Saliva is essential in oral homeostasis and health. On average, a human produces 0.5-1.5 liters of saliva daily.^1,2 Majority of the saliva comes from pairs of the parotid, submandibular, and sublingual salivary glands, with some coming from numerous minor salivary glands distributed in the oral mucosa.³ Saliva, as the first digestive fluid in the alimentary canal, assist in food intake and digestion of starch and lipids by acting as a solvent. Saliva also plays a crucial role in taste receptor and oral mucosa hydration and maintenance and teeth protection. Furthermore, saliva controls oral microflora with its antimicrobial properties and mechanical cleansing action. Thus, the loss of salivary function can have serious consequences.

Salivary dysfunctions associated with xerostomia or dry mouth (absence of saliva flow) and hyposalivation (reduced saliva flow) can contribute to both minor and severe health problems such as nutrition and dental and psychological health. Other problems caused by xerostomia include a constant sore throat, taste alteration, burning sensation in the mouth, and difficulty in speaking and swallowing. Salivary dysfunction left untreated can significantly affect the quality of life. The common causes of saliva dysfunction are (1) medications such as antihistamines, anticholinergics, diuretics, and sedatives,^4,5 (2) diseases such as Sjögren’s syndrome,⁶ and (3) cancer therapy including high doses of radiation to the head and neck.⁷ The evaluation of saliva dysfunction is performed through questionnaires or instruments to analyze and grade aspects related to taste, chewing, swallowing, speech, sleep, and quality of life. A consensus has not been reached on the definition of low salivary flow, and the definitive relationship between hyposalivation and xerostomia remain unknown. In some cases, people who suffer from dry mouth may have normal or even high salivary flow. However, xerostomia and hyposalivation prevalence is significant and conditions in terms of management can be challenging.

Treatment approaches in salivary dysfunction include patient education on basic oral hygiene, avoiding certain types of food such as acidic and spicy foods, and stopping smoking and alcohol intake. Other treatments include sugar-free chewing gums or toothpaste, mouthwashes that help stimulate and improve saliva secretion, and symptomatic relief.⁸ Pilocarpine and cevimeline systemic saliva stimulants have also been prescribed, but with many reported side effects.⁹ Thus, non-pharmacological methods have been studied and developed with varied success, such as acupuncture,¹⁰ electrostimulation,⁹ and low-level laser therapy (LLLT).^11,12 This review focuses on the studies that have been conducted using LLLT, also known as photobiomodulation therapy, in salivary dysfunction (Fig. 1).

Figure 1. Scheme showing cause and effect of xerostomia or dry mouth, and photobiomodulation as a treatment option discussed in this review. Created with Biorender.com.

Photobiomodulation (PBM) therapy uses low-power light to irradiate tissue typically ranging from 0.05 to 0.5 W of power to exclude potential heat effects.¹³ The mechanisms involved in PBM treatment are still not well understood. However, the main idea is that photons are absorbed by the target tissue converting it into useful energy that enhances the metabolic processes in the cell, such as increasing ATP production and reactive oxygen species (ROS) production.^14,15 PBM delivers photons on the cell mitochondria. Then photon energy is absorbed by cytochrome C oxidase (Cox), the last enzyme of the electron transportation chain that mediates electron transfer from the cytochrome c towards molecular oxygenation, consequently increasing ATP production and ROS concentration.¹⁶ Accelerated oxygenation and ATP production promote the regeneration of damaged cells and tissue.^17,18

The potential treatment effects and mode of action of PBM in salivary function have been elucidated previously in animal studies. A study measuring saliva flow rate in diabetic mice after PBM treatment suggested a beneficial effect.¹⁹ A study using a guinea pig animal model suggested that PBM could delay necrotic histological changes in the submandibular gland.²⁰ PBM has also been reported to prevent apoptosis and inflammation in diabetic rats. In addition, antioxidant effects and functional salivary enzyme activities were found for normal rats and diabetic rats.²¹ However, varying observations and conclusions were derived depending on the different protocols, light treatment parameters, and systemic conditions in the animals. Light parameters such as irradiance, power, energy, exposure time, and wavelength can be adjusted to modulate results.

The advantages of PBM that are known thus far include improved epithelial cell mitosis, increase in salivary ducts, and stimulation of protein synthesis in submandibular glands. Others report increase in anti-apoptotic protein expressions and intracellular calcium levels, and blood circulation in the salivary glands that lead to regeneration of salivary glands and improved functionality.

Radiotherapy in the treatment of cancer uses ionizing radiation to treat malignant neoplasms. Radiation for head and neck tumors typically distributed at the tumor site ranges between 50 and 70 Gy in total with a daily dose of 1.8-2.0 Gy. The mechanism involves direct damage on DNA structure or through the production of free radicals that disrupt the DNA integrity of proliferative cells. Salivary gland cells have low turnover but are highly sensitive to radiotherapy. Damage to membrane receptors, disruption in cytoplasmic granules, and changes in the levels of aquaporins have been reported as some possible mechanisms of salivary dysfunction induced by radiotherapy.^22,23 It has also been reported that the activation of p53 transcription due to DNA damage has a crucial role in salivary acinar cell radiosensitivity. The mechanisms of radiation-induced damage to salivary function remain uncertain, but atrophy and acinar degeneration are often found histologically. In a study, the accumulation of the p53 protein due to radiation was found to activate the up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (Bax) target genes with a pro-apoptotic effect.²⁴ The radiotherapy treatment areas are typically within the range of the salivary glands. Thus, patient develops hyposalivation and xerostomia. About 80-93 % of patients undergoing head and neck radiotherapy develop some degree of xerostomia.²⁵ Patients often complain of difficulty in oral lubrication, dysgeusia, and burning sensation. The risk of oral infections is also high due to the low amounts of enzymes and immunoglobulins present in the oral mucosa. Patients have also reported worsening quality of life attributed to radiation-induced hyposalivation.

At present, there is no effective treatment for radiation-induced xerostomia and hyposalivation. However, some alternatives that give relief, such as muscarinic agonists and amifostine, have demonstrated beneficial results to address xerostomia and hyposalivation but with side effects. Hence, the development of new treatments. Among the new treatments that have been studied is laser PBM. PBM has gained prominence because it is a safe and painless method that patients well accept. Clinical studies describe improvements in salivary function with laser treatment ranging from approximately 600-850 nm (Table 1).^26-30

Table 1 . Clinical studies of photobiomodulation effects on radiotherapy-induced salivary dysfunction

Case	Treatment parameters	Target area	Results	Yearref
Xerostomia	Laser (InGaAl, 660 & 810 nm, 40 mW, 10 & 25 J/cm2); 15 sessions	Intra- and extra-oral applications over salivary glands	No difference between groups was noted in relation to salivary flow and composition, xerostomia or quality of life	202026
Xerostomia	Laser (InGaAlP, 808 nm, 30 mW, 7.5 J/cm2); 24 sessions	Major salivary glands	Low-level laser therapy improved salivary hypofunction and increase salivary pH of patients leading to an improvement in quality of life	201727
Xerostomia	Laser (He-Ne, 630 nm, 30 mW, 5.16-16.2 J/cm2); 24 sessions	Extra-oral applications in parotid and submandibular gland	Reduced incidence of oral mucositis lesions, oral pain, and xerostomia	201728
Hyposalivation	Laser (InGaAlP, 660/ 780 nm, 40/15 mW, 10/3.8 J/cm2); 21 sessions	Intra- and extra-oral applications	Higher salivary flow rate	201629
Hyposalivation	Laser (InGaAlP, 685 nm, 35 mW, 2 J/cm2); 21 sessions	Intra-oral application avoiding tumor site	Lower degress of oral mucositis, pain and higher salivary flow	201330

In most cases, treatment is performed intra- or extra-orally in the buccal mucosa, tongue, and main salivary glands. Reports describe pain relief, improvement in salivary flow, and reduced dry mouth relative to sham or control groups. However, a few studies also report no distinguishable effects after laser treatment. The reason may depend on the cell destruction level caused by radiotherapy, especially on the major salivary glands. Nevertheless, xerostomia and hyposalivation consequently the quality of life seem to be improved with PBM treatment compared to being left untreated for patients undergoing radiotherapy. More comprehensive studies may be needed to understand better the mechanisms involved and how PBM treatment can be improved for salivary dysfunction induced by radiotherapy.

There is a lack of literature pertaining on the impact of PBM in patients with xerostomia or hyposalivation induced by drugs. Majority of the papers deal with xerostomia related to chemotherapy and radiotherapy. However, several drugs have been linked with salivary dysfunction as a side effect. Some diuretics are responsible for decreasing the amount of circulating intravascular and extracellular fluid in the body, including saliva, whereas anticholinergic drugs act directly on the hypothalamus, reducing salivary production. Drugs used to treat chronic diseases such as anticholinergics and β blockers are also known to influence the quantity and quality of saliva production directly.

A study on photobiomodulation effects in salivary production in patients with drug-induced hyposalivation describes PBM treatment’s ability to increase unstimulated salivary flow rate (Table 2).^31-35 However, the mechanism was not explained well in the study.

Table 2 . Other clinical studies of photobiomodulation treatments in salivary glands

Case	Treatment parameters	Target area	Results	Yearref
Scleroderma	Laser (InGaAl, 660 & 808 nm, 100 mW, 0.8 J/cm2); 6 sessions	Sublingual, parotid and submandibular glands	Increase in salivary flow, remission of the xerostomia, and an improvement in mastication and swallowing	202131
Drug-induced xerostomia	Laser (GaAlAs, 830 nm, 35 mW, 1.60 J/cm2); 14 sessions	Parotid, submandibular, and sublingual glands	Increased salivary flow rate	201632
Burning mouth syndrome	Laser (InGaAl, 660-970 nm, 3.2 W, frequency 1-20000Hz, spot size 1 cm2); 10 sessions	Oral cavity	Significant decrease in symptoms related to the burning mouth	201933
Burning mouth syndrome	Laser (InGaAl, 685 vs 830 nm, 30 mW, 3 J/cm2); 4 sessions	Areas affected by burning sensation w/ laser fiber tip in contact w/ mucosa	Combination laser therapy & alpha-lipoic acid (ALA) was efficient in reducing burning mouth symptoms, with LLLT being more efficient than ALA	201834
Sjögren's syndrome	Laser (AlGaAs, 808 nm, 100 mW, 133 J/cm2); 12 sessions	Sublingual glands	LLLT protocol used in this study affected no improvement in xerostomia or salivary flow rate	201735

Several other studies of PBM performed in the salivary glands can be found in the literature (Table 2). However, clinical reports were found to have low sampling or patients that meet set criteria for each study. There is also a difference in the observation periods and validation method, which makes PBM treatment establishment difficult clinically.

Salivary gland dysfunction is clinically relevant, and decreased salivary flow rate may cause chronic oral discomfort. As a result, the patient’s well-being and oral health-related quality of life are impaired. Despite considerable research over many years, little progress has been made in developing strategies to prevent severe xerostomia or hyposalivation. Existing studies indicate that photobiomodulation therapy can manage xerostomia and hyposalivation. However, a lack of standards in reporting light treatment parameters makes reproducing the results challenging. More comprehensive studies with standardized reporting of treatment protocols are needed.

None.