Cardiovascular Risk of Non-Opioid Pain Medications

项目总结 与普通民众相比，美国退伍军人经历的痛苦不成比例，特别是 剧烈的疼痛。事实上，疼痛管理是退伍军人寻求医疗帮助的最常见原因之一。 美国退伍军人事务部(VA)和退伍军人健康管理局(VHA)继续 将重点放在慢性疼痛管理上，这导致执行了新的准则和 优先考虑非阿片类药物治疗的系统。 目前用于治疗慢性疼痛的阿片类药物的替代药物包括：(1)外用和口服 利多卡因、对乙酰氨基酚和非类固醇消炎药(NSAIDs)等止痛药； 抗抑郁药；(3)抗惊厥药；和(4)肌肉松弛药。我们和其他人定义了心血管疾病 非甾体抗炎药和阿片类镇痛剂的毒性，但用于治疗慢性阻塞性肺疾病的其他药物类别的潜在毒性 疼痛的定义仍然很模糊。这对三类药物尤其重要：(1)选择性去甲肾上腺素 再摄取抑制剂(SNRIs)抗抑郁药，(2)抗癫痫药，和(3)肌松剂。在每一类药物中， 度洛西汀(SNRI)、普瑞巴林(抗癫痫药)和环苯扎林(肌肉松弛药)是最多的 经常开药方。这三种药物的使用产生了多个病例报告，并提出了具体的 对严重心血管事件风险增加的担忧。 目前，每年有数十万退伍军人为这些药物配药，而这些药物的使用 非阿片类止痛药正在增加。退伍军人是心血管疾病风险较高的弱势群体 和较高的慢性疼痛发生率；因此，他们出现药物不良反应的风险更高。压倒性多数 患有慢性疼痛的退伍军人中，有20%没有癌症或危及生命的疾病，这使得药物的前景 长期使用的毒性是一个特别重要的考虑因素。 临床试验在证明治疗的有效性方面起着至关重要的作用；然而，许多药物都是不可预见的 以及严重的副作用。因为临床试验必然在可推广性方面受到限制，且可以 不切实际的是，药物流行病学研究在我们了解长期副作用方面发挥着关键作用。 毒品的问题。拟议的药物流行病学研究试图提供关于 用于治疗慢性疼痛的三种广泛处方的非阿片类药物与心血管风险相关 经常给退伍军人医疗系统的退伍军人开处方。我们将使用最先进的技术和一个 退伍军人的大型数据库，以集合慢性非癌症疼痛患者的队列。目标1将定义 服用环苯扎平的患者有严重心血管后果的风险。目标2将定义严重的 与使用度洛西汀相关的心血管事件。目标3将定义相关的心力衰竭风险 在服用普瑞巴林的患者中。这些研究将把这些风险与观察到的风险进行比较 慢性疼痛服用两种活性比较剂：曲马多和塞来昔布。我们的首要目标是改善健康 对退伍军人的研究和预防负面副作用使这些研究非常适合退伍军人管理局的任务。

PROJECT SUMMARY When compared to the general population, U.S. Military Veterans disproportionately experience pain, especially severe pain. Indeed, pain management is one of the most common reasons Veterans seek medical assistance. The U.S. Department of Veterans Affairs (VA) and Veterans Health Administration (VHA) have continued to focus attention on chronic pain management, which has resulted in the implementation of new guidelines and systems that prioritize non-opioid treatments. Current pharmacologic alternatives to opioids for chronic pain management include: (1) topical and oral analgesics such as lidocaine, acetaminophen, and non-steroidal anti-inflammatories (NSAIDs); (2) antidepressants; (3) anticonvulsants; and (4) muscle relaxants. We and others have defined the cardiovascular toxicity of NSAIDs and opioid analgesics, but the potential toxicity of other drug classes used to treat chronic pain remains poorly defined. This is particularly important for three classes of drugs: (1) selective norepinephrine reuptake inhibitors (SNRIs) antidepressants, (2) antiepileptics, and (3) muscle relaxants. Within each drug class, duloxetine (SNRI), pregabalin (antiepileptic), and cyclobenzaprine (muscle relaxant) are among the most frequently prescribed. Usage of these three drugs has generated multiple case reports and raised specific concerns for increased risk of serious cardiovascular events. Currently, hundreds of thousands of Veterans are filling prescriptions for these drugs each year, and the use of non-opioid pain drugs is increasing. Veterans encompass a vulnerable population with high cardiovascular risk and high rates of chronic pain; thus, they are at higher risk for adverse drug effects. The overwhelming majority of Veterans with chronic pain do not have cancer or life-threatening illness, which makes the prospect of drug toxicity from long-term use a particularly important consideration. Clinical trials play a crucial role in demonstrating treatments' efficacy; however, many drugs have had unforeseen and serious side effects. Since clinical trials necessarily are limited with regard to generalizability and can be impractical, pharmacoepidemiologic studies play a critical role in our knowledge about the long-term side effects of drugs. The proposed pharmacoepidemiologic studies seek to provide critical information about the cardiovascular risks associated with three widely prescribed non-opioid medications used to treat chronic pain and frequently prescribed to Veterans in the VA health system. We will use state of the art techniques and a large database of Veterans to assemble a cohort of patients with chronic non-cancer pain. Aim 1 will define the risk for serious cardiovascular outcomes in patients taking cyclobenzaprine. Aim 2 will define the risk of serious cardiovascular events associated with the use of duloxetine. Aim 3 will define the risk of heart failure associated in patients taking pregabalin. These studies will compare those risks with the risk observed in patients with chronic pain taking two active comparators: tramadol and celecoxib. Our overarching goal to improve the health of Veterans and prevent negative side effects makes these studies an excellent fit with the VA mission.