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

Abstract

Background We investigated the efficacy and safety of twice‐daily bilayer sustained‐release tramadol hydrochloride tablets (35% immediate‐release; 65% sustained‐release) in patients with postherpetic neuralgia. Methods This was a Phase III treatment‐withdrawal study with 1–4‐week dose‐escalation, 1‐week fixed‐dose, and 4‐week randomized, double‐blind, placebo‐controlled withdrawal periods performed at 43 medical institutions in Japan. Patients aged ≥20 years, ≥3 months after the onset of herpes zoster with localized, persistent pain despite fixed‐dose analgesics for ≥2 weeks before enrollment were eligible. Patients started tramadol at 100 mg/day and its dose escalated to a maximum of 400 mg/day to achieve a reduction in their Numeric Rating Scale (NRS) for pain of ≥2 points. Eligible patients were randomized to continue tramadol or switched to placebo for 4 weeks (double‐blind period). Patients were withdrawn due to inadequate analgesia (NRS deteriorated on ≥2 consecutive days) or their request. Results Overall, 252 patients started tramadol and 173 were randomized (tramadol: 85; placebo: 88). Tramadol was superior to placebo for the primary endpoint (time from randomization to an inadequate analgesic effect) with log‐rank test p = 0.0005. The hazard ratio was 0.353 (95% confidence interval 0.190–0.657) in favor of tramadol and fewer patients in the tramadol group experienced inadequate analgesic effects (16.9% vs. 39.8%). Adverse events in ≥10% of patients in the open‐label period were constipation (43.8%), nausea (34.9%), somnolence (18.5%), and dizziness (11.6%). The frequencies of adverse events in the double‐blind period were similar in both groups. Conclusion Sustained‐release tramadol tablets with an immediate‐release component are effective and well tolerated for managing postherpetic neuralgia.

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.…”

“…Every evening, just before administering the study drug, the patients evaluated their pain at rest and during movement over the previous 24-h period using a 100-mm VAS. This information was used to determine the primary endpoint-the change in the VAS for pain at rest from baseline (averaged over the 3 days before starting treatment) to the end of treatment (EOT; averaged over study days [12][13][14] or at discontinuation (averaged over the 3 days before discontinuation). A clinically relevant change in the VAS for pain was defined as a moderate or greater improvement during treatment relative to the baseline score using the chart shown in Supplementary Table 1; this definition was developed and utilized in prior studies in Japan [13,14].…”

Development, Physicochemical Characteristics and Pharmacokinetics of a New Sustained-Release Bilayer Tablet Formulation of Tramadol with an Immediate-Release Component for Twice-Daily Administration

“…As part of the clinical development of this SR formulation of tramadol, two phase III, randomized placebo-controlled treatment-withdrawal studies were conducted in Japanese patients with chronic pain associated with knee osteoarthritis [ 18 ] or postherpetic neuralgia [ 21 ]. In both studies, tramadol was superior to placebo in terms of the time from randomization to an inadequate analgesic effect and the proportion of patients experiencing inadequate analgesic effects.…”