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Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin.

ABSTRACT: OBJECTIVE:To evaluate the safety, tolerability, and efficacy of adding milnacipran to pregabalin in patients with fibromyalgia who have experienced an incomplete response to pregabalin. METHODS:In this randomized, multicenter, open-label study, patients received pregabalin 300 or 450 mg/day during a 4- to 12-week run-in period. Patients with weekly recall visual analog scale (VAS) pain score of at least 40 and up to 90, Patient Global Impression of Severity score of at least 4, and Patient Global Impression of Change (PGIC) score of at least 3 were classified as incomplete responders and randomized to continue pregabalin alone (n = 180) or receive milnacipran 100 mg/day added to pregabalin (n = 184). The primary efficacy parameter was responder status based on PGIC score of up to 2. The secondary efficacy parameter was change from randomization in weekly recall VAS pain score. Safety parameters included adverse events (AEs), vital signs, and clinical laboratory tests. RESULTS:The percentage of PGIC responders was significantly higher with milnacipran added to pregabalin (46.4%) than with pregabalin alone (20.8%; p < 0.001). Mean improvement from randomization in weekly recall VAS pain scores was greater in patients receiving milnacipran added to pregabalin (-20.77) than in patients receiving pregabalin alone (-6.43; p < 0.001). During the run-in period, the most common treatment-emergent AEs with pregabalin were dizziness (22.8%), somnolence (17.3%), and fatigue (9.1%). During the randomized period, the most common treatment-emergent AEs with milnacipran added to pregabalin were nausea (12.5%), fatigue (10.3%), and constipation (9.8%). CONCLUSIONS:In this exploratory, open-label study, adding milnacipran to pregabalin improved global status, pain, and other symptoms in patients with fibromyalgia with an incomplete response to pregabalin treatment.

SUBMITTER: Mease PJ

PROVIDER: S-EPMC3707344 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin.

Mease Philip J PJ Farmer Mildred V MV Palmer Robert H RH Gendreau R Michael RM Trugman Joel M JM Wang Yong Y

Therapeutic advances in musculoskeletal disease 20130601 3

<h4>Objective</h4>To evaluate the safety, tolerability, and efficacy of adding milnacipran to pregabalin in patients with fibromyalgia who have experienced an incomplete response to pregabalin.<h4>Methods</h4>In this randomized, multicenter, open-label study, patients received pregabalin 300 or 450 mg/day during a 4- to 12-week run-in period. Patients with weekly recall visual analog scale (VAS) pain score of at least 40 and up to 90, Patient Global Impression of Severity score of at least 4, an ...[more]

PMID: 23858335

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Project description:BackgroundAlthough trazodone is frequently used by fibromyalgia patients, its efficacy on this disease has not been adequately studied. If effective, pregabalin, whose beneficial effects on pain and sleep quality in fibromyalgia have been demonstrated, could complement the antidepressant and anxiolytic effects of trazodone. The aim of the present study was to assess the effectiveness of trazodone alone and in combination with pregabalin in the treatment of fibromyalgia.MethodsThis was an open-label uncontrolled study. Trazodone, flexibly dosed (50-300 mg/day), was administered to 66 fibromyalgia patients during 12 weeks; 41 patients who completed the treatment accepted to receive pregabalin, also flexibly dosed (75-450 mg/day), added to trazodone treatment for an additional 12-week period. Outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI), the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), the Brief Pain Inventory (BPI), the Short-Form Health Survey (SF-36), and the Patients' Global Improvement scale (PGI). Emergent adverse reactions were recorded. Data were analyzed with repeated measures one-way ANOVA and paired Student's t test.ResultsTreatment with trazodone significantly improved global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities although without showing a direct effect on bodily pain. After pregabalin combination additional and significant improvements were seen on fibromyalgia severity, depression and pain interference with daily activities, and a decrease in bodily pain was also apparent. During the second phase of the study, only two patients dropped out due to side effects.ConclusionsTrazodone significantly improved fibromyalgia severity and associated symptomatology. Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in association was good.Trial registrationClinicalTrials.gov: NCT00791739.

Project description:BACKGROUND:Milnacipran is a serotonin-norepinephrine reuptake inhibitor (SNRI) that is sometimes used to treat chronic neuropathic pain and fibromyalgia. OBJECTIVES:To evaluate the analgesic efficacy and adverse effects of milnacipran in the management of chronic neuropathic pain or fibromyalgia. SEARCH METHODS:We searched CENTRAL, MEDLINE, and EMBASE to 4th of January 2012, together with reference lists of retrieved papers and reviews. SELECTION CRITERIA:We included randomised, double-blind studies of eight weeks duration or longer, comparing milnacipran with placebo or another active treatment in chronic neuropathic pain or fibromyalgia. DATA COLLECTION AND ANALYSIS:We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. MAIN RESULTS:Five studies (4138 participants) were included, all of which were placebo-controlled, involved participants with fibromyalgia, and used titration to a target dose of 100 mg or 200 mg milnacipran. There were no other active comparators or studies in other neuropathic pain conditions. Study quality was generally good, although the imputation method used in analyses of the primary outcomes could overestimate treatment effect.Both doses of milnacipran provided moderate levels of pain relief to about 40% of those treated, compared to 30% with placebo, giving a number needed to treat of 8 to 10. Adverse events were common in both milnacipran (87%) and placebo (78%) groups, but serious adverse events (< 2%) did not differ between groups. Nausea and constipation were the most common events showing the greatest difference between groups (number needed to treat for an additional harmful outcome of 7 and 13 respectively, compared with placebo).Withdrawals for any reason were more common with milnacipran than placebo, and more common with 200 mg than 100 mg (NNH of 23 and 8.8 respectively, compared with placebo). This was largely driven by adverse event withdrawals, where the NNH compared with placebo was 14 for 100 mg, and 7.0 for 200 mg). Withdrawals due to lack of efficacy were more common with milnacipran than placebo but did not differ between doses (number needed to treat to prevent an additional unwanted outcome of 45 and 41 respectively). AUTHORS' CONCLUSIONS:The evidence available indicates that milnacipran 100 mg or 200 mg is effective for a minority in the treatment of pain due to fibromyalgia, providing moderate levels of pain relief (at least 30%) to about 40% of participants, compared with about 30% with placebo. There were insufficient data to assess substantial levels of pain relief (at least 50%), and the use of last observation carried forward imputation may overestimate drug efficacy. Milnacipran is associated with increased adverse events and adverse event withdrawals, which were significantly greater for the higher dose. There were no data for the use of milnacipran for other chronic neuropathic pain conditions.

Project description:BackgroundPopulation mean changes are difficult to use in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. A consensus group has defined what constitutes minimal, moderate, and substantial benefit based on pain intensity and Patient Global Impression of Change scores.MethodsWe obtained individual patient data from four randomised double blind trials of pregabalin in fibromyalgia lasting eight to 14 weeks. We calculated response for all efficacy outcomes using any improvement (>or= 0%), minimal improvement (>or= 15%), moderate improvement (>or= 30%), substantial improvement (>or= 50%), and extensive improvement (>or= 70%), with numbers needed to treat (NNT) for pregabalin 300 mg, 450 mg, and 600 mg daily compared with placebo.ResultsInformation from 2,757 patients was available. Pain intensity and sleep interference showed reductions with increasing level of response, a significant difference between pregabalin and placebo, and a trend towards lower (better) NNTs at higher doses. Maximum response rates occurred at 4-6 weeks for higher levels of response, and were constant thereafter. NNTs (with 95% confidence intervals) for >or= 50% improvement in pain intensity compared with placebo after 12 weeks were 22 (11 to 870) for pregabalin 300 mg, 16 (9.3 to 59) for pregabalin 450 mg, and 13 (8.1 to 31) for pregabalin 600 mg daily. NNTs for >or= 50% improvement in sleep interference compared with placebo after 12 weeks were 13 (8.2 to 30) for pregabalin 300 mg, 8.4 (6.0 to 14) for pregabalin 450 mg, and 8.4 (6.1 to 14) for pregabalin 600 mg. Other outcomes had fewer respondents at higher response levels, but generally did not discriminate between pregabalin and placebo, or show any dose response. Shorter duration and use of 'any improvement' over-estimated treatment effect compared with longer duration and higher levels of response.ConclusionsResponder analysis is useful in fibromyalgia, particularly for pain and sleep outcomes. Some fibromyalgia patients treated with pregabalin experience a moderate or substantial pain response that is consistent over time. Short trials using 'any improvement' as an outcome overestimate treatment effects.

Dataset Information

Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin.

Publications

Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin.

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