Two PCORI-funded research studies looked at how well certain treatments help people with multiple sclerosis, or MS, feel less fatigue. The results of these studies can help people with MS work with their care team to make decisions about treating fatigue.


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Many people with MS experience fatigue. They may lack energy and feel like they need to rest. Fatigue can make it hard to work or do other activities.

The U.S. Food and Drug Administration, or FDA, has not approved any medicines to treat fatigue in people with MS. Instead, some people with MS use medicines approved to treat other health problems. But early studies of these medicines have not shown a clear benefit for MS fatigue. These medicines include:

Amantadine (sold under the brand names Gocovri®, Osmolex® ER, and Symmetrel®), which helps reduce uncontrolled movements in people with Parkinson’s disease.

Methylphenidate (Ritalin®, Methylin®, and other brands), which helps people with attention-deficit/hyperactivity disorder to focus.

Modafinil (Provigil®), which helps people with certain sleep disorders stay awake.

People with MS also sometimes use cognitive behavioral therapy, or CBT, as another treatment for fatigue. CBT is a type of talk therapy. In CBT, people learn to change patterns in their thinking and behavior. CBT can lessen the intensity and impact of fatigue and improve how people feel. People may also receive both medicine and CBT as part of their care. In two recent PCORI-funded research studies, researchers compared different treatments to help people with MS feel less fatigue.

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One PCORI-funded research study compared three medicines — amantadine, methylphenidate and modafinil — and a placebo. A placebo is a pill with no active ingredients. Patients taking the medicines reported some improvements in fatigue and quality of life, but not more than patients who took a placebo. More patients also reported side effects when taking one of the medicines than when taking placebo.

A second PCORI-funded research study compared CBT, modafinil, and CBT plus modafinil. This study did not include a placebo. The study found that all three treatments helped patients feel less fatigue. The treatments worked about the same. More patients who took modafinil alone or with CBT had side effects than patients who received CBT alone did.

Side effects of medicines in both studies included anxiety, feeling lightheaded or dizzy, headaches and insomnia.

Confirming My Fatigue Is Caused by MS

Talk to your MS care team about how fatigue affects your daily activities. Your MS care team can explore things that may cause or add to your fatigue. Understanding the cause can help with choosing the best ways to manage fatigue.

Things that can cause fatigue or make it worse are pain or sleep problems, mood disorders or stress. Health problems such as sleep apnea, other chronic medical conditions or side effects from medicines can also cause fatigue.

Questions to Ask My MS Care Team about the Studies

You may want to talk to your MS care team about these studies on treatments for MS-related fatigue. Questions to ask your care team could include:

What do these study results mean for me?

Is MS, or something else, causing my fatigue? How can we find out?

If my fatigue is not caused by MS, what are my next steps?

Do you think medicine, CBT, or both can help me feel less fatigue?

How do we choose which medicine I should take, if any?

If I am taking one of the medicines included in the studies, should I stop or change it?

If I am taking one of the medicines included in the studies, would adding CBT help me manage my fatigue?

What other things can I do to reduce my fatigue?

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About the Studies

The first study included 141 adults with MS and fatigue. Each participant in the study took each drug and the placebo, one at a time, in a specific order over seven to eight months.

The second study included 336 adults with MS and fatigue. The research team assigned patients by chance to use CBT, modafinil, or both CBT and modafinil. Patients using CBT talked with their therapist by phone eight times over 12 weeks. After that, they had two optional follow-up calls over the next four weeks. Patients took modafinil, either alone or with CBT, for 12 weeks.

Read more about these studies at and

Download this Evidence Update


© 2011–2023 Patient-Centered Outcomes Research Institute. “Comparing Medicines to Help Patients with Multiple Sclerosis Feel Less Fatigue -- The TRIUMPHANT-MS Study.” Last updated November 30, 2022.

© 2011–2023 Patient-Centered Outcomes Research Institute. “Comparing Treatments for Fatigue in Patients with Multiple Sclerosis -- COMBO-MS.” Last updated November 30, 2022.

Nourbakhsh B, Revirajan N, Morris B, et al. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2021;20(1):38-48.

Kratz AL, Alschuler KN, Ehde DM, et al. A randomized pragmatic trial of telephone-delivered cognitive behavioral-therapy, modafinil, and combination therapy of both for fatigue in multiple sclerosis: the design of the "COMBO-MS" trial. Contemp Clin Trials. 2019;84:105821.

The information in this publication is not intended to be a substitute for professional medical advice. This update summarizes findings from PCORI research awards to Johns Hopkins University and University of Michigan.

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