title: Effect of Milnacipran on Pain in Patients with Rheumatoid Arthritis with Widespread Pain: A Randomized Blinded Crossover Trial.
abstract: OBJECTIVE
  Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in noninflammatory pain conditions such as fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among patients with rheumatoid arthritis (RA) with widespread pain and stable RA disease activity.
  
  
  METHODS
  In this double-blind, crossover study, patients with RA with widespread pain, receiving a stable treatment regimen, were randomized (by a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and α = 0.05.
  
  
  RESULTS
  Of the 43 randomized subjects, 41 received the study drug, and 32 completed the 15-week study per protocol. On a 0-10 scale, average pain intensity decreased by 0.39 (95% CI -1.27 to 0.49, p = 0.37) more points during 6 weeks of milnacipran treatment compared with placebo. In the subgroup of subjects with swollen joint count ≤ 1, average pain intensity decreased by 1.14 more points during 6 weeks of milnacipran compared with placebo (95% CI -2.26 to -0.01, p = 0.04). Common adverse events included nausea (26.8%) and loss of appetite (9.7%).
  
  
  CONCLUSIONS
  Compared with placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain receiving stable RA medications.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01207453.
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital. ylee9@partners.org.
authors.forename: Yvonne C
authors.initials: YC
authors.lastname: Lee
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Elena
authors.initials: E
authors.lastname: Massarotti
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Edwards
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Bing
authors.initials: B
authors.lastname: Lu
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: ChihChin
authors.initials: C
authors.lastname: Liu
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Lo
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Wohlfahrt
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kim
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Clauw
authors.affiliation: From the Division of Rheumatology, Immunology and Allergy, and Department of Anesthesiology, Brigham and Women's Hospital; Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.Y.C. Lee, MD, MMSc, Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital; E. Massarotti, MD, Division of Rheumatology, Brigham and Women's Hospital; R.R. Edwards, PhD, Pain Management Center, Brigham and Women's Hospital; B. Lu, MD, DrPH, Division of Rheumatology, Brigham and Women's Hospital; C. Liu, PhD, Division of Rheumatology, Brigham and Women's Hospital; Y. Lo, MPH, Division of Rheumatology, Brigham and Women's Hospital; A. Wohlfahrt, BA, Division of Rheumatology, Brigham and Women's Hospital; N.D. Kim, MD, Division of Rheumatology, Immunology and Allergy, Massachusetts General Hospital; D.J. Clauw, MD, University of Michigan; D.H. Solomon, MD, MPH, Division of Rheumatology, Brigham and Women's Hospital.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Solomon
mesh_terms: D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology*; D016001:Confidence Intervals; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D059408:Pain Management / Q000379:methods; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D012016:Reference Values; D057566:Self Report; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States
chemical_list: D003521:Cyclopropanes; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors
keywords: ANALGESIA; PAIN; RHEUMATOID ARTHRITIS