The efficacy and safety of a once-daily extended-release formulation of tramadol hydrochloride (tramadol ER) was evaluated in patients with moderate to severe chronic pain of osteoarthritis (OA). This was a randomized, double-blind, placebo-controlled, parallel-group, 12-week study. Eligible patients with radiographically confirmed OA of the knee meeting the American College of Rheumatology diagnostic criteria, defined by knee pain and presence of osteophytes, plus at least age >50 years, morning stiffness <30 minutes in duration, and/or crepitus, entered a 2-7 day washout period during which all analgesics were discontinued. When pain at the index knee joint reached > or =40 mm (0-100 mm VAS), patients were randomized to tramadol ER or placebo. Tramadol ER was initiated at 100 mg QD and increased to 200 mg QD by the end of 1 week of treatment. After the first week, further increases to tramadol ER 300 mg or 400 mg QD were allowed. Outcome measures included Arthritis Pain Intensity Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Arthritis Scale (WOMAC) Pain, Stiffness, Physical Function VAS subscales, Patient and Physician Global Assessment of Therapy, Sleep, dropouts due to insufficient therapeutic effect, and adverse events. Two hundred forty-six patients were randomized (tramadol ER 124, placebo 122). There were no baseline differences between the two treatments. The mean age was 61 years, mean duration of OA 12.9 years, and the mean tramadol ER dose was 276 mg QD. All efficacy outcome measures favored tramadol ER over placebo. On the primary outcome variable of average change from baseline in Arthritis Pain Intensity VAS over 12 weeks, tramadol ER was superior to placebo (least squares mean change from baseline: 30.4 mm vs. 17.7 mm, P < 0.001). Significant differences from placebo were evident at week 1, the first post-treatment visit. Similarly, outcomes on the WOMAC Pain, Stiffness and Physical Function subscales, the WOMAC Composite Scale, dropouts due to insufficient therapeutic effect, Patient and Physician Global Assessment of Therapy, and Sleep were all significantly better with tramadol ER than placebo (P < 0.001 to < 0.05). Treatment with tramadol ER results in statistically significant and clinically important and sustained improvements in pain, stiffness, physical function, global status, and sleep in patients with chronic pain. A once-a-day formulation of tramadol has the potential to provide patients increased control over the management of their pain, fewer interruptions in sleep and improved compliance.