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Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial.

Abstract

BACKGROUND

Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM).

OBJECTIVE

This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM.

METHODS

This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18-70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (> or = 30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a > or = 6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial.

RESULTS

Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m(2). Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P<0.001 for both doses), physical function (SF-36 physical functioning domain-100 mg/d: P < 0.001; 200 mg/d: P = 0.02), and fatigue (Multidimensional Fatigue Inventory- 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients.

CONCLUSION

In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124.

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  • Authors+Show Affiliations

    ,

    Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan Medical School, Ann Arbor, Michigan 48106, USA. dclauw@umich.edu

    , , ,

    Source

    Clinical therapeutics 30:11 2008 Nov pg 1988-2004

    MeSH

    Adult
    Aged
    Capsules
    Constipation
    Cyclopropanes
    Dizziness
    Dose-Response Relationship, Drug
    Double-Blind Method
    Fatigue
    Female
    Fibromyalgia
    Humans
    Male
    Middle Aged
    Milnacipran
    Pain
    Pain Measurement
    Patient Satisfaction
    Placebos
    Serotonin Uptake Inhibitors
    Time Factors
    Treatment Outcome
    Vomiting

    Pub Type(s)

    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19108787

    Citation

    Clauw, Daniel J., et al. "Milnacipran for the Treatment of Fibromyalgia in Adults: a 15-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Multiple-dose Clinical Trial." Clinical Therapeutics, vol. 30, no. 11, 2008, pp. 1988-2004.
    Clauw DJ, Mease P, Palmer RH, et al. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008;30(11):1988-2004.
    Clauw, D. J., Mease, P., Palmer, R. H., Gendreau, R. M., & Wang, Y. (2008). Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clinical Therapeutics, 30(11), pp. 1988-2004. doi:10.1016/j.clinthera.2008.11.009.
    Clauw DJ, et al. Milnacipran for the Treatment of Fibromyalgia in Adults: a 15-week, Multicenter, Randomized, Double-blind, Placebo-controlled, Multiple-dose Clinical Trial. Clin Ther. 2008;30(11):1988-2004. PubMed PMID: 19108787.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. AU - Clauw,Daniel J, AU - Mease,Philip, AU - Palmer,Robert H, AU - Gendreau,R Michael, AU - Wang,Yong, PY - 2008/10/30/accepted PY - 2008/12/26/entrez PY - 2008/12/26/pubmed PY - 2009/2/24/medline SP - 1988 EP - 2004 JF - Clinical therapeutics JO - Clin Ther VL - 30 IS - 11 N2 - BACKGROUND: Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM). OBJECTIVE: This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM. METHODS: This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18-70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (> or = 30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a > or = 6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial. RESULTS: Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m(2). Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P<0.001 for both doses), physical function (SF-36 physical functioning domain-100 mg/d: P < 0.001; 200 mg/d: P = 0.02), and fatigue (Multidimensional Fatigue Inventory- 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients. CONCLUSION: In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124. SN - 0149-2918 UR - https://www.unboundmedicine.com/medline/citation/19108787/Milnacipran_for_the_treatment_of_fibromyalgia_in_adults:_a_15_week_multicenter_randomized_double_blind_placebo_controlled_multiple_dose_clinical_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(08)00403-7 DB - PRIME DP - Unbound Medicine ER -