Is ibuprofen associated with upper gastrointestinal bleeding? A systematic review and meta-analysis

Previous systematic reviews associated nonsteroidal anti-inflammatory drugs (NSAIDs) with upper gastrointestinal bleeding (UGIB) without comparing ibuprofen to paracetamol. We systematically reviewed and meta-analyzed studies comparing ibuprofen against paracetamol, placebo, non-users, or other NSAIDs on their association with UGIB.

We searched PubMed, CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and WHO ICTRP for randomized clinical trials (RCTs) and observational studies and assessed their risk of bias. We utilized random-effects models, calculated odds ratios (OR) or risk ratios (RR) with their 95% confidence intervals (CI), and evaluated the certainty of the evidence.

We identified seven RCTs and 10 observational studies recruiting 89,522 participants. Ibuprofen intake ranged mostly from up to 1,200 mg to 1,800 mg daily, and its median exposure window was 1.5 weeks. After removing a potentially influential case, ibuprofen compared to paracetamol was not associated with UGIB (OR: 0.96, 95% CI: 0.36 to 2.59, p = 0.9341, I²: 0). However, ibuprofen was associated with UGIB compared to non-users (OR: 2.51, 95% CI: 1.33 to 4.74, p = 0.0047, I²: 89.11%) and selective NSAIDs (OR: 2.05, 95% CI: 1.18 to 3.55, p = 0.0191, I²: 11.50%). Additionally, ibuprofen compared to placebo (RR: 3.51, 95% CI: 0.56 to 22.23, p = 0.1820, I²: 0%) and non-selective NSAIDs (OR: 0.81, 95% CI: 0.62 to 1.07, p = 0.1254, I²: 15.37%) was not associated with UGIB. We found predominantly a high risk of bias and ‘very low’ certainty of evidence.

Low-dose and short-term ibuprofen administration may not be associated with UGIB compared to paracetamol or other non-selective NSAIDs. Future research should investigate dose–response relationships.