Rheumatology International

https://doi.org/10.1007/s00296-018-4000-x
Rheumatology
INTERNATIONAL

CLINICAL TRIALS

Ultrasound plus low-level laser therapy for knee osteoarthritis

rehabilitation: a randomized, placebo-controlled trial
Fernanda Rossi Paolillo1   · Alessandra Rossi Paolillo2 · Jessica Patrícia João1 · Daniele Frascá1 · Marcelo Duchêne1 ·
Herbert Alexandre João1 · Vanderlei Salvador Bagnato1

Received: 8 January 2018 / Accepted: 20 February 2018

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
This study evaluated the synergistic effects of ultrasound (US) and low-level laser therapy (LLLT) with or without therapeutic
exercises (TE) in women with knee osteoarthritis. Forty-two Caucasian women with knee osteoarthritis were allocated into
three groups: (1) the placebo group who did not perform TE, but the prototype without emitting light or ultrasonic waves
was applied, (2) the US + LLLT group in which only the prototype was applied and (3) the TE + US + LLLT group that per-
formed TE before the prototype was applied. However, 35 women completed the full clinical trial. Pressure pain thresholds
(PPT) using an algometer and functional performance during the sit-to-stand test were carried out. The average PPT levels
increased for US + LLLT (41 ± 9 to 54 ± 15 N, p < 0.01) and TE + US + LLLT (32 ± 8 to 45 ± 9 N, p < 0.01) groups. The
number of sit-to-stands was significantly higher for all groups. However, the change between pre-treatment and post-treatment
(delta value) was greater for the US + LLLT (4 ± 1) and TE + US + LLLT groups (5 ± 1) than for the placebo group (2 ± 1)
with a significant intergroup difference (p < 0.05). This study showed reduced pain and increased physical functionality after
3 months of US + LLLT with and without TE.

Keywords  Osteoarthritis · Knee · Ultrasound · Laser therapy · Pain

Introduction

Osteoarthritis (OA) is a degenerative joint disease with

* Fernanda Rossi Paolillo pathological characteristics which leads to loss of hyaline
fer.nanda.rp@hotmail.com
articular cartilage associated with underlying bony changes.
Alessandra Rossi Paolillo The main symptom of OA is pain, which increases with joint
arpaolillo@gmail.com
use and is relieved by resting. Generally, quadriceps muscle
Jessica Patrícia João weakness is attributed to painful knee and disuse atrophy,
jessicapatriciaj@hotmail.com
causing reduced physical function in patients with knee OA
Daniele Frascá [1].
daniele.fernandes@usp.br
The Osteoarthritis Research Society International
Marcelo Duchêne (OARSI) published consensus recommendations from
marcelo.duchene@usp.br
experts based on evidence to treat knee OA, which includes
Herbert Alexandre João several modalities of non-pharmacological, pharmacological
herbert@ifsc.usp.br
and surgical interventions for OA [2]. In this context, physi-
Vanderlei Salvador Bagnato cal exercise programs and electro-mechanical–phototherapy
vander@ifsc.usp.br
modalities should be carried out regularly.
1
Optics Group from São Carlos Institute of Physics (IFSC), Various studies have shown the positive effects of low-
University of São Paulo (USP), Av. Trabalhador Sãocarlense, level laser therapy (LLLT) to treat knee OA in rats [3, 4],
400‑Centro, São Carlos, SP CEP 13560‑970, Brazil rabbits [5, 6] and clinical trials in humans [7–9]. In parallel,
2
Department of Occupational Therapy, Federal University therapeutic ultrasound (US) has also shown positive effects
of São Carlos (UFSCar), Rodovia Washington Luiz, on knee OA treatment, including in vitro models [10] and
Km. 235, São Carlos, SP CEP 13565‑905, Brazil

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in vivo studies carried out on animals [6] and in humans
[11–13]. The main positive effects of these modalities are,
for example, anabolic effects on cartilage [5, 10], anti-
inflammatory action [4], analgesia associated with muscle
relaxation [14] and improvements in microcirculation [9].
In addition, therapeutic exercises (TE) reduce joint pain
and enhance physical function in people with knee OA [15].
A literature review shows that TE is associated with LLLT
[14, 16–20] or US [14, 17, 18, 21] to treat knee OA. The idea
in these cases is that LLLT and US could alleviate delayed
onset muscle soreness or joint pain post-exercise [22] and
could also improve range of motion [23] to increase adher-
ence to exercise, leading to improved health and functional
status. Studies have shown positive results when LLLT is
associated with exercises. Montes et al. [24] showed that
LLLT, in conjunction with quadriceps exercises, is a safe
and effective treatment to reduce knee OA pain. An experi-
mental study carried out recently suggests that exercise
program and LLLT are effective in preventing cartilage
degeneration and modulate inflammatory processes due to
knee OA [25]. A systematic review showed that when LLLT
is applied before exercise, ergogenic and protective effects
occur on skeletal muscle [26] and when administered after
injury, LLLT protects cells from secondary damage due to
anti-inflammatory and antioxidant effects [27]. In the same
way, therapeutic US could enhance the effectiveness of
isokinetic exercise, improving functional outcomes among
subjects with bilateral knee OA [28]. Other research used
continuous and pulsed US, as well as home exercise which
resulted in pain relief, recovery of functional state, and qual-
ity of life in subjects with knee OA, without clinically sig-
nificant differences between the continuous and pulsed US
groups [29]. In this study, all subjects received conventional
physical therapy with hot packs, interferential currents and
quadriceps isometric exercise of both knees [29].
A previous study showed combined effects promoted by
a new prototype which includes diode laser beams around
the US transducer applied after TE to treat OA in women’s
hands [23]. In the same way, the present study aimed to
evaluate the synergistic effects of simultaneously applying
US plus LLLT with or without TE on pain and muscle func-
tion in women with knee OA. We hypothesized that the US
plus LLLT in conjunction with TE may reduce pain and
increase muscle function.
Materials and methods
This research was approved by the National Ethics Commit-
tee (approval no. 362.789) and the Federal University of São
Carlos Ethics Committee (approval no. 143.392) in Brazil.
The current study is registered with ClinicalTrials.gov, num-
ber NCT02154893. All subjects provided written informed
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consents before enrollment. The study was carried out over
4 months, including an initial screening procedure to deter-
mine the eligibility of each subject to take part in the study,
pre-measurements, treatments and post-measurements.
A longitudinal, randomized, placebo-controlled trial was
conducted. Subjects with knee OA from São Carlos City,
São Paulo State in Brazil were asked to participate in the
clinical trial using the media (newspapers, radio, TV, web-
sites and magazines). The subjects were selected according
to inclusion and exclusion criteria. The inclusion criteria
were Caucasian women aged 60–80 years with knee OA
and physically untrained. The exclusion criteria were signs
and symptoms of any psychiatric dysfunction, metabolic,
cardiovascular, pulmonary, neurological disease, thrombosis
and tumor. Furthermore, other exclusion criteria were knee
joint diseases other than that of the OA or musculoskeletal
disorders other than those affecting the knee joints, foot and/
or hip joints OA, intra-articular fluid effusion, any contrain-
dication for TE, lower limb arthroplasty, intra-articular infil-
tration, for example, corticosteroid, platelet-rich plasma or
hyaluronic acid infiltrations during the last 6 months.
A computer program was used for the randomization
process (http://www.rando​mizat​ion.com). After screening
the 437 subjects, 42 women were included and assigned
to 3 groups (14 per group), but 35 women completed the
full clinical trial: (1) the placebo group (n = 10) who did
not carry out TE, but the prototype without emitting light
or ultrasonic waves was applied (sham-irradiation); (2) the
US + LLLT group (n = 13) in which only the prototype was
applied and; (3) the TE + US + LLLT group (n = 12) who
carried out TE before the prototype was applied. The sche-
matic flow chart for this study is illustrated in Fig. 1.
Clinical features
Clinical features were assessed as previously described
[22]. The body mass index (BMI) and the waist-to-hip ratio
(WHR) were calculated [BMI = body weight/height (kg/cm2)
and WHR = waist circumference/hip circumference (cm/
cm)]. Bipolar bioimpedance of the upper limbs ­(OMRON®,
Kyoto, Japan) was used to measure body fat and hydration.
Regarding the diagnostic criteria, knee OA was defined
radiologically. The lateral and frontal X-rays of the knees
(Fig. 2) as well as Kellgren–Lawrence 0–4 grading scale
(K–L scale) for degenerative profiles were conducted.
Clinical protocol
Concerning the physical treatments, we used a prototype
which included a laser and US transducer. This prototype
emits mechanical and electromagnetic waves simultane-
ously [22]. The US parameters used were: 1 Mhz frequency,
1.0 W/cm2 intensity, 3.5 cm2 effective radiation area (ERA),
Rheumatology International

Fig. 1  Schematic flow chart

concerning the study methodol-
ogy

Fig. 2  Frontal X-rays of the

right (R) and left (L) knees for
the diagnosis of OA (asym-
metric joint space narrowing,
osteophyte formation and,
subchondral bone sclerosis and
cyst sclerosis formation) and
eight locations on the more
symptomatic knee to measure
PPT levels

continuous mode, for 3 min per knee region, a total of five
regions per knee and 15 min per knee per session, leading
to 3.150 J total energy. The power of each infrared laser
(808 nm) was set at ~ 100 mW. The treatment time was 3 min
per area, leading to an energy of 18 J and a fluence of 7 J/cm2
per each single laser diode or 72 J and 28 J/cm2 per region
(4-diode probe). Five areas were irradiated per knee, leading
to a total energy of 360 J and a fluence delivered close to
142 J/cm2 per knee. The LLLT was applied emitting con-
tinuous waves and using a non-contact scanning technique
(the distance between each laser and the patient’s skin was
~ 1 cm). Transparent gel was used. The transducer head was
moved at a constant circular motion (~ 4–5 cm/s) so as to
decrease the risk of burn injuries and pain in the patients due
to hot spots in the tissue that are developed from too much
energy emitted from one area of the transducer head [30].
The prototype was applied identically for all groups, but the
null dose was used in the placebo group (sham-irradiation).
In the treated groups, the prototype was turned on, emitting
appropriate energy and the patients knew they were being
treated. In the placebo group, the display was working, but
the prototype did not emit energy to the handpiece. How-
ever, the patients did not realize that they were not being
treated, because the ultrasonic waves and infrared radiation
are not visible to the naked eye. Therefore, the patients of the
placebo group incorrectly believed they were being treated.
All patients wore safety glasses due to infrared radiation or
sham-irradiation. The areas of applications of the handpiece
on the knee are shown in Fig. 3.
Both knees were treated. The prototype was applied after
the exercise program in the TE + US + LLLT group. The
exercise program consisted of two stretching exercises for
the lower limb (hamstring and quadriceps muscles stretch-
ing) and resistance training. The patients did an exercise
program (3 × 10 repetitions) at each session, including hip
flexion–extension in seated and standing positions, knee

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Fig. 3  US + LLLT protocol. The
treated regions over and around
the knee are the most painful
knee sites
flexion–extension in a standing position and hip abduc-
tion–adduction in a standing position, as exemplified in
Fig. 4. Three resistance levels for the ankle weights (1, 2 and
3 kg) and elastic bands [color-coded levels of elastic resist-
ance: 2.2 kgf (yellow—light), 3.3 kgf (green—medium) and
4.5 kgf (red—power) of force production using a stretched
band at 50%] were applied. The load was gradually increased
during 3 months. Each load was maintained for 1 month.
The prototype with or without an exercise program or
placebo treatment was applied once a week for 3 months.
Patients were evaluated at baseline, and again after 3 months
to measure the pressure pain thresholds (PPT) and to per-
form the sit-to-stand test.
All measures were done in a quiet and draught-free envi-
ronment. Moreover, the test room was maintained within a
comfortably constant temperature (22–24 °C) and humid-
ity (50–60%), because a climate-controlled environment is
important to eliminate extrinsic factors of measurement.
Pressure pain thresholds (PPT) measurement
The patients were instructed not to exercise on the previ-
ous day and were not allowed to take analgesics or a mus-
cle relaxant throughout the 72 h prior to testing. PPT were
assessed with an electronic algometer (Wagner Instru-
ments, Greenwich, CT, USA) as previously described
[23]. The patients were asked to sit down and pressure
was applied. PPT levels were assessed at eight locations
on the most symptomatic knee (see Fig. 2). The locations
were: (1) 2 cm distal to the inferior medial edge of the
patella; (2) 2 cm distal to the inferior lateral edge of the
Fig. 4  Therapeutic exercise program
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patella; (3) 3 cm lateral to the midpoint on the lateral edge
of the patella; (4) 2 cm proximal to the superior lateral
edge of the patella; (5) 2 cm proximal to the superior edge
of the patella; (6) 2 cm proximal to the superior medial
edge of the patella; (7) 3 cm medial to the midpoint on the
medial edge of the patella and; (8) at centre of the patella
[31]. The average PPT of the three measurements at each
location was calculated and interpolated using an inverse
distance weighted interpolation [22, 32] for the PPT distri-
bution on the most symptomatic knee of women with OA
(topographical pressure pain sensitivity maps).
Sit‑to‑stand test
The 30-s chair stand test is a reliable and valid measure-
ment method for lower extremity strength assessment,
widely used with elderly people, particularly those with
affected knees [33]. Muscular strength is an important
indicator of health and functionality [34]. The patients
were seated on the front part of a chair with their arms
crossed over their chest, eyes fixed straight ahead and both
feet on the floor. They were instructed to perform the sit-
to-stand movements as fast as possible in 30 s. The move-
ments were carried out at a self-selected speed and no
physical assistance was allowed throughout the functional
test. They were verbally encouraged by the investigator to
ensure the explosive movement. The number of completed
sit-to-stands in 30 s was recorded. The test was done three
times with 1 min of rest between trials. The average time
of three consecutive trials was calculated [33, 34].
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Statistical analysis Results

The Shapiro–Wilk test was used to analyze data normality.
The one-way analysis of variance (ANOVA) was carried
out to detect the differences between groups in the anthro-
pometry and body composition data. In addition, the Chi
square (χ2) test was used to compare proportions between
groups in radiographic findings. Two-way ANOVA with
repeated measures was used to compare changes before
and after the treatment for all groups. The delta between
the situations before and after the treatment (∆ = post–pre)
was used to compare groups using a one-way ANOVA.
When a significant difference was detected for one-way
and two-way ANOVA, post hoc Tukey tests were used to
identify the differences. Statistica for Windows Release
7 software (Statsoft Inc., Tulsa, OK, USA) was used for
the statistical analysis and the significance level was set
at 5% (p < 0.05).
Clinical features of the women with knee OA are listed in
Table 1. No significant differences were found between the
groups for anthropometric and body composition variables
(p ≥ 0.05). The proportions were not significantly different
between the groups in the radiographic findings (p ≥ 0.05).
The mean values, standard deviation and statistical results
of the PPT levels and the functional testing are shown in
Table 2. The PPT levels did not differ significantly for the
placebo group (form 43 ± 16 to 42 ± 11, p ≥ 0.05). How-
ever, there was a significant increase in the average PPT
only for US + LLLT (from 41 ± 9 to 54 ± 15 N, p = 0.04)
and TE + US + LLLT (from 32 ± 8 to 45 ± 9 N, p = 0.001)
groups. The change between pre-treatment and post-treat-
ment (delta value) in the PPT levels (Fig. 5a) was greater
for the US + LLLT (Δ = 13 ± 15 N) and TE + US + LLLT
(Δ = 13 ± 12  N) groups compared to the placebo group

Table 1  Clinical characteristics Placebo group US + LLLT group TE + US + LLLT group

of the women with knee
osteoarthritis Anthropometric and body composition
 Age (years) 65 ± 4 72 ± 5 66 ± 5
 Body mass (kg) 79 ± 19 78 ± 14 76 ± 17
 Body height (m) 1.57 ± 0.06 1.54 ± 0.06 1.59 ± 0.07
 BMI (kg/m2) 31 ± 7 33 ± 5 30 ± 7
 Waist (cm) 106 ± 13 109 ± 10 103 ± 14
 Hip (cm) 111 ± 13 114 ± 11 110 ± 10
 Waist-to-hip ratio (WHR) 0.95 ± 0.04 0.95 ± 0.05 0.93 ± 0.06
 Body fat (%) 45 ± 14 45 ± 12 43 ± 11
 Body hydration (%) 37 ± 10 38 ± 8 39 ± 7
Radiological evaluation (K–L scale)
 Grade 2 4(36.6%) 2(15%) 3(25%)
 Grade 3 4(36.5%) 5(39%) 5(42%)
 Grade 4 3(27%) 6(46%) 5(33%)
Involved knee
 Bilaterally 10(100%) 13(100%) 12(100%)
 Right (most severely affected) 1(10%) 3(23%) 2(17%)
 Left (most severely affected) – – 1(8%)

Table 2  Values of mean, Placebo group US + LLLT group TE + US + LLLT

standard deviation and statistical group
results of the functional testing
and the PPT levels Pre Post Pre Post Pre Post

Algometry
 Average PPT (N) 43 ± 16 42 ± 11 41 ± 9 54 ± 15** 32 ± 8 45 ± 9**
Sit-to-stand test
 Number of sit-to-stands 9 ± 3 11 ± 3* 9 ± 2 13 ± 2** 9 ± 3 14 ± 3**

*Significant difference for pre- vs post-treatment (p < 0.05)

**Significant difference for pre- vs post-treatment (p < 0.01)

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Fig. 5  The reduction of pain sensitivity (a) and the function gain (b).
The change between pre-treatment and post-treatment was signifi-
cantly greater for the US + LLLT and TE + US + LLLT groups than
the placebo group. *Significant intergroup difference (p < 0.05)
(Δ = − 1 ± 12 N) with a significant intergroup difference
(p = 0.04). The topographical maps can be seen in Fig. 6.
These data showed a decrease in pain sensitivity only for
US + LLLT and TE + US + LLLT groups. The number of sit-
to-stands was significantly higher for all groups [placebo
(from 9 ± 3 to 11 ± 3, p = 0.01); US + LLLT (from 9 ± 2 to
13 ± 2, p = 0.0001) and; TE + US + LLLT (from 9 ± 3 to
14 ± 3, p = 0.0001)]. However, the change between pre-treat-
ment and post-treatment (delta value) in the number of sit-
to-stands (Fig. 5b) was greater for the US + LLLT (Δ = 4 ± 1)
and TE + US + LLLT (Δ = 5 ± 1) groups compared to the
placebo group (Δ = 2 ± 1) with a significant intergroup dif-
ference (p = 0.02).
Discussion
The main outcome of this study was an increase of the pain
threshold and physical functionality after 3 months of treat-
ment with US plus LLLT with or without the TE program in
women with knee OA. A previous study showed that the US
and LLLT parameters applied simultaneously were appropri-
ate, leading to pain relief in hand OA [22]. In this previous
study, the authors [22] used the same LLLT and US parame-
ters of the present study, but the pulsed mode US (duty cycle
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50%) was applied. Various studies demonstrated individual
and comparative analysis of US and LLLT to treat knee OA.
Ravanbod et al. [6] showed that US (pulsed mode, 1/9 duty
cycle, 1 MHz, 0.4 W/cm2 and 150 s) was more effective than
LLLT (880 nm, 25 mW, 1 J/cm2), in reducing joint swelling
and articular joint friction. However, Rayegani et al. [18]
showed that LLLT (880 nm, 50 mW, continuous mode, 6 J/
point and 24 J/knee) was more effective than US (pulsed
mode, 1 MHz, 1.5 W/cm2, for 5 min per knee) to reduce
pain, joint stiffness and disability. In these studies, it can be
observed that LLLT with higher power and energy lead to
better results. In addition, pulsed US [11, 12, 22, 35] is used
for OA treatments in most studies, because pulsed US stimu-
lates cartilage repair and promotes anti-inflammatory and
analgesic responses without a predominant thermal effect.
On the other hand, we used continuous US in the present
study, because an increased temperature was desired.
Regarding an increased temperature, the absorption of the
ultrasonic vibrational energy by the human body promotes
molecular oscillations, producing heat and leading to thera-
peutic effects [36]. The thermal effects of the US include
increased metabolic activity and blood flow, a reduction in
subacute and chronic inflammation and muscle spasm, as
well as a momentary increase in the extensibility of col-
lagenous structures (e.g., tendons, ligaments and joint cap-
sules) and contracture of connective tissue. The analgesic
action may be caused by increased microvascular perme-
ability and cell metabolism, enhancement of fibrous con-
nective tissue extensibility and pain threshold elevation by
thermodynamic mechanisms [11, 37].
The thermal effect has demonstrated decreases in dis-
tal motor and sensory latencies, faster nerve conduction,
elevated pain threshold and analgesic action when continu-
ous US was used [38, 39]. Stimulation of thermoreceptors
and mechanoreceptors may help to reduce pain and swell-
ing through a counter-irritation effect and the gate control
theory. The neurophysiological basis of pain relief are: (1)
the response of dorsal horn neurons to a noxious stimulus is
reduced when another noxious stimulus is applied outside
their receptive field [40]. Furthermore, the endogenous opi-
oid systems especially plays a crucial role in regulating pain
transmission and also acting to moderate excessive inflam-
mation. In this context, infrared laser promotes increased
beta-endorphin [41]. Considering US, studies showed
antinociceptive effects [38, 44]. Furthermore, a clinical trial
[22] presented desensitization of mechanonociceptors post-
treatment with US plus LLLT in women with hand OA. This
finding [22] was similar to the present study with US plus
LLLT for knee OA treatment. Therefore, these technologies
may induce analgesia by mechanical and thermal effects,
as well as increase peripheral endogenous opioids associ-
ated with cytokine modulation and anti-inflammatory action
[42–44].
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Fig. 6  Pressure pain sensitivity

topographical maps. Pre-treat-
ment (right) and post-treatment
(left) for placebo group (a),
US + LLLT group (b), and
TE + US + LLLT group (c). The
color schemes for PPT values
measured at eight points on the
most symptomatic knee can be
observed. The red to yellow
color schemes (lower PPT lev-
els) indicated pressure hyperal-
gesia and the green to blue color
schemes (PPT levels increased)
indicated less sensitivity to pain
after 3 months, mainly for both
the US + LLLT group and the
TE + US + LLLT group

The women with knee OA who performed US plus LLLT
showed an increase in the PPT and pain relief, leading to
improved functional outcomes, as observed by the sit-to-
stand test. Elderly people and people with disabling dis-
eases are affected by changes in movement speed, initial
starting positions and balance control [45]. The sit-to-stand
movement causes displacement of the center of mass [46],
transferring energy and angular momentum from one body
segment to another. These movements require skills, such as
coordination, muscle strength, balance control, load-bearing
distribution at the lower limbs and stability. Thus, the sit-
to-stand movement is considered a fundamental prerequisite
for daily activities [47]. In this context, the US plus LLLT
promoted the function gain.
Regarding TE, there are no additional effects on function-
ality. The results of the present study can reflect therapeu-
tic effects promoted by US and LLLT regardless of the TE.
Probably, both exercise load and training volume were lower
and insufficient for additional functional improvement.
LLLT and US are generally safe, non-ionizing radiation
methods that are ideal for using in daily clinical practice,
mainly due to their cost-effectiveness, portability and user
friendliness [48]. However, limitations of studies include a
small-size trial, smaller amounts and loads of exercise, as
well as a lack of groups (exercise alone or US alone or LLLT
alone), absence of correlation between the algometry and
visual analogue scale (VAS) and a study conducted only with
Caucasian women (the sample is not totally representative of
the population).

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Conclusion
This study found that LLLT together with US reduce pain
and improve functional performance in women with knee
OA. Furthermore, there was no placebo effect. These find-
ings have important clinical implications for physical medi-
cine and rehabilitation, because the protocol used in this
study can be an important adjunct to treat OA.
Acknowledgements  We would like to thank the Fundação de Amparo à
Pesquisa do Estado de São Paulo (FAPESP)—Grant nos. 2013/07276-1
and 2013/14001-9. We also acknowledge the MM Optics and the Tech-
nological Support Laboratory (LAT) of the Optics Group from the
Physics Institute of São Carlos (IFSC), University of São Paulo (USP)
for development of the prototype.
Author contributions  FRP, ARP and VSB, conception and design of
10. Min BH, Woo JI, Cho HS, Choi BH, Park SJ, Choi MJ, Park SR
research; JPJ, DF and HJ performed experiments; FRP, MD and VSB
analyzed data, interpreted results of experiments, FRP, ARP and VSB
drafted manuscript; FRP and ARP edited and revised manuscript; FRP,
ARP, JPJ, DF, MD, HJ and VSB approved the final version of the
manuscript.
Funding  Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP)—Grant nos. 2013/07276-1 and 2013/14001-9.
Compliance with ethical standards  tol Clin 5(4):163–167
Conflict of interest Fernanda Rossi Paolillo, Alessandra Rossi Pao-
lillo, Jessica Patrícia João, Daniele Frascá, Marcelo Duchêne, Herbert
Alexandre João and Vanderlei Salvador Bagnato declare that they have
no conflict of interest.
Ethical approval  This research was approved by the National Ethics
Committee (approval no. 362.789) and the Federal University of São
Carlos Ethics Committee (approval no. 143.392) in Brazil. The present
study is registered with ClinicalTrials.gov, number NCT02154893. All
subjects provided written informed consents before enrollment.
References
1. Sarzi-Puttini P, Cimmino MA, Scarpa R, Caporali R, Parazzini F,
Zaninelli A, Atzeni F, Canesi B (2005) Osteoarthritis: an overview
of the disease and its treatment strategies. Semin Arthritis Rheum
35:1–10
2. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Beren-
baum F, Bierma-Zeinstra SM, Hawker GA, Henrotin Y, Hunter
DJ, Kawaguchi H, Kwoh K, Lohmander S, Rannou F, Roos EM,
Underwood M (2014) OARSI guidelines for the non-surgical man-
agement of knee osteoarthritis. Osteoarthritis Cartil 22:363–388
3. da Rosa AS, dos Santos AF, da Silva MM, Facco GG, Perreira
DM, Alves AC, Leal Junior EC, de Carvalho PT (2012) Effects
of low-level laser therapy at wavelengths of 660 and 808 nm
in experimental model of osteoarthritis. Photochem Photobiol
88:161–166
4. Pallotta RC, Bjordal JM, Frigo L, Leal Junior EC, Teixeira S,
Marcos RL, Ramos L, Messias FM, Lopes-Martins RA (2012)
Infrared (810-nm) low-level laser therapy on rat experimental
knee inflammation. Lasers Med Sci 27:71–78
13
Rheumatology International
5. Cho HJ, Lim SC, Kim SG, Kim YS, Kang SS, Choi SH, Cho
YS, Bae CS (2004) Effect of low-level laser therapy on osteo-
arthropathy in rabbit. In Vivo 18(5):585–591
6. Ravanbod R, Torkaman G, Esteki A (2013) Comparison between
pulsed ultrasound and low level laser therapy on experimental
haemarthrosis. Haemophilia 19(3):420–425
7. Alghadir A, Omar MT, Al-Askar AB, Al-Muteri NK (2014)
Effect of low-level laser therapy in patients with chronic knee
osteoarthritis: a single-blinded randomized clinical study.
Lasers Med Sci 29(2):749–755
8. Hsieh RL, Lo MT, Liao WC, Lee WC (2012) Short-term effects
of 890-nanometer radiation on pain, physical activity, and pos-
tural stability in patients with knee osteoarthritis: a double-
blind, randomized, placebo-controlled study. Arch Phys Med
Rehabil 93(5):757–764
9. Hegedus B, Viharos L, Gervain M, Gálfi M (2009) The effect
of low-level laser in knee osteoarthritis: a double-blind, ran-
domized, placebo-controlled trial. Photomed Laser Surg
27:577–584
(2006) Effects of low-intensity ultrasound (LIUS) stimulation
on human cartilage explants. Scand J Rheumatol 35(4):305–311
11. Tascioglu F, Kuzgun S, Armagan O, Ogutler G (2010) Short-
term effectiveness of ultrasound therapy in knee osteoarthritis.
J Int Med Res 38(4):1233–1242
12. Sánchez AL, Wakamatzu MAR, Zamudio JV, Casasola J, Cue-
vas CH, González AR, Tapia JG (2009) Effect of low-intensity
pulsed ultrasound on regeneration of joint cartilage in patients
with second and third degree osteoarthritis of the knee. Reuma-
13. Kozanoglu E, Basaran S, Guzel R, Guler-Uysal F (2003) Short
term efficacy of ibuprofen phonophoresis versus continuous
ultrasound therapy in knee osteoarthritis. Swiss Med Wkly
133(23–24):333–338
14. Hanif S, Salim AR, Lamina S, Isa UL (2010) Comparison of
the effect of laser therapy and therapeutic ultrasound in the
management of chronic osteoarthritic knee pain: a randomised
controlled trail. Niger J Med Rehabil (NJMR) 15(23):1–5
15. Fransen M, Mcconnell S (2008) Exercise for osteoarthritis of
the knee. Cochrane Database Syst Rev 4(4):1–93
16. Kheshie AR, Alayat MS, Ali MM (2014) High-intensity versus
low-level laser therapy in the treatment of patients with knee
osteoarthritis: a randomized controlled trial. Lasers Med Sci
29(4):1371–1376
17. Ungur R, Ciortea V, Onac I, Mocan T, Irsay L, Dronca M, Suciu
S, Borda IM (2014) Clinical effects of multimodal therapy in
patients with knee osteoarthritis. Palestrica Third millenn Civ
Sport 15:22–25
18. Rayegani SM, Bahrami MH, Elyaspour D, Saeidi M, Sanjari H
(2012) Therapeutic effects of low level laser therapy (LLLT) in
knee osteoarthritis compared to therapeutic ultrasound. J Lasers
Med Sci 3(2):71–74
19. Alfredo PP, Bjordal JM, Dreyer SH, Meneses SR, Zaguetti
G, Ovanessian V, Fukuda TY, Junior WS, Lopes Martins RA,
Casarotto RA, Marques AP (2012) Efficacy of low level laser
therapy associated with exercises in knee osteoarthritis: a ran-
domized double-blind study. Clin Rehabil 26(6):523–533
20. Gur A, Cosut A, Sarac AJ, Cevik R, Nas K, Uyar A (2003)
Efficacy of different therapy regimes of low-power laser in pain-
ful osteoarthritis of the knee: a double-blind and randomized-
controlled trial. Lasers Surg Med 33(5):330–338
21. Akinbo S, Owoeye O, Adesegun S (2011) Comparison of the
therapeutic efficacy of diclofenac sodium and methyl salicylate
phonophoresis in the management of knee osteoarthritis. Turk
J Rheumatol 26(2):111–119
Rheumatology International
22. Paolillo AR, Paolillo FR, João JP, João HA, Bagnato VS (2015)
Synergic effects of ultrasound and laser on the pain relief in
women with hand osteoarthritis. Lasers Med Sci 30:279–286
23. Calis HT, Berberoglu N, Calis M (2011) Are ultrasound, laser and
exercise superior to each other in the treatment of subacromial
impingement syndrome? A randomized clinical trial. Eur J Phys
Rehabil Med 47(3):375–380
24. Montes-Molina R, Madroñero-Agreda MA, Romojaro-Rodríguez
AB, Gallego-Mendez V, Prados-Cabiedas C, Marques-Lucas C,
Pérez-Ferreiro M, Martinez-Ruiz F (2009) Efficacy of interferen-
tial low-level laser therapy using two independent sources in the
treatment of knee pain. Photomed Laser Surg 27(3):467–471
25. Assis L, Milares LP, Almeida T, Tim C, Magri A, Fernandes KR,
Medalha C, Renno AC (2016) Aerobic exercise training and low-
level laser therapy modulate inflammatory response and degen-
erative process in an experimental model of knee osteoarthritis in
rats. Osteoarthritis Cartil 24:169–177
26. Leal-Junior EC, Vanin AA, Miranda EF, Carvalho PT, Dal Corso
S, Bjordal JM (2015) Effect of phototherapy (low level laser ther-
apy and light-emitting diode therapy) on exercise performance
and markers of exercise recovery: a systematic review with meta-
analysis. Lasers Med Sci 30(2):925–939
27. Borsa PA, Larkinm KA, True JM (2013) Does phototherapy
enhance skeletal muscle contractile function and postexercise
recovery? A systematic review. J Athl Train 48:57–67
28. Huang MH, Lin YS, Lee CL (2005) Use of ultrasound to increase
effectiveness of isokinetic exercise for knee osteoarthritis. Arch
Phys Med Rehabil 86:1545–1551
29. Ulus Y, Tander B, Akyol Y, Durmus D, Buyukakincak O, Gul
U, Canturk F, Bilgici A, Kuru O (2012) Therapeutic ultrasound
versus sham ultrasound for the management of patients with knee
osteoarthritis: a randomized double-blind controlled clinical
study. Int J Rheum Dis 15(2):197–206
30. Weaver SL, Demchak TJ, Stone MB, Brucker JB, Burr PO (2006)
Effect of transducer velocity on intramuscular temperature dur-
ing a 1-MHz ultrasound treatment. J Orthop Sports Phys Ther
36(5):320–325
31. Arendt-Nielsen L, Nie H, Laursen MB, Laursen BS, Madeleine P,
Simonsen OH, Graven-Nielsen T (2010) Sensitization in patients
with painful knee osteoarthritis. Pain 149(3):573–581
32. Fernández-de-Las-Peñas C, Madeleine P, Martínez-Perez A,
Arendt-Nielsen L, Jiménez-García R, Pareja JA (2010) Pressure
pain sensitivity topographical maps reveal bilateral hyperalgesia
of the hands in patients with unilateral carpal tunnel syndrome.
Arthritis Care Res (Hoboken) 62(8):1055–1064
33. Schwenk M, Gogulla S, Englert S, Czempik A, Hauer K (2012)
Test–retest reliability and minimal detectable change of repeated
sit-to-stand analysis using one body fixed sensor in geriatric
patients. Physiol Meas 33(11):1931–1946
34. Bohannon RW (1995) Sit-to-stand test for measuring performance
of lower extremity muscles. Percept Mot Skills 80:163–166
35. Huang MH, Yang RC, Lee CL, Chen TW, Wang MC (2005)
Preliminary results of integrated therapy for patients with knee
osteoarthritis. Arthritis Rheum 53(6):812–820
36. Cambier D, D’Herde K, Witvrouw E, Beck M, Soenens S, Vander-
straeten G (2001) Therapeutic ultrasound: temperature increase at
different depths by different modes in a human cadaver. J Rehabil
Med 33(5):212–215
37. Drape DO, Sunderland S, Kirkendall DT, Ricard M (1993) A
comparison of temperature rise in human calf muscles following
applications of underwater and topical gel ultrasound. J Orthop
Sports Phys Ther 17(5):247–251
38. Moore JH, Gieck JH, Ball DW, Perrin DH, Saliba EN, McCue
FC (2004) The biophysical effects of ultrasound on median nerve
distal latencies. Electromyogr Clin Neurophysiol 40:169–180
39. Kramer JF (1984) Ultrasound: evaluation of its mechanical and
thermal effects. Arch Phys Med Rehabil 65(5):223–227
40. Holdcroft A, Jaggar S (2005) Core topics in pain. Cambridge Uni-
versity Press, Cambridge
41. Hagiwara S, Iwasaka H, Okuda K, Noguchi T (2007) GaAlAs
(830 nm) low-level laser enhances peripheral endogenous opioid
analgesia in rats. Lasers Surg Med 39(10):797–802
42. Srbely JZ, Dickey JP, Lowerison M, Edwards AM, Nolet PS,
Wong LL (2009) Stimulation of myofascial trigger points with
ultrasound induces segmental antinociceptive effects: a rand-
omized controlled study. Pain 139:260–266
43. Alves ACA, de Paula VR, Leal-Junior ECP, dos Santos SA,
Ligeiro AP, Albertini R, Silva Junior JA, de Carvalho PDTC
(2013) Effect of low-level laser therapy on the expression of
inflammatory mediators and on neutrophils and macrophages in
acute joint inflammation. Arthritis Res Ther 15:R116
44. Guo H, Luo Q, Zhang J, Lin H, Xia L, He C (2011) Comparing
different physical factors on serum TNF-α levels, chondrocyte
apoptosis, caspase-3 and caspase-8 expression in osteoarthritis
of the knee in rabbits. Jt Bone Spine 78(6):604–610
45. Maki BE, McIlroy WE (2006) Control of rapid limb movements
for balance recovery: age-related changes and implications for fall
prevention. Age Ageing 2(35):ii12–ii18
46. Vander Linden DW, Brunt D, McCulloch MU (1994) Variant and
invariant characteristics of the sit-to-stand task in healthy elderly
adults. Arch Phys Med Rehabil 75(6):653–660
47. Janssen WG, Bussmann HB, Stam HJ (2002) Determinants of the
sit-to-stand movement: a review. Phys Ther 82(9):866–879
48. Srbely JZ (2008) Ultrasound in the management of osteoarthritis:
part I: a review of the current literature. J Can Chiropr Assoc
52:30–37
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