title: O-demethylation of codeine to morphine inhibited by low-dose levomepromazine.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Forensic Toxicology and Drug Abuse, Norwegian Institute of Public Health, P.O. Box 4404, Nydalen, Oslo 0403, Norway. meve@fhi.no
authors.forename: M
authors.initials: M
authors.lastname: Vevelstad
authors.forename: S
authors.initials: S
authors.lastname: Pettersen
authors.forename: C
authors.initials: C
authors.lastname: Tallaksen
authors.forename: O
authors.initials: O
authors.lastname: Brørs
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism*; D003061:Codeine / Q000008:administration & dosage / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D017116:Low Back Pain / Q000188:drug therapy; D008297:Male; D008728:Methotrimeprazine / Q000008:administration & dosage / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D010090:Oxidoreductases, O-Demethylating / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016482:Urinalysis
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000082:Acetaminophen; D008728:Methotrimeprazine; D010090:Oxidoreductases, O-Demethylating; D019389:Cytochrome P-450 CYP2D6; D003061:Codeine