Sparking Advancements in Genomic Medicine

激发基因组医学的进步

• 批准号: 10194573
• 负责人: Larisa Humma Cavallari
• 金额: $ 92.56万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-16 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194573
• 关键词: Acute; Acute Pain; Address; Adult; Affect; American; Analgesics; CYP2D6 gene; Cessation of life; Child Health; Childhood; Clinical; Codeine; Cost Effectiveness Analysis; Cytochrome P450; Data; Data Collection; Data Reporting; Delaware; Drug Interactions; Drug usage; Enrollment; Enzymes; Florida; Funding; Generations; Genetic Diseases; Genetic Polymorphism; Genomic medicine; Genotype; Health; Health Care Costs; Health system; Heart Diseases; Hospitalization; Hydrocodone; Lead; Leadership; Legal; Lung diseases; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Medicare/Medicaid; Metabolism; Minority; Operative Surgical Procedures; Opiate Addiction; Opioid; Oxycodone; Pain; Pain intensity; Pain management; Patient Care; Patient Outcomes Assessments; Patients; Perception; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Physicians; Population; Population Heterogeneity; Pragmatic clinical trial; Primary Health Care; Proteins; Randomized; Recommendation; Replacement Arthroplasty; Resources; Risk; Role; Schedule II opioids; Societies; Surveys; Testing; Toxic effect; Tramadol; United States National Institutes of Health; Ursidae Family; addiction; base; cancer pain; chronic pain; clinical practice; community setting; cost; cost effective; cost effectiveness; experience; genetic information; health care service utilization; improved; inhibitor/antagonist; loss of function; medically underserved; neonate; non-opioid analgesic; opioid epidemic; opioid misuse; opioid use; prescription opioid; public health emergency; response; stem; tool; treatment as usual

Abstract More Americans suffer from acute or chronic pain each year than are affected by heart disease, cancer and lung disease, and opioids represent the cornerstone of pain management. Prescriptions for opioids have tripled since 1999, paralleled by increases in opioid-related hospitalizations and deaths, and contributing importantly to the opioid epidemic. Hydrocodone, tramadol, and codeine are among the most commonly prescribed opioids, and the cytochrome P450 enzyme, CYP2D6, is central to generation of highly potent metabolites for these opioids. CYP2D6 has common genetic polymorphisms that lead to loss of function, reduced function, or increased function, conferring poor (PM), intermediate (IM), and ultrarapid (UM) metabolism phenotypes, respectively. Data suggest these three opioids should be avoided in PMs, IMs and UMs due to increased risk for poor response and toxicity, respectively. Leveraging our data from IGNITE-I, extensive stakeholder engagement, and to address the significant burden of both pain and opioid use in the U.S., we propose to test the hypothesis that CYP2D6 genotype-guided pain management leads to improved patient reported outcomes (PRO) for pain control and is cost-effective in a real-world setting. We propose a multicenter pragmatic clinical trial (PCT) of 2,100 patients with acute and chronic pain, randomized 2:1 to a genotype-guided versus usual care approach. We will enroll adults and children with cancer pain or at least 3 months of poorly controlled chronic pain and those undergoing total joint arthroplasty. Considering CYP2D6 genotype and relevant CYP2D6 inhibitor drug interactions, patients categorized as PM, IM, or UM will have a recommendation to avoid hydrocodone, tramadol and codeine. In those categorized as NM, use of tramadol will be preferred, as tramadol has lower risk of addiction than DEA Schedule II opioids. Our primary hypothesis of improved pain control with a genotype-guided strategy will be tested based on PRO of pain intensity using NIH PROMIS measures. We will utilize a multi-gene pharmacogenetic panel and also make recommendations on other drugs with established pharmacogenetic guidance. Our secondary hypothesis is that use of a pharmacogenetic panel to guide opioids and other commonly used drugs will improve patient wellbeing and reduce healthcare utilization. We will utilize validated PRO tools to assess wellbeing. Healthcare utilization and cost effectiveness analyses will be based on claims data from Medicare and Medicaid, supplemented with patient reported data on cost drivers for acute/chronic pain. We will also test physician perception of the benefit of a pharmacogenetic-guided approach to patient care. With these endpoints we can address the potential benefits of a genotype-guided approach to drug therapy that focuses on numerous stakeholders, including patients, the physicians who treat them, health systems/payers and society, relative to concerns about opioid use and addiction. To conduct this and other IGNITE-II PCTs we have assembled an outstanding team called the UF-Nemours Clinical Group, which brings to bear exceptional clinical resources.

摘要 每年，更多的美国人遭受急性或慢性疼痛，而不是心脏病，癌症和 肺部疾病和阿片类药物是疼痛管理的基石。阿片类药物的处方有 自1999年以来增加了两倍，其次是与阿片类药物有关的住院和死亡增加， 对阿片类药物的流行很重要氢可酮、曲马多和可待因是最常见的 处方阿片类药物，细胞色素P450酶，CYP 2D 6，是产生高效的 这些阿片类药物的代谢产物。CYP 2D 6具有导致功能丧失的常见遗传多态性， 功能降低或功能增加，导致不良（PM）、中度（IM）和超速（UM） 代谢表型。数据表明，这三种阿片类药物应避免在PM，IM和 分别由于不良反应和毒性风险增加导致的UM。利用IGNITE-1的数据， 广泛的利益相关者参与，并解决疼痛和阿片类药物使用的重大负担， 美国，我们建议测试CYP 2D 6基因型指导的疼痛管理导致改善疼痛的假设。 患者报告的疼痛控制结局（PRO），在现实世界中具有成本效益。我们提出了一个 多中心实用临床试验（PCT）的2,100例急性和慢性疼痛患者，随机2：1， 基因型指导与常规护理方法。我们将招募患有癌症疼痛的成人和儿童或至少3 慢性疼痛控制不佳的患者和接受全关节置换术的患者。考虑CYP 2D 6 基因型和相关的CYP 2D 6抑制剂药物相互作用，归类为PM、IM或UM的患者将有 建议避免使用氢可酮、曲马多和可待因。在归类为NM的患者中，使用曲马多 因为曲马多比DEA附表II阿片类药物成瘾的风险更低。我们的首要 将基于疼痛的PRO检验基因型指导策略改善疼痛控制的假设 使用NIH PROMIS测量强度。我们将利用多基因药物遗传学小组， 建议使用其他药物，并提供已建立的药物遗传学指导。我们的第二个假设是 使用药物遗传学小组来指导阿片类药物和其他常用药物将改善患者 健康和减少医疗保健的使用。我们将利用经过验证的PRO工具来评估健康状况。医疗保健 利用率和成本效益分析将基于医疗保险和医疗补助的索赔数据， 补充患者报告的关于急性/慢性疼痛的成本驱动因素的数据。我们还将测试医生 对药物遗传学指导的患者护理方法的益处的认识。有了这些端点， 探讨基因型指导的药物治疗方法的潜在益处， 利益攸关方，包括患者、治疗他们的医生、卫生系统/付款人和社会， 对阿片类药物使用和成瘾的担忧。为了进行这一点和其他IGNITE-II PCT，我们组装了一个 UF-Nemours Clinical Group是一个杰出的团队，它带来了卓越的临床资源。