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BLOCK-SAH is a phase II, multicenter, randomized, double-blinded, placebo-controlled clinical trial with a sequential parallel comparison design (SPCD) of bilateral pterygopalatine fossa (PPF) injections with 20mg ropivacaine + 4mg dexamethasone (active, PPF-block) compared to saline (placebo) for headache in survivors of aneurysmal subarachnoid hemorrhage (SAH), while monitoring intracranial arterial mean flow velocities with transcranial Doppler (TCD) peri-intervention (intervention = PPF-injections: active or placebo)

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the

Following criteria:

1. Provision of signed and dated ICF

2. Stated willingness to comply with all study procedures and availability for the duration of the study

3. Male or female, aged �18 and � 85 years

4. Admitted with a primary diagnosis of spontaneous, non-traumatic, SAH within 48 hours of ictus hemorrhage

5. Disease-specific inclusion criteria:

   1. Aneurysm identified as culprit of SAH

   2. modified Fisher grade 1-4 (on admission imaging)

   3. Hunt and Hess 1-3 or World Federation of Neurosurgeons grade 1-4 (on screening, included only if also fulfilling Glasgow Coma Scale verbal subscore �4)

   4. minimum Glasgow Coma Scale verbal subscore of 4 (on screening)

6. Able to verbalize pain scale scores according to 11-point numeric pain scale In order to be enrolled and undergo randomization in this study, an individual must

Meet all of the additional criteria:

1. Stabilization period criteria:

   1. A minimum of 4 hours from clipping or coiling procedure (whichever applicable)

   2. Successful treatment of culprit vascular lesion (i.e., �90% obliteration of aneurysm)

2. Requiring a minimum of 15mg OME prn for headache analgesia during any 24-hour period during eligibility period

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation

In this study:

1. Premorbid conditions:

   • Pre-existing neurologic, psychiatric, or other condition that would confound neurologic assessment or would make difficult/impossible to accurately assess neurologic and/or functional outcome

   • Pre-existing diffuse flow-limiting narrowing of arteries in the Circle of Willis, regardless of etiology (e.g., atherosclerosis, vasculitis, Moya-Moya syndrome)

   • Prior use of opioid or barbiturate analgesics for at least two-thirds of the days in previous month, regardless of indication

   • Diagnosis of substance use disorder in the previous year

   • Infected or wounded skin, or a skin lesion at the site of puncture for PPF- injection

2. Uncorrected coagulopathy

   • Platelet count < 50,000/μL, International Normalized Ratio (INR) > 1.7

   • Requiring use of systemic anticoagulation and antiplatelet therapy (except for aspirin monotherapy).

3. SAH-specific:

   • Head trauma as etiology of SAH

   • Infection as cause for aneurysm or SAH (i.e., mycotic aneurysms)

   • Inability to successfully treat culprit vascular lesion

   • Diffuse vasospasm on initial diagnostic CTA or DSA. Vasospasm is defined as moderate to severe arterial narrowing on DSA or CTA not attributable to atherosclerosis, catheter induced spasm, or vessel hypoplasia, as determined by a neuroradiologist or neurointerventionalist

4. Standard pain regimen conditions

   • Elevation of hepatic enzymes prohibiting use of scheduled APAP (i.e., AST or ALT > 3x upper limit level)

   • Chronic liver condition with absolute contra-indication for APAP (even at lower maximum daily doses)

5. Participation in a concurrent investigational/interventional study (observational studies allowed)

6. Known to be pregnant, or with a positive pregnancy test

7. Allergy or intolerance to the medications used in the PPF-block (i.e., ropivacaine, dexamethasone) or standard pain regimen (APAP)

8. Vulnerable populations such as prisoners and inmates (abiding GCP per the study IRB)

9. Unable to receive first PPF-injection within 96 hours of ictus hemorrhage