Control of Fatigue a Placebo effect?

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A cross-over trial of 3 different fatigue drugs showed no difference from the fake treatment. Maybe ProfG wil comment on this, but it shows why trials are done

Nourbakhsh B, Revirajan N, Morris B, Cordano C, Creasman J, Manguinao M, Krysko K, Rutatangwa A, Auvray C, Aljarallah S, Jin C, Mowry E, McCulloch C, Waubant E. Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial. Lancet Neurol. 2020 Nov 23:S1474-4422(20)30354-9. 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. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period. This trial is registered with ClinicalTrials.gov, 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: Data from 136 participants were available. 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. 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.

Funding: Patient-Centered Outcomes Research Institute.

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MouseDoctor

8 comments

  • This comes as no surprise. I was started on Amantadine by my neurologist and it made no difference. Modafinil helped, but disturbed my sleep so that over a period of time it’s direct positive effect on fatigue were offset by poorer sleep that made me more fatigued. Going to bed earlier, melatonin and good sleep hygiene has helped more than anything else.

  • For me a long brisk walk helps my fatigue. Last week after a 9 hour work shift, I walked quickly for 45 mins to night class, I felt wide awake and alert for the two hour advanced maths class.

    I’m not sure what this tells me about my fatigue?

  • I’ve been using modafinil for 15 years.

    What I’ve found is:

    1.) It’s important to stop using it to reduce acclimatisation – I find 5 consecutive days on, 2 consecutive days off seems to maintain efficacy without increasing dose.

    2.) It interrupts sleep – take before 11am or don’t bother.

    3.) Sometimes fatigue is due to other factors, I found increasing my water intake particularly beneficial.

    But likewise if I stop modafinil altogether, within a few days I’m unable to stay awake for more than about 5 hours – I did about 5 weeks without modafinil when I started on ocrevus, just to make sure I didn’t have anything interacting with the ocrevus and other bits we’re given at the same time. So – I know for me modafinil definitely does “something” (one anecdotal account only)

    • Wow, I have very similar observations to Simon after my 15 years of modinifil use. I find the drug makes an improvement in my quality of life. Like him, I take deliberate days off medication. There is no need to take it on a lazy or resting day. I plan my schedule around days I will take it. My dosing took a bit to figure out : 100mg early am to get moving and into day. At 11 am I evaluate what other tasks I want to accomplish for the remainder of the day and take another 100 mg if I have specific goals to accomplish involving driving, standing, walking. As Simon indicated, after 11am, it will impact sleep at night. On rare occasions, At 3 pm, If I feel I am absolutely unable to get through a work day or an event, I take another 100 mg. I feel modinifil motivates the body to be active when physical fatigue would normally be an obstacle. In addition, it keeps me focused and alert when I have a task that would be more difficult with a slower processing speed. Just like Simon, I also stopped before my Ocrevus infusion (and during a previous time I couldn’t afford it.). This study worries me because of how it may have measured fatigue. Did this study rate the level of activity or cognitive tasks the participants were engaged in? Were the fatigue levels self reported? I would guess that A decrease in fatigue is more noticeable on a weekly grocery shopping trip vs. during a passive activity such as watching t.v. I would be interested in an objective Fitbit type measurement of activity during each 5 week interval on each drug, placebo, and no treatment. Do you observe any weaknesses in the study’s design?

  • As the paper notes, MS fatigue is distinct from excessive daytime sleepiness (EDS), but the two can be hard to tell apart. The study drugs are also prescribed for PwMS with EDS, not least when it occurs as a side effect of medications such as baclofen, tizanidine and gabapentin. The presence of these drugs wasn’t an exclusion criterion in the study, nor was their presence in participants documented. Therefore their confounding potential wasn’t explored in the main results or in the post-hoc analysis, which *did* identify a possible pharmaceutical benefit in PwMS who experience EDS.

    It would be unfortunate if this study led clinicians to assume that the only alertness benefit obtainable from these drugs is due to placebo effect.

  • As the paper notes, MS fatigue is distinct from excessive daytime sleepiness (EDS), but the two can be hard to tell apart. The study drugs are also prescribed for PwMS with EDS, not least when it occurs as a side effect of medications such as baclofen, tizanidine and gabapentin. The presence of these drugs wasn’t an exclusion criterion in the study, nor was their use by participants documented. Therefore their confounding potential wasn’t explored in the main results or in t CB he post-hoc analysis, which *did* identify a possible pharmaceutical benefit in PwMS who experience EDS.

    It would be unfortunate if this study led clinicians to assume that the only alertness benefit obtainable from these drugs is due to placebo effect.

  • Would have liked to see ampyra in the mix as well to determine if it’s also effective just for better energy and not only as a ‘walking’ medicine so more ms patients could qualify for it next to the possible neoroprotective properties. What’s your vision on that Mousedoc?

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