Abstract
Purpose
Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6.
Methods
Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography–mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine.
Results
Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann–Whitney test) after the C/P treatment (0.092, range 0.041–0.096) than after the L+C/P treatment (0.031, range 0.009–0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011–0.042) vs. 0.026 (range 0.009–0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011–0.096) vs. 0.030 (range 0.009–0.042), respectively; P = 0.122].
Conclusions
Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.
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References
Desmeules J, Gascon MP, Dayer P, Magistris M (1991) Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 41:23–26
Sindrup SH, Brosen K (1995) The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 5:335–346
Beaver WT, Wallenstein SL, Houde RW, Rogers A (1966) A comparison of the analgesic effects of methotrimeprazine and morphine in patients with cancer. Clin Pharmacol Ther 7:436–446
Lasagna L, Dekornfeld TJ (1961) Methotrimeprazine: a new phenothiazine derivative with analgesic properties. JAMA 178:887–890
Dayer P, Desmeules J, Striberni R (1992) In vitro forecasting of drugs that may interfere with codeine bioactivation. Eur J Drug Metab Pharmacokinet 17:115–120
Syvalahti EK, Lindberg R, Kallio J, De Vocht M (1986) Inhibitory effects of neuroleptics on debrisoquine oxidation in man. Br J Clin Pharmacol 22:89–92
Gram LF, Hansen MG, Sindrup SH, Brosen K, Poulsen JH, Aaes-Jorgensen T, Overo KF (1993) Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 15:18–24
Kallio J, Huupponen R, Seppala M, Sako E, Iisalo E (1990) The effects of beta-adrenoceptor antagonists and levomepromazine on the metabolic ratio of debrisoquine. Br J Clin Pharmacol 30:638–643
Spina E, Sturiale V, Valvo S, Ancione M, Di Rosa AE, Meduri M, Caputi AP (1992) Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions. Acta Psychiatr Scand 86:364–366
Boulton DW, DeVane CL, Liston HL, Markowitz JS (2002) In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci 71:163–169
Hassan HE, Myers AL, Lee IJ, Coop A, Eddington ND (2007) Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel’s tissue distribution in Sprague Dawley rats. J Pharm Sci 96:2494–2506
Yue QY, Alm C, Svensson JO, Sawe J (1997) Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Ther Drug Monit 19:539–542
Vree TB, Verwey-van Wissen CP (1992) Pharmacokinetics and metabolism of codeine in humans. Biopharm Drug Dispos 13:445–460
Adler TK, Fujimoto JM, Way EL, Baker EM (1955) The metabolic fate of codeine in man. J Pharmacol Exp Ther 114:251–262
Shin JG, Soukhova N, Flockhart DA (1999) Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dispos 27:1078–1084
Brosen K, Zeugin T, Meyer UA (1991) Role of P450IID6, the target of the sparteine-debrisoquin oxidation polymorphism, in the metabolism of imipramine. Clin Pharmacol Ther 49:609–617
Hals PA, Dahl SG (1994) Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat. Pharmacol Toxicol 75:255–260
Suzuki A, Otani K, Ishida M, Yasui N, Kondo T, Mihara K, Kaneko S, Inoue Y, Shibata M, Ikeda K (1997) Increased plasma concentrations of bromperidol and its reduced metabolite with levomepromazine, but not with thioridazine. Ther Drug Monit 19:261–264
Grinshpoon A, Berg Y, Mozes T, Mester R, Weizman A (1993) Seizures induced by combined levomepromazine-fluvoxamine treatment. Int Clin Psychopharmacol 8:61–62
Steimer W, Zopf K, von Amelunxen S, Pfeiffer H, Bachofer J, Popp J, Messner B, Kissling W, Leucht S (2004) Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem 50:1623–1633
Acknowledgments
We gratefully acknowledge Gerd Volden for performing the drug analyses, and Stein Bergan and colleagues for genotyping.
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None of the authors have any potential conflicts of interest with commercial parties.
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Vevelstad, M., Pettersen, S., Tallaksen, C. et al. O-demethylation of codeine to morphine inhibited by low-dose levomepromazine. Eur J Clin Pharmacol 65, 795–801 (2009). https://doi.org/10.1007/s00228-009-0640-9
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DOI: https://doi.org/10.1007/s00228-009-0640-9