Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study

Abstract

Introduction: Three common haplotypes in the gene encoding catechol-O-methyltransferase (COMT) have been associated with pain modulation and the risk of developing chronic musculoskeletal pain, namely temporomandibular disorder (TMD). Haplotypes coding for higher enzymatic activity were correlated with lower pain perception. Rodent studies showed that COMT inhibition increases pain sensitivity through beta2/3-adrenergic receptors. We hypothesized that the nonselective beta-adrenergic antagonist propranolol will reduce clinical and experimental pain in TMD patients in a manner dependent on the individuals' COMT diplotype.

Methods: Forty Caucasian female participants meeting the Research Diagnostic Criteria for TMD were genotyped for COMT polymorphisms and completed a randomized, double-blind, placebo-controlled, two-period crossover pilot study. Each period consisted of a baseline assessment week followed by an intervention week (propranolol or placebo). Changes in clinical pain ratings, psychological status, and responses to heat and pressure stimuli between baseline and intervention weeks were compared across periods.

Results: The number of patients reporting a reduction in pain intensity rating was greater during propranolol treatment (P=0.014) compared with placebo. Propranolol significantly reduced a composite pain index (P=0.02) but did not decrease other clinical and experimental pain ratings. When stratified by the COMT high activity haplotype, a beneficial effect of propranolol on pain perception was noted in patients not carrying this haplotype, a diminished benefit was observed in the heterozygotes, and no benefit was noted in the homozygotes.

Conclusion: COMT haplotypes may serve as genetic predictors of propranolol treatment outcome, identifying a subgroup of TMD patients who will benefit from propranolol therapy.

Figures

Fig. 1

Schematic diagram of COMT gene. Boxes depict exons. Locations of the SNPs selected for the study are marked by arrows.

Fig. 2

Flow of the subjects through the study.

Fig. 3

Net changes in measures of the reported pain and experimental pain sensitivity categorized by the number of LPS alleles of COMT. Subjects not carrying LPS allele show the best response to propranolol therapy in all pain measures except thermal threshold. Data are expressed as Means±SE. *p<0.05 different from LPS homozygotes, **p<0.01 different from LPS hetero- and homozygotes with Tukey's post hoc test.