What antidepressant works best for fibromyalgia?

October 9, 2025 •

3 min read

Over 10 million U.S. adults are affected by fibromyalgia, which causes widespread pain, fatigue, and sleep disturbances. A key part of managing symptoms involves finding what antidepressant works best for fibromyalgia, often tailoring treatment to the individual's unique symptom profile.

Quick Summary

Duloxetine (Cymbalta) and milnacipran (Savella) are the primary FDA-approved antidepressants for fibromyalgia pain and fatigue. Other antidepressants like amitriptyline are used off-label, but the most effective approach depends on individual symptoms and potential side effects.

Key Points

FDA-Approved SNRIs: Duloxetine (Cymbalta) and milnacipran (Savella) are the only two FDA-approved antidepressants specifically for treating fibromyalgia.
Individualized Treatment: The best antidepressant for fibromyalgia varies by individual, as effectiveness depends on specific symptoms, comorbidities, and tolerance.
Multi-Symptom Relief: SNRIs like duloxetine can provide simultaneous relief for pain, fatigue, depression, and anxiety.
Sleep-Focused Options: Older tricyclic antidepressants, such as low-dose amitriptyline, and the new sublingual cyclobenzaprine (Tonmya), are particularly effective for improving sleep.
Off-Label Uses: Some SSRIs are used off-label to address mood symptoms but are less effective for managing the pain itself.
Integrated Care: Medication is one component of a broader, multi-faceted treatment plan that often includes exercise, physical therapy, and other lifestyle modifications.

Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, poor sleep, and other symptoms. Understanding that fibromyalgia involves central nervous system sensitization, where pain signals are amplified, has guided medication strategies. Antidepressants are frequently used, even without co-occurring depression, as they can regulate neurotransmitters like serotonin and norepinephrine, which influence both mood and pain pathways.

FDA-Approved Antidepressants for Fibromyalgia

Two Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) are specifically approved by the FDA for treating fibromyalgia. They increase serotonin and norepinephrine levels in the brain, helping to inhibit pain signals.

Duloxetine (Cymbalta)

Duloxetine, an SNRI, received FDA approval for fibromyalgia in 2008. Studies indicate it can reduce pain and improve function. It's also effective for associated depression and anxiety. Starting doses are typically 30mg daily, potentially increasing to 60mg. Higher doses don't usually provide more pain relief but increase side effects like nausea, dry mouth, constipation, and drowsiness.

Milnacipran (Savella)

Milnacipran, another SNRI, was FDA-approved for fibromyalgia in 2009. It may have a stronger effect on norepinephrine reuptake. Milnacipran has shown improvement in pain, well-being, and fatigue. Dosing starts low and is gradually increased, often to 100-200mg daily. Common side effects can include nausea, headache, constipation, and high blood pressure.

Other Antidepressants Used Off-Label

Older antidepressants are sometimes used off-label for fibromyalgia to improve sleep and manage specific types of pain. TCAs like amitriptyline are used off-label for pain and can improve sleep quality due to their sedative effects. Side effects such as drowsiness, dry mouth, constipation, and weight gain may limit their use. SSRIs, such as fluoxetine (Prozac), primarily affect serotonin and are generally less effective for pain than SNRIs, though they can treat co-occurring depression and anxiety. Combining an SSRI with a TCA is sometimes used. Common SSRI side effects include nausea, sexual dysfunction, and sleep issues. Muscle relaxants like cyclobenzaprine have also been used. A new sublingual cyclobenzaprine formulation (Tonmya) was recently FDA-approved for improving sleep quality in fibromyalgia.

Which Antidepressant is Right for You?

The most effective medication for fibromyalgia is a personalized choice based on individual symptoms and discussed with a doctor. Factors to consider include predominant symptoms (e.g., pain, fatigue, sleep disturbances), potential side effects, and coexisting conditions like depression or anxiety. Often, a multi-modal approach combining different medications or integrating non-pharmacological treatments is most effective.

Comparison of Fibromyalgia Antidepressants


Feature	Duloxetine (Cymbalta)	Milnacipran (Savella)	Amitriptyline (Elavil)
Drug Class	SNRI	SNRI	Tricyclic Antidepressant (TCA)
FDA-Approved for FM	Yes (2008)	Yes (2009)	No (Used off-label)
Primary Benefits	Reduces pain, fatigue; improves mood; effective for depression/anxiety.	Reduces pain, fatigue; improves well-being.	Improves sleep quality, pain, and fatigue.
Key Side Effects	Nausea, dry mouth, drowsiness, high blood pressure, sweating.	Nausea, headache, constipation, dizziness, high blood pressure.	Drowsiness, dry mouth, constipation, weight gain, dizziness.
Effectiveness for Pain	Moderate to significant improvement.	Significant improvement demonstrated.	Modest but significant improvement noted, especially for sleep.
Symptom Profile Match	Good for patients with co-occurring depression, anxiety, and widespread pain.	Potentially better for patients without depression, as its effect on pain can be independent of mood.	Strongest for sleep-related issues; side effects may limit use.

Conclusion

There is no single "best" antidepressant for fibromyalgia; effectiveness depends on individual factors. FDA-approved SNRIs, duloxetine (Cymbalta) and milnacipran (Savella), are often a starting point, targeting pain and fatigue. Amitriptyline is a traditional option for improving sleep, as is the newer sublingual cyclobenzaprine (Tonmya). A personalized treatment plan involving both pharmacological and non-pharmacological strategies is crucial for managing this complex condition. For more information on medications for fibromyalgia, the Arthritis Foundation offers a resource: {Link: Arthritis Foundation https://www.arthritis.org/diseases/more-about/medications-for-treating-fibromyalgia-symptoms}.

Frequently Asked Questions

Antidepressants regulate neurotransmitters involved in pain signaling, helping to reduce the amplified pain experienced in fibromyalgia, often independently of their effect on mood.

In August 2025, Tonmya (sublingual cyclobenzaprine) was FDA-approved for fibromyalgia in adults, specifically targeting improved sleep quality.

Both duloxetine (Cymbalta) and milnacipran (Savella) are FDA-approved SNRIs for fibromyalgia and can be effective. Differences in how they affect neurotransmitters may lead to varying results and side effects in different individuals.

Yes, older TCAs like amitriptyline are used off-label for fibromyalgia, especially at low doses for sleep improvement. However, their side effects can be a limiting factor.

SSRIs, including fluoxetine (Prozac), are generally less effective for fibromyalgia pain compared to SNRIs or TCAs. They are primarily used to treat co-occurring depression or anxiety.

Fibromyalgia often requires a multi-modal approach, including medication, physical therapy, exercise, and cognitive-behavioral therapy. Other medications, like anticonvulsants such as pregabalin (Lyrica), may also be considered.

Improvements can sometimes be seen within a couple of weeks, but full benefits may take several weeks to develop. Consistent use is key to assessing effectiveness.