Published online July 2, 2007
PEDIATRICS Vol. 120 No. 1 July 2007, pp. 237 (doi:10.1542/peds.2007-0768)
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LETTER TO THE EDITOR

Do We Need to Incorporate Pharmacogenetics in Randomized, Controlled Trials of Frequently Used Medicines?

John N. van den Anker, MD, PhD
Department of Pediatrics
George Washington University
Washington, DC 20010

To the Editor.—

Clark et al1 reported that in children 6 to 17 years old with pain from a musculoskeletal injury, ibuprofen (10 mg/kg) provided the best analgesia as compared with acetaminophen (15 mg/kg) and codeine (1 mg/kg). In their well-designed randomized, controlled trial, they used the standard doses of these 3 medications. However, it is important to note that although ibuprofen was more efficacious in providing adequate analgesia, only 52% of the children in this group could be defined as receiving "adequate analgesia," which left 48% of the children with "inadequate analgesia." Is this because the wrong dose was used, or does this reflect interindividual variation in pharmacokinetics and/or pharmacodynamics of the investigated medications? As a consequence, the question arises of whether the incorporation of pharmacogenetic analysis of drug-metabolizing enzymes, transporters, and/or receptors involved in the pharmacokinetics/pharmacodynamics of these drugs might result in more individualized adequate analgesia. In the case of ibuprofen, there is compelling information2 that mutations in cytochrome 2C8 (CYP2C8) significantly change the clearing capacity of the individuals who are heterozygous or homozygous mutants for this drug-metabolizing enzyme. Perhaps these individuals are represented by the children in this study who received adequate analgesia because they were just exposed longer to higher concentrations. I would like to hear from the authors how many children reached adequate analgesia in the codeine and acetaminophen groups. Especially the use of codeine, which is a prodrug and needs metabolism to morphine using cytochrome 2D6 (CYP2D6), clearly depends on the CYP2D6 phenotype of the children exposed to this drug.3

In general, I believe that in the (near) future incorporation of a pharmacogenetic component in randomized, controlled trials might improve the clinical usefulness of the results of these state-of-the-art investigations. Ideally, one would like to randomly assign children who have the same genetic background as it relates to drug-metabolizing enzymes, transporters, and receptors to be able to really decipher the differences between the drugs used for pain relief.

REFERENCES

  1. Clark E, Plint AC, Correll R, Gaboury I, Passi B. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics. 2007;119 :460 –467[Abstract/Free Full Text]
  2. Martinez C, Garcia-Martin E, Blanco G, Gamito FJ, Ladero JM, Agundez JA. The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol. 2005;59 :62 –69[CrossRef][ISI][Medline]
  3. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder JS. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet. 2006;368 :704[CrossRef][ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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S. Ali and T. P Klassen
Ibuprofen was more effective than codeine or acetaminophen for musculoskeletal pain in children
Evid. Based Med., October 1, 2007; 12(5): 144 - 144.
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