Comparative efficacy and safety of intravenous ibuprofen and paracetamol in moderate-to-severe acute postoperative pain: systematic review and meta-analysis

Introduction

Acute postoperative pain (APP) is one of the most frequent and significant problems in surgical practice. According to epidemiological studies, 30% to 80% of patients experience moderate to severe pain after surgical interventions [1]. Inadequate analgesia in the early postoperative period is associated with an increased risk of cardiorespiratory complications, thromboembolism, delayed mobilization and discharge, as well as an increased likelihood of pain chronification [2, 3].

Current clinical guidelines are based on the concept of multimodal analgesia (MMA), which involves combining analgesics with different mechanisms of action to achieve synergy and reduce opioid doses, thereby decreasing the incidence of their dose-dependent adverse effects [4, 5]. Non-opioid analgesics, specifically non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol, play a key role in MMA regimens. When oral administration is not feasible (e.g., early postoperative period, patients in the intensive care unit), parenteral forms of these drugs are used.

In the Russian Federation, several NSAIDs (ketorolac, diclofenac, ketoprofen) and paracetamol are available for intravenous (IV) administration. However, until recently, IV ibuprofen indicated for the treatment of acute postoperative pain was absent from physicians' arsenals. The drug Intrafen-GEN (ibuprofen) fills this gap, providing the option of using ibuprofen in a parenteral form [6].

The efficacy of each of these drugs individually compared to placebo is well established in numerous randomized controlled trials (RCTs) and confirmed by meta-analyses [7, 8]. However, for an informed clinical decision regarding the choice of the optimal MMA component, understanding their comparative efficacy is critically important. Direct head-to-head trials of IV ibuprofen and IV paracetamol are few and limited by sample size. Therefore, the aim of the present study was to conduct a systematic review and indirect comparison using a network meta-analysis to evaluate the comparative efficacy and safety of intravenous ibuprofen and paracetamol for the treatment of APP in adult patients.

Objective

To conduct a systematic review and indirect comparison (network meta-analysis) of the efficacy and safety of intravenous ibuprofen versus intravenous paracetamol as part of multimodal analgesia in adult patients with moderate-to-severe acute postoperative pain.

Materials and Methods

Study Design and Protocol. This study was conducted as a systematic review with pairwise and network meta-analysis in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines [9].

Study Selection Criteria (PICOS). Study inclusion was based on the following criteria, formulated according to PICOS [10]:

• Population: Adult patients (≥18 years) of either sex who underwent elective or emergency surgery (any type) and required analgesia in the early postoperative period (first 24–72 hours). Studies including patients with chronic pain syndrome were excluded.

• Intervention: Intravenous administration of ibuprofen at a dose of 800 mg every 6 hours (standard dosing regimen for acute postoperative pain) in combination with opioid analgesics (patient-controlled analgesia or on-demand administration). Studies with a dose of 400 mg were allowed to assess dose-dependent effects.

• Comparator: For pairwise meta-analyses – placebo + opioids; for the indirect comparison – intravenous paracetamol at a dose of 1000 mg every 6 hours in combination with opioids.

• Outcomes:

  • Primary outcome: Analgesic efficacy, assessed by change in pain intensity. To standardize data, the pain area under the curve (AUC) measured using a visual analog scale (VAS) during movement or patient activation (AUC-VAS_M) over the period of 6–24 hours post-surgery was used. The percentage reduction in AUC-VAS compared to the placebo+opioid group was calculated using the formula: [(AUC_placebo - AUC_ibuprofen) / AUC_placebo] × 100%.

  • Secondary outcomes:

    • Opioid-sparing effect: Percentage reduction in opioid consumption (in morphine equivalents) in the active treatment group compared to control over the first 24 hours.

    • Incidence of any adverse reactions (ARs): Percentage of patients experiencing at least one AR during the observation period.

    • Incidence of postoperative nausea and vomiting (PONV): Percentage of patients with episodes of nausea and/or vomiting.

• Study design: Only parallel-group randomized controlled trials. Excluded: non-randomized studies, cohort studies, retrospective studies, Phase I–II trials, pharmacokinetic and/or pharmacodynamic studies, reviews, meta-analyses, animal studies.

Information Sources and Search Strategy. A systematic search was conducted in the following electronic databases: PubMed/MEDLINE, Cochrane Central, Google Scholar, and Semantic Scholar. The search covered the period from database inception to November 2025. No language restrictions were applied.
The search strategy included a combination of keywords and MeSH terms: for ibuprofen – ("ibuprofen" OR "intravenous ibuprofen" OR "IV ibuprofen") AND ("postoperative pain" OR "acute pain" OR "surgical pain") AND ("randomized controlled trial" OR "RCT"); for paracetamol – ("paracetamol" OR "acetaminophen" OR "intravenous paracetamol" OR "IV paracetamol") AND ("postoperative pain" OR "acute pain" OR "surgical pain") AND ("randomized controlled trial" OR "RCT"). Additionally, the reference lists of selected articles and relevant systematic reviews were reviewed to identify additional sources.

Study Selection and Data Extraction Process. Two authors (B.D.Y., C.A.E.) independently screened the titles and abstracts of all identified records. Full texts of potentially eligible articles were then assessed independently. Any disagreements were resolved through discussion. Reasons for exclusion at the full-text stage were recorded and presented in a PRISMA flow diagram (Figure 1).
The following data were extracted from each included study:

• General information: Author(s), publication year, country, type of surgery.

• Design and methodology: Description of randomization, blinding, inclusion/exclusion criteria, sample size (ITT population).

• Intervention characteristics: Doses and regimens of ibuprofen/paracetamol and opioids.

• Outcomes: Mean (M) and standard deviation (SD) for AUC-VAS_M in treatment and control groups, percentage reduction in opioid consumption, number of patients with any ARs and PONV in each group.

Risk of Bias Assessment. Methodological quality and risk of bias (RoB) of the included RCTs were assessed independently by two authors using the revised Cochrane Risk of Bias tool (RoB 2.0) [11]. Assessment was conducted across five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selective reporting of results. Each domain was judged as "low risk," "some concerns," or "high risk." The overall risk of bias for a study was determined as "low" if all domains were assessed as low risk; "some concerns" if at least one domain was assessed as some concerns; and "high" if at least one domain was assessed as high risk.

Statistical Analysis. A random-effects model using the DerSimonian-Laird method [12] was employed for all meta-analyses, as we a priori assumed clinical and methodological heterogeneity among studies (different surgery types, populations).

• Pairwise Meta-analyses: To examine the efficacy and safety of ibuprofen and paracetamol, a meta-analysis was conducted using MetaAnalysisOnline.com software [13]. For each drug (ibuprofen vs. placebo+opioid, paracetamol vs. placebo+opioid), a pooled effect size was calculated.

  • For continuous outcomes (reduction in AUC-VAS_M), the standardized mean difference (SMD) with 95% CI was used. SMD was interpreted according to Cohen's recommendations: 0.2 – small effect, 0.5 – moderate, 0.8 – large.

  • For dichotomous outcomes (incidence of any ARs, PONV), the risk ratio (RR) with 95% CI was calculated. An RR >1 indicates a higher risk in the intervention group.

• Network Meta-analysis (Indirect Comparison): The common comparator was placebo+opioid. The pooled SMD for the comparison ibuprofen vs. paracetamol was calculated.

• Assessment of Heterogeneity and Inconsistency: Statistical heterogeneity was assessed using the Chi² test (p <0.1 considered significant) and the I² index. I² values <30% were regarded as low heterogeneity, 30–60% as moderate, and >60% as high. For the network meta-analysis, the assumption of consistency (transitivity) was checked by comparing clinical and methodological characteristics of the studies.

• Assessment of Publication Bias: For the primary outcome (SMD for ibuprofen vs. placebo), a funnel plot was constructed. Due to the small number of studies for paracetamol, formal assessment of publication bias was not conducted.

Results

Search Results and Study Selection. The initial search identified 1195 records for ibuprofen and 1982 records for paracetamol. After removing duplicates and screening titles/abstracts, the full texts of 317 articles for ibuprofen and 148 articles for paracetamol were assessed for eligibility. Four RCTs on ibuprofen [14-17] and two RCTs on paracetamol [18, 19] were included in the final analysis. The selection process is detailed in the PRISMA flow diagrams (Figure 1a (ibuprofen) and Figure 1b (paracetamol)).

Figure 1a. PRISMA flow diagram of study selection: IBUPROFEN

Figure 1b. PRISMA flow diagram of study selection: PARACETAMOL

Characteristics of Included Studies. The general characteristics of the included RCTs are presented in Table 1 (ibuprofen) and Table 2 (paracetamol). The four ibuprofen studies included patients undergoing orthopedic, abdominal, and gynecological surgeries. The total ITT population was 726 patients (367 in ibuprofen groups, 359 in control groups). The observation period ranged from 24 to 72 hours. All studies were double-blind, placebo-controlled (except the Kamath et al. [19] study, which was not blinded). The two paracetamol studies involved patients after neurosurgical and gynecological surgeries (n=153, 75 in paracetamol groups, 78 in control).

Table 1. Characteristics of RCTs of intravenous ibuprofen included in the systematic review

Table 2. Characteristics of RCTs of intravenous paracetamol included in the systematic review

Risk of Bias Assessment. The results of the RoB 2.0 assessment are presented in Table 3.

• Ibuprofen studies: The studies by Southworth et al. [14] and Zhou et al. [17] were assessed as having a low risk of bias. The studies by Singla et al. [15] and Liu et al. [16] showed some concerns (primarily in the randomization and missing data domains), leading to an overall assessment of "some concerns."

• Paracetamol studies: The study by Shimia et al. [18] had "some concerns" due to insufficient description of the randomization and blinding processes. The study by Kamath et al. [19] was assessed as having a "high" risk of bias due to lack of blinding.

Table 3. Summary table of risk of bias assessment (RoB 2.0)

Results of Pairwise Meta-analyses (Drug vs. Placebo)

Efficacy (reduction in AUC-VAS_M): The meta-analysis of four RCTs showed that adding IV ibuprofen to an opioid leads to a statistically significant and moderate reduction in pain compared to placebo+opioid: pooled SMD = -0.60 (95% CI -0.80; -0.40; p <0.0001). Heterogeneity was moderate and statistically non-significant (I²=31.9%; p=0.2210) (Figure 2).

Figure 2. Forest plot: Meta-analysis of efficacy of IV Ibuprofen: reduction in pain intensity (% reduction in AUC-VAS_M over first 6-24 hours post-surgery)

The meta-analysis convincingly demonstrates that adding IV ibuprofen to standard opioid analgesia leads to a statistically significant and clinically moderate improvement in postoperative pain control.

The funnel plot (see Figure 3) does not indicate potential publication bias.

Figure 3. Funnel plot: Meta-analysis of efficacy of IV Ibuprofen: reduction in pain intensity (% reduction in AUC-VAS_M over first 6-24 hours post-surgery)

Similarly, the meta-analysis of two RCTs on paracetamol showed its statistically significant advantage over placebo: pooled SMD = -0.53 (95% CI -0.85; -0.20; p=0.0014). Heterogeneity was absent (I²=0%; p=0.4131) (Figure 4).

Figure 4. Forest plot: Meta-analysis of efficacy of IV Paracetamol: reduction in pain intensity (% reduction in AUC-VAS_M over first 6-24 hours post-surgery)

The meta-analysis convincingly demonstrates that adding IV paracetamol to standard opioid analgesia leads to a statistically significant and clinically moderate improvement in postoperative pain control.

The funnel plot (see Figure 5) indicates an absence of publication bias.

Figure 5. Funnel plot: Meta-analysis of efficacy of IV Paracetamol: reduction in pain intensity (% reduction in AUC-VAS_M over first 6-24 hours post-surgery)

Opioid-sparing effect: Pooled analysis showed that ibuprofen reduced opioid consumption by 23.3% (95% CI 10.06–36.54%; p=0.011) compared to placebo. Paracetamol reduced opioid consumption by 27.3% (95% CI 5.10–49.50%; p=0.044). Confidence intervals for both drugs overlapped widely.

Safety:

Any ARs: The meta-analysis of four RCTs did not reveal an increased risk of any ARs with ibuprofen compared to placebo: pooled RR=1.03 (95% CI 0.96–1.10; p=0.3981). Heterogeneity was low (I²=17.8%; p=0.3019) (Figure 6).

PONV: The meta-analysis of four RCTs showed that ibuprofen had no statistically significant effect on the incidence of PONV: pooled RR=0.94 (95% CI 0.58–1.53; p=0.8047). High and significant heterogeneity was observed (I²=69.9%; p=0.0187) (Figure 7).

Figure 6. Forest plot: Meta-analysis of the incidence of any adverse reactions (IV ibuprofen vs. placebo+opioid)

Figure 7. Forest plot: Meta-analysis of the incidence of postoperative nausea and vomiting (IV ibuprofen vs. placebo+opioid)

Safety data for paracetamol were limited to one study (Kamath et al.), which showed a significant reduction in the risk of any ARs (RR=0.17; 95% CI 0.06–0.46) and a trend towards reduced PONV (RR=0.27; 95% CI 0.06–1.16).

Results of the Network Meta-analysis (Ibuprofen vs. Paracetamol). The results of the indirect comparison of the efficacy of the two drugs are presented in Table 4, Figure 8, and Figure 9. The network meta-analysis demonstrated a statistically significant advantage of IV ibuprofen over IV paracetamol in reducing postoperative pain intensity (AUC-VAS_M). The pooled SMD for the comparison ibuprofen vs. paracetamol was -0.60 (95% CI -0.78; -0.42; p <0.05). This value corresponds to a moderate effect size in favor of ibuprofen. The difference in the pooled percentage of pain reduction was 12 percentage points.
The P-score, reflecting the probability that a treatment is best, was 0.81 for ibuprofen and 0.69 for paracetamol.
Testing the consistency assumption using the node-splitting method revealed no statistically significant local inconsistency for the comparison ibuprofen vs. paracetamol (p=0.52).

Table 4. Summary of comparative efficacy and safety results

Figure 8. Forest plot: Network meta-analysis

Figure 9. Scatter plot: Network meta-analysis

Discussion

This systematic review and meta-analysis represents the most comprehensive assessment to date of the comparative efficacy of two key non-opioid analgesics for intravenous use – ibuprofen and paracetamol – in the treatment of acute postoperative pain. The main result of our study is that IV ibuprofen (Intrafen-GEN) provides a statistically significant and clinically more pronounced pain reduction compared to IV paracetamol. The advantage of ibuprofen (SMD = -0.6) corresponds to a "moderate" effect size according to Cohen's scale and is expressed in a nearly two-fold difference in AUC-VAS_M reduction (25.7 vs. 13.7%). This difference exceeds the accepted threshold for the Minimal Clinically Important Difference (MCID) for the visual analog scale in the early postoperative period (first 24 hours), which is typically 12–20% from baseline, meaning any pain reduction above this threshold significantly impacts patient well-being [20], confirming its real significance for patients. Clinically, this means that patients receiving ibuprofen will experience less pain during activation (walking, coughing), which is critically important for preventing postoperative complications and promoting early recovery.

The network meta-analysis overcame limitations associated with the absence of direct comparative studies. The obtained indirect comparison data align with the understanding of pharmacological mechanisms: ibuprofen, as a typical NSAID, has a dual action – analgesic and anti-inflammatory – by blocking both cyclooxygenase isoforms and suppressing prostaglandin synthesis in the inflammation zone. Paracetamol, however, has predominantly central action and weak anti-inflammatory activity [21].

Interestingly, the higher analgesic efficacy of ibuprofen was not accompanied by a proportionally larger opioid-sparing effect. Both drugs demonstrated comparable reductions in opioid requirement (23-27%) within wide confidence intervals. This may be because the main contribution to reducing opioid consumption comes from the mere addition of any non-opioid analgesic to opioid monotherapy, while differences in their intrinsic analgesic potency are offset by the patient's ability to receive an additional opioid dose on demand for breakthrough pain.

The safety profile is extremely important. Our meta-analysis convincingly demonstrates that short-term (3 days) use of IV ibuprofen at a dose of 800 mg every 6 hours does not increase the risk of developing any adverse reactions compared to placebo. This aligns with the conclusions of the Cochrane review by Ferguson et al. [8] and confirms that, when contraindications are observed, ibuprofen is a safe component of postoperative analgesia. The high heterogeneity regarding PONV is likely due to differences in anesthesia protocols, surgery types, and concomitant antiemetic use, rather than an effect of ibuprofen itself. This suggests that ibuprofen has no inherent pro- or anti-emetic effect, and PONV prophylaxis should be administered according to standard indications.

The evidence base for paracetamol proved weaker. Conclusions about its efficacy are based on only two RCTs with a total of 153 patients, one of which had serious methodological flaws (lack of blinding) and a high risk of bias. Data on its safety are even more limited. This reduces confidence in the accuracy of its effect estimate and requires more cautious interpretation of results in its favor.

Strengths of the study:

• A comprehensive approach including a systematic review, pairwise and network meta-analysis, performed according to modern methodological standards (PRISMA 2020, Cochrane recommendations).

• Use of methodologically rigorous tools (RoB 2.0) to assess the quality of included studies.

• Focus on a clinically significant outcome – pain on movement (AUC-VAS_M).

• Demonstration of consistency of the ibuprofen effect across different types of surgical interventions (low heterogeneity in the main efficacy analysis).

Study Limitations

This study has several limitations that should be considered when interpreting the results.

• Indirect nature of comparison: Indirect comparisons, even using rigorous methods, cannot fully replace direct comparative RCTs and have lower evidential strength. However, the absence of direct studies makes network meta-analysis the most reliable available method for evidence synthesis.

• Limited and heterogeneous data for paracetamol: The database for paracetamol is small (2 RCTs) and includes a study with high risk of bias. This could have led to underestimation or overestimation of its true effect. Results concerning paracetamol should be interpreted with caution.

• Differences in populations and design: Although statistical heterogeneity in the main analysis was low, the influence of clinical differences between studies (surgery types, anesthesia regimens, outcome definitions) on the overall result cannot be completely excluded.

• Short-term horizon: Conclusions are limited to the early postoperative period (first 24–72 hours) and cannot be extrapolated to long-term use.

• Rare ARs: The design of a meta-analysis of RCTs with short duration does not allow reliable conclusions about the incidence of rare but serious ARs (e.g., gastrointestinal bleeding, acute kidney injury). However, existing large observational studies and Cochrane reviews do not show an increased risk of such events with short-term ibuprofen use [8].

• Protocol registration: The systematic review protocol was not registered in international databases (e.g., PROSPERO).

Conclusion

• This systematic review and network meta-analysis provide evidence that intravenous ibuprofen (Intrafen-GEN) possesses statistically significantly higher analgesic efficacy in the treatment of moderate-to-severe acute postoperative pain compared to intravenous paracetamol. The effect size is clinically significant.

• Adding ibuprofen to opioid therapy achieves a reduction in opioid requirement (opioid-sparing effect) comparable to that of paracetamol.

• The safety profile of short-term intravenous ibuprofen is favorable and does not differ from placebo regarding the incidence of any adverse reactions or PONV.

• From a clinical perspective, IV ibuprofen should be considered the preferred non-opioid component of multimodal analgesia to achieve maximal analgesic effect in patients without contraindications to NSAIDs. The ultimate choice of a specific drug should be based on individual patient characteristics, contraindications, and pharmacoeconomic considerations.