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

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出现严重头痛。尽管镇痛剂的用量稳定，但SAH患者的疼痛控制程度明显较差。尽管患病率很高，但缺乏数据指导了SAH后头痛的最佳治疗。阿片类药物是治疗SAH后严重头痛的最常用止痛药。然而，基于阿片类药物的止痛存在相当大的风险：意识水平和呼吸动力降低，低血压，胃肠道传输缓慢，耐受性和成瘾频率高。此外，迫切和关键的是确定新的战略，以减轻SAH后令人痛苦和几乎普遍存在的头痛，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一种关键的知识缺口，这种疾病每年在美国困扰着近3万人。我们提出了一种廉价的、非阿片类药物治疗SAH后头痛的策略，在翼腭窝(PPF)内使用神经阻滞来改善疼痛控制和减少阿片类药物的需求。越来越多的关于神经阻滞剂在急性和慢性头痛疾病中使用的文献支持了我们的主要假设，即PPF-阻滞剂提供快速、非阿片类药物的止痛，是安全和耐受性良好的，并有望充分治疗SAH后头痛。这些头痛的病理生理机制是复杂的，涉及血液制品对脑膜的刺激、炎性细胞因子的释放、血管运动不稳定和中枢性疼痛敏感化。通过选择性调制，PPF阻滞剂从其起始处解决疼痛机制，靶向于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个中心进行了为期4天的双侧PPF注射的序贯平行对照设计。在动脉瘤治疗后，195名患有动脉瘤性蛛网膜下腔出血的成年人住院，他们正在经历严重的头痛，并可以用言语表达疼痛评分，他们将被随机分配到介入期间的头两天(第1天/第1阶段，第2天/第2阶段)，每天接受一次活动(罗比卡因+地塞米松)、假注射(生理盐水)或PPF注射。开放标记阶段跨越随后的2天(3-4天)，在此期间，受试者可以选择接受有效的PPF-块。这种两阶段设计利用了从汇集的顺序盲化阶段(即，阶段1和阶段2)生成数据的更高的效率，并减少了假响应的影响，因此，允许较小的样本大小而不损害统计能力。我们的主要目的是证明PPF阻滞剂与假手术相比对阿片类药物的节约性镇痛作用。我们的次要目标是评估PPF注射的耐受性，通过第二天第二次注射的接受率来衡量，以及它们的安全性，通过SAH患者开放标记期结束时的血管痉挛发生率来衡量。我们还将探索性别和种族差异在疼痛体验以及PPF-阻滞剂耐受性和有效性方面的潜在相互作用。这一举措融合了我们在神经外科、神经危重护理和急性疼痛麻醉学方面的专业知识，以解决SAH危重护理管理中历史上被忽视的一个方面。

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.