Photobiomodulation as a Therapeutic Strategy in Burning Mouth Syndrome: A Scoping Review

: Burning mouth syndrome (BMS) is considered an atypical oral clinical-symptomatological condition because its etiopathogenesis is not yet fully clariﬁed. It is mainly characterized by the symptom of burning, which occurs chronically and with various intensities. It is essential for making a diagnosis of BMS, clinical negativities, and instrumental investigations. It mainly affects the female sex, in the pre-post-climactic phases. A peripheral neuropathic matrix of the pain symptoms has been repeatedly demonstrated. However, this subjectivity is associated with personalities with anxiety-depressive traits, affective-behavioral difﬁculties, and disorders of the psycho-algogenic sphere. Numerous treatments are reported in the literature, which have rarely met lasting healing parameters. In this clinical landscape, photobiomodulation therapy (PBMT) can be considered a possible therapeutic alternative. Our study aims to present a scoping review of how photobiomodulation is used in BMS therapy and to analyze the outcome of the therapy. A literature review focused on the photobiomodulation treatment for burning mouth syndrome was conducted in the main scientiﬁc databases: PubMed, SCOPUS, and Web of Science. The results of our research highlight encouraging results regarding photobiomodulation, as in all studies, there is a reduction in symptoms.


Introduction
Burning mouth syndrome (BMS) is categorized as an idiopathic oral condition due to its yet-to-be-fully-understood etiology and pathogenesis, along with its atypical symptomatology and clinical characteristics [1][2][3]. In 1994, the International Association for the Study of Pain (IASP) identified three distinct groups of chronic oral and facial pain with neurogenic, vascular, and idiopathic origins.
Subsequently, the Headache Classification Committee of the International Headache Society (IHS) in 2013 and 2018, along with the International Classification of Orofacial Pain (ICOP) in 2020, defined BMS as "Intraoral burning or dysaesthesia sensation, recurring daily for more than 2 h per day over more than 3 months, without clinically evident causative lesions". A diagnosis of BMS is confirmed when individuals report oral burning symptoms without any observable clinical signs, and diagnostic investigations reveal a normal condition [2][3][4].
When oral symptomatology has a definable local and systemic cause, and locally there are clinical signs or instrumental tests that testify to a disease, it is correct to speak of secondary BMS [5,6].

Results
The primary search identified 186 articles based on MeSH terms. Following this, 160 articles were removed (5 abstracts of articles published in non-English languages, 98 duplicates, and 57 because they were not pertinent), and 26 articles were screened based on title and abstracts. The remaining 15 full-text articles were assessed for eligibility. Additionally, 4 full-text articles were further excluded because they were irrelevant articles. The 11 relevant articles were finally included and analyzed in this review. The flow chart of the review process is described in Figure 1.

Risk of Bias
The JBI critical appraisal tool was applied to assess the risk of bias in the studies included in this review (Table 1), using the judging criteria for risk of bias shown in Table S3 (Supplementary Materials). Table 1. The risk of bias in randomized controlled trials is represented by symbols (green for low risk of bias, yellow for high risk of bias, and blue for uncertain or unavailable data and medium risk of bias). Q1  Q2  Q3  Q4  Q5  Q6  Q7  Q8  Q9  Q10  Q11  Q12  Q13 Overall Appraisal Bardellini et al., 2019 [52] 6 of 15 le 1. The risk of bias in randomized controlled trials is represented by symbols (green for low risk of bias, yellow for high risk of bias, and blue for uncertain navailable data and medium risk of bias).     [52] e Pedro et al., 2020 [53] Hanna et al., 2022 [54] ončar-Brzak et al., 2022 [55] cardina et al., 2020 [56] ora et al., 2018 [57] panemberg al. 2015 [58] Sugaya et al., 2016 [59] un et al., 2021 [60] rduino et al., 2016 [61] lenzuela et al., 2017 [62] Appl. Sci. 2023, 13, x FOR PEER REVIEW 6 of 15                            Table 1. The risk of bias in randomized controlled trials is represented by symbols (green for low risk of bias, yellow for high risk of bias, and blue for uncertain or unavailable data and medium risk of bias

Risk of Bias
The JBI critical appraisal tool was applied to assess the risk of bias in the studies included in this review (Table 1), using the judging criteria for risk of bias shown in Table S3 (Supplementary Materials).

Discussion
The response to treatment in patients with primary BMS is influenced by various pathological factors, including neuropathic components, central vulnerability, and psychiatric comorbidity. These problems are often intricate and interconnected, and addressing them requires a comprehensive approach rather than relying on a single therapy [50]. Like other neuropathic pain conditions, BMS poses challenges in treatment. On average, only 40% of patients experience benefits from their current neuropathic pain medications [51].
Another issue related to BMS treatment is the lack of consistent and continuous medication usage. While psychotropic medications show effectiveness in BMS treatment, approximately 15% of patients discontinue their medication. Implementing motivational interviewing can enhance appropriate adherence to medication [52,53]. Often, a combination of medications is recommended, along with treatments utilized for other neuropathic pain conditions [52,53]. Tricyclic antidepressants such as amitriptyline and clomipramine have been tried for BMS, with only 19% of patients reporting very poor outcomes and side effects such as dry mouth [54,55]. Antidepressants belonging to the group of selective serotonin reuptake inhibitors (SSRIs) such as chlordiazepoxide, diazepam, amisulpride, paroxetine, or sertraline hydrochloride have also been recommended with good results, but with the most side effects such as dizziness, insomnia, nausea, and somnolence [54,55].
Trazodone was not effective in improving BMS symptoms [56]. Anticonvulsants such as gabapentin and pregabalin are routinely recommended in the pharmacotherapy of BMS, but therapeutic success has not been achieved [55,56]. Systemic and local treatment with clonazepam should be considered in the treatment of BMS.
Clonazepam is a benzodiazepine and a γ-aminobutyric acid (GABA) receptor agonist. This receptor is widely present in the central nervous system and peripheral tissues, and this drug acting on this receptor may have positive results in the treatment of this syndrome [55][56][57][58]. Pure small-fiber peripheral neuropathy may be better controlled with local clonazepam and central mechanisms may benefit more from systemic clonazepam [55][56][57][58]. Clonazepam, like other benzodiazepines, can cause side effects, mainly drowsiness, impairment of memory and cognitive functions, and dependence on long-term use. Although systemic absorption is low, no side effects have been reported with topical application [55][56][57][58].
α-lipoic acid (ALA) has been used to treat diabetic neuropathy because it is thought to act as a com-and coenzyme, produce energy (ATP), improve glucose metabolism and stimulate nerve growth factor (NGF) production. In addition, ALA stimulates the elevation of cellular glutathione levels and may prevent peripheral neuropathy [59][60][61][62][63].
There have been indications for the use of capsaicin in the pharmacological management of burning pain. Capsaicin induces desensitization and depletion of substance P leading to analgesia. A double-blind cross-over study revealed that a 0.025% capsaicin mouth rinse significantly reduced pain with no side effects [63][64][65][66]. Additionally, various topical treatments, such as saliva substitutes, may be helpful when a peripheral mechanism is suspected [66].
To talk about photobiomodulation, it is necessary to start from the assumption that light is a type of electromagnetic radiation and is considered an indispensable source of energy. A photochemical reaction is normally induced by the interaction of light, particularly ultraviolet, visible, and near-infrared light, with external matter. There are numerous examples of interactions between light and biological systems: photosynthesis; the reactions of the photoreceptors of the retina; the synthesis of vitamin D [67].
Since 2015, we have been talking about photobiomodulation (PBM) to describe the scientific basis of the use of non-ionizing electromagnetic energy to trigger photochemical changes within cellular structures and tissues [68].
PBM has analgesic and anti-inflammatory therapeutic effects, can stimulate biological tissues, and has documented antimicrobial effects [68]. Therefore, the correct use of the PBM can relieve painful symptoms, significantly reduce an inflammatory process, and accelerate and improve the healing of damaged tissues [69].
The mechanism of action of PBM is not yet fully understood. The most popular theory is that light is absorbed by mitochondrial cytochrome C oxidase (CcOx), causing an increase in adenosine triphosphate (Adenosine TriPhosphate ATP) [69,70].
PBM, on the other hand, can induce a brief rise in reactive oxygen species (ROS) before decreasing oxidative stress. Nitric oxide (NO) competes with oxygen and binds to CcOx in cells with varying degrees of hypoxia, limiting oxygen use and thus mitochondrial cell respiration. PBM may restore this inhibition by dissociating NO from its binding location on CcOx, allowing mitochondria to enhance ATP synthesis and cellular energy [69,70].
Another possible mechanism of PBM could be an increase in the concentrations of Ca 2+ ions, important for cellular metabolism and homeostasis, and cellular signal transmissions. Furthermore, the cellular temperature changes after a PBM must be considered [67][68][69][70][71][72][73].
PBM is not considered a heat treatment; however, selective absorption by CcOx can lead to intracellular thermal micro-changes that can positively influence the behavior of cells and tissues [73,74].
Primary BMS is to be considered a chronic oral pain pathology where PBM could perform a part of the new local therapeutic strategies. Indeed, in recent years, with the diagnostic and cognitive advances of the disease, PBM has emerged as a potential noninvasive treatment with no apparent side effects.
Many therapeutic experiences have provided encouraging results in the reduction of oral burning symptoms. However, further therapeutic experiences will be needed to confirm and better protocol PBM treatments and correctly relate them to the clinical and symptomatic data of patients with BMS [57][58][59][60].
In the analysis of the results in the literature, there are some studies where an improvement in pain symptoms in patients with BMS has been found. Sleep values were compared and measured with the VAS and the improvement rates ranged from 4 to 15% [58,59,62].
The study conducted by Scardina et al. highlights the improvement in microcirculatory patterns after photobiomodulation was applied in patients with BMS, analyzed by videocapillaroscope. The improvement of the pattern has been noticed lasting for a long time after the therapy [56].
As regards the parameters used by the authors of the articles analyzed, the wavelengths used are variable, from a minimum of 685 nm [55] to a maximum of 1064 nm [38] with a preference; however, for the wavelength of 810-830 nm [52][53][54]56,57,59,62]. All the studies confirm the improvement of the symptoms. For the evaluation of the symptoms, the OHIP-14 questionnaires and the VAS scale were mainly used [52][53][54][55][56][57][58][59][60][61][62]. In fact, all the studies report an improvement in VAS scale values and OHIP values, especially after almost three applications of photobiomodulation. The follow-up shows a prolonged analgesic effect, which was found by Hanna et al., even nine months after discontinuation of treatment. In all studies, the absence of side effects of photobiomodulation is highlighted, even in follow-ups. The therapy is well accepted by the patients and easy to perform for the operator. Finally, it should be noted that the results of the improvement in the quality of life are recorded on average after seven weeks of application of the therapy, with an average of one session per week. Table 2 shows the results of the literature review that satisfies the proposed research questions are summarized.

Conclusions
Various treatment options for BMS exist, but their efficacy based on evidence-based research remains unsatisfactory due to the diversity of studies and treatments employed. Among the treatments investigated, clonazepam and ALA have shown promising results in multiple studies, but further research with larger sample sizes is required to establish them as a first-line treatment for BMS patients. Notably, some studies have demonstrated similar outcomes between treatment and placebo evaluations, emphasizing the importance of exploring the psychological and/or psychiatric characteristics of patients. A multidisciplinary approach may be necessary for addressing BMS treatment. Photobiomodulation represents a potential therapeutic strategy for managing burning mouth symptoms. However, further investigation is warranted to fully understand its effectiveness in BMS treatment. Numerous studies on patients confirm that laser treatment can alleviate symptoms, with long-lasting effects. The advantages of this therapy are the easy execution by the clinician, the lack of adverse effects, and the good compliance by the patient. Despite this, it should be emphasized that it would be advisable to conduct future studies on larger patient samples; to standardize the operating protocols both in terms of therapeutic sessions, wavelengths to be used, and tests necessary to formulate a diagnosis precise; and correct classification of the symptomatology.

Supplementary Materials:
The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/app13158880/s1, Table S1: PRISMA-ScR Checklist; Table S2: Search strategies for electronic databases; Table S3: JBI critical appraisal checklist for randomized controlled trials, a tool used for risk of bias assessment.