COMT genetic variation may influence opioid dosing requirements in the treatment of cancer-related pain

Background: Opioid analgesics are the mainstay treatment for moderate to severe cancer-related pain. However, clinical studies suggest that genetic variability may result in significant differences in response to opioids. The m-opioid receptor (OPRM1) is the primary site of action for opioids. The polymorphism A118G is relatively frequent in Caucasians and causes an amino acid change from asparagine to aspartatic acid. This polymorphism seems to influence opioids action, with homozygous for A allele requiring lower doses of opioids. Catechol-O-methyltransferase (COMT) is involved in the metabolism of catecholamines, which have a role in the nociception mechanism. The functional polymorphism Val158Met codes the substitution of valine (Val) by methionine (Met). Individuals with the Met/Met genotype have the lowest activity of COMT and have been related to increased pain sensitivity and lower m-opioid system activation. Polymorphisms in multidrug resistance protein (MDR1) can have pharmacologic consequences after opioids administration. Two of the most frequent polymorphisms are C3435T and C1236T. Homozygous individuals for T allele of the C3435T have lower mRNA expression. C1236T was found to be in linkage disequilibrium with C3435T and was also related to different opioid doses, higher in TT individuals. Our purpose was to investigate the effects of these polymorphisms on several pain-related parameters in Caucasian cancer patients. Material and Methods: DNA samples from 30 cancer patients were genotyped for polymorphisms in OPRM1 (rs1799971), COMT (rs4680), and MDR1 (rs1128503, rs1045642) with Real-Time PCR. Daily doses were re-expressed as oral morphine equivalents. We examined the relation between the polymorphisms and opioid dose, pain intensity, performance status, adverse effects, age, gender, bone or CNS metastases and breakthrough pain. Results: Total morphine consumption was related to the polymorphism Val158Met in COMT gene, with carriers of Met allele showing to be significantly associated with higher dose of opioids (p = 0.004, Pearson c2 test), which was also confirmed by logistic regression adjust to age and gender (p = 0.013). All the other polymorphisms and parameters revealed no statistically significant association. Conclusion: This preliminary result indicates that genetic variation at COMT enzyme may influence opioid dosing requirements in the treatment of cancerrelated pain.