Photobiomodulation, Photomedicine, and Laser Surgery

Volume 40, Number 10, 2022

ª Mary Ann Liebert, Inc.
Pp. 698–707
DOI: 10.1089/photob.2022.0067
Open camera or QR reader and
scan code to access this article
and other resources online.

Customized Photobiomodulation Modulates Pain and Alters

Thermography Pattern in Patients with Knee Osteoarthritis:
A Randomized Double-Blind Pilot Study

Po ly
g
n/ On

in
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

Nathali Cordeiro Pinto, PhD,1,2,* Marcelo Victor Pires de Sousa, PhD,1,3,4,* Nathalia Lopes Ferreira, BS,5,6,*

st
Natalia Almeida Braga, BS,5 Alexandre Aldred, MD,7 Guilherme Gomes, PhD,7,8
George Miguel Góes Freire, MD,9 Hazem Adel Ashmawi, PhD,9,{ and Marucia Chacur, PhD5,{

tio se
Abstract
bu U
Background: Photobiomodulation therapy (PBMT) modulates a wide variety of biological processes, leading to
tri l
anti-inflammatory and analgesic effects. Understanding the mechanisms underlying therapeutic effects of
is na

PBMT remains challenging due to varying outcomes observed between wavelengths, dosage, and site of
application. Our research group has dedicated close attention to customization and individualization of do-
simetry for PBMT protocols. Preliminary data showed that using an individualized treatment could solve
o

contradictory results reported by previous studies. Based on literature and our preliminary data on light ab-
r D rs

sorption, the goal of the present pilot is to determine whether our individualized dosimetry is a feasible method
to assist osteoarthritis (OA) pain control.
Methods: This parallel two-arm controlled-pilot study aimed to assess whether personalized PBMT can be
fo e

effective in the treatment of painful chronic knee OA. Thirty-one patients were randomly allocated into
ot r P

treatment and placebo group (sham irradiation), and the treatment procedure was performed twice a week, for
5 weeks. The PBMT was applied using 850 nm with continuous wave and a total of 526–1402 J each session.
Individualized dosimetry was chosen based on each patient’s body mass index and skin color. Quality-of-life
(QOL) questionnaires and serum/urine analyses were performed before and after treatment was over. Both
N o

examiners and participants were blinded to group allocation.

Results: Pain scores were reduced significantly in the 4th, 5th, and 10th sessions and remained lower 6 weeks
F

posttherapy in the treatment group when compared to the placebo group. Moreover, the treatment group’s
results were improved in QOL questionnaires score, dopamine level, and in microcirculation.
Conclusions: The present results provide initial evidence that customized photobiomodulation (PBM) reduce
pain levels in short- and medium-term in patients with symptomatic knee OA when compared to placebo group.
Furthermore, we have provided evidence that customized PBM is able to improve the QOL of those patients.

1
Bright Photomedicine Ltd., São Paulo, Brazil.
2
Instituto do Coração do Hospital das Clı́nicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
3
Department of Physics, Federal University of Ceará (UFC), Fortaleza, Brazil.
4
D’Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil.
5
Departamento de Anatomia, Laboratório de Neuroanatomia Funcional da Dor, Instituto de Ciências Biomédicas, Universidade de
São Paulo, São Paulo, Brazil.
6
Departamento de Biofı́sica, Laboratório de Neuroendocrinologia do Estresse, Edifı́cio de Ciências Biomédicas, Universidade Federal de
São Paulo, São Paulo, Brazil.
7
Department of Science and R&D, Predikta Soluções em Pesquisa, São Paulo, Brazil.
8
Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics (IFSC), University of São Paulo (USP),
São Carlos, Brazil.
9
Anesthesiology Department, Faculdade; de Medicina da Universidade de São Paulo, São Paulo, Brazil.
*These authors are sharing first authorship.
{
These authors are sharing last authorship.

698
 CUSTOMIZED PHOTOBIOMODULATION THERAPY
Keywords: analgesic, arthritis, photobiomodulation therapy, low-level laser therapy, quality of life, ther-
mography
Introduction
O steoarthritis (OA) is a common manifestation of
degenerative joint disease and one of the leading causes of
disability and work absenteeism worldwide,1,2 affecting 303
million people globally in the year 2017.3 It is classically
characterized by focal loss of joint articular cartilage and sub-
chondral bone alterations such as bone remodeling and osteo-
Po ly
phyte formation.4 The knee joint is the most affected peripheral
g
site resulting in progressive loss of function, ongoing pain,
stiffness, and mobility impairment.1 Extensive studies have
n/ On
in
shown that a wide variety of factors such as sexual difference,
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.
age, body mass index (BMI), educational attainment, psycho-
st
logical factors, genetic factors, and local structural pathology
may be associated with pain in the knee.5–7 Also, peripheral and
tio se
central sensitization contribute to pain in knee OA, in which
most patients become unresponsive to the standard pharmaco-
logical treatment, and hence, it hinders pain management.3
Prescription drugs, such as non-steroidal anti-inflammatory
bu U
drugs (NSAIDs) and opioids, are currently the most common
treatment indicated by physicians to treat pain and inflammation
in mild to moderate cases of OA.3,8,9 However, those can be
tri l
is na
associated to side effects such as nausea, constipation, and de-
pression, and may even result in abuse disorder.10,11 A non-
pharmacological approach, such as physical activity and
physiotherapy, is often used alongside drug prescription al-
o
though not always effective nor tolerated by patients.10,12 Sur-
gical procedures are recommended with disease progression;
r D rs
however, it is often inefficient to solve patients’ pain.10,13,14
Thus, it becomes evident that there is a need for more effective
fo e
therapies and strategies for the treatment of painful knee OA.
Photobiomodulation therapy (PBMT) refers to the use of
ot r P
red and near-infrared light to promote wound healing, in-
flammation and edema reduction, neoangiogenesis, and
analgesia;7,15 it has been used to study its effect in a variety
of clinical settings such as disorders of the tendons and
N o
joints, traumatic injuries, chronic low back pain, and
neuromodulation.5–7 The primary biological effects of
F
PBMT have been suggested to be through photon absorption
in the mitochondria by cytochrome c oxidase, a substantial
chromophore in the cellular response, and calcium ion
channels in cell membranes. Among the secondary effects of
photon absorption, increase adenosine triphosphate produc-
tion, reactive oxygen species and nitric oxide, modulation of
calcium levels, induction of transcription factors related to
cell survival, cell proliferation and migration, synthesis of
new proteins, upregulation of antioxidant, and reduction of
oxidative stress are the most common effects reported.5–7
A few randomized placebo-controlled trials of PBMT in
patients with knee OA showed pain and disability reduction
that remained up to 2–4 weeks posttherapy without any ad-
verse events.16–22 However, there are variations among the
PBMT procedures used to treat knee OA mainly regarding
methods of application, treatment duration, dosage, and site of
application, resulting in different outcomes and lack of well-
held clinical trials to provide trustworthy scientific data.22 Of
late, it has been suggested that those methodological defi-
699
ciencies may be solved through the development of patient-
personalized dosimetry.23 However, there are no studies in
literature describing the appropriate dosimetry protocols for its
implementation in clinical practice.
As previously described, photobiomodulation (PBM) has
been used in the treatment of several chronic pain conditions
reporting benefits in pain, inflammation, and wound healing
in both human17,24–26 and animal models.27–29 Our goal with
the present pilot study was to assess whether customized
dosimetry is a feasible PBM-method for reducing pain
scores in patients suffering from chronic knee OA. The re-
sults provided in the present study will provide a much
needed, rigorous means of comparing the relative efficacy of
varying irradiation parameters, leading to a long overdue
standardization of treatment protocols for improving the
quality of life (QOL) of OA patients. This will be funda-
mentally important to both validate the efficacy of non-
pharmaceutical approaches as well as to understand
mechanisms underlying their positive effects for OA patients.
Materials and Methods
Study population
The current study was approved by the Ethics Committee
on Research of the Hospital das Clı́nicas da Faculdade de
Medicina da Universidade de São Paulo (CAAE:
93744418.5.0000.0068) and written informed consent was
obtained from all subjects included in the trial. The trial is
registered at ClinicalTrials.gov (NCT03924128). Data were
collected at the Pain Clinic of the Department of Anesthesia
from Hospital das Clı́nicas da Faculdade de Medicina da
Universidade de São Paulo. We initially performed a
screening procedure to identify and determine the eligibility
of each subject. This study lasted a total of 10 months, in-
cluding premeasurements, treatments, and postmeasurements.
This study was conducted as a parallel two-arm ran-
domized double-blind, placebo-controlled pilot trial. The
primary objective was to assess feasibility of customized
PBMT to measure pain intensity after PBMT in the treat-
ment of chronic knee OA. The secondary objectives of this
trial were (1) to determine whether customized PBMT is
able to improve patients’ QOL through Knee injury and
Osteoarthritis Outcome Score (KOOS) and World Health
Organization Quality of Life (WHOQOL)-bref question-
naires; (2) identify whether specific biochemical and hor-
monal markers could be modified after PBMT; and (3) to
investigate whether our therapy is able to alter thermo-
graphic inflammatory patterns of OA patients.
The sample size was calculated to detect a clinically
relevant difference (2 points) in pain intensity measured by
Numeric Rating Scale (NRS). In our study, the sample size
was calculated using the program G*Power 3 3.1. 9.7, effect
size (0.5), a statistical power of 80% (1-b error probability),
and an a error level probability of 0.05, requiring 26 par-
ticipants, an extra 20% was added due to probable dropouts
and total participants were 34 (17 per group). Simple ran-
domization generated by computer (www.random.org) was
 700 PINTO ET AL.

FIG. 1. Flowchart of the

Po ly
participation of volunteers in

g
the study.

n/ On

in
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

st
tio se
bu U
tri l
is na

used for participant allocation. After initial evaluation cluding: pain intensity, QOL questionnaire, physical function,
confirmed eligibility, thirty-one patients were set to two thermography, and blood biochemical analysis. Patients’ pain
o

different groups: (1) the placebo group (n = 16), in which the was weekly assessed for 4 months after treatment.
PBMT device was turned on, however, without emitting any
r D rs

energy and (2) the treatment group (n = 15) who effectively Inclusion criteria. Patients of both sexes, from 40 to 90
received the PBM treatment. The schematic flowchart for years, diagnosed with chronic knee OA according to
fo e

this study is illustrated in Fig. 1. American College of Rheumatology criteria and grades III
For this work, both the researchers and patients were or IV knee OA according to the Kellgren–Lawrence radio-
ot r P

blinded to the allocation of groups and the performance of
examinations. Thus, the patients did not know which group
they were allocated to, nor did the operator know which was
the active PBMT probe or placebo. A summary of the de-
N o
logical classification; we also assessed the individual’s
ability to remain independent and their willingness to par-
ticipate in the study, present knee pain, functional reduction
in the last 3 months, and capability of walking indepen-

mographic characteristics value of all subjects who completed dently with or without walking assistance devices.
the study is depicted in Table 1, where age, BMI, skin pho-
F

totype, energy, and affected knee are described. A total of 31 Exclusion criteria. The exclusion criteria for patients are
patients completed the study (93% of women and 7% men) described below: patients with a history of cancer dementia,
and all of them had chronic knee OA for ‡year. All patients neurological deficits, amputations, fractures of the lower
were evaluated before and after 5 weeks of treatment, in- limbs, cardiac pacemaker, and uncontrolled metabolic and

Table 1. Patients’ Demographic Characteristics

Total (n = 31 patients)
Placebo (n = 16) PBMT (n = 15)
Variables Mean – SEM Mean – SD Mean – SEM Mean – SD
Age 66 – 2.69 66 – 10.7 63 – 2.83 63 – 10.9
BMI 29.8 – 1.1 29.8 – 4.6 24.8 – 2.4 24.8 – 9.6
Sex 1 male, 15 females 1 male, 14 females
Affected side 2 left, 1 right, 13 both 2 left, 13 both
OA Kellgren–Lawrence classification III (9), IV (7) III (10), IV (5)
BMI, body mass index; OA, osteoarthritis; PBMT, photobiomodulation therapy; SD, standard deviation; SEM, standard error of the
mean.
 CUSTOMIZED PHOTOBIOMODULATION THERAPY 701

cardiovascular diseases of class 3 obesity (BMI ‡40 kg/m2).
Patients with disease affecting the knee, such as rheumatoid
arthritis or knee surgery, were also excluded.
Treatment procedure
Treatment was administered twice a week on the same
days over a period of 5 weeks with the system Light-Aid
(Bright Photomedicine, SP, Brazil), operated at a continuous
wave of 850 nm wavelength, or with a placebo probe of the
same appearance and display. The probes were numbered A
(active) and B (placebo). Treatment was administered in
contact to the skin over the patient’s knee. Both knees were
sorption and scattering of the photons that are increased due to
the increase in the fat thickness. As previously mentioned, the
lack of parameters and the difference in the physical character-
istics of each patient (as described in Table 2) is extremely im-
portant and this must be taken into account. Therefore, this is the
first work showing the importance of these parameters or the
improvement of the individual pathological picture.
Knee pain scores
NRS was used to evaluate pain. Patients were instructed
to number their level of pain from 0 (absence of pain) to 10
(worst possible pain). The NRS score was applied weekly
after each PBMT session and for 16 weeks after treatment.

Po ly
treated but statistical analysis was done in the knee with

g
higher pain intensity at numerical rating scale (NRS).
Placebo treatment was held identical to PBM treatment, Quality of life

n/ On

in
in a way that the device was turned on, but the probe was
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

Two QOL questionnaires were used: KOOS and

disabled without emitting any energy, ensuring that neither
WHOQOL-bref (WHOQOL-abbreviated). For the evaluation

st
the operator nor the subject could identify which group it
of QOL, both questionnaires were recorded and compared
belonged to. Probe device comprised a 100 light-emitting
before the first PBMT and after the last session of treatment.
diodes (LED) divided into 4 LED clusters with 25 LED

tio se
The KOOS questionnaire evaluates both short and long-term
each, which covered patients’ whole knee surface, the
consequences of knee injury and OA. It holds forty-two items in
treatment was applied using a constant 5–8 min to deliver a
five separately scored subscales; Pain, other Symptoms, Ac-
total of 526–1402 J each session and power density of 60–
bu U tivities in daily living (ADL), Function in Sport and Recreation
100 mW/cm2 (see Table 2 for parameters details).
(Sport/Rec), and knee-related QOL.33 The WHOQOL-bref
questionnaire is able to assess different individuals through the
Process to customize parameters for optical irradiation
tri l
context of their culture, values, in addition to an analysis of their
is na

PBMT parameters are currently the biggest challenge in personal goals, standards, and concerns.34
PBMT and in the scientific literature. It is still quite contro-
versial as to what the best irradiation parameters or site of ap- Physical function
o

plication are, with no specific well-established protocols for For functional assessments, the timed up and go test (TUG)
either. Proper selection of physical variables, such as power, and the sit-to-stand test (STS) were used. TUG is a mobility
r D rs

dose, energy density, and site of application are fundamental to test that evaluates the time patients take to stand from a sitting
achieve the desired results. Based on this, our group created position, walk a 3-m distance at a normal speed and return to
specific parameters customization, we relayed on the physical
fo e

the starting point without support or help of any kind. In the

principle that the higher the amount of melanin or the amount of case of STS, the patients were initially instructed to perform
ot r P

fat tissue, the higher its absorption and scattering, so less pho-
tons could reach the under-skin chromophores to trigger the
photobiological processes, which lead to the therapy itself.30–32
Considering these physical principles, we created Table 2 as a
N o
sitting and standing movements as quickly as possible within
30 sec. Then, the number of sit-to-stand completed during the
period described above was recorded.

first approach to the customization of the irradiation parameters

Knee thermography
of PBMT for knee OA. To customize the irradiation parameters
F

in accordance with the patient’s skin phototype, we increased the
irradiance as a first approximation to compensate the melanin
absorption. To customize the irradiation parameters in accor-
dance with the patient‘s amount of adipose tissue, we increased
the irradiance and irradiation time trying to compensate the ab-
In this test, the average surface temperature of the indi-
viduals’ lower limbs was selected and analyzed by specific
routines in the ThermaCAM 2.9 program (FLIR Systems,
Wilsonville, OR), Python language, and ImageJ software
(emissivity of 0.98).

Table 2. Photobiomodulation Therapy Parameters

k = 850 nm CW A = 7.3 cm2 4 spots
Irradiance Fluency Time Energy per Total
BMI (k/m2) n Skin phototype (mW/cm2) ( J/cm2) (min) LED ( J) energy ( J)
18.5–24.99 (3) I, II, III 60 18.0 5 5.3 526
(2) IV, V, VI 70 21.0 5 6.1 613
25–29.99 (10) I, II, III 80 28.8 6 8.4 842
(9) IV, V, VI 90 32.4 6 9.5 946
>30 (4) I, II, III 100 42.0 7 12.3 1226
(3) IV, V, VI 100 48.0 8 14.0 1402
A, area; CW, continuous wave; LED, light-emitting diodes; n, number of patients.
 Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

N oF
ot r P
fo e
r D rs
is nao

702
tri l
bu U
tio se
n/ On
Po ly
st
FIG. 2. NRS. (A) Mean – SD NRS scores of patients from both placebo and PBMT groups throughout the sessions.
in
(B) Follow-up for 4 months after the last session. Mean – SD NRS scores of patients from both placebo and PBMT
groups after last treatment. *p < 0.05 compared to first session (baseline); #p < 0.05 compared to PBMT group. (C) NRS
g
score of patients before (Pre) first PBM procedure versus final measure (Post), ***p < 0.001. ns, nonsignificant; NRS,
Numerical Rating Scale; PBM, photobiomodulation; PBMT, photobiomodulation therapy; SD, standard deviation.
 CUSTOMIZED PHOTOBIOMODULATION THERAPY 703

Baseline thermal images were obtained before the be-
ginning of the treatment and repeated at the end of the
treatment, thus obtaining the thermal profile before and after
PBMT. Thermal images were captured using the intensity of
the infrared radiation emitted in the regions of interest
(ROIs). The mean, maximum, and minimum temperatures
of different ROIs of the knees (anterior, posterior, medial,
and lateral) add up to more than 15 ROIs. The methodology
used for analysis is very similar to other studies associating
thermography with inflammatory processes in the knee.35–37
Biochemical and hormonal analysis
Tukey’s post hoc correction test was performed. For pre-
and post-intragroup analyses of serum/urine markers and
functional ability testing, a multiple comparisons two-way
ANOVA followed by Bonferroni–Dunn correction was
performed. A value of p < 0.05 was considered statistically
significant in this study and data are presented with
mean – standard deviation.
Results
Effect of PBM in the pain of knee osteoarthritis
(KOA) patients

Biochemical analysis was performed before and after Statistical analysis showed that NRS pain scores were

Po ly
g
protocol to evaluate possible alterations between pre- and significantly lower in the treatment group after the fourth
posttherapy. Patients’ blood and urine samples were col- session [F(9,225) = 9.2, p < 0.0001] (Fig. 2A). Intragroup

n/ On

in
lected 48 h before the first session and 48 h after the last analysis showed that patients assigned to the treatment group
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

session. Complete blood count, creatinine phosphokinase presented a baseline score mean of 6.2 – 2.5, decreasing to
4 – 3.1 after 4 sessions, to 3.3 – 2.4 after 5 sessions, 3.2 – 2.3

st
(CPK), erythrocyte sedimentation rate (ESR), creatinine,
serotonin, and dopamine (DA) tests were performed. after 6 sessions, 4 – 2.5 (7th sessions), 3.7 – 2.9 (8th session),
3.5 – 2.2 (9th session), and 2.9 – 2.5, after the 10th session

tio se
(*p < 0.05 compared all time points described above to
Statistical analysis
baseline). When compared to the placebo group, NRS score
GraphPad Prism version 9 (GraphPad Software Inc., San
bu U was reduced significantly in the 4th (4 – 3.1 vs. 6.6 – 2.2,
Diego, CA) was used to perform statistical analyses. Pain p < 0.05), 5th (3.3 – 2.4 vs. 6.3 – 2.1, p < 0.05), and 10th
scores data were analyzed using two-way analysis of variance (2.9 – 2.5 vs. 5.5 – 2.0, p < 0.05) sessions.
(ANOVA) with repeated measures and multiple comparisons Our results indicate that our customized dosimetry is able to
tri l
followed by Sidak-corrected post hoc test to determine pos- OA knee pain, whereas placebo treatment could not reduce
is na

sible differences between groups and pre- and posttreatment patients’ pain levels throughout the protocol; analysis of initial
measures within the same group. QOL questionnaires and and final measures of patients within the PBMT group revealed
thermography imaging data, two-way ANOVA followed by a significant reduction in subjects overall pain levels compared
o
r D rs
fo e
ot r P
N oF

FIG. 3. (A) KOOS. Mean – SD KOOS of patients from both placebo and PBMT groups before and after therapy.
Statistical significance was observed within PBMT group before and after therapy in Pain (*p < 0.05), Daily Activities
(**p < 0.01), and General Quality of Life (**p < 0.01) subscales. (B) Sit-to-Stand test and (C) Timed Up and Go test.
Mean – SD of patients from both groups, nonsignificant. KOOS, Knee Osteoarthritis Outcome Score; QOL, quality of life.
 704 PINTO ET AL.

Table 3. World Health Organization Quality of Life-Bref Questionnaire Results

Placebo (n = 15) PBMT (n = 16)
Mean – SD Mean – SD
WHOQOL-bref domains Pre Post p Pre Post p
Physical 57.2 – 12.3 61.1 – 16.4 0.8265 59.6 – 15.4 63.3 – 13.6 0.8071
Psychological 70 – 12.3 73.2 – 11.5 0.8433 74.5 – 14.1 74.8 – 15.2 0.9995
Social 73.2 – 13.4 74.1 – 17.0 0.9968 76.6 – 17.2 75.8 – 19.8 0.9985
Environmental 66.8 – 10.0 68.6 – 12.7 0.9501 71.4 – 12.6 69.8 – 15.4 0.9861
General quality of life 60 – 21.0 60 – 17.5 >0.9999 60 – 18.5 67.3 – 17.9 0.4693
PBMT, photobiomodulation therapy; WHOQOL, World Health Organization Quality of Life.

Po ly
g
to pretreatment [F(1,25) = 7.57, p < 0.001] (Fig. 2B). In addition, The variation in the thermal profile was approximate -0.06C

n/ On

in
follow-up measures (Fig. 2C) show that patients who received (F = 0.32, p = 0.570). In the PBMT group, there was a sig-
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

the PBMT remained 5 weeks with reduced pain, indicating the nificant difference between the baseline and after the last
short- to medium-term effects of PBM [F(15,390) = 8.6, treatment session. The thermal profile of anterior knees

st
p < 0.001] within the same group in the 1st week 2.2 – 2.0 vs. (average of 9 ROI) evaluated showed a greater infrared
5.3 – 1.8 ( p = 0.0067), 2nd week 2.5 – 2.1 vs. 5.8 – 2.0 radiation/heat dissipation after the treatment (increase of

tio se
( p = 0.0049), 3rd week 2.5 – 2.2 vs. 6 – 2.0 ( p = 0.0068), and 4th 0.65C in relationship to baseline, F = 44.97, p < 0.05; Fig. 5B).
week 2.9 – 2.5 vs. 6 – 1.9 ( p = 0.0326) after the last session.
bu U Discussion
Effect of PBM in QOL and mobility
Physical models of light tissue interaction demonstrate that
Correspondingly to our results, KOOS results were statis- skin color and the thickness of adipose tissue influence light
tically different [F(2.445,36.67) = 62.82] in Pain (35.2 – 11.2 distributions through the biological tissue.30,31 However, the
tri l
vs. 54.7 – 23.4), ADL (31.4 – 14.5 vs. 54.1 – 24.2), and Gen- skin phototypes and mass body indexes are not usually re-
is na

eral Quality of Life (17.9 – 8.7 vs. 34.4 – 18.9) segments pre- ported in the clinical PBMT articles, this makes difficult a
and postanalysis of treated patients ( p = 0.039, p = 0.003 and quantitative approach for PBMT customization. To overcome
p = 0.008, respectively; Fig. 3A). Analysis of pre- and post- the lack of an effective way of determining the irradiation
o

treatment scores of patients within the placebo group showed parameters, we ran a different study 2 years prior to the be-
no statistical difference (Fig. 3A). ginning of this study to standardize the customization pre-
r D rs

The WHOQOL-bref questionnaire showed no difference sented here. The customization presented here is far from
neither between initial and final measures nor between being definitive, but it is a path forward in the direction of
personalization of PBMT procedures.
fo e

groups (Table 3). Nevertheless, neither group showed im-

provement in intragroup analysis of the number of trials The clinical applications of PBM have grown in recent
ot r P

(STS) between pre- (5.6 – 2.9 and 5.6 – 3.0) and posttreat-
ments (6.0 – 3.8 and 6.5 – 3.2) or walking time (TUG) of
pre- and postanalysis (20.3 – 12.6 and 17.1 – 9.1, 19.2 – 11.2
and 18.5 – 14.3, respectively; Fig. 3B, C).
N o
years; several studies have been demonstrated its potential
analgesic effect since it has been shown to reduce proin-
flammatory factors and cytokines expression, such as inter-
leukin-1b (IL-1b), tumor necrosis factor a (TNFa), and

Prostaglandin E2.18,25,38 Moreover, the antinociceptive effect

Effect of PBM in patients’ biochemical of PBM may be associated with its effect in improving cellular
F

markers concentration microenvironment through the expression of growth factors

Notwithstanding its analgesic effect found in our results,
pre- and postmeasures biochemical analysis within the same
group did not show differences in CPK (91.6 – 47.1 vs.
91.8 – 56.4), ESR (24.4 – 26.9 vs. 23 – 22.3), serotonin
(142.2 – 101.4 vs. 99.6 – 65), and creatinine (0.809 – 0.15 vs.
0.805 – 0.16) serum values (data not shown). However, there
was an evident increase in urine levels of DA from 168.3 – 78.8
to 253 – 180.8 lg/L in the treated group ( p = 0.0878), although
not statistically significant, considering p < 0.05 (Fig. 4).

Thermography imaging profile of patients

submitted to PBMT
Pre- and posttreatment thermal profiles of the knees are
observed in Fig. 5A, and the average temperature of the ROI
of the pre- and post-knee in the different treatments are
observed in Fig. 5B. There was no difference in the placebo
group between baseline and after the last treatment session.
FIG. 4. Dopamine urine level. Mean – SD high-
performance liquid chromatography of dopamine urine
levels (lg/L) of patients from both placebo (n = 15) and
PBMT (n = 16) groups before (Pre) and after therapy (Post),
p = 0.08.
 CUSTOMIZED PHOTOBIOMODULATION THERAPY 705

FIG. 5. (A) Thermal image of knees in the

different treatments (placebo and PBMT) on
the left pretreatment (basal) and on the right
posttreatment with LEDs. (B) Thermal image
and mean – SD temperature of the knee ROIs
before and after treatment in the placebo and
PBMT groups. Statistical significance was ob-
served with the PBMT group before and after
therapy increase of 0.65C compared to base-
line, *p < 0.05. LEDs, light-emitting diodes;
ROIs, regions of interest.

Po ly
[vascular endothelial growth factor (VEGF) and fibroblast to the reduction of pain.45 Thermography showed improved

g
growth factor receptor-1 (FGFR-1), for instance], metallo- microcirculation in the irradiated areas in the PBMT group;

n/ On

in
proteinases secretion, and its property to decrease oxidative there was no change in temperature variation in the placebo
stress.5,15 In this pilot study, we observed that personalized group. Our results are in agreement with a previous study
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.

850 nm PBM treatment was able to reduce the pain scores that demonstrated an increase in temperature, suggesting

st
referred by patients, decreasing more than half of their NRS circulatory changes in patients with knee OA.21 The result
score as well as promoting a short-term analgesic effect up to 5 of the thermal profile may be associated with some increase

tio se
weeks after treatment was over. in blood circulation in this region.
It has been reported that patients living with chronic pain
may develop altered social and psychological symptoms, Conclusions
such as anxiety, depression, lack of sleep, and difficulties in
bu U
maintaining personal relationships,39 contributing to the
The present pilot study demonstrated feasibility of in-
dividualized PBMT in short- and medium-term control of
worsening of painful syndromes such as OA. Thus, it is
pain and QOL of patients with knee OA. The development
evident that improving patients’ QOL is of pivotal impor-
tri l
of a patient-customized PBMT dosage was applied twice a
is na

tance to have better treatment results. Our result indicates

week for 5 weeks, as shown by our group, could serve as
that individualized PBMT is able to improve some aspects
basis for a further definitive clinical trial, including in-
of patients’ lives, as attested by our KOOS results. It is
creased subject number to deepen our understanding and
important to note that we evaluated the isolated response of
o

validate customized-PBMT effect in bigger population

customized-PBMT in the short and medium term in both
proportions. In addition, a study comparing a fixed PBMT
pain and its impact in patients’ lives, which was not eval-
r D rs

dose with our customized-dose therapy is necessary to

uated in previous studies.
demonstrate the benefit and powerful effect of individu-
A study held by Vassão et al indicated that 808 nm PBMT
alized therapy. This new approach may provide a nonin-
fo e

associated with physical exercise was able to provide mus-

vasive treatment option for chronic patients suffering from
cle strengthening and improve mobility in OA patients.18 In
ot r P

adverse effects of drug therapy or those who are not

the present pilot study, we were unable to observe any al-
candidates for surgery.
teration in patients’ mobility through STS and TUG physical
tests, neither between pre- and postanalysis nor between
Authors’ Contributions
groups. However, a few studies have demonstrated that
N o

muscle performance is enhanced when PBMT is associated N.C.P., M.V.P.S., H.A.A., and M.C. conceived the idea for
with physical exercise and not PBM alone,40,41 suggesting the study and contributed to the design. N.C.P., N.L.F., N.A.B.,
F

that a larger trial associating our individualized PBMT with
physical exercise might be able to alter such parameters.
Interestingly, patients within the PBMT group presented
higher DA urine level when compared to placebo irradia-
tion, which may be related to a central analgesic effect. DA
is known to modulate painful perception and behavior by
activating supraspinal centers within the limbic system such
as the anterior cingulate cortex, amygdala, thalamus, and
periaqueductal gray.42–44 Our finding may indicate that the
individualized-PBM analgesic effect observed could be re-
lated to central mechanism of descending modulatory
pathways involving DA release, since studies showed that
dopaminergic neuron projections to the dorsal horn of the
spinal cord release DA and modulate inhibitory neurons,
downregulating nociceptive stimuli,42–44 although this spe-
cific mechanism requires further investigation.
Local temperature increase after PBM shown by ther-
mographic imaging in this study could be a result of a
positive effect on the microcirculation, leading, ultimately,
A.A., G.M.G.F., H.A.A., and M.C. performed screening,
quality assessment, and data extraction. N.L.F. and G.G. per-
formed data analysis. N.C.P., M.V.P.S., N.F.L., H.A.A., G.G.,
and M.C. were involved in drafting the article or revising it
critically for important intellectual content, and all authors
have read and approved the final version to be published.
Acknowledgments
The authors thank the patients, investigators, and medical
writing support. The guidance of the authors was provided
by Ana Carolina de Magalhães, PhD, Carlos Roberto Veiga
Kiffer, PhD, Gustavo Meirelles, PhD, and Thereza Cury
Fortunato, PhD.
Availability of Data and Material
The datasets generated during and/or analyzed during the
current study are available from the corresponding author on
reasonable request.
 706
Ethics Approval
All procedures were approved by the Ethics Committee
on Research of the Hospital das Clı́nicas da Faculdade de
Medicina da Universidade de São Paulo (CAAE: 93744
418.5.0000.0068).
Consent to Participate
Written informed consent was obtained from all subjects
included in the study.
Consent for Publication
Po ly
Written informed consent was obtained from all subjects
g
included in the study.
n/ On
in
Author Disclosure Statement
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.
st
N.C.P. is employee of Bright Photomedicine, and Mar-
celo Victor Pires de Sousa is shareholder of Bright Photo-
medicine.
tio se
Funding Information
This work was supported by CNPQ (Conselho Nacional
bu U
de Desenvolvimento Cientı́fico e Tecnológico—405853/
2018-1) and Bright Photomedicine.
tri l
is na
References
1. Hussain SM, Neilly DW, Baliga S, et al. Knee osteoar-
thritis: A review of management options. Scott Med J 2016;
o
61(1b):7–16; doi: 10.1177/0036933015619588.
2. Bacon K, Lavalley MP, Jafarzadeh SR, et al. Does cartilage
r D rs
loss cause pain in osteoarthritis and if so, how much? Ann
Rheum Dis 2020;79(8):1105–1110; doi: 10.1136/annrheumdis
-2020-217363.
fo e
3. Kloppenburg M, Berenbaum F. Osteoarthritis year in re-
view 2019: Epidemiology and therapy. Osteoarthr Cartil
ot r P
2020;28(3):242–248; doi: 10.1016/j.joca.2020.01.002.
4. Attur M, Zhou H, Samuels J, et al. Interleukin 1 receptor
antagonist (IL1RN) gene variants predict radiographic
severity of knee osteoarthritis and risk of incident disease.
N o
Ann Rheum Dis 2020;79:400–407; doi: 10.1136/annrheumdis
-2019-216055.
F
5. Hamblin MR. Mechanisms and mitochondrial Redox sig-
naling in photobiomodulation. Photochem Photobiol 2018;
94(2):199–212; doi: 10.1111/php.12864.
6. Hamblin MR. Mechanisms and applications of the anti-
inflammatory effects of photobiomodulation. AIMS Biophys
2017;4(3):337–361; doi: 10.3934/BIOPHY.2017.3.337.
7. Hamblin MR, Agrawal T, de Sousa MVP, (eds). Handbook of
Low-Level Laser Therapy. Jenny Stanford Publishing; 2016.
8. Tomazoni SS, Leal-Junior ECP, Frigo L, et al. Isolated and
combined effects of photobiomodulation therapy, topical
nonsteroidal anti-inflammatory drugs, and physical activity
in the treatment of osteoarthritis induced by papain.
J Biomed Opt 2016;21(10):108001; doi: 10.1117/1.jbo.21.
10.108001.
9. Bjordal JM, Ljunggren AE, Klovning A, et al. Non-steroidal
anti-inflammatory drugs, including cyclo-oxygenase-2 in-
hibitors, in osteoarthritic knee pain: Meta-analysis of rando-
mised placebo controlled trials. Br Med J 2004;329(7478):
1317–1320; doi: 10.1136/bmj.38273.626655.63.
PINTO ET AL.
10. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recom-
mendations for the management of hip and knee osteoar-
thritis, part I: Critical appraisal of existing treatment
guidelines and systematic review of current research evi-
dence. Osteoarthr Cartil 2007;15(9):981–1000; doi: 10.1016/
j.joca.2007.06.014.
11. Giannoudis P V., Hak D, Sanders D, et al. Inflammation,
bone healing, and anti-inflammatory drugs: An update.
J Orthop Trauma 2015;29:S6–S9; doi: 10.1097/BOT.0000
000000000465.
12. Wallace IJ, Worthington S, Felson DT, et al. Knee osteo-
arthritis has doubled in prevalence since the mid-20th
century. Proc Natl Acad Sci U S A 2017;114(35):9332–
9336; doi: 10.1073/pnas.1703856114.
13. Felson DT, Naimark A, Anderson J, et al. The prevalence
of knee osteoarthritis in the elderly. The Framingham Os-
teoarthritis Study. Arthritis Rheum 1987;30(8):914–918;
doi: 10.1002/art.1780300811.
14. Sah DWY, Ossipov MH, Porreca F. Neurotrophic factors as
novel therapeutics for neuropathic pain. Nat Rev Drug
Discov 2003;2(6):460–472; doi: 10.1038/nrd1107.
15. Chow RT, Armati PJ. Photobiomodulation: Implications
for anesthesia and pain relief. Photomed Laser Surg 2016;
34(12):599–609; doi: 10.1089/pho.2015.4048.
16. de Paula Gomes CAF, Leal-Junior ECP, Dibai-Filho AV,
et al. Incorporation of photobiomodulation therapy into a
therapeutic exercise program for knee osteoarthritis: A
placebo-controlled, randomized, clinical trial. Lasers Surg
Med 2018;50(8):819–828; doi: 10.1002/lsm.22939.
17. De Paula Gomes CAF, Politti F, De Souza Bacelar Pereira
C, et al. Exercise program combined with electrophysical
modalities in subjects with knee osteoarthritis: A rando-
mised, placebo-controlled clinical trial. BMC Musculoskelet
Disord 2020;21(1):258; doi: 10.1186/S12891-020-03293-3.
18. Vassão PG, de Souza MC, Silva BA, et al. Photo-
biomodulation via a cluster device associated with a
physical exercise program in the level of pain and muscle
strength in middle-aged and older women with knee oste-
oarthritis: A randomized placebo-controlled trial. Lasers
Med Sci 2020;35(1):139–148; doi: 10.1007/S10103-019-
02807-3.
19. Vassão PG, Parisi J, Penha TFC, et al. Association of
photobiomodulation therapy (PBMT) and exercises pro-
grams in pain and functional capacity of patients with knee
osteoarthritis (KOA): A systematic review of randomized
trials. Lasers Med Sci 2021;36:1341–1353; doi: 10.1007/
s10103-020-03223-8.
20. Alqualo-Costa R, Rampazo ÉP, Thome GR, et al. Inter-
ferential current and photobiomodulation in knee osteoar-
thritis: A randomized, placebo-controlled, double-blind
clinical trial. Clin Rehabil 2021;35(10):1413–1427; doi:
10.1177/02692155211012004.
21. Hegedus B, Viharos L, Gervain M, et al. The effect of low-
level laser in knee osteoarthritis: A double-blind, random-
ized, placebo-controlled trial. Photomed Laser Surg 2009;
27(4):577–584; doi: 10.1089/pho.2008.2297.
22. Stausholm MB, Naterstad IF, Joensen J, et al. Efficacy of
low-level laser therapy on pain and disability in knee os-
teoarthritis: Systematic review and meta-analysis of ran-
domised placebo-controlled trials. BMJ Open 2019;9(10):
e031142; doi: 10.1136/bmjopen-2019-031142.
23. Laakso EL. Personalizing photobiomodulation therapy.
Photomed Laser Surg 2017;35(1):1–2; doi: 10.1089/pho.
2016.4218.
 CUSTOMIZED PHOTOBIOMODULATION THERAPY
24. Langella LG, Casalechi HL, Tomazoni SS, et al. Photo-
biomodulation therapy (PBMT) on acute pain and inflam-
mation in patients who underwent total hip arthroplasty—
A randomized, triple-blind, placebo-controlled clinical
trial. Lasers Med Sci 2018;33(9):1933–1940; doi: 10.1007/
s10103-018-2558-x.
25. Da Silva Leal MV, Lima MO, Nicolau RA, et al. Effect of
modified laser transcutaneous irradiation on pain and
quality of life in patients with diabetic neuropathy. Photo-
biomodul Photomed Laser Surg 2020;38(3):138–144; doi:
10.1089/photob.2019.4714.
26. da Silva MM, Albertini R, de Tarso Camillo de Carvalho P,
et al. Randomized, blinded, controlled trial on effectiveness
of photobiomodulation therapy and exercise training in the
Po ly
g
fibromyalgia treatment. Lasers Med Sci 2018;33(2):343–
351; doi: 10.1007/s10103-017-2388-2.
n/ On
in
27. Oliveira CG, Freitas MF, De Sousa MVP, et al. Photo-
Downloaded by Mary Ann Liebert, Inc., publishers from www.liebertpub.com at 10/31/22. For personal use only.
biomodulation reduces nociception and edema in a CFA-
induced muscle pain model: Effects of LLLT and LEDT.
st
Photochem Photobiol Sci 2020;19(10):1392–1401; doi: 10
.1039/D0PP00037J.
tio se
28. de Freitas Rodrigues A, de Oliveira Martins D, Chacur M,
et al. The effectiveness of photobiomodulation in the
management of temporomandibular pain sensitivity in rats:
Behavioral and neurochemical effects. Lasers Med Sci
bu U
2020;35(2):447–453; doi: 10.1007/S10103-019-02842-0.
29. de Oliveira ME, Da Silva JT, Brioschi ML, et al. Effects of
photobiomodulation therapy on neuropathic pain in rats:
tri l
Evaluation of nociceptive mediators and infrared ther-
is na
mography. Lasers Med Sci 2021;36(7):1461–1467; doi:
10.1007/S10103-020-03187-9.
30. Souza-Barros L, Dhaidan G, Maunula M, et al. Skin color
o
and tissue thickness effects on transmittance, reflectance,
and skin temperature when using 635 and 808 nm lasers in
r D rs
low intensity therapeutics. Lasers Surg Med 2018;50(4):
291–301; doi: 10.1002/lsm.22760.
31. Bashkatov AN, Genina ÉA, Kochubey VI, et al. Optical
fo e
properties of the subcutaneous adipose tissue in the spectral
range 400–2500 nm. Opt Spectrosc 2005 995 2005;99(5):
ot r P
836–842; doi: 10.1134/1.2135863.
32. Palamoni OP, Magalhães AC de, Moriyama LT, et al.
Monte Carlo simulations to study light propagation through
the skin of different phototypes. Proc SPIE Tissue Opt
N o
Photon II 2022;12147:28–34; doi: 10.1117/12.2621670.
33. Roos EM, Toksvig-Larsen S. Knee Injury and Osteoar-
F
thritis Outcome Score (KOOS)—Validation and Com-
parison to the WOMAC in total knee replacement. Health
Qual Life Outcomes 2003;1:17; doi: 10.1186/1477-7525-
1-17.
34. Harper A, Power M, Orley J, et al. Development of the
World Health Organization WHOQOL-BREF Quality of
Life Assessment. Psychol Med 1998;28(3):551–558; doi:
10.1017/S0033291798006667.
35. Spalding SJ, Kent CK, Boudreau R, et al. Three-
dimensional and thermal surface imaging produces reliable
measures of joint shape and temperature: A potential tool
for quantifying arthritis. Arthritis Res Ther 2008;10(1):
R10; doi: 10.1186/ar2360.
707
36. Denoble AE, Hall N, Pieper CF, et al. Patellar skin surface
temperature by thermography reflects knee osteoarthritis
severity. Clin Med Insights Arthritis Musculoskelet Disord
2010;3:69–75; doi: 10.4137/CMAMD.S5916.
37. Lasanen R, Piippo-Savolainen E, Remes-Pakarinen T, et al.
Thermal imaging in screening of joint inflammation and
rheumatoid arthritis in children. Physiol Meas 2015;36(2):
273–282; doi: 10.1088/0967-3334/36/2/273.
38. de Sousa MVP, Kawakubo M, Ferraresi C, et al. Pain
management using photobiomodulation: mechanisms, lo-
cation, and repeatability quantified by pain threshold and
neural biomarkers in mice. J Biophotonics 2018;11(7):
e201700370; doi: 10.1002/jbio.201700370.
39. Hylands-White N, Duarte RV, Raphael JH. An overview of
treatment approaches for chronic pain management. Rheu-
matol Int 2017;37(1):29–42; doi: 10.1007/s00296-016-3481-8.
40. Ferraresi C, De Brito Oliveira T, De Oliveira Zafalon L,
et al. Effects of low level laser therapy (808 nm) on phys-
ical strength training in humans. Lasers Med Sci 2011;
26(3):349–358; doi: 10.1007/s10103-010-0855-0.
41. Fritsch CG, Dornelles MP, Teodoro JL, et al. Effects of
photobiomodulation therapy associated with resistance
training in elderly men: A randomized double-blinded
placebo-controlled trial. Eur J Appl Physiol 2019;119(3):
279–289; doi: 10.1007/s00421-018-4023-8.
42. Wood PB. Role of central dopamine in pain and analgesia.
Expert Rev Neurother 2008;8(5):781–797; doi: 10.1586/
14737175.8.5.781.
43. Treister R, Pud D, Ebstein RP, et al. Association between
polymorphisms in serotonin and dopamine-related genes
and endogenous pain modulation. J Pain 2011;12(8):875–
883; doi: 10.1016/j.jpain.2011.02.348.
44. Viisanen H, Ansah OB, Pertovaara A. The role of the do-
pamine D2 receptor in descending control of pain induced
by motor cortex stimulation in the neuropathic rat. Brain
Res Bull 2012;89(3–4):133–143; doi: 10.1016/j.brainres-
bull.2012.08.002.
45. Min S, Lee H, Kim SY, et al. Local changes in microcir-
culation and the analgesic effects of acupuncture: A laser
Doppler perfusion imaging study. J Altern Complement
Med 2015;21(1):46–52; doi: 10.1089/acm.2013.0442.
Address correspondence to:
Marucia Chacur, PhD
Departamento de Anatomia
Laboratório de Neuroanatomia Funcional da Dor
Instituto de Ciências Biomédicas
Universidade de São Paulo
2415 Prof. Lineu Prestes Ave
São Paulo 05508-000
Brazil
E-mail: chacurm@icb.usp.br
Received: June 19, 2022.
Accepted after revision: July 30, 2022.
Published online: October 10, 2022.