Evidence for morphine-independent central nervous opioid effects after administration of codeine: Contribution of other codeine metabolites

Lötsch, Jörn; Skarke, Carsten; Schmidt, Helmut; Rohrbacher, Maren; Hofmann, Ute; Schwab, Matthias; Geißlinger, Gerd

doi:10.1016/j.clpt.2005.09.005

Cited by 71 publications

(35 citation statements)

References 43 publications

(118 reference statements)

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“…Clinical studies in volunteers generally support the lack of analgesia in PMs, which is consistent with the belief that morphine is the key metabolite responsible for the antinociceptive effects of codeine (Desmeules et al, 1991;Sindrup et al, 1991;Poulsen et al, 1996b;Eckhardt et al, 1998). There is some evidence to suggest that other metabolites (e.g., codeine-6-glucuronide) may also contribute to the opioid effects (Lotsch et al, 2006). This contribution may explain the disparate findings of studies investigating the relationship between CYP2D6 and other opioid effects [e.g., slowed gastrointestinal (GI) transit time].…”

Section: Antipsychoticssupporting

confidence: 56%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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Section: Antipsychoticssupporting

confidence: 56%

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

2006

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“…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. 31 In addition, other non-Odemethylated metabolites might exert a certain opioid effect such as norcodeine, which is recovered in urine to 4%.…”

Section: Discussionmentioning

confidence: 79%

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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“…After oral administration of codeine, maximal plasma concentration is attained within 1 to 2 hours with plasma half-life of 2.5 to 3.5 hours and analgesia maintained for 4 to 6 hours (IR formulations). Codeine is partially metabolized to morphine and its metabolites and to codeine metabolites norcodeine (NORC) and codeine-6-glucuronide (C-6-G) (Lötsch et al, 2006). The analgesic effect of codeine is about equal to 1/10th of morphine analgesia.…”

Section: Codeinementioning

confidence: 99%

“…A pharmacokinetic/pharmacodynamic fit of the miotic effects by use of morphine as the only active compound was most significantly (P < 0.0001) improved when C-6-G as a second active moiety was added. CYP2D6-dependent formation of morphine does not explain exclusively the central nervous effects of codeine, and C-6-G is the most likely additional active moiety with possible contribution of NORC and the parent compound (Lötsch et al, 2006). Gasche et al depicted a patient who received oral codeine in a daily dose of 75 mg (25 mg three times a day) and who, after 4 days of treatment, experienced respiratory depression.…”

Section: Codeinementioning

confidence: 99%

“…Guidelines for maternal codeine use during breastfeeding were issued in Canada (Madadi et al, 2009a) but it seems safer not to use codeine and substitute it with other analgesics in this patient group. Apart from morphine glucuronides, codeine and its metabolites (C-6-G and NORC) also contribute to codeine analgesic effects (Lötsch et al, 2006).…”

Section: Codeinementioning

confidence: 99%

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