Effect of COMT (Catecholamine-O-methyltransferase) Genetic Polymorphisms on Response to Propranolol Therapy in Temporomandibular Disorder
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 200
- 试验地点
- 3
- 主要终点
- Change in the Weekly Mean Pain Index After 9 Weeks of Treatment
研究概览
简要总结
Purpose:
Primary: To evaluate the efficacy of extended-release (ER) propranolol compared to placebo in the reduction of a pain index in patients with temporomandibular disorder (TMD).
Secondary: To determine if extended-release propranolol efficacy varies according to participants' catechol-O-methyltransferase (COMT) genetic polymorphisms and to investigate the efficacy of extended-release propranolol compared with placebo using secondary endpoints.
Exploratory: To investigate whether the efficacy of extended-release propranolol in the reduction of the pain index varies according to participants' polymorphisms in 3 other genetic regions and according to various phenotypic characteristics.
Participants:
200 patients with chronic TMD will be randomly assigned, in a 1:1 parallel, double-blind fashion, to receive either extended-release propranolol or placebo at one of three study sites: University of North Carolina-Chapel Hill School of Dentistry; University of Florida-Gainesville College of Dentistry; and the State University of New York at Buffalo School of Dental Medicine.
Procedures (methods):
Randomization will be to either propranolol or placebo. The 10-week study treatment period is divided into: 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. The titration and tapering doses are 60 mg (capsules) once per day orally; the maintenance dose is 60 mg twice per day orally. Participants will attend 6 clinic visits over 12-15 weeks as follows: screening and baseline visit (Visit [V] 0, 7-21 days prior to V1); randomization and start of treatment (titration) (V1, study day 0); maintenance visit 2 (V2, 1 week post-randomization, study day 7+3); maintenance visit 3 (V3, 5 weeks post-randomization, study day 35 +/- 7); tapering visit (V4, 9 weeks post-randomization, study day 63 +/- 7); and tapering visit 5 (V5, 11 weeks post-randomization and 1 week after drug tapering ends, study day 77 +/- 7). Depending on the visit, procedures will include: reviews of medical history, weekly alcohol consumption, concomitant therapies and medications, adverse events, compliance, and eligibility; administration/review of questionnaires; blood draw; pregnancy test in women of childbearing potential; and dispensing of study drug.
详细描述
"Temporomandibular disorder" (TMD) encompasses all musculoskeletal disorders of the masticatory system and includes myalgia, arthralgia, temporomandibular joint (TMJ) disc displacements, and TMJ degenerative joint diseases. The prevalence of TMD ranges from 6% to 12% in the general population, with muscle dysfunction the most prevalent TMD diagnostic group. TMD is associated with substantial disability and suffering and negatively impacts quality of life. Jaw pain is the most common symptom that compels treatment seeking. In addition to facial pain, TMD patients frequently report comorbid pain conditions such as headache, low back pain, and fibromyalgia. New approaches to TMD therapy are urgently needed to improve clinical outcomes and reduce economic impact of this disorder.
There is currently no FDA-approved product labeled specifically to manage/treat TMD; however, classes of drugs are used to relieve TMD-associated pain, such as non-steroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory drugs, corticosteroids, benzodiazepines, sedative hypnotics, muscle relaxants, opioids, antidepressants, and anticonvulsants - although evidence to establish their efficacy and safety in this population is scarce. Practitioners' justification for their use may be based on poorly controlled clinical trials or clinical trials in other pain disorders such as acute postsurgical dental pain, arthritic pain, chronic lower back pain, and neuropathic pain. Thus, there is a need for controlled clinical trials to better understand the physiological mechanisms responsible for TMD symptoms.
Evidence suggests that enhanced β-adrenergic drive contributes to the pathogenesis of TMD and other complex persistent pain conditions. For example, individuals with myofascial pain conditions have elevated catecholamine levels and augmented sympathetic responses to stressors. While increased β-adrenergic drive appears to heighten pain, β-adrenergic antagonists can reduce clinical pain and/or nociceptive sensitivity. A recent study of a single infusion of propranolol in TMD and fibromyalgia patients revealed short-term improvement in clinical pain ratings. The antagonist pindolol was similarly efficacious in alleviating cardinal symptoms of fibromyalgia pain. In addition, intramuscular injections of low-dose propranolol in rats reduced inflammatory pain associated with carrageen-induced inflammation of the gastrocnemius muscle.
The study hypothesis is that therapy with the nonselective β-adrenergic receptor antagonist propranolol extended-release capsules (FDA approved to treat many cardiac conditions, tremor, migraine, and pheochromocytoma) will provide efficacious and safe treatment for painful TMD. It has well-studied pharmacodynamic, pharmacokinetic, and side-effect profiles. Peak blood level occurs at approximately 6 hrs, and the plasma half-life is approximately 10 hrs. The primary objective is to investigate the efficacy of propranolol compared with placebo over 9 weeks to reduce pain in patients with TMD. Secondary objectives are to: investigate by treatment group whether reduction in pain varies according to polymorphisms in the COMT gene coding region; and investigate the effect of propranolol compared with placebo to affect pain sensitivity, physical and emotional function, adverse effects, and use of rescue medications. Exploratory objectives are to: investigate gene-by-treatment group interaction to determine the effect of propranolol on reduction in the pain index according to polymorphisms in the COMT, beta-2 adrenergic receptor (ADRβ2), and beta-3 adrenergic receptor (ADRβ3) genetic coding regions.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Propranolol ER
Propranolol hydrochloride extended release (ER) capsules; 60 mg (Visit 1 and Visit 4); 120 mg (Visit 2 and Visit 3) given orally as: 60 mg once/day (Visit 1 and Visit 4) and 60 mg twice/day (Visit 2 and Visit 3).
干预措施: Propranolol ER (Drug)
Placebo
Capsules, identical in appearance to active comparator (propranolol), to be administered orally in exactly the same manner as propranolol at Visit 1 (once/day), Visit 2 (twice/day), Visit 3 (twice/day), and Visit 4 (once/day).
干预措施: Placebo (Drug)
结局指标
主要结局
Change in the Weekly Mean Pain Index After 9 Weeks of Treatment
时间窗: Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)
Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary and divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome.
次要结局
- Change in the Weekly Mean Pain Intensity After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the Weekly Mean Pain Duration After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-McGill Pain Questionnaire Affective Component After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-McGill Pain Questionnaire Sensory Component After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-McGill Pain Questionnaire Present Facial Pain Intensity After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Intensity After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-McGill Pain Questionnaire Weekly Average Facial Pain Duration After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-McGill Pain Questionnaire Weekly Fatigue After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Number of Participants Stratified Per Graded Chronic Pain Scale (GCPS) Grade After 9 Weeks of Treatment(Visit 4 (study day 63 +/-7))
- Change in the Jaw Functional Limitation Scale (JFLS) Global Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the Headache Impact Test (HIT-6) Global Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the Pittsburgh Sleep Quality Index (PSQI) Global Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Number of Participants Stratified Per Dichotomized Score From the Patient Global Impression of Change (PGIC) Scale After 9 Weeks of Treatment(Visit 4 (study day 63 +/-7))
- Change in the Perceived Stress Scale (PSS) Global Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the Hospital Anxiety and Depression Scale (HADS) Depression Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the Hospital Anxiety and Depression Scale (HADS) Anxiety Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the Symptom Checklist 90-Revised (SCL-90R) Somatization Scale Score After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-12 Health Survey v2 (SF-12v2) Physical Component Summary (PCS) After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in the SF-12 Health Survey v2 (SF-12v2) Mental Component Summary (MCS) After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Thermal Pain Threshold After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Thermal Pain Tolerance After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Pressure Pain Threshold at Temporalis Muscle After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Pressure Pain Threshold at Masseter Muscle After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/- 7))
- Change in Pressure Pain Threshold at Temporomandibular Joint After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Pressure Pain Threshold at Trapezius Muscle After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Pressure Pain Threshold at Lateral Epicondyle After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Pain-free Jaw Opening After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Maximum Unassisted Jaw Opening After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Maximum Assisted Jaw Opening After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Systolic Blood Pressure After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Diastolic Blood Pressure After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))
- Change in Heart Rate After 9 Weeks of Treatment(Visit 1 (study day 0) and Visit 4 (study day 63 +/-7))