Narrative Review

Pathophysiology of non-specific arm pain

Niamh A. Moloney1, Toby M. Hall2, Catherine M. Doody1
1
School of Public Health, Physiotherapy and Population Science, University College Dublin, Ireland, 2School of
Physiotherapy, Curtin Innovation Health Research Institute, University of Technology, Perth, WA, Australia

Background: Non-specific arm pain (NSAP) is a vague clinical entity which may constitute up to 53% of
work related upper limb disorders. The pathophysiology of NSAP is poorly understood with hypotheses
ranging from disturbance of muscle function and neuropathic arm pain to central sensitization.
Objectives: The purpose of this review was to investigate the current level of evidence to support three main
classifications of pain (peripheral neuropathic pain, nociceptive pain and central sensitization) in NSAP.
Major findings: There is evidence in the literature to support each of the three classifications of pain;
however, this evidence is weak. No one classification of pain is better supported than another. It is also
likely that overlap exists between pain classifications which present in NSAP.
Conclusion: Different pain classifications are likely to exist in NSAP and indeed may co-exist. In the
absence of definitive support for one classification over another, clinicians should be encouraged to
perform thorough pain assessments in individuals with NSAP in order to optimize clinical decision making.
Keywords: Non-specific arm pain, Work-related upper limb disorders, Pathophysiology, Pain classification, Peripheral neuropathic pain, Nociceptive pain,
Central sensitization

Background necessarily mutually exclusive.4 It should also be

Non-specific arm pain (NSAP) is defined as diffuse
pain in the forearm which may include neck, upper
arm and wrist pain.1,2 Associated features include
loss of function, weakness, cramp, muscle tenderness,
paraesthesia, allodynia, hyperalgesia, slowing of fine
movements and spontaneous pain.3 Given the ab-
sence of evidence to categorize the disorder as a
specific upper limb condition, many pathophysiolo-
gical mechanisms have been proposed from distur-
bance in muscle function4 to psychosocial features.5,6
Terminology relating to NSAP varies considerably,
so for the purpose of this paper the term NSAP will
be used throughout.1,2,7
Given the difficulties with defining NSAP and the
varied terminology used, identifying its prevalence is
a challenge. The incidence of work-related upper limb
disorders has been found to range between 2 and
53%,8 while other general population data show the
incidence of NSAP to be 25% with a further 18%
reporting non-specific dysaesthesia in the arm.9
Possible underlying pathophysiological mechanisms
relating to NSAP may include peripheral neuropathic
pain, nociceptive pain and central sensitization (includ-
ing psychosocial factors). It is likely that more than one
pathophysiological mechanism exists in disorders such
as NSAP and indeed proposed mechanisms are not
Correspondence to: School of Public Health, Physiotherapy and
Population Science, University College Dublin, Belfield, Dublin 4,
Ireland. Email: n_moloney@yahoo.com
acknowledged that a mechanisms-based classification
of pain is not always possible because of the difficulty
in identifying detailed pain mechanisms in single
cases. In other words, one pain mechanism may be
responsible for many different symptoms and the same
symptoms in two patients can be caused by different
mechanisms.10 With this caveat in mind, the purpose of
this review is to investigate the current level of evidence
to support three main classifications of pain (peripheral
neuropathic pain, nociceptive pain and central sensiti-
zation) in NSAP.
Peripheral Neuropathic Pain
The International Association for the Study of Pain
special interest group for neuropathic pain recently
proposed a redefinition for neuropathic pain as ‘pain
arising as a direct consequence of a lesion or disease
affecting the somatosensory system’.10 This is in
contrast with the previous definition of ‘pain initiated
or caused by a primary lesion or dysfunction in
the peripheral nervous system’.11 The omission of the
term dysfunction will likely challenge some of the
theories in relation to the presence of neuropathic
pain in conditions such as NSAP. Controversy exists
regarding the use of the term ‘neuropathic pain’ in
musculoskeletal conditions when evidence of a
definite nerve lesion is absent.12 In this section, the
literature will be discussed in terms of possible
indicators of neuropathic pain, and peripheral nerve
involvement in NSAP. For the purpose of this review,

ß W. S. Maney & Son Ltd 2011

DOI 10.1179/1743288X11Y.0000000028 Physical Therapy Reviews 2011 VOL . 16 NO . 5 321
Moloney et al. Pathophysiology of non-specific arm pain
these will be collectively referred to as ‘peripheral
neuropathic pain’.
In the absence of a gold standard for the diagnosis
of peripheral neuropathic pain, a number of algo-
rithms exist.10,13,14 Guidelines developed by Haanpää
et al.10 (see Table 1) encompass central and periph-
eral mechanisms while those outlined by Schafer
et al.13 relate to low back pain/low back related leg
pain. No similar classification models currently exist
for upper limb pain although criteria outlined by
Smart et al.14 encompass all musculoskeletal condi-
tions. None of these models have been validated in
populations with upper limb disorders. In light of the
criteria outlined by Haanpää et al.,10 consideration of
peripheral neuropathic pain as a possible underlying
mechanism in NSAP will be presented under the
following headings:
N presenting symptoms, distribution and history of
nerve injury;
N results from clinical testing;
N neurophysiological investigations.
Presenting symptoms, distribution and history of
nerve injury
Presenting symptoms
Cohen et al.15 observed more than 1000 patients with
NSAP and described their clinical features. Subjective
features reported were referred symptoms, shooting,
pulling and penetrating pain, pain of burning/electrical
quality, paraesthesia and dysaesthesia. Patients were
also found to present with difficulty performing fine
movements, cramps, rapid fatigue, hyperalgesia, allo-
dynia, hypoaesthesia, weakness without muscle wast-
ing and vasomotor and sudomotor changes. These
findings have been supported by a consensus of experts
in the field2 and recorded data in subsequent studies.
Greening et al.3 recorded a range of symptoms in a
small sample of people with NSAP (n517). Reported
symptoms included burning pain, aching, stiffness,
cramp and less frequently dystrophic changes, numb-
ness, heaviness and fatigue. Fourteen participants
reported paraesthesia. A more recent investigation of
21 computer users with NSAP revealed that all but one
experienced feelings of weakness/fatigability while 19
people experienced paraesthesia.16 In a further study,17
a third of the participants studied with arm pain
reported paraesthesia in the computer mouse operating
limb with weakness reported in less than 10%.
Table 1 Grading system for neuropathic pain (Haanpää et al., 2011)10
Criteria to be evaluated for each patient:
1. Pain with a distinct neuroanatomically plausible distribution
2. A history suggestive of a relevant lesion or disease affecting the peripheral (or central) somatosensory system
3. Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test (clinical and/or laboratory)
4. Demonstration of the relevant lesion or disease by at least one confirmatory test
Note: grading of certainty for the presence of neuropathic pain: Definite: all 1–4; Probable: 1 and 2 plus either 3 or 4; Possible: 1 and 2
without confirmatory evidence from 3 or 4.
322 Physical Therapy Reviews 2011 VOL . 16 NO .
Symptoms associated with peripheral neuropathy
reported in the literature include varying combina-
tions of altered sensation, pain, muscle weakness or
atrophy and autonomic symptoms.18 Pain question-
naires such as the Leeds Assessment for Neuropathic
Symptoms and Signs use the presence of symptoms
such as dysaesthesia, paraesthesia, trophic changes,
allodynia, paroxysms of pain and the presence of
burning pain as well as positive signs of hyperalgesia
and allodynia as indicative of neuropathic pain.19
It would appear, therefore, that the recorded sym-
ptoms in individuals with NSAP are consistent with
symptoms thought to indicate neuropathic pain.
However, it should be noted that some of these
symptoms can be present in non-neuropathic condi-
tions. Indeed, Bennett19 acknowledges that a high
score on the Leeds Assessment for Neuropathic
Symptoms and Signs simply indicates the possible
presence of neuropathic pain which should be
explored further.
Distribution of pain
Harrington et al.2 suggest that pain in NSAP is
predominantly in the forearm but may also affect the
cervical spine and upper arm while Greening et al.3
noted that the dominant feature in their sample was
aching pain over the forearms and hands together
with a non-dermatomal distribution of paraesthesia.
This apparent non-neuro-anatomical pattern of sym-
ptoms has been suggested to be inconsistent with
peripheral neuropathic pain.10,14 However, the con-
sistency of neuro-anatomical pain patterns may be
questionable since referral patterns from cervical
nerve root stimulation have demonstrated that
symptoms outside the classic dermatomal regions
can be frequently provoked.20 One reason may be the
high frequency of intra-thecal dorsal root anasto-
moses in the cervical spine.21
History of nerve injury
In the absence of evidence of specific nerve pathol-
ogy, the main hypotheses for nerve injury in NSAP
can be summarized as minor nerve compression and
neuritis.
Minor nerve compression
Adverse postures have been proposed to place direct
tension or compression on nerves, particularly where
nerves are located in potential entrapment sites, e.g.
5

the carpal tunnel.22–25 This mechanism of injury
has been implicated in carpal tunnel syndrome, a
condition largely considered to be neuropathic.26
Furthermore, a recent study found a forward head
posture to be more prevalent and more pronounced
in people with carpal tunnel syndrome than in
healthy controls.27 Although little evidence exists
for the association of poor posture with NSAP, it has
been identified as a common feature in NSAP with
78% of people with work related upper limb disorders
presenting with shoulder protraction and 71% with a
forward head posture.28 Greening et al.29 hypothesize
that the typical hand and arm postures assumed
during computer use may contribute to nerve
compression, particularly at sites such as the carpal
tunnel and support this with evidence of reduced
transverse movement of the median nerve in the
carpal tunnel in NSAP.30,31 They also suggest that
poor cervical spine postures commonly assumed by
office workers may cause shortening of the scalene
muscles and possible irritation of the neurovascular
bundle at the thoracic outlet.32 However, it should be
noted that findings from eight healthy subjects found
no significant change in median nerve excursion in
response to forward head posture.33
In a small study of healthy participants, a com-
bination of contralateral cervical side flexion and
scapular protraction has been shown to cause a
reduction in median nerve movement of 60% in
two upper and lower arm measurement sites.33
Furthermore, nine of the 13 participants reported
paraesthesia in the distribution of the median nerve
when scapular protraction was sustained for between
1 and 4 minutes. The authors postulate that this
nerve restriction is consistent with the concept that
shoulder protraction may cause a neurovascular
impingement in the shoulder region and may
contribute to the development of arm symptoms.
These findings may provide preliminary evidence for
the hypothesis that postures assumed during
office work can be linked with effects of neural
compromise, e.g. changes in nerve movement, inflam-
mation or altered circulation etc., with the potential
to cause symptoms. However, given the small sample
size in this study, these results must be considered
preliminary.
In a review of the literature, Rempel et al.24
highlighted the cascade of effects resulting from low
level nerve pressure, consisting of inhibition of
intraneural microvascular blood flow, axonal trans-
port and nerve function as well as endoneurial
oedema and displacement of myelin. Higher pressures
may have more profound effects including demyeli-
nation, inflammation, fibrosis, growth of new axons
and remyelination.24 In healthy people, non-neutral
positions of the wrist, finger and forearms as well
Moloney et al. Pathophysiology of non-specific arm pain
as loading of the fingertips have been shown
to increase extra-neural pressure in the carpal
tunnel.34,35 Similarly, it is possible that low level
neural compression from non-neutral postures may
occur in NSAP; however, without further evidence
this hypothesis remains purely speculative.
In an attempt to imitate mechanisms of nerve
injury in humans, the effect of prolonged shear stress
and longitudinal stretch on nerves in contained
spaces has been studied in rats, i.e. simulating the
constrained spaces surrounding normal human per-
ipheral nerve.36 Using this model, Wallerian degen-
eration was not found. However, demyelination of
the axons at the periphery of the nerves was found,
with central axons preserved. The myelin loss was
still present 8 months post-compression. In the early
stages post-compression, Schwann cell proliferation
was considerable. In the absence of Wallerian de-
generation, the possibility for Schwann cell prolifera-
tion by the low-level mechanical stimulus was con-
currently investigated within this study and shown to
increase after just 2 hours of mechanical stimulation,
with subsequent apoptosis (sudden cell death) of
these cells. These events occurred in the absence of
axonal injury and before conduction velocity reduced
significantly. That is, Schwann cell apoptosis and
proliferation occurred during a period when axons
were preserved. This may correlate with clinical
presentations of compression neuropathy in which
axonal function is preserved until late in the disease,
e.g. carpal tunnel syndrome,36,37 and may also be
relevant to NSAP.
It is plausible that presenting symptoms in condi-
tions such as NSAP may be secondary to compression
of neural structures and indeed, that the postures
commonly reported in NSAP may serve as the
compressing force. However, despite reported sub-
optimal postures in NSAP, a relationship between
posture and the causation of pain has never been
proven. Indeed, altered posture may simply be an
associative factor. This, together with the small sample
sizes in many of the aforementioned studies, means
that a true causal relationship between posture, nerve
injury and NSAP remains unsubstantiated and war-
rants further investigation.
Neuritis model
The effects of inflammation, in the absence of
axonal damage, in or close to neural structures have
been purported to contribute to certain clinical pain
states.38 In these situations, it has been proposed
that local nerve inflammation is mediated by the
nervi nervorum, a potential nociceptor within neural
tissue.39 The sequence of events that ensue may
cause a movement-induced pain, commonly asso-
ciated with conditions such as NSAP.38 Recent
Physical Therapy Reviews 2011 VOL . 16 NO . 5 323
Moloney et al. Pathophysiology of non-specific arm pain
studies have shown that inducing inflammation in
the sciatic nerves of rats can cause A- and C-fibre
mechanosensitivity to both pressure and stretch.40,41
Dilley et al.40 found that this mechanosensitivity was
evident in a sub-group of the nerves tested, and when
present, occurred at small percentages of stretch
(,5%), i.e. within the ranges of normal limb move-
ments. While signs of inflammation have been
identified in the soft tissues of rats performing
repetitive tasks and will be discussed in the muscle
section of this paper, inflammation has also been
identified in neural structures, in response to low
load repetitive tasks in rats. Inflammatory cytokines
have been identified in the median nerve42,43 and the
cervical spinal cord neurons in response to low load
tasks.43 Results from these studies support the
hypothesis that inflammation within neural tissue
could explain signs and symptoms that frequently
present in NSAP.
Results from clinical testing
Clinical tests of the nervous system comprise
the assessment of motor and sensory disturbance
through the neurological assessment of conduction
loss (reflexes, myotomes, and sensation), the assess-
ment of tactile allodynia and hyperalgesia,44 as
well as assessment of neural mechanosensitivity, i.e.
neurodynamics and nerve palpation.45–48 Neuro-
dynamic tests (NDTs) are sequences of movements
(usually passive) designed to assess the mechanics
and physiology of part of the nervous system.45,49
Nerve palpation involves the palpation of the
peripheral nerves at discrete sites.45 Positive tests
indicate abnormal neural sensitivity to mechanical
input.
Neurological examination of reflexes, myotomes
and sensation has been shown to be moderately
reliable50 but the validity of these tests remains
questionable despite their common use in clinical
practice. When positive, these tests may indicate signs
of conduction loss.13
The authors are unaware of any data pertaining to
the presence of altered reflexes or reduced sensation
in NSAP. In relation to myotomes, i.e. the assessment
of muscles innervated by particular nerve roots,
Greening et al.3 found myotomes to be normal, even
in the presence of minor muscle weakness. In this
case, minor muscle weakness was considered second-
ary to pain. Similarly, studies by Jensen et al.23,51
found minimal signs of muscle strength change. In
contrast, Jepsen and Thomsen17 found multiple sites
of minor muscle weakness in intensive computer users
who had either mild or no upper limb pain and
suggested this may reflect a pre-clinical state due to
computer use exposure. The protocol administered
by Jepsen and Thomsen was comprehensive for all
324 Physical Therapy Reviews 2011 VOL . 16 NO .
upper limb muscles and therefore included all
myotomes.
The presence of hyperalgesia and mechanical
allodynia has been reported in NSAP.3,17 In a study
of 96 intensive computer users (67 of whom had mild
upper limb pain), pin prick hyperalgesia was noted in
40 computer mouse operating limbs while 60
computer mouse operating limbs were found to have
mechanical allodynia.17 Touch evoked allodynia has
also been noted in 58% of participants with NSAP.3
A number of studies have reported abnormal
neural mechanosensitivity in NSAP. In a landmark
study by Elvey and Quintner,52 NDTs were positive
in 88% of patients with NSAP. These findings are
consistent with other studies.3,53 A further study of
485 computer users with arm symptoms found 70%
of participants to have positive NDTs.28 Indeed, the
frequency of abnormal neural mechanosensitivity in
NSAP has led some subsequent studies investigating
NSAP to include positive NDTs as one of the defining
criteria for this condition.31,32,54,55 The actual causes of
positive NDTs remain unclear. Previous hypotheses
proposing reduced nerve movement have yielded
mixed results 32,56 while other suggested explanations
include peripheral nerve inflammation40,57 and central
hyperexcitability.58
Nerve palpation, in addition to NDT, has been
found to be a reliable clinical measure of neural
mechanosensitivity.50 Further evidence of increased
neural tissue mechanosensitivity in NSAP is sup-
ported by studies investigating sensitivity to manual
pressure over nerve sites in the upper quadrant of
people with NSAP.16,17,32 This sensitivity has been
demonstrated in various sites in the upper quadrant
including the brachial plexus at cord level,17,59 the
median nerve17,32,59 pronator teres, the supraclavicu-
lar fossa32 and the posterior interossseous nerve.17,59
Neurophysiological investigations
In addition to nerve conduction studies, neurophy-
siological investigations include tests such as quanti-
tative sensory testing (QST). These have been studied
specifically in patient groups with NSAP and some
related conditions. Quantitative sensory testing is a
system of psychophysical measures, i.e. the subjects’
responses to various mechanical and thermal stimuli
are quantified, which assesses the function of thinly
myelinated Ad fibres, unmyelinated C fibres and large
diameter Ab fibres as well as the dorsal column and
spinothalamic tract.60,61 While QST findings will be
discussed in this section, it should be noted that QST
is not specifically diagnostic for neuropathic pain but
may support its diagnosis.62
Vibration
Vibration thresholds (VT) are the most common
sensory parameter that has been investigated thus far
5

in NSAP with VT frequently found to be elevated in
NSAP when compared to control groups.3,23,29,51,63,64
In these studies, the innervation territories of the
median, ulnar and radial nerves were examined;
however, a consistent pattern in relation to affected
nerve territory has not been established. Greening
et al.3,29 noted elevated VT in the median and ulnar
innervation territory, but not the radial nerve area, in
comparison to controls, a finding supported by
Jensen et al.23 In a follow-up study, Pilegaard and
Jensen51 compared VT in the median and radial nerve
distributions at baseline with an 18 month follow-up
and noted that the elevated median nerve VT found
at baseline had not changed. However, they did find
that the VT in the radial nerve innervation area had
become elevated compared with baseline and was
subsequently different to controls. Findings from
Laursen et al.63 and Tucker et al.64 revealed wide-
spread elevated VTs within all innervation territories
in comparison to controls.
While some authors suggest that findings of VT
changes in peripheral nerves may be indicative
of peripheral nerve dysfunction,3,29,63 widespread
findings may implicate a central nervous system
modulation.64
Pressure pain thresholds
While pressure pain thresholds (PPT) have not been
investigated in patients with NSAP, other occupa-
tional conditions have been studied. Johnston et al.65
assessed PPT in office workers with neck pain.
Thresholds were not found to be significantly lower
over neck muscles when compared to controls.
However, significant differences were found for the
median nerve site and tibialis anterior site between
participants with either mild or moderate pain and
dysfunction when compared with asymptomatic
groups. Lowered PPT at a distal point may suggest
widespread sensitization, while such changes at the
median nerve site may indicate either widespread
sensitivity or peripheral nerve dysfunction. It is
interesting to note that lowered PPTs have been found
in a wide range of neck and upper limb conditions
including whiplash66–69 and cervical radiculopathy.67
Thermal QST
Patients with NSAP have not been investigated using
thermal QST, although, again, related disorders have.
Johnston et al.65 measured thermal pain thres-
holds over the cervical muscles in office workers with
neck pain. They found that heat pain thresholds were
reduced in those with mild pain and disability
compared with workers without pain and non-office
workers (controls). Cold pain thresholds were found
to be lowered in the symptomatic group compared to
controls, i.e. the symptomatic group detected cold as
painful at higher temperatures than the control
Moloney et al. Pathophysiology of non-specific arm pain
group. In contrast, a study by Leffler et al.70 found
no differences in thermal detection or pain thresholds
in chronic trapezius myalgia.
Similar to altered PPT and VT, altered thermal
pain thresholds may implicate several mechanisms
including sensitization of the nociceptive primary
afferents,71 peripheral nerve dysfunction72 or central
nervous system modulation.73 More data are required
to elucidate these mechanisms further.
Nociceptive Pain (Arising Primarily from Muscle
Tissue)
Nociceptive pain can arise from stimulation of
nociceptive afferent fibres in any tissue such as
muscle, joint, fascia, viscera, etc.45 Nociceptive pain
in NSAP will be considered primarily in relation to
muscle tissue changes due to the extensive literature
in this area. A diagnosis of NSAP implies an exclusion
of cervical referred pain. However, while some referral
of pain from the cervical spine cannot be excluded,
there is a paucity of data pertaining to an articular
source of nociceptive pain in NSAP. Consequently, the
remainder of this section will address muscle tissue
pain and dysfunction as it relates to NSAP.
The primary indicators of nociceptive pain appear
to be: pain that is intermittent and sharp with
mechanical provocation, pain which is more of a
constant dull ache or throb at rest, pain with a clear
proportionate mechanical nature to aggravating and
easing factors, and the absence of indicators of
neuropathic pain.14,74 Nociceptive pain can cause
referral of pain to areas removed from the location of
the primary source of pain, i.e. somatic referred pain
or myofascial referred pain (see Bogduk75).
One question under review in this section is whether
low load muscle activity of a static or repetitive nature,
which has been suggested as a potential risk factor in
NSAP,76 can actually cause sufficient change to
explain symptoms in NSAP. The literature in relation
to nociceptive muscle pain and NSAP will be discussed
in relation to electromyography (EMG) and morpho-
logical changes as well as the results of biochemical
studies. While the results of these studies may also be
applicable to neuropathic pain and central sensitiza-
tion, they are discussed under the heading of nocicep-
tive pain because these studies aimed primarily to
investigate changes in local muscle tissue structure and
function, and how these changes pertain to the de-
velopment of upper limb pain, i.e. nociceptive pain.
EMG studies and morphological changes
Two recent studies by Calder et al. have investigated
EMG in people with NSAP.77,78 EMG findings such
as smaller motor unit potentials in the extensor carpi
radialis brevis muscle in NSAP compared with
controls led the authors to conclude that changes in
NSAP were largely myopathic in nature and affected
Physical Therapy Reviews 2011 VOL . 16 NO . 5 325
Moloney et al. Pathophysiology of non-specific arm pain
slow twitch muscle fibres preferentially.77 This sup-
ports previous research findings of increased numbers
of type I slow twitch muscle fibres and signs of
mitochondrial damage within the muscle fibres of
people with myalgia (ragged-red fibres).79–81 However,
it should be noted that some of these muscle changes
are also found in people who performed similar work
but who did not have pain, i.e. female cleaners with
and without trapezius myalgia.80 As such, muscle
changes like ragged-red fibres may simply reflect a
training effect within muscle from prolonged low-level
activity.
While not entirely specific to NSAP, related studies
have demonstrated sustained muscle activation using
EMG in people who perform prolonged computer
work in both the trapezius muscles82–86 and the
forearm extensor muscles.87 Research into activation
patterns of the trapezius muscle during prolonged
computer tasks has yielded mixed results with
increased activation shown in some individuals with
trapezius myalgia compared with controls 86,88 but
not in others.89 Szeto et al.88 also found that sym-
ptomatic individuals with neck and arm discomfort
related to computer use displayed less symmetrical
patterns of upper trapezius muscle activation than
those without pain. In those who presented with neck
and shoulder pain, higher activity of the upper
trapezius muscle has been shown to correlate with
higher reported levels of pain,88 although Sjors
et al.86 found no correlation between pain and
increased muscle activation. In contrast with previous
studies, Larsson et al.90 found that EMG of trapezius
muscle in people with cervico-brachial pain showed
lower activity in trapezius EMG on the painful side,
which they infer is suggestive of neuralgic pain
presentations rather than nociceptive pain.
The main findings from these studies demonstrate
changes in muscle activation patterns in response to
sustained or low load activities; however, a definite
link between sustained muscle activation and pain
has yet to be established in conditions like trapezius
myalgia and is also elusive in NSAP. EMG findings
in NSAP may point to pain that is myopathic77,78 and
as such nociceptive. However, a neurogenic origin
has also been suggested.90
Biochemical changes
Animal studies
The results from animal studies investigating the
effects of repetitive muscle activity provide greater
understanding into how muscle pain can occur in
the absence of frank muscle pathology. A large body
of work by a group of researchers, Barbe, Barr and
colleagues,91–94 has investigated the biochemical
changes in rats in response to tissue loading
and repetitive tasks. Of particular interest when
326 Physical Therapy Reviews 2011 VOL . 16 NO .
considering NSAP are studies investigating moderate
or high repetition activities with negligible force as
these best reflect the demands of low load, high
intensity work. In earlier studies using this model of
muscle loading in rats (reaching tasks), fibrotic
scarring was evident in the forearm flexors of the
active reaching limb at 6 weeks, accompanied by an
increase in activated exudate macrophages and a
reduction in reach rate.91 Interestingly, the inactive
limbs of the animals showed similar responses which
may be suggestive of a systemic inflammatory
response. The systemic nature of the response to
negligible load activity has been further demonstrated
by the presence of increased serum levels of IL-1
alpha, an inflammatory cytokine,91 as well as
increased serum levels of tumour necrosis factor-
alpha and macrophage inflammatory proteins.93 In
addition, substance P and neurokinin-1 have been
found to be increased in the dorsal horn of the spinal
cord at weeks 6 and 12 following repetitive low load
reaching tasks.93 In a similar rat model, increased
levels of interleukin-1 beta and tumour necrosis
factor-alpha have also been identified locally in the
forearm flexor muscle and tendons of rats performing
these tasks.94
Human studies
These authors are not aware of any study specifically
investigating the biochemical milieu in NSAP; how-
ever, a number of studies have identified the presence of
inflammatory mediators in people with upper extre-
mity musculoskeletal disorders.95–98 These findings in
conjunction with more detailed animal studies provide
a scientific basis for the presence of muscle pain in the
absence of frank muscle pathology. However, the
systemic nature of some of the findings may contradict
a singular nociceptive mechanism. Further research is
required to substantiate these findings in NSAP.
In summary, there is insufficient evidence to support
or negate the presence of nociceptive pain arising
primarily from muscle in NSAP. Certainly, biochem-
ical and morphological changes in upper limb muscles
have been demonstrated in animal and human studies
in response to low load high repetition work tasks.
However, further research investigating people with
NSAP is warranted.
Central Sensitization
Central sensitization has been described as an aug-
mentation of responsiveness of central neurons to input
from unimodal and polymodal receptors.99 It occurs
in all pain states with peripheral and central mechan-
isms unlikely to be mutually exclusive. However, in
some cases the features of central sensitization may
become more dominant.45 Characteristics of central
sensitization have been outlined by Butler45 with many
of the key features included in recently published
5

clinical criteria for the diagnosis of central sensitiza-
tion, for example, disproportionate and unpredictable
pattern of pain provocation and diffuse non-anatomic
areas of pain.14 Reported symptoms and clinical signs
of increased responsiveness to a variety of stimuli, e.g.
mechanical, cold, heat, noise etc. should also be
considered.100 Nijs et al.100 also advocate the use of
pressure algometry to determine central sensitization,
particularly if reduced PPT are found at numerous sites
and at sites remote from the site of reported pain. A
similar response to the application of heat and cold
stimuli would also support a diagnosis of central
sensitization. Finally, heightened bilateral responses to
neural tissue provocation tests101 as well as a reduced
pain tolerance in response to exercise have been
proposed as suggestive of central sensitization.100
Insufficient data exist to determine the contribu-
tion of central sensitization to NSAP. Although there
is evidence of non-dermatomal distribution of symp-
toms and mechanical allodynia in NSAP,3,17 it is
unknown whether these features are sufficient to
suggest central sensitization. Vibration thresholds in
relation to NSAP have already been discussed and
widespread changes found may support a central
sensitization model. Interestingly, other studies on
QST in carpal tunnel syndrome indicate that wide-
spread mechanical hypersensitivity is a feature of the
condition.102,103 This has also been shown in uni-
lateral lateral epicondylalgia.104 As previously dis-
cussed, widespread inflammatory changes have been
noted in response to low load activities which may
contribute to and/or reflect central sensitization.
Psychosocial factors and central sensitization
Psychosocial factors have been considered important
in work-related NSAP although the supporting
research varies. It is generally accepted that muscu-
loskeletal pain can be experienced in the absence of
evident physiological change or tissue damage with
such pain modulated by cognitive processes.105
Key factors in the development of work related
upper limb disorders such as poor job satisfaction,
stress, poor decision making control and considering
one’s job either too hectic or too boring have been
identified.106,107 However, it should be noted that in
both studies, physical factors were found to be
equally important. Further to this, the association
between high perceived job stress and upper extre-
mity problems108 is somewhat confused by findings of
a prospective study by Bonde et al.109 which revealed
no association between the reverse situation, i.e.
those performing repetitive work tasks and the
development of stress symptoms.
In studies specifically related to NSAP, Henderson
et al.5 found a strong correlation between the
presence of depression, helpless coping style and
Moloney et al. Pathophysiology of non-specific arm pain
being in receipt of state financial aid with disability in
NSAP. However, similar findings were identified in
carpal tunnel syndrome, which is interesting given the
more precise diagnostic category of carpal tunnel
syndrome. An earlier study by the same authors
revealed that the aetiology of NSAP is no more
psychiatric, psychological, behavioural or related to
personality than is the case of a similarly chronic and
painful condition of known pathology (carpal tunnel
syndrome).110 In fact, people with NSAP were found
to be less depressed and distressed and had less
sleep disturbance than the carpal tunnel syndrome
group,110 contradicting the hypothesis that non-
specific conditions are predominantly influenced by
psychosocial factors.
Psychological features such as catastrophizing,111
stress, psychoneuroticism and neurotic perfectionism112
as well as poor coping strategies5,113 have all been linked
with risk factors for work related upper limb disorders
and specifically non-specific disorders.5,111,112 In addi-
tion, the presence of higher scores in neuroticism and
alexithymia (the inability to recognize and express
emotions) in office workers with NSAP compared with
controls has been reported114 and as such may be
important in the development of NSAP.
The research findings discussed suggest that, along
with peripheral drivers of pain in NSAP, psycholo-
gical and psychosocial factors may play a role in the
onset and progression of this disorder and should be
considered during clinical and research evaluation
protocols. A causal relationship between psychoso-
cial factors and NSAP, however, is still speculative
and requires further research.
Conclusion
This review has explored the possible pathophysiolo-
gical and psychological mechanisms which may
underlie NSAP. The literature does not support
a predominance of one classification of pain over
another in this condition. Further research is war-
ranted investigating multiple aspects of pain features in
large cohorts of people with NSAP to elucidate the
presence of sub-groups or dominant pain mechanisms
in this patient group. In the meantime, clinicians would
be prudent to consider all classifications of pain in the
assessment of the NSAP patient.
Acknowledgements
This research was supported by a PhD scholarship
awarded by the Irish Research Council of Science,
Engineering and Technology.
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