Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study

Authors

  • J. Van Oosterwijck,

    1. From the  Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels
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  • J. Nijs,

    1. From the  Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels
    2.  Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Antwerp
    3.  Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels
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  • M. Meeus,

    1. From the  Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels
    2.  Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Antwerp
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  • I. Lefever,

    1. From the  Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels
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  • L. Huybrechts,

    1.  Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Antwerp
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  • L. Lambrecht,

    1.  Private Practice For Internal Medicine, Ghent/Aalst
    2.  CVS Contactgroep, Bruges, Belgium
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  • L. Paul

    1.  Nursing and Health Care, Faculty of Medicine, University of Glasgow, Glasgow, UK
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J. Nijs, Vrije Universiteit Brussel, Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Building L – 3rd floor, Pleinlaan 2, BE-1050 Brussels, Belgium.
(fax: +32 2 629 28 76; e-mail: Jo.Nijs@vub.ac.be).

Abstract

Abstract.  Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, Paul L (Vrije Universiteit Brussel, Brussels; Artesis University College Antwerp, Antwerp; University Hospital Brussels, Brussels; Private Practice For Internal Medicine, Ghent/Aalst; CVS Contactgroep, Bruges; Belgium; and University of Glasgow, Glasgow, UK). Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome. J Intern Med 2010; 268: 265–278.

Objectives.  To examine the efficacy of the pain inhibitory systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) during two different types of exercise and to examine whether the (mal)functioning of pain inhibitory systems is associated with symptom increases following exercise.

Design.  A controlled experimental study.

Setting and subjects.  Twenty-two women with ME/CFS and 22 healthy sedentary controls were studied at the Department of Human Physiology, Vrije Universiteit Brussel.

Interventions.  All subjects performed a submaximal exercise test and a self-paced, physiologically limited exercise test on a cycle ergometer. The exercise tests were undertaken with continuous cardiorespiratory monitoring. Before and after the exercise bouts, subjects filled out questionnaires to assess health status, and underwent pressure pain threshold measurements. Throughout the study, subjects’ activity levels were assessed using accelerometry.

Results.  In patients with ME/CFS, pain thresholds decreased following both types of exercise, whereas they increased in healthy subjects. This was accompanied by a worsening of the ME/CFS symptom complex post-exercise. Decreased pressure thresholds during submaximal exercise were associated with postexertional fatigue in the ME/CFS group (r = 0.454; = 0.034).

Conclusions.  These observations indicate the presence of abnormal central pain processing during exercise in patients with ME/CFS and demonstrate that both submaximal exercise and self-paced, physiologically limited exercise trigger postexertional malaise in these patients. Further study is required to identify specific modes and intensity of exercise that can be performed in people with ME/CFS without exacerbating symptoms.

Introduction

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience a debilitating fatigue accompanied by secondary symptoms including sore throat, memory and concentration impairments, headache, sleep disorders and, most often, muscle and joint pain. Not only do people with ME/CFS often report a fluctuating pattern to their symptoms and physical and cognitive capabilities, they also show severe symptom and pain exacerbation following physical exercise [1, 2]. This postexertional malaise is present in 95% of ME/CFS patients [3] and is one of the best predictors of the differential diagnosis of ME/CFS and major depressive disorder [4]. The severe exacerbation of symptoms following exercise, as seen in ME/CFS patients, is not present in other disorders where fatigue is a predominant symptom such as depression, rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis [5, 6].

Why do patients with ME/CFS experience an increase in symptoms following activity or exercise peaks? It seems that the pain inhibitory systems in these patients do not respond to exercise as they do in healthy subjects. In normal circumstances, pain thresholds increase during physical activity due to the release of endogenous opioids, growth factors [7] and other strong pain inhibitory mechanisms (‘descending inhibition’) orchestrated by the central nervous system [8]. However, in patients with ME/CFS, a decrease in pressure pain thresholds (PPTs) during and after exercise has been observed, suggesting a lack of descending inhibition during exercise [2, 9]. This decrease in pain thresholds could be responsible for the postexertional pain experienced by ME/CFS patients. In addition to the possibility of impaired descending pain inhibitory pathways in ME/CFS during exercise, we previously showed that the diffuse noxious inhibitory controls (DNICs) of ME/CFS patients react more slowly to spatial summation of thermal noxious stimuli compared to healthy controls, resulting in hyperalgesia that is proportional to the stimulated surface [10]. Although pain inhibitory mechanisms have been studied in ME/CFS patients to a small degree, currently there is no research available demonstrating an association between the impaired pain inhibition and the severe symptom exacerbation experienced by ME/CFS patients following exercise.

If postexertional malaise is caused by insufficient activation of the pain inhibitory systems during exercise, further research into the possible contributing factors is required. Indeed, it has been reported that ME/CFS patients are able to perform light to moderate exercise (40% of peak oxygen capacity) without exacerbating their symptoms [11–13]. If the exacerbation of symptoms following physical exertion is related to the intensity and duration of attempted activities, it would be valuable to examine different types of exercise.

It has been suggested that submaximal exercise testing is an appropriate means of assessing physical function in ME/CFS subjects [14]. Anaerobic but not aerobic exercise has been shown to increase symptoms in people with ME/CFS [15–17]. On the other hand, energy management strategies, such as pacing self-management techniques, involve the constant monitoring and manipulation of exercise/activity in terms of intensity, duration and rest periods in order to avoid possible over-exertion and worsening of the symptoms, and therefore could be indicated [18, 19].

In this study, we examined the efficacy of the pain inhibitory systems during two different types of exercise (submaximal and self-paced, physiologically limited bicycle exercise test), and investigated whether this is associated with symptom increase following exercise in ME/CFS patients. This report is the second from a study examining various aspects of postexertional malaise in patients with ME/CFS. The first report highlighted the findings in relation to circulating elastase activity and levels of interleukin 1β and complement C4a [20].

Methods

Subjects

Patients with ME/CFS were referred for study participation from a private practice for internal medicine. For study inclusion, subjects had to fulfil the Center for Disease Control and Prevention criteria for ME/CFS (i.e. a clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset and which results in a substantial reduction in the previous levels of occupational, educational, social or personal activities [1]). Furthermore, at least four of the following symptoms must have persisted during 6 or more consecutive months, but not predated the fatigue: impairment of short-term memory or concentration, tender cervical or axillary lymph nodes, generalized muscle pain, multi-joint pain, headache, unrefreshing sleep and postexertional malaise for more than 24 h [1]. Any active medical condition that may explain the presence of chronic fatigue precludes the diagnosis of ME/CFS and therefore all patients underwent an extensive medical evaluation. All patients were diagnosed by the same internal medicine physician. Pain is considered to be an important aspect of postexertional malaise. Therefore, as well as suffering from ME/CFS, patients included in the study had to present with chronic widespread pain [21]. Patients were asked to attend the first visit with a healthy, sedentary relative, friend or acquaintance to participate in the control group. Sedentary was defined as having a seated occupation and performing a maximum of 1 h of sports per week [22]. Pooling of gender data has been identified as an important source of bias in studies of exercise physiology in ME/CFS patients [23]. Therefore, this study focused on Dutch-speaking women (18 and 65 years old). The power analysis revealed that 22 people with ME/CFS were required for the study [24]. The control group consisted of 22 healthy women matched for age and body mass index (BMI).

Procedure

On the first day of data collection, study participants were asked to read an information leaflet and then to provide written informed consent. The study protocol, information leaflet and informed consent form were approved by the Ethics Committee of the University Hospital Brussels/Vrije Universiteit Brussel. After collecting personal characteristics (e.g. age, use of analgesics or anti-depressants) participants’ height and weight were measured, and they were provided with a tri-axial accelerometer for monitoring activity (Actical Mini Mitter, Bend, OR, USA). Participants were asked to wear the accelerometer continuously during the study. In addition, participants were instructed not to use analgesics for a minimum of 7 days prior to the first experiment (experiment 1).

One week after the first visit, participants returned for to take part in experiment 1. First, they completed baseline measurements that included filling out questionnaires, venous blood sampling and PPT measurements. The following questionnaires were used to assess their health status: the CFS Symptom List, the Medical Outcomes Study 36-item short form health survey (SF-36) and the Checklist Individual Strength (CIS). After completing the questionnaires, four venous blood samples (32.5 cc in total) were collected by an experienced nurse. The results of the blood tests are presented and discussed elsewhere [20]. Subsequently, PPTs were measured by an assessor who was blinded to the subjects’ health status (ME/CFS patient or healthy control). Next, study participants undertook a submaximal exercise stress test (Aerobic Power Index) with continuous cardiorespiratory monitoring (ergospirometry), and blood sampling every 2 min for lactate determination. Figure 1 shows a flow diagram of the study protocol.

Figure 1.

Flow diagram showing the study protocol.

Immediately after exercise, the study participants were subjected to the same PPT measurements as at baseline. At 1 h post-exercise, patients filled out the same questionnaires again and another venous blood sample was taken. Finally, to monitor post-exercise malaise up to 24 h, subjects were given two questionnaires (CFS Symptom List and SF-36) to fill out exactly 24 h after exercise. The subjects were asked to return the completed questionnaires to the Vrije Universiteit Brussel by post (prestamped envelopes were provided). On day 14 of the trial (1 week after experiment 1), the study participants returned to the department for experiment 2. The procedure was the same as described in experiment 1 except that the test consisted of self-paced and physiologically limited bicycle exercise.

Exercise testing

The exercise tests were performed in a sitting position on an electrically braked cycle ergometer (Excalibur Lode, Groningen, the Netherlands) at a room temperature of 18–20 °C. The saddle and handlebars were positioned to suit each subject. After 3–5 min of adjustment to the rest position, baseline data were collected. The oxygen analyser was calibrated with known gas mixtures of 18% O2 and 5% CO2. Room air was automatically calibrated before each test to update the CO2 analyser baseline and the O2 analyser gain so that they coincided with atmospheric values. An open-circuit spirometer (Cortex Metamax I, Biophysik, GmbH, Germany) with automatic printout every 30 s was used to collect pulmonary data during the test. The Cortex Metamax I is a reliable instrument for routine exercise testing in sports medical and research settings [25]. A two-way breathing valve attached to a mask, which covered the patient’s nose and mouth, was used to collect the expired air. The air was analysed continuously for ventilatory and metabolic variables. Patients were instructed to cycle at a pedalling rate of 60–70 rates per minute. Heart rate was recorded at the end of each minute during the exercise test using a heart rate telemetry band Polar T61-Coded (Polar Electro OY, Kempele, Finland). Lactate concentrations were measured to determine the anaerobic threshold during exercise, thus blood samples (20 mL) were drawn from an arterialized earlobe every 2 min during the exercise test. Lactate concentrations were determined enzymatically (EKF, BIOSEN 5030, Magdeburg, Germany).

Experiment 1: submaximal exercise.  The submaximal exercise protocol consisted of a submaximal cycle test known as the aerobic power index test [26], which has been shown to generate reliable data in sedentary and ME/CFS populations [intra-class correlation coefficient (ICC) = 0.98 and 0.97, respectively] [27, 28]. In people with ME/CFS, the submaximal exercise data generated by the aerobic power index correlates highly with peak exercise data [29]. According to the description of the aerobic power index, the workload was increased by 25 W every minute, and the submaximal level was defined as 75% of the age-predicted target heart rate [6]. If subjects were unable to reach their individual target heart rate, then the workload (W) achieved during the last full minute of exercise was recorded as the final power output.

Experiment 2: self-paced and physiologically limited exercise.  Self-paced and physiologically limited bicycle exercise was performed by all subjects with three ‘safety breaks’ or exercise limits. First, the heart rate could not exceed 80% of the rate that corresponded to the anaerobic threshold during the submaximal exercise test. When the anaerobic threshold was not achieved during submaximal exercise, 80% of the highest achieved heart rate was used. In cases, where the heart rate exceeded the upper limit (80% of the heart rate corresponding to the anaerobic threshold) during the paced exercise test, the workload was lowered and if necessary subjects were instructed to reduce their cycling frequency. Second, the workload was kept below 80% of that corresponding to the anaerobic threshold. Heart rate and workload limits were chosen to maintain aerobic exercise, well below the anaerobic threshold, during experiment 2. Third, the exercise duration was determined by asking the patients to pace themselves by estimating how long they would be able to perform the exercise without exacerbating their symptoms. The activity duration estimated by the participants was reduced to account for typical overestimations. To ensure that the patients did not exceed their energy boundaries, 75% of the estimated time was used when the patients reported having a ‘good’ day and 50% was used when they reported having a ‘bad’ day [30]. For the controls, the estimated time was always decreased by 25%. Thus, all subjects performed one bicycle exercise below all three safety breaks.

Self-reported measures

The CFS Symptom List is a self-reported measure for assessing symptom severity in ME/CFS patients. It encompasses the 19 most frequently reported symptoms in a large sample (1578) of ME/CFS patients [15]. To assess the severity of the symptoms included in the CFS Symptom List, visual analogue scales (100 mm) are used. The CFS Symptom List demonstrates excellent consistency (Cronbach’s α = 0.88), test–retest reliability (ICC ≥ 0.97), internal content and concurrent validity [31, 32].

The SF-36 assesses functional status and well-being or quality of life [33]. It is reliable and valid in a wide variety of patient populations [14, 34, 35] and appears to be the most frequently used measure in ME/CFS research [36].

The CIS quantifies subjective fatigue and related behavioural aspects [37]. The CIS consists of 20 statements to be scored on a seven-point scale. The statements refer to four aspects of fatigue: fatigue severity, reduced motivation, reduced activity and reduced concentration. A score of at least 35 on the dimension ‘fatigue severity’ indicates the presence of severe fatigue. The CIS is well validated within the clinical setting and is able to discriminate between different patient populations and between patients and healthy subjects [38].

Pain pressure thresholds

Algometry provides a reliable and valid measure of PPTs [39]. PPTs were measured bilaterally with an analogue Fisher algometer (Force Dial model FDK 10 and model FDK 40 Push Pull Force Gage, Wagner Instruments, Greenwich, CT, USA) in the skin web between thumb and index finger, at the proximal third of the calf and 5 cm lateral to the spinous process of L3 [2, 40]. Because of the reliability of this procedure, the threshold was determined as the mean of the two last values of three consecutive measurements (10 s between each) [41].

Real-time activity monitoring throughout the study

The Actical (Mini Mitter) water-resistant accelerometer was used for real-time monitoring of physical behaviour in all study participants. This accelerometer has an omnidirectional sensor that functions via a cantilevered rectangular piezoelectric bimorph plate and seismic mass, and it is capable of detecting movements in the range of 0.5–3 Hz. Voltage generated by the sensor is amplified and filtered via analogue circuitry. The amplified and filtered voltage is passed 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 are the gold standard for measuring physical behaviour during daily activities. The Actical accelerometer has been shown to be valid for the real-time assessment of physical behaviour [42]. For the present study, the monitors were initialized to save data in 1 min intervals.

Statistical analysis

All data were analysed using spss 16.0 for Windows (spss Inc., Chicago, IL, USA). Normality of the variables was tested with the Kolmogorov–Smirnov test and appropriate descriptive statistics were calculated. Baseline comparisons between ME/CFS patients and controls were performed using Student’s t-test.

For each type of exercise (i.e. submaximal exercise and exercise bout with safety breaks), possible changes in any of the outcome measures in response to exercise were compared between the two groups using repeated measures anova (time × group interaction). Parametric variables related to exercise and respiratory performance were analysed using the independent sample t-test; nonparametric variables were analysed using the Mann–Whitney U-test.

Likewise, for each group (ME/CFS patients and sedentary healthy controls) possible differences in the response of each of the outcome measures to exercise were examined using repeated measures anova (time × group interaction). Normally distributed outcomes related to exercise and respiratory performance were examined with the paired samples t-test. Nonparametric data were examined using the Wilcoxon signed rank test. The significance level was set at 0.05.

Pearson correlation analysis was used to examine the association between PPTs and fatigue severity. Daily physical activity levels were compared between the groups using independent sample t-tests, whereas day-to-day fluctuations were controlled using repeated measures anova (time × group interaction).

Results

Twenty-two ME/CFS female patients and 22 healthy women were recruited for the study. The mean age of the patients was 34.3 ± 8.8 years and their mean BMI was 24.1 ± 4.7 kg m−2. The mean age of the control subjects was 38.9 ± 15 years and their BMI was 24.5 ± 4.8 kg m−2. These BMI values indicate normal weight in both groups. The independent samples t-test showed no significant difference in age (= 0.229) or BMI (= 0.852) between the patient and the control groups. At baseline, 12 patients used analgesics and 10 patients used anti-depressants. In the control group, one subject used anti-depressants.

Daily physical activity levels

To establish daily activity levels at baseline, subjects were asked to wear a tri-axial accelerometer from the first visit until experiment 1. No significant differences were found between the ME/CFS and the control groups for daily physical activity levels during baseline (6 days before experiment 1) (= 0.365). Therefore, we conclude that the two groups were comparable.

To monitor the potential influences of daily activity levels on exercise performance during experiment 2, and as a potential confounder of symptom fluctuations, subjects were asked to wear a tri-axial accelerometer continuously between the post-exercise assessments of experiment 1 and the pre-exercise interventions of experiment 2. In two subjects, the devices were defective and did not register the daily physical activity; the device only registered for 3 days in one subject. No significant differences were found between the ME/CFS group and the healthy, sedentary controls with regard to daily physical activity levels or day-to-day fluctuations in activity patterns (F = 0.838, = 0.365).

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

Submaximal exercise stress test.  Baseline measurements showed a mean heart rate of 79 ± 12 bpm and mean lactate levels of 1.12 ± .47 mmol L−1 at rest for the control group. The ME/CFS group had a mean heart rate of 81 ± 10 bpm and mean lactate level of 0.90 ± 0.24 mmol L−1 at rest. ME/CFS patients cycled for 3.9 ± 1.3 min at a maximum workload of 109 ± 29 W. At the end of the exercise test, their lactate levels reached 2.96 ± 1.46 mmol L−1. The control subjects cycled for 4.2 ± 1.2 min and reached a maximum workload of 118 ± 30 W. At the end of exercise, lactate levels reached 2.60 ± 1.09 mmol L−1. No significant differences (> 0.05) were found for heart rate, lactate levels, workload or cycled time between the ME/CFS and control groups. However, the peak respiratory exchange ratio (RER) during submaximal exercise was significantly higher in the ME/CFS group (mean 1.25 ± 0.98) compared to the sedentary control group (mean 0.92 ± 0.11) (= 0.002). One control subject refused respiratory monitoring because of a claustrophobic reaction to the mask.

At baseline, ME/CFS patients showed decreased PPTs measured near L3, indicating the presence of hyperalgesia of the lower back (= 0.031). After performing the exercise test, a significant difference in pain thresholds was found between the ME/CFS and the control groups, as shown in Fig. 2. The PPTs measured on the back and the calf increased in the control group whereas they decreased in the patient group (= 0.006 and = 0.018, respectively). PPTs measured in the skin web between thumb and index finger showed the same effect although the difference was not significant (= 0.077).

Figure 2.

Changes in pain pressure thresholds in response to submaximal exercise in women with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (n = 22) and sedentary women (n = 22).

There was a significant difference between patients and controls with regard to the change over time (baseline, post-exercise, 24 h post-exercise) in the subscale ‘physical functioning’ of the SF-36 score (= 0.029). Control subjects showed stable scores but ME/CFS patients showed a decrease in the scores over time, indicating postexertional malaise in the patient group. ME/CFS patients showed a worsening of symptoms from baseline to post-exercise and 24 h post-exercise, as measured by the CFS Symptom List, whereas controls showed symptom improvement (Table 1). The difference between the two groups was significant (< 0.001). The CIS showed no significant differences (> 0.05) between the two groups. One patient failed to return the questionnaires to evaluate postexertional malaise up to 24 h after exercise.

Table 1. Changes in health status in response to submaximal exercise in patients with ME/CFS (n = 22) and healthy sedentary control subjects (n = 22)
 ME/CFS patients (mean ± standard deviation)Control subjects (mean ± standard deviation)Within-groups comparison (F-value; P-value)
  1. Comparisons were performed using two-way repeated measures anova. Statistically significant results are given in bold.

  2. CIS, Checklist Individual Strength; SF-36, Medical Outcomes Short Form 36 Health Status Survey.

Pain (mm)
 Pre-exercise45.7 ± 24.89.5 ± 14.7 
 Post-exercise64.8 ± 24.710.2 ± 16.610.1; 0.003
 24 h post-exercise67.8 ± 27.14.9 ± 6.629.9; <0.001
Fatigue (mm)
 Pre-exercise68.6 ± 14.215.6 ± 18.1 
 Post-exercise78.3 ± 21.114.2 ± 21.45.4; 0.025
 24 h post-exercise84.0 ± 18.412.8 ± 18.88.8; 0.005
Concentration difficulties (mm)
 Pre-exercise54.8 ± 24.45.3 ± 7.1 
 Post-exercise62.8 ± 29.84.4 ± 5.33.6; 0.064
 24 h post-exercise68.0 ± 28.05.9 ± 8.88.2; 0.006
CFS Symptom List total score (mm)
 Pre-exercise53.2 ± 12.110.6 ± 8.4 
 Post-exercise58.1 ± 14.98.4 ± 8.718.5; <0.001
 24 h post-exercise63.4 ± 16.96.1 ± 7.727.3; <0.001
CIS fatigue
 Pre-exercise50.9 ± 5.820.9 ± 7.7 
 Post-exercise52.3 ± 5.518.5 ± 7.43.4; 0.072
CIS concentration difficulties
 Pre-exercise28.4 ± 6.210.5 ± 4.5 
 Post-exercise27.6 ± 7.69.4 ± 4.30.9; 0.765
CIS motivation
 Pre-exercise15.5 ± 5.18.6 ± 4.0 
 Post-exercise17.0 ± 6.78.0 ± 3.02.6; 0.117
CIS physical activity
 Pre-exercise15.5 ± 5.16.3 ± 2.7 
 Post-exercise16.1 ± 5.66.3 ± 3.21.1; 0.305
SF 36 bodily pain
 Pre-exercise41.4 ± 17.689.3 ± 11.6 
 Post-exercise45.0 ± 15.289.8 ± 12.51.2; 0.271
 24 h post-exercise41.1 ± 15.689.9 ± 11.80.038; 0.846
SF-36 physical functioning
 Pre-exercise40.0 ± 16.790.2 ± 12.9 
 Post-exercise39.1 ± 19.193.4 ± 7.51.2; 0.271
 24 h post-exercise34.3 ± 22.093.6 ± 8.55.1; 0.029
SF-36 role limitations due to physical functioning
 Pre-exercise5.6 ± 10.790.9 ± 26.2 
 Post-exercise9.1 ± 22.693.2 ± 22.10.018; 0.893
 24 h post-exercise7.5 ± 23.189.1 ± 28.20.172; 0.680
SF-36 role limitations due to emotional problems
 Pre-exercise66.7 ± 44.893.9 ± 22.1 
 Post-exercise62.1 ± 46.495.5 ± 15.62.02; 0.162
 24 h post-exercise63.3 ± 48.293.9 ± 22.11.91; 0.175
SF-36 social functioning
 Pre-exercise36.4 ± 21.195.4 ± 9.9 
 Post-exercise39.2 ± 24.596.6 ± 9.60.136; 0.714
 24 h post-exercise34.4 ± 22.595.5 ± 9.10.122; 0.729
SF-36 mental health
 Pre-exercise63.1 ± 17.478.7 ± 8.2 
 Post-exercise64.7 ± 20.580.4 ± 10.30.000; 0.983
 24 h post-exercise66.0 ± 21.082.0 ± 9.10.340; 0.563
SF-36 vitality
 Pre-exercise30.9 ± 11.772.5 ± 11.1 
 Post-exercise30.9 ± 14.976.8 ± 12.03.43; 0.071
 24 h post-exercise31.8 ± 16.777.9 ± 9.91.01; 0.322
SF-36 general health perception
 Pre-exercise16.6 ± 9.663.6 ± 12.4 
 Post-exercise18.0 ± 13.264.8 ± 9.50.008; 0.928
 24 h post-exercise17.5 ± 10.661.6 ± 12.71.31; 0.260

Self-paced and physiologically limited exercise.  One control subject refused respiratory monitoring because of a claustrophobic reaction to the mask, and the data from two other subjects were lost because of computer problems. No significant differences in ventilatory variables could be established between the two test groups (> 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, resting mean heart rate was 79 ± 9 bpm and mean lactate levels were 1.07 ± 0.35 mmol L−1. In ME/CFS patients, the mean workload during exercise was 46 ± 10 W and lactate levels at the end of the exercise test reached 1.91 ± 0.82 mmol L−1. The control subjects reached a mean workload of 46 ± 17 W during the exercise test and, lactate levels reached 1.65 ± 0.66 mmol L−1 at the end of exercise. Patients’ paced time (5.0 ± 2.4 min) was shorter than that for the controls (9.3 ± 5.2 min); subsequently, controls (9.3 ± 5.2 min) cycled for significantly (= 0.001) longer than ME/CFS patients (4.7 ± 2.5 min). Moreover, whereas only one subject in the control group was unable to cycle for the total self-predicted duration, six patients with ME/CFS stopped cycling before the self-predicted cycle time was reached (= 0.042). No significant differences (> 0.05) were found between the two groups for heart rate, workload or lactate levels.

In the control group, PPTs increased in response to the exercise test. In the patient group, only the PPT measured at the lower back increased whereas the thresholds on the calf and the skin web between the index finger and thumb decreased. The differences between the patient and control groups were found to be significant for all PPT measurements [i.e. hand (= 0.002), back (= 0.008) and calf (= 0.015)] and are shown in Fig. 3.

Figure 3.

Changes in pain pressure thresholds in response to self-paced, physiologically limited exercise in women with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (n = 22) and sedentary women (n = 22).

Three subjects did not return the questionnaires to evaluate postexertional malaise 24 h after exercise, despite receiving a prestamped envelope and being contacted by the researchers several times. The CIS is a questionnaire that quantifies subjective fatigue and related behaviour. High scores are associated with higher fatigue levels. Comparing the CIS score before and after exercise between the groups showed a significant difference in the subscales fatigue (= 0.002), reduced motivation (= 0.038) and reduced activity (= 0.006). In the patient group, the scores on these subscales increased after the exercise test whereas in the control group the scores decreased slightly (Table 2). Changes over time in the SF-36 subscale ‘physical functioning’ (= 0.007) and CFS Symptom List total score (= 0.002) were different between the two groups. Whereas the scores from the control group improved after exercise in comparison to the baseline scores, the scores declined in the ME/CFS patient group. This indicates that the second exercise bout (i.e. the paced exercise test with application of three safety breaks) increased symptoms in this group of women with ME/CFS.

Table 2. Changes in health status in response to self-paced, physiologically limited exercise in patients with ME/CFS (n = 22) and healthy sedentary control subjects (n = 22)
 ME/CFS patients (mean ± standard deviation)Control subjects (mean ± standard deviation)Within-groups comparison (F-value; P-value)
  1. Comparisons were performed using two-way repeated measures anova. Statistically significant results are given in bold.

  2. CIS, Checklist Individual Strength; SF-36, Medical Outcomes Short Form 36 Health Status Survey.

Pain (mm)
 Pre-exercise61.9 ± 29.85.5 ± 8.9 
 Post-exercise71.0 ± 26.33.3 ± 7.617.6; <0.001
 24 h post-exercise73.3 ± 25.45.8 ± 10.44.9; 0.034
Fatigue (mm)
 Pre-exercise76.6 ± 18.610.7 ± 9.5 
 Post-exercise84.5 ± 13.25.9 ± 6.120.2; <0.001
 24 h post-exercise87.4 ± 19.36.5 ± 8.212.9; 0.001
Concentration difficulties (mm)
 Pre-exercise62.6 ± 26.25.8 ± 8.7 
 Post-exercise66.5 ± 25.63.3 ± 6.25.0; 0.031
 24 h post-exercise68.4 ± 28.53.4 ± 6.87.2; 0.011
CFS Symptom List total score (mm)
 Pre-exercise57.3 ± 16.76.4 ± 5.7 
 Post-exercise60.5 ± 14.64.2 ± 4.713.3; 0.001
 24 h post-exercise63.7 ± 18.74.5 ± 5.110.6; 0.002
CIS fatigue
 Pre-exercise52.2 ± 3.620.1 ± 7.6 
 Post-exercise52.8 ± 3.718.2 ± 8.111.0; 0.002
CIS concentration difficulties
 Pre-exercise28.4 ± 5.510.3 ± 5.3 
 Post-exercise29.0 ± 5.69.8 ± 4.32.9; 0.096
CIS motivation
 Pre-exercise16.6 ± 7.18.7 ± 4.6 
 Post-exercise17.0 ± 7.07.7 ± 4.04.6; 0.038
CIS physical activity
 Pre-exercise16.2 ± 4.96.7 ± 3.4 
 Post-exercise16.5 ± 4.76.0 ± 3.18.2; 0.006
SF 36 bodily pain
 Pre-exercise41.8 ± 18.288.9 ± 11.1 
 Post-exercise41.2 ± 17.589.4 ± 13.20.590; 0.447
 24 h post-exercise40.1 ± 15.990.2 ± 12.53.8; 0.061
SF-36 physical functioning
 Pre-exercise39.6 ± 19.091.8 ± 9.3 
 Post-exercise36.6 ± 19.392.6 ± 9.87.36; 0.010
 24 h post-exercise31.8 ± 19.092.4 ± 10.07.98; 0.007
SF-36 role limitations due to physical functioning
 Pre-exercise6.8 ± 22.195.5 ± 21.3 
 Post-exercise6.8 ± 22.191.7 ± 22.83.5; 0.069
 24 h post-exercise1.3 ± 5.692.9 ± 22.60.487; 0.489
SF-36 role limitations due to emotional problems
 Pre-exercise62.1 ± 45.295.5 ± 21.3 
 Post-exercise60.6 ± 44.493.7 ± 22.70.001; 0.974
 24 h post-exercise58.3 ± 45.793.7 ± 22.70.507; 0.481
SF-36 social functioning
 Pre-exercise38.6 ± 23.894.9 ± 12.0 
 Post-exercise37.8 ± 21.595.2 ± 12.80.309; 0.581
 24 h post-exercise33.4 ± 18.695.8 ± 12.12.25; 0.142
SF-36 mental health
 Pre-exercise64.1 ± 19.080.9 ± 11.6 
 Post-exercise64.0 ± 17.683.2 ± 8.52.59; 0.116
 24 h post-exercise65.6 ± 18.181.3 ± 11.10.320; 0.575
SF-36 vitality
 Pre-exercise31.5 ± 16.775.2 ± 12.4 
 Post-exercise32.7 ± 16.276.2 ± 11.30.013; 0.909
 24 h post-exercise28.8 ± 14.377.9 ± 9.91.4; 0.244
SF-36 general health perception
 Pre-exercise15.7 ± 10.561.6 ± 9.3 
 Post-exercise15.9 ± 10.461.0 ± 10.70.214; 0.646
 24 h post-exercise15.0 ± 7.661.7 ± 10.20.583; 0.450

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

As expected, there were no significant differences between the two exercise tests (submaximal exercise stress test and exercise with safety breaks) with regard to heart rate and lactate concentrations at rest. Using continuous ergospirometry during exercise, control subjects had a lower peak ventilation (VE) (= 0.010) and peak oxygen uptake (VO2) (= 0.002) during the exercise bout with safety breaks (peak VE = 24.4 ± 4.9 L min−1; peak VO2 = 17.1 ± 3.1 mL min−1 kg−1) compared to the submaximal 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/CFS patients (peak VE, < 0.001; peak VO2, = 0.009). During submaximal exercise and during exercise with safety breaks, ME/CFS patients had a peak VE of 36.1 ± 13 and 25.5 ± 5.7 L min−1, and a peak VO2 of 24.1 ± 13.9 and 17.9 ± 11.2 mL min−1 kg−1, respectively. There was also a significantly lower peak RER (= 0.005) during the exercise bout with safety breaks (RER = 1.77 ± 4) as compared to the submaximal exercise stress test (RER = 1.25 ± 0.89) in the patient group. Although the exercise duration was longer during experiment 2, the intensity of the exercise was lower compared to experiment 1. Participants cycled for longer during the exercise with safety breaks, but lactate levels were significantly lower (ME/CFS group = 0.011, control group = 0.001) than during the submaximal exercise test. All these results support our initial intention of studying two different exercise bouts in the same group of subjects.

No significant differences were found for the post-exercise PPTs between the two types of exercise in the ME/CFS group. Although, significant differences were found in terms of symptom occurrence and quality of life (CFS Symptom List, SF-36, CIS) between the ME/CFS and control groups, there were no differences between the two exercise tests in the ME/CFS group. In the control group, there were significantly fewer complaints about ‘cold hands and feet’ during the self-paced and physiologically limited bicycle exercise test (F = 11.69; = 0.001).

Association between exercise-induced pain inhibition and postexertional malaise

Submaximal exercise stress test.  We investigated the association between changes in PPTs and changes in symptom occurrence post-exercise. A decrease in PPTs measured near L3 after exercise correlated with an increase in fatigue (r = 0.454; = 0.034) after exercise in the ME/CFS group, as measured with the CFS Symptom List. No association was found in the control group.

Self-paced and physiologically limited exercise.  No associations between changes in PPTs and changes in symptom occurrence could be established post-exercise.

Discussion

The results of this study suggest an impairment of pain inhibition during both a submaximal exercise test and a self-paced and physiologically limited exercise bout in patients with ME/CFS, resulting in postexertional malaise. During submaximal exercise, control subjects showed increased PPTs whereas PPTs decreased in ME/CFS patients. Likewise, significant differences were found between the control subjects and the ME/CFS patients during the self-paced and physiologically limited exercise. During these two types of submaximal exercise, the pain inhibitory systems in patients with ME/CFS did not respond to exercise as they did in healthy subjects. These results extend the evidence provided by others [2, 9], indicating that people with ME/CFS have an impaired pain inhibition during submaximal exercise. This is the first study to demonstrate impaired pain inhibition during self-paced and physiologically limited exercise in patients with ME/CFS.

It is possible that dysfunction of the pain inhibition mechanisms during exercise results in decreased PPTs, causing ME/CFS patients to be more susceptible to symptom increase. This could explain why the decreased PPTs during exercise were accompanied by a worsening of the ME/CFS symptom complex and a reduction in the ability to perform physical activities post-exercise. Further decreased PPTs during exercise were associated with postexertional fatigue in the ME/CFS group. Therefore, this evidence supports the association between an impaired pain inhibition during exercise and the symptom increase following exercise in ME/CFS patients. However, except for fatigue no other associations were observed between impaired pain inhibition and postexertional pain, or any other assessed symptoms. The term ‘postexertional malaise’ is used to describe the exacerbation of symptoms following physical exertion. Postexertional fatigue is only one of many symptoms included in the full cluster of symptoms of postexertional malaise. Although many of these symptoms were assessed using the CFS Symptom List, and were significantly increased after exercise, they were not directly related to impaired pain inhibition in response to exercise.

It should be acknowledged that mechanisms other than impaired pain inhibition in response to exercise may play a role in the cluster of pathological postexertional symptoms seen in ME/CFS patients. Deficiency in hypothalamic–pituitary–adrenal axis functioning might cause pathological immune activation with release of pro-inflammatory cytokines [43] and induction of the so-called ‘sickness response’. The symptoms of this response (lethargia and malaise, social withdrawal, flu-like symptoms, mood lowering, concentration difficulties and generalized pain hypersensitivity) [44] also characterize the cluster of pathological postexertional symptoms seen in ME/CFS patients. In line with this are the findings of pathological immune activation (e.g. complement activation and increased oxidative stress) in response to exercise in patients with ME/CFS [6, 16]. This study include measurement of immune activation (blood samples), but these results have been presented and discussed elsewhere [20].

Although it has been reported that exercise and postexertional malaise can cause a significant decrease in activity levels in ME/CFS patients [45], we found no evidence in the present study to support this. Rather, the current results support the findings of Bazelmans et al. that fatigue in ME/CFS patients increases after exercise, but that the level of actual physical activity remains unchanged [46].

During self-paced and physiologically limited exercise, control subjects were able to cycle significantly longer than the ME/CFS patients without experiencing postexertional malaise. It is possible that ME/CFS patients exercised less because they experienced symptoms during exercise. On the other hand, we cannot exclude the possibility that these patients have developed behavioural patterns to limit their exercise as they know that ‘they will pay for it later’. Whereas the control group improved their physical functioning and reported fewer complaints post-exercise, ME/CFS patients reported a worsening of their physical functioning and symptoms. The ME/CFS patients experienced not only symptom increases 24 h post-exercise, but also impaired pain inhibition during exercise. As no significant changes in activity levels were observed after the submaximal exercise test, it is unlikely that the results were biassed by the daily physical activity levels during the study period.

In the ME/CFS group, ventilatory (peak VE and VO2) and metabolic (lactate levels) variables were significantly lower during the self-paced and physiologically limited exercise, compared with during the submaximal stress test. However, the ME/CFS patients cycled for a longer period during the self-paced and physiologically limited exercise. Therefore, it seems that self-paced and physiologically limited exercise is more appropriate for ME/CFS patients despite the fact that both types of exercise provoked a decrease in PPTs resulting in symptom exacerbation.

The self-paced, physiologically limited exercise protocol applied strategies that are used to implement ‘safe’ exercise therapy and self-management for people with ME/CFS [28, 30]. In a previous study, Nijs et al. applied a similar but less stringent approach to limit postexertional malaise in people with ME/CFS [47]. It was shown that the use of exercise limits (limiting both the intensity and duration of exercise) can prevent postexertional malaise, but cannot prevent an acute increase in symptoms following walking exercise in people with ME/CFS [47]. Based on that experience, we made the exercise limits more stringent by decreasing the intensity to 80% of the heart rate corresponding to the anaerobic threshold of the first (submaximal) exercise bout. Nevertheless, we were unable to prevent postexertional malaise in this group of women with ME/CFS. These results highlight the fact that one should be cautious when evaluating exercise in people with ME/CFS. More work is required to address the issue of preventing postexertional malaise. This could be done by using exercise limits to maintain a lower intensity of exercise, as in previous randomized controlled clinical trials of exercise therapy in people with ME/CFS (e.g. exercise intensity based on the heart rate value obtained at the midpoint during a submaximal exercise test or the heart rate corresponding to 40% of peak oxygen consumption during a maximal exercise test [27, 28, 47]).

The results should be interpreted in the light of the study limitations. To account for bias due to pooling of gender data, only women were studied [5]. Therefore, care should be taken with the extrapolation of these results to the complete ME/CFS population and further studies in males with ME/CFS are required. Baseline PPTs for experiment 2 could have been decreased as a result of the first exercise test, suggesting that 1 week between tests was not enough for patients to recover. On the other hand, the study has several strengths. The patient group was sufficiently powered and selectively chosen to study an important and debilitated subgroup within the ME/CFS population. Using real-time physical activity monitoring allowed us to account for potential bias resulting from physical activities performed by the patients prior to the first exercise bout and between exercise sessions. A final strength worth mentioning is that the study strongly builds on previous work in the area of ME/CFS; the submaximal exercise protocol is the only protocol known to be reliable and valid for testing people with ME/CFS [27, 29] and the self-paced, physiologically limited exercise protocol applied strategies used to implement ‘safe’ exercise therapy and self-management for people with ME/CFS [12, 48].

In conclusion, the results of this study showed that submaximal exercise and self-paced, physiologically limited exercise trigger postexertional malaise in people with ME/CFS. During both types of exercise, PPTs decreased following exercise in ME/CFS patients, whereas they increased in healthy subjects. Patients experienced a worsening of the ME/CFS symptom complex and a reduction in the ability to perform physical activities post-exercise. Decreased PPTs during submaximal exercise were associated with postexertional fatigue in the ME/CFS group. These observations indicate the presence of abnormal central pain processing during exercise in people with ME/CFS.

Acknowledgements

This study was funded by ME Research UK (MERUK), a national charity that funds biomedical research into ME/CFS. The authors are grateful to Lieve De Hauwere for taking the blood samples and assisting in the exercise tests. Jessica Van Oosterwijck is financially supported by grant no. OZR1596 from the research council of the Vrije Universiteit Brussel, Brussels, Belgium. Mira Meeus is a postdoctoral fellow of the Fund for Scientific Research Flanders (FWO).

Conflict of interest statement

No conflict of interest was declared.

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