BackgroundUp to 30% of patients with knee osteoarthritis (KOA) have evidence of sensitization, with a similar proportion experiencing severe pain during procedures. Most patients with KOA are elderly and often develop side effects from intravenous sedation. Our study investigated the effectiveness of a methoxyflurane inhaler combined with local anesthesia in reducing procedural pain from genicular nerve block compared with local anesthesia alone.Methods42 adults with refractory KOA were randomized into two groups. Methoxyflurane group received a self-titrated methoxyflurane inhaler with local anesthesia whereas lidocaine group received local anesthesia only. The primary outcome was pain score on a 0–10 verbal numerical rating scale (VNRS) during the procedure. Secondary outcomes included changes in VNRS and behavioral pain scale (critical care pain observational tool) during the procedure, hemodynamic changes, anxiety level, sedation score, and adverse events.Results42 patients with a mean age of 66±12 years participated in this study. There were no significant baseline differences. During the procedure, the methoxyflurane group experienced a significantly greater VNRS pain reduction from baseline (2 (1, 4) vs −1 (−2, 0); p<0.01) and greater VNRS reduction over time (p=0.01) compared with the lidocaine group, with a higher sedation score (p<0.01). Immediately postprocedure, anxiety levels were lower in the methoxyflurane group compared with the lidocaine group (median State-Trait Anxiety Inventory score 21 (IQR 20, 24) vs 27 (23, 29); p=0.02), but the median reduction in anxiety level was not significant (6 (1, 12) vs 5 (0, 14); p=0.61). There were no differences in behavioral pain scores, hemodynamic parameters, recovery or discharge times, and adverse effects between the two groups.ConclusionA methoxyflurane inhaler combined with local anesthesia provided better procedural pain control than local anesthesia alone with no observable differences in adverse effects. Future studies evaluating the impact of a methoxyflurane inhaler on different types of painful procedures are warranted.