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INTRODUCTION
At first glance, pain seems relatively straightforward –
hitting one’s thumb with a hammer hurts one’s
thumb. Such experiences are easily understood with a
structural-pathology model, which supposes pain
provides an accurate indication of the state of the tis-
sues. However, on closer inspection, pain is less
straightforward. Much of the pain we see clinically
fits into this less straightforward category, where pain
cannot be understood as a marker of the state of the
tissues. This paper argues that the biology of pain is
never really straightforward, even when it appears to
be. There are four key points: (i) that pain does not
provide a measure of the state of the tissues; (ii) that
pain is modulated by many factors from across
somatic, psychological and social domains; (iii) that
the relationship between pain and the state of the tis-
sues becomes less predictable as pain persists; and (iv)
that pain can be conceptualised as a conscious corre-
late of the implicit perception that tissue is in danger.
These points will be discussed in light of their clinical
implications and will form the basis of one approach
to understanding complex regional pain syndrome.
Pain does not provide a measure of the state of the
tissues
In 1965, the gate control theory
2
was proposed to
explain the variable response of animals to noxious
stimuli. The theory proposed that noxious input was
modulated at the spinal cord by other non-noxious
input from the periphery, and by descending input
from higher centres. That theory was interrogated in
many animal experiments (see Wall and McMahon
3
for a review). A typical experiment would involve the
insertion of recording electrodes into the nociceptors
of the study animal, applying a defined injury and
recording nociceptor activity. Finally, experimenters
would record behaviours of the animal that implied
that the animal was in pain. These behaviours might
be relatively simple; for example, the reaction time of a
withdrawal reflex. They might be relatively complex;
© W. S. Maney & Son Ltd 2007 DOI 10.1179/108331907X223010
RECONCEPTUALISING PAIN ACCORDING TO
MODERN PAIN SCIENCE
G. LORIMER MOSELEY
Oxford Centre for fMRI of the Brain, Department of Physiology,
Anatomy & Genetics, Oxford University, Oxford, UK
This paper argues that the biology of pain is never really straightforward, even when it appears
to be. It is proposed that understanding what is currently known about the biology of pain
requires a reconceptualisation of what pain actually is, and how it serves our livelihood. There
are four key points: (i) that pain does not provide a measure of the state of the tissues; (ii) that
pain is modulated by many factors from across somatic, psychological and social domains; (iii)
that the relationship between pain and the state of the tissues becomes less predictable as pain
persists; and (iv) that pain can be conceptualised as a conscious correlate of the implicit
perception that tissue is in danger. These issues raise conceptual and clinical implications,
which are discussed with particular relevance to persistent pain. Finally, this conceptualisation
is used as a framework for one approach to understanding complex regional pain syndrome.
Keywords: Pain, re-evaluation, persistent pain, pain syndrome
Physical Therapy Reviews 2007; 12: 169–178
for example, the ratio between time spent in a non-
preferred environment (e.g. illuminated box) with a
cool floor, and time spent in a preferred environment
(e.g. dark box) with a heated floor.
4
Two findings consistently emerged from those stud-
ies. First, the injury, or noxious stimulation, initiates
the change in behaviour. Second, neither pain behav-
iour nor nociceptor activity hold an isomorphic rela-
tionship with the state of the tissues. By clearly
demonstrating these things, those studies provided
the first experimental evidence that pain does not pro-
vide a measure of the state of the tissues.
One limitation of animal experiments is that they
do not tell us about pain. Human experiments, how-
ever, can. Although it is difficult to justify injuring
human volunteers, it is possible to deliver non-harm-
ful noxious stimuli, for example brief thermal, electri-
cal or mechanical stimuli (see Handwerker and
Kobal
5
for a review of various methods of experimen-
tally inducing pain). By recording activity in nocicep-
tors while simultaneously recording subjects’ pain
ratings, experimenters have been able to evaluate the
relationship between the state of the tissues (in the
absence of tissue damage), activity in nociceptors,
and pain.
6
Human pain experiments corroborated both find-
ings from the animal data. Specifically, noxious stim-
ulation is necessary for nociceptor activity, which
usually reflects the intensity of the stimulus, and noci-
ceptor activation does not provide an accurate mea-
sure of the state of the tissues.
6
The human
experiments went further because they showed that
the relationship between pain ratings and nociceptor
activation is variable. In fact, some authors have pro-
posed that the notion of nociceptors is misleading
because small diameter fibres (Aδ and C fibres)
respond to very small (non-harmful) changes in the
internal state of the body.
7
That said, some small
diameter fibres are not responsive to small changes
(so-called high-threshold neurons) and this sub-class
of small diameter fibres may reflect what we call noci-
ceptors. Regardless, it is clear that experimental stud-
ies do not show an isomorphic relationship between
pain and nociceptor activity, nor between pain and
the state of the tissues. Rather, they show a variable
relationship that is modulated by many factors.
Pain is modulated by many factors from across somatic,
psychological and social domains
Anecdotal evidence that somatic, psychological and
social factors modulate pain is substantial – sport-
related and war-related stories are common (see
Butler and Moseley
8
for several examples). However,
numerous experimental findings corroborate the
anecdotal evidence (see Fields et al.
9
for a review of
central nervous system mechanisms of modulation).
Other factors that are known to modulate the pain
evoked by a standardised stimulus include inflamma-
tory mediators (increase nociceptor activity), tissue
temperature (increased temperature increases noci-
ceptor activity via summation), and blood flow
(decreased blood flow increases nociceptor activity
via summation induced by H
+
ions). See Meyer et al.
6
for a review of peripheral mechanisms of modulation.
Experiments that manipulate the psychological
context of a noxious stimulus often demonstrate clear
effects on pain, although the direction of these effects
is not always consistent. For example, a large amount
of literature concerns the effect of attention on pain,
and of pain on attention.
10–22
Despite the wealth of
data, consensus is lacking: some data suggest that
attending to pain amplifies it and attending away
from pain nullifies it, but others suggest the opposite.
Anxiety also seems to have variable effects on pain.
Some reports link increased anxiety to increased pain
during clinical procedures
23–26
and during experimentally
induced pain,
27
but other reports suggest no effect.
28,29
Relevant reviews conclude that the influence of anxiety
on pain is probably largely dependent on attention.
28,30
Expectation also seems to have variable effects on
pain. As a general rule, expectation of a noxious stimu-
lus increases pain if the cue signals a more intense or
more damaging stimulus
22,31–35
and decreases pain if the
cue signals a less intense or less damaging stimulus (see
Fields
34
and Wager
36
for reviews). Further, cues that sig-
nal an impending decrease in pain, for example the
process of taking an analgesic, usually decrease pain.
Thus, expectation is thought to play a major role in
placebo analgesia.
37,38
The common denominator of the effect of attention,
anxiety and expectation on pain seems to be the underly-
ing evaluative context, or meaning of the pain. That is
demonstrated by the consistent effect that some cognitive
states seem to have on pain. For example, catastrophic
interpretations of pain are associated with higher pain rat-
ings in both clinical and experimental studies (see Sullivan
et al.
39
for a review). Believing pain to be an accurate indi-
cator of the state of the tissues is associated with higher
pain ratings,
40
whereas believing that the nervous system
amplifies noxious input in chronic pain states increases
pain threshold during straight leg raise.
41
The social context of a noxious stimulus also affects the
pain it evokes. Initiation practices and sadomasochistic
sexual practices are two examples that highlight the
importance of social context. Overall, the effects of social
context are again variable but again seem to be under-
pinned by the underlying evaluative context, or meaning
(see Butler and Moseley
8
for a review of pain-related data
170 MOSELEY
and Moerman
42
for exhaustive coverage of the role of
meaning in health and medicine).
To review the very large amount of literature on
somatic, psychological and social influences on pain is
beyond the scope of this paper. However, it is appropriate,
and clinically meaningful, to reiterate the theme that
emerges from that literature: that the influences are vari-
able and seem to depend on the evaluative context of the
noxious input.
The relationship between pain and the state of the
tissues becomes weaker as pain persists
The nervous system is dynamic. This means that the func-
tional properties of individual neurones and of synergies
of neurones change in response to activity. To review all
the changes that have been identified is beyond the scope
of this paper and the expertise of this author. However,
the nature of the changes can be summarised thus: that
the neurones that transmit nociceptive input to the brain
become sensitised as nociception persists, and that the
networks of neurons within the brain that evoke pain,
become sensitised as pain persists. The molecular and sys-
tems biology of these changes have been discussed at sev-
eral levels.
8,43,44
The clinical manifestations of these
changes are: hyperalgesia (formerly painful stimuli
become more painful) and allodynia (formerly non-
painful stimuli become painful). These terms are used
widely, most often in reference to tactile stimuli, but also
in reference to movement and to thermal stimuli.
One aspect of the changes that occur when pain persists
is that the proprioceptive representation of the painful
body part in primary sensory cortex changes.
45–47
This
may have implications for motor control because these
representations are the maps that the brain uses to plan
and execute movement.
48
If the map of a body part
becomes inaccurate, then motor control may be compro-
mised – it is known that experimental disruption of corti-
cal proprioceptive maps disrupts motor planning.
49
The
notion of distorted proprioceptive representation has
been discussed with regard to its impact on motor con-
trol
50,51
and, more recently, in a theoretical way with
regard to pain.
52
Although exceptions exist,
53
there is
mounting evidence that changes in cortical representation
occur in association with chronic pain, and it is feasible
that these changes may become part of the problem.
46
Conceptualising pain as a conscious correlate of the
implicit perception that tissue is in danger
The biology of pain is complex. One response to this
complexity is to develop clinically viable conceptual
RECONCEPTUALISING PAIN ACCORDING TO MODERN PAIN SCIENCE 171
Fig. 1. Many inputs affect the implicit perception of threat to body tissues, labelled here as ‘How dangerous is this really?’
Those inputs have wider meaning effects, which in turn seems to affect anxiety, attention and expectation. The implicit
perception of threat to body tissues determines pain and in turn influences other inputs.
paradigms that incorporate what is now known about
that complexity. One such paradigm that is gaining sup-
port is the neuromatrix theory (see Melzack
55
for a con-
textual review),
54
which conceptualises pain as one
output of the central nervous system that occurs when
the organism perceives tissue to be under threat. There
are two important components of this conceptualisa-
tion. First, there are other central nervous system out-
puts that occur when tissue is perceived to be under
threat, and second, that it is the implicit perception of
threat that determines the outputs, not the state of the
tissues, nor the actual threat to the tissues (Fig. 1).
When tissue is under threat, a range of local and seg-
mental responses occur. For example, inflammatory
mediators are released, the body part is usually with-
drawn via short and long latency reflex loops, there are
rapid changes in blood flow and in the excitability of
peripheral nociceptors (so-called peripheral sensitisa-
tion).
56
The nociceptive system transforms this threat
into electrical activity in peripheral neurones. If this
message of threat is then transmitted by spinal neurones
to higher centres, the responses become more complex.
For example, immune mediators are released into the
blood stream,
57
voluntary and postural muscle activity
are altered
58
and conscious knowledge of the threat (i.e.
pain) may emerge. Within this context, pain will not
emerge until the nociceptive input to the brain has been
evaluated, albeit at an unconscious level (see Moseley
59
and Gifford et al.
60
for further discussion).
The second important component of the neuromatrix
theory is that pain depends on the perceived degree of
threat. This means that pain can be conceptualised as the
conscious correlate of the implicit perception of threat to
body tissues.
8,59
That psychosocial factors are very impor-
tant in most chronic pain states is well established.
61–65
This paper argues that the mass of data regarding psy-
chosocial factors can be gathered within the proposed
conceptualisation that pain is one output of the central
nervous system that occurs when the organism perceives
tissue to be under threat. The conceptualisation has limi-
tations and strengths. One limitation is that it does not
attempt to describe the biology of implicit evaluation of
threat, nor of how this might emerge into consciousness.
In this sense it adds little to theories first proposed
decades ago (see, for example, Hebb
66
). However, a
strength of this conceptualisation is that it can easily be
integrated into a clinical context where making sense of
the influence of factors from across somatic, psychologi-
cal and social domains is valuable.
Implications for clinical practice
That pain does not reflect the state of the tissues, but
rather is a conscious driver of behaviour aimed at
protecting those tissues, has implications for clinical
practice. One implication is that to base clinical rea-
soning on what is currently known about the biology
of pain requires that the skills and knowledge of the
clinician are broader than those related to anatomy
and biomechanics. That is, the clinician must have a
sound knowledge of diagnostic tools, tissue dynamics,
healing and remodelling, peripheral and central sensi-
tisation, and psychological and social factors that
might affect the implicit perception of threat to body
tissues. This information is readily available and there
is evidence that clinicians can understand modern
concepts with relatively limited training.
67
That said,
it may be unrealistic to expect clinicians to keep up-
to-date with progress in knowledge across these areas.
This points to a strength of the conceptualisation of
pain as the conscious correlate of the implicit percep-
tion threat to body tissues because the clinician can
use the conceptual model to guide treatment. That is,
rather than know and understand all the evidence
about which somatic, psychological and social factors
have been demonstrated to modulate pain, and the
nature of their modulation, the clinician can consider
each factor in terms of what effect it might have on
the implicit perception of threat. This conceptual
model seeks to synthesize that wide body of evidence
into a principle.
Another implication that is worthy of special men-
tion is that patients should be helped to base their rea-
soning, about their condition and their pain, on
similar information. This is important because teach-
ing patients about modern pain biology leads to
altered beliefs and attitudes about pain
40
and
increased pain thresholds during relevant tasks.
41
Moreover, when education about pain biology is
incorporated into physiotherapy management of
patients with chronic pain, pain and disability are
reduced.
68,69
A key objective of such education is to
encourage patients to apply the same principle as that
advocated for clinicians, summarised here as ‘what
effect might this (factor) have on the implicit percep-
tion of threat’, or in patient-appropriate language,
‘how does this affect the answer to the question, how
dangerous is this really?’.
8
USING THIS CONCEPTUALISATION TO
UNDERSTAND CRPS AND GUIDE NEW
OPTIONS FOR MANAGEMENT
Complex regional pain syndrome (CRPS) is a debili-
tating condition that can occur after minor trauma,
and sometimes without peripheral trauma, for exam-
ple, post-stroke.
70
Much is known about the patho-
physiology of CRPS, including facilitated neurogenic
172 MOSELEY
inflammation
71,72
and tissue hypoxia
73
at the injury
site,
74,75
autonomic,
76
immune,
77–79
motor,
80,81
tactile
82–85
and proprioceptive
86
dysfunction (Fig. 2).
The syndromic pattern of signs and symptoms
includes pain, hyperalgesia, allodynia, dystonia,
swelling, abnormal blood flow, abnormal sweating,
hair and nail growth. The sensitivity to provocation
can be remarkable, for example, elicitation of pain,
swelling and (anecdotally) blood flow changes in
response to imagined movements
87
or when the
patient receives visual input that the limb is being
touched, even though it is not in fact being touched
(‘dysynchiria’).
88
The wide-spread and multisystemic
nature of the pathophysiology of CRPS implies that,
although CRPS is usually initiated by peripheral
insult, it is a disorder of the central nervous system.
75
When one tries to make sense of such a multisystemic
and exaggerated response to minor injury, the conceptual-
isation that pain is a conscious correlate of the implicit
perception of the threat to body tissue can be useful. That
pain is just one output by which the brain might try to
protect the tissues – one aspect of a homeostatic
response
89
– lends itself to CRPS because the other
responses are so patent. That pain is a correlate of implic-
itly perceived threat to body tissue, rather than the state of
the tissues, or the actual threat to the tissues, is particu-
larly relevant to CRPS in the absence of any tissue or
neural injury, for example, as a stress response.
90
RECONCEPTUALISING PAIN ACCORDING TO MODERN PAIN SCIENCE 173
Fig. 2. Schematic overview of pathophysiology of complex regional pain syndrome. Adapted from Janig and Baron.
75
Each of the pathological findings that have been
documented in patients with CRPS might be consid-
ered a protective response, whether it be an immune,
motor, sensory, vascular, autonomic or conscious
response. consistent with attempts to protect the part
in question, by utilising immune, motor, sensory, vas-
cular and autonomic systems as well as conscious-
ness. Reducing the threshold for activation of these
protective responses would seem a particularly effec-
tive way to protect the body part in question, for
example making it so sensitive that even looking at it
being touched activates a protective response.
88
174 MOSELEY
Fig. 3.Response to different components of motor imagery. Pain (A) and functional capacity (B): Recog = laterality recognition
whereby patients make left/right judgements of pictured hands; Imag. = imagined movements; Mirror = mirror movements.
Three groups are shown: group 1 undertook the motor imagery program, group 2 performed imagined movements first, then
laterality recognition and then mirror movements, group 3 performed laterality recognition, followed by mirror movements and
then back to laterality recognition. Note that group 1 had a largest reduction in pain. Note also, variable responses to imagined
and mirror movements, depending on the order of components. From Moseley
1
and Moseley
93
with permission.
Recognition
Neuropathic
pain scale
Task-specific
NRS
Time (weeks)
Time (weeks)
Imagined
Mirror
A
B
The challenge for those trying to understand CRPS
according to this paradigm is to identify why the
implicit perception of threat to body tissues is so
exaggerated in some patients and in some situations,
but not in others. Fundamental to the paradigm is
that anything that modulates implicitly perceived
threat should be relevant. That means that psychoso-
cial factors, including anxiety, depression, attitudes
and beliefs, social context or work status may all play
an important role. Although patients with CRPS do
not demonstrate a ‘typical’ psychosocial profile, psy-
chosocial contributors are probably relevant in the
majority of cases. Finally, there is initial evidence for
a genetic contribution to CRPS,
91
but more data are
required to clarify that possibility.
Clinical response to CRPS according to this paradigm
If CRPS is an exaggerated protective response, then it
seems sensible to devise treatment that aims first to
find a baseline that is sufficiently conservative to not
elicit the unwanted protective responses (to ‘get under
the radar’), and second to expose the limb gradually
to threat while continuing to avoid elicitation of the
unwanted responses. This approach underpins graded
motor imagery for CRPS,
92,93
whereby patients begin
training by making left/right judgements of pictured
limbs. It is known that this task activates cortical net-
works that involve representation of the limb and
preparation for movement,
94
but this task does not
activate primary sensory and motor cortices.
95
Graded motor imagery progresses from left/right lat-
erality judgements to imagined movements, which do
activate primary sensory and motor cortices,
95,96
and
then to mirror movements. The order of these compo-
nents seems to be important in the effect on pain and
disability in patients with chronic CRPS (Fig. 3).
1
In
patients with acute (or anecdotally less severe) CRPS,
it may be sufficient to begin training (conceptualised
here as exposure to threat) with mirror movements.
97
One of the key issues outlined earlier is that the ner-
vous system changes when nociception and pain persist.
There is a large amount of evidence that the cortical rep-
resentation of the affected limb undergoes substantial
changes in patients with CRPS
47,74,75,83,98–100
and these
changes have been implicated in the maintenance of
pathological pain syndromes (although see Moseley
53
for a word of caution).
46
If distorted cortical representa-
tion contributes to CRPS, then it would seem sensible to
attempt to normalise cortical representation of the limb.
This has been done in patients with phantom limb
pain,
101
which is associated with changes in primary sen-
sory cortex that are probably similar to those observed
in CRPS (see Acerra et al.
102
for a review of common
findings in phantom limb pain, stroke and CRPS). In
that study with amputees, sensory discrimination train-
ing evoked normalisation of cortical representation,
improvement in tactile acuity on the stump and reduc-
tion/elimination of phantom limb pain.
101
Increase in
tactile acuity, normalisation of cortical representation
and reduction in pain were positively related.
Finally, if CRPS reflects an exaggerated implicit
perception of threat to body tissue, then it would
seem sensible to attempt to reduce the perception of
threat. One approach that has been studied exten-
sively in other populations is the explanation to the
patient of the underlying biology of their pain.
Preliminary data from patients with CRPS appear
promising,
103
but clinical trials are required.
CONCLUSIONS
Extensive experimental data corroborate anecdotal
evidence that pain does not provide a measure of the
state of the tissues and that pain is modulated by
many factors from across somatic, psychological and
social domains. It is now known that as nociception
and pain persist, the neuronal mechanisms involved
in both become more sensitive, which means that the
relationship between pain and the state of the tissues
becomes weaker and less predictable. One paradigm,
which considers the current thought in pain biology,
conceptualises pain as the conscious correlate of the
implicit perception of threat to body tissue. This con-
ceptualisation can be applied clinically to identify fac-
tors from across somatic, psychological and social
domains that may affect the perceived threat to tissue
damage. Further, it suggests approaches to treatment
that target those factors. Evidence from clinical trials
suggests that clinical strategies based on this concep-
tualisation can be effective in patients with disabling
complex and chronic pain.
ACKNOWLEDGEMENTS
The author is supported by the Nuffield Dominions
Trust, Oxford University, UK. The conceptual approach
for CRPS draws heavily on unpublished work of Michael
Thacker, King’s College London, London, UK.
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G. LORIMER MOSELEY
Nuffield Medical Research Fellow, Le Gros Clark Building, Department of Physiology, Anatomy & Genetics,
Oxford University, Oxford OX1 3QX, UK
Tel: +44 (0)1865 282658; Fax: +44 (0)1865 282656; E-mail: lorimer.moseley@medsci.ox.ac.uk
