Is Savella (milnacipran) a suitable treatment option for a patient with fibromyalgia?

Savella (Milnacipran) for Fibromyalgia

Savella (milnacipran) is an effective and FDA-approved treatment option for fibromyalgia, providing moderate pain relief to approximately 40% of patients at doses of 100-200 mg/day, and should be considered as a first-line pharmacological option when non-pharmacological interventions provide insufficient relief. 1, 2

Evidence for Efficacy

Milnacipran demonstrates Level Ia, Grade A evidence for pain reduction and functional improvement in fibromyalgia. 1 The medication works as a serotonin-norepinephrine reuptake inhibitor (SNRI) with preferential inhibition of norepinephrine over serotonin, which is thought to attenuate pain signals in the central nervous system. 3

Clinical Trial Results

• Two pivotal FDA trials demonstrated that approximately 40% of milnacipran-treated patients achieved at least 30% pain reduction combined with global improvement, compared to 30% with placebo (NNT 6-10). 2, 4
• Using stricter responder criteria, about 26% of milnacipran patients versus 17% of placebo patients achieved meaningful benefit (NNT 11). 4
• Some patients experience pain relief as early as week 1 of treatment, with sustained effects throughout 6-month studies. 2
• Long-term data shows sustained therapeutic effects for up to 15 months of treatment. 3, 5

Dosing Protocol

The recommended target dose is 100-200 mg/day given in divided doses, with gradual titration over approximately 1 week to minimize side effects. 1, 2

• Start with lower doses and escalate to target maintenance doses of 100-200 mg/day in divided doses. 1
• The 200 mg/day dose does not provide additional benefit over 100 mg/day but increases adverse events and withdrawals. 2, 4
• Therefore, 100 mg/day should be the preferred target dose, with consideration of 200 mg/day only if 100 mg provides partial but insufficient benefit. 2

Safety Profile

• Adverse events are common with milnacipran (86%) compared to placebo (78%), but most are mild to moderate in severity. 4
• The most common adverse events are nausea (NNH 5.7), constipation (NNH 13), and headache (NNH 29). 4
• Serious adverse events do not differ from placebo (less than 2%). 4
• Adverse event withdrawals occur more frequently with 200 mg (NNH 7.0) than 100 mg (NNH 14) compared to placebo. 4
• Increases in heart rate and blood pressure have been observed in some patients and require monitoring. 3

Place in Treatment Algorithm

Milnacipran should be initiated only after non-pharmacological interventions (exercise, cognitive behavioral therapy) have been tried for 4-6 weeks with insufficient relief. 6

• Non-pharmacological therapies, particularly aerobic and strengthening exercise, remain first-line treatment with the strongest evidence (Level Ia, Grade A). 1
• When pharmacological treatment is needed, milnacipran is equivalent in evidence quality to duloxetine and pregabalin as first-line options. 1
• Milnacipran may be particularly advantageous for patients who experience problematic sedation, dizziness, edema, or weight gain with pregabalin or gabapentin. 7
• Milnacipran may also benefit fibromyalgia-associated symptoms including fatigue and cognitive dysfunction. 7, 3

Important Clinical Considerations

• Set realistic expectations: only about 1 in 3-4 patients will achieve substantial benefit from milnacipran. 4
• Therapeutic effects typically emerge over 3-7 weeks, requiring adequate trial duration before determining efficacy. 6
• Regular reassessment every 4-8 weeks is essential to evaluate pain levels, function, and side effects. 1
• If partial relief occurs at 100 mg/day, consider adding another first-line medication from a different class (amitriptyline or pregabalin) rather than escalating to 200 mg/day. 1
• Avoid combining milnacipran with duloxetine, as both are SNRIs with redundant mechanisms. 1

What NOT to Do

• Do not use milnacipran as monotherapy without implementing exercise and behavioral interventions. 1
• Do not escalate beyond 200 mg/day, as higher doses provide no additional benefit but increase adverse events. 2
• Do not add corticosteroids or strong opioids, which lack efficacy and cause significant harm in fibromyalgia. 1