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Copyright ${year} Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.
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
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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
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Key words: arthralgia, physical therapy techniques, manual therapy, diffuse noxious inhibitory
control
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INTRODUCTION
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Pain is one of the primary symptoms of osteoarthritis (OA) leading to impaired function and
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decreased quality of life. In elderly subjects with knee OA, pain is the leading cause of impaired
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mobility.21 Studies have indicated that knee pain and radiographic evidence of osteoarthritic joint
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degeneration are not always correlated.5,18 This suggests that OA and OA-related pain may be
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two separate but related processes. Thus, understanding the mechanisms underlying pain and
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Two important mechanisms are recognized as contributing to heightened pain in knee OA.
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population.4,12 This central sensitization has been shown to produce enhanced pain response,
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spread of pain, and other signs and symptoms, thereby promoting a state of chronic pain in
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individuals with this disease.4 These signs and symptoms include sensory deficits, such as
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decreased pressure pain thresholds (PPT) and vibratory perception deficits.30 Secondly, studies
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have also demonstrated faulty and ineffective pain inhibition in persons with OA.4,20,34,43,48
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Conditioned pain modulation (CPM) is a method of examining pain inhibitory mechanisms, and
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is mediated by the rostral ventromedial medulla, the periaqueductal gray (PAG), and subnucleus
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reticularis dorsalis,9,39 with potential prefrontal cortex and cingulate contribution as well.7 In
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basic terms, application of a noxious stimulus at a remote site causes inhibition of pain at the
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initial site (e.g., the OA knee). Tonic descending pain inhibition provides a persistent dampening
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of the perception of pain. It has been suggested that these supraspinal mechanisms are both
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facilitatory and inhibitory, and impairment is a result of an imbalance between these inputs.52
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Contributors to this imbalance may be a persistent nociceptive input from the periphery, or
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In human studies, CPM has been examined experimentally through use of protocols which
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typically induce cold46 or ischemic4,20 pain. The effect of surgical,20,34 and TENS14 interventions
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on impaired CPM has been studied, but outcomes of manual therapy management have not been
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previously examined. Non-thrust joint manipulation, also called joint mobilization, is commonly
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used by physical therapists to manage painful joint conditions and typically involves the
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application of rhythmic oscillatory motion of the joint surfaces within normal joint range.37 Some
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studies have suggested successful outcomes with its use in knee OA when incorporated into a
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However, a recent randomized controlled trial has demonstrated the independent contribution of
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manual therapy for knee OA treatment outcomes.1 Conversely, successful outcomes were not
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demonstrated in one clinical trial where joint mobilization was applied at a distant site from the
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knee (ie, thoracic spine).6 Mechanistic studies have shown a decrease in central excitability of
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nociceptive pathways and pain measures following a treatment of knee joint mobilization in an
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animal model49 and in humans with knee OA.13 However, the effect of joint mobilization on
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descending inhibitory pain mechanisms, measured via CPM, has not been investigated in knee
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OA.
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The purpose of this study was to determine the effect of joint mobilization on impaired CPM
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in individuals with painful OA of the knee. We hypothesized that CPM would become more
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decreased resting pain. A secondary hypothesis was that vibratory deficits would normalize
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mechanisms underlying the treatment effects of joint mobilization may allow for more targeted
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METHODS
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Subjects
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Individuals with knee OA were enrolled, through use of recruitment flyers, from the outpatient
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clinics of the University of Illinois at Chicago. Individuals were included in the study if they had
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been diagnosed by their orthopedic physician with OA of the tibiofemoral joint ( Grade II
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Kellgren and Lawrence radiographic changes). Since knee OA is commonly bilateral, subjects
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with bilateral knee OA were also enrolled in the study. It was confirmed that one knee was more
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were excluded from the study if they had total knee arthroplasty, reported previous history of any
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deficiency. They were instructed to avoid use of anti-inflammatory or pain medications 24 hours
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prior to testing, and to avoid any unusual change in activity levels. The Institutional Review
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Board of the University of Illinois at Chicago (USA) approved the study and all subjects signed
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Each of the participants was questioned about date of onset of OA, and their knee pain at
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rest using a Visual Analog Scale (VAS).44 They also completed the Knee Outcome Survey-
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Activities of Daily Living Scale (KOS).26 This survey is a 14-item scale designed to assess how
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knee symptoms and knee condition affect the ability to perform daily functions. Scores are
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presented as percentages of the maximal score where 100% represents full perceived knee
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The screening protocol was completed with the subject lying in supine, in approximately
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20 of hip and knee flexion with the lower limb comfortably supported. The most painful site
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was identified on the medial aspect of the affected knee and confirmed through gentle palpation
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by the tester (typically at the medial joint line). This site was marked and maintained for
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subsequent testing sessions. Pressure pain threshold was established at the experimental knee.
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The tip of an algometer (JTECH Medical, Salt Lake City, UT) was applied perpendicular to the
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most painful site at the medial knee on the affected limb, at a rate 50 kPa/s until the subject
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reported a change from pressure to a painful sensation30,45. The procedure was performed 3 times
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at 20 second intervals, and the average calculated to determine PPT.45 After being educated on
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the procedure, both tester and subject were blinded to all subsequent scores during the session.
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Conditioned pain modulation was tested using the upper extremity submaximal effort
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tourniquet test.34 Specifically, the subject was asked to elevate their contralateral arm for one
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minute. A blood pressure cuff was then inflated to a pressure of 280mm Hg. Participants rated
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the tourniquet-induced pain intensity of the arm on a VAS. The cuff was deflated at the 6 minute
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interval and 3 trials of PPT measures at the 3 sites were taken immediately following deflation.
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Impaired CPM was operationally defined as no change or a negative change in PPT measures,
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taken directly following termination of the conditioning stimulus (tourniquet test). These
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testing.56
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Individuals who were found to demonstrate impaired CPM were asked to attend two
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subsequent sessions that were scheduled one week apart. Each subject was randomly assigned
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via sealed envelope to one of two groups, which indicated which of two experimental
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interventions would be applied in the first of the two subsequent sessions. The other intervention
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Experimental Procedure
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Prior to testing for each of the two subsequent testing sessions, the subjects were
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acclimated to a room temperature of approximately 70 F for 10-15 minutes for the purpose of
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standardizing the environment for sensory testing.31 The testing protocol (FIGURE 1) was again
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completed with the subject lying in supine, in approximately 20 of hip and knee flexion with the
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lower limb comfortably supported. Prior to testing, all subjects were educated on vibration
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perception and pressure pain procedures at a proximal site until the subject was capable of
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responding reliably.50 Subjects were not informed on the purpose of applying the experimental
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interventions.
Resting Pain
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Assessment of resting knee pain of the experimental limb was performed using the VAS at two
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specific intervals during testing: baseline and following the subsequent testing of CPM.
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Vibration perception threshold was assessed at baseline and at the completion of testing.
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It was measured bilaterally at bony landmarks at the medial femoral condyle, using a
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13mm in diameter, vibrating at 100 Hz, was allowed to rest at the site of application. The
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amplitude of vibration (expressed in biothesiometer units54) was increased until the participant
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reported an initial sensation of vibration.47 The biothesiometer was left in place and a second
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assessment was made.47 The average of these 2 results was calculated and recorded.
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Pressure pain threshold was applied as described above.30,45 The procedure was also
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performed at the corresponding site on the contralateral knee and at the web space between the
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1st and 2nd metacarpophalangeal joints on the contralateral side. The procedure was performed 3
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times at each location and the average calculated to determine PPT.45 As mentioned above, a 20
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second time interval was maintained between applications to prevent sensitization of pain
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responses. Blinding to scores was maintained during each session. PPT was assessed at baseline,
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Experimental Conditions
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After establishing baseline measures in VPT, PPT at each of the 3 sites, and resting pain,
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one of the two interventions was applied: 1) oscillatory joint mobilization into slight tissue
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resistance (intervention), or 2) hands-on cutaneous input only to the knee (control). All
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interventions were applied by the same physical therapist, who was fellowship trained in
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Orthopedic Manual Physical Therapy. The oscillatory joint mobilization technique was executed
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by placing both hands on the knee of the subject and gliding the tibia forward and back on the
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femur in an oscillatory manner within a pain-free range, moving slightly into tissue resistance
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(FIGURE. 2A).37 The hands-on cutaneous input technique was executed by lightly placing both
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hands on the subjects knee (FIGURE. 2B). Each experimental condition was applied for 2*3
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min with a 30 sec interval between.13 PPT, at all three sites, and resting knee pain were measured
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pre-intervention, post-intervention and post-CPM re-assessment. Both subject and tester were
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Statistical Analyses
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Descriptive statistics (means and standard deviations) were used to describe the sample
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and plots were examined for outcome variable distributions. Students t-test or Mann-Whitney
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U-test (for continuous variables) and chi-square or Fisher exact tests (for categorical variables)
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were applied to analyze differences in sample demographics between CPM impaired and CPM
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intact patients.
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Our hypotheses were tested using mixed effect regression models with random intercepts
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for each person to account for within-person correlations due to repeated measurements using
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SAS 9.3 software. All models included the main effects for treatment session (joint mobilization,
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cutaneous input), and time point, dummy coded using 2 variables representing either baseline,
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post-intervention, or post-CPM (if measured) depending on the desired reference group, as well
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as treatment by time interactions, controlling for order of treatment session. To assess post-
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intervention differences between treatment sessions, the interaction term represented the
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levels, unless otherwise indicated. Effect sizes were calculated from the interaction terms by the
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formula: interaction estimate/ (standard error * square root (degrees of freedom)), i.e., the
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difference in group means divided by the standard deviation estimate.25 Initial models also
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assessed if treatment differences were moderated by order, i.e., did the treatment by time effect
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differ when cutaneous input only was received first compared to when joint mobilization was
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RESULTS
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Forty individuals (mean age 598 years; 13 male; BMI: 36.813.4) were enrolled in the study
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with baseline demographic and clinical measurements presented in TABLE 1. Almost all
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subjects (n=38) had bilateral OA, with one limb more painful than the other, and 85% reported
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occasions of knee giving way. Resting pain of the tested knee, measured with the VAS, was
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27.824.8 (100 mm scale), while vibratory perception acuity was significantly diminished on the
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more painful limb (TABLE 1). Participants had been diagnosed with the disease for 11.98.9
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years and reported greater than 50% deficit (45.613.7) in function as measured by the KOS. Of
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this group, 73% (29 participants) demonstrated impaired CPM (TABLE 2). The mean change in
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PPT in the intact CPM group was 27.912.1% while the mean change in the impaired CPM
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group was -9.715.5%. Impaired and non-impaired groups were similar, except that the
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individuals with impaired CPM had a longer history of the disease (13.17 versus 8.67 years;
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P=0.01) and they demonstrated a higher systolic blood pressure (1286 versus 1219 mm Hg;
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Results of the mixed effect regression models are presented in TABLE 3. Our results
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showed small to moderate effects between treatments with the greatest impact on resting pain
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level [F(1, 84)=21.49, p<.0001 for treatment by time interaction effect], followed by PPTs at the
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affected knee [treatment by time interactions: F(1, 140)=16.81, p<.0001 for post-intervention
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The hypoalgesic effect generalized to the hand [treatment by time interactions: F(1, 140)=8.5,
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p=0.0041 for post-intervention compared to baseline, F(1, 140)=4.66, p=0.0325 for post-CPM
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compared to post-intervention], and to a lesser extent, the contralateral knee [treatment by time
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interactions:
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PPT were comparable across the three sites following CPM as compared to post-intervention
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levels.
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treatment by time interaction effects], but were also demonstrated at the unaffected knee to a
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lesser extent [F(1, 84)=3.21, p=0.0767]. No effect was noted from cutaneous input only.
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DISCUSSION
Vibration effects were larger in the affected knee [F(1, 84)=16.38, p=0.0001 for
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The main finding of the current study was that impaired CPM was enhanced following
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application of the joint mobilization intervention. Research studies have suggested that joint
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mobilization intervention may have beneficial effects on pain and function in knee OA
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populations.1,15,16,29 Conspicuous in these studies is the fact that manual therapy treatment was
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directed at the painful joint (the knee), suggesting that homotopic rather than heterotopic input to
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the central nervous system, delivered via manual therapy, may facilitate an enhanced analgesic
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effect. A similar notion has been previously proposed in laboratory based research.32
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Accordingly, the lack of beneficial effects found in one knee OA clinical trial6 may be due to the
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fact that manual therapy was directed at the thoracic spine rather than at the knee. In laboratory
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studies, both in an animal model49 and in humans13 with knee OA, joint mobilization intervention
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has been demonstrated to down-modulate spinal excitability, indicating at least in part, a central
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effect of this intervention. Vanegas et al52 stated that CPM impairment may occur due to an
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imbalance between facilitatory and inhibitory inputs. The results of the present study support the
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idea that manual therapy may alter this imbalance, thereby enhancing descending pain
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modulation. Importantly, these findings were demonstrated in individuals with impaired CPM.
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Other studies have reported augmented CPM following therapeutic interventions such as
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surgical,20,34 and TENS14 interventions. Critical to these studies and the present study, is the fact
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that impaired CPM was present or assumed to be present in these patient populations. While the
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effect of joint mobilization on individuals with intact CPM was not examined in our study, it is
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possible that rehabilitative interventions such as manual therapy, exercise, and TENS, mediate
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their effect, at least in part, by accentuating CPM whether impaired or not. Clinically, this would
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require a paradigm shift in how these interventions are explained to patients, as treatment
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response is often described in terms of its mechanical effect. The consequences of approaching
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chronic pain in this manner could be significant; patients would gain a deeper understanding of
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their chronic condition, and thereby, greater insight into self management.
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A secondary objective in this study was to determine the effect of the joint mobilization
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intervention on VPT. Vibration perception threshold findings at the medial knee were similar to
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previous knee OA studies,30,47 with elevated VPT measures suggesting hypoesthesia to vibratory
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stimulus. Vibratory perception deficits have been reported in other musculoskeletal conditions,
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vibration detection acuity has been associated with perceived instability during a functional
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task.30 A study utilizing experimentally induced pain has suggested that pain may inhibit
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vibrotactile sensitivity due to spinal or supraspinal level mechanisms,3 indicating that perceptual
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deficits associated with chronic musculoskeletal conditions may be due to central neuroplastic
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changes rather than peripheral nerve insult. While it may be argued that peripheral neuropathy
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cannot be accurately identified using only the above described methods, our finding that VPT
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measures at the medial knee significantly decreased (indicating better acuity) following the joint
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mechanism underlying these sensory changes rather than peripheral nerve damage. An
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alternative explanation for these findings is that chronic knee pain, as found in our subject
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population, may cause an attentional modulation of sensory perception, meaning that pain may
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cognitively interfere with the ability to detect a sensory stimulus.17,27,55 A recent study
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demonstrated, however, that cognitive loading had a limited effect on pain induced vibratory
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hypoesthesia,22 suggesting that the mechanism involved is more of a sensory rather than
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cognitive interference.
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limb following the joint mobilization intervention, nor was there change in either limb following
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the hands-on cutaneous input intervention. Widespread effects on pain have been reported
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following joint mobilization,40 however it is possible that the effect on innocuous sensory acuity
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vibrotactile hypoesthesia is that the deficit typically occurs in the vicinity of the induced pain
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area.8 Accordingly, resolution of this sensory inhibition may be localized and focal in nature.
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Further research into the hypoesthetic effects of joint mobilization may aid in our understanding
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Importantly, not all of our subjects with chronic knee OA demonstrated impaired CPM.
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Of the 40 participants in the study with moderate to severe knee OA, 73% demonstrated
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impaired pain modulation, as measured via CPM (TABLE 2). Developing clinical tools that can
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identify impairment in pain modulation may be of value in rehabilitative settings and during
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surgical consults.57 The 2 groups, impaired and unimpaired CPM, were similar on many patient
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characteristics, including resting pain and level of function; however the group with impaired
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group. Duration of disease has been correlated to pain and symptoms in knee OA11,19,30 and
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studies have suggested that prevalence of knee pain in persons with OA increases over time,
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independent of age.41 However, little research has addressed how duration of the symptoms or
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disease may affect central pain regulatory mechanisms. It is possible that over time, the constant
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barrage of painful input to the central nervous system from a painful degenerative knee
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eventually alters or causes an imbalance in the function of descending pain processing. If so, it is
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clear that controlling pain in this population, in the early stages of the disease process, is critical
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Systolic blood pressure was also significantly higher in the subjects with impaired CPM,
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with average levels in the pre-hypertensive range. Previous studies have explored the
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relationship between knee OA and high systolic blood pressure,42 and cardiovascular disease.28
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In healthy individuals, acute onset hypertension (e.g., stress induced hypertension) typically
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causes hypoalgesia (i.e., decreased pain). However, in chronic pain, this mechanism which
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dampens pain can be impaired, likely occurring through sympathetic nervous system
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mechanisms.10 Studies have demonstrated impaired pain inhibition in persons with both high
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systolic blood pressure and chronic temporomandibular dysfunction38 and low back pain,23
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supporting the idea that aberrant descending pain mechanisms are linked to certain
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cardiovascular measures. Further research on the relationship between systolic blood pressure
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The following study had several limitations. First, measurement of PPTs is based upon a
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subjective perception and understanding of what represents a painful stimulus, thus this outcome
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can be variable. However, a recent study has reported PPT to be a valid test stimulus measure for
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CPM.33 To prevent high variability, we provided education to each participant prior to data
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collection. Furthermore, to avoid bias both study participant and tester were blinded to test
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results during each session. Second, it is possible that subjects with impaired CPM believed that
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joint mobilization, rather than cutaneous input only, was the experimental intervention. To
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prevent this, we avoided using terminology that suggested subjects were receiving treatment, and
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we refrained from asking about resting pain following intervention, which may have cued them
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to expectations from the interventions. A third potential limitation of this study is that we did not
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examine the effect of intervention on PPT in the unimpaired CPM group. It is not known if
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application of joint mobilization in these subjects would increase activation of descending pain
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techniques would be beneficial for understanding the pain mechanisms underlying CPM, and for
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directing its clinical use. In addition, although gender was included as covariate, gender
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differences in activation of CPM were not detected after the joint mobilization intervention. A
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recent systematic review and meta-analysis on CPM found that studies involving female
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participants exhibited significantly larger effect sizes than those involving both male and female
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participants.36 The study also found that increased age was a factor in the individuals with
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impaired CPM.36
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would be interesting to determine if these changes would persist over time or with repeated
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treatment sessions.
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CONCLUSION
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The current study suggests that joint mobilization enhances CPM in patients with painful
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knee OA, demonstrated by an apparent global decrease in deep tissue sensitivity to pressure. In
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addition, we also found an enhanced somatosensory acuity, particularly at the knee receiving
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intervention, following joint mobilization. Joint mobilization may be a useful intervention for
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KEY POINTS:
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FINDINGS: In individuals with chronic knee OA, joint mobilization intervention resulted in a
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global decrease in pain sensitivity and improvement of impaired descending pain inhibition,
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indicating that joint mobilization may aid in facilitating central inhibitory mechanisms.
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Diminished baseline VPT acuity was enhanced following joint mobilization at the knee which
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IMPLICATIONS: Focal somatosensory deficits, which may be pain induced and found in
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individuals with chronic pain conditions, may be normalized with pain relieving therapeutic
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CAUTION: Inferences from these findings in individuals with chronic knee OA should be
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480
481
20
487
488
489
490
491
493
Legends of Figures
492
494
21
Yes? (n=29)
Randomize
A. Cutaneous Input
or
B. Cutaneous Input +
Joint Mobilization
No? (n=11)
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
504
23
A.
B.
C.
505
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
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
527
528
529
25
533
534
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
547
26