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.

项目总结：围手术期阿片类药物不良反应-来自常见但不太严重的术后 恶心和呕吐到更严重的呼吸抑制和死亡-是目前但可以预防的 管理手术疼痛的挑战。严重的手术疼痛仍然管理不善，但临床医生也必须 避免不可预测和危及生命的阿片类药物不良反应以及长期使用/滥用阿片类药物。这 应用创新性地提出将证据转化为积极的临床实践，以优化后， 控制手术疼痛和减少阿片类药物相关副作用。目前的证据表明阿片类药物- 阿片类药物的禁忌、镇痛和副作用受遗传变异的影响。FDA警告 禁止儿童使用可待因和曲马多（由于术后缺氧性脑损伤和死亡） 以及哺乳期的母亲（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- CYP 2D 6检测的有效性和保险范围，由于翻译瓶颈，缺乏基础设施， 在如何使阿片类药物的使用和剂量精确个性化以获得最佳结果方面存在结构和知识差距。 因此，存在对围手术期精确镇痛基础设施的迫切且未满足的关键需求，以 克服转化障碍，提高阿片类药物在儿童和护士中的安全性和有效性- 的母亲。基于遗传风险的个性化镇痛将减少阿片类药物的使用，副作用， 加速基于价值的护理机会。然而，这些机会受到缺乏跨- 国际平台和我们对如何个性化和精确剂量阿片类药物的理解存在重大差距。在 这个合作CTSA项目，我们建议通过开发一个创新的， 有效的围手术期精确镇痛平台（PPAP），以减少阿片类药物的严重不良后果， 并提高阿片类药物的安全性：1）接受痛苦手术的儿童，2）哺乳期母亲及其 婴儿。我们在包括CYP 2D 6在内的遗传风险因素方面拥有强大的证据和实施专业知识 以及阿片类药物镇痛效果和阿片类药物相关严重不良反应的其他遗传变异， 在电子健康记录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化工具，用于电子患者报告结局 参与CTSA中心。这种应用与创新的术前基因分型，整合个性化 决策支持旨在加强对阿片类药物代谢、个性化阿片类药物选择、 在新生儿、儿童和哺乳期母亲中的临床结果，并传播研究结果 其他CTSA中心一个统一的CTSA范围内的PPAP将使遗传风险预测和个性化的， 在最大限度地缓解疼痛的同时，最大限度地减少阿片类药物的使用和对数百万儿童的不良影响 和哺乳期的母亲接受手术。