pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an...

doi: 10.1111/j.1365-2796.2010.02228.x

Pain inhibition and postexertional malaise in myalgicencephalomyelitis ⁄chronic fatigue syndrome:An experimental study

J. Van Oosterwijck1, J. Nijs1,2,3, M. Meeus1,2, I. Lefever1, L. Huybrechts2, L. Lambrecht4,5 & L. Paul6

Fromthe1DepartmentofHumanPhysiology,FacultyofPhysicalEducation&Physiotherapy,VrijeUniversiteitBrussel,Brussels; 2DivisionofMusculoskeletalPhysiotherapy,DepartmentofHealthCareSciences,ArtesisUniversityCollegeAntwerp,Antwerp; 3DepartmentofPhysicalMedicineandPhysiotherapy,UniversityHospitalBrussels,Brussels; 4PrivatePracticeFor InternalMedicine,Ghent ⁄Aalst, 5CVSContactgroep,Bruges,Belgium;and6 NursingandHealthCare,FacultyofMedicine,UniversityofGlasgow,Glasgow,UK

Abstract. VanOosterwijck J, Nijs J,MeeusM, Lefever I,Huybrechts L, Lambrecht L, Paul L (Vrije UniversiteitBrussel, Brussels; Artesis University CollegeAntwerp, Antwerp; University Hospital Brussels,Brussels; Private Practice For Internal Medicine,Ghent ⁄Aalst; CVS Contactgroep, Bruges; Belgium;andUniversityofGlasgow,Glasgow,UK).Pain inhibi-tion and postexertional malaise in myalgic encepha-lomyelitis ⁄chronic fatigue syndrome. J Intern Med2010;268: 265–278.

Objectives.Toexamine theefficacyof thepain inhibitorysystems in patients with myalgic encephalomyeli-tis ⁄chronic fatigue syndrome (ME ⁄CFS) during twodifferent typesof exerciseandtoexaminewhether the(mal)functioning of pain inhibitory systems is associ-atedwithsymptomincreases followingexercise.

Design.Acontrolledexperimental study.

Setting and subjects. Twenty-two women with ME ⁄CFSand 22 healthy sedentary controls were studied attheDepartmentofHumanPhysiology,VrijeUniversi-teitBrussel.

Interventions. All subjects performed a submaximalexercise test and a self-paced, physiologically limitedexercise test on a cycle ergometer. The exercise tests

were undertaken with continuous cardiorespiratorymonitoring. Before and after the exercise bouts, sub-jectsfilledoutquestionnaires toassesshealthstatus,and underwent pressure pain threshold measure-ments.Throughout thestudy, subjects’ activity levelswereassessedusingaccelerometry.

Results. In patients with ME ⁄CFS, pain thresholds de-creased followingbothtypesofexercise,whereas theyincreased inhealthysubjects. Thiswasaccompaniedby a worsening of the ME ⁄CFS symptom complexpost-exercise.Decreasedpressure thresholds duringsubmaximal exercise were associated with postexer-tional fatigue in the ME ⁄CFS group (r = 0.454;P = 0.034).

Conclusions. These observations indicate the presenceof abnormal central pain processing during exercisein patients with ME ⁄CFS and demonstrate that bothsubmaximal exercise and self-paced, physiologicallylimited exercise trigger postexertional malaise inthese patients. Further study is required to identifyspecific modes and intensity of exercise that can beperformed inpeoplewithME ⁄CFSwithoutexacerbat-ingsymptoms.

Keywords: algometry, ME ⁄CFS, pain, postexertionalmalaise,submaximal exercise.

Introduction

Patients with myalgic encephalomyelitis ⁄chronicfatigue syndrome (ME ⁄CFS) experience a debilitatingfatigueaccompaniedbysecondarysymptoms includ-ing sore throat, memory and concentration impair-ments, headache, sleep disorders and, most often,muscle and joint pain. Not only do people withME ⁄CFS often report a fluctuating pattern to their

symptoms and physical and cognitive capabilities,they also show severe symptom and pain exacerba-tion following physical exercise [1, 2]. This postexer-tional malaise is present in 95% of ME ⁄CFS patients[3] and is one of the best predictors of the differentialdiagnosis of ME ⁄CFS and major depressive disorder[4]. The severe exacerbation of symptoms followingexercise, as seen in ME ⁄CFS patients, is not presentin other disorders where fatigue is a predominant

ª 2010 Blackwell Publishing Ltd 265

Original Article |

symptom such as depression, rheumatoid arthritis,systemic lupuserythematosusandmultiplesclerosis[5,6].

WhydopatientswithME ⁄CFSexperiencean increasein symptoms following activity or exercise peaks? Itseems that the pain inhibitory systems in these pa-tients donot respond to exercise as theydo inhealthysubjects. In normal circumstances, pain thresholdsincrease during physical activity due to the release ofendogenous opioids, growth factors [7] and otherstrongpaininhibitorymechanisms(‘descendinginhi-bition’) orchestrated by the central nervous system[8]. However, in patients withME ⁄CFS, a decrease inpressure pain thresholds (PPTs) during and afterexercise has been observed, suggesting a lack ofdescending inhibition during exercise [2, 9]. This de-crease inpain thresholds couldbe responsible for thepostexertionalpainexperiencedbyME ⁄CFSpatients.In addition to the possibility of impaired descendingpain inhibitorypathways inME ⁄CFSduringexercise,wepreviously showed that thediffusenoxious inhibi-tory controls (DNICs) of ME ⁄CFS patients react moreslowly to spatial summationof thermalnoxious stim-uli compared to healthy controls, resulting in hyper-algesia that is proportional to the stimulated surface[10].Althoughpaininhibitorymechanismshavebeenstudied in ME ⁄CFS patients to a small degree, cur-rently there is no research available demonstratingan association between the impaired pain inhibitionandtheseveresymptomexacerbationexperiencedbyME ⁄CFSpatients followingexercise.

If postexertional malaise is caused by insufficientactivation of the pain inhibitory systems during exer-cise, further research into the possible contributingfactors is required. Indeed, it has been reported thatME ⁄CFS patients are able to perform light to moder-ate exercise (40% of peak oxygen capacity) withoutexacerbating their symptoms [11–13]. If the exacer-bation of symptoms following physical exertion is re-lated to the intensity anddurationof attemptedactiv-ities, it would be valuable to examine different typesofexercise.

It has been suggested that submaximal exercise test-ing is an appropriate means of assessing physicalfunction inME ⁄CFS subjects [14]. Anaerobic but notaerobic exercise has been shown to increase symp-toms in people with ME ⁄CFS [15–17]. On the otherhand, energymanagementstrategies, suchaspacingself-management techniques, involve the constantmonitoring and manipulation of exercise ⁄activity interms of intensity, duration and rest periods in order

to avoid possible over-exertion and worsening of thesymptoms,andthereforecouldbe indicated [18,19].

In this study, we examined the efficacy of the paininhibitory systems during two different types of exer-cise (submaximalandself-paced,physiologically lim-ited bicycle exercise test), and investigated whetherthis is associated with symptom increase followingexercise in ME ⁄CFS patients. This report is the sec-ond from a study examining various aspects of post-exertionalmalaise inpatientswithME ⁄CFS.Thefirstreport highlighted the findings in relation to circulat-ing elastase activity and levels of interleukin 1b andcomplementC4a [20].

Methods

Subjects

PatientswithME ⁄CFSwere referred for studypartici-pation from a private practice for internal medicine.For study inclusion, subjects had to fulfil the Centerfor Disease Control and Prevention criteria forME ⁄CFS (i.e. a clinically evaluated,unexplained,per-sistent or relapsing chronic fatigue that is of new ordefinite onset and which results in a substantialreduction in the previous levels of occupational, edu-cational, social or personal activities [1]). Further-more, at least four of the following symptoms musthavepersisted during6 ormore consecutivemonths,but not predated the fatigue: impairment of short-termmemory or concentration, tender cervical or ax-illary lymph nodes, generalized muscle pain, multi-joint pain, headache, unrefreshing sleep and postex-ertional malaise for more than 24 h [1]. Any activemedical condition that may explain the presence ofchronic fatigue precludes the diagnosis of ME ⁄CFSand therefore all patients underwent an extensivemedical evaluation. All patients were diagnosed bythesame internalmedicinephysician.Pain is consid-ered to be an important aspect of postexertionalmal-aise.Therefore,aswellassuffering fromME ⁄CFS,pa-tients included in the study had to present withchronic widespread pain [21]. Patients were asked toattendthefirstvisitwithahealthy, sedentaryrelative,friend or acquaintance to participate in the controlgroup. Sedentary was defined as having a seatedoccupation and performing a maximum of 1 h ofsports per week [22]. Pooling of gender data has beenidentified as an important source of bias in studies ofexercise physiology in ME ⁄CFS patients [23]. There-fore, this study focused on Dutch-speaking women(18 and 65 years old). The power analysis revealedthat 22 people with ME ⁄CFS were required for the

J. Van Oosterwijck et al. | Pain inhibition and postexertional malaise in ME ⁄ CFS

266 ª 2010 Blackwell Publishing Ltd Journal of Internal Medicine 268; 265–278

study [24]. The control group consisted of 22 healthywomenmatched forageandbodymass index (BMI).

Procedure

On the first day of data collection, study participantswere asked to read an information leaflet and then toprovide written informed consent. The study proto-col, information leaflet and informed consent formwereapprovedbytheEthicsCommitteeof theUniver-sity Hospital Brussels ⁄Vrije Universiteit Brussel.After collecting personal characteristics (e.g. age, useof analgesics or anti-depressants) participants’heightandweightweremeasured, and theywerepro-vided with a tri-axial accelerometer for monitoringactivity (Actical Mini Mitter, Bend, OR, USA). Partici-pants were asked to wear the accelerometer continu-ouslyduring thestudy. Inaddition,participantswereinstructed not to use analgesics for a minimum of7 daysprior to thefirstexperiment (experiment1).

One week after the first visit, participants returnedfor to take part in experiment 1. First, they completed

baseline measurements that included filling outquestionnaires, venous blood sampling and PPTmeasurements. The following questionnaires wereused to assess their health status: the CFS SymptomList, theMedicalOutcomesStudy36-itemshort formhealth survey (SF-36) and the Checklist IndividualStrength (CIS). After completing the questionnaires,four venous blood samples (32.5 cc in total) were col-lected by an experienced nurse. The results of theblood tests are presented and discussed elsewhere[20].Subsequently,PPTsweremeasuredbyanasses-sor who was blinded to the subjects’ health status(ME ⁄CFSpatient orhealthy control).Next, studypar-ticipants undertook a submaximal exercise stresstest (Aerobic Power Index) with continuous cardiore-spiratory monitoring (ergospirometry), and bloodsampling every 2 min for lactate determination.Figure1showsaflowdiagramof thestudyprotocol.

Immediately after exercise, the study participantswere subjected to the same PPT measurements as atbaseline. At 1 h post-exercise, patients filled out thesamequestionnairesagainandanothervenousblood

CDC*-defined ME / CFS† patients (n = 22)

Healthy, sedentary controls(n = 22)

1st visit 1. Information leaflet + informed consent2. Weight & height measured3. Accelerometer

Experiment 1 1. Questionnaires, blood sampling, algometry2. Submaximal exercise stress test3. 1-hour break4. Algometry5. Questionnaires, blood sampling6. Questionnaires at 24 hours post-exercise

1 week accelerometry

1 week accelerometry

Experiment 2 1. Questionnaires, blood sampling, algometry2. Paced exercise with ‘3 saftey breaks’3. 1-hour break4. Algometry5. Questionnaires, blood sampling6. Questionnaires at 24 hours post-exercise

* Centre for Disease Control and Prevention† Myalgic encephalomyelitis/chronic fatique syndrome

Fig.1 Flow diagramshowingthestudyprotocol.


ª 2010 Blackwell Publishing Ltd Journal of Internal Medicine 268; 265–278 267

sample was taken. Finally, to monitor post-exercisemalaiseup to24 h, subjectswere given twoquestion-naires (CFS Symptom List and SF-36) to fill outexactly 24 h after exercise. The subjects were askedto return the completed questionnaires to the VrijeUniversiteit Brussel by post (prestamped envelopeswere provided). On day 14 of the trial (1 week afterexperiment 1), the study participants returned to thedepartment for experiment 2. The procedure wasthe same as described in experiment 1 except thatthe test consisted of self-paced and physiologicallylimitedbicycle exercise.

Exercise testing

Theexercise testswereperformed inasittingpositionon an electrically braked cycle ergometer (ExcaliburLode, Groningen, theNetherlands) at a room temper-ature of 18–20 �C. The saddle and handlebars werepositioned to suit each subject. After 3–5 min ofadjustment to the rest position, baseline data werecollected. The oxygen analyser was calibrated withknowngasmixtures of18%O2and5%CO2.Roomairwas automatically calibrated before each test to up-date the CO2 analyser baseline and the O2 analysergain so that they coincided with atmospheric values.An open-circuit spirometer (Cortex Metamax I, Bio-physik, GmbH, Germany) with automatic printoutevery 30 swasused to collect pulmonarydata duringthe test. The Cortex Metamax I is a reliable instru-ment for routine exercise testing in sports medicaland researchsettings [25]. A two-waybreathing valveattached to amask, which covered the patient’s noseand mouth, was used to collect the expired air. Theair was analysed continuously for ventilatory andmetabolic variables. Patientswere instructed to cycleat a pedalling rate of 60–70 rates per minute. Heartrate was recorded at the end of each minute duringthe exercise test using a heart rate telemetry bandPolar T61-Coded (Polar Electro OY, Kempele, Fin-land). Lactate concentrations were measured todetermine the anaerobic threshold during exercise,thusbloodsamples (20 mL)weredrawn fromanarte-rialized earlobe every 2 min during the exercise test.Lactate concentrations were determined enzymati-cally (EKF,BIOSEN5030,Magdeburg,Germany).

Experiment 1: submaximal exercise. The submaxi-malexerciseprotocolconsistedofasubmaximalcycletestknownastheaerobicpower index test [26],whichhasbeenshowntogenerate reliabledata insedentaryand ME ⁄CFS populations [intra-class correlationcoefficient (ICC) = 0.98 and 0.97, respectively] [27,28]. InpeoplewithME ⁄CFS,thesubmaximalexercise

data generated by the aerobic power index correlateshighly with peak exercise data [29]. According to thedescription of the aerobic power index, the workloadwas increased by 25 W every minute, and thesubmaximal level was defined as 75% of the age-predicted targetheart rate [6]. If subjectswereunableto reach their individual target heart rate, then theworkload (W) achieved during the last full minuteofexercisewasrecordedasthefinalpoweroutput.

Experiment 2: self-paced and physiologically limitedexercise. Self-paced and physiologically limitedbicycle exercise was performed by all subjects withthree ‘safety breaks’ or exercise limits. First, theheartrate could not exceed 80% of the rate that corre-sponded to the anaerobic threshold during the sub-maximal exercise test.When the anaerobic thresholdwas not achieved during submaximal exercise, 80%of the highest achieved heart ratewas used. In cases,where theheart rate exceeded theupper limit (80%oftheheart rate corresponding to theanaerobic thresh-old) during the paced exercise test, the workload waslowered and if necessary subjects were instructed toreduce their cycling frequency. Second, theworkloadwas kept below 80% of that corresponding to theanaerobic threshold. Heart rate and workload limitswere chosen to maintain aerobic exercise, well belowthe anaerobic threshold, during experiment 2. Third,the exercise duration was determined by asking thepatients to pace themselves by estimating how longthey would be able to perform the exercise withoutexacerbating their symptoms. The activity durationestimatedby theparticipantswasreduced toaccountfor typical overestimations. To ensure that the pa-tients did not exceed their energy boundaries, 75%ofthe estimated time was used when the patients re-ported having a ‘good’ day and 50% was used whenthey reportedhavinga ‘bad’ day [30].For thecontrols,the estimated time was always decreased by 25%.Thus, all subjects performed one bicycle exercise be-lowall threesafetybreaks.

Self-reported measures

The CFS Symptom List is a self-reportedmeasure forassessing symptom severity in ME ⁄CFS patients. Itencompasses the 19most frequently reported symp-toms in a large sample (1578) of ME ⁄CFS patients[15]. To assess the severity of the symptoms includedin the CFS Symptom List, visual analogue scales(100 mm) are used. The CFS Symptom List demon-strates excellent consistency (Cronbach’s a = 0.88),test–retest reliability (ICC ‡ 0.97), internal contentandconcurrent validity [31,32].



The SF-36 assesses functional status and well-beingor quality of life [33]. It is reliable and valid in a widevariety of patient populations [14, 34, 35] andappears to be the most frequently used measure inME ⁄CFSresearch [36].

The CIS quantifies subjective fatigue and relatedbehavioural aspects [37]. The CIS consists of 20statements to be scored on a seven-point scale. Thestatements refer to four aspects of fatigue: fatigueseverity, reducedmotivation, reducedactivity andre-duced concentration. A score of at least 35 on thedimension ‘fatigue severity’ indicates the presence ofsevere fatigue. The CIS is well validated within theclinical setting and is able to discriminate betweendifferent patient populations and between patientsandhealthysubjects [38].

Pain pressure thresholds

Algometry provides a reliable and valid measure ofPPTs [39]. PPTs were measured bilaterally with ananalogue Fisher algometer (Force Dial model FDK 10and model FDK 40 Push Pull Force Gage, WagnerInstruments, Greenwich, CT, USA) in the skin webbetween thumb and index finger, at the proximalthird of the calf and 5 cm lateral to the spinous pro-cessof L3 [2, 40].Becauseof the reliability of this pro-cedure, the threshold was determined as themean ofthe two last values of three consecutive measure-ments (10 sbetweeneach) [41].

Real-time activity monitoring throughout the study

The Actical (Mini Mitter) water-resistant accelerome-ter was used for real-time monitoring of physicalbehaviour in all study participants. This accelero-meter has an omnidirectional sensor that functionsvia a cantilevered rectangular piezoelectric bimorphplate and seismicmass, and it is capable of detectingmovements in the range of 0.5–3 Hz. Voltage gener-ated by the sensor is amplified and filtered via ana-logue circuitry. The amplified and filtered voltage ispassed through an analogue-to-digital converter,and the process is repeated 32 times per second(32 Hz). The resulting 1 s value is divided by four,and then added to an accumulated activity value(activity counts) for the epoch. Accelerometers arethe gold standard for measuring physical behaviourduring daily activities. The Actical accelerometer hasbeen shown to be valid for the real-time assessmentof physical behaviour [42]. For the present study,the monitors were initialized to save data in 1 minintervals.

Statistical analysis

All data were analysed using spss 16.0 for Windows(spss Inc., Chicago, IL, USA). Normality of the vari-ables was tested with the Kolmogorov–Smirnov testand appropriate descriptive statistics were calcu-lated. Baseline comparisons between ME ⁄CFS pa-tients andcontrolswereperformedusingStudent’s t-test.

For each type of exercise (i.e. submaximal exerciseand exercise bout with safety breaks), possiblechanges in any of the outcome measures inresponse to exercise were compared between thetwo groups using repeated measures anova (time ·group interaction). Parametric variables related toexercise and respiratory performance were analysedusing the independent sample t-test; nonparametricvariables were analysed using the Mann–WhitneyU-test.

Likewise, for each group (ME ⁄CFS patients and sed-entaryhealthycontrols)possibledifferences inthere-sponse of each of the outcome measures to exercisewere examined using repeated measures anova(time · group interaction). Normally distributed out-comes related to exercise and respiratory perfor-mancewere examinedwith the paired samples t-test.Nonparametric data were examined using the Wilco-xon signed rank test. The significance level was set at0.05.

Pearsoncorrelationanalysiswasused to examine theassociation between PPTs and fatigue severity. Dailyphysical activity levels were compared between thegroups using independent sample t-tests, whereasday-to-day fluctuations were controlled using re-peatedmeasuresanova (time · group interaction).

Results

Twenty-two ME ⁄CFS female patients and 22 healthywomenwere recruited for the study. Themean age ofthe patients was 34.3 ± 8.8 years and their meanBMIwas24.1 ± 4.7 kg m)2. Themeanageof the con-trol subjects was 38.9 ± 15 years and their BMI was24.5 ± 4.8 kg m)2.TheseBMIvalues indicatenormalweight in both groups. The independent samples t-test showed no significant difference in age(P = 0.229) or BMI (P = 0.852) between the patientand the control groups. At baseline, 12 patients usedanalgesics and10patients used anti-depressants. Inthe control group, one subject used anti-depres-sants.



Daily physical activity levels

To establish daily activity levels at baseline, subjectswere asked to wear a tri-axial accelerometer fromthe first visit until experiment 1. No significant dif-ferences were found between the ME ⁄CFS and thecontrol groups fordaily physical activity levelsduringbaseline (6 days before experiment 1) (P = 0.365).Therefore,weconcludethat the twogroupswerecom-parable.

To monitor the potential influences of daily activitylevels on exercise performance during experiment 2,and as a potential confounder of symptom fluctua-tions, subjects were asked to wear a tri-axial acceler-ometer continuously between the post-exerciseassessments of experiment 1 and the pre-exerciseinterventionsofexperiment2. In twosubjects, thede-vices were defective and did not register the dailyphysical activity; the device only registered for 3 daysin one subject. No significant differences were foundbetween the ME ⁄CFS group and the healthy, seden-tary controlswith regard to daily physical activity lev-els or day-to-day fluctuations in activity patterns(F = 0.838,P = 0.365).

Exercise response, exercise capacity and exercise-induced pain inhibition:comparison between patients and controls

Submaximal exercise stress test. Baselinemeasure-ments showed amean heart rate of 79 ± 12 bpmandmean lactate levels of 1.12 ± .47 mmol L)1 at rest forthe control group. The ME ⁄CFS group had a meanheart rate of 81 ± 10 bpm and mean lactate level of0.90 ± 0.24 mmol L)1 at rest. ME ⁄CFS patientscycled for 3.9 ± 1.3 min at a maximum workload of109 ± 29 W. At the end of the exercise test, theirlactate levels reached 2.96 ± 1.46 mmol L)1. Thecontrol subjects cycled for 4.2 ± 1.2 min and

reached a maximum workload of 118 ± 30 W. Atthe end of exercise, lactate levels reached 2.60 ±1.09 mmol L)1. No significant differences (P > 0.05)were found for heart rate, lactate levels, workload orcycled timebetween theME ⁄CFSandcontrol groups.However, the peak respiratory exchange ratio (RER)during submaximal exercise was significantly higherin the ME ⁄CFS group (mean 1.25 ± 0.98) comparedto the sedentary control group (mean 0.92 ± 0.11)(P = 0.002). One control subject refused respiratorymonitoring because of a claustrophobic reaction tothemask.

At baseline, ME ⁄CFS patients showed decreasedPPTs measured near L3, indicating the presence ofhyperalgesia of the lower back (P = 0.031). After per-forming the exercise test, a significant difference inpain thresholdswas foundbetween theME ⁄CFS andthe control groups, as shown inFig. 2. ThePPTsmea-suredonthebackandthecalf increased inthecontrolgroup whereas they decreased in the patient group(P = 0.006 and P = 0.018, respectively). PPTs mea-sured in the skin web between thumb and index fin-ger showed the same effect although the differencewasnotsignificant (P = 0.077).

There was a significant difference between patientsand controls with regard to the change over time(baseline, post-exercise, 24 h post-exercise) in thesubscale ‘physical functioning’ of the SF-36 score(P = 0.029). Control subjects showed stable scoresbut ME ⁄CFS patients showed a decrease in thescores over time, indicating postexertional malaisein the patient group. ME ⁄CFS patients showed aworsening of symptoms from baseline to post-exer-cise and 24 h post-exercise, as measured by theCFS Symptom List, whereas controls showed symp-tom improvement (Table 1). The difference between

7.0

6.5

6.0

5.5

5.0

4.5

4.0

4.75

5.00

5.25

5.50

5.755.2

5.0

4.8

4.6

4.4

4.2

4.0

Pre-exercise Post-exercise Pre-exercise Post-exercise Pre-exercise Post-exercise

4.41 ± 1.524.45 ± 1.98

5.97 ± 2.50

6.81 ± 2.59 5.74 ± 1.66

4.76 ± 1.68

4.29 ± 1.67

4.69 ± 1.46

5.09 ± 1.73

4.16 ± 1.76

4.89 ± 2.514.87 ± 1.53

Back (P = 0.006) Calf (P = 0.018) Hand (P = 0.077)

ControlME/CFS

ControlME/CFS

ControlME/CFS

Pai

n pr

essu

re t

hres

hold

s (k

g/cm

2 )

Pai

n pr

essu

re t

hres

hold

s (k

g/cm

2 )

Pai

n pr

essu

re t

hres

hold

s (k

g/cm

2 )

Fig. 2 Changes in pain pressure thresholds in response to submaximal exercise in women with myalgic encephalomyeli-tis ⁄ chronic fatiguesyndrome (ME ⁄CFS) (n = 22)andsedentarywomen(n = 22).



Table 1 Changes inhealthstatus inresponsetosubmaximalexercise inpatientswithME/CFS(n = 22)andhealthysedentarycon-

trol subjects (n = 22)

ME ⁄CFSpatients

(mean ± standard

deviation)

Control subjects

(mean ± standard

deviation)

Within-groups

comparison

(F-value;P-value)

Pain (mm)

Pre-exercise 45.7 ± 24.8 9.5 ± 14.7

Post-exercise 64.8 ± 24.7 10.2 ± 16.6 10.1;0.003

24 hpost-exercise 67.8 ± 27.1 4.9 ± 6.6 29.9;<0.001

Fatigue (mm)

Pre-exercise 68.6 ± 14.2 15.6 ± 18.1

Post-exercise 78.3 ± 21.1 14.2 ± 21.4 5.4;0.025

24 hpost-exercise 84.0 ± 18.4 12.8 ±18.8 8.8;0.005

Concentrationdifficulties (mm)

Pre-exercise 54.8 ± 24.4 5.3 ± 7.1

Post-exercise 62.8 ± 29.8 4.4 ± 5.3 3.6;0.064

24 hpost-exercise 68.0 ± 28.0 5.9 ± 8.8 8.2;0.006

CFSSymptomList total score (mm)

Pre-exercise 53.2 ± 12.1 10.6 ± 8.4

Post-exercise 58.1 ± 14.9 8.4 ± 8.7 18.5;<0.001

24 hpost-exercise 63.4 ± 16.9 6.1 ± 7.7 27.3;<0.001

CIS fatigue

Pre-exercise 50.9 ± 5.8 20.9 ± 7.7

Post-exercise 52.3 ± 5.5 18.5 ± 7.4 3.4;0.072

CISconcentrationdifficulties

Pre-exercise 28.4 ± 6.2 10.5 ± 4.5

Post-exercise 27.6 ± 7.6 9.4 ± 4.3 0.9;0.765

CISmotivation

Pre-exercise 15.5 ± 5.1 8.6 ± 4.0

Post-exercise 17.0 ± 6.7 8.0 ± 3.0 2.6;0.117

CISphysical activity

Pre-exercise 15.5 ± 5.1 6.3 ± 2.7

Post-exercise 16.1 ± 5.6 6.3 ± 3.2 1.1;0.305

SF36bodilypain

Pre-exercise 41.4 ± 17.6 89.3 ± 11.6

Post-exercise 45.0 ± 15.2 89.8 ± 12.5 1.2;0.271

24 hpost-exercise 41.1 ± 15.6 89.9 ± 11.8 0.038;0.846

SF-36physical functioning

Pre-exercise 40.0 ± 16.7 90.2 ± 12.9

Post-exercise 39.1 ± 19.1 93.4 ± 7.5 1.2;0.271

24 hpost-exercise 34.3 ± 22.0 93.6 ± 8.5 5.1;0.029

SF-36role limitationsdue tophysical functioning

Pre-exercise 5.6 ± 10.7 90.9 ± 26.2

Post-exercise 9.1 ± 22.6 93.2 ± 22.1 0.018;0.893

24 hpost-exercise 7.5 ± 23.1 89.1 ± 28.2 0.172;0.680



the two groups was significant (P < 0.001). The CISshowed no significant differences (P > 0.05) bet-ween the two groups. One patient failed to returnthe questionnaires to evaluate postexertional mal-aise up to 24 h after exercise.

Self-paced and physiologically limited exercise. Onecontrol subject refused respiratory monitoring be-cause of a claustrophobic reaction to the mask, andthe data from two other subjects were lost because ofcomputerproblems.Nosignificantdifferences inven-tilatory variables could be established between thetwotest groups (P > 0.05).

The control group had a mean heart rate of 79 ±12 bpm and mean lactate levels of 1.27 ±0.36 mmol L)1 at rest. In the ME ⁄CFS group, restingmean heart rate was 79 ± 9 bpm and mean lactatelevels were 1.07 ± 0.35 mmol L)1. In ME ⁄CFS pati-ents, the mean workload during exercise was46 ± 10 Wand lactate levels at the endof the exercise

test reached 1.91 ± 0.82 mmol L)1. The control sub-jects reached a mean workload of 46 ± 17 W duringthe exercise test and, lactate levels reached1.65 ± 0.66 mmol L)1at theendofexercise.Patients’paced time (5.0 ± 2.4 min) was shorter than that forthe controls (9.3 ± 5.2 min); subsequently, controls(9.3 ± 5.2 min) cycled for significantly (P = 0.001)longer than ME ⁄CFS patients (4.7 ± 2.5 min). More-over, whereas only one subject in the control groupwas unable to cycle for the total self-predicted dura-tion,sixpatientswithME ⁄CFSstoppedcyclingbeforethe self-predicted cycle timewas reached (P = 0.042).No significant differences (P > 0.05) were found be-tween the two groups for heart rate, workload or lac-tate levels.

In the control group, PPTs increased in response tothe exercise test. In the patient group, only the PPTmeasured at the lower back increased whereas thethresholds on the calf and the skin web between theindex finger and thumb decreased. The differences

Table1 (Continued)

ME ⁄CFSpatients

(mean ± standard

deviation)

Control subjects

(mean ± standard

deviation)

Within-groups

comparison

(F-value;P-value)

SF-36role limitationsdue toemotionalproblems

Pre-exercise 66.7 ± 44.8 93.9 ± 22.1

Post-exercise 62.1 ± 46.4 95.5 ± 15.6 2.02;0.162

24 hpost-exercise 63.3 ± 48.2 93.9 ± 22.1 1.91;0.175

SF-36social functioning

Pre-exercise 36.4 ± 21.1 95.4 ± 9.9

Post-exercise 39.2 ± 24.5 96.6 ± 9.6 0.136;0.714

24 hpost-exercise 34.4 ± 22.5 95.5 ± 9.1 0.122;0.729

SF-36mentalhealth

Pre-exercise 63.1 ± 17.4 78.7 ± 8.2

Post-exercise 64.7 ± 20.5 80.4 ± 10.3 0.000;0.983

24 hpost-exercise 66.0 ± 21.0 82.0 ± 9.1 0.340;0.563

SF-36vitality

Pre-exercise 30.9 ± 11.7 72.5 ± 11.1

Post-exercise 30.9 ± 14.9 76.8 ± 12.0 3.43;0.071

24 hpost-exercise 31.8 ± 16.7 77.9 ± 9.9 1.01;0.322

SF-36generalhealthperception

Pre-exercise 16.6 ± 9.6 63.6 ± 12.4

Post-exercise 18.0 ± 13.2 64.8 ± 9.5 0.008;0.928

24 hpost-exercise 17.5 ± 10.6 61.6 ± 12.7 1.31;0.260

Comparisonswereperformedusingtwo-wayrepeatedmeasuresanova.Statisticallysignificantresultsaregiven inbold.CIS,Checklist IndividualStrength;SF-36,MedicalOutcomesShortForm36HealthStatusSurvey.



between thepatient andcontrol groupswere found tobe significant for all PPT measurements [i.e. hand(P = 0.002), back (P = 0.008) and calf (P = 0.015)]andareshowninFig.3.

Three subjects did not return the questionnaires toevaluate postexertional malaise 24 h after exercise,despite receiving a prestamped envelope and beingcontactedbythe researchersseveral times.TheCIS isaquestionnaire thatquantifiessubjective fatigueandrelated behaviour. High scores are associated withhigher fatigue levels. Comparing theCIS score beforeand after exercise between the groups showed asignificant difference in the subscales fatigue (P =0.002), reduced motivation (P = 0.038) and reducedactivity (P = 0.006). In the patient group, the scoreson these subscales increased after the exercise testwhereas in the control group the scores decreasedslightly (Table 2). Changes over time in the SF-36subscale ‘physical functioning’ (P = 0.007) and CFSSymptom List total score (P = 0.002) were differentbetween the two groups.Whereas the scores from thecontrol group improved after exercise in comparisonto the baseline scores, the scores declined in theME ⁄CFS patient group. This indicates that thesecond exercise bout (i.e. the paced exercise test withapplication of three safety breaks) increased symp-toms inthisgroupofwomenwithME ⁄CFS.

Exercise response, exercise capacity and exercise-induced pain inhibition:comparison between the two exercise protocols

As expected, there were no significant differencesbetween the two exercise tests (submaximal exercisestress test and exercise with safety breaks) withregard to heart rate and lactate concentrations atrest. Using continuous ergospirometry duringexercise, control subjects had a lower peak ventila-

tion (VE) (P = 0.010) and peak oxygen uptake (VO2)(P = 0.002) during the exercise bout with safetybreaks (peak VE = 24.4 ± 4.9 L min)1; peak VO2 =17.1 ± 3.1 mL min)1 kg)1) compared to the sub-maximal exercise stress test (peak VE = 30.5 ±8.9 L min)1; peak VO2 = 27.6 ± 24.7 mL min)1

kg)1). The same difference was seen in ME ⁄CFSpatients (peak VE, P < 0.001; peak VO2, P = 0.009).During submaximal exercise and during exercisewith safety breaks, ME ⁄CFS patients had a peak VEof 36.1 ± 13 and 25.5 ± 5.7 L min)1, and a peakVO2 of 24.1 ± 13.9 and 17.9 ± 11.2 mL min)1 kg)1,respectively.Therewasalsoasignificantly lowerpeakRER (P = 0.005) during the exercise bout with safetybreaks (RER = 1.77 ± 4)as compared to thesubmax-imal exercise stress test (RER = 1.25 ± 0.89) in thepatient group. Although the exercise duration waslonger during experiment 2, the intensity of theexercise was lower compared to experiment 1. Par-ticipants cycled for longer during the exercise withsafety breaks, but lactate levels were significantlylower (ME ⁄CFS group P = 0.011, control groupP = 0.001) than during the submaximal exercisetest. All these results support our initial intention ofstudying two different exercise bouts in the samegroupofsubjects.

No significant differences were found for the post-exercise PPTsbetween the two types of exercise in theME ⁄CFS group. Although, significant differenceswere found in terms of symptom occurrence andquality of life (CFS Symptom List, SF-36, CIS)between the ME ⁄CFS and control groups, there wereno differences between the two exercise tests in theME ⁄CFS group. In the control group, there were sig-nificantly fewer complaints about ‘cold hands andfeet’ during the self-paced andphysiologically limitedbicycleexercise test (F = 11.69;P = 0.001).

Pai

n pr

essu

re t

hres

hold

s (k

g/cm

2 )

Pai

n pr

essu

re t

hres

hold

s (k

g/cm

2 )

Pai

n pr

essu

re t

hres

hold

s (k

g/cm

2 )

Back (P = 0.008) Calf (P = 0.015) Hand (P = 0.002)

ControlME/CFS

ControlME/CFS

ControlME/CFS

Pre-exercise Post-exercise Pre-exercise Post-exercise Pre-exercise Post-exercise

4.80 ± 1.67

5.03 ± 2.31

5.92 ± 2.30

5.22 ± 1.945.20 ± 1.49

4.99 ± 1.99

5.69 ± 1.574.86 ± 1.68

4.60 ± 1.67

4.99 ± 1.77

4.10 ± 1.83

6.98 ± 2.50

4.5

5.0

5.5

6.0

6.5

7.0 5.8

5.6

5.4

5.2

5.0

4.8 4.0

4.2

4.4

4.6

4.8

5.0

Fig. 3 Changes in pain pressure thresholds in response to self-paced, physiologically limited exercise in women with myalgicencephalomyelitis ⁄ chronic fatiguesyndrome (ME ⁄CFS) (n = 22)andsedentarywomen (n = 22).



Table 2 Changes in health status in response to self-paced, physiologically limited exercise in patientswithME ⁄CFS (n = 22) and

healthysedentarycontrol subjects (n = 22)

ME ⁄CFSpatients

(mean ± standard

deviation)

Control subjects

(mean ± standard

deviation)

Within-groups

comparison

(F-value;P-value)

Pain (mm)

Pre-exercise 61.9 ± 29.8 5.5 ± 8.9

Post-exercise 71.0 ± 26.3 3.3 ± 7.6 17.6;<0.001

24 hpost-exercise 73.3 ± 25.4 5.8 ± 10.4 4.9;0.034

Fatigue (mm)

Pre-exercise 76.6 ± 18.6 10.7 ± 9.5

Post-exercise 84.5 ± 13.2 5.9 ± 6.1 20.2;<0.001

24 hpost-exercise 87.4 ± 19.3 6.5 ± 8.2 12.9;0.001

Concentrationdifficulties (mm)

Pre-exercise 62.6 ± 26.2 5.8 ± 8.7

Post-exercise 66.5 ± 25.6 3.3 ± 6.2 5.0;0.031

24 hpost-exercise 68.4 ± 28.5 3.4 ± 6.8 7.2;0.011

CFSSymptomList total score (mm)

Pre-exercise 57.3 ± 16.7 6.4 ± 5.7

Post-exercise 60.5 ± 14.6 4.2 ± 4.7 13.3;0.001

24 hpost-exercise 63.7 ± 18.7 4.5 ± 5.1 10.6;0.002

CIS fatigue

Pre-exercise 52.2 ± 3.6 20.1 ± 7.6

Post-exercise 52.8 ± 3.7 18.2 ± 8.1 11.0;0.002

CISconcentrationdifficulties

Pre-exercise 28.4 ± 5.5 10.3 ± 5.3

Post-exercise 29.0 ± 5.6 9.8 ± 4.3 2.9;0.096

CISmotivation

Pre-exercise 16.6 ± 7.1 8.7 ± 4.6

Post-exercise 17.0 ± 7.0 7.7 ± 4.0 4.6;0.038

CISphysicalactivity

Pre-exercise 16.2 ± 4.9 6.7 ± 3.4

Post-exercise 16.5 ± 4.7 6.0 ± 3.1 8.2;0.006

SF36bodilypain

Pre-exercise 41.8 ± 18.2 88.9 ± 11.1

Post-exercise 41.2 ± 17.5 89.4 ± 13.2 0.590;0.447

24 hpost-exercise 40.1 ± 15.9 90.2 ± 12.5 3.8;0.061

SF-36physical functioning

Pre-exercise 39.6 ± 19.0 91.8 ± 9.3

Post-exercise 36.6 ± 19.3 92.6 ± 9.8 7.36;0.010

24 hpost-exercise 31.8 ± 19.0 92.4 ± 10.0 7.98;0.007

SF-36role limitationsdue tophysical functioning

Pre-exercise 6.8 ± 22.1 95.5 ± 21.3

Post-exercise 6.8 ± 22.1 91.7 ± 22.8 3.5;0.069

24 hpost-exercise 1.3 ± 5.6 92.9 ± 22.6 0.487;0.489



Association between exercise-induced pain inhibition and postexertionalmalaise

Submaximalexercisestress test. Weinvestigated theassociation between changes in PPTs and changesin symptom occurrence post-exercise. A decrease inPPTsmeasurednear L3 after exercise correlatedwithan increase in fatigue (r = 0.454; P = 0.034) afterexercise in theME ⁄CFS group, asmeasuredwith theCFS Symptom List. No association was found in thecontrol group.

Self-paced and physiologically limited exercise. Noassociations between changes in PPTs and changesin symptom occurrence could be established post-exercise.

Discussion

The results of this study suggest an impairment ofpain inhibition during both a submaximal exercise

test andaself-pacedandphysiologically limitedexer-cise bout in patients withME ⁄CFS, resulting in post-exertional malaise. During submaximal exercise,control subjects showed increased PPTs whereasPPTsdecreased inME ⁄CFSpatients. Likewise,signif-icantdifferenceswere foundbetween thecontrol sub-jects and theME ⁄CFS patients during the self-pacedand physiologically limited exercise. During thesetwo typesof submaximal exercise, thepain inhibitorysystems in patients with ME ⁄CFS did not respond toexerciseas theydid inhealthysubjects.These resultsextend the evidence providedbyothers [2, 9], indicat-ing that people with ME ⁄CFS have an impaired paininhibition during submaximal exercise. This is thefirst study to demonstrate impaired pain inhibitionduring self-paced and physiologically limited exer-cise inpatientswithME ⁄CFS.

It is possible that dysfunction of the pain inhibitionmechanisms during exercise results in decreased

Table2 (Continued)

ME ⁄CFSpatients

(mean ± standard

deviation)

Control subjects

(mean ± standard

deviation)

Within-groups

comparison

(F-value;P-value)

SF-36role limitationsdue toemotionalproblems

Pre-exercise 62.1 ± 45.2 95.5 ± 21.3

Post-exercise 60.6 ± 44.4 93.7 ± 22.7 0.001;0.974

24 hpost-exercise 58.3 ± 45.7 93.7 ± 22.7 0.507;0.481

SF-36social functioning

Pre-exercise 38.6 ± 23.8 94.9 ± 12.0

Post-exercise 37.8 ± 21.5 95.2 ± 12.8 0.309;0.581

24 hpost-exercise 33.4 ± 18.6 95.8 ± 12.1 2.25;0.142

SF-36mentalhealth

Pre-exercise 64.1 ± 19.0 80.9 ± 11.6

Post-exercise 64.0 ± 17.6 83.2 ± 8.5 2.59;0.116

24 hpost-exercise 65.6 ± 18.1 81.3 ± 11.1 0.320;0.575

SF-36vitality

Pre-exercise 31.5 ± 16.7 75.2 ± 12.4

Post-exercise 32.7 ± 16.2 76.2 ± 11.3 0.013;0.909

24 hpost-exercise 28.8 ± 14.3 77.9 ± 9.9 1.4;0.244

SF-36generalhealthperception

Pre-exercise 15.7 ± 10.5 61.6 ± 9.3

Post-exercise 15.9 ± 10.4 61.0 ± 10.7 0.214;0.646

24 hpost-exercise 15.0 ± 7.6 61.7 ± 10.2 0.583;0.450

Comparisonswereperformedusing two-wayrepeatedmeasuresanova.Statisticallysignificantresultsaregiven inbold.CIS,Checklist IndividualStrength;SF-36,MedicalOutcomesShortForm36HealthStatusSurvey.



PPTs, causingME ⁄CFS patients to bemore suscepti-ble to symptom increase. This could explain why thedecreased PPTs during exercise were accompaniedby a worsening of the ME ⁄CFS symptom complexand a reduction in the ability to perform physicalactivities post-exercise. Further decreased PPTsdur-ing exercise were associated with postexertional fati-gue in the ME ⁄CFS group. Therefore, this evidencesupports the association between an impaired paininhibition during exercise and the symptom increasefollowing exercise in ME ⁄CFS patients. However, ex-cept for fatigue no other associations were observedbetween impaired pain inhibition and postexertionalpain, or any other assessed symptoms. The term‘postexertional malaise’ is used to describe the exac-erbation of symptoms following physical exertion.Postexertional fatigue is only one of many symptomsincluded in the full cluster of symptoms of postexer-tional malaise. Although many of these symptomswere assessed using the CFS Symptom List, andwere significantly increased after exercise, they werenot directly related to impaired pain inhibition inresponse to exercise.

It should be acknowledged that mechanisms otherthan impaired pain inhibition in response to exer-cise may play a role in the cluster of pathologicalpostexertional symptoms seen in ME ⁄CFS patients.Deficiency in hypothalamic–pituitary–adrenal axisfunctioning might cause pathological immune acti-vation with release of pro-inflammatory cytokines[43] and induction of the so-called ‘sickness re-sponse’. The symptoms of this response (lethargiaand malaise, social withdrawal, flu-like symptoms,mood lowering, concentration difficulties and gener-alized pain hypersensitivity) [44] also characterizethe cluster of pathological postexertional symptomsseen in ME ⁄CFS patients. In line with this are thefindings of pathological immune activation (e.g.complement activation and increased oxidativestress) in response to exercise in patients withME ⁄CFS [6, 16]. This study include measurement ofimmune activation (blood samples), but these re-sults have been presented and discussed elsewhere[20].

Although it has been reported that exercise andpost-exertionalmalaisecancauseasignificantdecrease inactivity levels in ME ⁄CFS patients [45], we found noevidence in the present study to support this. Rather,thecurrent results support thefindingsofBazelmanset al. that fatigue inME ⁄CFS patients increases afterexercise, but that the level of actual physical activityremainsunchanged [46].

During self-paced and physiologically limited exer-cise, control subjects were able to cycle significantlylonger than the ME ⁄CFS patients without experienc-ingpostexertionalmalaise. It ispossible thatME ⁄CFSpatients exercised less because they experiencedsymptoms during exercise. On the other hand, wecannot exclude the possibility that these patientshave developed behavioural patterns to limit theirexercise as they know that ‘they will pay for it later’.Whereas the control group improved their physicalfunctioningandreported fewercomplaintspost-exer-cise, ME ⁄CFS patients reported a worsening of theirphysical functioning and symptoms. The ME ⁄CFSpatients experienced not only symptom increases24 h post-exercise, but also impaired pain inhibitionduring exercise. As no significant changes in activitylevels were observed after the submaximal exercisetest, it is unlikely that the results were biassed by thedailyphysical activity levelsduring thestudyperiod.

In the ME ⁄CFS group, ventilatory (peak VE and VO2)and metabolic (lactate levels) variables were signifi-cantly lower during the self-paced and physiologi-cally limited exercise, comparedwith during the sub-maximal stress test. However, the ME ⁄CFS patientscycled for a longer period during the self-paced andphysiologically limited exercise. Therefore, it seemsthat self-pacedandphysiologically limited exercise ismore appropriate for ME ⁄CFS patients despite thefact thatboth typesof exerciseprovokedadecrease inPPTsresulting insymptomexacerbation.

Theself-paced,physiologically limitedexerciseproto-col applied strategies that are used to implement‘safe’ exercise therapy and self-management for peo-ple with ME ⁄CFS [28, 30]. In a previous study, Nijset al. applied a similar but less stringent approach tolimit postexertional malaise in people with ME ⁄CFS[47]. Itwasshownthat theuseofexercise limits (limit-ing both the intensity and duration of exercise) canprevent postexertional malaise, but cannot preventan acute increase in symptoms following walkingexercise in people with ME ⁄CFS [47]. Based on thatexperience, we made the exercise limits more strin-gent by decreasing the intensity to 80% of the heartrate corresponding to the anaerobic threshold of thefirst (submaximal) exercise bout. Nevertheless, wewere unable to prevent postexertionalmalaise in thisgroup of women with ME ⁄CFS. These results high-light the fact that one shouldbecautiouswhenevalu-ating exercise in people with ME ⁄CFS. More work isrequired to address the issue of preventing postexer-tional malaise. This could be done by using exerciselimits to maintain a lower intensity of exercise, as in



previous randomized controlled clinical trials of exer-cise therapy in people with ME ⁄CFS (e.g. exerciseintensity based on the heart rate value obtained atthe midpoint during a submaximal exercise test orthe heart rate corresponding to 40% of peak oxygenconsumption during amaximal exercise test [27, 28,47]).

The results should be interpreted in the light of thestudy limitations. To account for bias due to poolingof gender data, only women were studied [5]. There-fore, care should be taken with the extrapolation ofthese results to the complete ME ⁄CFS populationand further studies in males with ME ⁄CFS are re-quired. Baseline PPTs for experiment 2 could havebeen decreased as a result of the first exercise test,suggesting that1 weekbetweentestswasnotenoughfor patients to recover. On the other hand, the studyhas several strengths. The patient group was suffi-ciently powered and selectively chosen to study animportant and debilitated subgroup within theME ⁄CFS population. Using real-time physical activ-itymonitoringallowedustoaccount forpotentialbiasresulting from physical activities performed by thepatients prior to the first exercise bout and betweenexercise sessions. A final strength worth mentioningis that the study strongly builds on previous work inthe area of ME ⁄CFS; the submaximal exercise proto-col is the only protocol known to be reliable and validfor testing people with ME ⁄CFS [27, 29] and the self-paced, physiologically limited exercise protocol ap-plied strategies used to implement ‘safe’ exercisetherapy and self-management for people withME ⁄CFS [12,48].

In conclusion, the results of this study showed thatsubmaximal exercise and self-paced, physiologicallylimitedexercise trigger postexertionalmalaise inpeo-plewithME ⁄CFS.Duringboth typesof exercise, PPTsdecreased following exercise in ME ⁄CFS patients,whereas they increased in healthy subjects. Patientsexperienced a worsening of the ME ⁄CFS symptomcomplex and a reduction in the ability to performphysical activities post-exercise. Decreased PPTsduring submaximal exercise were associated withpostexertional fatigue in the ME ⁄CFS group. Theseobservations indicate the presence of abnormal cen-tral pain processing during exercise in people withME ⁄CFS.

Acknowledgements

Thisstudywas fundedbyMEResearchUK (MERUK),a national charity that funds biomedical research

into ME ⁄CFS. The authors are grateful to Lieve DeHauwere for taking the blood samples and assistingin the exercise tests. Jessica Van Oosterwijck isfinancially supported by grant no.OZR1596 from theresearch council of the Vrije Universiteit Brussel,Brussels, Belgium. Mira Meeus is a postdoctoral fel-low of the Fund for Scientific Research Flanders(FWO).

Conflict of interest statement

Noconflict of interestwasdeclared.

References

1 FukudaK, Straus SE, Hickie I, SharpeMC,Dobbins JG, Komar-

off A. The chronic fatigue syndrome, a comprehensive approach

to itsdefinitionandstudy.Ann InternMed1994;121:953–9.

2 Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain

threshold inchronic fatiguesyndrome.Pain2004;109:497–9.

3 Knoop H, Bleijenberg G, Gielissen MF, van der Meer JW, White

PD. Is a full recovery possible after cognitive behavioural therapy

for chronic fatigue syndrome? Psychother Psychosom 2007; 76:

171–6.

4 Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of

chronic fatigue syndrome and major depressive disorder. Int J

BehavMed2006;13:244–51.

5 Ohashi K, Yamamoto Y, Natelson BH. Activity rhythm degrades

after strenuousexercise inchronic fatigue syndrome.PhysiolBe-

hav2002;77:39–44.

6 SorensenB, Streib J, StrandM et al.Complement activation in a

model of chronic fatigue syndrome. J Allergy Clin Immunol 2003;

12:397–403.

7 KoltynKF,ArbogastRW.Perception of painafter resistance exer-

cise.BrJSportsMed1998;32:20–4.

8 Millan MJ. Descending control of pain. Prog Neurobiol 2002; 66:

355–474.

9 MeeusM. Biopsychosocial nature of chronic widespread pain in

chronic fatigue syndrome.PhDDissertation.Brussels: VrijeUni-

versiteitBrussel, 2008.

10 MeeusM,Nijs J, VandeWauwerN, Toeback L, Truijen S.Diffuse

noxious inhibitory control is delayed in chronic fatigue syn-

drome:anexperimentalstudy.Pain2008;2:439–48.

11 Clapp LL, Richardson MT, Smith JF, WangM, Clapp AJ, Pieroni

RE. Acute effects of thirtyminutes of light-intensity, intermittent

exercise on patients with chronic fatigue syndrome. Phys Ther

1999;79:749–56.

12 Cook DB, Nagelkirk PR, Peckerman A, Poluri A, Mores J, Natel-

son BH. Exercise and cognitive performance in chronic fatigue

syndrome.MedSciSportsExerc2005;37:1460–7.

13 Wallman KE, Morton AR, Goodman C, Grove R, Guilfoyle AM.

Randomised controlled trial of graded exercise in chronic fatigue

syndrome.MedJAustr2004;180:444–8.

14 Wallman K, Morton A, Goodman C, Grove R. Physiological re-

sponses during a submaximal cycle test in chronic fatigue syn-

drome.MedSciSportsExerc2004;36:1682–8.

15 DeBecker P,McGregorN,DeMeirleir K. A definition-based anal-

ysisof symptoms ina largecohortof patientswith chronic fatigue

syndrome.J InternMed2001;250:234–40.



16 Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S.

Chronic fatigue syndrome: assessment of increased oxidative

stress and alteredmuscle excitability in response to incremental

exercise.J InternMed2005;257:299–310.

17 LappCW. Exercise limits in chronic fatigue syndrome.AmJMed

1997;103:83–4.

18 CFS ⁄ ME Working Group. Report to the Chief Medical Officer of

an Independent Working Group. London: Department of Health,

2001. Available at: http://www.dh.gov.uk/en/Publicationsand

statistics/Publications/PublicationsPolicyAndGuidance/DH_

4064840.

19 Shephard C. Pacing and exercise in chronic fatigue syndrome.

Physiotherapy2001;87:395–6.

20 Nijs J, Van Oosterwijck J, MeeusM et al.Unravelling the nature

of post-exertionalmalaise inmyalgic encephalomyelitis ⁄ chronicfatigue syndrome: the role of elastase, complement C4a and

interleukin 1beta. J Intern Med, in press, doi: 10.1111/j.1365-

2796.2009.02178.x.

21 Wolfe F, Smythe HA, Yunus MB et al. The American College of

Rheumatology 1990 Criteria for the Classification of Fibromyal-

gia. Report of the Multicenter Criteria Committee. Arthritis

Rheum1990;33:160–72.

22 De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir

K. Exercise capacity in chronic fatigue syndrome. Arch Int Med

2000;160:3270–7.

23 SargentC,ScroopGC,NemethPM,BurnetRB,BuckleyJD.Max-

imal oxygen uptake and lactate metabolism are normal in

chronic fatiguesyndrome.MedSciSportsExerc2002;34:51–6.

24 Nijs J, Meeus M, McGregor NR et al. Chronic fatigue syndrome:

exercise performance related to immune dysfunction. Med Sci

SportsExerc2005;37:1647–54.

25 Meyer T,Georg T, Becker C,KindermannW.Reliability of gas ex-

change measurements from two different spiroergometry sys-

tems. IntJSportsMed2001;22:593–7.

26 Telford R,Minikin B, Hahn A, Hooper L. A simplemethod for the

assessment of general fitness: the tri-level profile.Aust J Sci Med

Sport1989;21:6–9.

27 WallmanK,GoodmanC,MortonA,GroveR,DawsonB.Test-ret-

est reliability of the Aerobic Power Index Test in patients with

chronic fatigue syndrome.JChronic FatigueSyndr2003;11:19–

32.

28 WallmanK,GoodmanC,MortonA,GroveR,DawsonB.Test-ret-

est reliabilityof theaerobicpower indexcomponentof thetri-level

fitness profile in a sedentary population.JSciMedSport2003;6:

443–54.

29 Nijs J, Demol S,Wallman K. Can submaximal exercise variables

predictpeakexerciseperformance inwomenwithchronic fatigue

syndrome?ArchMedRes2007;38:350–3.

30 Nijs J, Paul L, Wallman K. Chronic fatigue syndrome: an ap-

proach combining self-management with graded exercise to

avoidexacerbations.JRehabilMed2008;40:241–7.

31 Nijs J, Aerts A, De Meirleir K. Generalized joint hypermobility is

more common in chronic fatigue syndrome than in healthy con-

trols.JManipulativePhysiolTher2006;29:32–9.

32 Nijs J, Thielemans A. Kinesiophobia and symptomatology in

chronic fatigue syndrome: apsychometric studyof two question-

naires.PsycholPsychother2008;81(pt3):273–83.

33 Ware J, Snow K, Kosinski M, Gandek B. SF-36 Health Survey

Manual and Interpretation Guide. Boston, MA: New England

MedicalCenter,TheHealth Institute,1993.

34 McHorney CA, Ware JE, Lu JFR, Sherbourne CD. The MOS 36-

itemShort FormHealth Survey (SF-36): III. Tests of data quality,

scaling assumptions, and reliability across diverse patients

groups.MedCare1994;32:40–66.

35 WellsK,StewartA,HaysRetal.The functioningandwell-beingof

depressed patients. Results from the Medical Outcomes Study.

JAMA1989;262:914–9.

36 Nijs J, Vaes P, VanHoof E, DeBecker P,McGregor N,DeMeirleir

K. Activity limitations and participation restrictions in patients

withchronic fatiguesyndrome–constructionofadiseasespecific

questionnaire.JChronicFatigueSyndr2002;10:3–23.

37 Vercoulen JHMM, Swanink CMA, Fennis JFM, Galama JMD,

van der Meer JWM, Bleijenberg G. Dimensional assessment of

chronic fatiguesyndrome.JPsychosomRes1994;38:383–92.

38 VercoulenJHMM,AlbertsM,BleijenbergG.Dechecklist individ-

ualstrength (CIS).Gedragstherapie1999;32:131–6.

39 Vanderweeen L, Oostendorp RA, Vaes P, Duquet W. Pressure

algometry inmanual therapy.ManTher1996;1:258–65.

40 Farasyn A, Meeusen R. The influence of non-specific low back

painonpressurepain thresholdsanddisability.Eur JPain2005;

9:375–81.

41 FarasynA,MeeusenR. Pressure pain thresholds in healthy sub-

jects: influenceofphysicalactivity,historyof lowerbackpain fac-

tors and the use of endermology as a placebo-like treatment. J

BodyworkMovTher2003;7:53–61.

42 Finn KJ, Specker B. Comparison of Actiwatch activity monitor

and Children’s Activity Rating Scale in children. Med Sci Sports

Exerc2000;32:1794–7.

43 Raison CL, Miller AH. When not enough is too much: the role of

insufficientglucocorticoidsignaling in thepathologyof stress-re-

lateddisorders.AmJPsychiatry2003;160:1554–65.

44 Maier SF, Watkins LR. Cytokines for psychologists: implications

of bidirectional immune-to-brain communication for under-

standing behaviour, mood, and cognition. Psychol Rev 1998;

105:83–107.

45 SistoSA,TappWN,LaMancaJJetal.Physical activity beforeand

after exercise in women with chronic fatigue syndrome. QJM

1998;91:465–73.

46 BazelmansE,BlijenbergG,VoetenMJM,vanderMeerJWM,Fol-

gering H. Impact of a maximal exercise test on symptoms and

activity in chronic fatigue syndrome. J PsychosomRes 2005;59:

201–8.

47 NijsJ,AlmondF,DeBeckerP,TruijenS,PaulL.Canexercise lim-

its prevent post-exertionalmalaise in chronic fatigue syndrome?

Anuncontrolledclinical trialClinRehabil2008;22:426–35.

48 Fulcher KY, White PD. Randomised controlled trial of graded

exercise inpatientswith thechronic fatigue syndrome.BritMedJ

1997;314:1647–52.

Correspondence: J. Nijs, Vrije Universiteit Brussel, Department of

Human Physiology, Faculty of Physical Education & Physiotherapy,

BuildingL–3rdfloor,Pleinlaan2,BE-1050Brussels,Belgium.

(fax:+3226292876;e-mail: [email protected]).



pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an...

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