Pain in patients with chronic fatigue syndrome: Does nitric oxide trigger central sensitisation?

Medical Hypotheses (2005) 64, 558–562

http://intl.elsevierhealth.com/journals/mehy

Pain in patients with chronic fatigue syndrome: Does nitric oxide trigger central sensitisation? Jo Nijsa,b,*, Bart Van de Veldeb,1, Kenny De Meirleira a

Department of Human Physiology, Faculty of Physical Education and Physical Therapy, Vrije Universiteit Brussel (VUB), Belgium b Division of Musculoskeletal Physical Therapy, Department of Health Sciences, Hogeschool Antwerpen (HA), Belgium Received 14 July 2004; accepted 19 July 2004

Summary Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with chronic fatigue syndrome (CFS): pain severity may account for 26–34% of the variability in the CFS patient’s activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology. It is hypothesised that a nitric oxide (NO) – dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients. In CFS patients, deregulation of the 20 ,50 -oligoadenylate synthetase/RNase L pathway is accompanied by activation of the protein kinase R enzyme. Activation of the protein kinase R and subsequent nuclear factor-jB activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, Epstein–Barr Virus, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system. c 2004 Elsevier Ltd. All rights reserved.




Introduction: pain in CFS Chronic fatigue syndrome (CFS) is a debilitating disorder, characterised by persistent fatigue lasting for more than six months, in addition to many other *

Corresponding author. Present address: MFYS/SPORT KRO-1 VUB, Laarbeeklaan 101, B-1090 Brussel, Belgium. Tel.: +32 2 477 4604; fax: +32 2 477 4607. E-mail address: [email protected] (J. Nijs). 1 Bart Van de Velde is financially supported by a PhD grant supplied by the Association of Higher Education and Universities of Antwerp.




signs and symptoms (myalgia, arthralgia, low-grade fever, concentration difficulties) [1,2]. The symptoms are not improved by bed rest and may be aggravated by physical or mental activity [1,2]. The pathogenesis of CFS has not been completely delineated, and no specific diagnostic tests, with adequate sensitivity and specificity, are available. Individuals with CFS must function at a lower level of activity than they were capable of before the onset of the illness. In essence, chronic fatigue has been arbitrary put forward as the primary symptom of CFS pa-

0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.07.037

Pain in patients with chronic fatigue syndrome tients, as was the case with chronic widespread pain in fibromyalgia syndrome (FMS) subjects. Nishikai et al. [3] found that 85 of the 114 (74.6%) patients with CFS reported muscle pain, and 74 (64.9%) complained of multi-joint pain. In another study, 24 of 44 (54.5%) consecutive CFS patients reported widespread pain [4]. There is a growing international consensus that the CFS population should be subclassified, because more homogeneous subgroups are less likely to reveal conflicting data among investigators [5]. Chronic fatigue with musculoskeletal system disorders such as widespread muscle and joint pain has been suggested as an important subclass of CFS [5]. This notion was supported by the observed association between pain severity and activity limitations/participation restrictions (r = 0.51) in CFS patients, which was similar to the association between fatigue severity and activity limitations/participation restrictions (r = 0.50) [6]. For interpreting correlation coefficients, they can be squared to obtain the coefficient of determination [7]. Using this approach, it can be concluded that pain severity may account for 26.0% of the variability in the CFS patient’s activity limitations and participation restrictions, while fatigue severity may account for 25.0% of the variability in activity limitations/ participation restrictions. Likewise, another cross-sectional study of 88 CFS patients reported an association between bodily pain, assessed with the SF-36, and self-reported activity limitations and participation restrictions (Pearson’s r = 0.58) [8]. Thus, bodily pain may account for 33.6% of the variability in the CFS patient’s activity limitations and participation restrictions. From these data it is concluded that pain accounts for at least 25% of the variability in the CFS patient’s activity limitations and participation restrictions. One should not assume unidirectional causal progression from disease to impairments to activity limitations/participation restrictions [9]. Some impairments may not be related to the patients’ activity limitations/participation restrictions and therefore need not become a focus of treatment [10]. This is a difficult yet critical step in the clinical reasoning process. Evidence supportive of the clinical importance of widespread pain in CFS patients has been provided. The etiology of widespread pain in patients with CFS, however, remains to be elucidated. Few studies have addressed this issue. This manuscript explores a hypothesis regarding the etiology of widespread pain in CFS patients, based on our current understanding of CFS. It is postulated that central sensitisation accounts for widespread pain in patients with CFS, and that our current understanding of

559 both pathoimmunity and psychopathology of CFS fits the central sensitisation-hypothesis.

Central sensitisation in patients with CFS? In the past, studies have provided (preliminary) evidence for the role of sensitisation into the manifestation of a wide variety of ‘subjective health complaints’ [11]; chronic low back pain, FMS [12–14], chronic whiplash associated disorders [14–16], functional gastrointestinal problems, and multiple chemical sensitivity disorders [17]. It has been suggested that sensitisation takes part in the pathophysiology of CFS [17,18]. Likewise, it has been postulated that sensitisation might explain the high prevalence of bronchial hyper-responsiveness in CFS patients (73 of 137 patients) [19]. Surprisingly, studies addressing central sensitisation in CFS are essentially lacking. One issue supporting the hypothesis that central sensitisation might be an issue in CFS is the overlap between FMS and CFS. FMS and CFS are apparently different but overlapping disorders [20–22] both characterised by sleep impairments, fatigue, headache, muscle and joint aches, nausea, gastro-intestinal symptoms and neurocognitive disturbances. As mentioned earlier, evidence for central sensitisation in FMS has been provided [12–14].

Intracellular immune deregulation as a possible etiology for central sensitisation in CFS Vikman et al. [23] demonstrated that long-term treatment of cultured spinal dorsal horn neurons with interferon-gamma (IFN-c) triggers NO dependent reduction of GluR1 clustering on dendrites (GluR1 together with GluR2 are the two most prominent AMPA receptors in the superficial dorsal horn), accompanied by an enhanced spontaneous activity in the neuronal network. Since GluR1 is mainly associated with inhibitory neurons, these observations underscore the role of a NO-dependent reduction in inhibitory activity of the central nervous system in central sensitisation. These observations might explain chronic widespread pain in patients with CFS. Our current understanding of pathoimmunity of CFS, together with the observations by Vikman et al. [23], provides a hypothetical explanation

560

Nijs et al.

for chronic widespread pain as seen in a large subgroup of CFS patients. The deregulation of the 20 ,50 -oligoadenylate (2-5A) synthetase/RNase L pathway in subsets of CFS patients has been reported at length in the scientific literature [24,25]. Both elastases and calpain are capable of initiating high molecular weight RNase L (83 kDa) proteolysis, generating two major fragments with molecular masses of 37 (a truncated low molecular weight RNase L) and 30 kDa, respectively, [26] (Fig. 1). Besides triggering the 2-5A synthetase/ RNase L activation, type I interferons induce the expression of the double-stranded RNA dependent protein kinase R (PKR). Activation of this enzyme, as typically seen during viral infection or cellular stress, results in a blockade of protein synthesis and consequent cell death (apoptosis). Experimental data point to an activation of the PKR enzyme, parallel to the 83 kDa RNase L proteolysis, in subsets of CFS [27]. PKR activation leads to phosphorylation of the inhibitor of NF (nuclear factor)-jB (IjB) and consequently NF-jB activation, which in turn causes inducible nitric oxide synthetase (iNOS) expression [28]. iNOS generates increased production of NO by monocytes/macrophages. Elevated NO levels have been documented in CFS patients by Kurup and Kurup [29], and oxidative stress has found to be associated with symptom expression in CFS patients [30]. PKR-dependent elevated NO-levels are likely to be caused by a wide variety of infectious agents,

as typically observed in CFS patients. An increased prevalence of Mycoplasma infections in CFS patients compared to healthy subjects has consistently been reported in the scientific literature [31–33]. Among the different Mycoplasma species studied, M. fermentans is one of the most prevalent in patients with CFS. M. fermentans produces a lipopeptide, named 2-kDa macrophage-activating lipopeptide (MALP-2), which stimulates macrophages [34]. Macrophages, activated by MALP-2, release nitric oxide [35–37]. Furthermore, NO is synthesized in response to, and has potent antiviral activity against a number of viruses, for instance Coxsackie B virus [38], and Epstein–Barr virus [39]. Both Epstein–Barr Virus and Coxsackie B virus have been suggested as cofactors in CFS pathophysiology; antibodies to Coxsackie B virus are commonly found in blood samples taken from CFS patients [40,41], while an infection of the B lymphocytes by Epstein–Barr Virus was long considered as the cause of CFS [42]. Taken together, evidence for elevated NO levels in CFS patients has been provided, and this observation fits our current understanding of CFS pathophysiology. Vikman et al. [23] showed an NO-dependent reduction of inhibitory activity of the central nervous system and consequent central sensitisation of cultured spinal dorsal horn neurons. It is tempting to speculate that excessive NO-levels trigger central sensitisation in CFS patients. Part from the hypothetical interaction between infec-

type I IFN

inactive 2-5A synthetases inactive PKR active 2-5A synthetases active PKR inactive RNase L

NF-κB activation

active RNase L (83 kDa) elastase / calpain

[NO] ↑↑ 37 kDa RNase L + 30 kDa RNase L

? ?

inhibitory activity of CNS ↓↓

?

?

behavioural changes

central sensitisation

Figure 1 Immunopathology of CFS and the hypothetical interaction with central sensitisation: IFN, interferon; 2-5A, 20 ,50 -oligoadenylate; PKR, protein kinase R; NF, nuclear factor; NO, nitric oxide; CNS, central nervous system; ?, hypothetical interaction.

Pain in patients with chronic fatigue syndrome tions, NO, and central sensitisation, additional pathways linking infectious agents to altered central pain processing have been revealed. Infection triggers the release of the pro-inflammatory cytokine interleukin-1b (IL-1b), which is known to play a major role in inducing cyclooxygenase-2 (COX-2) and prostaglandin E2 expression in the central nervous system [43,44]. Upregulation of COX-2 and prostaglandin E2 leads to neuronal hyperexcitability (in peripheral nerve terminals, the spinal cord, and supraspinal centers).

561

[4]

[5] [6]

[7]

[8]

Behavioral changes might enhance central sensitisation in CFS Furthermore, a body of literature providing evidence for behavioural changes like somatization [45–47], catastrophizing [48,49], and activity– avoidance [50–53] in CFS patients is available. These cognitive styles and personality traits may result in sensitisation of dorsal horn spinal cord neurons (through inhibition of descending tracks in the central nervous system), or are the result of central sensitisation [54]. Since exercise has been shown to lower the pain threshold in CFS patients [55], avoidance behaviour towards physical activity is more likely to be a consequence rather than the cause of central sensitisation. In addition, anxious persons have a cognitive processing priority for fear-related information [56].

[9] [10]

[11]

[12]

[13]

[14]

[15]

Conclusion It is concluded that a study examining the role of central sensitisation in CFS-related pain physiology is warranted. If evidence supportive of altered central pain processing in CFS patients can be provided, than the associations between immunopathology, psychopathology, NO, and central pain processing in CFS patients require further investigation.

[16]

[17]

[18]

[19]

References [20] [1] Holmes GP, Kaplan JE, Gantz NM et al. Chronic fatigue syndrome: a working case definition. Ann Int Med 1988;108:387–9. [2] Fukuda K, Strauss SE, Hickie I et al. The chronic fatigue syndrome, a comprehensive approach to its definition and study. Ann Int Med 1994;121:953–9. [3] Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka S et al. Autoantibodies to a 68/48 kDa protein in

[21]

[22]

chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology 2001;40:806–10. Nijs J, De Meirleir K, Truyen S. Hypermobility in patients with chronic fatigue syndrome: preliminary observations. J Musculoskelet Pain 2004;12:9–17. Tan EM, Sugura K, Gupta S. The case definition of chronic fatigue syndrome. J Clin Immunol 2002;22:8–12. Nijs J, Vaes P, McGregor N, Van Hoof E, De Meirleir K. Psychometric properties of the Dutch chronic fatigue syndrome–activities and participation questionnaire (CFS–APQ). Phys Ther 2003;83:444–54. Dawson-Saunders B, Trapp RG. Basic and clinical biostatistics. 2nd ed. London: Prentice-Hall International Inc.; 1994. p. 53–54. Nijs J, Cloostermans B, McGregor N, Vaes P, De Meirleir K. Construct validity and internal consistency of the chronic fatigue syndrome-activities and participation questionnaire (CFS–APQ). Physiother Theor Pract 2004;20:31–40. American Physical Therapy Association. Guide to physical therapy practice. 2nd ed. Phys Ther 2001;81(1). O’Sullivan SB. Clinical decision making: planning effective treatments. In: O’Sullivan SB, Schmitz TJ, editors. Physical rehabilitation: assessment and treatment. 3rd ed. Philadelphia: FA: Davis Company; 1994. p. 1–8. chapter 1. Ursin H, Eriksen HR. Sensitization, subjective health complaints, and sustained arousal. Ann NY Acad Sci 2001;933:119–29. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001;91:165–75. Price DD, Staud R, Robinson ME, Mauderli AP, Cannon R, Vierck CJ. Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 2002;99:49–59. Banic B, Petersen-Felix S, Andersen OK, Radanov BP, Villiger PM, Arendt-Nielsen L et al. Evidence for spinal cord hypersensitivity in chronic pain after whiplash injury and in fibromyalgia. Pain 2004;107:7–15. Sterling M, Treleaven J, Edwards S, Jull G. Pressure pain thresholds in chronic whiplash associated disorder: further evidence of altered central pain processing. J Musculoskelet Pain 2002;10:69–81. Sterling M, Jull G, Vicenzino B, Kenardy J. Sensory hypersensitivity occurs soon after whiplash injury and is associated with poor recovery. Pain 2003;104:509–17. Bell IR, Baldwin CM, Schwartz GE. Illness from low levels of environmental chemicals: relevance to chronic fatigue syndrome and fibromyalgia. Am J Med 1998;105:74S–82S. Aaron LA, Buchwald D. Chronic diffuse musculoskeletal pain, fibromyalgia and co-morbid unexplained clinical conditions. Best Practice Res Clin Rheumatol 2003;17:563–74. Nijs J, De Becker P, De Meileir K, Demanet K, Vincken W, Schuermans D et al. Associations between bronchial hyperresponsiveness and immune cell parameters in patients with chronic fatigue syndrome. Chest 2003;123:998–1007. Bombardier CH, Buchwald D. Chronic fatigue, chronic fatigue syndrome, and fibromyalgia. Disability and health care use. Med Care 1996;34:924–30. Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 1991;3:247–58. Klimas N, Salvato F, Morgan R, Fletcher MA. Immunological abnormalities in chronic fatigue syndrome. J Clin Microbiol 1990;28:1403–10.

562 [23] Vikman KS, Hill RH, Backstro ¨m E, Robertson B, Kristensson K. Interferon-gamma induces characteristics of central sensitization in spinal dorsal horn neurons in vitro. Pain 2003;106:241–51. [24] Suhadolnik RJ, Reichenbach NL, Hitzges P et al. Upregulation of the 2-5A synthetase/Rnase L antiviral pathway associated with chronic fatigue syndrome. Clin Infect Dis 1994;18:S96–104. [25] De Meirleir K, Bisbal C, Campine I et al. A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome. Am J Med 2000;108:99–105. [26] Demettre E, Bastide L, D’Haese A et al. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. J Biol Chem 2002;277:35746–51. [27] Englebienne P, Fre ´mont M, Vaeyens F, Herst V, Verhas M, De Becker P, et al. Chronic fatigue syndrome (CFS) and multiple sclerosis (MS) as subsets of a group of cellular immunity disorders. ME/CFS: The medical practitioners’ challenge. Proceedings at Sydney International Conference, 2001:35–42. [28] Uetani K, Der SD, Zamanian-Daryoush M, de la Motte C, Lieberman BY, Williams BRG et al. Central role of doublestranded RNA-activated protein kinase in microbial induction of nitric oxide synthase. J Immunol 2000;165:988–96. [29] Kurup RK, Kurup PA. Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. Int J Neurosci 2003;113:683–701. [30] Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome. Redox Rep 2000;5:35–41. [31] Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome. Eur J Clin Microbiol Infect Dis 1999;18:859–65. [32] Vojdani A, Choppa PC, Tagle C, Andrin R, Samini B, Lapp CW. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with chronic fatigue syndrome. FEMS Immunol Med Microbiol 1998;22:355–65. [33] Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunol Med Microbiol 2002;34:209–14. [34] Pall ML, Satterle JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder. Ann NY Acad Sci 2001;933:323–9. [35] Piec G, Mirkovitch J, Palacio S et al. Effect of MALP-2, a lipopeptide from Mycoplasma fermentans, on bone resorption in vitro. Infect Immunol 1999;67:6281–5. [36] Rawadi G. Mycoplasma fermentans interaction with monocytes/macrophages: molecular basis. Microbes Infect 2000;2:955–64. [37] Takeuchi O, Kaufmann A, Grote K et al. Cutting edge: Preferentially the R-stereoisomer of the Mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88dependent signalling pathway. J Immunol 2000;164:554–7.

Nijs et al. [38] Zaragoza C, Ocampo CJ, Saura M, McMillan A, Lowenstein CJ. Nitric oxide inhibition of coxsackievirus replication in vitro. J Clin Invest 1997;100:1760–7. [39] Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS. Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein–Barr virus reactivation. Cell 1994;79: 1137–46. [40] Bell EJ, McCartney RA, Riding MH. Coxsackie B viruses and myalgic encephalomyeltitis. J R Soc Med 1988;81: 329–31. [41] Yousef GE, Bell EJ, Mann GF, Murugesan V, Smith DG, McCartney RA. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988;1:146–50. [42] Levy J. Viral studies of chronic fatigue syndrome, introduction. Clin Infect Dis 1994;18(Suppl. 1):S117. [43] Bazan NG. COX-2 as a multifunctional neuronal modulator. Nat Med 2001;7:414–5. [44] Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S et al. Interleukin-1 beta-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471–5. [45] Wessely S. Chronic fatigue syndrome: a 20th century illness?. Scand J Work Environ Health 1997;23:S17–34. [46] Fischler B, Dendale P, Michiels V, Cluydts R, Kaufman L, De Meirleir K. Physical fatigability and exercise capacity in chronic fatigue syndrome: association with disability, somatization and psychopathology. J Psychosom Res 1997;42:369–78. [47] Johnson SK, DeLuca J, Natelson BH. Assessing somatization disorder in the chronic fatigue syndrome. Psychosom Med 1996;58:50–7. [48] Petrie K, Moss-Morris R, Weinman J. The impact of catastrophic beliefs on functioning in chronic fatigue syndrome. J Psychosom Res 1995;39:31–7. [49] Sharpe M. Cognitive behavior therapy for chronic fatigue syndrome: efficacy and implications. Am J Med 1998;105:104S–9S. [50] Demitrack MA. Chronic fatigue syndrome and fibromyalgia: dilemmas in diagnosis and clinical management. Psychiatr Clin North Am 1998;21:671–92. [51] Silver A, Haeney M, Vijayadurai P et al. The role of fear of physical movement and activity in chronic fatigue syndrome. J Psychosom Res 2002;52:485–93. [52] Nijs J, De Meirleir K, Duquet W. Kinesiophobia in chronic fatigue syndrome: Assessment and associations with disability. Arch Phys Med Rehabil 2004;85 [in press]. [53] Nijs J, Vanherberghen K, Duquet W, De Meirleir K. Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability. Phys Ther 2004;84:696–705. [54] Zusman M. Forebrain-mediated sensitization of central pain pathways: ‘non-specific’ pain and a new image for MT. Man Ther 2002;7:80–8. [55] Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain threshold in chronic fatigue syndrome. Pain 2004;109: 497–9. [56] Eriksen HR, Ursin H. Subjective health complaints, sensitization, and sustained cognitive activation (stress). J Psychosom Res 2004;56:445–8.