1. edmonds m. et al. exercise therapy for chronic fatigue syndrome. cochrane database syst rev 2004...

8/18/2019 1. Edmonds M. Et Al. Exercise Therapy for Chronic Fatigue Syndrome. Cochrane Database Syst Rev 2004 3 CD00…

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Exercise therapy for chronic fatigue syndrome (Review)

Edmonds M, McGuire H, Price JR

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2004, Issue 3

http://www.thecochranelibrary.com

Exercise therapy for chronic fatigue syndrome (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7 AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15 ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18 WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iExercise therapy for chronic fatigue syndrome (Review)



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[Intervention Review]

Exercise therapy for chronic fatigue syndrome

Melissa Edmonds1

, Hugh McGuire2

, Jonathan R Price3

1Lambeth Forensic Mental Health Services, Lambeth Hospital, London, UK. 2National Collaborating Centre for Women’s and

Children’s Health, London, UK. 3 Department of Psychiatry, University of Oxford, Oxford, UK

Contact address: Jonathan R Price, Department of Psychiatry, University of Oxford, The Warneford Hospital, Headington, Oxford,

OX3 7JX, UK. [email protected] .

Editorial group: Cochrane Depression, Anxiety and Neurosis Group.

Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 8, 2013.

Review content assessed as up-to-date: 8 May 2004.

Citation: Edmonds M, McGuire H, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews

2004, Issue 3. Art. No.: CD003200. DOI: 10.1002/14651858.CD003200.pub2.


A B S T R A C T

Background

Chronic fatigue syndrome (CFS) is an illness characterised by persistent medically unexplained fatigue. CFS is a serious health-care

problem with a prevalence of up to 3%. Treatment strategies for CFS include psychological, physical and pharmacological interventions.

Objectives

To investigate the relative effectiveness of exercise therapy and control treatments for CFS.

Search methods

CCDANCTR-Studies and CENTRAL were searched using “Chronic Fatigue” and Exercise. The Journal of Chronic Fatigue Syndrome

and CFS conferences were handsearched. Experts in the field were contacted. Clinicaltrials.gov and controlled-trials.com were searched.

Selection criteria

Only Randomised Controlled Trials (RCT) including participants with a clinical diagnosis of CFS and of any age were included.

Data collection and analysis

The full articles of studies identified were inspected by two reviewers (ME and HMG). Continuous measures of outcome were

combined using standardised mean differences. An overall effect size was calculated for each outcome with 95% confidence intervals.

One sensitivity analysis was undertaken to test the robustness of the results.

Main resultsNine studies were identified for possible inclusion in this review, and five of those studies were included. At 12 weeks, those receiving

exercise therapy were less fatigued than the control participants (SMD -0.77, 95% CIs -1.26 to -0.28). Physical functioning was

significantly improved with exercise therapy group (SMD -0.64, CIs -0.96 to -0.33) but there were more dropouts with exercise therapy

(RR 1.73, CIs 0.92 to 3.24). Depression was non-significantly improved in the exercise therapy group compared to the control group

at 12 weeks (WMD -0.58, 95% CIs -2.08 to 0.92).

Participants receiving exercise therapy were less fatigued than those receiving the antidepressant fluoxetine at 12 weeks (WMD -1.24,

95% CIs -5.31 to 2.83). Participants receiving the combination of the two interventions, exercise + fluoxetine, were less fatigued than

1Exercise therapy for chronic fatigue syndrome (Review)


mailto:[email protected]:[email protected]


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those receiving exercise therapy alone at 12 weeks, although again the difference did not reach significance (WMD 3.74, 95% CIs -

2.16 to 9.64).

When exercise therapy was combined with patient education, those receiving the combination were less fatigued than those receiving

exercise therapy alone at 12 weeks (WMD 0.70, 95% CIs -1.48 to 2.88).

Authors’ conclusions

There is encouraging evidence that some patients may benefit from exercise therapy and no evidence that exercise therapy may worsen

outcomes on average. However the treatment may be less acceptable to patients than other management approaches, such as rest or

pacing. Patients with CFS who are similar to those in these trials should be offered exercise therapy, and their progress monitored

Further high quality randomised studies are needed.

P L A I N L A N G U A G E S U M M A R Y

Exercise for chronic fatigue syndrome

Based on five included studies, this systematic review cautiously concludes that exercise therapy is a promising treatment for chronic

fatigue syndrome. However, studies of higher quality are needed that involve different patient groups and settings, and that measureadditional outcomes such as adverse effects, quality of life and cost effectiveness over longer periods of time.

B A C K G R O U N D

Chronic fatigue syndrome (CFS) is an illness characterised by per-

sistent medically unexplained fatigue of more than six months

duration. Sufferers experience significant disability and distress,

which may be further exacerbated by a lack of understanding fromothers, including health professionals. CFS is a serious problem

thought to affect up to 1% of the general population ( Wessely

1995) though the reported prevalence ranges from 0.006% to 3%

depending on the setting and criteria used ( Afari 2003). It has

also been known as Royal Free disease, Iceland disease, neuras-

thenia, myalgic encephalomyelitis (’ME’), and post-viral fatigue

syndrome. However, CFS is the term that has been adopted and

clearly defined for the purpose of research in this area.

Non-persistent medically unexplained fatigue (fatigue of more

than 3 months but less than 6 months) is more common but 75%

of these patients have fatigue that do not meet CFS (Ridsdale

2001). With usual medical care typically in a general practice set-

ting 70-75% of these patients report that their fatigue symptoms

become chronic (Ridsdale 1993).

Many sufferers in the community attend their local general prac-

titioners for assessment. However, diagnosis is poor due to nor-

mal or equivocal findings on physical examination or investiga-

tion. As a result some attend alternative practitioners, whilst oth-

ers are referred to out-patient clinics for assessment. Referrals are

made to a variety of specialist clinics including general medicine,

endocrinology, infectious disease, neurology, and psychiatry. This

reflects the uncertainty, and often disagreement between doctors

and sufferers regarding the causes of CFS, which in turn may lead

to unsatisfactory patient-professional relationships, and ultimately

dissatisfied patients.

Opinions regarding the causes of CFS have generally focused on

either physical or psychological explanations, although more re-

cently there has been an increasing awareness of the potential in-

teraction of physical and psychological factors in the development

and maintenance of the disorder. Psychosocial factors appear to

be important. While there is some evidence for abnormalities in

the hypothalamic-pituitary-adrenal axis similar to those evident in

post-traumaticstress disorder, it is uncertainwhether thesechanges

are causal or a result of the disorder. The current scientific con-

sensus is that CFS involves the neuro-endocrine system, but not

in a manner identical to depression.

Treatment strategies for CFS include psychological, physical andpharmacological interventions. Randomised controlled trials have

been carried out to assess the effectiveness of treatments as diverse

as exercise therapy (Fulcher 1997; Wearden 1998), self-help treat-

ment (Chalder 1997), antidepressants (Behan 1995; Vercoulen

1996; Wearden 1998), and dietary supplementation with fatty

acids ( Warren 1999) and folic acid (Kaslow 1989). A recent sys-

tematic review found that cognitive behaviour therapy was effec-

tive for CFS in adults (Price 2000).




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Exercise therapy has been shown to improve strength, cardiovas-

cular function, and psychological status in general populations

(Bouchard 1993) but no review has looked at the efficacy or effec-

tiveness of exercise therapy for CFS. An earlier systematic review

of randomised controlled trials of treatments for CFS ( Whiting

2001) found three trials of exercise therapy, and reported an over-all beneficial effect.

Two furtherstudies haverecently been completed and are included

in this systematic review and meta-analysis.

O B J E C T I V E S

1) To systematically review all randomised controlled trials of ex-

ercise therapy for adults with CFS.

2) To investigate the relative effectiveness of exercise therapy alone

or as part of a treatment plan.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Onlyrandomised controlled trials, published or unpublished, were

included.

Types of participants

Subjects were adult men and women of all ages with a clinical di-

agnosis of Chronic Fatigue Syndrome according to ICD 10 crite-

ria ( WHO 1992), Oxford criteria (Sharpe 1991), CDC (Fukuda

1994) or any other validated criteria.

Types of interventions

All studies in which exercise therapy was compared with a control

group (i.e. treatment as usual or control treatments such as relax-

ation) or other active interventions (such as psychological treat-

ments or pharmacotherapy). Treatment as usual comprises medi-

cal assessments and advice to exercise when capable.

The following treatment comparisons were made;

1. Exercise therapy versus treatment as usual or relaxation + flexi-

bility

2. Exercise therapy versus pharmacotherapy (fluoxetine).

3. Exercise therapy alone versus exercise therapy + pharmacother-

apy (fluoxetine)

4. Exercise therapy alone versus exercise therapy + patient educa-

tion

Types of outcome measures

Fatigue symptoms are the main outcome of this review. The pri-

mary outcome measure is theChalder Fatigue Scale, a 14 item self-

rated scale measuring physical and mental fatigue (Chalder 1993)

or any other fatigue scale.

The secondary outcome measures used were depression using any scale, and quality of life using any scale. Other possible measures

include timed walking tests and tests of strength or of aerobic

capacity.

Other secondary outcomes were as follows;

1) symptoms e.g. pain.

2) health service resource use e.g. primary care consultation rate,

secondary care referral rate, use of alternative practitioners.

3) dropouts.

4) adverse effects.

Search methods for identification of studies

1. ELECTRONIC SEARCHING

a/ The Cochrane Collaboration Depression, Anxiety & Neurosis

Controlled Trials Register (CCDANCTR-Studies) was searched

using the following terms

Diagnosis = “Chronic Fatigue”

and

Intervention = “Exercise”.

b/ The Cochrane Central Register of Controlled Trials (CEN-

TRAL) on the Cochrane Library (Issue 1, 2004) was searched

using the following terms (Chronic Fatigue Syndrome or CFS)

combined with ((aerobic or anaerobic or exercise) and therapy)

c/ We searched for ongoing studies at Clinicaltrials.gov and con-

trolled-trials.com.2. HANDSEARCHING

a/ The Journal of Chronic Fatigue Syndrome (1995 - 2003) was

searched by ME to identify relevant studies

b/ The following conferences were searched.

Alison Hunter Memorial Foundation (AHMF) Conference 1999

Alison Hunter Memorial Foundation (AHMF) Conference 2001

3. Experts in the field were contacted to identify trials either pub-

lished or unpublished.

4. Reference lists of retrieved studies and reviews were searched.

Data collection and analysis

STUDY SELECTION

The full articles of studies for possible inclusion were inspected

by the principal reviewer (ME). All articles were re-inspected by

HMG. Studies that were identified by citation tracking or per-

sonal communication were also screened by both ME and HMG.

Eligibility criteria were used to select relevant studies. There was

no disagreement on studies to be included.

QUALITY ASSESSMENT OF TRIALS




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The assessment of methodological quality was conducted accord-

ing to the Cochrane Collaboration Handbook criteria ( Alderson

2004). Concealment of allocation was the main quality criterion

for included studies. The adequacy of allocation concealment was

rated as adequate (A), unclear (B) or inadequate (C) or not used

(D). We also used the CCDANQuality Rating System (Moncrieff 2001) which includes the following criteria;

(1) Objectives and specification

(2) Sample size (no per group)

(3) Planned duration of trial including follow up

(4) Power calculation

(5) Method of allocation

(6) Concealment of allocation

(7) Clear description of treatment (including doses of drugs) &

adjunctive treatment

(8) Blinding of subjects

(9) Source of subjects described and representative sample recruit-

ment

(10) Use of diagnostic criteria (or clear specification of inclusioncriteria)

(11) Record of exclusion criteria and number of exclusions and

refusals reported

(12) Description of sample demographics

(13) Blinding of assessor

(14) Assessment of compliance with experimental treatments (in-

cluding attendance for therapy)

(15) Details on side-effects

(16) Record of number and reasons for withdrawal by group

(17) Outcome measures described clearly or use of validated in-

struments

(18) Information on comparability and adjustment for differences

in analysis(19) Inclusion of withdrawals in analysis (ITT or endpoint)

(20) Presentation of results with inclusion of data for re-analysis

of main outcomes (e.g. SDs)

(21) Appropriate statistical analysis (including correction for mul-

tiple tests where applicable)

(22) Conclusions justified

(23) Declaration of interests (e.g. source of funding).

Each item is scored between 0 and 2, with a maximum total score

of 46. Two reviewers (ME and HMG) carried out the quality

assessment and disagreements were resolved by discussion.

DATA EXTRACTION

Data from included studies were independently extracted by ME

and JRP using a standardised extraction sheet. The mean scores atendpoint, the standard deviation (SD) or standard error (SE) of

these values, andthe numberof patientsincluded in these analyses,

were extracted. When only the SE was reported, it was converted

intoSD. Clarificationfrom the authors wassought when necessary.

For dichotomous outcomes, such as drop-outs, the number was

extracted. Disagreement between ME and JRP was resolved by

discussion between all reviewers.

DATA ANALYSIS

Post-treatment outcomes

The main outcome in thetrials forthis reviewwere symptom levels

measured by rating scales, at 12 weeks and/or 24 weeks follow-

up, presented as continuous data (means and SD). These were

measured in the following waysa. Fatigue (using any scale)

b. Depression (using any scale)

c. Quality of life (using any scale)

Analyses were performed using Review Manager 4.2.

For continuous outcomes the weighted mean difference (WMD)

was calculated when the same scale was used in a similar manner

across studies. Where results for continuous outcomes were pre-

sented using different scales or different versions of the same scale,

we used standardised mean differences (SMD). For dichotomous

outcomes the effect sizes were expressed in terms of relative risk

(RR).

Due to the potential statistical heterogeneity among studies, the

random-effect model was used as the default method of analysis,because the alternative fixed effect model assumes that the true

treatment effect in each trial is the same and that the observed

differences are due to chance. Heterogeneity was investigated by

performing a formal statistical test of heterogeneity.

No sensitivity analyses were planned a-priori. However a post-hoc

sensitivity analysis was carried out by removing one study that had

used a shortened version of the Chalder Fatigue Scale.

Where sufficient numbers of trials allowed a meaningful presenta-

tion, funnel plots were constructed to establish whether other po-

tential biases could be operating. Funnel plots provide a graphical

display of sample size plotted against effect size that can be used to

investigate publication bias. When many studies havebeen located

that estimate the same effect, the distribution of points shouldresemble a funnel shape with a widening in the spread of effect

sizes as sample size decreases. A gap on one side of the wide part

of the funnel indicates that some studies have not been published

or located.

R E S U L T S

Description of studies

Nine studies for possible inclusion were identified of which five

were included. One study ( White 2003) is ongoing and one

(Stevens 1999) is awaiting assessment as this has only been pub-

lished as a PhD thesis in the USA and we have not acquired the

full hardcopy. Neither of the two excluded studies met the inclu-

sion criteria as the diagnosis used was “Gulf War Veterans Illness”

(Guarino 2001) and subclinical chronic fatigue (Darbishire 2003).

Included Studies




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Five studies Appleby 1995; Fulcher 1997; Powell 2001; Moss-

Morris 2003 and Wallman 2004 met our inclusion criteria. Four

were published in peer-reviewed journals and written in English

and the fifth (Moss-Morris 2003) has been submitted for pub-

lication. Three studies took place in tertiary-care settings in the

United Kingdom. One study took place in a GP setting in Aus-tralia ( Wallman 2004), and one study took place in a specialist GP

service in New Zealand (Moss-Morris 2003). The five studies ran-

domised a total of 336 participants. Ethics approval was obtained

for all studies and sponsors/funders were listed.

Study Demographics

The levels of comorbid depression (as measured by diagnostic

criteriaor by antidepressant usage) wassimilar across all fivestudies

and the percentage of females ranged from 57% to 87%. The

median duration of illness was similar in the three groups that

reported these data.

Table 1

Intervention Characteristics

The exercise therapy regime lasted 12 weeks in all five studies andall used aerobic graded exercise therapy but with mixed levels in

terms of intensity 40% VO2max to 70%VO2max and between 3

to 5 sessions/week with a target duration of 30 mins per session.

Contact with the therapist was minimal usually once a week and

most of the studies used exercise logs to measured adherence to

treatment. The control interventions used weretreatment as usual,

relaxation + flexibility, pharmacotherapy and patient education.

Table 2

Risk of bias in included studies

Type of Study

Each study was a single-centre controlled study with random al-location of individual participants.

Quality

All studies had blind allocation and used independent administra-

tors. Three (Fulcher 1997; Moss-Morris 2003; Powell 2001) con-

cealed allocation using opaque envelopes. Scores on the CCDAN

Quality Rating System averaged 29.8 from a total score of 46 and

the totals are presented in Table 03.

Table 3

Intention-to-treat analysis

Fourstudies carried outan intentionto treat analysis(Powell 2001;

Appleby 1995; Fulcher 1997; Moss-Morris 2003), and in the fifth

study ( Wallman 2004) this was not clear. Three studies ( Appleby

1995; Moss-Morris 2003; Powell 2001)managedmissingdatabya

last observation carried forward approach, and one study (Fulcher

1997) by classifying patients with missing data as non-improvers.

One study ( Wallman 2004) reported no dropouts.

Definition of inclusion/exclusion criteria

All five studies had well defined inclusion/exclusion criteria in-

cluding a diagnosis according to Oxford criteria ( Appleby 1995;

Fulcher 1997; Powell 2001) or CDC criteria (Moss-Morris 2003;

Wallman 2004). Comorbiddepression or antidepressant usagewas

not a criterion for exclusion in any trial.

Compliance

Compliance was measured in four studies. Fulcher 1997 used an

activity diary to record duration and response to exercise. Appleby

1995 asked participants to complete a chart to monitor pre-postexercise heart rate and perceived exertion. Powell 2001 reported

weekly supportive/motivational sessions with subjects where ques-

tions or problems with the intervention were answered. Wallman

2004 also used a daily exercise log.

Effects of interventions

Exercise Therapy vs. Control (treatment as usual or relaxation+

flexibility)

All 5 studies contributed to this analysis at 12 weeks but only two

studies contributed at 24 weeks.

A - Fatigue At 12 weeks, exercise therapy was significantly more effective than

treatment as usual on the Chalder Fatigue Scale (SMD -0.77, 95%

CIs -1.26 to -0.28). This difference was not significant at 24 weeks

(SMD -1.04, 95% CIs -2.49 to 0.40).

As the Powell 2001 study used a shortened version of the Chalder

Fatigue Scale, we carried out a sensitivity analysis excluding this

study and calculated the Weighted Mean Difference method. Ex-

ercise therapy was again significantly more effective than control

at 12 weeks (WMD -5.09, 95% CIs -8.79 to -1.40) but this was

reduced to non-significance at 24 weeks (WMD -3.45, 95% CIs

-9.70 to 2.80).

B - Depression

Three studies ( Appleby 1995; Fulcher 1997; Wallman 2004) con-tributed to this analysis at 12 weeks and one ( Appleby 1995) con-

tributed at 24 weeks. The studies all used the Hospital Anxiety

and Depression Scale - Depression subscale (Zigmond 1983). Ex-

ercise therapy was favoured slightly over control at both 12 weeks

(WMD -0.58, 95% CIs -2.08 to0.92) and 24 weeks (WMD0.50,

95% CIs -1.32 to 2.32).

C - Quality of life

Three studies (Fulcher 1997; Moss-Morris 2003; Powell 2001)

contributed to this analysis using the Physical Functioning scale

of the SF-36. Physical functioning improved significantly with

exercise therapy (SMD -0.64, CIs -0.96 to -0.33).

Scores on the SleepProblem Questionnaire improved significantly

in the exercise therapy group in the Powell 2001 study (WMD -

4.70, CIs -7.02 to -2.38).

Functional work capacity improved in the exercise therapy group

compared to the control group at 12 weeks (WMD -4.40, CIs -

.9.10 to 0.30) and at 26 weeks (WMD -2.89, CIs -7.71 to 1.93)

in the Appleby 1995 study, but at neither time was the difference

statistically significant.

D - Drop-out




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Drop-out was more common among exercise therapy participants

(23/161) than among control participants (13/154) (RR 1.73,

95% CIs 0.92 to 3.24,), although the difference was not signifi-

cant.

E - Adverse effects

No data for this outcome were reportedExercise Therapy vs. Pharmacotherapy (Fluoxetine)

Only one trial ( Appleby 1995) contributed to this comparison. It

compared exercise therapy + drug placebo with exercise placebo +

fluoxetine. We decided to assume that the effects of the two place-

bos would cancel each other out, in which case this comparison

becomes exercise versus fluoxetine.

A - Fatigue

Exercise therapy was more effective than fluoxetine at 12 weeks on

the Chalder Fatigue Scale (WMD -1.24, 95% CIs -5.31 to 2.83)

and at 24 weeks (WMD -1.99, 95% CIs -8.28 to 4.30), although

at neither time did the difference reach statistical significance.

B - Depression

Fluoxetine was more effective than exercise therapy at 12 weekson the Hospital Anxiety and Depression Scale (WMD 0.96, 95%

CIs -0.91 to 2.83) and at24 weeks (WMD0.15, 95% CIs -2.11 to

2.41), although at neither time did the difference reach statistical

significance.

C - Quality of life

Functional work capacity was higher in the exercise therapy group

at 12 weeks (WMD -0.74, 95% CIs -4.63 to 3.15), although the

difference was not statistically significant. However, at 24 weeks,

fluoxetine was significantly more effective than exercise therapy

(WMD 15.85, 95% CIs 12.64 to 19.06).

D - Drop-out

Drop-out was more common among the exercise therapy group

(11/34) than for the fluoxetine group(10/35) (RR 1.13, 95% CIs0.55 to 2.31), although the difference was not significant.

E - Adverse effects

No data for this outcome were reported

Exercise Therapy vs. Exercise therapy + Pharmacotherapy (Fluox-

etine)

Only one trial ( Appleby 1995) contributed to this comparison,

and compared exercise therapy + drug placebo to exercise therapy

+ fluoxetine.

A - Fatigue

Exercisetherapy combinedwith fluoxetinewasmoreeffectivethan

exercise therapy alone at 12 weeks on the Chalder Fatigue Scale

(WMD 3.74, 95% CIs -2.16 to 9.64) and at 24 weeks (WMD

1.87, 95% CIs -6.01 to 9.75), although at neither time did thedifference reach significance.

B - Depression

There was no difference between exercise therapy combined with

fluoxetine and exercise therapy alone at 12 weeks (WMD 0.73,

95% CIs -1.31 to 2.77) or at 24 weeks (WMD 0.42, 95% CIs -

2.06 to 2.90).

C - Quality of Life

Exercise therapy combined with fluoxetine improved functional

work capacity more than exercise therapy alone at 12 weeks

(WMD 1.87, 95% CIs -6.01 to 9.75) and at 24 weeks (WMD

3.74, 95% CIs -2.16 to 9.64), although at neither time did the

difference reach statistical significance.

D - Drop-outDrop-out was more common among the combined treatment

group (14/33) than among the exercise therapy only group (11/

34) (RR 0.76, 95% CIs 0.41 to 1.43), although the difference was

not significant.

E - Adverse effects


Exercise Therapy vs. Exercise therapy + Patient Education

Only one trial (Powell 2001) contributed to this comparison It

compared treatment as usual to exercise therapy and three levels

of patient education. These levels varied between explanation of

graded exercise and design of an exercise programme (minimal in-

tervention, equivalent to exercise therapy) and minimal interven-

tion plus seven one-hour face to face educational sessions (maxi-mal intervention, equivalent to exercise therapy + patient educa-

tion)

A - Fatigue

Exercise therapy combined with patient education was more ef-

fective than exercise therapy alone at 12 weeks on the Chalder Fa-

tigue Scale (WMD 0.70, 95% CIs -1.48 to 2.88) and at 24 weeks

(WMD 0.40, 95% CIs -1.43 to 2.23), although at neither time

was the difference statistically significant.

B - Depression

There was no significant difference between exercise therapy alone

andexercise therapy + patient educationat either12 weeks (WMD

0.30, 95% CIs -1.39 to 1.99) or at 24 weeks (WMD 0.40, 95%

CIs -1.51 to 2.31).C - Quality of life

There was no significant difference between exercise therapy alone

and exercise therapy + patient education on the Sleep Problem

Questionnaire at 6 months (WMD -0.80, 95%CIs -2.85 to 1.25).

D - Drop-out

Drop-out was more common among the combined treatment

group (8/38) than among the exercise therapy alone group (5/37)

(RR 0.64, 95% CIs 0.23 to 1.78), although the difference was not

significant.

E - Adverse effects


D I S C U S S I O N

CFSis a major healthproblem andexerciseis a common treatment

approach. The strength of this review lies in its rigorous meth-

ods, which include thorough searching for evidence, systematic

appraisal of study quality, and systematic and well defined data

synthesis. Its main limitation is the lack of evidence with which




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to inform its results and conclusions. It is disappointing that de-

spite thorough searching only nine randomised studies of exercise

therapy for CFS were found of which five were included with a

total of 336 participants randomised, two were excluded, one is

undergoing assessment and one is ongoing.

The main conclusion of the review is that fatigue, as measuredby the Chalder fatigue scale, was improved at three months by

exercise therapy when compared to the control group (relaxation

+ flexibility or treatment as usual). This result was robust when a

sensitivity analysis was performed in which Powell 2001 (using a

shortened version of the Chalder Fatigue Scale) was excluded. In

addition to the primary outcome measure, measures of health-re-

lated quality of life, sleep, and functional work capacity all showed

benefit of graded exercise over control that were either significant

or close to significance.

The benefit of exercise therapy over the control group (relaxation

+ flexibility or treatment as usual) did not diminish between three

and six months, but became non-significant. As only 118 partic-ipants contributed to the analysis at 6 months, this may be the

result of a lack of power to detect an effect that still exists. Further

trials with longer follow-up are needed.

There is some evidence that fluoxetine provides an added benefit

when administered alongside exercise therapy but further studies

are needed to examine this.

An intensive patient educational intervention added to exercise

therapy delivered no added benefit when compared to exercise

therapy with usual explanation. This is encouraging for the feasi-

bility of the intervention, as it supports the view that exercise ther-

apy does not require large amounts of professional time in order

to be effective.

Dropouts from treatment were most frequent in Appleby 1995,

and this study is the only one in which exercise is not significantly

more effective than control on the main outcome. The partici-

pants in Appleby 1995 are similar to the other studies, and it may

be that the much higher exercise intensity (75% VO2max com-

pared to 40% in the other two studies which reported exercise

intensity) is responsible for higher dropout and consequently to

poorer outcome.

The limited evidence base limits the precision of the results. It

also means that a single unidentified trial, or further trials, could

have a substantial effect on the results and conclusions of the

review. As there are few studies, indirect methods of identifying publication bias such as funnel plots are of very limited value, and

were therefore not conducted.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Thereis encouraging evidencethat somepatients may benefitfrom

exercise therapy. Patients with CFS who are similar to those in

these trials should be offered exercise therapyand their subsequent

progress monitored.

Implications for research

It is disappointing that one of the commonest treatment ap-

proaches to CFS - exercise - has not been more extensively studied.

The results of the trial in progress ( White 2003) which compares

exercise therapy with treatment as usual are awaited with interest.

Even when the results of that study are available, it is possible that

uncertainty will remain. Further randomised studies are needed,

with longer follow-up, to determine whether patients who respond

to exercise stay well or relapse.

A C K N O W L E D G E M E N T S

We would like to thank Dr Peter White for advice and additional

information, Dr Alison Wearden and Dr Karen Wallman for addi-

tional information, and Dr Rona Moss-Morris for information on

the unpublished studies, the CCDAN editorial base for support

and advice and the external referees for their comments on the

first draft of this review.

R E F E R E N C E S

References to studies included in this review

Appleby 1995 {published data only}

Appleby L. Aerobic exercise and fluoxetine in the treatment

of chronic fatigue syndrome. National Research Register

1995.

Morriss R, Wearden A, Mullis R, Strickland P, Appleby

L, Campbell I, et al.A double-blind placebo-controlled

treatment trial of fluoxetine and graded exercise for chronic

fatigue syndrome (CFS). 8th Congress of the Association of

European Psychiatrists, London. 1996.

Wearden A, Morriss R, Mullis R, Strickland P, Pearson

D, Appleby L, et al.A double-blind, placebo controlled

treatment trial of fluoxetine and a graded exercise

programme for chronic fatigue syndrome. Anglo-

Portuguese Consultation Liaison Psychiatry Conference,

Lisbon. 1996.∗ Wearden AJ, Morriss RK, Mullis R, Strickland PL, Pearson

DJ, Appleby L, et al.Randomised, double-blind, placebo-




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controlled treatment trial of fluoxetine and graded exercise

for chronic fatigue syndrome. British Journal of Psychiatry

1998;178:485–92.

Fulcher 1997 {published data only}∗ Fulcher KY, White PD. Randomised controlled trial of

graded exercise in patients with chronic fatigue syndorme.

BMJ 1997;314(7095):1647–52.

White PD, Fulcher KY. A randomised controlled trial of

graded exercise in patients with a chronic fatigue. Royal

College of Psychiatrists Winter Meeting, Cardiff. 1997.

Moss-Morris 2003 {unpublished data only}∗ Moss-Morriss R, Wash C, Tobin R, Baldi JC. Mechanisms

of change during a randomized controlled graded exercise

trials for Chronic Fatigue Syndrome. Submitted for

publication 2003.

Powell 2001 {published data only}∗ Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised

controlled trial of patient education to encourage graded

exercise in chronic fatigue syndrome. BMJ 2001;322

(7283):387–90. Wallman 2004 {published and unpublished data}

∗ Wallman KE, Morton AR, Goodman C, Grove R,

Guilfoyle AM. Randomised controlled trial of graded

exercise in chronic fatigue syndrome. Medical Journal of

Australia 2004;180(9):444–8.

References to studies excluded from this review

Darbishire 2003 {published data only}

Darbishire L, Ridsdale L, Seed PT. Distinguishing patients

with chronic fatigue from those with chronic fatigue

syndrome: a diagnostic study in UK primary care. British

Journal of General Practice 2003;53(491):441–5.

McCrone P, Darbishire L, Ridsdale L, Seed P. The economic

cost of chronic fatigue and chronic fatigue syndrome in UK primary care. Psychological Medicine 2003;33(2):253–61.∗ Ridsdale L, Darbishire L, Seed PT. Is graded exercise

better than cognitive behaviour therapy for fatigue? A UK

randomized trial in primary care. Psychological Medicine

2004;34(1):37–49.

Guarino 2001 {published data only}∗ Guarino P, Peduzzi P, Donta ST, Engel CE Jr, Clauw

DJ, Williams DA, et al.A multicenter two by two factorial

trial of cognitive behavior therapy and aerobic exercise for

Gluf War Veterans’ Illness: Design of a Veterans Affairs

Cooperative Study (CSP #470). Controlled Clinical Trials

2001;22(3):310–32.

References to studies awaiting assessment

Stevens 1999 {published data only}∗ Stevens MW. Chronic fatigue syndrome: a

chronobiologically oriented controlled treatment outcome

study. Dissertation Abstracts International 1999;60(4-B):

1907.

References to ongoing studies

White 2003 {unpublished data only}∗ White P. RCT of CBT, graded exercise, and pacing

versus usual medical care in chronic fatigue syndrome.

www.controlled-trials.com 2003.

Additional references

Afari 2003

Afari N, Buchwald D. Chronic fatigue syndrome: a review.

American Journal of Psychiatry 2003;160(2):221–36.

Alderson 2004

Alderson P, Green S, Higgins JP, editors. Cochrane

Reviewers’ Handbook 4.2.2 [updated December 2003].

The Cochrane Library . Vol. Issue 1, Chichester, UK: John

Wiley & Sons, Ltd, 2004.

Behan 1995

Behan PO, Hannifah H. 5-HT reuptake inhibitors in CFS.

EOS Rivista di Immunologia ed Immunofarmacologia 1995;

15(1-2):66–9.

Bouchard 1993Bouchard C, Shepherd RJ, Stephens T. Physical activity,

fitness, and health. Champagne, IL: Human Kinetics

Publishers, 1993.

Chalder 1993

Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely

S, Wright D, et al.Development of a fatigue scale. Journal of

Psychosomatic Research 1993;37(6):147–53.

Chalder 1997

Chalder T, Wallace P, Wessely S. Self-help treatment of

chronic fatigue in the community: A randomized controlled

trial. British Journal of Health Psychology 1997;2:189–97.

Deale 1998

Deale A, Chalder T, Wessely S. Commentary on:randomised, double-blind, placebo-controlled trial of

fluoxetine and graded exercise for chronic fatigue syndrome.

British Journal of Psychiatry 1998;172:491–2.

Fukuda 1994

Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins

JG, Komaroff A. The chronic fatigue syndrome; a

comprehensive approach to its definition and study. Annals

of Internal Medicine 1994;121(12):953–9.

Fulcher 1997

Fulcher KY, White PD. Randomised controlled trial

of graded exercise in patients with the chronic fatigue

syndrome. BMJ 1997;314(7095):1647–52.

Kaslow 1989Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-

cyanocobalamin vs placebo for chronic fatigue syndrome.

Archives of Internal Medicine 1989;149(11):2501–3.

Moncrieff 2001

Moncrieff J, Churchill R, Drummond C, McGuire H.

Development of a quality assessment instrument for trials of

treatments for depression and neurosis. International Journal

of Methods in Psychiatric Research 2001;10(3):126–33.




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Price 2000

Price JR, Couper J. Cognitive behaviour therapy for adults

with chronic fatigue syndrome. The Cochrane Library 2000,

Issue Issue 3.

Ridsdale 1993

Ridsdale L, Evans A, Jerrett W, Mandalia S, Osler K, Vora

H. Patients with fatigue in general practice: a prospectivestudy. BMJ 1993;307(6896):103–6.

Ridsdale 2001

Ridsdale L, Godfrey E, Chalder T, Seed P, King, M, Wallace

P, et al.Chronic fatigue in general practice: is counselling

as good as cognitive behaviour therapy? A UK randomised

trial. British Journal of General Prcatice 2001;51(462):

19–24.

Sharpe 1991

Sharpe M, Archard L, Banatvala J, Borysiewicz LK, Clare A

W, David A, et al.Chronic fatigue syndrome: guidelines for

research. Journal of the Royal Society of Medicine 1991;84

(2):118–21.

Vercoulen 1996Vercoulen JH, Swanink CM, Zitman FG, Vreden SG,

Hoofs MP, Fennis JF, et al.Randomised, double-blind,

placebo-controlled study of fluoxetine in chronic fatigue

syndrome. Lancet 1996;347(9005):858–61.

Warren 1999

Warren G, McKendrick M, Peet M. The role of essential

fatty acids in chronic fatigue syndrome. A case-controlled

study of red-cell membrane essential fatty acids (efa) and a

placebo-controlled treatment study with high dose of efa.

Acta Neurologica Scandinavica 1999;99(2):112–6.

Wearden 1998

Wearden AJ, Morriss RK, Mullis R, Strickland PL, Pearson

DJ, Appleby L, et al.Randomised, double-blind, placebo-controlled trial of fluoxetine and graded exercise for chronic

fatigue syndrome. British Journal of Psychiatry 1998;172:

485–90.

Wessely 1995

Wessely S. The epidemiology of chronic fatigue syndrome.

Epidemiologic Reviews 1995;17(1):139–51.

Whiting 2001

Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow

CD, Ramirez G. Interventions for the treatment and

management of Chronic Fatigue Syndrome. JAMA 2001;

286(11):1360–8.

WHO 1992

World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders . 10th Edition. Geneva:

WHO, 1992.

Zigmond 1983

Zigmond AS, Snaith RP. The hospital anxiety and

depression scale. Acta Psychiatrica Scandinavica 1983;67(6):

361–70.∗ Indicates the major publication for the study




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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Appleby 1995

Methods RCT

Computer generated random numbers in blocks of 10

Participants Diagnostic Criteria: Oxford

Age: 38.7 (+/- 10.8)

Setting: Secondary/Tertiary Care

Interventions Group 1. Graded exercise + Fluoxetine

Group 2. Graded exercise + drug placebo

Group 3. Exercise placebo + Fluoxetine

Group 4. Exercise placebo + drug placebo

Outcomes 1. Chalder Fatigue Scale

2. Hospital Anxiety and Depression Scale

3. Clinical Interview Schedule

4. Physiological assessments

Notes Group 4 was used as treatment as usual as patients were not given any specific advice on

exercise but were advised to exercise when they felt capable

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Low risk A - Adequate

Fulcher 1997

Methods RCT

Random number tables in sealed envelopes


Age: 37.2 (+/- 10.7)


Interventions Group 1. Exercise therapy (12 sessions) with 5 home sessions a week prescribed.

Group 2. Flexibility and relaxation (12 sessions) with 5 home session prescribed per week

Outcomes 1. Self-rated clinical global impression


3. Chalder Fatigue Scale

4. Pittsburgh Sleep Quality Index




13/22

Fulcher 1997 (Continued)

5. SF-36

6. Physiological Assessments

Notes

Risk of bias



Moss-Morris 2003

Methods RCT

Participants Diagnostic Criteria: CDC

Age: Gp1 = 36.7 (+/- 11.8), Gp2 = 45.5 (+/- 10.5)

Setting: Specialist CFS General Practice

Interventions Group 1. Graded exercise therapy (12 weeks).

Group 2. Treatment as usual

Outcomes 1. Global Rating of Improvement

2. SF-36 - Physical Function


4. Activity levels

5. Cognitive function

6. Physiological Assessments7. Acceptability

Notes Treatment as usual was not explained

Risk of bias


Allocation concealment (selection bias) Unclear risk B - Unclear

Powell 2001

Methods RCT

Computer generated random numbers in sealed envelopes, stratified for depression scores


Age: Gp1 = 34 (+/- 10.5), Gp2 = 34 (+/- 10.7), Gp3 = 32 (+/- 9.5), Gp4 = 33 (+/- 10.7)





14/22

Powell 2001 (Continued)

Interventions Group 1: Treatment as usual

Group 2: Exercise therapy + 2 sessions (total 3 hrs)

Group 3: Exercise therapy + 7 telephone sessions (total 3.5 hrs)Group 4: Exercise therapy + 7 sessions (total 7 hrs)

Outcomes 1. Physical functioning subscale of SF-36



4. Sleep inventory

5. Global Impression of change

6. Illness beliefs and experience of treatment

Notes Group 2. Exerciset herapy + MinimumPatient Education wast aken a sequivalent a sexercise

therapy alone on the advice of experts in the field

Treatment as usual comprised a medical assessment, advice and an information booklet that

encouraged graded activity and positive thinking but gave no explanations for symptoms

Risk of bias



Wallman 2004

Methods RCT

Participants Diagnostic Criteria: CDC Age: Gp1 = 43.3 (+/- 12.7), Gp2 = 45.7 (+/- 12.5)

Setting: Primary Care

Interventions Group 1. Prescribed exercise therapy (12 weeks).

Group 2. Flexibility and relaxation (12 weeks)

Outcomes 1. Clinical Global Impression



4. Activity levels

5. Cognitive function

6. Physiological Assessments

Notes

Risk of bias





15/22

Wallman 2004 (Continued)

Allocation concealment (selection bias) Unclear risk B - Unclear

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Darbishire 2003 RCT

No clinical diagnosis of Chronic Fatigue Syndrome

Guarino 2001 RCT

No clinical diagnosis of Chronic Fatigue Syndrome




16/22

D A T A A N D A N A L Y S E S

Comparison 1. Exercise Therapy vs Control (treatment as usual or relaxation + flexibility)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Chalder Fatigue Scale 5 Std. Mean Difference (IV, Random, 95% CI) Subtotals only

1.1 12 Weeks 5 286 Std. Mean Difference (IV, Random, 95% CI) -0.77 [-1.26, -0.28]

1.2 24 Weeks 2 118 Std. Mean Difference (IV, Random, 95% CI) -1.04 [-2.49, 0.40]

2 Chalder Fatigue Scale (Powell

2001 excluded)

4 Mean Difference (IV, Random, 95% CI) Subtotals only

2.1 12 Weeks 4 220 Mean Difference (IV, Random, 95% CI) -5.09 [-8.79, -1.40]

2.2 24 Weeks 1 52 Mean Difference (IV, Random, 95% CI) -3.45 [-9.70, 2.80]

3 Acceptability of Treatment 5 315 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [0.92, 3.24]

4 Hospital Anxiety and Depression

Scale - Depression subscale



4.2 24 Weeks 1 68 Mean Difference (IV, Random, 95% CI) 0.5 [-1.32, 2.32]

5 Quality of Life - SF-36 Physical

Functioning subscale

3 Std. Mean Difference (IV, Random, 95% CI) Subtotals only

5.1 12 Weeks 3 162 Std. Mean Difference (IV, Random, 95% CI) -0.64 [-0.96, -0.33]

6 Quality of Life - Sleep Problem

Questionnaire


6.1 24 weeks 1 64 Mean Difference (IV, Random, 95% CI) -4.70 [-7.02, -2.38]

7 Quality of Life - Functional

Work Capacity


7.1 12 weeks 1 58 Mean Difference (IV, Random, 95% CI) -4.40 [-9.10, 0.30]

7.2 26 weeks 1 51 Mean Difference (IV, Random, 95% CI) -2.89 [-7.71, 1.93]

Comparison 2. Exercise Therapy vs Pharmacotherapy (Fluoxetine)


studies

No. of


1 Chalder Fatigue Scale 1 Mean Difference (IV, Random, 95% CI) Subtotals only








3 Quality of Life 1 Mean Difference (IV, Random, 95% CI) Subtotals only


3.2 24 Weeks 1 50 Mean Difference (IV, Random, 95% CI) 15.85 [12.64, 19.06]





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Comparison 3. Exercise Therapy vs Exercise Therapy + Pharmacotherapy (Fluoxetine)


studies

No. of














Comparison 4. Exercise Therapy vs Exercise Therapy + Patient Education


studies

No. of











3.1 Sleep Problem

Questionnaire (6 Months)

1 66 Mean Difference (IV, Random, 95% CI) -0.80 [-2.85, 1.25]


A D D I T I O N A L T A B L E S

Table 1. Study Demographics

Study ID Depressed / AD usage Gender Duration of illnes Socioeconomic Status

Appleby 1995 46/136 were depressed

(DSM-III-R)

Female =97/136 Median = 2.3 years 114/136 had recently changed occupa-

tion

Fulcher 1997 30/66 on AD Female = 49/66 Median = 2.7 years Not supplied




18/22


19/22

F E E D B A C K

Feedback

Summary

The two reviews about Chronic Fatigue Syndrome (on exercise and CBT) are important documents in a controversial field. However,

they seem to be listed on the website as mental health topics, alongside depression etc. CFS is not a form of mental illness, though of

course there may be a psychological component in individual cases that can be addressed during treatment. May I suggest that you

place them elsewhere, as it is misleading and confusing to have them with under the mental health umbrella?

Reply

Many thanks for your comment on the two Cochrane CFS reviews. Apologies for the delay in responding, I have been on annual leave.

We appreciate your observations about the placement of these reviews on The Cochrane Library. Feedback on reviews is normally dealt

with by the relevant reviewer but, in this case I am responding, as your query relates more to an organisational issue. These reviews are

listed as topics under a mental health heading because, as a result of the psychological component to which you refer, both reviews aresupported by a mental health Cochrane group. Similar arrangements are in place for reviews of treatments for other disorders involving

a variety of component problems and which, as a result, do not easily fit within the scope of one Cochrane group. These reviews can

however be accessed in a number of different ways, for example by searching for the specific topic (CFS and associated terminology,

exercise and associated terminology, CBT and associated terminology); by searching for the authors; under subject headings etc. The

subject headings are not really intended as a comment on/guide to the aetiology of an illness, but sometimes do reflect the services

involved in the management of the condition. I have copied this response to the review authors in case they wish to comment further

on this. Many thanks for your feedback.

Contributors

Cathy Stillman-Lowe (Occupation freelance editor/science writer)

[email protected]

Submitter agrees with default conflict of interest statement:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of

my feedback.

Types of evidence included, 3 June 2013

Summary

Unfortunately this review ignores the large body of patient testimony that many persons with severe myalgic encephalomyelitis have

been harmed by graded exercise therapy.

Since it was prepared the International Consensus Primer and Guidelines for medical practitioners have been published.Current thinking is to stay within your energy envelope. People with ME tend to overdo not underdo what they are capable of....

Care must be taken to NOT encourage them to do too much.

Further there are many definitions of CFS which muddies the waters.

I agree with the conflict of interest statement below:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of

my feedback.




20/22

Reply

Thank you for your comments on this Cochrane Review.

In conducting this review, our aim was to gather and synthesise a specific type of evidence - randomised controlled trials. We fully

accept that patient testimony, particularly that gathered and synthesised by high quality qualitative research, is invaluable in any clinical

area, and particularly in an area as challenging for patients and health care professionals as CFS-ME. However, this project was not

designed to incorporate such evidence. We do consider the possibility of harm arising from graded exercise therapy, by considering reported adverse events. Clearly this is an

important issue to consider with any therapeutic intervention. Moreover, in the usual course of any illness, some patients improve (with

or without treatment) and some patients worsen (with or without treatment). It is only through the use of randomised controlled trials

that the effects (whether beneficial or adverse) of putative treatments can reliably be disentangled from the natural history of illness.

You raise the important point that (some) ’people with ME tend to overdo not underdo what they are capable of ’. The critical point

is the extent to which patients should be ’encouraged to do more’, and the way in which they should be encouraged to do so. These

are important research questions. As you know, new randomised evidence is available from the PACE trial, published in 2011 in the

Lancet. Whilst this is a controversial trial, it is an important randomised comparison of graded exercise therapy and ’adaptive pacing’.

We look forward to further randomised evidence becoming available in due course.

We also look forward to continuing to work in this clinical area, in the hope that we can advance our understanding of the impact of

this treatment approach.

Contributors

Submitter: Adrienne

Response prepared by: Jonathan Price

W H A T ’ S N E W

Last assessed as up-to-date: 8 May 2004.

Date Event Description

7 August 2013 Feedback has been incorporated Feedback incorporated regarding type of evidence

H I S T O R Y

Protocol first published: Issue 3, 2001

Review first published: Issue 3, 2004

Date Event Description

16 April 2010 Amended Authorline corrected (reverting back to original author-

line). Lillebeth Larun and JanOdegaard-Jensen are now

producing a version of this review based on individual

patient data

1 November 2008 Amended Converted to new review format.




21/22

(Continued)

8 May 2004 New citation required and conclusions have changed Substantive amendment

C O N T R I B U T I O N S O F A U T H O R S

ME and HMG wrote the protocol.

JRP revised protocol.

HMG developed and wrote the search strategy.

ME and HMG conducted the searches and checked trials for inclusion and exclusion criteria.

ME and JRP extracted data.

ME, HMG and JRP analysed the data

ME, HMG and JRP wrote the discussion and results section.

D E C L A R A T I O N S O F I N T E R E S T

None

S O U R C E S O F S U P P O R T

Internal sources

• University of Surrey, UK.

•

King’s College Institute of Psychiatry, UK.• University of Oxford Department of Psychiatry, UK.

External sources

• No sources of support supplied

N O T E S

This review is in the process of being updated. A new co-author is now invovled with the review update.




22/22

I N D E X T E R M S

Medical Subject Headings (MeSH)

∗Exercise Therapy; Depression [therapy]; Fatigue Syndrome, Chronic [psychology; ∗therapy]; Randomized Controlled Trials as Topic

MeSH check wordsHumans



1. edmonds m. et al. exercise therapy for chronic fatigue syndrome. cochrane database syst rev 2004...

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