Abstract: We included three RCTs (327 children) which were assessed at low to moderate risk of bias. One RCT included 219 children with AOM, and used a three-arm, parallel group, double-blind design to compare paracetamol versus ibuprofen versus placebo. All children also received antibiotics and those with fever > 39 °C could have received paracetamol (30 mg to 60 mg) additionally to the studied treatments. Another RCT involved 156 febrile children (26 of whom had AOM). The study design was a three-arm, parallel group, double-blind design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol. The third RCT included 889 children with respiratory tract infections (82 of whom had AOM). This study applied a 3 x 2 x 2 factorial, open-label design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol. Study participants were randomised to one of the three treatment groups as well as two dosing groups (regular versus as required) and two steam inhalation groups (steam versus no steam). Authors of two RCTs provided crude subgroup data on children with AOM. We used data from the remaining trial to inform comparison of paracetamol versus placebo (148 children) and ibuprofen versus placebo (146 children) assessments. Data from all included RCTs informed comparison of ibuprofen versus paracetamol (183 children); data from the two RCTs informed comparison of ibuprofen plus paracetamol versus paracetamol alone (71 children). We found evidence, albeit of low quality, that both paracetamol and ibuprofen as monotherapies were more effective than placebo in relieving pain at 48 hours (paracetamol versus placebo: proportion of children with pain 10% versus 25%, RR 0.38, 95% CI 0.17 to 0.85; number needed to treat to benefit (NNTB) 7; ibuprofen versus placebo: proportion of children with pain 7% versus 25%, RR 0.28, 95% CI 0.11 to 0.70; NNTB 6). Very low quality evidence suggested that adverse events did not significantly differ between children treated with either paracetamol, ibuprofen or placebo. We found insufficient evidence of a difference between ibuprofen and paracetamol in relieving ear pain at 24 hours (2 RCTs, 39 children; RR 0.83, 95% CI 0.59 to 1.18; very low quality evidence), 48 to 72 hours (3 RCTs, 183 children; RR 0.91, 95% CI 0.54 to 1.54; low quality evidence) and four to seven days (2 RCTs, 38 children; RR 0.74, 95% CI 0.17 to 3.23; very low quality evidence). Data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone came from two RCTs that provided crude subgroup data for 71 children with AOM. The small sample provided imprecise effect estimates and we were consequently unable to draw any firm conclusions (very low quality evidence). Despite explicit guideline recommendations on its use, current evidence on the effectiveness of paracetamol or NSAIDs, alone or combined, in relieving pain in children with AOM is limited. Low quality evidence indicates that both paracetamol and ibuprofen as monotherapies are more effective than placebo in relieving short-term ear pain in children with AOM. There is insufficient evidence of a difference between ibuprofen and paracetamol in relieving short-term ear pain in children with AOM, whereas data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone were insufficient to draw any firm conclusions. Further research is needed to provide insights into the role of ibuprofen as adjunct to paracetamol, and other analgesics such as anaesthetic eardrops, for children with AOM.

Plain-language summary: We included data from three trials of low to moderate risk of bias of 327 children with AOM. One trial (219 children) compared paracetamol versus ibuprofen versus a dummy drug in children with AOM. In this trial, all children also received antibiotic treatment and those with fever > 39 °C may have received paracetamol in addition to the studied treatments. Two other trials compared the effects of paracetamol versus ibuprofen versus ibuprofen plus paracetamol in children with fever and patients with respiratory tract infections, respectively. The authors of these two trials provided crude subgroup data on children with AOM (26 and 82 children, respectively). In one trial, paracetamol, ibuprofen and a dummy drug were supplied by a pharmaceutical company (Ethypharm). No further details were provided about the role of this company in the design, conduct, analysis, or reporting of the trial. The other two trials were funded by governmental (non-commercial) grants. In one trial the drugs were purchased from and provided by two companies (Pfizer and DHP Investigational Medicinal Products) which had no role in the design, conduct, analysis, or reporting of the trial. Very limited information was available to assess how useful painkillers are for relieving children's pain due to AOM. We found that both paracetamol and ibuprofen when used alone were more effective than a dummy drug in relieving ear pain at 48 hours (25% of children receiving a dummy drug had residual pain at 48 hours versus 10% in the paracetamol group and 7% in the ibuprofen group). The adverse events reported in the trials did not significantly differ between children treated with either paracetamol, ibuprofen or dummy drug, but this finding should be interpreted cautiously, given there were few participants, and infrequent occurrence of adverse events. We found insufficient evidence of a difference between paracetamol and ibuprofen in relieving short-term (at 24 hours, 48 to 72 hours and 4 to 7 days) ear pain in children with AOM. We could not draw any firm conclusions on the effects of ibuprofen plus paracetamol versus paracetamol alone in relieving ear pain in children with AOM mainly because of the very limited number of participants (very small sample size). Evidence quality for ear pain relief at 48 hours for the comparisons paracetamol versus a dummy drug and ibuprofen versus a dummy drug was judged low (study limitations and questions about the applicability of evidence affected our confidence in the results); the quality of evidence for adverse events was judged very low (study limitations, small sample size and infrequent occurrence of adverse events affected our confidence in the results). Evidence quality for ear pain relief at 48 to 72 hours for the comparison ibuprofen versus paracetamol was judged low (study limitations and questions about the applicability of evidence affected our confidence in the results); the quality of evidence for ear pain relief at 24 hours and four to seven days was judged very low (study limitations and very small sample size affected our confidence in the results). Evidence quality for all outcomes in the trials comparing ibuprofen plus paracetamol versus paracetamol alone was very low (study limitations and very small sample size affected our confidence in the results).