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%的患者在突厥出血后出现。尽管稳定地使用镇痛药，但SAH患者的疼痛控制程度非常差。尽管如此高的患病率，缺乏数据指导sah后头痛的最佳管理。阿片类药物是严重sah后头痛的最常用止痛药。然而，基于阿片类药物的镇痛存在相当大的风险：意识和呼吸驱动水平下降，低血压，胃肠运输缓慢，耐受性和成瘾性高。此外，确定新的策略来减轻sah后的痛苦和几乎普遍的头痛，同时减轻阿片类药物使用的后果，这是迫切和关键的。这种未被满足的治疗需求反映了一个关键的知识缺口，在美国，每年有近3万人受到这种疾病的折磨。我们提出了一种廉价的阿片类药物节约策略，用于sah后头痛，使用神经阻滞进入翼腭窝（PPF）来改善疼痛控制和减少阿片类药物需求。越来越多关于神经阻滞在急慢性头痛疾病中的应用的文献支持了我们的总体假设，即ppf阻滞提供快速、不使用阿片类药物的镇痛，安全且耐受性良好，有望充分治疗sah后头痛。这些头痛的病理生理是复杂的，涉及血液制品对脑膜的刺激、炎症细胞因子的释放、血管舒张性不稳定和中枢性疼痛致敏。通过选择性调节，ppf阻滞在其起源处解决疼痛机制，靶向上颌神经和蝶腭神经节，包括其分支。我们提出了一项多中心II期、随机、双盲、安慰剂对照研究，采用顺序平行比较设计，在12个中心进行为期4天的双侧ppf注射。在动脉瘤治疗后，195名患有严重头痛并能说出疼痛评分的动脉瘤性SAH住院的成年人将在干预期的连续前2天（第1天/第1阶段，第2天/第2阶段）随机分为每日一次活动（罗哌卡因+地塞米松）或假（生理盐水）或ppf注射。开放标签阶段持续2天（第3-4天），在此期间受试者可以选择接受活性ppf阻滞。这种两阶段设计利用了从合并的顺序盲法阶段（即阶段1和阶段2）中提高的数据生成效率，并减少了虚假反应的影响，因此，在不影响统计能力的情况下允许更小的样本量。我们的主要目的是证明ppf阻滞与假药的镇痛效果。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，以及通过开放标签期结束时血管痉挛率来衡量SAH患者的安全性。我们还将探讨性别和种族差异在疼痛体验和PPF阻滞耐受性和疗效方面的潜在相互作用。这一举措融合了我们在神经外科、神经危重症护理和急性疼痛麻醉学方面的专业知识，以解决SAH危重症护理管理的历史上被忽视的方面。

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.