Sparking Advancements in Genomic Medicine

激发基因组医学的进步

基本信息

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
项目类别：
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

项目摘要

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.

抽象的每年患有急性或慢性疼痛的美国人比患有心脏病、癌症和癌症的美国人还要多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，同时与阿片类药物相关的住院和死亡人数也增加，对阿片类药物流行至关重要。氢可酮、曲马多和可待因是最常见的药物处方阿片类药物和细胞色素 P450 酶 CYP2D6 是产生高效阿片类药物的核心这些阿片类药物的代谢物。 CYP2D6 具有导致功能丧失的常见遗传多态性，功能降低或功能增强，分别为差 (PM)、中 (IM) 和超快 (UM) 分别表示代谢表型。数据表明，这三种阿片类药物应避免在 PM、IM 和 UM 分别是由于反应不良和毒性风险增加。利用 IGNITE-I 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在美国，我们建议检验以下假设：CYP2D6 基因型引导的疼痛管理可改善疼痛患者报告疼痛控制结果 (PRO)，并且在现实环境中具有成本效益。我们提出一个多中心实用临床试验 (PCT)，纳入 2,100 名急性和慢性疼痛患者，按 2:1 随机分组基因型指导与常规护理方法。我们将招募患有癌症疼痛或至少 3 名的成人和儿童数月的慢性疼痛控制不佳以及接受全关节置换术的患者。考虑CYP2D6 基因型和相关 CYP2D6 抑制剂药物相互作用，分类为 PM、IM 或 UM 的患者将出现建议避免使用氢可酮、曲马多和可待因。在那些被归类为 NM 的患者中，使用曲马多将是首选，因为曲马多的成瘾风险低于 DEA Schedule II 阿片类药物。我们的主要通过基因型引导策略改善疼痛控制的假设将基于疼痛 PRO 进行检验使用 NIH PROMIS 测量的强度。我们将利用多基因药物遗传学小组，并制作对具有既定药物遗传学指导的其他药物的建议。我们的次要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的病情福祉并减少医疗保健利用率。我们将利用经过验证的 PRO 工具来评估健康状况。卫生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，补充了患者报告的有关急性/慢性疼痛成本驱动因素的数据。我们也会测试医生对药物遗传学指导的患者护理方法的益处的看法。有了这些端点，我们可以解决基因型引导药物治疗方法的潜在益处，该方法侧重于许多利益相关者，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。为了进行本次和其他 IGNITE-II PCT，我们组装了一个 UF-Nemours 临床小组是一个优秀的团队，拥有卓越的临床资源。