Background: Acetaminophen and ibuprofen effectively reduce childhood fever. Studies indicate that ibuprofen is superior; however, because they act through different mechanisms, a combination may be more effective than either drug alone. Studies of combination therapy have had conflicting conclusions and have not focused on community-based populations. Hay and colleagues compared the effectiveness of combined acetaminophen and ibuprofen with monotherapy in children with fever.

The Study: The randomized controlled trial included children six months to six years of age from English general practices. Participants had fevers of 100.0 to 105.8°F (37.8 to 41.0°C) caused by illnesses that could be managed at home. After completing a baseline questionnaire, the 156 eligible participants were randomly assigned to up to 48 hours of treatment with acetaminophen every four to six hours (maximum of four doses in 24 hours), ibuprofen every six to eight hours (maximum of three doses in 24 hours), or both drugs. Doses were calculated by the child's weight: 15 mg per kg for acetaminophen and 10 mg per kg for ibuprofen. The first dose was given in the presence of a research nurse who also provided all participants' caretakers with advice on fever management. Any remaining study medications were collected after 48 hours. The monotherapy group also received placebo to ensure blinding.

The primary outcomes were minutes without fever in the first four hours after the initial dose of medication, and the proportion of children without symptoms at 48 hours. Secondary outcomes included time to resolution of fever and time without fever in 24 hours, and symptoms at 48 hours and five days. Caregivers were asked about adverse effects four hours, 24 hours, and five days after the initial dose of medication.

Results: In addition to fever, more than 90 percent of the children reported discomfort, reduced activity, abnormal appetite, or change in sleeping patterns. For time without fever, children receiving combination therapy had significantly better outcomes during the first four hours and the first 24 hours, compared with those receiving either medication alone. The time to resolution of fever was similar for children receiving combined therapy and ibuprofen alone. Children treated with ibuprofen appeared to have better resolution of associated symptoms than other groups, but this outcome was not statistically significant. The frequency of reported adverse effects (e.g., vomiting, rash, diarrhea, cough, cold to touch) did not differ across groups.

Conclusion: The authors conclude that fever resolves more rapidly and children have longer periods without fever when treated with combined therapy or ibuprofen alone than with acetaminophen alone. Although combined therapy offers advantages, the authors are concerned about the potential to exceed recommended doses—up to 13 percent of parents exceeded maximum recommended doses in 24 hours during this supervised study. Overall, the authors recommend initial therapy with ibuprofen and consideration of the potential benefits and risks of combined therapy over 24 hours.

editor's note: A related editorial reiterates the concern about exceeding recommended doses and emphasizes that this study lacks the power to convincingly recommend combined therapy over ibuprofen monotherapy for febrile children.¹ Guidelines for the evidence-based treatment of several common conditions in children increasingly advocate symptom control and observation for up to 72 hours, instead of immediate antibiotic therapy. However, the editorial also stresses the importance of identifying the cause of fever before relying on symptomatic therapy.¹ The potential costs to families and health services for medications are addressed in a related article that found little difference between the three regimens.² Hidden costs to families, such as stress and impact on work and daily activities, have not been quantified.—a.d.w.