Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes

Excerpt:

Muscle fatigue and pain are among the most common complaints at emergency rooms and clinics across the country. Fatigue and pain are often acute, remitting spontaneously or appearing to be attenuated by a variety of drugs and treatment modalities.

In spite of these remissions, popular magazines (e.g., Time) estimate that each year Americans spend over $30 billion on herbal remedies and $50 billion on alternative therapies to treat symptoms that include muscle pain and fatigue. These statistics indicate that even acute muscle pain and fatigue are serious health problems that are not adequately addressed by current medical practice. Occasionally, muscle pain and fatigue take on a chronic nature, leading to syndromes including chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS)—devastating conditions characterized by continuing, debilitating fatigue, which is made worse by even mild exercise in the case of CFS and by chronic widespread pain (CWP) with a particular emphasis in the muscles, which can prevent most or all activities in the case of FMS.

Both of these conditions are frequently associated with each other and with a variety of other illnesses, such as temporomandibular disorder (TMD), irritable bowel syndrome (IBS), and multiple chemical sensitivity. These syndromes destroy lives, respond poorly to current treatment strategies, and can lead to exhaustion of the financial resources of afflicted patients. Together, these disorders affect 7 to 20 million people in the United States each year, as reported by various authorities (Reeves et al. 2007). Clearly, patients with these syndromes deserve a concerted research effort to understand, treat, and eventually cure these illnesses. In contrast to cutaneous pain, which has been thoroughly studied and is comparatively well understood, the molecular mechanisms for muscle pain are still unknown.

Even more enigmatic is the symptom of debilitating fatigue. Mosso, in his compendious volume on the subject a century ago, remarked that all cultures seem to have just one word for fatigue (Mosso 1904). Yet fatigue describes many conditions, including failure of muscle fibers to shorten normally, deficient motor command signals, feelings of tiredness, heaviness, pressure, and weakness from muscles, and a feeling of mental fatigue that impedes concentration and performance of conceptual tasks.

The subject of most physiological investigations of fatigue has been voluntary muscle contraction. Decreased function causing failure of voluntary muscle contraction can occur at all levels of the neuromuscular system, including the motor cortex, signaling to motoneurons, motoneuron signals to the muscle, excitation-contraction coupling in the muscle, and actin-myosin filament interactions. However, the most common failure is a decrease in the motor command signal from the motor cortex (see recent reports and reviews by Bellinger et al. 2008; Gibson et al. 2003; Noakes et al. 2005; St Clair and Noakes 2004).

A recent review suggests that failures in voluntary muscle contraction are most often caused by a central comparator that integrates homeostatic inputs from many physiological systems and shuts down motor commands when energy resources are threatened (Noakes 2007). One of the homeostatic inputs is suggested to “originate from a difference between subconscious representations of baseline physiological homeostatic state and the state of physiological activity induced by physical activity, which creates a second order representation which is perceived by consciousnessproducing structures as the sensation of fatigue” (Gibson et al. 2003, page 174).

We suggest that there is a simpler sensation of fatigue that is triggered by inputs from specific receptors that are sensitive to metabolites produced by muscle contraction. We further propose that this elementary sensation is transduced, conducted, and perceived within a unique sensory system with properties analogous to other sensory modalities such as pain. We call it the “sensation of muscle fatigue.”

Copyright © 2010 by Taylor and Francis Group, LLC.

 

Source: Light AR, Vierck CJ, Light KC. Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes. In: Kruger L, Light AR, editors. Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis; 2010. Chapter 11. Frontiers in Neuroscience. https://www.ncbi.nlm.nih.gov/books/NBK57253/ (Full chapter)

 

In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome

Abstract:

BACKGROUND: Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. In the late nineties, it was first hypothesised that chronic fatigue syndrome (CFS) is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation). Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies.

MATERIALS AND METHODS: Narrative review.

RESULTS: Various studies showed generalised hyperalgesia in CFS for a variety of sensory stimuli, including electrical stimulation, mechanical pressure, heat and histamine. Various tissues are affected by generalised hyperalgesia: the skin, muscle tissue and the lungs. Generalised hyperalgesia in CFS is augmented, rather than decreased, following various types of stressors like exercise and noxious heat pain. Endogenous inhibition is not activated in response to exercise and activation of diffuse noxious inhibitory controls following noxious heat application to the skin is delayed.

CONCLUSIONS: The observation of central sensitisation in CFS is in line with our current understanding of CFS. The presence of central sensitisation in CFS corroborates with the presence of several psychological influences on the illness, the presence of infectious agents and immune dysfunctions and the dysfunctional hypothalamus-pituitary-adrenal axis as seen in these severely debilitated patients.

© 2011 The Authors. European Journal of Clinical Investigation

© 2011 Stichting European Society for Clinical Investigation Journal Foundation.

 

Source: Nijs J, Meeus M, Van Oosterwijck J, Ickmans K, Moorkens G, Hans G, De Clerck LS. In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome. Eur J Clin Invest. 2012 Feb;42(2):203-12. doi: 10.1111/j.1365-2362.2011.02575.x. Epub 2011 Jul 27. https://www.ncbi.nlm.nih.gov/pubmed/21793823

 

The relationship between posttraumatic stress disorder, illness cognitions, defence styles, fatigue severity and psychological well-being in chronic fatigue syndrome

Abstract:

This study investigated, firstly, the rate of posttraumatic stress disorder (PTSD) and the level of psychological well-being amongst people with chronic fatigue syndrome (CFS); and secondly, the extent to which illness cognitions, defence styles and PTSD symptom severity related to fatigue severity and psychological well-being.

Seventy-eight participants with a diagnosis of CFS completed the Chalder Fatigue Scale, the General Health Questionnaire-28, the Posttraumatic Stress Diagnostic Scale, the Illness Cognition Questionnaire and the Defence Style Questionnaire. Fifty-nine participants were recruited from the general public to form the non-fatigued control group.

CFS participants had significantly higher levels of PTSD symptoms, lower levels of psychological well-being and more traumatic life events compared to the non-fatigued controls. Trauma exposure and PTSD severity both predicted CFS status. However, regression analyses demonstrated no significant relationship between PTSD symptoms and fatigue severity or the degree of psychological well-being. ‘Helplessness’ predicted both physical and mental fatigue and psychological well-being, whilst the ‘mature’ defence styles predicted fatigue severity only.

The results offer support to previous research showing that the rate of traumatic life events and PTSD are significantly higher amongst the CFS population. The lack of relationship between PTSD symptoms and fatigue severity or psychological well-being indicates that these processes may operate independently of one another, via different appraisal processes. This study focused on fatigue severity, but it may be that the role of pain in CFS is a key element in the previously reported association between PTSD and CFS.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

 

Source: Eglinton R, Chung MC. The relationship between posttraumatic stress disorder, illness cognitions, defence styles, fatigue severity and psychological well-being in chronic fatigue syndrome. Psychiatry Res. 2011 Jul 30;188(2):245-52. doi: 10.1016/j.psychres.2011.04.012. Epub 2011 May 19. https://www.ncbi.nlm.nih.gov/pubmed/21600664

 

Diagnostic accuracy of symptoms characterising chronic fatigue syndrome

Abstract:

PURPOSE: To determine the diagnostic accuracy for single symptoms and clusters of symptoms to distinguish between individuals with and without chronic fatigue syndrome (CFS).

METHODS: A cohort study was conducted in an exercise physiology laboratory in an academic setting. Thirty subjects participated in this study (n = 16 individuals with CFS; n = 14 non-disabled sedentary matched control subjects). An open-ended symptom questionnaire was administered 1 week following the second of two maximal cardiopulmonary exercise tests administered 24 h apart.

RESULTS: Receiver operating characteristics (ROC) curve analysis was significant for failure to recover within 1 day (area under the curve  =  0.864, 95% confidence interval [CI]: 0.706-1.00, p = 0.001) but not within 7 days. Clinimetric properties of failure to recover within 1 day to predict membership in the CFS cohort were sensitivity 0.80, specificity 0.93, positive predictive value 0.92, negative predictive value 0.81, positive likelihood ratio 11.4, and negative likelihood ratio 0.22. Fatigue demonstrated high sensitivity and modest specificity to distinguish between cohorts, while neuroendocrine dysfunction, immune dysfunction, pain, and sleep disturbance demonstrated high specificity and modest sensitivity. ROC analysis suggested cut-point of three associated symptoms (0.871, 95% CI: 0.717-1.00, p < 0.001). A significant binary logistic regression model (p < 0.001) revealed immune abnormalities, sleep disturbance and pain accurately classified 92% of individuals with CFS and 88% of control subjects.

CONCLUSIONS: A cluster of associated symptoms distinguishes between individuals with and without CFS. Fewer associated symptoms may be necessary to establish a diagnosis of CFS than currently described.

 

Source: Davenport TE, Stevens SR, Baroni K, Van Ness M, Snell CR. Diagnostic accuracy of symptoms characterising chronic fatigue syndrome. Disabil Rehabil. 2011;33(19-20):1768-75. doi: 10.3109/09638288.2010.546936. Epub 2011 Jan 6. https://www.ncbi.nlm.nih.gov/pubmed/21208154

 

The search for pain relief in people with chronic fatigue syndrome: a descriptive study

Abstract:

The purpose of this study was to investigate the use and perceived benefit of complimentary and alternative medicine (CAM) and physiotherapy treatments tried by people with chronic fatigue syndrome (CFS) to ease painful symptoms. This study used a descriptive, cross-sectional design.

People with CFS who experienced pain were recruited to this study. Participants were asked during a semistructured interview about the treatments they had tried to relieve their pain. Each interview was conducted in the home of the participant. Fifty participants were recruited, of which, 10 participants were severely disabled by CFS. Eighteen participants were trying different forms of CAM treatment for pain relief at the time of assessment. Three participants were currently receiving physiotherapy.

Throughout the duration of their illness 45 participants reported trying 19 different CAM treatments in the search for pain relief. Acupuncture was reported to provide the most pain relief (n=16). Twenty-seven participants reported a total of 16 different interventions prescribed by their physiotherapist. The results of this study suggest some physiotherapy and CAM treatments may help people manage painful CFS symptoms. Future research should be directed to evaluating the effectiveness of interventions such as acupuncture or gentle soft tissue therapies to reduce pain in people with CFS.

 

Source: Marshall R, Paul L, Wood L. The search for pain relief in people with chronic fatigue syndrome: a descriptive study. Physiother Theory Pract. 2011 Jul;27(5):373-83. doi: 10.3109/09593985.2010.502554. Epub 2010 Nov 1. https://www.ncbi.nlm.nih.gov/pubmed/21039301

 

Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study

Abstract:

OBJECTIVE: The aims of this study were to examine: (i) baseline pressure pain thresholds in patients with chronic fatigue syndrome and those with chronic low back pain compared with healthy subjects; (ii) the change in mean pain threshold in response to exercise; and (iii) associations with exercise-induced increase in nitric oxide.

PARTICIPANTS: Twenty-six patients with chronic fatigue syndrome suffering of chronic pain, 21 patients with chronic low back pain and 31 healthy subjects.

METHODS: Participants underwent a submaximal aerobic exercise protocol on a bicycle ergometer, preceded and followed by venous blood sampling (nitric oxide) and algometry (hand, arm, calf, low back).

RESULTS: Patients with chronic fatigue syndrome presented overall lower pain thresholds compared with healthy subjects and patients with chronic low back pain (p < 0.05). No significant differences were found between healthy subjects and patients with chronic low back pain. After submaximal aerobic exercise, mean pain thresholds decreased in patients with chronic fatigue syndrome, and increased in the others (p < 0.01). At baseline, nitric oxide levels were significantly higher in the chronic low back pain group. After controlling for body mass index, no significant differences were seen between the groups at baseline or in response to exercise. Nitric oxide was not related to pain thresholds in either group.

CONCLUSION: The results suggest hyperalgesia and abnormal central pain processing during submaximal aerobic exercise in chronic fatigue syndrome, but not in chronic low back pain. Nitric oxide appeared to be unrelated to pain processing.

 

Source: Meeus M, Roussel NA, Truijen S, Nijs J. Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: an experimental study. J Rehabil Med. 2010 Oct;42(9):884-90. Doi: 10.2340/16501977-0595. https://www.medicaljournals.se/jrm/content/html/10.2340/16501977-0595 (Full article)

 

Pain physiology education improves pain beliefs in patients with chronic fatigue syndrome compared with pacing and self-management education: a double-blind randomized controlled trial

Abstract:

OBJECTIVE: To examine whether pain physiology education was capable of changing pain cognitions and pain thresholds in patients with chronic fatigue syndrome (CFS) and chronic widespread pain.

DESIGN: Double-blind randomized controlled trial.

SETTING: Specialized chronic fatigue clinic in university hospital.

PARTICIPANTS: A random sample of patients (N=48) with CFS patients (8 men, 40 women) experiencing chronic pain, randomly allocated to the control group (n=24) or experimental group (n=24). Two women in the experimental group did not complete the study because of practical issues (lack of time and restricted mobility).

INTERVENTIONS: One individual pain physiology education session (experimental) or 1 pacing and self-management education session (control).

MAIN OUTCOME MEASURES: Algometry, the Neurophysiology of Pain Test, and questionnaires evaluating pain cognitions-the Pain Coping Inventory, the Pain Catastrophizing Scale, and the Tampa Scale for Kinesiophobia-version CFS-were completed immediately before and immediately after the intervention.

RESULTS: After the intervention, the experimental group demonstrated a significantly better understanding of the neurophysiology of pain (P<.001) and a reduction of the Pain Catastrophizing Scale subscale “ruminating” (P=.009) compared with controls. For these variables, moderate to large Cohen d effect sizes were revealed (.79-2.53).

CONCLUSIONS: A 30-minute educational session on pain physiology imparts a better understanding of pain and brings about less rumination in the short term. Pain physiology education can be an important therapeutic modality in the approach of patients with CFS and chronic pain, given the clinical relevance of inappropriate pain cognitions.

Comment in: Educational programs for chronic fatigue syndrome need to take cognizance of the condition’s abnormal response to exercise. [Arch Phys Med Rehabil. 2011]

 

Source: Meeus M, Nijs J, Van Oosterwijck J, Van Alsenoy V, Truijen S. Pain physiology education improves pain beliefs in patients with chronic fatigue syndrome compared with pacing and self-management education: a double-blind randomized controlled trial. Arch Phys Med Rehabil. 2010 Aug;91(8):1153-9. doi: 10.1016/j.apmr.2010.04.020. https://www.ncbi.nlm.nih.gov/pubmed/20684894

 

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

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 postexertional fatigue in the ME/CFS group (r = 0.454; P = 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.

Comment in: Chronic fatigue syndrome reflects loss of adaptability. [J Intern Med. 2010]

 

Source: Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, Paul L. Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. J Intern Med. 2010 Sep;268(3):265-78. doi: 10.1111/j.1365-2796.2010.02228.x. Epub 2010 Mar 3. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2010.02228.x/full (Full article)

 

Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) patients often report symptom flare (SF) for >24 h after moderate exercise (post-ex). We hypothesized that SF is linked to increases in circulating cytokines and CD40 Ligand (CD40L). In 19 CFS patients and 17 controls, mental and physical fatigue and pain symptom ratings were obtained together with serum for 11 cytokines and CD40L before and at 0.5, 8, 24, and 48 h post-ex.

Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1beta, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFalpha (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings.

 

Source: White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010 Jul 1;47(4):615-24. doi: 10.1111/j.1469-8986.2010.00978.x. Epub 2010 Mar 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378647/ (Full article)

 

Evidence for generalized hyperalgesia in chronic fatigue syndrome: a case control study

Abstract:

Several studies provided evidence for generalized hyperalgesia in fibromyalgia or whiplash-associated disorders. In chronic fatigue syndrome, however, pain is a frequently reported complaint, but up to now, evidence for generalized hyperalgesia is lacking.

The aim of this study is to examine whether the pressure pain thresholds (PPTs) at both symptomatic and asymptomatic sites differ in chronic fatigue syndrome (CFS) patients with chronic pain, compared to healthy controls.

Therefore, 30 CFS patients with chronic pain and 30 age- and gender-matched healthy controls indicated on a Margolis Pain Diagram where they felt pain lasting longer than 24 h in the past 4 weeks. After completing a test battery of questionnaires evaluating pain cognitions, functional status and symptomatology, a blinded researcher assessed PPTs bilaterally at seven nonspecific sites on both trunk and extremities. PPTs were compared for the two complete groups.

In addition, PPTs of patients and controls who did not report pain in a respective zone were compared. PPTs of the patients were significantly lower (p<0.001) compared to those of the control group, also when pain-free samples per zone were compared (p<0.001). The mean PPT was 3.30 kg/cm2 in all CFS patients and 8.09 kg/cm2 in the controls. No confounding factors responsible for the observed differences, as, e.g., catastrophizing and depression, could be revealed.

These findings provide evidence for the existence of hyperalgesia even in asymptomatic areas (generalized secondary hyperalgesia). The generalized hyperalgesia may represent the involvement of a sensitized central nervous system.

 

Source: Meeus M, Nijs J, Huybrechts S, Truijen S. Evidence for generalized hyperalgesia in chronic fatigue syndrome: a case control study. Clin Rheumatol. 2010 Apr;29(4):393-8. doi: 10.1007/s10067-009-1339-0. https://www.ncbi.nlm.nih.gov/pubmed/20077123