Pharmacogenetics of Oxycodone, Personalized Care and Persistent Surgical Pain

羟考酮的药物遗传学、个性化护理和持续性手术疼痛

• 批准号: 9543612
• 负责人: Senthilkumar Sadhasivam
• 金额: $ 52.95万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9543612
• 关键词: ABCB1 gene; Absence of pain sensation; Acute; Adult; Adverse effects; Affect; American; Analgesics; Anxiety; Binding; Breastfed infant; CYP2D6 gene; Cessation of life; Child; Childhood; Chronic; Clinical; Codeine; DRD2 gene; Data; Dependence; Diabetes Mellitus; Dose; Drug Kinetics; Economic Burden; Economics; Environmental Risk Factor; Epigenetic Process; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Heart Diseases; Heritability; Home environment; Hospitals; Individual; Infant; Injury; Inpatients; Knowledge; Life; Malignant Neoplasms; Medical; Methylation; Morphine; Nausea and Vomiting; North America; Operative Surgical Procedures; Opiate Addiction; Opioid; Oral; Outcome; Outpatients; Overdose; Oxycodone; Oxymorphone; Pain; Pain management; Panthera leo; Pathway interactions; Patients; Perception; Perioperative; Perioperative Care; Persistent pain; Pharmacogenetics; Phase; Physiological; Postoperative Nausea and Vomiting; Postoperative Pain; Postoperative Period; Predisposing Factor; Psychological Factors; Psychophysiology; Public Health; Reporting; Research; Risk; Risk Factors; Safety; Sensory; Therapeutic Index; Thinking; Time; Tonsillectomy; United States Food and Drug Administration; Variant; Vehicle crash; Ventilatory Depression; addiction; adverse outcome; base; chronic pain; cost; drug of abuse; experience; fatty acid amide hydrolase; genetic risk factor; genetic variant; high risk; improved; insight; inter-individual variation; mu opioid receptors; multidisciplinary; neurophysiology; non-genetic; novel; nursing mothers; personalized care; personalized intervention; point of care; prescription opioid; prevent; psychologic; public health relevance; repaired; response; risk minimization; socioeconomics; surgical pain

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.

项目摘要：在美国，每年有超过600万儿童和超过3500万成年人接受痛苦的手术。 虽然阿片类药物是减少手术疼痛的首选镇痛药，但有几例死亡和严重的不良反应 如阿片类药物引起呼吸抑制，尤其是儿童。此外，高达50%的这些手术 患者因围手术期阿片类药物而出现疼痛缓解不足和/或严重不良反应， 他们狭窄的治疗指数和不可预测的个体间变异之间的遗传不同， 患者花了20多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 从CYP 2D 6基因变异的儿童接受扁桃体切除术和母乳喂养的婴儿。作为替代 与可待因相比，羟考酮更常用于接受扁桃体切除术的儿童; 不是婴儿和哺乳母亲可待因的安全替代品。目前，没有证据表明 表明羟考酮比可待因对接受手术的儿童更安全此外，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 造成不可持续的社会经济负担，丧失生产性生活。这些不良后果目前 由于对疼痛感知和阿片类药物的患者间差异存在严重的知识差距，因此难以避免 应答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 通过术前评估，最大限度地减少长期残疾问题的社会负担，CPSP和OD 风险预测和个性化给药和疼痛管理与正确剂量的正确止痛药， 每个孩子。总的目标是确定遗传、心理、感官和 与羟考酮的药代动力学、手术疼痛缓解和不良反应相关的环境风险因素 结果，CPSP和儿童OD。我们的中心假设是特定的心理和感官因素 沿着参与疼痛和阿片途径的基因多态性， 临床给药、镇痛、即刻围手术期不良反应，包括呼吸抑制（RD）和 儿童术后恶心呕吐（PONV）和长期不良结局（CPSP和OD）。 具体目标是：1）确定影响羟考酮在儿童中安全性和有效性的遗传因素， 2)确定CYP 2D 6变体对羟考酮临床给药的影响，以及3）确定遗传、直接 围手术期和心理因素易使儿童发生长期不良结局：CPSP和OD。 该应用具有重要意义，因为它有望提高临床医生术前识别风险的能力 儿童严重的术后问题和个性化的围手术期护理与定制的护理点 阿片类药物给药，以最大限度地缓解疼痛，同时最大限度地降低慢性持续性疼痛和阿片类药物依赖的风险 用正确剂量的止痛药治疗数百万的外科病人。