In this secondary analysis of a public double-blind randomized dataset, preemptive versus preventive timing of intravenous acetaminophen/ibuprofen in RALP was associated with similar observed rest pain burden (mean difference − 6.7; 95% CI − 21.7 to 7.3), opioid consumption, and patient-reported recovery. Point estimates for all efficacy, tolerability, and safety endpoints were small; however, confidence intervals were sufficiently wide that clinically meaningful differences in either direction cannot be excluded.

Our findings of similar outcomes across timing strategies are consistent with a body of evidence questioning the magnitude of preemptive analgesia effects, although timing effects may be context-dependent, procedure-specific, and agent-specific rather than universally absent. Møiniche et al. systematically reviewed 80 trials and concluded that preemptive analgesia failed to demonstrate consistent benefits, catalyzing a conceptual shift in perioperative pain management [18]. Ong et al. subsequently analyzed 66 RCTs and found that while preemptive NSAIDs modestly improved analgesic consumption, they did not improve pain scores compared with postincisional administration [7]. Dahl and Kehlet recommended abandoning “pre-emptive” terminology, emphasizing that duration and efficacy of multimodal coverage matter more than precise incision timing [19].

For minimally invasive surgery, Coughlin et al. meta-analyzed 26 laparoscopic surgery RCTs and found no timing effect for incision-site infiltration [20]. In RALP specifically, Sisa et al. demonstrated no benefit of preemptive pregabalin when multimodal analgesia was employed (24-hour consumption: 15 versus 17 mg morphine equivalents; P = 0.44), consistent with our findings using a different non-opioid agent [21]. Notably, the same intravenous acetaminophen/ibuprofen fixed-dose combination demonstrated significant opioid-sparing effects in video-assisted thoracic surgery, reducing consumption by 100–140 µg fentanyl equivalent at 24–48 h compared with placebo [22], confirming the analgesic efficacy of this combination even though timing effects remain negligible.

The 24-hour fentanyl consumption observed (255–284 µg, approximately 25–28 mg morphine equivalents) falls within established RALP benchmarks. Ashrafi et al. demonstrated 67% opioid reduction with aggressive ERAS implementation (15 versus 46 mg morphine equivalents) [23], while Taninishi et al. reported 200–210 µg fentanyl with TAP blocks. Our results represent adequate systemic multimodal analgesia without regional techniques [24]. Lee et al. showed that a comprehensive non-opioid multimodal protocol combining pregabalin, paracetamol, and regional blocks was non-inferior to morphine-based PCA for RALP, with 58% of patients requiring no opioids for 48 h [25]. Our results represent adequate systemic multimodal analgesia without regional techniques.

The PROSPECT guidelines recommend scheduled paracetamol and NSAIDs as foundational analgesia for prostatectomy [1]. Importantly, ERAS protocols typically involve scheduled repeated dosing of non-opioid analgesics, often initiated orally hours before surgery and continued postoperatively. Our analysis examines only the timing of a single intravenous fixed-dose combination within a standardized anesthetic protocol; consequently, these findings should not be extrapolated to the broader question of scheduled multimodal analgesic timing within comprehensive ERAS pathways. Within the scope of single-dose timing, the effect may be subtle and difficult to detect without larger samples. The fixed-dose combination itself has robust efficacy evidence: Daniels et al. demonstrated superior analgesia compared with monotherapy [6], and a meta-analysis by Abushanab and Al-Badriyeh confirmed a relative risk of 2.60 for achieving ≥ 50% pain relief versus placebo [26].

The QoR-15 K decline (31–35 points) mirrors that observed in the Korean validation study (4), which reported a median decrease of 36.5 points. This represents approximately four times the established MCID of 8 points [13], indicating expected deterioration consistent with major surgery. The between-group point estimate (− 4.4 points; 95% CI − 10.8 to 1.8) fell below this threshold; however, the upper bound of the confidence interval (− 10.8) exceeds the MCID of 8 points in absolute value, indicating that a clinically meaningful difference in favor of preventive timing cannot be excluded with certainty.

The absence of renal or hepatic signal is consistent with the Lee et al. Cochrane review, which found NSAIDs cause only clinically unimportant transient changes in renal function among adults with normal baseline values [15]. These findings are consistent with a comparable short-term safety profile across timing strategies within this sample, though the study was not powered to detect rare adverse events.

The clinical significance of opioid-sparing extends beyond acute hospitalization. Brummett et al. established that 5.9–6.5% of opioid-naïve surgical patients develop persistent use [3] Santosa et al. demonstrated an associated hazard ratio for mortality of 3.44. For prostatectomy specifically, rates are lower (< 1–1.3%), but minimizing exposure remains prudent [27].

This analysis operationalized pain burden using an AUC framework integrating multiple assessments [14], with distributional visualizations clarifying heterogeneity. To contextualize the clinical meaning of the primary AUC metric, the observed 6.7 NRS·h difference over the 46-hour observation window corresponds to approximately 0.15 NRS points averaged across all time points—a magnitude well below the threshold patients can typically perceive. The exploratory prediction model achieved high discrimination (AUC 0.84) but included postoperative variables representing time-ordering leakage. Critically, this model should not be interpreted as a clinically deployable predictive tool; it serves only as an exploratory association analysis identifying variables correlated with high opioid consumption across the perioperative period. Among baseline predictors, associations were modest, suggesting that clinically useful prospective prediction from preoperative data remains elusive and would require dedicated prediction studies with appropriate selection of temporal variables.

Several limitations warrant consideration. First, and most importantly, this study was designed as a superiority trial and was neither designed nor powered as an equivalence or non-inferiority trial; no equivalence margin was prespecified. Consequently, the absence of a statistically significant difference does not establish that the two timing strategies produce equivalent outcomes, and clinically meaningful differences in either direction cannot be excluded. Second, follow-up was limited to 48 h, precluding evaluation of persistent opioid use and longer-term recovery. Third, the sample size (n = 152) may be insufficient for detecting small but meaningful differences. Fourth, this single-centre Korean dataset may limit generalizability. Fifth, the modest operative duration imbalance (95 versus 90 min; P = 0.048), though addressed in sensitivity analyses, represents imperfect randomization. Sixth, the analysis evaluates only the timing of a single intravenous fixed-dose combination, whereas ERAS protocols typically employ scheduled repeated multimodal analgesic dosing beginning preoperatively; therefore, these single-dose findings cannot be generalized to the timing effects of scheduled multimodal regimens within comprehensive ERAS pathways. Seventh, regional techniques were not employed; PROSPECT recommends TAP blocks as the first-choice regional technique, which might modify timing effects. Eighth, near-ceiling preoperative QoR-15 K scores may limit sensitivity to detect differences. Finally, the exploratory prediction model included time-ordering leakage, which limits its clinical applicability.

Several avenues merit further investigation. First, larger multicenter trials with extended follow-up (≥ 90 days) are needed to evaluate whether analgesic timing influences persistent opioid use, chronic postsurgical pain, and long-term functional recovery.

Second, factorial designs comparing timing effects across different non-opioid combinations (e.g., acetaminophen/ibuprofen versus acetaminophen/ketorolac versus acetaminophen/COX-2 inhibitors) would clarify whether the null timing effect is agent-specific or generalizable.

Third, studies incorporating regional techniques should examine whether systemic analgesic timing interacts with regional blockade effectiveness.

Fourth, patient stratification based on preoperative pain sensitivity phenotyping, psychological factors, or genetic polymorphisms affecting drug metabolism may identify subgroups who differentially benefit from optimized timing.

Fifth, implementation research examining how timing flexibility affects perioperative workflow efficiency, medication safety, and protocol adherence in high-volume centers would translate these findings into practice.

Sixth, primary research comparing the timing effects of scheduled multimodal analgesic regimens, including oral preoperative loading and postoperative continuation, within comprehensive ERAS protocols for RALP is needed to determine whether timing effects differ when non-opioid analgesics are administered as part of a scheduled dosing strategy rather than as a single perioperative dose.

Finally, incorporating patient-reported experience measures beyond the QoR-15, including satisfaction with pain control, sleep quality, and return to baseline activities, would provide a more comprehensive assessment of recovery quality.