Take another look at acetaminophen, ibuprofen or both for managing fever

October 2006

Acetaminophen and ibuprofen have been compared in many published evaluations. Their efficacy has been comparable when given at maximum dosages. Both agents are available in a variety of strengths and dosage forms to maximize ease of patient acceptability and administration. One topic of antipyretic therapy that has been recently addressed in the medical literature is the use of alternating doses of acetaminophen and ibuprofen. The first controlled trial evaluating this method of antipyretic therapy has been published (Sarrell), and will be discussed in this month’s column.

The use of alternating doses of acetaminophen and ibuprofen for the treatment of fever is relatively common, despite no evidence documenting its efficacy. In 2000, Mayoral published results of a survey of physicians’ prescribing habits of acetaminophen and ibuprofen in the treatment of fever. Of 161 physicians surveyed, 50% advised to alternate doses of acetaminophen and ibuprofen for their child’s fever. While several doing regimens of alternating drugs were used, acetaminophen given every 4 hours alternating with ibuprofen given every 6 hours was most commonly recommended. Many of the surveyed physicians also recommended maximum doses of acetaminophen (15 mg/kg every 4 hours) or ibuprofen (10 mg/kg every 6 hours) as single agent therapy. When this survey was undertaken, a published controlled trial evaluating the safety and efficacy of alternating doses had not been published.

Controlled trial

The objective of the controlled trial by Sarrell and colleagues was to compare the antipyretic efficacy of acetaminophen or ibuprofen monotherapy with an alternating regimen of both drugs in 464 children aged 6 months to 36 months. This trial was conducted in a randomized, double-blind manner using parallel groups in Israel. Three treatment groups were compared: 1) acetaminophen 12.5 mg/kg every 6 hours, 2) ibuprofen 5 mg/kg every 8 hours, and 3) alternating acetaminophen 12.5 mg/kg and ibuprofen 5 mg/kg every 4 hours, all given for a treatment duration of 3 days. Loading doses of acetaminophen 25 mg/kg or ibuprofen 10 mg/kg were given initially in the study office, and the scheduled treatment doses were given at home by the child’s caregivers. Body temperatures were measured rectally at least three times daily and had to be at least 101.1°F to be enrolled in the study.

The most common diagnoses included upper respiratory infections, acute otitis media and viral illness. The mean age of enrolled children was approximately 19 months. There were no baseline differences among the three treatment groups, other than the alternating dosing group had a higher initial stress score. Outcome measures included the presence of fever (<100.04°F was considered to be afebrile), stress score (a measure of pain in children unable to communicate verbally), amount of antipyretic used during the three-day study period and total days that a primary caretaker had to stay home from work to care for an ill child. The mean height of fever (approximately 104.9°F) did not differ among the groups initially. Differences in mean height of fever became apparent between the monotherapy groups (approximately 103.1°F) and the alternating treatment group (approximately 101.3°F) on days 2 and 3 (P<0.001). The mean height of fever in all groups at day 3 was >100.04°F, the temperature considered to be afebrile in this study: acetaminophen - 102.8°F, ibuprofen -103.4°F, and alternating acetaminophen with ibuprofen - 101.4°F (P<0.001).

It is not clear when the caregivers took body temperatures in relation to administering antipyretics. While stress scores were reduced in all three treatment groups, the reduction was steepest in the alternating dosing group. However, the alternating dosing group differed, by having a higher measured stress score at the beginning of the study (P<0.001). All groups at day 3 continued to have a mean stress score that was considered to be abnormal by the scale used (Noncommunicating Children’s Pain Checklist). Fewer children in the alternating dosing group were absent from day care and caregivers missed less work as compared to the monotherapy groups (P<0.001). Children receiving alternating doses received fewer antipyretic medication doses per day (1.48-2.57) as compared to the monotherapy groups (2.84-4.33).

Implications

What are the implications of this study of alternating acetaminophen and ibuprofen dosing for fever treatment? This trial is the first evaluation of alternating antipyretic dosing completed in a controlled manner, which is a significant contribution. The method of alternating doses – dosing every 4 hours — compares favorably with the most common alternating dosing schedule —acetaminophen every 4 hours alternating with ibuprofen every 6 hours — identified in the survey completed by Mayoral. An additional benefit of the trial by Sarrell includes the inclusion of practical, clinical markers of antipyretic therapy – stress scoring and time away from day care and parental missed work due to fever.

However, there are several methodological characteristics that limit Sarrell’s study. Perhaps the most important limitation is the dose employed in the acetaminophen and ibuprofen monotherapy groups. Acetaminophen was dosed at 12.5 mg/kg, a dose midrange of the accepted dosing range of 10 mg/kg to 15 mg/kg. Ibuprofen was dosed at the low end of the accepted dosing range of 5 mg/kg to 10 mg/kg.

Higher doses

Several studies have shown that higher doses of ibuprofen and acetaminophen more effectively reduce fever. Wilson and colleagues compared ibuprofen 5 mg/kg, 10 mg/kg, and acetaminophen 12.5 mg/kg given as a single dose using several means of evaluating temperature reduction (e.g., change in temperature at a given time, area under the curve for change in temperature). Wilson concluded that ibuprofen 10 mg/kg provided superior antipyretic efficacy as compared to ibuprofen 5 mg/kg. Wilson also concluded that antipyretic efficacy can vary depending upon initial temperature and age (less antipyretic efficacy at initial temperature >101.8°F). Ibuprofen 10 mg/kg was more efficacious than acetaminophen 12.5 mg/kg in children with higher initial temperatures.

In another study, Walson compared several doses of ibuprofen (2.5 mg/kg, 5 mg/kg and 10 mg/kg) given every 6 hours with acetaminophen 15 mg/kg every 6 hours in a controlled manner for 48 hours. He concluded that ibuprofen 10 mg/kg and acetaminophen 15 mg/kg were the most effective antipyretic dosing regimens, and are equally effective. In an earlier study, Walson used computer modeling to predict that acetaminophen 13.3 mg/kg every 4 hours may be the most effective antipyretic regimen.

Alternating regimens

Sarrell’s trial contributes significantly to the topic of antipyretic drug therapy and the common practice of alternating drug dosing regimens. However, the question of comparative efficacy of alternating dosing to monotherapy has not been fully answered. Additional studies are warranted. These studies should evaluate maximal antipyretic dosing – ibuprofen 10 mg/kg and acetaminophen 15 mg/kg. Additionally, means to provide a more thorough assessment of antipyretic efficacy (e.g., timed temperature and drug dosing measurement) may be more informative.

The potential for synergistic toxicity with alternating acetaminophen and ibuprofen has been raised in the published literature. Several published reports have addressed the potential for renal toxicity when acetaminophen and nonsteroidal anti-inflammatory agents, such as ibuprofen, are given together. Toxicity may be more likely to occur when volume depletion or reduced renal perfusion occurs. In this scenario, prostaglandin vasodilator effects may be inhibited by non-steroidal anti-inflammatory drug use, leading to renal ischemia. Oxidative metabolites of acetaminophen may accumulate in the renal medulla, resulting in medullary cellular necrosis. While evidence supporting this contention is limited, it cannot be discounted.

Conclusion

Acetaminophen and ibuprofen are equally effective as antipyretics, when appropriate dosages are employed. Alternating dosing of acetaminophen and ibuprofen is commonly recommended by physicians, and with the publication of the first controlled trial evaluating this treatment strategy, some support for its use is available. Unfortunately, this issue is not yet settled, as several methodological flaws limit the conclusions reached by this study. Additional studies evaluating maximized dosing regimens are needed. Until these studies are completed, pediatric clinicians should still consider acetaminophen or ibuprofen monotherapy, with maximal dosing when necessary, the preferred antipyretic pharmacotherapeutic management strategy.

For more information:

• Sarrell EM. Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch Pediatr Adoles Med. 2006;160:197-202.
• Del Vecchio MT. Alternating antipyretics: is this an alternative (comment). Pediatrics. 2001;108:1236-1237.
• Mayoral CE. Alternating antipyretics: is this an alternative? Pediatrics. 2000;105:1009-1012.
• McIntre SC. Acute flank pain and reversible renal dysfunction associated with nonsteroidal anti-inflammatory drug use. Pediatrics. 1993;92:459-460.
• Walson PD. Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child. 1992;146:626-632.
• Wilson JT. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J Pediatr. 1991;119:803-811
• Walson PD. Ibuprofen, acetaminophen, and placebo treatment of febrile children. Clin Pharma Therap. 1989;46:9-17.
• Edward Bell, PharmD, BCPS, is an Associate Professor of Pharmacy Practice at Duke University College of Pharmacy and a Clinical Specialist at Blank Children’s Hospital in Des Moines, Iowa.