Milnacipran for Fibromyalgia

woman sitting on bed with back and shoulder pain

The Bottom Line

Milnacipran (Savella®) is one of three medications the FDA has approved to treat fibromyalgia (FM). It raises the levels of serotonin and norepinephrine in the central nervous system. Side effects are usually mild, but milnacipran can interact with other medications that raise serotonin levels leading to a hazardous condition known as serotonin syndrome. 

man with neck pain taking medicine

The Full Story

Fibromyalgia (FM) is a poorly understood condition that affects muscles, ligaments, and tendons. It is characterized by chronic widespread pain and tenderness in muscles and joints. Its exact cause has not been identified, but research suggests that the central nervous system (CNS) in FM patients overreacts to painful stimuli and exaggerates the sensation of pain. 

Unlike other painful conditions, FM does not produce detectable inflammation or abnormal lab tests. Fatigue, sleep disturbances, and difficulty concentrating (“fibro fog”) usually accompany the chronic pain. Up to 50% of people also experience depression or anxiety. Migraine or muscle tension headaches occur in more than 50% of FM patients. 

Although there is no cure for FM, a variety of nondrug and medication-based treatments exist. A combination of different treatment approaches usually works best. Research has shown that physical activity such as aerobic exercise, Tai Chi, and yoga is the most effective treatment for FM. Mindfulness is a type of meditation that eases stress and also significantly improves FM symptoms. Medications for FM are aimed at either increasing brain neurotransmitters involved in pain control (serotonin, norepinephrine) or reducing the hyperactivity of nerves that carry pain signals.

Although other drugs like antidepressants and some plant-based medicines might be prescribed for pain in FM, only three medications are approved by the FDA. Milnacipran (Savella®) and duloxetine (Cymbalta) are serotonin-norepinephrine reuptake inhibitors (SNRIs), which increase the amounts of these pain-controlling chemicals at nerve endings in the brain and spinal cord (CNS). The third FDA-approved treatment for FM is pregabalin (Lyrica®), which is a medication given for seizures that calms excitable nerves in the CNS. None of these drugs have been compared against the others in clinical trials.

Milnacipran was approved by the FDA in 2009 solely for the treatment of FM. It is moderately effective at relieving chronic widespread pain and improving people’s ability to function. It also helps relieve fatigue and bolster thought processes. About half of patients taking milnacipran in clinical studies reported noticing benefits after 1 week of treatment. Although milnacipran is marketed in other countries for the treatment of depression, it is not FDA-approved for this purpose in the United States.

What should someone watch for when taking milnacipran? The most frequent side effects include nausea, headache, and constipation. Rarely, a doctor might discontinue the medication if a person’s heart rate or blood pressure goes up too much with treatment. Liver enzyme blood tests should be watched for increasing levels, which happens rarely. Milnacipran should not be stopped abruptly, but rather tapered down gradually to avoid withdrawal symptoms such as irritability, anxiety, and sleep problems.

Serotonin syndrome can result from mixing drugs like milnacipran with other medications that raise serotonin levels. Many types of antidepressants (SSRIs, SNRIs, bupropion, tricyclics, MAO inhibitors) can add to the serotonin-boosting effects of milnacipran and cause serotonin syndrome, so ask your pharmacist or doctor if you already take an antidepressant. Other medications that might interact this way with milnacipran include some migraine drugs, opioid analgesics, herbal supplements, and cough suppressants. Serotonin syndrome can be severe and cause symptoms like muscle rigidity, fever, confusion, tremors, and seizures and usually requires treatment in a hospital. For more information about the symptoms and which drugs might interact, see What is Serotonin Syndrome?

Normal doses of milnacipran start at 12.5 mg once a day by mouth and are increased slowly to a maximum dose of 100–200 mg daily. There are case reports of people who took larger doses (1000 to 2800 mg) and experienced only vomiting and drowsiness. Rarely, people taking in excess of 3000 mg have developed serious symptoms like increased or decreased blood pressure, heart arrhythmias, loss of consciousness, and cardiac and respiratory arrest.

If you suspect someone has unintentionally taken milnacipran or is experiencing its side effects, get help now online or call 1-800-222-1222. Both options are free and available 24 hours a day.

Leslie A. McCament-Mann, PhD, RPh
Clinical Toxicologist

Poisoned?

Call 1-800-222-1222 or

HELP ME online

Prevention Tips

  • Ask your pharmacist or doctor about possible interactions between milnacipran and other medications you take including prescriptions, over-the-counter products, and herbal remedies.
  • Be aware of the symptoms of serotonin syndrome, and know which medications to avoid that increase your risk for this condition (see “For More Information”). 
  • To avoid withdrawal symptoms, do not stop taking milnacipran suddenly. Consult with your health care provider about how to safely discontinue the medication.
  • Keep medications in child-resistant containers stored well out of the reach of children and pets.

This Really Happened

Case 1. A 59-year-old woman took 3000 mg of milnacipran in an attempt at self-harm. Her blood pressure dropped to 70/50 mmHg and her heart rate was low at 58 beats per minute. She soon became unresponsive. Her breathing was shallow. She was placed on a ventilator and received IV medications for blood pressure. She went on to develop severe heart dysfunction and arrhythmias along with fluctuating blood pressure requiring several days of treatment in an ICU. She also had symptoms of serotonin syndrome (tremors, fever) due to milnacipran’s interaction with paroxetine, an SSRI antidepressant she was taking chronically. The woman made a full recovery after several days in a hospital (Levine et al. 2011).

Case 2. A 76-year-old man was prescribed milnacipran for newly diagnosed fibromyalgia. He was already taking paroxetine (an SSRI) for depression. A few days after starting milnacipran, he became lethargic and severely confused. He developed a fever, rapid heart rate, fluctuating blood pressure, and rigid muscles. He was diagnosed with serotonin syndrome resulting from the drug interaction between milnacipran and paroxetine. His symptoms resolved after 2 days of treatment in a hospital with a medication that blocks serotonin (cyproheptadine) and IV medications for blood pressure (Yacoub et al. 2010).


For More Information

Fibromyalgia. Atlanta: American College of Rheumatology; updated Dec 2021 [cited 27 Apr 2022].

Milnacipran (oral route). Rochester (MN): Mayo Clinic; updated 01 May 2022 [cited 16 May 2022].

Serotonin syndrome. Cleveland: Cleveland Clinic; last reviewed 24 Mar 2022 [cited 17 May 2022].

Serotonin syndrome. Rochester (MN): Mayo Clinic [cited 17 May 2022].


References

Kasper S, Pail G. Milnacipran: a unique antidepressant? Neuropsychiatr Dis Treat. 2010;6(Suppl I):23–31.

Kia S, Choy E. Update on treatment guideline in fibromyalgia syndrome with focus on pharmacology. Biomedicines. 2017 Jun;5(2):20.

Levine M, Truitt CA, O'Connor AD. Cardiotoxicity and serotonin syndrome complicating a milnacipran overdose. J Med Toxicol. 2011 Dec;7(4):312–6.

Maffei ME. Fibromyalgia: recent advances in diagnosis, classification, pharmacotherapy and alternative remedies. Int J Mol Sci. 2020 Nov;21(21):7877.

Milnacipran. Lexi-Drugs. Hudson (OH): Lexicomp; updated 19 Apr 2022 [cited 10 May 2022].

Montgomery SA, Prost JF, Solles A, Briley M. Efficacy and tolerability of milnacipran: an overview. Int Clin Psychopharmacol. 1996 Sep;11 (Suppl 4):47–51.</span">

Nonopioid drugs for pain. Med Lett Drugs Ther. 2018 Feb 12;60(1540):25–32.

Savella (milnacipran HCl) prescribing information. Madison (NJ): Allergan; revised Sep 2021 [cited 13 May 2022].

Yacoub HA, Johnson WG, Souayah N. Serotonin syndrome after administration of milnacipran for fibromyalgia. Neurology. 2010 Feb 23;74(8):699–700.

Poisoned?

Call 1-800-222-1222 or

HELP ME online

Prevention Tips

  • Ask your pharmacist or doctor about possible interactions between milnacipran and other medications you take including prescriptions, over-the-counter products, and herbal remedies.
  • Be aware of the symptoms of serotonin syndrome, and know which medications to avoid that increase your risk for this condition (see “For More Information”). 
  • To avoid withdrawal symptoms, do not stop taking milnacipran suddenly. Consult with your health care provider about how to safely discontinue the medication.
  • Keep medications in child-resistant containers stored well out of the reach of children and pets.

This Really Happened

Case 1. A 59-year-old woman took 3000 mg of milnacipran in an attempt at self-harm. Her blood pressure dropped to 70/50 mmHg and her heart rate was low at 58 beats per minute. She soon became unresponsive. Her breathing was shallow. She was placed on a ventilator and received IV medications for blood pressure. She went on to develop severe heart dysfunction and arrhythmias along with fluctuating blood pressure requiring several days of treatment in an ICU. She also had symptoms of serotonin syndrome (tremors, fever) due to milnacipran’s interaction with paroxetine, an SSRI antidepressant she was taking chronically. The woman made a full recovery after several days in a hospital (Levine et al. 2011).

Case 2. A 76-year-old man was prescribed milnacipran for newly diagnosed fibromyalgia. He was already taking paroxetine (an SSRI) for depression. A few days after starting milnacipran, he became lethargic and severely confused. He developed a fever, rapid heart rate, fluctuating blood pressure, and rigid muscles. He was diagnosed with serotonin syndrome resulting from the drug interaction between milnacipran and paroxetine. His symptoms resolved after 2 days of treatment in a hospital with a medication that blocks serotonin (cyproheptadine) and IV medications for blood pressure (Yacoub et al. 2010).