Updated: January 13, 2026

Milnacipran (Savella) Drug Interactions: What to Avoid and What to Tell Your Doctor

Author

Peter Daggett

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The Most Dangerous Interaction: MAOIs (Contraindicated)
Serotonin Syndrome Risk: Other Serotonergic Drugs
Cardiovascular Interactions
Bleeding Risk: NSAIDs and Blood Thinners
Liver and Alcohol Warning
What to Tell Every Healthcare Provider

Milnacipran (Savella) has several serious drug interactions that every patient should know. Learn what medications and supplements to avoid and what to always tell your doctor.

Milnacipran (Savella) can interact with a surprisingly wide range of medications, supplements, and substances. Some of these interactions are minor inconveniences; others can be life-threatening. This guide covers the most important ones — what to absolutely avoid, what to watch carefully, and what to always disclose to your healthcare team.

Never start, stop, or change any medication while taking Milnacipran without consulting your doctor or pharmacist first.

The Most Dangerous Interaction: MAOIs (Contraindicated)

The most critical interaction to know: never combine Milnacipran with monoamine oxidase inhibitors (MAOIs). This combination can cause severe, potentially fatal serotonin syndrome — a dangerous overload of serotonin in the nervous system.

MAOIs include:

Phenelzine (Nardil)

Tranylcypromine (Parnate)

Isocarboxazid (Marplan)

Selegiline (Eldepryl, Zelapar) at doses >10 mg

Linezolid (Zyvox) — an antibiotic with MAOI properties

Intravenous methylene blue (used in some surgical procedures)

Rasagiline (Azilect), procarbazine, and safinamide

Required washout periods:

Wait at least 14 days after stopping a MAOI before starting Milnacipran

Wait at least 5 days after stopping Milnacipran before starting a MAOI

Serotonin Syndrome Risk: Other Serotonergic Drugs

Combining Milnacipran with other drugs that increase serotonin levels significantly raises the risk of serotonin syndrome. Serotonin syndrome symptoms include fever, rapid heart rate, agitation, sweating, muscle twitching, and confusion — it is a medical emergency requiring immediate care.

Drugs that can interact via serotonin syndrome risk:

Other SNRIs: Duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima)

SSRIs: Sertraline (Zoloft), fluoxetine (Prozac), escitalopram (Lexapro), paroxetine (Paxil), citalopram (Celexa)

Triptans (migraine medications): Sumatriptan (Imitrex), rizatriptan (Maxalt), and others

Tramadol (Ultram): A pain medication with serotonergic activity

Fentanyl (Actiq, Duragesic): Some opioids have serotonergic activity

Metoclopramide (Reglan): Nausea medication with serotonergic activity

Tryptophan (supplement): A serotonin precursor sold as a dietary supplement

St. John's Wort: An herbal supplement with serotonergic activity — often overlooked because it's "natural"

Cardiovascular Interactions

Because Milnacipran strongly inhibits norepinephrine reuptake, it can interact with cardiovascular medications:

Parenteral epinephrine and norepinephrine (IV medications): Can cause severe paroxysmal hypertension and arrhythmia. Always tell any anesthesiologist, ER physician, or surgical team that you take Milnacipran.

IV digoxin: Should be avoided. Co-administration of Savella and IV digoxin is contraindicated.

Clonidine: Milnacipran may reduce the blood pressure-lowering effect of clonidine, potentially causing blood pressure to rise.

Other blood pressure medications: Milnacipran can raise blood pressure, which may counteract antihypertensive therapy. Your doctor may need to adjust your BP medications.

Bleeding Risk: NSAIDs and Blood Thinners

Milnacipran can increase bleeding risk, particularly when combined with:

NSAIDs: Ibuprofen (Advil, Motrin), naproxen (Aleve), indomethacin, ketoprofen, ketorolac. This combination significantly increases the risk of upper GI bleeding. Use with caution and tell your doctor if you take NSAIDs regularly.

Aspirin: Even low-dose (81 mg) aspirin for cardiac protection can increase bleeding risk when combined with Milnacipran.

Anticoagulants: Warfarin (Coumadin), apixaban (Eliquis), rivaroxaban (Xarelto). While Milnacipran does not significantly affect warfarin pharmacokinetics, the combined platelet and anticoagulation effects increase bleeding risk.

Liver and Alcohol Warning

Milnacipran can elevate liver enzymes and should not be taken by patients with substantial alcohol use or evidence of chronic liver disease. The FDA and Savella's prescribing information explicitly state that Savella should not be prescribed to patients with substantial alcohol use. Alcohol may worsen the liver effects. Drinking while on Milnacipran is not recommended.

What to Tell Every Healthcare Provider

Always tell these healthcare providers that you take Milnacipran:

Any prescribing physician (PCP, specialist, urgent care, ER)

Your pharmacist (before adding any OTC drug, vitamin, or supplement)

Anesthesiologists or surgical teams (critical due to epinephrine/IV medication risks)

Dentists (who may use epinephrine-containing local anesthetics)

For a broader overview of Milnacipran's side effect profile, read our complete side effects guide. If you're struggling to find Milnacipran in stock, medfinder can help you locate it at pharmacies near you.

Frequently Asked Questions

MAOIs (phenelzine, tranylcypromine, isocarboxazid, selegiline at >10mg, rasagiline, safinamide, procarbazine), linezolid, and IV methylene blue are absolutely contraindicated with Milnacipran. The combination can cause life-threatening serotonin syndrome. A minimum 14-day washout is required after stopping a MAOI before starting Milnacipran; wait 5 days after stopping Milnacipran before starting a MAOI.

Use with caution and only after discussing with your doctor. NSAIDs like ibuprofen and naproxen significantly increase the risk of upper GI bleeding when combined with Milnacipran. If you need pain relief for occasional headaches or muscle soreness, acetaminophen (Tylenol) is generally a safer option — but always check with your pharmacist or prescriber first.

Drinking alcohol while taking Milnacipran is not recommended. Alcohol can worsen liver enzyme elevation already associated with Milnacipran. Milnacipran is contraindicated in patients with substantial alcohol use or chronic liver disease. Occasional light drinking may be discussed with your prescriber, but regular or heavy drinking should be avoided.

No. St. John's Wort is an herbal supplement with serotonergic activity. Combining it with Milnacipran increases the risk of serotonin syndrome. Many patients forget to mention herbal supplements to their doctors because they're 'natural' — but serotonin syndrome does not distinguish between prescription drugs and herbs. Always disclose all supplements to your prescriber and pharmacist.

Yes. Dentists sometimes use epinephrine-containing local anesthetics (like lidocaine with epinephrine) to prolong numbing and reduce bleeding. Because Milnacipran inhibits norepinephrine reuptake, parenteral epinephrine can cause paroxysmal hypertension and arrhythmia. Alert your dental team before any procedure involving local anesthesia.

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