Pterygopalatine Fossa (PPF) Block as an Opioid Sparing Treatment for AcuteHeadache in Aneurysmal Subarachnold Hemorrhage

翼腭窝 (PPF) 阻滞作为阿片类药物节省治疗动脉瘤性蛛网膜下腔出血的急性头痛

• 批准号: 10584712
• 负责人: Katharina Maria Busl
• 金额: $ 351.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584712
• 关键词: Absence of pain sensation; Activities of Daily Living; Acute; Acute Brain Injuries; Acute Pain; Address; Adult; Adverse event; Affect; Analgesics; Anesthesiology; Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Bilateral; Blinded; Blood Vessels; Caring; Chronic Headaches; Clinical; Clinical Trials; Common Data Element; Complex; Conscious; Constipation; Consumption; Critical Care; Dangerousness; Data; Data Coordinating Center; Depressed Level of Consciousness; Depressed mood; Dexamethasone; Disparity; Double-Blind Method; Enrollment; Ethnic Origin; Fiber; Fossa; Frequencies; Functional disorder; Funding; Future; Ganglia; Gastrointestinal Transit; Generations; Goals; Grant; Headache; Headache Disorders; Hemorrhage; High Prevalence; Hospitalization; Hospitals; Hour; Hyperalgesia; Hypotension; Individual; Inflammatory; Injections; Intervention; Intervention Studies; Knowledge; Lead; Learning; Literature; Managed Care; Massachusetts; Measures; Mediating; Meningeal; Migraine; Minority Groups; National Institute of Neurological Disorders and Stroke; Nerve Block; New York; Numeric Rating Scale; Opioid; Oral; Pain; Pain Measurement; Pain Research; Pain intensity; Pain management; Patients; Phase; Placebo Effect; Procedures; Race; Randomized; Recovery; Regimen; Regulation; Research Design; Risk; Safety; Saline; Sample Size; Serious Adverse Event; Severities; Site; Standardization; Subarachnoid Hemorrhage; Survivors; Therapeutic; Thunderclap Headaches; Time; Ultrasonography; United States National Institutes of Health; Universities; Vasomotor; Vasospasm; Woman; Work; addiction; adjudication; blood product; central pain; central sensitization; cerebrovascular; clinically significant; craniofacial; cytokine; design; ethnic minority population; experience; follow-up; hospital readmission; improved; innovation; instrument; irritation; maxillary nerve; morphine equivalent; multimodality; neglect; neurosurgery; novel strategies; novel therapeutic intervention; open label; opioid epidemic; opioid mortality; opioid sparing; opioid use; pain perception; pain reduction; pain score; phase III trial; placebo controlled study; prescription opioid; racial disparity; racial minority population; recruit; respiratory; response; ropivacaine; sex; sex disparity; side effect; sociodemographic factors; socioeconomics; theories; ultrasound; verbal

Severe headache is ubiquitous in subarachnoid hemorrhage (SAH), present in 90% of patients after ictus bleed. Despite steady consumption of analgesics, the degree of pain control in SAH patients is remarkably poor. In spite of this high prevalence, a dearth of data guides optimal management of post-SAH headache. Opioids are the most prescribed pain medication for severe post-SAH headache. However, opioid-based analgesia presents considerable risks: depressed level of consciousness and respiratory drive, hypotension, slow gastrointestinal transit, and high frequency of tolerance and addiction. Furthermore, it is urgent and critical to identify novel strategies to alleviate the excruciating and nearly universal headache post-SAH, while mitigating consequences of opioid use. This unmet therapeutic need reflects a key knowledge gap in a condition afflicting nearly 30,000 individuals each year in the US. We present an inexpensive, opioid-sparing strategy for post-SAH headache, using a nerve-block into the pterygopalatine fossa (PPF) to improve pain control and lessen opioid needs. A growing body of literature on the use of nerve-blocks in acute and chronic headache disorders supports our overarching hypothesis that PPF-block provides rapid, opioid-sparing analgesia, is safe and well-tolerated, and holds promise to adequately treat post-SAH headache. The pathophysiology of these headaches is complex and involves meningeal irritation from blood products, release of inflammatory cytokines, vasomotor instability, and central pain sensitization. Through selective modulation, PPF-blocks address pain mechanisms at their origin, targeting the maxillary nerve and sphenopalatine ganglion, including their branches. We propose a multicenter phase II, randomized, double-blinded, placebo-controlled study with sequential parallel comparison design of bilateral PPF-injections over 4 days at 12 centers. Following aneurysm treatment, 195 adults hospitalized with aneurysmal SAH, who are experiencing severe headaches and can verbalize pain scores, will be randomized to once daily active (ropivacaine + dexamethasone) or sham (saline) or PPF-injections during the first 2 consecutive days of the intervention period (Day 1/Stage 1, Day 2/Stage 2). The open-label phase spans the subsequent 2 days (Days 3-4), during which subjects may opt to receive an active PPF-block. This two-stage design leverages increased efficiency in data generation from the pooled sequential blinded stages (i.e., Stages 1 & 2) and reduced impact of sham responses, and thus, allows for smaller sample size without compromising statistical power. Our primary objective is to demonstrate the opioid-sparing analgesic effect of PPF-blocks vs sham. Our secondary objective is to assess the tolerability of PPF-injections as measured by rates of acceptance of second injection on Day 2, and their safety as measured by vasospasm rates at the end of the open-label period in patients with SAH. We will also explore the potential interplay of sex and racial disparities in pain experiences and both PPF- block tolerability and efficacy. This initiative merges our expertise in neurosurgery, neurocritical care, and acute- pain-anesthesiology to tackle a historically neglected aspect of the critical care management of SAH.

严重头痛在蛛网膜下腔出血 (SAH) 中普遍存在，90% 的患者在发作出血后都会出现剧烈头痛。尽管持续使用镇痛药，SAH 患者的疼痛控制程度仍然很差。尽管患病率很高，但缺乏指导 SAH 后头痛最佳治疗的数据。阿片类药物是治疗 SAH 后严重头痛最常用的止痛药。然而，基于阿片类药物的镇痛存在相当大的风险：意识水平和呼吸驱动力下降、低血压、胃肠道传输缓慢以及高耐受性和成瘾性。此外，迫切且关键的是确定新的策略来缓解 SAH 后令人痛苦且几乎普遍的头痛，同时减轻阿片类药物使用的后果。这种未得到满足的治疗需求反映了美国每年有近 30,000 人患这种疾病的关键知识缺口。我们提出了一种廉价的、节省阿片类药物治疗 SAH 后头痛的策略，即使用翼腭窝 (PPF) 神经阻滞来改善疼痛控制并减少阿片类药物需求。越来越多关于使用神经阻滞治疗急性和慢性头痛疾病的文献支持了我们的总体假设，即 PPF 阻滞提供快速、省阿片类药物的镇痛，安全且耐受性良好，并有望充分治疗 SAH 后头痛。这些头痛的病理生理学很复杂，涉及血液制品对脑膜的刺激、炎性细胞因子的释放、血管舒缩不稳定和中枢疼痛敏化。通过选择性调节，PPF 阻滞从根源上解决疼痛机制，针对上颌神经和蝶腭神经节，包括它们的分支。我们提出了一项多中心 II 期、随机、双盲、安慰剂对照研究，在 12 个中心对双侧 PPF 注射进行 4 天的序贯平行比较设计。动脉瘤治疗后，195 名因动脉瘤性蛛网膜下腔出血住院的成年人，他们正在经历严重的头痛，并且可以用语言表达疼痛评分，他们将在治疗的前 2 天被随机分配到每天一次的主动注射（罗哌卡因 + 地塞米松）或假注射（盐水）或 PPF 注射组。干预期（第 1 天/第 1 阶段，第 2 天/第 2 阶段）。开放标签阶段跨越随后的 2 天（第 3-4 天），在此期间受试者可以选择接受主动 PPF 阻滞。这种两阶段设计利用了汇集的连续盲阶段（即阶段 1 和 2）的数据生成效率的提高，并减少了假反应的影响，因此，在不影响统计能力的情况下允许更小的样本量。我们的主要目标是证明 PPF 阻滞剂与假手术相比，可节省阿片类药物的镇痛效果。我们的次要目标是评估 PPF 注射的耐受性（通过第 2 天第二次注射的接受率来衡量），以及通过 SAH 患者开放标签期结束时的血管痉挛率来衡量其安全性。我们还将探讨性别和种族差异在疼痛体验以及 PPF 阻滞耐受性和疗效方面的潜在相互作用。该计划融合了我们在神经外科、神经重症监护和急性疼痛麻醉学方面的专业知识，以解决 SAH 重症监护管理中历史上被忽视的一个方面。