2016 Joint Mobilization Enhances Mechanisms of Conditioned Pain Modulation in Individuals With Osteoarthritis of The Knee

Journal of Orthopaedic & Sports Physical Therapy
Downloaded from www.jospt.org at Deakin University on January 4, 2016. For personal use only. No other uses without permission.
Copyright ${year} Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.
Joint mobilization enhances mechanisms of conditioned pain

modulation in individuals with osteoarthritis of the knee
Carol A. Courtney PT, PhD1, Alana D. Steffen PhD1, Csar Fernndez-de-lasPeas PT, PhD2,3, John Kim PT, DPT4, Samuel J. Chmell MD1
1
University of Illinois at Chicago, Chicago IL

Universidad Rey Juan Carlos, Alcorcon, Madrid, Spain
3
Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark
4
React Physical Therapy, Chicago IL
2
Funded by the Orthopaedic Section, American Physical Therapy Association

The Office for the Protection of Research Subjects (OPRS) at the University of Illinois at
Chicago (UIC) has reviewed and approved this study protocol.
Word Count: 3753

I affirm that I have no financial affiliation (including research funding) or involvement with any
commercial organization that has a direct financial interest in any matter included in this
manuscript, except as disclosed in an attachment and cited in the manuscript.

Joint mobilization enhances mechanisms of conditioned pain

modulation in individuals with osteoarthritis of the knee
I affirm that I have no financial affiliation (including research funding) or involvement with any
commercial organization that has a direct financial interest in any matter included in this
manuscript, except as disclosed in an attachment and cited in the manuscript.

ABSTRACT
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
STUDY DESIGN: Experimental laboratory study with repeated measures crossover design.
BACKGROUND: Treatment effects of joint mobilization may occur in part by decreasing
excitability of central nociceptive pathways. Impaired conditioned pain modulation (CPM) has
been found experimentally in persons with knee and hip osteoarthritis (OA), indicating impaired
inhibition of central nociceptive pathways. We hypothesized increased effectiveness of CPM
following application of joint mobilization, determined via measures of deep tissue hyperalgesia.
OBJECTIVES: To examine the effect of joint mobilization on impaired CPM. METHODS:
Examination of 40 individuals with moderate/severe knee OA identified 29 (73%) with impaired
CPM. Subjects were randomized to receive 6 minutes of knee joint mobilization (intervention) or
light manual cutaneous input only, one week apart. Deep tissue hyperalgesia was examined via
pressure pain thresholds (PPT) bilaterally at knee medial joint line and the hand, at baseline,
post-intervention and post-CPM testing. Further, vibration perception threshold (VPT) was
measured at medial knee epicondyle at baseline and post-CPM testing. RESULTS: Joint
mobilization, but not cutaneous input intervention, resulted in a global increase in PPT, indicated
by diminished hyperalgesic responses to pressure stimulus. Further, CPM was significantly
enhanced following joint mobilization. Diminished baseline VPT acuity was enhanced following
joint mobilization at the knee that received intervention, but not the contralateral knee. Resting
pain was also significantly lower following the joint intervention. CONCLUSION: CPM was
enhanced following joint mobilization, demonstrated by global decrease in deep tissue pressure
sensitivity. Joint mobilization may act via enhancement of descending pain mechanisms, in
patients with painful knee OA.
Level of Evidence: 2B
24
25
Key words: arthralgia, physical therapy techniques, manual therapy, diffuse noxious inhibitory
control
26

27
28
INTRODUCTION
29
Pain is one of the primary symptoms of osteoarthritis (OA) leading to impaired function and
30
decreased quality of life. In elderly subjects with knee OA, pain is the leading cause of impaired
31
mobility.21 Studies have indicated that knee pain and radiographic evidence of osteoarthritic joint
32
degeneration are not always correlated.5,18 This suggests that OA and OA-related pain may be
33
two separate but related processes. Thus, understanding the mechanisms underlying pain and
34
pain modulation are critical when developing a plan of care.
35
Two important mechanisms are recognized as contributing to heightened pain in knee OA.
36
First, hyperexcitability of central nociceptive pathways has been demonstrated in this
37
population.4,12 This central sensitization has been shown to produce enhanced pain response,
38
spread of pain, and other signs and symptoms, thereby promoting a state of chronic pain in
39
individuals with this disease.4 These signs and symptoms include sensory deficits, such as
40
decreased pressure pain thresholds (PPT) and vibratory perception deficits.30 Secondly, studies
41
have also demonstrated faulty and ineffective pain inhibition in persons with OA.4,20,34,43,48
42
Conditioned pain modulation (CPM) is a method of examining pain inhibitory mechanisms, and
43
is mediated by the rostral ventromedial medulla, the periaqueductal gray (PAG), and subnucleus
44
reticularis dorsalis,9,39 with potential prefrontal cortex and cingulate contribution as well.7 In
45
basic terms, application of a noxious stimulus at a remote site causes inhibition of pain at the
46
initial site (e.g., the OA knee). Tonic descending pain inhibition provides a persistent dampening
47
of the perception of pain. It has been suggested that these supraspinal mechanisms are both
48
facilitatory and inhibitory, and impairment is a result of an imbalance between these inputs.52
49
Contributors to this imbalance may be a persistent nociceptive input from the periphery, or

50
central processes such as hypervigilance35 or catastrophizing.53 Impaired CPM has been
51
suggested as a clinical predictor of chronic pain.36,51,57
52
In human studies, CPM has been examined experimentally through use of protocols which
53
typically induce cold46 or ischemic4,20 pain. The effect of surgical,20,34 and TENS14 interventions
54
on impaired CPM has been studied, but outcomes of manual therapy management have not been
55
previously examined. Non-thrust joint manipulation, also called joint mobilization, is commonly
56
used by physical therapists to manage painful joint conditions and typically involves the
57
application of rhythmic oscillatory motion of the joint surfaces within normal joint range.37 Some
58
studies have suggested successful outcomes with its use in knee OA when incorporated into a
59
multi-modal rehabilitation program, including decreased pain and improved function.15,16
60
However, a recent randomized controlled trial has demonstrated the independent contribution of
61
manual therapy for knee OA treatment outcomes.1 Conversely, successful outcomes were not
62
demonstrated in one clinical trial where joint mobilization was applied at a distant site from the
63
knee (ie, thoracic spine).6 Mechanistic studies have shown a decrease in central excitability of
64
nociceptive pathways and pain measures following a treatment of knee joint mobilization in an
65
animal model49 and in humans with knee OA.13 However, the effect of joint mobilization on
66
descending inhibitory pain mechanisms, measured via CPM, has not been investigated in knee
67
OA.
68
The purpose of this study was to determine the effect of joint mobilization on impaired CPM
69
in individuals with painful OA of the knee. We hypothesized that CPM would become more
70
effective following application of joint mobilization, demonstrated by increased PPT and
71
decreased resting pain. A secondary hypothesis was that vibratory deficits would normalize
72
following joint mobilization intervention. Understanding the potential neurophysiologic

3

73
mechanisms underlying the treatment effects of joint mobilization may allow for more targeted
74
use in the management of knee OA pain.

75
76
METHODS
77
Subjects
78
Individuals with knee OA were enrolled, through use of recruitment flyers, from the outpatient
79
clinics of the University of Illinois at Chicago. Individuals were included in the study if they had
80
been diagnosed by their orthopedic physician with OA of the tibiofemoral joint ( Grade II
81
Kellgren and Lawrence radiographic changes). Since knee OA is commonly bilateral, subjects
82
with bilateral knee OA were also enrolled in the study. It was confirmed that one knee was more
83
painful, with moderate to severe degenerative changes demonstrated on imaging. Participants
84
were excluded from the study if they had total knee arthroplasty, reported previous history of any
85
diagnosed neurological or rheumatoid condition, diabetes, or history of knee ligamentous
86
deficiency. They were instructed to avoid use of anti-inflammatory or pain medications 24 hours
87
prior to testing, and to avoid any unusual change in activity levels. The Institutional Review
88
Board of the University of Illinois at Chicago (USA) approved the study and all subjects signed
89
an informed consent to participate prior to testing.
90
Baseline Demographic Data and Conditioned Pain Modulation Screening
91
Each of the participants was questioned about date of onset of OA, and their knee pain at
92
rest using a Visual Analog Scale (VAS).44 They also completed the Knee Outcome Survey-
93
Activities of Daily Living Scale (KOS).26 This survey is a 14-item scale designed to assess how
94
knee symptoms and knee condition affect the ability to perform daily functions. Scores are

95
presented as percentages of the maximal score where 100% represents full perceived knee
96
function during activities of daily living.
97
Screening for Impaired Conditioned Pain Modulation
98
The screening protocol was completed with the subject lying in supine, in approximately
99
20 of hip and knee flexion with the lower limb comfortably supported. The most painful site
100
was identified on the medial aspect of the affected knee and confirmed through gentle palpation
101
by the tester (typically at the medial joint line). This site was marked and maintained for
102
subsequent testing sessions. Pressure pain threshold was established at the experimental knee.
103
The tip of an algometer (JTECH Medical, Salt Lake City, UT) was applied perpendicular to the
104
most painful site at the medial knee on the affected limb, at a rate 50 kPa/s until the subject
105
reported a change from pressure to a painful sensation30,45. The procedure was performed 3 times
106
at 20 second intervals, and the average calculated to determine PPT.45 After being educated on
107
the procedure, both tester and subject were blinded to all subsequent scores during the session.
108
Conditioned pain modulation was tested using the upper extremity submaximal effort
109
tourniquet test.34 Specifically, the subject was asked to elevate their contralateral arm for one
110
minute. A blood pressure cuff was then inflated to a pressure of 280mm Hg. Participants rated
111
the tourniquet-induced pain intensity of the arm on a VAS. The cuff was deflated at the 6 minute
112
interval and 3 trials of PPT measures at the 3 sites were taken immediately following deflation.
113
Impaired CPM was operationally defined as no change or a negative change in PPT measures,
114
taken directly following termination of the conditioning stimulus (tourniquet test). These
115
methods correspond to recent recommendations on practice of conditioned pain modulation
116
testing.56
117
Assignment of Individuals with Impaired CPM into Experimental Groups

118
Individuals who were found to demonstrate impaired CPM were asked to attend two
119
subsequent sessions that were scheduled one week apart. Each subject was randomly assigned
120
via sealed envelope to one of two groups, which indicated which of two experimental
121
interventions would be applied in the first of the two subsequent sessions. The other intervention
122
was applied during the second session a week later.
123
Experimental Procedure
124
Acclimatization and Education on Testing Procedures
125
Prior to testing for each of the two subsequent testing sessions, the subjects were
126
acclimated to a room temperature of approximately 70 F for 10-15 minutes for the purpose of
127
standardizing the environment for sensory testing.31 The testing protocol (FIGURE 1) was again
128
completed with the subject lying in supine, in approximately 20 of hip and knee flexion with the
129
lower limb comfortably supported. Prior to testing, all subjects were educated on vibration
130
perception and pressure pain procedures at a proximal site until the subject was capable of
131
responding reliably.50 Subjects were not informed on the purpose of applying the experimental
132
interventions.
Resting Pain
133
134
Assessment of resting knee pain of the experimental limb was performed using the VAS at two
135
specific intervals during testing: baseline and following the subsequent testing of CPM.
136
Vibration Perception Threshold
137
Vibration perception threshold was assessed at baseline and at the completion of testing.
138
It was measured bilaterally at bony landmarks at the medial femoral condyle, using a
139
biothesiometer (Bio-Medical, OH) as it has been described previously.47 A cylindrical stylus,
140
13mm in diameter, vibrating at 100 Hz, was allowed to rest at the site of application. The

141
amplitude of vibration (expressed in biothesiometer units54) was increased until the participant
142
reported an initial sensation of vibration.47 The biothesiometer was left in place and a second
143
assessment was made.47 The average of these 2 results was calculated and recorded.
144
Pressure Pain Threshold
145
Pressure pain threshold was applied as described above.30,45 The procedure was also
146
performed at the corresponding site on the contralateral knee and at the web space between the
147
1st and 2nd metacarpophalangeal joints on the contralateral side. The procedure was performed 3
148
times at each location and the average calculated to determine PPT.45 As mentioned above, a 20
149
second time interval was maintained between applications to prevent sensitization of pain
150
responses. Blinding to scores was maintained during each session. PPT was assessed at baseline,
151
after the experimental intervention and at the completion of testing.
152
Experimental Conditions
153
After establishing baseline measures in VPT, PPT at each of the 3 sites, and resting pain,
154
one of the two interventions was applied: 1) oscillatory joint mobilization into slight tissue
155
resistance (intervention), or 2) hands-on cutaneous input only to the knee (control). All
156
interventions were applied by the same physical therapist, who was fellowship trained in
157
Orthopedic Manual Physical Therapy. The oscillatory joint mobilization technique was executed
158
by placing both hands on the knee of the subject and gliding the tibia forward and back on the
159
femur in an oscillatory manner within a pain-free range, moving slightly into tissue resistance
160
(FIGURE. 2A).37 The hands-on cutaneous input technique was executed by lightly placing both
161
hands on the subjects knee (FIGURE. 2B). Each experimental condition was applied for 2*3
162
min with a 30 sec interval between.13 PPT, at all three sites, and resting knee pain were measured

163
pre-intervention, post-intervention and post-CPM re-assessment. Both subject and tester were
164
blinded to the PPT results during the session.
165
Statistical Analyses
166
Descriptive statistics (means and standard deviations) were used to describe the sample
167
and plots were examined for outcome variable distributions. Students t-test or Mann-Whitney
168
U-test (for continuous variables) and chi-square or Fisher exact tests (for categorical variables)
169
were applied to analyze differences in sample demographics between CPM impaired and CPM
170
intact patients.
171
Our hypotheses were tested using mixed effect regression models with random intercepts
172
for each person to account for within-person correlations due to repeated measurements using
173
SAS 9.3 software. All models included the main effects for treatment session (joint mobilization,
174
cutaneous input), and time point, dummy coded using 2 variables representing either baseline,
175
post-intervention, or post-CPM (if measured) depending on the desired reference group, as well
176
as treatment by time interactions, controlling for order of treatment session. To assess post-
177
intervention differences between treatment sessions, the interaction term represented the
178
difference between treatments compared to baseline. To assess post-CPM differences, the
179
interaction term represented the difference between treatments compared to post-intervention
180
levels, unless otherwise indicated. Effect sizes were calculated from the interaction terms by the
181
formula: interaction estimate/ (standard error * square root (degrees of freedom)), i.e., the
182
difference in group means divided by the standard deviation estimate.25 Initial models also
183
assessed if treatment differences were moderated by order, i.e., did the treatment by time effect
184
differ when cutaneous input only was received first compared to when joint mobilization was

185
received first, using 3-way interaction terms.
These terms were not significant and, thus,
186
excluded from the final models.
187
RESULTS
188
Forty individuals (mean age 598 years; 13 male; BMI: 36.813.4) were enrolled in the study
189
with baseline demographic and clinical measurements presented in TABLE 1. Almost all
190
subjects (n=38) had bilateral OA, with one limb more painful than the other, and 85% reported
191
occasions of knee giving way. Resting pain of the tested knee, measured with the VAS, was
192
27.824.8 (100 mm scale), while vibratory perception acuity was significantly diminished on the
193
more painful limb (TABLE 1). Participants had been diagnosed with the disease for 11.98.9
194
years and reported greater than 50% deficit (45.613.7) in function as measured by the KOS. Of
195
this group, 73% (29 participants) demonstrated impaired CPM (TABLE 2). The mean change in
196
PPT in the intact CPM group was 27.912.1% while the mean change in the impaired CPM
197
group was -9.715.5%. Impaired and non-impaired groups were similar, except that the
198
individuals with impaired CPM had a longer history of the disease (13.17 versus 8.67 years;
199
P=0.01) and they demonstrated a higher systolic blood pressure (1286 versus 1219 mm Hg;
200
P=0.01) (TABLE 1).
201
Results of the mixed effect regression models are presented in TABLE 3. Our results
202
showed small to moderate effects between treatments with the greatest impact on resting pain
203
level [F(1, 84)=21.49, p<.0001 for treatment by time interaction effect], followed by PPTs at the
204
affected knee [treatment by time interactions: F(1, 140)=16.81, p<.0001 for post-intervention
205
compared to baseline, F(1, 140)=5.48, p=0.0207 for post-CPM compared to post-intervention].
206
The hypoalgesic effect generalized to the hand [treatment by time interactions: F(1, 140)=8.5,
207
p=0.0041 for post-intervention compared to baseline, F(1, 140)=4.66, p=0.0325 for post-CPM

208
compared to post-intervention], and to a lesser extent, the contralateral knee [treatment by time
209
interactions:
210
140)=6.11, p=0.0146 for post-CPM compared to post-intervention] (FIGURE. 3). Changes in
211
PPT were comparable across the three sites following CPM as compared to post-intervention
212
levels.
213
treatment by time interaction effects], but were also demonstrated at the unaffected knee to a
214
lesser extent [F(1, 84)=3.21, p=0.0767]. No effect was noted from cutaneous input only.
215
DISCUSSION
F(1, 140)=3.92, p=0.0496 for post-intervention compared to baseline, F(1,
Vibration effects were larger in the affected knee [F(1, 84)=16.38, p=0.0001 for
216
The main finding of the current study was that impaired CPM was enhanced following
217
application of the joint mobilization intervention. Research studies have suggested that joint
218
mobilization intervention may have beneficial effects on pain and function in knee OA
219
populations.1,15,16,29 Conspicuous in these studies is the fact that manual therapy treatment was
220
directed at the painful joint (the knee), suggesting that homotopic rather than heterotopic input to
221
the central nervous system, delivered via manual therapy, may facilitate an enhanced analgesic
222
effect. A similar notion has been previously proposed in laboratory based research.32
223
Accordingly, the lack of beneficial effects found in one knee OA clinical trial6 may be due to the
224
fact that manual therapy was directed at the thoracic spine rather than at the knee. In laboratory
225
studies, both in an animal model49 and in humans13 with knee OA, joint mobilization intervention
226
has been demonstrated to down-modulate spinal excitability, indicating at least in part, a central
227
effect of this intervention. Vanegas et al52 stated that CPM impairment may occur due to an
228
imbalance between facilitatory and inhibitory inputs. The results of the present study support the
229
idea that manual therapy may alter this imbalance, thereby enhancing descending pain
230
modulation. Importantly, these findings were demonstrated in individuals with impaired CPM.
10


231
Other studies have reported augmented CPM following therapeutic interventions such as
232
surgical,20,34 and TENS14 interventions. Critical to these studies and the present study, is the fact
233
that impaired CPM was present or assumed to be present in these patient populations. While the
234
effect of joint mobilization on individuals with intact CPM was not examined in our study, it is
235
possible that rehabilitative interventions such as manual therapy, exercise, and TENS, mediate
236
their effect, at least in part, by accentuating CPM whether impaired or not. Clinically, this would
237
require a paradigm shift in how these interventions are explained to patients, as treatment
238
response is often described in terms of its mechanical effect. The consequences of approaching
239
chronic pain in this manner could be significant; patients would gain a deeper understanding of
240
their chronic condition, and thereby, greater insight into self management.
241
A secondary objective in this study was to determine the effect of the joint mobilization
242
intervention on VPT. Vibration perception threshold findings at the medial knee were similar to
243
previous knee OA studies,30,47 with elevated VPT measures suggesting hypoesthesia to vibratory
244
stimulus. Vibratory perception deficits have been reported in other musculoskeletal conditions,
245
such as painful temporomandibular disorder24 and patellofemoral joint pain.2 Diminished
246
vibration detection acuity has been associated with perceived instability during a functional
247
task.30 A study utilizing experimentally induced pain has suggested that pain may inhibit
248
vibrotactile sensitivity due to spinal or supraspinal level mechanisms,3 indicating that perceptual
249
deficits associated with chronic musculoskeletal conditions may be due to central neuroplastic
250
changes rather than peripheral nerve insult. While it may be argued that peripheral neuropathy
251
cannot be accurately identified using only the above described methods, our finding that VPT
252
measures at the medial knee significantly decreased (indicating better acuity) following the joint
253
mobilization intervention would support the argument of a potential central inhibitory

11


254
mechanism underlying these sensory changes rather than peripheral nerve damage. An
255
alternative explanation for these findings is that chronic knee pain, as found in our subject
256
population, may cause an attentional modulation of sensory perception, meaning that pain may
257
cognitively interfere with the ability to detect a sensory stimulus.17,27,55 A recent study
258
demonstrated, however, that cognitive loading had a limited effect on pain induced vibratory
259
hypoesthesia,22 suggesting that the mechanism involved is more of a sensory rather than
260
cognitive interference.
261
Interestingly, no significant change in vibrotactile acuity was noted on the contralateral
262
limb following the joint mobilization intervention, nor was there change in either limb following
263
the hands-on cutaneous input intervention. Widespread effects on pain have been reported
264
following joint mobilization,40 however it is possible that the effect on innocuous sensory acuity
265
may be somatotopically organized. Specifically, a key characteristic of experimentally induced
266
vibrotactile hypoesthesia is that the deficit typically occurs in the vicinity of the induced pain
267
area.8 Accordingly, resolution of this sensory inhibition may be localized and focal in nature.
268
Further research into the hypoesthetic effects of joint mobilization may aid in our understanding
269
of how rehabilitation may accentuate sensory acuity and possibly function.
270
Importantly, not all of our subjects with chronic knee OA demonstrated impaired CPM.
271
Of the 40 participants in the study with moderate to severe knee OA, 73% demonstrated
272
impaired pain modulation, as measured via CPM (TABLE 2). Developing clinical tools that can
273
identify impairment in pain modulation may be of value in rehabilitative settings and during
274
surgical consults.57 The 2 groups, impaired and unimpaired CPM, were similar on many patient
275
characteristics, including resting pain and level of function; however the group with impaired
276
CPM demonstrated a significantly longer history of OA disease as compared to the non-impaired

12


277
group. Duration of disease has been correlated to pain and symptoms in knee OA11,19,30 and
278
studies have suggested that prevalence of knee pain in persons with OA increases over time,
279
independent of age.41 However, little research has addressed how duration of the symptoms or
280
disease may affect central pain regulatory mechanisms. It is possible that over time, the constant
281
barrage of painful input to the central nervous system from a painful degenerative knee
282
eventually alters or causes an imbalance in the function of descending pain processing. If so, it is
283
clear that controlling pain in this population, in the early stages of the disease process, is critical
284
for better long term prognosis.
285
Systolic blood pressure was also significantly higher in the subjects with impaired CPM,
286
with average levels in the pre-hypertensive range. Previous studies have explored the
287
relationship between knee OA and high systolic blood pressure,42 and cardiovascular disease.28
288
In healthy individuals, acute onset hypertension (e.g., stress induced hypertension) typically
289
causes hypoalgesia (i.e., decreased pain). However, in chronic pain, this mechanism which
290
dampens pain can be impaired, likely occurring through sympathetic nervous system
291
mechanisms.10 Studies have demonstrated impaired pain inhibition in persons with both high
292
systolic blood pressure and chronic temporomandibular dysfunction38 and low back pain,23
293
supporting the idea that aberrant descending pain mechanisms are linked to certain
294
cardiovascular measures. Further research on the relationship between systolic blood pressure
295
and chronic knee OA pain may be warranted.
296
The following study had several limitations. First, measurement of PPTs is based upon a
297
subjective perception and understanding of what represents a painful stimulus, thus this outcome
298
can be variable. However, a recent study has reported PPT to be a valid test stimulus measure for
299
CPM.33 To prevent high variability, we provided education to each participant prior to data
13


300
collection. Furthermore, to avoid bias both study participant and tester were blinded to test
301
results during each session. Second, it is possible that subjects with impaired CPM believed that
302
joint mobilization, rather than cutaneous input only, was the experimental intervention. To
303
prevent this, we avoided using terminology that suggested subjects were receiving treatment, and
304
we refrained from asking about resting pain following intervention, which may have cued them
305
to expectations from the interventions. A third potential limitation of this study is that we did not
306
examine the effect of intervention on PPT in the unimpaired CPM group. It is not known if
307
application of joint mobilization in these subjects would increase activation of descending pain
308
modulation. Future studies which examine the neurophysiologic effects of rehabilitative
309
techniques would be beneficial for understanding the pain mechanisms underlying CPM, and for
310
directing its clinical use. In addition, although gender was included as covariate, gender
311
differences in activation of CPM were not detected after the joint mobilization intervention. A
312
recent systematic review and meta-analysis on CPM found that studies involving female
313
participants exhibited significantly larger effect sizes than those involving both male and female
314
participants.36 The study also found that increased age was a factor in the individuals with
315
impaired CPM.36
316
would be interesting to determine if these changes would persist over time or with repeated
317
treatment sessions.
318
CONCLUSION
Finally, only short-term changes in CPM were examined in this study. It
319
The current study suggests that joint mobilization enhances CPM in patients with painful
320
knee OA, demonstrated by an apparent global decrease in deep tissue sensitivity to pressure. In
321
addition, we also found an enhanced somatosensory acuity, particularly at the knee receiving
14


322
intervention, following joint mobilization. Joint mobilization may be a useful intervention for
323
rehabilitation of painful knee OA through enhancement of descending pain mechanisms.
324
KEY POINTS:
325
FINDINGS: In individuals with chronic knee OA, joint mobilization intervention resulted in a
326
global decrease in pain sensitivity and improvement of impaired descending pain inhibition,
327
indicating that joint mobilization may aid in facilitating central inhibitory mechanisms.
328
Diminished baseline VPT acuity was enhanced following joint mobilization at the knee which
329
received intervention, but not the contralateral knee.
330
IMPLICATIONS: Focal somatosensory deficits, which may be pain induced and found in
331
individuals with chronic pain conditions, may be normalized with pain relieving therapeutic
332
interventions such as joint mobilization.
333
CAUTION: Inferences from these findings in individuals with chronic knee OA should be
334
applied to other chronic pain populations with caution.
335
15


336
337
338
339
340
341
342
343
344
345
REFERENCES
1. Abbott JH, Chapple CM, Fitzgerald GK, et al. The Incremental Effects of Manual Therapy or
Booster Sessions in Addition to Exercise Therapy for Knee Osteoarthritis: A Randomized
Clinical Trial. Journal of Orthopaedic & Sports Physical therapy. [Epub Ahead of Print]
doi:10.2519/jospt.2015.6015.
346
347
3. Apkarian AV, Stea RA, Bolanowski SJ. Heat-induced pain diminishes vibrotactile perception:
A touch gate. Somatosens Mot Res. 1994;11(3):259-67.
348
349
4. Arendt-Nielsen L, Nie H, Laursen M, et al. Sensitization in patients with painful knee

osteoarthritis. 2010;193(3):573.
350
351
352
5. Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: A
systematic search and summary of the literature. BMC Musculoskelet Disord. 2008;9:116,24749-116 10.1186/1471-2474-9-116; 10.1186/1471-2474-9-116.
353
354
355
6. Bennell KL, Hinman RS, Metcalf BR, et al. Efficacy of physiotherapy management of knee
joint osteoarthritis: A randomised, double blind, placebo controlled trial. Ann Rheum Dis.
2005;64(6):906-12 64/6/906 [pii].
356
357
7. Bingel U, Tracey I. Imaging CNS modulation of pain in humans. Physiology (Bethesda).

2008;23:371-80 10.1152/physiol.00024.2008; 10.1152/physiol.00024.2008.
358
359
8. Bolanowski SJ, Maxfield LM, Gescheider GA, et al. The effects of stimulus location on the
gating of touch by heat- and cold-induced pain. Somatosens Mot Res. 2000;17(2):195-204.
360
361
9. Bouhassira D, Villanueva L, Bing Z, et al. Involvement of the subnucleus reticularis dorsalis

in diffuse noxious inhibitory controls in the rat. Brain Res. 1992;595(2):353-7.
362
363
10. Bruehl S, McCubbin JA, Harden RN. Theoretical review: Altered pain regulatory systems in
chronic pain. Neurosci Biobehav Rev. 1999;23(6):877-90 S0149763499000391 [pii].
364
365
366
11. Collins JE, Katz JN, Dervan EE, et al. Trajectories and risk profiles of pain in persons with
radiographic, symptomatic knee osteoarthritis: Data from the osteoarthritis initiative.
Osteoarthritis Cartilage. 2014;22(5):622-30 10.1016/j.joca.2014.03.009 [doi].
367
368
12. Courtney CA, Lewek MD, Witte PO et al. Heightened flexor withdrawal responses in
subjects with knee osteoarthritis. J Pain. 2009;10(12):1242-9 10.1016/j.jpain.2009.05.004.
369
370
371
13. Courtney CA, Witte PO, Chmell SJ et al. Heightened flexor withdrawal response in
individuals with knee osteoarthritis is modulated by joint compression and joint mobilization. J
Pain. 2010;11(2):179-85 10.1016/j.jpain.2009.07.005.
2. Akseki D, Erduran M, Ozarslan S, et al. Parallelism of vibration sense with proprioception

sense in patients with patellofemoral pain syndrome: A pilot study. Eklem Hastalik Cerrahisi.
2010;21(1):23-30.
16


372
373
374
14. Dailey DL, Rakel BA, Vance CG, et al. Transcutaneous electrical nerve stimulation reduces
pain, fatigue and hyperalgesia while restoring central inhibition in primary fibromyalgia. Pain.
2013;154(11):2554-62 10.1016/j.pain.2013.07.043 [doi].
375
376
377
15. Deyle GD, Allison SC, Matekel RL, et al. Physical therapy treatment effectiveness for
osteoarthritis of the knee: A randomized comparison of supervised clinical exercise and manual
therapy procedures versus a home exercise program. Phys Ther. 2005;85(12):1301-17.
378
379
380
16. Deyle GD, Henderson NE, Matekel RL, et al. Effectiveness of manual physical therapy and
exercise in osteoarthritis of the knee. A randomized, controlled trial. Ann Intern Med.
2000;132(3):173-81.
381
382
17. Eccleston C, Crombez G. Pain demands attention: A cognitive-affective model of the

interruptive function of pain. Psychol Bull. 1999;125(3):356-66.
383
384
385
18. Finan PH, Buenaver LF, Bounds SC, et al. Discordance between pain and radiographic
severity in knee osteoarthritis: Findings from quantitative sensory testing of central sensitization.
Arthritis Rheum. 2013;65(2):363-72 10.1002/art.34646; 10.1002/art.34646.
386
387
388
19. Graven-Nielsen T, Arendt-Nielsen L. Assessment of mechanisms in localized and

widespread musculoskeletal pain. Nat Rev Rheumatol. 2010;6(10):599-606
10.1038/nrrheum.2010.107.
389
390
391
392
20. Graven-Nielsen T, Wodehouse T, Langford RM, et al. Normalization of widespread

hyperesthesia and facilitated spatial summation of deep-tissue pain in knee osteoarthritis patients
after knee replacement. Arthritis Rheum. 2012;64(9):2907-16 10.1002/art.34466;
10.1002/art.34466.
393
394
395
21. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on
the functional limitations of elders in the framingham study. Am J Public Health.
1994;84(3):351-8.
396
397
22. Harper DE, Hollins M. Is touch gating due to sensory or cognitive interference? Pain.
2012;153(5):1082-90 10.1016/j.pain.2012.02.011 [doi].
398
399
400
23. Heuch I, Heuch I, Hagen K, et al. Does high blood pressure reduce the risk of chronic low
back pain? the nord-trondelag health study. Eur J Pain. 2014;18(4):590-8 10.1002/j.15322149.2013.00398.x [doi].
401
402
24. Hollins M, Sigurdsson A, Fillingim L et al. Vibrotactile threshold is elevated in

temporomandibular disorders. Pain. 1996;67(1):89-96.
403
404
25. Hox JJ. Multilevel Analysis: techniques and applications. 2nd edition. New York: Routledge;
2010.
405
406
26. Irrgang JJ, Snyder-Mackler L, Wainner RS, et al. Development of a patient-reported measure
of function of the knee. J Bone Joint Surg Am. 1998;80(8):1132-45.
407
408
27. Johansen-Berg H, Christensen V, Woolrich M, et al. Attention to touch modulates activity in

both primary and secondary somatosensory areas. Neuroreport. 2000;11(6):1237-41.
17


409
410
411
28. Kadam UT, Jordan K, Croft PR. Clinical comorbidity in patients with osteoarthritis: A casecontrol study of general practice consulters in England and Wales. Ann Rheum Dis.
2004;63(4):408-14.
412
413
414
29. Kappetijn O, van Trijffel E, Lucas C. Efficacy of passive extension mobilization in addition
to exercise in the osteoarthritic knee: An observational parallel-group study. Knee.
2014;21(3):703-9 10.1016/j.knee.2014.03.003 [doi].
415
416
417
30. Kavchak AJ, Fernandez-de-Las-Penas C, Rubin LH, et al. Association between altered
somatosensation, pain, and knee stability in patients with severe knee osteoarthrosis. Clin J Pain.
2012;28(7):589-94 10.1097/AJP.0b013e31823ae18f; 10.1097/AJP.0b013e31823ae18f.
418
419
420
31. Keizer D, van Wijhe M, Post WJ, et al. Quantifying allodynia in patients suffering from
unilateral neuropathic pain using von frey monofilaments. Clin J Pain. 2007;23(1):85-90
10.1097/01.ajp.0000210950.01503.72.
421
422
423
32. Klein T, Magerl W, Hopf HC, et al. Perceptual correlates of nociceptive long-term
potentiation and long-term depression in humans. J Neurosci. 2004;24(4):964-71
10.1523/JNEUROSCI.1222-03.2004 [doi].
424
425
426
33. Klyne DM, Schmid AB, Moseley GL, et al. Effect of types and anatomic arrangement of
painful stimuli on conditioned pain modulation. J Pain. 2015;16(2):176-85
10.1016/j.jpain.2014.11.005 [doi].
427
428
429
34. Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning
stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief.
Pain. 2000;88(1):69-78.
430
431
432
433
35. Lautenbacher S, Huber C, Kunz M, et al. Hypervigilance as predictor of postoperative acute

pain: Its predictive potency compared with experimental pain sensitivity, cortisol reactivity, and
affective state. Clin J Pain. 2009;25(2):92-100 10.1097/AJP.0b013e3181850dce;
10.1097/AJP.0b013e3181850dce.
434
435
436
36. Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic
pain: A systematic review and meta-analysis. J Pain. 2012;13(10):936-44
10.1016/j.jpain.2012.07.005; 10.1016/j.jpain.2012.07.005.
437
37. Maitland GD. Peripheral manipulation. 3rd ed. London: Butterworth-Heinemann; 1991.
438
439
440
38. Maixner W, Fillingim R, Kincaid S, et al. Relationship between pain sensitivity and resting
arterial blood pressure in patients with painful temporomandibular disorders. Psychosom Med.
1997;59(5):503-11.
441
39. Millan MJ. Descending control of pain. Prog Neurobiol. 2002;66(6):355-474.
442
443
40. Moss P, Sluka K, Wright A. The initial effects of knee joint mobilization on osteoarthritic
hyperalgesia. Man Ther. 2007;12(2):109-18 10.1016/j.math.2006.02.009.
18


444
445
446
41. Nguyen US, Zhang Y, Zhu Y, et al. Increasing prevalence of knee pain and symptomatic
knee osteoarthritis: Survey and cohort data. Ann Intern Med. 2011;155(11):725-32
10.7326/0003-4819-155-11-201112060-00004 [doi].
447
448
42. Olsen RB, Bruehl S, Nielsen CS, et al. Chronic pain and cardiovascular stress responses in a
general population: The tromso study. J Behav Med. 2014 10.1007/s10865-014-9568-3 [doi].
449
450
451
43. Petersen KK, Arendt-Nielsen L, Simonsen O, et al. Presurgical assessment of temporal

summation of pain predicts the development of chronic postoperative pain 12 months after total
knee replacement. Pain. 2015;156(1):55-61 10.1016/j.pain.0000000000000022 [doi].
452
453
44. Price DD, McGrath PA, Rafii A, et al. The validation of visual analogue scales as ratio scale
measures for chronic and experimental pain. Pain. 1983;17(1):45-56.
454
455
45. Rolke R, Magerl W, Campbell KA, et al. Quantitative sensory testing: A comprehensive
protocol for clinical trials. Eur J Pain. 2006;10(1):77-88 10.1016/j.ejpain.2005.02.003.
456
457
458
46. Schliessbach J, Siegenthaler A, Streitberger K, et al. The prevalence of widespread central

hypersensitivity in chronic pain patients. Eur J Pain. 2013:1-20 10.1002/j.15322149.2013.00332.x; 10.1002/j.1532-2149.2013.00332.x.
459
460
47. Shakoor N, Agrawal A, Block JA. Reduced lower extremity vibratory perception in
osteoarthritis of the knee. Arthritis Rheum. 2008;59(1):117-21 10.1002/art.23241.
461
462
463
48. Skou ST, Graven-Nielsen T, Rasmussen S, et al. Widespread sensitization in patients with
chronic pain after revision total knee arthroplasty. Pain. 2013;154(9):1588-94
10.1016/j.pain.2013.04.033 [doi].
464
465
466
49. Sluka KA, Wright A. Knee joint mobilization reduces secondary mechanical hyperalgesia
induced by capsaicin injection into the ankle joint. Eur J Pain. 2001;5(1):81-7
10.1053/eujp.2000.0223.
467
468
50. Stohler CS, Kowalski CJ, Lund JP. Muscle pain inhibits cutaneous touch perception. Pain.
2001;92(3):327-33.
469
470
471
51. van Wijk G, Veldhuijzen DS. Perspective on diffuse noxious inhibitory controls as a model
of endogenous pain modulation in clinical pain syndromes. J Pain. 2010;11(5):408-19
10.1016/j.jpain.2009.10.009.
472
473
52. Vanegas H, Schaible HG. Descending control of persistent pain: Inhibitory or facilitatory?
Brain Res Brain Res Rev. 2004;46(3):295-309 10.1016/j.brainresrev.2004.07.004.
474
475
476
53. Vissers MM, Bussmann JB, Verhaar JA, et al. Psychological factors affecting the outcome of
total hip and knee arthroplasty: A systematic review. Semin Arthritis Rheum. 2012;41(4):576-88
10.1016/j.semarthrit.2011.07.003; 10.1016/j.semarthrit.2011.07.003.
477
478
479
54. von Schlippe M, Fowler CJ, Harland SJ. Cisplatin neurotoxicity in the treatment of
metastatic germ cell tumour: Time course and prognosis. Br J Cancer. 2001;85(6):823-6
10.1054/bjoc.2001.2006.
19

55. Wiech K, Seymour B, Kalisch R, et al. Modulation of pain processing in hyperalgesia by

cognitive demand. Neuroimage. 2005;27(1):59-69 S1053-8119(05)00221-1 [pii].
482
483
56. Yarnitsky D, Bouhassira D, Drewes AM, et al. Recommendations on practice of conditioned

pain modulation (CPM) testing. Eur J Pain. 2015;19(6):805-6 10.1002/ejp.605 [doi].
484
485
486
57. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic post-operative pain: Preoperative DNIC testing identifies patients at risk. Pain. 2008;138(1):22-8
10.1016/j.pain.2007.10.033.

480
481
20


487
488
489
490
491
493
Legends of Figures
492
FIGURE 1: Flowchart of the study protocol
494
21

Tourniquet Test (n=40)

Conditioned Pain
Modulation Impaired?
Yes? (n=29)
Randomize
A. Cutaneous Input
or
B. Cutaneous Input +
Joint Mobilization
No? (n=11)
A. PPT (B med knee, hand)

B. VPT (B med knee)
C. Resting knee pain
Apply specific input (2x3 min)
Repeat measurement of PPT
Apply tourniquet test
Repeat measurement of PPT,
VPT and resting pain
2nd Visit
Repeat protocol
applying 2nd input

495
FIGURE 2: Interventions applied in this study A) hands-on cutaneous input, B) oscillatory joint
496
mobilization
497
498
499
500
22

501
FIGURE 3: A comparison of the effects of intervention and conditioned pain modulation (CPM)
502
on pressure pain threshold at A) the affected knee, B) the unaffected knee, and C) the hand
503
(mean - standard error).
504
23

A.

B.

C.
505
TABLE 1: Demographic information about participants

CPM Impaired
(n=29)

Total (n=40)
Mean
59.13
SD
8.28
Mean
59.41
SD
8.33
Mean
58.36
SD
8.48
p
value
0.7251
125.93
74.45
11.92
7.99
7.54
8.95
127.76
75.07
13.15
6.67
6.55
7.69
121.09
72.82
8.66
9.44
9.87
11.43
0.0164
0.4061
0.0189
27.80
24.84
28.03
24.70
27.18
26.41
0.9271
63.50 11.89 62.13 11.66

36.85 13.46 36.85 15.35
45.63 13.73 47.47 12.78
110.31 78.11 89.63 59.97
Vibration Perception Threshold*
Painful affected limb
28.66
8.01
28.91
8.57
Less affected limb
25.55
7.55
26.45
5.33
Comparison of VPT* between limbs at baseline:
n
%
n
%
Gender (female)
27
67.5
16
55.2
Give way (yes)
34
85.0
26
89.7
Visual Analog Scale
Body Mass Index
Knee Outcome Survey
Pressure Pain Threshold
*VPT - measured in bioesthesiometer units
67.09
36.86
40.77
151.68
12.30
7.21
15.56
103.3
0.2647
0.9985
0.1716
0.0859
28.01
25.13
6.63
8.29
0.6849
0.1493
<0.01
n
11
8
%
100.0
72.7
Characteristics
Age (years)
Blood pressure (mmHg)
Systolic
Diastolic
Length of injury (years)
Resting Pain at the knee
(VAS: 0-100 mm)
Conditioning Stimulus Pain
at the arm (VAS: 0-100 mm)
2
BMI (kg/m )
KOS (0-100%)
PPT (kPa)
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
CPM Intact
(n=11)
24

0.0074
0.3193
TABLE 2: Percent change in pressure pain threshold* following conditioned pain

modulation (CPM) screening^

527
528
529
Impaired CPM (n=29)

Intact CPM (n=11)
-7
0
0
6
0
-6
-9
29
-1
-47
-2
25
-7
0
0
35
-11
0
-9
13
-1
-16
-8
44
-13
0
-4
23
-3
-6
35
-50
-2
41
-11
-5
38
-60
-1
18
Average percent change in
pressure standard deviation
-9.715.5%
27.912.1
*tested at the most painful location on the affected knee
^using the upper extremity sub-maximal effort tourniquet test
530
531
532
25

533
534
TABLE 3: Pre-post outcomes in resting pain, pressure pain threshold and

vibratory perception threshold
535
536
Intervention (n=29)
Joint Mobilization Cutaneous Input
(29)
Only (29)

Variable
537
538
539
540
541
542
543
544
545
546
Mean
SD
Mean
SD
pvalue
Effect
Size
Resting Knee Pain (VAS) (0-100 mm)

Baseline
27.34
23.75
26.34
23.86
Post-intervention*
9.38
11.04
29.9
26.03
0.51
<.0001
Pressure Pain Threshold Affected Knee (kPa)
Baseline
84.18
54.12
88.32 54.12
Post-intervention*
0.35
115.49 54.19
84.12 54.19
<.0001
b
Post-CPM ~
0.0207
0.20
136.38 54.05
84.67 54.12
Pressure Pain Threshold Less Affected Knee (kPa)
Baseline
105.90 62.81
99.49
62.95
Post-intervention*
0.0496
0.17
118.31 62.88
97.15
62.95
Post-CPM~
0.0146
0.21
135.34 62.95
95.70
62.95
Pressure Pain Threshold Hand (kPa)
Baseline
74.26
51.30
76.60
51.30
Post-intervention*
0.0041
0.25
86.80
51.30
75.43
51.30
Post-CPM~
0.0325
0.18
97.84
51.30
76.26
51.30
Vibration Perception Threshold Affected Knee
Baseline
28.39
8.69
27.92
8.34
Post-CPM^
23.34
7.63
27.30
7.88
0.0001 -0.44
Vibration Perception Threshold Less Affected Knee
Baseline
25.61
8.00
24.65
7.24
Post-CPM^
24.48
8.15
25.29
6.97
0.0770 -0.2000
Visual Analog Scale
b
Conditioned Pain Modulation
Note: p-value is for interaction term comparing differences in change between joint mobilization
and cutaneous input only, within mixed effect regression model, controlling for treatment order.
Effect sizes25 represent this change in standard deviation units.
*Test of treatment difference in change from baseline level
~Test of treatment difference in change from post-intervention
Bioesthesiometer units
^ Test of treatment difference in change from baseline level
547
26

2016 Joint Mobilization Enhances Mechanisms of Conditioned Pain Modulation in Individuals With Osteoarthritis of The Knee

Încărcat de

Informații document

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

2016 Joint Mobilization Enhances Mechanisms of Conditioned Pain Modulation in Individuals With Osteoarthritis of The Knee

Încărcat de

Drepturi de autor:

Formate disponibile

Journal of Orthopaedic & Sports Physical Therapy

Joint mobilization enhances mechanisms of conditioned pain

University of Illinois at Chicago, Chicago IL

Funded by the Orthopaedic Section, American Physical Therapy Association

Word Count: 3753

Journal of Orthopaedic & Sports Physical Therapy

Joint mobilization enhances mechanisms of conditioned pain

Journal of Orthopaedic & Sports Physical Therapy

Journal of Orthopaedic & Sports Physical Therapy

pain modulation are critical when developing a plan of care.

First, hyperexcitability of central nociceptive pathways has been demonstrated in this

Journal of Orthopaedic & Sports Physical Therapy

central processes such as hypervigilance35 or catastrophizing.53 Impaired CPM has been

suggested as a clinical predictor of chronic pain.36,51,57

multi-modal rehabilitation program, including decreased pain and improved function.15,16

effective following application of joint mobilization, demonstrated by increased PPT and

following joint mobilization intervention. Understanding the potential neurophysiologic

use in the management of knee OA pain.

Journal of Orthopaedic & Sports Physical Therapy

painful, with moderate to severe degenerative changes demonstrated on imaging. Participants

diagnosed neurological or rheumatoid condition, diabetes, or history of knee ligamentous

an informed consent to participate prior to testing.

Baseline Demographic Data and Conditioned Pain Modulation Screening

Journal of Orthopaedic & Sports Physical Therapy

function during activities of daily living.

Screening for Impaired Conditioned Pain Modulation

methods correspond to recent recommendations on practice of conditioned pain modulation

Assignment of Individuals with Impaired CPM into Experimental Groups

Journal of Orthopaedic & Sports Physical Therapy

was applied during the second session a week later.

Acclimatization and Education on Testing Procedures

Vibration Perception Threshold

biothesiometer (Bio-Medical, OH) as it has been described previously.47 A cylindrical stylus,

Journal of Orthopaedic & Sports Physical Therapy

Pressure Pain Threshold

after the experimental intervention and at the completion of testing.

Journal of Orthopaedic & Sports Physical Therapy

blinded to the PPT results during the session.

difference between treatments compared to baseline. To assess post-CPM differences, the

interaction term represented the difference between treatments compared to post-intervention

Journal of Orthopaedic & Sports Physical Therapy

received first, using 3-way interaction terms.

These terms were not significant and, thus,

excluded from the final models.

P=0.01) (TABLE 1).

compared to baseline, F(1, 140)=5.48, p=0.0207 for post-CPM compared to post-intervention].

Journal of Orthopaedic & Sports Physical Therapy

140)=6.11, p=0.0146 for post-CPM compared to post-intervention] (FIGURE. 3). Changes in

F(1, 140)=3.92, p=0.0496 for post-intervention compared to baseline, F(1,

Journal of Orthopaedic & Sports Physical Therapy

such as painful temporomandibular disorder24 and patellofemoral joint pain.2 Diminished

mobilization intervention would support the argument of a potential central inhibitory

Journal of Orthopaedic & Sports Physical Therapy

Interestingly, no significant change in vibrotactile acuity was noted on the contralateral

may be somatotopically organized. Specifically, a key characteristic of experimentally induced

of how rehabilitation may accentuate sensory acuity and possibly function.

CPM demonstrated a significantly longer history of OA disease as compared to the non-impaired

Journal of Orthopaedic & Sports Physical Therapy

for better long term prognosis.

and chronic knee OA pain may be warranted.

Journal of Orthopaedic & Sports Physical Therapy

modulation. Future studies which examine the neurophysiologic effects of rehabilitative

Finally, only short-term changes in CPM were examined in this study. It