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.

Subarachnoid hemorrhage (SAH) causes excruciating headaches in nearly all patients during the days, weeks, or even years after the bleeding. We propose a new way to treat these severe headaches—limiting the use of opioids, which can cause addiction and have dangerous side effects—using a nerve-block procedure that has been successful in treating other types of headaches, such as migraines. If this new way of pain treatment proves successful, it could be the beginning of a huge change in how we treat pain in SAH patients, and in acute brain injury in general.