Alternating acetaminophen and ibuprofen

Parents and caregivers are often highly concerned about fevers in children and are often misinformed about the beneficial effects of elevated body temperatures (1–4). The most important consideration in the management of a febrile child is to determine, if possible, the cause of the fever. Treating the fever itself, to provide symptomatic relief, is important if a child is uncomfortable.

Alternating acetaminophen and ibuprofen to reduce temperatures is a common practice, with one study reporting that 50% of paediatricians surveyed recommended this combination (5). Because acetaminophen is most commonly administered at a dose of 10 mg/kg to 15 mg/kg every 4 h and ibuprofen at a dose of 10 mg/kg every 6 h, a simple alternating regimen is not readily apparent (6). Parent and practitioner confusion may result in accidental overdoses (5, 7).

Three case reports of reversible renal failure with this combination suggest a theoretical drug interaction (8, 9). Nonsteroidal anti-inflammatory drugs inhibit prostaglandin synthesis, which reduces the production of glutathione and renal perfusion. Oxidative metabolites of acetaminophen are detoxified by conjugation with glutathione. Therefore, when administered simultaneously, these metabolites may accumulate in the renal medulla and cause tubular necrosis and renal toxicity, although this has never been substantiated (8). Several studies have been performed to evaluate the efficacy and safety of alternating these antipyretics.

A double-blind, multicentre study (10) conducted in India included 89 inpatients aged one to three years, with axillary temperatures of at least 38.5ºC. The patients were randomly assigned to receive acetaminophen 10 mg/kg, nimesulide 1.5 mg/kg or a combination of acetaminophen 10 mg/kg and ibuprofen 10 mg/kg. In each regimen, drugs were administered three times daily. Children were sponged if temperatures over 39.5ºC persisted for longer than 2 h. If a child’s temperature did not decrease, then they were given ibuprofen 10 mg/kg. Temperature readings were recorded at predetermined intervals over five days, and no statistically significant differences in temperature readings were found among the groups at any time.

A randomized, double-blind study (11) was conducted in 480 Israeli outpatients aged six to 36 months, with rectal temperatures of at least 38.4ºC. The investigators concluded that alternating acetaminophen 12.5 mg/kg with ibuprofen 5 mg/kg every 4 h resulted in fewer antipyretic doses, fewer fever recurrences on days 5 and 10, and less daycare absenteeism than monotherapy with either ibuprofen 5 mg/kg every 8 h or acetaminophen 12.5 mg/kg every 6 h (P < 0.001). All patients were randomly assigned to receive a loading dose of either acetaminophen 25 mg/kg or ibuprofen 10 mg/kg. The regimens used in all three treatment arms and the use of loading doses differ from usual practice. Interestingly, none of the patients met the authors’ definition of being afebrile after the three-day treatment period. Some children experienced mild, transient elevations in liver or kidney function tests, but there were no significant differences among the groups, and all levels normalized within 14 days. Blinding was compromised by different dosing intervals in each study arm. It is unclear whether parents were given instructions regarding the timing of drug administration and temperature readings, which may have invalidated the reported temperatures. Based on these limitations, the results of this study are somewhat questionable.

Shortly thereafter, a double-blind pilot study (12) conducted in Lebanon randomly assigned 70 inpatients aged six months to 14 years, with rectal temperatures of at least 38.8ºC, to receive a single dose of ibuprofen 10 mg/kg followed 4 h later by either a single dose of acetaminophen 15 mg/kg or placebo. More patients in the intervention group were afebrile 6 h after the administration of the first medication (83.3% versus 57%; P = 0.018) and time to fever recurrence was longer (7.4 h versus 5.7 h; P < 0.001). The calculated sample size was not achieved due to difficulty in recruiting patients. No adverse effects were reported in this study. This trial was seriously flawed given that the efficacy of two doses of antipyretic was compared with a single dose.

A blinded, randomized study (13) from the United Kingdom evaluated acetaminophen 15 mg/kg, ibuprofen 5 mg/kg or both given simultaneously in 123 children aged six months to 10 years, with tympanic temperatures of at least 38ºC, presenting to an emergency department. Patients who received the combination experienced a 0.35ºC greater temperature reduction than acetaminophen monotherapy 1 h after drug administration (P = 0.028). This was statistically significant but is likely not clinically significant. There was no difference between the combination and ibuprofen alone or between either of the single drug regimens.

Design flaws in the studies performed to date limit the reliability and generalizability of the findings. Nevertheless, the studies consistently found that alternating acetaminophen and ibuprofen provides little or no advantage over monotherapy. Therefore, at this time, monotherapy should be considered as first-line treatment. A recent meta-analysis (14) has concluded that a single dose of ibuprofen (5 mg/kg to 10 mg/kg) is superior to a single dose of acetaminophen (10 mg/kg to 15 mg/kg) for the treatment of fever. This meta-analysis did not address the effects of repeated dosing, which are most often used in general practice. Furthermore, there are several patient populations for whom ibuprofen would not be appropriate.

Fever phobia is widespread. As many as 91% of caregivers believe that elevated temperatures may cause harmful effects, with 85% saying they would awaken their children to administer antipyretics (1). Recommending the use of two antipyretics may give the false impression that controlling fevers is of clinical benefit or can prevent febrile seizures (15,16). Therefore, re-education of caregivers should be a priority. In a review similar to our own, Hay et al (17) recognized the dichotomy between the current evidence and clinicians’ and caregivers’ desires to treat febrile children. They concluded that while combined treatment should not be withheld from all children, “parents should be advised to use the minimum treatment necessary.”

In rare cases in which the patient has failed monotherapy, and where alternating acetaminophen and ibuprofen may be indicated, parents must be given clear instructions on how to alternate, and patients should be closely monitored to ensure they are well hydrated. Alternating antipyretics should be used with caution, especially in patients with chronic illness, and the duration should be limited to minimize the risk of adverse outcomes. For the vast majority, treatment with either acetaminophen or ibuprofen monotherapy should be sufficient to provide comfort for febrile paediatric patients.