Effect of COMT genetic polymorphism on response to propranolol therapy in TMD

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DESCRIPTION (provided by applicant): This R34 proposal seeks funds for one year to develop a Phase II clinical trial that will evaluate the efficacy of the non-selective ¿-adrenergic antagonist, propranolol, compared to placebo for treatment of pain in patients with temporomandibular disorder (TMD). TMD, one of the most common chronic musculoskeletal pain conditions, is ineffectively treated. Growing evidence suggests that diminished activity of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines), which results in elevated levels of catecholamines and increased activity of ¿2/3-adrenergic receptors, contributes to enhanced pain states. Three common haplotypes in the COMT gene have been associated with pain modulation and the risk of developing TMD. In a pilot study of TMD patients, we found evidence suggesting that analgesic efficacy of propranolol varied according to polymorphism in the COMT gene. We now propose to develop a Phase II trial to evaluate the efficacy of propranolol in reducing pain in TMD patients in a manner dependent on individuals' COMT diplotype. During the one-year period we will finalize a research team; develop the trial protocol, the Manual of Procedures, and other required documentation; and establish tools for data management and oversight of the research needed to study 200 Caucasian female TMD patients, genotyped for COMT polymorphisms, in a randomized, multicenter, blinded, placebo-controlled, parallel assignment clinical trial of propranolol (LA 60 mg twice daily). This trial wil consist of a 1-week baseline phase, an 8-week treatment maintenance phase, and a 1-week follow-up. Patient pain ratings, responses to heat and pressure stimuli, physical functioning, psychological status, global improvement, and symptoms will be compared across the baseline week and the last week of the treatment maintenance phase. The primary endpoint will be change in one-week, mean pain index, calculated as a product of the pain intensity score multiplied by the pain duration score from a daily pain diary. The plan for statistical analysis wil evaluate our two study hypotheses: 1) propranolol is efficacious compared with placebo in reducing the pain index among TMD patients, and 2) efficacy of propranolol varies according to patients' COMT polymorphism. Continuous measures will be analyzed using methods for mixed- model repeated measures, with baseline scores as covariates. Sensitivity analyses will be conducted to assess potential impact of alternative methods for imputing missing data. The outcome of the proposed study will contribute to the investigation of previously unexploited pharmacologic targets (e.g., ¿-adrenergic receptors) for the development of effective therapy for persistent pain, as well as to offer potential for genetically-tailored pharmacogenetic approach for TMD treatment. In addition, the results of this study may explain the variability of treatment responses to ¿-blockers for a broad spectrum of diseases in which this class of medications is currently used. PUBLIC HEALTH RELEVANCE: Temporomandibular disorders (TMD) are amongst the most common chronic musculoskeletal pain conditions. Despite the use of various treatment approaches, TMD are still ineffectively treated. Evaluation of propranolol efficacy for TMD therapy and identification of genetic predictors of the outcome of propranolol therapy will apply recent advances in genetic research to clinical practice.