Using a target trial framework to compare the effect of high/low opioid dosing strategies at post-surgical discharge on newly developed opioid use disorder

Background: Despite post-surgical opioid addiction and abuse occurring at high rates, no randomized clinical trial has been conducted to evaluate opioid dosing strategies at post-surgical discharge. The maximum recommended dose of total morphine milligram equivalents (MME) to prescribe at post-surgical discharge remains unclear.

Objectives: To emulate a randomized clinical trial with real world data to compare opioid prescribing strategies at post-surgical discharge for opioid naïve adult patients.

Methods: A two-step target trial emulation was conducted. A cohort of opioid naïve adult patients who had undergone their first major/minor surgeries and were discharged with opioids were identified. The data source is electronic medical records from an integrated academic health system in the US, 2010-2019. The primary outcome investigated was newly developed opioid use disorder (OUD) within two years after post-surgical discharge. Secondary outcomes were emergency department (ED) visit, all-cause mortality and persistent opioid use at 90 days and a decline of estimated glomerular filtration rate (eGFR) of more than 40% than baseline after surgery in the first year. The treatment strategy was either high total MME (> 200 MME) or low total MME (≤ 200 MME). Log-binomial regression with stabilizing inverse probability treatment weighting of propensity score to receive treatment strategies was used to control confounders to estimate the relative risk (RR) of outcomes. Sensitivity analysis examined the robustness by different years of OUD outcome (e.g., 1-yr OUD and 3-yr OUD) and different threshold of high/low total MME (e.g., 135 MME, 300 MME, and 450 MME).

Results: A total of 67,030 eligible patients were identified with 47.3 % of patients (n=31,698) prescribed opioids with high MME (> 200 total MME) at post-surgical discharge. The average follow up was 3.2 years. Compared to low total MME group (≤ 200 MME), the high total MME group had a significantly higher risk of new OUD at 2 years (RR=1.73, 95% CI [1.28-2.33]). The high total MME group also had a higher risk of ED visit, persistent opioid use and all-cause mortality at 90 days (RR= 1.09, 95% CI [1.02-1.16], RR=1.25, 95% CI [1.17-1.33], and RR=1.43, 95% CI [1.01-2.03], respectively). The high total MME was not significantly associated with a decline of eGFR of greater than 40% (RR=0.84, 95% CI [0.55-1.23]). Sensitivity analyses suggested similar findings; there were trends suggesting post-discharge MME dose-related effects.

Conclusions: High total MME (> 200 MME) prescribed at post-surgical discharge is significantly associated with newly developed OUD at 2 years and other adverse outcomes such as persistent opioid use, ED visit and all-cause mortality at 90 days than low total MME (≤ 200 ME).