Sparking Advancements in Genomic Medicine

摘要 每年遭受急性或慢性疼痛的美国人比心脏病、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，与阿片类药物有关的住院和死亡人数增加，并做出了贡献 对阿片类药物泛滥很重要。氢可酮、曲马多和可待因是最常见的 处方的阿片类药物，细胞色素P450酶，细胞色素P450酶，细胞色素P450酶，是产生高效的 这些阿片类药物的代谢物。CYP2D6具有常见的导致功能丧失的基因多态， 功能降低或功能增强，导致差(PM)、中等(IM)和超快(UM) 代谢表型。数据表明，在PM、IMS和IMS中应避免这三种阿片类药物 UMS分别由于不良反应和毒性的风险增加。利用我们来自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在 美国，我们建议测试这一假设，即CYP2D6基因引导的疼痛管理会带来改善 患者报告的结果(PRO)用于疼痛控制，在现实世界中具有成本效益。我们提出了一个 对2100名急慢性疼痛患者进行的多中心实用临床试验(PCT)，随机2：1至1 基因导引与常规护理方法的对比。我们将招收患有癌症疼痛或至少3岁以下的成年人和儿童 几个月的慢性疼痛控制不佳和接受全关节置换术的患者。考虑到CYP2D6 基因型和相关的CYP2D6抑制剂药物相互作用，被归类为PM、IM或UM的患者将有 建议避免氢可酮、曲马多和可待因。在那些被归类为NM的患者中，使用曲马多 将首选曲马多，因为曲马多比DEA阿片类药物成瘾风险低。我们的初选 将根据疼痛的PRO来测试通过基因引导策略改善疼痛控制的假说 强度使用NIH PROMIS测量。我们将利用多基因药物遗传学小组，还将使 对其他已有药物遗传学指导的药物的建议。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 并降低医疗保健利用率。我们将利用经过验证的PRO工具来评估幸福感。医疗保健 利用率和成本效益分析将基于Medicare和Medicaid的索赔数据， 辅以患者报告的急性/慢性疼痛成本驱动因素数据。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。有了这些终端，我们可以 阐述了以基因为导向的药物治疗方法的潜在好处，该方法侧重于 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，与 对阿片类药物使用和成瘾的担忧。为了进行这个和其他IGNITE-II PCT，我们组装了一个 名为UF-Nemour临床组的杰出团队带来了卓越的临床资源。

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.