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The pain-relieving qualities of exercise in knee osteoarthritis

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The purpose of this review article is to explore the role of therapeutic exercise in managing the pain associated with knee osteoarthritis (OA). Therapeutic exercise is often recommended as a first-line conservative treatment for knee OA, and current evidence supports exercise as an effective pain-relieving intervention. We explore the current state of evidence for exercise as a pain-relieving intervention for knee OA. Next, the mechanisms by which knee OA pain occurs and the potential ways in which exercise may act on those mechanisms are discussed. Clinical applicability and future research directions are suggested. Although evidence demonstrates that exercise reduces knee OA pain, optimal exercise mode and dosage have not been determined. In addition, it is not clearly understood whether exercise provides pain relief via peripheral or central mechanisms or a combination of both. Published clinical trials have explored a variety of interventions, but these interventions have not been specifically designed to target pain pathways. Current evidence strongly supports exercise as a pain-relieving option for those with knee OA. Future research needs to illuminate the mechanisms by which exercise reduces the pain associated with knee OA and the development of therapeutic exercise interventions to specifically target these mechanisms.
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Open Access Full Text Article
http://dx.doi.org/10.2147/OARRR.S53974
The pain-relieving qualities of exercise in knee
osteoarthritis
Allyn M Susko
G Kelley Fitzgerald
Department of Physical Therapy,
University of Pittsburgh, Pittsburgh,
PA, USA
Correspondence: G Kelley Fitzgerald
University of Pittsburgh Department of
Physical Therapy, 6053 Forbes Tower,
Pittsburgh, PA 15260, USA
Tel +1 412 383 6643
Email ktzger@pitt.edu
Abstract: The purpose of this review article is to explore the role of therapeutic exercise
in managing the pain associated with knee osteoarthritis (OA). Therapeutic exercise is often
recommended as a first-line conservative treatment for knee OA, and current evidence supports
exercise as an effective pain-relieving intervention. We explore the current state of evidence
for exercise as a pain-relieving intervention for knee OA. Next, the mechanisms by which
knee OA pain occurs and the potential ways in which exercise may act on those mechanisms
are discussed. Clinical applicability and future research directions are suggested. Although
evidence demonstrates that exercise reduces knee OA pain, optimal exercise mode and dosage
have not been determined. In addition, it is not clearly understood whether exercise provides
pain relief via peripheral or central mechanisms or a combination of both. Published clinical
trials have explored a variety of interventions, but these interventions have not been specifically
designed to target pain pathways. Current evidence strongly supports exercise as a pain-relieving
option for those with knee OA. Future research needs to illuminate the mechanisms by which
exercise reduces the pain associated with knee OA and the development of therapeutic exercise
interventions to specifically target these mechanisms.
Keywords: knee, OA, exercise, pain
Background
Knee osteoarthritis (OA) is the most common form of OA in the USA, with an esti-
mated prevalence of symptomatic knee OA in 10%–16% of older adults in the USA
according to the Centers for Disease Control and Prevention.
1,2
Prevalence of knee
OA increases with age, ranging from 3% among those aged 45–54 years old to 44%
in those at least 80 years old.
3
These prevalence estimates are expected to increase as
the US population continues to age and obesity rates rise.
4
Risk factors for knee OA include advancing age and previous history of trauma.
5
Familial clustering and twin studies have shown a probable genetic component for
the development of knee OA, though environmental factors may also play a role in its
development.
6,7
The presence of obesity has been shown to be associated with increased
risk of knee OA, and may also increase the rate of articular cartilage degeneration.
8,9
The most commonly reported symptom of knee OA is pain, and pain has been identi-
fied as the top clinical concern for those with OA.
10
Overall, higher levels of pain from
knee OA are linked to lower physical function and lower quality of life.
6
Thus, relief
of pain is paramount in improving the lives of those with knee OA.
Conservative treatments for knee OA pain are numerous. More than half of those
with knee OA report taking over-the-counter pain medications, while approximately
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Susko and Fitzgerald
one-third use vitamins or other dietary supplements and
various topical ointments.
11
Physical modalities such as
transcutaneous electrical nerve stimulation, laser, electroa-
cupuncture, magnets, and therapeutic ultrasound have been
studied with varying results.
12,13
The benefits of supplements
such as glucosamine and chondroitin sulfate continue to be
under investigation, with results as yet inconclusive.
14
Some
with knee OA also attempt to manage pain with psychological
interventions such as cognitive behavioral therapy and pain-
coping skills training.
15,16
Injections of cortisone or hyaluronic
acid are quite common. Despite myriad treatment options,
one study found that 19% of those with knee OA report that
their pain is not adequately controlled.
17
Therapeutic exercise is often recommended as a first-
line conservative treatment for knee OA. The American
Academy of Orthopaedic Surgeons 2013 guidelines for the
treatment of knee OA include a strong recommendation for
strengthening, low-impact aerobic exercise, neuromuscular
education, and physical activity for those with symptomatic
OA,
18
while the American College of Rheumatology’s 2012
recommendations for the management of knee OA include a
strong recommendation for aerobic and/or resistance land-
based exercise as well as aquatic exercise.
19
Similarly, the
2008 expert consensus guidelines from the Osteoarthritis
Research Society International advocate regular aerobic,
strengthening, and range-of-motion exercise for all patients
with knee OA.
1
The overall aim of this review is to explore the role of
therapeutic exercise in managing pain associated with knee
OA. Specifically, we rst discuss current evidence supporting
exercise as a pain-relieving intervention then the mechanisms
of pain generation in knee OA are explored, and how exer-
cise may act on these mechanisms to relieve knee OA pain.
Finally, the clinical applicability of the current evidence and
directions for future research are suggested.
Evidence supporting exercise
as pain relieving
Despite increased public awareness of the importance of
exercise and physical activity, only 27.8% of those with
knee OA engage in regular moderate or vigorous physical
activity.
20
The evidence base supporting exercise as a means
to reduce pain in knee OA continues to grow.
Published in 2005, the MOVE consensus outlines recom-
mendations for the use of exercise to manage hip and knee
OA.
21
These recommendations promote both strengthening
and aerobic exercise as a means to reduce OA pain, with the
addition of behavioral interventions to promote long-term
lifestyle changes to maintain increased levels of physical
activity. The authors also recommend that exercise therapy
be individualized based on age and comorbidities, but group
and home exercise are equally effective. Finally, the authors
support the effectiveness of exercise in all stages of OA and
state that exercise may reduce the progression of knee OA,
although they acknowledge that these recommendations are
based on expert opinion and are not supported by evidence in
existence at the time of publication. Given the fairly generous
number of effectiveness studies published since 2005 in the
area of exercise for knee OA, these recommendations may
be ripe for reassessment and updating.
Several recent reviews have been published regarding
the strength of evidence supporting exercise as a pain-
relieving intervention for those with knee OA.
15,22–26
Most
have reported that exercise does indeed reduce pain, but
effect sizes are small to moderate at best. Relatively small
effect size, inadequate dosage, and lack of research compar-
ing different modes of exercise are common limitations of
the current evidence.
A 2009 Cochrane systematic review of 32 studies of
land-based exercise for knee OA concluded that platinum-
level evidence supports land-based therapeutic exercise for
at least short-term pain reduction, but long-term effects are
unclear and pooled effect sizes are small.
24
Unfortunately,
this review did not consider the mode of intervention used
both aerobic and strengthening interventions were included,
both weight-bearing (WB) and non-weight-bearing (NWB)
interventions were included, and none of the authors’ com-
parisons attempted to note whether any particular mode was
most effective for pain relief. The review did conclude that
studies that provided an individual intervention produced
greater pain relief than class- or home-based interventions;
however, no conclusions could be made regarding the most
effective mode or dosage of exercise for knee OA pain.
Although modest effect sizes appear to be a common
denominator among published studies of exercise for knee
OA pain, the quality and dosage of the interventions provided
are also limiting factors. In the aforementioned Cochrane
review of land-based exercise for knee OA,
24
only 12 of the
32 studies included provided interventions at least twice per
week for at least 8 weeks. Several focused on strengthening
only one muscle group (the quadriceps femoris) or provided
very elementary interventions such as education about exer-
cise or simple range-of-motion exercises, which are unlikely
to independently produce a training effect or significant pain
relief. Many of the included studies involved home-based
interventions with minimal supervision. The overall pooled
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The pain-relieving qualities of exercise in knee osteoarthritis
effect size for pain relief of the 32 studies was 0.40. Of the
12 studies that provided an intervention likely to produce
an effect, only one had an effect size for pain relief below
0.40. Thus, it appears that mode, intensity, and frequency of
intervention play a large role in pain relief.
Following, we explore the pain-relieving effects of
various modes of exercise that have been studied, including
the appropriate dosage to provide pain relief for those with
knee OA.
Aerobic
Evidence appears to support aerobic exercise as effective
for pain relief, but the current published research is lacking
quality information on the optimal mode and dosage. Two
recent studies noted pain relief following a community-based
walking intervention
27
and following a group stationary
cycling program.
28
However, the walking intervention study
had a very large dropout rate at the follow-up period, and
effect sizes for pain were small to moderate.
27
The stationary
cycling study demonstrated moderate to large effect sizes for
pain variables, but there was no follow-up beyond the end
of the intervention period, so it is unknown whether these
effects were sustained.
28
Strength
A recent meta-analysis of randomized controlled trials deter-
mined that both NWB [standardized mean difference (SMD)
-1.42] and WB (SMD -0.7) strengthening exercises are more
efficacious for pain relief than aerobic exercise (SMD -0.45).
29
A strength of this particular analysis is that the authors only
included studies with an exercise frequency of at least three
sessions per week; thus, the interventions were most likely
of an adequate intensity to produce a real effect. Other recent
randomized controlled trials (RCTs) investigating strengthen-
ing interventions have noted significantly reduced pain fol-
lowing strengthening interventions but have failed to provide
evidence supporting any particular intensity or dosage that
may be most effective for knee OA pain.
30–32
Table 1 outlines
the design, results, and relevance of recent RCTs.
A 2008 systematic review examined 18 RCTs of strength-
ening exercise for knee OA and noted that more than half of
the studies demonstrated significant improvements in self-
reported pain.
33
Among the included studies, the intervention
ranged from two to seven sessions per week, each lasting
from 10 to 60 minutes each, consisting of three to ten sets
of three to 20 repetitions of strengthening exercise. Several
of the included studies failed to publish the intensity of the
intervention, and many did not report how the intervention
was progressed to produce a training effect. This again
highlights the lack of useful data available for clinicians to
prescribe the best, most effective strengthening program to
provide pain relief for those with knee OA.
Muscle weakness, particularly in the quadriceps femoris,
is associated with increased pain levels and poorer physical
function.
34,35
Strong muscles are less fatigable and exhibit
greater motor control, thus avoiding damaging increases
in shear forces and peak joint forces that have been found
during activity in those with weak muscles.
35
A rabbit study
found that even a very short period of muscle weakness
may be a risk factor for articular cartilage degeneration.
36
A human study found that providing pain relief via injection
of local anesthetic into the knee joint resulted in improved
maximum voluntary contraction of the quadriceps muscles.
37
Thus, focusing on strengthening exercises may help to avoid
destructive joint forces and is likely to be associated with
reduced pain levels.
Aquatic
A 2009 Cochrane review of aquatic exercise for knee and
hip OA concluded that gold-level evidence supports that
aquatic exercise probably slightly reduces pain over
3 months.
26
However, this review studied both hip and knee
OA. Only one of the included studies
38
compared aquatic
with land therapy specifically for those with knee OA, and
a large effect was found for pain relief with aquatic resis-
tance training (SMD 0.86) compared with land exercise. In
addition, the modes of interventions provided in the studies
included in the Cochrane review were widely variable. Of
the included studies, treatment ranged from flexibility to
strengthening to aerobics to simple joint range of motion.
Dosage of exercise and length of intervention were also quite
variable – interventions ranged from 6 weeks to 9 months.
Thus, while this review supports the pain-relieving efficacy
of aquatic exercise, it does little to determine which mode,
intensity, or length of intervention may provide optimal pain
relief for those with knee OA.
Other
A 2013 systematic review pooled ve RCTs investigating the
effects of tai chi for knee OA and found moderate evidence
for pain relief in the short-term but no long-term effects.
39
However, only one of the five included studies found a large
effect size for pain relief with tai chi,
40
and its participants
were asked to perform tai chi daily for 48 weeks. It is unclear
whether a lower frequency of tai chi would be as effective in
providing pain relief.
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Susko and Fitzgerald
Table 1 Summary of published studies 2008–2013 with exercise intervention for participants with knee OA and pain as an outcome variable
Authors Intervention N Dosage/length of intervention Outcome(s) Comment(s)
Aerobic exercise
Salacinski
et al
28
Group stationary
cycling
37 (18 intervention
and 17 control)
12 weeks, at least two sessions
per week, 40–60 minutes per session
16.5 mm improvement in walking
pain compared with control
group, 95% CI 2.1–31.0
Lack of an attention control may limit ndings,
but group cycling may be effective in providing
pain relief at 12 weeks. No follow-up beyond
end of intervention period
Brosseau
et al
27
Walking intervention
at moderate intensity
(50%–70% of maximum
heart rate)
222 (75 walking +
behavioral intervention,
81 walking only,
84 self-directed
control)
12 months, three sessions per week,
10-minute warm-up plus 45-minute
walk per session
Signicant reduction in arthritis
pain among walking and behavioral
intervention group at 12 and
18 months, and control at
18 months. Overall results
extremely variable; effect sizes
for pain relief were small
Large dropout rate in this study may limit
ability to make conclusions from its results.
Variability in results on pain relief makes the
overall results largely inconclusive
Resistance exercise
Farr et al
30
Resistance training
protocol: stretching,
balance, exibility,
muscle strength, and
aerobic components
171 (52 resistance
training, 62 resistance
training + self-
management,
57 self-management)
Resistance training: 9 months,
three sessions per week, 1 hour
per session. Self-management
(self-efcacy, coping, fear avoidance):
9 months, one 90-minute session
per week for the rst 12 weeks
followed by one telephone call to
reinforce knowledge for 24 weeks
Signicant reduction in OA pain
at 3 months for resistance
group; no other signicant pain
reductions in other groups or
at other time points. When two
resistance groups were combined,
signicant reduction in OA pain
at 3- and 9-month follow-up
Study may have been underpowered to detect
an effect. Authors ultimately combined the
resistance and resistance + self-management
groups for analysis, which leads to suspicious
conclusions. Lack of follow-up beyond the end
of the intervention period also raises question
of whether any pain-relieving effects were
maintained
Fitzgerald
et al
66
Agility and
perturbation training
183 (92 in standard
exercise group
and 91 in agility
and perturbation
training group)
Both groups received standard
lower extremity stretching and
strengthening and treadmill,
plus home program. Agility and
perturbation group also performed
dynamic gait/balance and perturbation
techniques using uneven surfaces
No reduction in knee pain in
either group at 2-, 6-,
or 12-month follow-up
Neither intervention resulted in pain
reduction. Only approximately half of
participants had .80% adherence with the
intervention, which may have limited results
Sayers
et al
31
High- vs slow-speed
strengthening
33 (12 high-speed
power training,
ten slow-speed
strength training,
eleven control)
12 weeks, three sessions per week,
using knee extension strengthening
equipment. High-speed group
performed fast repetitions at 40%
of maximum, and slow-speed
group performed slow repetitions
at 80% of maximum
Signicant reduction
in WOMAC pain subscale
(P=0.02) across all groups
No differences between high-speed power
training, slow-speed strength training, or
control (stretching and warm-up exercises)
for self-reported pain. Sample had very mild
knee OA, which may not be representative of
general knee OA population. Small sample size
may have limited ability to detect a difference
between groups
Lin
32
Proprioceptive
training vs strength
training
108 (split into
proprioception
training, strength
training, or no
exercise)
8 weeks, three sessions per week,
no follow-up period. Strength group
performed NWB LE strengthening;
proprioception group performed
NWB proprioception exercises using
target pedals, guided by a computer
Both interventions resulted in
signicant decrease in pain relative
to control group; effect sizes
were large for both groups.
No between-group differences
for pain
Both interventions may be useful for pain
reduction. The proprioception exercises being
entirely NWB is not consistent with real-life
situations, thus their clinical utility may be
limited
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The pain-relieving qualities of exercise in knee osteoarthritis
Balance/exibility exercise
Ebnezar
et al
67
Hatha yoga 235 (118 yoga group,
117 control)
40 minutes of daily yoga with
instructor for 2 weeks, followed
by 12 weeks of daily independent
practice. Control group: general
therapeutic exercise
Compared with baseline,
37% reduction in walking pain at
15 days, 65% reduction in walking
pain at 90 days. (Control group:
25% and 42% reductions in
walking pain, respectively)
Hatha yoga resulted in greater improvements
in walking pain than general therapeutic
exercise but both effect sizes were very large.
Minimal supervision for the intervention raises
question of adherence
Wang
et al
40
Tai chi 40 (20 tai chi group,
20 attention control
group)
12 weeks, two sessions per week,
60 minutes per session with instruction
of tai chi master. Participants also given
a DVD and handouts and encouraged
to continue practicing until 48-week
follow-up visit
Pain was signicantly more improved
in tai chi group than attention
control group at 12 weeks,
but these between-group
differences were not maintained
at 24- and 48-week follow-up
Effect sizes for tai chi group were large for
both WOMAC pain subscale and VAS at all
follow-up points. Tai chi is probably effective
at reducing knee OA pain
Combination exercise
Hurley
et al
68
Individualized
exercise program +
coping-strategies
intervention
418 (278 in intervention
arm, 140 in usual care)
(ESCAPE knee pain
trial)
6 weeks, two sessions per week.
15–20 minutes of discussion of coping
strategies followed by 35–40 minutes
of individualized exercise prescribed
by a PT
Intervention group had signicantly
less pain (P,0.001) at 6-week
follow-up, but results were not
maintained at 6-, 18-, or 30-month
follow-ups
ESCAPE intervention effective for short-term
pain relief but results not maintained. Large
dropout rate at 30-month follow-up. Analysis
combined data from those who performed
exercise individually with PT with those in
groups of eight; no information was given on
whether results differed according to individual
vs group mode
Abbott
et al
69
Individualized
exercise program
206 (51 exercise
therapy, 54 manual
therapy, 50 combined
exercise + manual
therapy, 51 control)
Seven visits within the rst 9 weeks
of the trial, and two “booster”
sessions in week 16; each session
lasted 50 minutes. Exercise therapy
consisted of warm-up/aerobic,
muscle strength, stretching,
and neuromuscular control exercises
Exercise, manual therapy,
and manual therapy + exercise
groups demonstrated signicantly
less pain at 1-year follow-up
Effect sizes for exercise groups were small
to moderate. Intensity was fairly limited
(,1 exercise session per week), which may
have resulted in limited effects on pain
Jan et al
70
High- vs low-
resistance strength
training
102 (34 high resistance,
34 low resistance,
34 control)
8 weeks, three sessions per week.
Sessions lasted 30 minutes for the
high-resistance (60% of 1RM) group
and 50 minutes for the low-resistance
(10% of 1RM) group
Both groups demonstrated
signicant improvement in pain
using WOMAC pain subscale;
no change in control group;
large effect sizes seen for both but
higher for high-resistance group
Intensity used for low-resistance group does
not match what would be used clinically
(10% of 1RM is likely insufcient for a training
effect). Nonetheless, effect sizes for reduction
in WOMAC pain are large for both the
high- and low-resistance groups. No follow-up
beyond intervention period raises questions
regarding whether effects were maintained
Abbreviations: CI, condence interval; ESCAPE, Enabling Self-management and Coping with Arthritic Knee Pain through Exercise; LE, lower extremity; NWB, non-weight bearing; OA, osteoarthritis; PT, physical therapist; RM, repetition
maximum; VAS, visual analog scale; vs, versus; WOMAC, Western Ontario and McMaster Universities Arthritis Index; N, sample size; IRM, one repetition maximum.
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Susko and Fitzgerald
Concluding comments regarding
the current evidence
The majority of published systematic reviews and meta-
analyses regarding exercise for relief of OA pain include
studies published in 2007 and earlier; however, several ran-
domized clinical trials have been published since that time
[see Table 1 for a summary of recent evidence (within the
past 5 years)] investigating exercise interventions for pain
relief in knee OA.
Perhaps the greatest limitation of the current evidence
regarding the pain-relieving qualities of exercise for knee
OA is the fact that interventions are not designed to specifi-
cally target pain. While some interventions such as NWB
strengthening and aquatherapy aim to minimize joint forces
and thus reduce pain, none of the intervention studies spe-
cifically targets the mechanisms believed responsible for
generation of pain in knee OA.
Understanding the mechanisms by which knee OA pain
may occur is important in furthering our ability to provide
proper modes and dosages of exercise to effectively design
pain-relieving exercise interventions. It has been suggested
that, since knee pain reduces strength in the surrounding
muscles by 5%–15%,
41
those with knee pain are trapped in
a “vicious cycle” of pain, which is followed by decreased
activity levels as a strategy to avoid pain, which results in
increased muscle weakness. The evidence suggests that exer-
cise can interrupt this cycle by reducing pain levels for those
with OA. However, research into the specific mechanisms by
which exercise provides pain relief is a developing topic.
Exercise and its potential to
inuence pain mechanisms in OA
Although OA is a disease characterized by degeneration
of articular cartilage, cartilage is aneural, thus cannot be
the source of OA pain. Much research into the genesis of
knee OA pain has focused on investigation of other struc-
tures that may be producing pain, including the synovium,
periosteum, subchondral bone, infrapatellar fat pad, and joint
capsule.
42,43
More recently, research has begun to focus on the
different mechanisms by which knee pain may occur. These
mechanisms may generally be categorized into peripheral
and central pathways.
Peripheral pathways
Peripheral sensitization occurs when peripheral nociceptive
afferents become more spontaneously active and overly
sensitive to unpleasant stimuli such as excessive movement
or loading. Peripheral sensitization in OA is associated with
local pain at the involved joint. The term “primary hyperalge-
sia” refers to increased sensitivity of peripheral nociceptors
at the site of tissue damage.
44
Local inammatory pathways and effects
of mechanical loading
While OA was previously thought a noninflammatory dis-
ease, evidence now clearly demonstrates the activation of
inflammatory pathways in osteoarthritic joints, which play
a role in peripheral sensitization. Cytokines are an important
part of most inflammatory processes in the body. In the syn-
ovial fluid and serum of those with OA, increased levels of
several cytokines, including interleukin (IL)-6, IL-8, IL-1B,
and IL-15, have been observed.
45–47
Several studies have
demonstrated that the elevation of cytokines in a joint with
OA is related to cartilage breakdown.
43
In addition, cytokines
such as IL-1B can inhibit aggrecan and collagen production,
thus decreasing the joint’s ability to produce extracellular
matrix.
48
Cytokines have also been shown to cause upregula-
tion of cyclooxygenase-2 (COX-2), which causes increased
prostaglandins and other lipid mediators in joints with OA.
Prostaglandins have been shown to play a role in inflamma-
tion and formation of new blood vessels as well as inducing
cartilage damage mediated by cytokines.
49,50
In addition to cytokines, another group of mediators
called “adipokines” may play a role in inducing inflam-
mation in osteoarthritic joints. Adipokines, derived mostly
from adipose tissue, have been shown to cause cartilage
breakdown and may play a role in the relationship between
obesity and OA.
43,51
Several recent studies have provided insight into how
the inflammatory component of OA may be associated with
peripheral sensitization. One study demonstrated that injec-
tion of an immunopotentiating agent into the knee joints of
geriatric mice resulted in joint edema, macrophage infiltra-
tion, formation of new blood vessels, and sprouting of both
sensory and sympathetic nerve fibers into the synovium and
periosteum.
52
Studies in humans have found that inducing
experimental knee pain by injecting hypertonic saline into
the infrapatellar fat pad results in peripheral sensitization,
measured as immediate pressure hyperalgesia on the fat
pad.
53–55
Another study noted that those with increased local
pain sensitivity also had higher C-reactive protein and IL-6
blood levels.
56
Excessive joint compression and shear forces are associ-
ated with knee OA, and much research has investigated the
effects that these forces may have on pain generation. While
many previously thought that exercise would be detrimental
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The pain-relieving qualities of exercise in knee osteoarthritis
to an osteoarthritic joint, research now shows that graded
exercise may promote cartilage homeostasis and reduce
inflammation.
Bevill and colleagues determined that different regions of
the tibial plateau respond differently to in vitro mechanical
loading.
57
They hypothesized that spatial variation in gene
expression of tibial plateau chondrocytes was probably due
to differences in loading. In a porcine model, they confirmed
that gene expression changed following mechanical loading.
These results may be important in humans at risk for knee
OA, specifically those with any condition that may put chon-
drocytes at risk of bearing unexpected loads. Specifically,
knee instability due to prior anterior cruciate ligament or
meniscal injury may cause mechanical loads on areas of
the tibial plateau in which the chondrocytes do not typically
anticipate loading – thus, the articular cartilage in that area
may lack the necessary thickness and strength to handle such
loads. This may lead to cartilage degeneration.
Implications for exercise and pain relief
In an osteoarthritic joint, IL-1B induces the release of prosta-
glandins and nitrous oxide, which ultimately results in reduced
proteoglycan synthesis and reduced extracellular cartilage
matrix. Chowdhury and colleagues showed that dynamic
compression of chondrocytes actually counteracts this release
of prostaglandins and nitrous oxide.
48
Thus, it is suggested
that dynamic mechanical compression of the osteoarthritic
knee joint may inhibit the inflammatory process. This com-
pression could be mimicked during therapeutic exercise by
performance of exercises that apply a dynamic, physiologic
load to the knee joint. This could be achieved for those with
knee OA with dynamic WB exercises.
Another study found that the cyclic tensile strain of chon-
drocytes in vitro results in IL-1B suppression and ultimately
reduces catabolism of articular cartilage.
58
In addition, cyclic
tensile strain results in increased proteoglycan and aggrecan
synthesis, needed to promote cartilage homeostasis. The
strain applied to chondrocytes in this study was designed to
mimic continuous passive motion, a technique often used in
knee rehabilitation to reduce joint stiffness and inflammation.
The results of this study may support the use of continuous
passive motion as an effective means of inhibiting the inflam-
matory process in an osteoarthritic knee joint. In addition, this
may provide insight into the pathways by which repetitive
exercises such as stationary cycling may provide pain relief,
as was the case in the study by Salacinski and colleagues.
28
Evidence from outside the OA literature also supports the
ability of exercise to reduce peripheral sensitization. A study
investigating neck pain found an immediate local hypoalgesia
following completion of deep cervical flexor activation and
endurance exercises, with an increase in the local pressure
pain threshold.
59
The mechanism is unclear, but no systemic
hypoalgesia or sympathetic nervous system excitation was
observed. Because those with cervical pathology often have
altered posture in the upper cervical spine, it is possible that
activation of the deep upper cervical muscles relieved pain
by temporarily improving posture and reducing stress on
local irritated tissues. This may be applicable to the knee
OA population, because it suggests that even exercises to
activate specific muscles, without moving through a large
arc of motion, can relieve pain, which may be particularly
useful for those with end-stage knee OA who cannot tolerate
exercises throughout the joint range of motion.
Overall, research suggests that peripheral mechanisms
play a large role in the generation of knee OA pain and that
exercise can inhibit these mechanisms to reduce pain. This
information should be used for additional human studies
aimed at designing specific exercise protocols to inhibit
peripheral pain pathways.
Central sensitization
In addition to knee pain, those with OA often report referred
pain and allodynia at a location distant from the involved
joint. These phenomena are likely due to central sensitiza-
tion, in which there is increased excitability and/or decreased
inhibition at the spinal or cortical level. The term “secondary
hyperalgesia” refers to increased sensitivity of neurons in the
dorsal horn of the spinal cord in the segments corresponding
to the primary site. OA pain has also been shown to activate
the prefrontal limbic region of the cortex, suggesting that
this region, also associated with emotional responses, may
play a role in generation of OA pain.
44
It is proposed that the phenomenon of central sensitization
plays a very important role in the chronicity of OA pain, as
well as pain in other chronic diseases. A few studies have
also related central sensitization to OA pain. The aforemen-
tioned study by Joergensen noted that experimental knee
pain caused increased temporal summation of pain signals
in the surrounding musculature, which was thought to be a
marker of central sensitization.
55
It has been suggested that physical activity in general
results in a decrease in excitability of the motor cortex and
reduces pain by creating a motor-evoked potential drop,
27
which would seem to suggest that pain relief is possible
regardless of the mode of exercise undertaken. A trial con-
ducted in rats showed that treadmill exercise reversed signs
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Susko and Fitzgerald
of neuropathic pain and resulted in increased opioid content
in the regions of the brainstem that help to modulate pain.
60
The results of this study support exercise as a means to reduce
central sensitization.
Two other human studies found that exercise resulted in
immediate reduction in pain at sites distant from the involved
area.
61,62
In the first study, people with chronic low back
pain performed 25 minutes of aerobic cycle ergometry.
61
At 2 and 32 minutes post-exercise, pressure pain threshold
was significantly greater at the nondominant index finger,
suggesting a reduction in central sensitization. In the second
study, healthy women performed submaximal isometric hand
exercises.
62
Following exercise, pressure thresholds signifi-
cantly increased and pain ratings significantly decreased in
both the ipsilateral and contralateral hands. Although the
modes of exercise used were different in the two studies, both
were successful at inhibiting central pain pathways.
Another trial suggests that pain relief may occur both
peripherally and centrally by reducing inflammation.
63
In
that study, inflammation was triggered in mice via injec-
tion of lipopolysaccharide. Some mice were then subjected
to exercise. Nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-κB), an immune response regula-
tor, was then measured at several time points. Mice who
exercised following the injection showed near-full suppres-
sion of NF-κB activation (compared with little change in
NF-κB activity in mice that received the injection but did
not exercise and mice that exercised but did not receive the
injection). In the study, exercise inhibited inflammation
systemically via NF-κB suppression both in lymph nodes
distant from the injection site and locally at the injection site.
In addition, both exercise prior to and exercise following
the injection resulted in suppression of pro-inflammatory
cytokines. The suppressive effects of exercise lasted only
24 hours following exercise. If these results were translated
to a human model, it could be supposed that exercise must
be performed quite frequently to maximize its inflammatory
suppressive effects.
An ongoing clinical trial in Denmark (ClinicalTrials.gov
identifier NCT01545258) seeks to apply a similar model in
humans by investigating both peripheral and central mecha-
nisms of exercise in knee OA. Participants are performing
supervised exercise training three times per week for 1 hour
and are then assessed for changes in pain threshold and
temporal summation of pain. In addition, pro-inflammatory
cytokines and biomarkers of cartilage breakdown in blood
and urine will be measured, as well as knee inflammation
on advanced imaging.
Overall, human studies investigating the mechanism of
pain relief provided by exercise for people with knee OA
are in their infancy. Human studies in non-OA populations
indicate that both peripheral and central mechanisms play
a role in pain reduction following exercise, and continued
research into the specific mechanisms in those with OA is
needed.
Future directions
While animal and in vitro studies are beginning to increase
knowledge of how exercise may promote pain relief in
an osteoarthritic joint, these theories have not yet been
adequately tested in humans. Many studies continue to
investigate the pain-relieving effects of exercise, but without
knowledge of the particular mechanisms by which pain relief
may occur, it is difficult to determine the most beneficial
mode and dosage of exercise. Thus, more research needs to
be done in humans to understand the mechanisms by which
exercise reduces pain and to determine appropriate exercise
parameters to maximize pain relief.
A particular challenge in the study of peripheral and
central mechanisms by which OA causes pain and by which
exercise relieves such pain is the limitation of methods
to identify pain. Most instruments for identifying pain-
processing mechanisms are laboratory based, thus expensive
and not terribly clinically relevant.
64
Pressure algometers
have been shown to be fairly reliable and inexpensive tools
for measuring general sensitivity to pressure stimuli but are
not yet widely used in clinics and do not distinguish between
peripheral and central pain mechanisms.
64
The ability to
clinically determine whether a person’s pain is related more
to peripheral or central mechanisms may significantly assist
in treatment decisions, thus this is an area ripe for research.
It is quite possible that certain exercise approaches will be
useful for peripheral pain, while others may be more useful
for central pain. Research needs to be done to identify those
who will respond to certain types of pain-relieving exercises
depending on the type of pain experienced.
In addition to selection of an appropriate mode and
dosage of exercise to provide pain relief, further research is
needed to explore other factors that may affect the outcome
of exercise on pain. For example, is there a positive interac-
tion between exercise and pharmacologic treatment? Does
timing of exercise and medication schedule affect pain relief?
Disease severity has been shown to be a potential predictor
of responsiveness to rehabilitation;
65
thus, different exercise
approaches may need to be used for those with early versus
late-stage knee OA in order to provide optimal pain relief.
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The pain-relieving qualities of exercise in knee osteoarthritis
Behavioral factors are also likely to influence the outcomes of
exercise. Lower fear of physical activity has been associated
with increased odds of a positive response to exercise.
66
Pain
in OA is also related to a number of psychological variables
such as anxiety, depression, poor pain-coping skills, and
greater fear avoidance.
34
The specific effects of these vari-
ables on the outcomes of exercise for those with knee OA
need to be examined.
Conclusion
Overall, research consistently supports exercise as an effec-
tive means of relieving pain. As the specific mechanisms
of OA pain and how exercise may interrupt these pain
pathways are discovered, this information can be used by
clinical researchers to determine optimal mode and dosage
of exercise to provide maximal pain relief to those with
knee OA.
Disclosure
The authors declare no conflicts of interest in this work.
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The pain-relieving qualities of exercise in knee osteoarthritis
... 12-week exercise programme; twice per week) compared to the control group. With respect to the joint pain, evidence suggests that aerobic and strength training are able to reduce knee pain associated with osteoarthritis [39]. Moreover, it has been demonstrated that muscle weakness is associated with increased pain levels and poorer physical function in osteoarthritis [40,41]. ...
Article
Full-text available
Background Pain, related to Raynaud’s phenomenon or digital ulceration, has been identified as very prevalent and debilitating symptoms of systemic sclerosis (SSc), both significantly affecting patients’ quality of life (QoL). Pharmacological therapeutic strategies were found not to be sufficiently effective in the management of SSc-induced pain and fatigue, and evidence for exercise is scarce. As yet, the effects of a long-term, tailored exercise programme on pain and fatigue in patients with SSc have not been explored. In addition to pain and fatigue, this study aims to evaluate the effects of exercise on QoL, physical fitness, functional capacity, and vascular structure in people with SSc (PwSSc). Methods This will be a multicentre ( n = 6) randomised controlled clinical trial to assess the effect of a previously established, supervised 12-week combined exercise programme on pain and fatigue as compared to no exercise in PwSSc. The study will recruit 180 patients with SSc that will be allocated randomly to two groups. Group A will perform the exercise programme parallel to standard usual care and group B will receive usual care alone. Patients in the exercise group will undertake two, 45-min sessions each week consisting of 30-min high-intensity interval training (HIIT) (30-s 100% peak power output/30-s passive recovery) on an arm crank ergometer and 15 min of upper body circuit resistance training. Patients will be assessed before as well as at 3 and 6 months following randomisation. Primary outcomes of the study will be pain and fatigue assessed via questionnaires. Secondary outcomes include quality of life, structure of digital microvasculature, body composition, physical fitness, and functional capacity. Discussion Data from this multi-centre research clinical trial will primarily be used to establish the effectiveness of a combined exercise protocol to improve pain and fatigue in SSc. In parallel, this study will be the first to explore the effects of long-term exercise on potential microvascular alterations assessed via NVC. Overall, this study will provide sufficient data to inform current clinical practice guidelines and may lead to an improvement of QoL for patients with SSc. Trial registration ClinicalTrials.gov NCT05234671. Registered on 14 January 2022
... Knee osteoarthritis is one of the most common musculoskeletal disorders and is associated with pain and disability. 1 Exercise therapy is frequently prescribed for alleviating symptoms and improving physical function. 2,3 However, patient adherence is low, 4 and the pain felt during and after the exercise has been suggested as a potential explanation. 5 Functional knee alignment can be quantified as the frontal plane projection angle (FPPA), which is the frontal plane angle between the segments defined from ankle to knee joint center and knee to hip joint center. ...
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Pain felt while performing rehabilitation exercises could be a reason for the low adherence of knee osteoarthritis patients to physical rehabilitation. Reducing compressive forces on the most affected knee regions may help to mitigate the pain. Knee frontal plane positioning with respect to pelvis and foot (functional knee alignment) has been shown to modify the mediolateral distribution of the tibiofemoral joint contact force in walking. Hence, different functional knee alignments could be potentially used to modify joint loading during rehabilitation exercises. The aim was to understand whether utilizing different alignments is an effective strategy to unload specific knee areas while performing rehabilitation exercises. Eight healthy volunteers performed 5 exercises with neutral, medial, and lateral knee alignment. A musculoskeletal model was modified for improved prediction of tibiofemoral contact forces and used to evaluate knee joint kinematics, moments, and contact forces. Functional knee alignment had only a small and inconsistent effect on the mediolateral distribution joint contact force. Moreover, the magnitude of tibiofemoral and patellofemoral contact forces, knee moments, and measured muscle activities was not significantly affected by the alignment. Our results suggest that altering the functional knee alignment is not an effective strategy to unload specific knee regions in physical rehabilitation.
... Aside from therapeutic uses, pressure algometers were used in research, such as the investigation of pathophysiological mechanisms implicated in musculoskeletal pain disorders. (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) ...
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Algometers are instruments that measure actual pressure and/or pressure that causing a pressure pain threshold to be surpassed. In pressure pain threshold studies, it has been discovered that the rate at which mechanical force is applied should be steady in order to offer the maximum precision. The accuracy and composite reliability of an algometer (1000-Hz sampling rate) were tested in this study by manually applying force to a maximum force (500-Hz sampling rate). The pressure level is the lowest amount of force (pressure) that causes discomfort. The pressures threshold metre (PTM) is indeed a strength measure with a 1cm2 surface circular polymer applicator surfaces rubber disc, as well as the maximum stress measurement was examined using SEM and t-test. This device has proved beneficial in the treatment of deep muscular soreness, trigger points, fibrositis, and myalgia patches. PTM can identify arthritis activity as well as measure reduction in pain.
... Geographically, the incidence and prevalence of SSc varies across Europe. More 65 specifically, a North-South gradient in Europe has been previously proposed 2 with Northern 66 European countries such as UK, Finland and Iceland presenting lower rates compared to 67 Southern European countries such as France and Greece. ...
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Background Pain, related to Raynaud’s phenomenon or digital ulceration has been identified as very prevalent and debilitating symptoms of systemic sclerosis (SSc), both significantly affecting patients’ quality of life (QoL). Pharmacological therapeutic strategies were found not to be sufficiently effective in the management of SSc-induced pain and fatigue, and evidence for exercise is scarce. As yet, the effects of a long-term, tailored exercise programme on pain and fatigue in patients with SSc have not been explored. In addition to pain and fatigue, this study aims to evaluate the effects of exercise on QoL, physical fitness, functional capacity, and vascular structure in people with SSc (PwSSc). Methods This will be a multicentre (n=6) randomised controlled clinical trial to assess the effect of a previously established, supervised 12-week combined exercise programme on pain and fatigue as compared to no exercise in PwSSc. The study will recruit 180 patients with SSc that will be allocated randomly to two groups. Group A will perform the exercise programme parallel to standard usual care and Group B will receive usual care alone. Patients in the exercise group will undertake two, 45-min sessions each week consisting of 30 min High Intensity Interval Training (HIIT) (30s 100% peak power output/30 s passive recovery) on an arm crank ergometer and 15 min of upper body circuit resistance training. Patients will be assessed before as well as at 3- and 6-months following randomisation. Primary outcomes of the study will be pain and fatigue assessed via questionnaires. Secondary outcomes include quality of life, structure of digital microvasculature, body composition, physical fitness, and functional capacity. Discussion Data from this multi-centre research clinical trial will primarily be used to establish the effectiveness of a combined exercise protocol to improve pain and fatigue in SSc. In parallel, this study will be the first to explore the effects of long-term exercise on potential microvascular alterations assessed via NVC. Overall, this study will provide sufficient data to inform current clinical practice guidelines and may lead to an improvement of QoL for patients with SSc. Trial registration: ClinicalTrials.gov (NCT number): NCT05234671, January 14, 2022.
... In addition, an illustration booklet developed by the researchers after extensive literature review was used that contained information regarding the patient's concern on a daily basis as follows: daily regular exercises, how to maintain knee joints, diet, fluid intake, compliance to medication and its side effects, organizing daily activities, stress control, sleeping habit, etc.) besides instruction of laboratory investigation importance related to calcium and vitamin D. To maintain patients' adherence to the given instructions, researchers kept contact with them over the period of research through either direct contact with the patients at the hospital departments or by phone for outpatient clinic patients. In the evaluation phase, follow-up was done for both the study and control groups 2 weeks after baseline data collection based on a Cochrane systematic review of 32 studies of land-based exercise for KOA in Susko and Fitzgerald (2013). In addition, the second and third measurements was taken through filling out the pain numerical scale (tool II) and MAF scale (tool III). ...
... A qualitative assessment of patient beliefs prior to knee arthroplasty revealed erroneous beliefs about the disease process: that their knee was "bone on bone" or caused by "wear and tear," and that joint vulnerability would only be exacerbated by exercise and physical activity. 31 These potentially harmful beliefs can preclude progress and effective care delivery, especially since exercise and physical activity are core recommendations in most guidelines for the management of knee osteoarthritis 17,32 and considered front-line treatment, 33 and there is no evidence to indicate they should be avoided, even in cases with severe joint degeneration. 34 Many patients have doubts about the effect of exercise as a treatment, 35 especially when they've been given a pathobiological diagnosis. ...
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Orthopaedic surgery has revolutionized the expectations for restoration of physical function after musculoskeletal injury and, along with physical therapy, has transformed the limits of recovery. Many orthopaedic procedures have a high success rate for improving quality of life and patient-reported outcomes, yet these procedures carry some level of risk, including postoperative complications. The stepped-care model of health care delivery, when applied to musculoskeletal care, recommends implementing less-intense and lower-risk treatments with known efficacy, such as promotion and education of self-management strategies and physical therapy, before more-invasive and higher-risk treatments such as surgery. This model of managing musculoskeletal disability can improve efficiency of care delivery and reduce medical costs at the health system level. Unfortunately, there is a documented lack of implementing an appropriate course of conservative care, especially physical therapy, prior to surgery across multiple orthopaedic disciplines including sports, spine, and trauma medicine and joint arthroplasty. Failure to respond to nonsurgical treatment has been suggested as a requisite component of the surgical appropriateness criteria, yet practical application can be elusive. Multiple barriers to adequate utilization of conservative treatment exist, including U.S. payment models that increase out-of-pocket expense for patients, negative patient perception of therapy, unreasonable patient expectations from therapy versus surgery, and communication barriers between patient, surgeon, and therapist. Surgeons should ensure that high-quality guideline-appropriate care is delivered early and adequately to their patients. Rehabilitation professionals have a responsibility to deliver high-value care, properly documenting the type and extent of treatment to improve surgical decision-making between surgeons and patients. Criteria to determine appropriateness for surgery should include a standardized and extensive assessment of failed therapies prior to certain elective surgeries. Improved collaboration between surgeons and rehabilitation professionals can result in improved outcomes for patients with musculoskeletal disorders. Level of Evidence V, expert opinion
... Increased theta band activity is required to trigger fine initiation of lower-limb movement in individuals with PD 51 . In the context of OA, more movement is associated with less pain, therefore individuals with high theta activity display higher motor function and motor control, which relates to the inverse relationship between theta activity and pain; individuals with better motor function have less pain, observed in individuals with increased theta oscillations, according to this study's results 45 . ...
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This study aims to investigate the multivariate relationship between different sociodemographic, clinical, and neurophysiological variables with resting-state, high-definition, EEG spectral power in subjects with chronic knee osteoarthritis (OA) pain. This was a cross-sectional study. Sociodemographic and clinical data were collected from 66 knee OA subjects. To identify associated factors, we performed independent univariate and multivariate regression models by frequency bands (delta, theta, alpha, beta, low-beta, and high-beta) and by pre-defined regions (frontal, central, and parietal). From adjusted multivariate models, we found that: (1) increased frontocentral high-beta power and reduced central theta activity are positively correlated with pain intensity (β = 0.012, 95% CI 0.004–0.020; and β = − 0.008; 95% CI 0.014 to − 0.003; respectively); (2) delta and alpha oscillations have a direct relationship with higher cortical inhibition; (3) diffuse increased power at low frequencies (delta and theta) are associated with poor cognition, aging, and depressive symptoms; and (4) higher alpha and beta power over sensorimotor areas seem to be a maladaptive compensatory mechanism to poor motor function and severe joint degeneration. Subjects with higher pain intensity and higher OA severity (likely subjects with maladaptive compensatory mechanisms to severe OA) have higher frontocentral beta power and lower theta activity. On the other hand, subjects with less OA severity and less pain have higher theta oscillations power. These associations showed the potential role of brain oscillations as a marker of pain intensity and clinical phenotypes in chronic knee OA patients. Besides, they suggest a potential compensatory mechanism of these two brain oscillators according to OA severity.
... This study also showed a control group that performed a land treadmill, but the group couldn't reach HIIT because of load-elicited pain. 30,31 In six weeks of a twice-weekly high-intensity interval of cycle training also shows metabolic changes, which can be seen from the reducing acylcarnitine. Acylcarnitine plays a key role in regulating lipid and sugar metabolism. ...
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One of the most often musculoskeletal disorders in adults is osteoarthritis, which occurs due to degenerative pro-cesses in the joints, through wear and tear mechanism, especially in the articular cartilage. The treatment options for osteoarthritis are classified into symptomatic therapy and disease modification therapy. However, many people who suffer from osteoarthritis have limitations in their daily activities, thus preventing them from modifying their lifestyles. Many types of exercise exist, yet the best exercise for symptomatic osteoarthritis hasn’t been found. In daily practices, Moderate Intensity Continuous Training (MICT) is the most recommended and the type of exercise commonly performed by patients with OA because MICT has a range of cardiovascular health benefits and main-tains body weight. However, MICT may not provide enough stimulus to increase lower muscle mass and strength, articular changes that might contribute to the pain, stiffness, and functional limitations seen in patients with knee OA. Some new studies found that High-Intensity Interval Training (HIIT) is more efficient than MICT as a classic exercise after six to eight weeks of exercise. HIIT in symptomatic osteoarthritis can significantly improve a patient’s fitness, visceral fats, and symptoms. HIIT can be a treatment option in resolving symptomatic knee osteoarthritis.
... Change in life style or daily activities modification, weight reduction, exercise, physical therapy, hydrotherapy etc. sss some analgesics like paracetamol, opioids, NSAIDS or topical gels can be suggested or some injection therapy can also plays an important role in pain relief in individuals with mild to moderate level of pain [5] For the conservative management of knee OA therapeutic exercises are frequently suggested as a favorite plan of treatment and present studies suggests or prove exercises as an important and effectual pain soothing treatment. We investigate modern situation of proof for therapeutic exercises as a pain diminishing management for knee OA. [6] Exercise therapy decrease pain and patient-described dysfunction in knee Osteoarthritis (OA), now the ideal exercise administration has not been recognized. As this disorder has a great effect on person's life style so exercise plays a major role in prevention and care of disabling disorder. ...
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Objectives: To find out the effects of corrective exercise training for improving neuropathic pain and function in knee OA patients. Materials & Methods: This study was a quasi-experimental study. It was conducted at horizon hospital Johar Town Lahore. The study was completed in six months. Consecutive sampling technique was used to collect the data. The sample size of 16 patients was taken in this study to find out the effects of corrective exercises training for improving neuropathic pain and function in patients with knee osteoarthritis. For descriptive analysis we used frequency, percentages and charts. For quantitative measure, repeated measured ANOVA was used. Results: The mean age of patients was 71.56 years ± 4.55 years. There were 7(43.8%) males and 9(57.2%) females participated in this study. The mean and standard deviation of numeric pain rating scale at baseline, at week 4 and at post treatment were, 4.31 ± 0.71, 3.31 ± 0.70 and 2.44 ± 0.73 (p=0.0001) respectively. The mean and standard deviation of DN4-questionnaire at baseline, at week 4 and at post treatment were, 6.38 ± 1.67, 4.06 ± 1.29 and 1.81 ± 1.33 (p=0.0001) respectively. The mean and standard deviation of WOMAC scale at baseline, at week 4 and at post treatment were, 58.13 ± 9.37, 48.75 ± 7.81 and 39.25 ± 7.90 (p=0.0001) respectively. Conclusion: Corrective exercises significantly reduced knee osteoarthritis neuropathic pain and improved functional capacity. The corrective exercises appear to be a safe and effective treatment for neuropathic knee pain.
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Dexamethasone (DEX) has been widely used to treat a variety of diseases, including autoimmune diseases, allergies, ocular disorders, cancer, and, more recently, COVID-19. However, DEX usage is often restricted in the clinic due to its poor water solubility. When administered through a systemic route, it can elicit severe side effects, such as hypertension, peptic ulcers, hyperglycemia, and hydro-electrolytic disorders. There is currently much interest in developing efficient DEX-loaded nanoformulations that ameliorate adverse disease effects inhibiting advancements in scientific research. Various nanoparticles have been developed to selectively deliver drugs without destroying healthy cells or organs in recent years. In the present review, we have summarized some of the most attractive applications of DEX-loaded delivery systems, including liposomes, polymers, hydrogels, nanofibers, silica, calcium phosphate, and hydroxyapatite. This review provides our readers with a broad spectrum of nanomedicine approaches to deliver DEX safely.
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Osteoarthritis (OA) has traditionally been classified as a noninflammatory arthritis; however, the dichotomy between inflammatory and degenerative arthritis is becoming less clear with the recognition of a plethora of ongoing immune processes within the OA joint and synovium. Synovitis is defined as inflammation of the synovial membrane and is characteristic of classical inflammatory arthritidies. Increasingly recognized is the presence of synovitis in a significant proportion of patients with primary OA, and based on this observation, further studies have gone on to implicate joint inflammation and synovitis in the pathogenesis of OA. However, clinical OA is not one disease but a final common pathway secondary to many predisposing factors, most notably age, joint trauma, altered biomechanics, and obesity. How such biochemical and mechanical processes contribute to the progressive joint failure characteristic of OA is tightly linked to the interplay of joint damage, the immune response to perceived damage, and the subsequent state of chronic inflammation resulting in propagation and progression toward the phenotype recognized as clinical OA. This review will discuss a wide range of evolving data leading to our current hypotheses regarding the role of immune activation and inflammation in OA onset and progression. Although OA can affect any joint, most commonly the knee, hip, spine, and hands, this review will focus primarily on OA of the knee as this is the joint most well characterized by epidemiologic, imaging, and translational studies investigating the association of inflammation with OA.
Article
Background: Osteoarthritis is a chronic disease characterized by joint pain, tenderness, and limitation of movement. At present, no cure is available. Thus only treatment of the person's symptoms and treatment to prevent further development of the disease are possible. Clinical trials indicate that aquatic exercise may have advantages for people with osteoarthritis. This is an update of a published Cochrane review. Objectives: To evaluate the effects of aquatic exercise for people with knee or hip osteoarthritis, or both, compared to no intervention. Search methods: We searched the following databases up to 28 April 2015: the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library Issue 1, 2014), MEDLINE (from 1949), EMBASE (from 1980), CINAHL (from 1982), PEDro (Physiotherapy Evidence Database), and Web of Science (from 1945). There was no language restriction. Selection criteria: Randomized controlled clinical trials of aquatic exercise compared to a control group (e.g. usual care, education, social attention, telephone call, waiting list for surgery) of participants with knee or hip osteoarthritis. Data collection and analysis: Two review authors independently selected trials for inclusion, extracted data and assessed risk of bias of the included trials. We analysed the pooled results using standardized mean difference (SMD) values. Main results: Nine new trials met the inclusion criteria and we excluded two earlier included trials. Thus the number of participants increased from 800 to 1190 and the number of included trials increased from six to 13. Most participants were female (75%), with an average age of 68 years and a body mass index (BMI) of 29.4. Osteoarthritis duration was 6.7 years, with a great variation of the included participants. The mean aquatic exercise duration was 12 weeks. We found 12 trials at low to unclear risk of bias for all domains except blinding of participants and personnel. They showed that aquatic exercise caused a small short term improvement compared to control in pain (SMD -0.31, 95% CI -0.47 to -0.15; 12 trials, 1076 participants) and disability (SMD -0.32, 95% CI -0.47 to -0.17; 12 trials, 1059 participants). Ten trials showed a small effect on quality of life (QoL) (SMD -0.25, 95% CI -0.49 to -0.01; 10 trials, 971 participants). These effects on pain and disability correspond to a five point lower (95% CI three to eight points lower) score on mean pain and mean disability compared to the control group (scale 0 to 100), and a seven point higher (95% CI 0 to 13 points higher) score on mean QoL compared with control group (scale 0 to 100). No included trials performed a radiographic evaluation. No serious adverse events were reported in the included trials with relation to aquatic exercise. Authors' conclusions: There is moderate quality evidence that aquatic exercise may have small, short-term, and clinically relevant effects on patient-reported pain, disability, and QoL in people with knee and hip OA. The conclusions of this review update does not change those of the previous published version of this Cochrane review.
Article
This paper aimed to systematically review and meta-analyze the effectiveness of Tai Chi for osteoarthritis of the knee. MEDLINE, the Cochrane Library, EMBASE, Scopus, PsycInfo and CAMBASE were screened through April 2013. Randomized controlled trials (RCTs) comparing Tai Chi to control conditions were included. Two authors independently assessed risk of bias using the risk of bias tool recommended by the Cochrane Back Review Group. Outcome measures included pain, physical functional, joint stiffness, quality of life, and safety. For each outcome, standardized mean differences and 95% confidence intervals were calculated. 5 RCTs with a total of 252 patients were included. Four studies had a low risk of bias. Analysis showed moderate overall evidence for short-term effectiveness for pain, physical function, and stiffness. Strong evidence was found for short-term improvement of the physical component of quality of life. No long-term effects were observed. Tai Chi therapy was not associated with serious adverse events. This systematic review found moderate evidence for short-term improvement of pain, physical function and stiffness in patients with osteoarthritis of the knee practicing Tai Chi. Assuming that Tai Chi is at least short-term effective and safe it might be preliminarily recommended as an adjuvant treatment for patients with osteoarthritis of the knee. More high quality RCTs are urgently needed to confirm these results.
Article
Concentrations of interleukin (IL)-6 and IL-8 in serum and synovial fluid obtained from patients with osteoarthritis (OA) of the knee were determined by the chemiluminescence–ELISA (CL–ELISA) method, the sensitivity of which is 100–1000 times greater than that of the conventional ELISA method. The results were compared with those obtained from patients with rheumatoid arthritis (RA) and from healthy subjects. The mean IL-6 and IL-8 levels in synovial fluid indicated higher concentrations in RA than in OA. The IL-6 and IL-8 levels in serum were significantly higher in RA and OA relative to controls. Among OA patients in whom remarkable improvement was noted in hydrarthrosis, the synovial fluid IL-6 and IL-8 levels at the initial examination were relatively higher, and were markedly decreased after treatment with sodium hyaluronate (NaHA). Among those in whom no improvement was noted in hydrarthrosis, the synovial fluid IL-6 and IL-8 levels at the time of initial examination were relatively lower, and hydrarthrosis was not significantly improved even after treatment with NaHA. In addition, there was a tendency for the synovial fluid IL-6 and IL-8 levels to decrease as HA levels increased. Evaluation of X-ray findings revealed that the IL-6 levels in synovial fluid at the initial examination in low-grade cases tended to be significantly higher than in high-grade cases. In low-grade cases, as determined by X-ray findings, there was a significant decrease in IL-6 levels in synovial fluid after treatment with NaHA.
Article
Objective We performed a systematic review and meta-analysis of randomized controlled trials to investigate the differences in the efficacies between strengthening and aerobic exercises for pain relief in people with knee osteoarthritis. Data sources This search was applied to Medline, Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, and the Cumulative Index to Nursing and Allied Health Literature. All literature published from each source’s earliest date to March 2013 was included. Review methods Trials comparing the effects of exercise intervention with those of either non-intervention or psycho-educational intervention were collected. Meta-analysis was performed for trials in which therapeutic exercise was carried out with more than three sessions per week up to eight weeks, for pain in people with knee osteoarthritis. All trials were categorised into three subgroups (non-weight-bearing strengthening exercise, weight-bearing strengthening exercise, and aerobic exercise). Subgroup analyses were also performed. Results Data from eight studies were integrated. Overall effect of exercise was significant with a large effect size (standardised mean difference (SMD): −0.94; 95% confidence interval −1.31 to −0.57). Subgroup analyses showed a larger SMD for non-weight-bearing strengthening exercise (−1.42 [−2.09 to −0.75]) compared with weight-bearing strengthening exercise (−0.70 [−1.05 to −0.35]), and aerobic exercise (−0.45 [−0.77 to −0.13]). Conclusion Muscle strengthening exercises with or without weight-bearing and aerobic exercises are effective for pain relief in people with knee osteoarthritis. In particular, for pain relief by short-term exercise intervention, the most effective exercise among the three types is non-weight–bearing strengthening exercise.
Article
Objective Obesity is an important risk factor for osteoarthritis (OA) and is associated with changes in both the biomechanical and inflammatory environments within the joint. However, the relationship between obesity and cartilage deformation is not fully understood. The goal of this study was to determine the effects of body mass index (BMI) on the magnitude of diurnal cartilage strain in the knee. Methods Three-dimensional maps of knee cartilage thickness were developed from 3T magnetic resonance images of the knees of asymptomatic age- and sex-matched subjects with normal BMI (18.5-24.9 kg/m(2)) or high BMI (25-31 kg/m(2)). Site-specific magnitudes of diurnal cartilage strain were determined using aligned images recorded at 8:00 AM and 4:00 PM on the same day. ResultsSubjects with high BMI had significantly thicker cartilage on both the patella and femoral groove, as compared to subjects with normal BMI. Diurnal cartilage strains were dependent on location in the knee joint, as well as BMI. Subjects with high BMI, compared to those with normal BMI, exhibited significantly higher compressive strains in the tibial cartilage. Cartilage thickness on both femoral condyles decreased significantly from the AM to the PM time point; however, there was no significant effect of BMI on diurnal cartilage strain in the femur. Conclusion Increased BMI is associated with increased diurnal strains in articular cartilage of both the medial and lateral compartments of the knee. The increased cartilage strains observed in individuals with high BMI may, in part, explain the elevated risk of OA associated with obesity or may reflect alterations in the cartilage mechanical properties in subjects with high BMI.
Article
This study evaluated the deep-tissue pressure pain sensitivity and temporal summation of pain within and around healthy knees exposed to experimental pain. The study was designed as a randomized crossover trial, with each subject tested on 1 day. All tests were carried out at the Laboratory for Musculoskeletal Pain and Motor Control, Center for Sensory-Motor Interaction, Department of Health Science and Technology at Aalborg University, Denmark. Seventeen healthy subjects (10 males) participated in this study. Experimental pain model. Pain was induced in the infrapatellar fat pad by injection of hypertonic saline and the contralateral infrapatellar fat pad was injected with isotonic saline as control. Pressure pain thresholds, temporal summation of pressure pain, and cutaneous mechanosensitivity were assessed on three occasions: baseline, immediately after the injection, and when pain had vanished. Assessments sites were located in the peripatellar region, vastus lateralis, and tibialis anterior muscles. The experimental knee pain model demonstrated 1) hyperalgesia to pressure stimulation on the infrapatellar fat pad during experimental pain, and 2) facilitated temporal summation of pressure pain at the infrapatellar fat pad and knee-related muscles. The increased sensitivity and temporal summation found in this study were exclusive to deep -tissue with no contralateral decreased pain sensitivity. The study showed that acute knee joint pain leads to hyperalgesia and facilitated temporal summation in the infrapatellar fat pad and in muscles located distant to the injection site, in subjects with no history of knee pain.