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Joint inflammation is associated with pain sensitization in knee osteoarthritis: The Multicenter Osteoarthritis Study

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Arthritis & Rheumatology
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Objective: Pain sensitization is associated with pain severity in knee osteoarthritis, but its cause in humans is not well-understood. We examined whether inflammation, assessed as synovitis and effusion on MRI, or mechanical load, assessed as bone marrow lesions (BMLs), were associated with sensitization in knee osteoarthritis. Methods: Subjects in the Multicenter Osteoarthritis Study, a NIH-funded cohort of persons with or at risk of knee osteoarthritis, had knee radiographs and MRIs, and standardized quantitative sensory testing (QST) measures (temporal summation, pressure pain threshold (PPT)) at the wrist and patellae obtained at baseline and two years later. We examined the relation of synovitis, effusion, and BMLs to temporal summation and PPT cross-sectionally and longitudinally. Results: There were 1111 subjects in the study sample (mean age 67, mean BMI 30, 62% female). Synovitis was associated with a significant decrease in PPT at the patella (i.e., more sensitized) over two years (adjusted beta: -0.30, 95% CI -0.52 to -0.08). Effusion was similarly associated with a decrease in PPT at the wrist (-0.24, 95% CI -0.41 to -0.24) and with risk of incident temporal summation (adjusted OR 1.54, 95% CI 1.01-2.36). BMLs were not associated with either QST measure. Conclusion: Inflammation, as evidenced by synovitis or effusion, is associated with pain sensitization in knee osteoarthritis. In contrast, BMLs do not appear to contribute to sensitization in knee osteoarthritis. Early targeting of inflammation is a reasonable strategy to test for prevention of sensitization and through this, reduction of pain severity in knee osteoarthritis. This article is protected by copyright. All rights reserved.
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Joint inflammation is associated with pain sensitization in knee osteoarthritis: The
Multicenter Osteoarthritis Study
1
Tuhina Neogi, MD, PhD
2
Ali Guermazi, MD
2
Frank Roemer, MD
3
Michael Nevitt, PhD
4
Joachim Scholz, MD
5
Lars Arendt-Nielsen, Dr.Med.Sci., PhD
6
Clifford Woolf, MB, BCh, PhD
1
Jingbo Niu, DSc
7
Laurence A. Bradley, PhD
1
Emily Quinn, BSc
8
Laura Frey Law, MPT, MS, PhD
1
Boston University School of Medicine, Clinical Epidemiology Unit, Boston, MA;
2
Boston
University School of Medicine, Radiology, Boston, MA;
3
UCSF, Epidemiology and Biostatistics,
San Francisco, CA;
4
Columbia University College of Physicians and Surgeons, Anesthesiology, NY,
NY;
5
Aalborg University, Health Science and Technology, Aalborg, Denmark;
6
Boston Children’s
Hospital, FM Kirby Neurobiology Center, Boston, MA;
7
University of Alabama at Birmingham,
Clinical Immunology and Rheumatology, Birmingham, AL;
8
University of Iowa Carver College of
Medicine, Physical Therapy & Rehabilitation Science, Iowa City, IA
Running Title: MRI lesions and sensitization in knee OA
Funding Acknowledgement:
Dr. Neogi: NIH P60 AR47785, R01 AR062506
The MOST Study: NIH U01
AG18820, U01 AG18832, U01 AG18947, and U01AG19079
No support from commercial sources
No financial conflicts of interest
Corresponding Author:
Tuhina Neogi, MD, PhD, FRCPC, 650 Albany Street, Suite X200, Clin Epi Unit, Boston, MA, 02118
Fax: 617-638-5239
Email: tneogi@bu.edu
Full Length
Arthritis & Rheumatology
DOI 10.1002/art.39488
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as an
‘Accepted Article’, doi: 10.1002/art.39488
© 2015 American College of Rheumatology
Received: May 29, 2015; Revised: Aug 03, 2015; Accepted: Oct 22, 2015
This article is protected by copyright. All rights reserved.
2
Abstract
Objective: Pain sensitization is associated with pain severity in knee osteoarthritis, but its cause
in humans is not well-understood. We examined whether inflammation, assessed as synovitis
and effusion on MRI, or mechanical load, assessed as bone marrow lesions (BMLs), were
associated with sensitization in knee osteoarthritis.
Methods: Subjects in the Multicenter Osteoarthritis Study, a NIH-funded cohort of persons with
or at risk of knee osteoarthritis, had knee radiographs and MRIs, and standardized quantitative
sensory testing (QST) measures (temporal summation, pressure pain threshold (PPT)) at the
wrist and patellae obtained at baseline and two years later. We examined the relation of
synovitis, effusion, and BMLs to temporal summation and PPT cross-sectionally and
longitudinally.
Results: There were 1111 subjects in the study sample (mean age 67, mean BMI 30, 62%
female). Synovitis was associated with a significant decrease in PPT at the patella (i.e., more
sensitized) over two years (adjusted beta: -0.30, 95% CI -0.52 to -0.08). Effusion was similarly
associated with a decrease in PPT at the wrist (-0.24, 95% CI -0.41 to -0.24) and with risk of
incident temporal summation (adjusted OR 1.54, 95% CI 1.01-2.36). BMLs were not associated
with either QST measure.
Conclusion: Inflammation, as evidenced by synovitis or effusion, is associated with pain
sensitization in knee osteoarthritis. In contrast, BMLs do not appear to contribute to
sensitization in knee osteoarthritis. Early targeting of inflammation is a reasonable strategy to
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test for prevention of sensitization and through this, reduction of pain severity in knee
osteoarthritis.
Introduction
Pain remains the primary symptomatic complaint of persons with knee osteoarthritis, the most
common form of arthritis in the United States,
1
yet the determinants of this pain remain poorly
understood. Identification of key factors leading to pain is critical to improving management of
the symptoms of knee osteoarthritis and preventing the emergence of such symptoms.
Alterations in the neurologic processing of nociceptive signaling leading to an enhanced pain
facilitation has been increasingly recognized as one mechanism by which pain in knee
osteoarthritis may become chronic and persistent.
2
Specifically, an increased responsiveness
(sensitization) of peripheral or central nociceptive neurons appears to contribute to the pain
experience in knee osteoarthritis. Sensitization leads to heightened pain sensitivity, thereby
contributing to a more severe pain experience. Pain sensitization, as assessed by quantitative
sensory testing, has been associated with painful knee osteoarthritis when compared with pain-
free controls,
3-10
and with pain severity independent of knee osteoarthritis severity.
11-13
While
such sensitization may be a promising target for ameliorating pain severity in knee
osteoarthritis, the mechanisms by which this sensory sensitization occurs in humans is
incompletely understood. Addressing this knowledge gap would identify a potentially novel
therapeutic strategy for prevention of the typically inevitable progression of pain worsening in
knee osteoarthritis. In animal models, sustained inflammatory stimuli or mechanical tissue
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injury can lead to peripheral and central sensitization.
14-22
Whether the same types of stimuli
are important in the development of sensitization in humans is not known, however. There is
some suggestion, though, that sensitization may in fact be influenced by genetic predisposition
with generalized lower pain thresholds that may become manifest once nociceptive input from
the osteoarthritic joint is received.
13
On the other hand, it is possible that only certain pathologic features of osteoarthritis, such as
those that are inflammatory or those that reflect mechanical injury of the bone, which is richly
innervated with nociceptors, lead to sensitization. While knee osteoarthritis is traditionally
considered a systemically non-inflammatory arthritis, contemporary studies using magnetic
imaging resonance (MRI) have demonstrated local inflammation as evidenced by synovitis and
effusion; the latter is also often evident clinically. In contrast, bone marrow lesions (BMLs) are
considered to be predominantly (micro-)traumatic lesions related to excessive mechanical load
or remodeling related to tissue injury. Both the inflammatory lesions (i.e., synovitis and
effusion) and BMLs are the primary pathologic lesions that have been consistently associated
with pain in knee osteoarthritis,
23-25
but the mechanism by which they contribute to pain has
not been elucidated. Given the development of sensitization in animal models related to
inflammatory and/or tissue injury, we sought to determine whether inflammatory and
mechanical lesions in knee osteoarthritis are associated with pain sensitization in humans. If
either of these types of lesions were to lead to sensitization, they would be attractive as early
therapeutic targets to prevent the occurrence of sensitization, with the expectation that this
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would in turn prevent the eventual development of chronic and/or more severe pain in knee
osteoarthritis.
Materials and Methods
Study Sample
The Multicenter Osteoarthritis (MOST) Study is a NIH-funded longitudinal cohort of older adults
with or at risk of knee osteoarthritis. At baseline, there were 3026 subjects, aged 50-79, who
were recruited from Birmingham, Alabama and Iowa City, Iowa. Details of the cohort have been
published elsewhere.
26
In brief, subjects were assessed at baseline, 30-months, 60-months, and
84-months with imaging, standardized questionnaires, and objective measures of relevance to
knee osteoarthritis. The institutional review boards at the University of Alabama at
Birmingham, University of Iowa at Iowa City, University of California at San Francisco, and
Boston University Medical Center approved the study protocol.
The current study sample comprised subjects who attended the 60-month and 84-month study
visits; these were the first visits at which standardized quantitative sensory testing, i.e.,
measures of sensitization, were obtained. Eighty-eight subjects who screened positive for
possible peripheral neuropathy
27
were excluded from this analysis. For the purposes of this
study, the 60-month visit will be considered the baseline visit, and the 84-month visit will be
considered the follow-up visit.
MRI Acquisition and Assessment
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MRIs of both knees were obtained on a 1.0 Telsa dedicated extremity unit (ONI MSK Extreme
1.0 T, GE Healthcare, Wilmington, MA) with a circumferential extremity coil using fat-
suppressed fast spin-echo intermediate-weighted sequences in two planes, sagittal (TR = 4800
ms, TE = 35 ms, 3 mm slice thickness, 0 mm interslice gap, 32 slices, 288 x 192 matrix, 2
excitations (NEX), 140 x 140 mm field of view (FOV), echo train length (ETL) = 8) and axial (TR =
4680 ms, TE = 13 ms, 3 mm slice thickness, 0 mm interslice gap, 20 slices, 288 x 192 matrix, 2
NEX, 140 x 140 mm FOV, ETL = 8), and a short tau inversion-recovery (STIR) sequence in the
coronal plane (TR = 6650 ms, TE = 15 ms, TI = 100 ms, 3 mm slice thickness, 0 mm interslice gap,
28 slices, 256 x 192 matrix, 2 NEX, 140 mm
2
FOV, ETL = 8). Examinations were performed at the
University of Alabama at Birmingham and at the University of Iowa at Iowa City using the same
MRI unit at baseline and follow-up. Although these are non-contrast-enhanced sequences,
both synovitis and effusion assessments have been validated using this approach,
28-32
and
synovitis on non-contrast-enhanced MRI has been correlated with macroscopic and microscopic
evidence of inflammation.
33
All subjects in MOST who attended the 60- and 84-month study visits had bilateral knee MRIs
obtained unless there were contraindications or endstage OA was present (i.e., Kellgren and
Lawrence grade 4). For each subject, one knee with acceptable quality MRIs at both time-points
was selected for longitudinal reading; if both knees were eligible for readings, one was
randomly selected. The MRIs were read by four experienced musculoskeletal radiologists,
blinded to clinical and radiographic data, using the Whole-Organ Magnetic Resonance Imaging
Score (WORMS).
34
Synovitis was scored 0-3 in the intercondylar region and infrapatellar fat pad
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(Hoffa’s fat pad), which represent a surrogate for true synovitis,
29
and is known as Hoffa-
synovitis.
28
Effusion was scored 0-3 in the suprapatellar pouch, often referred to as effusion-
synovitis because it reflects a composite of effusion and synovitis on non-contrast enhanced
MRIs.
28,31
BMLs were scored 0-3 in all 14 WORMS’ subregions of the knee, and excluded tibial
spinous BMLs since this region is not subchondral. Examples of each grade of each MRI lesion
are provided in Figure 1. The ranges of weighted kappas for inter-reader reliability among all
four readers for presence vs. absence of each feature were: 0.80-0.89 for BMLs; 0.16-0.60 for
synovitis; and 0.57-0.86 for effusion.
Quantitative Sensory Testing
Pressure pain threshold (PPT), a measure of sensitivity to pain evoked by mechanical
stimulation of nociceptors,
35-37
can be reliably assessed in knee osteoarthritis with pressure
algometry.
4-7,9,13
We obtained PPTs at baseline and follow-up 24 months later at both patellae
and at the wrist, as published previously.
13
In brief, PPT assessed at a diseased site (e.g., knee
with osteoarthritis) is thought to reflect peripheral sensitization, while when assessed at a
distant, normal site (e.g., wrist), it is thought to reflect central sensitization, or a generalized
level of pain sensitivity. PPT was assessed by applying an algometer (1cm
2
rubber tip; Wagner,
FDIX25, Greenwich, CT) at a rate of 0.5 kg/second as the point at which participants verbally
indicated the pressure first changed to slight pain. The PPT at each anatomic site was calculated
by averaging 3 trials; the position of the algometer was slightly altered with each trial to avoid
sensitization at the test site. Lower PPTs represent a greater degree of sensitization or pain
sensitivity.
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Mechanical temporal summation, an augmented response to repetitive mechanical stimulation,
is a sensitive and valid measure of central pain amplification, a feature of central sensitization,
in knee OA.
9,11,13
Mechanical temporal summation was assessed at baseline and follow-up 24
months later using a weighted 60g monofilament (Aalborg University, Denmark) at the patellae
and wrist, as previously described.
13
In brief, subjects provided a numerical pain rating (0-10) to
an initial trial of 4 stimulations, followed by a pain rating at the end of a train of 30 stimulations
applied at a frequency of 1 Hz, and again 15 seconds post-stimulation (“after-sensations”).
Temporal summation was defined as being present when, compared with the initial trial, the
subject reported increased pain following the repeated mechanical stimulation at the site being
tested.
Assessors were blinded to clinical and imaging data. Fourteen-day test-retest reliability for PPT
was 0.85-0.90 (intra-class coefficients) and for temporal summation was 0.61 (kappa).
We refer to these measures as ‘sensitization’ hereafter, but acknowledge that they may also
reflect heightened pain sensitivity.
Potential confounders
Potential confounders included age, sex, body mass index (BMI), race, study site, radiographic
osteoarthritis severity (Kellgren and Lawrence grade for the tibiofemoral joint, and presence of
patellofemoral osteoarthritis), depressive symptoms (Center for Epidemiologic Studies
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Depression Scale
38
), catastrophizing (from the Coping Strategies Questionnaire
39
), widespread
pain using a validated standard homunculus,
40
and use of analgesics (NSAIDs, COX-2 inhibitors,
opiates, acetaminophen).
Statistical Analysis
We defined each MRI feature of interest (i.e., synovitis, effusion, and BMLs) as being present if
their WORMS score was ≥1. For BMLs, we additionally evaluated a “BML burden” as a sum of
the BML scores across all of the subregions.
To examine the relation of these MRI features to baseline presence of pain sensitization,
change in pain sensitization (assessed as change in PPT) over two years, and to the new
development of pain sensitization (assessed as development of temporal summation) over two
years, we performed the following. Among all subjects, we evaluated the relation of each MRI
feature at baseline in separate models to baseline PPT and to change in PPT over two years
using linear regression (change in PPT at both the patella and at the wrist was normally
distributed). We evaluated the relation of each of the MRI features at baseline to baseline
presence of temporal summation and to incident temporal summation (i.e., new development
of summation) over two years among subjects who were free of temporal summation at
baseline using logistic regression. In exploratory analyses, we examined the relation of
persistence and resolution of the MRI features compared with their absence at both time-
points to change in PPT over two years using linear regression. To address the same question
for temporal summation, which is a binary outcome, we used a self-matched case-control
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study, in which subjects who exhibited temporal summation in one visit, but not the other,
were analyzed using conditional logistic regression.
For all analyses, the MRI features were examined in relation to the quantitative sensory testing
measurement in the ipsilateral patella and at the wrist in separate models. All analyses were
adjusted for the potential confounders listed above. Analyses were conducted using SAS
version 9.3 (SAS Institute, Gary, NC).
Results
Of the 1185 subjects whose knee MRIs were read at baseline and follow-up, 1,111 subjects had
quantitative sensory testing at both the patella and the wrist at baseline and follow-up 24-
months later; these subjects were included in the evaluation of the relation of the MRI feature
to baseline quantitative sensory measurement and to change in PPT. Of these subjects, 716
were eligible for the evaluation of the relation of MRI features to incident temporal summation
(i.e., 716 were free of temporal summation at baseline). The mean age of the whole study
sample was 66.9 years (SD 7.5), with a mean BMI of 29.7 kg/m
2
(SD 4.8); 62% were female
(Table 1). Thirty-eight percent had radiographic knee osteoarthritis at baseline, the mean
WOMAC pain score was 2.2 (SD 2.9), and 21% reported frequent knee pain at baseline. The
range of the change in PPT over 24 months at the patella was -7.35 to 7.15 kg/cm
2
; for the
wrist, the range was -6.20 to 7.28 kg/cm
2
.
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At baseline, there was synovitis in 60% of knees, effusion in 66%, and BMLs in 79% on MRI
among the whole study sample (n=1111). When evaluating the relation of these MRI lesions to
the quantitative sensory testing measurements at the patella, we found the following. Among
the whole study sample, those with synovitis at baseline had a statistically significantly lower
PPT at baseline (adjusted beta -0.42, 95% CI -0.67 to -0.18), and a statistically significant
decrease in PPT at the patella 24 months later, indicating that they had become more sensitized
(adjusted beta -0.30, 95% CI -0.52 to -0.08). However, synovitis was not associated with
temporal summation at baseline. Baseline effusion and BMLs were not associated with baseline
PPT, baseline temporal summation, or change in PPT at the patella over 24 months (Table 2).
Among those who were free of temporal summation at baseline (n=716), 22.6% exhibited
temporal summation at the patella 24 months later. In this sample, 62% had synovitis, 67% had
effusion, and 79% had BMLs on MRI at baseline. Knees with synovitis did not have an increased
risk of developing incident temporal summation at the patella (adjusted odds ratio (OR) 1.12,
95% CI 0.75-1.66, p=0.6), but those with effusion at baseline had a 54% increased risk of
incident temporal summation (adjusted OR 1.54, 95% CI 1.01-2.36, p=0.04). BML presence and
BML burden were not associated with risk of incident temporal summation (Table 3).
The relation of the MRI features to the sensory testing measurements at the wrist were as
follows. Baseline presence of synovitis was associated with lower PPT at baseline (adjusted beta
-0.19, 95% CI -0.35 to -0.03), but not with change in PPT at the wrist. In contrast, presence of
effusion was significantly associated with baseline PPT (adjusted beta -0.24, 95% CI -0.40 to -
0.07) and with decreased PPT (greater sensitivity) at the wrist over two years (adjusted beta -
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0.24, 95% CI -0.41 to -0.08, p=0.004) (Table 2). BML presence and burden were not associated
with baseline PPT or change in PPT at the wrist, consistent with the findings at the patella.
Neither synovitis, effusion, nor BMLs were associated with incident temporal summation at the
wrist (Table 3).
Finally, in exploratory analyses, persistence of synovitis over the two time-points was
associated with a decrease in PPT over the same time period at both the patella and wrist,
though not statistically significantly at the patella (patella: adjusted beta -0.24, 95% CI -0.54 to
0.06; wrist: adjusted beta -0.26 (-0.48 to -0.03)). In contrast, resolution of synovitis was not
associated with a change in PPT. Similarly, persistence of effusion was associated with a
decrease in PPT over two years (adjusted beta -0.27, 95% CI -0.46 to -0.09), but its resolution
was not associated with change in PPT. Persistence or resolution of BMLs was not associated
with change in PPT. There were no significant associations for change in any MRI feature with
change in temporal summation in the self-matched case-control study (data not shown).
Discussion
We have, for the first time, examined the relation of inflammatory lesions (synovitis and
effusion) and BMLs, which are thought to be largely reflective mechanical injury, to concurrent
and longitudinal change in pain sensitization in a large, well-characterized cohort. Congruent
with animal models of sensitization,
14-22
our findings support the potential relevance of
inflammation in the development and heightening of sensitization in knee osteoarthritis in
humans. We found that synovitis was associated with lower PPT and a decrease in PPT at the
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patella over time, indicating increased pain sensitization or sensitivity. Effusion was associated
with development of new temporal summation at the patella, and with a decrease in PPT at the
wrist, a site distant to the site of pathology; both findings suggest the involvement of central
sensitization. Thus, inflammation appears to influence the development of and perhaps
amplification of sensitization. In addition, in our exploratory analyses, we found that
persistence of synovitis and effusion were associated with a decrease in PPT over time,
primarily at the wrist, suggesting spreading sensitization over time. In contrast, resolution of
these inflammatory features on MRI did not result in a significant change in PPT, suggesting
that perhaps once sensitization or heightened sensitivity has occurred, removal of the
inflammatory stimulus may not be sufficient to alter the sensitization. This may also explain
why we found no change in temporal summation with change in these MRI features. In
contrast, BML presence and burden were not associated with either measure of sensitization.
This would imply that in human knee osteoarthritis, tissue injury per se may not influence
sensitization. Thus, BMLs appear to contribute to the pain experience through mechanisms that
are not directly related to sensitization.
The differences we found in the relations of synovitis and of effusion with our measures of
sensitization, and in the findings at the patella and at the wrist merits discussion. Inflammation
of the synovium manifests as activation of the synovial membrane, i.e., synovial thickening, or
joint effusion. In the current study, synovitis was assessed using the surrogate imaging marker
of Hoffa-synovitis (i.e., assessed as hyperintensity in the infrapatellar (Hoffa’s) fat pad on fluid-
sensitive fat-suppressed sequences). This is a sensitive but non-specific marker of synovial
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inflammation and cannot distinguish inflamed synovium from other entities such as mechanical
impingement of the fat pad or hypervascularity for other reasons.
41,33
Thus Hoffa-synovitis may
reflect local effects of inflamed synovium and/or fatty tissue that may lead to local elaboration
of adipokines that could influence local pain sensitivity.
42,43
Effusion was assessed as effusion-
synovitis, which is defined by the presence of fluid-equivalent signal in the joint cavity.
Differences in inflammatory mediators that may be relevant in effusion vs. Hoffa’s fat pad
synovitis are not well understood presently. Distension of the suprapatellar pouch may result in
effects on local pain sensitivity. Additionally, the lack of a blood-synovial barrier may potentially
implicate factors in the systemic circulation. Nonetheless, with non-contrast enhanced MRIs,
we cannot truly differentiate synovitis from effusion, and acknowledge that the signal changes
within Hoffa’s fat pad are non-specific given that the fat pad is an extrasynovial structure.
44
While BMLs are thought to primarily reflect mechanical injury and reparative attempts, we also
recognize that BMLs may have a mixed pathology, including findings consistent with localized
remodeling processes including microtrauma, fibrosis, and foci of necrosis that may have an
additional inflammatory component.
45,46
Nonetheless, unlike in rheumatoid arthritis,
inflammatory cell infiltrate does not appear to be a major feature in knee osteoarthritis.
46
Further, the results were consistently close to the null for the relation of BMLs with each of the
measures of sensitization at both the patella and the wrist.
As it is hypothesized that prolonged exposure to inflammation or tissue injury can induce
sensitization, it is possible that the time exposed to the pathologies is an important factor. It
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may be that in some (or even many) individuals, the MRI features were present for quite some
time, either persistently or in a fluctuating manner, and this could have bearing on our findings,
particularly for temporal summation. Further, our assessment of temporal summation may not
be sufficiently sensitive, as the initial pain ratings were relatively low. Indeed, temporal
summation is most frequently observed with higher initial intensity nociceptive stimuli.
Nonetheless, the differences between the two indirect measures of sensitization may also
suggest that multiple types of assessments may be needed to fully characterize different
aspects of sensitization. The combined effects of coexisting MRI lesions may provide additional
insights; however, this was beyond the scope of the current study. Additionally, there may be
pathology in other joints that we did not assess that could have contributed to pain
sensitization, thereby contributing to exposure misclassification in our study. We also
acknowledge that our findings indicate small effects; however, because factors contributing to
pain sensitization are likely multifactorial, this is not unexpected. As well, pain change over two
years is a relatively short time-frame in the broader context of knee osteoarthritis, a condition
that individuals often live with for decades.
47
We did not measure conditioned pain modulation
in our study, which may provide additional insights regarding descending inhibition of pain.
However, we were primarily interested in enhanced pain facilitation because of the
hypothesized effects of inflammation and/or injury on causing sensitization.
In conclusion, inflammation within the knee, as related to synovitis and effusion, may drive
peripheral and central sensitization in knee osteoarthritis, consistent with findings from animal
models of osteoarthritis. Since sensitization is associated with pain severity in knee
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osteoarthritis, and may potentially contribute to the transition from acute to chronic, persistent
pain in knee osteoarthritis, preventing sensitization from developing would be a potentially
effective and novel means of preventing worsening of pain in knee osteoarthritis. Early
targeting of inflammation in knee osteoarthritis may therefore be a reasonable strategy to test
for prevention of sensitization, and thereby reduction of pain severity.
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Table 1: Participant Characteristics
Baseline Participant
Characteristics
Whole study sample
(N=1,111)
Study sample that was free
of temporal summation at
baseline (N=716)
Mean age (SD), years 66.9 (7.5) 66.3 (7.4)
% Female 62 61
Mean BMI (SD), kg/m
2
29.7 (4.8) 29.7 (4.8)
% Radiographic knee
osteoarthritis
38 37
% Frequent knee pain 21 20
Mean WOMAC pain (0-20) (SD) 2.2 (2.8) 1.8 (2.7)
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Table 2: Relation of MRI lesions to baseline PPT and change in PPT over 24 months
MRI lesion at baseline
(N=1,111)
(Prevalence)
Patella
Adjusted* beta (95% CI),
p-value
Wrist
Adjusted* beta (95% CI),
p-value
Baseline PPT Change in PPT Baseline PPT Change in PPT
Synovitis (60%)
-0.42
(-0.67 to -0.18)
p=0.0007
-0.30
(-0.52 to -0.08)
p=0.01
-0.19
(-0.35 to -0.03)
p=0.02
-0.10
(-0.26 to 0.06)
p=0.2
Effusion (66%)
0.23
(-0.03 to 0.49)
p=0.08
-0.04
(-0.28 to 0.19)
p=0.7
-0.24
(-0.40 to -0.07)
p=0.004
-0.24
(-0.41 to -0.08)
p=0.004
BML (79%)
0.14
(-0.16 to 0.44)
p=0.4
0.03
(-0.25 to 0.31)
p=0.8
0.05
(-0.14 to 0.25)
p=0.6
-0.10
(-0.29 to 0.10)
p=0.3
Sum of BMLs (“BML
burden”) (Range: 0-19)
0.03
(-0.01 to 0.08)
p=0.2
-0.01
(-0.05 to 0.04)
p=0.8
0.00
(-0.03 to 0.03)
p=0.9
0.00
(-0.03 to 0.03)
p=1.0
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*Adjusted for age, sex, BMI, race, study site, radiographic OA severity, depressive symptoms,
catastrophizing, widespread pain, and analgesic use.
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Table 3: Relation of MRI lesions to baseline temporal summation and incident temporal
summation over 24 months
MRI lesion at baseline
(Prevalence)
Patella
Adjusted* OR (95% CI),
p-value
Wrist
Adjusted* OR (95% CI),
p-value
Baseline
temporal
summation
(N=1,111)
Incident
temporal
summation
(N=716)
Baseline
temporal
summation
(N=1,111)
Incident
temporal
summation
(N=716)
Synovitis (62%)
0.83 (0.63-1.08)
p=0.2
1.12 (0.75-1.66)
p=0.6
0.84 (0.64-1.10)
p=0.2
1.22 (0.85-1.75)
p=0.2
Effusion (67%)
0.89 (0.67-1.18)
p=0.4
1.54 (1.01-2.36)
p=0.04
1.13 (0.85-1.51)
p=0.4
0.94 (0.66-1.35)
p=0.7
BML (79%)
0.95 (0.68-1.32)
p=0.8
0.92 (0.56-1.49)
p=0.7
1.04 (0.74-1.45)
p=0.8
1.05 (0.68-1.62)
p=0.8
Sum of BMLs (“BML
burden”) (Range: 0-19)
0.98 (0.93-1.03)
p=0.4
1.00 (0.92-1.07)
p=0.9
0.98 (0.93-1.04)
p=0.5
1.00 (0.94-1.07)
p=1.0
*Adjusted for age, sex, BMI, race, study site, radiographic OA severity, depressive symptoms,
catastrophizing, widespread pain, and analgesic use.
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Figure Legends
Figure 1: Examples of magnetic resonance imaging (MRI) lesion grading. Panel A depicts bone marrow
lesions (BMLs), Panels B and C depict synovitis (Hoffa-synovitis) in the intercondylar and infrapatellar
regions, respectively, and Panel D depicts effusion (effusion-synovitis) on non-contrast-enhanced MRI.
Note that BMLs are assessed on a per-subregion basis summing all BMLs in the subregion with regards
to the percent involved, while Hoffa-synovitis and effusion-synovitis are assessed on a knee basis. The
first column provides examples of grade 1 lesions, the second column provides examples of grade 2
lesions, and the final column provides examples of grade 3 lesions.
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Figure 1
254x190mm (300 x 300 DPI)
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... Most evidence on this topic originates from rodent studies [17]. Previous studies in OA patients have predominantly focused on systemic biomarkers or estimated joint inflammation using imaging methods [14,[18][19][20][21][22]. However, recent recommendations [18,23] advocate for measuring intra-articular levels of biomarkers that reflect the state of the affected joint instead of blood-based circulating levels [18]. ...
... Additionally, Neogi et al. demonstrated an inverse relationship between PPT and synovitis. However, in that study, synovitis was estimated based on the Whole-Organ Magnetic Resonance Imaging Score [20]. ...
Article
Full-text available
Background/Objectives: To investigate if intra-articular biomarkers relate to peripheral and central sensitization in patients with late-stage knee osteoarthritis (KOA). Methods: A total of 17 (6M, 11F) patients (aged 69 ± 10 years) were assessed for peripheral (pressure pain thresholds (PPT)) and central (temporal summation (TS) and conditioned pain modulation (CPM)) sensitization the day before total knee arthroplasty. Synovial fluid was collected during surgery and assayed for IL-6, IL-8, IL-10, TNF-α, CXCL-10, BDNF, NGF, CCL2, CCL5, VEGF, IL-1RI, MMP-1, MMP-7, IL-1β, and CXCL-9. Associations of biomarkers and their combinations reflecting chronic (CXCL-9) and acute ((CCL2×CXCL-10)/IL-10)) inflammation, cartilage degeneration (MMP-1×MMP-7), and neurotrophy (NGF×BDNF) with PPT, TS, and CPM were analyzed by bivariate correlations and by multiple linear regression analyses corrected for BMI, sex, and age. Results: The medial joint line and the superior medial joint region showed the lowest PPT. Higher acute inflammation related significantly to worse pressure tenderness at the superior medial joint region (R² = 0.642; p = 0.010). Cartilage degeneration and chronic inflammation were associated with both absolute (R² = 0.827; p = 0.001) and relative CPM (R² = 0.882; p < 0.001). Acute inflammation and neurotrophy were related to relative TS at the m. tibialis anterior (R² = 0.728; p = 0.02). Conclusions: This study demonstrates that increased levels of intra-articular biomarkers of acute inflammation are related to peripheral sensitization and that biomarkers of cartilage degeneration and chronic inflammation are associated with central sensitization. These results may be a stepping-stone toward a better understanding of the working mechanism of peripheral and central sensitization in KOA pain and the development of more targeted therapeutic interventions.
... For the following 30 seconds, a mechanical stimulus was applied to the same position at one second intervals. 13,23 At the end of 30 seconds, participants were asked to rate their pain on the same verbal NPRS. As with previous work, 13,23 increased pain in response to repeated mechanical stimulation was considered indicative of temporal summation of pain. ...
... 13,23 At the end of 30 seconds, participants were asked to rate their pain on the same verbal NPRS. As with previous work, 13,23 increased pain in response to repeated mechanical stimulation was considered indicative of temporal summation of pain. ...
... Thus, early joint inflammation plays an important role in the pathogenesis of pain in this OA model, besides the structural cartilage damage, which develops about 14 days after MIA injection (Lockwood et al., 2019). In patients with OA, pain sensitization has been shown to be independent of radiographic severity, but appears to be related to synovitis and effusion (Neogi et al., 2015(Neogi et al., , 2016. In addition, there is only a moderate association between structural joint damage and the presence of pain (Hannan et al., 2000;Hunter & Bierma-Zeinstra, 2019). ...
Article
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Background and Purpose Vortioxetine, a multimodal‐acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference. Experimental Approach In the monoiodoacetate (MIA)‐induced rat model of knee OA, pain‐related behaviour was assessed in weight‐bearing and Von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain‐related mediators (Ngf, Il‐1β, Tnf‐α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol. Key Results Vortioxetine and duloxetine dose dependently reduced weight‐bearing asymmetry and mechanical hyperalgesia of the paw ipsilateral to the MIA‐injected knee. Vortioxetine reduced the increased Ngf mRNA expression in the MIA‐injected knees to the level in sham‐injected counterparts. It reduced oxidative stress parameters in the affected knees, more effectively in females than males. Duloxetine showed no effect on Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain‐related mediators in the lumbar L3–L5 ipsilateral DRGs and spinal cords, which were up‐regulated in MIA‐injected rats. This effect was male‐specific. Conclusion and Implications Vortioxetine may be effective against the development of chronic pain in OA. Its antihyperalgesic effect may be mediated, at least in part, by normalization of NGF expression in the affected joint. Decrease of localized oxidative stress and of expression of pain‐related mediators that contribute to central sensitization are also involved in vortioxetine's antihyperalgesic effect, in a sex‐specific pattern.
... Previous studies thought that the pain of KOA patients is caused by regional peripheral afferents injury [46]. However, recent studies have found that central nociceptive sensitization plays a crucial role in KOA, leading to local and widespread nociceptive hyperalgesia in these patients [47][48][49]. tDCS is a non-invasive neuromodulator acting on the central nervous system and can alter neuronal excitability [50][51][52]. Therefore, tDCS may improve endogenous central pain inhibition in elderly KOA patients by attenuating the effects of central sensitization and modulating brain activity that processes pain, resulting in pain relief [53]. ...
Article
Full-text available
Background Keen Osteoarthritis (KOA) is a common chronic disabling disease characterized by joint pain and dysfunction, which seriously affects patients’ quality of life. Recent studies have shown that transcranial direct current stimulation (tDCS) was a promising treatment for KOA. Purpose Investigate the effects of tDCS on pain and physical function in patients with KOA. Methods Randomized controlled trials related to tDCS and KOA were systematically searched in the PubMed, Embase, Medline, Cochrane Library, CINHL, and Web of Science databases from inception to July 23, 2024. The pain intensity was evaluated using the visual analog scale or the numeric rating scale, and the pain sensitivity was assessed using conditioned pain modulation, pressure pain threshold, heat pain threshold, or heat pain tolerance. The physical function outcome was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index or the Knee injury and Osteoarthritis Outcome Score. Statistical analysis was performed using Review Manager 5.4. Results Seven studies with a total of 503 participants were included. Compared to sham tDCS, tDCS was effective in reducing the short-term pain intensity (SMD: -0.58; 95% CI: -1.02, -0.14; p = 0.01) and pain sensitivity (SMD: -0.43; 95% CI: -0.70, -0.16; p = 0.002) but failed to significantly improve the long-term pain intensity (SMD: -0.26; 95% CI: -0.59, 0.08; p = 0.13) in KOA patients. In addition, tDCS did not significantly improve the short-term (SMD: -0.13; 95% CI: -0.35, 0.08; p = 0.22) and long-term (SMD: 0.02; 95% CI: -0.22, 0.25; p = 0.90) physical function in patients with KOA. Conclusions The tDCS can reduce short-term pain intensity and sensitivity but fails to significantly relieve long-term pain intensity and improve the physical function in patients with KOA. Thus, tDCS may be a potential therapeutic tool to reduce short-term pain intensity and pain sensitivity in patients with KOA.
... After sensitization, the elimination of inflammatory stimuli may not be adequate to reverse the sensitization process. 30 To guide clinical decisions and develop intervention measures, it is essential to identify the source of symptoms and understand the relationship between symptoms and disease progression. ...
Article
Full-text available
Objective Weight is an influential factor in knee osteoarthritis (KOA). However, the effect of abnormal body weight on chitosan's efficacy in treating KOA is unclear. This study aimed to explore the differences in the effectiveness of arthroscopic surgery combined with intra‐articular chitosan injection for KOA in patients with abnormal body weight. Methods Patients with stage II‐III KOA (Kellgren–Lawrence rating, K‐L) undergoing arthroscopic surgery were recruited for this clinical study from January 2020 to September 2021. Based on body mass index (BMI) and intra‐articular chitosan injection, patients with KOA undergoing arthroscopic surgery (138 patients) were divided into four groups: low‐weight‐non‐injection (Lw‐N, BMI <18.5); low‐weight‐chitosan injection (Lw‐CS, BMI <18.5); overweight‐non‐injection (Ow‐N, BMI ≥25); overweight‐chitosan injection (Ow‐CS, BMI ≥25). A 2‐year follow‐up was conducted to evaluate various indicators, including the visual analogue scale (VAS) and the Western Ontario and McMaster Universities osteoarthritis index score (WOMAC). Statistical analyses were performed using relevant parametric or non‐parametric tests. Results In total, 138 patients with KOA were included in this study. There were no significant differences in gender, age, and incidence of chronic residual pain after arthroscopy among the four groups (p > 0.05). The proportion of patients undergoing subsequent knee arthroplasty during the 2‐year follow‐up period was significantly higher in the Ow‐CS group (20/35) than in the Lw‐CS group (12/39) (p < 0.05). The K‐L rating showed an overall increasing trend over time, with the K‐L rating in the Ow‐N and Ow‐CS groups significantly higher than that in the Lw‐CS group at the final follow‐up (p < 0.05). VAS and WOMAC scores significantly decreased at 1 and 3 months post‐arthroscopy and then increased. One month after arthroscopy, VAS was significantly lower (p < 0.05) in the intra‐articular chitosan injection groups (Lw‐CS and Ow‐CS) compared with the non‐injection groups (Lw‐N and Ow‐N). VAS was lower in the Ow‐CS group than in the Lw‐CS group (p < 0.05). There was no significant difference in WOMAC between the intra‐articular chitosan injection and non‐injection groups at each time point (Lw‐N vs. Lw‐CS, Ow‐N vs. Ow‐CS, p > 0.05). Conclusion Arthroscopic surgery combined with intra‐articular chitosan injection shows short‐term positive effects in treating KOA. Intra‐articular chitosan injection appears to have a greater short‐term pain relief effect in obese patients.
Article
Objective: To investigate the relationship between sacroiliac joint (SIJ) involvement and central sensitization (CS) in patients with axial spondyloarthritis (axSpA). Patients and Methods: Twenty-four patients with axSpA were included in this study. CS was investigated via pressure pain threshold (PPT), temporal summation (TS), conditional pain modulation (CPM), and the central sensitization inventory (CSI). Sacroiliac joint involvement was assessed using the magnetic resonance imaging (MRI)-based Canadian Spondyloarthritis Research Consortium (SPARCC) scoring system. CS-related parameters and SPARCC score correlations were analyzed. Results: The median (IQR) sacroiliac PPT score for the right SIJ was calculated as 17.47 (4.43) and 17.67 (4.57) for the left SIJ. In the TS measurement, the right SIJ TS median (IQR) value was calculated as 4.0 (3.5) and 4.0 (2.75) for the left side. The median (IQR) value was 149.67 (107.5) for CPM and 45.0 (27.75) for CSI. The median (IQR) sacroiliac inflammation score was calculated as 3.0 (8.75), and the median (IQR) structural score was calculated as 7.0 (11.5). No correlation was found between SPARCC scores and PPT, TS, CPM, and CSI values. Conclusion: In axSpA patients, there was no association observed between pain sensitivity measures and sacroiliac involvement. Further comprehensive studies are required, taking into account the complex nature of CS.
Article
Obesity has a pivotal and multifaceted role in pain associated with osteoarthritis (OA), extending beyond the mechanistic influence of BMI. It exerts its effects both directly and indirectly through various modifiable risk factors associated with OA-related pain. Adipose tissue dysfunction is highly involved in OA-related pain through local and systemic inflammation, immune dysfunction, and the production of pro-inflammatory cytokines and adipokines. Adipose tissue dysfunction is intricately connected with metabolic syndrome, which independently exerts specific effects on OA-related pain, distinct from its association with BMI. The interplay among obesity, adipose tissue dysfunction and metabolic syndrome influences OA-related pain through diverse pain mechanisms, including nociceptive pain, peripheral sensitization and central sensitization. These complex interactions contribute to the heightened pain experience observed in individuals with OA and obesity. In addition, pain management strategies are less efficient in individuals with obesity. Importantly, therapeutic interventions targeting obesity and metabolic syndrome hold promise in managing OA-related pain. A deeper understanding of the intricate relationship between obesity, metabolic syndrome and OA-related pain is crucial and could have important implications for improving pain management and developing innovative therapeutic options in OA.
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Polymodal nociceptors respond to mechanical, thermal and chemical stimuli. Whereas sensitivities to heat and to the irritant substance capsaicin have recently been linked via the properties of the vanilloid receptor type 1 receptor ion channel, sensitivity to noxious mechanical stimuli such as the pinpricks used in clinical neurology seems to be unrelated. We investigated the peripheral neural basis of pinprick pain using quantitative psychophysical techniques combined with selective conduction block by nerve compression and selective desensitization by topical capsaicin treatment. Complete A-fibre block by compression of the superficial radial nerve (criterion: loss of first pain sensation) lowered the stimulus–response function for pinprick pain (–82 ± 6% versus baseline). Topical pretreatment of the skin with a 10% capsaicin cream also lowered the pinprick stimulus–response function (–32 ± 10%), whereas laser-evoked heat pain was eliminated completely (–96 ± 2%). Under combined capsaicin desensitization and A-fibre blockade, pinprick pain was eliminated completely (–98 ± 1%). Intradermal injection of 40 μg capsaicin into normal skin between two skin areas that had been pretreated with either capsaicin cream or vehicle produced secondary hyperalgesia with a 260% enhancement of the stimulus–response function for pinprick pain in both areas. In contrast, axon reflexive flare spread only into the vehicle-treated area. These results suggest that capsaicin-sensitive afferents, including polymodal A-fibre and C-fibre nociceptors, make a small contribution to pinprick pain and that capsaicin-insensitive C-fibres do not contribute significantly to either mechanical or heat pain. Pinprick pain is mediated primarily by capsaicin-insensitive A-fibre nociceptors, which include high-threshold mechanoreceptors and type I mechano-heat nociceptors. In addition, central sensitization to input from these A-fibre nociceptors is the primary mechanism that accounts for the enhanced pain in response to punctate mechanical stimuli in the zone of secondary hyperalgesia. These capsaicin-insensitive A-fibre nociceptors may also mediate hyperalgesia in neuropathic pain.
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Objective Radiographic measures of the pathologic changes of knee osteoarthritis (OA) have shown modest associations with clinical pain. We sought to evaluate possible differences in quantitative sensory testing (QST) results and psychosocial distress profiles between knee OA patients with discordant versus congruent clinical pain reports relative to radiographic severity measures. MethodsA total of 113 participants (66.7% women; mean ± SD age 61.05 ± 8.93 years) with knee OA participated in the study. Radiographic evidence of joint pathology was graded according to the Kellgren/Lawrence scale. Central sensitization was indexed through quantitative sensory testing, including heat and pressure–pain thresholds, tonic suprathreshold pain (cold pressor test), and repeated phasic suprathreshold mechanical and thermal pain. Subgroups were constructed by dichotomizing clinical knee pain scores (median split) and knee OA grade scores (grades 1–2 versus 3–4), resulting in 4 groups: low pain/low knee OA grade (n = 24), high pain/high knee OA grade (n = 32), low pain/high knee OA grade (n = 27), and high pain/low knee OA grade (n = 30). ResultsMultivariate analyses revealed significantly heightened pain sensitivity in the high pain/low knee OA grade group, while the low pain/high knee OA grade group was less pain-sensitive. Group differences remained significant after adjusting for differences on psychosocial measures, as well as age, sex, and race. Conclusion The results suggest that central sensitization in knee OA is especially apparent among patients with reports of high levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathologic changes of knee OA.
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Purpose: Our aim was to investigate whether serum and synovial-fluid (SF) concentrations of interleukin-6 (IL-6), leptin, adiponectin, resistin or visfatin are associated with joint pain in hip and knee in end-stage osteoarthritis (OA). Methods: A cross-sectional study assessing patients with hip and knee OA undergoing total joint arthroplasty between January and December 2010 was conducted at a large university hospital. Serum and SF cytokine and adipokine concentrations were determined in samples obtained on the day of surgery. The main outcome was pain severity measured pre-operatively using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analogue scale (VAS) pain scores. Results: A total of 206 patients were involved (112 with hip and 94 with knee OA). Median age was 72 years [interquartile range (IQR) 66-79], 59% were women. All adipokine levels were significantly higher in the SF of hip joints than in that of knee joints, except for leptin, which tended to be higher in the knee. In both hip and knee OA, median serum concentrations of leptin, adiponectin, resistin and visfatin exceeded those in SF, whereas for IL-6, median concentrations were much higher in SF than in serum. In hip OA, worse pain was significantly associated with high SF concentrations of IL-6, visfatin and leptin; in knee OA, it was associated with high SF leptin and low SF adiponectin concentrations and a low adiponectin-leptin ratio. Conclusion: Our findings support a connection between intra-articular concentrations of several adipokines and severity of preoperative OA pain. However, the specific adipokines differed by joints: in hip OA, pain was associated with IL-6 and visfatin and in knee OA with adiponectin; leptin played a role in both hip and knee OA.
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An acute experimental arthritis was induced in the right knee joint of adult cats anesthetized with chloralose, and the activity of single fine afferent units of the medial articular nerve was recorded from filaments of the saphenous nerve. All units included in this study were sensitive to local mechanical probing of the medial and anteromedial aspects of the knee joint. The units were identified by their conduction velocity as belonging either to group III (2.5-20 m/s, 48 U) or group IV (less than 2.5 m/s, 29 U). After the identification, the resting activity was measured, and the evoked activity was determined using local mechanical stimulation with glass rods and von Frey hairs, and passive movements of the knee joint. The results were compared with those obtained in a similar study of fine articular units from normal joints. Resting activity was observed in 75% of the group III and 83% of the group IV units. The discharges were irregular and often of high frequency. Both the percentages of units with resting activity and the frequencies of their discharges were more than twice as high as in the control sample. Nearly all units from inflamed joints had low threshold to movements (group III 89%, group IV 72%), and most units responded well to flexion and extension. In contrast, in units from normal joints only 33% of the group III and 10% of the group IV units responded well to passive movements in the normal working range of the joint. In inflamed as well as in normal joints the responses were mostly tonic in character and adapted slowly or not at all when the joint was held in a new position. In normal joints 24% of the group III and 36.5% of the group IV afferent units with local mechanosensitive receptive fields could not be excited by any physiological or noxious joint movements. Such units were only very occasionally seen in the present sample. The average number of receptive fields per unit found in inflamed joints exceeded considerably that in normal units, but no systematic drop in von Frey thresholds was seen when comparing the control sample with the inflamed one. From the above data we conclude that an acute inflammation sensitizes many fine articular units, making them active at rest and increasing the responsiveness more readily to normally innocuous joint movements. Both nociceptors and units with low threshold to movement seem to become sensitized by the inflammation.(ABSTRACT TRUNCATED AT 400 WORDS)
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Fibromyalgia (FM) is a disorder that is characterized by widespread, musculoskeletal pain and abnormal pain sensitivity at multiple anatomic sites. Laboratory studies involving psychophysical and neuroimaging methods suggest that central augmentation of low intensity stimulation may contribute to abnormal pain sensitivity in FM. Recently, several investigators, using similar laboratory methods, have shown that patients with knee or hip osteoarthritis (OA) exhibit abnormal pain sensitivity or abnormal pain inhibition at anatomic sites distal to affected joints. Consistent with animal models of central sensitization, differences between patients and healthy controls in pain processing and pain inhibition at these distal sites are eliminated after nociceptive input is eliminated following total joint replacement surgery. This paper reviews these findings from our laboratory and those of independent investigators. It also presents verbal, psychophysical and neuroimaging data concerning ethnic group differences in affective and cognitive pain responses among patients with knee OA. We suggest that central sensitization as well as centrally-mediated cognitive and affective factors influence the pain responses of patients with knee OA. In addition, ethnic group differences in pain cognition and affect may contribute to differences among these groups in preferences for healthcare interventions such as total joint replacement.
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Pain-related beliefs and pain coping strategies are central components of current cognitive-behavioral models of chronic pain, and have been found in numerous studies to be associated significantly with psychosocial and physical disability. However, the length of most measures of pain-related beliefs and coping restricts the ability of clinicians and researchers to perform a thorough assessment of these variables in many Situations. The availability of very brief versions of existing scales would make possible the assessment of a range of important pain beliefs and coping strategies in settings where Subject or patient assessment burden is an issue. In this study, one- and two- item versions of the subscales of several commonly used measures of pain beliefs and coping strategies were developed using both rational and empirical procedures. The findings support the validity of these brief subscales. The appropriate use and limitations of these measures are discussed.
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Background In a cohort of well-characterized patients with different degrees of knee osteoarthritis (OA) and pain, the aims were to utilize mechanism-based quantitative sensory testing (QST) to (1) characterize subgroups of patients; (2) analyse the associations between clinical characteristics and QST; and (3) develop and apply a QST-based knee OA composite pain sensitivity index for patient classification.Methods Two hundred seventeen OA pain patients and 64 controls were included. Kellgren and Lawrence (KL) grading scores were obtained, and pressure pain thresholds (PPTs), temporal summation of pain to repeated painful pressure stimulation and conditioning pain modulation (CPM) were assessed. Associations between pain score/area/duration, radiological findings and QST-related parameters were analysed. A pain sensitivity index was developed and applied based on PPT, temporal summation and CPM. z-Score, as statistical tool, was calculated for statistically comparing the pain index of a single patient with a healthy control group.ResultsHigh knee pain associated with low KL grade showed particular signs of pain sensitization. Patients showed significant associations between clinical knee pain intensity/duration and lowering of knee PPTs (p < 0.01), facilitation of temporal summation (p < 0.01), reduction of CPM function (p < 0.01) and high pain sensitivity index (p < 0.01). The index classified 27–38% of the OA patients and 3% of the controls as highly sensitive with no association to KL. The index increased for high knee pain intensities and long pain duration.Conclusions Radiological scores, contrary to clinical pain intensity/duration, were poorly associated with QST parameters. The pain sensitivity index could classify OA patients with different degrees of OA and pain.
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The purpose of this study was to examine the reliability and validity of measuring pain threshold (PT) of persons with osteoarthritis (OA) of the knee. The PTs of women with and without OA of the knee were measured on 3 occasions at 6 sites at the knee with a pressure dolorimeter. Subjects with OA also recorded their pain on a visual analogue scale (VAS) and on the McGill Pain Questionnaire (MPQ). The reliability coefficients for repeated measures of PT vaned from 0.61 to 0.91 in the OA group and from 0.71 to 0.90 in the control group. PT was lower in the OA group at all sites. Only the control group demonstrated significant differences between sites. The correlations between PT and measures of pain intensity were poor. It is concluded that the measurement of PT at the knee distinguishes OA from healthy controls, and that it has moderate reliability. However, it cannot substitute for a measure of pain intensity.
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It is not clear whether heightened pain sensitivity in knee osteoarthritis (OA) is related to sensitisation induced by nociceptive input from OA pathology ('state') versus other confounding factors. Conversely, some individuals may be predisposed to sensitisation irrespective of OA ('trait'). The Multicenter Osteoarthritis Study is a longitudinal cohort of persons with or at risk of knee OA. We obtained knee X-rays, pain questionnaires and comprehensive assessment of factors that can influence pain sensitivity. We examined the relation of sensitisation and sensitivity assessed by mechanical temporal summation (TS) and pressure pain thresholds (PPTs) to knee OA and knee pain severity. To test whether sensitisation and sensitivity is a 'state' induced by OA pathology, we examined the relation of PPT and TS to knee OA duration and severity. In 2126 subjects (mean age 68, mean body mass index (BMI) 31, 61% female), PPT and TS were not associated with radiographic OA (ORs 0.9-1.0 for PPT and TS; p>0.05). However, PPT and TS were associated with pain severity (ORs: 1.7-2.0 for PPT; 1.3-1.6 for TS; p<0.05). Knee OA duration and radiographic severity were not associated with PPT or TS. PPT and TS were associated with OA-related pain, but not radiographic OA after accounting for pertinent confounders in this large cohort. Lack of association with disease duration suggests at least some sensitisation and pain sensitivity may be a trait rather than state. Understanding the relationship between pathological pain and pain sensitivity/sensitisation offers insight into OA pain risk factors and pain management opportunities.