Milnacipran hydrochloride is used for the management of fibromyalgia in adults.
Fibromyalgia, which is estimated to affect from 2-4% of the population in the US, is a complex syndrome associated with chronic widespread musculoskeletal pain and a reduced pain threshold, with hyperalgesia and allodynia (pain-related behavior in response to normally innocuous stimuli). Some associated clinical features include fatigue, depression and other mood disorders, anxiety, sleep disturbances, headache (including migraine), changes in bowel habits (including irritable bowel syndrome), diffuse abdominal pain, and urinary frequency.
The American College of Rheumatology (ACR) initially published criteria for the classification of fibromyalgia in 1990, which included a history of widespread pain for at least 3 months and the presence of pain in at least 11 of 18 specific tender point sites. In 2010, the ACR developed new diagnostic criteria for fibromyalgia that no longer included tender point counts and focused more on patient symptoms, including use of a widespread pain index (WPI) and symptom severity (SS) scale. According to the 2010 diagnostic criteria, a diagnosis of fibromyalgia can be made if a patient has a WPI of 7 or greater and SS scale score of 5 or greater or a WPI of 3-6 and SS scale score of 9 or greater; symptoms must have been present at a similar level for at least 3 months and the patient should not have a disorder that would otherwise explain the pain. Due to the complex nature of the fibromyalgia syndrome, optimal treatment often requires a combination of nonpharmacologic therapy (e.g., cognitive behavioral therapy, education, exercise and other forms of physical therapy) and pharmacologic therapy (e.g., selective serotonin-reuptake inhibitors [SSRIs], SNRIs, tricyclic antidepressants, other agents [e.g., pregabalin], topical and systemic analgesics).
Efficacy of milnacipran for the management of fibromyalgia has principally been established in 2 double-blind, placebo-controlled, multicenter studies conducted in the US in 2084 adults with a diagnosis of fibromyalgia based on the 1990 ACR criteria. Approximately 35% of the patients in these studies had a history of depression. Study 1 was of 6 months' duration and study 2 was of 3 months' duration; both studies compared total daily milnacipran hydrochloride dosages of 100 mg and 200 mg with placebo. In these studies, a larger proportion of patients treated with milnacipran than those treated with placebo experienced a simultaneous reduction in pain from baseline of at least 30% on the visual analog scale (VAS) and rated themselves as much improved or very much improved on the Patient Global Impression of Change (PGIC) scale. In addition, a larger proportion of patients treated with milnacipran met the criteria for treatment response as measured by the composite endpoint that concurrently evaluated improvement in pain (VAS), physical function (Short Form-36 Physical Component Summary), and the PGIC. In both studies, some patients who rated themselves as much or very much improved experienced a decrease in pain as early as week 1 of treatment with a stable milnacipran dosage, and the pain reduction persisted throughout the studies. Neither study demonstrated an additional therapeutic benefit of 200 mg of milnacipran hydrochloride daily compared with 100 mg daily.
A multicenter, randomized, blinded extension of study 1, which was of 6 months' duration, subsequently demonstrated that continuing milnacipran therapy (100 or 200 mg daily) for an additional 6 months provides sustained efficacy for up to 1 year and generally is well tolerated in patients with fibromyalgia.
Fatigue is one of the core symptoms associated with fibromyalgia and affects patients both physically and mentally. In a pooled analysis of 3 randomized, placebo-controlled clinical trials of milnacipran (100 or 200 mg daily) in patients with fibromyalgia, milnacipran-treated patients experienced substantial and clinically important reductions in fatigue as measured by the Multidimensional Fatigue Inventory (MFI; a scale that assesses physical, mental, and psychosocial aspects of fatigue). The improvement in fatigue observed in the milnacipran-treated patients could not be completely attributed to indirect effects of the drug on pain reduction.
Major Depressive Disorder
Although milnacipran has been used in the treatment of major depressive disorder and is approved for treating depression in some countries outside the US, this indication is not an FDA-labeled use. Levomilnacipran hydrochloride (Fetzima), the 1S,2R-enantiomer of milnacipran, is labeled by the FDA for the treatment of major depressive disorder.
There are insufficient data, to date, to determine if the efficacy and tolerability of milnacipran as an antidepressant are superior, inferior, or equal to that of other antidepressant agents for the acute phase treatment of major depressive disorder. However, some studies indicate improved tolerability with milnacipran when compared with tricyclic antidepressants.