Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice

Abstract

Central sensitization plays an important role in the pathophysiology of numerous musculoskeletal pain disorders, yet it remains unclear how manual therapists can recognize this condition. Therefore, mechanism based clinical guidelines for the recognition of central sensitization in patients with musculoskeletal pain are provided. By using our current understanding of central sensitization during the clinical assessment of patients with musculoskeletal pain, manual therapists can apply the science of nociceptive and pain processing neurophysiology to the practice of manual therapy. The diagnosis/assessment of central sensitization in individual patients with musculoskeletal pain is not straightforward, however manual therapists can use information obtained from the medical diagnosis, combined with the medical history of the patient, as well as the clinical examination and the analysis of the treatment response in order to recognize central sensitization. The clinical examination used to recognize central sensitization entails the distinction between primary and secondary hyperalgesia.

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Masterclass
Recognition of central sensitization in patients with musculoskeletal pain:
Application of pain neurophysiology in manual therapy practice
Jo Nijs
a
,
b
,
c
,
*
, Boudewijn Van Houdenhove
d
, Rob A.B. Oostendorp
e
a
Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Belgium
b
Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Belgium
c
Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Belgium
d
Faculty of Medicine, Katholieke Universiteit Leuven, Belgium
e
Research Centre of Allied Health Sciences, Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre, The Netherlands
article info
Article history:
Received 8 June 2009
Accepted 18 October 2009
Keywords:
Pain
Musculoskeletal disorders
Central sensitization
Clinical reasoning
Manual therapy
abstract
Central sensitization plays an important role in the pathophysiology of numerous musculoskeletal pain
disorders, yet it remains unclear how manual therapists can recognize this condition. Therefore, mecha-
nism based clinical guidelines for the recognition of central sensitization in patients with musculoskeletal
pain are provided. By using our current understanding of central sensitization during the clinical assess-
ment of patients with musculoskeletal pain, manual therapists can apply the science of nociceptive and
pain processing neurophysiology to the practice of manual therapy. The diagnosis/assessment of central
sensitization in individual patients with musculoskeletal pain is not straightforward, however manual
therapists can use information obtained from the medical diagnosis, combined with the medical history of
the patient, as well as the clinical examination and the analysis of the treatment response in order to
recognize central sensitization. The clinical examination used to recognize central sensitization entails the
distinction between primary and secondary hyperalgesia.
Ó2009 Elsevier Ltd. All rights reserved.
1. Introduction
Even with acute pain the nervous system undergoes some
changes. When tissue is damaged and pain persists for a few days
with adaptation of unimodal nociceptors, the responsiveness of
polymodal nociceptive endings is enhanced by substances released
from various sources (i.e. serotonin released by platelets) (Purves
et al., 1997). This process is called primary hyperalgesia or peripheral
sensitization of nociceptors, and represents a protective action by the
human body in order to prevent further use of damaged structures
and consequent further damage of the traumatized and surrounding
tissues. Secondary hyperalgesia refers to increased responsiveness of
dorsal horn neurons localized in the spinal segments of the primary
source of nociception. While peripheral sensitization is a local
phenomenon, central sensitization is a central process of the nervous
system.
Central sensitization is defined as an augmentation of respon-
siveness of central neurons to input from unimodal and polymodal
receptors (Meyer et al., 1995). Central sensitization encompasses
altered sensory processing in the brain (Staud et al., 2007),
malfunctioning of descending anti-nociceptive mechanisms
(Meeus et al., 2008), increased activity of pain facilitatory path-
ways, temporal summation of second pain or wind-up (Meeus and
Nijs, 2007; Staud et al., 2007), and long-term potentiation of
neuronal synapses in the anterior cingulate cortex (Zhuo, 2007).
Besides top-down mechanisms included in the pathophysiology of
central sensitization, it is important to realize that there are
bottom-up mechanisms as well (Fig. 1). For example, peripheral
injury and other forms of stressors trigger the release of pro-
inflammatory cytokines, with the consequent activation of spinal
cord glia with cyclooxygenase-2 and prostaglandin E2 expression in
the central nervous system (Maier and Watkins, 1998; Watkins and
Maier, 1999; Bazan, 2001; Samad et al., 2001). The outcome of the
processes involved in central sensitization is an increased respon-
siveness to a variety of peripheral stimuli including mechanical
pressure, chemical substances, light, sound, cold, heat, and elec-
trical stimuli. The increased sensitivity to variable stimuli results in
a large decreased load tolerance of the senses and the
*Corresponding author at: University College Antwerp, Van Aertselaerstraat 31,
B-2170 Merksem, Belgium. Tel.: þ32 3 6418265; fax: þ32 3 641827.
E-mail address: jo.nijs@vub.ac.be (J. Nijs).
Contents lists available at ScienceDirect
Manual Therapy
journal homepage: www.elsevier.com/math
1356-689X/$ – see front matter Ó2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.math.2009.12.001
Manual Therapy 15 (2010) 135–141

Author's personal copy
neuromusculoskeletal system. Further details addressing the
pathophysiology of central sensitization is beyond the scope of the
present manuscript; interested readers are referred to Fig. 1 and
comprehensive reviews on the subject (Vierck, 2006; Nielsen and
Henriksson, 2007; Yunus, 2007a).
Central sensitization is frequently present in various chronic
musculoskeletal pain disorders, including chronic whiplash asso-
ciated disorders (Curatolo et al., 2001), temporomandibular disor-
ders (Maixner et al., 1998), chronic low back pain (Giesecke et al.,
2004), rheumatoid arthritis (Yunus, 2007b), fibromyalgia (Vierck,
2006), as well as others. The presence of central sensitization in
patients with musculoskeletal pain implies an increased complexity
of the clinical picture (i.e. an increase in unrelated symptoms and
hence a more difficult clinical reasoning process) (Nijs et al., 2009),
as well as decreased odds for a favorable rehabilitationoutcome (Jull
et al., 2007). Guidelines for the prevention and treatment of central
sensitization in patients with musculoskeletal pain have been pre-
sented elsewhere (Nijs and Van Houdenhove, 2009; Nijs et al.,
2009). These guidelines enable clinicians to consider conservative
treatments, including manual therapy skills, for the process of
central sensitization in patients with chronic whiplash associated
disorders (Nijs et al., 2009) and fibromyalgia (Nijs and Van Hou-
denhove, 2009). However, it remains unclear how manual thera-
pists can recognize the process of central sensitization in individual
patients. For some therapists, central sensitization remains a theo-
retical concept that is unlikely to occur in the patients they are
treating. Therefore, increasing awareness for the possibility of
central sensitization occurring in patients with musculoskeletal
pain is useful in daily clinical practice.
The present manuscript provides clinical guidelines for the
recognition and assessment of central sensitization in patients with
musculoskeletal pain. Currently, an international consensus defini-
tion or clinical criteria for central sensitization is essentially lacking.
A body of scientific literature reporting original data of signs and
symptoms in relation to established measures of central sensitiza-
tion in patients with musculoskeletal pain is currently available (e.g.
Curatolo et al., 2001; Desmeules et al., 2003; Banic et al., 2004;
Meeus et al., 2008), and is used here to provide clinical guidelines for
the recognition and assessment of central sensitization. Application
of our current understanding of central sensitization in the clinical
assessment of patients with musculoskeletal painwill allow manual
therapists to apply the science of pain neurophysiology to the
practice of manual therapy.
2. Using the medical diagnosis to recognize central
sensitization
Central sensitivity syndromes is a term first used by Yunus in
2000 to describe a group of overlapping conditions bound by
a common pathophysiological mechanism of central sensitization
(Yunus, 2007a). Many patients present in clinical practice with
a medical diagnosis that was established by a physician. In
a number of cases, the medical diagnosis can provide the clinician
with important information in relation to central sensitization. Of
relevance, a body of literature is available linking medical diagnosis
to central sensitization. Here, the scientific literature can be applied
to manual therapy practices. In some cases, such as fibromyalgia
(Nielsen and Henriksson, 2007; Meeus and Nijs, 2007; Yunus,
2007a) and chronic fatigue syndrome (Meeus and Nijs, 2007;
Meeus et al., 2008), the medical diagnosis most often implies the
presence of central sensitization. If the clinical picture as well as the
symptom presentation (see below) matches the presence of central
sensitization in patients with these types of diagnoses, then manual
therapists can conclude that central sensitization is present. Hence,
therapists should account for the processes involved in central
sensitization when applying therapy.
However, in many cases it is not an all-or-nothing situation.
Many medical diagnoses (e.g. non-specific low back pain, whiplash
associated disorders) are associated but not uniformly character-
ized by central sensitization (Table 1). In these cases, the clinician
should be aware of the possibility that central sensitization is
present. However, the possibility exists that central sensitization
does not play a role in the patient’s complex clinical picture.
In order to illustrate the reasoning presented above, let us take
a closer look at some medical diagnoses frequently seen in manual
therapy practice. While there is consistent evidence for altered
central processing of nociception and central sensitization in
people with chronic whiplash associated disorders (Curatolo et al.,
Musculoskeletal
system
periphery spinal cord brainstem diencephalon cortex
I
VIII
VII
VI
V
IV
III
II
IX
Dorsal
column
nuclei
VB
SI
SII
PAG
Hypothalamus Thalamic
relay
Intralaminar
thalamus
Whole
cortex,
especially
prefrontral
cortex
RF
Aβ
Aδ
Aδ
Fig. 1. Simplified block diagram displaying nociceptive processing in the nervous system. Input from the musculoskeletal system is transferred through A
d
and C nociceptive fibres
and low threshold A
b
fibres. Dashed lines represent inhibiting (mainly descending) pathways, the ultimate effect of which is inhibitory in lamina II of the spinal cord. Numbers I–IX
represent the corresponding laminae of the spinal cord. RF, reticular formation; PAG, periaqueductal grey matter; VB, ventrobasal nuclear complex of the thalamus; SI, primary
somatosensory cortex; SII, secondary somatosensory cortex. Modified from: Wells et al. (1996, Fig. 8.3).
J. Nijs et al. / Manual Therapy 15 (2010) 135–141136

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2001; Sterling et al., 2003, 2006; Herren-Gerber et al., 2004),
central sensitization is not present in all whiplash cases and is not
a feature of chronic idiopathic neck pain (Scott et al., 2005). Typi-
cally, only a minority of acute whiplash patients develop chronic
symptoms. Abnormal nociceptive processing appears very soon
(<7 days) after the initial whiplash trauma, and once present it has
important predictive ability for the development of chronic whip-
lash associated disorders (Sterling et al., 2003, 2006; Kasch et al.,
2005). Thus, not all (sub)acute patients are characterized by central
sensitization, however manual therapists should be aware of this
possibility.
Another example is chronic non-specific low back pain. Some
studies provided evidence in support of the presence of central
sensitization in patients with non-specific chronic low back pain
(Giesecke et al., 2004; Schmidt-Wilcke et al., 2006), while others
refute such an association (Hoffman et al., 2005; Julien et al., 2005).
It is concluded that central sensitization is present in some cases of
chronic non-specific low back pain, possibly representing one of
the subgroups of this frequent musculoskeletal disorder (Wand and
O’Connell, 2008).
The myofascial variety within the heterogeneous group of
temporomandibular disorders is also characterized by central
sensitization (Yunus, 2007a). Likewise, regional chronic pain
conditions that present with tender and/or trigger points in the
absence of structural pathology (frequently referred toas myofascial
pain syndrome) should alert the manual therapist to the possibility
that central sensitization is determining the clinical picture (Yunus,
2007a). However, to our knowledge available evidence in support of
central sensitization in patients with myofascial pain syndrome is
limited to chronic whiplash associated disorders, temporoman-
dibular disorders and chronic non-specific low back pain.
Furthermore, various subgroups of headache, chronic tension-
type headache (Langemark et al., 1993; Pielsticker et al., 2005) and
migraine (Burnstein et al., 2000; Weissman-Fogel et al., 2003) can
be viewed as central sensitivity syndromes. Finally, rheumatoid
arthritis and osteoarthritis are examples of local musculoskeletal
disorders possibly causing continuous activation of polymodal
nociceptors that initiate or sustain central sensitization (Yunus,
2007a). Although an important subgroup (20–35%) of patients with
rheumatoid arthritis fulfil the diagnostic criteria for fibromyalgia
(Wolfe and Michaud, 2004), research evidence in support of central
sensitization is currently lacking. One study found evidence in
support of enhanced central mechanisms in rheumatoid arthritis
that in turn contributed to clinical features, including tenderness of
peripheral joints (Morris et al., 1997). However, their data points to
secondary hyperalgesia rather than central sensitization.
3. History taking in order to recognize central sensitization
Simply listening to the story of the patient (Van Houdenhove,
2004) will provide a number of clues that potentially point towards
the presence of sensitization of the central nervous system. Central
sensitization entails much more than generalized hypersensitivity
to pain: it is characterized by an increased responsiveness to
a variety of stimuli including mechanical pressure (Desmeules
et al., 2004), chemical substances (Morris et al., 1997), cold
temperature (Kasch et al., 2005), heat temperature (Meeus et al.,
2008), electrical stimuli (Banic et al., 2004; Desmeules et al., 2004),
stress, emotions, and mental load. The clinical picture is suggestive
of a general intolerance to all kinds of physical and emotional
stressors and hence a large decreased load tolerance of the human
body in general. It is therefore recommended to question the
patients with suspected central sensitization regarding their
hypersensitivity to bright light, sound, smell, hot or cold sensations,
pressure, touch and mechanical loading (Table 2). Some patients
spontaneously mention that a hug by their partner can be painful.
Others wear sunglasses inside buildings even during the winter
time, while others turn down the radio volume even when it is
already low. These examples make it easy to recognize hypersen-
sitivity to pressure, light and sound respectively. Hyper-respon-
siveness to mechanical stimuli entails exaggerated responses to
touch and active and passive movement. The latter two can be
further assessed during the physical examination.
In addition, less obvious symptoms may also be related to
central sensitization. Although there is currently no convincing
evidence in support of their association with central sensitization,
‘central’ symptoms such as fatigue, concentration difficulties, sleep
disturbances, and non-refreshing sleep are all frequently experi-
enced by patients with central sensitization (Wolfe et al., 1990,
Yunus, 2007b). Thus, questioning the patient with musculoskeletal
pain about the presence of these symptoms might be warranted
when searching for central sensitization.
When using Table 2 for the recognition of central sensitizationin
clinical practice, one must be careful when interpreting symptoms
such as increased sensitivity to mechanical pressure, heat, or cold.
Table 1
Medical diagnosis associated with an increased likelihood for central sensitization.
a
Medical diagnosis Central sensitization
is a characteristic of
the disorder
Central sensitization
is present in a subgroup
Chronic low back pain U
Chronic whiplash
associated disorders
U
(Sub)acute whiplash
associated disorders
U
Temporomandibular
disorders
U
Myofascial pain
syndrome
U
Osteoarthritis U
Rheumatoid arthritis U
Fibromyalgia U
Chronic fatigue
syndrome
U
Chronic headache U
Irritable bowel
syndrome
U
a
Based on evidence from scientific studies (Langemark et al., 1993; Morris et al.,
1997; Maixner et al., 1998; Burnstein et al., 2000; Curatolo et al., 2001; Weissman-
Fogel et al., 2003; Giesecke et al., 2004; Wolfe and Michaud, 2004; Pielsticker et al.,
2005; Schmidt-Wilcke et al., 2006; Vierck, 2006; Yunus, 2007b; Meeus et al., 2008).
Table 2
Symptoms related to the presence of central sensitization.
Symptom Characteristic of CS Might be
related to CS
Hypersensitivity to bright light U
Hypersensitivity to touch U
Hypersensitivity to noise U
Hypersensitivity to pesticides U
Hypersensitivity to
mechanical pressure
U
Hypersensitivity to medication U
Hypersensitivity to temperature
(high and low)
U
Fatigue U
Sleep disturbances U
Unrefreshing sleep U
Concentration difficulties U
Swollen feeling (e.g. in limbs) U
Tingling U
Numbness U
CS, central sensitization.
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‘Hypersensitivity’ generally means widespread rather than local or
peripheral hypersensitivity to certain stimuli. In addition, it is
important to realize that none of the symptoms listed above have
strong diagnostic value for central sensitization. Rather, they each
represent clues potentially pointing towards central sensitization.
When two or three of these symptoms are present, searching for
additional proof for central sensitization during the clinical exam-
ination is warranted. Even in the absence of a medical diagnosis
known to be related to central sensitization, the presence of
symptoms characteristic of central sensitization should alert the
manual therapist. A flow diagram representing the diagnostic
clinical reasoning process in case of suspected central sensitization
is presented in Fig. 2.
In addition to the symptoms related to central sensitization
explained above, other types of information reported by the patient
can be of value in recognizing central sensitization. Firstly, the
presence of a local pain condition prior to the onset of a trauma or
injury increases the probability for developing peripheral and
central sensitization. This is evidenced by research data in people
with whiplash associated disorders (Carstensen et al., 2008). The
premorbid pain condition can be localized at the same location or
at a site distinct from the current condition. Secondly, at least in the
bottom-to-top model (Nielsen and Henriksson, 2007), an ongoing
source of peripheral nociception is required before the process of
peripheral sensitization can establish central sensitization (Nijs and
Van Houdenhove, 2009). Tissue injury healing and focal pain
recovery should occur as soon as possible to prevent development
of central sensitization (Vierck, 2006). Examples that fit within this
model are those patients with long-standing musculoskeletal pain
due to rheumatoid arthritis, a severe whiplash injury and patients
reporting several unsuccessful treatment attempts. All these cases
can be categorized under the heading ‘abnormal disease course’,
despite the fact that the primary source of nociception remains the
same (or decreases or even disappears), the symptom area and
symptom severity increases. Thus, questioning the patient about
the disease course, recovery course and premorbid medical
conditions might provide the clinician with important information
in relation to central sensitization.
4. Clinical examination to recognize central sensitization
When central sensitization is suspected based on the medical
diagnosis and the information gathered during the history taking of
the patient, the manual therapist may wish to examine the
patient’s response to certain stimuli (Fig. 2). The goals for using
clinical tests assessing sensory processing can be diverse. Firstly,
they may be used to establish the presence of central sensitization
(diagnostic purpose). Secondly, they can be used to assess the
severity of central sensitization. Thirdly, they can monitor pre-
versus post-treatment progression of central sensitization. Finally,
they can be used to determine the appropriate treatment param-
eters (e.g. intensity, amplitude and frequency of various manual
therapy techniques).
One of the main characteristics of central sensitization in
patients with musculoskeletal pain is a generalized rather than
a localized decrease in their pressure pain threshold. Here,
‘generalized’ implies more than a segmental spreading of the
symptom area, in that it means that the increased sensitivity is
localized at sites segmentally unrelated to the primary source of
nociception (e.g. the lower limbs in case of a whiplash trauma).
Lower pressure pain thresholds at symptomatic areas most often
represent primary hyperalgesia due to sensitized polymodal noci-
ceptors within injured musculoskeletal structures. By measuring
pressure pain thresholds outside the area of primary nociception,
widespread hyperalgesia or secondary hyperalgesia can be detec-
ted. In cases of secondary hyperalgesia, a reduced pressure pain
threshold in the various tissues innervated by the same segment (or
two neighboring segments) can be detected. Findings of numerous
areas of hyperalgesia at sites outside and remote from the symp-
tomatic site, together with a non-segmental general decrease in
Musculoskeletal pain
Is the medical diagnosis related to CS*? (see table 1)
Yes, CS is
characteristic of the
disorder
CS
Yes, CS is present
in a subgroup of the
disorder
No
Listen to the story of the patient
No clues for
CS (table 2)
No CS
Some clues for
CS (table 2)
No CS
Further questioning about CS (table 2)
Very few and
inconsistent signs
At least a few
consistent signs
Clinical examination
(table 3)
No CS
* CS=central sensitization
Fig. 2. Diagnostic clinical reasoning process to recognize central sensitization. CS, central sensitization.
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pressure pain threshold, may imply a generalized hyperexcitability
of central nociceptive pathways (Sterling et al., 2004).
Based on this reasoning, research has shown evidence in
support of generalized hypersensitivity to mechanical pressure in
patients with chronic whiplash associated disorders (Koelbaek
Johansen et al., 1999; Sterling et al., 2004), as well as in a subgroup
of the chronic low back pain population (Giesbrecht and Battie,
2005). To apply this to clinical practice, pressure pain threshold can
be assessed using commercially available pressure algometers. A
pressure pain threshold below 4 kg/cm
2
can be used to identify
points of increased sensitivity to pressure (Wolfe et al., 1990).
Pressure algometry provides a reliable and valid measure of the
pressure pain threshold (Vanderweeen et al., 1996; Farasyn and
Meeusen, 2003). In the absence of a pressure algometer, manual
palpation can be used. Even when a manual therapist is not sus-
pecting central sensitization, the finding of generalized hypersen-
sitivity to manual palpation during routine clinical examination
should alert the clinician.
Hypersensitivity to other stimuli can be demonstrated clini-
cally by using a cold or hot item and placing it for a couple of
seconds on the skin (e.g. a cold pack). Depending on the temper-
ature, the cold or hot item should be perceived as cold or hot
respectively, but should not elicit pain. If it does trigger pain, then
localized hypersensitivity to cold or heat is established. Again,
findings of numerous areas of cold or heat hyperalgesia located at
sites outside and remote from the symptomatic site are crucial for
differentiating primary or secondary hyperalgesia from general-
ized hyperalgesia. Likewise, augmented responses to sensory
testing or mechanical stimuli like vibration at sites remote from
the primary source of nociception (e.g. the medial malleolus in
a patient with chronic shoulder pain) can generate important
information addressing central sensitization. Quantitative sensory
testing is suitable for assessing the presence and severity of
central sensitization, however the equipment is expensive and
therefore limited to specialized (chronic) pain clinics. Moreover, it
is the goal of the present mechanism based clinical guidelines to
alert manual therapists to recognize central sensitization in
individual cases with musculoskeletal pain without the use of
such equipment.
Heightened bilateral responses to the brachial plexus provoca-
tion tests have been proposed as a sign of central sensitization in
patients with chronic whiplash associated disorders (Sterling and
Kenardy, 2008). Like every other tissue in the human body,
peripheral nerves and nervous tissues (including connective tissue)
themselves can become hypersensitive to mechanical stimuli such
as tension and pressure. Pain provocation during neurodynamic
testing is a stable phenomenon and the range of elbow extension
corresponding with the moment of ‘pain onset’ and ‘submaximal
pain’ can be measured reliably (Coppieters et al., 2002). A bilateral
loss of elbow extension that is 30

, which is also associated with
moderate reports of pain when testing is taken to the pain
threshold might indicate central hyperexcitability in patients post-
whiplash (Sterling and Kenardy, 2008). Again, this should be
interpreted together with the other signs and symptoms of central
sensitization. It should not be viewed as a unique sign indicating
central sensitization. Likewise, increased sensitivity of muscle and
joint tissue to pressure and tension can be assessed using muscle
and joint end feel testing.
Besides the passive tests listed above (Table 3), altered sensory
processing can be demonstrated during exercise. Pain thresholds
increase during physical activity in healthy individuals and can stay
augmented for up to 30 min post-exercise. This is the result of
endogenous opioid release (Koltyn and Arbogast, 1998)andrelated
activation of several (supra)spinal anti-nociceptive mechanisms
such as the adrenergic and serotonergic pathways (Millan, 2002). In
certain chronic pain populations, these anti-nociceptive mechanisms
appear unable to respond to a variety of stressors, including the
exercise trigger (Whiteside et al., 2004; Staud et al., 2005). In
subjects with chronic low back pain, pain thresholds increase nor-
mally in response to exercise (Hoffman et al., 2005), indicating the
inability to generalize the finding of deregulated anti-nociceptive
mechanisms during exercise to all chronic pain populations.
Increased pain perception in response to exercise could be indicative
of a deregulated anti-nociceptive mechanism. Stress (particularly
when chronic) may well trigger lower pain thresholds. This was
demonstrated by Suarez-Roca et al. (2008) who reported reduced
GABA neurotransmission and consequent hyperalgesia in rats after
repeated forced swimming stress.
The assessment of the pressure pain threshold in response to
exercise represents an easilyapplied test. The patient is required to
cycle on a stationary bike at a constant speed (Whiteside et al.,
2004). The resistance is gradually increased (20–50 kW/min) from
a very low starting point (10–50 kW). Pressure pain thresholds are
measured every 1 or 2 min during the exercise test at an anatom-
ically standardized location at a site distinct from the primary
source of nociception (e.g. the skin web between thumb and index
finger in patients with chronic low back pain). The test is termi-
nated as soon as the pattern of pain threshold change (decrease,
increase or no change) becomes apparent and prior to the onset of
lower leg muscle soreness or the point where post-exertional
malaise may be triggered. In the case of the normal functioning of
central anti-nociceptive mechanisms, a gradual increase in the pain
threshold during and following exercise is observed (Koltyn and
Arbogast, 1998; Whiteside et al., 2004). A constant or decreased
pain threshold during and following exercise suggests malfunc-
tioning of these anti-nociceptive mechanisms (Whiteside et al.,
2004) and hence central sensitization. An abnormal pain threshold
response to exercise should be regarded as one of the many
possible signs of central sensitization. If present, it means that the
patient can become increasingly susceptible to all kinds of noci-
ceptive stimuli during exercise (interventions), which to a further
extent may be indicative of general stress loading intolerance.
Caution is required when applying exercise or activity interven-
tions to such patients, especially when applying time contingent
exercise interventions as is usually the case with graded exercise
therapy programs (Nijs et al., 2009).
5. Analyzing the treatment response to recognize central
sensitization
In some cases of musculoskeletal pain, the process of central
sensitization is not present at the time of treatment initiation, but
Table 3
Overview of the clinical examination of patients with suspected central
sensitization.
a
Clinical tests
1. Assessment of pressure pain thresholds at sites remote from
the symptomatic site
2. Assessment of sensitivity to touch during manual palpation at sites
remote from the symptomatic site
3. Assessment of sensitivity to vibration at sites remote from
the symptomatic site
4. Assessment of sensitivity to heat at sites remote from the symptomatic site
5. Assessment of sensitivity to cold at sites remote from the symptomatic site
6. Assessment of pressure pain thresholds during and following exercise
7. Assessment of joint end feel
8. Brachial plexus provocation test
a
For all the tests used for the assessment of central sensitization, hypersensitivity
to a stimulus needs to be demonstrated at both symptomatic and distant sites
(Yunus, 2007a).
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becomes apparent during the rehabilitation process. This is most
often the case when physical and emotional stressors combine,
resulting in an overall load that is beyond the load tolerance of the
individual patient. One should be aware that manual therapy aims
at increasing the patient’s load tolerance, but on the other hand the
therapy itself can be a stressor as well. The signs and symptoms
listed above can provide manual therapists with important clues for
alterations in central sensory processing that can take place during
the transition from acute to chronic pain. In addition to the
appearance of new symptoms during the treatment course, existing
symptoms may aggravate and expand, even to sites outside and
remote from the symptomatic site. In case of the latter, manual
therapists are well trained to differentiate referred sensations from
new onset symptoms. Other factors that relate to the treatment
response (non-responders, post-exertional malaise, decreased pain
threshold during hands-on treatment) may point towards deficient
central processing of nociception, as discussed below.
Data are available suggesting that the presence of sensory
hypersensitivity influences outcome in physical rehabilitation for
patients with chronic whiplash associated disorders (Jull et al.,
2007). Those patients having both widespread cold and mechanical
hyperalgesia showed least improvement. Certainly not all cases of
unsuccessful treatment responses fall within the category of central
sensitization, but some do. Manual therapists are recommended to
consider the possibility of central sensitization in cases of poor
treatment progress. The report of a strong increase in symptom
severity post-treatment represents another sign possibly pointing
towards central sensitization. Manual therapists may trigger
symptom increases when applying too vigorous exercises or
aggressive hands-on therapy, such as high velocity joint manipu-
lation. Further aggressive forms of myofascial treatment such as
ischemic compression could further accelerate the process of
central sensitization (Nijs and Van Houdenhove, 2009; Nijs et al.,
2009). Even during treatment, the patient with central sensitiza-
tion may respond differently: if central sensitization is presentthen
pain thresholds may further decrease during the use of high-
intensity hands-on treatment. This is a clinical sign of the inability
of the descending anti-nociceptive pathways to suppress temporal
summation or wind-up in patients with central sensitization. As
explained above, the reporting of strong increases in symptoms in
response to low to moderate exercise therapy (i.e. in the context of
post-exertional malaise) may point towards impaired anti-noci-
ceptive mechanisms during exercise.
6. Conclusion
By using our current understanding of central sensitization
during the clinical assessment of patients with musculoskeletal
pain, manual therapists can apply the pure science of nociceptive
and pain neurophysiology to the practice of manual therapy. The
diagnosis of central sensitization in individual patients with
musculoskeletal pain is not straightforward, however manual
therapists can use information obtained from the medical diag-
nosis, history taking of the patient, clinical examination, and the
analysis of the treatment response to recognize central sensitiza-
tion (a summary guide is presented in Table 4). The outcome of the
diagnostic process can be used to determine the appropriate
treatment parameters (e.g. intensity and frequency of various
manual therapy techniques). The guidelines presented here require
large scale testing in clinical populations to generate clear-cut
diagnostic decision trees (in line with the one presented in Fig. 2).
Acknowledgements
The need for the present manuscript was inspired by the
workshops led by the first author at the annual seminar of the
Norwegian Manual Therapy Association (Oslo, February 2009). The
authors are grateful to Dr Karen Wallman (School of Sport Science,
Exercise and Health, The University of Western Australia, Crawley,
Western Australia) for language editing of the manuscript.
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