Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies.

BACKGROUND: The efficacy of tapentadol extended release (ER) for managing chronic pain has been demonstrated in large-scale, randomized, controlled, phase 3 studies (N=318-1,030) in patients with chronic osteoarthritis (OA) pain, low back pain (LBP), and pain related to diabetic peripheral neuropathy (DPN), which led to registration in many regions, including the United States and Europe. 2 pilot 12-week, randomized, double-blind, placebo-controlled phase 2 studies of tapentadol ER for chronic pain (OA knee pain or LBP, n=91; DPN or peripheral herpetic neuralgia [PHN] pain; n=91) were conducted in Japan. These small exploratory studies were substantially underpowered compared with the registration trials. METHODS: Patients in both studies were randomized (2:1) to tapentadol ER (25-250 mg) or placebo for 12 weeks (≤6-week titration plus maintenance periods). RESULTS: For the primary efficacy endpoint (change in pain intensity from baseline to last week of treatment; last observation carried forward), both studies failed to differentiate between tapentadol ER and placebo; least-squares mean differences (95% confidence intervals) for tapentadol ER vs. placebo were -0.1 (-1.04, 0.80) in the OA/LBP study and -0.1 (-1.10, 0.99) in the DPN/PHN study. More than 80% of patients took concomitant analgesics during these studies. Tapentadol was well tolerated. CONCLUSIONS: Both studies were associated with methodological issues, including populations with different disease entities, small sample sizes, use of concomitant analgesics, and possible placebo effect that may have led to the failure to differentiate between tapentadol ER and placebo.

Direct conversion from tramadol to tapentadol prolonged release for moderate to severe, chronic malignant tumour-related pain.

BACKGROUND: A recent randomized-withdrawal, active- and placebo-controlled, double-blind phase 3 study showed that tapentadol prolonged release (PR) was effective and well tolerated for managing moderate to severe, chronic malignant tumour-related pain in patients who were opioid naive or dissatisfied with current treatment (Pain Physician, 2014, 17, 329-343). This post hoc, subgroup analysis evaluated the efficacy and tolerability of tapentadol PR in patients who previously received and were dissatisfied with tramadol for any reason and who had a pain intensity ≥5 (11-point numerical rating scale) before converting directly to tapentadol PR. METHODS: In the original study, eligible patients had been randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulphate-controlled release (40-100 mg bid) over 2 weeks. The present report focuses on results during the titration period for a subgroup of patients randomized to tapentadol PR after having been on tramadol treatment prior to randomization in the study (n = 129). Results for this subgroup are compared with results for all 338 patients who received tapentadol PR during titration (overall tapentadol PR group). RESULTS: Responder rates (responders: completed titration, mean pain intensity <5 [0-10 scale] and ≤20 mg/day rescue medication during last 3 days) were slightly better for the tramadol/tapentadol PR subgroup (69.8% [90/129]) vs. the overall tapentadol PR group (63.9% [214/335]). Tolerability profiles were comparable for both groups. CONCLUSIONS: Results of this subgroup analysis indicate that patients with cancer pain could safely switch from prior treatment with the weak centrally acting analgesic tramadol directly to the strong centrally acting analgesic tapentadol PR, for an improved analgesic therapy for severe pain. WHAT DOES THIS STUDY ADD?: Results of this post hoc analysis show that patients who had received prior tramadol therapy could switch directly to tapentadol PR, with the majority (˜70%) experiencing improved efficacy.

A thorough QT/QTc study of multiple doses of tapentadol immediate release in healthy subjects.

OBJECTIVE: This randomized, double-blind, placebo- and positive-controlled 4-way crossover study evaluated the effects of tapentadol immediate release (IR) on the QT/QTc interval. MATERIALS AND METHODS: Healthy subjects received tapentadol IR 100 mg or 150 mg, or placebo, every 6 h on Days 1 and 2, with a >= 7-day washout between treatments. Moxifloxacin 400 mg was the positive control. Serial triplicate 12-lead electrocardiograms (ECGs) were performed; the Fridericia correction (QTcF) was the primary correction method. Serial blood sampling was performed for pharmacokinetic analyses. RESULTS: Of the 75 subjects who were randomized, 68 received at least 1 dose of study medication, and 59 completed the study. Upper limits of the 90% confidence intervals (CIs) for the difference in mean DeltaQTcF between tapentadol IR 100 or 150 mg and placebo were < 10 ms (non-inferiority criterion) for all time points. The lower limit of the 90% CI for mean DeltaQTcF between moxifloxacin and placebo exceeded 5 ms from 1 to 6 h after dosing, establishing assay sensitivity. No subject had a postdose QTc interval > 480 ms, change from baseline > 60 ms, or clinically relevant change in heart rate or other ECG variables. Steady-state concentrations were reached within 18 to 24 h. Common adverse events were vertigo (central nervous system (CNS) origin), headache, somnolence, nausea, vomiting, and feeling drunk. CONCLUSION: Therapeutic and supratherapeutic doses of tapentadol do not affect the QT/QTc interval.