Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in ME/CFS: A Randomized, Double-Blind,Placebo-Controlled Trial,2021,Castro-Marrero

Preprint

Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

"
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem, and profoundly debilitating condition, probably of multifactorial etiology. No effective approved drugs are currently available for its treatment. Several studies have proposed symptomatic treatment with melatonin and zinc supplementation in chronic illnesses; however, little is known about the synergistic effect of this treatment on fatigue-related symptoms in ME/CFS.

The primary endpoint of the study was to assess the effect of oral melatonin plus zinc supplementation on fatigue in ME/CFS.
Secondary measures included participants’ sleep disturbances, anxiety/depression, and health-related quality of life.
A proof-of-concept, 16-week, randomized, placebo-controlled, double-blind trial was conducted in 50 ME/CFS patients assigned to receive either oral melatonin (1 mg) plus zinc (10 mg) supplementation (n = 24) or matching placebo (n = 26) once daily.
Endpoint outcomes were evaluated at baseline and then reassessed at 8 and 16 weeks of treatment and 4 weeks after treatment cessation, using self-reported outcome measures. Treatment was safe and well-tolerated.

The most relevant results were the significant reduction in the perception of physical fatigue in the active group at the final follow-up versus placebo (p < 0.05), and the significant improvement in the physical component summary at all follow-up visits in the experimental group.

Our findings suggest that oral melatonin plus zinc supplementation for 16 weeks is safe and potentially effective in reducing fatigue and improving the quality of life in ME/CFS. This clinical study was registered on ClinicalTrials.gov (NCT03000777)."
https://www.preprints.org/manuscript/202103.0234/v1

 

Just the title of that paper tells me something about the perception the authors have of ME/CFS, and it has the subtlety of being hit by a hammer.

Edit : Added the following...

Existing title : Effect of Melatonin Plus Zinc Supplementation on Fatigue Perception in ME/CFS: A Randomized, Double-Blind,Placebo-Controlled Trial:2021,Castro-Marrero

My suggested title : Effect of Melatonin Plus Zinc Supplementation on Fatigue in ME/CFS: A Randomized, Double-Blind,Placebo-Controlled Trial:2021,Castro-Marrero

I've changed the title to something I'm much happier with.

 

Funding: JC-M received financial support from Laboratorios Viñas, S.A. (Barcelona, Spain). This study was supported by the Vall d'Hebron University Hospital and Vall d’Hebron Research Institute (both in Barcelona, Spain). Laboratorios Viñas, S.A. supplied both treatments (melatonin plus zinc supplement and placebo).​

The "significant reduction in the perception of physical fatigue" does not seem to be much more than a cherry-picked result (table below). It isn't corroborated by the SF-36 physical functioning subscale (one of the secondary outcomes) on which there was no improvement.

Interestingly, though, they found that "the [SF-36] physical functioning domain worsened significantly after treatment withdrawal":

- melatonin + zinc: 19.77 ± 16.44 at 4-week post-treatment vs. 26.09 ± 17.32 at 16-week (p=0.011)
- placebo: 26.14 ± 21.04 at 4-week post- treatment vs. 21.75 ± 19.21 at 16-week (only a trend, no p-value computed)

I'm not sure what this last point tells us. According to table 1, the active treatment group seemed to be slightly, but not significantly, more affected than the placebo group, with more being ill for >10 years and on concomitant drugs (antidepressants).

The authors and the title are correct and in line with the results -- subjective questionnaires measure the perception of fatigue. Objective outcomes like actimetry, even if they are surrogate, would do a better job of measuring fatigue.

 

I'm not an expert, or a statistician, but don't those numbers, when gathered via what seems to be a self reported questionnaire, with all the 'reliability' and 'accuracy' that suggests, say that there was no effect, at all?

TBH even if they were 100% objective, gathered by actual meaningful measurements, then they would still suggest no effect at all, at least to me.

 

N=1

I take 10mg zinc every night (best to avoid taking it with meals or when fibre is consumed as it binds to the fibre).

1 also take 2mg Circadin which is prescription slow release melatonin.

Does it affect my ME in any significant way? Not really.

Zinc is helpful as I am hypothyroid and have a tendency to be low in zinc (it was tested). Circadin is helpful for sleep - it doesn't guarantee it mind. I still regularly struggle to nod off at times, I still wake up during the night every night though not as often as before. I still feel absolutely awful on waking.

Anything that improves quality of life is good but it's not that significant an improvement.

 

Havent read yet, but my first thought is that there is absolutely no way that Melatonin and zinc has an significant impact on ME functioning.

This paper can probably tell us a lot about how useless questionnaires are in ME research (without objective endpoints like actometer, school/work-attendance etc)

Its important we stay similarily critical of biomedical research (I feel we do that here, as the comments above me show)

If it stinks, its probably a dead fish

 

Not sure if related but zinc was pretty big in the LC community early on. I think it was mostly inspired by the early nonsense over HCQ, which was often used with zinc for some reason.

I doubt there is anything there.

 

It also looks like they didn't do an intention to treat analysis because they say they randomized 72 patients, but only analyse the results of 50.

Anyway, the results clearly show no meaningful differences between the two groups, even if the authors tried to search for them by analyzing all the subscales of their primary outcome at different time points. Yet they write:

The results clearly do not support this treatment advice. This shows that it is not only psychosomatic ME/CFS research that is problematic.

 

I agree that it looks like cherrypicking, and only a teeny tiny cherry at that.

I also agree that "perception of fatigue" is correct for the title. If they're not measuring actual physical or mental fatigue, their data is only people's self-judgements about perception of fatigue. ME doesn't seem to cause me abnormal physical fatigue, but I certainly perceive what feels something like fatigue.

 

Exactly, I´d say. Fatique is nothing that is perceived, as pain is not. It´s instead on the site of perception itself.

But they might have wanted to convey that there is no physical correlate for the fatique, and this thought would/could be right.

Being exact with terms though should be seen as a prerequisite for progress in any field of science.

 

Perhaps the title I suggested is the research they should have done i.e. actually study the effect of zinc and melatonin on fatigue itself, rather than the "perception of fatigue".

 

I don't think that is true when the medication is something really obvious like melatonin. But I agree with you all, that this is a weak result.

 

I tend to disagree cause that sort of what fatigue is: a perception. So I don't see the difference between fatigue and the perception of fatigue.

When it comes to measuring fatigue I think that questionnaires will be more accurate than surrogate measures like actigraphy. One can be really fatigued but still walk a lot (someone doing overwork with little sleep for example) while people with little to no fatigue can be too disabled to walk much (for example because they have other symptoms than fatigue that prevent them from doing much).

Perhaps you meant to emphasise that fatigue isn't an accurate measure of disability. In that case, I very much agree.

 

To be exact: no.

Its not, true, about physical lack of energy or so, say in the muscles, but about the sensory data. And these data are - as data of pain are - no self judgements, although only accessable via self-judgements (from the patients, and this will not be sidestepped in the nearer future, I am afraid).


In so far the term "mental fatique" is even more confusing as sensory data might be seen as "mental". But with "mental" then there must be only meant - for the sake of one to one relation - something comparable to e.g. muscles.

An exact title might be: "Effect ... on fatique sensory data." And sensory data are nothing which you can deny - you have them or you have them not.

This also illustrates pretty much the nonsense in psychosomatic medicine, when they want make the data to judgements, which indeed can be changed. Only that the sensory data do not obey.

 

No one can even agree on what the perception of fatigue actually is.

Is it an altered perception of effort? Is is unusual muscular pain or feeling of muscle stiffness? Is it unexpectedly poor performance when undergoing a task? Is it an unexpected feeling of weakness? Poor memory or word recall? Poor concentration? Or something else?

I agree that actigraphy on it's own is not sufficient, I'd advocate something JE suggested quite a while ago, the development of composite outcome measures that take into account baseline status, that rely on both PROMs and objective measures. That will cover the cases of people feeling less symptoms because they're doing less and people experiencing more symptoms because they're doing more.

 

You might see though the difference between a laugh and a perception of a laugh, as for sure some even would be keen of indeed.

But the machinery of immediate estimation of the ability to walk can be ill nevertheless, in so far it would be dangerous to rely on the physical ability.


The problem might be that e.g. psychosomatic medicine understands the term "perception of fatique" as a genitivus objectivus.

I have to admit that in the sense of a genitivus subjectivus it would apply to non-self-judgement-fatique in a reasonable manner.

Maybe one can write "Fatique-Perception", which would be different to a perceived fatique, which is in first place nonsense and possibly misleading and even dangerous.


Also a matter of difficulty is, that e.g. in Parkinson the fatique is sometimes and reasonably thought to arise from the dopamine system, which is sometimes and reasonably described as a machinery for judgement. But it´s (at least meanwhile) clearly not that self-judgement that can be influenced.

 

This comment seem to disregard the profound loss of function with ME

But please enlighten me