title: Methodological Issues in Conducting Pilot Trials in Chronic Pain as Randomized, Double-blind, Placebo-controlled Studies.
abstract: 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.
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tominaga
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Koga
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Uchida
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Wanibe
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Janssen Japan, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Global Medical Affairs, Janssen-Cilag AG, Zug, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Richarz
authors.affiliation: Janssen Research & Development, LLC, Raritan, New Jersey, United States.
authors.forename: M
authors.initials: M
authors.lastname: Etropolski
mesh_terms: D000328:Adult; D000700:Analgesics / Q000627:therapeutic use; D059350:Chronic Pain / Q000188:drug therapy*; D003692:Delayed-Action Preparations / Q000627:therapeutic use; D004311:Double-Blind Method; D006801:Humans; D010147:Pain Measurement / Q000187:drug effects; D010636:Phenols / Q000627:therapeutic use*; D010865:Pilot Projects; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D000077432:Tapentadol; D055815:Young Adult
chemical_list: D000700:Analgesics; D003692:Delayed-Action Preparations; D010636:Phenols; D000077432:Tapentadol