Review A Perspective on the Role of Metformin in Treating [...] (ME/CFS) and Long COVID (2025) Fineberg et al

[Utsikt]

I felt you implied it in your statement about how very obvious and logical it is to not over exert but it's not all that logical if over exerting isn't obvious or consistent.

But ok, I understand what you mean here.

The principles of pacing are very logical.

Answering the question of should I stop now or later is a different beast. You can attempt to devise rules, but because there doesn’t appear to be any extremely consistent patterns and PEM or just general symptom worsening due to fatiguability, etc. is a scale and not binary, it’s always going to be a trade off between attempting to avoid PEM/too uncomfortable or disabling symptoms and attempting to maximise FC/QoL within a very dynamic system.

In short: Understanding that you should pace in general is logical. Doing it is a nightmare.

 

[MelbME]

I’m sorry for missing that. But I don’t understand what «the reality of what people are doing» has to do with if it should be that way, which is what I’ve assumed we’re talking about?

Is there anything else you feel I’ve missed out on?

It’s getting late so I’ll come back to this sometime tomorrow.

Well what you and I agree on is what should happen in an ideal world.

What I'm trying to say in the world we are in there is already advice being circulated on treatments or management strategies to trial.

So at what point do you attempt to try sift through that advice to find better vs worse advice in the world that exists currently in an attempt to push it towards the better? Or as an idealist do you just ignore it all?

 

[Hutan]

We don't have good trial data and yet some medications already get recommended like LDN or advice is given like pacing or avoid PEM. Clinicians try many things on patients over the years but these stand out as getting ongoing positive feedback in ME/CFS and have even become mainstays in Long COVID treatment.

I think you are fundamentally misunderstanding what pacing is. As I think @Utsikt said, it's avoiding PEM. It's doing that so as to retain some ability to do things. By 6 months, pretty much everyone with ME/CFS will be pacing in some way. Giving up your Saturday tennis game is pacing. Giving up work or study, or working from home is pacing. Choosing to not have children is pacing. Moving in with your parents and having them deliver you your meals is pacing. Lying in a dark room with no sound is pacing. It's doing what is needed to not get worse. If you don't do less activity, you get worse, and so you end up being forced to do less activity.

That was the major flaw in the PACE trial - they supposedly trialled pacing, but almost all of the participants would have been already pacing, they would have found some balance between activity and rest that did not result in a worsening, and so we would not expect the 'pacing' treatment arm to show any benefits. Ridiculous imposed schedules as in the APT arm is not pacing.

So you don't think management strategies like pacing should be trialled? I mean without the PACE trial we'd probably have many more patients on GET. What if pacing is doing more harm than good longterm? We don't know and yet some advice you feel comfortable providing, why do you think that is?

Yes trialling is good but it's expensive and it hasn't been common for ME research to attract that type of funding.

I don't think pacing is something that can be ethically trialled. What would you do - force people to keep working 40 hours a week when it makes them worse? You would find that many people eventually just could not get out of bed. That's the essence of ME/CFS - activity results in an inability to continue to be active. Pacing is basically a voluntary reduction in activity, in order to not get to the point where you have no choice but to reduce activity (and feel horrendous).

Sounds like your position might be that without trailed treatments the clinicians should offer no advice or recommendations. The patient goes through the expense of diagnosis process and at the end are told that there is nothing they can try. Is that right?

Well, yes, regarding medications, if there is nothing that is likely to help. As others have said, there is still a lot of useful things that a doctor can do. The doctor has a lot of power to make it easier for people to pace, for example by assisting with applications for financial assistance. A lot of the problems we and other people with diseases have endured stem from doctors' inability to recognise and admit that they have no useful intervention to offer and to instead provide support.

But pacing is just common sense, it just means to avoid doing things that is usually followed by you feeling a lot worse for a long period of time.
We could probably trial not hitting yourself with a hammer as well, but at some point common sense has to be good enough..

Indeed.

Pacing isn't simply rest, that might be common sense. It usually requires some intervening information on how to do it. Most patients without advice on how to really do pacing will simply rest and then when feeling better they will be active again. Just listening to their body gets them in to trouble. Pacing is different. At least how I define it.

Maybe after resting and being active and getting PEM in ongoing cycles eventually teaches the patient, point of pacing as an intervention is to get the patient to the point of understanding to rest when they feel well and looking for warning signs far earlier than they would land naturally by self-learning.

That is a very patronising view of pacing - that people can't and don't work out things for themselves, that they have to have a clinician tell them how to do it. Virtually everyone can and does work things out for themselves. Personality and circumstances can make it harder for some people to do it than others of course. Where did you get this view of pacing as something that people require instruction in?

Too often pacing advice becomes overly complicated, wrapped up in complicated formulae for which there is no good evidence, focusing on the minutiae of scheduled 15 minute rests, and removing people's agency.

I don’t think we know enough about ME/CFS to justify a blanket ban. If some meds help some patients, they should be available off-label. Everyone has a different risk appetite, and that choice should be the patient’s, not imposed on them.

Some people report improvements of certain symptoms from prescription antihistamines. Afaik, they’ve never been trialled specifically for ME/CFS. In your view, would I not be allowed to request them from my doctor just because I don’t have hay fever? I'm not sensitive to medication and if I don't see an effect, I'll just stop taking them.

OC, no one is suggesting blanket bans. If people research something and want to try it, and find a doctor willing to prescribe it, well, good for them. But, that's not a reason to put speculative treatments in clinical guidelines.


I'm going to say it again, because it is so important. @MelbME, if the new Australian clinical guidelines contain recommendations for a range of unevidenced medicines and even things like salt loading, for which there is no good evidence of benefit (because you think people with ME/CFS need something, something to try to give hope, or for some other reason), then you and the guideline panel will have failed us.

Please have a good think about what each recommendation actually means for people with ME/CFS. You might recommend CoQ10 and think 'oh, it can't hurt'. But think about how much money people with ME/CFS will then spend on that supplement, how much time they will spend buying it, remembering to take the tablets with them when they travel, and getting up to take it. Think of the effort carers will go to make up the daily supplement collection, use scarce funds to buy it and give it to their loved one. Think of what doctors in a hospital will think of someone who comes in with their collection of supplements. Read our thread on CoQ10 and think about the evidence. If you are recommending CoQ10 for inclusion in the clinical guideline then I think you have not taken enough time to review the evidence.

Salt loading is not without risks - many people are recommended to reduce salt. And again, it's an imposition on lives that are already deeply constrained and difficult. Trying to follow these unevidenced strategies can make us appear to be odd hypochondriacs. You must be sure that each recommendation is worth the cost that will fall on people with ME/CFS, because, when you agree to those recommendations, you yourself are playing a part in imposing those costs on people.

Being on that committee is a substantial responsibility. To all the members, please be sure that you are putting an adequate amount of time to it to do a good job and are not simply going with ideas that have been around so long 'they must be right'.

 

[Kitty]

So at what point do you attempt to try sift through that advice to find better vs worse advice in the world that exists currently

You don't need to sift at all when there is only one management strategy, which is the case here: pacing is the sole management tool available to prevent deterioration. Nothing has been shown to produce improvement yet, so our objective is to preserve what function we have.

As @Utsikt said, the difficult bit is doing it. It isn't difficult to understand.

[Edited to add quote]

 

[Hutan]

No management with medications that haven't been trialled in that disease? No pain meds? Nothing that hasn't gone through clinical trials for that disease?

If people have pain, doctors know how to provide pain relief. If people have insomnia, doctors have some ideas on how to treat it (some of which may be good, some probably not good).

It is enough to say that if people with ME/CFS have symptoms such as debilitating pain or insomnia, use standard strategies to treat them. A clinical guideline on ME/CFS does not need to go into detail.

 

[Holinger]

I don’t think a guideline should point to a particular therapy without decent evidence of safety and efficacy. But the worst possible outcome would be for a doctor or guideline to ban doing anything for a severe long term patient where there is no hope and death is likely. Trying a drug therapy is the only hope realistically of shifting something. I get the impression from others experience that a cns stimulant might fall under this rationale for some but very few patients. This kept someone I know likely alive.

 

[OrganicChilli]

OC, no one is suggesting blanket bans. If people research something and want to try it, and find a doctor willing to prescribe it, well, good for them. But, that's not a reason to put speculative treatments in clinical guidelines.

It read to me as if in Utiskt's ideal and imo highly restricted world my doctor would discourage or prevent me from trying off-label drugs if they haven't been trialled specifically for ME/CFS, but perhaps I misunderstood.

 

[MelbME]

If people have pain, doctors know how to provide pain relief. If people have insomnia, doctors have some ideas on how to treat it (some of which may be good, some probably not good).

It is enough to say that if people with ME/CFS have symptoms such as debilitating pain or insomnia, use standard strategies to treat them. A clinical guideline on ME/CFS does not need to go into detail.

This is all that I'm saying though.

I think I already said this early but I'm not talking about guidelines here or at any point during this thread.

I don't know why you keep bringing it up? Perhaps you missed it when I replied to you at beginning of thread.

This discussion has nothing to do with Australian guidelines, the discussion is a disagreement between myself and Utsikt/Jo Edwards around whether GPs should try a treatment on a patient without it being clinically trialled in that population previously.

I think we agree ideally but I'm saying in real practice you have GPs prescribing all sorts of medications and interventions to patients that haven't been trialled in that population.

 

[MelbME]

You don't need to sift at all when there is only one management strategy, which is the case here: pacing is the sole management tool available to prevent deterioration. Nothing has been shown to produce improvement yet, so our objective is to preserve what function we have.

As @Utsikt said, the difficult bit is doing it. It isn't difficult to understand.

[Edited to add quote]

Right, but based on what I understand from others in this thread, nothing should be promoted by GPs for ME/CFS as no trial has proven that anything works yet, not even pacing. This rule extends to comorbidities like POTS that also don't have clinical trials on even the base treatment strategies recommended by all specialists treating these patients.

I think some in the thread say Pacing isn't a treatment strategy either, it's logical and intuitive. In that case it shouldn't be recommended by GPs either as people already just do it. I think Hutan even suggested it's patronizing to try train people to pace as a treatment strategy.

This is at least my understanding of what is being discussed here. I don't disagree in the ideal world but in that ideal world people have done the trials. What our source of disagreement is that I think in the real world we are now they haven't done these clinical trials but there is a large population of clinicians in agreement that pacing strategy works for ME and salt/water/compression helps POTS. I'm arguing that this sort of recommendation has a weight of experience behind it even though there has not been robust clinical trials.

 

[MelbME]

If people have pain, doctors know how to provide pain relief. If people have insomnia, doctors have some ideas on how to treat it (some of which may be good, some probably not good).

It is enough to say that if people with ME/CFS have symptoms such as debilitating pain or insomnia, use standard strategies to treat them. A clinical guideline on ME/CFS does not need to go into detail.

Yes I agree with this. I think maybe you're missing the context of my discussion with Utsikt.

They propose that what a doctor thinks they know isn't actually true if a robust clinical trial hasn't been trialled in that patient population to prove that treatment does actually help these symptoms.

Though I've found the position confusing as we seem to disagree on a few terms and it appears maybe it's not a hard and fast rule for all interventions. @Utsikt maybe you can clarify?

 

[MelbME]

I'm going to say it again, because it is so important. @MelbME, if the new Australian clinical guidelines contain recommendations for a range of unevidenced medicines and even things like salt loading, for which there is no good evidence of benefit (because you think people with ME/CFS need something, something to try to give hope, or for some other reason), then you and the guideline panel will have failed us.

Not sure who you are referring to when you say 'fail us' but I only have one vote amongst 20+ others. And this is just to vote on a a recommendation to someone who may not even listen to us. The guidelines committee doesn't have the influence to be solely responsible for the outcome, one individual really has no chance to influence it all and it's a process designed to be that way to avoid bias.

They have details on this process publicly somewhere. But I'm also not able to discuss the advice or outcomes in any specifics.

I know it clearly matters a great deal to you and I'm sure you'd love to be able to write the guidelines yourself. I also hope for a good outcome.

 

[Jonathan Edwards]

That's not just the rhetoric of therapist professionals, that's the advice of standard GPs who don't know enough about the condition.

Who have been indoctrinated by the rhetoric of therapist professionals - including the rehabilitation physicians who may have trained them directly.

And anyway this is non-sequitur. The point is that this is not common sense, it is the mantra of old fashioned physical medicine carried over because nobody is prepared to admit they don't know what they are doing when it comes to ME/CFS.

No they go in to specializing ME/CFS because they usually know someone with the condition and want to help the many without help. It's far easier to be a standard GP.

@MelbME, I have worked amongst these people all my life. I could give you the names of half a dozen physicians who trained in my department who went into this sort of practice, out of a total of maybe a hundred. I will not say more but 'wanting to help' is not a virtue if you have no idea what you are doing.

Pacing is not the default recommendation for ME/CFS by GPs, it's the default of GPs that are ME/CFs literate (which is rarer).

That has nothing to do with what I said. We aren't going to get far if you misread everything people say. Pacing is what you end up with if you do not follow a specific treatment regimen. It is just coping. What do you use as a control to test that? There isn't one.

 

[Jonathan Edwards]

What do you mean provide support and advise? What does that look like?

It sounds as if you have no idea what being a doctor is about @MelbME. What does a mother do when I child is ill - she provides support and advice. It is probably the most important and rewarding activity humans have available to them - looking after each other. For a patient with hronic disease it is largely just knowing that somebody is there to talk to. When I started in medicine most chronic diseases were untreatable. We provided support.

And we followed Hippocrates' first do no harm.

No management with medications that haven't been trialled in that disease? No pain meds? Nothing that hasn't gone through clinical trials for that disease?

You are twisting things. Lots of medications are licensed for use in many situations having been through trials that provide data that can reasonably be extrapolated to any underlying condition. That is standard for analgesia. But sure, no medications that have not been trialled in a relevant situation. Medicines like naltrexone, fludrocortisone or metformin are not benign. Children pick them up by mistake and die apart from anything.

 

[Jonathan Edwards]

So at what point do you attempt to try sift through that advice to find better vs worse advice in the world that exists currently in an attempt to push it towards the better?

Look at the reality. I was recently on a government working group looking at research for ME/CFS that might be worth doing. Trials of drugs were specifically flagged as a top priority option. So eveyone agreed that it made sense to recommend trials of promising looking drugs - which more or less by definition would be re-purposed from other contexts.

We sat several times over about two years. But nobody could come up with a drug that they even thought was worth considering because nobody could see any meaningful reason to think they would work. The one drug we agreed might be worth a trial was naltrexone, but essentially on the basis that there had been so much debate about it that it would be worth doing a trial to be sure that it didn't work.

This is a committee of about thirty people with all sorts of relevant interests - patients, physicians, scientists, carers, - most of the well known names in ME/CFS advocacy in the UK. Nobody could think of anything they thought was really going to work.

 

[EndME]

This is at least my understanding of what is being discussed here. I don't disagree in the ideal world but in that ideal world people have done the trials. What our source of disagreement is that I think in the real world we are now they haven't done these clinical trials but there is a large population of clinicians in agreement that pacing strategy works for ME and salt/water/compression helps POTS. I'm arguing that this sort of recommendation has a weight of experience behind it even though there has not been robust clinical trials.

Whose weight of experience? There are plenty of people with weight of experience that claim ME/CFS should be treated with CBT/GET. Should their experience be neglected even if they have seen more patients and have a much higher scientific pedigree than anybody that swears on LND (take for example Sir Simon Wessely - h-index 156, knighted, president of the Royal College of Psychiatrists, President of the Royal Society of Medicine etc). I think everbody has to quickly see that these approaches lead nowhere because they either include "everything" or only include "things that I specifically enjoy".

I think the discussion on “ideal world” vs “what we can do now” misses a whole lot of context. You mentioned drugs like LDN or other drugs in the Long-Covid field which clinicans feel are promising but unfortunately lack clinical evidence due to a lack of trials. I think it should be very clear that these “feelings” tend to mean very little. Firstly the drug in the Long-Covid that most clinicans felt was most promising was Paxlovid, which has now very clearly failed in clinical trials. Even something like LDN which is hyped and “felt to be highly effectivity” much more in the field of Fibromyalgia than Long-Covid or ME/CFS, has already yielded a negative trial result in Fibromyalgia. Other clinicans had also already sworn on Rituximab prior to the study having negative results. It is clearly not just a matter of "unfortunately the resources haven't been there to do trials".

It sometimes feels like this talk of “ideal world” vs “what we can do now” is just an excuse for people to prescribe things without having to do rigorous scientific work. I know you’re currently trialling medications in your LIFT trial, which is highly appreciated and clearly shows that you’re not using any excuses. But I think this new approach of “off-label treatments” in the Long-Covid and ME/CFS field will be very much to the detriment of patients in the long run. Especially because any sensible person can see that the “off-label treatments” can’t all be working simultaneously due to their mechanisms of action (there's no way Paxlovid vs LDN vs Abilify vs Immunadsorption vs Metformin are all working). So any sensible person can only think that these people don't have anything worth caring about if you can just satisfy them with nonsense.

Others have already mentioned that drugs for pain, insomnia ect can be treated via the standard strategies, one doesn't have to do much more than that on that aspect. If there are situations where more can be extrapolated that also deserves mention, but I think we're all to often seeing things extrapolated out of thin air.

(Btw thanks a lot for engaging @MelbME, I know this conversation cannot be easy!)

 

[Jonathan Edwards]

They propose that what a doctor thinks they know isn't actually true if a robust clinical trial hasn't been trialled in that patient population to prove that treatment does actually help these symptoms.

Which is the bedrock of responsible medicine. But note that 'that patient population' need not be a specific disease. It can be all people with pain.

We are back to Richard Feynman's 'the easiest person to fool is yourself'. A good doctor learns that early on. Some don't.

 

[MelbME]

It sounds as if you have no idea what being a doctor is about @MelbME. What does a mother do when I child is ill - she provides support and advice. It is probably the most important and rewarding activity humans have available to them - looking after each other. For a patient with hronic disease it is largely just knowing that somebody is there to talk to. When I started in medicine most chronic diseases were untreatable. We provided support.

And we followed Hippocrates' first do no harm.


You are twisting things. Lots of medications are licensed for use in many situations having been through trials that provide data that can reasonably be extrapolated to any underlying condition. That is standard for analgesia. But sure, no medications that have not been trialled in a relevant situation. Medicines like naltrexone, fludrocortisone or metformin are not benign. Children pick them up by mistake and die apart from anything.

I do understand but I'm guessing we disagree on what constitutes the term treatment. I was asking the questions to better understand what you meant.

Children also die from picking up analgesia so I'm not sure if that example is necessary.

But I get your point on analgesia having trials that can be used across diseases. LDN has pain relief properties though I don't know of proper trials exist in fibro for it.

 

[MelbME]

Which is the bedrock of responsible medicine. But note that 'that patient population' need not be a specific disease. It can be all people with pain.

We are back to Richard Feynman's 'the easiest person to fool is yourself'. A good doctor learns that early on. Some don't.

I agree that it's the bedrock of responsible medicine. I just think there is more nuance when many clinicians report similar value in similar drugs globally for this population yet there haven't been proper clinical trials conducted because of funding. Especially because there is worse forms of advice for treatments with higher risk profiles or indications of making patients worse as a whole. I worry about the void of options giving a free way to worse options.

 

[MelbME]

Whose weight of experience? There are plenty of people with weight of experience that claim ME/CFS should be treated with CBT/GET. Should their experience be neglected even if they have seen more patients and have a much higher scientific pedigree than anybody that swears on LND (take for example Sir Simon Wessely - h-index 156, knighted, president of the Royal College of Psychiatrists, President of the Royal Society of Medicine etc). I think everbody has to quickly see that these approaches lead nowhere because they either include "everything" or only include "things that I specifically enjoy".

I think the discussion on “ideal world” vs “what we can do now” misses a whole lot of context. You mentioned drugs like LDN or other drugs in the Long-Covid field which clinicans feel are promising but unfortunately lack clinical evidence due to a lack of trials. I think it should be very clear that these “feelings” tend to mean very little. Firstly the drug in the Long-Covid that most clinicans felt was most promising was Paxlovid, which has now very clearly failed in clinical trials. Even something like LDN which is hyped and “felt to be highly effectivity” much more in the field of Fibromyalgia than Long-Covid or ME/CFS, has already yielded a negative trial result in Fibromyalgia. Other clinicans had also already sworn on Rituximab prior to the study having negative results. It is clearly not just a matter of "unfortunately the resources haven't been there to do trials".

It sometimes feels like this talk of “ideal world” vs “what we can do now” is just an excuse for people to prescribe things without having to do rigorous scientific work. I know you’re currently trialling medications in your LIFT trial, which is highly appreciated and clearly shows that you’re not using any excuses. But I think this new approach of “off-label treatments” in the Long-Covid and ME/CFS field will be very much to the detriment of patients in the long run. Especially because any sensible person can see that the “off-label treatments” can’t all be working simultaneously due to their mechanisms of action (there's no way Paxlovid vs LDN vs Abilify vs Immunadsorption vs Metformin are all working). So any sensible person can only think that these people don't have anything worth caring about if you can just satisfy them with nonsense.

Others have already mentioned that drugs for pain, insomnia ect can be treated via the standard strategies, one doesn't have to do much more than that on that aspect. If there are situations where more can be extrapolated that also deserves mention, but I think we're all to often seeing things extrapolated out of thin air.

(Btw thanks a lot for engaging @MelbME, I know this conversation cannot be easy!)

I haven't seen anything promising from Long COVID.

The treatments I think have strongest weight of evidence amongst majority of clinicians with least risk (though without trials) are pacing for ME, LDN for Fibro, salt/water for POTS.

 

[Jonathan Edwards]

I just think there is more nuance when many clinicians report similar value in similar drugs globally for this population yet there haven't been proper clinical trials conducted because of funding.

I have lived my life amongst these clinicians. There is no nuance that I can see. There is simply fashion.Even with drugs backed up by trials like methotrexate for RA everyone shifted because it was the fashion. It turned out to have the lowest complete remission rate of all available treatments. Nighttime amitriptyline became fashionable through what are now seen to be pretty dubious trials. Clinicians swear by it by the patients I see say it doesn't work.

The void for RA was never a problem because people knew they were being believed. The problems for ME/CFS stem from other things - being dismissed or patronised.