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

描述（由申请人提供）：本U 01申请寻求为期3年的资金，以进行一项II期临床试验，该试验将评价非选择性β-肾上腺素能拮抗剂普萘洛尔与安慰剂相比治疗颞下颌关节紊乱病（TMD）患者疼痛的疗效。TMD是最常见的慢性肌肉骨骼疼痛疾病之一，治疗效果不佳。越来越多的证据表明，儿茶酚-O-甲基转移酶（COMT;一种代谢儿茶酚胺的酶）的活性降低会增强疼痛状态，这会导致儿茶酚胺水平升高和β 2/3肾上腺素能受体活性增加。COMT基因中的三种常见单倍型与疼痛调节和患上TMD的风险相关。在TMD患者的初步研究中，我们发现普萘洛尔的镇痛效果根据COMT基因的多态性而变化。我们现在建议进行普萘洛尔（LA 60 mg，每日两次）的II期随机、设盲、安慰剂对照、平行分配临床试验。主要目的是评估普萘洛尔在减轻TMD患者疼痛方面的疗效;次要目的是确定普萘洛尔疗效是否根据患者的COMT双体型而变化。我们将招募200名白人女性TMD患者，进行COMT多态性基因分型。本试验将包括1周基线期、10周治疗期和1周随访期。主要终点为每周平均疼痛指数，计算方法为每日症状日志中疼痛强度评分乘以疼痛持续时间评分的乘积。患者疼痛评级、对热和压力刺激的反应、身体功能、情感功能、整体改善、症状和不良事件的发生以及补救药物的使用将作为次要终点进行测量。统计分析将评估三个试验假设：1）普萘洛尔与安慰剂相比在降低疼痛指数方面有效，2）普萘洛尔的疗效根据患者的COMT多态性而变化，3）普萘洛尔在改善次要终点方面有效。将使用混合模型重复测量方法分析“意向治疗”样本中的连续测量值，以基线评分作为协变量。将使用符合方案样本进行敏感性分析。在R34资助下，我们已经创建了拟议临床试验所需的方案、知情同意书、程序手册、病例报告表和研究计划。这项拟议的研究将产生关于通过以前未开发的药理学靶点治疗疼痛的新证据（例如，β-肾上腺素能受体）。该研究为TMD治疗提供了一种遗传定制的药物遗传学方法，并可能解释β受体阻滞剂用于治疗其他疾病时治疗反应的变异性。

DESCRIPTION (provided by applicant): This U01 application seeks funds for 3 years to conduct a Phase II clinical trial that will evaluate the efficacy of the non-selective Beta-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 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 Beta 2/3-adrenergic receptors. 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 that analgesic efficacy of propranolol varied according to polymorphisms in the COMT gene. We now propose to conduct a Phase II randomized, masked, placebo-controlled, parallel assignment clinical trial of propranolol (LA 60 mg twice daily). The primary objective is to evaluate the efficacy of propranolol in reducing pain in TMD patients; a secondary objective will determine if propranolol efficacy varies according to patients' COMT diplotype. We will enroll 200 Caucasian female TMD patients, genotyped for COMT polymorphisms. This trial will consist of a 1-week baseline phase, a 10-week treatment phase, and a 1-week follow-up. The primary endpoint will be a weekly mean pain index, calculated as a product of the pain intensity score multiplied by the pain duration score from a Daily Symptom Diary. Patient pain ratings, responses to heat and pressure stimuli, physical function, emotional function, global improvement, occurrence of symptoms and adverse events, and use of rescue medication will be measured as secondary endpoints. Statistical analysis will evaluate three trial hypotheses: 1) propranolol is efficacious compared with placebo in reducing the pain index, 2) efficacy of propranolol varies according to patients' 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 the baseline scores as covariates. Sensitivity analyses will be conducted with the per-protocol sample. Under an R34 grant, we have created the protocol, informed consent forms, the Manual of Procedures, case report forms, and study plans needed for the proposed clinical trial. The proposed study will generate new evidence about treating pain through previously unexploited pharmacologic targets (e.g., Beta-adrenergic receptors). The study offers potential for a genetically-tailored pharmacogenetic approach for TMD treatment and may explain variability of treatment responses to Beta-blockers when used to treat other diseases.