Ibuprofen vs. acetaminophen for acute mild-to-moderate pain management: A systematic review and meta-analysis of safety with a focus on paediatric populations

Aims: The purpose of this study is to compare the safety of ibuprofen and acetaminophen (paracetamol) for acute mild-to-moderate pain in children and adolescents through a systematic review and meta-analysis. Methods: PubMed, Scopus and Web of Science were searched from inception to May 2026 for randomized controlled trials (RCTs) in patients aged 0–18 years that reported safety outcomes. RCTs enrolling adult or mixed-age populations in acute pain settings were also considered eligible when paediatric-relevant safety data could be extracted. The review was conducted and reported in accordance with the PRISMA 2020 statement. Primary outcomes were total adverse events (AEs), gastrointestinal, renal, hepatic and bleeding events. The risk of bias was assessed using RoB 2. Random-effects meta-analyses were expressed as risk ratios (RR) with 95% confidence intervals (CI). Results: Fifteen studies (2847 patients) were included across postoperative pain, musculoskeletal trauma, orthodontic pain and emergency department settings, with follow-up ranging from single-dose assessments to 12 months. Three studies, including 937 participants, contributed to the primary meta-analysis of any adverse event. Ibuprofen was not associated with a statistically significant difference in the risk of any adverse event compared with acetaminophen (RR 0.80, 95% CI 0.36–1.79; I2 = 2.9%). No serious renal or hepatic adverse events were reported. Conclusions: Available RCT evidence did not show a clear difference in short-term safety between ibuprofen and acetaminophen in paediatric and acute pain populations; however, the certainty of the evidence is limited. Patient factors and clinical context should guide drug choice. Larger RCTs with standardized safety reporting are needed.