Safety and Efficacy of Esreboxetine in Patients With Fibromyalgia: An 8-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

Background: Esreboxetine is an investigational, highly selective norepinephrine reuptake inhibitor that has been reported to have antinociceptive effects in preclinical pain models. Objective: This study assessed the efficacy and safety profile of esreboxetine in the management of fibromyalgia. Methods: This was a multicenter, randomized, doubleblind, placebo-controlled trial in patients aged >= 18 years who met American College of Rheumatology criteria for fibromyalgia. Eligible patients were required to have a score 40 mm on the 100-mm visual analog scale of the Short-Form McGill Pain Questionnaire at screening and randomization, and a mean score >= 4 on an 11-point pain rating scale (from 0 = no pain to 10 = worst possible pain) based on the weekly mean pain score in the week before randomization. After a 1-week baseline period and a 2-week, single-blind, placebo run-in period, patients were randomized to receive esreboxetine or placebo for 8 weeks, followed by a 1-week follow-up period. Esreboxetine dosing was started at 2 mg/d and was escalated by 2 mg/d every 2 weeks until attainment of a dose of 8 mg/d or the maximum tolerated dose. The primary efficacy outcome was the change from baseline to week 8 in weekly mean pain scores, as derived from patients' daily pain ratings on the 11-point scale. Additional primary efficacy outcomes included changes in the Fibromyalgia Impact Questionnaire (FIQ) total score and the Patient Global Impression of Change (PGIC). The safety profile was evaluated based on observed and spontaneously reported adverse events, laboratory tests, and other safety measures. Results: One hundred thirty-four patients were randomized to each study group, but 1 patient in the placebo group did not receive treatment. Thus, the study population consisted of 267 patients (89.5% female; 88.4% white; mean age, similar to 50 years [range, 20-84 years]). Twenty-seven patients in each group discontinued the study. Adverse events were the most common reason for discontinuation in the esreboxetine group (11 patients), compared with 3 discontinuing due to adverse events in the placebo group. Patient default (withdrawal of consent and loss to follow-up) was the most common reason for discontinuation in the placebo group (13 patients), compared with 10 in the esreboxetine group. The esreboxetine group had significantly greater improvement in the weekly mean pain score compared with the placebo group (mean [SE] change from baseline: -1.55 [0.16] vs -0.99 [0.16], respectively; P = 0.006). A significantly greater percentage of patients in the esreboxetine group reported a >= 30% reduction in pain scores compared with the placebo group (37.6% [50/133] vs 22.6% [30/133]; P = 0.004). Esreboxetine was associated with significant improvement compared with placebo in the FIQ total score (mean change from baseline: -15.63 [1.56] vs -8.07 [1.54]; P < 0.001). On the PGIC, significantly more patients in the esreboxetine group than in the placebo group reported their condition much or very much improved (odds ratio = 2.42; 90% CI, 1.549-3.786; P < 0.001). Esreboxetine also was associated with significant improvements in secondary outcomes compared with placebo. These included fatigue, as reflected in scores on the Multidimensional Assessment of Fatigue (mean [SE] change from baseline: -6.39 [0.75] vs -2.82 [0.75], respectively; P < 0.001), and scores on measures of patient function and health-related quality of life, including the 36-item Short Form Health Survey (SF-36) Physical Component Summary (mean change from baseline: 4.36 [0.59] vs 1.86 [0.59]; P = 0.002), the SF-36 Mental Component Summary (mean change from baseline: 4.25 [0.83] vs 1.81 [0.83]; P = 0.019), and the Sheehan Disability Scale total score (mean change from baseline: -6.50 [0.64] vs -2.79 [0.61]; P < 0.001). Numerically more patients in the esreboxetine group than in the placebo group reported at least one adverse event (71.6% vs 57.1%), most commonly constipation (17.2% vs 5.3%), insomnia (15.7% vs 3.0%), dry mouth (15.7% vs 2.3%), and headache (10.4% vs 2.3%). Conclusions: In this 8-week trial in patients with fibromyalgia, esreboxetine was associated with significant reductions in pain scores compared with placebo. It was also associated with improvements in outcomes relevant to fibromyalgia, including the PGIC, function, and fatigue. Clinical Trials.gov identifier: NCT00357825. (Clin Ther. 2010;32:1618-1632) (C) 2010 Excerpta Medica Inc.