Pharmacoepidemiologic Studies of Prescription Opioid Analgesic Risks

 描述(申请人提供)：最近美国和世界各地阿片类止痛药处方的增加与阿片类药物相关发病率和死亡率的增加不谋而合。然而，正如2015年美国国立卫生研究院的一份研讨会报告和同行评议的健康期刊上的多篇评论所描述的那样，处方阿片类镇痛剂的确切危害-及其在正在进行的阿片类药物流行中的确切作用-仍不清楚。这种不确定性是由随机对照试验的有限样本量和后续持续时间，以及在观察性研究中排除有偏见的选择和其他混淆的挑战造成的。值得注意的是，接受处方阿片类药物治疗的患者也更有可能患有物质使用障碍等预先存在的疾病。这一过程被称为“逆向选择”，它表明一些观察性研究先前对阿片类药物危害的估计可能被人为夸大了。因此，拟议研究的总体目标是使用先进的药物流行病学方法来确定处方阿片类药物对行为的损害程度。特别是，拟议的研究将估计处方阿片类药物的风险。 对于物质使用障碍、机动车事故、抑郁和自杀行为，在以前的文献中，每一种都被确定为潜在的阿片类药物危害。在两个人口层面的数据集中--包括190万阿片类药物接受者来自整个瑞典人口和2600万阿片类药物接受者来自美国保险索赔--这些研究将评估处方阿片类药物与行为损害有关的中心假设，这将与真正的不良反应相一致。首先，拟议的研究将检查在存在先前存在的物质使用障碍、情绪障碍和其他社会和行为因素的情况下，患者更频繁地接受处方阿片类药物的程度。在确定了这些潜在的混淆之后，分析将随后估计阿片类药物处方与短期和长期行为损害之间的风险关联。具体地说，分析将使用人内比较，隐含地排除所有时不变混淆的来源，以及时变统计协变量，明确排除时变混淆的来源。这种方法的基本原理是，结合个人内分析、时变协变量和来自两个人群的数据，将有助于对处方阿片类药物的不良影响产生更准确的估计。拟议的研究将辅之以以下方面的培训：(A)药物流行病学和其他准实验研究；(B)临床疼痛研究；(C)协作科学；(D)负责任地开展 研究。在完成拟议的活动后，预计申请者将实现建立一个独立方案的长期目标，该方案研究阿片类药物和其他物质使用的原因和后果。

 DESCRIPTION (provided by applicant): Recent increases in opioid analgesic prescribing in the US and worldwide have coincided with increases in opioid-related morbidity and mortality. As described in a 2015 NIH workshop report and in multiple commentaries in peer-reviewed health journals, however, the exact harms of prescription opioid analgesics- and their precise role in the ongoing opioid epidemic-remain unclear. This uncertainty has been driven by the limited sample sizes and follow-up durations of randomized, controlled trials, as well as the challenge of ruling out biased selection and other confounding in observational studies. Notably, patients who receive prescription opioids may also be more likely to have pre-existing conditions such as substance use disorders. This process is referred to as "adverse selection," and it suggests that prior estimates of opioid harms from some observational studies may have been artificially inflated. The overall objective of the proposed research is, therefore, to use advance pharmacoepidemiologic approaches to determine the extent to which prescribed opioids have behavioral harms. In particular, the proposed studies will estimate the risks of prescribed opioids for substance use disorders, motor vehicle accidents, depression, and suicidal behavior, each of which has been identified in prior literature as a potential opioid harm. In 2 population-level datasets-including 1.9 million opioid recipients drawn from the whole Swedish population and 26 million opioid recipients drawn from US insurance claims-these studies will evaluate the central hypothesis that prescribed opioids are associated with behavioral harms, which would be consistent with true adverse effects. First, the proposed research will examine the extent to which patients receive prescription opioids more frequently in the presence of pre- existing substance use disorders, mood disorders, and other social and behavioral factors. Having identified these potential confounds, analyses will subsequently estimate risk associations between opioid prescriptions and both short-term and long-term behavioral harms. Specifically, analyses will use within-person comparisons, which implicitly rule out all sources of time-invariant confounding, and time-varying statistical covariates, which explicitly rule out sources o time-varying confounding. The rationale for this approach is that the combination of within-person analyses, time-varying covariates, and data from two populations will help generate more accurate estimates of the adverse effects of prescribed opioids. The proposed research will be complemented with training in (a) pharmacoepidemiology and other quasi-experimental research, (b) clinical pain research, (c) collaborative science, and (d) the responsible conduct of research. Upon the completion of the proposed activities, the applicant is expected to have reached the long-term goal of establishing an independent program researching the causes and consequences of opioid and other substance use.