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

COMT基因多态性对TMD普萘洛尔治疗反应的影响

• 批准号: 8303958
• 负责人: Samuel Arbes
• 金额: $ 23.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303958
• 关键词: Address; Adrenergic Agents; Adrenergic Antagonists; Adrenergic Receptor; Affective; Analgesics; Blinded; Case Report Form; Catechol O-Methyltransferase; Catecholamines; Caucasians; Caucasoid Race; Chronic; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical trial protocol document; Code; Consent Forms; Data; Development; Disease; Documentation; Dopamine; Dose; Enzymes; Epinephrine; Evaluation; Female; Fibromyalgia; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genotype; Goals; Grant; Haplotypes; Heating; Individual; Institutional Review Boards; Investigation; Letters; Maintenance; Manuals; Measures; Medicine; Methods; Methyltransferase Gene; Modeling; Monitor; Multicenter Trials; Musculoskeletal Diseases; Musculoskeletal Pain; National Institute of Dental and Craniofacial Research; Norepinephrine; Outcome; Pain; Pain intensity; Pamphlets; Patients; Perception; Persistent pain; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phase II Clinical Trials; Physical Function; Pilot Projects; Placebo Control; Placebos; Predisposition; Procedures; Process; Propranolol; Protocols documentation; Questionnaires; Randomized; Reporting; Research; Research Personnel; Risk; Safety; Sensory; Specific qualifier value; Staging; Stimulus; Subgroup; Symptoms; System; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Therapeutic; U-Series Cooperative Agreements; Variant; Woman; adrenergic; clinical practice; data management; diaries; effective therapy; follow-up; genetic variant; indexing; intravenous administration; men; pressure; psychologic; quality assurance; response; tool; treatment duration; treatment response

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.

描述（由申请人提供）：这项R34提案寻求为期一年的资金，以开发一项II期临床试验，该试验将评估非选择性肾上腺素能受体拮抗剂的疗效。 拮抗剂普萘洛尔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，导致儿茶酚胺水平升高和<$2/3-肾上腺素能受体活性增加，有助于增强疼痛状态。COMT基因中的三种常见单倍型与疼痛调节和发展TMD的风险相关。在TMD患者的初步研究中，我们发现证据表明，普萘洛尔的镇痛效果根据COMT基因的多态性而变化。我们现在建议开展一项II期临床试验，以评估普萘洛尔在减轻TMD患者疼痛方面的疗效，其方式取决于个体的COMT双体型。在这一年期间，我们将最后确定一个研究小组;制定试验方案、程序手册和其他所需文件;并建立数据管理和监督研究所需的工具，以研究200名白人女性TMD患者，在普萘洛尔（LA 60 mg，每日两次）的随机、多中心、盲法、安慰剂对照、平行分配临床试验中进行COMT多态性基因分型。本试验将包括1周基线期、8周治疗维持期和1周随访期。将比较基线周和治疗维持期最后一周的患者疼痛评级、对热和压力刺激的反应、身体功能、心理状态、总体改善和症状。主要终点将是一周内平均疼痛指数的变化，计算方法为每日疼痛日记中疼痛强度评分乘以疼痛持续时间评分的乘积。统计分析计划将评估我们的两个研究假设：1）普萘洛尔与安慰剂相比在降低TMD患者的疼痛指数方面是有效的，2）普萘洛尔的疗效根据患者的COMT多态性而变化。将使用混合模型重复测量方法分析连续测量，基线评分作为协变量。将进行敏感性分析，以评估插补缺失数据的替代方法的潜在影响。拟议研究的结果将有助于研究以前未开发的药理学靶点（例如，肾上腺素能受体）用于开发持续性疼痛的有效疗法，以及为TMD治疗提供遗传定制的药物遗传学方法的潜力。此外，这项研究的结果可以解释目前使用这类药物的广泛疾病对β-受体阻滞剂的治疗反应的变异性。 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疾病之一。尽管使用了各种治疗方法，但TMD仍然无法有效治疗。普萘洛尔治疗TMD的疗效评价和普萘洛尔治疗结果的遗传预测因素的确定将应用遗传学研究的最新进展，以临床实践。

项目成果

COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial.

• DOI: 10.1177/0022034520962733
• 发表时间: 2021-03
• 期刊: Journal of dental research
• 影响因子: 7.6
• 作者: Slade GD;Fillingim RB;Ohrbach R;Hadgraft H;Willis J;Arbes SJ Jr;Tchivileva IE
• 通讯作者: Tchivileva IE

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial.

• DOI: 10.1177/0333102421989268
• 发表时间: 2021-06
• 期刊: Cephalalgia : an international journal of headache
• 作者: Tchivileva IE;Ohrbach R;Fillingim RB;Lim PF;Giosia MD;Ribeiro-Dasilva M;Campbell JH;Hadgraft H;Willis J;Arbes SJ Jr;Slade GD
• 通讯作者: Slade GD

Clinical, psychological, and sensory characteristics associated with headache attributed to temporomandibular disorder in people with chronic myogenous temporomandibular disorder and primary headaches.

• DOI: 10.1186/s10194-021-01255-1
• 发表时间: 2021-05-22
• 期刊: The journal of headache and pain
• 作者: Tchivileva IE;Ohrbach R;Fillingim RB;Lin FC;Lim PF;Arbes SJ Jr;Slade GD
• 通讯作者: Slade GD

Efficacy and safety of propranolol for treatment of temporomandibular disorder pain: a randomized, placebo-controlled clinical trial.

普萘洛尔治疗颞下颌关节紊乱疼痛的功效和安全性：一项随机、安慰剂对照临床试验。

• DOI: 10.1097/j.pain.0000000000001882
• 发表时间: 2020
• 期刊: Pain
• 影响因子: 7.4
• 作者: Tchivileva,InnaE;Hadgraft,Holly;Lim,PeiFeng;DiGiosia,Massimiliano;Ribeiro-Dasilva,Margarete;Campbell,JohnH;Willis,Janet;James,Robert;Herman-Giddens,Marcus;Fillingim,RogerB;Ohrbach,Richard;ArbesJr,SamuelJ;Slade,GaryD
• 通讯作者: Slade,GaryD