Introduction The objective of this study was to evaluate the long-term tolerability and safety of 2 tablets of extended-release hydrocodone 15 mg/acetaminophen 500 mg (HC/APAP CR) administered twice daily in osteoarthritis or mechanical chronic low back pain patients. Methods Patients were recruited from 74 US sites. 431 patients enrolled in the titration period and took 1 tablet HC/APAP CR once daily for 3 days followed by 1 tablet twice daily for 4 days. During maintenance, patients took 2 tablets HC/APAP CR twice daily for 56 weeks. Following 56-week maintenance, patients had their medication tapered over one week. Patients received rescue medication (acetaminophen) up to three times per week. Efficacy was evaluated by a pain-intensity Likert Scale, and safety was assessed by adverse event (AE), vital sign and laboratory assessment. Results 415/431 patients comprise the efficacy evaluable dataset reported in the primary analysis population. Pain intensity decreased from baseline at all subsequent evaluations (Table 1). The most commonly reported treatment-emergent AEs (°Ã10% of patients) were constipation, nausea, headache, and somnolence. The incidence and prevalence of these common AEs generally decreased over time. 124 (29%) patients discontinued due to AE(s). The most common (©ø 2% of subjects) AEs that led to discontinuation were nausea, somnolence, constipation, dizziness, vomiting, headache, and fatigue. 25 (6%) patients experienced SAE(s); OA (4/431; 1%) was the most common SAE reported. APAP use decreased after the first 30 days of treatment and remained low for the rest of the study. There were no reports of hepatotoxicity. Conclusion HC/APAP CR was efficacious in the management of chronic non-malignant pain over a duration of 56 weeks. The safety profile of HC/APAP CR in this study was consistent with that of a mu-opioid receptor agonist-containing agent.