Clinical Pharmacy

Clinical Pharmacy Note Regarding: Is the combination of acetaminophen and ibuprofen superior to either drug alone at decreasing fever and maintaining that reduction in children?

Background:

Acetaminophen (paracetamol) and ibuprofen are considered to be the most commonly used analgesic/antipyretic over the counter products for the treatment of fever and pain in children They are often misused by parents or caregivers when given to febrile children and can lead many parents to the emergency department for further treatment Many parents tend to use the incorrect dose (under dosing more frequent than overdosing) when administering acetaminophen and ibuprofen liquid to their children despite the fact that dosing devices are being provided

Acetaminophen increases the pain threshold and reduces pain in the CNS by inhibiting cyclooxygenase COX-1 and COX-2, a collection of enzymes involved in prostaglandin (PG) synthesis. It does not inhibit cyclooxygenase in the periphery; thus it does not have peripheral anti-inflammatory or anti-platelet properties like ibuprofen.2 In addition, acetaminophen acts as an analgesic by inhibiting the synthesis or actions of chemical mediators that sensitize the pain receptors to mechanical or chemical stimulation.2 Its antipyretic effect is exerted by blocking endogenous pyrogen on the hypothalamic heat-regulating center due to PG synthesis.2 Acetaminophen can be given orally (tablet, liquid form or rectally (suppository).2 It is primarily metabolized in the liver via glucuronidation and sulfate conjugation and only 10-15% undergoes CYP450 (CYP 2E1 and 1A2) oxidative metabolism leading to the formation of a heaptotoxic metabolite.2Its half life in patients with normal liver function is about 2-4 hours and is mostly excreted as the glucuronide conjugate.2 When taken orally, acetaminophen is rapidly absorbed from the GI tract and reaches the peak plasma concentrations within 30-60 minutes.2 Only 25% of the dose undergoes first pass metabolism and 85% is excreted in the urine.2 Dose adjustment is necessary in patients with hepatic failure.2 It is considered to be preferred over NSAIDs because it has fewer hematologic, renal, and GI issues.2 Acetaminophen overdose is the major adverse effect leading to hepatotoxicity. 2

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) which inhibits cyclooxygenase isoenzymes, COX-1 and COX-2 by blocking arachidonate binding thus exerting analgesic, antipyretic, and anti-inflammatory effects.2 It acts both centrally and peripherally.2 COX-1 is present in almost all tissues and is involved in prostaglandin synthesis and maintenance of normal renal function, hemostasis, and gastric mucosal integrity.2 COX-2 is mainly present in bones, brain, kidney, reproductive organs and some neoplasms and it can be induced in many cells by mediators of inflammation.2 Antipyretic activity is exerted by suppressing the synthesis of prostaglandins (PGE2) in circumventricular organs in and near the hypothalamus and thus returning to normal body temperature.2 Ibuprofen can be given orally and intravenously.2 The volume of distribution depends in patient age and body temperature.2 It is highly protein bound at serum concentrations>20mcg/ml.2 It is metabolized via hepatic CYP450 2C9 oxidative metabolism to inactive metabolites.2 The half life is between 2-4 hours and is excreted in the urine (50-60% as metabolites and 10% as unchanged drug).2Once administered, the bioavailability is similar among the dosage forms but the suspension form reaches the peak concentration the fastest and the tablet form is the slowest2. In children, oral ibuprofen decreases fever within the first hour and reaches the maximum effect within 2-4 hours.2 The major adverse effects to ibuprofen are GI bleeding, renal failure and hypersensitivity reactions.2

Literature search:

Literature search was conducted using PubMed. Key words used included acetaminophen, ibuprofen, and fever reduction in children. The search was limited to humans, English language, children and clinical trials. The number of articles found was 11, however, 1 article was chosen for further evaluation.

Literature Analysis:

Hay at al. performed an individualized, randomized blinded controlled three arm trial in primary care and households in England in which 156 febrile children participated They were recruited and followed up between January 2005 and May 2007. The inclusion criteria required children between 6 months and 6 years old with axillary temperatures of at least 37.8oC and up to 41oC Although groups were comparable at baseline; there could have been some differences such as sex, method of recruitment, and activity Upon completion of a questionnaire, children were randomly assigned to one of the three trial arms (acetaminophen alone, ibuprofen alone, acetaminophen plus ibuprofen)Parents received two medicine bottles; one or both with active drugs; the other was placebo. The dose of the drug was based on the child's weight. Acetaminophen was dosed at 15 mg/kg per dose every 4-6 hours (maximum of four does in 24 hours) Ibuprofen was dosed at 10 mg/kg per dose every 6-8 hours (maximum of three doses in 24 hours) The doses were measured at the baseline visit and the first doses were given in the presence of a research nurse and were timed so that they could coincide with the child's next dose Parents were asked to give the drugs from four to 24 hours for up to 28 hours based on the child's symptoms. After 48 hours, the parents were informed to use over the counter products if necessary

The primary endpoints of the study were the number of minutes without fever (<37oC) in the first four hours and the number of children who reported as being comfortable based on a discomfort scale after fever relief at 48 hours Secondary outcomes were fever clearance, the time spent without fever over 24 hours, and fever associated symptoms such as decreased appetite, sleep disturbances, discomfort and reduced activity Parents were asked regarding the fever associated symptoms, adverse effects and temperature at 48 hours and at day 5. At the end of the study, almost all children experienced some type of discomfort symptoms

Ibuprofen showed to be superior to acetaminophen in decreasing fever faster and for longer in the first four hours Children in the ibuprofen group spent an extra 39 minutes without fever when compared to the acetaminophen group In addition, acetaminophen plus ibuprofen showed to reduce fever faster and for longer than acetaminophen alone in the first four hours Children in the acetaminophen plus ibuprofen group spent 55 extra minutes without fever in the first four hours when compared to acetaminophen(adjusted difference 55 minutes, 95% CI 33 to 77;p<0.001). Children in the ibuprofen group in comparison to acetaminophen group showed to reduce fever as good as acetaminophen plus ibuprofen group in the first four hours(16 minutes,-7 to 39 minutes;p=.2).

Acetaminophen plus ibuprofen showed to be better than acetaminophen at reducing fever and maintaining that reduction over 24 hours (4.4 hours, 95%CI 2.4-6;p<0.001) and when compared to ibuprofen (2.5 hours, 95% CI 0.6-4.4, p<0.008). In conclusion, acetaminophen plus ibuprofen was more effective in increasing time without fever by 4.4 hours when compared with acetaminophen and by 2.5 hours when compared with ibuprofen. There were no major differences in the adverse effects and the fever associated symptoms between groups

Summary:

* Parents, caregivers, or health care professionals taking care of febrile children should be recommended to use ibuprofen first and consider using the combination therapy (acetaminophen plus ibuprofen) over 24 hours

* Administer ibuprofen based on the child's weight 10 mg/kg by mouth every 6-8 hours

* Administer acetaminophen based on child's weight 15 mg/kg by mouth every 4-6 hours

* Monitor the child for any signs of dehydration (e.g., a decrease in urination), or if the child becomes delirious

* Other non-pharmacological interventions are such as: drink plenty of fluids, lightweight dressing, lightweight bedding, and cool room temperature

* Primary care provider should be contacted if high fever (>104oF) persists for more than 24 hours

* Monitor the child for any side effects such as GI upset which is common with ibuprofen and can be reduced if taken with food or milk

* Advise parents to always measure the dose with the appropriate measuring device in order prevent overdose

* Monitor the child for adverse effects such as GI bleeding, renal failure with ibuprofen and acetaminophen hepatotoxicity

 

References:

1. Dlugosz CK, Chater RW, Engle JP. Appropriate Use of Nonprescription Analgesics in Pediatric Patients. J Pediatr Health Care. 2006; 20: 316-325. http://www.jpedorg.com/cgi/content/full/20/316-325. Accessed March 14, 2010.

2. Clinical Pharmacology Web site. http://cpip.gsm.com.ezproxy.samford.edu/. Accessed March 14, 2010.

3. Hay AD, Costelloe C, Redmond NM. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomized controlled trial. BMJ.2008; 227:a1302. http://www.bmj.com/cgi/content/full/337/337:a1302

Accessed March 7, 2010.

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