Tapentadol Prolonged Release for Managing Moderate to Severe, Chronic Malignant TumorRelated Pain

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 andmorphine controlled release (CR) for managing moderate to severe chronic malignant tumor-related pain.Study Design: Randomized-withdrawal, parallel group, active- and placebo-controlled, double-blindphase 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) wererandomized (2:1) and titrated to their optimal dose of tapentadol PR (100 – 250 mg bid) or morphine sulfateCR (40 – 100 mg bid) over 2 weeks. Morphine sulfate immediate release 10 mg was permitted as neededfor rescue medication (no maximum dose). Patients who completed titration and, during the last 3 daysof 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 duringtitration 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 ashaving: 1) completed the maintenance period, 2) a mean pain intensity < 5 during maintenance, and 3) usedan average of ≤ 20 mg/day of rescue medication during maintenance. Response at the end of titration wasdefined 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 evaluablefor efficacy. The adjusted responder rate estimate during maintenance (logistic regression adjusting fortreatment group, pooled center, and pain intensity at start of maintenance) was significantly higher withtapentadol 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-groupsdifference (−15.5%) was within the pre-specified 20% non-inferiority margin. During titration, incidencesof 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 PRthan 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 todescriptive statistics during the maintenance period because of the pre-selection of responders totapentadol 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-relatedpain. Based on results obtained during titration, tapentadol PR provides comparable efficacy to that ofmorphine sulfate CR (40 – 100 mg bid), but is associated with better gastrointestinal tolerability.Key words: Tapentadol PR, cancer pain, tumor-related pain, malignant pain, chronic pain, morphineCR, non-inferiority, efficacy, tolerability