The effects of nefopam and ketamine on pain control and rehabilitation after total knee replacement were compared in a prospective, double blinded study. Seventy-five patients were randomly assigned to receive a 0.2mg kg(-1) bolus of nefopam or ketamine, followed by a 120microg kg(-1) h(-1) continuous infusion until the end of surgery, and 60microg kg(-1) h(-1) until the second postoperative day, or an equal volume of saline considered as placebo. Pain scores measured on a visual analog scale at rest and on mobilization, and patient-controlled intravenous morphine consumption, were assessed during 48h. We measured the maximal knee flexion on the third postoperative day, and the delay to obtain a 90 degrees flexion. Ketamine and nefopam reduced morphine consumption (p<0.0001). Pain scores, were lower at rest and on mobilization in the ketamine group compared to the two other groups at all times of measurement. Pain score were lower in patients receiving nefopam compared to placebo, on arrival in the recovery room and at 2h. Ketamine improved knee flexion on post operative day 3 (59 degrees [33-63] vs. 50 degrees [47-55] and 50 degrees [44-55] in ketamine, placebo and nefopam groups, respectively, p<0.0002) and decreased the delay to flex the knee at 90 degrees (9.1+/-4.2 vs. 12.3+/-4.0 days, in ketamine and placebo groups, respectively, p=0.01). Ketamine produces opioid-sparing, decreases pain intensity, and improves mobilization after total knee replacement. Nefopam achieves less significant results in that circumstances.