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

描述(由申请人提供)：这份R34提案寻求为期一年的资金，以开发一项第二阶段临床试验，评估非选择性肾上腺素能的疗效 拮抗剂心得安与安慰剂治疗颞下颌关节紊乱病(TMD)患者疼痛的比较。TMD是最常见的慢性肌肉骨骼疼痛之一，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)活性降低，导致儿茶酚胺水平升高和2/3肾上腺素能受体活性增加，导致疼痛状态增强。COMT基因中有三种常见的单倍型与疼痛调节和发生TMD的风险有关。在对TMD患者的初步研究中，我们发现有证据表明，心得安的止痛效果因COMT基因的多态性而异。我们现在建议开展一项第二阶段试验，以评估心得安减轻TMD患者疼痛的效果，其方式取决于个体的COMT双倍型。在为期一年的时间里，我们将最终确定一个研究团队；制定试验方案、程序手册和其他必要的文件；并建立数据管理和研究监督所需的工具，以研究200名高加索女性TMD患者，她们的COMT基因多态，在一项随机、多中心、双盲、安慰剂对照、平行分配的普奈洛尔临床试验中(LA 60 mg，每天两次)。这项试验将包括1周的基线阶段，8周的治疗维持阶段和1周的随访。患者的疼痛评级、对热和压力刺激的反应、身体功能、心理状态、整体改善和症状将在基线周和治疗维持阶段的最后一周进行比较。主要终点将是一周内平均疼痛指数的变化，计算方法为疼痛强度分数乘以每日疼痛日记中的疼痛持续时间分数。统计分析计划将评估我们的两个研究假设：1)与安慰剂相比，心得安在降低TMD患者疼痛指数方面是有效的，2)心得安的疗效因患者的COMT基因多态性而异。将使用以基线分数为协变量的混合模型重复测量方法来分析连续测量。将进行敏感性分析，以评估用于推算缺失数据的替代方法的潜在影响。建议的研究结果将有助于研究以前未开发的药理靶点(如肾上腺素能受体)，以开发有效的持续性疼痛治疗方法，并为TMD治疗的基因定制药物遗传学方法提供可能性。此外，这项研究的结果可能解释了阻滞剂对目前使用这类药物的广泛疾病的治疗反应的差异性。 公共卫生相关性：颞下颌关节紊乱病(TMD)是最常见的慢性肌肉骨骼疼痛症状之一。尽管使用了各种治疗方法，但TMD仍未得到有效治疗。评估心得安治疗TMD的疗效和确定普萘洛尔治疗结果的遗传预测因子将把遗传学研究的最新进展应用于临床实践。

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.