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

基本信息

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
项目类别：
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

项目摘要

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，> 600万儿童和> 3500万成年人每年接受痛苦的手术。阿片类药物是减轻手术疼痛的首选镇痛药，但几种死亡和严重的不良反应尤其是在儿童中，阿片类药物发生的呼吸抑郁症。此外，其中多达50％的手术患者的疼痛缓解不足和/或围手术期阿片类药物的严重不良影响，因为它们狭窄的治疗指标和基因不同的不同个体间变化患者。认识到与可待因相关的威胁生命的并发症和死亡，花了20年的时间来自接受扁桃体切除术和母乳喂养儿童的CYP2D6遗传变异。作为替代方案对于可待因，羟考酮在接受扁桃体切除术的儿童中更频繁地使用。它已经显示不是为婴儿和护理母亲的可待因提供安全的选择。目前，没有证据证明羟考酮在接受手术的儿童中比可待因更安全。另外，两个可能可预防的长期并发症与大型手术和阿片类药物有关：慢性持续外科手术疼痛（CPSP）和阿片类药物依赖/成瘾（OD）。所有这些可预防的公共卫生危机会议不可持续的社会经济负担，失去生产力。这些不良结果目前是由于对疼痛感知和阿片类药物的患者间变化的关键知识差距很难避免回答。我们的长期目标是提高阿片类药物的安全性和疗效术前药物，并模仿术前的长期问题，CPSP和OD的社会负担风险预测和个性化的给药和疼痛管理，正确的止痛药的正确剂量每个孩子。总体目标是确定遗传，心理，感觉和与羟考酮的药代动力学，外科疼痛缓解和不良反应有关的环境风险因素儿童的结果，CPSP和OD。我们的中心假设是特定的心理和感觉因素以及参与疼痛和阿片类药物途径的基因的多态性，显着影响羟考酮临床剂量，镇痛，立即围手术期不良反应，包括呼吸抑郁（RD）和儿童的术后恶心和呕吐（PONV）以及长期不良后果（CPSP和OD）。具体目的是1）确定遗传因素损害儿童中羟考酮的安全性和功效， 2）确定CYP2D6变体对羟考酮的临床剂量的影响，3）确定遗传，即时围手术期和心理因素使儿童长期不良后果：CPSP和OD。该应用很重要，因为预计它将提高临床医生在术前识别风险的能力儿童严重的手术后问题，并通过量身定制的护理个性化围手术期护理阿片类药物给药以最大化疼痛缓解，同时最大程度地减少慢性持续性疼痛和阿片类药物依赖的风险每年有数百万名手术患者的正确剂量正确的镇痛药。