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\begin{document}

\title{Effect of Vascular Photobiomodulation in a patient with severe
xerostomia: Clinical case report}



\author[1]{Ana Carolina Santos Menezes Barros}%
\author[1]{Ana Julia Lacerda}%
\author[1]{Anna Carolina  Horliana}%
\author[1]{Cinthya Cosme Gutierrez Duran}%
\author[1]{Bussadori SK}%
\author[1]{Lara Jansiski Motta}%
\affil[1]{Universidade Nove de Julho - Campus Vergueiro}%


\vspace{-1em}



  
  \date{June 13, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Fluoxetine is a widespread antidepressant medication, with side effects,
including xerostomia. In search of treatments to reduce discomfort, PBM
is one of the alternatives that has proven to be effective. This article
aims to demonstrate the clinical evolution of a female patient, L.R.O.,
55 years old, who reported severe oral discomfort due to lack of saliva.
The selected treatment was the Low Power Laser - EccoFibras with
vascular photobiomodulation, in radial artery for 30 minutes, wavelength
660nm and power of 100mW, with 180J energy delivery. After the first
treatment session, the patient reported improvement and satisfaction
and, due to the unpredictability of psychiatric discharge, she tried to
perform weekly applications. With each session, she reported a decrease
in symptoms, which encouraged her attendance. With the prevention of
xerostomia, the pacient achieved a clear increase in her quality of
life, demonstrating that vascular photobiomodulation can be an
interesting low-cost non-invasive treatment.%
\end{abstract}%



\sloppy


\textbf{Effect of Vascular Photobiomodulation in a patient with severe
xerostomia: Clinical case report}

Barros, ACSM\selectlanguage{ngerman}¹; Lacerda, AJ¹; Horliana, ACRT¹; Duran CC¹; Bussadori, SK¹;
Motta, LJ¹.

Universidade Nove de Julho -- Programa de Pós Graduação em Medicina
Biofotônica

\textbf{ABSTRACT}

Fluoxetine is a widespread antidepressant medication, with side effects,
including xerostomia. In search of treatments to reduce discomfort, PBM
is one of the alternatives that has proven to be effective. This article
aims to demonstrate the clinical evolution of a female patient, L.R.O.,
55 years old, who reported severe oral discomfort due to lack of saliva.
The selected treatment was the Low Power Laser - EccoFibras with
vascular photobiomodulation, in radial artery for 30 minutes, wavelength
660nm and power of 100mW, with 180J energy delivery. After the first
treatment session, the patient reported improvement and satisfaction
and, due to the unpredictability of psychiatric discharge, she tried to
perform weekly applications. With each session, she reported a decrease
in symptoms, which encouraged her attendance. With the prevention of
xerostomia, the pacient achieved a clear increase in her quality of
life, demonstrating that vascular photobiomodulation can be an
interesting low-cost non-invasive treatment.

KEYWORDS: xerostomia, photobiomodulation, laser therapy, side effects.

Abbreviations: ATP: adenosine triphosphate; PBM: photobiomodulation;
LLLT: low level light therapy; ROS: reactive oxygen species; nm:
nanometers; mW: milliwatts; mL: milliliters; min: minutes; J: Joules;
LASER: light amplification by stimulated emission of radiation;

\textbf{INTRODUÇÃO}

Total saliva is a complex of secretions that come in part from the pairs
of parotid, submandibular and sublingual glands, and in part from
numerous minor salivary glands distributed in the oral mucosa (Mese,
2007). In the mouth, this compound is formed by gingival fluid,
desquamated epithelial cells, microorganisms, products of bacterial
metabolism, food residues, leukocytes, mucus from the nasal cavity and
pharynx. Saliva has several functions, including tissue repair,
buffering, protection, digestion, taste, antimicrobial action,
maintenance of tooth integrity and antioxidant defense system. (Falcão,
2013).

Saliva, as the first digestive fluid in the alimentary canal, assists in
the ingestion of food and the digestion of starch and lipids, acting as
a solvent. Saliva also plays a crucial role in hydrating and maintaining
the taste receptor and oral mucosa and protecting the teeth.
Furthermore, saliva controls oral microflora with its antimicrobial
properties and mechanical cleaning action. Therefore, the loss of
salivary function can have several serious consequences (Abueva, 2022).

The ``unstimulated'' flow is approximately 0.3 to 0.4mL/min but with
wide variation between subjects and is sustained presumably by minor
reflex activity and central nervous system activity since the flow of
saliva decreases during sleep to around 0.1mL/min (Proctor, 2021).
However, the speed at which saliva reaches the mouth shows great
variation between individuals (Proctor, 2016). Parasympathetic
stimulation results in increased saliva secretion through cholinergic
transmission and action on M3 muscarinic receptors, while sympathetic
stimulation alters salivary protein content through noradrenergic
transmission and action on \selectlanguage{greek}α \selectlanguage{english}and \selectlanguage{greek}β \selectlanguage{english}receptors (de Almeida, 2008).

Several factors are capable of altering salivary flow. Such changes may
vary from individual to individual, and in the same individual under
different circumstances. Body hydration, tobacco use, medication use,
saliva stimulation, some illnesses, among other factors, are capable of
generating changes in salivary production. (Almeida, 2008). Complaints
of dry mouth occur when there is insufficient production of saliva or
changes in its composition. Dry mouth is called xerostomia, and one of
the most common causes is due to the side effect of medications (Scully,
2003).

Drug-induced hyposalivation also can be an extension of the drug's
intended action, as seen with the parasympatholytic agents (such as
atropine), or as an anticholinergic side effect withdrugs such as
tricyclic antidepressant (Guggenheimer, 2008). Hyposalivation is a
condition that can be very debilitating for patients and is likely to be
increasingly common, so dentists should be aware of its diagnosis and
treatment. (Mese, 2007)

Medications with anticholinergic activity can cause hyposalivation by
decreasing acetylcholine released by the parasympathetic system (Turner,
2016). Both the parasympathetic and sympathetic nervous systems
innervate the salivary glands (Guggenheimer, 2008). SNRIs are believed
to produce central accumulation of norepinephrine, activation of \selectlanguage{greek}α\selectlanguage{english}2
receptors, and inhibition of parasympathetic salivary neurons in the
brainstem, resulting in decreased salivary secretion. (Proctor, 2016).

Salivary dysfunction may be accompanied by symptoms of dry mouth, called
xerostomia. The presence of xerostomia is not predictive of
hyposalivation, as both conditions can manifest independently. However,
the greater the hyposalivation, the greater the patient's tendency to
present xerostomia (Pedersen, 2018). Reduced salivary flow is a common
disorder, and it is estimated that around 20\% of the general population
has this change. (Falc\selectlanguage{ngerman}ão, 2013).

According to the World Health Organization (2017), mental disorders are
common and contribute to morbidity, disability, injuries and premature
mortality and increasing the risk and involvement of other health
conditions. Worldwide, it is estimated that more than 300 million
people, of all ages, suffer from depression, equivalent to 4.4\% of the
world population, being more prevalent among women.

Psychiatric medications can cause side effects with repercussions on the
stomatognathic system, such as hyposalivation (Kossioni, 2013). Patients
who use medication for a long time experience side effects with
repercussions on the oral cavity, for example, on the salivary glands,
altering the flow and composition of saliva (de Ameida, 2012). It is
worth mentioning that side effects represent one of the main reasons for
discontinuing treatments (Bull, 2002).

A study analyzed medications and observed ten out of 15 antidepressants
showed significantly higher rates of short-term dry mouth than placebo,
with the following decreasing order of incidence: duloxetine,
desvenlafaxine, reboxetine, venlafaxine, sertraline, bupropion,
paroxetine, escitalopram, levomilnacipran and fluvoxamine. Five out of
15 antidepressants (agomelatine, citalopram, fluoxetine, mirtazapine and
vortioxetine) did not differ from placebo in terms of dry mouth rates
(Oliva, 2021). In another bibliographic survey it was reported fifty-six
medications showed strong evidence of interference with the function of
the salivary glands, thirty-six of which belonged to the main nervous
system category of the ATC (Anatomical Therapeutic Chemical), and the
most cited in the literature are oxybutynin (21 articles), tolterodine
(19 ), duloxetine (19), quetiapine (14), bupropion (12), olanzapine
(11), solifenacin (11), clozapine (9), fluoxetine (9) and venlafaxine
(8) (Wolff, 2017).

Fluoxetine is an effective antidepressant when administered in dosages
of 20 to 80 mg per day (60 to 80 mg being clinically usual) for patients
with unipolar depression (Benfield, 1986). The approved dose range is up
to 80 mg/day, and when higher doses are used, adverse events are more
common (Wernicke, 2004). Adverse events commonly associated with the
initiation of fluoxetine therapy tended to decrease, and no adverse
events reported initially became more frequent at the end of therapy
(Zajecka, 1999). Dysgeusia has been reported following administration of
fluoxetine (Wolff, 2017).

Clinical signs of dry mouth, identified during a physical examination,
include glossy oral mucosa, altered gingiva, fissured tongue or loss of
lingual papillae, and foamy saliva. Once a diagnosis is made and an
underlying etiology is identified, there are many therapeutic options
for management that can help alleviate the clinical manifestations of
xerostomia (Millsop, 2017).

The theory of stimulated emission was first described by Einstein in
1917. The word LASER is the acronym for ``Light Amplification by
Stimulated Emission of Radiation'' (Genovese, 2007).

The mechanisms involved in the treatment of PBM are not yet completely
understood. However, the main idea is that photons are absorbed by the
target tissue, converting them into useful energy that enhances
metabolic processes in the cell, such as increased ATP production and
the production of reactive oxygen species (ROS) (Sousa, 2019).

Low-power laser light therapy has been shown to be effective in the
treatment of the most diverse conditions or diseases, as it promotes
biomodulation of cellular metabolism, analgesia and anti-inflammatory
effects, without mutagenic and photothermal effects (Gonelli, 2016). Its
effects are based on transforming laser light into biomodulatory energy
(Saleh, 2014).

The photobiomodulation effect depends on the number of absorbed photons
which is correlated to the wavelength, the photon delivery rate (power)
and the correct selection of spectrum and time parameters (Schubert,
2007). There is some research on the use of photobiomodulation to
recover salivary glands and increase salivary flow. However, there is
great variability between studies according to the photobiomodulation
light parameters used and therefore results are rarely comparable
(Golez, 2022). The wavelength used in low-level laser therapy is not
fixed, so it is worth studying the laser equipment and defining the
wavelength indicated for therapeutic efficacy. (Xu, 2015).

Photobiomodulation, previously called low-intensity light therapy
(LLLT), is a method in which radiation power is generally between 0.05
and 0.5 W to avoid thermal or cytotoxic effects on tissue (Huang 2009,
Sousa 2019). Low-power laser is an efficient agent for attenuating
salivary hypofunction (Gonelli, 2016).

Laser and LED light induce a photobiomodulation (PBM) effect that is
used to accelerate healing by increasing cell viability by stimulating
ATP synthesis by mitochondrial photoreceptors and the cell membrane
(Dompe, 2020). Wavelength of 810 nm can be absorbed by the chromophore
cytochrome c-oxidase and other chromophores to improve mitochondrial
activity. The cytochrome c-oxidase activity increases the accumulation
of mitochondrial activity, which leads to greater ATP production. (Wang,
2017)

Studies have shown that photobiomodulation has been widely used to
improve the functionality of the major salivary glands, as well as
salivary flow. Different in vivo protocols react differently to light
depending on various radiometric parameters and systemic condition
(Loncar, 2011; Fidelix, 2018)

Despite different photobiomodulation methods, it is known that modified
ILIB (Intravascular Laser Irradiation Blod) therapy has been studied
since 1981 by Soviet scientists (Karu, 1998). The proposal with ILIB was
the control of cardiovascular physiology, through the delivery of red
laser therapy (660nm), through an optical fiber in the arteries or
vessels, crossing the skin and introducing it into the blood vessel to,
there, deposit the irradiation of a laser with 3 to 5mW of power for 20
to 30 minutes. Researchers realized in 1981 that in the heart attack
area, sudden deaths decreased, because red laser therapy had probably
photo-switched off nitric oxide from hemoglobin molecules and thus
induced relaxation of the vessel walls and improved blood flow and
tissue oximetry. The wavelength chosen for intravenous irradiation will
influence the benefits reaped. Irradiation in the infrared spectrum
(above 800 nm) accelerated the release of oxygen, while wavelengths
between 630-670 nm promoted improvement in the transport of oxygen from
the blood (Xu, 2015).

The change in the name of ILIB to Vascular Systemic Photobiomodulation
(Hamblin, 2016), is more suitable for the process where light sources,
lasers or LEDs, are used to deposit photonic energies, previously
determined, on the skin, in the place where large blood vessels
(arteries or veins) have their greatest projection towards the skin, and
then evolving towards transmucosal applications, where we find a large
concentration of blood vessels, that is, in the intranasal region and/or
the mouth floor -- sublingual.

Vascular photobiomodulation therapy promotes the absorption of red
wavelength light by the blood, causing an increase in metabolism and
synthesis of the enzyme superoxide dismutase, the main physiological
protein regulating the body's oxidative system. Superoxide dismutase
inhibits the action of reactive oxygen species (ROS), leads to the
protection of cells against mutations by fighting free radicals.
Therefore, the therapy aims at the functional recovery of the
antioxidant enzymatic system, maintaining the balance of the organism as
a whole, providing functional optimization of each system (Chamusca,
2012).

PBM to stimulate salivary production by the glands is not yet a
consensus in the literature (Sousa, 2019), however there are already
studies that report a significant increase (Gonelli 2016; Saleh, 2014,
Loncar, 2011), and PBM in the salivary glands is safe, well tolerated
and there are no reports of incidents or deleterious effects of the
therapy (Sousa, 2019).

Furthermore, vascular photobiomodulation directly or indirectly affects
an organism's immune cells, hormones, and metabolic processes, thereby
improving not only the function of the vascular system, but also the
body's other systems (Mikhaylov 2015).

One of the side effects of medications indicated for psychiatric
treatment is hyposalivation or xerostomia. In search of treatments to
reduce discomfort, PBM is one of the alternatives that has proven to be
effective. This article aims to demonstrate the clinical improvement of
a patient with severe xerostomia after treatment with vascular PBM, so
that further studies in the area are possible and dosimetric parameters
are defined.

\textbf{CASE REPORT AND DISCUSSION}

Patient L.R.M.O., female, 55 years old, sought care reporting intense
dry mouth. The patient reported that she always had the symptom of
xerostomia, but the condition worsened after undergoing psychiatric
treatment with the combination of the drug Fluoxetine Hydrochloride
20mg. The patient was already using the drugs daily: Simvastatin 20mg
and Fenofibrate 200mg. When contacting the Postgraduate Program in
Medicine -- Biophotonics, at Nove de Julho University, the patient was
referred to the clinical trial: ``Effect of photobiomodulation on flow,
pH and salivary immunoglobulin level in individuals with xerostomia:
controlled clinical trial and randomized''. Etthics Committee - number:
5.305.375

The participant was instructed to swallow before collection and then
instructed not to swallow, allowing the saliva to flow between the lips
(which will be separated) into a test tube (aspirator) connected to a 15
mL Flacon tube positioned close to the mouth (Navazesh,
Christensen,1982). Collection time was 5 minutes. Saliva volume was
measured and salivary flow rate determined (mL/min) (Vieira, 2018). An
aliquot (1 mL) of saliva was immediately transferred to a small tube
(capacity: 5 mL) and a pH meter (Procyon 720 A, Procyon, São Paulo,
Brazil) was used (Garcia, 2009; Vieira, 2018).

During the clinical examination, no oral and/or dental changes were
observed that could compromise the smooth progress of the treatment. A
specific anamnesis was taken and a questionnaire on xerostomia was
administered (Table 1), in which the patient scored 28. The patient was
then selected through a randomizer.org draw for group B.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
XEROSTOMIA & XEROSTOMIA & XEROSTOMIA & XEROSTOMIA &
XEROSTOMIA\tabularnewline
Questions: & Questions: & never & sometimes & always\tabularnewline
1 & Do you drink some liquid to help swallow the food? & &
&\tabularnewline
2 & Do you feel your mouth is dry during meals? & & &\tabularnewline
3 & Do you get up at night to take liquids? & & &\tabularnewline
4 & Do you feel dry mouth? & & &\tabularnewline
5 & Do you have difficulty eating dry foods? & & &\tabularnewline
6 & Do you eat candy or treats to relieve dry mouth? & &
&\tabularnewline
7 & Do you have difficulty swallowing certain foods? & &
&\tabularnewline
8 & Does your face feel dry? & & &\tabularnewline
9 & Do your eyes feel dry? & & &\tabularnewline
10 & Do your lips feel dry? & & &\tabularnewline
11 & Does the inside of your nose feel dry? & & &\tabularnewline
SCORE: & SCORE: & SCORE: & SCORE: & SCORE:\tabularnewline
ANSWER OPTIONS: NEVER = 1; SOMETIMES = 2; ALWAYS = 3. & ANSWER OPTIONS:
NEVER = 1; SOMETIMES = 2; ALWAYS = 3. & ANSWER OPTIONS: NEVER = 1;
SOMETIMES = 2; ALWAYS = 3. & ANSWER OPTIONS: NEVER = 1; SOMETIMES = 2;
ALWAYS = 3. & ANSWER OPTIONS: NEVER = 1; SOMETIMES = 2; ALWAYS =
3.\tabularnewline
\bottomrule
\end{longtable}

Table 1 -- Xerostomia Questionnaire

The therapeutic protocol to perform photobiomodulation was defined as:
Diode laser (EccoFibras\selectlanguage{ngerman}®, Campinas, Brazil), with a beam area of
approximately 0.04 cm2, wavelength of 660nm and power of 100mW,
delivering energy of 180J for 1800 seconds at a single irradiation point
in contact with the patient's wrist (Figure 1).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1 -- ILIB in position for vascular photobiomodulation
enforcement.

After collecting samples for the first phase and a single session of
vascular photobiomodulation, the patient got in touch reporting an
improvement in the xerostomia symptom for up to 5-7 days and expressing
her interest in continuing the experimental treatment.

The first irradiation and collect was in 08/03/2023, subsequently, the
patient then underwent PBM on the following days: 08/03, 15/03, 22/03,
29/03, 11/04, 18/04, 28/04, 03/05, 10/05, 19/05, 25/05, 01/06 e 07/06.

Pre-irradiation salivary collect were performed to quantify the
cumulative effect of the benefit of vascular photobiomodulation.\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Collection Day & Flow (ml) & pH\tabularnewline
\midrule
\endhead
08/03 pre-irradiation & 0,2 & not possible to measure\tabularnewline
08/03 immediate post irradiation & 0,9 & 7\tabularnewline
08/03 30 min post Irradiation & 0,9 & 7\tabularnewline
15/03 after 7 days & 1 & 7\tabularnewline
18/04 pre-irradiation & 1 & 7\tabularnewline
10/05 pre-irradiation & 1,2 & 7\tabularnewline
\bottomrule
\end{longtable}

Tabela 2 -- Salivary Sampling.

The parameters used in photobiomodulation are important to achieve the
expected result. In the present report, the patient showed improvement
in symptoms with vascular photobiomodulation at the red wavelength
(660nm), although infrared in direct local application under the
salivary glands is usually indicated in cases of xerostomia. This result
is in agreement with studies that demonstrated the systemic action of
vascular photobiomodulation (Lizarelli, 2023; Mikhaylov, 2015).

Further to the wavelength, other parameters are important such as the
power, which was 100mW, the energy per point which was 180J and the
equipment beam area (0.04 cm\selectlanguage{ngerman}²). It's important to note that all
parameters must be informed so that clinicians and readers know exactly
what treatment was performed and that, if they so wish, they can
reproduce the same protocol with their patient. The number of
irradiations must also be questioned. There are no reports in the
literature in which the effect of the benefit of photobiomodulation is
sustained for more than 7-10 days, however the ideal minimum interval
time still needs to be defined (Abueva, 2022; Sousa 2019; Brzak, 2018).

Many authors report in their studies a reduction in xerostomia and an
improvement in salivary flow, pH, IgA content and saliva buffering
capacity. Some studies claim that PBM is able to regenerate salivary
gland tissue (Plavnik, 2003A review suggests the effectiveness of PBM in
the treatment of xerostomia (Sousa, 2019). A study in humans observed
the effects of PBM on salivary glands of patients with xerostomia, where
the authors used different parameters, infrared laser \selectlanguage{greek}λ \selectlanguage{english}= 830 nm and red
laser \selectlanguage{greek}λ \selectlanguage{english}= 685 nm, and found an improvement in flow in both, being even
better in patients treated with \selectlanguage{greek}λ \selectlanguage{english}= 830 nm, this effect was observed in
the long term, suggesting a regenerative effect on the salivary glands
(Brzak, 2018). However, there is not enough evidence to support the
claim of a cumulative or regenerative effect of PBM in a general sense,
as studies were carried out on few patients or without control groups
(Golez, 2022).

Close communication between the dentist (who has to deal with adverse
effects) and the prescribing physician is necessary to obtain the best
outcome for the patient (Wolff, 2017). Although xerostomia was a
commonly reported outcome, objectively measured salivary flow rate was
rarely reported. Furthermore, xerostomia was assessed primarily as an
adverse effect rather than the primary outcome of medication use.
(Wolff, 2017).

In this clinical case presented, the patient's psychiatric treatment is
not expected to end, so the protocol is now applied in a preventive
manner and not just to cure the symptoms. Studies have observed a
cumulative effect of salivary gland repair when locally irradiated. With
the prevention of xerostomia, the patient achieved a clear increase in
her quality of life, reported by herself with the following words:

``Dry mouth can't be resolved even with water, but the laser has
improved it a lot. I stayed really well for a week, I was fine for
several days, so much so that I couldn't wait to do it again, because I
was feeling good and wanted to stay well''.

At each session, the patient reported a reduction in symptoms, which
encouraged her to attend, as she noticed that she no longer needed to
wake up to drink water. With the prevention of xerostomia, the patient
achieved a clear increase in her quality of life, demonstrating that
vascular photobiomodulation can be an interesting low-cost non-invasive
treatment.

The effect of laser exposure was demonstrated not only in fluids
subjected to direct irradiation, but also in fluids from organs located
far from the irradiation zone, providing evidence of one of the
potential mechanisms behind the proven systemic effect of PBM
(Mikhaylov, 2015).

In a systematic review, it can be concluded that there is sufficient
evidence about the beneficial effect of PBM on unstimulated salivary
flow and other salivary parameters. However, there is not enough
evidence to prove that the effects of PBM are long-lasting enough to
improve patients' quality of life (Golez, 2022).

It was observed that laser therapy has good acceptance in the dental
field, where it has been widely used in xerostomy conditions, due to its
positive tissue biomodulation effects (Loncar, 2011). The advantages of
PBM known to date include improvement in epithelial cell mitosis,
enlargement of salivary ducts and stimulation of protein synthesis in
submandibular glands (Abueva, 2022), in addition to low-intensity laser
therapy being effective in reducing mucosal inflammation. oral, being
important in the treatment of hyposalivation (Oliveira, 2022).

\textbf{CONCLUSION}

Based on the protocol used in this clinical case, PBM was effective in
treating the symptoms of medicinal xerostomia, increasing the quality of
life of the patient undergoing psychiatric treatment using the
medication Fluoxetine. Although the field is still under construction,
evidence from clinical experiences can build an important track record
of applications. However, further studies in the form of randomized
controlled clinical trials with adequate samples are needed to confirm
the findings of this case report, and in vitro studies are needed to
evaluate the exact mechanism involved in PBM and salivary glands.

\textbf{ACKNOWLEDGEMENTS}

We would like to thank the Postgraduate Program in Medicine -
Biophotonics for the support with the patient and the financial support
from the Coordination for the Improvement of Higher Education
Personnel---Brazil (CAPES) - Finance Code 001.

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