Intended for healthcare professionals

Letters Chronic fatigue treatment trial

PACE trial authors’ reply to letter by Kindlon

BMJ 2013; 347 doi: (Published 15 October 2013) Cite this as: BMJ 2013;347:f5963

Re: PACE trial authors’ reply to letter by Kindlon

Lynch suggests that resources should be made available for pragmatic trials to test cognitive-behavioural interventions for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) in clinical settings [1].

It would be worthwhile to examine the priorities of the patients the research is intended to benefit. In 2013, Action for ME (one of the UK’s largest ME/CFS patient organisations) carried out a survey asking ME/CFS patients and their carers to list their priorities for future research. At the top of the list of priorities was investigation of the underlying pathology of ME/CFS, which received 41% of the 'first priority' votes. The fewest overall votes went to investigations into 'psychological aspects' which received only 0.7% of the 'first priority' votes [2].

A large study (n=834) of health outcomes after treatment in CFS/ME specialist clinics in England’s National Health Service (NHS) was published in 2013 [3]. Clinics that offer only cognitive behavioural therapy (CBT) and graded exercise therapy (GET) were assessed alongside clinics that offer only ‘activity management’, and the latter were found to be marginally more effective. The two primary outcome measures used for the study were the same as for the PACE Trial (i.e. self-reported Chalder fatigue and SF-36 physical function scales) [4].

Overall, NHS specialist clinics were found to be clinically ineffective at improving physical function.

For improving fatigue, Crawley et al. describe the NHS clinical services as moderately effective. However, roughly half of the treated patients’ data was lost at follow-up and, considering that this study had no control group, the results are not robust. This is particularly the case considering that the PACE trial demonstrated that perception of fatigue improves for 65% of CFS patients over time (i.e. a 65% improvement rate without CBT or GET), when receiving similar basic medical care (i.e. usual medical care, symptomatic treatment, information about ME/CFS, and advice about avoiding extremes of activity) that patients attending NHS CFS/ME specialist clinics receive alongside cognitive-behavioural interventions. In the PACE Trial, such treatment was referred to as 'specialist medical care' (SMC).

As is typical for cognitive-behavioural trials for CFS, the PACE Trial was open-label. It also lacked an adequate placebo control, and had different levels of encouragement and optimism between intervention groups [4,5].

These are common problems in cognitive-behavioural intervention studies [5,6] and are particularly relevant when objective measures do not match self-reported improvements [4,7].

The net clinical response rate of CBT and GET for the self-reported primary outcomes in the PACE Trial, was an average of 13% (i.e. the additional number of participants who achieved a clinically useful improvement when CBT or GET were added to SMC). This translates to a Number Needed to Treat of 1 in 8.

These results are compatible with a placebo response in CFS [8]. If the same results were reported in a homeopathy study with similar methodology as the PACE Trial (i.e. open-label and uncontrolled), the value of the results would rightly be widely questioned.

A previous Cochrane systematic review of CBT for CFS reported that CBT was not superior to a waiting list control group, with the authors commenting that a possible explanation for this was that being on the waiting list for treatment had positive influence on participants [9].

An under-reported result of the PACE trial was that CBT failed to significantly improve any objectively measured outcomes, including: physical disability (in a six minute walking distance test); employment hours; welfare benefit claims or private insurance claims. GET had similar results, but with a modest improvement (small effect size) in objectively measured physical disability [4,10].

For the PACE Trial, CBT and GET were based on a hypothesis whereby illness is said to be perpetuated by a ‘maladaptive avoidance of activity', 'exercise intolerance', and 'deconditioning' [11,12]. The disappointing results of the PACE trial suggest that the tested hypotheses are not supported by the data, and that symptoms and disability are caused by a different mechanism.

ME/CFS patients describe experiencing sudden relapses (i.e. sudden symptom exacerbation) in response to over-exertion, despite sometimes experiencing relatively active periods of health in the run-up to a relapse [13]. This does not seem to fit with the PACE Trial’s tested cognitive-behavioural hypotheses which do not anticipate or describe suddenly induced exercise intolerance or deconditioning after relatively active periods of health.

Until these issues are acknowledged, candidly, by the medical and academic communities, then the (widely reported) mistrust between patients and professionals in the field of CFS/ME is perhaps unlikely be resolved.


1. Lynch S (2013) Beyond Pace - Moving The Debate Forward. BMJ Rapid Response. (Internet) (Last accessed 14th Nov 2013)

2. Action for ME. (2013). Research priorities survey results. (Internet) (Last accessed 14th Nov 2013)

3. Crawley E, Collin SM, White PD, Rimes K, Sterne JA, May MT; CFS/ME National Outcomes Database. (2013) Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. QJM. 106:555-65.

4. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 377:823-36.

5. Boot WR, Simons DJ, Stothart C, Stutts C. (2013) The Pervasive Problem With Placebos in Psychology Why Active Control Groups Are Not Sufficient to Rule Out Placebo Effects. Perspect Psychol Sci. 8:445-454.

6. Berger D. (2013) Cognitive Behavioral Therapy: Escape From the Binds of Tight Methodology. (Internet) (last accessed 14th Nov 2013)

7. Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. (2010) How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 40:1281-7.

8. Cho HJ, Hotopf M, Wessely S. (2005) The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis. Psychosom Med. 67:301-13.

9. Price JR, Mitchell E, Tidy E, Hunot V. (2009) Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. CD001027.

10. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. (2012) Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS ONE 7: e40808.

11. Bavinton J, Darbishire L, White PD, On behalf of the PACE trial management group. PACE Manual For Therapists: Graded Exercise Therapy for CFS/ME. Final Trial Version Version 7. (Internet) (last accessed 10 Sep 2013)

12. White PD, Sharpe MC, Chalder T, et al. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 7:6.

13. Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration (FDA) (2013) The Voice of the Patient. A series of reports from the U.S. Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development Initiative. Chronic Fatigue Syndrome and Myalgic Encephalomyelitis. (Internet) (Last accessed 14th Nov 2013)

Competing interests: No competing interests

18 November 2013
Robert Courtney