Savella Research

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The U.S. Food and Drug Administration approved Savella (Milnacipran) for the treatment of fibromyalgia in January of 2009. This approval was based on safety and efficacy data from two pivotal randomized, double-blind, placebo-controlled trials (the “gold standard” of research design for studies investigating the effectiveness of a treatment) (Clauw et al., 2008; Mease et al., 2009). Together, these trials included more than 2,000 patients who met the American College of Rheumatology (ACR) criteria for the diagnosis of fibromyalgia. These studies unanimously found that patients who took Savella experienced at least a 30% reduction in their pain when compared to those who received placebo. Self-reported functioning was also higher among those in the Savella groups. These studies also established the recommended daily dose of Savella at 100mg/day, with the potential to increase to 200mg/day if needed. In addition, two subsequent large-scale studies further confirmed the efficacy of Savella for the treatment of fibromyalgia (Arnold et al., 2010; Branco et al., 2010).

The first of these four studies was published in 2008 and evaluated the efficacy and tolerability of Milnacipran for the treatment of multiple fibromyalgia symptoms. Of the 1,196 patients enrolled in the study, 399 received Savella (100mg/day), 396 received Savella(200mg/day) and 401 received placebo. A vast majority of the patients were female (96.2%) and white (93.5%), and the average age of each patient was 50. At the conclusion of this 15 week study, the researchers found that many patients who received Savella experienced significant improvement in pain after just one week of treatment, as well as improved overall functioning, physical functioning, and fatigue. The most frequent side effects experience by patients in this study included nausea, headache, and constipation. In addition, 19.5% of patients who received the 100mg/day dose and 23.7% of patients who received the 200mg/dose ended their participation in the study early due to side effects; this is in contrast to only 9.5% of patients who received placebo. Nevertheless, the findings from this study conclusively demonstrated that both 100mg/day and 200mg/day doses of Savella can result in substantial improvements in pain and other fibromyalgia-related symptoms (Clauw et al., 2008).

The second study was published in 2009 by Mease et al. and investigated the safety and effectiveness of Savella in 888 fibromyalgia patients over a 27 week course of treatment. This study was also randomized, double-blind, and placebo-controlled in design, and like that of Clauw et al. (2008), evaluated both 100mg/day and 200mg/day doses of Savella. Also like the Clauw study, Mease et al. found that many patients experienced significant reductions in pain after as little as one week of treatment with both 100mg/day and 200mg/day doses of Savella. In addition, after 15 weeks of treatment, the 200mg/dose was found to be significantly better than placebo at improving pain, fatigue, measures of cognitive functioning, and overall health and well-being. Based on these findings, this study demonstrated the  safety and efficacy of Savella for the treatment of multiple fibromyalgia symptoms.

Arnold et al., (2010) also investigated the safety and efficacy of Savella in 1,025 fibromyalgia patients in another randomized, double-blind, placebo-controlled trial. After various dosing configurations, the data showed that those patients who were treated with Savella had clinically significant improvement in their measurements of pain, as well as additional assessments of overall health and well-being, pain severity, mental function, and fatigue, when compared to those who received placebo. This study also found that Savella was well-tolerated by a majority of patients, with the most common side effect being nausea. Additional research conducted by Branco et al. (2010) among 884 fibromyalgia patients confirmed the effectiveness and safety of Savella for the treatment of pain and other symptoms in fibromyalgia patients.

Savella-related research has continued to gain momentum on the heels of these four groundbreaking studies. In 2011, Branco et al. investigated the long-term effectiveness of three different doses of Savella (100mg/day, 150mg/day, and 200mg/day). Following one year of therapy, analysis of the data revealed that year-long therapy at all three doses resulted in safe and sustainable symptom improvements for fibromyalgia patients. Additionally, Savella has been included in recent analyses and comparisons of various fibromyalgia-approved drugs (Hauser et al., 2012; Choy et al., 2011). The review by Choy et al. confirmed the effectiveness of treatment with Savella and suggested that combination therapy with a selective norepinephrine reuptake inhibitor (SNRI) drug, such as Savella, and another drug (Lyrica), should be pursued in future research studies. Although Hauser et al. state in their review that Savella is one of several medications that should be used as standard therapy for the treatment of fibromyalgia, they point out that patients frequently experience considerable side effects (to Savella and other drugs in the antidepressant class of medications), and some patients do not experience significant benefits from these drugs.

The remaining research related to Savella and fibromyalgia is diverse in scope but limited in quantity. Examples include animal studies pertaining to the way in which Savella works in the body to relieve pain, and individual case reports regarding specific side effects, among others. Saxe et al. found that patients who were treated with Savella over a 12 week period and who were immediately switched to a placebo at the end of those 12 weeks (per study design) experienced increased pain and decreased overall functioning within two weeks (Saxe et al., 2012). Forman et al. (2011) published a case report about a 42 year old female patient who had both connective tissue disease and fibromyalgia. They describe how this patient developed severe, but reversible, heart muscle disease (known as cardiomyopathy) while taking Savella at the recommended daily dose. Her symptoms included abnormally rapid heart rate, high blood pressure, and abnormal blood work; however, when treatment with Savella was discontinued her symptoms resolved completely within six months. The authors suggest in their discussion that this case possibly represents the first and only known report of Savella-related cardiomyopathy (Forman et al., 2011). A paper published in 2009 described how magnetic resonance imagery (MRI; a non-invasive test similar to a CAT scan that records images of structures inside the body) has demonstrated evidence to show how Savella acts to increase activity in brain regions that are involved in regulating pain sensations (Mainguy 2009).

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References

1.        Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial [published correction appears in ClinTher. 2009;31:446]. Clin Ther. 2008;11:1988-2004.

2.        Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, et al. The efficacy and safety of milnacipran for the treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial [published correction appears in J Rheumatol. 2009;36:661]. J Rheumatol. 2009;36:398-409.

3.        Arnold LM, Gendreau RM, Palmer RH, Gendreau JF, Wang Y. Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010;62(9):2745-2756.

4.        Branco JC, Zachrisson O, Perrot S, Mainguy Y; Multinational Coordinator Study Group. A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. J Rheumatol. 2010;37(4):851-859.

5.        Branco JC, Cherin P, Montagne A, Bouroubi A; Multinational Coordinator Study Group. Longterm therapeutic response to milnacipran treatment for fibromyalgia. A European 1-year extension study following a 3-month study. J Rheumatol. 2011;38(7):1403-12.

6.        Hauser W, Wolfe F, Tolle T, Uceyler N, Sommer C. The role of antidepressants in the management of fibromyalgia syndrome: a systematic review and meta-analysis. CNS Drugs. 2012;26(4):297-307.

7.        Choy E, Marshall D, Gabriel ZL, Mitchell SA, Gylee E, Dakin HA. A systematic review and mixed treatment comparison of the efficacy of pharmacological treatments for fibromyalgia. Semin Arthritis Rheum. 2011;41(3):335-345.

8.        Saxe PA, Arnold LM, Palmer, RH, Gendreau RM, Chen W. Short-term (2-week) effects of discontinuing milnacipran in patients with fibromyalgia. Curr Med Res Opin. 2012;28(5):815-821.

9.        Forman MB, Sutej PG, Jackson EK. Hypertension, tachycardia, and reversible cardiomyopathy temporally associated with milnacipran use. Tex Heart Inst J. 2011;38(6):714-718.

Mainguy Y. Functional magnetic resonance imagery (fMRI) in fibromyalgia and the response to milnacipran. Functional magnetic resonance imagery (fMRI) in fibromyalgia and the response to milnacipran. Hum Psychopharmacol. 2009;24 Suppl 1:S19-23.

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