Manual Therapy ] (]]]]) ]]]–]]]
Chronic musculoskeletal pain in chronic fatigue syndrome: Recent
developments and therapeutic implications
Jo Nijsa,b,?, Mira Meeusa,b,1, Kenny De Meirleira
aDepartment of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Belgium
bDepartment of Health Sciences, Division of Musculoskeletal Physiotherapy, Higher Institute of Physiotherapy, Hogeschool Antwerpen, Belgium
Received 10 October 2005; received in revised form 8 March 2006; accepted 30 March 2006
Patients with chronic fatigue syndrome (CFS) experience chronic musculoskeletal pain which is even more debilitating than
fatigue. Scientific research data gathered around the world enables clinicians to understand, at least in part, chronic musculoskeletal
pain in CFS patients. Generalized joint hypermobility and benign joint hypermobility syndrome appear to be highly prevalent
among CFS sufferers, but they do not seem to be of any clinical importance. On the other hand, pain catastrophizing accounts for a
substantial portion of musculoskeletal pain and is a predictor of exercise performance in CFS patients. The evidence concerning
pain catastrophizing is supportive of the indirect evidence of a dysfunctional pain processing system in CFS patients with
musculoskeletal pain. CFS sufferers respond to incremental exercise with a lengthened and accentuated oxidative stress response,
explaining muscle pain, postexertional malaise, and the decrease in pain threshold following graded exercise in CFS patients.
Applying the scientific evidence to the manual physiotherapy profession, pacing self-management techniques and pain
neurophysiology education are indicated for the treatment of musculoskeletal pain in CFS patients. Studies examining the
effectiveness of these strategies for CFS patients are warranted.
r 2006 Elsevier Ltd. All rights reserved.
The main feature of chronic fatigue syndrome (CFS)
diagnosis is the exclusion of all conditions other than
CFS (e.g. diabetes, cancer, and obesity), together with
the presence of a debilitating fatigue lasting for at least 6
months (Holmes et al., 1988; Fukuda et al., 1994).
Worsening of symptoms (pain, fatigue) is typically seen
after previously well-tolerated levels of exercise/physical
Chronic fatigue has been arbitrarily put forward as
the primary symptom of CFS. Between 54% and 75%
of CFS patients experience chronic widespread pain
(Nishikai et al., 2001). Chronic fatigue with widespread
muscle and joint pain has been suggested as an
important subclass of CFS (Tan et al., 2002), and the
observed associations between musculoskeletal pain
severity and disability (r between 0.51 and 0.58) was
similar to the association between fatigue severity and
disability (r ¼ 0:50) (Nijs et al., 2003a, 2004a). The latter
suggests musculoskeletal pain to be as important as
fatigue to CFS patients.
A few years ago, little was known about the nature of
chronic musculoskeletal pain in CFS. To date, scientific
research data gathered around the world enables
clinicians to understand, at least in part, chronic
musculoskeletal pain in CFS patients. The present
manuscript provides the reader with our current under-
standing of chronic musculoskeletal pain in CFS
In the US, patients with CFS are often seen in
chiropractic practise. Studying the health-care use of 402
ARTICLE IN PRESS
1356-689X/$-see front matter r 2006 Elsevier Ltd. All rights reserved.
?Corresponding author. Vrije Universiteit Brussel, MFYS/SPORT,
KRO-gebouw –1, Laarbeeklaan 101, B-1090 Brussels, Belgium.
Tel.: +3224774604; fax: +3224774607.
E-mail address: email@example.com (J. Nijs).
1Mira Meeus is financially supported by a Ph.D. grant (‘‘Chronic
pain in chronic fatigue syndrome: a biopsychosocial approach’’)
supplied by the Higher Institute of Physiotherapy, Department of
Health Care Sciences, Hogeschool Antwerpen, Antwerp, Belgium.
patients from a university-based chronic fatigue clinic, it
was found that 27% of CFS patients visited chiroprac-
tors, and 12% visited osteopaths (Bombardier and
Buchwald, 1996). Nearly 56% of the studied patients
fulfilling the diagnostic criteria for both CFS and
Fibromyalgia visited chiropractors, and 15.3% visited
osteopaths. Although studies examining the effective-
ness of interventions aiming at reducing musculoskeletal
pain in CFS are scarce, the knowledge addressing
chronic musculoskeletal pain in CFS enables clinicians
to provide a plausible treatment strategy. Therefore, this
manuscript provides suggestions for manual phy-
siotherapists to treat chronic musculoskeletal pain in
2. Musculoskeletal pain in CFS: is generalized joint
hypermobility an issue?
If generalized joint hypermobility appears to be an
issue in CFS, then physiotherapists should include joint
hypermobility in the assessment and management of
CFS. Generalized joint hypermobility (assessed using
the Beighton et al., 1973 criteria) was more prevalent in
patients with CFS than in matched healthy controls
(21% versus 4%; P ¼ 0:004) (Nijs et al., 2006). The
majority of CFS patients (58.8%) fulfilled the criteria
for benign joint hypermobility syndrome (BJHS) (as
described by Grahame et al., 2000). Knee propriocep-
tion was similar in both groups (P ¼ 0:81), and no
associations were found between generalized joint
hypermobility and self-reported pain severity, disability,
or knee proprioception. There appears to be no
association between musculoskeletal pain and joint
hypermobility in CFS patients (Nijs et al., 2004b). A
review of the evidence on generalized joint hypermobi-
lity in Fibromyalgia and CFS, together with an overview
on assessment and treatment strategies, is presented
elsewhere (Nijs, 2005). If generalized joint hypermobility
is not of clinical importance to CFS patients, then other
factors must explain chronic musculoskeletal pain in
3. Musculoskeletal pain in CFS: a biopsychosocial
The study showing decreased pain threshold following
graded exercise in CFS patients (Whiteside et al., 2004)
suggested a link between impaired exercise performance
and pain experience in CFS patients (in healthy subjects,
a substantial increase in pain threshold in response to
exercise is typically observed). A recent study (Nijs et al.,
under review) provided evidence supportive of this
assumption: pain catastrophizing was identified as a
major predictor of exercise performance in female CFS
patients experiencing chronic widespread pain. In
addition, pain catastrophizing was found to predict
bodily pain, even after controlling for depression. From
previous studies, it is concluded that fear of movement
(‘kinesiophobia’) is not related to exercise performance
in CFS patients (Nijs et al., 2004c,d). In addition,
kinesiophobia in general (fear of an exercise-triggered
increase in general symptom severity), rather than pain-
related fear of movement, was related to self-reported
disability in CFS patients (Nijs et al., 2004c).
There is a body of literature providing evidence for
somatization (Johnson et al., 1996; Fischler et al., 1997)
and activity-avoidance (Nijs et al., 2004c) in CFS
patients. These cognitive styles and personality traits,
together with pain catastrophizing, may result in
sensitization of dorsal horn spinal cord neurons
(through inhibition of descending tracks in the central
nervous system), or are the result of central sensitization
(Zusman, 2002). Central sensitization is defined as ‘‘an
augmentation of responsiveness of central pain-signal-
ling neurons to input from low-threshold mechanor-
supporting the central sensitization hypothesis in CFS
patients is currently lacking. Still, the observed de-
creased pain threshold following graded exercise in CFS
patients is indicative of a dysfunctional central anti-
nociceptive mechanism in CFS (Whiteside et al., 2004),
and evidence of a deregulated serotonergic neurotrans-
mission in the brain of CFS patients, consistent with
altered pain processing, has been provided (Yamamoto
et al., 2004). Strong evidence supportive of altered
central sensory processing (i.e. central sensitization)
among patients with Fibromyalgia has been published
(Staud et al., 2001, 2003; Price et al., 2002; Banic et al.,
2004). Studies examining whether these data apply to
CFS patients with chronic widespread pain are under-
The central sensitization hypothesis fits our current
understanding of CFS psychopathology and pathophy-
siology. The link with CFS psychopathology has been
outlined in the preceding paragraph. From a pathophy-
siologic perspective, the evidence of a high prevalence of
opportunistic infections (e.g. Vojdani et al., 1998; Nijs
et al., 2002) is consistent with the numerous reports of
deregulated and suppressed immune functioning in CFS
patients (e.g. Suhadolnik et al., 1997; Levine et al., 1998;
Nijs et al., 2003b). Deregulation of intracellular immune
function was even found to be a predictor of physiolo-
gical exercise parameters (Nijs et al., 2005). Infection
triggers the release of the pro-inflammatory cytokine
interleukin-1b, which is known to play a major role in
inducing cyclooxygenase-2 (COX-2) and prostaglandin
E2 expression in the central nervous system (Bazan,
2001; Samad et al., 2001). Upregulation of COX-2 and
prostaglandin E2 sensitizes peripheral nerve terminals.
Indeed, even peripheral infections activate spinal cord
ARTICLE IN PRESS
J. Nijs et al. / Manual Therapy ] (]]]]) ]]]–]]]
glia (both microglia and astrocytes), which in turn
enhance the pain response by releasing nitric oxide (NO)
and proinflammatory cytokines (for a detailed descrip-
tion of these complex pathophysiological interactions,
the interested readers are referred to Maier and
Watkins, 1998; Watkins and Maier, 1999). These
dynamic immune-to-brain communication pathways
can explain a wide variety of psychological and
physiological symptoms (the ‘sickness response’) seen
in patients with CFS.
In addition, Vikman et al. (2003) demonstrated that
long-term treatment of cultured spinal dorsal horn
neurons with interferon-gamma 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
sensitization. Since elevated NO levels have been
documented in CFS patients (Kurup and Kurup,
2003), and oxidative stress was found to be associated
with symptom expression (including musculoskeletal
pain) in CFS patients (Richards et al., 2000; Vecchiet
et al., 2003; Kennedy et al., 2005), the observations by
Vikman et al. (2003) may explain part of the chronic
pain experience in patients with CFS. Moreover,
experimental evidence has shown that CFS patients
respond to incremental exercise with a lengthened and
accentuated oxidative stress response, explaining muscle
pain and postexertional malaise as typically seen in CFS
subjects (Jammes et al., 2005).
On the other hand, substance P levels do not seem to
be upregulated in CFS patients (Evengard et al., 1998).
Substance P, a peptide involved in the neurotransmis-
sion of pain from the periphery to the central nervous
system, is typically elevated in patients with Fibromyal-
gia. Still, from the available evidence it is concluded that
patients fits our current understanding of the complex
biopsychosocial interactions in CFS.
4. Manual physiotherapy as a treatment for chronic
musculoskeletal pain in CFS patients?
What can the manual physiotherapy profession offer
to patients with CFS experiencing chronic widespread
musculoskeletal pain? From our current understanding
of chronic musculoskeletal pain in CFS, as presented
above, it is clear that hands-on manual therapy
techniques are not indicated for treating chronic
musculoskeletal pain in all CFS cases. Still, local
musculoskeletal problems like thoracic outlet compres-
sion syndrome, low back pain, and neck pain are often
seen in CFS patients. In selected cases, the local
musculoskeletal problems may be more than epipheno-
mena: from our own clinic we recall patients reporting
the onset of CFS symptoms after a Whiplash trauma, or
after a rupture of the symphysis pubis during delivery
and consequent lumbopelvic instability. In these pa-
tients, appropriate manual physiotherapy did not cure
the disease, but was able to resolve the localized
musculoskeletal pain problem and associated disability.
Trained manual physiotherapists are able to differenti-
ate between a localized and a central pain problem, even
in a complex disorder like CFS. In case of the former,
local manual therapy techniques are indicated, but
should be adopted in respect to the reduced pain
threshold and pathophysiology of the patient. In case
of the latter, behavioural treatment strategies and pain
neurophysiology education are indicated. This will be
explained in the next paragraphs.
What kind of behavioural treatment can diminish
musculoskeletal pain in CFS patients? The effectiveness
of graded exercise therapy and cognitive behavioural
therapy for CFS patients has frequently been examined.
In many of the published studies, graded exercise
therapy has been adopted as a component of the
cognitive behavioural programme (i.e. graded exercise
was used as a way to diminish avoidance behaviour
towards physical activity). According to the Cochrane
Library, both treatment strategies are effective in the
short term for treating CFS patients (Price and Couper,
1998; Edmonds et al., 2004). Unfortunately, the studies
examining the effectiveness of graded exercise therapy/
cognitive behavioural therapy in CFS did not use
(musculoskeletal) pain as an outcome measure (e.g.
Deale et al., 1997; Fulcher and White, 1997; Powell
et al., 2001; Prins et al., 2001). Secondly, none of the
studies referenced here applied the current diagnostic
criteria for CFS (Fukuda et al., 1994), making it difficult
to extrapolate these results to other settings. Thirdly,
from a large treatment audit among British CFS
patients, it was concluded that approximately 50% of
the patients stated that graded exercise therapy wor-
sened their condition (Shephard, 2001). Finally, graded
exercise therapy does not comply with our current
understanding of CFS exercise physiology. As outlined
above, experimental evidence is now available showing
increased oxidative stress in response to (sub)maximal
exercise and subsequent increased fatigue and muscu-
loskeletal pain (postexertional malaise).
Pacing, a strategy where patients are encouraged to
achieve an appropriate balance between activity and rest
in order to avoid exacerbation and to set realistic goals
for increasing activity, is an alternative for the cognitive
behavioural approach (CFS/ME Working Group, 2001;
Shephard, 2001). This energy management strategy
involves avoiding activities to a degree that exacerbates
ARTICLE IN PRESS
J. Nijs et al. / Manual Therapy ] (]]]]) ]]]–]]]
symptoms or interspersing activity with periods of rest
(CFS/ME Working Group, 2001; Shephard, 2001).
Contrary to the cognitive behavioural approach, pacing
takes into account the considerable fluctuations in
symptom severity (Shephard, 2001) and the delayed
recovery from exercise (Paul et al., 1999) that typically
occurs in patients with CFS. The pacing approach is
consistent with the recent observations regarding the
interactions between malfunctioning of the immune
system, physical activity, and musculoskeletal pain in
CFS patients. The first goal of the pacing approach is to
enable the CFS patient to manage his/her daily activities
in a way he/she no longer experiences fluctuations in
symptoms (stabilization phase). Next, the physiothera-
pist can start to grade activity and exercise levels
(grading phase). During the grading phase, the same
pacing techniques are applied to grade both activity
level and exercise level (i.e. flexible, accounting for the
fluctuating nature of the disorder). To prevent over-
active patients in exceeding their own limits, heart rate
monitoring can be applied for intensity control (heart
rate guidelines are obtained from the exercise stress test
with continuous cardiorespiratory monitoring). This
type of graded exercise has been found to be superior
over relaxation and flexibility training in CFS patients
(Wallmann et al., 2004).
Finally, pain neurophysiology education might be
indicated for CFS patients with musculoskeletal pain.
As outlined above, pain processing is likely to be
abnormal in CFS patients, and evidence showing that
pain catastrophizing accounts for a substantial portion
of musculoskeletal pain in CFS has been provided. Pain
neurophysiology education was found to be effective in
reducing pain catastrophizing in chronic low back pain
patients (Moseley, 2002; Moseley et al., 2004).
Recent studies have provided new insights into our
understanding of chronic widespread musculoskeletal
pain in CFS patients. Generalized joint hypermobility
and BJHS appear to be highly prevalent among CFS
sufferers, but they do not seem to be of any clinical
importance. On the other hand, pain catastrophizing
accounts for a substantial portion of musculoskeletal
pain and exercise performance in CFS patients. The
evidence concerning pain catastrophizing is supportive
of the indirect evidence of a dysfunctional pain
processing system in CFS patients with musculoskeletal
pain. CFS sufferers respond to incremental exercise with
a lengthened and accentuated oxidative stress response,
explaining muscle pain, postexertional malaise, and the
decrease in pain threshold following graded exercise in
CFS patients. Applying the scientific evidence on
musculoskeletal pain to the practise of manual phy-
siotherapy, pacing self-management techniques, and
pain neurophysiology education are indicated for the
treatment of musculoskeletal pain in CFS patients.
Studies examining the effectiveness of these strategies
for CFS patients are warranted.
Banic B, Petersen-Felix S, Andersen OK, et al. Evidence for spinal
cord hypersensitivity in chronic pain after whiplash injury and in
fibromyalgia. Pain 2004;107:7–15.
Bazan NG. COX-2 as a multifunctional neuronal modulator. Nature
Beighton PH, Solomon L, Soskolne CL. Articular mobility in an
African population. Annals of the Rheumatic Diseases 1973;32:
Bombardier CH, Buchwald D. Chronic fatigue, chronic fatigue
syndrome, and fibromyalgia. Disability and health-care use.
Medical Care 1996;34:924–30.
CFS/ME Working Group. Report to the Chief Medical Officer of an
independent working group, Department of Health, London, 2001.
Deale A, Chalder T, Marks I, Wessely S. Cognitive behavior therapy
for chronic fatigue syndrome: a randomized controlled trial.
American Journal of Psychiatry 1997;154:408–14.
Edmonds M, McGuire H, Price J. Exercise therapy for chronic fatigue
Evengard B, Nilsson CG, Lindh G, Lindquist, Eneroth P, Fredrikson
S, et al. Chronic fatigue syndrome differs from fibromyalgia. No
evidence for elevated substance P levels in cerebrospinal fluid of
patients with chronic fatigue syndrome. Pain 1998;78:153–5.
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 psycho-
pathology. Journal of Psychosomatic Research 1997;42:369–78.
Fukuda K, Straus S, Hickie I, et al. The chronic fatigue syndrome: a
comprehensive approach to its definition and study. Annals of
Internal Medicine 1994;121:953–9.
Fulcher KY, White PD. Randomised controlled trial of graded
exercise in patients with the chronic fatigue syndrome. British
Medical Journal 1997;314:1647–52.
Grahame R, Bird HA, Child A. The revised (Brighton 1998) criteria
for the diagnosis of benign joint hypermobility syndrome (BJHS).
Journal of Rheumatology 2000;27:1777–9.
Holmes G, Kaplan J, Gantz J, et al. Chronic fatigue syndrome: a
Jammes Y, Steinberg JG, Mambrini O, Bre ´ geon F, Delliaux S.
Chronic fatigue syndrome: assessment of increased oxidative stress
and altered muscle excitability in response to incremental exercise.
Journal of Internal Medicine 2005;257:299–310.
Johnson SK, DeLuca J, Natelson BH. Assessing somatization disorder
inthe chronicfatigue syndrome.
Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ.
Oxidative stress levels are raised in chronic fatigue syndrome and
are associated with clinical symptoms. Free Radical Biology and
Kurup RK, Kurup PA. Hypothalamic digoxin, cerebral chemical
dominance and myalgic encephalomyelitis. International Journal
of Neuroscience 2003;113:683–701.
Levine PH, Whiteside TL, Friberg D, et al. Dysfunction of natural
killer cell activity in a family with chronic fatigue syndrome.
Clinical Immunology and Immunopathology 1998;88(1):99–104.
of Internal Medicine
ARTICLE IN PRESS
J. Nijs et al. / Manual Therapy ] (]]]]) ]]]–]]]
Maier SF, Watkins LR. Cytokines for psychologists: implications of
bidirectional immune-to-brain communication for understanding
behavior, mood, and cognition. Psychological Review 1998;105:
Meyer RA, Campbell JN, Raja SN. Peripheral neural mechanisms of
nociception. In: Wall PD, Melzack R, editors. Textbook of Pain.
third ed. Edinburgh: Churchill Livingstone; 1995. p. 13–44.
Moseley L. Combined phsyiotherapy and education is efficacious for
chronic low back pain. Australian Journal of Physiotherapy
Moseley GL, Nicholas MK, Hodges PW. A randomized controlled
trial of intensive neurophysiology education in chronic low back
pain. Clinical Journal of Pain 2004;20:324–30.
Nijs J. Generalized joint hypermobility: an issue in fibromyalgia and
chronic fatigue syndrome? (review). Journal of Bodywork and
Movement Therapies 2005;9:310–7.
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
Immunology and Medical Microbiology 2002;34:209–14.
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). Physical
Nijs J, De Becker P, De Meirleir K, Demanet C, Vincken W,
Schuermans D, et al. Associations between immune cell parameters
and bronchial hyperresponsiveness in patients with chronic fatigue
syndrome. Chest 2003b;123:998–1007.
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).
Physiotherapy Theory and Practice 2004a;20:31–40.
Nijs J, De Meirleir K, Truyen S. Hypermobility in patients with
chronic fatigue syndrome: preliminary observations. Journal of
Musculoskeletal Pain 2004b;12:9–17.
Nijs J, De Meirleir K, Duquet W. Kinesiophobia in chronic fatigue
syndrome: assessment and associations with disability. Archives of
Physical Medicine and Rehabilitation 2004c;85:1586–92.
Nijs J, Vanherberghen K, Duquet W, De Meirleir K. Chronic fatigue
syndrome: lack of association between pain-related fear of move-
ment and exercise capacity and disability. Physical Therapy
Nijs J, Meeus M, McGregor NR, Meeusen R, De Schutter G, Van
Hoof E, et al. Chronic fatigue syndrome: exercise performance
related to immune dysfunction. Medicine and Science in Sports and
Nijs J, Aerts A, De Meirleir K. Generalized joint hypermobility is
more common in chronic fatigue syndrome than in healthy
controls. Journal of Manipulative and Physiological Therapeutics
Nijs, J., Van de Putte, K., Louckx, F., Truyen, S., De Meirleir, K.
under review. Exercise performance and chronic pain in chronic
fatigue syndrome: the role of pain catastrophizing.
Nishikai M, Tomomatsu S, Hankins RW, Takagi S, Miyachi K, Kosaka
S, et al. Autoantibodies to a 68/48kDa protein in chronic fatigue
syndrome and primary fibromyalgia: a possible marker for hyper-
somnia and cognitive disorders. Rheumatology 2001;40:806–10.
Paul L, Wood L, Behan WMH, Maclaren WM. Demonstration of
delayed recovery from fatiguing exercise in chronic fatigue
syndrome. European Journal of Neurology 1999;6:63–9.
Price JR, Couper J. Cognitive behaviour therapy for chronic fatigue
syndrome in adults. Cochrane Database Systematic Reviews
Price DD, Staud R, Robinson ME, et al. Enhanced temporal
summation of second pain and its central modulation in
fibromyalgia patients. Pain 2002;99:49–59.
Prins JB, Bleijenberg, Bazelmans E, Elving LD, de Boo TM, Severens
JL, et al. Cognitive behaviour therapy for chronic fatigue
syndrome: a multicenter randomised controlled trial. Lancet
Powell P, Bentall RP, Nye FJ, Edwards RHT. Randomised controlled
trial of patient education to encourage graded exercise in chronic
fatigue syndrome. British Medical Journal 2001 322-1-5.
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 Report
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
Shephard C. Pacing and exercise in chronic fatigue syndrome.
Staud R, Vierck CJ, Cannon RL, et al. Abnormal sensitization and
temporal summation of second pain (wind-up) in patients with
fibromyalgia syndrome. Pain 2001;91:165–75.
Staud R, Robinson ME, Vierck Jr. CJ, Price DD. Diffuse noxious
inhibitory controls (DNIC) attenuate temporal summation of
second pain in normal males but not in normal females or
fibromyalgia patients. Pain 2003;101:167–74.
Suhadolnik RJ, Peterson DL, O’Brien K, et al. Biochemical evidence
for a novel low molecular weight 2–5A-dependent RNase L in
chronic fatigue syndrome. Journal of Interferon and Cytokine
Tan EM, Sugura K, Gupta S. The case definition of chronic fatigue
syndrome. Journal of Clinical Immunology 2002;22:8–12.
Vecchiet J, Cipollone F, Falasca K, Mezzetti A, Pizzigallo E,
Bucciarelli T, et al. Relationship between musculoskeletal symp-
toms and blood markers of oxidative stress in patients with chronic
fatigue syndrome. Neuroscience Letters 2003;335:151–4.
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.
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-
ogy and Medical Microbiology 1998;22:355–65.
Wallmann KE, Morton AR, Goodman C, Grove R, Guilfoyle AM.
Randomised controlled trial of graded exercise in chronic fatigue
syndrome. Medical Journal of Australia 2004;180:444–8.
Watkins LR, Maier SF. Implications of immune-to-brain commu-
nication for sickness and pain. Proceedings of the National
Academy of Science USA 1999;96:7710–3.
Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain threshold
in chronic fatigue syndrome. Pain 2004;109:497–9.
Yamamoto S, Ouchi Y, Onoe H, Yoshikawa E, Tsukawa E, Takahashi
T, et al. Reduction of serotonin transporters of patients with
chronic fatigue syndrome. NeuroReport 2004;15:2571–4.
Zusman M. Forebrain-mediated sensitization of central pain path-
ways: ‘non-specific’ pain and a new image for MT. Manual
ARTICLE IN PRESS
J. Nijs et al. / Manual Therapy ] (]]]]) ]]]–]]]