The solution for fatigue: getting tired (both of us!)


Nourbakhsh et al. have the honour of publishing the first article of 2021 that will change my practice. As bright and shiny as all the monoclonal antibodies on our treatment shelf are compared to the dusty and lacklustre drugs used to treat the symptoms of MS. However, the symptomatic treatments determine day-to-day life for many pwMS: fatigue, spasms, neuropathic pain, etc.

For fatigue, the most frequently prescribed drug is amantadine. This drug seems to be a “Jack-of-all-trades”. In 1963, it was discovered because of its antiviral properties in treating people infected by the influenza virus. In 1969, the mythical duo Schwab and England discovered its soothing effect on tremor and dyskinesias in people with Parkinson’s disease. In 1974, Shapira tested whether there was an effect of amantadine in pwMS and that appeared to be fatigue reduction. The underlying hypothesis: MS is potentially caused by a viral infection (speaking of off-target). Other drugs that we use to treat fatigue: modafinil (mode of action unknown) and methylphenidate (especially in the US, also used to treat ADHD). 

The effect of these compounds on fatigue has been explored in several publications over the past decades. However, the majority of these trials were characterised by significant flaws. It is important to be aware of three important facts before reading anything around this topic:

  • Amantadine, modafinil and methylphenidate are adverse-effect prone drugs. If you compare them 1:1 or in a cross-over trial (e.g. in which pwMS first take 4 wks the active drug and afterwards 4 wks placebo) to placebo, there is no such thing as blinding. 
  • Placebo reduces the scores of the Modified Fatigue Impact Scale (MFIS) (ranging from 0 (no fatigue) to 84 (a lot of fatigue)) with on average 10 points. 
  • Statistical significance does not equal clinical relevance. The minimal important difference on the MFIS is lies between 4 and 8 points, even if lower differences between placebo and drugs generate a significant P-value. 

Does anybody see the link between these two pictures? 

Solution: Although it’s tempting to focus in these COVID-19-times on the Italian variant (where you can sip from Aperol spritz), the link between both of these pictures is the fact that it’s a Latin square. The mathematical significance of a Latin square is an n x n array filled with n different symbols, each occurring exactly once in each row and exactly once in each column. 

And this is the exact concept that Nourbakhsh et al. applied in their fatigue study: 

  1. Amantadine 6wks – Nothing 2wks – Placebo 6 wks – Nothing 2 wks – Modafinil 6 wks – Nothing 2 wks – Methylphenidate 6 wks
  2. Placebo 6 wks – Nothing 2wks – Methylphenidate 6 wks –  Nothing 2 wks – Amantadine 6 wks – Nothing 2 wks – Modafinil 6 wks
  3. Modafinil 6 wks – Nothing 2 wks – Amantadine 6 wks –  Nothing 2 wks – Methylphenidate 6 wks- Nothing 2 wks –  Placebo 6 wks
  4. Methylphenidate 6 wks – Nothing 2 wks – Modafinil 6 wks – Nothing 2 wks – Placebo 6 wks – Nothing 2 wks – Amantadine 6 wks 

This means that pwMS were subjected to 4 different sequences of treatment while being blinded for the actual treatments. At week 5 of each treatment cycle, pwMS had to fill out the MFIS. 

The beauty of this design is that the confounding effect of placebo becomes significantly less relevant. People are exposed to four treatment cycles with the same drugs and have essentially no clue anymore when they would be on an active component and when not. The results of the study are very clear: none of the drugs exerted a significant effect on the MSIF. Hence, none of them reduced fatigue in pwMS. The MSIF even increased with 0.7 points when using amantadine and there were marginal reductions in MSIF for methylphenidate (2.0 points) and modafinil (1.6 points). Of note, the active drugs caused about double the number of moderate adverse effects compared to placebo.

This contrasts with data on the effect of exercising in MS. A Cochrane review of 2015 found that various type of exercise therapy reduce fatigue with 6.9 points on the MSIF. Exercise therapy was interpreted very liberally. One of the schemes incorporated the Nintendo Wii Balance board that trains your balance while snowboarding in the French Alps. Moreover, programming consistently more exercise is a healthy habit with no side effects (unless you overdo it :-)). However, motivating pwMS for daily or frequent exercise is unfortunately much more difficult than prescribing a tablet. Both pwMS and health care practitioners plead guilty of being complacent on this matter. Brainstorming with pwMS on how to be more active, even when having a disability, is much more time-consuming and requires much more out-of-the-box thinking than prescribing an extra tablet for the dosset box. I accept the challenge after reading this article. What about you?

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

Bardia Nourbakhsh, Nisha Revirajan, Bridget Morris, Christian Cordano, Jennifer Creasman, Michael Manguinao, Kristen Krysko, Alice Rutatangwa, Caroline Auvray, Salman Aljarallah, Chengshi Jin, Ellen Mowry, Charles McCulloch, Emmanuelle Waubant

DOI: 10.1016/S1474-4422(20)30354-9


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

Methods: In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. 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 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with, NCT03185065 and is closed.

Findings: Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).

Interpretation: Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.

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Ide Smets


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  • No surprise, really. When you consider how difficult it appears to be for the majority of the population to keep to an exercise regime,,,, then factor in MS, this is a big ask. When you’re feeling ill, it’s the very last thing you want to do. The only thing that trumped this for me was fear. I was told soon after diagnosis by a stern neurophysio that exercise was ABSOLUTELY FUNDAMENTAL to managing MS. I believed her and the prospect of losing capacity was terrifying so I started a regime. Not that I was in the least bit sporty but it was the lesser of two evils. What hasn’t been mentioned here is psychological benefit: setting and adhering to fitness goals puts you back in the driving seat and gives back some of the control that MS stole from you. It may also open doors socially.

    • I totally agree, the benefits of regular exercising are much broader than merely improving fatigue. Thanks for your comment, and keep going!

  • I think the Wii is a great idea. It gives people something active to do with their televisions! The gamification of it makes it fun and a little addictive. I’ve only tried it once, many years ago, but I can see the appeal.

    That said, I think my brother and sister-in-law have one and they remain as unfit as ever. I find it exasperating to see them fall into poor health due to their own actions (or lack of action). Whereas I work so hard on my health and fitness all the time but couldn’t prevent MS.

    • Sometimes you only realise what you have, when it becomes conditional. Sitting is definitely the new smoking, independent of having MS. Anyhow, happy to hear that you are exercising and I also love the idea of the Wii. Especially for people with significant disability as it could be a safe way for them to exercise. All others should obviously go outdoors 🙂

      • I started using the Wii Fit, Wii Fit Plus and now Ring Fit Adventure on the Switch because of my MS diagnosis. It has been brilliant for me almost exclusively because I don’t have to waste and precious cognitive ‘spoons’ on learning new exercises and routines. It just tells me what to do, and I don’t have to think about it. Unfortunately, I do seem to get bored of them around day 500… which is still 490 days longer than any other exercise regime I’ve tried.

  • Exercise works for me. I’ve mentioned this several times before, that I brisk walk to work five days a week and it helps with fatigue. May be because brisk walking is a cardio workout, that’s why helps fatigue??

    ‘Even if you’re confined to a chair or wheelchair, it’s still possible to perform cardiovascular exercise’.
    The website does mention swimming is a cardio workout, but I always get tired with swimming, so that doesn’t work for me.

    • This link is very useful!, it ties together with Gavin’s previous blogpost on DIY standing tables. Even small efforts make the difference.

  • Wonderful post Ide. I am lucky not to have any MS symptoms as I’m NEDA, but also medication averse and will perform somersaults to stay off the pills, almost literally. But I do understand the barriers to exercise if you’re disabled and I feel for my fellow pwMS who have pain, spasms, foot drop and much worse. I do try to run an hour and a quarter a day and sea swim most weeks, but it takes discipline. I admire your other respondents who do what they can while living with disability. It DOES BRING psychological rewards if you do manage to do it and you don’t have to be as active as me. I have dropped my régime occasionally through depression and it’s certainly hard to resume once I’m better. But if you push yourself initially, make yourself do it and you will often surprise yourself. You don’t have to run or swim if these things tire you. Just a walk is absolutely better than no exercise. If that’s impossible, try resistance training. Lifting weights (and they can be a couple of baked bean tins). If you stick at it for a fortnight or so, research shows you may make it a habit. BTW, not only was I the kid that no-one ever wanted to pick for the team, I went to 5 schools and never once was allowed to take part in Sports Day, not even the sack or egg and spoon races because I couldn’t run, jump or throw. I may be trying to prove something but at 72 (73 next month) I think I really love it now.

  • Also, is the exercise message sufficiently embedded in the guidance to PwMS on the need to avoid co-morbidities? It wasn’t for me. Guidance at diagnosis from my (excellent) MS team centred on overall healthy living, and I didn’t understand how having other conditions was likely to worsen the MS. I also think I remember a comment from Prof G on this blog that exercise could be as powerful an intervention as a DMT. As it appears to tick so many MS boxes surely exercise merits explicit patient information and should be included as a criterion for MS monitoring.

  • As a user of Modafinil and a keen proponent of exercise I’d argue that the researchers are looking for the wrong effect with Modafinil.

    Exercise, sleep, diet, and a decent DMT help control the feelings of fatigue. The Modafinil is a big, albeit temporary, help with cognitive function.

    It doesn’t (well, it can’t) make me any smarter. It does allow me to think more like my old self. I can read several complex things, internalise their arguments, and hold that in my head whilst comparing and contrasting to arrive at my own argument. Then I can write that down to work on on and shape.

    It wasn’t until I took Modafinil for the first time did I realise how an ability I previously took for granted had slowly and subtlety ebbed away.

    Apart from the the slightly discombobulating jolt back to a temporary state the secondary emotion was one of upset at how my cognitive abilities had slowly drifted away. I could get through life thinking in a linear fashion but it is far less satisfying that being able to think laterally in a way I once did.

    That was my ‘Come to Jesus’ moment when I started to take Modafinil. Not a reduction of G’s I guess, though I can see why to an outsider the two may be conflated. The neurologist who prescribed it to me had tried it themselves.

    Perhaps more neurologists and researchers ought to do that before standing back one step removed. It won’t hurt you and may serve as o help you understand what effect I can bring to a patient.

By Ide Smets



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