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44 49, 2009
Copyright 2008 World Federation for Ultrasound in Medicine & Biology
Printed in the USA. All rights reserved
0301-5629/09/$see front matter
doi:10.1016/j.ultrasmedbio.2008.07.009
Original Contribution
(Received 6 December 2007; revised 20 June 2008; in final form 24 July 2008)
AbstractA randomized double blind clinical trial was conducted to determine the effectiveness of ultrasound
(US) therapy in knee osteoarthritis (OA). Sixty-seven patients (mean age 54.8 7) were randomized to receive
either 1 MHz frequency or 1 watt/cm2 power continuous ultrasound for 5 min (n 34) or sham US (n 33) as
a placebo. Ten sessions of treatment were applied to the target knee of the patient. A blinded evaluation at
baseline and after treatment was made. Primary outcome was pain on movement assessed by visual analog scale
(VAS). Secondary outcomes consisted of the Western Ontario and McMaster Universities Osteoarthritis Index
(WOMAC) scores and 50 meters walking time. Both groups showed significant improvements in knee pain on
movement. In the treatment group, the improvement in VAS score was statistically and significantly higher (p <
0.001) and more pronounced than in the placebo group. Pain reduction averaged 47.76% in the treatment group
(p 0.013). Secondary outcomes improved in both groups but reached statistical significance only in the
treatment group: p 0.006 for the mean change in total WOMAC scores and p 0.041 for 50 meters walking
time. Results suggest that therapeutic US is safe and effective treatment modality in pain relief and improvement
of functions in patients with knee OA. (E-mail: levento26@yahoo.com) 2008 World Federation for Ultra-
sound in Medicine & Biology.
44
Effects of therapeutic ultrasound in knee osteoarthritis L. ZGNENEL et al. 45
trolled randomized study, we assessed the effectiveness Table 1. Demographic characteristics of patients
of therapeutic US in knee OA. Characteristics Placebo Ultrasound
Table 2. Pre-treatment and post-treatment VAS interval. The minimum number of subjects per group was
measurements in the placebo and treatment groups are given estimated to be 26 to attain an 80% probability of being
as mean standard deviation
able to detect a treatment effect (alpha 0.05).
Placebo Treatment group
RESULTS
Pre-treatment VAS measurements 5.1 2.3 6.7 1.8
Post-treatment VAS measurements 4.0 2.6 3.9 2.0 The number of patients enrolled into the treatment
p* 0.022 p* 0.001 group and the placebo group were 34 and 33, respec-
Mean change from baseline 20.6% 45.9% 42.8% 23.1%
p 0.05 p 0.013 tively, which was sufficiently powered. The mean age of
the patients in the placebo group and the treatment group
VAS visual analog scale. were 56.2 8.0 y and 53.6 6.9 y, respectively. The
* Significance level when pre-treatment and post-treatment mea-
surements are compared majority of patients were female in both groups (78.8%
in the placebo and 82.4% in the treatment groups). The
demographic data and baseline characteristics of the pa-
In the placebo group, sham ultrasound (an applica- tients are summarized in Table 1.
tor disconnected from the back to working ultrasound Primary outcomes
machine) was applied to the target knee in the same Both groups showed reduced knee pain on move-
manner described above, using the same acoustic gel, 5 ment following intervention. The VAS measurements
min per session. Patients were not able to see whether the improved significantly both in the placebo group and the
cable was disconnected or not. treatment group patients (p 0.0022 and p 0.001,
respectively). Pain reduction averaged 20.6% in the pla-
Statistical analysis cebo group (p 0.05) and 42.8% in the treatment group
SPSS 10.0 for Windows package program was used (p 0.013) (Table 2).
for statistical analysis. For nonparametric variables, i.e.,
WOMAC and VAS scores, Mann-Whitney U test was Secondary outcomes
employed to compare outcome scores among treatment WOMAC scores improved in all domains in the
groups and Wilcoxon signed-rank test was used to com- treatment group at a significant level. Although an over-
pare post-therapy scores to baseline. The improvement in all improvement was noticeable in all parameters in the
WOMAC scores was also assessed as percent change placebo-treated group, only the total WOMAC scores
from baseline and compared between treatment groups and those for the physical function domain showed sta-
using one-way analysis of variance. For parametric vari- tistically significant changes (Table 3). Change in 50
ables, i.e., knee ROM measurements, paired t-test was meters walking time showed a statistically significant
employed to compare outcome scores among treatment improvement only in the treatment group (Table 4).
groups and to compare post-therapy scores to baseline. P
values 0.05 were considered significant. Mean change Adverse events
in scores within groups and differences in change scores There were no adverse events during and after in-
between groups were calculated with 95% confidence terventions. In the placebo group, two patients used
Table 3. Pre-treatment and post-treatment WOMAC measurements in the placebo and treatment groups are given as
mean standard deviation
Placebo group Treatment group
Table 4. Walking time measurements in the placebo and The improvement in stiffness and ROM of knee and
treatment groups are given as mean standard deviation walking time may depend on the healing and thermal
Placebo Treatment effects of US on periarticular structures of knee joint.
Deep heating with US can produce a temporary increase
Pre-treatment 40.9 9.8s 40.9 13.5s in the extensibility of highly collagenous structures such
Post-treatment 36.4 7.6s 35.5 6.7 s
p* 0.809 p* 0.041 as tendons, ligaments and joint capsule. Besides its ther-
mal effects, nonthermal effects of US can modulate cell
* Significance level when pre-treatment and post-treatment mea- diffusion, fibroblast production, collagen synthesis, alter
surements are compared.
extracellular matrix arrangement, break down adhesion
and accelerate healing (Ng et al. 2003). Enwemeka
(1989) showed that daily application of 1 MHz therapeu-
analgesics because of increased pain and were thus tic ultrasound at intensity of 1W/cm2 for 5 min in the
dropped out of the study. continuous mode for 10 d augments the tensile strength
and energy absorption capacity of rabbit Achilles ten-
dons. He reported that therapeutic US may have bio-
DISCUSSION
chemical effects on healing tendon. Daily application of
In this report, we present the findings of a random- 1 MHz therapeutic US either at 1W/cm2 or 2W/cm2 to
ized double blind placebo controlled trial of US therapy hemitransected Achilles tendons of rats accelerates the
in knee OA. Both pain and joint function improved after healing process of the ruptured tendon (Ng et al. 2003).
10 sessions of therapy spanning over 2 wk with either the In a recent study, Kozanoglu et al. (2003) reported
real US or the sham US. Patients receiving the actual US comparing the effectiveness of ibuprofen phonophoresis
treatment showed statistically significant improvement in with conventional US therapy in knee OA. Continuous
all pain measurements (VAS and WOMAC) and 50 ultrasonic waves of 1 MHz frequency and 1 Watt/cm2
meter walking time, whereas the patients enrolled in the power applied for 5 min to target knee for 10 sessions.
sham US group showed improvement only in some pain Pain scores, knee ROM degrees, walking time and
scores (VAS) and function. Based on these results, we WOMAC scores improved significantly in both groups.
conclude that US therapy has been superior over placebo The method and results of this study are similar and
in the treatment of OA of the knee. consistent with our study. In a study by Huang et al.
Analgesia induced by therapeutic US may be due to (2005), US treatment (1 MHz, 1.5 W/cm2 for 5 min)
both thermal and nonthermal mechanisms. The reduction increased the effectiveness of isokinetic exercise for
of soft tissue pain by US could result from increased functional improvement for knee OA. In this study, pa-
capillary permeability and tissue metabolism, enhance- tients had better compliance than those in the group with
ment of fibrous tissue extensibility and elevation of pain only exercise therapy, which supports analgesic effect of
threshold by thermal mechanism. However, nonthermal US.
mechanisms may act in pain relief by stimulating tissue Despite the popularity of US therapy in the treat-
regeneration, changing cell membrane permeability and ment of musculoskeletal disorders, its clinical efficacy is
increasing intracellular calcium in the nervous system controversial. In a review of 35 randomized controlled
(Baker et al. 2001). It is hypothesized that therapeutic US trials of therapeutic US published between 1975 and
may block pain transmission in nociceptive fibers. 1999 (Robertson and Baker 2001), only 10 studies were
Mardiman and Wessel (1995) applied 5 min of continu- judged to have acceptable methods, and of these, in only
ous 1.1 MHz ultrasound at 1 W/cm2 on the dorsal aspect two (Ebenbicher et al. 1998, 1999) US proved to be more
of one forearm and sham US to the other arm as a control effective than placebo in treating clinical musculoskele-
group in healthy subjects. They measured pain threshold tal problems. Similarly two meta-analyses (Gam and
with a dolorimeter on treated and untreated areas before Johannsen 1995; van der Windt et al. 1999) have con-
and after interventions and concluded that US could raise cluded that there is poor evidence to support the use of
the pain threshold. therapeutic US in the treatment of musculoskeletal dis-
US application may also decrease pain by modulat- orders. A recent Cochrane (Welch et al. 2001) review
ing nociceptive neurons. Nitric oxide, a transmitter of about therapeutic US for knee OA found no benefit over
nociception in the spinal cord, is produced in the nitric placebo for patients with knee OA for pain relief, range
oxide synthase-like neurons, which can be induced with of motion or functional status. Briefly, all reviewers
peripheral inflammation. In rats with peripheral inflam- reported finding little evidence that therapeutic US was
matory arthritis, US treatment significantly suppressed more effective than placebo in treating people with pain
nitric oxide synthase-like neurons in spinal cord (Hsieh or a range of musculoskeletal injuries or in promoting
2005). soft tissue healing.
48 Ultrasound in Medicine and Biology Volume 35, Number 1, 2009
A study judged to have acceptable methodological response to treatment (McQuay and Moore 2005). In
quality according to the above-mentioned Cochrane re- larger samples, this effect dwindles. Therefore, this prob-
view (Falconer et al. 1992), tested the efficacy of thera- lem should be addressed in future studies by increasing
peutic US followed by exercise treatment when con- the sample size.
trolled with placebo. US therapy did not demonstrate any Because of a lack of an objective tool to assess
superiority over placebo in this report; however, patients musculoskeletal pain and function, the scientific commu-
in this study had chronic knee contracture and eight nity depends on subjective assessment tools (WOMAC
patients had total knee replacement. In our study, our and VAS scores) that we employed in our study. The
patients had no knee contracture and the patients with validity of these scoring systems have been well estab-
any knee operation were excluded from the study. The lished (Whitehouse et al. 2008; Wassell et al. 2008) and
patients in Falconers study were older than our subjects the results are reproducible. The Likert scales that we
(mean age 67.5 y versus 54.8 y, respectively). This have used to quantify WOMAC indices can be biased,
suggests that a subset of patients with knee OA free of however, as the respondents may avoid using extreme
contractures may respond better to US treatment. In scores.
Falconers study, knees were sonated for 3 min and Long-term effectiveness of US should also be as-
intensity of the US was not constant. Additionally, in our sessed in a continuing study. Other dosages and appli-
study, continuous ultrasonic waves with constant fre- cation forms of therapeutic US also need to be investi-
quency (1 MHz) and intensity (1 W/cm2) were applied gated.
for 5 min. In conclusion, we suggest that therapeutic US is a
We observed improvement in pain and function in safe and effective treatment modality in pain relief and
placebo group. The mechanism of the placebo effect is improvement of function in patients with knee OA.
not quite clear, although there is evidence that placebo
induced analgesia is mediated by the release of endoge-
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