Pain inhibition and post-exertional malaise in ME/CFS

Dolphin

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Another Belgian exercise study

http://www3.interscience.wiley.com/journal/123308811/abstract?CRETRY=1&SRETRY=0

Pain inhibition and post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome

Jessica Van Oosterwijck a , Jo Nijs a,b,c , Mira Meeus a,b , Inne Lefever a , Lynn Huybrechts b , Luc Lambrecht d and Lorna Paul e

a Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium
b Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Antwerp, Belgium
c Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium
d Private practice for internal medicine, Ghent / Aalst, Belgium & CVS Contactgroep, Bruges, Belgium
e Nursing and Health Care, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom

Copyright C 2010 Blackwell Publishing Ltd

KEYWORDS pain . post-exertional malaise . submaximal exercise . algometry . ME/CFS

ABSTRACT

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 post-exertional fatigue in the ME/CFS group (r=.454; p=.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 post-exertional 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.
 
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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 post-exertional fatigue in the ME/CFS group (r=.454; p=.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 post-exertional 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.
So - in my naive way - I see that there are good guys and bad guys doing research in Belgium. And these seem to be the good guys - objective science.

Really like that they found PEM both with with both types of exercise, and via self-assessment AND through measurement it seems, but I'm not clear what that measurement is. But objective measurement of PEM seems important.

I always want to know how long after the exercise assessments (subjective/objective) are made.
 

Dolphin

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Some information from the paper (minus discussion)

All patients were diagnosed by the same internal medicine physician. Pain is considered to be an important aspect of post-exertional malaise. Therefore, as well as suffering from ME/CFS, patients included in the study had to present with chronic widespread pain [21].
Definition of self-paced (not exciting but so people now what happened):
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 in order 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 and50% 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.
Results::
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) (p=.365). Therefore, we conclude that the two groups were comparable.
Also for period between experiment 1 and 2:
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=.838, p=.365).
They say this in the discussion on the finding:
Although it has been reported that exercise and post-exertional 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].
One way of saying this is that patients don’t “boom and bust” as some psychiatrists, etc like to say.

Submaximal exercise stress test

At baseline, ME/CFS patients showed decreased PPTs measured near L3, indicating the presence of hyperalgesia of the lower back (p=.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 figure 2. The PPTs measured on the back and the calf increased in the control group whereas they decreased in the patient group (p=.006 and p=.018, respectively). PPTs measured in the skin web between thumb and index finger showed the same effect although the difference was not significant (p=.077).

There was a significant difference between patients and controls with regard to the change over time (baseline, post-exercise, 24 hours post-exercise) in the subscale ‘physical functioning’ of the SF-36 score (p=.029). Control subjects showed stable scores but ME/CFS patients showed a decrease in the scores over time, indicating post-exertional malaise in the patient group. ME/CFS patients showed a worsening of symptoms from baseline to post-exercise and 24 hours post-exercise, as measured by the CFS Symptom List, whereas controls showed symptom improvement (table 1). The difference between the two groups was significant (p<.001). The CIS showed no significant differences (p>.05) between the two groups. One patient failed to return the questionnaires to evaluate post-exertional malaise up to 24 hours after exercise.
Self-paced and physiologically limited 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 (p=.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 (p=.042). No significant differences (p>.05) were found between the two groups for heart rate, workload or lactate levels.
*This means what the people doing the test predicted they should do (75% of estimate if good day, 50% if bad day)

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 (p=.002), back (p=.008) and calf (p=.015)] and are shown in figure 3.

Three subjects did not return the questionnaires to evaluate post-exertional malaise 24 hours after exercise, despite receiving a pre-stamped 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 (p=.002), reduced motivation (p=.038) and reduced activity (p=.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’ (p=.007) and CFS Symptom List total score (p=.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.
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; p=.001).
Association between exercise-induced pain inhibition and post-exertional malaise

Submaximal exercise stress test We investigated the association between changes in PPTs and changes in symptom occurrence postexercise. A decrease in PPTs measured near L3 after exercise correlated with an increase in fatigue (r=.454; p=.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 postexercise.
 

Dolphin

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A couple of comments

They point out in the abstract that
Decreased pressure thresholds during submaximal exercise were associated with post-exertional fatigue in the ME/CFS group (r=.454; p=.034).
However, they actually checked for lots of such correlations. It is unclear to me how many. It could be the 19 symptom of the CFS Symptom List x2 (both tests). So the normal statistical test is whether p<0.05/n where n is the number of symptoms. Which would be p<0.05/38=0.0013 which is not reached. [Aside: I also think such testing is very strict but at the same time they should have at least mentioned they didn't adjust. If they did do 38 comparisons then this could easily be a chance finding].

This is all they say in the Methods - Statistical analysis section about the number of comparisons:

Pearson correlation analysis was used to examine the association between PPTs and fatigue severity.
This is what they say in discussion
except for fatigue no other associations were observed between impaired pain inhibition and postexertional
pain, or any other assessed symptoms. The term ‘post-exertional malaise’ is used to describe the
exacerbation of symptoms following physical exertion. Post-exertional fatigue is only one of many symptoms
included in the full cluster of symptoms of post-exertional 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.
They may have only checked the symptoms where there was a worsening which would mean less than 38 comparisons.

The reason you do this is can be seen by tossing a coin 6 times.
The probability of getting all heads with an unbiased coin is (.5)^6=0.015625.
The probability of getting all tails with an unbiased coin is (.5)^6=0.015625.
The probability of getting all heads or all tails with an unbiased coin is 0.015625*2=0.03125.
If one sets a threshold of p<0.05, then one can say this is unlikely to happen by chance.
However, if one had one hundred people toss a coin each six times, there is a good chance, that one or more will have all heads (or all tails). But one can't surmise that that individual coin is biased - it could be a chance finding because one did so many comparisons.

==========
Point #2:

This didn't work out as intended for Nijs et al.

They thought that the patients would have a better response to the "Self-paced and physiologically limited exercise" and so this might be useful in an exercise program.

However, there were actually more examples of significant worsening after the second test than after the first test!

The results in each category didn't reach significance:
"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."
but it still is interesting.

You couldn't recommend a management regime that involved the amount of exercise in the "self-paced and physiologically limited exercise", based on these results.
 
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==========
Point #1:

This didn't work out as intended for Nijs et al.

They thought that the patients would have a better response to the "Self-paced and physiologically limited exercise" and so this might be useful in an exercise program.

However, there were actually more examples of significant worsening after the second test than after the first test!

The results in each category didn't reach significance:

but it still is interesting.

You couldn't recommend a management regime that involved the amount of exercise in the "self-paced and physiologically limited exercise", based on these results.
Oh - I'm getting so confused - so Nijs has taken part in some of the previous "bad" research, but here had to publish the results of "good" research???:Retro redface:

I so appreciate your last 2 posts Tom - the breaking up of the text alone helps me be able to try to decode the info, and your translations into layman's terms are incredibly helpful for me. And then, the piece de resistance - explaining the relevance of it all in Point #1 - priceless.
 

Dolphin

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Oh - I'm getting so confused - so Nijs has taken part in some of the previous "bad" research, but here had to publish the results of "good" research???:Retro redface:

I so appreciate your last 2 posts Tom - the breaking up of the text alone helps me be able to try to decode the info, and your translations into layman's terms are incredibly helpful for me. And then, the piece de resistance - explaining the relevance of it all in Point #1 - priceless.
Thanks IF. :Retro smile:

Nijs is too into exercise for my liking. Apart from physical therapists/physiotherapists who have the illness themselves, I'm afraid I tend to distrust them and have reason to distrust him from several papers in the past.

That doesn't mean that when they do objective science it can't be good. But they and he can still spin the results a bit - not as much as others but it can still cause problems. Whether he/they knew they should adjust for multiple testing, we'll never know but one sees it enough in studies that if you read enough research papers, you should think of it even if you have forgotten some of your statistics education.
 

Esther12

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This is relatively interesting for a paper like this - which is a shocking reminder of just how boring these papers are.

It does seem like there is some really slow and painful progress being made in building up evidence about CFS. Maybe we'll start to get a positive cycle as evidence increases, and study design becomes less driven by the prejudices of the academics involved?

Thanks for posting the details TomK.
 

jspotila

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Tomk, I haven't been able to find the full text of this paper. Do you have it in pdf format (or can you point me to a source)? Thanks!!!