title: Efficacy of long-term milnacipran treatment in patients meeting different thresholds of clinically relevant pain relief: subgroup analysis of a randomized, double-blind, placebo-controlled withdrawal study.
abstract: BACKGROUND
  Fibromyalgia patients from a long-term, open-label study of milnacipran (50-200 mg/day) were eligible to participate in a 12-week, randomized, placebo-controlled withdrawal study. The withdrawal study evaluated loss of therapeutic response in patients who achieved ≥50% pain improvements after receiving up to 3.25 years of milnacipran. This post-hoc analysis investigated whether patients who met lower thresholds of pain improvement also experienced worsening of fibromyalgia symptoms upon treatment withdrawal.
  
  
  METHODS
  Among patients who received milnacipran ≥100 mg/day during the long-term study, three subgroups were identified based on percentage of pain reduction at randomization: ≥50% (protocol-defined "responders"; n=150); ≥30% to <50% (patients with clinically meaningful pain improvement; n=61); and <30% (n=110). Efficacy assessments included the visual analog scale (VAS) for pain, Fibromyalgia Impact Questionnaire-Revised (FIQR), 36-Item Short-Form Health Survey Physical Component Summary (SF-36 PCS), and Beck Depression Inventory (BDI).
  
  
  RESULTS
  In the ≥30 to <50% subgroup, significant worsening in pain was detected after treatment withdrawal. The difference between placebo and milnacipran in mean VAS score changes for this subgroup (+9.0, P<0.05) was similar to the difference in protocol-defined responders (+9.4, P<0.05). In the <30% subgroup, no worsening in pain was observed in either treatment arm. However, patients in this subgroup experienced significant worsening in FIQR scores after treatment withdrawal (placebo, +6.9; milnacipran, -2.8; P<0.001), as well as worsening in SF-36 PCS and BDI scores.
  
  
  CONCLUSIONS
  Patients who experienced ≥30% to <50% pain reduction with long-term milnacipran had significant worsening of fibromyalgia symptoms after treatment withdrawal. These results suggest that the conventional ≥30% pain responder cutoff may be adequate to demonstrate efficacy in randomized withdrawal studies of fibromyalgia. Patients in the <30% pain reduction subgroup had worsening scores on the FIQR and other multidimensional measures after treatment withdrawal, indicating the importance of identifying and managing the multiple symptoms of fibromyalgia.
authors.affiliation: Swedish Medical Center and University of Washington, Seattle, WA, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Mease
authors.affiliation: Chronic Pain and Fatigue Research Center, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Clauw
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Trugman
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Palmer
authors.affiliation: Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
keywords: fibromyalgia; post-hoc analysis; responders; symptoms