Chronic Postconcussive Headache: A Placebo-Controlled Treatment Trial of Prazosin

慢性脑震荡后头痛：哌唑嗪安慰剂对照治疗试验

• 批准号: 9260709
• 负责人: Cynthia L Mayer
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260709
• 关键词: Academic Training; Address; Adrenergic Agents; Adverse effects; Affect; Afghanistan; Alcohol consumption; Analgesic Overuse Headaches; Analgesics; Benign; Blast Cell; Board Certification; Brain Concussion; Brain Injuries; Case Series; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Comorbidity; Competence; Contracts; Controlled Clinical Trials; Controlled Study; Craniocerebral Trauma; Data; Data Analyses; Department of Defense; Development; Development Plans; Discipline of Nuclear Medicine; Distress; Dose; Double-Blind Method; Education; Elements; Evaluation; Follow-Up Studies; Fostering; Foundations; Frequencies; Functional disorder; Funding; Future; General Population; Generic Drugs; Goals; Grant; Growth; Guidelines; Headache; Healthcare Systems; High Prevalence; Home environment; Hour; Human; Injury; International; Intractable Pain; Iraq; Learning; Legal patent; Length; Longevity; Measures; Medical; Mental Depression; Mental disorders; Mentors; Methods; Migraine; Military Personnel; Moods; Neurologic; Neurology; Opiates; Opioid; Oral; Outcome; Outcome Measure; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Population; Positioning Attribute; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prazosin; Price; Private Sector; Prophylactic treatment; Public Health; Publishing; Quality of life; Randomized; Refractory; Rehabilitation therapy; Reporting; Research; Research Design; Research Personnel; Resistance; Risk; Role; Services; Severities; Sleep; Social Welfare; Societies; Solid; Source; Symptoms; Syndrome; System; Target Populations; Testing; Tracer; Training; Training Programs; Veterans; Workplace; Writing; alcohol craving; alpha-1 adrenergic receptors; alpha-adrenergic receptor; apprenticeship; base; career; career development; chronic pain; combat; cost; design; disability; economic incentive; experience; health related quality of life; interest; mild traumatic brain injury; noradrenergic; open label; placebo controlled study; power analysis; primary outcome; programs; prophylactic; public health relevance; screening; secondary outcome; service member; skills; treatment duration; treatment trial

DESCRIPTION: Background and Study Objective: Posttraumatic headaches (PTHAs) following mild traumatic brain injury (mTBI) are common, often refractory to standard therapies, and can progress to become a debilitating chronic pain syndrome. Studies of the centrally acting alpha-1 adrenergic receptor (AR) blocker prazosin for treating combat-related posttraumatic stress disorder (PTSD) have coincidentally shown evidence for ameliorating co- morbid headaches (HAs). A large open-label case series and anecdotal reports have additionally noted beneficial effect of prazosin on HAs, in particular, those following blast mTBI. The objective of the proposed study is to rigorously evaluate the efficacy of prazosin for prophylaxis of chronic PTHA following combat mTBI. Study Design and Methods: This is a double-blind placebo-controlled clinical trial based on International Headache Society Guidelines for migraine prophylactic drug studies. The trial length is 16 weeks, including a 4-week pre-treatment screening period followed by a 12-week treatment period, in which participants will be randomized 1:1 to prazosin or placebo. Primary outcome measures will include change from baseline in HA frequency and cumulative HA hours. Secondary outcome measures will include change in other HA measures, PTSD symptoms, sleep quality, depression, alcohol use, cognition, health-related quality of life, and global clinical status. Based on a power analysis for the primary outcome measures, we will need 37 subjects per group to achieve 80% power using a 5% Type I error level. Career Goals: My primary career goal is to combine research and service, working with a population whose needs are diverse and challenging. The VA Healthcare System provides an excellent opportunity for this. Neurologic issues are of particular relevance to Veterans, both as service-related and across the life-span. My intentions in the proposed study are to evaluate a potential treatment for a condition that significantly impacts the welfare of Veterans, as well as to lay the foundation for future studies of the pathophysiology of PTHAs. The demonstration of favorable effects of prazosin on PTSD, sleep disruption, and likely on PTHAs suggests a common pathway involving the alpha-1 adrenergic system. Characterization of this pathway would be expected to foster development of more precisely targeted treatments. For example, HAs are a leading cause for opioid prescribing, with opiate use becoming a public health issue for both the Department of Defense and the VA. Identifying noradrenergic mechanisms in PTHAs could serve as a foundation for efforts to reduce the use of opiates for treating this condition. The Northwest Network Mental Illness Research, Education, and Clinical Center has taken a multi-faceted approach to addressing some of these questions, with several related ongoing studies, including development of a PET tracer for alpha ARs. A long-term goal is to integrate my background in nuclear medicine/PET imaging with the expertise I hope to develop in TBI and HA neurology. Key Elements of the Research Career Development Plan: (1) Develop competence in designing and conducting human clinical trials; (2) Obtain a strong conceptual base for current and future research efforts through didactic and other training; (3) Gain experience in analyzing/interpreting results and publishing/presenting findings; (4) Learn grantsmanship skills; (5) Develop solid clinical expertise in the subspecialties of mTBI and HA evaluation and management; (6) Obtain Board Certification in neurology. Mentoring/Training Plan: My team of mentors can provide the depth of clinical training I need to become a HA expert and nurture my growth as a competent, independent clinical researcher though one-on-one apprenticeship training. Other elements of my training plan include: (1) A didactic training program with selected courses relevant to my current and long-term research interests; (2) Participation in seminars and educational programs relevant to TBI and HAs design and conduct of human clinical trials, and grant writing; (3) Experience in oral and written presentation of research findings.

描述： 背景和研究目的：轻度创伤性脑损伤 (mTBI) 后的创伤后头痛 (PTHA) 很常见，标准疗法通常难以治愈，并且可能发展成为一种使人衰弱的慢性疼痛综合征。对中枢作用的 α-1 肾上腺素能受体 (AR) 阻滞剂哌唑嗪治疗战斗相关创伤后应激障碍 (PTSD) 的研究巧合地显示了改善共病头痛 (HA) 的证据。大量开放标签病例系列和轶事报告还指出了哌唑嗪对 HA 的有益作用，特别是对于急变性 mTBI 后的患者。本研究的目的是严格评估哌唑嗪预防战斗 mTBI 后慢性 PTHA 的功效。研究设计和方法：这是一项基于国际头痛协会偏头痛预防药物研究指南的双盲安慰剂对照临床试验。试验长度为 16 周，包括 4 周的治疗前筛选期和随后的 12 周治疗期，其中参与者将按 1:1 的比例随机分配至哌唑嗪或安慰剂。主要结果指标将包括 HA 频率和累积 HA 小时数相对于基线的变化。次要结果指标将包括其他 HA 指标、PTSD 症状、睡眠质量、抑郁、饮酒、认知、健康相关生活质量和全球临床状态的变化。根据主要结果指标的功效分析，我们需要每组 37 名受试者才能使用 5% 的 I 类错误水平达到 80% 的功效。职业目标：我的主要职业目标是将研究和服务结合起来，与需求多样化且具有挑战性的人群合作。 VA 医疗保健系统为此提供了绝佳的机会。神经系统问题与退伍军人尤其相关，无论是与服役相关还是在整个生命周期中。我在拟议研究中的目的是评估对严重影响退伍军人福利的疾病的潜在治疗方法，并奠定基础 为未来研究 PTHA 的病理生理学奠定了基础。哌唑嗪对 PTSD、睡眠中断以及可能对 PTHA 的有利作用的证明表明涉及 α-1 肾上腺素能系统的共同途径。该途径的表征有望促进更精确的靶向治疗的开发。例如，HA 是阿片类药物处方的主要原因，阿片类药物的使用已成为国防部和退伍军人管理局的公共卫生问题。确定 PTHA 中的去甲肾上腺素能机制可以为减少使用阿片类药物治疗这种疾病的努力奠定基础。西北网络精神疾病研究、教育和临床中心采取了多方面的方法来解决其中一些问题，正在进行多项相关研究，包括开发 α AR 的 PET 示踪剂。长期目标是将我在核医学/PET 成像方面的背景与我希望在 TBI 和 HA 神经病学方面发展的专业知识相结合。研究职业发展计划的关键要素：（1）培养设计和进行人体临床试验的能力； (2) 通过教学和其他培训为当前和未来的研究工作奠定坚实的概念基础； (3) 获得分析/解释结果和发表/展示研究结果的经验； （4）学习资助技能； (5) 在 mTBI 和 HA 评估和管理的亚专业领域发展扎实的临床专业知识； (6) 获得神经病学委员会认证。指导/培训计划：我的导师团队可以提供我成为 HA 专家所需的深度临床培训，并通过一对一的学徒培训培养我成长为一名有能力、独立的临床研究员。我的培训计划的其他要素包括：（1）教学培训计划，其中包含与我当前和长期研究兴趣相关的精选课程； (2) 参加与 TBI 和 HA 设计和进行人体临床试验以及资助撰写相关的研讨会和教育计划； (3) 有口头和书面陈述研究成果的经验。