Updated NICE guidance on chronic fatigue syndromeBMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4774 (Published 16 December 2020) Cite this as: BMJ 2020;371:m4774
All rapid responses
Professors Turner-Stokes and Wade claim that the PACE Trial produced ‘overall positive results’ for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) for patients with chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (M.E.).
The phrase, ‘overall positive results’ is uninformative but the implication is that CBT and GET in the PACE Trial (Turner-Stokes and Wade, reference #5) were effective for treating patients with M.E. and CFS. I disagree.
Firstly, the PACE Trial did not study the conditions that Turner-Stokes and Wade mention. It studied an heterogeneous cohort of patients with fatigue as their, “main symptom, accompanied by significant disability, in the absence of an exclusionary medical or psychiatric diagnosis”.
Secondly, the results did not provide evidence of efficacy with either CBT or GET. On the contrary – the randomised, controlled clinical trial provided compelling evidence that CBT and GET do not treat M.E., CFS or even chronic fatigue.
The Lancet publication of the PACE trial defined a ‘clinically useful difference’ as 2 points (out of 0 to 33) on the Chalder Fatigue Questionnaire (CFQ) and 8 points (out of 0 to 100) on the Short-Form 36 physical function subscale (SF36pf). Around 15% of participants in the CBT and GET groups reported these minor subjective improvements over and above the control or comparison group. This produces a Number Needed to Treat (NNT) of 7, and shows that 85% of participants had zero treatment effect one year after starting either CBT or GET.
Furthermore, with the Six Minute Walk Test (6MWT) outcome measure, the means of the CBT and control groups were virtually identical (the control group mean was fractionally better). The GET group were marginally better at walking at outcome, but the mean distance achieved by the group was shockingly poor at 379 metres. This is far below an average 70 to 80 year old according to data published by Casanova et al. The Chetta et al reference values for healthy subjects 20–50 years old, report distances of 593 ± 57 for women and 638 ± 44 for men. Note, the average age of PACE Trial participants was 38(SD 12) years.
There are numerous possibilities as to why around 15% of PACE trial participants might have reported minor subjective improvements with CBT or GET over the control group. However, the key question is – do the 15% represent an anomalous group, or do the 85% represent an anomalous group?
The obvious difference in size between these groups provides a simple answer. For 85% of participants in the PACE trial there was no treatment effect because neither CBT nor GET are treatments for a cohort with chronic fatigue which might include a number of M.E. and CFS patients.
1. White PD, Goldsmith KA, Johnson AL, 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.
2. Lynne Turner-Stokes, T Wade. Updated NICE guidance on chronic fatigue syndrome (editorial). BMJ 2020;371:m4774.
3. Casanova C, Celli BR, Barria P. et al. The 6-min walk distance in healthy subjects: reference standards from seven countries. Eur Respir J. 2011 37: 150−156; doi: 10.1183/09031936.00194909.
4. Chetta A, Zanini A, Pisi G, Aiello M, Tzani P, Neri M, Olivieri D. Reference values for the 6-min walk test in healthy subjects 20-50 years olds. J.Rmed. Vol 100, Issue 9, 1573 - 1578. http://dx.doi.org/10.1016/j.rmed.2006.01.001.
Competing interests: No competing interests
The recent editorial from Professors Turner-Stokes and Wade about the new draft of clinical guidelines for ME/CFS from the National Institute for Health and Care Excellence (NICE) is problematic on multiple fronts. 
For three decades, a small group of medical professionals have forcefully promoted the claim that two specific interventions -- cognitive behaviour therapy (CBT) and graded exercise therapy (GET) -- can lead not just to improvement but to full recovery from what they prefer to call chronic fatigue syndrome. In 2011, The Lancet published the results from the largest randomised trial of CBT and GET for the illness, the so-called PACE trial; at first glance, the study appeared to support these views. 
The PACE investigators referred to their trial as the “definitive” test of their preferred approach to therapeutic intervention for this disabling illness. Lancet editor Richard Horton hailed the research that appeared in his journal as “remarkable” and “utterly impartial”.  No less an eminence than Professor Sir Simon Wessely, who was involved with PACE but was not a co-author, proclaimed it “a thing of beauty”. 
Professor Wade himself declared the following about PACE in a statement released on his behalf by the Science Media Centre, a communications agency with close ties to the trial investigators: “Randomised controlled trials provide the best and only reliable evidence on safety and effectiveness of any intervention in any condition. The trial design in this study was very good, and means that the conclusions drawn can be drawn with confidence.” 
The PACE trial, of course, has since been widely discredited for “unacceptable methodological lapses” , and Professor Wade has apparently changed his mind about its probative value. The editorial he has co-authored argues that randomised controlled trials (RCTs) should not be viewed as acceptable for assessing “complex interventions for complex conditions.” It is noteworthy that he is publicly espousing this position after the renowned trial he previously championed has come to be regarded as fatally flawed.
The editorial’s main argument is that non-pharmacological treatments with multiple elements cannot be appropriately evaluated using the standard GRADE system. Trials of these therapies, the authors declare, are inevitably hampered by built-in limitations, such as the difficulty of blinding interventions and the need to use subjective outcomes in the absence of physiological measures. Whether or not GRADE is adequate for these kinds of non-pharmacological interventions, challenging the process and the rules after-the-fact raises questions about whether such protests are primarily principled or self-interested.
Indeed, the arguments advanced in this effort to discard a long-standing approach to the assessment of clinical trial evidence are easily dismissed.
First, objections raised about PACE and related studies have not been about the lack of blinding on its own or subjective outcomes on their own. It is the combination of the two in a single study that makes much of this research hard to interpret. This study design inevitably leads to unknown amounts of bias. When blinding is impossible, subjective findings must be accompanied by some sort of objective data to confirm that the results are genuine and not solely a factor of the study design.
The absence of biomedical tests has not prevented investigators from incorporating a range of other objective measures in some of these studies. In PACE, the investigators chose four—how participants performed on a six-minute walking test and on a step-test for fitness, whether they were working or not, and whether they were on social benefits or not. None of these measures matched the subjective reports of improvement from CBT or GET. The PACE authors subsequently dismissed them as irrelevant or not objective after all, and claimed success anyway.
As part of the guideline development process, NICE commissioned an independent review of the evidence base for ME/CFS treatments. The independent review assessed dozens of studies, including PACE, that collectively covered 236 treatment outcomes--findings that have been used to support claims that CBT or GET were effective. Of these 236 outcomes, the evidence for 205 was deemed to be of “very low quality”, and 31 were deemed to represent evidence of “low quality”. Not a single outcome was supported by evidence that exceeded this abysmal threshold.
During the independent review, the most common methodological problem identified in this evidence base was “risk of bias.” This is not surprising, given the tendency of the PACE investigators and their like-minded colleagues to design studies relying on unblinded interventions and subjective outcomes.
Second, just because you believe that you cannot meet a high theoretical standard does not entitle you to demand that you be judged against a lower one. The fact that your research falls short does not make the theoretical standard less important. Nor does it magically infuse your efforts with robustness or diminish the need for reliable data in order to assess performance.
Professors Turner-Stokes and Wade argue that their “complex interventions” cannot easily be standardized and are therefore incompatible with RCTs. For them, appropriate therapy is “the equivalent of a well tailored [sic] suit, fitted to the individual patient.” This sounds a lot like the special pleading employed by homeopaths, crystal therapists, and chiropractors to argue that their treatments, too, are difficult to research. In other words, the logic used is akin to pseudoscience.
By stating that the “rigid structure” of RCTs is inappropriate for testing the effectiveness of rehabilitative strategies involving CBT and GET, Professors Turner-Stokes and Wade are throwing the once-vaunted PACE trial and all related research under the bus. They are also demanding that the rest of us change our own positions about the importance of maintaining research standards. While stating that some people with the illness get better, they provide no reliable or valid evidence that their individualised rehabilitative approach has improved patients’ health more than, say, the passage of time on its own.
This lax attitude to evidentiary standards has implications beyond the domain of ME/CFS. In a perplexing passage, Professors Turner-Stokes and Wade credit “appropriate support and rehabilitation” for improvements seen among people experiencing prolonged symptoms after an acute bout of Covid-19. Their claim is unwarranted. That some or many long-Covid patients have improved and even recovered, for reasons that remain unclear, proves nothing more than that some or many long-Covid patients improve and recover. Any definitive statement about effective treatment will need to await properly conducted research.
In our view, the concerns expressed by Professors Turner-Stokes and Wade about the draft NICE guidelines for ME/CFS are misguided. Complex therapies for complex conditions should be judged against the best available standards, and these standards should not be compromised simply in order to make a preferred treatment look better. In this regard, NICE is to be commended for evaluating the relevant research with objectivity and thoroughness.
The new draft NICE guidelines for ME/CFS are extremely welcome and long overdue.
Competing interests: David Tuller is a senior fellow in public health and journalism at the Center for Global Public Health at the University of California, Berkeley. Members of the ME/CFS patient and advocacy community have donated to crowdfunding campaigns in support of Tuller’s position at Berkeley.
The recent editorial by Turner-Stokes and Wade on NICE guidance on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) includes several problematic statements.
The editorial writes, for example, that “trials in people with CFS/ME typically allocate participants to one or more isolated interventions—such as cognitive behavioural therapy, graded exercise therapy, or adaptive pacing— regardless of their actual needs or preferences.” It should be noted that some randomized trials tested a combination of these approaches and nonetheless reported disappointing results. [1, 2] By using a metaphor that some patients were provided with trousers only, and others with just a jacket instead of a well-tailored suit, the editorial makes a caricature of how these trials were conducted. In the largest study, for example, exercise therapy was already well-tailored to the individual with participant feedback and mutual planning of personal goals between patient and therapist. Despite this, the exercise group failed to outperform a passive control group at long-term follow-up. 
Turner-Stokes and Wade also argue that the quality criteria used by the GRADE system are poorly applicable to trials on complex interventions such as rehabilitation for people with ME/CFS. As an example, they mention that double-blinding is impossible in trials on interventions that require patients’ active participation. In such instances, however, quality criteria usually recommend using objective outcomes (in addition to subjective ones) as these are less prone to various biases.  Randomized trials on rehabilitative interventions for ME/CFS have included several objective outcomes such as work resumption, healthcare utilization, actigraphy, and various fitness tests. The results of these objective outcomes were summarized in a review by Vink & Vink-Niese.  Overall these showed no clinically significant improvements which was likely one of the reasons for the NICE guideline committee to downgrade the evidence for rehabilitative interventions to low or very low quality. If large effects were seen on objective outcomes including ME/CFS patients returning to work, increasing their fitness level, or requiring less healthcare, the committee would likely not have downgraded the results of these trials.
The editorial pleads for “systematic collection and longitudinal analysis of real life clinical data on a large scale.” Data from routine clinical practice already exists and generally supports the above-mentioned conclusion. In Belgium, for example, exercise therapy and cognitive behavioral therapy were used as the standard treatments for ME/CFS since the creation of government-funded centers in 2002. The data collected by these centers indicate that patients did not increase their fitness level or return to work.  Turner-Stokes and Wade also write that “many patients do recover from chronic fatigue symptoms”. If this statement refers to ME/CFS, the subject of the draft guideline, then it is at odds with a systematic review on the prognosis of ME/CFS which indicates low recovery rates with a median of only 5 percent. 
Lastly, Turner-Stokes and Wade suggest that the general concept of exercise is seen as harmful in the ME/CFS patient community because “many find themselves fobbed off with a prescription for gym membership or a course of exercise classes under the pretext of evidence based practice.” Surveys by ME/CFS patient organizations however indicate that reports of harm following exercise therapy are also high if treatment was guided by an NHS specialist. As noted by Kirke, “poor implementation does amplify this harm, but well-implemented GET still causes worsening for most patients.” 
1. Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta J-M, Godás-Sieso T, Gomez-Gil E. 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;30:381–9.
2. Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, et al. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010;340:c1777.
3. Sharpe M, Goldsmith KA, Johnson AL, Chalder T, Walker J, White PD. Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial. The Lancet Psychiatry. 2015;2:1067–74.
4. Savović J, Jones H, Altman D, Harris R, Jűni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technol Assess. 2012;16:1–82.
5. 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 Psychol Open. 2018;5:2055102918805187.
6. Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. 2008. https://kce.fgov.be/sites/default/files/atoms/files/d20081027358.pdf.
7. Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005;55:20–31.
8. Kirke KD. PACE investigators’ response is misleading regarding patient survey results. J Health Psychol. 2017;22:1168–76.
Competing interests: No competing interests
I am sorry to say that I think the recent editorial  on the draft NICE guidelines for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is ill-informed, confused and unhelpful.
Having been involved in the guideline process as an expert witness I am confident that the downgrading of quality of evidence for therapist-delivered treatments for ME/CFS was not a result of the well-recognised failings of the GRADE system. If anything GRADE makes it difficult to adequately downgrade very poor randomised studies. The committee found a sensible way to do so .
Further arguments raised by Turner-Stokes and Wade about evidence quality are puzzling and contradictory. They imply that the evidence for efficacy of therapist-delivered modalities such as CBT and exercise is good. Yet they point out that the types of trial available for evaluation are not appropriate. Such trials cannot be blinded (they note), so with subjective endpoints are hopelessly at risk of expectation bias. As I pointed out in my written testimony to the guideline committee , you cannot say that if the best you can do must fall short of reliability you can then treat it as reliable. Turner-Stokes and Wade must surely be arguing that NICE made the right decision.
There is also an accusation (unsubstantiated) that NICE was swayed by qualitative evidence from patients, ignoring the fact that the bar for evidence is set lower for harm than efficacy. Further confusion then comes when the authors say they think we need new forms of assessment – which appear to rest on qualitative uncontrolled observations of patients. This reinforces the agreed point, made cogently by Geraghty , that we need new types of trial design for therapist-delivered modalities because the traditional format has failed, but surely not to fall back on uncontrolled clinical practice accounts.
The authors appear to assume that we can know that therapist-delivered treatments are effective on clinical practice grounds. Yet, as I explained in my testimony to NICE, the available trials show that any benefits, even if due to more than expectation bias, would be too marginal to separate from spontaneous improvement in clinical practice. Unfortunately, the presumption that the benefits of rehabilitative treatments can be reliably identified in routine practice is ingrained into the sector. Recent trials have shown this to be unjustified.
It was because of the impact of this muddled type of thinking from a small group of service providers that NICE decided to review the ME/CFS guidelines. The draft proposals look to be an enormous improvement to the very large patient community interested in the quality of the science. What is particularly important now is that muddled thinking is not used to justify ‘rehabilitation’ of people with persistent unexplained symptoms after Covid-19 infection. We have no reason to think that post-viral syndromes are likely to benefit from anything other than time and not trying to do too much. There is no valid analogy with stroke or trauma.
1. Turner-Stokes, L. and Wade, D. (2020). Updated NICE guidance on chronic fatigue syndrome. BMJ, 371, m4774.
2. National Institute for Health and Care Excellence. (2020). Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. Draft guidance consultation.
3. Edwards, J.C.W. (2020). In: National Institute for Health and Care Excellence. (2020). Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. Draft guidance consultation. Supporting documentation.
4. Geraghty, K.J. (2017) PACE-Gate: When clinical trial evidence meets open data access. J Health Psychol. 22(9):1106-1112.
Competing interests: No competing interests
John McLaren-Howard, Sarah Myhill and Norman Booth discovered that mitochrondrial dysfunction is the main cause of chronic fatigue syndrome or myalgic encephalitis. It has never been sensible to expect patients with severe mitochondrial dysfunction to exercise or have psychotherapy before the underlying causes of mitochondrial dysfunction have been diagnosed and treated. These usually include important essential nutrient deficiencies and toxic metals like nickel, cadmium, or dental mercury amalgams.[1-3]
Mitochondrial dysfunction in CFS/ME needs testing and treating. Also four women are affected for every one man. In my experience, this is because most women take or have taken progestogens and/or oestrogens for contraception or HRT. Hormone use lowers zinc, increases copper levels, lowers copper stores, causes magnesium deficiency and increases toxic DNA adducts. [4,5] More recently higher arsenic levels are becoming more common from contaminated rice.
Mitochondrial dysfunction and essential nutrient testing should be more widely available and must be more cost effective than any regime which does not include investigating and correcting biochemistry.
1 Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) - a clinical audit.
Int J Clin Exp Med. 2013;6(1):1-15. Epub 2012 Nov 20.
2 Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).Int J Clin Exp Med. 2012;5(3):208-20.
3 Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction.Int J Clin Exp Med. 2009;2(1):1-16. Epub 2009 Jan 15.
4 Howard JM. The detection of DNA adducts (risk factors for DNA damage. A method for genomic DNA, the results and some effects of nutritional intervention, J Nutr Environ Med 2002;12:19-31.
5 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105-116.
Competing interests: No competing interests
I note in the editorial: 'Instead, the new draft emphasises the potential harms of exercise, based on qualitative evidence provided by a small number of service users,'.
The proper response to this criticism would be to present detailed statistics of lack of harms to patients and dropouts from collected statistics by the services, as the allegations of harm have been ongoing for many years and the precautionary principle would surely encourage this.
The paper 'Monitoring treatment harm in myalgic encephalomyelitis/chronic fatigue syndrome: A freedom-of-information study of National Health Service specialist centres in England https://journals.sagepub.com/doi/abs/10.1177/1359105319854532 by Kindlon et al. investigated harm monitoring.
"Clinics were highly inconsistent in their approaches to the issue of treatment-related harm. They placed little or no focus on the potential for treatment-related harm in their written information for patients and for staff. Furthermore, no clinic reported any cases of treatment-related harm, "
On the claim that these treatments are rehabilititive, I skip past the highly questionable definitions of 'recovery' in the papers involved and encourage people to look at the largest study in the area, the PACE trials cost effectiveness report by the original authors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411573/ (Interested parties may wish to investigate the expression of concern).
Specifically table 4.
The number of people receiving various forms of benefits due to being unable to work a year after the intervention is 8-12% worse in any of the treatment arms than in the control arm. (Control arm also worsened)
NICE found the treatments were ineffective because the treatments were ineffective at best.
Competing interests: No competing interests