Two PCORI-funded comparative clinical effectiveness research studies assessed the benefits and harms of interventions to reduce fatigue in patients with multiple sclerosis (MS).1-4 These findings can contribute to clinician and patient discussions about treatments to reduce MS-related fatigue.


A middle-aged Asian female rubbing her eyes as she sits at a table.

Fatigue is the most common symptom of MS, affecting about 80% of patients with MS.5 MS-related fatigue can be highly debilitating, making it difficult for patients to work and affecting their quality of life. Existing interventions include both behavioral and pharmacological treatments. However, evidence on the comparative clinical effectiveness of these interventions is limited and inconsistent. The U.S. Food and Drug Administration (FDA) has not approved any medicines to treat MS-related fatigue. In addition, combinations of behavioral and pharmacological interventions remain understudied.

PCORI has funded several comparative clinical effectiveness research studies on MS. Two clinical trials that examined treatments for MS-related fatigue have finished. The TRIUMPHANT-MS trial compared three medicines commonly used off-label — amantadine (Gocovri®, Osmolex® ER, or Symmetrel®); methylphenidate (Ritalin® or Methylin®); and modafinil (Provigil®) — with a placebo.1,3 The COMBO-MS trial compared telephone-based cognitive behavioral therapy (CBT) alone, modafinil (Provigil®) alone, and combination therapy with CBT plus modafinil.2,4

Icon for findings


TRIUMPHANT-MS Study: Amantadine, methylphenidate, and modafinil were not superior to placebo in improving MS-related fatigue. More patients experienced moderate to severe adverse events when taking one of the medications than when taking placebo.

COMBO-MS Study: Telephone-based CBT, modafinil, and combination therapy each reduced the impact and intensity of MS-related fatigue about the same. Overall, patients had a low number of adverse events. However, patients who used modafinil and combination therapy reported more adverse events than those who used CBT alone.

Outcome Measures

Both studies used the Modified Fatigue Impact Scale (MFIS) to measure fatigue as the primary outcome. The MFIS is a validated 21-item questionnaire that assesses the physical, cognitive and psychosocial dimensions of fatigue.


The TRIUMPHANT-MS study collected MFIS scores at baseline and again after five weeks of treatment with each medicine.

Outcome/Measure Finding
MFIS scores* were no different than placebo across all medicines (p=0.20).
Quality of life
(Quality of Life in Neurological Disorders [Neuro-QoL] fatigue item bank)
No treatments improved fatigue-related quality of life (p=0.42).
Daytime sleepiness
(Epworth Sleepiness Scale)
No treatments improved daytime sleepiness (p=0.071).
Adverse events A higher percentage of patients reported adverse events while taking amantadine (39%), methylphenidate (40%), and modafinil (40%) than when taking the placebo (31%). The most commonly reported nervous system or psychiatric adverse events included headaches, insomnia, lightheadedness and dizziness, and anxiety. The most common gastrointestinal adverse events were nausea, dry mouth and constipation.

*Mean values for the MFIS total scores were collected at the highest tolerated dose in each medication period.


The COMBO-MS study collected MFIS scores at baseline and again 12 weeks later.

Outcome/Measure Finding
Reductions in MFIS scores* did not differ by treatment. Of note, all three treatments were associated with statistically and clinically significant (i.e., >10 points) reductions in total MFIS scores.
Adverse events A total of 0, 27, and 32 adverse events were determined to be related to treatment in the CBT, modafinil and combination therapy groups, respectively. The most commonly reported adverse events were anxiety, headache and insomnia (related to modafinil and combination therapy only).

*Lower MFIS total scores are indicative of improved symptoms.

Of note, key differences between these studies are important in the interpretation of their results. Differences include study design — in the TRIUMPHANT-MS study, reductions in MFIS scores were compared to placebo, while in the COMBO-MS study, they were not. Also important, the length of follow-up was longer in the COMBO-MS study. Finally, the dosing levels and strategies for modafinil differed between the two studies.

Professional Guidance

Guidance from the Multiple Sclerosis Council for Clinical Practice Guidelines (the Council) precedes both studies and does not reflect these findings. The Council suggested providing education and counseling on fatigue self-management and referral to physical and occupational therapy for confirmed MS-related fatigue. The Council also indicated that amantadine may be used off-label in addition to or following unsuccessful self-management.5, 6

Other professional organizations acknowledge that medicines such as amantadine, methylphenidate and modafinil are used off-label to treat MS-related fatigue; however, most organizations do not explicitly advise for or against the use of these medicines to treat fatigue.6-10 The Consortium of Multiple Sclerosis Centers recommends CBT as a treatment for MS-related fatigue.10

Many factors can contribute to MS-related fatigue including common medical comorbidities.5 MS professional organizations recommend that clinicians complete a comprehensive evaluation to determine the factors contributing to a patient’s fatigue and appropriate interventions. For example, sleep disturbances, neuropathic pain, mood disorders and medication side effects can cause or exacerbate fatigue.

Talking with Patients with MS about Fatigue

A patient-friendly version of this update is available to help care teams talk with patients with MS and caregivers about these research findings and more generally about treating MS-related fatigue. Topics for discussion include:

The relevance of the research findings for patient treatment decisions.

Whether a patient may want to consider medication, CBT, or both to treat MS-related fatigue.

Medication side effects.

The importance of identifying and treating non-MS-related causes of fatigue.

Other approaches to reducing symptoms of fatigue such as exercise, meditation, and yoga.

Icon for about the studies

About the Studies

In the TRIUMPHANT-MS study, researchers conducted a double-blind, crossover randomized controlled trial in Maryland and California. The study included 141 adults with MS and fatigue. The majority of the participants were female (77%) and White (75%). The average age was 47. Most patients (75%) were diagnosed with relapsing-remitting MS.

Researchers randomly assigned patients to one of four treatment sequences. Patients took a single medicine or a placebo for six weeks. Then they stopped the medicine and waited two weeks before starting the next medicine in their assigned sequence. Patients repeated this process until they had taken all three medicines and the placebo. Patients completed online surveys about fatigue, sleepiness and quality of life. Study staff contacted patients by phone, email or text to ask about adverse events. Patients with MS, clinicians and a member of an advocacy group helped plan the study.

In the COMBO-MS study, researchers conducted a randomized controlled trial in Michigan and Washington. The study included 336 adults with MS and fatigue. Of these patients, 76% were female, and 85% were White. The average age was 49. Most patients (71%) were diagnosed with relapsing-remitting MS.

Researchers randomly assigned patients to one of three treatment groups: telephone-based CBT alone, modafinil alone or combination therapy with CBT plus modafinil. CBT included eight telephone calls over 12 weeks with a therapist to help patients manage fatigue, followed by two optional follow-up calls over the following four weeks. CBT addressed topics such as setting goals, improving sleep and conserving energy. During the follow-up calls, patients made plans for managing fatigue in the future. Patients took modafinil, either alone or with CBT, for 12 weeks. Patients with MS, their providers, health insurers and national and regional MS organizations helped to design the study and recruit patients.

Read more about these studies at and

Download this Evidence Update


1. © 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.

2. © 2011–2023 Patient-Centered Outcomes Research Institute. “Comparing Treatments for Fatigue in Patients with Multiple Sclerosis -- COMBO-MS.” Last updated November 30, 2022.

3. 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.

4. 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. 

5. Multiple Sclerosis Council for Clinical Practice Guidelines. Fatigue and Multiple Sclerosis: Evidence-Based Management Strategies for Fatigue in Multiple Sclerosis. Clinical Practice Guidelines. Paralyzed Veterans of America; 1998. Accessed February 7, 2022.

6. National Multiple Sclerosis Society. Fatigue: What You Should Know. A Guide for People with MS. National Multiple Sclerosis Society; 2019. Accessed August 4, 2022.

7. Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004;70(10):1935-1944.

8. Multiple Sclerosis Association of America. “Fatigue.” Last updated January 17, 2023.

9. Multiple Sclerosis Foundation. “Fighting Fatigue.” Last updated July 2009.

10. The Consortium of Multiple Sclerosis Centers. “Comprehensive Care in Multiple Sclerosis: A Core Curriculum.” Last updated May 2022.

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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