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：
9185658
负责人：
Senthilkumar Sadhasivam
金额：
$ 52.64万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185658
关键词：
ABCB1 gene Absence of pain sensation Acute Adult Adverse effects Affect American Analgesics Anxiety Binding Breast Feeding CYP2D6 gene Cessation of life Child Childhood Chronic Clinical Codeine DRD2 gene Data Dependence Diabetes Mellitus Discipline of Nursing Dose Drug Kinetics Economic Burden Economics Environmental Risk Factor Epigenetic Process Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals Heart Diseases Home environment Hospitals Individual Infant Injury Inpatients Knowledge Life Malignant Neoplasms Medical Methylation Morphine Mothers Motor Vehicles Nausea and Vomiting 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 Public Health Reporting Research Risk Risk Factors Safety Sensory Therapeutic Index Thinking Time Tonsillectomy United States Food and Drug Administration Variant Ventilatory Depression addiction adverse outcome base chronic pain 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 personalized care personalized intervention point of care prescription opioid prevent psychologic public health relevance repaired response 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，每年有超过 600 万儿童和超过 3500 万成人接受痛苦的手术。虽然阿片类药物是减少手术疼痛的首选镇痛药，但仍有数人死亡和严重不良反应例如阿片类药物会导致呼吸抑制，尤其是儿童。此外，高达 50% 的手术患者在围术期阿片类药物中经历疼痛缓解不足和/或严重不良反应，因为其狭窄的治疗指数和基因不同的个体之间不可预测的差异患者。花了超过 20 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来自接受扁桃体切除术的儿童和母乳喂养的婴儿的 CYP2D6 遗传变异。作为替代方案与可待因相比，羟考酮更常用于接受扁桃体切除术的儿童；它已经被证明了对于婴儿和哺乳期母亲来说，不能作为可待因的安全替代品。目前，没有证据表明研究表明，对于接受手术的儿童，羟考酮比可待因更安全。此外，还有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）和阿片类药物依赖/成瘾（OD）。所有这些可预防的公共卫生危机都赋予不可持续的社会经济负担以及生产力生活的丧失。目前这些不良后果由于患者之间对疼痛感知和阿片类药物的差异存在严重的知识差距，因此难以避免回应。我们的长期目标是提高围手术期阿片类药物的安全性和有效性周期，并尽量减少长期致残问题、CPSP 和 OD 术前的社会负担风险预测、个性化剂量和疼痛管理，使用正确剂量的正确镇痛药每个孩子。总体目标是确定遗传、心理、感觉和与羟考酮药代动力学、手术疼痛缓解和不良反应相关的环境危险因素儿童的结局、CPSP 和 OD。我们的中心假设是特定的心理和感觉因素与疼痛和阿片类药物途径相关的基因多态性显着影响羟考酮临床剂量、镇痛、围手术期即时不良反应，包括呼吸抑制 (RD) 和儿童术后恶心和呕吐 (PONV) 以及长期不良后果（CPSP 和 OD）。具体目标是 1) 确定影响儿童羟考酮安全性和有效性的遗传因素， 2) 确定 CYP2D6 变异对羟考酮临床剂量的影响，以及 3) 识别遗传性、即时性导致儿童出现长期不良后果的围手术期和心理因素：CPSP 和 OD。该应用意义重大，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，并通过量身定制的护理点进行个性化围手术期护理阿片类药物剂量可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每年为数百万手术患者提供正确剂量的正确镇痛药。