Quick Onset of Severe Abdominal Pain After Codeine in an Ultrarapid Metabolizer of Debrisoquine

Abstract

The authors describe a 33-year-old woman who experienced severe pain in the epigastrium after codeine intake. This side-effect is consistent with that of morphine. Later, the patient was phenotyped and genotyped as an ultrarapid metabolizer with high capacity to metabolize codeine to morphine.

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication

“…The obtained PCR product was used as a template for the single-base primer extension reaction (SNaPshot, Applied Biosystems) designed to genotype the polymorphic position 4180G4C of the upstream gene-copy and positions À1584G4C and 100C4T of the downstream gene-copy. The following primers were used for the extension reactions: À1584G4C, 5 0 -(A) 9 CCT GGA CAA CTT GG AAG AAC C-3 0 ; 100C4T, 5 0 -(A) 31 CAA CGC TGG GCT GCA CGC TAC-3 0 and 4180G4C, 5 0 -(A) 37 CAA AGC TCA TAG GGG GAT GGG-3 0 . The single-base primer extension reactions were performed according to the manufacturer's instructions (SNaPshot, Applied Biosystems, Weiterstadt, Germany).…”

“…8 On the other hand, several case reports have described severe opioid side effects after intake of codeine in individuals later identified as ultra-rapid metabolizers (UM) of CYP2D6 substrates. 9,10 The CYP2D6 gene duplication leads to ultra-rapid metabolism if the duplicated genes are fully active and if the duplication is combined with another active CYP2D6 allele. Usually, these individuals have high CYP2D6 activity, and a nearly linear gene-dose effect depending on the number of active CYP2D6 alleles has been shown.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Theoretically, UMs may convert codeine to morphine more rapidly, thus resulting in increased opioid effects for a given dose. Evidence for this theory is suggestive but is limited to isolated case reports (Dalen et al, 1997;Gasche et al, 2004).…”

Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications

“…For example, coadministration of the antiarrhythmic quinidine with codeine to an EM individual can result in the loss of the analgesic effect of codeine because of the inhibition of CYP2D6 by quinidine [15]. Conversely, codeine given to UMs can result in excessive formation of morphine, leading to side effects such as abdominal pain [60].…”

“…This is exemplified by the TCA nortryptyline (Pamelor ® ; Mallinckrodt Inc., St. Louis), which is effective in PMs at doses as low as 10-20 mg, but which requires doses up to 500 mg in UMs [61]. Thus, administration of standard doses of CYP2D6-metabolized drugs to UM individuals may result in therapeutic failure because of a low plasma concentration of active drug [14], or conversely, may lead to supratherapeutic levels of active metabolite formation and potentially serious side effects [60].…”