Why is milnacipran (Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)) not often used as a first-line treatment for adults with depression or chronic pain, such as fibromyalgia?

Why Milnacipran Is Not Often Used

Milnacipran is rarely used in clinical practice because duloxetine has become the overwhelmingly preferred SNRI for both depression and chronic pain conditions, offering superior cardiovascular safety, simpler once-daily dosing, broader FDA approvals, and equivalent or better efficacy with a more favorable side effect profile. 1, 2

Primary Reasons for Limited Use

Duloxetine's Dominance as First-Line SNRI

• The American Geriatrics Society explicitly recommends duloxetine as the preferred SNRI for use with pain medications and muscle relaxants, citing strong evidence for safety and efficacy in chronic pain conditions. 1
• Duloxetine has FDA approval for multiple pain conditions including diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain, and chronic low back pain at doses of 60-120 mg/day, whereas milnacipran is only approved for fibromyalgia. 1, 2
• The once-daily dosing of duloxetine (versus twice-daily for milnacipran) significantly improves medication adherence and simplifies treatment regimens. 1, 2

Cardiovascular Safety Concerns

• Milnacipran causes increases in heart rate and blood pressure in some patients, which is a significant clinical limitation. 3, 4
• The FDA drug label for milnacipran specifically warns about cardiovascular effects, whereas duloxetine has a more favorable cardiovascular profile with no clinically important ECG changes or significant blood pressure alterations. 4, 2
• This cardiovascular concern is particularly problematic in older adults and patients with pre-existing cardiac conditions, who represent a large proportion of chronic pain patients. 4

Limited Efficacy Data

• For fibromyalgia treatment, milnacipran has a number needed to treat (NNT) of 8 for achieving moderate benefit (>30% pain relief), which is less impressive than other available options. 5
• The 2022 CDC guideline notes that both milnacipran and duloxetine show small short- and intermediate-term improvements in pain and quality of life for fibromyalgia, but duloxetine additionally demonstrates benefits across multiple other pain conditions. 5
• The 2017 EULAR guidelines give milnacipran only a "weak for" recommendation (100% agreement) for fibromyalgia, indicating limited enthusiasm from expert consensus. 5

Tolerability Issues

• Side effects significantly limit milnacipran tolerability, including headache, nausea, tachycardia, hypertension, hypotension, and increased bleeding risk. 6, 4
• The FDA label warns about multiple serious adverse effects including hyponatremia, activation of mania, dysuria (particularly in males with prostatic hypertrophy), sexual dysfunction, and angle closure glaucoma. 4
• Male patients are particularly prone to genitourinary adverse effects such as dysuria, urinary retention, testicular pain, and ejaculation disorders with milnacipran. 4
• The drug requires slow up-titration starting at low doses to maximize tolerability, adding complexity to prescribing. 6

Lack of Depression Indication in the United States

• Milnacipran is not FDA-approved for depression in the United States, despite being used as an antidepressant in other countries. 7, 8
• This severely limits its utility compared to duloxetine, which treats both depression and pain simultaneously—a critical advantage since fibromyalgia and chronic pain patients frequently have comorbid depression. 5, 9
• The 2008 EULAR guidelines recommend antidepressants including milnacipran for fibromyalgia, but this was before duloxetine's broader pain indications were established. 5

Alcohol and Liver Concerns

• The FDA label specifically states that milnacipran should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease, as it may aggravate pre-existing liver disease. 4
• This contraindication further narrows the already limited patient population for whom milnacipran would be appropriate. 4

Clinical Context

When Milnacipran Might Still Be Considered

• Milnacipran may be a reasonable alternative for fibromyalgia patients who cannot tolerate duloxetine's side effects or for whom sedation, dizziness, edema, or weight gain with gabapentin/pregabalin is problematic. 9
• The drug has greater potency in inhibiting norepinephrine reuptake relative to serotonin (2.2:1 ratio) compared to duloxetine (1:10) and venlafaxine (1:30), which theoretically could benefit patients with specific symptom profiles. 7
• Milnacipran may be effective for fibromyalgia-associated symptoms including fatigue and cognitive dysfunction. 6, 9

Practical Prescribing Reality

• The 2018 Annual Review of Medicine guideline acknowledges that all FDA-approved nonopioid medications for chronic pain—including milnacipran—have clinical limitations including partial efficacy, side effects, and slower onset of action than opioids. 5
• Milnacipran works best when used as part of a multidisciplinary treatment regimen including resistance and aerobic exercise, patient education, and behavioral therapies—but this is true for all fibromyalgia medications. 6
• The drug has minimal potential for cytochrome P450-mediated drug-drug interactions, which is an advantage in polypharmacy situations. 7, 8

Bottom Line

Duloxetine has effectively replaced milnacipran in clinical practice due to superior safety, broader indications, simpler dosing, and equivalent efficacy, relegating milnacipran to a rarely-used alternative for the narrow indication of fibromyalgia in patients who fail or cannot tolerate first-line options. 1, 2