Understanding the Impact of Allelic Gene Variants on Pediatric Pain Relief
Studies have shown that higher expression of CYP2D6 alleles in adults results in excessive production of active metabolites, leading to either therapeutic failure, increased exposure, or more severe adverse effects.
Pharmacogenomics, the study of genetic variants that impact drug effects, has been well studied and integrated into pain management practice for adults. The CYP2D6 cytochrome P450 enzyme responsible for opioid metabolism has more than 80 unique alleles and variations in expression known to affect both drug metabolism and efficacy of these drugs.1
Studies have shown that higher expression of CYP2D6 alleles in adults results in excessive production of active metabolites, leading to either therapeutic failure, increased exposure, or more severe adverse effects.2
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Pain Reports highlighted a recent Canadian study that looked at how the metabolic function of CYP2C9 or CYP3A4/CYP2D6 would affect the clinical effectiveness and safety of ibuprofen or oxycodone prescribed to children aged 4 to 16 years discharged from the emergency department (ED) with acute, non-operative fracture.
The primary genetic study outcomes measured the frequency of known CYP2C9, CYP3A4, and CYP2D6 allelic variants for ibuprofen and oxycodone. Clinical outcome measures were post-medication use pain score reduction and occurrence of adverse events on days 1 to 3 after ED discharge.3
A total of 210 children (n = 140 ibuprofen and n = 70 oxycodone) had DNA analyses for inclusion in the study. Just over one-quarter of the children in the study had an allelic variation known to impact clinical outcomes for CYP2C9 and over one-third had “nonnormal” phenotype classification. Less than 4% of the children showed decreased CYP3A4 functioning alleles and over one-third had decreased functioning phenotype for CYP2D6.3
Although this study assessed the clinically relevant impact of variation in metabolic phenotypes on pain to personalize treatment for children, the results show that CYP2D6 and CYP3A4 allelic variants did not alter the clinical effectiveness or adverse events associated with oxycodone. The study also found children with a CYP2C9*2 variant allele given ibuprofen had fewer adverse event occurrences instead of the expected increase seen in adults in previous studies.3
Due to the small sample size, confirmation of these results from a larger population may help further determine if allelic variations known to affect adult pain medication metabolism, including rarer CYP variants, also impact clinical outcomes in children. Perhaps children’s metabolism and ibuprofen’s clinical effects are influenced by more than pharmacogenetics alone.
A better understanding of pharmacogenetics in children may support individualized tailoring of drug choice to minimize adverse reactions and optimize medication response but further studies are needed.
REFERENCES
1. Kaye AD, Garcia AJ, Hall OM, et al. Update on the pharmacogenomics of pain management. Pharmgenomics Pers Med. 2019;12:125-143. doi:10.2147/PGPM.S179152
2. Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology. 2011;87(5-6):274-285. doi:10.1159/000326085
3. Ali S, Yukseloglu A, Ross CJ, et al. Effects of pharmacogenetic profiles on pediatric pain relief and adverse events with ibuprofen and oxycodone. Pain Rep. 2023;8(6):e1113. doi:10.1097/PR9.0000000000001113
