Genetics-based personalized approaches to pain management have received a setback because of the nonreproducibility of functional genetic associations such as the pain-modulatory effect of the catechol-O-methyl transferase (COMT) gene 472G>A single-nucleotide polymorphism. Given that many of the pain-relevant genetic variants are common (allelic frequencies of 10-50%), we hypothesized that a major reason for difficulties in reproducing demonstrations of genetic influences on pain is the concomitant presence in a single individual of several functional genetic polymorphisms that act as confounders.