Milnacipran: A New Treatment Option for Fibromyalgia
On January 14, 2009, milnacipran (SavellaTM, Forest Pharmaceuticals, Inc.) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia (FM), a chronic disorder that affects an estimated 2%-4% of the US population and primarily occurs in women.1,2 The approval of milnacipran represents continued progress in the development of medications to manage this disorder. This approval was based on the results of several large clinical trials, using novel composite endpoints that demonstrated the benefits of milnacipran for not only pain, but also the patient’s overall fibromyalgia experience and function. The drug has been generally well tolerated. Detailed discussion of the drug’s pharmacology, efficacy, and safety data is provided. The FDA approval of milnacipran (SavellaTM) for the treatment of fibromyalgia is a welcome development. Milnacipran joins two other medications approved for the management of FM: pregabalin (Lyrica®, Pfizer, Inc.) and duloxetine (Cymbalta®, Eli Lilly & Co.).
In 1990, the American College of Rheumatology (ACR) published classification criteria for FM that were based on the symptom of chronic widespread pain.3 These criteria require the presence of pain for at least 3 months in all 4 quadrants of the body, as well as the presence of pain in 11 of 18 tender points upon digital palpation. Although the ACR criteria have been adapted by researchers and physicians, their usefulness in clinical practice may be limited.2,4 One major limitation is that the criteria focus on pain and do not address the other symptoms of FM, thereby failing to capture the complexity of this disorder. As reported in an internet survey of FM patients that was conducted in collaboration with the National Fibromyalgia Association (NFA),5 other common symptoms include stiffness, fatigue, sleep problems, cognitive dysfunction, anxiety, and depressed mood.
The importance of assessing the multiple symptoms of FM in clinical research is being addressed by the working group of Outcome Measures in Rheumatology (OMERACT). Patients and clinician-investigators achieved consensus on key domains to be assessed in clinical trials of FM, such as pain, fatigue, impaired multidimensional function, sleep disturbance, cognitive dysfunction, mood disorder, stiffness, and tenderness.6,7 In collaboration with the World Health Organization’s (WHO) International Classification of Functioning Disability and Health (ICF) and the US National Institutes of Health’s Patient Reported Outcome Measures Information System network (PROMIS), work is under way to develop more specific and sensitive instruments to measure these symptom domains and to demonstrate change with effective therapy. One method currently on the OMERACT agenda is the use of a composite responder index, which can simultaneously assess clinically-meaningful improvements in pain and other FM-associated symptoms in one outcome.6 In contrast to outcomes that only allow for comparisons among treatment groups in a single domain (e.g., pain scores, patient global changes, or function), composite responder rates identify the proportion of individual patients in a treatment group who experience simultaneous improvements in multiple domains.6,8 The phase three clinical trials of milnacipran used composite responder analyses as primary endpoints, pioneering this approach in FM.
Milnacipran is a dual norepinephrine and serotonin reuptake inhibitor and has an approximately three-fold greater potency for norepinephrine reuptake inhibition over that of serotonin.9 These neurotransmitters have been found to mediate endogenous analgesic mechanisms through descending pain inhibitory pathways in the brain and spinal cord.10 In animal models of pain, milnacipran and other dual reuptake inhibitors of norepinephrine and serotonin that augment the effects of these neurotransmitters have shown analgesic effects, whereas agents that augment just serotonin—such as selective serotonin reuptake inhibitors—exhibited little or no effect.11 Such results highlight the importance of norepinephrine in the modulation of pain.12 In clinical studies, patients with FM were found to have decreased cerebral spinal fluid (CSF) levels of norepinephrine and serotonin metabolites.13 Therefore, dysfunction of the norepinephrine and serotonin systems may be a potential mechanism for the pain experienced by FM patients.14-17
Milnacipran Clinical Studies
The first study of milnacipran was a Phase 2 dose escalation trial in which 125 patients meeting the 1990 ACR criteria for FM were randomized to receive placebo (n=28), milnacipran 200mg/day once-daily (n=46), or milnacipran 200mg/day in divided doses (n=51) for 12 weeks.18 Results showed that milnacipran 200mg/day—dosed twice daily—was more effective than once-daily dosing in improving pain and multiple other symptoms such as fatigue and physical function.
Results from two Phase 3 pivotal trials of milnacipran were the basis of US FDA approval.19,20 In both of these trials, 2-measure and 3-measure composite responder rates were used as primary efficacy endpoints. For the 2-measure composite responder, individual patients were required to have concurrent improvements in pain and global status, as defined by the following criteria: ≥30% improvement from baseline in 24-hour recall pain scores (recorded on electronic diaries) and a score of 1 (“very much improved”) or 2 (“much improved”) on the Patient Global Impression of Change (PGIC) (see Figure 1). For the more stringent 3-measure composite responder, patients were required to meet the above criteria for simultaneous improvements in pain and PGIC, as well as improvements in physical function, defined as a ≥6-point improvement from baseline in the Short Form-36 Health Survey (SF-36) Physical Component Summary (PCS) score. Secondary outcome measures in the milnacipran FM pivotal trials included assessments for weekly recall pain, real-time pain, physical and mental function (Fibromyalgia Impact Questionnaire [FIQ], SF-36), fatigue (Multidimensional Fatigue Inventory [MFI]), and cognition (Multiple Ability Self-report Questionnaire [MASQ]).
The first milnacipran pivotal trial was a 27-week study that enrolled 888 FM patients who were randomized to placebo (n=223), milnacipran 100mg/day (n=224), or milnacipran 200mg/day (n=441).19 Efficacy was evaluated at both 15 and 27 weeks in this study. Composite responder results from this trial demonstrated the benefits of milnacipran in treating the multiple symptoms of FM. In observed cases at the 15-week endpoint, a significantly higher proportion of patients in the milnacipran treatment groups met the 2-measure composite criteria than in the placebo group: placebo, 27.2%; milnacipran 100mg/day, 45.2% (P=0.003); milnacipran 200mg/day, 45.4% (P≤0.001). Significant differences between milnacipran and placebo-treated patients were also observed for the 3-measure composite responder analysis: placebo, 17.3%; milnacipran 100mg/day, 32.8% (P=0.003); milnacipran 200mg/ day, 32.8% (P<0.001).