Two comments so far - from Peter White et al and Tom Kindlon and myself:
PD White, MD,1 DJ Clauw, MD,2 JWM van der Meer, MD,3 R Moss-Morris, PhD,4 RR Taylor, PhD,5
1. Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University, London, UK 2. Department of Anesthesiology, Medicine and Psychiatry, University of Michigan
Conflict of Interest: PDW, JWMvdM and RMM were principal investigators or co-investigators in some of the trials reviewed. PDW does consultancy work for the UK government and a re-insurance company.
In their systematic review, Smith and colleagues concluded that “trials of … counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for …. harms is insufficient.”(1)
While we support the general conclusion of benefit with these treatments, we suggest that some aspects of this review may be misinterpreted. Firstly, the most frequently tested behavioural intervention has been cognitive behaviour therapy (CBT), which aims to reduce symptoms and improve functioning, and it would be unusual to consider this as “counseling”, which has different objectives and content. One would not combine different types of medicines in a review; why do this with therapies? A review that combines counselling and CBT simply dilutes the efficacy of CBT, which has been amply demonstrated in several previous meta-analyses (2).
Secondly, there is little evidence of harm caused by graded exercise therapy (GET); a Cochrane systematic review of eight trials of exercise therapy for chronic fatigue syndrome (CFS), published this year, concluded that “..no evidence suggests that exercise therapy may worsen outcomes.” (3) Suggesting evidence of harm by stating that “one trial reported significantly more serious adverse events ….and more nonserious adverse events … in the GET versus comparison groups,…” without mentioning that serious adverse events were independently judged to be unrelated to the intervention, and that the differences between non-serious adverse events was not statistically significant, is a potentially misleading representation of the evidence. Adding that “..in a trial of GET, 20% of patients declined to repeat exercise testing because of perceived harm of testing” encourages further misunderstanding by failing to mention that the exercise testing was not part of the therapy and that the proportion of patients in the control intervention who also declined exercise testing was 50% (4). (Incidentally the proportion declining testing in the GET arm was 44%, not 20%.4) There is a world of difference between the effects of maximum exercise testing and graded exercise therapy. It is important not to overemphasise the harms associated with an effective treatment when there are so few others available.
Finally, the authors concluded that we need trials with analyses of patients meeting different case definitions; we agree and this has already happened. White and colleagues found no statistically significant differences in the efficacy of CBT and GET in sub-groups of those patients meeting Oxford criteria for CFS who also met either CDC defined CFS or myalgic encephalomyelitis (ME)(5).
Note: Seven other CFS clinical scientists supported and approved this letter.
References
1. Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a national Institutes of Health pathways to prevention workshop. Ann Intern Med 2015; 162: 841-50.
2. Castell BD, Kazantzis N, Moss-Morris RE. Cognitive behavioral therapy and graded exercise for chronic fatigue syndrome: A meta-analysis Clin Psychol Sci Prac 2011; 18: 311–24.
3. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD003200.
4. Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol 2005; 10: 245–59.
5. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, 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. The Lancet 2011;377:823-36.
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Posted on July 9, 2015
Tom Kindlon1, Charles Shepherd2
1. Irish ME/CFS Association, Ireland. 2. ME Association, United Kingdom
Conflict of Interest:
TK is Information Officer and a committee member of the Irish ME/CFS Association. All his work for the Association is unpaid.
CS is medical adviser to a charity (the ME Association) that collects and publishes patient evidence relating to safety and efficacy of graded exercise therapy and pacing.
We concur with Smith and colleagues that evidence regarding harms for therapies such as graded exercise therapy (GET) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is insufficient.(1,2)
The focus in GET trials for ME/CFS has been on efficacy measures which do not provide good information on whether adverse events occurred.(2)
A recently published systematic review included an assessment of the reporting of "treatment side effects" in 16 randomized controlled trials (RCTs).(3) Eleven were allocated the lowest mark with only one, the PACE Trial, awarded the top mark.(3,4)
One RCT is generally seen as insufficient to make firm recommendations.
Moreover, questions remain about the level of compliance with GET in the PACE Trial: the only reported measure of treatment adequacy was the number of appointments attended, not the type, intensity, or duration of activity/exercise performed each week. If participants dutifully complied with the exercise program one would not expect no improvement in fitness in the GET cohort as has recently been reported.(4)
If participants do not take their medication in a trial, reliable information on safety will not be provided; similarly if participants do not adhere to an exercise regime, good information will not be obtained about the safety or otherwise of complying with the intervention.
An earlier review of three trials of graded activity-oriented interventions for CFS found that following treatment participants had not actually increased their activity levels (objectively measured using actometers) compared to the controls.(5)
Data from outside of RCTs can be useful to assess the safety or otherwise of interventions.(2)
A clinical trial can represent a somewhat artificial environment and so outcomes may not correspond directly to those in routine practice.(2)
One of us (TK) previously reviewed the data from eight ME/CFS patient surveys from four countries.(2) Fifty-one percent of survey respondents (range 28-82%, n=4338) reported that GET worsened their health.
Such findings, along with the aforementioned poor reporting of harms in trials of GET for ME/CFS and the lack of evidence regarding adherence to the intervention in the trial with better harms reporting, mean we should not rush to accept any claims that GET has been found to be safe for ME/CFS.
References
1. Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a national Institutes of Health pathways to prevention workshop. Ann Intern Med. 2015;162:841-50.
2. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bull IACFS ME.
2011;19:59-111.
3. Marques MM, De Gucht V, Gouveia MJ, Leal I, Maes S. Differential effects of behavioral interventions with a graded physical activity component in patients suffering from Chronic Fatigue (Syndrome): An updated systematic review and meta-analysis. Clin Psychol Rev.
2015;40:123-137.
4. 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;2:141–152.
5. Kindlon T. Harms of cognitive behaviour therapy designed to increase activity levels in chronic fatigue syndrome: questions remain. Psychother Psychosom. 2011;80:110-1.
