What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults

Abstract:

The new NICE guideline for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), published in October 2021, makes significant changes in treatment recommendations. It acknowledges the complexity of this chronic medical condition, which always impacts quality of life and can be profoundly disabling, recognising the prejudice and stigma that people with ME/CFS often experience in the absence of any specific diagnostic test.

The guideline outlines steps for accurate diagnosis, recognising post-exertional malaise as a core symptom; importantly, ME/CFS can now be diagnosed after just 3 months in a bid to improve long-term health outcomes. It recommends the need for individual, tailored management by a multi-disciplinary team, ensuring that the wellbeing of the individual is paramount. The guideline makes clear that any programme based on fixed incremental increases in physical activity or exercise, for example graded exercise therapy (GET), should not be offered as a treatment for ME/CFS and emphasises that cognitive behavioural therapy (CBT) should only be offered as a supportive intervention.

Because of the rigorous methodology required by NICE Committee review and the inclusion of the testimony of people with lived experience as committee members, this guideline will influence the future diagnosis and management of ME/CFS in the UK and beyond.

Source:  Kingdon, C.C.; Lowe, A.; Shepherd, C.; Nacul, L. What Primary Care Practitioners Need to Know about the New NICE Guideline for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Adults . Preprints 2022, 2022110016 (doi: 10.20944/preprints202211.0016.v1).  https://www.preprints.org/manuscript/202211.0016/v1 (Full text available as PDF file)

NICE sets out steps NHS must take to implement ME/CFS guidelines

Abstract:

The National Institute for Health and Care Excellence has issued an unprecedented implementation statement setting out the practical steps needed for its updated guideline on the diagnosis and management of myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) to be implemented by the NHS.

Such statements are only issued when a guideline is expected to have a “substantial” impact on NHS resources, and this is thought to be the first. It outlines the additional infrastructure and training that will be needed in both secondary and primary care to ensure that the updated ME/CFS guideline, published in October 2021, can be implemented.

The statement is necessary because the 2021 guideline completely reversed the original 2007 guideline recommendations that people with mild or moderate ME/CFS be treated with cognitive behavioural therapy (CBT) and graded exercise therapy (GET). Instead, the 2021 guideline says that CBT should be only offered to support patients to manage their symptoms and that any exercise programme should be overseen by an ME/CFS specialist team.

Many areas have no or very limited specialist ME/CFS services, meaning that services must be commissioned, specialist health professionals need to be trained to deliver these services, and GPs need training in how to care for their patients. “With no nationally commissioned service for ME/CFS in either primary or secondary care, it will be for local systems to determine how to structure their services to achieve the aims of the guideline,” said Paul Chrisp, director of the Centre for Guidelines at NICE.

The 2007 recommendations were overturned during a long and difficult guideline development process. Patient groups had long argued that the recommendations were inappropriate, ineffective, and potentially harmful, and hindered research into the disease. But health professionals raised concerns about the proposed guidelines and the process that underpinned them. Just weeks before the final guideline was due to be published three members of the development committee resigned, royal colleges and other professional bodies signalled that they would not support it, and NICE had to delay publication. The guideline was finally published after a meeting was arranged with stakeholders to iron out differences, but concerns among medical leaders persisted.

When the 2021 guideline was published, Charles Shepherd, honorary medical adviser of the ME Association, told The BMJ that the recommendations were “something that currently cannot be coped with.” After publication of the implementation statement, he said, “I think NICE have gone as far as they can. It is now up to individual clinical services to reposition what they do in order to comply with the recommendations and for commissioners to start setting up new clinical services where none currently exist—especially in Wales and Northern Ireland.

“A lot of people with ME/CFS are clearly not getting the medical care and support that they need in both primary care and secondary care, especially those who are severely affected and do not have access to any form of domiciliary service or a dedicated inpatient facility.” He added: “It would obviously be helpful if the royal colleges could also express their support for implementation of the changes, as it’s not clear whether they remain unhappy with the recommendations downgrading CBT and the removal of GET.”

The same day NICE published its implementation statement, Sajid Javid, health and social care secretary, announced the publication of research priorities for ME/CFS by Action for ME, a charity that supports people with ME.  “We are committed to funding research into this important area,” he said. Javid and his chief scientific adviser, Lucy Chappell, will co-chair an advisory board of experts on ME/CFS, including patients, to discuss what needs to happen next and liaise with the devolved nations.

“We will be developing our own delivery plan later this year and will be working with stakeholders to understand how we can improve experiences and outcomes for people with these debilitating conditions,” he said. “At the heart of the delivery plan will be two core principles. Firstly, that we do not know enough about ME/CFS, which must change if we are to improve experiences and outcomes. Secondly, we must trust and listen to those with lived experience of ME/CFS.”

The BMJ asked three royal colleges for a response to the implementation statement, but none responded before publication.

Source: Ingrid Torjesen. NICE sets out steps NHS must take to implement ME/CFS guidelines. BMJ 2022;377:o1221. https://www.bmj.com/content/377/bmj.o1221

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union

Abstract:

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients.

The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients. A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research. We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches.

For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines. Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies.

The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.

Source: Strand EB, Nacul L, Mengshoel AM, Helland IB, Grabowski P, Krumina A, Alegre-Martin J, Efrim-Budisteanu M, Sekulic S, Pheby D, Sakkas GK, Sirbu CA, Authier FJ; European Network on ME/CFS (EUROMENE). Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union. PLoS One. 2019 Dec 5;14(12):e0225995. doi: 10.1371/journal.pone.0225995. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225995 (Full article)

Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review

Abstract:

Cognitive behavioural therapy and graded exercise therapy have been promoted as effective treatments for patients with myalgic encephalomyelitis/chronic fatigue syndrome. However, criticism on the scientific rigour of these studies has been raised. This review assessed the methodological quality of studies on the effectiveness of cognitive behavioural therapy and graded exercise therapy. The methodological quality of the 18 included studies was found to be relatively low, as bias was prominently found, affecting the main outcome measures of the studies (fatigue, physical functioning and functional impairment/status). Future research should focus on including more objective outcome measures in a well-defined patient population.

Source: Ahmed SA, Mewes JC, Vrijhoef H. Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review. J Health Psychol. 2019 May 10:1359105319847261. doi: 10.1177/1359105319847261. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31072121

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

Abstract:

Cognitive behavioural therapy and graded exercise therapy are promoted as evidence-based treatments for myalgic encephalomyelitis/chronic fatigue syndrome. This article explores patients’ symptom responses following these treatments versus pacing therapy, an approach favoured by many sufferers. We analyse data from a large cross-sectional patient survey ( n = 1428) and compare our findings with those from comparable patient surveys ( n = 16,665), using a mix of descriptive statistics and regression analysis modelling.

Findings from analysis of primary and secondary surveys suggest that cognitive behavioural therapy is of benefit to a small percentage of patients (8%-35%), graded exercise therapy brings about large negative responses in patients (54%-74%), while pacing is the most favoured treatment with the lowest negative response rate and the highest reported benefit (44%-82%).

Source: Geraghty K, Hann M, Kurtev S.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. doi: 10.1177/1359105317726152. [Epub ahead of print] http://journals.sagepub.com/eprint/hWSxVIBTzDtqisvafkhE/full (Full article)

Response to the editorial by Dr Geraghty

Abstract:

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty’s views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Source: White PD, Chalder T, Sharpe M, Angus BJ, Baber HL, Bavinton J, Burgess M, Clark LV, Cox DL, DeCesare JC, Goldsmith KA, Johnson AL, McCrone P, Murphy G, Murphy M, O’Dowd H, Potts L, Walwyn R, Wilks D. Response to the editorial by Dr Geraghty. J Health Psychol. 2017 Aug;22(9):1113-1117. doi: 10.1177/1359105316688953. Epub 2017 Jan 24. https://www.ncbi.nlm.nih.gov/pubmed/28805524

Do evidence based interventions for chronic fatigue syndrome improve sleep? A systematic review and narrative synthesis

Abstract:

Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) are recommended evidence based treatments for chronic fatigue syndrome (CFS), with research supporting their effectiveness in reducing fatigue and functional impairment. However, little research has focussed on the effect of these treatments on sleep, despite high reported sleep disturbance in CFS.

Using a narrative synthesis approach, we aimed to 1) systematically identify and summarise the current evidence for the effectiveness of CBT and GET in improving sleep; 2) consider factors influencing treatment effectiveness, including incorporation of sleep management techniques; and 3) consider the appropriateness of sleep outcome measures used within evaluations. Studies evaluating CBT and/or GET for CFS, and including a sleep outcome were eligible for inclusion. Eight studies were identified.

We found that GET interventions can improve sleep but this effect is inconsistent across studies. For CBT the evidence is limited with only one of two evaluations demonstrating sleep-related improvements.

We conclude from existing research that we know little about the effects of including sleep management components within CBT and GET interventions. We suggest that future research should explore the effectiveness of sleep components within interventions, and sleep specific interventions, using comprehensive outcome measures that fully capture the range of sleep difficulties experienced in CFS.

Copyright © 2016 Elsevier Ltd. All rights reserved.

 

Source: Russell C, Kyle SD, Wearden AJ. Do evidence based interventions for chronic fatigue syndrome improve sleep? A systematic review and narrative synthesis. Sleep Med Rev. 2016 May 13. pii: S1087-0792(16)30012-0. doi: 10.1016/j.smrv.2016.05.001. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27524207

 

Neurocognitive improvements after best-practice intervention for chronic fatigue syndrome: Preliminary evidence of divergence between objective indices and subjective perceptions

Abstract:

BACKGROUND: Neurocognitive difficulties are commonly reported by patients suffering from chronic fatigue syndrome (CFS). Moderate improvements from ‘best practice’ therapy are promising, but to date reported efficacy is based entirely on subjective measures. This is problematic, given the well-documented divergence between subjective perceptions and actual neurocognitive performance, including in this patient group.

MATERIAL AND METHODS: Subjective and objective measures of neurocognitive performance were obtained from 25 patients with well-characterized CFS before and after the completion of a 12-week graded-activity program incorporating a cognitive training component. Additionally, self-reported symptoms, cardiac autonomic activity (a relevant biomarker of stress responsivity), and their relation to neurocognitive improvements were examined.

RESULTS: Substantive post-intervention improvements in subjective (p=0.006) and objective (including faster responses speeds and greater accuracy, p’s<0.001) neurocognitive performance were documented. Participants also demonstrated reduced autonomic reactivity to the cognitive challenge at follow-up (p’s≤0.01). These improvements were accompanied by improvements in symptom ratings (p’s≤0.01). However, subjective ratings of neurocognitive difficulties, and CFS-related symptoms were not linked to objective performance improvements.

CONCLUSIONS: These initial data provide the first evidence of objective neurocognitive performance improvements accompanied by a significant reduction in responsiveness in stress-related neural pathways consequent to cognitive-behavioral/graded exercise therapy programs. These findings provide support for the effectiveness of such programs in remediating clinical status. These promising findings warrant further investigation, including replication in a larger sample utilizing more controlled study designs.

Copyright © 2016 Elsevier Inc. All rights reserved.

 

Source: Cvejic E, Lloyd AR, Vollmer-Conna U. Neurocognitive improvements after best-practice intervention for chronic fatigue syndrome: Preliminary evidence of divergence between objective indices and subjective perceptions. Compr Psychiatry. 2016 Apr;66:166-75. doi: 10.1016/j.comppsych.2016.02.002. Epub 2016 Feb 9. https://www.ncbi.nlm.nih.gov/pubmed/26995250

 

Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial

Abstract:

BACKGROUND: The PACE trial found that, when added to specialist medical care (SMC), cognitive behavioural therapy (CBT), or graded exercise therapy (GET) were superior to adaptive pacing therapy (APT) or SMC alone in improving fatigue and physical functioning in people with chronic fatigue syndrome 1 year after randomisation. In this pre-specified follow-up study, we aimed to assess additional treatments received after the trial and investigate long-term outcomes (at least 2 years after randomisation) within and between original treatment groups in those originally included in the PACE trial.

METHODS: The PACE trial was a parallel-group randomised controlled trial of patients meeting Oxford criteria for chronic fatigue syndrome who were recruited from six secondary care clinics in the UK between March 18, 2005, and Nov 28, 2008. Participants were randomly allocated to receive SMC alone or plus APT, CBT, or GET. Primary outcomes (were fatigue measured with Chalder fatigue questionnaire score and physical functioning with short form-36 subscale score, assessed 1 year after randomisation. In this long-term follow-up, we sent postal questionnaires to assess treatment received after the trial and outcomes a minimum of 2 years after randomisation. We assessed long-term differences in outcomes within and between originally randomised groups. The PACE trial is registered at http://isrctn.org, number ISRCTN54285094.

FINDINGS: Between May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires. Median time from randomisation to return of long-term follow-up assessment was 31 months (IQR 30-32; range 24-53). 210 (44%) participants received additional treatment (mostly CBT or GET) after the trial; with participants originally assigned to SMC alone (73 [63%] of 115) or APT (60 [50%] of 119) more likely to seek treatment than those originally assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0·0001). Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained (within-group comparison of fatigue and physical functioning, respectively, at long-term follow-up as compared with 1 year: CBT -2·2 [95% CI -3·7 to -0·6], 3·3 [0·02 to 6·7]; GET -1·3 [-2·7 to 0·1], 0·5 [-2·7 to 3·6]). Participants allocated to APT and to SMC alone in the trial improved over the follow-up period compared with 1 year (fatigue and physical functioning, respectively: APT -3·0 [-4·4 to -1·6], 8·5 [4·5 to 12·5]; SMC -3·9 [-5·3 to -2·6], 7·1 [4·0 to 10·3]). There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up.

INTERPRETATION: The beneficial effects of CBT and GET seen at 1 year were maintained at long-term follow-up a median of 2·5 years after randomisation. Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment. Future research should identify predictors of response to CBT and GET and also develop better treatments for those who respond to neither.

FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, King’s College London.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: 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. Lancet Psychiatry. 2015 Dec;2(12):1067-74. doi: 10.1016/S2215-0366(15)00317-X. Epub 2015 Oct 28. https://www.ncbi.nlm.nih.gov/pubmed/26521770

Comment in

Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial

Abstract:

BACKGROUND: Cognitive behaviour therapy (CBT) added to specialist medical care (SMC), or graded exercise therapy (GET) added to SMC, are more effective in reducing fatigue and improving physical function than both adaptive pacing therapy (APT) plus SMC and SMC alone for chronic fatigue syndrome. We investigate putative treatment mechanisms.

METHODS: We did a planned secondary mediation analysis of the PACE trial comparing SMC alone or SMC plus APT with SMC plus CBT and SMC plus GET for patients with chronic fatigue syndrome. 641 participants were recruited from six specialist chronic fatigue syndrome clinics in the UK National Health Service between March 18, 2005, and Nov 28, 2008. We assessed mediation using the product of coefficients method with the 12 week measure of the mediators and the 52 week measure of the outcomes. The primary outcomes were fatigue measured by the Chalder fatigue scale and physical function measured by the physical function subscale of the SF-36. We included confounder covariates and used treatment by mediator interaction terms to examine differences in mediator-outcome relations by treatment group.

FINDINGS: The largest mediated effect for both CBT and GET and both primary outcomes was through fear avoidance beliefs with an effect of larger magnitude for GET (standardised effects ×10, CBT vs APT, fatigue -1.22, 95% CI -0.52 to -1.97, physical function 1.54, 0.86 to 2.31; GET vs APT, fatigue -1.86, -0.80 to -2.89, physical function 2.35, 1.35 to 3.39). Increase in exercise tolerance (6 min walk distance) was a potent mediator of the effect of GET (vs APT, fatigue -1.37, 95% CI -0.76 to -2.21, physical function 1.90, 1.10 to 2.91), but not CBT.

INTERPRETATION: Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome.

FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, and Institute of Psychiatry, Psychology, and Neuroscience, King’s College London.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry. 2015 Feb;2(2):141-52. doi: 10.1016/S2215-0366(14)00069-8. Epub 2015 Jan 28. https://www.ncbi.nlm.nih.gov/pubmed/26359750

Comment in

COMMENTS

  • Robert Courtney 2016 Feb 16 10:20 a.m

    A study that uses questionable assumptions rather than empirical evidence leads to conclusions that stretch credibility.

    Chalder et al. [1] used the “single mediation model” for their methodology, which is explained in detail in a book by MacKinnon [2]. Explaining the methodology MacKinnon says a temporal separation between variables must be observed (i.e. changes in mediating variable must occur before changes in the mediated variable) for a mediation effect to be empirically and robustly established.

    Chalder et al. were working to this model and acknowledged that they failed to establish a clear temporal separation between variables, and therefore did not empirically establish a causal mediation effect: “Given the pattern of change in the mediators was similar to the pattern of change in the outcomes it is possible that the variables were affecting each other reciprocally”.

    However, despite the lack of robust empirical evidence to support a mediation effect, the investigators concluded that they had established mediation effects, e.g: “Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET.”

    The study’s conclusion relied upon an assumption that the investigators’ favoured hypothetical model of illness for ME/CFS has a robust empirical evidence base and is applicable to this study. The hypothesis is based upon the idea that symptoms and disability in ME/CFS are perpetuated by unhelpful or maladaptive illness beliefs, fear, and an avoidance of activity.

    However, the prestigious National Academy of Medicine (formerly known as the Institute of Medicine) recently released a comprehensive report [3] into ME/CFS that rejected such a hypothetical model of illness, and unambiguously concluded that ME/CFS does not have a psychological or cognitive-behavioural basis, but is an organic illness that requires biomedical research.

    Chalder et al. discussed the possibility that more frequent measurements may have potentially demonstrated a temporal separation between the variables, and therefore a mediation effect. However, this raises the possibility of whether changes in the primary outcome variables (self-report physical function and fatigue) may, in fact, have occurred before changes in the presumed mediator variables. Such an outcome would entirely contradict the investigators’ premature conclusions. According to MacKinnon [2] and Wiedermann et al. [4], unexpected outcomes should not be ruled out.

    Chalder et al. concluded that symptoms and physical impairment, in ME/CFS patients, are mediated by activity avoidance and other factors. (e.g. This would mean that a decrease in activity would cause an increase in symptoms.) However, from a common sense point of view, this seems like rather a convoluted conclusion, and it seems more likely that increased symptoms would be the direct cause of activity avoidance in any illness, rather than vice versa. To conclude that activity avoidance causes fatigue (rather than fatigue being a direct cause of activity avoidance), is similar to concluding that a person has flu because they’ve taken a day off work, rather than the obvious conclusion that they’ve taken a day off work because they have flu.

    In the case of fatigue, flu-like malaise and other symptoms of ME/CFS, it seems reasonable to consider the possibility that, as the symptoms fluctuate, patients may intuitively or rationally adapt their activity levels according to what is comfortable and safe. i.e. patients reduce activity levels because they are fatigued. The investigators have concluded that patients are fatigued because they have reduced activity levels.

    Perhaps patients’ perspectives and insights would help clarify the issues but, unfortunately, patients were not consulted for this study.

    References:

    1. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 2015; 2: 141–52.
    2. MacKinnon DP. Introduction to Statistical Mediation Analysis. Taylor and Francis: New York 2008.
    3. IOM (Institute of Medicine). 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies Press. http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx
    4. Wiedermann W, von Eye A. Direction of Effects in Mediation Analysis. Psychol Methods 2015; 20: 221-44.

    Tom Kindlon 2015 Sep 15 09:53 a.m.

    Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial

    [Originally posted here: http://www.bmj.com/content/350/bmj.h227/rr-10]

    This BMJ article and a flurry of articles in the lay media this week followed the publication in Lancet Psychiatry of an analysis of the mediators of change in the important PACE Trial, a chronic fatigue syndrome (CFS) trial which cost UK taxpayers £5 million[1,2]. What seems to have been lost in the coverage is that, although there were some modest improvements in the self-report measures, there was an almost complete absence of improvements in objectively measured outcomes for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) compared to the control group (specialist medical care only (SMC)).

    This is a non-blinded trial, where participants were told CBT and GET had previously been found to be effective in CFS and other conditions[3,4]: one way to look at the mediation results for subjective measures when there was a lack of objective improvements is that they may merely tell us how response biases and/or placebo effects are mediated[5].

    The focus on subjective measures in some CFS studies was previously criticised in a systematic review published back in 2001 (long before the PACE Trial started)[6]. They suggested instead “a more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities.”

    The model presented for cognitive behaviour therapy (CBT) in the PACE Trial manuals posits that the impairments and symptoms are reversible with the therapy[3,7]. However, the latest paper shows that fitness, as measured by a step test, didn’t improve following CBT[2]. An earlier PACE Trial publication reported that the addition of CBT to SMC did not result in an improvement in 6-minute walking test scores compared to SMC alone[8].

    The PACE Trial was part funded by the UK Department of Work and Pensions, a rare move for them, presumably done due to an expectation that the therapies would improve measures of employment and levels of benefit receipt. However, again CBT brought about no improvement using objective measures, such as days of employment lost, levels of disability benefits received and levels of receipt of insurance payments[9].

    These results are in line with earlier studies of CBT. For example, an analysis of three randomized controlled trials of CBT interventions for CFS found no improvement in objectively measured activity, despite participants reporting a reduction in (self-reported) fatigue and (sometimes) functional impairments[10]. Similar results were found in another uncontrolled trial where changes in objectively measured activity did not predict fatigue levels, and objectively measured activity on completion remained low compared to population norms[11]. An uncontrolled study found improvements in self-reported physical functioning and fatigue were reported despite a numerical decrease in (objectively measured) activity[12]. In another study, the level of self-reported cognitive impairment in CFS patients decreased significantly after CBT, however, cognition had not improved when it was measured objectively using neuropsychological test performance[13].

    It is unsurprising that 15 sessions of CBT (and the associated homework exercises and management program) might alter how participants respond to self-report questionnaires. A PACE Trial manual itself says “the essence of CBT is helping the participant to change their interpretation of symptoms”: this could lead to altered or biased fatigue scores, one of the two primary outcome measures[14]. Also, one of the aims of CBT (for CFS) has been said to be “increased confidence in exercise and physical activity”[15]. The possible responses for the other primary outcome measure, the SF-36 physical functioning subscale, are “yes, limited a lot”, “yes, limited a little” and “no, not limited at all” to questions on a range of physical activities. Such responses could be easily be artificially altered following a therapy like CBT for CFS.

    The results were not that different with the GET cohort in the PACE Trial. Again the manuals predicted that the impairments and symptoms are reversible using the intervention[4,15]. The model said there was no reason participants should not be able to get back to full functioning. Deconditioning was posited to be an important maintaining factor. However, GET did not result in an improvement in fitness, as measured by the step test. GET did result in a small improvement on the six minute walking test to a final distance of 379 metres, or 35 metres more than the SMC-only group[7]. However, as Knoop and Wiborg commented in an accompanying editorial in Lancet Psychiatry: “an increase in distance walked during a test situation without an increased fitness suggests that patients walk more because of a change in cognitive processes (eg, daring to do more or an increased self-efficacy with respect to activity), not because of a change in physiological capacity”[16]. The result remained very poor given that normative data would suggest a group of similar age and gender should walk an average of 644 or so metres[17]. The distance walked remained comparable to people with many serious conditions[18-21], and considerably worse than the distance walked by healthy elderly adults[22,23], despite the PACE trial cohort having a mean age of only 40[8]. Also, to be allowed entry into CFS research studies such as the PACE Trial one can not have a range of chronic illnesses so with genuine recovery one would expect results comparable to healthy people[8].

    As with CBT, measures relating to employment showed no improvement following GET in days of work missed, which remained very high, nor a reduction in levels of benefits (financial support from the state) or payments from insurance companies[9].

    These results are in line with an audit of Belgian rehabilitation centres for CFS offering CBT and GET[24-26]. Some improvements in subjective measures were found, but there was no improvement in the results of the exercise test and hours in employment actually decreased.

    Probably the main contribution of the PACE Trial has been to add to a growing body of evidence that while CBT and GET for CFS have resulted in some changes on subjective measures, they haven’t lead to improvements on objective measures.

    Competing interests: I am a committee member of the Irish ME/CFS Association and perform various types of voluntary work for the Association.

    (continues)

    • Tom Kindlon 2015 Sep 15 09:55 a.m.

      (Contd.)

      References:

      1 Torjesen I. Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ 2015;350:h227 http://www.bmj.com/content/350/bmj.h227

      2 Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 14 Jan 2015, doi:10.1016/S2215-0366(14)00069-8.

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