Acetaminophen or ibuprofen for fever: Does it matter?

September 2002

Acetaminophen and ibuprofen are among the most commonly used drugs in children, if not the most commonly used. Despite this commonality and years of experience with their use, controversy over the most appropriate means of using these drugs continues to exist. Which agent is most effective? What dose and dosing schedule should be used? Does it matter which agent and dose are used? Is alternating one agent with the other more effective than using one agent alone?

These questions probably arise frequently, although they may not be given much conscious thought. Clinicians are generally aware that fever, the main indication for use of acetaminophen or ibuprofen, in-and-of-itself, is not inherently concerning. The underlying cause of the fever, the overall health of the patient and the adverse effects of the fever on the patient are generally worthy of more consideration by clinicians. Published evidence indicates that fever plays a beneficial role in the immune response to infection. On the other hand, parents often view fever as a serious concern and an indication for immediate drug therapy. “Fever phobia” has been documented and described in the literature. Because of these considerations, it becomes interesting to review the published literature for the use of these agents.

Acetaminophen has been available as an antipyretic for use in children for over 25 years. Ibuprofen has become available over-the-counter (OTC) only relatively recently (approximately seven years ago). The relative efficacy and dosing of acetaminophen and ibuprofen remain controversial. Acetaminophen frequently is mentioned in published review articles as the antipyretic agent of choice, while ibuprofen is also commonly recommended to be given for “high fevers,” implying it is more “potent” or is a more effective antipyretic. Acetaminophen may often be recommended initially perhaps because of the years of clinical experience we have with it, and because of its proven safety profile (when given in therapeutic doses). Ibuprofen may be regarded by some as more “potent” (and thus more effective) because of published studies (see below) and perhaps because of its change from prescription to OTC availability.

Studies reviewed

Numerous studies have been published comparing acetaminophen with ibuprofen. A thorough evaluation of all these studies is beyond the scope of this column. However, several recent trials will be discussed. While numerous studies have been published, the quality and usefulness of many of them are limited. Concerns can be raised about the appropriateness of comparative dosing, therapeutic endpoints used to evaluate efficacy, questionable statistical analysis and small patient numbers. The most concerning limitation of many of these studies is comparative dosing. The generally accepted dosing for acetaminophen is 10-15 mg/kg/dose given every four to six hours (maximum of five doses/24 hours); dosing for ibuprofen is 5-10 mg/kg/dose every six to eight hours (maximum 40 mg/kg/24 hours). The OTC labeled dose for ibuprofen is 7.5 mg/kg/dose. Many studies have compared acetaminophen with ibuprofen “mg-for-mg” (ie, 10 mg/kg ibuprofen compared with acetaminophen 10 mg/kg), an inappropriate comparison. Additional studies have compared various other doses, eg, ibuprofen 7 mg/kg to acetaminophen 8 mg/kg or ibuprofen 7.5 mg/kg to acetaminophen 10 mg/kg. The most appropriate comparison would seem to be minimal dose vs. minimal dose or, more importantly, maximal dose vs. maximal dose (ie, ibuprofen 10 mg/kg/dose compared with acetaminophen 15 mg/kg/dose). Comparing acetaminophen and ibuprofen at these doses in a randomized, blinded, controlled manner in a large number of patients, with assessment for clinical improvement, would be most revealing for comparisons of efficacy. It would be important to assess appropriate efficacy parameters – absolute temperature reduction or temperature reduction — in concert with clinical efficacy (eg, assessment for improvement in patient comfort or fluid and nutritional intake). Few studies meet these criteria.

One study compared ibuprofen liquid at doses of 2.5, 5 or 10 mg/kg every six hours to acetaminophen liquid 15 mg/kg every six hours in a randomized, double-blind, multidose (24-48 hours), parallel-group manner. Sixty-one febrile (39°-40.5°C) children were evaluated; the most common diagnosis was viral pharyngitis. Ibuprofen at doses of 2.5 mg/kg and 5 mg/kg was less effective (rate of temperature reduction and maximal reduction of fever) than ibuprofen 10 mg/kg and acetaminophen 15 mg/kg for the first dose only. For all doses thereafter there were no differences in temperature reduction among the four treatment groups. Ibuprofen 10 mg/kg was similarly effective to acetaminophen 15 mg/kg for all doses. Other published studies comparing maximal doses of each agent were not identified in a search of the literature.

As described above, other studies have compared acetaminophen to ibuprofen in a variety of doses and in a variety of study designs (many of which are of questionable quality). Some studies found equivalent efficacy among various doses (eg, ibuprofen 5 mg/kg = acetaminophen 12.5 mg/kg; ibuprofen 10.3 mg/kg = acetaminophen 9.8 mg/kg [mean doses]), while other study authors concluded that ibuprofen was more effective (eg, ibuprofen 7.5 mg/kg and 10 mg/kg > acetaminophen 10 mg/kg). When differences in temperature reduction were found among acetaminophen and ibuprofen, the difference typically was 0.8°C or less. For most of these studies, correlations with clinical effect (ie, patient comfort) were not made. Thus, one may wonder if such a difference, while perhaps statistically significant, is clinically significant. One study evaluated not only comparative efficacy of acetaminophen (12.5 mg/kg) and ibuprofen (5, 10 mg/kg) in a single-dose design but also assessed the pharmacodynamics and pharmacokinetics of each drug. A complex assessment of various measurements of temperature reduction was completed. The investigators concluded that various factors may affect the response to antipyretic therapy, including initial temperature and age of the child. Antipyretic efficacy was increased in children with lower initial temperatures (<38.8°C), a finding the authors described as “nonlinear pharmacodynamics.” Maximal antipyresis was found to occur at approximately four hours for both drugs. The investigators additionally concluded that ibuprofen 10 mg/kg was more effective for antipyresis than acetaminophen 12.5 mg/kg.

Thus, it is reasonable to question the results of studies comparing ibuprofen 10 mg/kg with acetaminophen at doses <15 mg/kg. Pharmacodynamic studies of acetaminophen alone suggest that it exhibits a dose-response effect for doses greater than 10 mg/kg. Comparisons of maximal doses of each agent would appear to be the most appropriate.

An additional limitation on many published comparative studies of acetaminophen and ibuprofen includes a lack of clinical assessment for drug efficacy. One may surmise that a reduction in absolute febrile temperature equates to clinical improvement, manifesting as subjective improvement or improvements in nutritional intake or sleep. With differences in temperature reduction typically of less than 1°C between ibuprofen and acetaminophen in studies, differences in clinical scores may not be significant. One study (ibuprofen 10 mg/kg compared to acetaminophen 12.5 mg/kg) did evaluate for changes in irritability and clinical condition using clinical scoring scales and found no differences among the groups.

Alternating doses

The use of alternating doses of acetaminophen and ibuprofen is a common practice that has no published literature support as compared with the use of acetaminophen or ibuprofen alone. A survey of pediatric practitioners published in 2000 found interesting results. The investigators surveyed 161 pediatric practitioners during a professional meeting. Fifty percent of respondents stated that they recommend alternating acetaminophen with ibuprofen for fever to their patients. Thirty-one percent of these did not recommend a specific method for alternating agents. Of those who did specify a regimen, several methods were given. The most commonly recommended method was acetaminophen every four hours alternating with ibuprofen every six hours. Extrapolating this method to the 12-hour mark leads to the potential for administration of both drugs, as both are due at this time. With this method, and others, it is not difficult to imagine the confusion caregivers may develop. Thirty-three percent of surveyed practitioners generally recommend acetaminophen 10 mg/kg every 4 hours (a dose potentially producing less than desirable results) as their treatment of choice. Respondents were also surveyed on their basis for choosing a specific regimen. Twenty-nine percent stated American Academy of Pediatrics guidelines’ on the treatment of fever, guidelines which do not exist. The results of this survey indicate room for improvement in the therapy of fever.

The treatment of fever, a very common therapeutic scenario in the pediatric population, remains controversial. Both acetaminophen and ibuprofen are effective antipyretic agents. They should be considered equal in their efficacy. Published studies concluding that one agent is more effective than the other are limited in their design, often evaluating these drugs in inappropriate comparative dosage regimens. The use of alternating acetaminophen with ibuprofen has not been proven to be beneficial over the use of maximal doses of either agent and may only lead to confusion among caregivers and an increased potential for dosing errors. It is important to educate caregivers on the natural course of fever and its clinical impact as well as the goals of treatment. Although both acetaminophen and ibuprofen are safe when used appropriately, the potential for serious hepatotoxicity with acetaminophen dictates that practitioners review and stress with caregivers the importance of proper dosing, dose measurement, dosage form selection and poison prevention.

For more information:

• Walson PD. Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child. 1992;146:626-32.
• Wilson JT. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J Pediatr. 1991;119:803-11.
• McIntyre J. Comparing efficacy and tolerability of ibuprofen and paracetamol in fever. Arch Dis Childhood. 1996;74:164-7.
• Mayoral CE. Alternating antipyretics: is this an alternative? Pediatrics. 2000;105:1009-1012.
• Temple AR. Pediatric dosing of acetaminophen. Pediatr Pharmacol. 1983;3:321-7.