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

Abstract

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 Patients with inadequate efficacy (increase in NRS ≥2 points/patient request) were withdrawn.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. Trial registration JapicCTI-132103 (Japan Pharmaceutical Information Center; registration date February 25, 2015) Supplementary Information The online version contains supplementary material available at 10.1007/s40261-022-01139-5.

Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator

“…During the treatment period, AEs were reported for 77.0% and 80.8% of patients in the bilayer tablet and IR capsule groups, respectively, while ADRs were reported for 58.7% and 53.6%, respectively. These values seem reasonable when we consider the frequencies of AEs reported in the initial open-label treatment escalation periods (80.6% and 78.7% in the knee osteoarthritis and postherpetic neuralgia studies, respectively) of two previous dose-withdrawal studies using the bilayer tablet formulation [11,12]. We enrolled opioid-naïve patients, which may increase the risk of opioid-related AEs and ADRs.…”

“…Clinical guidelines position opioids, including tramadol, as options for managing cancer pain [4][5][6][7][8]. If acetaminophen or NSAIDs do not provide sufficient pain control, it may be possible to switch to these bilayer tramadol tablets, which have already shown good long-term efficacy and tolerability in patients with chronic non-cancer pain [10][11][12]. These bilayer tablets could be started early in the patient's clinical course and stepped down when no longer required, in accordance with WHO recommendations for the initiation, maintenance, and cessation of opioids [4].…”

“…1). In the treatment period with a double-dummy procedure, the patients took bilayer tablets (active drug or placebo) twice daily (morning and evening) and IR capsules (placebo or active drug) four times per day (morning, noon, evening, and before bed) according to the random allocation method in a blinded manner for up to 14 days (study days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. The rationale for the 14-day treatment period is described in the Supplementary Methods.…”

Efficacy and safety of twice‐daily tramadol hydrochloride bilayer sustained‐release tablets with an immediate release component for postherpetic neuralgia: Results of a Phase III, randomized, double‐blind, placebo‐controlled, treatment‐withdrawal study

“…Pharmacokinetic studies have demonstrated that the immediate‐release component is rapidly absorbed and the maximum plasma concentrations of tramadol and its active metabolite (M1) were reached within 1–2.6 h after a single dose (NZ‐687‐I‐J1 pharmacokinetic study). The sustained‐release component is absorbed slowly and ensures the plasma tramadol trough concentrations are maintained at a stable, therapeutic level with twice‐daily administration 18 . As part of its clinical development, we performed a Phase III, randomized, double‐blind, placebo‐controlled, treatment‐withdrawal study to investigate the efficacy and safety of these bilayer tramadol tablets in patients with PHN.…”

“…The sustained-release component is absorbed slowly and ensures the plasma tramadol trough concentrations are maintained at a stable, therapeutic level with twice-daily administration. 18 As part of its clinical development, we performed a Phase III, randomized, doubleblind, placebo-controlled, treatment-withdrawal study to investigate the efficacy and safety of these bilayer tramadol tablets in patients with PHN.…”