Medication for MS fatigue

Comparing Three Medicines to Treat Fatigue in Patients with Multiple Sclerosis (MS) — The TRIUMPHANT-MS Study

Project Summary

PCORI has identified multiple sclerosis (MS) as an important research topic. Patients, clinicians, and others want to learn how different treatment strategies aimed at changing specific symptoms or the overall course of MS affect patients’ symptoms and quality of life. To address this issue, PCORI launched a funding initiative in 2015 on Treatment of Multiple Sclerosis. This research project is one of the studies PCORI awarded as part this program.

This research project is in progress. PCORI will post the research findings on this page within 90 days after the results are final.

What is the research about?

About 400,000 Americans have MS. This health problem is one of the main causes of disability in young adults. MS affects the central nervous system and makes it hard for the brain to communicate with the rest of the body. As a result, people with MS may have fatigue, numbness, vision changes, bladder problems, and problems moving. Fatigue is one of the most common symptoms of MS; it can be disabling. Fatigue is also a major cause of patient unemployment and distress for many patients and their families. Little research has taken place on medicines to treat fatigue in patients with MS.

The US Food and Drug Administration hasn’t approved any medicines to treat fatigue in patients with MS. But doctors often use amantadine, modafinil, and methylphenidate to treat fatigue in such patients. These medicines have been approved to treat other health problems. This study looks at whether these three medicines lessen fatigue in patients with MS. Researchers also are looking at whether any of the medicines is better at treating fatigue than the others.

Who can this research help?

This research can help patients with MS and their doctors decide whether to use medicine to treat fatigue.

What is the research team doing?

The research team is working with 136 adults with MS who have fatigue. At different times, patients are taking each of the three medicines, as well as a placebo (a pill with no active ingredients). Patients start with one medicine and take it for six weeks. Patients then wait two weeks before taking another medicine for six weeks. Patients repeat this process until they have taken all three medicines and the placebo.

Different patients take the medicines in different orders. The research team wants to learn whether the order in which patients take the medicines makes a difference in the way patients feel while taking each of the different medicines. Changing the order for different patients helps the researchers understand if changes in fatigue are due to the medicine a patient is currently taking instead of due to medicines the patient took earlier.

Researchers follow up with patients about five weeks after they start taking each medicine. The research team uses a questionnaire to measure patients’ fatigue and find out how fatigue affects patients’ lives. Researchers are also trying to find out whether some medicines work better for some groups of patients. These groups of patients include those with progressive or relapsing-remitting forms of MS and those with higher or lower levels of disability.

The research team is seeking advice from patients and partners such as the National Multiple Sclerosis Society and experts in MS-related fatigue and research on how to design and carry out the study. Patients are suggesting ways to enroll others in the study. Other study partners are helping advertise the study and making sure doctors and patients know about study results.

Research methods at a glance

Design Element Description
Study Design Randomized controlled trial
Population Patients aged 18 years and older with multiple sclerosis (MS) and fatigue
  • Amantadine
  • Modafinil
  • Methylphenidate
  • Placebo

Primary: fatigue’s effect on patients’ lives

Secondary: quality of life, sleepiness

Timeframe 5-week follow-up for primary outcome for each medicine

Journal Articles

Project Details

Principal InvestigatorBardia Nourbakhsh, MD Project StatusIn progress; Enrollment complete Project TitleRandomized, Double-Blind, Crossover, Placebo-Controlled Trial of Amantadine, Modafinil, and Methylphenidate for Treatment of Fatigue in Multiple Sclerosis Board Approval DateJuly 2016 Project End DateSeptember 2020 OrganizationJohns Hopkins University^ Year Awarded2016 State Maryland Project Type Research Project Health Conditions Neurological Disorders Multiple Sclerosis Intervention Strategies Drug Interventions Populations Individuals with Disabilities Funding AnnouncementTreatment of Multiple Sclerosis Project Budget $2,065,534 Study Registration Information


Patient/Caregiver Partners

  • Rebecca Gemignani; National MS Society

Other Stakeholder Partners

  • Jennifer Graves MD, PhD

^Bardia Nourbakhsh, MD, was affiliated with The Regents of the University of California when this project was initially awarded.

Page Last Updated: January 22, 2020

Multiple Sclerosis: Fatigue

Fatigue is the most common symptom of multiple sclerosis (MS). It occurs in 75 percent to 95 percent of patients with MS. Fatigue can occur at all stages of the disease. The symptom is not related to the severity or to the duration of MS. At times, fatigue interferes with function and is an important symptom to manage. There are a variety of ways to combat fatigue in MS.

What causes fatigue in patients with multiple sclerosis?

The exact cause of MS-related fatigue is still unknown. There are several theories on the subject:

  • One theory is that fatigue is related to the general activation of the immune system. Chemical messengers are called cytokines; these levels are higher in patients with MS and may be higher still in patients with fatigue. One way of describing this is that you may feel like you have a virus all of the time.
  • Another theory is that people with MS may have to use more parts of their brain to do the same task as someone without MS; in essence, they are working harder.
  • Another theory is that fatigue is related to reduced electrical transmission of signals in the brain.

Whatever the theory, we know that fatigue from MS is a very real part of the disease.

What are symptoms of fatigue?

There are two major types of fatigue in MS. These two types of fatigue are probably separate problems related to the MS.

The first type is a general feeling of tiredness. It may feel as if one has not slept the night before. This feeling may be worse in the afternoons or after activity. People may feel that they are unable to do as many tasks without getting tired as they did before.

A second type of fatigue is muscular. In this type, there is increased weakness after repeated activity. Often, this occurs with walking. People may find that they are dragging one leg or are more unsteady.

Are there other causes of fatigue besides the MS?

Obviously, people with MS can be tired for other reasons. For example, they may have sleep disorders that interfere with restful sleep. People with MS may have a condition called restless leg syndrome, where they feel that they have to move their legs to get relief. They may also have periodic leg movements, which is when legs kick involuntarily during sleep. Another condition affecting sleep is sleep apnea, which is also common among the general population.

Certain medications may affect sleep or cause fatigue. Alcohol or drug use may alter sleep or cause drowsiness. Sometimes, people have other medical conditions, such as infections, anemia, or a reduced thyroid function, which can increase fatigue.

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6 Fatigue Fighters

Fatigue is a common symptom of many neurologic disorders, and multiple sclerosis (MS) is no exception. Unlike weariness and a sense of exhaustion from exercise, manual labor, and stress, MS-related fatigue consistently interferes with your ability to do everyday activities such as cooking, cleaning, socializing, and working.

Although many patients describe their fatigue vividly—“It’s like swimming with a fur coat on,” or “I feel like I’m wearing a lead coat”—it’s invisible. Since no one can tell by looking at you how tired you are, friends and family may be puzzled that you can’t do the things you once did. Coworkers or supervisors may mistakenly and unfairly assume you are lazy or unmotivated. Reactions like these contribute to difficulties at home and at work.

Two Kinds of Fatigue

MS patients experience two types of fatigue. One, called primary, is a symptom of the disease itself. The other, called secondary, is due to factors such as sleep disturbances, medication side effects, and the increased effort it takes to get through each day. Primary fatigue is further subdivided into lassitude and nerve fiber fatigue. Lassitude is an overwhelming sense of tiredness that comes on suddenly and without warning. It isn’t typically related to exercise or being overheated, but it can be exacerbated by those things as well as stress, poor sleep, and medication.

While fatigue is a reality of MS, it can be managed with consistent self-care. Here are some expert-recommended strategies to consider.

  1. Make Time for Exercise
    It sounds counterintuitive to tell a fatigued person to exercise. In fact, until about 20 or 30 years ago, doctors discouraged people with MS from exercising, fearing it would deplete what little energy they had. Today, a large and growing body of research shows that people with MS tolerate exercise well and it improves their quality of life. It also builds strength, tones muscles, improves balance and coordination, and deters depression. Even people with advanced disability benefit from exercise. By contrast, those with lassitude who don’t exercise may spiral down into increased fatigue, deconditioning, and depression.
  2. Choose Your Activity Carefully
    There is no single best kind of exercise program for people with MS. It depends on what type of MS you have, your level of ability, and whether you are vulnerable to overheating or overexertion. For people with nerve fiber fatigue, exercise can temporarily intensify symptoms. These temporary symptoms are neither relapses nor signs of damage. And often they can be resolved by rest and cooling off. Experiment with different types of activity—swimming, cycling, yoga, tai chi, strength training—to determine which one works the best and which one you like the best.
  3. Talk to Your Doctor About Medication
    Several drugs have proved useful in combatting fatigue. Amantadine (Symmetrel), an anti-viral drug used to treat influenza, reduces fatigue in about 50 percent of patients. For some people, the drug’s effectiveness wears off over time, but if you take a several-days’ break, it may become more effective again. In general, the risk of side effects is low. If you take it late in the day, it may cause insomnia.

    In several studies, modafinil (Provigil), a prescription drug that promotes wakefulness and alertness, has been shown to reduce fatigue. Like amantadine, it can cause sleep problems if taken too late in the day. Other side effects include jitteriness, headache, nausea, and rapid heart rate.

    Stimulants such as methylphenidate (Ritalin) and the mixture of amphetamine and dextroamphetamine (Adderall) are also prescribed to treat fatigue. Both are potentially addictive, but a 2009 study by the National Institute of Drug Abuse found a low potential for tolerance or addiction when methylphenidate was used for medical purposes.

    Antidepressants are also helpful in reducing fatigue, especially if it’s associated with depression. They may boost energy and improve mood and concentration. None of these medications are approved by the US Food and Drug Administration to treat fatigue, so prescriptions for them are considered off-label.

  4. Stay Cool
    Nerve fiber fatigue is related to damage to myelin, the fatty insulation that protects nerve fibers and helps them transmit signals from the central nervous system to the rest of the body. When nerve fibers are damaged, they can still send signals, but not as well as undamaged fibers. When these damaged nerve fibers are overused or become overheated due to sustained exertion or heat exposure, the nerves are less and less able to send signals. Once the body cools off, the nerve fibers start working again. Anything you can do to lower your body temperature, especially during exercise or in hot weather, will delay or prevent nerve fiber fatigue. Cooling vests, hats, and neck wraps, icy drinks, or even a splash of cold water on the hands and face can help forestall nerve fiber fatigue.
  5. Ask About Physical and Occupational Therapy
    Certain medication used to treat MS such as antidepressants, drugs used to treat spasticity, and pain relievers, can cause sleepiness or fatigue. In addition, if muscles grow weak or tire quickly, it becomes harder to perform normal daily activities, and the extra exertion leads to more fatigue. Physical and occupational therapy can help by teaching you to work smarter rather than harder. Planning activities in ways that conserve energy helps with pacing and may result in more consistent energy levels.
  6. Address Sleep Problems

Poor sleep contributes to low daytime energy. Work with your doctor to identify what’s disrupting your sleep whether it’s sleep apnea, restless legs syndrome, depression, muscles spasms, or problems with bladder control. Treating the particular problem will also likely reduce sleep disruptions. If you simply have a hard time getting to sleep, staying asleep, or both, talk to your doctor about how to maintain good sleep habits.

Adapted from Navigating Life with Multiple Sclerosis by Kathleen Costello, MS; Ben W. Thrower, MD; and Barbara S. Giesser, MD, FAAN. The book, part of the American Academy of Neurology’s Neurology Now™ Books series published in 2015 by Oxford University Press, is available to purchase in English from all major booksellers.

Many of us with multiple sclerosis have heard the saying, “I go to bed wired and wake up tired.” This is quite accurate, as fatigue is one of the most prevalent aspects of living with MS. So often I hear from well-meaning individuals who, in an effort to empathize, say they are tired. I give an imaginary eye-roll, not because I am upset with them; rather it’s because I find the disparity difficult to quantify.

We’ve all been tired, weary, or exhausted as a direct result of a long workday or weekend activity, but this is different. This is not a tiredness remedied by restorative sleep, as MS-related fatigue lacks logical cause and effect. Fatigue from multiple sclerosis afflicts the entire body and can be low-level or downright paralyzing. I often say it’s akin to walking through quicksand with your entire body — each move slow and deliberate.

For a while after my diagnosis and subsequent progression, this unique fatigue beguiled and frustrated me. I craved the energy I once took for granted and found it extremely difficult to reconcile with this new norm. I felt like a voyeur, watching life go on without me. The world continued to spin, but I was motionless. It wasn’t until my sadness morphed into a low-level depression that I made a conscious decision to move.

Ironically enough, I migrated toward the fatigue instead of running from it. Knowledge is power, and I not only educated myself about the realities of living with MS-related fatigue, I also learned how to co-exist with its presence. I am still learning; it’s a continuum as the progression has heightened the fatigue. For me, heat exposure, infection, and overexertion all exacerbate fatigue, sometimes so extreme I am relegated to lying down days at a time. It’s imperative to find both what helps and worsens your symptoms, as we are alike only in our diagnosis, each case of MS autonomous from the next.

As I sit here and write, I am powering through my second day of extreme fatigue. Knowing my limitations, I chose to push them aside as my need for human connection trumped the inevitable fallout. You’d think I went skydiving or surfing, but alas I ventured out in excessive heat and enjoyed a long lunch with a good friend.

And here I am. It took me a long time to let go of my resentment toward MS, along with people who could enjoy even the simplest of pleasures without repercussions. It took a change in cognition, as well as continued prayer and meditation. Energy is powerful. Positive or negative, our intent becomes a self-fulfilling prophecy — the Law of Attraction. I am not suggesting we can change the course of our disease (although that is definitely debatable). Rather, we can change our reaction to what it hands us.

Fatigue is an inevitable part of living with multiple sclerosis and there will be days when it becomes overwhelming. Succumb and accept. Work within your limitations, keeping in mind the infinite possibilities that lie there. Be good to yourself and, if possible, adjust your day so you can rest comfortably with a good movie or enjoyable music. Ask for help from friends or family and remember that this, too, shall pass.


Note: Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Multiple Sclerosis News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to multiple sclerosis.

  • Author Details

Jennifer Powell is a health writer and weekly columnist on Multiple Sclerosis. She is also an active advocate in the MS community. Jennifer imparts her hopeful optimism into real-life challenges facing the MS community. Prior to writing her column, Jennifer freelanced for several online periodicals including WebMD. When not writing, Jennifer enjoys volunteering with animal rescue, traveling and spending time with her Golden Retriever. ×Jennifer Powell is a health writer and weekly columnist on Multiple Sclerosis. She is also an active advocate in the MS community. Jennifer imparts her hopeful optimism into real-life challenges facing the MS community. Prior to writing her column, Jennifer freelanced for several online periodicals including WebMD. When not writing, Jennifer enjoys volunteering with animal rescue, traveling and spending time with her Golden Retriever. Latest Posts

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