This application requests funds for a 1-year renewal of a 3-year (09/12/2014-08/31/2017) U01 grant for a parallel-group, masked, multicenter randomized clinical trial entitled ?Effect of COMT Genetic Polymorphisms on Response to Propranolol Therapy in Temporomandibular Disorder,? aka SOPPRANO (Study of Orofacial Pain and PropRANOolol). SOPPRANO is a Phase II clinical trial that aims to evaluate the efficacy of the non- selective ?-adrenergic antagonist, propranolol, compared to placebo, for treatment of pain in patients with temporomandibular disorders (TMD). TMD, one of the most common chronic musculoskeletal pain conditions, is ineffectively treated. Growing evidence suggests that pain states are enhanced by 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. Three common haplotypes in the COMT gene have been associated with pain modulation and risk of developing TMD. In a pilot study, we found that the analgesic efficacy of propranolol varied according to COMT polymorphisms. The primary objective of the current trial is to evaluate the efficacy of propranolol LA (60 mg twice daily) in reducing pain in TMD subjects; a secondary objective will determine if propranolol efficacy varies according to COMT diplotype. We propose to enroll 200 chronic TMD subjects, genotyped for COMT polymorphisms. This trial consists of a 1- week baseline phase, a 10-week treatment phase, and a 1-week follow-up. The primary endpoint is a weekly mean pain index, computed as the product of the pain intensity score multiplied by the pain duration score, as reported in the Daily Symptom Diary. Subject pain ratings, response to heat and pressure stimuli, physical function, emotional function, global improvement, occurrence of symptoms and adverse events, and use of rescue medication are measured as secondary endpoints. Statistical analysis will evaluate three trial hypotheses: 1) propranolol is efficacious compared to placebo in reducing the pain index; 2) efficacy of propranolol varies according to subjects' COMT polymorphism; and 3) propranolol is efficacious in improving secondary endpoints. Continuous measures will be analyzed in the ?intent-to-treat? sample using methods for mixed-model repeated measures, with baseline scores as covariates. Sensitivity analyses will be conducted with the per-protocol sample. This project, now in its final year, has enrolled 125 subjects as of 06/01/2017. To achieve the original aims of the SOPPRANO trial and to reach the enrollment target of 200 subjects, we are requesting a 1-year competing renewal award in which funds will be used to complete subject enrollment, conduct data analyses, and prepare publications. The outcomes of the trial will generate new evidence about treating pain through previously unexploited pharmacologic targets (e.g., ?-adrenergic receptors). The study offers potential for a tailored pharmacogenetic approach for TMD treatment and may explain variability of treatment responses to ?-blockers in other diseases.