Source: Manual Therapy
        Preprint
Date:   June 13, 2006
URL:    http://www.sciencedirect.com/science/journal/1356689X


Chronic musculoskeletal pain in chronic fatigue syndrome: Recent developments
and therapeutic implications

Jo Nijs(a,b,*), Mira Meeus(a,b,1), Kenny De Meirleir(a)
a Department of Human Physiology, Faculty of Physical Education and
  Physiotherapy, Vrije Universiteit Brussel, Belgium
b Department of Health Sciences, Division of Musculoskeletal Physiotherapy,
  Higher Institute of Physiotherapy, Hogeschool Antwerpen, Belgium
* Corresponding author. Vrije Universiteit Brussel, MFYS/SPORT, KRO-gebouw 
  - 1, Laarbeeklaan 101, B-1090 Brussels, Belgium.
  Tel.: +32 2 4774604; fax: +32 2 4774607. E-mail address: jo.nijs@vub.ac.be
  (J. Nijs).
1 Mira 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.

Received 10 October 2005; received in revised form 8 March 2006; accepted
30 March 2006



Abstract

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.


1. Introduction

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 activity.

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=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 understanding of chronic musculoskeletal pain in CFS patients.

In the US, patients with CFS are often seen in chiropractic practise.
Studying the health-care use of 402 patients from a university-based chronic
fatigue clinic, it was found that 27% of CFS patients visited chiropractors,
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 effectiveness 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 physiotherapists to treat chronic musculoskeletal pain in CFS
patients.


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=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=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
CFS.


3. Musculoskeletal pain in CFS: a biopsychosocial explanation

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-signalling neurons to input from low-threshold mechanor-eceptors' (Meyer
et al., 1995). Direct evidence supporting the central sensitization
hypothesis in CFS patients is currently lacking. Still, the observed
decreased pain threshold following graded exercise in CFS patients is
indicative of a dysfunctional central antinociceptive mechanism in CFS
(Whiteside et al., 2004), and evidence of a deregulated serotonergic
neurotransmission 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 underway.

The central sensitization hypothesis fits our current understanding of CFS
psychopathology and pathophysiology. The link with CFS psychopathology has
been outlined in the preceding paragraph. From a pathophysiologic
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 physiological 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 glia (both microglia and astrocytes), which in turn enhance the
pain response by releasing nitric oxide (NO) and proinflammatory cytokines
(for a detailed description 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
neurotransmission of pain from the periphery to the central nervous system,
is typically elevated in patients with Fibromyalgia. Still, from the
available evidence it is concluded that chronic widespread musculoskeletal
pain in CFS 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 compression syndrome, low back
pain, and neck pain are often seen in CFS patients. In selected cases, the
local musculoskeletal problems may be more than epiphenomena: 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 patients, 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 differentiate 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 worsened 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 musculoskeletal
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 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
physiotherapist 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 overactive 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).


5. Conclusion


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 physiotherapy, 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.


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