Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6–12 months) safety of acetaminophen in adult patients with osteoarthritis

Objective: This study evaluated the safety of acetaminophen 4 g/d administered for up to 12 months to adult patients with osteoarthritis pain, using naproxen 750 mg/d as an active comparator. Methods: This multicenter, multidose, single-dummy, randomized, double-blind, active-controlled, parallel-group study enrolled patients with mild to moderate osteoarthritis pain of the hip or knee. Patients received acetaminophen 4 g/d or naproxen 750 mg/d for 12 months (group 1) or 6 months (group 2). Patients in both groups had follow-up visits at months 1, 3, and 6 of treatment (or at the time of study withdrawal). Patients in group 1 also had follow-up visits at months 9 and 12 (or at the time of study withdrawal). Tolerability evaluations consisted of determinations of hepatic (aminotransferase activities) and renal (serum creatinine) function, adverse events, and physical examinations. Adverse events reported by the patient or observed by the investigator during clinical evaluation were recorded. In addition, patients were questioned at each visit regarding the occurrence of adverse events using a nonspecific question. Investigators rated the intensity of adverse events and their subjective assessment of the relationship to study medication while blinded to the treatment group. At all visits, patients completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), in visual analog scale format, to assess pain, stiffness, and physical function over the previous 2 weeks. The primary efficacy end point was the mean change from baseline in the WOMAC pain subscale score at 6 months. Data from the 6- and 12-month groups were combined for analysis. Results: Of 581 randomized patients, the safety population included 571 patients who received ≥1 dose of study medication. The 571 patients had a mean (SD) age of 59.3 (8.6) years, 395 (69.2%) were female, and 480 (84.1%) were white. Of 290 patients randomized to receive acetaminophen, 134 completed 3 months of treatment, 96 completed 6 months, 60 completed 9 months, and 55 completed a full 12 months. The median dose adherence ranged from 95.5% to 98.6% during the trial. The completion and adherence patterns were similar for patients receiving naproxen. Of 291 patients randomized to receive naproxen, 151 completed 3 months, 124 completed 6 months, 85 completed 9 months, and 80 completed 12 months. The median dose adherence ranged from 96.4% to 98.4% during the trial. No patient in either treatment group experienced hepatic failure, hepatic dysfunction, aminotransferase levels ≥2x the upper limit of the reference range, renal failure, or serum creatinine levels ≥1.5x the upper limit of the reference range. No statistically significant differences were observed between the 2 treatment groups in the proportion of patients who reported ≥1 adverse event (206 [71.8%] acetaminophen, 209 [73.6%] naproxen) or in the proportion of patients who discontinued treatment because of adverse events (71 [24.7%] acetaminophen, 63 [22.2%] naproxen). Among adverse events considered to be drug related and reported by ≥1% of patients, constipation and peripheral edema were reported more frequently in the naproxen group than in the acetaminophen group (9.9% vs 3.1% [P<0.002] and 3.9% vs 1.0% [P<0.033], respectively). No adverse event reported in the acetaminophen group was considered both serious and related to study medication. One subject in the naproxen group had an event that was considered serious and related to study drug: gastrointestinal bleeding. No statistically significant differences were observed between the 2 treatment groups for the primary efficacy end point. Conclusion: With physician supervision, acetaminophen was found to be generally well tolerated in these patients for the treatment of osteoarthritis pain of the hip or knee for periods of up to 12 months.