A 52-week, multicenter, open-label extension study was performed to evaluate the safety, tolerability, and effectiveness of oxymorphone extended release (ER), a novel tablet formulation of oxymorphone hydrochloride, in 153 patients with moderate to severe chronic osteoarthritis-related pain. Sixty-one patients (39.9%) completed the study. Common opioid-related nonserious adverse events (AEs) caused most withdrawals. However, approximately one-half of withdrawals due to AEs were among opioid-naive patients who received placebo in a previous trial and were started on a dose of 20 mg every 12 hours, suggesting that tolerability can be improved by titrating from a lower initial dose. Mean pain scores initially decreased as previously opioid-naive patients achieved adequate pain relief, reached stable levels after the first 6 weeks, and remained stable at mild levels throughout the remainder of the study (average pain, 20-25 mm on 100-mm Visual Analog Scale). Average daily dosing remained stable throughout the study (median, 40 mg/d). At each assessment, at least 80% of patients rated their global satisfaction with oxymorphone ER as excellent, very good, or good. Oxymorphone ER provides a new 12-hour analgesic for the treatment of moderate to severe chronic osteoarthritis-related pain in patients who may require long-term opioid therapy.