title: Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain.
abstract: BACKGROUND
  Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy.
  
  
  RESULTS
  We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype.
  
  
  CONCLUSIONS
  This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. trude.rakvag@ntnu.no
authors.forename: Trude T
authors.initials: TT
authors.lastname: Rakvåg
authors.forename: Joy R
authors.initials: JR
authors.lastname: Ross
authors.forename: Hiroe
authors.initials: H
authors.lastname: Sato
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.forename: Stein
authors.initials: S
authors.lastname: Kaasa
authors.forename: Pål
authors.initials: P
authors.lastname: Klepstad
mesh_terms: D000368:Aged; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010146:Pain / Q000188:drug therapy* / Q000235:genetics*; D017288:Pain Threshold; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D009020:Morphine; D002394:Catechol O-Methyltransferase