Amitriptyline for Fibromyalgia & Chronic Fatigue Syndrome

Amitriptyline is an antidepressant that has been used for years as a frontline treatment for fibromyalgia and chronic fatigue syndrome (ME/CFS). It works by increasing serotonin levels in the brain, which can help ease nerve pain in people with fibromyalgia and improve fatigue in people with ME/CFS.

With the advent of newer FDA-approved fibromyalgia treatments, amitriptyline use for these conditions has declined. Even so, it is still prescribed off-label by many healthcare providers. When taken at a lower dose, side effects like nausea and drowsiness may be minimized.

This article explains how amitriptyline is used to treat fibromyalgia and chronic fatigue syndrome. It also describes the recommended dosage and possible side effects and drug interactions.

How Amitriptyline Works

Amitriptyline is a tricyclic antidepressant (TCA) available only in generic form in the United States. It was first approved for use in 1961 by the U.S. Food and Drug Administration (FDA) under the brand name Elavil for the treatment of depression.

Amitriptyline works by increasing serotonin and norepinephrine levels in the brain. Serotonin is a neurotransmitter that helps regulate moods, while norepinephrine can mobilize the brain to increase energy and attentiveness levels. These dual effects are known to be effective in treating depression.

These same actions have been shown to help some people with chronic pain disorders like fibromyalgia. Chronic fatigue syndrome, a condition closely related to fibromyalgia, is also seen to improve with antidepressants like amitriptyline.

Amitriptyline for Fibromyalgia

Fibromyalgia is believed to be caused by central sensitization, a phenomenon in which the central nervous system (composed of the brain and spinal cord) is abnormally sensitive to certain stimuli. With fibromyalgia, pain signals to the brain are exaggerated and amplified, causing chronic—and sometimes unrelenting—nerve pain.

Amitriptyline was one of the first antidepressants thought to reduce fibromyalgic nerve pain by reducing the hypersensitivity of peripheral nerves (the nerves emerging from the spinal cord that service the rest of the body).

Anecdotal evidence during the early 2000s led to widespread use of the drug for the treatment of fibromyalgia, in part, because no drug options were available.

Controversy

The presumed effects of amitriptyline have been questioned in recent years by health experts. As early as 2012, a review of available studies stated that there was "no good quality evidence" to support the use of amitriptyline for fibromyalgia.

A 2015 review published in the Cochrane Database of Systematic Reviews echoed the findings, stating that there was no "evidence of benefit or harm" and that the quality of studies was "generally poor."

While the researchers reported that amitriptyline may be helpful in one out of four cases, they also noted that one out of three people taking the drug experience side effects that interfere with treatment.

Since that time, the introduction of FDA-approved drugs like Cymbalta (duloxetine), Lyrica (pregabalin), or Savella (milnacipran) has reduced the popularity of a drug once considered the "gold standard" for fibromyalgia treatment.

This shouldn't suggest that amitriptyline is no longer relevant in the treatment of fibromyalgia.

Current Understanding

According to a 2022 study in JAMA Network Open, although Cymbalta was shown to be far superior to amitriptyline in reducing fibromyalgia pain and depression, amitriptyline was more successful at improving sleep, fatigue, and health-related quality of life.

Given that symptoms of fibromyalgia can vary from one person to the next, the investigators suggest that amitriptyline may still have a place in the treatment of fibromyalgia, and having it in the drug arsenal allows for a more tailored approach to treatment.

Amitriptyline for Chronic Fatigue Syndrome

Chronic fatigue syndrome is thought to involve central sensitization and, as such, may benefit from the same treatment as fibromyalgia. This was the thinking when amitriptyline was first proposed as a treatment for ME/CFS despite a lack of clinical research.

Even so, there is evidence that amitriptyline can be useful for ME/CFS by relieving symptoms such as sleeplessness and low energy. Moreover, it appears to do so at doses lower than those used for depression, potentially reducing the risk of side effects.

At the same time, people with severe ME/CFS appear to be able to tolerate higher doses of amitriptyline than that used for depression if needed.

These benefits were reinforced by a 2022 study in JAMA Open Network in which amitriptyline was shown to significantly improve fatigue in people with fibromyalgia.

To date, there is no FDA-approved treatment for ME/CFS.

Amitriptyline Dosage

There are no guidelines for the use of amitriptyline for fibromyalgia or chronic fatigue syndrome. Generally speaking, the drug should be started at the lowest possible dose and increased as tolerated until the optimal effect is achieved.

Amitriptyline is available in tablet form in 10, 25, 50, 75, 100, and 150 milligram (mg) formulations.

Studies involving people with fibromyalgia report that daily doses of 25 mg to 50 mg were well tolerated. For ME/CFS, several authorities recommend starting at a daily dose of 10 mg and increasing to a maximum of 75 mg if needed.

It can take up to three or four weeks for you to feel the benefits of treatment.

Amitriptyline can be taken with or without food. To avoid daytime drowsiness, take the dose one to two hours before bedtime.

Amitriptyline Side Effects and Risk

As with all antidepressants, amitriptyline carries a black box warning about an increased risk of suicidal thoughts or actions in people under 24 years of age. The drug should never be used in this group.

Amitriptyline has a long list of possible side effects, including:

• Nausea
• Vomiting
• Drowsiness
• Weakness or tiredness
• Nightmares
• Headaches
• Dry mouth
• Constipation
• Difficulty urinating
• Blurred vision
• Pain, burning, or tingling in the hands or feet
• Reduced sex drive
• Erectile dysfunction
• Excessive sweating
• Changes in appetite or weight
• Confusion
• Unsteadiness

Amitriptyline Drug Interactions

Amitriptyline can interact with certain medications. These include drugs that use the same enzyme that amitriptyline uses to be broken down (called CYP-450). When taken together, the drugs will "compete" for the available enzyme and either increase the concentration of the drug in the blood (increasing the risk of side effects) or decrease in concentration (decreasing its effectiveness).

Some interactions are minimal and don't require any action. Others are significant and may require a dose adjustment or a change of treatment, so it's important to speak with your healthcare provider.

Let your healthcare provider know if you take any of the following before starting amitriptyline:

• Celexa (citalopram)
  
• Codeine
  
• Cyclobenzaprine
• Cymbalta (duloxetine)
• Desyrel (trazodone)
• Flexeril (cyclobenzaprine)
• Lyrica (pregabalin)
• OxyContin (oxycodone)
• Prozac (fluoxetine)
  
• Synthroid (levothyroxine)
• Topamax (topiramate)
• Ultram (tramadol)
• Vicodin (hydrocodone)
• Xanax (alprazolam)
• Zoloft (sertraline)

Summary

Amitriptyline is a tricyclic antidepressant that has long been used off-label for the treatment of fibromyalgia and chronic fatigue syndrome. The evidence supporting its use is mixed and other drugs may be better suited for treatment (particularly FDA-approved fibromyalgia medications like Cymbalta).

Even so, amitriptyline may be beneficial for some people with fibromyalgia and ME/CFS, helping increase alertness and reduce fatigue. Benefits may be felt within three to four weeks.