PACE trial for chronic fatigue syndrome (still) being put through its paces: a reply

I'm bringing the paper published by Michael Sharpe and colleagues [1] to your attention today in the interest of balance and peer-reviewed 'right to reply'.

The Sharpe paper concerns the PACE trial, the study which reported that "when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS [chronic fatigue syndrome], than both adaptive pacing therapy and specialised medical care alone."

Anyone with a little bit of knowledge about the PACE trial will know that it's a 'contentious' topic within CFS (and ME, myalgic encephalomyelitis) circles. Indeed, the Sharpe paper comes about as a direct result of a reanalysis paper (see here) which reported findings raising "serious concerns about the robustness of the claims made about the efficacy of CBT [cognitive behavioural therapy] and GET [graded exercise therapy]" in the context of CFS/ME. 'Serious concerns' is putting it mildly considering how others have described the PACE trial and some of its tenets (see here).

Sharpe et al, who were authors listed on the original PACE trial paper [2], have had to defend their work/findings before in the peer-reviewed realm (see here). Same as before, the name Carolyn Wilshire is addressed and her teams reanalysis of the PACE trial data [3]. Said data was, I might add, (partially) released only following intervention from the Information Commissioners Office (ICO) here in Blighty (see here). More recent events have similarly reiterated that 'access to raw study data' is something that CFS/ME researchers perhaps need to bear in mind at study conception (see here).

I'm not going to clinically dissect the Sharpe paper in this post because (a) 'interpretation' forms quite a bit of the reply to the Wilshire reanalysis, and (b) your opinion on the scientific quality of the Sharpe reply is most likely going to be shaped by where you stand in terms of the whole CBT/GET for CFS/ME discussion. Indeed, a peer-reviewer of the Sharpe paper also said as much (see here). What I will comment on is how the Wilshire reanalysis paper and the more recent Sharpe reply to the reanalysis paper might further inform research more generally with CFS/ME in mind.

Oh, and it's probably just a coincidence that the Sharpe paper comes out only days after a news headline reads "Online activists are silencing us, scientists say" talking about a familiar topic.

So:

• Point 1: Design a good trial analysis plan and stick to it. From my 'outsider looking in' perspective, the changes made to "the scoring of the pre-specified outcomes" regarding fatigue and physical functioning in the PACE trial, however innocent they might have been, have created tension. Lots of tension. Such changes, whether agreed by "Trial Data Monitoring and Steering Committees" or not, can be construed in various different ways. It's better not to make such changes in the first place.
• Point 2: If you are going to study something like physical functioning in relation to CFS/ME, don't just rely on things like questionnaires and Likert scales; use actigraphy too. Self-report is always a good thing but I've never understood why, with the wide range of cost-effective technology out there (available I believe, even in the early 2000s), wearable trackers such as pedometers or similar were not also utilised during such studies (see here). If you're spending £5 million on a trial, a few quid for some pedometers is not exactly going to break the bank and will inevitably bring some further quality data to the table.
• Point 3: Recovery. As per other discussions (see here), most people would characterise recovery as a complete remission of symptoms and/or return to typical functioning. If you're not going to use this description, don't use the word recovery. Use something else instead. Indeed, use 'partial remission' or 'improvement' if you need to but don't call anything less than the complete remission of symptoms 'recovery'.
• Point 4: Long-term outcomes. It's probably best to avoid any sweeping statements after the arms of a trial - a "randomised trial" not necessarily a "randomised controlled trial" according to Wilshire et al - have been completed. More so when you're measuring such long-term outcomes via a postal question minus any objective measure(s) (see point 2). It's probably also a good idea to ask patients about their quality of life too and whether that has changed (see here).
• Point 5: Even if your paper states in no uncertain terms that: "The effectiveness of behavioural treatments does not imply that the condition is psychological in nature" the use of something like CBT for CFS/ME implies that you probably think there is a substantial psychological 'component' to the condition. This is compounded when you're for example, a Professor of Psychological Medicine. If you were pitting CBT in particular against a specific pharmacological or biological intervention 'for CFS/ME' (see here for example), I'd be more inclined to see your view in a more 'rounded sense'. Indeed, if you were to study one or two biological parameters as well as behavioural ones looking for any change following intervention, you might convince more people that psychology is not the primary line you take. And whilst on the topic of psychology and CFS/ME, it's probably also best not to use 'psychobabble' terms like 'deconditioning' in your research. Such terms are pretty much scientifically untestable and, given the recent discussions about the legacy of some adherents to something like psychosomatic research (see here), is likely to be consigned to the scientific dustbin as some later point.

I think I've covered the main points as I see them. Please feel free to agree/disagree as you wish.

End of Line.

Addition: 26 March 2019. Not quite 'End of Line' it seems, as a reply to a reply to a reply emerges [4]. Peer reviewed science is far from slow...

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[1] Sharpe M. et al. The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al. BMC Psychology. 2019; 7: 15.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377(9768):823-36.

[3] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[4] Wilshire CE. & Kindlon T. Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings. BMC Psychology. 2019; 7: 19.

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"Having accessed treatment was associated with reporting lower levels of work/school attendance"

I have to admit that I did a bit of a double-take when I came across the quote titling this post - "Having accessed treatment was associated with reporting lower levels of work/school attendance" - in the paper published by Sheila Ali and colleagues [1] (open-access available here).

The findings came from a study that set out to investigate the "factors associated with fatigue, disability and school attendance in young people with severe CFS/ME [chronic fatigue syndrome/myalgic encephalomyelitis]." Part of the study also looked (in a preliminary manner) at whether some of the therapeutic options offered 'for ME/CFS' were up to scratch based on participants' responses and views.

"Questionnaire data were collected in two waves: at baseline (T1), and at follow-up (T2), which was 3–9 months later" as such data were collected from 51 young people "required to have a self-reported diagnosis of CFS/ME." Researchers mention how they focused on participants with "severe CFS" as measured by a self-report 'functional ability scale'. That being said, recruitment phases for the Ali study were not uniform, as two different thresholds for severity were eventually used in different recruitment phases.

No mind, Ali et al asked participants to complete various questionnaires around things like mobility, meaningful education and/or work (including attendance), and level of fatigue. Bearing in mind the use of words like 'fear avoidance' in the Ali paper (possibly denoting the biopsychosocial (BPS) 'sway' of some of the authors), various 'psychological' concepts were also included for study. The data were collated and analysed.

Results: although data for 51 participants were eventually analysed, nearly 400 young people were sent a letter inviting them to participate in the Ali study. Only 56 responses (consent forms and questionnaires) were eventually received which, even taking into account the 'severe CFS' inclusion criteria, represents a pretty low study turnout. This seems to follow a trend among certain types of study of ME/CFS (see here) which is starting to become quite noticeable.

"Thirty-seven (72.5%) participants reported using assistive equipment such as crutches, walking frames, ramps, stair-lifts and shower chairs. Thirty-three participants (64.7%) reported that they used a wheelchair. Nine participants (17.6%) reported that they were bed-bound." Contained within those sentences is the real cost of ME/CFS to something like mobility. On top of all that, researchers also observed that approaching 90% of their cohort were also taking some form of medication (I assume pertinent to things like mobility issues and beyond). In terms of how things like mobility issues impacted on participation in 'meaningful' education and/or work, we are told that only a quarter of participants "had been able to attend school, college or work in the past year." That's 'in the past year'.

Then back to those 'treatments' and their effects. So: "Although this was a naturalistic study and not an evaluation of treatment, it is notable that the majority of participants reported that they had accessed some form of treatment, and yet the mean scores for fatigue and social functioning had not changed considerably by T2." What sorts of treatments had they tried I hear you ask? Well, table 1 (see here) provides some details. The most popular treatment 'accessed' was "CBT, GET or both with at least one other treatment" closely followed by "CBT, GET or both." Allied to other independent data suggesting that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are failing many patients with ME/CFS (see here and see here and see here), and the case grows ever stronger for new treatment directions to be pursued. Such research directions should perhaps also be minus words like 'fear avoidance' or other psychobabble inclinations that have pervaded ME/CFS thought down the years. Indeed, one has to ask who would advocate for treatments that are seemingly at best ineffective and at worst downright detrimental to the patient group who are 'accessing' them?

There are some other points noted in the Ali paper including things like how "low mood is a consequence of having CFS/ME" and how "symptoms of CFS/ME and levels of functioning can fluctuate over time." These follow similar sentiments expressed in other research (see here and see here) along the lines of CFS/ME being very much a real physical illness with both physical and psychological effects.

There are some obvious caveats to mention about the Ali study, specifically around the sole use of questionnaires without any other 'actigraphic' form of inquiry (to measure something like activity levels), the representativeness of results, and the reliance on self-report when it came to diagnoses. Although I've also been pretty harsh on the effectiveness of the treatment options accessed, I will direct you to some author comments on this issue and how "the effects of treatment would not be seen within such a short period of time." I'm not too sure about such sentiments but, in the interests of balance, give them airtime in this study write-up.

Despite all that, the Ali findings add further to our knowledge about ME/CFS in young adults. They demonstrate how 'life-destroying' the illness is (are) and can be, and what that means to those who suffer with it (them). They also add to the multiple voices - research and patient voices - demanding a greater clinical focus on ME/CFS, and how objective, biological science in particular, needs to be front-and-centre of any new direction. But I'll also reiterate that any new focus and new direction needs to be minus the psychobabble; indeed it may be unethical not to [2]...

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[1] Ali S. et al. Psychological and demographic factors associated with fatigue and social adjustment in young people with severe chronic fatigue syndrome/myalgic encephalomyelitis: a preliminary mixed-methods study. J Behav Med. 2019 Jan 25.

[2] O'Leary D. et al. Ethical classification of ME/CFS in the United Kingdom. Bioethics. 2019 Feb 8.

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"A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME" but...

I did um-and-ah about whether I should blog about the findings reported by Bjarte Stubhaug and colleagues [1] observing that "a brief, concentrated treatment program for CFS/ME might be highly beneficial."

The reasoning behind my reticence was primarily to do with the study design whereby "a 4-day group intervention program, comprised by education, cognitive group therapy sessions, mindfulness sessions, physical activity and writing sessions, within a context of cognitive behavioral therapy, mindfulness, acceptance and commitment model" was delivered to over 300 people diagnosed with Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME) and self-report results plotted "1 week before and 1 week after the intervention program, and at 3 months and 1 year after the intervention" without any control group or any kind of blinding. Even the researchers themselves wrote that their study design make "conclusion of the actual effect of the treatment program [in part or whole] and its impact on the clinical course through the follow-up period difficult." But, here I am...

As you can see from the picture accompanying this post, others are also just a little bit critical of the Stubhaug paper and findings. Although I can't speak for anyone else, I imagine some of the 'criticism' of the study and results rightly follows on from the methodology employed by the authors. I did also wonder if some feeling might also be there because of the subject matter, and specifically, the continuing idea in some quarters that the application of the biopsychosocial (BPS) model to CFS/ME should carry weight. To quote from the authors: "The therapeutic rationale behind the program was to increase the medical knowledge and interpretation of bodily distress, challenge and modify dysfunctional illness perceptions as well as illness behavior, and through acceptance and commitment strategies contribute to behavioral change and clinical improvement." Sounds about as BPS as you can get I reckon.

Focusing for now on the methodological and related side of the Stubhaug paper, the starting point for the study was the authors' observation that: "The most promising treatment so far seem to be cognitive-behavioral treatment programs... and graded exercise." Just before anyone gets angry about this, authors do also highlight how "the effectiveness of interventions and robustness of findings are continuously being questioned" in this area. Yes, yes they are being questioned (see here and see here for examples) and by lots and lots of different people. Nonetheless, researchers decided to test whether their 4-day program, encompassing quite a few elements, might impact on some of the signs and symptoms of CFS/ME in their cohort. Said program included education: an "introduction to stress medicine with focus on physiological and psychological stress", cognitive group therapy, mindfulness and writing experience ("patients were instructed to write for 15 min about positive experiences and emotions"). They also talk about the use of "daily walking sessions of 60–90 min, in low to moderate pace" which, considering other research (see here), sounds pretty 'full on' to me, in light of some of principal issues that define CFS/ME (see here).

Relying on self-report measures such as the Chalder Fatigue Scale and the Short Form Health Survey-36 (SF-36), researchers reported their results as per the timescales already mentioned. The picture that emerged was a fairly positive one as various statistically significant group changes (improvements) were noted across the testing sessions, even when taking into account different ways of diagnosing CFS and across the various instruments used. Most participants also said that they were pretty satisfied with the intervention program and the service they received. In short, the study met it's aims quite successfully.

But... not to pour cold water on the findings, one cannot forget about the 'open study' shortcomings of the study design. So on top of what has already been mentioned: "Many patients with CFS/ME tend to be critical to biopsychosocial interventions, and possibly most of these patients did not accept referral to the clinic, contributing to the possible selection bias." I'd say that this was another quite important *issue* that faced the Stubhaug study. The authors go on to note that their results "clearly represent a CFS population, albeit not representing the total body of CFS/ME patients" so perhaps clarifying the caution needed in this area of science specifically around any sweeping generalisations. And as an example: "At 1 year follow-up, half of the patients completing assessments (56%) still report levels of fatigue representing substantial fatigue." Such an intervention is therefore no panacea for CFS/ME.

What else? Well, the continued focus on subjective questionnaires over and above more objective measures is also apparent in the Stubhaug findings (see here). As I've mentioned on more than one occasion, it's perfectly acceptable to ask patients how they are feeling and about related issues like quality of life for example (see here). But when it comes to a condition or set of conditions like ME/CFS defined by fatigue and other symptoms that very much impact on core issues such as activity, it strikes me that one should really include an objective measure of activity if one wants to study it in its entirety. So yes, actigraphy would have been a good feature to see in this study (with before and after results). Even a pedometer costing a few quid, used a few times a week over a number of different weeks would be something at least. And once again, how about also including some biological parameters into such studies too? Y'know, just on the off-chance that things like mindfulness, minus any grand sweeping claims, for example, could have possible biological effects too [2]?

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[1] Stubhaug B. et al. A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME. An Open Study, With 1-Year Follow-Up. Front Psychiatry. 2018;9:720.

[2] Hoge EA. et al. The effect of mindfulness meditation training on biological acute stress responses in generalized anxiety disorder. Psychiatry Res. 2018 Apr;262:328-332.

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"Fatigue, fluctuation and payback were described by all adolescents with CFS/ME in this study"

The quote titling this post - "Fatigue, fluctuation and payback were described by all adolescents with CFS/ME in this study" - comes from the findings reported by Roxanne Parslow and colleagues [1] during their study designed "to explore outcomes important in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) and what improvements in fatigue and disability are key."

Indeed, this latest study seems to follow a theme of looking at the personal experiences of CFS/ME [2] by members of this authorship team, potentially onward to the development of a PROM (Patient Reported Outcome Measure) [3] specifically with children and adolescents in mind. If this was a goal, I wondered if perhaps this *could* also be linked to some other work from some of the Parslow paper authors that has also been previously discussed on this blog too (see here)?

I specifically wanted to talk about this paper because of the word 'payback' and it's particular use to mean an "increase in fatigue and symptoms following activity." Mentioning it only twice in their article (one of those occasions being the use of a reference), I think the authors mean post-exertional malaise (PEM) (see here and see here for more discussion of this concept). They however, seemed a little reluctant to use that term. In answering one of the reviewers of their paper prior to acceptance for publication, the authors did say: "Payback is defined as a core symptom in NHS guidance, and is used in the clinical setting." They also clarified how "the term ‘payback’ was used instead of exhaustion."

No mind, based on interviews with "21 adolescents and their parents (20 mothers and 2 fathers)", most adolescents being female with a mean age of around 14 years, several key themes emerged. To reiterate: "All adolescents with CFS/ME report fatigue, a natural fluctuation of the condition, as well as an increase in fatigue and symptoms after activity (payback)." Several sub-themes also emerged from such reporting including how: "Adolescents and parents reflected on how CFS/ME naturally fluctuates" and "Adolescents and parents recognised patterns of good and bad days" and "Adolescents were limited in the amount of time they could spend on activities, which ranged from minutes, ‘5 min’ to hours, ‘an hour at the most’." These aren't exactly novel findings by any means but it's always useful to see them described in the peer-reviewed research domain.

Heading back to that 'payback' issue, researchers mention how their results are "consistent with previous research where children described the intensity of symptoms fluctuating as well as ‘overextension’ making it worse, resulting in ‘paying the price’." Accepting that such payback or PEM or 'payback exhaustion resulting in fatigue and other symptoms following activity' if you prefer, is widely present in CFS/ME (albeit individual and 'variable' in nature), one might see the Parslow results perhaps as further justification for being slightly critical of the use of something like graded exercise therapy (GET) in relation to CFS/ME (see here). GET relies on the assumption that increasing or grading in physical activity will eventually 'help' facets of CFS/ME. Unfortunately, whilst still expounded in some circles, there is accumulating (peer-reviewed) evidence that many patients with CFS/ME experience GET as more of a hindrance rather than a help for their symptoms (see here). Indeed, allied to terms like 'deconditioning' as part of suite of 'psychobabble' that seems to have enveloped CFS/ME down the years, the idea that CFS/ME is something that can be just 'exercised out of' seems to have been a truly damaging policy that has not seemingly served many patients particularly well.

The Parslow findings are revealing and add something further to the idea that an overhaul of current thinking on CFS/ME in children and adults is perhaps required (see here). Obviously the results are small-scale and require some follow-up, but listening to patients and their parents/caregivers and their collected experiences is a good idea in my book; particularly when it comes to a group of conditions like CFS/ME that have seen more than their fair share of 'assumptions' down the years.

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[1] Parslow RM. et al. Adolescent’s descriptions of fatigue, fluctuation and payback in chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): interviews with adolescents and parents. BMJ Paediatr Open. 2018;2(1):e000281.

[2] Parslow RM. et al. Children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review and meta-ethnography of qualitative studies. BMJ Open. 2017 Jan 13;7(1):e012633.

[3] Parslow RM. et al. Important factors to consider when treating children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): perspectives of health professionals from specialist services. BMC Pediatr. 2017 Feb 1;17(1):43.

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"contrary to its findings, there is no evidence that graded exercise therapy is effective" for myalgic encephalomyelitis / chronic fatigue syndrome

Things can sometimes move pretty fast in the world of peer-reviewed science. I had originally scheduled this post to appear in November (2018) but there's been some recent 'movement' in this area (see here) so I've decided to publish it now.

The original post is shown below. And below that are a few extra thoughts in light of the reported decision to remove the Larun article (at least for now)...

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The re-analysis paper published by Mark Vink & Alexandra Vink-Niese [1] makes for some really interesting reading. Not only because it adds to other voices in the peer-reviewed domain (see here) questioning the usefulness and safety of the intervention known as graded exercise therapy (GET) 'for' myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but also because it kinda fits in with a narrative suggesting that 'trusted evidence' is almost always open to interpretation (see here).

So, graded exercise therapy (GET) and ME/CFS. I have to say that out of all the interventions / treatments that I've come across down the years that have been indicated for various diagnostic labels, GET is probably one of the most reviled by the population it is supposed to be aimed at. The reasons for such a scenario are multiple and complex, but one of the more vocal arguments seems to be the lack of regard for harm caused by the use of a stepped physical activity schedule on a population whose illness is defined by boom-bust symptom profiles caused by physical exertion. Of particular importance to this line of thinking is the idea that post-exertional malaise (PEM) needs to have a lot more prominence attached to it when it comes to ME/CFS, minus any psychobabble 'deconditioning' chatter or related explanations.

The Vink-Vink-Niese paper is based on a Cochrane review paper of GET published by Lillebeth Larun and colleagues [2]. Yes, the same Cochrane that is going through a bit of turmoil at the moment. The Larun paper concluded a few things such as: "Exercise therapy did not worsen symptoms for people with CFS" and "Moderate‐quality evidence showed exercise therapy was more effective at reducing fatigue compared to ‘passive’ treatment or no treatment." This based on the examination of "eight randomised controlled studies" with "reported data from 1518 participants." To be fair to the Larun review paper, the authors did also mention that: "Serious side effects were rare in all groups, but limited information makes it difficult to draw firm conclusions about the safety of exercise therapy" and "further studies should be carried out to discover what type of exercise is most beneficial for people affected by CFS, which intensity is best, the optimal length, as well as the most beneficial delivery method." This, on the basis that CFS/ME is best described as a heterogeneous condition and accepting that exercise can come in various different forms, some of which might be more applicable than others when it comes to individuals with fatigue-related labels (see here for example) minus any sweeping generalisations.

Some familiar themes crop up in the Vink re-review paper - "Entry score requirements were not sufficiently strict" and "The review used subjective fatigue measured by questionnaires as the primary outcome" - which have quite notably hindered the research in this area. I note also that authors mention about attrition (dropout) rates in the reviewed studies and how, in some studies, over a third of participants placed in exercise conditions withdrew from such investigations. Such statistics will no doubt have an important influence on any final results, as well as providing an important clue that such an intervention might not be sufficiently well tolerated by quite a few [3].

Vink concludes by saying that: "The GET trials reviewed here are inherently biased: use of exercise may attract only the mildly affected and may deter the more disabled patients from participating" and that: "The flaws in the review and the trials... all created a bias in favour of the exercise intervention."

On the basis of their interpretation of the scientific data, I'm in agreement with Vink & Vink-Niese that the evidence base for the universal application of GET to ME/CFS is by no means indicated. You might well say that GET is not universally rolled out for everyone with ME/CFS but, as things currently stand at the time of writing, it is still part of the clinical guidance for the condition(s) here in Blighty (for now) and hence potentially something that can be suggested for anyone diagnosed with ME/CFS. The ethos behind GET also being tied into another biopsychosocial (BPS) favourite - CBT - also makes for a good reason why psychology really shouldn't be let anywhere near such clinical issues, particularly when the evidence against such 'interventions' is seemingly mounting (see here). Indeed, although little comfort to those currently living with ME/CFS, I'm sure one day we'll look back at the whole BPS 'involvement' with ME/CFS and truly say WTF?

And finally, whilst on the topic of 'not listening to your target population' I would also draw your attention to the recent findings from McManimen and colleagues [4] highlighting what could happen when those with ME/CFS face stigma (and dogma). Oh, and because the Cochrane name is part-and-parcel of today's post, I'll also draw your attention to an important message concerning some of their other advice pertinent to CFS...

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What else to add to this post? Well, a quote appearing in that Reuters report on the decision to temporarily withdraw the Larun review suggesting that "the withdrawal decision set a worrying precedent for scientific evidence being over-ridden by the opinions of activists" is, to my mind, inappropriate. Aside from the feedback received regarding the Larun article (see here) the Vink paper for example, is peer-reviewed science and published peer-reviewed science at that. It's not some activist randomly throwing around allegations and the like on social media or blogs(!). It's published peer-reviewed-science that calmly calls into question the conclusions of the original Larun analysis. Indeed, it's part of a trend for serious scientific conversations being held in the peer-reviewed science domain concerning some of the science and clinical practice around ME/CFS (see here). Nothing vexatious.

As I mentioned, given that other Cochrane reviews covering the topic of CFS have also been recently withdrawn [5] (see here for more on the withdrawal notice) it strikes me that Cochrane is perhaps also wisely ensuring that it's previous high standards are maintained and confidence restored in its 'evidence-based' name particularly when it comes to research into ME/CFS. Given also the turbulent few weeks that have just passed (see here) and seemingly, are still continuing (see here) for the 'collaboration', it's also a timely reappraisal that fits the important narrative that ME/CFS is a long-term physical health condition (see here) and not a mental disorder or worse. And intervention options need to recognise this fact...

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[1] Vink M. & Vink-Niese A. Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. Health Psychology Open. 2018;5(2):2055102918805187.

[2] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2016 Jun 24;(6):CD003200.

[3] Cheshire A. et al. Guided graded Exercise Self-help for chronic fatigue syndrome: patient experiences and perceptions. Disabil Rehabil. 2018 Oct 16:1-10.

[4] McManimen SL. et al. Effects of unsupportive social interactions, stigma, and symptoms on patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Community Psychol. 2018 Nov;46(8):959-971.

[5] Adams D. et al. WITHDRAWN: Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2018 Oct 15;10:CD006348.

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On the question of suicide risk and chronic fatigue syndrome / myalgic encephalomyelitis continued

The paper by Andrew Devendorf and colleagues [1] brought me back to a complicated and sensitive topic previously discussed on this blog (see here) regarding the issue of suicide risk in the context of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, the Devendorf findings provide some potentially important information about the possible reasoning behind suicide risk in the context of ME/CFS: "(1) feeling trapped and (2) loss of self, loss of others, stigma and conflict."

Based on discussions with 29 people diagnosed with ME/CFS "who endorsed suicidal ideation but did not meet depression criteria" researchers, including one Leonard Jason (see here), discussed some of the hows-and-whys of such suicidal ideation. As per the 'did not meet depression criteria' sentiments of the research, this work was less about 'mental health diagnoses affecting suicide risk' and more about how thoughts, feelings and situational factors might play a role. And as per the two variables highlighted by the study - 'feeling trapped' and 'loss of self & others and the stigma and conflict' generated by this incapacitating condition(s), some clear areas for further research and clinical attention emerged.

I've covered the sensitive issue of suicide (risk, ideation, completion) quite a few times on this blog for all-manner of different reasons (see here and see here for examples). In the most part, my musings have been on research into suicide where a specific label/condition/disorder has been diagnosed, and how facets of such labels/conditions/disorders *might* at least partially, 'intrinsically' elevate the risk of suicide ideation or beyond. The Devendorf findings kinda deviate from such 'intrinsic' sentiments, insofar as examining the implications of an acquired physical disability (see here and see here) and the onward the physical (and mental) restrictions of a condition seemingly elevating the risk of suicidality. By saying all that, I'm not making any sweeping generalisations...

I don't think anyone should really be surprised by the Devendorf results. With ME/CFS you have a condition that literally steals life from people; for example, rendering previously fit and active people to sometimes being bed-bound for days and days (or even longer) at a time. Add in a 'boom-bust' pattern of symptoms (see here) and the various 'environmental' effects (to employment, finances, social life, etc) of the condition, and well, I'm often surprised how resilient people with ME/CFS are.

I noted also how the words 'stigma' and 'conflict' were also detailed in the Devendorf study, and what implications this might have for quite a few areas of current research and clinical practice in relation to ME/CFS. I'm thinking specifically about the whole 'biopsychosocial (BPS) thing' that seems to have pervaded ME/CFS thinking down the years (see here), and how psychology in particular, seems to have over-stepped it's usefulness in relation to ME/CFS. It's kind of a coincidence that as I write this post, another article including Keith Geraghty [2] on the authorship list, is published discussing how some ME/CFS patients and patient groups have been labelled as 'militant' (or similar words and phrases) on the basis of them pushing back against medical dogma as a function of their own experiences of BPS-backed 'intervention' for example (see here). Militant is one word that has been used, 'vexatious' is another (see here).

"Participants emphasized that they were not depressed, but felt trapped by the lack of treatments available." This sentence serves to reiterate that suicidality in the context of ME/CFS is perhaps not something that should necessarily be thought of as intrinsic to the condition(s). It emphasises how issues like 'hopelessness' at the state of medical knowledge about ME/CFS, about the lack of biological explanation for the condition, and the lack of intervention options (not BPS guided I might add) may play a role in thoughts and feelings related to suicidality. It also provides another rather pressing reason why less 'psychologising' and more biological science needs to be dedicated to the hows-and-whys of ME/CFS and the search for a cure...

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[1] Devendorf AR. et al. Suicidal ideation in non-depressed individuals: The effects of a chronic, misunderstood illness. J Health Psychol. 2018 Jul 1:1359105318785450.

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A short-term aquatic exercise intervention for (some) individuals with CFS/ME?

I have to say that I did um-and-ah about whether or not to make this blog entry on the results published by Suzanne Broadbent and colleagues [1]. In it, researchers talked about the use of "a short-term aquatic exercise programme" with a small group of women diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

My 'in two minds' state was because the words 'exercise as intervention' and 'CFS/ME' have a rather poor history both in research and clinical terms; as proposals like 'graded exercise therapy' (GET) have the ability to invoke some rather adverse memories and reports for some/many people (see here and see here). As you can see, I did in the end decide that science should be seen and heard, even if it might be a tad uncomfortable. As hopefully you'll see, the Broadbent results might even provide some much needed focus in the area of activity and exercise with CFS/ME in mind minus any sweeping generalisations and psychobabble explanations which have typically followed such research.

Before progressing through their paper, it is worth mentioning that some of the authors on this most recent paper have some 'research form' when it comes to looking at exercise in the context of CFS/ME. Yes, there is mention of the words 'graded exercise' [2] in previous publications, but interestingly this is wrapped in the context of "immune system dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)" and their looking at various biological aspects of exercise [3] with an immune system slant to it. This is not your regular 'de-conditioning' thinking...

Aquatic exercise was the name of the research game on this most recent occasion, and an open trial detailing various physiological and behavioural measures pre- and post-use of "an initial 20-min aquatic exercise session then two self-paced 20-min sessions per week for 4 weeks" with 11 women. As you can already see, this was not a controlled trial and there was no comparison group used; just an initial research foray looking at whether their fairly brief water-based exercise program might produce some meaningful results or not. I assume that the authors were conscious that water-based exercise has some advantages over er, not water-based activity, in relation to impact (aquatic exercise is typically termed 'low impact) and also strength-building (water resistance is much greater than air resistance). I might also add that others have been following the development of this trial with some interest (see here).

'First, do no harm' is a primary tenet in all of medicine, and on the basis of "no reports of symptom exacerbation" in their small participant cohort, the authors can tick an important item of their research checklist on this occasion. Alongside, authors detail results based on various physiological parameters: "6 min Walk Test (6MWT), perceived exertion (RPE), hand grip strength, Sit-to-Stand, Sit-Reach test, Apley's shoulder test" as well as monitoring heart rate after each session. There's even mention of "24- and 48-h post-session tiredness/pain scores" which, I assume, could be stretched to mean looking at aspects of an important symptom: post-extertional malaise (PEM). And on that basis the authors reported that many of those physiological parameters did show changes between pre- and post-intervention in relation to things like grip strength, the 6MWT and also pain ("24-h post-test tiredness and pain decreased"). Ergo, aquatic exercise was seemingly well-tolerated in their small participant group and further - more scientifically 'stronger' - investigations are perhaps indicated to substantiate this finding.

When I first tweeted about the Broadbent article, it did create some discussion (see here). I wasn't surprised by this given the nature of the trial and some of the references to other peer-reviewed research made by authors. It's not easy to put into words how much damage has been done by the widespread (universal?) advocacy of something like GET when it comes to ME/CFS. Suffice to say that for many people with CFS/ME, any study that mentions 'exercise' as an intervention is likely to be met with a degree of scepticism. Once bitten and all that. And I also note the words "raising the possibility that there could be future lawsuits from ME patients whose condition has worsened from the treatment" have recently been mentioned in relation to GET...

But I do think there is more research to be done in this area on the back of the Broadbent results. Minus hype, sweeping generalisation and again importantly without any 'psychological theory' input, further analysis of the physiological effects of exercise on those with ME/CFS is a must, particularly with something like PEM in mind. No, I'm not advocating research practices that unethically put people with CFS/ME onto exercise regimes, but rather smaller research steps starting, for example, with the greater use of actigraphy on a day-to-day basis. It's been a real point of contention that actigraphy - the (objective) study of rest and activity cycles - has not been more incorporated into CFS/ME research (see here). Particularly, when discussions about 'recovery' from ME/CFS have been prominent in many quarters (see here) seemingly without mention of objective ways and means of establishing parameters of such recovery. I'd also suggest that the authors' previous work on immune function following exercise could also be applied to further aquatic exercise research too...

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[1] Broadbent S. et al. Effects of a short-term aquatic exercise intervention on symptoms and exercise capacity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis: a pilot study. Eur J Appl Physiol. 2018 Jun 19.

[2] Broadbent S. & Coutts R. Intermittent and graded exercise effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8+CD38+ in chronic fatigue syndrome/myalgic encephalomyelitis. Physiol Rep. 2017 Mar;5(5). pii: e13091.

[3] Broadbent S. & Coutts R. Graded versus Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome. Med Sci Sports Exerc. 2016 Sep;48(9):1655-63.

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PACE trial for chronic fatigue syndrome (still) being put through its paces

'Chronic fatigue trial results 'not robust', new study says' went the BBC headline reporting on the findings published by Carolyn Wilshire and colleagues [1].

Authors report peer-reviewed results following their re-examining various aspects of the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" - with regards to chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME).

This latest research and accompanying media attention continues a quite long-running saga (see here) known in some quarters as 'PACE-gate' (see here) where questions have been raised about a premier study that was "designed to examine the effectiveness of graded exercise therapy (GET) and cognitive behavioural therapy (CBT)" in relation to CFS/ME. Quite a few of those interventions are set within the still unfortunately believed idea that CFS/ME represents a 'biopsychosocial' illness (see here) and that 'changing mindsets and/or behaviour' will magically transform peoples lives. I say 'still unfortunately believed' because patient experiences do not seemingly match some of the peer-reviewed science in this area (see here).

The various twists-and-turns (see here and see here) around the PACE trial have involved bigger discussions about trial design, outcome threshold 'issues' and even the accessibility of research study data. Indeed, the Information Commissioner here in Blighty has even played a hand in the PACE saga (see here) leading to some rather messy and very public arguments.

The paper by Wilshire et al continues a theme from this research group re-examining the PACE trial protocols and findings. It encompasses various elements in terms of definitions of 'overall improvement' and even 'recovery' (see here) between 'specified in trial protocol' and 'used in published reports'. Wilshire and colleagues report: "Our findings suggest that, had the investigators stuck to their original primary outcome measure, the outcomes would have appeared much less impressive."

Insofar as recovery rates - other work [2] related to the original PACE trial paper had indicated some impressive recovery rates following CBT and/or GET - Wilshire has more things to say here too. So: "when recovery rates were calculated using the definition specified in the published protocol, these were extremely low across the board, and not significantly greater in the CBT or GET groups than in the Control group." It might seem like common-sense to know what recovery should look like when it comes to CFS/ME, but again, the waters have been continually muddied (see here).

"Some notable strengths of the PACE study included the large sample size..., the random allocation of patients to treatment arms, the use of a well-formulated protocol to minimise drop-outs, and the reporting of the full CONSORT trial profile (including detailed information about missing data)." Wilshire et al illustrate how the PACE trial was, initially, a good piece of science from a methodological point of view, but: "the design, analysis and reporting of the results introduced some significant biases."

And now it may be time to move on: "The time has come to look elsewhere for effective treatments." CBT and/or GET are still the topics of study when it comes to ME/CFS (see here and see here) but are seemingly finding it more and more difficult to find acceptance. The recent news that NICE are looking to update their guidance on CFS/ME in light of 'changes' made by other official bodies (see here) and some significant patient (and political) power, reflect an increasingly changing mood. An increasing realisation that talking and exercise therapies might not be the best treatment options for a somatic condition that has the propensity to *significantly* drain both health and other aspects of quality of life (see here).

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[1] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[2] White PD. et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35.

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What nearly 1500 patients with ME/CFS actually think about CBT, GET and pacing therapy

Today I'm discussing the findings reported by Keith Geraghty and colleagues [1] (open-access might be available here).

Looking at some interesting data derived from a rather large patient survey, authors examined what people diagnosed with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) actually thought about / experienced when it came to three intervention options: cognitive behavioural therapy (CBT), graded exercise therapy (GET) and pacing therapy (PT). A little bit of context about these interventions can be seen here including reference to some other peer-reviewed published work from members of this authorship group.

Based on the results of a survey offered by one of the premier UK organisations devoted to ME/CFS - certainly the one I tend to use when it comes to defining the spectrum that is ME/CFS - Geraghty et al add something to a body of research looking at the 'real world' impact (or not) of the various interventions currently advised for 'treating' CFS/ME (at least here in the UK). Their analyses suggested that: "While a small percentage of patients report some benefit from either CBT or GET, the majority experience no benefit." Even worse: "GET brings about a substantive deterioration in symptoms for almost half of patients"; something important to mention in the context of other, similar, intervention results being published earlier this year (see here).

At this point, I'll also refer you to other discussions of the Geraghty paper (see here).

Details are important to the Geraghty results. Including quite a sizeable cohort (N=1428) and asking over 200 questions "regarding treatment, particularly CBT, GET or PT", results were also compared against other patient survey results in the context of the intervention(s) being scrutinised. The combined results painted a similar sort of picture when it comes to experiences of the interventions insofar as "CBT brought about improvement in symptoms for approximately 35 per cent of respondents (65% unchanged/worse)" and "25 per cent of GET reported improvement in symptoms (17% unchanged/54% worse)." All this needs to be read in the context of the primary medical tenet: first, do not harm.

Geraghty et al acknowledge that there are limitations to their study results; not least that recall bias might be a potentially important issue and also that delivery of said interventions  might not have been carried out in "a uniform manner" (something also mentioned in the paper by Collin & Crawley [2]). With all due respect to the respondents, I might also add that independent confirmation of their diagnosis - knowing how important this - might also have provided some further methodological strength to the results too.

But in the context that patient surveys "offer a valuable insight into the ‘patient experience’" and how controversial some (all?) of these intervention options have been/continue to be in relation to CFS/ME (see here), these latest results represent an important research voice. They suggest yet again, that blanket recommendations for treating CFS/ME may have lots of potential effects (some positive but also quite a few negative) for many, many people diagnosed with such debilitating conditions. And once again, in the words of Jonathan Edwards [3] "If they [those diagnosed with ME/CFS] are still ill, presumably these approaches have failed and the priority is to find something more effective." Indeed (but don't hold your breath at least here in Blighty).

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[1] Geraghty K. et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients' reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. J Health Psychol. 2017 Aug 1:1359105317726152.

[2] Collin SM. & Crawley E. Specialist treatment of chronic fatigue syndrome/ME: a cohort study among adult patients in England. BMC Health Serv Res. 2017 Jul 14;17(1):488.

[3] Edwards J. PACE team response shows a disregard for the principles of science. J Health Psychol. 2017 Aug;22(9):1155-1158.

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Is current guidance for the management of CFS/ME in England fit for purpose?

"This multi-centre study in the NHS has shown that CFS/ME [chronic fatigue syndrome/myalgic encephalomyelitis] is a long term condition that persists for the majority of adult patients even after receiving specialist treatment."

So said the study results published by Simon Collin & Esther Crawley [1] (open-access) providing important information on some 400 patients diagnosed with CFS/ME who were in receipt of "NHS specialist CFS/ME services in England." Said specialist services, we are told, follow "guidance provided by the National Institute for Health & Care Excellence (NICE), including specific guidelines for diagnosis, specialist care, and ongoing management, with an overall patient-centred approach to treatment."

In case you've not followed the link to the NICE guidance covering CFS/ME, specialist care here in England generally describes various elements including the use of cognitive behavioural therapy (CBT) and/or graded exercise therapy (GET) based on the PACE trial results [2] and findings from other studies. Yes, the same PACE trial that 'continues to give' when it comes to arguments/debates (delete as appropriate) in CFS/ME circles (see here); see also the end of this post for more links to more recent happenings.

The Collin/Crawley research looked at several groups - newly referred and former patients - who attended one of eleven CFS/ME specialist services and who completed various questionnaires concerning the presentation  of fatigue, physical function and other aspects like mood and pain. Importantly: "They were also asked “Do you think that you are still suffering from CFS/ME?”" at follow-up either some 1 year after their initial clinical assessment or in some cases, 2-5 years later.

Results: "50–65% experienced little or no change in their condition 1–5 years after accessing a specialist service and 10–20% reported a deterioration, up to 30% of patients reported very much or much better health (and the majority of those who experienced little or no change had improved slightly)."

There are a few ways you could look at such results. You could say that specialist CFS/ME services are doing a fairly good job for approximately a third of patients who use them based on the figures reported. The authors do note some variability between the services that were included for analysis and given also that CFS/ME probably includes various 'sub-groups' under its banner, I'm not surprised therefore that there were potential best-responders and non-responders to the intervention(s) put in place.

The other way you could look at these data is with slightly less enthusiasm. Upwards of about two-thirds of patients surveyed saw no real difference to their symptoms long-term even after accessing such specialist services. More worryingly, a significant minority ("10-20%") reported deterioration; assuming this deterioration was in part or whole linked to their receipt of said specialist services, this is potentially in direct contravention of the tenet: first do no harm. These percentages - cumulatively up to 70%+ of patients - suggesting that specialist treatment might not necessarily be fit for purpose, need also to be analysed in the context of the costs associated with such specialist provisions in these days of rationing in many other parts of the NHS (see here for an example).

There is another detail included in the Collin/Crawley paper that requires comment: "Comparison with previous literature." The authors specifically focus in on the results for CBT and GET described in the PACE trial. They note: "The proportions of PACE trial participants (in the CBT and GET arms) who rated their overall health as very much or much better at 12 and 31 months were 41% and 42–48%, respectively, compared with 28% and 30% in our study (at 12 months and 2–5 years)." The authors suggest that differences in the number/intensity of sessions provided in the PACE trial and in 'real-life' might be one variable to account for the disparity reported on but I think we have to be a little bit careful here before saying specialist services either 'aren't doing it right' or 'aren't providing enough of a service'. There is for example, a debate currently rumbling on whether the recovery statistics subsequently produced from the PACE trial were entirely representative of the data produced (see here and see here for discussion on the authors reply). Minus any sweeping generalisations but in that context, I think one has to consider that there may be simpler answers to the disparity between studies: in a real-life context, CBT and GET are not as good an intervention for CFS/ME as some people might think. Indeed, it's potentially relevant that the US CDC has omitted CBT and GET from their current guidance for CFS/ME (see here) on top of similar changes to other guidance on this topic (see here). I know there may be some push-back to the idea that CBT and GET may not be the most suitable methods for 'treating' CFS/ME but nonetheless...

The Collin/Crawley paper provides a good snapshot of what patients themselves are saying about the current methods of treating/managing CFS/ME here in England. The picture the data paints is one of quite a bit more to do when it comes to how we care for some of the most ill people in society (see here for the quality of life comparisons). The focus on CBT for example, and the idea that those with the condition perhaps just need 'a change of attitude' towards their illness, is seemingly not working as well as some might wish. Although GET has shown some signs of efficacy for some with CFS/ME (see here), the sweeping generalisation that such an intervention is suitable for all with CFS/ME is also not borne out by the data and indeed, could potentially be quite damaging to some.  And patients are now saying that in the peer-reviewed science arena as well as on other forums too. Indeed, I again draw your attention to a quote from the opinion piece by Jonathan Edwards [3]: "If they [people with CFS/ME] are still ill, presumably these approaches have failed and the priority is to find something more effective." Who would disagree with such a sentiment?

To close, and related to today's post, has the dust settled yet regarding that special issue about the PACE trial published in the Journal of Health Psychology? I would say not...

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[1] Collin SM. & Crawley E. Specialist treatment of chronic fatigue syndrome/ME: a cohort study among adult patients in England. BMC Health Services Research. 2017; 17: 488.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36.

[3] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

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On your marks, GETSET...

I don't doubt that the article published by Lucy Clark and colleagues [1] (open-access) on the topic of testing "the efficacy and safety of graded exercise delivered as guided self-help" in the context of chronic fatigue syndrome (CFS) is going to divide opinion. I say that on the basis that graded exercise therapy (GET) as part of a suite of interventions linked into the PACE trial for example, has taken up masses of column inches in the lay and science media over the years and seems set to do so for some time to come.

I'm going to try and talk about the Clark paper as context-free as I can, bearing in mind that science does not exist in some sort of vacuum detached from real-life. I say that on the basis that this is supposed to be a science-related blog and whilst being very much aware of the discussion/politics around the potential rights-and-wrongs of various components of the PACE trial, I don't want them to necessarily spill over to this piece of new science.

So, GETSET - graded exercise therapy guided self-help trial - was the name of trial [2] and the design was such that "an open-label, pragmatic randomised controlled trial done at two UK National Health Service (NHS) secondary-care clinics for chronic fatigue syndrome in central London and Kent" was employed. Over 200 participants diagnosed with CFS - "who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome" - were included for study; half of which were allocated to receive 'specialist medical care' (SMC) with the other half receiving SMC with "additional guided graded exercise self-help (GES)." The trial lasted for 8-12 weeks and the primary outcomes were "fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale)" delivered at baseline and 12 weeks and relying on self-report. We are also told that "Participants were also followed up at 12 months after randomisation, and these results will be published in a separate paper."

Results: as per some further commentary on the study [3] by someone not totally unknown to some of the authors on the Clark paper, the use of SMC + GES did seem to show some effects on self-reported fatigue scores insofar as correlating with "significantly lower mean fatigue score... and higher self-reported physical function score... than did patients managed with specialist medical care alone." They also reported that: "participants in the GES groups had better outcomes than did participants in the control group for work and social adjustment scores, depression, and anxiety, but not for general physical symptoms." Importantly however, it is noted that (a) "physiotherapists reported that 43 participants (42%) adhered to GES completely or very well, 31 (30%) moderately well, and 30 (29%) slightly or not at all" and (b) only about 20% of those receiving GES "noted improvements (“much” or “very much better”) in overall health" and even less (15%) in relation to the symptoms of CFS. This was not a study demonstrating total and universally successful outcomes.

Outside of just those outcomes, the important issue of side-effects or adverse events potentially associated with intervention were also analysed: "non-serious adverse events were reported by 27 (28%) of 97 participants who received guided graded exercise self-help and by 23 (23%) of 102 patients who received specialist medical care only, with no significant differences between the two groups." A couple of participants also dropped out of the study who were using GES but generally intervention seemed to be "well-tolerated" according to the authors.

Limitations? Well, the authors do discuss a few; not least that 'self-report' was the main avenue for data collection. Likewise: "We did not measure any objective outcomes, such as actigraphy, which might have tested the validity of our self-rated measures of physical activity." That last point is quite a large study weakness throughout a lot of research looking at physical activity in many areas, particularly given the availability of some rather accurate and reliable equipment these days (see here). Indeed, the fact that the GES intervention was supervised by physiotherapists yet seemingly had no objective measures of anything physiotherapist-related is a little unusual. I might also add that whilst fatigue is a primary symptom of CFS, there are various other symptom manifestations (e.g. post-exertional malaise, PEM) that also require a lot more investigation in terms of effects from intervention; something particularly pertinent to any intervention that has an 'exertional' component to it. It's also important to note something else discussed by authors: "this trial was not designed to test causative factors in chronic fatigue syndrome, and the relative efficacy of a behavioural intervention does not imply that chronic fatigue syndrome is caused by psychological factors." Perhaps something of an olive branch is meant by that statement, particularly in light of the issues noted with something like the biopsychosocial (BPS) model being [deleteriously] applied to CFS down the years (see here).

There is a need for further research in this area before anyone gets ahead of themselves with the Clark results as some media headlines seem to have. Other studies [4] combined with opinion from some patient organisations (see here) have highlighted potential issues following the use of GET, and in particular it's use as a 'blanket form of treatment' for CFS. Indeed, 'blanket forms of treatment' have in my mind, been a source of real pain and discomfort to many people suffering (yes, suffering) with CFS; something hopefully being addressed by other research talking about subgroups and phenotypes (see here) and expected changes to clinical guidance here in Blighty for example due quite soon.

As to the question of mechanism(s) pertinent to GET being applied to 'some' CFS, we're still left wanting. I could speculate about issues such as 'de-conditioning' that is bound to be part-and-parcel of CFS and how GET could be targeting this variable. But really, nobody knows everything there is to know about how something like GET might impact on physiology because no-one seems to have measured it in any great detail. Again, quite a few of the trials from the group(s) behind GETSET and PACE have tended to be quite 'light' on physiological measurements before and after intervention; something that perhaps needs to be addressed.

So, there you have it. Some potentially important results but also an area that requires any awful lot more study before any sweeping generalisations are made and made without patient involvement. I await also the follow-up results from this research team to see what happened in the longer term...

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[1] Clark LV. et al. Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. Lancet. 2017. June 22.

[2] Clark LV. et al. Graded Exercise Therapy Guided Self-Help Trial for Patients with Chronic Fatigue Syndrome (GETSET): Protocol for a Randomized Controlled Trial and Interview Study. JMIR Res Protoc. 2016 Jun 8;5(2):e70.

[3] Clauw DJ. Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. Lancet. 2017. June 22.

[4] Núñez M. et al. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9.

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The continuing trials and tribulations of PACE

I honestly hadn't intended talking about the PACE trial - "pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation" in relation to chronic fatigue syndrome (CFS) - quite so much on this blog. Others have done it so much better than I ever could.

My interest however keeps being piqued in relation to the results originally produced suggesting that: "CBT [cognitive behaviour therapy] and GET [graded exercise therapy] can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome" and the subsequent myriad of voices quite unanimously suggesting that one perhaps needs to be a little careful with such sweeping generalisations (see here).

OK, for anyone new to this topic, below are a few of the previous occasions that it has been discussed on this blog in chronological order:

• Chronic Fatigue Syndrome and various factors (2014) (see here)
• Chronic fatigue syndrome and the detrimental application of the 'biopsychosocial model' (2016) (see here)
• PACE-gate! (2016) (see here)
• PACE trial recovery data and chronic fatigue syndrome (2017) (see here)
• PACE trial recovery data and chronic fatigue syndrome - a reply (2017) (see here)

I want to add a few more 'science references' to this issue because some important things are being discussed in the peer-reviewed domain, in the context that CBT and GET at the moment, are considered 'best practice' here in the UK and beyond when it comes to CFS. That may change in future times (see here) as it has in other parts of the world (see here) but that's where we are at the time of writing. I might add that the addition of new references to this post is a rather more descriptive thing minus too much additional commentary from me, and that the views represented are those of the authors. I wrote this post on 9 April 2017 so it is accurate up to that point.

OK, starting with the editorial from Keith Geraghty [1] mentioned in that PACE-gate! post, we have an authors reply to some of the points raised [2]. The main crux of the reply is to correct "misunderstandings and misrepresentations of the PACE trial." Next up was a paper by Leonard Jason [3] (someone with quite an impressive research track record when it comes to CFS) and some comments on the pacing intervention (adaptive pacing therapy, APT) used and "patient selection ambiguity." This is a particularly interesting paper because APT - "based on the envelope theory of chronic fatigue syndrome" where the symptoms of CFS are "not reversible by changes in behaviour" - did not hit the 'research spot' according to the original PACE trial results.

I want to next include the paper by Luis Nacul and colleagues [4] into proceedings, and a role for "selection bias and disease misclassification" when it comes to studies on CFS (and myalgic encephalomyelitis, ME). To quote from them: "When studies using the broad Oxford criteria... were excluded, a virtual disappearance of effect for graded exercise therapy (GET), cognitive behaviour therapy (CBT) and other psychological therapies recommended by the NICE guidelines (National Institute for Health and Care Excellence.. was revealed." Guess which criteria (among the many available) were used in the original trial?

Onward. The paper by Steven Lubet [5] titled: 'Investigator bias and the PACE trial' sets out quite an 'accusation' in that: "the PACE investigators “impartiality might reasonably be questioned”." This is a theme that crops up again shortly. The paper by Tom Kindlon [6] asked whether graded exercise in particular, could be thought of as 'safe and risk-free'? I set this question within the context that the original PACE trial did find that: "Non-serious adverse events were common" and GET did seem to produce the largest number of 'serious adverse effects' in number if not in participants.

Nearly there. Next up is the paper from Carolyn Wishire [7] who, when talking about "lively discussion", reports on various potential forms of bias in behavioural intervention studies using the PACE study as a kind of template. This author was the lead on the recent peer-reviewed commentary (open-access) re-analysing the 'recovery' data subsequently published in relation to the PACE trial. Then, we have the paper by Jonathan Edwards [8] who notes that the PACE trial represents a lesson in how research design needs to develop further when it comes to science in general. To quote: "The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed." And finally Charles Shepherd [9] provides further commentary on the PACE trial and a call for independent review.

And rest.

There is quite a lot to take in from those various publications and I don't doubt that this is not the last we are going to hear about the PACE trial. Allied to articles such as this one describing how: "Physicians used to dismiss the disease as psychosomatic" (past tense) it certainly would not out of place to suggest that there are still questions that need to be answered about the design and results obtained from the PACE trial and their applicability to the (very) wide CFS/ME population. To quote again from the paper by Edwards [8]: "If they are still ill [those diagnosed with CFS/ME], presumably these approaches have failed and the priority is to find something more effective." Wise words indeed.

To close, it's here... the first glimpse of The Last Jedi.

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[1] Geraghty KJ. ‘PACE-Gate’: When clinical trial evidence meets open data access. J Health Psychology. 2016. Nov 1.

[2] White PD. et al. Response to the editorial by Dr Geraghty. J Health Psychology. 2017. Jan 24.

[3] Jason LA. The PACE trial missteps on pacing and patient selection. J Health Psychology. 2017. Feb 1.

[4] Nacul L. et al. How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? J Health Psychology. 2017. March 1.

[5] Lubet S. Investigator bias and the PACE trial. J Health Psychology. 2017. March 7.

[6] Kindlon T. Do graded activity therapies cause harm in chronic fatigue syndrome? J Health Psychology. 2017. March 20.

[7] Wilshire C. The problem of bias in behavioural intervention studies: Lessons from the PACE trial 2017. J Health Psychology. March 23.

[8] Edwards J. PACE team response shows a disregard for the principles of science. 2017. J Health Psychology. March 28.

[9] Shepherd CB. PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome – true or false? It’s time for an independent review of the methodology and results. J Health Psychology. April 9.

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Edwards, J. (2017). PACE team response shows a disregard for the principles of science Journal of Health Psychology DOI: 10.1177/1359105317700886





White, P., Chalder, T., Sharpe, M., Angus, B., Baber, H., Bavinton, J., Burgess, M., Clark, L., Cox, D., DeCesare, J., Goldsmith, K., Johnson, A., McCrone, P., Murphy, G., Murphy, M., O’Dowd, H., Potts, L., Walwyn, R., & Wilks, D. (2017). Response to the editorial by Dr Geraghty Journal of Health Psychology DOI: 10.1177/1359105316688953