Background <p>Vacuum assisted closure (VAC) is an effective treatment that promotes wound healing in clinical practice. However, the pain caused by Vacuum assisted closure VAC dressing removal is still a challenge for patients and medical staff. The purpose of this study was to investigate the analgesic effect and safety of premixed nitrous oxide/oxygen in the treatment of pain caused by VAC dressing removal.</p> Methods/design <p>This study is a single center, randomized, placebo-controlled, double-blind clinical trial. A total of 100 patients requiring VAC dressing removal were recruited and randomly divided into an intervention group and a control group. The intervention group will receive routine treatment plus a premixed nitrous oxide/oxygen mixture, and the control group will receive routine treatment plus oxygen. Participants and researchers are all blind to the operation process. The results of each group will be monitored at baseline (T0), 5&#xa0;min after intervention (T1), and 5&#xa0;min after finishing intervention (T2), 15&#xa0;min after finishing intervention (T3). The primary outcome measure was pain intensity. Secondary outcomes included physiological parameters, adverse reactions, operators, and patients’ satisfaction.</p> Discussion <p>This study will explore the analgesic effect of oxide/oxygen mixture on VAC dressing removal. If it is beneficial to patients with VAC dressing change, it will be helpful for pain management of VAC dressing removal.</p> Trial registration <p>Chinese Clinical Trial Register ChiCTR2200056742. Registered on February 13, 2022.</p>