Nijs – American ME and CFS Society

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms.

Methods: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software.

Results: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01).

Conclusion: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Source: Hendrix J, Fanning L, Wyns A, Ahmed I, Patil MS, Richter E, Van Campenhout J, Ickmans K, Mertens R, Nijs J, Godderis L, Polli A. Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis. Eur J Clin Invest. 2024 Sep 25:e14318. doi: 10.1111/eci.14318. Epub ahead of print. PMID: 39319943. https://pubmed.ncbi.nlm.nih.gov/39319943/

The Role of Autonomic Function in Exercise-induced Endogenous Analgesia: A Case-control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Healthy People

Abstract:

Background: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are unable to activate brain-orchestrated endogenous analgesia (or descending inhibition) in response to exercise. This physiological impairment is currently regarded as one factor explaining post-exertional malaise in these patients. Autonomic dysfunction is also a feature of ME/CFS.

Objectives: This study aims to examine the role of the autonomic nervous system in exercise-induced analgesia in healthy people and those with ME/CFS, by studying the recovery of autonomic parameters following aerobic exercise and the relation to changes in self-reported pain intensity.

Study design: A controlled experimental study.

Setting: The study was conducted at the Human Physiology lab of a University.

Methods: Twenty women with ME/CFS- and 20 healthy, sedentary controls performed a submaximal bicycle exercise test known as the Aerobic Power Index with continuous cardiorespiratory monitoring. Before and after the exercise, measures of autonomic function (i.e., heart rate variability, blood pressure, and respiration rate) were performed continuously for 10 minutes and self-reported pain levels were registered. The relation between autonomous parameters and self-reported pain parameters was examined using correlation analysis.

Results: Some relationships of moderate strength between autonomic and pain measures were found. The change (post-exercise minus pre-exercise score) in pain severity was correlated (r = .580, P = .007) with the change in diastolic blood pressure in the healthy group. In the ME/CFS group, positive correlations between the changes in pain severity and low frequency (r = .552, P = .014), and between the changes in bodily pain and diastolic blood pressure (r = .472, P = .036), were seen. In addition, in ME/CHFS the change in headache severity was inversely correlated (r = -.480, P = .038) with the change in high frequency heart rate variability.

Limitations: Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

Conclusions: Reduced parasympathetic reactivation during recovery from exercise is associated with the dysfunctional exercise-induced analgesia in ME/CFS. Poor recovery of diastolic blood pressure in response to exercise, with blood pressure remaining elevated, is associated with reductions of pain following exercise in ME/CFS, suggesting a role for the arterial baroreceptors in explaining dysfunctional exercise-induced analgesia in ME/CFS patients.

Source: Oosterwijck JV, Marusic U, De Wandele I, Paul L, Meeus M, Moorkens G, Lambrecht L, Danneels L, Nijs J. The Role of Autonomic Function in Exercise-induced Endogenous Analgesia: A Case-control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Healthy People. Pain Physician. 2017 Mar;20(3):E389-E399. PMID: 28339438. https://www.painphysicianjournal.com/linkout?issn=&vol=20&page=E389 (Full text)

The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms

Abstract:

Oxidative stress can be induced by various stimuli and altered in certain conditions, including exercise and pain. Although many studies have investigated oxidative stress in relation to either exercise or pain, the literature presents conflicting results. Therefore, this review critically discusses existing literature about this topic, aiming to provide a clear overview of known interactions between oxidative stress, exercise, and pain in healthy people as well as in people with chronic pain, and to highlight possible confounding factors to keep in mind when reflecting on these interactions. In addition, autonomic regulation and epigenetic mechanisms are proposed as potential mechanisms of action underlying the interplay between oxidative stress, exercise, and pain.

This review highlights that the relation between oxidative stress, exercise, and pain is poorly understood and not straightforward, as it is dependent on the characteristics of exercise, but also on which population is investigated. To be able to compare studies on this topic, strict guidelines should be developed to limit the effect of several confounding factors. This way, the true interplay between oxidative stress, exercise, and pain, and the underlying mechanisms of action can be revealed and validated via independent studies.

Source: Hendrix J, Nijs J, Ickmans K, Godderis L, Ghosh M, Polli A. The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms. Antioxidants (Basel). 2020 Nov 23;9(11):1166. doi: 10.3390/antiox9111166. PMID: 33238564; PMCID: PMC7700330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700330/ (Full text)

Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study

Abstract:

BACKGROUND: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients.

OBJECTIVES: We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated.

STUDY DESIGN: A controlled, randomized cross-over trial.

SETTING: University Hospital Brussels.

METHODS: Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties.

RESULTS: There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01).

LIMITATIONS: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises.

CONCLUSION: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise.

Source: Malfliet A, Pas R, Brouns R, De Win J, Hatem SM, Meeus M, Ickmans K, van Hooff RJ, Nijs J. Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study. Pain Physician. 2018 Jan;21(1):E13-E24. https://www.ncbi.nlm.nih.gov/pubmed/29357332 Full article can be viewed as a PDF here: http://www.painphysicianjournal.com/current/pdf?article=NTAwOA%3D%3D&journal=109

Influence of morphine and naloxone on pain modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome/Fibromyalgia and controls: a double blind randomized placebo-controlled cross-over study

Abstract:

BACKGROUND: Impaired pain inhibitory and enhanced pain facilitatory mechanisms are repeatedly reported in patients with central sensitization pain. However, the exact effects of frequently prescribed opioids on central pain modulation are still unknown.

METHODS: A randomized, double-blind, placebo-controlled cross-over trial was carried out. Ten CFS/FM patients, 11 RA patients and 20 controls were randomly allocated to the experimental (10 mg morphine or 0.2 mg/ml Naloxone) and placebo (2 ml Aqua) group. Pressure Pain Thresholds (PPTs) and temporal summation at the Trapezius and Quadriceps were assessed by algometry. Conditioned Pain Modulation (CPM) efficacy and Deep Tissue Pain pressure were assessed by adding ischemic occlusion at the opposite upper arm.

RESULTS: Deep Tissue Pain pressure was lower and temporal summation higher in CFS/FM (p=0.002 respectively p=0.010) and RA patients (p=0.011 respectively p=0.047) compared to controls at baseline. Morphine had only a positive effect on PPTs in both patient groups (p time =0.034). Accordingly, PPTs increased after placebo, and no effects on the other pain parameters were objectified. There were no significant effects of naloxone nor nocebo on PPT, Deep Tissue Pain, temporal summation or CPM in the control group.

CONCLUSIONS: This study revealed anti-hyperalgesia effects of morphine in CFS/FM and RA patients. Nevertheless, these effects were comparable to placebo. Besides, neither morphine nor naloxone influenced Deep Tissue Pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA.

Source: Hermans L, Nijs J, Calders P, De Clerck L, Moorkens G, Hans G, Grosemans S, Roman De Mettelinge T, Tuynman J, Meeus M. Influence of morphine and naloxone on pain modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome/Fibromyalgia and controls: a double blind randomized placebo-controlled cross-over study. Pain Pract. 2017 Jul 19. doi: 10.1111/papr.12613. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/28722815

Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome

Abstract:

OBJECTIVE: Cognitive behaviour therapy (CBT) is an effective treatment for chronic fatigue syndrome (CFS). Main aim was to determine whether treatment effects were maintained up to 10years after treatment.

METHODS: Participants (n=583) of previously published studies on the effects of CBT for CFS were contacted for a long-term follow-up assessment. They completed questionnaires on main outcomes fatigue severity (CIS) and physical functioning (SF-36). The course of these outcomes since post-treatment assessment was examined using mixed model analyses.

RESULTS: Between 21 and 125months after finishing CBT, 511 persons (response rate 88%) completed a follow-up assessment. At follow-up, mean fatigue severity was significantly increased to 37.60 (SD=12.76) and mean physical functioning significantly decreased to 73.16 (SD=23.56) compared to post-treatment assessment. At follow-up still 37% of the participants had fatigue scores in the normal range and 70% were not impaired in physical functioning.

CONCLUSION: Positive effects of CBT for CFS on fatigue and physical functioning were partly sustained at long-term follow-up. However, a subgroup of patients once again reported severe fatigue, and compromised physical functioning. Further research should elucidate the reasons for this deterioration to facilitate the development of treatment strategies for relapse prevention.

Source: Janse A1, Nikolaus S2, Wiborg JF2, Heins M2, van der Meer JWM3, Bleijenberg G4, Tummers M5, Twisk J6, Knoop H7. Long-term follow-up after cognitive behaviour therapy for chronic fatigue syndrome. J Psychosom Res. 2017 Jun;97:45-51. doi: 10.1016/j.jpsychores.2017.03.016. Epub 2017 Mar 27. https://www.ncbi.nlm.nih.gov/pubmed/2860649

Endogenous Pain Facilitation Rather Than Inhibition Differs Between People with Chronic Fatigue Syndrome, Multiple Sclerosis, and Controls: An Observational Study

Abstract:

BACKGROUND: Commonalities in the core symptoms of fatigue and cognitive dysfunction experienced by chronic fatigue syndrome (CFS, also known as ME) and multiple sclerosis (MS) patients have been described. Many CFS and MS patients also experience chronic pain, which has been attributed to central sensitization in both groups of patients. However, the characteristics of pain in CFS and MS patients have not been compared.

OBJECTIVES: To compare experimental pain measurements in patients with CFS or MS and healthy controls.

STUDY DESIGN: Observational study.

SETTING: This study took place in Belgium at Vrije Universiteit Brussel and the University of Antwerp.

METHODS: Pressure pain thresholds, temporal summation, conditioned pain modulation, and occlusion cuff pressure thresholds rated as painful (1st cuff pressure threshold) and as 3/10 on a verbal numerical scale (2nd cuff pressure threshold) were measured in patients with CFS (n = 48), MS (n = 19) and healthy pain-free controls (n = 30). Adjusted between-group differences were estimated using linear regression models.

RESULTS: Finger pain pressure thresholds of patients with CFS, compared with patients with MS, were 25% lower (difference ratio 0.75 [95% CI 0.59, 0.95], P = 0.02) and shoulder pain pressure thresholds were 26% lower (difference ratio 0.74 [0.52, 1.04], P = 0.08). Compared with patients with MS, patients with CFS had 29% lower first cuff pressure threshold (difference ratio 0.71 [0.53, 0.94], P = 0.02) and 41% lower 2nd cuff pressure threshold (0.59 [0.41, 0.86], P = 0.006). Finger temporal summation was higher in patients with CFS than in patients with MS (mean difference 1.15 [0.33, 1.97], P = 0.006), but there were no differences in shoulder temporal summation or conditioned pain modulation at either site. Differences between patients with CFS and MS tended to be greater than between either patient group and healthy controls. Pain pressure thresholds and cuff pressure thresholds tended to be positively correlated, and temporal summation negatively correlated, with higher physical function and lower fatigue in both groups of patients. Subjective pain in patients with CFS but not in patients with MS was strongly negatively correlated with pain pressure thresholds and cuff pressure thresholds, and positively correlated with temporal summation.

LIMITATIONS: The main limitations of our study are the relatively small sample sizes, its cross-sectional design, and its exploratory nature.

CONCLUSIONS: We found differences in the characteristics of pain symptoms reported by patients with CFS and patients with MS, which suggest different underlying mechanisms. Specifically, overactive endogenous pain facilitation was characteristic of pain in patients with CFS but not in patients with MS, suggesting a greater role for central sensitization in CFS.

Source: Collin SM, Nijs J, Meeus M, Polli A, Willekens B, Ickmans K. Endogenous Pain Facilitation Rather Than Inhibition Differs Between People with Chronic Fatigue Syndrome, Multiple Sclerosis, and Controls: An Observational Study. Pain Physician. 2017 May;20(4):E489-E497. http://www.painphysicianjournal.com/linkout?issn=1533-3159&vol=20&page=E489 (Full article available as PDF.)

The Role of Autonomic Function in Exercise-induced Endogenous Analgesia: A Case-control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Healthy People

Abstract:

BACKGROUND: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are unable to activate brain-orchestrated endogenous analgesia (or descending inhibition) in response to exercise. This physiological impairment is currently regarded as one factor explaining post-exertional malaise in these patients. Autonomic dysfunction is also a feature of ME/CFS.

OBJECTIVES: This study aims to examine the role of the autonomic nervous system in exercise-induced analgesia in healthy people and those with ME/CFS, by studying the recovery of autonomic parameters following aerobic exercise and the relation to changes in self-reported pain intensity.

STUDY DESIGN: A controlled experimental study.

SETTING: The study was conducted at the Human Physiology lab of a University.

METHODS: Twenty women with ME/CFS- and 20 healthy, sedentary controls performed a submaximal bicycle exercise test known as the Aerobic Power Index with continuous cardiorespiratory monitoring. Before and after the exercise, measures of autonomic function (i.e., heart rate variability, blood pressure, and respiration rate) were performed continuously for 10 minutes and self-reported pain levels were registered. The relation between autonomous parameters and self-reported pain parameters was examined using correlation analysis.

RESULTS: Some relationships of moderate strength between autonomic and pain measures were found. The change (post-exercise minus pre-exercise score) in pain severity was correlated (r = .580, P = .007) with the change in diastolic blood pressure in the healthy group. In the ME/CFS group, positive correlations between the changes in pain severity and low frequency (r = .552, P = .014), and between the changes in bodily pain and diastolic blood pressure (r = .472, P = .036), were seen. In addition, in ME/CHFS the change in headache severity was inversely correlated (r = -.480, P = .038) with the change in high frequency heart rate variability.

LIMITATIONS: Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

CONCLUSIONS: Reduced parasympathetic reactivation during recovery from exercise is associated with the dysfunctional exercise-induced analgesia in ME/CFS. Poor recovery of diastolic blood pressure in response to exercise, with blood pressure remaining elevated, is associated with reductions of pain following exercise in ME/CFS, suggesting a role for the arterial baroreceptors in explaining dysfunctional exercise-induced analgesia in ME/CFS patients.

Reduced gait automaticity in female patients with chronic fatigue syndrome: Case-control study

Abstract:

Patients with chronic fatigue syndrome (CFS) report difficulties walking for a prolonged period of time. This study compares gait automaticity between women with CFS and nondisabled controls. The “stops walking with eyes closed with secondary cognitive task” test is based on the classic “stops walking while talking” test but compares walking with eyes closed while performing a secondary cognitive task in a female CFS population (n = 34) and in female nondisabled controls (n = 38).

When initiating gate, 23.5% of patients with CFS looked toward the ground compared with only 2.6% of nondisabled controls. After 7 m, subjects were asked to close their eyes, and after another 7 m, they were asked, “How much is 100 minus 7?” Of the patients with CFS, 55.9% stopped walking compared with 5.3% of nondisabled controls. Less automated walking was observed in patients with CFS than in nondisabled controls (p < 0.001). The test-retest reliability is moderate for global stopping. This simple test observed reduced gait automaticity in patients with CFS for the first time. Dual tasking could be helpful to address the functional limitations found in this particular study.

Source: Eyskens JB, Nijs J, Wouters K, Moorkens G. Reduced gait automaticity in female patients with chronic fatigue syndrome: Case-control study. J Rehabil Res Dev. 2015;52(7):805-14. doi: 10.1682/JRRD.2014.11.0293. http://www.rehab.research.va.gov/jour/2015/527/JRRD-2014-11-0293.html (Full article)

Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter

Abstract:

BACKGROUND: In addition to the frequently reported pain complaints, performance-based cognitive capabilities in patients with chronic fatigue syndrome (CFS) with and without comorbid fibromyalgia (FM) are significantly worse than those of healthy controls. In various chronic pain populations, cognitive impairments are known to be related to pain severity. However, to the best of our knowledge, the association between cognitive performance and experimental pain measurements has never been examined in CFS patients.

OBJECTIVES: This study aimed to examine the association between cognitive performance and self-reported as well as experimental pain measurements in CFS patients with and without FM.

STUDY DESIGN: Observational study.

SETTING: The present study took place at the Vrije Universiteit Brussel and the University of Antwerp.

METHODS: Forty-eight (18 CFS-only and 30 CFS+FM) patients and 30 healthy controls were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, experimental pain measurements (pressure pain thresholds [PPT], temporal summation [TS], and conditioned pain modulation [CPM]) took place and participants were asked to fill out 3 questionnaires to assess self-reported pain, fatigue, and depressive symptoms.

RESULTS: In the CFS+FM group, the capacity of pain inhibition was significantly associated with cognitive inhibition. Self-reported pain was significantly associated with simple reaction time in CFS-only patients. The CFS+FM but not the CFS-only group showed a significantly lower PPT and enhanced TS compared with controls.

LIMITATIONS: The cross-sectional nature of this study does not allow for inferences of causation.

CONCLUSIONS: The results underline disease heterogeneity in CFS by indicating that a measure of endogenous pain inhibition might be a significant predictor of cognitive functioning in CFS patients with FM, while self-reported pain appears more appropriate to predict cognitive functioning in CFS patients without FM.

Source: Ickmans K, Meeus M, De Kooning M, Lambrecht L, Pattyn N, Nijs J. Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter. Pain Physician. 2015 Sep-Oct;18(5):E841-52. http://www.painphysicianjournal.com/current/pdf?article=MjQxOA%3D%3D&journal=91 (Full article as PDF file)