Tramadol Hydrochloride Extended-Release is bioequivalent under fasting conditions to another extended-release tramadol product [see CLINICAL PHARMACOLOGY (12.3)] which did demonstrate efficacy in two of four clinical trials of patients with chronic pain. To qualify for inclusion into these studies, patients were required to have moderate to moderately severe pain as defined by a pain intensity score of ≥40 mm, off previous medications, on a 0 – 100 mm visual analog scale (VAS).

In one 12-week randomized, double-blind, placebo-controlled study, patients with moderate to moderately severe pain due to osteoarthritis of the knee and/or hip were administered doses from 100 mg to 400 mg daily. Treatment with the extended-release tramadol product was initiated at 100 mg once daily for four days then increased by 100 mg per day increments every five days to the randomized fixed dose. Between 51% and 59% of patients in active treatment groups completed the study and 56% of patients in the placebo group completed the study. Discontinuations due to adverse events were more common in the extended-release tramadol product 200 mg, 300 mg and 400 mg treatment groups (20%, 27%, and 30% of discontinuations, respectively) compared to 14% of the patients treated with the extended-release tramadol product 100 mg and 10% of patients treated with placebo.

Pain, as assessed by the WOMAC Pain subscale, was measured at 1, 2, 3, 6, 9, and 12 weeks and change from baseline assessed. A responder analysis based on the percent change in WOMAC Pain subscale demonstrated a statistically significant improvement in pain for the 100 mg and 200 mg treatment groups compared to placebo (see Figure 2).

In one 12-week randomized, double-blind, placebo-controlled flexible-dosing trial of the extended-release tramadol product in patients with osteoarthritis of the knee, patients titrated to an average daily dose of approximately 270 mg/day. Forty-nine percent of patients randomized to the active treatment group completed the study, while 52% of patients randomized to placebo completed the study. Most of the early discontinuations in the active treatment group were due to adverse events, accounting for 27% of the early discontinuations in contrast to 7% of the discontinuations from the placebo group. Thirty-seven percent of the placebo-treated patients discontinued the study due to lack of efficacy compared to 15% of active-treated patients. The active treatment group demonstrated a statistically significant decrease in the mean Visual Analog Scale (VAS) score, and a statistically significant difference in the responder rate, based on the percent change from baseline in the VAS score, measured at 1, 2, 4, 8, and 12 weeks, between patients receiving the extended-release tramadol product and placebo (see Figure 3).

Figure 3

Four randomized, placebo-controlled clinical trials of Tramadol Hydrochloride Extended-Release were conducted, none of which demonstrated efficacy but which differed in design from the preceding clinical studies described. Two trials were 12-week randomized placebo-controlled trials of Tramadol Hydrochloride Extended-Release 100 mg/day, 200 mg/day, and 300 mg/day versus placebo in patients with moderate to moderately severe osteoarthritis pain of the hip and knee. The other two 12 week trials were similar in design, but only studied Tramadol Hydrochloride Extended-Release 300 mg/day. In this fixed-dose design, subjects were required to titrate to a fixed dose, even if their pain responded to a lower titration dose.