BACKGROUND: Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain.
OBJECTIVES: To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain.
STUDY DESIGN: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303).
SETTING: Primary, secondary, and tertiary care settings in 16 countries.
METHODS: Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulfate CR (40-100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use = 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: (1) completed the maintenance period, (2) a mean pain intensity < 5 during maintenance, and (3) used an average of = 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration.
RESULTS: Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively.
LIMITATIONS: Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration.
CONCLUSIONS: Results obtained during maintenance indicate that tapentadol PR (100-250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40-100 mg bid), but is associated with better gastrointestinal tolerability.
BACKGROUND AND OBJECTIVES: The effectiveness and tolerability of tapentadol extended release (ER), a centrally acting analgesic with μ-opioid receptor agonist and norepinephrine (noradrenaline) reuptake inhibitor activities, have been demonstrated in patients with chronic pain, including those switching directly from prior opioid therapy. The objective of the current study was to evaluate the effectiveness and safety of conversion to oral tapentadol ER (50-250 mg twice daily) from previous around-the-clock strong opioid therapy in patients with moderate to severe, chronic malignant tumor-related cancer pain that was well-controlled.
METHODS: This randomized, open-label, phase III study, which was conducted in Japan, included a 1- to 2-week screening period (on previous opioid) and an 8-week, open-label treatment period. Eligible patients, who were taking a strong opioid analgesic and had a mean pain intensity score <4 during the 3 days prior to randomization (adequate pain control on previous strong opioid), were randomized (1:1) to receive twice-daily treatment with tapentadol ER (100-500 mg/day) or morphine sustained release (SR; 20-140 mg/day; reference for assay sensitivity). Initial doses were estimated based on the conversion ratio of tapentadol ER:oxycodone:morphine:fentanyl = 10:2:3:0.03. The primary effectiveness endpoint was the proportion of patients who maintained pain control [change from baseline in mean pain intensity (11-point numerical rating scale) less than +1.5 for 3 consecutive days and no more than two doses of rescue medication per day for 3 consecutive days) during the first week of open-label treatment.
RESULTS: In the tapentadol ER group (n = 50), 84.0 % of patients (42/50; 95 % CI, 70.89-92.83) maintained pain control during Week 1. On the Patient Global Impression of Change, 2.1 % (1/48), 2.1 % (1/48), 22.9 % (11/48), and 50.0 % (24/48) of patients in the tapentadol ER group reported that their overall condition was "very much improved," "much improved," "minimally improved," and "not changed," respectively, at Week 1 compared with 0 %, 10.7 % (3/28), 28.6 % (8/28), and 53.6 % (15/28) reporting these ratings at Week 8. The sensitivity of effectiveness analyses was validated based on results using morphine SR; 98.0 % (49/50; 95 % CI, 89.35-99.95) of patients in the morphine SR group maintained pain control after 1 week of treatment. The overall safety profile was similar to that demonstrated in previous studies; tapentadol ER was associated with a lower incidence of gastrointestinal treatment-emergent adverse events than morphine SR [38.0 % (19/50) vs. 54.0 % (27/50)], including constipation [12.0 % (6/50) vs. 20.0 % (10/50)] and vomiting [6.0 % (3/50) vs. 26.0 % (13/50)].
CONCLUSIONS: Overall, results indicate that conversion from previous strong opioids to tapentadol ER (50-250 mg twice daily) was successful and resulted in safe and effective pain control with improved gastrointestinal tolerability versus morphine SR in patients with moderate to severe cancer-related pain that was well-controlled on their previous opioid.
Abstract OBJECTIVE: This phase 3 study evaluated the efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for the management of moderate to severe, chronic malignant tumor-related cancer pain. Research design and methods: This randomized, double-blind, active-controlled study included Japanese and Korean patients with moderate to severe, chronic malignant tumor-related pain. Patients were randomized (1:1) to receive oral tapentadol ER (25-200 mg bid) or oral oxycodone HCl CR (5-40 mg bid) for 4 weeks of double-blind treatment. ClinicalTrials.gov identifier: NCT01165281. Main outcome measures: This study was designed to evaluate the non-inferiority of the efficacy provided by tapentadol ER versus oxycodone CR, based on the mean change in average pain intensity (11 point numerical rating scale) from baseline to the last 3 days of study drug administration. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. RESULTS: Of the 374 patients who were screened, 343 were randomized and 236 completed treatment. The least-squares mean difference in the change in pain intensity from baseline to the last 3 days of study treatment between tapentadol ER and oxycodone CR was -0.06 (95% confidence interval [CI], -0.506 to 0.383). The upper limit of the 95% CI was <1 (the predefined threshold value for non-inferiority), indicating that tapentadol ER provided analgesic efficacy that was non-inferior to that of oxycodone CR. The percentage of patients reporting at least one TEAE was similar in the tapentadol ER (87.5% [147/168]) and oxycodone CR (90.1% [155/172]) treatment groups, but the incidence of gastrointestinal TEAEs was lower in the tapentadol ER group (55.4% [93/168]) than in the oxycodone CR group (67.4% [116/172]). CONCLUSIONS: Tapentadol ER (25-200 mg bid) provides analgesic efficacy that is non-inferior to that provided by oxycodone HCl CR (5-40 mg bid) for the management of moderate to severe, chronic malignant tumor-related pain, and is well tolerated overall, with a better gastrointestinal tolerability profile than oxycodone CR.
Tapentadol prolonged release (PR) is effective and well tolerated for chronic osteoarthritis, low back, and diabetic peripheral neuropathic pain.
OBJECTIVES:
To evaluate the efficacy and tolerability of tapentadol PR compared with placebo and morphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain.
STUDY DESIGN:
Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blind phase 3 study (NCT00472303).
SETTING:
Primary, secondary, and tertiary care settings in 16 countries.
METHODS:
Eligible patients (pain intensity ≥ 5 [11-point numerical rating scale] on prior analgesics) were randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulfate CR (40-100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as needed for rescue medication (no maximum dose). Patients who completed titration and, during the last 3 days of titration, had mean pain intensity < 5 (based on twice-daily ratings) and mean rescue medication use = 20 mg/day continued into a 4-week maintenance period; patients who received morphine CR during titration continued taking morphine CR, and those who received tapentadol PR were re-randomized (1:1) to tapentadol PR or placebo bid. Response during maintenance (primary efficacy endpoint) was defined as having: (1) completed the maintenance period, (2) a mean pain intensity < 5 during maintenance, and (3) used an average of = 20 mg/day of rescue medication during maintenance. Response at the end of titration was defined similarly, with pain intensity and rescue medication averages based on the last 3 days of titration.
RESULTS:
Of 622 patients screened, 496 were randomized, treated during titration, and evaluable for safety; 327 were re-randomized, treated during maintenance, and evaluable for safety; and 325 were evaluable for efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting for treatment group, pooled center, and pain intensity at start of maintenance) was significantly higher with tapentadol PR (64.3%) than with placebo (47.1%; odds ratio (OR), 2.02 [95% confidence interval (CI), 1.12 - 3.65]; P = 0.02). Based on responder rates at the end of titration, tapentadol PR (76.0% [174/229]) was non-inferior to morphine CR (83.0% [83/100]). The lower limit of the 95% CI for the between-groups difference (-15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidences of treatment-emergent adverse events (TEAEs) were 50.0% (169/338) with tapentadol PR and 63.9% (101/158) with morphine CR; incidences of nausea, vomiting, and dry mouth were lower with tapentadol PR than with morphine CR. During maintenance, incidences of TEAEs were 56.3% (63/112), 62.3% (66/106), and 62.4% (68/109) with placebo, tapentadol PR, and morphine CR, respectively.
LIMITATIONS:
Statistical comparisons between tapentadol PR and morphine CR were limited to descriptive statistics during the maintenance period because of the pre-selection of responders to tapentadol PR or morphine CR during titration.
CONCLUSIONS:
Results obtained during maintenance indicate that tapentadol PR (100-250 mg bid) is effective compared with placebo for managing moderate to severe chronic malignant tumor-related pain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that of morphine sulfate CR (40-100 mg bid), but is associated with better gastrointestinal tolerability.
