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Diclofenac does not interact with codeine metabolism in vivo: a study in healthy volunteers.

Ammon S, Marx C, Behrens C, Hofmann U, Mürdter T, Griese EU, Mikus G - BMC Clin Pharmacol (2002)

Bottom Line: In terms of side effects, both treatments were well tolerated.Diclofenac did not significantly influence the analgesic effects of codeine in the cold pressor test.In contrast to recent in vitro data, a single oral dose of diclofenac did not alter the glucuronidation of codeine in healthy volunteers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Internal Medicine VI - Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany. susanne.ammon@medizin.uni-magdeburg.de

ABSTRACT

Background: Previously, we have demonstrated a marked inhibition of codeine glucuronidation by diclofenac in human liver tissue homogenate. We therefore aimed to investigate whether diclofenac inhibits glucuronidation of codeine also in vivo in healthy volunteers.

Methods: In a randomised, placebo-controlled, double-blind, cross-over study, 12 healthy volunteers received a singe of 100 mg codeine phosphate plus 50 mg diclofenac sodium or codeine phosphate plus placebo. Over a 36 hour period serum concentrations of codeine and its metabolites as well as urinary excretion were analysed using LC-mass spectrometry. Side effects were recorded and analgesic efficacy was determined using the cold pressor test (0-6 h).

Results: A single dose of diclofenac did not alter the formation of codeine-6-glucuronide in healthy volunteers. Metabolic clearance of codeine to morphine was not affected by diclofenac. In terms of side effects, both treatments were well tolerated. Diclofenac did not significantly influence the analgesic effects of codeine in the cold pressor test.

Conclusions: In contrast to recent in vitro data, a single oral dose of diclofenac did not alter the glucuronidation of codeine in healthy volunteers.

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The chemical structures of codeine and its major metabolites in humans.
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Figure 1: The chemical structures of codeine and its major metabolites in humans.

Mentions: The weak opioid codeine is widely used in the management of pain. Various studies have demonstrated a synergistic analgesic effect of an opioid-NSAID combination [1-4], particularly if repeated doses are given. [5-7] The synergistic effect is thought to be caused by the known different pharmacodynamic mechanisms, opioids acting via opioid receptors in the central nervous system, NSAIDs affecting the synthesis of prostaglandins due to inhibition of the enzyme cyclooxygenase. NSAIDs have also been postulated to display additional antinociceptive effects in the central nervous system. [8] Moreover, a synergistic effect is also possible via a pharmacokinetic interaction between the two classes of drugs: NSAIDs may decrease the renal excretion of the pharmacologically active metabolite of morphine M-6-G (morphine-6-glucuronide).[9] We have previously demonstrated a marked inhibition of codeine glucuronidation in human liver tissue homogenate by diclofenac (Ki of 7.9 μM).[10] Others have shown [11] a more than 50% inhibition of the glucuronidation of the codeine structural analogue, dihydrocodeine, by 50 μM diclofenac in vitro. Codeine is predominantly metabolised by glucuronidation to C-6-G (codeine-6-glucuronide) (Figure 1). Minor metabolic pathways include N-demethylation to norcodeine and O-demethylation to morphine.[12,13] The latter is catalysed by the polymorphically expressed CYP2D6. [14-16] There is increasing evidence, that the analgesic effect of codeine is mediated by its O-demethylated metabolite morphine [17,18] and that the glucuronidated metabolite M-6-G possesses even greater analgesic potency than morphine itself.[19] In humans, the analgesic activity of C-6-G has not been reported; however, antinociceptive responses after intracerebroventricular administration have been reported in rats. [20] Since in vitro findings may not necessarily be of clinical relevance, we aimed to investigate whether diclofenac inhibits codeine glucuronidation in vivo in healthy volunteers in terms of pharmacokinetics, analgesic efficacy and side effects.


Diclofenac does not interact with codeine metabolism in vivo: a study in healthy volunteers.

Ammon S, Marx C, Behrens C, Hofmann U, Mürdter T, Griese EU, Mikus G - BMC Clin Pharmacol (2002)

The chemical structures of codeine and its major metabolites in humans.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC101395&req=5

Figure 1: The chemical structures of codeine and its major metabolites in humans.
Mentions: The weak opioid codeine is widely used in the management of pain. Various studies have demonstrated a synergistic analgesic effect of an opioid-NSAID combination [1-4], particularly if repeated doses are given. [5-7] The synergistic effect is thought to be caused by the known different pharmacodynamic mechanisms, opioids acting via opioid receptors in the central nervous system, NSAIDs affecting the synthesis of prostaglandins due to inhibition of the enzyme cyclooxygenase. NSAIDs have also been postulated to display additional antinociceptive effects in the central nervous system. [8] Moreover, a synergistic effect is also possible via a pharmacokinetic interaction between the two classes of drugs: NSAIDs may decrease the renal excretion of the pharmacologically active metabolite of morphine M-6-G (morphine-6-glucuronide).[9] We have previously demonstrated a marked inhibition of codeine glucuronidation in human liver tissue homogenate by diclofenac (Ki of 7.9 μM).[10] Others have shown [11] a more than 50% inhibition of the glucuronidation of the codeine structural analogue, dihydrocodeine, by 50 μM diclofenac in vitro. Codeine is predominantly metabolised by glucuronidation to C-6-G (codeine-6-glucuronide) (Figure 1). Minor metabolic pathways include N-demethylation to norcodeine and O-demethylation to morphine.[12,13] The latter is catalysed by the polymorphically expressed CYP2D6. [14-16] There is increasing evidence, that the analgesic effect of codeine is mediated by its O-demethylated metabolite morphine [17,18] and that the glucuronidated metabolite M-6-G possesses even greater analgesic potency than morphine itself.[19] In humans, the analgesic activity of C-6-G has not been reported; however, antinociceptive responses after intracerebroventricular administration have been reported in rats. [20] Since in vitro findings may not necessarily be of clinical relevance, we aimed to investigate whether diclofenac inhibits codeine glucuronidation in vivo in healthy volunteers in terms of pharmacokinetics, analgesic efficacy and side effects.

Bottom Line: In terms of side effects, both treatments were well tolerated.Diclofenac did not significantly influence the analgesic effects of codeine in the cold pressor test.In contrast to recent in vitro data, a single oral dose of diclofenac did not alter the glucuronidation of codeine in healthy volunteers.

View Article: PubMed Central - HTML - PubMed

Affiliation: Internal Medicine VI - Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany. susanne.ammon@medizin.uni-magdeburg.de

ABSTRACT

Background: Previously, we have demonstrated a marked inhibition of codeine glucuronidation by diclofenac in human liver tissue homogenate. We therefore aimed to investigate whether diclofenac inhibits glucuronidation of codeine also in vivo in healthy volunteers.

Methods: In a randomised, placebo-controlled, double-blind, cross-over study, 12 healthy volunteers received a singe of 100 mg codeine phosphate plus 50 mg diclofenac sodium or codeine phosphate plus placebo. Over a 36 hour period serum concentrations of codeine and its metabolites as well as urinary excretion were analysed using LC-mass spectrometry. Side effects were recorded and analgesic efficacy was determined using the cold pressor test (0-6 h).

Results: A single dose of diclofenac did not alter the formation of codeine-6-glucuronide in healthy volunteers. Metabolic clearance of codeine to morphine was not affected by diclofenac. In terms of side effects, both treatments were well tolerated. Diclofenac did not significantly influence the analgesic effects of codeine in the cold pressor test.

Conclusions: In contrast to recent in vitro data, a single oral dose of diclofenac did not alter the glucuronidation of codeine in healthy volunteers.

Show MeSH