M.E. Beth Smith, DO; Elizabeth Haney, MD; Marian McDonagh, PharmD; Miranda Pappas, MA; Monica Daeges, BA; Ngoc Wasson, MPH; Rongwei Fu, PhD; Heidi D. Nelson, MD, MPH
Disclaimer: The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of the Agency for Healthcare Research and Quality (AHRQ). No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank following individuals for their contributions to this project: Richard Bryant, MD, for providing expert consultation throughout the report; Andrew Hamilton, MLS, MS, for conducting literature searches; and Spencer Dandy, BS, for assistance with preparing this report (all are located at the Oregon Health & Science University). They also thank Suchitra Iyer, PhD, Task Order Officer at the Agency for Healthcare Research and Quality; Carmen Green, MD, National Institutes of Health (NIH) Working Group Chair; the NIH Working Group; the Technical Expert Panel; and reviewers of the draft report.
Financial Support: By the Agency for Healthcare Research and Quality (contract 290-2012-00014-I, task order 4), Rockville, Maryland.
Disclosures: Dr. Fu reports funds under contract for the Evidence-based Practice Centers IV Program from Oregon Health & Science University during the conduct of this study. Ms. Daeges reports grants from Agency for Healthcare Research and Quality during the conduct of this study. Dr. Nelson reports grants from Agency for Healthcare Research and Quality during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0114.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: M.E. Beth Smith, DO, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Smith, Haney, McDonagh, Fu, and Nelson; Ms. Pappas, Ms. Daeges, and Ms. Wasson: 3181 SW Sam Jackson Park Road, Mail Code: BICC, Portland, OR 97239.
Author Contributions: Conception and design: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, H.D. Nelson.
Analysis and interpretation of the data: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, N. Wasson, R. Fu, H.D. Nelson.
Drafting of the article: M.E.B. Smith, M. McDonagh, M. Pappas, N. Wasson, H.D. Nelson.
Critical revision of the article for important intellectual content: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, N. Wasson, R. Fu, H.D. Nelson.
Final approval of the article: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, R. Fu, H.D. Nelson.
Provision of study materials or patients: M. Daeges.
Statistical expertise: R. Fu.
Obtaining of funding: M.E.B. Smith, M. McDonagh, H.D. Nelson.
Administrative, technical, or logistic support: M. Pappas, M. Daeges, N. Wasson, H.D. Nelson.
Collection and assembly of data: M.E.B. Smith, E. Haney, M. Pappas, N. Wasson, H.D. Nelson.
Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition affecting more than 1 million adults in the United States.
To determine benefits and harms of treatments for adults with ME/CFS and identify future research needs.
MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; reference lists; and manufacturer information.
English-language randomized trials of the effectiveness and adverse effects of ME/CFS treatments.
Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria; discrepancies were resolved through consensus.
Among 35 treatment trials enrolling participants primarily meeting the 1994 Centers for Disease Control and Prevention and Oxford case definitions of CFS, the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence). Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence). Counseling therapies and graded exercise therapy compared with no treatment, relaxation, or support improved fatigue, function, global improvement, and work impairment in some trials; counseling therapies also improved quality of life (low to moderate strength of evidence). Harms were rarely reported across studies (insufficient evidence).
Trials were heterogeneous and were limited by size, number, duration, applicability, and methodological quality.
Trials of rintatolimod, counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for other treatments and harms is insufficient. More definitive studies comparing participants meeting different case definitions, including ME, and providing subgroup analysis are needed to fill research gaps.
Agency for Healthcare Research and Quality. (PROSPERO: CRD42014009779)
Summary of evidence search and selection.
CAM = complementary and alternative medicine; CBT = cognitive behavioral therapy.
* Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and the Cochrane Database of Systematic Reviews.
† Identified from such sources as reference lists, hand searches, and suggestions by experts.
‡ Studies that provided data and contributed to the body of evidence were considered "included."
§ Studies may be included in more than 1 published article, and this number indicates the number of unique studies included, representing a total of 45 publications. Studies may have provided data for more than 1 type of treatment.
|| Studies included for the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome are reported in the companion article in this issue (71).
Appendix Table 1. Summary of Trials of Therapies
Effects of various types of counseling therapies on the SF-36 physical function subscale.
CBT = cognitive behavioral therapy; SF-36 = Short Form-36.
* Therapy intended to change behavioral and belief factors that may trigger and maintain symptoms.
† Compared with all participants in control groups in the trial.
‡ Teaches coping and self-sufficiency strategies.
§ Strategies to promote a gradual progression of activity.
|| Use of informative booklets with assignments.
Meta-analysis of trials of the effects of CBT on the SF-36 physical function subscale.
* Compared with all participants in control groups in the trial.
Meta-analysis of trials of the effects of graded exercise therapy on the SF-36 physical function subscale.
Graded exercise therapy involved an exercise plan with structured incremental increases in exercise over time, qigong exercise, and home orthostatic training. SF-36 = Short Form-36.
Meta-analysis of trials of the effects of graded exercise therapy on the clinical global impression of change scale.
Graded exercise therapy involved an exercise plan with structured incremental increases in exercise over time, qigong exercise, and home orthostatic training.
Appendix Table 2. Summary of Evidence by Outcomes for Trials With Statistically Significant Between-Group Differences
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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
June 30, 2015
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.
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
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.References1. 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.
Tom Kindlon1, Charles Shepherd2
1. Irish ME/CFS Association, Ireland. 2. ME Association, United Kingdom
July 9, 2015
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.References1. 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.
Lily Chu, MD, MSHS (1), Lucinda Bateman, MD (2), Todd Davenport, PT, DPT, OCS (3), Eleanor Stein, MD, FRCP(C) (4), Staci Stevens, MA (5)
(1) Independent Consultant, Burlingame, CA, USA; (2) Bateman Horne Center, Salt Lake City, UT, USA; (3) Department of Physical Therapy, Thomas J. Long School of Pharmacy and Health Sciences,
July 11, 2015
Conflict of Interest:
All authors are involved in ME/CFS research. LB, ES, TD, and SS are involved in the clinical care of ME/CFS patients. LB, SS, and TD were members of the International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis Primer Writing Committee. No funding was received in support of this work.
First, do no harm: graded exercise therapy and myalgic encephalomyelitis/ chronic fatigue syndrome
We concur with Smith et al. (1) that graded exercise therapy (GET) can cause harm in some patients with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). However, we believe the benefits from GET would have been reduced and the harms assessed as even greater if the following points had been considered.
(1) The authors recognized that the non-specific nature of the Oxford criteria might recruit subjects “with other fatiguing illnesses or illnesses that resolve spontaneously” (1) yet they analyzed studies using Oxford criteria with those using Fukuda criteria together. This is similar to lumping people who have congestive heart failure, chronic obstructive pulmonary disease, and pneumonia together because all three diagnoses share shortness of breath as a symptom. It would have been more informative had they assessed trials using Fukuda and Oxford separately and then compared those results to the combined results. Darbishire et al. found that the factor most predictive of a poor outcome when a GET or cognitive behavioral therapy (CBT) regimen was applied to a group of subjects suffering chronic fatigue was fitting Fukuda criteria (2).
(2) Nunez et. al. is classified in Appendix Table 1 as not reporting any harms (1). However, this study found not just that the combined GET/ CBT intervention had no benefit but that these treatments caused a significant decline in physical function and increase in bodily pain scores as measured by the SF-36 at 12 months.
(3) Smith et al. appropriately suggest that future research should strive to include the input of patients and advocates. Because their review was based on clinical trials, however, it did not include clinician and patient experiences outside of trials. On average, 50% of thousands of patients internationally have reported worsened health due to treatments involving exercise (3). Clinicians specializing in ME/CFS do not recommend GET and instead advise patients to balance their active periods with rest breaks (4). This cautious attitude is supported by studies (5) showing that patients with ME/CFS do not respond to or recover from physical activity in the same way as healthy people or people with other medical conditions.
As with any medical condition, clinicians need to tailor treatments to the individual patient. If patients describe exacerbation of symptoms and no improvement with exercise-related therapies, rather than attributing those reports to low motivation, distorted thinking, or exaggeration, clinicians should consider that there is a problem and stop the treatment.
(1) Smith MB, 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;162:841-850. doi:10.7326/M15-0114
(2) Darbishire L, Seed P, Risdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005; 186 (4) 350-351.
(3) Kindlon T. Reporting of harms associated with graded exercise therapy and cognitive behavioral therapy in myalgic encephalomyelitis/ chronic fatigue syndrome [Internet]. Chicago, Illinois: International Association for Chronic Fatigue Syndrome/ Myalgic Encepahlomyelitis; 2011 October [cited 2015 July 8]. Available from: http://iacfsme.org/PDFS/Reporting-of-Harms-Associated-with-GET-and-CBT-in.aspx
(4) International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis Primer Writing Committee. ME/CFS: a primer for clinical practitioners [Internet]. Chicago, IL: International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis; 2014 July [cited 2015 July 8]. Available from: http://iacfsme.org/portals/0/pdf/Primer_Post_2014_conference.pdf
(5) Institute of Medicine: Committee on the Diagnostic Criteria for myalgic encephalomyelitis/ chronic fatigue syndrome. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness [Internet]. Washington, DC: National Academies Press; 2015 Feb [cited 2015 July 8]. Available from: http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx
July 13, 2015
Diagnostic sub-group analyses in the PACE trial may be unreliable
In their comment on this article , White et al. state that "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)".However, the ad-hoc application of these case definitions in the PACE trial (pacetrial.org) may undermine the reliability of those sub-group analyses. All trial participants were first screened using the Oxford CFS criteria and then further stratified into sub-groups meeting modified versions of CDC CFS criteria and London ME criteria:a) The Oxford criteria is not entirely compatible with other case definitions, as it uniquely requires that fatigue is the dominant symptom , and the medical assessments in the trial may have excluded clinical characteristics of ME which are allowed in other case definitions.b) The trial only counted additional CFS symptoms (including postexertional malaise) over the previous week instead of six months as required by the CDC criteria.  Evans & Jason studied different recall time frames for each of the eight additional CDC symptoms and reported that the optimal time frame for reliable reporting was six months for postexertional malaise, unrefreshing sleep, memory/concentration difficulties, muscle pain, headaches, lymph node pain, and sore throat, with one month for joint pain.  The authors concluded that researchers interested in the assessment of CFS symptoms should take recall time frame into account.c) While the modified version of the rarely used London ME criteria requires postexertional fatigue or fatiguability, it does not require postexertional malaise or the fluctuation of other significant symptoms usually worsened or precipitated by either physical or mental exercise, which the original version stipulated was "absolutely characteristic" (see meassociation.org.uk). Goudsmit, one of the authors of the original London ME criteria, has publicly rejected the version used in the trial as flawed, incomplete, and non-representative. In conclusion, none of the diagnostic criteria as applied in that trial adequately measured or required post-exertional symptomatology. The Institute of Medicine recently released new diagnostic criteria for CFS that require postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance; the IOM noted that participants in therapy trials have not meet these requirements, and called for the retirement of the obsolete Oxford criteria as it can result in the "selection of participants with other fatiguing illnesses or illnesses that resolve spontaneously". References1. Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, Fu R, Nelson HD. Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015 Jun 16;162(12):841-50. PMID: 26075755. http://annals.org/article.aspx?articleid=23228012. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991 Feb;84(2):118-21. PMID: 1999813. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12931073. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35. PMID 23363640. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC37762854. Evans M, Jason LA. Effects of Time Frame on the Recall Reliability of CFS Symptoms. Eval Health Prof. 2013 Sep 23. [Epub ahead of print] PMID: 24064428. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/240644285. Ellen Goudsmit on PubMed Commons: http://www.ncbi.nlm.nih.gov/myncbi/ellen m.goudsmit.1/comments
Response to White et al.
I would like to make two points in response to White et al.Firstly, counselling, with its more modest non-curative goal of helping patients adapt to limitations imposed by chronic disease and disability, does not posit a primary etiological role for cognitive behavioural factors. Whereas the cognitive behavioural model for chronic fatigue syndrome (CFS) does posit such a role, and hence claims curative potential by modifying those factors via cognitive behavioural therapy (CBT).There are no clinical trials directly comparing counselling and CBT for CFS, but there are two for chronic fatigue, a defining symptom of CFS. Ridsdale et al (2001) reported “equivalent” therapeutic outcomes for counselling and CBT, with the authors suggesting that the choice between the two approaches depends on non-therapeutic factors like cost and accessibility.  Ridsdale et al (2012) found no difference between counselling, graded exercise therapy (GET), and usual care plus a CBT booklet. Smith et al were also unable to distinguish between counselling and CBT for efficacy.These results, plus the low-moderate effect sizes of CBT and GET for CFS, the predominantly subjective self-report basis of those effects and their general discordance with the more objective outcome measures (particularly for CBT), and the principle of parsimony, all question the value of assuming a primary etiological role for cognitive behavioural factors in CFS.[2,5]Secondly, if CFS patients are already operating at or near maximum physical capacity, then they may not find a “world of difference between the effects of maximum exercise testing and graded exercise therapy.“ In clinical trials patients may be, of necessity, substituting formal exercise therapy for other activities without increasing their overall fitness or physical activity. Alternatively, patients may not be adhering to the therapy protocol, and not accurately reporting that fact. Both possibilities could also affect harms reporting.References1. White et al response to Smith et al (Reference 5). 2. 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;377:823-36.3. Leone Ridsdale, Emma Godfrey, Trudie Chalder, Paul Seed, Michael King, Paul Wallace, Simon Wessely and the Fatigue Trialists’ GroupChronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trialBritish Journal of General Practice, 2001, 51, 19-24.4. L. Ridsdale, M. Hurley, M. King, P. McCrone1 and N. DonaldsonThe effect of counselling, graded exercise and usual care for people with chronic fatigue in primary care: a randomized trialPsychological Medicine (2012), 42, 2217–2224.5. 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.
Miak Speedy, MD
July 21, 2015
Graded Exercise Therapy for ME/CFS: ineffective at best, harmful in reality
Smith et al. concluded that “trials of ... counseling therapies, and graded exercise therapy suggest benefit for some ... whereas evidence for …. harms is insufficient.”(1)As a doctor, bedridden with ME for over a decade and totally dependent on others, all thanks to a major relapse caused by Graded Exercise Therapy (GET), I'm in a unique position to answer how harmful GET and CBT really are. The basis of GET and CBT is false illness beliefs, meaning it is all in the mind, ignoring all the evidence, for example intracellular immune dysfunctions, which not only restrict exercise capacity, but are also made worse by exercise , that this is a physical disease. ME's main characteristic is an abnormally delayed muscle recovery after doing trivial things, not chronic fatigue, and GET and CBT force you to ignore your symptoms to exercise your way back to full fitness. If you do that, you go over your limit, causing a relapse, and the more you go over your limit, the bigger the relapse and the less likely you are to recover from it.Many ME patients have been made homebound/bedridden, the result of a major relapse caused by GET and we will only get our health/independence back if we get proper medication. The Norwegian Rituximab studies suggest that ME is an autoimmune disease and 2/3 of responders are still in remission at the 36-month follow-up.  The ME Association recently published a big study, concluding there's no role for CBT, which increases the risk of making things worse, and GET is harmful and should be withdrawn immediately.  Falk Hvidberg et al. recently found that ME/CFS patients have the lowest health-related quality of life of 21 conditions looked at, which included chronic renal failure, strokes, lung cancer etc.  In reality, only two sorts of ME patients can do graded exercise therapy. A small minority where the disease is in remission, and "ME" patients were the diagnosis is wrong.In all other ME patients, GET causes severe relapses and BREACHES the do no harm principle of medicine.The alarming findings by Falk Hvidberg et al.  show that CBT and GET, tried by most ME patients, are not effective, and that there is an urgent need for effective medication for this debilitating disease, so that we get our health and independence back, can come off benefits and go back to work. 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. Nijs J, Nees A, Paul L, DeKooning M, Ickmans K, Meeus M, et al. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. 2014;20:94-116. 3. Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, et al. (2015) B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS ONE 10(7): e0129898. doi:10.1371/journal.pone.0129898 4. ME Association, Our CBT, GET and Pacing Report calls for major changes to therapies offered for ME/CFS, 29 May 2015, http://www.meassociation.org.uk/2015/05/23959/ (accessed 18 July 2015) 5. Falk Hvidberg M, Brinth LS, Olesen AV, Petersen KD, Ehlers L (2015) The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS ONE 10(7): e0132421. doi:10.1371/journal.pone.0132421
M.E. Beth Smith†, DO; Elizabeth Haney†, MD; Heidi D. Nelson†¶, MD, MPH
†Pacific Northwest Evidence-based practice Center, Oregon Health & Science University and ¶Providence Cancer Center, Providence Health and Services Oregon, Portland, Oregon
July 30, 2015
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop
We thank the authors for their comments and Dr. Speedy for sharing his personal experience. Regarding Dr. White’s comments about the harms of exercise, we acknowledge that exercise testing is distinct from graded exercise programs. However, both forms of exercise may be considered harmful by patients. To clarify the results of the Moss-Morris trial, while 44% of participants in the intervention group declined repeat exercise testing, 20% declined because of their perception of harm.1 Also, although the Cochrane review did not identify harms of exercise, the authors drew similar conclusions to ours stating that, “limited information makes it difficult to draw firm conclusions about the safety of exercise therapy.” 2
To address Dr. Chu’s comment about safety data in the Nunez trial, we agree that a decline in physical function and pain were reported in the intervention group. However, the trial reported within-group differences, not between-group differences,3 which are necessary to support results of comparisons of interventions in the trial.
Dr. Chu’s comment regarding the importance of analyzing data based on case definitions used for inclusion to trials is consistent with our approach. For example, in the trials of cognitive behavioral therapy (CBT) using the SF-36 physical function item as an outcome measure, the two studies using Oxford criteria indicated improvement, while the two using CDC criteria reported no improvement.4 We also agree with Dr. White’s comment that combining counseling and CBT trials in a meta-analysis may dilute the effectiveness of each individually, which is why our meta-analysis included only trials of CBT.
The studies referenced by Drs. Chu and Kirby, regarding the effectiveness of CBT and graded exercise therapy (GET) and predictors of outcomes, were excluded from our analysis because they included participants with chronic fatigue rather than ME/CFS.5,6 Of the fatigued participants, 31% met criteria for CFS (CDC Fukuda). Although CFS participants had more fatigue and functional impairment compared to other participants, no case definitions were compared and outcomes for the CFS participants based on intervention were not evaluated.
(1) 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.
(2) 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.
(3) Nunez M, Ferna´ndez-Sola J, Nunez E, Ferna´ndez-Huerta JM, Godas-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.
(4) 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;162:841-850. doi:10.7326/M15-0114
(5) L. Ridsdale, M. Hurley, M. King, P. McCrone1 and N. Donaldson
The effect of counselling, graded exercise and usual care for people with chronic fatigue in primary care: a randomized trial
Psychological Medicine (2012), 42, 2217–2224.
(6) Darbishire L, Seed P, Risdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005; 186 (4) 350-351
Lily Chu, MD, MSHS
Independent consultant, Burlingame, CA
December 15, 2015
Conflict of Interest:
I am involved in ME/CFS research.
Between-group difference in Nunez et al. trial/ differences in outcomes from GET depending on symptoms
I thank Smith et al. for replying to my prior letter. I am writing again to clarify two points. 1) In their paper, Nunez et al. (1) analyzed both within-group and between-group differences. At trial initiation, intervention and control groups started out with similar SF-36 pain scores (27.09±24.22 vs. 27.41±19.04). Under the heading of “Between-group differences,” the researchers wrote, “At 12-months, SF-36 pain dimension scores were significantly lower in the intervention group [ME/CFS patients who received graded exercise therapy (GET) and cognitive behavioral therapy (CBT)] (21.81±21.43 vs. 29.34±21.58 [control group], p=0.040).” For the SF-36, a lower score denotes a decreased level of function. In the discussion section they reiterated this point, writing, “Between-group analysis showed that the intervention group had worse SF-36 bodily pain dimension scores at 12 months.” 2) In an accompanying paper (3) to the one I previously cited (2), Risdale et al. showed, in subgroup analysis, that among a group of chronically fatigued subjects assigned to graded exercise therapy, those fitting Fukuda criteria were much less likely to recover by the end of the trial compared to those who did not (19% vs. 65%). The symptom criteria for entry into their study was fatigue as “a main or important problem” for at least 3 months.(2) I bring up these two papers because they show the wide differences in outcomes from GET depending on what symptoms are present in a patient. Although Risdale et al. did not directly compare subjects fitting Oxford criteria with those fitting Fukuda criteria, their studies’ results suggest that patients fitting Oxford criteria, which require no other symptoms except chronic fatigue, might respond differently to GET than those fitting Fukuda criteria, which requires at least 4 other specific symptoms besides chronic fatigue. Thus, combining trials of GET using Oxford criteria with those using Fukuda criteria could lead to inaccurate conclusions. References: (1) Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta JM, Godás-Sieso T. 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. (2) Darbishire L, Seed P, Risdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005; 186 (4) 350-351. (3) Ridsdale L, Darbishire L, Seed PT. Is graded exercise better than cognitive behaviour therapy for fatigue? A UK randomized trial in primary care. Psychol Med. 2004 Jan;34(1):37-49.
Independent Consultant, Burlingame, CA
August 24, 2016
Strength of evidence downgraded for CBT and GET for subjects fitting criteria other than Oxford
Since this paper was published, in response to comments, Dr. Smith and her colleagues have conducted sensitivity analyses on the data, assessing the impact of CBT and GET on various outcomes when only subjects fitting Oxford criteria are considered versus when only subjects fitting non-Oxford case definitions (i.e. 1994 Fukuda) are considered. They concluded in an Addendum to the original report that:"Our sensitivity analysis would result in a downgrading of our strength of evidence onseveral outcomes which can be attributed to the decrease in power, dominance of one large trial, or lack of trials using criteria other than the Oxford (Sharpe, 1991) case definition for inclusion. Blatantly missing from this body of literature are trials evaluating effectiveness of interventions in the treatment of individuals meeting case definitions for ME or ME/CFS."Almost all patients are diagnosed in the United States using the Fukuda criteria, rather than the Oxford criteria used primarily in the United Kingdom. This means that US clinicians need to be aware of low strength of evidence or the lack of evidence behind CBT and GET when considering this treatment for their ME/CFS patients. The full revised report may be read at: https://effectivehealthcare.ahrq.gov/ehc/products/586/2004/chronic-fatigue-report-160728.pdf
Smith MB, 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;162:841–850. doi: 10.7326/M15-0114
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Published: Ann Intern Med. 2015;162(12):841-850.
Chronic Fatigue Syndrome/Fibromyalgia, Rheumatology.
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