OBJECTIVE: The authors explored the use of continuous postoperative subpleural paravertebral ropivacaine alone combined with intraoperative S(+)-ketamine or perioperative parecoxib as a new approach to pain control after major thoracotomy.DESIGN: A randomized study.SETTINGS: A single university hospital.PARTICIPANTS: Eighty patients underwent elective thoracotomy under general anesthesia.METHODS: Study patients were assigned to 1 of 3 groups: group K (n = 27) received intraoperative S(+)-ketamine (0.5 mg/kg as a preincisional bolus followed by a continuous infusion 400 μg/kg/h), group P (n = 27) received perioperative parexocib (40 mg before extubation and 12 hours postoperatively), and group C (n = 26) served as the control group. At the end of surgery, all patients received a subpleural paravertebal infusion of ropivacaine.MEASUREMENTS AND MAIN RESULTS: Pain was assessed by visual analog scores and supplemental morphine consumption with PCA up to 48 hours postoperatively. The duration of stay and postoperative functional parameters also were collected. Compared with ropivacaine alone, S(+)-ketamine significantly reduced pain scores at rest and during movement at 4, 12, 24, and 48 hours postoperatively. Moreover, at 24 and 48 hours, pain was less after S(+)-ketamine compared with parexocib. S(+)-ketamine also reduced morphine needs in comparison to placebo at 4, 12, 24, and 48 hours and in comparison to parexocib at 48 hours after thoracotomy. There were no differences in parameters for lung or bowel function, mobilization time, or ICU and hospital stay.CONCLUSIONS: In patients with thoracotomy, postoperative paravertebral ropivacaine combined with intraoperative S(+)-ketamine provided better early postoperative pain relief than ropivacaine and perioperative parexocib or ropivacaine alone.