Cochrane in context: Combined and alternating paracetamol and ibuprofen therapy for febrile children.

BACKGROUND: Health-care professionals frequently recommend fever treatment regimens for children who either combine paracetamol and ibuprofen or alternate them.However, there is uncertainty about whether these regimens are better than using single agents and about the adverse effect profile of combination regimens.

OBJECTIVES: To assess the results and side effects of combining paracetamol and ibuprofen, or alternating them in consecutive treatments, compared with monotherapy for treating fever in children.

SEARCH METHODS: In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS and International Pharmaceutical Abstracts (2009-2011).

SELECTION CRITERIA: We included randomized controlled trials that compared alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever.

DATA COLLECTION AND ANALYSIS: One review author and two assistants independently screened the searches and applied the inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted various analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy and combined therapy versus alternating therapy).

MAIN RESULTS: Six studies, enrolling 915 participants, are included. Compared to administering a single antipyretic alone, administering combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at 1 hour after treatment (mean difference -0.27 ∘C, 95% confidence interval -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at 4 hours (mean difference -0.70 ∘C, 95% confidence interval -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least 4 hours after treatment (relative risk 0.08, 95% confidence interval 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever, associated symptoms at 24 and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded). In practice, caregivers are often advised to initially provide a single agent (paracetamol or ibuprofen), and then provide a further dose of the alternative if the child;s fever fails to resolve or recurs. Giving alternating treatment in this manner may result in a lower mean temperature at 1 hour after the second dose (mean difference -0.60 ∘C, 95% confidence interval -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to 3 hours after it is given (relative risk 0.25, 95% confidence interval 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence) Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature or in the number of febrile children at 1, 4 or 6 hours (one trial, 40 participants, very low quality evidence). In all the trials, there were no serious adverse events that were directly attributed to the medications used.

AUTHORS' CONCLUSIONS: There is some evidence that both alternating and combined antipyretic therapies may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to decide which of combined or alternating therapy might be more beneficial. Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapies.