Safety and tolerability of tapentadol extended release in moderate to severe chronic osteoarthritis or low back pain management: pooled analysis of randomized controlled trials.

INTRODUCTION: This analysis of pooled data from four randomized, controlled-dose adjustment, phase 3 studies (three 15-week, double-blind, placebo- and active-controlled studies and a 1-year, open-label, active-controlled safety study) in patients with chronic osteoarthritis hip or knee pain or low back pain evaluated the safety and tolerability of tapentadol extended release (ER) for the management of moderate to severe, chronic pain. METHODS: In the three 15-week studies, patients were randomized (1:1:1) to twice-daily (bid) doses of placebo, tapentadol ER (100-250 mg), or oxycodone hydrochloride (HCl) controlled release (CR; 20-50 mg). In the 1-year safety study, patients were randomized (4:1) to tapentadol ER (100-250 mg bid) or oxycodone HCl CR (20-50 mg bid). Adverse events (AEs) and discontinuations were recorded in each study; pooled results were analyzed by treatment group. RESULTS: In the placebo (n = 993), tapentadol ER (n = 1,874), and oxycodone CR (n = 1,224) groups, respectively, 40.7%, 48.4%, and 62.3% of patients discontinued treatment prematurely and 58.7%, 79.0%, and 86.6% of patients experienced ≥ 1 treatment-emergent AE (TEAE). Incidences of gastrointestinal TEAEs in the placebo, tapentadol ER, and oxycodone CR groups, respectively, were 26.6%, 47.3%, and 65.4%; incidences of nervous system TEAEs were 22.5%, 42.6%, and 45.1%, respectively. Moderate or severe gastrointestinal TEAEs were reported for 10.9% of patients who received placebo, 25.3% of patients who received tapentadol ER, and 42.3% of patients who received oxycodone CR, and moderate or severe nervous system TEAEs were reported for 10.6%, 22.1%, and 25.2% of patients, respectively. In the placebo, tapentadol ER, and oxycodone CR groups, respectively, incidences of gastrointestinal TEAEs leading to study discontinuation were 2.1%, 8.3%, and 24.1%; incidences of nervous system TEAEs leading to discontinuation were 1.4%, 7.9%, and 16.3%, respectively. CONCLUSION: Results from this large patient population showed that tapentadol ER (100-250 mg bid) had improved gastrointestinal tolerability compared with oxycodone CR, based on the overall incidence of gastrointestinal TEAEs, the incidence of moderate or severe gastrointestinal TEAEs, and the incidence of gastrointestinal TEAEs leading to discontinuation.

Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study.

BACKGROUND: Tapentadol is a novel, centrally acting analgesic with mu-opioid receptor agonist and norepinephrine reuptake inhibitor activity. OBJECTIVE: to evaluate the efficacy and safety of Tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain. METHODS: this was a randomized, double-blind, active- and placebo-controlled, parallel-arm, multicentre, phase III study during which patients received Tapentadol ER, oxycodone CR or placebo for a 3-week titration period followed by a 12-week maintenance period. The study was carried out at sites in Australia, Canada, New Zealand and the US. A total of 1030 patients with chronic osteoarthritis-related knee pain were randomized to receive Tapentadol ER 100-250 mg twice daily, oxycodone HCl CR 20-50 mg twice daily or placebo. Primary endpoints (as determined prior to initiation of the study) were the changes from baseline in average daily pain intensity (rated by patients on an 11-point numerical rating scale) over the last week of maintenance and over the entire 12-week maintenance period; last observation carried forward was used to impute missing values after early treatment discontinuation. RESULTS: efficacy and safety were evaluated for 1023 patients. Tapentadol ER significantly reduced average pain intensity from baseline to week 12 of the maintenance period versus placebo (least squares mean [LSM] difference [95% CI], -0.7 [-1.04, -0.33]), and throughout the maintenance period (-0.7 [-1.00, -0.33]). Oxycodone CR significantly reduced average pain intensity from baseline throughout the maintenance period versus placebo (LSM difference [95% CI], -0.3 [-0.67, -0.00]) but not at week 12 (-0.3 [-0.68, 0.02]). A significantly higher percentage of patients achieved > or =50% improvement in pain intensity in the Tapentadol ER group (32.0% [110/344]) compared with the placebo group (24.3% [82/337]; p = 0.027), indicating a clinically significant improvement in pain intensity, while a significantly lower percentage of patients achieved > or =50% improvement in pain intensity in the oxycodone CR group (17.3% [59/342]; p = 0.023 vs placebo). In the placebo, Tapentadol ER and oxycodone CR groups, respectively, 61.1% (206/337), 75.9% (261/344) and 87.4% (299/342) of patients reported at least one treatment-emergent adverse event (TEAE); incidences of gastrointestinal-related TEAEs were 26.1% (88/337), 43.0% (148/344) and 67.3% (230/342). CONCLUSION: treatment with Tapentadol ER 100-250 mg twice daily or oxycodone HCl CR 20-50 mg twice daily was effective for the management of moderate to severe chronic osteoarthritis-related knee pain, with substantially lower incidences of gastrointestinal-related TEAEs associated with treatment with Tapentadol ER than with oxycodone CR.

Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.

BACKGROUND: Tapentadol is a novel, centrally acting analgesic with 2 mechanisms of action: µ-opioid receptor agonism and norepinephrine reuptake inhibition. This randomized, open-label phase 3 study (ClinicalTrials.gov Identifier: NCT00361504) assessed the long-term safety and tolerability of tapentadol extended release (ER) in patients with chronic knee or hip osteoarthritis pain or low back pain. METHODS: Patients were randomized 4:1 to receive controlled, adjustable, oral, twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCl controlled release (CR; 20 to 50 mg) for up to 1 year. Efficacy evaluations included assessments at each study visit of average pain intensity (11-point numerical rating scale) over the preceding 24 hours. Treatment-emergent adverse events (TEAEs) and discontinuations were monitored throughout the study. RESULTS: A total of 1,117 patients received at least 1 dose of study drug. Mean (standard error) pain intensity scores in the tapentadol ER and oxycodone CR groups, respectively, were 7.6 (0.05) and 7.6 (0.11) at baseline and decreased to 4.4 (0.09) and 4.5 (0.17) at endpoint. The overall incidence of TEAEs was 85.7% in the tapentadol ER group and 90.6% in the oxycodone CR group. In the tapentadol ER and oxycodone CR groups, respectively, TEAEs led to discontinuation in 22.1% and 36.8% of patients; gastrointestinal TEAEs led to discontinuation in 8.6% and 21.5% of patients. CONCLUSION: Tapentadol ER (100 to 250 mg bid) was associated with better gastrointestinal tolerability than oxycodone HCl CR (20 to 50 mg bid) and provided sustainable relief of moderate to severe chronic knee or hip osteoarthritis or low back pain for up to 1 year.

Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain.

INTRODUCTION: This pooled analysis of data from three phase 3 studies in patients with chronic osteoarthritis knee or low back pain evaluated the efficacy and tolerability of tapentadol prolonged release (PR; 100-250 mg twice daily) compared with placebo and oxycodone hydrochloride (HCl) controlled release (CR; 20-50 mg twice daily). METHODS: Patients in each study were randomized to receive twice-daily doses of placebo, tapentadol PR (100-250 mg), or oxycodone HCl CR (20-50 mg) for a 12-week maintenance period, preceded by a 3-week titration period. Primary endpoints were change from baseline in average pain intensity (11-point numeric rating scale) at week 12 of the maintenance period and for the overall maintenance period using last observation carried forward for imputation of values missing after treatment discontinuation. RESULTS: A total of 2968 patients were evaluated for efficacy; 2974 patients were evaluated for safety. Compared with placebo, treatment with tapentadol PR or oxycodone CR resulted in significantly greater reductions in pain intensity from baseline at week 12 and for the overall maintenance period (all P<0.001). For both primary endpoints, the efficacy of tapentadol PR was noninferior to oxycodone CR (P<0.001), and tapentadol PR had superior gastrointestinal tolerability compared with oxycodone CR (P<0.001). Results of analyses of responders, patient global impression of change, Short Form-36 domains (except general health), and the EuroQol 5-Dimension health status index were significantly better for tapentadol PR than oxycodone CR (all P