This evidence map provides an overview of the benefits and harms of individual interventions for fatigue in patients with multiple sclerosis. It summarizes evidence from available randomized controlled trials (RCT) that compared each intervention displayed with an inactive control group. This means that interventions are not being directly compared with one another in this map. See MS evidence map #3 for a summary of available head-to-head trials. Read more about Using This Map and overarching Research Insights gained from this map. For the best map interaction experience, we recommend viewing this evidence map on desktop-sized devices in a Chrome, Safari, or Firefox browser.

Abbreviations used on this map:
CBT – Cognitive behavioral therapy
CPAP – Continuous positive airway pressure
FACETS – Fatigue: Applying Cognitive behavioral and Energy effectiveness Techniques to lifeStyle
RRMS – Relapsing remitting multiple sclerosis

The ECRI Institute-Penn Medicine Evidence-based Practice Center developed this map for PCORI.

Using This Map

This map summarizes evidence from 45 randomized trials comparing a treatment to inactive control (e.g. placebo, sham, waitlist, passive education). Each intervention’s effect on fatigue and quality of life is displayed.

Axes: The x-axis (horizontal axis along the top) depicts outcomes (e.g., fatigue). The y-axis (vertical axis on the left) displays interventions grouped by overarching category (e.g., pharmacologic, exercise). The categories can be collapsed by clicking on the bracketed arrows.

Bubbles: Each bubble summarizes the number of trials studying that intervention; the estimated effect size for the intervention (larger bubbles indicate a larger effect size); whether the intervention is effective, was found to be associated with adverse effects, or if there is insufficient evidence to reach a conclusion; and a statement about the strength of the evidence underpinning the conclusion. For example, under exercise, yoga represents four trials (which are listed with clickable links to PubMed) with moderate strength of evidence of a small positive effect (12 points on the Modified Fatigue Impact Scale [MFIS] scale).

The estimated effect size, strength of evidence, number of studies and hyperlinks to abstracts for each intervention can be viewed by hovering over each bubble. When studies reported both the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS), MFIS was used to calculate the effect size.

Bubble colors represent the treatment’s effectiveness. Green bubbles indicate beneficial effects, and yellow bubbles indicate inconclusive data. Furthermore, each bubble’s size corresponds to the magnitude of benefit (expressed as Hedges’ g: approximately the between-group difference in change scores divided by the pooled standard deviation. For example, for yoga, the Hedges' g of 0.79 corresponds to a 1.03-point difference on the 1-7 FSS, and a 12-point difference on the 0-84 MFIS). Adverse effects (reported in these studies) are represented by small, medium or large red bubbles, reflecting a judgment about the risk and severity. Studies stating that no adverse effects occurred are represented by small red bubbles. Where a red bubble is present, specific details about harms can be found by hovering over the bubble and clicking “for more information.”

A blue outline around a bubble indicates PCORI is funding one or more studies on that topic; a dashed black outline indicates one or more ongoing trials on that topic. (Hovering over the bubble will provide links to the study’s PCORI webpage or its registration on

When no bubble appears in a given location, no studies mentioned that outcome.

Filters: The filters above the map allow selective display by fatigue measurement instrument, type of MS, and length of follow-up. In addition, users may select to display interventions from registered studies. Progressive MS was not reported separately in these trials.

Research Insights

  • For exercise interventions, based on three RCTs, aquatic exercise produced notable changes in scores measuring reductions in fatigue and improved quality of life. However, caution is warranted in interpreting this finding:
    • These trials were all performed in Iran in predominantly younger women and may not be generalizable to the United States.
    • More research should be conducted to clarify the minimally important difference (MID) for the outcome scales used (e.g., Fatigue Severity Scale, MFIS). This is crucial to assess if observed effects are large enough to matter in the day-to-day lives of patients.
  • For pharmacologic treatments, only paroxetine demonstrated evidence of efficacy (with low strength of evidence) for treating fatigue. All were associated with adverse effects. Insufficient evidence for amantadine, modafinil, and methylphenidate is noteworthy given their common use in clinical practice. PCORI is currently funding a trial assessing these treatments.

Modified Fatigue Impact Scale (MFIS) & Fatigue Severity Scale (FSS)

About the Modified Fatigue Impact Scale (MFIS)

The MFIS contains 21 statements, each one involving fatigue during the past four weeks (listed below). Patients rate their agreement from 0 to 4 where 0 indicates "Never" and 4 indicates "Almost Always." Therefore, higher scores indicate greater fatigue. Studies report the total score, which ranges from 0-84.

  1. I have been less alert.
  2. I have had difficulty paying attention for long periods of time.
  3. I have been unable to think clearly.
  4. I have been clumsy and uncoordinated.
  5. I have been forgetful.
  6. I have had to pace myself in my physical activities.
  7. I have been less motivated to do anything that requires physical effort.
  8. I have been less motivated to participate in social activities.
  9. I have been limited in my ability to do things away from home.
  10. I have trouble maintaining physical effort for long periods.
  11. I have had difficulty making decisions.
  12. I have been less motivated to do anything that requires thinking.
  13. My muscles have felt weak.
  14. I have been physically uncomfortable.
  15. I have had trouble finishing tasks that require thinking.
  16. I have had difficulty organizing my thoughts when doing things at home or at work.
  17. I have been less able to complete tasks that require physical effort.
  18. My thinking has been slowed down.
  19. I have had trouble concentrating.
  20. I have limited my physical activities.
  21. I have needed to rest more often or for longer periods.

About the Fatigue Severity Scale (FSS)

The FSS contains nine statements, each one involving fatigue (listed below). Patients rate their agreement from 1-7, where 1 indicates "Strongly disagree" and 7 indicates "Strongly agree". Therefore, higher scores indicate greater fatigue. Some studies report the total score (ranging from 9-63); other studies report average score (ranging from 1-7).

  1. My motivation is lower when I am fatigued.
  2. Exercise brings on my fatigue.
  3. I am easily fatigued.
  4. Fatigue interferes with my physical functioning.
  5. Fatigue causes frequent problems for me.
  6. My fatigue prevents sustained physical functioning.
  7. Fatigue interferes with carrying out certain duties and responsibilities.
  8. Fatigue is among my most disabling symptoms.
  9. Fatigue interferes with my work, family, or social life.

Posted: March 6, 2019

What's Happening at PCORI?

The Patient-Centered Outcomes Research Institute sends weekly emails about opportunities to apply for funding, newly funded research studies and engagement projects, results of our funded research, webinars, and other new information posted on our site.

Subscribe to PCORI Emails


Hand pointing to email icon