22 patients with knee osteoarthritis (>6 month duration with the pain intensity (PI) while standing <=5 on a 0-10 numeric rating scale (NRS)) were selected. Patients performed multiple 20-minute treadmill walks on Day 1 and Day 3 at a consistent self-selected pace, predetermined at screening in 3 period cross over study once, each while taking naproxen, combination of tramadol and acetaminophen, or a placebo. Results indicated that, on the third day of treatment, both naproxen and tramadol/acetaminophen were had significantly better time-weighted average (TWA) change in pain intensity (PI) for the high-pace walks, but only tramadol/acetaminophen had significantly better TWA change in PI for self-pace walks. Furthermore, both treatment groups improved all pain and function scores significantly compared to placebo. Safety was similar between the two treatments, and was no serious adverse events were reported.