TITLE: Contralateral Sensory and Motor Effects of Unilateral Kaltenborn Mobilization
in Patients with Thumb Carpometacarpal Osteoarthritis: A Secondary
Analysis

  ABSTRACT:
 [Purpose] The aim of this study was to determine changes in pressure sensitivity and
pinch strength in patients with thumb carpometacarpal (CMC) osteoarthritis (OA) in the
contralateral hand after unilateral Kaltenborn mobilization on the symptomatic hand.
[Subjects and Methods] Twenty-nine females with dominant hand thumb CMC osteoarthritis
participated (age 70–90), and were randomized into 2 groups. The experimental group
received a Kaltenborn mobilization, and the placebo group received a nontherapeutic dose
of intermittent ultrasound. Pressure pain thresholds (PPT) at the thumb CMC joint,
scaphoid bone and hamate bone and tip and tripod pinch strength were assessed before and
after the intervention and 1 week (1st follow-up) and 2 weeks (2nd follow-up) after the
intervention. [Results] Significant increases in PPT in the experimental group at all
follow-up periods as compared with baseline data were found. The post-intervention
between-group mean differences for PPT were 1.1 (95%CI 0.4–1.8) for the CMC joint, 1.1
(95%CI 0.2–2.1) for the scaphoid, and 1.5 (95%CI 0.5–2.8) for the hamate. The
post-intervention between-group mean differences were 0.5 (95%CI 0.2–0.9) for the tip
pinch and 0.3 (95%CI 0.1–0.6) for the tripod pinch. [Conclusion] The current secondary
analysis found that Kaltenborn mobilization for the symptomatic hand reduces pressure pain
sensitivity (PPT increases) and also produces motor changes in the contralateral
non-treated hand compared with a placebo group.

BODY.INTRODUCTION:
Thumb carpometacarpal (CMC) osteoarthritis (OA) is a common condition after the age of 50,
especially in females1). The main cause of
thumb CMC OA is a degenerative progressive alteration of the thumb CMC joint2). This degeneration includes chronic
deterioration of superficial surfaces of the joint and ectopic bone regeneration3,4,5), which results in pain at the base of the
thumb5, 6).  Central sensitization is defined as an intensification of the responsiveness of central
pain-signaling neurons from low-threshold mechanoreceptors7). Central sensitization includes changes in sensory processing and
regulation down of descending pain-inhibitory mechanisms8). The importance of central sensitization processes underlies a
mechanism of pain in OA, which has recently gained interest.  Some studies have investigated the involvement of central pain modulation in OA knee
pain9,10,11). Imamura et al.9) found that patients with moderate to severe
persistent knee pain and disability exhibited significantly lower pressure pain thresholds
as compared with healthy controls. Similarly, Bajaj et al.10) described deep hyperalgesia and increased referred pain areas in
the tibialis anterior muscle in patients with knee OA, observing bilateral effects as a sign
of central sensitization. More importantly, these mechanisms appeared to respond to local
analgesics. Creamer et al.11) reported
that injection of local anesthetic into one knee relieves pain in the contralateral
non-injected knee. These studies suggest a possible role of the central nervous system in
the maintenance of chronic pain in individuals with unilateral knee OA, indicating
sensitization mechanisms at the contralateral side of the symptoms.  In fact, the presence of contralateral sensitization mechanisms has been reported in
unilateral local pain syndromes of the upper extremity. Fernández-de-las-Peñas et al.12) found a bilateral widespread pressure pain
hypersensitivity in women with strictly unilateral carpal tunnel syndrome, whereas
Fernández-Carnero et al.13) showed similar
findings in individuals with unilateral lateral epicondylalgia. These studies suggest that
unilateral local pain syndromes exhibit contralateral sensitization mechanisms.  It has been previously found that manual therapies induce mechanical hypoalgesia (which
causes an increase in pressure pain thresholds; PPT) concurrent with sympathetic nervous
system14) and motor15) excitation. Previous studies investigating hypoalgesic
mechanical effects of manual therapies have focused on different passive mobilization
techniques, i.e., lateral glide of the cervical spine16), posterior-anterior joint mobilization15) or mobilization-with-movement17). These studies mainly investigated manual therapy targeted
at the cervical spine, explaining that spinal joint interventions can exert bilateral
effects. We have recently conducted a randomized controlled trial analyzing changes in
pressure sensitivity after treatment with Kaltenborn mobilization in patients with thumb CMC
OA18). However, the data regarding the
contralateral hand have not yet been analyzed.  Some studies have demonstrated that unilateral interventions exhibit bilateral effects,
suggesting a central rather than peripheral effect of manual therapies19,20,21). Nevertheless, it is unknown whether the use of a
unilateral Kaltenborn mobilization on the symptomatic-affected side induces sensory and
motor effects on the contralateral hand in individuals with thumb CMC OA. In the current
work, we conducted a secondary exploration of our previous randomized controlled trial by
analyzing changes occurring within the contralateral hand. We hypothesized that unilateral
Kaltenborn mobilization applied on the symptomatic hand in individuals with thumb CMC OA
would also induce contralateral mechanical hypoalgesia and motor effects.

BODY.SUBJECTS AND METHODS:
We conducted a secondary analysis of data previously reported in a randomized controlled
clinical trial. The recruitment methods and a description of the trial have been previously
described18). Here we have summarized
the most relevant parts of the design (Fig. 1Fig. 1. Flow diagram of criteria in the study).  Patients with dominant hand thumb CMC OA were recruited from the "Residenze Sanitarie
Assistenziali" (Avigliana and Sangano, Italy). The Inclusion criteria included patients who
used their dominant hand on a regular basis (e.g., ex-factory workers and home workers), age
between 70–90 years and those diagnosed with CMC OA in the dominant hand by X-ray detection
of stage III–IV according to the Eaton-Littler-Burton Classification22). The diagnosis of CMC OA was confirmed by a hand surgeon
following X-ray examination. Patients with a medical history of carpal tunnel syndrome,
prior surgical interventions to thumb CMC joint, or De Quervain's tenosynovitis were
excluded, as well as those presenting degenerative or non-degenerative neurological
conditions in which pain perception was altered5). This study was approved by the Local Ethics Committee (Azienda
Sanitaria Locale 3, Collegno, Italy) and registered in the clinical trials database as
ISRCTN06361999. All patients provided informed consent before enrollment in the study. They
were randomly assigned to either the experimental or sham group by using a simple
randomization with a random number generator. Blocked or stratified randomization was not
used in this study18).  Participants were randomly assigned to one of two groups: the experimental group received
Kaltenborn mobilization therapy, whereas the control group received a placebo therapy. The
treatment was performed unilaterally and only applied to the symptomatic (ipsilateral) hand.
From all the possible treatments, we chose joint mobilization because of the improvement
with respect to the limited ROM and therefore reduction in pain induced by traction and
glide. As previously described18), the
intervention group received unilateral Kaltenborn mobilization consisting of
posterior-anterior gliding with Grade 3 distraction in of the thumb CMC joint of the
dominant hand. Grade 3 distraction was chosen to avoid contact between the articular
surfaces and to stimulate hypoalgesic factors. The treatment duration was 6 sessions over a
period of 2 weeks (3 sessions/ week). The mobilization was applied over the course of 3
minutes with a 1-minute pause; the action was repeated three times. The physiotherapist
gripped the right thumb metacarpal bone of the subject with his right thumb and index finger
and made a specific Kaltenborn mobilization of posterior-anterior gliding with a short
amplitude and distraction of the thumb CMC joint.  Participants in the placebo group received a sham dose of intermittent ultrasound therapy
in the thumb region in 10 minutes for 6 sessions over 2 weeks23,24,25). Interventions were applied by an experienced physical therapist
with a 4 year Postgraduation Certificate in Manual Therapy and more than 11 years of
experience in the management of musculoskeletal pain disorders.  In the first study, we analyzed the results from the symptomatic hand. The current
secondary analysis was focused on the contralateral hand. The pressure pain threshold was
measured bilaterally over the thumb CMC joint at the anatomical snuffbox, the tubercle of
the scaphoid bone, and the unciform apophysis, of the hamate bone, to represent the spread
of hyperalgesia in central sensitization. The pressure was applied approximately at
0.1 kg/cm2/s (until the onset of pain)2,
18, 26,27,28).
Participants were seated in a standardized position, and 2 trials of both tip and tripod
pinch strength were taken using a pinch. Pinch strength measurements were taken bilaterally
for each participant. The between-group differences in pain pressure threshold and pinch
strength for the contralateral hand were analyzed in this study. PPT measurements were
expressed in kg/cm2, and pinch strength was expressed in kg. For every outcome,
three measurements was calculated and used for the main analysis. A 1-minute rest period was
allowed between each measurement. The subjects were assessed at baseline, immediately after
treatment, and 1 and 2 weeks after the treatment by an assessor blinded to their allocation
group18).  Data were analyzed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). The results are
expressed as means, standard deviations, and/or 95% confidence intervals. Normal
distribution of the sample was analyzed using the Kolmogorov-Smirnov test (p>0.05).
Baseline demographic and clinical variables were compared between the groups using
independent Student t-tests for continuous data and χ2 tests of independence for
categorical data. A 2-way analysis of variance (ANOVA) was used to evaluate differences for
PPT and strength measurements between sides (affected/unaffected in patients) as the
within-subjects factor and groups (experimental or sham) as the between-subject factor. A
repeated measures ANOVA test was used to evaluate the differences in PPT at over time point
and pinch strength levels with time as the within-subjects factor and group (experimental or
placebo) as the between-subjects factor. The hypothesis of interest was group-by-time
interaction. Post hoc comparisons were performed with the Bonferroni test. In those
variables for which the baseline data were different, an analysis of covariance (ANVOCA) was
conducted by including the baseline value as a covariate. Finally, between-group effect
sizes were calculated using Cohen's d coefficient29). An effect size greater than 0.8 was considered large, around 0.5
was considered moderate, and less than 0.2 was considered small29). The statistical analysis was conducted at a 95%
confidence level, and a p<0.05 was considered statistically significant.

BODY.RESULTS:
Twenty-nine women with thumb CMC OA, mean age 81 ±7 years, met all the inclusion criteria
and agreed to participate. No significant statistical differences were found in any outcome
at baseline between groups, except for the scaphoid bone. Baseline data of the participants
are summarized in Table 1Table 1. Baseline characteristics of participantsCharacteristicRandomized (n = 29)Exp (n = 14)Con (n = 15)Age (yr), mean (SD)81 (8)80 (7)Gender, n females (%)14 (100)15 (100)Exp = experimental group, Con = control group, CMC = carpometacarpal joint.  The ANOVA revealed significant group-by-time interactions for PPT over the thumb CMC joint
(F=9.591; p=0.005), scaphoid (F=9.083; p=0.006), and hamate (F=2.979; p=0.036) bones. The
post hoc testing revealed significant increases in PPT within the experimental group for all
follow-up periods as compared with the baseline data (p<0.01 for all groups). No
differences between the post-intervention and follow-up periods were found (p>0.10). No
significant changes were found within the control group. The post-intervention between-group
mean differences for PPT were 1.1 (95%CI 0.4–1.8) for the CMC joint, 1.1 (95%CI 0.2–2.1) for
the scaphoid bone, and 1.5 (95%CI 0.5–2.8) for the hamate bone. The data are summarized in
Table 2Table 2. Mean (SD) for outcomes at all study visits for each group, mean (SD) difference
within groups, and mean (95% CI) difference between groupsOutcomeGroupsDifference within groupsDifference between groupsWeek 0Week 2Week 3Week 4Week 2 minus Week 0Week 3 minus Week 0Week 4 minus Week 0Week 2 minus Week 0Week 3 minus Week 0Week 4 minus Week 0ExpConExpConExpConExpConExpConExpConExpConExp minus ConExp minus ConExp minus Con(n=14)(n=15)(n=14)(n=15)(n=14)(n=15)(n=14)(n=15)CMC joint PPT,(kg/cm2)3.03.23.93.03.63.13.63.10.9−0.20.6−0.10.6−0.11.10.70.7(1.2)(1.0)(1.5)(1.2)(1.3)(1.0)(1.5)(1.1)(0.9)(0.9)(0.7)(1.0)(1.0)(0.7)(0.4 to 1.8)(0.3 to 1.3)(0.3 to 1.4)Scaphoid PPT,(kg/cm2)3.64.84.94.84.54.94.54.01.30.00.90.10.9−0.81.10.81.7(1.1)(1.7)(2.0)(1.1)(1.1)(1.4)(1.7)(1.4)(1.0)(1.6)(1.0)(1.4)(1.6)(1.2)(0.2 to 2.1)(0.2 to 1.6)(0.8 to 2.6)Hamate PPT,(kg/cm2)4.65.86.05.75.65.75.65.51.4−0.11.0−0.11.0−0.31.51.11.3(1.6)(2.0)(1.3)(2.2)(1.3)(1.6)(1.8)(1.9)(1.8)(1.5)(2.1)(2.0)(2.3)(2.1)(0.5 to 2.8)(0.4 to 2.5)(0.3 to 2.6)Tip pinch strength,(kg)2.12.32.22.52.62.12.32.00.10.20.5−0.20.2−0.30.50.70.6(0.6)(0.8)(1.1)(0.8)(1.1)(0.9)(1.0)(0.9)(1.9)(1.3)(1.9)(1.7)(2.2)(1.0)(0.2 to 0.9)(0.2 to 1.0)(0.1 to 0.6)Tripod pinch strength,(kg)2.72.83.12.93.42.93.02.50.40.10.70.10.3−0.20.30.60.6(1.2)(0.9)(1.6)(1.1)(2.0)(0.9)(1.4)(1.0)(0.6)(0.6)(0.6)(0.7)(0.8)(0.7)(0.1 to 0.6)(0.3 to 1.3)(0.1 to 0.9)Exp: experimental group; Con: control group; CMC: carpo-meta carpal joint; PPT: pressure-pain threshold.  The ANOVA revealed a significant group-by-time interaction for tip pinch (F=5.343; p=0.029)
and tripod pinch strength (F=7.834; p=0.009). The post hoc testing revealed significant
increases in tip and tripod pinch strength in the experimental group for all follow-up
periods compared with the baseline data (p<0.05 for all groups), with no differences
between the post-intervention and follow-up periods (p>0.50). Again, no significant
changes were observed within the control group. The post-intervention between-group mean
differences for strength were 0.5 (95%CI 0.2–0.9) for tip pinch, and 0.3 (95%CI 0.1–0.6) for
the tripod pinch. Between-group effect sizes were small to moderate
(d=0.35) for tip pinch and small to moderate (d=0.39) for
tripod pinch strength (Table 2).

BODY.DISCUSSION:
The current secondary analysis found that application of a unilateral Kaltenborn
mobilization to the symptomatic hand induces hypoalgesic effects, which can be monitored by
increases in PPT in the contralateral hand in women with thumb CMC OA. Motor changes were
also observed, as shown by increased tip and tripod pinch strength, in the contralateral
hand. However, some of these changes were small, and their clinical relevance should be
considered with caution particularly considering that they refer to the non-symptomatic
side. Current and previous18) findings
suggest a bilateral hypoalgesic and unilateral contralateral motor effect after the
application of a unilateral manual mobilization in women with thumb CMC OA.  Historically, it was hypothesized that mechanisms by which manual therapies exert their
effects were primarily biomechanical in nature; however, it has been recently proposed that
these effects are neurophysiological origin30). Among the different theories, it is accepted that manual therapies
affect central mechanisms by stimulating descending inhibitory pain mechanisms, particularly
in the periaqueductal gray area30). This
assumption is based on the premise that manual therapies result in a decrease in pressure
pain sensitivity (by increasing PPT) and motor system excitation to a greater magnitude than
in sham or control groups14, 21).  In the current secondary analysis, we found that a unilateral Kaltenborn mobilization
applied to the symptomatic hand in patients with thumb CMC OA increased PPT levels in the
thumb CMC joint and scaphoid and hamate bones on the contralateral hand a greater magnitude
than the placebo intervention. In fact, PPT increased by around 35% at all the points
analyzed, showing large effect sizes. Regarding these magnitudes, it is important to note
that different structures may or may not exhibit similar values. Prushansky et al.31) established that differences ranging from
20% to 25% are required to indicate a relevant clinical interpretation. However, we should
consider that this study investigated changes in pressure pain sensitivity over the cervical
spine and in healthy people, so extrapolation of the percentage improvement in this specific
group cannot be directly transferred to other body parts in subjects in a totally different
age group with a particular disease, and therefore, the results should be considered with
caution at this stage. Therefore, our records are greater than this preestablished cutoff
value, emphasizing the calidity of the changes we found. Nevertheless, we should recognize
that this study was focused on PPT in the cervical spine, where decreases in pain are more
difficult to achieve. Additionally, previous studies analyzing changes in PPT after the use
of different manual interventions reported changes between 15–25%14, 21). Again, the PPT
changes obtained in the current study on the contralateral hand were similar, or sometimes,
greater than these values since they were greater than 20% of pre-intervention scores at all
points; however, the current results should not be compared with the ones from other
studies, since the features of the present protocol were different.  The findings obtained in the present study along with previous results18) suggest a bilateral hypoalgesic effect of unilateral
Kaltenborn mobilization, supporting that manual mobilization may exert a central effect, at
least an effect referred to the contralateral side. In fact, it has been suggested that
manual therapies, e.g., manipulative therapy, may provide counter-inflammatory effects
mediated by inhibition of neuroplastic changes associated with central sensitization at the
dorsal horn of the spinal cord32).
However, this theory is based on studies investigating spinal manipulative therapy but not
manipulations applied to peripheral joints. The results of our study would support the idea
that use of unilateral mobilization for a local peripheral joint (CMC) induces bilateral and
mirror-type changes in PPT in related areas at the contralateral side. However, the
mediators and mechanism of these effects remain unknown.  We also found that a unilateral Kaltenborn mobilization exerted motor effects on the
contralateral hand by increasing the tip and tripod pinch strength in women with thumb CMC
OA. In fact, the tip and tripod pinch strength increased 22% and 26% respectively,
supporting a motor effect after the intervention. However, some of these changes were small,
and their clinical relevance should be considered with caution particularly considering that
they refer to the non-symptomatic side. When the findings obtained in the current study
along with previous results18) are taken
together, it seems that an unilateral mobilization of the thumb CMC joint may be able to
elicit contralateral motor responses in patients with thumb CMC OA. It is interesting to
note that the application of unilateral mobilization of the thumb for the symptomatic joint
only induces a contralateral motor effect, which was unexpected. This may be related to the
fact that the symptomatic joint exhibited degenerative changes on X-ray and pain, and it is
possible that a single mobilization session is not able to induce motor changes.  The presence of contralateral motor responses after unilateral manual mobilization would
support the idea of, at least, centrally-mediated responses. Animal studies have shown that
stimulation of the dorsal periaqueductal gray matter provokes increased activity of alpha
motor neurons in rodents33). Similarly, in
humans, manual mobilization enhances motor activity in combination with mechanical
hypoalgesic effects by stimulating the dorsal periaqueductal gray matter34). The current secondary analysis found an
hypoalgesic effect concurrent with a motor effect in the contralateral hand, supporting
findings from previous studies conducted on the cervical spine14, 15, 35). It is possible that structures such as the mesencephalon
coordinate motor effects through a direct link involving neuronal networks and projections
to the motor cortex36,37,38,39). Therefore, we can hypothesize that peripheral unilateral
stimulation of the affected joint (CMC in this case) via central structures may increase
motor activity. However this hypothesis remains to be tested for the CMC since we only found
contralateral motor responses after a single session of mobilization of the CMC joint.  Although the results of this study are promising, we recognize several limitations. First,
we only applied a localized intervention for the symptomatic peripheral joint, which does
not represent the common clinical practice for these patients. It would be of great interest
to investigate sensory and motor changes after the inclusion of interventions targeted at
the thoracic and cervical innervated areas, which may serve as nodes for sharing
information. In fact, it is possible that the application of a single joint intervention
explains the motor effects found just in the contralateral side. Second, the advanced age of
the patients may present concomitant pathologies that could affect the results. Third, we
had only evaluated sensory and motor changes in segment-related areas. In addition, we only
assessed PPT. It would be interesting to determine changes in other sensory modalities, such
as thermal, electrical or cutaneous thresholds, to determine more relevant changes. To
finally confirm a central effect of manual interventions, future studies should analyze
widespread hypoalgesic and motor changes. In fact, we did not evaluate activation of
cortical brain areas after intervention. Therefore, we cannot confirm that the hypoalgesic
and motor changes observed in the current study are directly associated with activation of
central structures. Finally, the analyses reported in the present study were exploratory and
hypothesis-generating rather than confirmatory. Further studies are now needed to
investigate the mechanisms underling our findings and fully investigate the nervous system
mediators involved.  The current secondary analysis found that a unilateral Kaltenborn mobilization for the
symptomatic hand reduced pressure pain sensitivity by increasing PPTs in the CMC joint and
the scaphoid and hamate bones of the contralateral hand in patients with CMC OA.
Furthermore, we also observed positive motor changes including an increase in tip and tripod
pinch strength of the contralateral hand. Future studies with larger sample sizes are needed
to further examine the effects of joint mobilization on motor and sensory effects.

Question: Compared to Placebo therapy what was the result of Kaltenborn mobilization therapy on Pressure pain thresholds at the thumb CMC joint, scaphoid bone and hamate bone?
Evidence: No significant statistical differences were found in any outcome
at baseline between groups, except for the scaphoid bone. 
Answer: significantly increased