Comparative Safety of Pain Medications

项目摘要 临床医生、患者和研究人员在治疗慢性疼痛的努力中遇到了许多挑战 有效和安全。慢性疼痛影响大约三分之一的美国人，每年的费用高达6350亿美元 一年的治疗和生产力损失；阿片类药物的过量处方已经升级为一场危机。非- 阿片类止痛药是疼痛管理的一种替代治疗方法；然而，关于这些的数据 药物仅限于缺乏适当评估安全结果的能力的临床研究。 尽管临床试验在确定治疗效果方面起着至关重要的作用，但许多药物都没有预料到 以及严重的长期副作用。药物流行病学研究提供了研究这些风险的机会， 特别是在经常被排除在临床试验之外的弱势人群中。我们提出了三项这样的研究 目的是提供与广泛使用三种药物相关的心血管风险的关键信息 用于治疗慢性疼痛的非阿片类处方药：环苯扎平(肌肉松弛药)， 度洛西汀(5-羟色胺-去甲肾上腺素再摄取抑制剂)和普瑞巴林(止痛抗惊厥药)。我们选择了 这些药物的原因如下：1)数以百万计的患者使用这些药物；2)多个病例报告提出 对严重心血管事件风险增加的担忧；以及3)它们的作用机制显著提高 对心血管毒性的担忧。更具体地说，环苯扎平在结构上类似于阿米替林，即 广泛认为对心脏有毒性的药物；度洛西汀提高肾上腺素能活动，这可能增加 有心肌梗死的风险。普瑞巴林会导致大量液体滞留，因此会加重心力衰竭。 因此，极有必要确定这些药物的风险，特别是严重的心血管风险。 导致住院或死亡的后果。 我们建议研究联邦医疗保险D部分受益人，因为他们的风险增加和多种并发症 增加心血管副作用的可能性。随着对阿片类药物的审查和限制越来越多 处方(2016年每三个受益人中就有一个至少收到一张阿片类药物处方)， 为这些非阿片类药物开出处方的医疗保险受益人--已经有数百万人--可能会 增加，尽管缺乏高质量的长期安全数据。 我们将使用最先进的药物流行病学技术和医疗保险参保人的大型数据库来 召集一组患有慢性非癌症疼痛的患者。目标1将定义严重心血管疾病的风险 服用环苯扎平的患者的结局。目标2将定义严重心血管事件的风险 与度洛西汀的使用有关。目标3将定义与服用以下药物相关的心力衰竭风险 普瑞巴林。这些研究将把这些风险与慢性疼痛患者观察到的风险进行比较。 加巴喷丁，一种没有心血管副作用的临床信号的抗惊厥药物。

Project Summary Clinicians, patients, and researchers encounter numerous challenges in their efforts to treat chronic pain effectively and safely. Chronic pain affects approximately 1 out of 3 Americans and costs up to $635 billion a year for treatment and lost productivity; the excessive prescription of opioids has escalated into a crisis. Non- opioid pain medications are one alternative treatment method for pain management; however, data on these medications are limited to clinical studies that lacked the power to evaluate safety outcomes appropriately. Despite the crucial role of clinical trials in establishing treatments’ efficacy, many drugs have had unforeseen and serious long-term side effects. Pharmacoepidemiologic studies offer the opportunity to study these risks, particularly among vulnerable populations often excluded from clinical trials. We propose three such studies aimed to provide critical information about the cardiovascular risks associated with the use of three widely prescribed non-opioid medications used to treat patients with chronic pain: cyclobenzaprine (muscle relaxant), duloxetine (serotonin-norepinephrine reuptake inhibitor), and pregabalin (analgesic anticonvulsant). We selected these drugs for the following reasons: 1) they are used by millions of patients; 2) multiple case reports raise concern for increased risk of serious cardiovascular events; and 3) their mechanisms of action raise significant concern about cardiovascular toxicity. More specifically, cyclobenzaprine is structurally similar to amitriptyline, a drug widely-recognized to be cardiotoxic; duloxetine raises adrenergic activity, which potentially increases the risk of myocardial infarction. Pregabalin causes significant fluid retention, and thus can exacerbate heart failure. Consequently, there is an immense need to define these drugs’ risks, specifically serious cardiovascular outcomes resulting in hospitalization or death. We propose to study Medicare Part D beneficiaries because their increased risks and multiple comorbidities heighten the potential for cardiovascular side effects. With increasing scrutiny and limitations placed on opioid prescriptions (one in three beneficiaries received at least one opioid prescription in 2016), the number of Medicare beneficiaries filling prescriptions for these non-opioid drugs—already in the millions—is likely to increase, despite the lack of high quality long-term safety data. We will use state of the art pharmacoepidemiologic techniques and a large database of Medicare enrollees 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 with patients taking pregabalin. These studies will compare those risks with the risk observed in patients with chronic pain taking gabapentin, an anticonvulsant with no clinical signals of cardiovascular side effects.