Efficacy and Safety of Ibuprofen Plus Paracetamol in a Fixed-Dose Combination for Acute Postoperative Pain in Adults: Meta-Analysis and a Trial Sequential Analysis.

BACKGROUND

Ibuprofen and paracetamol (acetaminophen) are very commonly used for analgesia and pain. In 2020, the US FDA gave its first approval of a fixed-dose combination (FDC) of the two drugs in the same tablet for postoperative pain. There has been no quantitative, summative analysis of the FDC effect size measures against postoperative pain in adults. Similar analyses exist, but only in pediatric patients.

OBJECTIVE

This was the first meta-analysis to compare the efficacy and safety outcomes of the ibuprofen/paracetamol FDC against placebo, administered postoperatively, for moderate to severe pain relief in adults.

METHODS

The MEDLINE, EMBASE, and Cochrane CENTRAL databases, in addition to the grey literature, were searched for clinical trials until April 2020, to identify comparative literature studies of the ibuprofen/paracetamol FDC in acute postoperative pain in adults. No restrictions on doses, formulations (oral, intravenous), and underlying type of surgery were applied. Independent reviewers performed the study selection, data extraction, and the risk-of-bias and quality-of-evidence assessments based on the Cochrane criteria. The outcome measures of interest in the meta-analysis were ≥ 50% pain relief , need for rescue medications, and occurrence of adverse drug events. Statistical analyses using a random-effects model were performed, at a statistical significance of p < 0.05. The RevMan software was used for analysis. A trial sequential analysis (TSA) was conducted to assess how precise and conclusive the meta-analysis outcomes are.

RESULTS

Seven double-blind, randomized controlled trials with 2947 participants were included. The FDC dose was at three different levels: 75-100 mg ibuprofen/250 mg paracetamol, 150-200 mg ibuprofen/500 mg paracetamol (FDA-approved dose level), and 292.5-400 mg ibuprofen/975-1000 mg paracetamol. The ≥ 50% pain relief outcome was more achieved with the FDC compared to placebo (risk ratio [RR] 2.60, 95% confidence interval [CI] 2.11-3.20, p < 0.00001), as was the reduced need for rescue medications (RR 0.51, 95% CI 0.37-0.71, p < 0.0001). While inconclusive based on TSA, the FDC was at the highest doses at least as well tolerated as placebo regarding the occurrence of adverse events, including severe, common, and treatment-related adverse events, as well as those that lead to discontinuation, but it was also significantly associated with lower rates of headache and nausea. Subgroup analyses confirmed that the efficacy and safety of the FDC were maintained regardless of doses and formulations. The sensitivity analysis confirmed outcomes against potential publication bias and identified sources of heterogeneity in analyses.

CONCLUSION

The ibuprofen plus paracetamol FDC is conclusively an effective analgesic against placebo in acute postoperative, moderate to severe pain in adults. It is also superiorly well tolerated, including at the higher dose of 292.5-400 mg ibuprofen/975-1000 mg paracetamol; however, safety outcomes were inconclusive. Future studies need to confirm the safety of FDC and its benefits against other marketed analgesics in postoperative pain.