The role of active metabolites in dihydrocodeine effects

Schmidt, Helmut; Vormfelde, Stefan Viktor; Walchner-Bonjean, Monika; Klinder, Klaus; Freudenthaler, Stefan M.; Gleiter, Christoph H.; Gundert‐Remy, Ursula; Skopp, Gisela; Aderjan, R.; Fuhr, Uwe

doi:10.5414/cpp41095

Cited by 46 publications

(35 citation statements)

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“…Interestingly, the small PM group had a even longer period of miosis, an observation that was however statistically not significant owing to the small sample size. This finding is similar to that for dihydrocodeine, which also leads to miosis in individuals (PMs) not metabolizing dihydrocodeine to dihydromorphine, 29 and also fits to recent data where an additional effect of codeine itself on miosis was observed when comparing equal concentrations of morphine and its metabolites with or without codeine. 30 These observations suggest that single dose of codeine has an opiate receptormediated effect of its own despite its 7-14 times lower potency than morphine.…”

Section: Discussionsupporting

confidence: 90%

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

et al. 2006

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Codeine is an analgesic drug acting on m-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17) mg h l À1 in EMs and 16 (10-24) mg h l À1 in UM (P ¼ 0.02). In urine collected over 12 h, the metabolic ratios of the codeine þ codeine-6-glucuronide divided by the sum of morphine þ its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P ¼ 0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P ¼ 0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.

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Section: Discussionsupporting

confidence: 90%

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

et al. 2006

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“…EMs have 7-fold higher dihydromorphine concentrations (Fromm et al, 1995), with quinidine producing a 3-to 4-fold decrease in dihydromorphine concentrations (Wilder-Smith et al, 1998). Contrary to what might be expected, dihydrocodeine 60 mg seems to produce similar analgesic effects in EM and PM volunteers (Wilder-Smith et al, 1998;Schmidt et al, 2003). However, in one of the studies, no analgesic effect of dihydrocodeine was seen in the pain threshold model in either EMs or PMs, whereas pupillary diameter was PHARMACOGENETICS, DRUG METABOLISM, AND CLINICAL PRACTICE reduced comparably in both groups (Schmidt et al, 2003).…”

Section: Antipsychoticsmentioning

confidence: 92%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…It may be concluded that DHC undergoes the first pass effect after oral administration, which is connected with the formation of significantly higher amount of metabolites after oral than after parenteral administration (Rowell et al, 1983). Studies performed to date (Schmidt et al, 2003;Webb et al, 2001) indicate that DHC analgesia is independent of CYP2D6 activity (Leppert and Majkowicz, 2010).…”

Section: Dihydrocodeinementioning

confidence: 99%

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients

Leppert¹

2012

Pain Management - Current Issues and Opinions

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The role of active metabolites in dihydrocodeine effects

Cited by 46 publications

References 0 publications

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

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

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

The Role of Opioid Analgesics in the Treatment of Pain in Cancer Patients

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