<p>Healthcare-related pain associated with hypodermic needles is prevalent and undertreated in pediatric patients. Currently available topical anesthetics provide insufficient pain relief due to poor drug skin permeability, especially when rapid onset is desired. Herein, our goal was to assess the speed and efficacy of local lidocaine/epinephrine/tetracaine (LET) gel enabled by STAR particles in a first-in-humans clinical trial. Twenty-two children (10 – 15&#xa0;yr) were randomized in a placebo-controlled, cross-over trial to receive topical treatment of LET gel applied to the antecubital fossa for 10 or 20&#xa0;min either with or without STAR particle pretreatment. STAR particle pretreatment decreased skin barrier function, demonstrated by increased trans-epidermal water loss compared to placebo (25.0 ± 8.7&#xa0;g/m²h vs. 14.8 ± 4.3&#xa0;g/m²h, P &lt; 0.0001). STAR particle pretreatment followed by LET gel (STAR-LET group) resulted in decreased sharp sensations from needle probing after 10&#xa0;min (51.6 ± 29.2% vs 82.0 ± 18.6%, P = 0.014) and 20&#xa0;min (55.7 ± 21.8% vs 89.0 ± 15.6%, P = 0.006) compared to LET gel without STAR particle pretreatment (LET group). After hypodermic needle insertion, pain decreased at 10&#xa0;min (3.1 ± 1.8 vs. 4.1 ± 1.9, P = 0.11) and 20&#xa0;min (4.2 ± 1.0 vs. 5.3 ± 1.5, P = 0.02) in the STAR-LET group compared to the LET group. STAR particle pretreatment was described as comfortable and without pain by most participants. No adverse skin reactions were observed immediately after STAR-LET application or during the 7-day follow-up period. STAR particle skin treatment in combination with LET gel in children was safe, well-tolerated, and effective to rapidly reduce painful sensations associated with hypodermic needles. Trial Registration: Lidocaine Administration Using STAR Particles, NCT06034340, <a href="https://classic.clinicaltrials.gov/ct2/show/NCT06034340">https://classic.clinicaltrials.gov/ct2/show/NCT06034340</a></p> Graphical Abstract <p></p>