Elsevier

Clinical Therapeutics

Volume 32, Issue 14, December 2010, Pages 2433-2440
Clinical Therapeutics

Pediatric, adolescent, & maternal therapeutics
Original research
Efficacy of Standard Doses of Ibuprofen Alone, Alternating, and Combined With Acetaminophen for the Treatment of Febrile Children

https://doi.org/10.1016/j.clinthera.2011.01.006Get rights and content

Abstract

Background

Many pediatricians recommend, and many parents administer, alternating or combined doses of ibuprofen and acetaminophen for fever. Limited data support this practice with standard US doses.

Objective

This study compared the antipyretic effect of 3 different treatment regimens in children, using either ibuprofen alone, ibuprofen combined with acetaminophen, or ibuprofen followed by acetaminophen over a single 6-hour observation period.

Methods

Febrile episodes from children aged 6 to 84 months were randomized into the 3 treatment groups: a single dose of ibuprofen at the beginning of the observation period; a single dose of ibuprofen plus a single dose of acetaminophen at the beginning of the observation period; or ibuprofen followed by acetaminophen 3 hours later. Ibuprofen was administered at 10 mg/kg; acetaminophen at 15 mg/kg. Temperatures were measured hourly for 6 hours using a temporal artery thermometer. The primary outcome was temperature difference between treatment groups. Adverse-event data were not collected in this single treatment period study.

Results

Sixty febrile episodes in 46 children were assessed. The mean (SD) age of the children was 3.4 (2.2) years, and 31 (51.7%) were girls. Differences among temperature curves were significant (P < 0.001; the combined and alternating arms had significantly better antipyresis compared with the ibuprofen-alone group at hours 4 to 6 (hour 4, P < 0.005; hours 5 and 6, P < 0.001). All but one of the children in the combined and alternating groups were afebrile at hours 4, 5, and 6. In contrast, for those receiving ibuprofen alone, 30%, 40%, and 50% had temperatures >38.0°C at hours 4, 5, and 6, respectively (hour 4, P = 0.002; hours 5 and 6, P < 0.001).

Conclusion

During a single 6-hour observation period for these participating children, combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than ibuprofen alone at 4 to 6 hours. ClinicalTrials.gov identifier: NCT00267293.

Introduction

Despite a lack of evidence to support their fears, a majority of parents1, 2, 3, 4, 5, 6, 7 and pediatric health care providers8, 9, 10, 11 believe that fever can be dangerous to a child. This “fever phobia” has caused caregivers to treat fever aggressively with antipyretics such as ibuprofen and acetaminophen, often in combination.12 Although there are limited data to support the use of these medications together for the treatment of fever,13, 14, 15, 16, 17, 18 it has been reported that 50% of pediatric practitioners advise parents to alternate acetaminophen and ibuprofen in an attempt to achieve greater antipyresis.12

Pharmacologic evidence suggests that acetaminophen and ibuprofen may be well tolerated when used together because the 2 medications have different pathways of metabolism that are not affected by each other.19, 20, 21 Both drugs are generally well tolerated,22, 23, 24 with wide therapeutic margins if proper dosing is used, and a combined preparation of the 2 compounds has been available outside the United States for more than a decade.25 Furthermore, despite theoretical concerns regarding misdosing, reports of adverse events from alternating or combined use of acetaminophen and ibuprofen are rare given the frequency of coadministration of the 2 drugs.12 Because acetaminophen and ibuprofen are commonly coadministered to febrile children, further evidence on this practice is required. Thus, we conducted a 3-arm, randomized, controlled trial comparing the effectiveness of a single dose of ibuprofen with the combined administration of ibuprofen and acetaminophen, as well as ibuprofen followed 3 hours later by acetaminophen. Ibuprofen was chosen as the comparator instead of acetaminophen because clinicians prefer it for high fevers12 and because the single study that compared the 2 drugs when administered at their maximum recommended dose found no significant difference between them.26 We hypothesized that the 2 treatment groups using both ibuprofen and acetaminophen would experience greater antipyresis than would the group using ibuprofen alone during the 6-hour observation period.

Section snippets

Participants

From March 2006 through July 2009, children aged 6 months through 8 years were recruited from outpatient clinics and child day-care facilities to participate in this 6-hour-long study at a single academic medical center in Hershey, Pennsylvania. Inclusion criteria for the study required an initial temperature of ≥38.0°C when measured by a temporal artery thermometer (TemporalScanner, Exergen Corporation, Watertown, Massachusetts). A temperature of 38.0°C was chosen because it is the most widely

Results

Children with 60 febrile episodes meeting eligibility criteria were enrolled in this trial, with all 60 completing the 6-hour observation study. The mean (SD) age of participants was 3.4 (2.2) years and 31 (51.7%) were girls, with no significant difference between treatment groups (Table I). Forty-nine (81.7%) of the febrile episodes occurred in children who were white and non-Hispanic. The mean temperature at baseline was 38.7°C, again with no significant difference among treatment groups (

Discussion

This study found that over a single 6-hour observation period, combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than did ibuprofen alone. The findings from the last 3 hours of observation confirmed the hypothesis at the study's outset and are consistent with other studies that tested combinations of acetaminophen and aspirin decades ago.30, 31 Additionally, the data describing greater antipyresis in the treatment group in which ibuprofen and

Conclusions

The findings of this study suggest that combined and alternating doses of ibuprofen and acetaminophen provided greater antipyresis than ibuprofen alone at 4 to 6 hours in these children. Future studies may be needed to evaluate the safety of the antipyretic regimens described in this study and of repeated doses of these 2 drugs when used in combination.

Acknowledgments

This study was supported by a research grant from the George L. Laverty Foundation and in part by a General Clinical Research Center (GCRC) grant from the National Institutes of Health (M01RR10732) and a CGRC Construction Grant (C06RR016499) awarded to the Pennsylvania State University College of Medicine.

Dr. Paul had full access to all the data in the study and is responsible for the integrity of the data and the accuracy of the data analysis. Dr. Paul supervised all aspects of the project,

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