# Preemptive versus preventive intravenous acetaminophen/ibuprofen fixed-dose combination after robot-assisted radical prostatectomy: a comprehensive secondary analysis of a public double-blind randomized dataset

## TL;DR

This study compares giving pain medications before or after robot-assisted prostate surgery and finds no major differences in pain or recovery.

## Contribution

The study provides new evidence on the timing of non-opioid pain medications in postoperative care for prostate surgery.

## Key findings

- No significant difference in rest pain burden between preemptive and preventive medication timing.
- Opioid consumption and recovery scores were similar across both groups.
- Exploratory analysis showed good prediction of opioid use but with limitations due to time-ordering leakage.

## Abstract

Multimodal, opioid-sparing analgesia is central to enhanced recovery after robot-assisted radical prostatectomy (RALP), yet the incremental value of altering the timing of non-opioid fixed-dose combinations within standardized pathways is uncertain. Using a public, de-identified dataset from a double-blind randomized trial, we performed a comprehensive secondary analysis emphasizing pain burden, trajectories, recovery, and tolerability. Adults undergoing RALP were randomized 1:1 to intravenous acetaminophen 1,000 mg plus ibuprofen 300 mg administered either before incision (preemptive) or at the end of surgery (preventive). The primary endpoint was rest pain burden across 2–48 h, operationalized as the area under the curve (AUC) of numeric rating scale scores. Secondary endpoints included cough pain, opioid consumption, QoR-15 K recovery at 24 h, rescue analgesia, adverse effects, and postoperative day 1 laboratory changes. Linear mixed-effects models analyzed repeated measures. An exploratory elastic-net logistic regression evaluated predictors of high 24-h fentanyl use. Among 152 participants (76 per group), rest pain burden showed no statistically significant between-group difference (mean difference − 6.7, 95% CI − 21.7 to 7.3; Cohen’s d = − 0.14; P = 0.378). Cumulative fentanyl AUC was not significantly different between groups (P = 0.247; SMD = − 0.22). QoR-15 K at 24 h showed no statistically significant difference (mean difference − 3.6, 95% CI − 10.2 to 3.0; P = 0.280). Creatinine change from baseline to postoperative day 1 was similar between groups (P = 0.333). Exploratory prediction of high opioid use (≥ 520 µg) achieved good discrimination (cross-validated AUC 0.84); however, top predictors included postoperative variables, indicating time-ordering leakage that limits prospective clinical utility. Preemptive versus preventive timing of intravenous acetaminophen/ibuprofen was associated with similar observed opioid consumption, rest pain burden, and early recovery within the precision of this sample. These findings are consistent with comparable short-term outcomes across timing strategies; however, the study was not designed as an equivalence trial, and small clinically meaningful differences cannot be excluded.

Trial registration: The dataset derives from a double-blind randomized controlled trial registered at ClinicalTrials.gov (NCT05685342). This manuscript reports a secondary analysis of the public de-identified dataset.

The online version contains supplementary material available at 10.1007/s11701-026-03239-2.