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: 10368457
• 负责人: Senthilkumar Sadhasivam
• 金额: $ 112.95万
• 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/10368457
• 关键词: ABCB1 gene; Absence of pain sensation; 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; Discipline of Nursing; Dose; Drug Kinetics; Economic Burden; Effectiveness; Electronic Health Record; Enzymes; Genetic; 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; Patient Outcomes Assessments; Patients; Perioperative; Population; Postoperative Nausea and Vomiting; Postoperative Pain; Postoperative Period; Postpartum Depression; Predisposing Factor; Protocols documentation; Public Health; Publishing; Risk; Safety; Science; Spinal Fusion; Surgical Management; Testing; Time; Tramadol; Translating; Translational Research; Variant; Ventilatory Depression; Vulnerable Populations; Woman; adverse outcome; antagonist; base; chronic pain; clinical decision support; clinical practice; cost effectiveness; digital; 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 use; pain relief; personalized care; personalized decision; personalized intervention; practice setting; precision medicine; prescription opioid; prevent; public health relevance; risk prediction; socioeconomics; surgical pain; tool; translational barrier

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不良反应——常见但不太严重的术后副作用 恶心和呕吐导致更严重的呼吸抑制和死亡——虽然是当前现象，但可以预防 控制手术疼痛方面面临的挑战仍然是管理不善，但也必须如此。 避免不可预测和危及生命的阿片类药物副作用以及长期使用/滥用阿片类药物。 应用程序创新地提出将证据转化为积极主动的临床实践，以优化术后治疗 控制手术疼痛并减少阿片类药物相关的不良反应。 FDA 警告说，代谢、阿片类药物的镇痛和不良反应受到遗传变异的影响。 反对儿童使用可待因和曲马多（由于术后缺氧性脑损伤和死亡） 以及哺乳期母亲（由于严重的呼吸问题和婴儿死亡）。 尽管有证据、监管警告、CPIC 指南、成本- 由于转化瓶颈、缺乏基础设施，CYP2D6 测试的有效性和保险范围 在如何个性化阿片类药物的使用和精确剂量以获得最佳结果方面存在结构和知识差距。 因此，对围手术期精准镇痛基础设施的迫切需求尚未得到满足 克服转化障碍并提高阿片类药物对儿童和护士的安全性和有效性 根据遗传风险进行个性化镇痛将减少阿片类药物的使用、不良反应和 加速基于价值的护理机会 然而，这些机会因缺乏跨界服务而受到限制。 我们对如何个性化和精确剂量阿片类药物的理解存在合理的平台和主要差距。 在这个合作 CTSA 项目中，我们建议通过开发创新技术来克服转化障碍 vative围手术期精准镇痛平台（PPAP）可减少阿片类药物的严重不良后果， 并提高阿片类药物在以下人群中的安全性：1) 接受痛苦手术的儿童，以及 2) 哺乳期母亲及其母亲 我们拥有关于 CYP2D6 等遗传风险因素的强有力的证据和实施专业知识。 以及阿片类药物镇痛功效和阿片类药物相关严重不良反应的其他遗传变异，方法 在电子健康记录、基因型中实施具有临床决策支持的基因型的ODS 基于围手术期阿片类药物的使用和创新的数字工具，用于电子患者报告结果 该应用程序具有创新的术前基因分型、集成的个性化功能。 决策支持旨在增强对阿片类药物代谢、个性化阿片类药物选择、预治疗的了解 新生儿、儿童和哺乳母亲的切开给药和临床结果，并传播研究结果 统一的 CTSA 范围内的 PPAP 将实现遗传风险预测和个性化信息。 采取干预措施，最大限度地缓解数百万儿童的疼痛，同时最大限度地减少阿片类药物的使用和不良反应 以及每年接受手术的哺乳母亲。