The analgesic effects of tramadol ER were initially explored in patients with moderate to moderately severe chronic pain due to osteoarthritis and/or low back pain in 12-week, randomized, double-blind, placebo-controlled trials (Ultram ER PI 2006). Moderate to moderately severe pain was defined by a pain intensity score of ≥ 40 mm, off previous medications, on a 0 to 100 mm visual analog scale (VAS). In one of these studies, patients with moderate to moderately severe pain due to OA of the knee and/or hip received tramadol ER 100 mg to 400 mg daily (Ultram PI 2006 ). Treatment was initiated at 100 mg for 4 days, and then increased every 5 days by 100 mg increments up to 400 mg. Pain was measured by the the Western Ontario and McMaster Universities (WOMAC) Pain subscale. Change in baseline pain was assessed at 1, 2, 3, 6, 9, and 12 weeks after treatment. A responder analysis, based on the percent change in the WOMAC Pain subscale, demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups, compared with placebo (Figure 4 ) (Ultram PI 2006 ). Surprisingly, the proportion of patients achieving improvement in pain with tramadol ER 300 mg and 400 mg was not significantly different from placebo. A 12-week, randomized, double-blind, placebo-controlled, flexible-dose study of patients with OA f the knee showed improvement in pain based on the Arthritis Pain Intensity VAS (Ultram PI 2006 ). Significant improvement was observed with a tramadol ER mean daily dose of 270 mg (Ultram PI 2006 ). The analgesic efficacy of tramadol ER was also examined in a 12-week, randomized, double-blind, placebo-controlled, flexible-dose study of 246 patients with osteoarthritis of the knee and moderate to severe chronic pain (Babul et al 2004 ). Patients with a mean age of 61 years and average disease duration of 12–13 years were randomized to tramadol ER (n = 124) or placebo (n = 122) (Babul et al 2004 ). Tramadol ER 100 mg was administered once daily for the first 4–8 days according to treatment tolerability and then increased to 200 mg (Babul et al 2004 ). Further titrations up to 300 mg or 400 mg were allowed based on analgesic efficacy and tolerability (Babul et al 2004 ). The mean tramadol ER dose was 276 mg, close to the highest recommended daily dose of 300 mg (Babul et al 2004 ; Ultram PI 2006 ). Analgesic efficacy was assessed as reduction of pain from baseline through 12 weeks using the Arthritis Pain Intensity VAS (Figure 5 ) (Babul et al 2004 ). After 1 week of treatment, VAS scores were decreased by 25% for tramadol ER compared with 14% for placebo (Babul et al 2004 ). Improvements in pain scores increased over time and were sustained up to 12 weeks; the mean change in VAS from baseline to 12 weeks was significantly greater for tramadol ER (49%) than placebo (27%; p < 0.001) (Babul et al 2004 ). It should be noted that the placebo response rate of 27% is not uncommon in analgesia trials (Turner et al 1994 ). WOMAC OA subscales were evaluated as a further measure of pain, stiffness, and physical function (Figure 6 ) (Babul et al 2004 ). As with the Arthritis Pain Intensity VAS, the WOMAC pain subscale improved significantly from baseline over the 12-week period following treatment with tramadol ER (Babul et al 2004 ). Tramadol ER significantly improved the mean WOMAC pain score from baseline by 45% compared with 25% for placebo (p < 0.001); an effect consistent with changes observed in the Arthritis Pain Intensity VAS (Babul et al 2004 ). Similar improvements in the WOMAC stiffness and physical function scores were observed following 12 weeks of tramadol ER therapy. Stiffness and physical function scores were increased by 43% and 44% for tramadol ER compared with 18% and 21% in the placebo group (p < 0.001) (Babul et al 2004 ).Efficacy of tramadol ER in patients with osteoarthritis using the WOMAC pain, stiffness, and physical function subscales. Mean percentage change in subscales were assessed from baseline to 12 weeks of treatment. Tramadol ER significantly improved pain, … Patient Global Assessment and Physician Global Assessment of pain were significantly better for tramadol ER than placebo from baseline to 12 weeks of therapy (p < 0.001) (Babul et al 2004 ). Treatment discontinuation was significantly lower with tramadol ER (19%) than placebo (38%; p < 0.001) (Babul et al 2004 ).