Sphenopalatine Ganglion Modulation in Stroke-Associated Headache: Mechanistic Insights and Future Therapeutic Directions

Abstract Stroke-associated headache remains a common yet underrecognized symptom in acute cerebrovascular disease. Although its prevalence varies across ischemic and hemorrhagic stroke populations, the symptom contributes significantly to patient discomfort, agitation, impaired neurological assessment, and overall clinical burden. Current management strategies remain largely non-specific and are often limited to conventional analgesics. The sphenopalatine ganglion (SPG), a major extracranial parasympathetic ganglion involved in trigemino-autonomic signaling, has emerged as a therapeutic target in several primary headache disorders including cluster headache and migraine. Experimental and clinical evidence suggests that trigeminovascular activation, autonomic dysregulation, cortical spreading depolarization, and meningeal nociceptive signaling may also contribute to stroke-associated headache, raising the possibility that SPG modulation could have relevance in this setting. This review examines the neurobiological rationale linking SPG pathways to secondary headache generation in acute stroke. Existing evidence surrounding transnasal SPG blockade, oxygen-mediated trigeminovascular modulation, and autonomic neurovascular interactions is discussed, with emphasis on translational applicability to stroke-associated headache. Practical procedural considerations, safety concerns, and limitations of current evidence are also reviewed. Preliminary clinical observations from our center suggested that transnasal SPG modulation combined with titrated oxygen therapy may be associated with symptomatic improvement in selected hypoxic stroke patients with severe headache. However, these observations are hypothesis-generating only and should not be interpreted as evidence of therapeutic efficacy. Further mechanistic studies and sham-controlled clinical trials are warranted to determine whether SPG modulation represents a meaningful therapeutic pathway in stroke-associated headache.