Analgesic therapy failure in a COMT HPS/HPS diplotype carrier heterozygous for the CYP2D6 *4 allele with fibromyalgia—a case report

Abstract

Introduction: The cytochrome P450 enzyme 2D6 (CYP2D6) and the catechol-O-methyltransferase (COMT) enzyme are involved in catecholamine metabolism, potentially influencing pain modulation. Catechol-O-methyltransferase has 3 major haplotypes related to pain sensitivity: low (LPS), average (APS), and high (HPS). However, the reliability of these haplotypes in predicting clinical outcomes is not well investigated. We present a 40-year-old female patient with fibromyalgia. Despite extensive pharmacotherapy with 120 mg/ d duloxetine, 150 mg/d pregabalin, 80 mg/d oxycodone, 2 g/d paracetamol, and 1.6 g/d ibuprofen, she suffered from severe pain. Objectives: We aim to investigate the patient’s susceptibility to analgesic therapy failure (TF) and pain sensitivity with pharmacogenotyping. Methods: PGx panel testing, including CYP2D6 and COMT rs4680, was conducted by a commercial provider. Additional genotyping of COMT rs6269, rs4633 and rs4818 was performed applying PCR, restriction fragment length polymorphism assay and sanger sequencing. Results: The patient was identified as COMT HPS/HPS diplotype carrier and CYP2D6 intermediate metabolizer. CYP2D6 is mainly responsible for the bioactivation of oxycodone into oxymorphone. Reduced CYP2D6 activity may result in a lower oxycodone activation. Considering the coadministration of duloxetine (a moderate CYP2D6 inhibitor), the TF of oxycodone could also be the result of a drug–drug–gene interaction. No other medications were affected by her genetic profile. Conclusion: We hypothesize that the broad TF of pain medications and associated high pain sensitivity could be related to the patient’s genetic predisposition in CYP2D6 and COMT, warranting further investigation in a larger patient sample.