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Scandinavian Journal of Pain

Official Journal of the Scandinavian Association for the Study of Pain

Editor-in-Chief: Breivik, Harald

CiteScore 2018: 0.85

SCImago Journal Rank (SJR) 2018: 0.494
Source Normalized Impact per Paper (SNIP) 2018: 0.427

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Volume 19, Issue 1


Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – a secondary analysis of experimental comparative studies

Andrea Polli
  • Corresponding author
  • Pain in Motion Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussels, Laarbeeklaan 103, 1090 Jette, Brussels, Belgium, Phone/Fax: +32 (0) 2 477 45 29
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jessica Van Oosterwijck
  • Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
  • Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Mira Meeus
  • Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
  • Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Antwerp, Belgium
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Luc Lambrecht / Jo Nijs
  • Pain in Motion Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussels, Laarbeeklaan 103, 1090 Jette, Brussels, Belgium
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kelly Ickmans
  • Pain in Motion Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussels, Laarbeeklaan 103, 1090 Jette, Brussels, Belgium
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2018-10-16 | DOI: https://doi.org/10.1515/sjpain-2018-0075


Background and aims

The interaction between the immune system and pain has been thoroughly explored in the recent decades. The release of inflammatory mediators from immune cells has the capability of activating neurons and glial cells, in turn sensitizing the nervous system. Both immune system alterations and pain modulation dysfunctions have been shown in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) following exercise. However, no studies tried to explore whether these two phenomena are linked and can explain exercise-induced symptoms worsening in people with ME/CFS. We hypothesized that exercise-induced changes in descending pain modulation is associated to changes in immune system functions. We used complement system product C4a and elastase activity as indicators of immune system activity.


The study design was a secondary analysis of controlled experimental studies. Twenty-two patients with ME/CFS and 22 healthy sedentary controls were enrolled. In experiment 1, subjects performed an aerobic submaximal exercise test; in experiment 2 they underwent a self-paced exercise test. One week of rest period were set between the two exercise tests. Before and after each experiment, subjects underwent clinical assessment, pain thresholds (PPTs) measurement, and blood sampling. Immune system function was assessed measuring complement system C4a products and elastase activity.


Changes in elastase activity were not associated to changes in PPTs. Associations were observed in the ME/CFS group between changes in PPTs and C4a products, following both types of exercise. After submaximal exercise, the change in C4a products was associated with the change in PPT at the thumb in patients (r=0.669, p=0.001). Similarly, after self-paced exercise the change in C4a products was associated witht the change in PPT at the calf in patients (r=0.429, p=0.047). No such correlations were found in healthy controls. Regression analysis showed that C4a changes after the submaximal exercise significantly predicted the change in PPTs (R2=0.236; p=0.02).


Moderate associations between exercise-induced changes in PPTs and immune system activity were found only in ME/CFS. The change in the complement system following submaximal exercise might be able to explain part of the change in patient’s pain thresholds, providing evidence for a potential link between immune system alteration and dysfunctional endogenous pain modulation. These results have to be taken with caution, as only one out of three measures of PPTs was found associated with C4a changes. We cannot reject the hypothesis that C4a might therefore be a confounding factor, and changes during exercise might be mediated by other mechanism.


Immune system changes following exercise might contribute to exercise-induced symptoms worsening in patients with ME/CFS. However, the role of the complement system is questionable.

Keywords: pain; immune system; exercise; chronic fatigue syndrome; pain threshold; hyperalgesia


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About the article

aPain in Motion International Research Group, www.paininmotion.be

Received: 2018-04-26

Revised: 2018-08-17

Accepted: 2018-08-20

Published Online: 2018-10-16

Published in Print: 2019-01-28

Authors’ statements

Research funding: The study was funded by ME Research UK, a national charity funding biomedical research into myalgic encephalomyelitis/chronic fatigue syndrome. Jo Nijs is holder of the Chair “Exercise immunology and chronic fatigue in health and disease” funded by the Berekuyl Academy, The Netherlands. Kelly Ickmans is a postdoctoral research fellow of the Agency for Innovation by Science and Technology (IWT) – Applied Biomedical Research Program (TBM), Belgium. Jessica Van Oosterwijck is a Postdoctoral Fellow funded by the Research Foundation – Flanders (FWO). Andrea Polli is a PhD research fellow founded by ME Research UK, for research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Conflict of interest: Authors declare no conflict of interests.

Informed consent: All subjects were well informed about the aim of the study and the procedures and provided written informed consent before data collection was initiated.

Ethical approval: The Ethics Committee of our University Hospital approved the study protocol.

Citation Information: Scandinavian Journal of Pain, Volume 19, Issue 1, Pages 183–192, ISSN (Online) 1877-8879, ISSN (Print) 1877-8860, DOI: https://doi.org/10.1515/sjpain-2018-0075.

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