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: 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
• 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

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.

项目总结：在美国，每年有600万儿童和3500万成年人接受痛苦的手术。