This evidence map provides an overview of the direct comparative effectiveness of interventions for fatigue in patients with multiple sclerosis. It also documents where evidence gaps exist in understanding which of two treatment options may work best. 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.

* For logistical reasons, CBT (with additional comparisons to modafinil, group psychotherapy and relaxation) also appears in a column.
** This PCORI funded trial also compares modafinil and methylphenidate to each other, a comparison not captured in this grid.

Additional comparisons from studies listed on (click for more information):
Supervised aerobic exercise interval walking vs Supervised aerobic exercise conventional
Resistance training vs balance training
Education on physical activity vs supervised aerobic exercise
Unsupervised aerobic exercise vs relaxation training
General education vs education on physical activity
CBT alone vs CBT + weekly emails
Virtual reality vs dynamic balance training
Video game therapy vs balance platform therapy

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

Using This Map

The map summarizes evidence from the 15 available randomized controlled trials that performed head-to-head studies of one (or more) treatments versus another.

Axes: The x-axis (horizontal axis along the top) and y-axis (vertical axis along the left side) each list individual treatments that were directly evaluated against one another in at least one clinical trial.

Bubbles: Each bubble summarizes the number of trials studying that intervention; the estimated difference in effect size between the compared interventions (larger bubbles indicate a larger difference); a statement about the strength of the evidence underpinning the conclusion; the fatigue instrument used; and the length of study follow-up. Hovering over each bubble provides this information. For example, where cognitive behavioral therapy (CBT) and relaxation intersect, there is one trial (which has a clickable link to PubMed) with 24 weeks of follow-up, with moderate strength of evidence favoring CBT (a difference of 2.7 points on the Chalder Fatigue scale).

Bubble colors represent the treatment’s effectiveness. The absence of a bubble for an intervention under a specific outcome means no studies are reported on that endpoint. Green bubbles indicate that one treatment was favored over another. Yellow bubbles represent comparisons for which a study was conducted but there was insufficient evidence to determine whether one treatment was more efficacious. A blue bubble indicates PCORI is funding a study on that topic; a dashed black bubble indicates one or more ongoing trials on that topic. (Hovering over the bubbles will provide links to the study’s PCORI webpage or registration on

The Notes section provides links to additional ongoing comparative effectiveness studies at that look at other treatments not captured by the options listed on the map.

Research Insights

  • Most active-treatment comparisons have only been addressed by single studies, and the overall number of head-to-head studies of fatigue treatments in multiple sclerosis is low (15 trials).
  • Most comparisons have assessed interventions within the same category (e.g., comparing two medications) rather than across categories (e.g., comparing a medication to a behavioral intervention).
  • For most comparisons, the data were inconclusive (due to wide confidence intervals). Studies were generally small, and often patients’ fatigue levels improved for both treatments under study.
  • PCORI-funded trials are examining several novel comparisons, including modafinil versus CBT, the effect of adding CBT to modafinil, amantadine versus modafinil or methylphenidate, and teleconference versus face-to-face self-management programs.

Posted: March 6, 2019

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