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Common MS fatigue meds Provigil, Ritalin, Symmetrel, fail to help fatigue in MS

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  • Common MS fatigue meds Provigil, Ritalin, Symmetrel, fail to help fatigue in MS

    Lancet Neurol. Author manuscript; available in PMC 2021 Jan 1.
    Published in final edited form as:
    Lancet Neurol. 2021 Jan; 20(1): 38–48.
    Published online 2020 Nov 23. doi: 10.1016/S1474-4422(20)30354-9

    Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomized, crossover, double-blind trial

    Bardia Nourbakhsh, M.D.,1 Nisha Revirajan, M.B.B.S.,2 Bridget Morris, M.S.N.,1 Christian Cordano, M.D.,2 Jennifer Creasman, M.S.P.H,3 Michael Manguinao, B.S.,2 Kristen Krysko, M.D.,2 Alice Rutatangwa, D.O.,2 Caroline Auvray, M.D.,2 Salman Aljarallah, M.B.B.S.,1 Chengshi Jin, Ph.D.,3 Prof Ellen Mowry, M.D.,1,4 Prof Charles McCulloch, Ph.D.,3 and Prof Emmanuelle Waubant, M.D.2
    Author information Copyright and License information Disclaimer
    The publisher's final edited version of this article is available at Lancet NeurolAssociated Data

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    Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis (MS); however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications against each other and placebo in patients with MS-related fatigue.


    In this randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, patients with MS who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic MS centers in the US. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to six weeks. All patients were to receive all four study medications, in turn, with two-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications, in blocks of eight, to a consecutive series of numbers. At the time of enrollment, study pharmacists assigned each participant to the next consecutive number (and hence the sequence of study medications). The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were blinded to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week five of each medication period, analyzed using a linear mixed-effect regression model. This trial is registered with, NCT03185065.


    Between October 4, 2017, and February 27, 2019, 141 patients were enrolled and randomly assigned to one of four medication administration sequences (35 patients to amantadine, placebo, modafinil, methylphenidate sequence; 34 patients to placebo, methylphenidate, amantadine, modafinil sequence; 35 patients to modafinil, amantadine, methylphenidate, placebo sequence; and 37 patients to methylphenidate, modafinil, placebo, amantadine sequence). Data from 136 participants were available for the intent-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores (95% CI) at baseline and the maximal tolerated dose were as follows: 51.3 (49.0 to 53.6) at baseline, 40.6 (38.2 to 43.1) with placebo, 41.3 (38.8 to 43.7) with amantadine, 39.0 (36.6 to 41.4) with modafinil, and 38.6 (36.2 to 41.0) with methylphenidate (P=0.20 for the overall medication effect in the linear mixed-effect regression model). As compared to placebo [38 patients (31%)], higher proportions of participants reported adverse events while taking amantadine [49 patients (39%)], modafinil [50 patients (40%)], and methylphenidate [51 patients (40%)]. Three serious adverse events (SAEs) occurred during the study (pulmonary embolism and myocarditis while taking amantadine and an MS exacerbation requiring hospitalization while taking modafinil).


    Amantadine, modafinil, and methylphenidate were not superior to placebo in improving MS-related fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, and methylphenidate for the treatment of fatigue in MS.
    Dave Bexfield

  • #2
    This placebo-controlled study about drugs for MS fatigue is eye opening, pardon the pun. They don't work.

    The full study is available here for free:
    Dave Bexfield


    • #3
      And now, neurologists are facing an ethical dilemma. -D

      Ethical considerations in the treatment of multiple sclerosis fatigue

      BardiaNourbakhshaEmmanuelleWaubantbAndrea W.M.EverscAndrew J.Solomond


      Fatigue is the most common symptom and a leading cause of disability multiple sclerosis (MS). Despite the lack of evidence, several medications are frequently prescribed by physicians to ameliorate fatigue in patients with MS. However, a recent study demonstrated that improvement in fatigue severity with these medications appears to be due to placebo effect and is also is associated with more frequent adverse events than the placebo. These findings raise ethical concerns surrounding the initiation and discontinuation of these treatments for fatigue in MS.

      Starting these medications for the treatment of MS fatigue for their placebo effect may not be justified. However, stopping the medications in patients who report symptomatic benefits and have no side effects may also not be ethical. In MS care non-pharmacological approaches for fatigue treatment, such as exercise and cognitive behavioral therapy, should now be prioritized. Novel study designs may be necessary to address placebo response in future clinical trials evaluating interventions for fatigue in MS.
      Dave Bexfield


      • #4
        Well, this is timely and interesting. I just started taking Ritalin which I have not used in 15 years. My insurance company has rejected paying for it. Maybe they know of this study! I do not take it for fatigue. When I take Ritalin I can concentrate much better…even follow a thought all the way to the end of a sentence. I am much more articulate with it….my brain is awake when I take Ritalin.


        • #5
          I can attest to the ineffectiveness of provigil. Sure, I was awake... but attentive, functioning, not exhausted... no.

          I used to take adderall for ADHD, and I'm back on that at 20mg in the morning and 10mg in the afternoon as need. My fatigue management is much improved on Adderall for sure, and I am even attentive and functioning, so that med is a win for me.



          • #6
            There is another concern with fatigue meds. Unintended side effects. -D

            Delayed amantadine toxicity causing apparent progression of multiple sclerosis

            Lloyd Bradley
            First Published September 5, 2021


            Amantadine is sometimes used to treat fatigue in multiple sclerosis.

            To report a patient with secondary progressive multiple sclerosis (SPMS) who developed late-onset side effects of amantadine which were initially felt to represent a progression of her SPMS.

            A single retrospective case report.

            Symptoms of cognitive deterioration, ataxia and hallucinations resolved completely on cessation of the amantadine she had been prescribed several years beforehand.

            Clinicians involved in the management of the symptoms of SPMS should be aware of the potential for cumulative side effects of drugs used to treat symptoms and consider their potential role in precipitating neurological deterioration.
            Dave Bexfield