药物在围手术期的安全性和有效性。 周期性，并通过术前最大限度地减少使长期问题失能的社会负担，CPSP和OD 使用正确剂量的正确止痛剂进行风险预测、个性化剂量和疼痛管理 每个孩子。总体目标是确定遗传、心理、感觉和 羟考酮的药代动力学、手术止痛和不良反应相关的环境危险因素 儿童的预后、CPSP和OD。我们的中心假设是特定的心理和感官因素 与疼痛和阿片通路相关的基因多态性显著影响羟考酮 临床剂量、止痛、围手术期即时不良反应，包括呼吸抑制(RD)和 儿童术后恶心和呕吐(PONV)和长期不良后果(CPSP和OD)。 具体目标是1)确定影响羟考酮在儿童中的安全性和有效性的遗传因素， 2)确定CYP2D6变异对羟考酮临床剂量的影响，以及3)确定遗传、即刻 导致儿童长期不良后果的围术期和心理因素：CPSP和OD。 这一应用具有重要意义，因为它有望提高临床医生在手术前识别风险的能力 了解儿童手术后的严重问题，并通过量身定制的护理点实现围手术期护理的个性化 阿片类药物剂量，最大限度地缓解疼痛，同时最大限度地减少慢性持续性疼痛和阿片类药物依赖的风险 每年给数百万外科病人服用合适剂量的镇痛剂。

Project Summary: In the US, >6 million children and >35 million adults undergo painful surgery each year. While opioids are the preferred analgesics to reduce surgical pain, several deaths and serious adverse effects such as respiratory depression occur with opioids especially in children. Further, up to 50% of these surgical patients experience inadequate pain relief and/or serious adverse effects from perioperative opioids because of their narrow therapeutic indices and unpredictable inter-individual variations among genetically dissimilar patients. It took >20 years to recognize the life-threatening complications and deaths associated with codeine from CYP2D6 genetic variations in children undergoing tonsillectomy and breastfed infants. As an alternative to codeine, oxycodone is used more frequently in children undergoing tonsillectomy; and it had been shown NOT to be a safe alternative to codeine for infants and nursing mothers. Currently, there is no evidence to show that oxycodone is safer than codeine in children undergoing surgery. In addition, two potentially preventable long-term complications are associated with major surgery and opioids: chronic persistent surgical pain (CPSP) and opioid dependence/addiction (OD). All these preventable public health crises confer unsustainable socioeconomic burden with loss of productive life. These adverse outcomes are currently difficult to avoid due to a critical knowledge gap on inter-patient variations in pain perception and opioid responses. Our long-term goals are to improve safety and efficacy of opioids in the immediate perioperative perioid, and to mimimize the societal burden of disabling long-term problems, CPSP and OD by preoperative risk predictions and personalized dosing and pain management with the right dose of the right analgesic for each child. The overall objective is to determine the impact of genetic, psychological, sensory and environmental risk factors associated with oxycodone's pharmacokinetics, surgical pain relief and adverse outcomes, CPSP and OD in children. Our central hypothesis is that specific psychological and sensory factors along with polymorphisms of genes involved in pain and opioid pathways significantly impact oxycodone's clinical dosing, analgesia, immediate perioperative adverse effects including Respiratory Depression (RD) and Post-Operative Nausea and Vomiting (PONV), and long-term adverse outcomes (CPSP and OD) in children. The specific aims are 1) Determine genetic factors compromising safety and efficacy of oxycodone in children, 2) Determine the impact of CYP2D6 variants on oxycodone's clinical dosing, and 3) Identify genetic, immediate perioperative and psychological factors predisposing children to long-term adverse outcomes: CPSP and OD. This application is significant because it is expected to improve clinician's ability to preoperatively identify risks of serious post-surgical problems in children and personalize perioperative care with tailored point-of-care opioid dosing to maximize pain relief while minimizing risks of chronic persistent pain and opioid dependence with the right doses of the right analgesics in millions of surgical patients every year.