Investigating Why Comparing Intravenous and Perineural Dexamethasone Is Scientifically Unfounded

Dexamethasone is a widely used adjuvant in regional anesthesia, yet debate persists over whether intravenous (IV) and perineural routes are interchangeable. This editorial argues that head-to-head comparisons are mechanistically unsound and clinically misleading. IV dexamethasone distributes systemically after cardiopulmonary transit, yielding low, variable target-site bioavailability at the nerve; systemic anti-inflammatory and antiemetic effects within enhanced recovery pathways dominate its benefits. Perineural dexamethasone creates a high-concentration depot at the neural interface, prolonging block reliability through reduced vascular uptake and a locally anti-inflammatory microenvironment, while conferring neuroprotection via antiedema, antifibrotic, microcirculatory, and antineurotoxic actions. Published studies reporting either superiority of perineural dosing or equivalence between routes likely reflect heterogeneity in populations, procedures, timing, anesthetic strategies, and adjuvant regimens rather than true pharmacologic parity. Methodological parity of milligram dosing across routes is a key flaw; concentration- or exposure-matched designs are needed. Clinically, IV dexamethasone should be used for systemic modulation (including postoperative nausea and vomiting reduction), whereas perineural dexamethasone should be selected to extend block duration and protect the nerve; combined use can be synergistic when both aims matter. Reframing the debate from competition to context-specific integration aligns practice with pharmacology and may improve patient-centered outcomes.