DISCUSSION
postoperative pain, renal impairment, swelling, Postoperative pain, throat, pain
RENAL IMPAIRMENT, DELAYED WOUND HEALING, ORAL MUCOSITIS, COMPLICATION, DRY SOCKETS
This single‐center, double‐blind, placebo‐controlled, crossover study investigated the efficacy and safety of ibuprofen gargle in reducing postoperative pain after mandibular third molar extraction. Our findings revealed that the primary endpoint of the ibuprofen gargle was not statistically significant, with a difference of −2.01 mm (95% CI: −5.45 to 1.44, The split‐mouth randomized controlled trial is a popular study design in oral health (Ceccheti et al., Postoperative pain is a major complication of mandibular third molar extraction, necessitating symptomatic pharmacological treatment. Notably, oral administration of flurbiprofen, lornoxicam, and phytotherapeutic drugs has shown efficacy in managing pain following third molar surgery (Isola, Alibrandi, et al., The primary endpoint of this study was not met because the results of ΔVAS varied widely among patients, which did not comply with our preliminary power analysis. This could be explained by the fact that the painful site after third molar extraction is deep in the tissues, unlike oral mucositis, and the local analgesic effect of the gargle was not as strong as expected. In addition, there is a potential for confounding effects from loxoprofen administration. Moreover, the Pell–Gregory classification, Winter's classification, surgeon's experience, and baseline VAS distributions were imbalanced across the two groups, which may affect the results. Therefore, future study designs aimed at improving the high SD of VAS scores may require a more limited study design or balanced patient background factors, such as Pell–Gregory and Winter classifications. Additionally, alternative methods to gargling should be considered.To reduce the likelihood of systemic absorption, the ibuprofen gargle solution was held in the mouth for 1 min before being expelled. In addition, the concentration of ibuprofen used in the study (600 mg ibuprofen/100 mL) was comparable to the recommended maximum daily dose (600 mg) for oral ibuprofen administration. Thus, the concentration of any drug accidentally ingested could be less than the maximum daily allowance. This study did not detect apparent dry sockets due to delayed wound healing or renal impairment due to COX inhibition caused by ibuprofen gargling. The only TRAEs observed were unpleasant taste and irritation at the back of the mouth and throat. Ibuprofen gargle is considered acceptable from a safety perspective.This study has some major limitations. First, we used VAS as our primary endpoint. Previous studies have employed objective outcomes such as the degree of swelling and opening, which should have been analyzed in this study (Isola, Matarese, Ramaglia, Cicciù, et al., 