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Take another look at acetaminophen, ibuprofen or both for managing fever
In a survey, half of 161 pediatricians said they advised parents to alternate doses of acetaminophen and ibuprofen for their child’s fever.
This month’s Pharmacology Consult column reviews a common topic discussed in several past columns — the use of acetaminophen or ibuprofen for fever.
Why this topic again, some readers may wonder? Parents frequently use both of these medications. Acetaminophen and ibuprofen have been compared in many published evaluations, and 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 by Sarrell et al, and will be discussed in this month’s column.
The use of alternating doses of acetaminophen and ibuprofen for the treatment of fever in children is relatively common, despite no evidence documenting its efficacy. In 2000, Mayoral et al published results of a survey of pediatricians’ prescribing habits of acetaminophen and ibuprofen in the treatment of fever. Of 161 pediatricians surveyed, 50% have advised parents to alternate doses of acetaminophen and ibuprofen for their child’s fever. Although 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 results
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 about 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 (about 104.9°F) did not differ among the groups initially. Differences in mean height of fever became apparent between the monotherapy groups (about 103.1°F) and the alternating treatment group (about 101.3°F) on days 2 and 3 (P <0.001). Loading doses with either acetaminophen or ibuprofen had no statistical effect. The mean height of fever in all groups at day 3 was greater than 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 <.001). Although 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 <.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 with the monotherapy groups (P <.001). Children receiving alternating doses received fewer antipyretic medication doses per day (1.48-2.57) as compared with the monotherapy groups (2.84-4.33).
| Dosing of Acetaminophen and Ibuprofen for Fever | ||
| Drug | Dose | Comments |
| Acetaminophen |
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| Ibuprofen |
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| Alternating acetaminophen and ibuprofen |
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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. An additional benefit of the trial by Sarrell et al 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.
Study limitations
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 to 15 mg/kg. Ibuprofen was dosed at the low end of the accepted dosing range of 5 to 10 mg/kg.
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 (eg, 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 compared with 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, 5, 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.
Thus, the doses employed by Sarrell may not be the most appropriate comparative regimens when evaluating single-drug therapy with alternating dosing therapy. Sarrell addressed how the monotherapy dosing regimens were chosen, although the data supporting the chosen dose are not clear, as the reference cited for ibuprofen is a safety study of ibuprofen 5-10 mg/kg. Other methodological concerns include assessment of antipyretic effects of the dosing regimens. Using maximal daily temperature, while helpful, may not be as accurate a measure of antipyretic efficacy as the methods used in the studies mentioned above, where temperatures were obtained at discrete time points after drug administration. It is not clear in the study by Sarrell when body temperatures were taken in relationship to drug administration. The study by Sarrell was double-blind, as the medication bottles dispensed at study initiation were similar. However, the dosing regimens were not similar – every 6 hours for acetaminophen, every 8 hours for ibuprofen and every 4 hours for alternating acetaminophen and ibuprofen. It is possible that this may have affected some parents’ assessment of stress scoring or other assessments. The scale used to assess child stress primarily seemed to measure pain, which may be affected by other factors other than body temperature.
Although it is useful to assess additional clinical measures of fever other than temperature, such as missed day care, and other factors, such as individual parent comfort level for return to day care, may affect missed day care or parental work time.
In summary, 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 (eg, 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 nonsteroidal anti-inflammatory drug use, leading to renal ischemia. Oxidative metabolites of acetaminophen may accumulate in the renal medulla, resulting in medullary cellular necrosis. Although evidence supporting this contention is limited, it cannot be discounted.
Conclusion
Fever is a common clinical scenario encountered by pediatric clinicians, and drug therapy with acetaminophen or ibuprofen is frequently recommended. Acetaminophen and ibuprofen are equally effective as antipyretics, when appropriate dosages are employed. Alternating dosing of acetaminophen and ibuprofen is commonly recommended by pediatricians, 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, Wietunsky E, Cohen HA. 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, Sundel ER. Alternating antipyretics: is this an alternative (comment). Pediatrics. 2001;108:1236-1237.
- Mayoral CE, Marino RV, Rosenfeld W, et al. Alternating antipyretics: is this an alternative? Pediatrics. 2000;105:1009-1012.
- McIntire SC, Rubenstein RC, Garther JR Jr, et al. Acute flank pain and reversible renal dysfunction associated with nonsteroidal anti-inflammatory drug use. Pediatrics. 1993;92:459-460.
- Walson PD, Galletta G, Chomilo F, et al. Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child. 1992;146:626-632.
- Wilson JT, Brown RD, Kearns GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J Pediatr. 1991;119:803-811.
- Walson PD, Galletta G, Braden NJ, et al. Ibuprofen, acetaminophen, and placebo treatment of febrile children. Clin Pharma Therap. 1989;46:9-17.