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

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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.