The effect of quinidine on the analgesic effect of codeine

SummaryWe have studied the hypoalgesic effect of codeine (100 mg) after blocking the hepatic O-demethylation of codeine to morphine via the sparteine oxygenase (CYP2D6) by quinidine (200 mg). The study was performed in 16 extensive metabolizers of sparteine, using a double-blind, randomized, four-way, cross-over design. The treatments given at 3 h intervals during the four sessions were placebo/placebo, quinidine/placebo, placebo/codeine, and quinidine/codeine. We measured pin-prick pain and pain tolerance thresholds to high energy argon laser stimuli before and 1, 2, and 3 h after codeine or placebo.After codeine and placebo, the peak plasma concentration of morphine was 6–62 (median 18) nmol·.l−1. When quinidine pre-treatment was given, no morphine could be detected (<4 nmol·l−1) after codeine. The pin-prick pain thresholds were significantly increased after placebo/codeine, but not after quinidine/codeine compared with placebo/placebo. Both placebo/codeine and quinidine/codeine increased pain tolerance thresholds significantly. Quinidine/codeine and quinidine/placebo did not differ significantly for either pin-prick or tolerance pain thresholds.These results are compatible with local CYP2D6 mediated formation of morphine in the brain, not being blocked by quinidine. Alternatively, a hypoalgesic effect of quinidine might have confounded the results.

[1]  A. Somogyi,et al.  Morphine formation from codeine in rat brain: a possible mechanism of codeine analgesia. , 1990, Life sciences.

[2]  S. Joel,et al.  ANALGESIC ACTIVITY OF MORPHINE-6-GLUCURONIDE , 1988, The Lancet.

[3]  W. Kalow,et al.  Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. , 1984, Life sciences.

[4]  R. Tyndale,et al.  The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. , 1990, Archives of biochemistry and biophysics.

[5]  L. Arendt-Nielsen,et al.  Sensory and pain threshold characteristics to laser stimuli. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[6]  L. Lasagna,et al.  Analgesic potency of normorphine in patients with postoperative pain. , 1958, The Journal of pharmacology and experimental therapeutics.

[7]  U. Meyer,et al.  Absence of hepatic cytochrome P450bufI causes genetically deficient debrisoquine oxidation in man. , 1988, Biochemistry.

[8]  J. Fujimoto,et al.  The metabolic fate of codeine in man. , 1955, The Journal of pharmacology and experimental therapeutics.

[9]  P. Dayer,et al.  Impact of environmental and genetic factors on codeine analgesia , 2004, European Journal of Clinical Pharmacology.

[10]  J. Kaufman,et al.  Drug distribution in dog brain studied by positron emission tomography , 1988, Biopharmaceutics & drug disposition.

[11]  L. Bertilsson,et al.  Extensive metabolizers of debrisoquine become poor metabolizers during quinidine treatment. , 1987, Pharmacology & toxicology.

[12]  R. Tyndale,et al.  Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6. , 1991, Molecular pharmacology.

[13]  S. Otton,et al.  Sparteine oxidation polymorphism in Denmark. , 2009, Acta pharmacologica et toxicologica.

[14]  H. Juan.  Inhibition of the algesic effect of bradykinin and acetylcholine by mepacrine , 1977, Naunyn-Schmiedeberg's Archives of Pharmacology.

[15]  S Senn,et al.  Analysis of serial measurements in medical research. , 1990, BMJ.

[16]  S. Matin,et al.  Liquid chromatography of codeine in plasma with fluorescence detection. , 1982, Clinical chemistry.

[17]  S. Snyder,et al.  Properties of opiate-receptor binding in rat brain. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M J Campbell,et al.  Statistics in Medicine: Calculating confidence intervals for some non-parametric analyses , 1988 .

[19]  W. D. Mason,et al.  Plasma Codeine and Morphine Concentrations After a Single Oral Dose of Codeine Phosphate , 1990, Journal of clinical pharmacology.

[20]  Peter Bjerring,et al.  Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine , 1990, Clinical pharmacology and therapeutics.

[21]  U. Meyer,et al.  Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. , 1990, The Journal of biological chemistry.

[22]  S. Otton,et al.  Sparteine oxidation is practically abolished in quinidine-treated patients. , 1986, British journal of clinical pharmacology.

[23]  C. Alm,et al.  Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. , 1989, British journal of clinical pharmacology.

[24]  U. Meyer,et al.  Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: Relationship to the presence of immunoidentified cytochrome P‐450IID1 , 1990, Clinical pharmacology and therapeutics.

[25]  T. Leemann,et al.  Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI). , 1988, Biochemical and biophysical research communications.

[26]  U. Gundert-Remy,et al.  Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations , 2004, European Journal of Clinical Pharmacology.

[27]  A. Somogyi,et al.  POLYMORPHIC O-DEMETHYLATION OF CODEINE , 1988, The Lancet.

[28]  M. Voegelin,et al.  Studies on the cutaneous pricking pain threshold in man. Circadian and circatrigintan changes. , 1970, Research and clinical studies in headache.

[29]  W. El,et al.  The metabolic fate of codeine in man. , 1955, The Journal of pharmacology and experimental therapeutics.

[30]  U. Bondesson,et al.  Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration , 2004, European Journal of Clinical Pharmacology.