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Amantadine, modafinil, and methylphenidate for MS-related fatigue

MS Virtual 2020
For fatigue, one of the most prevalent subjective symptoms in MS patients, methylphenidate, modafinil, and amantadine are commonly prescribed. Substantial evidence supporting their efficacy is however lacking. In the randomised crossover TRIUMPHANT-MS trial, none of these 3 agents was superior to placebo in improving MS-related fatigue, but they did cause more adverse events [1].

The TRIUMPHANT-MS trial compared the efficacy of twice-daily oral methylphenidate, modafinil, and amantadine against each other and placebo. Eligible patients had MS-related fatigue with a Modified Fatigue Impact Scale (MFIS) score of >33. EDSS score at the time of screening ranged from 0.0 to 7.0. A total of 141 adult patients received 1 of 4 treatment sequences:

  1. amantadine, placebo, modafinil, methylphenidate;
  2. placebo, methylphenidate, amantadine, modafinil;
  3. modafinil, amantadine, methylphenidate, placebo; or
  4. methylphenidate, modafinil, placebo, amantadine.

Each medication was titrated over 4 weeks to the participants' highest tolerated dose or pre-defined highest dose. Each intervention was given up to 6 weeks, with a 2-week washout period between treatments. The primary outcome measure was the MFIS score in week 5, when the highest tolerated dose was used.

The estimated mean value of the MFIS total score at baseline was 51.3. In week 5 of treatment, the MFIS total score was 41.2 with amantadine, 39.0 with modafinil, 38.7 with methylphenidate, and 40.7 with placebo (P=0.20 for overall medication effect). In the subgroup of patients with a higher baseline daytime sleepiness (Epworth Sleepiness Scale) score, both modafinil and methylphenidate were superior to placebo in improving MFIS score (-4.1 for both interventions).

In the amantadine, modafinil, and methylphenidate groups, 38.6%, 40.0% and 39.5% of participants reported adverse events, respectively, versus 30.6% in the placebo group. The authors concluded that these agents should not be used indiscriminately for the treatment of MS-related fatigue.

  1. Nourbakhsh B, et al. Randomized Trial of Amantadine, Modafinil and, Methylphenidate for Multiple Sclerosis Fatigue. MSVirtual 2020, Abstract PS13.03.


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