Scientific Studies Showing Serious Adverse Effects from GET?

[A.B.]

Don't forget the high rates (drop outs) patiënts who stop with the therapy because it is to heavy.

The high drop out rates are very curious indeed. The research tends to accentuate the positive and seems unconcerned about the negative. Do we even know why patients stop?

 

[barbc56]

Do we even know why patients stop?

That's an interesting question. Do any studies even do this?

What about studies on medications? They do list side effects but is there any information if the side effects caused anyone to drop out?

I would think you could get valuable information if studies did this.

 

[barbc56]

This isn't a prmary empirical study, but its at least a published source that discusses the reports of risk, and considers the possible basis of the effect

If you don't already know, there's a lot of controversy with Maes. Most of his "studies" turn out to be opinion pieces where some of his conclusions are questionable.

Many scientist doing very good research do not consider him a credible source and I agree with this assessment.

Barb

 

[biophile]

http://www.jpsychores.com/article/S0022-3999(14)00188-3/fulltext

Looking at the paper Bob posted, CBT and GET didn't show more deterioration when defined as the opposite of improvement.

CBT showed the least deterioration and APT showed the worst physical function deterioration.

A niggling problem with these scores is how CBT and GET teaches the re-interpretation of symptoms and disability. If biases in subjective measures over-estimate modest improvements, you can be sure they also under-estimate modest deterioration. APT also had an ambiguous 70% rule, which may have impacted on the reporting of physical function. From the other papers it doesn't seem like the APT group became (significantly) less active or more deconditioned or walked less etc.

Re dropouts: IIRC, the dropout rate was relatively low, but dropouts were excluded from some analyses despite claims to have used intention to treat? Anyway, keep in mind that this was already a highly pruned Oxford criteria cohort which only represented 20% of all the candidates. A decent proportion of those excluded couldn't comply with the protocol or refused randomization or assessment (the most common reason for refusal was a strong treatment preference). It's probably safe to say that "a clear preference for a specific PACE trial treatment" usually meant pacing and avoiding CBT/GET.

Again, PACE showed that encouraging exercise, without actually maintaining it, seems relatively "safe" in a highly pruned Oxford criteria cohort. No evidence to show that *sustained* increases in exercise and/or total activity levels are safe. It seems that patients encouraged to do more maybe test the waters but probably realize that they were already at their limit.

 

[lansbergen]

If you don't already know, there's a lot of controversy with Maes. Most of his "studies" turn out to be opinion pieces where some of his conclusions are questionable.
Many scientist doing very good research do not consider him a credible source and I agree with this assessment.
Barb

I always found Frank Twisk a reliable source.

 

[MeSci]

Can someone post a list of randomized scientific studies showing serious adverse effects from GET, as compared to a control group? By "scientific study", I mean something peer reviewed and published in the scientific literature. By "randomized" I mean a study where one group got GET and other group(s) got other treatments or even no specific treatment, and then numbers of SAEs were compared for the different groups.

If there is nothing for serious adverse effects, but something for adverse effects, then I'd be interested in the studies showing adverse effects.

I'm not interested in marketing style surveys, unless they were done on comparative groups that got GET and didn't get it. I'm also not interested in letters to the editor, or other reports which are not published (in the scientific sense) or not peer reviewed.

I thought there would be a list somewhere, but I haven't found it.

Joshua Levy

This may not be what you want, but here is what I found from a PubMed search for 'exercise' and 'chronic fatigue' in the title and 'adverse' in the title or abstract.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106394/

a small study which found no adverse short-term effects, but it says:

"...people with MS or CFS were excluded if they had experienced exacerbation of their symptoms in the 3 months prior to the study..."

http://www.ncbi.nlm.nih.gov/pubmed/24528544

another small, 'double-blinded' (with regard to pain relief) study which looked at pain after exercise (again short-term).

http://www.ncbi.nlm.nih.gov/pubmed/21304571

A meta-analysis

and the PACE crap.

I tried replacing 'chronic fatigue' with 'myalgic' and only got PACE.

 

[MeSci]

That's an interesting question. Do any studies even do this?

What about studies on medications? They do list side effects but is there any information if the side effects caused anyone to drop out?

I would think you could get valuable information if studies did this.

I think I have read a lot of studies or other reports on pharmacological interventions where reasons for dropout are given. I think I have also seen this in other types of research but can't be 100% sure without checking.

I just tried a quick PubMed search for examples, but came across this review of clinical trials which says that a lot of them don't report (adequate) info about dropouts and missing data.

I seem to have omitted the link. I think this is it.

 

[Valentijn]

Maybe someone mentioned this, but I missed it:

SAE's were defined so narrowly in PACE that people had to basically end up deathly ill in the hospital and/or be severely disabled for at least a month (or two?) to qualify as having experienced an SAE. Hence most episodes of PEM would not qualify as SAE's, even if someone was bedbound for weeks as a result.

The application of GET, according to the therapist manual, was also not traditional GET, but rather based on symptoms. Hence for patients reacting adversely to increased activity, activity would be scaled back until they stopped having symptoms in response to activity. So for the ME patients in the study, GET would have been little different from pacing, aside from the guilt-tripping and promises of a miraculous recovery.

So at the end of the day, PACE generally tells us nothing of use in forming any conclusions about anything

 

[MeSci]

Just found this. It's a review.

J R Soc Med. Oct 2006; 99(10): 506–520.

doi: 10.1258/jrsm.99.10.506

PMCID: PMC1592057

Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review

Duncan Chambers,1 Anne-Marie Bagnall,2 Susanne Hempel,1 and Carol Forbes1

It says:

In the RCT of patient education to encourage GET, 21 of 148 patients (14.1%) entering the trial withdrew; 19 of these were in the groups randomized to GET, but the reasons for withdrawal were not reported clearly enough to be sure how many were attributable to adverse events.

It also says:

Our review did not find any new evidence of adverse effects (sufficient to cause withdrawal from treatment) associated with GET or CBT. However, reasons for withdrawals were often poorly reported and should be investigated in more detail in future studies.

I guess White et al didn't read it...

 

[worldbackwards]

"...people with MS or CFS were excluded if they had experienced exacerbation of their symptoms in the 3 months prior to the study..."

What, any? At all? Do they know what this is?

 

[Dolphin]

That journal did require peer review, but I think it has since closed.

Yes, that's correct:

http://www.iacfsme.org/BulletinArchives/tabid/309/Default.aspx
The Bulletin of the IACFS/ME is a peer review online journal that was published by IACFS/ME from 2005-2012. It set the stage for, and has now been superceded by, our new journal, Fatigue: Biomedicine, Health & Behavior.

Although it wasn't a PubMed-listed journal, 2 papers from this journal are listed on PubMed:

Bull IACFS ME. 2008 Fall;16(3):19-33.
Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS).
Torres-Harding S1, Sorenson M, Jason LA, Maher K, Fletcher MA.
http://www.ncbi.nlm.nih.gov/pubmed/21234277

Bull IACFS ME. 2009;17(3):88-106.
CFS: A Review of Epidemiology and Natural History Studies.
Jason LA, Porter N, Brown M, Anderson V, Brown A, Hunnell J, Lerch A.
http://www.ncbi.nlm.nih.gov/pubmed/21243091

This facility to upload to PubMed peer-reviewed papers from non-PubMed-listed journals in this way is only available to NIH-funded researchers to the best of my knowledge

 

[alex3619]

We have been looking at direct harm from GET and CBT. In the psych literature they discuss three types of harms.

The first is direct, as in showing how a patient responds.

The second is indirect, what is called opportunity cost. Patients could be doing something better.

The third is credibility cost. The profession can be undermined, both generally and with respect to patients. Its about loss of trust. Such loss of trust can induce an opportunity cost as well.

We all know that the third type is weighing heavily on the psychogenic therapies - they have no credibility for many of us, and indeed for many of the general public, scientists, doctors etc. The backlash against DSM-V is an example of this type.

 

[joshualevy]

Those who think its harmful may have ethical obligations to not pursue this kind of study. Those who think its not harmful may not design a study rigorous enough to detect the problem.

I wanted to put in some general responses, but especially to this quote.

This applies to all research, not just ME/CFS or PACE! All researchers think that the treatments they are testing are good, and if this were a serious problem, there would be no data on SAEs for anything! It's not a common problem for two reasons: 1. editors, publishers, and researchers in general know that SAEs are very important, and so therefore they know that papers without them are second class. 2. The FDA requires SAEs for approval. So if your treatment gets that far, and your phase-III trials don't include SAE discussion, it will all be wasted. The FDA will not approve. Reason #1 tends to put SAE discussion for phase-I and phase-II trials, and #2 tends to put it in phase-III trials (to a lessor degree phases-I and II).

Someone said that PACE defined SAEs badly. I don't think that is an option. In the US, at least, it is a federal standard what an SAE is. I know PACE was UK, but all US studies use a similar definition, based on the federal one.

For my part, I see SAE or AE in almost all studies I read (in non-ME/CFS areas), but usually it is just two sentences. Something like: No significant difference was seen between the groups in SAEs. The treated group had more AEs, but these were minor and included rash around the injection site (or whatever).

I think the overall drop out rate is a good measure of patient happyness in shorter studies. Most studies I read do not discuss why someone drops, but the few that did basically found these reasons:
* For long studies, moving away from the trial center often caused drop out.
* For studies with repeated treatments, AEs often caused drop out.
* The studies that I look at rarely have SAEs, but I assume when these happen they often cause drop outs.

I was just looking at a clinical trial for type-1 diabetes. It had two outpatient surgeries to start, lasted a year, had two 10 person groups, and was not blinded. They reported that one person dropped from the treatment group, because they moved away, one from the untreated group ("lack of motivation"). Also, two people dropped from the untreated group after randomization, but before start of trial. (No reason given, but it sounds like "we're know we're not being treated so why bother"). As compared to PACE, this trial had 10% drop out, for a 1 year trial.

Joshua

 

[Dolphin]

I wanted to put in some general responses, but especially to this quote.

This applies to all research, not just ME/CFS or PACE! All researchers think that the treatments they are testing are good, and if this were a serious problem, there would be no data on SAEs for anything! It's not a common problem for two reasons: 1. editors, publishers, and researchers in general know that SAEs are very important, and so therefore they know that papers without them are second class. 2. The FDA requires SAEs for approval. So if your treatment gets that far, and your phase-III trials don't include SAE discussion, it will all be wasted. The FDA will not approve. Reason #1 tends to put SAE discussion for phase-I and phase-II trials, and #2 tends to put it in phase-III trials (to a lessor degree phases-I and II).

Someone said that PACE defined SAEs badly. I don't think that is an option. In the US, at least, it is a federal standard what an SAE is. I know PACE was UK, but all US studies use a similar definition, based on the federal one.

This is true for drugs and devices. However, other types of non-pharmacological approaches such as exercise regimes or psychological interventions don't require FDA approval.

 

[Gingergrrl]

I can't speak for the UK but in the US, the pharmaceutical lobby has an unbelievable amount of political power with both parties. A drug can have significant adverse events but still make it through the FDA and remain on the market. If anyone doubts this, read Bitter Pills by Stephen Fried. The PACE trial is meaningless IMO b/c politics won out over science.

 

[Countrygirl]

I have only glanced at this thread, but as I had just read this I thought I would post it here.

http://niceguidelines.blogspot.co.uk/2011/03/pace-trials-prof-peter-white-exercise.html

PACE trial's Prof Peter White: Exercise causes Immunological damage in Chronic Fatigue Syndrome and is NOT safe

Prof Peter White, Prof A. J. Pinching, et al:

The main finding of this pilot study was the elevated median concentration of transforming growth factor beta, which seemed to be related to activity. We also found significantly fewer CD3+ and CD4+ lymphocytes and fewer expressing HLA DR, but there was no difference between groups in response to exercise, but no importance should be attached to this in view of the small numbers of subjects in this study.

Finally, we found that exercise induced a sustained elevation in the concentration of TNF-α, which was still present three days later, and this only occurred in CFS patients.

TGF-β was grossly elevated when compared to controls before exercise, and showed no differential response to exercise, but did show an increase in response to the exercise entailed in getting to the study center.

These data replicate three out of four previous studies finding elevated TGF-β in subjects with CFS (6, 7, 9, 10).

These preliminary findings require replication in a larger single blind case-control study before we can judge their significance, particularly since we were aware of case-control status for some subjects.

These preliminary data suggest that “ordinary” activity (i.e., that involved in getting up and traveling some distance) may induce anti-inflammatory cytokine release (TGF-β), whereas more intense exercise may induce pro-inflammatory cytokine release (TNF-α) in patients with CFS (21, 28, 29).

The causal mechanisms involved and the direction of the relationship between these mechanisms remain to be elucidated. Altered cytokine balance, for example, following an infection, may modify the threshold at which cytokine release occurs with exercise or activity, setting up a vicious circle. These processes could contribute to the postexertional
malaise, myalgia and the central fatigue that characterize CFS (1, 2, 4). Future studies should study patients at truly resting baseline levels, over a longer time-course, and should examine gene expression of cytokines, as well as circulating levels (17).

My note: nothing of this sort was done in the BOGUS PACE trial yet this study and the PACE trial were done by Prof White !!
So this study clearly showed that GET is harmful, yet pacing is not !!

Also, why did the PACE trial NOT check any cytokines in their so called CFS patients ? Too many vested interest at stake so it seems ...

Read full study

Sadly, the paper seems to have disappeared from the 'net'.

 

[MeSci]

I have only glanced at this thread, but as I had just read this I thought I would post it here.

http://niceguidelines.blogspot.co.uk/2011/03/pace-trials-prof-peter-white-exercise.html

Sadly, the paper seems to have disappeared from the 'net'.

I did some searching. The abstract for the cited study is still in the ME Research UK database of research abstracts.

A recent paper in similar vein is discussed here.

 

[Esther12]

I have only glanced at this thread, but as I had just read this I thought I would post it here.

http://niceguidelines.blogspot.co.uk/2011/03/pace-trials-prof-peter-white-exercise.html



Sadly, the paper seems to have disappeared from the 'net'.

I did some searching. The abstract for the cited study is still in the ME Research UK database of research abstracts.

A recent paper in similar vein is discussed here.

It looks like this is the paper:

http://www.researchgate.net/profile...ilot_Study/links/0deec529d945499349000000.pdf

 

[MeSci]

It looks like this is the paper:

http://www.researchgate.net/profile...ilot_Study/links/0deec529d945499349000000.pdf

That link seems to require registration. This one (from the thread I linked to) doesn't.

EDIT - Oh, I see - yours is the White one.

 

[Woolie]

Hi @MeSci, the paper you posted looks to be very carefully done, and being a review, is eligible for inclusion in things like wikipedia pages. But that would depend on the source. I don't suppose you know where it was published?