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

围手术期精准医学：将科学转化为临床实践，提高阿片类药物对新生儿、儿童和哺乳期母亲的安全性和有效性

• 批准号: 10676237
• 负责人: Senthilkumar Sadhasivam
• 金额: $ 108.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-03 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676237
• 关键词: ABCB1 gene; Absence of pain sensation; Acceleration; Acute; Address; Adult; Adverse effects; Analgesics; Anoxic Encephalopathy; Brain Death; Breastfed infant; Breathing; CYP2B6 gene; CYP2D6 gene; Caring; Case Study; Cesarean section; Cessation of life; Child; Chronic; Clinical; Codeine; Dependence; Deterioration; Discipline of Nursing; Dose; Drug Kinetics; Economic Burden; Effectiveness; Electronic Health Record; Enzymes; Genetic Risk; Genetic Variation; Genomics; Genotype; Guidelines; Heritability; Hydrocodone; Individual; Infant; Infrastructure; Insurance Coverage; Knowledge; Length of Stay; Life; Link; Liver; Metabolism; Methadone; Methods; Mothers; N-Methylaspartate; Newborn Infant; Nursing infant; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Analgesics; Other Genetics; Outcome; Outpatients; Oxycodone; Oxymorphone; Pain; Pain management; Patients; Perioperative; Population; Postoperative Nausea and Vomiting; Postoperative Pain; Postoperative Period; Postpartum Depression; Productivity; Protocols documentation; Public Health; Publishing; Risk; Safety; Science; Spinal Fusion; Surgical Management; Testing; Tramadol; Translating; Translational Research; Variant; Ventilatory Depression; Vulnerable Populations; Woman; adverse outcome; antagonist; chronic pain; clinical decision support; clinical practice; cost effectiveness; digital; digital tool; electronic patient reported outcomes; evidence base; follow-up; genetic risk factor; genetic variant; high risk; improved; infant death; innovation; inpatient surgery; multidisciplinary; neonate; nursing mothers; opioid epidemic; opioid mortality; opioid overdose; opioid use; pain relief; personalized care; personalized decision; personalized intervention; practice setting; precision medicine; prescription opioid; prevent; public health relevance; risk prediction; socioeconomics; surgical pain; translational barrier; translational potential

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.

项目摘要：围手术期阿片类药物的不良反应 - 术后常见但官方不那么严重 恶心和呕吐到更严重的呼吸道抑郁和死亡 - 是最新的，但可以预防 管理手术疼痛方面的挑战。严重的手术疼痛仍然管理不善，但临床医生也必须 避免不可预测和威胁生命的阿片类药物不良反应以及长期使用/滥用。这 对应用程序进行了创新的建议，以将证据转化为主动的临床实践，以优化后 手术疼痛控制并减少阿片类药物相关的不良反应。当前的证据表明阿片类药物 - Tabolism，阿片类药物的镇痛作用和不良影响受遗传变异的影响。 FDA警告 反对儿童使用可待因和曲马多（由于术后缺氧和死亡） 以及护士母亲（由于严重的呼吸问题和婴儿死亡）。术前基因分型 个性化的镇痛不是实践概念证据，监管警告，CPIC指南，成本 - 由于翻译瓶颈而导致的CYP2D6测试的有效性和保险范围 在如何个性化阿片类药物使用和剂量方面的结构和知识差距是为了获得最佳结果。 这是紧急且未满足的至关重要的需求，需要定期精确镇痛基础设施 克服翻译障碍并提高阿片类药物对儿童和护士的安全性和有效性 - 母亲。基于遗传风险的个性化镇痛将减少阿片类药物的使用，不良影响和 加速基于价值的护理机会。但是，由于缺乏跨性能，这些机会受到限制 理性平台和我们对如何个性化和精确剂量阿片类药物的理解的主要差距。 这个协作的CTSA项目，我们建议通过开发一个创新的转化障碍来克服转化障碍 围手术期精度镇痛平台（PPAP），以减少阿片类药物的严重不良结果， 并提高阿片类药物的安全：1）接受疼痛手术的儿童，以及2）护士母亲及其 婴儿。我们对包括CYP2D6在内的遗传风险因素有强大的证据和实施专业知识 以及阿片类药物镇痛有效性和阿片类药物相关的严重不良反应的其他遗传变异 在电子健康记录中具有临床决策支持的基因型实施的ODS，基因型 - 基于电子患者的基于的周期性阿片类药物使用和创新的数字工具报告了结果 参与CTSA轮毂。该应用具有创新的术前基因分型，集成个性化的 决策支持旨在增强对阿片类药物代谢，个性化阿片类药物的选择，预先的理解 切除剂量和新生儿，儿童和护士母亲的临床结果，并传播发现 到其他CTSA轮毂。统一的CTSA范围PPAP将实现遗传风险预测，并个性化 减少阿片类药物的使用和数百万儿童的不良影响，以最大程度地缓解疼痛 以及护士母亲每年接受手术。