This comparative randomized controlled trial aimed to compare Cryotherapy and Ketorolac Tromethamine (KT) against a control group of Room-Temperature Saline (RtS) irrigations using Interleukin-8 (IL-8) expression and pain-intensity scale in single-visit endodontic treatment of symptomatic irreversible pulpitis superimposed by apical periodontitis. This evidence concerns the gene CXCL8 and periapical periodontitis.