Perioperative Precision Medicine: Translating Science to Clinical Practice to Improve Safety and Efficacy of Opioids in Neonates, Children and Nursing Mothers

项目摘要：围手术期阿片类药物不良反应--术后常见但不太严重的不良反应 恶心和呕吐导致更严重的呼吸抑制和死亡-目前是可以预防的 管理手术疼痛的挑战。严重的手术疼痛仍然没有得到很好的处理，但临床医生也必须 避免不可预测和危及生命的阿片类药物不良影响以及长期使用/误用阿片类药物。这 应用程序创新地提出将证据转化为主动的临床实践，以优化后 控制手术疼痛，减少阿片类药物相关不良反应。目前的证据表明阿片类药物让我- 代谢、阿片类药物的止痛和不良反应受遗传变异的影响。FDA警告说 反对儿童使用可待因和曲马多(因术后缺氧性脑损伤和死亡) 以及哺乳母亲(由于严重的呼吸问题和婴儿死亡)。术前基因分型 尽管有证据、监管警告、CPIC指南、成本- 由于翻译瓶颈、缺乏基础设施而导致的CYP2D6测试的有效性和保险覆盖范围 在如何使阿片类药物的使用个性化和精确给药以获得最佳结果方面存在结构和知识差距。 因此，存在着对围手术期精确止痛基础设施的迫切而未得到满足的需求 克服翻译障碍，提高阿片类药物在儿童和护士中的安全性和有效性- 我的母亲们。基于遗传风险的个性化止痛将减少阿片类药物的使用、不良反应和 加速提供基于价值的护理机会。然而，这些机会受到缺乏跨境贸易的限制。 国家平台和我们对如何个人化和精确剂量阿片类药物的理解存在重大差距。在……里面 这个协作的CTSA项目，我们建议通过开发INNO- 围手术期精准止痛平台(PPAP)减少阿片类药物严重不良反应 并提高阿片类药物的安全性：1)接受痛苦手术的儿童，2)哺乳的母亲和她们的 婴儿。我们在包括CYP2D6在内的遗传风险因素方面拥有强有力的证据和实施专业知识 阿片类药物的止痛效果和与阿片类药物相关的严重不良反应的其他遗传变异。 在电子健康档案中实施具有临床决策支持的基因分型的消耗臭氧层物质，基因分型 基于围手术期阿片类药物的使用和电子患者报告结果的创新数字工具 参与CTSA的枢纽。这项应用具有创新性的术前基因分型，集成了个性化 决策支持旨在加强对阿片新陈代谢、个性化阿片类药物选择、预 新生儿、儿童和哺乳母亲的精确剂量和临床结果，并传播研究结果 到其他CTSA枢纽。统一的CTSA范围的PPAP将支持遗传风险预测和个性化- 最大限度地减轻疼痛，同时将阿片类药物的使用和不良反应降至最低的特效治疗数百万儿童 以及每年接受手术的哺乳母亲。

Project Summary: Perioperative opioid adverse effects--from common but less-serious post-operative nausea and vomiting to the more serious respiratory depression and death—are current but preventable challenges in managing surgical pain. Severe surgical pain is still poorly managed, yet clinicians must also avoid unpredictable and life-threatening opioid adverse effects as well as long-term opioid use/misuse. This application innovatively proposes to translate evidence into a proactive clinical practice to optimize post- surgical pain control and decrease opioid-related adverse effects. Current evidence shows that opioid me- tabolism, opioids’ analgesic and adverse effects are influenced by genetic variations. The FDA warns against the use of codeine and tramadol in children (due to postoperative anoxic brain injuries and deaths) and in nursing mothers (due to serious breathing problems and infantile death). Preoperative genotyping and personalized analgesia are not practiced despite evidence, regulatory warnings, CPIC guidelines, cost- effectiveness and insurance coverage for CYP2D6 testing due to translational bottlenecks, lack of infra- structure and knowledge gaps in how to personalize opioid use and dose precisely for optimal outcomes. Thus, there is an urgent and unmet critical need for a perioperative precision analgesia infrastructure to overcome the translational barriers and to improve safety and effectiveness of opioids in children and nurs- ing mothers. Personalizing analgesia based on genetic risks will reduce opioid use, adverse-effects, and accelerate value-based care opportunities. However, these opportunities are constrained by lack of trans- lational platforms and major gaps in our understanding of how to personalize and precisely dose opioids. In this collaborative CTSA project, we propose to overcome the translational barriers by developing an inno- vative perioperative precision analgesia platform (PPAP) to reduce serious adverse outcomes of opioids, and improve safety of opioids in: 1) children undergoing painful surgery, and 2) nursing mothers and their infants. We have robust evidence and implementation expertise on genetic risk factors including CYP2D6 and other genetic variations for opioids’ analgesic efficacy and opioid-related serious adverse effects, meth- ods of implementation of genotypes with clinical decision support in electronic health records, genotype- based perioperative opioid use and innovative digital tools for electronic patient reported outcomes at all participating CTSA hubs. This application with innovative preoperative genotyping, integrated personalized decision support aims to enhance understanding of opioid metabolism, personalized opioid selection, pre- cision dosing, and clinical outcomes in neonates, children, and nursing mothers, and to disseminate findings to other CTSA hubs. A unified CTSA-wide PPAP will enable genetic risk predictions and personalized in- terventions to maximize pain relief while minimizing opioid use and adverse effects in millions of children and nursing mothers undergoing surgery each year.