Fever in children: combining or alternating acetaminophen and ibuprofen

It is a busy Saturday morning at your community pharmacy when a worried father, Juan, approaches the counter holding a bottle of children’s ibuprofen. “My four-year-old daughter Tala has been running a fever since last night. I gave her some acetaminophen around midnight, but the fever came back four hours later, so I gave her ibuprofen. Is it okay to alternate them, or should I stick with just one?”BackgroundFever is a frequent reason for pediatric healthcare visits.1 Although typically self-limiting and even beneficial in fighting infection, pediatric fever often causes significant anxiety for caregivers, leading to the use of antipyretics such as acetaminophen and ibuprofen.1,2 While lowering temperature can ease symptoms and minimize water loss, it carries risks such as masking the underlying diagnosis, delaying appropriate treatment and adverse drug effects.1 The primary goals in the treatment of pediatric fever should be to improve the patient’s overall comfort, maintain hydration and address signs of serious illness.1Acetaminophen and ibuprofen are safe and effective when used appropriately, but whether alternating or combining them offers added benefit without increased risk remains uncertain.1,2 A survey of 256 parents or caregivers found that 67% reported alternating acetaminophen and ibuprofen for fever control, with 81% doing so based on advice from a healthcare provider.3 While the most commonly reported dosing interval was every four hours, other intervals including every two, three or six hours were used, highlighting a lack of consensus.1,3This inconsistency is reflected in the literature, in online resources and in healthcare provider recommendations. For example, a prospective study of pharmacists found that 82% recommended alternating acetaminophen and ibuprofen for treatment of pediatric fever using various dosing schedules.4 Similarly, a survey of pediatricians showed that 50% recommended alternating the two medications.5 Given this variability, pharmacists have a crucial role in offering evidence-based, consistent recommendations.Evidence summaryOver the past 20 years, studies have explored whether combining or alternating acetaminophen and ibuprofen is more effective than either alone.1Combination studiesA single-dose pilot study published in 2006 found that the combination of acetaminophen and ibuprofen provided superior antipyretic effects compared to ibuprofen monotherapy at six, seven and eight hours post dose.6 The doses used were ibuprofen 10 mg/kg and acetaminophen 15 mg/kg.6A randomized controlled trial (RCT) comparing a single dose of acetaminophen 15 mg/kg plus ibuprofen 5 mg/kg to either medication alone in children aged six months to 10 years found that the combination reduced fever more effectively than acetaminophen alone, but not ibuprofen alone, at one hour.7 However, the authors noted that the temperature difference (0.35°C) between the combination and acetaminophen groups was not clinically significant.7Alternating studiesA RCT published in 2006 compared acetaminophen 12.5 mg/kg every six hours or ibuprofen 5 mg/kg every eight hours to alternating acetaminophen 12.5 mg/kg and ibuprofen 5 mg/kg every four hours for three days.8 This study concluded that an alternating treatment regimen was more effective than monotherapy in lowering fever in infants six to 36 months of age.8Similarly, a RCT published in 2008, which included children aged six months to six years, found that alternating acetaminophen 15 mg/kg and ibuprofen 10 mg/kg was more effective than using either medication alone in reducing the number of children with fever over a 24-hour period.9 In this study, acetaminophen was given every four to six hours (maximum 4 doses in 24 hours) and ibuprofen was given every six to eight hours (maximum 3 doses in 24 hours).9 Randomization was used to determine which drug was given first.9 Although this study was not powered to assess patient discomfort, no difference was observed in overall patient discomfort.9Another RCT published in 2008 compared acetaminophen 15 mg/kg given at hour 0 and hour 4 to alternating acetaminophen 15 mg/kg and ibuprofen 10 mg/kg in children eight months to six years of age.10 In the alternating group acetaminophen was given at hour 0, ibuprofen at hour 3, and placebo at hour 4. No significant temperature differences were found between the two groups at 0, 3 or 6 hours.10 Although the alternating group had lower average temperatures at four and five hours, parents did not report any noticeable difference in fever control between the groups.10A 2013 Cochrane review, including these six RCTs, concluded that while there is some evidence that both alternating and combined therapy may lower fever more effectively than acetaminophen or ibuprofen monotherapy, the impact on discomfort is unclear, and more research is needed to assess both safety and patient-centred outcomes.11A 2024 network meta-analysis of 31 trials involving children aged 1.4–5.9 years found that both combined and alternating acetaminophen and ibuprofen, as well as high-dose (7.5–10 mg/kg) ibuprofen, were superior to acetaminophen in becoming afebrile at hour 4.12 At the 6-hour mark, both combination and alternating therapy appeared more effective than acetaminophen alone for maintaining an afebrile state, while high-dose ibuprofen demonstrated similar efficacy to acetaminophen.12 There were no differences in adverse events.12 Notably, this study was limited by looking only at the impact to six hours, which misses the real-life context where children will often require more than one dose.13Although the studies cited above did not identify an increased risk with combination or alternating use, case reports have documented reversible renal failure when acetaminophen and ibuprofen are used concurrently in multiple doses.2,14 Furthermore, with combination or alternating treatment, the risk of incorrect or excessive dosing is heightened as parents may not receive or fully understand dosing instructions.1Based on the preceding information, guidelines such as those from the American Academy of Pediatrics recommend against routine use of combination or alternating therapy due to the increased risk of medication dosing errors, overdose and the potential for adverse effects.1Back to the patient caseReturning to Juan and his daughter Tala, you take a moment to reassure him that fever is a normal response to infection and often not harmful. You explain that either acetaminophen or ibuprofen can be used safely on its own, and that alternating or combining them is generally not recommended. Given Tala’s age and symptoms, you suggest continuing with one medication, dosed appropriately by weight and administered with an accurate measuring device (e.g., oral syringe). You also advise Juan to focus on Tala’s comfort such as ensuring she is drinking fluids, resting and not overly bundled. You provide a dosing chart and explain signs that would warrant medical attention.SummaryWhile studies of combination therapy suggest enhanced antipyretic effects, they are generally limited to single-dose studies, and the clinical significance of the observed temperature reduction compared to monotherapy is uncertain. In contrast, alternating acetaminophen and ibuprofen has been studied over longer durations, typically one to three days. Although alternating appears to have enhanced antipyretic effects in some studies, the impact on patient discomfort and overall adverse effects is not well established. Current best practice supports monotherapy with doses of either medication based on the patient’s weight to minimize the risk of dosing errors and to avoid caregiver confusion.Katelyn Halpape is a clinical pharmacist at the Dube Centre for Mental Health in Saskatoon, SK, and an associate professor in the College of Pharmacy and Nutrition at the University of Saskatchewan.References:Sullivan JE, Farrar HC. Fever and antipyretic use in children. Pediatrics 2011;127(3):e20103852.Shortridge L, Harris V. Alternating acetaminophen and ibuprofen. Paediatr Child Health 2007;12(2):127-8.Wright AD, Liebelt EL. Alternating antipyretics for fever reduction in children: an unfounded practice passed down to parents from pediatricians. Clin Pediatr (Phila) 2007;46(2):146-50.Chung AM, Cobb EA. An evaluation of community pharmacy recommendations regarding alternating antipyretics in children. J Am Pharm Assoc 2020; 60(2):368-73.e1.Mayoral CE, Marino RV, Rosenfeld W, et al. Alternating antipyretics: is this an alternative? Pediatrics 2000;105(5):1009-12.Nabulsi MM, Tamim H, Mahfoud Z, et al. Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study. BMC Med 2006;4(1):4.Erlewyn-Lajeunesse MDS, Coppens K, Hunt LP, et al. Randomised controlled trial of combined paracetamol and ibuprofen for fever. Arch Dis Child 2006;91:414-6.Sarrell EM, Wielunsky E, Cohen HA. Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch Pediatr Adolesc Med 2006;160(2):197-202.Hay AD, Costelloe C, Redmond NM, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ 2008;337:a1302.Kramer LC, Richards PA, Thompson AM, et al. Alternating antipyretics: antipyretic efficacy of acetaminophen versus acetaminophen alternated with ibuprofen in children. Clin Pediatr (Phila) 2008;47(9):907-11.Wong T, Stang AS, Ganshorn H, et al. Combined and alternating paracetamol and ibuprofen therapy for febrile children. Cochrane Database Syst Rev 2013(10):CD009572.De la Cruz-Mena JE, Veroniki AA, Acosta-Reyes J, et al. Short-term dual therapy or mono therapy with acetaminophen and ibuprofen for fever: a network meta-analysis. Pediatrics 2024;154(4):e2023065390.Wade KC, Mathis C. Antipyretic strategies: is fever clearance enough to justify dual therapy? Pediatrics 2024;154(4):e2024067408.Nabulsi M. Is combining or alternating antipyretic therapy more beneficial than monotherapy for febrile children? BMJ 2009;339:b3540 doi:10.1136/bmj.b3540.