Efficacy and Safety of Tramadol Hydrochloride Twice-Daily Sustained-Release Bilayer Tablets with an Immediate-Release Component for Chronic Pain Associated with Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled, Treatment-Withdrawal Study

Background and Objectives Knee osteoarthritis pain is a chronic form of pain for which conventional non-steroidal anti-inflammatory drugs may provide insufficient analgesia. Twice-daily tramadol hydrochloride (65% sustained-release/35% immediate-release) bilayer tablets are a novel formulation of tramadol developed for managing chronic pain. The objectives of this study were to examine the effectiveness and safety of this formulation in patients with chronic knee osteoarthritis pain. Methods This was a multicenter, randomized, placebo-controlled, double-blind, parallel-group, treatment-withdrawal study. Patients with a reduction in Numeric Rating Scale (NRS) for pain of >= 2 points during a 1-3-week, open-label, tramadol dose-escalation period (100-300 mg/day) were randomized to continue tramadol or switched to placebo for 4 weeks (double-blind period). Patients with inadequate efficacy (increase in NRS >= 2 points/patient request) were withdrawn. Outcomes included the time to inadequate analgesic efficacy from randomization (primary endpoint), the cumulative retention rate, and safety. Results Overall, 249 and 160 patients entered the dose-escalation and double-blind periods, respectively (tramadol 79; placebo 81). Kaplan-Meier analysis revealed superiority of tramadol (log-rank p = 0.042), and a hazard ratio of 0.50 (95% confidence interval [CI] 0.25-0.99). Documentation of an inadequate analgesic effect was less frequent in the tramadol group (15.4%, 95% CI 8.2-25.3% vs. 30.9%, 95% CI 21.1-42.1%). The cumulative retention rate was greater in the tramadol group (83.7% vs. 69.0%). Adverse events occurred in 80.6% (200/248) of patients in the open-label period, and in 38.5% (30/78) and 13.6% (11/81) of patients in the tramadol and placebo groups, respectively, in the double-blind period. Opioid-associated adverse events, such as nausea, vomiting, constipation, somnolence, and dizziness, were the most frequent events. Conclusion This study demonstrated the analgesic efficacy and safety of sustained-release tramadol tablets with an immediate-release component for chronic knee osteoarthritis pain.