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Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 61, No. 9, September 15, 2009, pp 1226 –1234
DOI 10.1002/art.24837
© 2009, American College of Rheumatology
ORIGINAL ARTICLE
Psychophysical and Functional Imaging Evidence
Supporting the Presence of Central Sensitization
in a Cohort of Osteoarthritis Patients
STEPHEN E. GWILYM,1 JOHN R. KELTNER,1 CATHERINE E. WARNABY,1 ANDREW J. CARR,1
BORIS CHIZH,2 IAIN CHESSELL,2 AND IRENE TRACEY1
Objective. The groin pain experienced by patients with hip osteoarthritis (OA) is often accompanied by areas of referred pain
and changes in skin sensitivity. We aimed to identify the supraspinal influences that underlie these clinical manifestations that
we consider indicative of possible central sensitization.
Methods. Twenty patients with hip OA awaiting joint replacement and displaying signs of referred pain were recruited into
the study, together with age-matched controls. All subjects completed pain psychology questionnaires and underwent quantitative sensory testing (QST) in their area of referred pain. Twelve of 20 patients and their age- and sex-matched controls
underwent functional magnetic resonance imaging (MRI) while the areas of referred pain were stimulated using cold stimuli
(12°C) and punctate stimuli (256 mN). The remaining 8 of 20 patients underwent punctate stimulation only.
Results. Patients were found to have significantly lower threshold perception to punctate stimuli and were hyperalgesic to the
noxious punctate stimulus in their areas of referred pain. Functional brain imaging illustrated significantly greater activation
in the brainstem of OA patients in response to punctate stimulation of their referred pain areas compared with healthy
controls, and the magnitude of this activation positively correlated with the extent of neuropathic-like elements to the patient’s
pain, as indicated by the PainDETECT score.
Discussion. Using psychophysical (QST) and brain imaging methods (functional MRI), we have identified increased activity
with the periaqueductal grey matter associated with stimulation of the skin in referred pain areas of patients with hip OA. This
offers a central target for analgesia aimed at improving the treatment of this largely peripheral disease.
INTRODUCTION
Patients with osteoarthritis (OA) are historically considered to have a peripheral disease, with nociceptive damage
at the joint level accounting solely for the pain they experience. Using this model, however, it has been appreciated
for many years that anomalies exist in terms of the degree
of pathology found at the joint and pain experienced by
the patients (1).
Two other clinical features seen in OA are also difficult
Supported by an unrestricted grant from GlaxoSmithKline.
The Centre for Functional MRI of the Brain was supported by
the MRC of the UK and Northern Ireland. Dr. Gwilym’s work
was supported by the Arthritis Research Campaign and the
Botnar Research Centre (NIHR Biomedical Research Unit).
1
Stephen E. Gwilym, MD, MRCS, John R. Keltner, MD, PhD,
Catherine E. Warnaby, PhD, Andrew J. Carr, FRCS, Irene
Tracey, PhD: University of Oxford, Oxford, UK; 2Boris Chizh,
MD, PhD, Iain Chessell, PhD: GlaxoSmithKline, Cambridge,
UK.
Address correspondence to Stephen E. Gwilym, MD,
MRCS, Centre for Functional MRI of the Brain (FMRIB),
John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU,
UK. E-mail: sgwilym@fmrib.ox.ac.uk.
Submitted for publication December 16, 2008; accepted in
revised form June 17, 2009.
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to explain using an exclusively peripheral model of pain:
the high incidence of referred pain (2– 4) and changes in
skin sensitivity at sites away from the joint (5– 8). We use
these latter observations as a mechanism to explore possible altered central processing of nociceptive stimuli in
patients with OA of the hip akin to alterations found in
patients with neuropathic pain.
Classically, referred pain (somatic) is thought to occur
because of segmental embryology, although since the term
was initially used by Head (9), details as to the exact
mechanism by which referred pain occurs have remained
controversial. Several theories exist, but all include how
higher centers misinterpret the peripheral source of nociception (10). The presence of referred pain in patients with
painful OA is suggestive of central nervous system
changes in nociceptive processing.
Secondary hyperalgesia is a phenomenon of increased
pain report and sensitivity to nociceptive stimuli at sites
distant to the primary injury, and is thought to involve
central sensitization (11). The literature relating to models
of musculoskeletal pain suggest that OA is associated with
enhanced nociceptive transmission at the dorsal horn
(12,13), a hallmark of secondary hyperalgesia. This enhanced excitability of dorsal horn neurons to nociceptive
inputs is termed central sensitization, and is manifested by
Functional MRI Evidence of Central Sensitization in Hip OA
1) increased response to input from an injured or inflamed
region, 2) increased response from regions adjacent to or
remote from the injured/inflamed region, and 3) expansion
of the receptive field of the spinal cord neuron (14). As
such, secondary hyperalgesia that is seen in patients with
OA offers a peripheral manifestation of central sensitization that can be experimentally confirmed.
It is increasingly appreciated that the descending pain
modulatory system with its inhibitory and facilitatory
components (15) directly modulate nociceptive processing
in the dorsal horn. Descending facilitation plays a pivotal
role in the maintenance of central sensitization and accounts for the chronicity of pain states where central sensitization is a component (15–18).
Animal studies have clearly proven that brainstem influences on dorsal horn excitability play a role in experimental pain models involving altered peripheral sensitivity (17,19). Furthermore, previous and current work from
our laboratory has translated these findings from animal
studies to humans using functional neuroimaging, identifying that brainstem areas within the descending modulatory network are involved in the amplification of noxious
mechanical stimuli in the area of secondary hyperalgesia
(20,21). This work has also highlighted that brainstem
regions are modulated by pharmacologic agents effective
at treating neuropathic pain patients, providing support
for their use as markers of central sensitization in humans.
Therefore, based on our previous findings that use brainstem activity as a marker for central sensitization and other
human literature supporting abnormalities in brainstem
processing in patients with chronic pain (22–25), we hypothesize that in patients with OA, referred pain and altered skin sensitivity are likely to involve increased activity within the brainstem modulatory network in response
to noxious mechanical provocation within their areas of
referred pain. We focus this first application to OA on the
periaqueductal grey (PAG) matter because it has been most
commonly reported as abnormal across all of these studies.
We believe that by confirming the presence of hyperalgesia and increased brainstem involvement in the pain
manifestations experienced by patients with OA, this will
have significant implications in future rational analgesic
therapy. Specifically, it will provide a rationale for exploring pharmacologic modulation of central sensitization,
either directly (e.g., with agents reducing spinal hyperexcitability) or indirectly (e.g., by attenuating descending
facilitation or facilitating descending inhibition) in OA
patients with clinical and/or sensory signs of central sensitization.
SUBJECTS AND METHODS
Subjects. The Central Oxfordshire Research Ethics
Committee provided ethical approval for this study.
Twenty right-handed subjects were recruited from the orthopaedic outpatient clinic of the Nuffield Orthopaedic
Centre, Oxford. All of the subjects had right-sided hip pain
secondary to primary OA of the hip and had been placed
on the waiting list for hip arthroplasty. Subjects were
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excluded if they had previously undergone any form of
orthopaedic surgery.
During the screening interview, subjects were asked
about the presence or absence of referred pain that was
felt along the right thigh. All of the patients seen reported
this phenomenon. Subject selection was confirmed after
screening for other chronic pain conditions, diabetes, and
neurologic or psychiatric disorders.
Controls. Twelve healthy right-handed control subjects
were recruited through poster advertisements within our
institution. Subjects were selected after screening for previous history of arthritis, chronic pain conditions, diabetes, and neurologic or psychiatric disorders.
In both the patient and control groups, written informed
consent was obtained. All of the subjects underwent comprehensive verbal screening to ensure that they did not
meet any of the exclusion criteria for magnetic resonance
experimentation.
Methods. Patients and controls were invited to attend
our unit, where a process of behavioral, psychophysical,
and functional imaging experimentation took place, as
outlined in Figure 1.
Behavioral testing began with the completion of a number of self-administration questionnaires: the Beck Depression Inventory (BDI) (26), the Pain Catastrophizing Scale
(PCS) (27), the Tampa Scale for Kinesiophobia (TSK) (28),
the State Anxiety Index (STAI) and Trait Anxiety Index
(TRAI) (29), and PainDETECT (30). PainDETECT has been
developed and validated for the purpose of identifying
neuropathic elements of a patient’s pain (30,31). The result
is a composite score ranging from 0 to 39, where higher
scores are more suggestive of neuropathic pain and lower
scores are indicative of the pain being nociceptive.
Following the completion of the questionnaires, all of
the subjects and controls underwent a detailed examination prior to imaging in line with quantitative sensory
testing (QST) protocols developed by the German Research
Network on Neuropathic Pain (32). The elements of QST to
be applied in the study were chosen after pilot work (data
not shown) demonstrated the high yield of sensory abnormalities in patients with hip arthritis for the following
domains: punctate stimulus detection threshold, punctate
hyperalgesia, changes in thermal perception thresholds,
and thermal pain threshold levels. For the chosen elements (punctate and thermal stimuli), a standardized protocol was developed that exactly replicated the methodologic techniques described by the German Research
Network on Neuropathic Pain (32).
Magnetic resonance imaging (MRI) data acquisition.
Imaging was conducted using a 3T Varian-Siemens wholebody MR scanner (Varian, Palo Alto, CA). A head-only
gradient coil was used with a birdcage radiofrequency coil
for pulse transmission and signal reception. A whole-brain
gradient echo-planar imaging sequence was used to acquire blood oxygenation level– dependent (BOLD) functional images with an echo time (TE) of 30 msec (43 contiguous 3-mm–thick slices, 64 ⫻ 64 matrix, field of view
224 ⫻ 224, voxel size 3.5 ⫻ 3.5 ⫻ 3.5 mm3). The repetition
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Gwilym et al
Figure 1. Illustration of the experimental paradigm performed by the subjects. All parts of
the paradigm were performed on the same day. BDI ⫽ Beck Depression Inventory; PCS ⫽
Pain Catastrophizing Scale; TSK ⫽ Tampa Scale for Kinesiophobia; STAI ⫽ State Anxiety
Index; TRAI ⫽ Trait Anxiety Index; vF ⫽ von Frey.
time (TR) was 3 seconds, with 260 and 140 volumes collected for the cold and punctate stimuli experiments, respectively. The first 5 volumes were discarded to permit
equilibration of the BOLD signal. After acquisition of the
functional scans, a T1 structural scan was acquired using a
3-dimensional fast low-angle shoot sequence with inversion recovery (TR 204 msec, TE 5.56 msec, inversion recovery time 1,100 msec, flip angle 8°, isotropic volume
acquisition, rectangular field of view, voxel size 1 mm3) for
coregistration purposes.
Stimuli. Cold stimuli. Cold stimuli were generated using a 30 ⫻ 30 –mm ATS thermode (Medoc, Ramat Yishai,
Israel) and applied to an area of skin 5 cm distal and 2 cm
anterior to the greater trochanter of the right hip while
functional MRI acquisitions were obtained.
During piloting, and based on normal range data for
thermal cutaneous pain sensitivity on the lower extremity,
it was established that a cold thermal stimulus of 12°C
applied for 10 seconds would be used to dichotomize
subjects into those who were normoesthetic to cold pain
and those who were hypoesthetic to cold pain. The thermode cycled through a cooling/warming paradigm 8
times, as shown in Figure 1.
After the scanning session, subjects were asked to rate if
the cold stimulus was painful (stinging, burning, or prickling) during the experiment or not. Twelve of the patient
group and all 12 of the control group underwent cold
stimuli. The remaining 8 patients in the patient group did
not undergo cold experimentation due to equipment failure during the research period.
Punctate stimuli. In the second part of the same functional imaging session, punctate stimuli were applied to an
area 5 cm distal and 2 cm anterior to the greater trochanter using a 256-mN von Frey hair (MARSTOCKnervtest2,
Fruhstorfer, Germany) while functional MRI scanning took
place. A total of 15 stimuli were applied over a 7-minute
experimental period, guided by a predetermined timing
model incorporating a jitter for optimal event-related sampling of the BOLD response. All 20 patients and 12 controls underwent punctate stimulation during functional
MRI scanning. Subjects were instructed to keep their
eyes closed and to keep as still as possible during the
experiments.
Analysis of stimulus-evoked functional MRI signal
changes. The process of functional MRI analysis was performed as detailed in our previous study (33). All of the
analyses were performed using the Centre for Functional
MRI of the Brain (FMRIB) Expert Analysis Tool, version
5.67, which is part of the FMRIB Centre Software Library
(online at www.fmrib.ox.ac.uk/fsl).
The following standard preprocessing was applied to
each subject’s time series of functional MRI volumes: nonbrain removal using a brain extraction tool (34), motion
correction (35), spatial smoothing using a Gaussian kernel
of full width at half maximum of 5 mm, demeaning of each
voxel time course, and nonlinear high-pass temporal filtering (cutoff of 100 seconds).
The functional MRI signal in response to thermal or
punctate stimulation was modeled using a general linear
model approach. The regressor of interest was constructed
by convolving the stimulus input function with a gamma
hemodynamic response function (mean ⫾ SD lag time 6 ⫾
3 seconds). The estimated time courses of the head motion
parameters (translation in the x, y, and z direction and
rotation about the x, y, and z axis) were included as covariates of no interest to further control for the subject
movement.
Brain registration included coregistration of the functional scan onto the individual T1 high-resolution structural image, and then registration onto a standard brain
(Montreal Neurological Institute 152 brain, Montreal, Quebec, Canada) using the FMRIB Centre Nonlinear Image
Registration Tool.
For individual subject analysis, a general linear model
was applied to these data on a voxel-by-voxel basis using
the FMRIB Centre improved linear model to produce parameter estimates of the BOLD response to thermal and
mechanical stimulation.
All of the group analyses were performed using the
FMRIB Centre Local Analysis of Mixed Effects (36).
Functional MRI Evidence of Central Sensitization in Hip OA
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Table 1. Results of psychophysical testing performed in line with the quantitative
sensory testing methods described by the German Research Network on
Neuropathic Pain*
Punctate detection threshold, median mN
Cool detection threshold, °C
Warm detection threshold, °C
Cold pain detection threshold, °C
Heat pain detection threshold, °C
Sharpness of 256-mN stimulus (log10)§
Patients,
right side
(n ⴝ 12)
Controls,
right side
(n ⴝ 12)
P
0.5
27.4 ⫾ 1.73
37.3 ⫾ 2.6
8.3 ⫾ 13.2
44.6 ⫾ 2.3
1.37 ⫾ 0.30
16
27.0 ⫾ 1.48
36.2 ⫾ 1.64
12.2 ⫾ 11.6
45.7 ⫾ 2.7
1.12 ⫾ 0.23
⬍ 0.001†
0.556‡
0.215‡
0.862†
0.298†
0.028‡
* Values are the mean ⫾ SD unless otherwise indicated. Results show the actual and statistical differences
between skin sensitivity in the region of referred pain in patients and an identical area of skin in control
subjects.
† By Mann-Whitney test between groups.
‡ By unpaired t-test between groups.
§ The results reported by subjects in response to stimulation with a 256-mN von Frey hair, measured
using a rating scale of 0 –100, showed that patients found this punctate stimulation significantly more
sharp/painful (median sharpness rating of 12.9 and 29.4 for the control and patient groups, respectively).
However, because the data are not normally distributed, they are reported as their logarithmic transform
to generate normally distributed data for statistical analysis so they can be compared with those produced
by the German Research Network on Neuropathic Pain (35).
Several conditions were explored: 1) punctate stimuli
from both patient and control groups (n ⫽ 12), 2) cold
stimuli from both patient and control groups (n ⫽ 12), and
3) punctate data from the patient group with low
PainDETECT scores and punctate data from the patient
group with high PainDETECT scores, grouped using a
median split of their scores. Unfortunately, cold data for
the patients (n ⫽ 20) were incomplete due to equipment
problems during the course of the study, and therefore
comparisons of cold pain processing between high and
low PainDETECT groups was not possible. For the purpose
of group analysis, the significance threshold was Z scores
greater than 2.3, with a cluster threshold of P values less
than 0.05 to correct for multiple comparisons.
Finally, based on the a priori hypothesis of activation
within the brainstem descending modulatory PAG region
being present in patients with cutaneous areas of referred
pain and secondary hyperalgesia, this anatomic region was
masked by hand on each of the subjects’ high-resolution
structural scans, and a region of interest analysis was
performed as described by previous authors (37). The
mean volume of the PAG mask was 15 voxels (643 mm3).
RESULTS
Behavioral and psychophysical results. Both the patient
and control groups had a similar ratio of men to women
(6:6 and 5:7, respectively), with a mean ⫾ SD age of
63 ⫾ 8 years and 64 ⫾ 9 years, respectively. The high
PainDETECT and low PainDETECT groups also had similar demographics (6:4 and 5:5 for the sex ratio, respectively, and a mean ⫾ SD age of 67 ⫾ 8 years and 62 ⫾ 8
years, respectively).
Analysis of the data obtained by the questionnaires
showed no significant difference between the patient and
control groups for the following domains: BDI (mean ⫾ SD
3.92 ⫾ 4.62 and 6.67 ⫾ 4.23, respectively; P ⫽ 0.14 by
Student’s t-test), STAI (mean ⫾ SD 46.92 ⫾ 5.18 and
43.75 ⫾ 7.10, respectively; P ⫽ 0.280 by Mann-Whitney
test), TRAI (mean ⫾ SD 46.83 ⫾ 2.70 and 46.58 ⫾ 3.66,
respectively; P ⫽ 0.954 by Mann-Whitney test), and PCS
(mean ⫾ SD 11.17 ⫾ 0.64 and 13.17 ⫾ 10.39, respectively;
P ⫽ 0.613 by Student’s t-test).
Significant differences were found between the controls
and patients for the following domains: TSK (mean ⫾ SD
22.5 ⫾ 8.37 and 31.33 ⫾ 5.61, respectively; P ⫽ 0.006 by
Student’s t-test), PainDETECT (mean ⫾ SD 0 ⫾ 0 and
12.33 ⫾ 5.55, respectively; P ⬍ 0.001 by Mann-Whitney
test), and average pain score over the last 4 weeks (mean ⫾
SD 0 ⫾ 0 and 5.56 ⫾ 2.02, respectively; P ⬍ 0.001 by
Student’s t-test).
The QST data were assessed for normality of distribution and logarithmic transforms applied to non-normally
distributed data, which is in line with previous descriptions (32). Parametric statistics were applied where normality was seen in the original or transformed data. The
results of this analysis are shown in Table 1.
Imaging results. During functional MRI data acquisition, patients were asked to identify discomfort (described
as stinging, pricking, or pain) during the cold pain paradigm. Nine subjects in the control group felt discomfort,
whereas only 4 of the patients recorded similar sensations
(P ⬍ 0.05 by chi-square test).
A comprehensive list of activated areas for all conditions for the controls and patients is shown in Table 2,
with representative images of these same activations
shown in Figure 2.
Supporting the psychophysical data, where significantly more controls than patients found the cold stimuli
painful, the mixed-effects analysis with the thresholds of
Z score ⬎2.3 and P ⬍ 0.05 showed significant activation
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Gwilym et al
Table 2. Areas of brain activation induced by different stimuli applied to the area of
referred pain on the right thigh in patients and a matched area in controls*
Punctate stimuli in Punctate stimuli in Cold stimuli in
the patient group the control group the control group
Right insula
Left insula
Right SII
Left SII
Right SI
Left SI
Right lateral occipital cortex
Left premotor cortex
Right premotor cortex
Right middle temporal gyrus
Left middle temporal gyrus
Left supramarginal gyrus
Right supramarginal gyrus
Left anterior cingulate cortex
Right precentral gyrus
Left precentral gyrus
Right middle frontal gyrus
Left middle frontal gyrus
Left frontal pole
Right angular gyrus
3.93
4.13
4.31
4.67
4.27
4.33
3.70
3.06
4.26
4.22
3.67
3.62
4.32
-
3.82
4.38
4.63
5.18
4.76
4.97
4.28
4.71
-
3.66
3.19
3.75
3.9
3.44
3.98
3.54
3.46
3.51
2.94
3.75
* Values are the peak Z score activity from the mixed-effects group analysis (corrected for multiple
comparisons, Z score ⬎2.3, P ⬍ 0.05). Threshold activation was not achieved for any brain area on
whole-brain analysis of the cold stimuli in the patient group at a Z score ⬎2.3.
SII ⫽ secondary somatosensory cortex; SI ⫽ primary somatosensory cortex.
in brain areas associated with pain perception when considering the contrast of more controls than patients (data
not shown). There were no significant activations (mixedeffects analysis, corrected for multiple comparisons, Z
score ⬎2.3, P ⬍ 0.05) in the contrast of patients ⬎ controls
in response to the cold stimulus.
Considering punctate stimulation, the contrast analysis
between the patient group and the control group, however,
revealed significantly greater activation in the patient
group in the following regions: the anterior cingulate cortex, the right dorsolateral prefrontal cortex, the left middle
frontal gyrus, and the left lateral occipital cortex (mixedeffects analysis, corrected for multiple comparisons, Z
score ⬎2.3, P ⬍ 0.05). This patient group also reported this
stimulus as significantly more sharp compared with the
control group (P ⫽ 0.028 by unpaired t-test). There were no
activations that achieved threshold significance (Z score
⬎2.3, P ⬍ 0.05) for the reverse contrast (controls ⬎ patients).
Considering the whole-brain group means and contrasts
between experimental groups (patient group mean, control
group mean, patients ⬎ controls, and controls ⬎ patients),
region of interest masks were applied to the PAG region
based on our a priori hypothesis. The same group means
and contrast analyses were performed, but limiting the
results to this region of interest. The results of these analyses are shown in Figure 3A, and show an increased PAG
activity in response to punctate stimulation of the referred
pain area in patients (and homologous area in controls)
compared with controls (patients ⬎ controls, mixed-effects analysis, corrected for multiple comparisons, Z score
⬎2.3, P ⬍ 0.05).
Secondary analysis on our region of interest was
done after performing a median split of the patients’
PainDETECT questionnaire scores into a low group and
a high group. From this, low PainDETECT and high
PainDETECT groups of patients were derived (mean ⫾ SD
score 5.0 ⫾ 2.16 and 17.7 ⫾ 3.23, respectively; P ⬍ 0.0001
by Student’s t-test). These groups therefore represent those
patients who display less (low PainDETECT score) and
more (high PainDETECT score) neuropathic-like symptoms.
From a psychophysical perspective, there was a significant difference between the high and low PainDETECT
groups in terms of how they rated the punctate stimulus,
with the high PainDETECT group rating sharpness of
the punctate stimulus significantly higher than the low
PainDETECT group (mean ⫾ SD sharpness rating 22.3 ⫾
16.1 and 48.5 ⫾ 25.2, respectively; P ⬍ 0.05 by Student’s
t-test).
The imaging data derived from contrasting the activity
in the PAG region of interest in response to punctate
stimulation for the contrast of more high PainDETECT
scores than low PainDETECT scores are shown in Figure
3B. This clearly shows a significantly increased PAG
activity in response to punctate stimulation of the referred pain area in the high PainDETECT group compared
with the low PainDETECT group (mixed-effects analysis,
corrected for multiple comparisons, Z score ⬎2.3, P ⬍
0.05).
The relationship between PAG activation and clinical
manifestation of central sensitization in patients, as defined by their PainDETECT score, is further shown by
the significant positive correlation of these 2 variables
(Figure 4).
Functional MRI Evidence of Central Sensitization in Hip OA
Figure 2. Results of a mixed-effects analysis of the average group response for the 2 groups
(controls and patients) in response to the 2 stimuli (cold and punctate). All of the results are
corrected for multiple comparisons (Z score ⬎2.3, P ⬍ 0.05). The images shown are z ⫽ 8 and
y ⫽ ⫺18, and are representative. All areas of activation above the threshold limits are listed
in Table 2. Images are shown anatomically. SI ⫽ primary somatosensory cortex; SII ⫽
secondary somatosensory cortex; ACC ⫽ anterior cingulate cortex.
Figure 3. A, Mixed-effects group analysis for periaqueductal grey (PAG) activation for the
contrast of patients ⬎ controls in response to punctate stimuli (masked for PAG, thresholds
of Z score ⬎2.3 and P ⬍ 0.05, corrected for multiple comparisons). B, Mixed-effects group
analysis for PAG activation for the contrast of high PainDETECT ⬎ low PainDETECT
(analysis masked for the PAG, thresholds of Z score ⬎2.3 and P ⬍ 0.05, corrected for
multiple comparisons).
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Figure 4. Correlation between clinical manifestations of central
sensitization (as shown by total score on the PainDETECT) and
periaqueductal grey (PAG) activation in response to punctate
stimulation in patients. Activation is defined using the percentage
change in the parameter estimate of the peak active voxel (vmax)
within the masked region of interest of the PAG (r ⫽ 0.60, P ⫽
0.006).
DISCUSSION
The discordance between the degree of articular pathology
and pain experienced by patients with OA is a longstanding and validated observation. This anomaly may be partly
explained by the variable modulation exerted on the
peripheral nociceptive input to the spinal dorsal horn
between individuals from the descending modulatory system. These descending systems affect dorsal horn excitability and as a result, cause the individual to alter the
magnitude of nociceptive inputs relayed to supraspinal
structures, where these signals are further processed to
produce the experience of pain.
In addition to the variability in pain perception with
OA, some patients experience symptoms considered more
typical of neuropathic pain, such as sudden electric shock
sensations, allodynia, and referred pain. We first used the
patient history of referred pain, and then the presence of
neuropathic-like elements of pain identified by the questionnaires plus alteration in the results of QST, to identify
patients with specific neuropathic-like symptoms. We
considered several of these symptoms to be manifestations
of central sensitization, with the aim of investigating, by
the use of functional neuroimaging, the involvement of
supraspinal structures capable of modulating spinal nociceptive transmission.
Central sensitization in musculoskeletal disease identified by lowered pressure pain thresholds (6,38), increased
area of referred pain secondary to induced muscle pain
(39), and hyperalgesia to mechanical stimuli (5,8) have
been previously reported, and our results for punctate
stimulation (Table 2) confirm these findings in the areas of
referred pain in our cohort of patients with hip OA.
The work described here attempted to address the mechanisms behind these observations. The need for such insights in order to develop rational new therapies for OA
pain has been recently highlighted (38). Functional MRI is
Gwilym et al
used because it offers a valid method of identifying how
and where pain processing occurs in the human brain
(40,41), and also important, how this process differs between groups.
Activation within the brain areas associated with pain
perception is shown in Figure 2. These results parallel the
psychophysical response of the 2 groups to the stimulation
modalities. Pain perception by the control group in response to cold stimulation, and by both groups in response
to punctate stimulation, is associated with activity in areas
commonly associated with the pain experience (primary
and secondary somatosensory cortices, insular and prefrontal cortices). An absence of perceived pain in the patient group exposed to cold stimulation was associated
with a lack of activation of similar pain-relevant brain
regions. Significant behavioral punctate hyperalgesia in
the patient group compared with the normoalgesic control
group was associated with additional activity in the patients’ anterior cingulate cortex and ipsilateral dorsolateral
prefrontal cortex, together with the contralateral left middle frontal gyrus and left lateral occipital cortex activity.
Other studies published in the literature investigating different clinical conditions with possible central sensitization present but not characterized as done in this study
have shown additional active brain areas when compared
with controls (42,43). However, those studies are methodologically quite different from ours in terms of stimulus
modality and data analysis; additionally, those patients
experienced higher pain compared with patients in our
study and it is likely that this fact mostly accounts for any
differences.
In response to punctate stimulation in the patient group,
the activation defined using a region of interest PAG mask
is significantly greater compared with controls (Figure
3A). This is associated with clinical hyperalgesia to the
stimulus.
The a priori hypothesis that the brainstem would be
preferentially activated in conditions where neuropathiclike symptoms are present was based on previous work
investigating brainstem activity in experimentally induced
secondary hyperalgesia and central sensitization (16,
20,21). We can therefore perhaps consider activity within
the brainstem to be a biomarker of central sensitization in
humans. Figure 3A shows a key finding from our study:
that punctate hyperalgesia in patients is indeed associated
with significant PAG activity compared with controls,
which is in line with our a priori hypothesis.
The observation of increased brainstem activation during punctate hyperalgesia is further explored in Figure 3B
by the division of the patients into 2 groups using the
median split of their PainDETECT scores. The group with
higher PainDETECT scores, who also had significantly
greater ratings of punctate hyperalgesia on sensory testing,
showed a significantly higher activation in the PAG region
compared with patients with less neuropathic symptoms
and signs. It therefore appears that PAG activity is related
to the clinical manifestations of disease rather than the
presence of disease alone, and this is further supported by
the significant positive correlation between PainDETECT
scores and PAG activity (Figure 4).
One potential confound in this study is the differences
Functional MRI Evidence of Central Sensitization in Hip OA
in medication use by the various groups of patients
(controls versus patients, high PainDETECT versus low
PainDETECT scores). Although both the patients and controls were excluded from the study if they were taking
neuroleptic medications, there were predictable differences in the uptake of other categories of medications
between patients and controls. Specifically, the patients
were significantly more likely to be taking opioids and
nonsteroidal antiinflammatory drugs (NSAIDs; P ⬍ 0.001
by chi-square test). The uptake of other categories of medications (antihypertensives, others) was not significantly
different between the patients and controls. Between the
high PainDETECT score and low PainDETECT score
groups, there were no significant differences in the uptake
of any category of medications (opioid analgesics, NSAIDs,
antihypertensives, others; P ⬎ 0.05 using chi-square analysis for all comparisons).
Current analgesic treatments address both peripheral
and central processes in pain perception, although the bias
within the arthritis field remains toward the periphery
(44). Animal studies using arthritis models investigating
the analgesic efficacy of centrally acting compounds
known to be effective in neuropathic conditions (i.e., gabapentin) support the view that targeting both the peripheral
origin and central promoters of pain may be a valuable
approach in OA (45). Furthermore, there is some clinical
evidence of efficacy in OA of duloxetine, a monoamine
reuptake inhibitor (46), suggesting that at least some patients with painful OA may benefit from treatments targeting endogenous pain modulatory systems. Our results in
humans support these new findings, and describe some
neural markers that can be used to select patients whose
pain is exacerbated and confounded by the likely presence
of central sensitization.
Pain in OA is often associated with hyperalgesia, referred pain, and spontaneous pain (pain at rest) (47,48).
These features cannot be explained by peripheral changes
and peripheral sensitization alone. We have shown in
humans that the PAG matter is involved in the neuroplasticity associated with central sensitization in osteoarthritic pain. In the future, a mechanism-based classification of the differing manifestations of osteoarthritic pain
will promote development of mechanism-aligned analgesic strategies.
To our knowledge, this work is the first to explore the
supraspinal mechanisms that underlie the clinical manifestations of referred pain and changes in skin sensitivity
in OA patients. The need for such information has been
recently highlighted (38). Understanding the implications
of these bedside observations may allow patient care to be
directed toward their individual pain phenotype, with
patients displaying signs of central sensitization having
both the peripheral and central components to their pain
managed to improve patient outcomes.
ACKNOWLEDGMENTS
The authors would like to thank the surgeons at the
Nuffield Orthopaedic Centre, Oxford, for their assistance
in identifying suitable patients for this study.
1233
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved the final version to be published. Dr. Gwilym had full
access to all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Study conception and design. Gwilym, Keltner, Carr, Chessell,
Tracey.
Acquisition of data. Gwilym, Keltner, Warnaby.
Analysis and interpretation of data. Gwilym, Keltner, Chizh,
Tracey.
ROLE OF THE STUDY SPONSOR
GlaxoSmithKline was involved in the hypothesis generation,
study design, and partial funding of the project. The content of the
manuscript was approved by our GlaxoSmithKline collaborators,
but publication of the manuscript was not contingent on the
approval of GlaxoSmithKline.
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