Assessing real-world evidence of the effects of opioid analgesic tapering on substance-related problems

项目摘要/摘要 在大力缓解长期阿片类药物不良反应(Ltd OT)的背景下 对于慢性疼痛，人们非常担心这些人中出现意外有害后果的风险 逐渐减少阿片类药物剂量或停止使用。出于这个原因，2020年的国家医学科学院 讨论文件和最近的多篇评论强调了现实世界的迫切需要 关于Ltd OT缩减的好处和坏处的证据。这项提议的总体目标是 利用大规模的医疗保健数据和严格的药物流行病学设计来加强证据 关于Ltd OT缩减在多大程度上影响4种物质相关结果的风险的基础：过量服药， 阿片类药物使用障碍(OUD)、其他物质使用障碍(SUD)和故意过量/其他自我伤害。这个 中心假设是，与维持LtOT-And相比，缩减的不利影响最小 其影响仅限于特定的临床背景和亚组。这项提议的理由是，将 基于设计的和统计控制的混杂与测量的严格性，锥度，和 与物质相关的结果对于加强关于Ltd OT缩减的证据至关重要。该项目将对 它的中心假设有两个具体目标：(1)估计Ltot缩减对严重物质相关的影响 结果，以及(2)确定更容易受到Ltd-OT缩减的估计影响的患者群体。这两个目标 将涉及在全国范围内接受Ltd OT治疗的患者的分析，来自商业和 Medicare Advantage医疗保险索赔。在目标1中，项目将估计Ltd.OT的程度 逐渐减少与物质相关的结果的风险(过量、OUD、其他SUD和故意 自残)。主要的分析方法将是个人内部的设计，排除所有人的混淆 时间稳定因素，通过利用个体内部随时间变化，并辅之以统计 协变量，以帮助解释时变混杂。目标2将在以下方面采用这种个人内部的方法 分组，以确定持续时间较长的个人(A)与缩减相关的伤害是否更大 (B)使用更高剂量的LtOT，(C)经历更快速的缩减，(D)使用预先存在的SUD或其他 (E)被边缘化的(黑人或西班牙裔/拉丁裔/a)种族和族裔群体。这个 该提案的创新之处在于：(A)严谨的研究设计，以减少混淆和其他偏见，(B) 考虑到缩减效应的异质性，以及(C)跨学科、国际研究小组。这个 提案意义重大，因为它将指导损害惠益计算和最佳做法(例如，缩减比率) 对于政策，以及对个别患者。如果没有这些信息，缩减的建议仍然必须是 使用的证据一再被描述为不充分。因此，拟议的研究具有 增强决策的潜力，以最大限度地减轻痛苦，最大限度地提高安全性和公平性。

Project Summary/Abstract Against the background of major efforts to alleviate the adverse effects of long-term opioid therapy (LtOT) for chronic pain, there is great concern about the risk of unintended harmful consequences among those tapering opioid dosage or discontinuing LtOT. For this reason, a 2020 National Academy of Medicine discussion paper and multiple other recent commentaries have highlighted the urgent need for real-world evidence regarding the benefits and harms of LtOT tapering. The overall objective of this proposal is to leverage large-scale healthcare data and rigorous pharmacoepidemiologic designs to strengthen the evidence base concerning the extent to which LtOT tapering affects risk of 4 substance-related outcomes: overdose, opioid use disorder (OUD), other substance use disorder (SUD), and intentional overdose/other self-harm. The central hypothesis is that there are minimal adverse effects of tapering compared with maintaining LtOT—and that the effects are limited to certain clinical contexts and subgroups. The proposal’s rationale is that combining design-based and statistical control of confounding with rigor in measurement of LtOT, tapering, and substance-related outcomes is essential to strengthening evidence on LtOT tapering. The project will evaluate its central hypothesis in 2 specific aims: (1) estimate the effects of LtOT tapering on serious substance-related outcomes, and (2) identify patient groups more vulnerable to the estimated effects of LtOT tapering. Both aims will involve the analysis of patients receiving LtOT in nationwide, longitudinal data from commercial and Medicare Advantage healthcare insurance claims. In aim 1, the project will estimate the extent to which LtOT tapering is associated with risk of substance-related outcomes (overdose, OUD, other SUD, and intentional self-harm). The primary analytic approach will be a within-individual design that rules out confounding from all time-stable factors by capitalizing on intra-individual variability over time, complemented with statistical covariates to help account for time-varying confounding. Aim 2 will employ this within-individual approach in subgroups to determine whether tapering-related harms are greater among individuals (a) with longer-duration LtOT, (b) with higher-dose LtOT, (c) experiencing more rapid tapering, (d) with pre-existing SUD or other mental health conditions, or (e) from marginalized (Black or Hispanic/Latino/a) racial and ethnic groups. The innovation of the proposal is in its (a) rigorous research designs to reduce confounding and other biases, (b) consideration of heterogeneity in tapering effects, and (c) interdisciplinary, international research team. The proposal is significant because it will guide harm-benefit calculations and best practices (e.g., tapering rates) for policy, as well as for individual patients. Without this information, tapering recommendations must still be made using evidence that has been repeatedly described as inadequate. Thus, the proposed research has the potential to enhance decision-making to maximize pain relief, safety, and equity in LtOT tapering.