Introduction: Radiofrequency (RF) microneedling requires minimal downtime; however, patients’ tolerance of the procedural pain can limit cosmetic results. The goal of this study was to determine the patient tolerance of RF microneedling with sufentanil sublingual tablet (SST) 30 μg and topical local anesthetic compared with topical local anesthetic alone. Materials and Methods: The study was a one-way crossover study of patients undergoing RF microneedling of the face or abdomen. Topical local anesthetic was applied 45 minutes prior to the initial procedure to one side of the face or abdomen (control side), followed by topical local anesthetic and SST administered 45 and 30 minutes, respectively, prior to the procedure on the opposite side (SST-treated side). The primary endpoint was patient completion of the procedure with additional endpoints of Richmond Agitation Sedation Scale scores, patient and provider satisfaction ratings, vital signs, oxygen saturation levels, and adverse events. Results: A total of 51 patients were enrolled averaging 44.8 ± 11.1 (SD) years of age. Forty-five percent of patients successfully completed the control side compared with 96% of patients successfully completing the SST-treated side ( P < .001). Patients were less restless or agitated during the SST-treated side (6%) compared with the control side (51%; P < .001). Patient and provider satisfaction scores were significantly improved with SST ( P < .001). Vital signs remained stable with SST treatment compared with the control side. Discussion: The SST is a safe and effective sublingual analgesic allowing patients to be awake and alert while increasing patient tolerance of RF microneedling as well as patient and provider satisfaction with the procedure. Conclusion: The SST is a novel analgesic that can be used in office-based settings with appropriate safety equipment available.