Nonpharmacological Interventions in the Management of Xerostomia: A Review on Topical Treatments, Alternative Medicine, and Innovative Therapies

Abstract

Background: Despite incidence rates and complications, the clinical management of xerostomia lacks guidelines. Aim: The aim of this overview is to summarize the clinical experience over the past 10 years of treating xerostomia using non-pharmacological interventions. Materials and Methods: A literature search was conducted across PubMed, EMBASE, Web of Science, ScienceDirect, and Google Scholar databases, covering publications from 1 January 2013 to 30 January 2023. Results: Topical therapies are the mainstays in cases of longstanding oral dryness. Their aim is to relieve oral discomfort by retaining mouth moisture. Macro-molecular lubricants were largely used in xerostomia due to radiotherapy for Head and Neck cancer (HNC) and xerostomia due to the chronic use of drugs. However, none of them provided stable relief for dry mouth. Traditional Medicine (TM), through the administration of different medicinal herbs and plants, has recently been evaluated against xerostomia in clinical trials. Matricaria chamomilla L., Linum usitatissimum, and Malva sylvestris L. together with Althea digitata Boiss, Licorice root, and Salvia Officinalis are among the most used compounds. They were formulated as water extracts with health benefits that are attributed to the presence of polyphenols. However, the low number of clinical evaluations represents the greatest limitation for validating the efficacy of TM against xerostomia. Regarding acupuncture, it did not show significant effects in the trials in comparison to the control groups. Further, electrostimulation, photo-biomodulation and hyperbaric therapy need more randomized clinical evaluations to effectively demonstrate their ability to relieve dry mouth. Conclusions: No topical treatment has shown stable relief of xerostomia. Consequently, the management of xerostomia and its devastating complications remain a significant void in daily clinical practice.

1. Introduction

Saliva is a highly complex fluid composed mainly of water mixed with electrolytes, minerals, buffers, lipids, growth factors, enzymes, cytokines, proteins, and immunoglobulins [1]. Salivary enzymes initiate the digestion of starches and fats in the mouth, while other salivary components, such as epidermal growth factors, promote tissue growth and cell differentiation, and facilitate wound-healing [2]. The antibacterial, antifungal, and antiviral agents in saliva help balance the oral biofilm, preventing dysbiosis, while the mineral components maintain the integrity of teeth, antagonizing demineralization processes [3]. Additionally, salivary glycoproteins, primarily represented by mucins, together with electrolytes, protect mucosal structures from mechanical, microbial, and chemical injury. However, to fulfill all these roles in the oral cavity, a continuous flow and a balanced composition of saliva are necessary. Salivary fluid, nevertheless, can often become impaired throughout life. Patients suffering from saliva alterations are frequently affected by xerostomia, which can be identified as the subjective sensation of a dry mouth [4]. A chronic intake of medications a recurrent cause of salivary fluid dysfunction [5]. More than 400 pharmacological treatments, including antidepressants, antihypertensives, anti-neoplastic, opiates, bronchodilators, proton pump inhibitors, antipsychotics, antihistamines, and diuretics, are frequently reported as causes of xerostomia [6,7,8,9]. Several studies have demonstrated that radiation therapy for Head and Neck Cancer (HNC) affects the major and minor salivary glands, leading to temporary or permanent impairment of secretion [10]. The salivary flow rate can be compromised within the first two weeks of radiotherapy, or after the completion of the cycles, becoming evident as a delayed form of xerostomia [11]. In such cases, no significant difference has been reported between the serous (parotid), the seromucous (sub-mandibular) and mucous (sub-lingual) glands [12]. Additionally, autoimmune conditions such as Sjögren’s Syndrome, rheumatoid arthritis, dysmetabolic diseases (i.e., diabetes), and infections such as hepatitis C virus, as well as the recent SARS-COVID-19 infection, are implicated in the development of xerostomia.

Oral and systemic evidence of xerostomia generally emerges when saliva is altered by 40–50% compared to the physiological status [13,14]. In most instances, dry mouth is experienced when resting saliva decreases to ≤0.1 mL/min and stimulated saliva decreases to ≤0.5 mL/min [15]. However, xerostomia does not necessarily refer to a reduced salivary flow, as it can exist without the presence of hyposalivation due to alterations in saliva. In particular, a relationship between the saliva produced by the minor salivary glands and the sensation of dryness has been suggested [16]. This could be attributed to alterations in the concentration of the salivary mucin. In fact, mucin acts as lubricant for the mouth allowing the subject to perceive symptoms of oral dryness. Consequently, an alteration in the concentration of mucin contributes to the development of the disease. In any case, xerostomia is accompanied by a shift in oral biofilm due to a lowering of the salivary pH, together with the evidence of viscous saliva. In such a situation, gingivitis and caries commonly develop [3]. Additionally, patients may experience taste disturbances, dysarthria, and odynophagia [2,17]. Taste disturbances can be attributed to injury in the chemoreceptor cells caused by the lack of saliva, which lead to (1) a decrease in the number of these cells; (2) an alteration in their structure; and (3) an interruption of neural coding. Partial (dysgeusia) or total (ageusia) taste disturbance are often accompanied by mucositis, with ulceration and infections of the oral epithelial tissue, severely impairing the Quality of Life (QoL) of the individual [18,19]. The resulting malnutrition and weight loss [20,21] significantly compromise patient survival [22].

Nevertheless, the management of xerostomia remains a significant clinical challenge. The treatments have mainly focused on increasing salivary flow through pharmacological interventions. However, the application of systemic cholinergic drugs has not resulted in a significant or sustained relief of xerostomia. Furthermore, their use is significantly limited due to the high toxicity associated with their administration [23].

As an alternative, topical therapy has been suggested to antagonize the disease. This mainly involves chemical preparations applied in the mouth such as sprays, gel, or mouthwashes. Additionally, Traditional Medicine (TM) and complementary medicine have been evaluated, supported by the increasing demand for their services sustained by the WHO [24]. Furthermore, electrostimulation, photo biomodulation, and hyperbaric therapy have recently been introduced as therapeutic approaches. However, their benefits are widely debated by the scientific community.

Given the above considerations and the need for clinical indications in the management of xerostomia, the intention of the present review is to summarize the literature about treating the disease by using topical product, TM, and innovative therapies, and to group the data in relation to the pathological condition from which xerostomia develops.

2. Materials and Methods

2.1. Search Strategy

A search of the existing literature, published between 1 January 2013 and 30 January 2023, was performed in the PubMed/MEDLINE using the MeSH terms “xerostomia”, and “dry mouth” with the subheadings “topical therapy”, “TM”, “alternative therapies”, and “prevention and control”. The search was restricted to the English language. Further, a search of the Cochrane Library was also performed using the same MeSH terms for the entire database. Additionally, a search of Web of Science (WoS) was conducted using the terms ‘xerostomia’ with the results restricted to the English language, and randomized control trials published between 1 January 2013 and 30 January 2023. Finally, the search results from each of the electronic databases were combined, and duplicated publications were removed. The search results were imported into the computerized database Review Manager 5.2. The search results from each of the electronic databases were combined, and duplicated publications were eliminated.

2.2. Study Selection

At first, the studies were included based on the relevance of the titles and abstracts. The remaining studies were evaluated in their whole length and those which met the following criteria were included: randomization; placebo-controlled trial (RCT); diagnosis of xerostomia based on the xerostomia VAS; original data and oral complications associated with cancer therapies/or pharmacological treatments/or autoimmune conditions/or rheumatoid arthritis/or dysmetabolic diseases/or infections.

2.3. Study Quality Assessment

Using the Cochrane Collaboration tool for assessing the risk of bias in RCTs, the following domains were assessed for each study: selection bias (i.e., inappropriate randomization), performance bias (i.e., not blinding researchers giving treatment), detection bias (i.e., not blinding researchers assessing outcome), attrition bias (i.e., patient withdrawals from the study), and reporting bias (i.e., selective presentation of data) [25]. Each domain was assigned high, low, or unclear risk.

2.4. Flow of Article Selection

A PRISMA flowchart illustrating the flow of article selection is provided in Figure 1. It shows the number of studies retrieved, the removal of the duplicates, and the final number of articles included in the review.

3. Results

3.1. Topical Therapies

Topical therapies are the mainstays of therapy in cases of longstanding oral dryness. The aim of the topical therapy is to relieve oral discomfort by keeping mouth moisture at an standard level.

They include the following: (1) salivary substitutes in the form of liquids, gels, or spray applications attempting to provide a moisture-retaining coating to the oral mucosa, and (2) salivary stimulants in the form of lozenges, chewing gum, and toothpastes mainly focusing on stimulating saliva production.

Topical therapy has been studied in all types of dry mouth patients. Clinically, the benefits of topical agents have been evaluated by comparing the baseline Visual Analogue Scale (VAS) values to those obtained at the end of the study, and long-term (up to 3 months after the treatment). Data were measured as a dichotomous outcome, or as a continuous measurement such as the xerostomia score [5]. Primarily, the VAS has been applied in the form of a questionnaire (VXQ) or as a measure of isolated items (such as oral dryness, speech difficulty, or swallowing difficulty) [26]. Also, the data have been evaluated using the Xerostomia Inventory (XI) questionnaire and the Oral Health Impact Profile 14 (OHIP-14) [27]. Additionally, the unstimulated whole saliva (UWS) has been monitored during the studies. Generally, it has been measured as saliva weight or volume production over a 5 min period. Often, the QoL has been included as an additional parameter of the treatment efficacy. In such a case, the Health-Related Quality of Life (HRQoL) or the Head and Neck Cancer Quality of Life (HNQoL) questionnaires have been applied. Sometimes, the subjective satisfaction or taste preferences between the tested products are reported in the trials. Occasionally, the oral health assessment using the plaque index or the gingival index, the evidence of oral mucositis by the International Grade Scale, the number of oral infections, and tooth loss by pre- and post-comparison have also been reported.

3.1.1. Saliva Substitutes

Saliva substitutes try to provide moisture as well as lubrication to the oral surfaces in order to prevent the damages from a reduction in the natural fluid. In fact, a lack of salivary lubrication leads to an increase in the coefficient of friction between the tongue and tooth enamel [28]. This situation generates discomfort in patients suffering from xerostomia. A great variety of molecules has been tested in the formulation of salivary substitutes with the intent to reduce friction. In particular, macro-molecular lubricants can reduce the friction coefficient through various mechanisms of lubrication. Many of these are hydrophilic macromolecules based on carboxymethylcellose [29], hydroxyethyl cellulose [30,31], hydroxypropyl methylcellulose [32], or polyglycerylmethacrylate [30]. Also, the ability of lipids to provide lubrication to the oral surfaces has been investigated. It depends on their capacity to coat the oral mucosa, therefore reducing the friction coefficient through the viscous dissipation of friction energy [33]. This mechanism of action differentiates lipids from other macromolecules, which act through water retention and hydration [34].

Further important components in the substitutes are olive oil and linseed extract [35,36], xanthan gum [37], rapeseed oil, animal mucin [38], glycerin [39], oxygenated glycerol triester(s) [40], prophylin [41], or olive oil enriched with lycopene [27]. Sometimes, medicinal herbs such as Matricaria Chamomile and Linum Usitatissimum are also included in the substitutes [42], along with various gustatory substances (i.e., lemon flavor), natural cholinergic compounds, antimicrobial, enzymatic agents, electrolytes, lubricants, and/or stabilizers (

Table 1. Clinical Trials on Salivary Substitutes.

Ref.	Experimental Preparation	Main Component and Vector	Sample Characteristics	Study Design	Time Treatment	Daily Applications	Time Points Assessment	Results
Navarro-Morante et al. 2017 [27]	Surat® vs. control	Lycopene-enriched virgin olive oil as a spray	60 patients with drug-induced xerostomia	RCT	12 weeks	Four times per day (1.5 mL)	Baseline vs. 12 weeks	A significant improvement (p < 0.05) and quality of life (p = 0.001);
Nuchit et al. 2020 [29]	OMJ vs. control	Carboxymethylcellulose, glycerol, and xanthan gum as a gel	73 HNC patients with radiation-induced xerostomia	RCT	2 months	Six times per day (1–2 teaspoon)	Baseline vs. 1, 2 months	A significant improvement (p < 0.0001)
Barbe et al. 2018 [31]	GUM Hydral vs. control	Betaine, taurine, and hyaluronic acid as a mouth rinse and gel	40 patients with drug-induced xerostomia	RCT	4 weeks	Mouthrinse two times per day (15 mL); gel five time per day (1–2 cm)	Baseline vs. 4 weeks	A significant improvement (p < 0.05)
Kvalheim et al. 2019 [32]	Glycerol preparation vs. controls	Glycerol solution as an oral moisturizer	30 patients with drug-induced xerostomia	RCT	3 days	Once per day	Baseline vs. immediately after, and 2 h after the application	A significant improvement (p < 0.001)
Paterson et al. 2019 [33]	Visco-ease TM vs. control	Lamellar Body Mimetic (multi-lipid system) as an oral spray	43 HNC patients with radiation-induced xerostomia	RCT	6 weeks	At least two times per day (unspecified dose)	Baseline vs. 1, 2, 3, 4, 5, 6 weeks	No significant difference (p = 0.90).
Kerr et al. 2010 [43]	OraMoist vs. control	Carbomer homopolymer and triglycerides as a mucoadhesive disk	27 patients with non-homogeneous xerostomia	RCT	1 week	One disk three times per day	Baseline vs. 1, 2, 3 weeks	A significant improvement (p < 0.005) and UWS (p < 0.001)
Salom et al. 2015 [44]	Novasial vs. control	Ovalbumin and other egg derivatives as a liquid saliva substitute	210 patients with non-homogeneous xerostomia	RCT	2 weeks	Four times per day (5 mL)	Baseline vs. 2 weeks	A significant improvement (p < 0.0001)
Apperley et al. 2017 [45]	RBO Alfa One™ vs. control	Rice bran oil and soy lecithin emulsion as a spray	40 HNC patients with radiation-induced xerostomia	RCT	1 week	At least four times per day (50 mL)	Baseline vs. 1 week	A significant improvement (p = 0.02)
Lòpez-Pintor et al. 2018 [46]	Xerostom vs. control	Olive oil, betaine as a mouth rinse, and toothpaste	28 patients with Sjögren’s syndrome-induced xerostomia	RCT	4 weeks	Three times per day (7 mL mouthrinse + 0.5 g toothpaste)	Baseline vs. 4 weeks	A significant improvement (p < 0.05) and quality of life (p = 0.04)
Marimuthu et al. 2021 [47]	Oral7®mouthwash vs. control	Lactoperoxidase, lysozyme, glucose oxidase, and lactoferrin as a mouth rinse	94 HNC patients with radiation-induced xerostomia	RCT	4 weeks	Three times per day (2 puffs)	Baseline vs. 4 weeks	A significant improvement (p < 0.0001)
Lung 2021 [48]	Biotène Spray vs. control	Glycerin, carboxymethylcellulose (CMC), as spray	25 patients with non-homogenous xerostomia	RCT	Single dose	Once per session (3 puffs)	Baseline vs. every 15 min up to 2 h	No significant improvement (p = 0.88)
Martìn 2017 [49]	Xerostom (no control)	Olive oil, betaine, as toothpaste, mouthwash, gel, and spray	40 HNC patients with radiation-induced xerostomia	RCT	2 weeks	Toothpaste: 3 times daily; spray: ≥8 times daily; mouthwash and gel as needed	Baseline vs. after 2 weeks	A significant improvement (p < 0.05)

).

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Salivary substitutes in radiation-induced xerostomia

In patients suffering from xerostomia due to radiotherapy for HNC, different saliva substitutes have been evaluated clinically. Among these studies, Shahad et al. conducted an interesting evaluation which included 20 patients with post-radiotherapy xerostomia [30]. The patients were randomly divided into two groups and instructed to use Biotene Oral Balance (BO) and BioXtra (BX) dry mouth system, both including a toothpaste and a mouthwash. The patients used either BO then BX, or vice versa, for 2 weeks, with a 1-week wash-out period in between. According to the VAS scores, both the agents were effective in reducing dry mouth. However, a significantly improved relief in dryness and in recovery of the taste were obtained using BX in comparison to BO. Similar results were showed by Dirix et al. [50], who also reported a greater increase in QoL using BX, compared to BO.

Recently, the efficiency and safety of an active saliva substitute (Oral7^®) enriched by natural enzymes (lactoperoxidase, lysozyme, glucose oxidase, and lactoferrin) was evaluated in HNC survivors undergoing radiotherapy or chemo-radiotherapy [47]. The results showed that Oral7^® mouthwash significantly reduced the subjective sensation of dry mouth, and at the same time increased the UWS.

Further, the capacity of natural biopolymers have been extensively evaluated as saliva substitutes in radiation-induced xerostomia [51]. This is because of the similarity in their rheological and elastic properties to human saliva, which give the polymers a high capacity for lubricating the oral surfaces. These polymers include Xialine, a natural compound with viscoelastic properties based on xanthan gum. This study was conducted on 30 radiotherapy patients in a randomized double-blinded and placebo-controlled crossover design. The aim was to detect differences in radiation-induced xerostomia and xerostomia-related symptoms in the group using Xialine, in comparison to those of the control group. The data were analyzed by the head and neck cancer module EORTC QLQ-H&N35. A marked improvement in dry mouth and sticky saliva after the completion of radiotherapy was reported in both of the studied groups. Meanwhile, a significant improvement regarding speech and the other senses was only found in the patients who used Xialine during radiotherapy.

Further, two complex mixtures of polymers, salivary stimulants, and natural flavors—OMJ and GC—were compared in post-radiation HNC patients with xerostomia [29]. The participants in the study group were instructed to swallow 1–2 teaspoons of OMJ 6 times per day for 2 months. The subjects in the control group were instructed to topically apply a pea-sized drop of GC dry mouth gel in the oral cavity 6 times per day for 2 months. The analysis of the data showed that the saliva substitute OMJ was better than the topical saliva gel GC regarding the relief of dry mouth and difficulty in swallowing. Conclusively, OMJ better improved the clinical nutritional status of the patients in comparison to GC.

Additionally, various formulations of olive oil have been experimented as saliva substitutes in xerostomia after radiotherapy. This is because the richness of the polyphenols in the oil can antagonize oxidative stress, inflammation, and microbial proliferation phenomena, which can easily develop in radiotherapy patients. To increase this previous activity, a sample of olive oil was enriched by betaines and xylitol in a formulation called xerostom, including toothpaste, mouth rinse, and a mouth spray and gel. Specifically, the presence of betaine tends to increase the anti-inflammatory ability of the olive oil, while xylitol enhances the antimicrobial activity of the compound, leading to an anti-caries effect [52]. The use of xerostom in patients suffering from xerostomia after radiotherapy for HNC resulted in a greater improvement of both the symptoms and QoL [49]. Also, the statistical analysis demonstrated an increase in UWS in comparison to the control groups.

Further, a rice bran oil was investigated for treating xerostomia in HNC patients under radiation therapy [45]. As control groups, a methylcellulose suspension and water were applied. According to the Shortened Xerostomia Inventory (SXI9), the rice bran oil significantly improved dry mouth in comparison to the control groups.

Moreover, in radiotherapy-related xerostomia, Paterson et al. carried out a trial evaluating the capacity of Visco-ease spray, a multi-lipid mimetic derived from a natural lamellar body [33].

The main aim of the research was to evaluate the ability of Visco-ease in reducing saliva viscosity due to the lipidic composition. However, according to the Groningen Radiotherapy-Induced Xerostomia (GRIX), no differences were found between the agent and the placebo groups at the end of the study.

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Salivary substitutes in drug-induced xerostomia

Many studies have been conducted with the purpose of finding a saliva substitute for xerostomia related to drug use.

In a multicenter comparative study conducted by Salom et al. [44], the efficacy of BO was compared to Novasial (a natural compound based on chicken egg white) and to Aequasyal (an oxygenated glycerol triester). Despite Novasial being more effective in treating taste disorders, the VAS scores indicated similar efficacy in both the agents in improving the patients’ oral condition.

More recently, Barbe et al. [31] studied the efficacy of BO plus gel in patients with drug-induced xerostomia in a randomized clinical trial. BO plus gel is enriched in glycerin and propylene glycol in comparison to the simple compound. In the study, BO plus was compared to GUM Hydral, which is based on betaine, taurine, and hyaluronic acid. GUM Hydral resulted in a significant improvement of xerostomia and QoL in comparison to BO plus gel. However, the relief was temporary after the suspension of the agent. This result confirms the benefit of any substitute mainly depends on the continuous application of the compound over time [48].

BO gel was also investigated as an agent for antagonizing microbial infections in xerostomia. The results showed that BO gel helps in reducing the development of oral diseases associated with aerobic and anaerobic bacteria, in addition to those sustained by C. albicans [53].

Also, the safety and efficacy of xerostom as a dry mouth system, consisting of toothpaste, a mouth rinse, an oral spray, and a gel, was evaluated in drug-derived xerostomia. Forty adults were included into a single-blinded, open-label, crossover clinical study. In comparison to the control group, the results demonstrated that the use of the topical dry mouth significantly increased UWS flow rates, reduced the complaints of xerostomia, and improved xerostomia-associated QoL. Furthermore, no clinically significant adverse events were observed from the use of xerostom [54].

Also, Oral moist disks, consisting of carbomer and triglyceride homopolymers, have been used as a palate lozenge-shaped mucoadhesive preparation to antagonize xerostomia due to drugs. A double-blind randomized controlled crossover study [43] compared the efficacy of Oral moist disks to that of a placebo mucoadhesive disk. After 60 min of application, the results showed that both the disks were associated with a significant improvement in salivary flow, while there was no statistical difference between the groups regarding oral moisture [43].

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Salivary substitutes in xerostomia suffered in elderly

Many studies have been carried out on elderly patients suffering from xerostomia. Among them, Mouly et al. [40] evaluated the capacity of Aequasyal, an oxygenated glycerol triester oral spray, in antagonizing mouth dryness. The agent was compared to Saliveze, a substitute enriched by the presence of electrolytes. The results demonstrated that Aequasyal was superior to Saliveze in improving xerostomia and lubricating the oral tissues in the patients.

Moreover, Morante et al. [27] evaluated the clinical performance of lycopene-enriched virgin olive oil in spray form to treat an elderly group of patients (n = 60) with drug-induced xerostomia. The agent was compared to a placebo group in a double-blind, randomized clinical trial. The data were evaluated using the XI and the OHIP-14 before and after 12 weeks of application. The results demonstrated that, albeit differently, the topical application of lycopene-enriched virgin olive oil and the placebo counterpart both improved xerostomia-related symptoms using the XI scale. Conversely, a significant improvement (p = 0.001) in QoL by the OHIP-14 was identified in the treatment group, with no significant differences in the placebo group (p > 0.05).

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Salivary substitutes in xerostomia suffered in Sjögren’s syndrome

A large amount of products have been evaluated regarding Sjögren’s syndrome in order to mitigate the dry mouth of the patients. Among these agents, linseed was studied due to its great capacity to bind water with oral surfaces and the possible resistance of mucilage toward oral mechanical forces [36].

Sometimes, chlorhexidine is also added to linseed extract to antagonize the development of caries, gingivitis, oral candidosis and other infections of the dried oral mucosa [35]. There are doubts regarding a possible decrease in the lubricating effect of the saliva substitute with the use of chlorhexidine. A study on the effects of two salivary substitutes containing linseed extract, without (Salinum) and with the addition of Salinum chlorhexidine, was conducted with the intention of comparing their abilities in relieving dry mouth, together with the effects on the composition of the oral microbiota, dental plaque formation and gingivitis. The results showed that the dental plaque and bleeding upon probing were reduced after the use of both the agents. Friction was reduced after both treatments. The total count of anaerobically cultured microorganisms and mutans Streptococci decreased after the use of Salinum with chlorhexidine (p < 0.05 and p < 0.001). Speech problems and burning mouth symptoms only improved after the use of Salinum (p < 0.05).

Additionally, the capacity of xerostom as toothpaste and mouthwash in reducing dry mouth was evaluated in patients suffering from Sjögren [46]. A double-blinded, randomized study allocated 28 patients into 2 groups, one of them using xerostom and the other using a placebo. The patients applied the products 3 times a day for 28 days. Using the VAS, a statistical decrease in dry tongue, dry mouth and dry throat was seen in the test group. Further, the OHIP-14 total scores demonstrated a significant difference between the groups. Other important data that emerged from this study were the absence of the adverse effects of using xerostom.

3.1.2. Salivary Stimulants

The capacity of sialagogue-containing acidic substances as saliva stimulants was studied in dry mouth. In fact, acidic compounds are well-known for their ability to stimulate saliva fluids, even if a possible lowering of pH resulting in tooth decay limits their use.

In the time period we have selected to carry out this review, the clinical evaluation of saliva stimulants as saliva substitutes was mainly conducted on patients suffering from xerostomia due to drug use [55,56,57,58]. Just one study discussed the efficacy of saliva stimulants on patients suffering from post-radiotherapy xerostomia [59]. Similarly, only one study focused on xerostomia in patients with Sjögren’s syndrome [60]. Furthermore, several studies evaluated saliva stimulants in patients with non-specified xerostomia [61,62,63] (

Table 2. Clinical Trials on Salivary Stimulants.

Ref.	Experimental Preparation	Main Component and Vector	Sample Characteristics	Study Design	Time Treatment	Daily Applications	Time Points Assessment	Results
Marìn 2021 [55]	Xeros Dentaid spray vs. control	Malic acid (1%) as a spray	51 patients with drug-induced xerostomia	RCT	2 weeks	Up to 8 times per day	Baseline vs. after 2 weeks	No significant improvement between interventions (p > 0.05)
Femiano et al. 2011 [56]	Citric acid preparation vs. control	Citric acid (3%) as a mouth rinse	54 patients with drug-induced xerostomia	RCT	30 days	Four times per day (5 mL)	15 min and 1 h after	A significant improvement in dry mouth symptoms (p = 0.0047)
Gomez-Moreno 2013 [57]	Xeros Dentaid spray© vs. control	Malic acid (1%) as a spray	45 patients with drug-induced xerostomia	RCT	2 weeks	On demand, up to a maximum of eight applications per day	Baseline vs. 2 weeks	A significant improvement in dry mouth symptoms, UWS and SWS (p < 0.05)
Niklander et al. 2018 [58]	Xeros Dentaid Spray vs. control	Malic acid (1%) as a spray	70 patients with drug-induced xerostomia	RCT	2 weeks	On demand, up to a maximum of eight applications per day	Baseline vs. 2 weeks	A significant improvement (p < 0.001)
Kaae et al. 2020 [59]	Saliva stimulant vs. control	Chew gum (unspecified component)	91 HNC patients with radiation-induced xerostomia	RCT	1 month	Five minutes for five times per day	Baseline vs. 1 month	A significant improvement (p = 0.05)
da Mata et al. 2019 [60]	Xeros® System vs. control	Malic acid (4.33%) as lozenges	110 patients with Sjogren’s syndrome-induced dry mouth	RCT	2 weeks	Four times per day	Baseline vs. 15, 30, 45 days	A significant improvement (p < 0.05).
Mizuhashi et al. 2021 [61]	Flavored gels vs. control	Japanese apricot extract as a gel	56 patients with non-homogeneous xerostomia	CT	Not reported	Single application during test session	Baseline, immediately after, and 10, 20, 30 min after	A significant improvement by the Japanese apricot extract gel (p < 0.05).
Bielfedt et al.2021 [62]	Ipatal Hydro Med vs. control	Gum arabic as pastilles	26 patients with non-homogeneous xerostomia	RCT	3 days	Single application during test session	Baseline vs. 3 days	A significant improvement (p = 0.0016) and in SWS (p < 0.0001)
Bardellini et al. 2019 [63]	Salivaktive® vs. control	Malic acid (1%) as a spray	28 transplanted patients	RCT	2 weeks	Four times per day	Baseline vs. 2 weeks	A significant improvement (p < 0.05)

).

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Salivary stimulants in radiation-induced xerostomia

A study was carried out to evaluate the efficacy of chewing gum [59]. It was experimented in a group of cancer survivors after radiotherapy completion who were suffering from radiation-induced xerostomia. A tasteless and sugar-free chewing gum was developed in accordance with the preference of the patients. An optimal size and texture was determined according to the subject’s needs. The effects of the chewing were changes in the scoring of xerostomia as defined by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 45. The patients were invited to chew the gum five times daily for at least five minutes. UWS and SWS sialometry were performed upon entry to the study (Visit 1) and at the follow-up (Visit 2). The data were compared to a control group of radiation-induced xerostomia patients, who did not use the chewing-gum. The results demonstrated statistical differences (p = 0.05) in dry mouth between the test group and the control group. The study also demonstrated an immediate and stimulating effect toward the salivary flow with a reduction in viscosity after five minutes of chewing gum. Nevertheless, changes in flow or viscosity over time between the groups were not significant. The study concluded that intervention with tasteless and sugar-free chewing gum might have the benefit of alleviating subjective symptoms of xerostomia after RT.

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Salivary stimulants in drug-induced xerostomia

In patients suffering from xerostomia due to drug use, the potency of 3% citric acid was evaluated by Femiano et al. [56]. The test group was compared to two control groups where either artificial saliva or distilled water were used. All of the groups applied the agent as mouthwash 4 times a day for 30 days. The patients’ unstimulated whole saliva was measured before and after the application of any test solution. They also noted any symptomatologic changes which happened between 15 and 60 min after each daily intake in a daily diary. The results showed that both artificial saliva and citric acid provided immediate relief from oral dryness. Furthermore, the administration of citric acid greatly improved oral dryness with longer-lasting effect than the aqueous solutions.

Malic acid was also studied as a salivary stimulant. Its capacity is based on the ability to release hydronium ions in water, leading to different formulations characterized by a stable pH. One interesting study [57] evaluated 45 patients suffering from xerostomia-induced by antihypertensive drugs. The subjects were divided into 2 groups: the first group received malic acid 1% as a topical spray, whereas the second group received a placebo. Both of the preparations were administered on demand for 2 weeks. A dry mouth questionnaire was used in order to evaluate xerostomia before and after the administration of the agents. Unstimulated and stimulated salivary flows rates were also measured, before and after any application. The results demonstrated that malic acid improved xerostomia and the production of saliva, in comparison to the placebo group.

Further, the potential of a sialagogue based on 1% malic acid combined with xylitol and sodium fluoride, was examined in a randomized double-blind trial enrolling patients suffering from drug-induced xerostomia and idiopathic xerostomia [58]. The placebo group used a topical spray based on xylitol and sodium fluoride. According to the VAS score, both the agents improved dry mouth, and the intervention group showed greater relief in QoL. UWS significantly increased in the intervention group from (p < 0.001).

Similarly, Marín et al. compared the efficacy of 1% malic acid spray to that of a betaine-based mouthwash in a group of drug-induced xerostomia and idiopathic xerostomia patients [55]. The 51 participants were randomly allocated into three groups, two intervention groups and one control (placebo). The QoL and the severity of xerostomia were assessed. Stimulated and non-stimulated salivary flow rates were measured before and after the treatments. Both interventions significantly improved dry mouth symptoms and QoL, in comparison to the placebo group. However, no significant difference between the two intervention groups was reported.

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Salivary stimulants in elderly-induced xerostomia

Only one paper was found discussing xerostomia suffered by the elderly [41]. Some common issues for the elderly include reduced salivary flow, poor oral hygiene, and high levels of cariogenic bacteria. The study enrolled fourteen elderly people, with subjective dry mouth sensation. They were treated at random with the following: (i) Profylin fluoride gel with buffering components, (ii) Profylin fluoride gel without buffering components, and (iii) water rinsing. The treatments were made 4 times a day for 16 days. However, frequent applications of the gel did not result in an improvement in the patients.

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Salivary stimulants in xerostomia in Sjögren’s syndrome patients

A study was conducted by Da Mata et al. [60] with the aim of investigating the impact of gustatory stimulants on patients suffering from Sjögren’s syndrome. The self-perception of xerostomia, the OHRQoL, and the salivary secretion were monitored to quantify the effectiveness of a malic acid lozenge or a citric acid mouthwash. The data showed both the stimulants elicited a reduction in xerostomia and related symptoms. Additionally, the QoL and the salivary output significantly increased in the malic acid lozenge group, in comparison to the citric acid mouthwash group.

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Salivary stimulants in xerostomia due to unspecified causes

Different tastes can increase the secretion of saliva. Mizuhashi and colleagues conducted a study on increasing saliva using flavored moisturizing gels [61]. In this study, a group of patients suffering from oral dryness were compared to a healthy group. Moisturizing gels of 5 different aromas (sweet taste, sour taste with citric acid, sour taste with Japanese apricot extract, and Japanese apricot scent) were used. The efficacy of the flavored gels was compared to that of a tasteless and odorless gel. The oral moisture and saliva volume were measured before the application of the gels, immediately after, and after 10, 20, and 30 min. The differences were statistically analyzed. The results demonstrated that the effectiveness of the moisturizing gels in increasing saliva secretion varied according to the flavor of the agent.

Also, sucking pastilles were used to stimulate salivary flow using mechanical and gustatory effects. An interesting study investigated whether a taste pastille containing polysaccharides (gum arabic, natrosol, sodium hyaluronate, and carrageenan) could increase salivary flow and relieve the symptoms of dry mouth. The pastille [62] was administered to 26 patients with non-homogeneous xerostomia and the efficacy was compared to a control group where paraffin wax was administered. The salivary flow rate and dry mouth sensation assessed through the VAS were used to evaluate the differences between the groups.

The pastille was well-tolerated and effective in increasing the salivary flow rate and reducing mouth dryness after sucking, with statistical differences in the test group in comparison to the control group (p < 0.0001). These results further strengthen the capacity of the gum arabic due to its detection in saliva for up to 10 min after sucking the pastille.

3.2. Traditional and Complementary Medicine

3.2.1. Traditional Medicinal Herbs

Different types of medicinal herbs have been used for centuries to treat a wide variety of oral symptoms, which according to current knowledge, could include dry mouth [64,65,66]. Oral diseases have been mostly treated by topically applying medicinal compounds, or by using the common method of water extraction alongside daily administration of infusions or decoctions rich in polyphenols [64,67,68]. In fact, polyphenols are extremely important bioactive molecules capable of antagonizing homeostasis disturbance and the consequent development or maintenance of diseases [69].

Recently, the ability of TM for treating dry mouth was reported in several studies. However, the data are controversial and difficult to interpret due to significant differences in materials and methods used in the research [23].

Thyme, Rosemary, Sage, Lemon balm, and Malva silvestris have been the most common herbs used for oral diseases and significantly, they were investigated for treating oral dryness (

Table 3. Medicinal herbs and complementary medicine.

Ref.	Main Component and Vector	Sample Characteristic	Study Design	Time Treatment	Daily Application	Time Points Assessment	Results
Morales-Bozo et al. 2017 [42]	Matricaria chamomilla and linseed-extract mouthwash vs. conventional saliva substitute	74 patients with non-homogeneous xerostomia	RCT	3 weeks	Four times per day (2 mL)	Baseline vs. 8 and 22 days	74 patients with non-homogeneous xerostomia
Charalambous et al. 2017 [70]	Thyme honey mouthwash vs. saline	72 HNC patients with chemoradiation-induced xerostomia	RCT	4 weeks	Three times per day	Baseline vs. 1, 6 months	A significant improvement in xerostomia severity (p < 0.001), pain (p < 0.001), and dysphagia (p = 0.033)
Heydarirad et al. 2017 [71]	Alcea digitata and Malva sylvestris oral infusion vs. artificial saliva	60 HNC patients with radiation-induced xerostomia	RCT	4 weeks	Three times per day	Baseline vs. 4 weeks	Significant improvement in dry mouth and quality of life in the herbal group (p = 0.017)
Chamani et al. 2016 [72]	Ginger capsules vs. placebo	61 patients with radiation therapy- induced xerostomia	RCT	14 days	Three times per day	Baseline vs. 14 days	Slight improvement in xerostomia (p = 0.057)
Yu et al. 2016 [73]	Licorice mouthwash vs. water gargle vs. no gargle	122 hemodialysis patients with xerostomia	RCT	10 days	Three times per day	Baseline vs. 5, 10 days	Significant increase in UWS with licorice mouthwash and reduction in xerostomia score (p < 0.001)
Atashi et al. 2018 [74]	Aloe vera-Peppermint moisturizing gels vs. placebo	80 ICU patients with xerostomia	RCT	5 days	Two times per day	Baseline vs. 3, 5 days	Significant reduction in mouth dryness and improved oral health (p = 0.0001)
Pfister et al. 2010 [75]	Acupuncture vs. standard care	58 HNC patients with radiation therapy-induced xerostomia	RCT	4 weeks	30 min (once weekly)	Baseline vs. 1 week	A significant improvement (p = 0.02)
Braga et al. 2010 [76]	Acupuncture vs. no treatment	24 HNC patients with radiation therapy-induced xerostomia	RCT	Before and during radiotherapy (5–7 weeks)	20 min (twice weekly)	After radiotherapy completion	A significant improvement in salivary flow rates (p < 0.001) and reduced xerostomia symptoms (p < 0.05).
Garcia et al. 2019 [77]	True acupuncture vs. sham acupuncture vs. standard care	399 HNC patients with radiation therapy-induced xerostomia	RCT	During radiotherapy	20 min (3 session per week)	Baseline vs. end of radiotherapy vs. 3, 6, and 12 months post-treatment	Significant reduction in xerostomia score for true acupuncture vs. standard care (p = 0.001); no significant difference vs. sham acupuncture (p = 0.06)

).

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Medicinal herbs in radiation-induced xerostomia

Thyme honey, belonging to the Lamiaceae family, was evaluated for the treatment of radiation-induced xerostomia [70]. The study selected a group of 72 HNC patients receiving radiotherapy and/or chemotherapy. They were divided into two groups, with the test group receiving Thyme honey as an oral rinse, while the control group received a saline-based oral rinse. The assessments of both the groups were conducted at the baseline, at 1 month, and at 6 months following completion of the intervention using a VAS and a questionnaire, in addition to clinical visits. Results showed the statistically significant effect of the intervention with relief of xerostomia, pain, and dysphagia, together with an improvement in QoL. The study also demonstrated the safety and efficacy of Thyme honey in managing various grades of xerostomia in HNC patients.

Moreover, Malva sylvestris L., belonging to Malvacee family, has been frequently proposed in treating dry mouth.

In a randomized clinical trial, Heydarirad et al. (2017) evaluated the efficacy of a traditional medicine containing Alcea digitata and Malva sylvestris for the treatment of radiation-induced xerostomia in patients with HNC. The study found that the herbal preparation significantly improved the quality of life and reduced xerostomia more effectively than artificial saliva (Hypozalix) [71].

Additionally, the efficacy of Zingiber officinale was studied as a remedy for dry mouth in xerostomia due to radiotherapy for HNC [72]. The patients received ginger capsule or placebo three times daily over a 2-week period. Before and after the study, a VAS was used to monitor dry mouth and QoL. The data showed that the use of Zingiber did not lead to benefits in comparison to the control group.

Also, in 120 patients with xerostomia after radiotherapy for HNC, four different saliva substitutes—Aloe vera (L.) Burm. f. in gel form, carmellose spray, rapeseed oil, and mucin spray—were tested in a prospective crossover design. Xerostomia was assessed at the baseline and during treatment with each compound using a questionnaire. Rapeseed oil was evaluated in radiation-induced xerostomia [38]. All compounds significantly improved xerostomia in comparison to the baseline values (p < 0.0001). However, the Aloe vera gel was rated the highest, while the carmellose spray was rated the lowest. The results further validate the capacity of Aloe as a wound healing and anti-inflammatory agent.

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Medicinal herbs in drug-induced xerostomia

TM was applied to treat xerostomia in hospitalized patients undergoing multidrug therapy. To this end, several studies have researched the use of gargling Liquorice root (Radix Glycyrrhizae, Glycyrrhiza glabra L.) for treating xerostomia. In particular, a liquorice mouthwash was used in hemodialyzed patients suffering from oral dryness [73]. The results demonstrated an improvement in the rate of salivary flow in comparison to the controls. The research further attested the high anti-inflammatory effect of liquorice [78,79,80], which also reduced throat dryness and throat pain.

Finally, Aloe vera-Peppermint (Veramin) was used for patients suffering from xerostomia in an Intensive Care Unit. The results showed that the agent was useful in relieving mouth dryness, preventing dental plaque formation, and improving oral health [74,81].

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Medicinal Herbs in xerostomia in elderly

Chamomile (Matricaria chamomilla L.), a well-known medicinal plant from the Asteraceae family, has been extensively used for treating oral and throat disturbances.

Regarding xerostomia, the efficacy of chamomile flowers and linseed extract were evaluated in comparison to polysaccharide carboxymethyl cellulose as saliva substitutes in elderly patients. The study was designed as a double-blind RCT involving 74 participants with non-homogeneous xerostomia. The participants alternated a mouth rinse based on Matricaria chamomilla with another based on linseed-extract and a control. The agents were applied four times daily. The outcomes were assessed at the baseline, 8 days, and 22 days using VAS, and salivary flow rate. The chamomile–linseed rinse showed significant improvements in dry mouth (p < 0.05), thick saliva (p = 0.028), and difficulty swallowing (p = 0.001), compared to the control [42].

3.2.2. Acupuncture

Acupuncture involves the use of specific needles inserted into the acupuncture points of the body with the purpose of activating nerve fibers and peripheral receptors. In this way, acupuncture produces sensory interactions with the central nervous system generating anti-inflammatory, neuroendocrine, and neuroimmune signals [82,83].

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Acupuncture in chemotherapy and radiotherapy-induced xerostomia

Several studies have examined the efficacy of acupuncture in managing xerostomia caused by cancer treatments.

Braga et al. [76] conducted a study involving 24 patients with HNC undergoing radiotherapy. The patients were divided into two groups: one receiving preventive acupuncture twice-weekly during radiotherapy and the other receiving standard care. The acupuncture group showed significant improvements in both UWS and SWS flow rates, along with reduced patient-reported symptoms on the VAS (p < 0.05).

Additionally, to assess the effects of a true acupuncture (TA) compared to a sham acupuncture (SA), Cho et al. [84] conducted a randomized study including 12 patients. Acupuncture was delivered twice weekly during radiotherapy. The TA group showed a significant improvement in UWS (p < 0.05) and in xerostomia symptoms. While there were no significant differences in the SWS between TA and SA.

Similarly, Garcia et al. [77] conducted a multicenter phase-3 randomized trial involving 339 patients with HNC undergoing radiotherapy. This study compared TA, SA, and standard care control (SCC). Acupuncture was delivered twice weekly during radiotherapy and transitioned to weekly sessions for four weeks post-treatment. Twelve months after the competition of radiotherapy, the xerostomia severity was evaluated. The TA group showed significantly lower scores compared to the SCC (p = 0.001), indicating a reduction in the symptoms. However, the difference between TA and SA was not statistically significant (p = 0.06).

Pfister et al. [75] further evaluated acupuncture in a cohort of 58 patients with chronic pain or dysfunction after neck dissection, with xerostomia assessed as a secondary endpoint in those who underwent radiotherapy. The study demonstrated significant improvements in subjective xerostomia severity scores (p < 0.05) in the acupuncture group compared to the control group.

Furthermore, Johnstone et al. [85] evaluated acupuncture as a palliative treatment in radiotherapy-induced xerostomia. The study was carried out on a small subset of 50 patients suffering from xerostomia due to Sjögren’s syndrome or chemotherapy. The patients underwent weekly acupuncture sessions. Sugar-free lozenges were used alongside acupuncture to stimulate further salivation.

The results showed that 70% of the patients reported an improvement in the subjective symptoms and a low increase in UWS, ranging from 0.1 mL/min to 0.14 mL/min. Significantly, 26% of the patients maintained symptom relief for over three months without additional treatments.

Despite these promising outcomes, the study lacks a control group. Further, potential confounding factors, such as the use of lozenges, are used by the patients, therefore limiting the ability to isolate acupuncture’s effectiveness.

3.3. Innovative Therapies in the Treatment of Xerostomia

Several clinical trials were conducted to evaluate the capacity of the following innovative therapies against xerostomia (

Table 4. Innovative therapies.

Ref.	Interventions	Sample Characteristic	Study Design	Time Treatment	Daily Application	Time Points Assessment	Results
Alajbeg et al. 2012 [86]	Intraoral Electrostimulation	94 patients with non-homogeneous xerostomia	RCT	11 months	1, 5, or 10 min per session, up to once every hour	Baseline vs. 5, 8, 11 months of dressing	A significant improvement (p < 0.05), and in UWS (p < 0.001), and SWS (p < 0.05).
Strietzel et al. 2011 [87]	Intraoral electrostimulations vs. placebo	114 patients with Sjogren’s syndrome-induced dry mouth	RCT	5 months	10 min per session (up to 4 times daily)	Baseline vs. 1 month, and 5 months	A significant improvement in dryness severity (p = 0.0001) and UWS (p = 0.01).
Wong et al. 2015 [88]	ALTENS vs. pilocarpine	148 HNC patients with radiation therapy-induced xerostomia	RCT	12 weeks	Twenty minutes per day, (twice weekly)	Baseline vs. 4, 6, 9, 15 months after treatment	No significant difference
Dalbem Paim et al. 2019 [89]	TENS vs. standard care	68 HNC patients with radiation therapy-induced xerostomia	RCT	4 weeks	Twenty minutes per day (twice weekly)	Baseline vs. 1, 3, 6 months after treatment	A significant improvement QoL, and SWS (p < 0.0001)
Lakshman et al. 2015 [90]	TENS vs. no treatment	40 HNC patients with radiotherapy-induced xerostomia	RCT	During and after radiotherapy	5 min per session	Baseline vs. 3, 6 weeks of radiotherapy and 1-month post-radiotherapy	A significant improvement in salivary flow rate (p < 0.001);
El Mobadder et al. 2019 [91]	Photo-biomodulation	1 HNC patient with radiation therapy-induced xerostomia	CS	5 days	Five minutes per day	Baseline vs. 24 h of treatment	A significant improvement (p < 0.05)
Vidmar et al. 2022 [92]	HBOT vs. no treatment	18 HNC patients with radiation therapy-induced xerostomia	CT	20 days	Ninety minutes per day	Baseline vs. 3, 7 days after treatment	A significant improvement (p < 0.01)
Forner et al. 2022 [93]	HBOT vs. standard care	97 HNC patients with radiation therapy-induced xerostomia	RCT	6 weeks (first trial), 2 weeks (second trial)	Ninety minutes per day (five days/week)	Baseline vs. 3-month, 1 year	No significant differences
Grønhøj et al. 2018 [94]	Mesenchymal stem cells (MSC) vs. placebo	30 HNC patient with radiation-induced xerostomia	RCT	Single administration	N/A	Baseline vs. 1 month, and 4 months	A significant improvement in UWS (at 1 month, p = 0.048; at 4 months, p = 0.003) and xerostomia symptoms.
Lynggaard et al. 2022 [95]	Allogeneic adipose tissue-derived MSCs	10 HNC patient with radiation-induced xerostomia	OL	Single administration	N/A	Baseline vs. day 1, day 5, 1 month, and 4 months	A significant improvement in UWS (p = 0.0009) and SWS (p = 0.017)
Blitzer et al. 2024 [96]	Autologous IFNγ-stimulated bone marrow MSCs	6 HNC patient with radiation-induced xerostomia	First-in-human pilot clinical trial	Single administration	N/A	Baseline, 1 month, and 3 months post-injection	Improvement in salivary production (unstimulated saliva: +46% at 3 months) and QoL.
Jakobsen et al. 2024 [97]	Allogeneic adipose-derived MSCs vs. placebo	120 HNC patient with radiation-induced xerostomia	RCT	Single administration	N/A	Baseline, 4 months post-injection	A significant UWS increase for MSCs (p = 0.01); no significant difference between groups (p = 0.11).
Baum et al. 2012 [98]	Adenoviral-mediated aquaporin-1 gene therapy (AdhAQP1)	11 HNC patient with radiation-induced xerostomia	OL	Single administration	N/A	Baseline vs. days 7, 14, 28, and 42	Significant improvement in parotid saliva flow (p = 0.032).

).

3.3.1. Electrostimulation

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Electrostimulation in radiation-induced xerostomia

The capacity of electrostimulation to increase saliva has been studied in several trials. It is proposed that the electrical impulses can reach the salivatory nuclei of the medulla and subsequently the salivation control system. However, it is not clear how the electric current can affect gland function yet.

In one study, lingual nerve electrostimulation by an intraoral device resulted in an increase in the salivary production by stimulating the submandibular and sublingual glands.

In HNC patients with radiation-induced xerostomia, Paim et al. [89] reported a significant improvement in salivary flow using transcutaneous electrical nerve stimulation (ALTENS). Compared to the standard care control group, the electrostimulation improved both the QoL and the salivary flow.

Other studies conducted on patients suffering from radiation-induced xerostomia demonstrated that acupuncture had similar efficacy to pilocarpine for increasing saliva secretion [88]. Conversely, the increase in saliva fluid was non-significant in this study, although the toxicity of ALTENS was lower than that of pilocarpine.

Lakshman et al. (2015) [90] carried out a trial studying the capacity to stimulate saliva using a transcutaneous electrical nerve stimulation (TENS) unit. A total of 40 subjects who were to undergo radiotherapy for HNC were selected. The results of the investigation showed that the TENS therapy was effective in stimulating the salivary flow in conjunction with radiation therapy by reducing the side-effects of radiation therapy. Hence, TENS therapy can be used as an adjunctive method for the treatment of xerostomia along with other treatment modalities.

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Electrostimulation in xerostomia suffered in Sjögren’s syndrome

Strietzel et al. [87] evaluated the effectiveness of an electrostimulation device on 114 patients suffering from xerostomia due to Sjögren’s syndrome. The clinical trial showed that the daily application of the intraoral device resulted in alleviating the oral dryness, discomfort, and some other complications of xerostomia, such as speech and sleeping difficulties. Further, the device increased the salivary output.

3.3.2. Photobiomodulation

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Photobiomodulation in chemotherapy and radiotherapy-induced xerostomia

Photobiomodulation (PBM) is a novel approach that aims to modulate biological activities using light at red and near-infrared wavelengths. It is hypothesized that light energy is converted into metabolic energy, thus modulating cellular functions.

A case series has demonstrated that PBM can be beneficial in oral mucositis, dysphagia, burning mouth, oral dryness, and taste alterations [91]. Specifically, an increase in the amount of saliva at rest and the SWS was observed after the treatment [91].

Recently, a systematic review further supported these findings, indicating that PBM can improve salivary flow and reduce oral dryness. However, its long-term effects on saliva production remain unclear [99].

3.3.3. Hyperbaric Therapy

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Hyperbaric therapy in radiation-induced xerostomia

Hyperbaric therapy is a treatment method that aims to prevent oral soft tissue necrosis and osteoradionecrosis caused by radiotherapy [100]. The therapy works by improving blood circulation in postischemic tissues and by reducing edema. Moreover, it enhances oxygen diffusion in tissues and accelerates the activation of stem cells [92]. Such activities in irradiated patients can lower the risk of osteoradionecrosis following tooth extraction. Hyperbaric treatment may also improve salivary gland function, swallowing, taste sensation, and saliva volume.

Consequently, hyperbaric therapy has been investigated in several studies as a method of treating xerostomia. One study reported a relief in xerostomia and mouth pain scores using the therapy [101]. Forner et al. [93] and Bennet et al. [100] assessed the efficacy of hyperbaric therapy in stimulating the total saliva volume, decreasing the VAS score, and increasing the QoL. Additionally, Vidmar et al. [92] evaluated the influence of hyperbaric oxygenation therapy in patients undergoing radiotherapy for HNC. They utilized the T2 mapping MRI technique to detect salivary gland changes before and after hyperbaric therapy along with clinical salivary tests. The data revealed a statistically significant increase in UWS and buffering capacity of the saliva. However, additional research is required to precisely determine the efficacy of the therapy in treating dry mouth.

3.3.4. Stem Cell Therapy

Stem cell therapies are emerging as promising solutions for radiation-induced xerostomia. The therapy aims to restore salivary gland function through a regenerative mechanism and inflammation modulation. Mesenchymal stem cells (MSCs) are recognized for their ability to differentiate into multiple cell types and to secrete immunomodulatory paracrine factors. These properties have been the focus of various clinical trials exploring their efficacy and safety [102,103].

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Stem cell therapy in radiation-induced xerostomia

A study by Grønhøj et al. [94] was conducted on patients suffering from xerostomia after radiotherapy. The study explored the use of adipose-derived MSCs. In this randomized placebo-controlled trial, 30 patients received intraglandular injections of MSCs directly into their salivary glands. The primary endpoint was to assess the safety and tolerability of the MSCs, while the secondary outcomes were to assess the volume of unstimulated and stimulated salivary flow rates, and dry mouth relief from the therapy. The results demonstrated a significant increase in unstimulated saliva production and a marked improvement in xerostomia symptoms without major adverse events. The conclusions highlighted the therapeutic potential of MSCs in xerostomia due to radiotherapy.

In a similar investigation, Lynggaard et al. [95] conducted an open-label study involving 10 patients with xerostomia following radiotherapy for HNC. The intervention consisted of an injection of allogeneic adipose-derived MSCs into the submandibular and parotid glands. Over four months, the trial reported a significant increase in both unstimulated and stimulated salivary flow rates and an increase in the QoL of the patients. Importantly, no serious treatment-related adverse events were observed, underscoring the safety and feasibility of this approach.

Blitzer et al. [96] introduced a novel method involving autologous MSCs stimulated with interferon-gamma. Six patients with chronic xerostomia, who were treated with radiotherapy over two years prior to the study, received submandibular gland injections of MSCs. The study evaluated the safety and efficacy of the therapy in such a group of patients. The results indicated an improvement of salivary production and the QoL, demonstrating the potential of autologous MSCs in managing radiation-induced salivary gland damage.

Furthermore, Jakobsen et al. [97] conducted a randomized, double-blind, placebo-controlled trial involving 120 patients with hyposalivation due to radiotherapy for HNC. Patients randomly received either allogeneic adipose-derived MSC injections or placebo. While both groups experienced improvements in dry mouth symptoms, the MSC group showed a statistically significant increase in UWS compared to the baseline. However, no statistically significant difference was observed between the MSCs and the placebo groups, suggesting the need for further investigation.

-

Stem cell therapy in xerostomia suffered in Sjögren’s syndrome

MSC-based therapies have also been investigated for their efficacy in treating primary Sjögren’s syndrome.

A six-month randomized, triple-blind, and placebo-controlled trial involving 74 patients suffering from Sjögren’s syndrome evaluated the effects of injecting adipose-derived MSCs into the bilateral salivary glands.

The results demonstrated a significant improvement in salivary and lachrymal secretions as early as three months after the MSC treatment (p < 0.05). A reduction in the systemic inflammation markers were also observed in the MSC group. The patients reported a subjective improvement in dry mouth and eye symptoms, highlighting the local and systemic benefits of MSC therapy [104].

3.3.5. Gene Therapy

Gene therapy offers innovative approaches to address radiation-induced xerostomia. Some clinical trials have explored the use of a viral vector in delivering the aquaporin-1 (AQP1) gene into the salivary glands. This strategy enhanced saliva secretion and alleviated dry mouth symptoms [105].

-

Gene therapy in radiation-induced xerostomia

Baum et al. [98] conducted a phase I study involving 11 patients with radiation-induced xerostomia, testing the adenoviral-mediated transfer of the AQP1 cDNA to irradiated salivary glands. The salivary flow was assessed by measuring absolute volume (mL/min) and proportional changes compared to the baseline, while subjective symptoms of oral dryness and saliva presence were evaluated using a VAS.

The therapy resulted in significant improvements in salivary flow rates for six patients (p < 0.05). Additionally, five of these six patients reported reduced oral dryness and increased saliva presence on the VAS (p < 0.05).

Although gene therapy shows promising results in improving salivary flow and alleviating symptoms of radiation-induced xerostomia, further clinical trials are required to validate its efficacy and safety on a larger scale.

4. Discussion

In this overview, the past 10 years of literature regarding advancement in treating xerostomia using topical drugs, TM, and innovative treatments were reviewed. As a result of this research, it can be said that regardless of the great number of agents studied in the trials, as yet, no compound has reached the goal of relieving xerostomia in a stable way. This is true independently of the basal disease that causes evidence of dry mouth.

Through discussing the data, we suggest that a correct diagnosis is one of the most important steps in the management of xerostomia. It allows us to differentiate between patients with subjective complaints of xerostomia and those suffering from other forms of salivary gland disfunctions. In the analyzed trials, we observed that diagnosis and monitoring of xerostomia mainly focused on the measurement of the UWS, SWS, the VAS, and the QoL. However, since alteration to oral homeostatic mechanisms is the base of xerostomia, independently of iposalivation, subclinical changes in saliva composition, measurements of properties or components of saliva need to be searched in exposed patients to diagnose early forms. Alterations include changes in the fluid via rheological, adsorption, and tribological measurements, or biochemical changes in some components, i.e., salivary proteins, like lactoferrin and Mucin 5, to which the hydration capacity of the saliva is connected [26].

After this, preventive measures against the development of oral infections or damage to taste receptors have to be addressed. In this regard, it would be worth correcting or controlling hydration by water intake, the elimination of tobacco and alcohol, and eventual changes chronic therapies using xerogenic medications. In this context, daily water intake needs to be carefully considered with attention to dry mouth. In fact, daily water consumption strongly influences the body’s secretions, including glandular functions, and it is highly related to a series of complex mechanisms regulating homeostasis [106]. For these reasons, water is considered essential for life and health, and the European Food Safety Authority has revised the existing recommended intake of water to 2.0 L/day for females and 2.5 L/day for males. Although appropriate water volume cannot completely resolve dryness, considering the ingestion of adequate quantity of water per day could be necessary for reducing dry mouth.

Many different therapeutic managements of xerostomia aim to relieve oral dryness by retaining mouth moisture. With this intent, artificial salivary substitutes are frequently applied in dry mouth. They have been largely evaluated in trials in many types of patients suffering from xerostomia, including xerostomia after radiotherapy for HNC and xerostomia due to chronic drugs consumption. Saliva substitutes are formulated in various forms (i.e., gel, spray, or mouthwash) but regardless of the preparation, a collective limitation is the short activity time. Consequently, a frequent application of the agent is required by the patients to maintain stable coverage of the compound on the tissue.

Polymers are a fundamental part of the substitutes due to their pivotal role as thickening and lubricating agents. Conversely, mucoadhesive polymers (i.e., polymers, synthetic or natural) which can attach to mucosal surfaces are frequently used for prolonging the treatment effect [107].

Linseed mucilage has been extensively investigated for its ability to form highly viscous solutions in water. This property is attributed to the arabinoxylan composition of its mucilage, which provides resistance to the oral mechanical forces, as well as being lubricating and moisturizing. Nevertheless, the protective layer formed by the mixture tends to detach from the oral surfaces due to a lack of bonding between the biomolecules and the tissues.

Additionally, salivary stimulants containing acidic substances, such as citric and malic acids, are used to stimulate glandular secretion. These sialagogues are often enriched by sodium fluoride or xylitol to reduce the risk of demineralization by lowering saliva pH. Also, gustatory substances and aromas are included in sucking pastilles and chewing gums to mechanically increase the release of saliva. However, instead of being solubilized in saliva fluid to stimulate the activity of the salivary glands, the substances tend to precipitate as complex gelatinous mixtures in the oral surfaces. This results in a minimal secretory stimulus for chemoreceptors, as evidenced in several trials.

Pharmaceutical herbs possess a wide range of activities, justifying their widespread use as a remedy for oral and pharyngeal diseases. This has strengthened their potential for xerostomia treatment. However, from a scientific standpoint, only a few studies have documented the efficacy of medicinal herbs as recommended by popular tradition. Generally, the European Ethical Committee imposes modifications to the traditional remedy which, at the same time, may affect the efficacy of polyphenols in water extracts. An example of this is the exclusive administration of water extracts as gargles, rather than popular oral beverages. Obviously, the gargle may result in a reduction in the recommended dose range required by polyphenols to show their beneficial effects. TM remains to be verified as a capable method of antagonizing oral dryness. In fact, synergistic activity between polyphenols is capable of inducing hormesis mechanisms through a hormetic stimulatory dose range. In this way, the molecules are capable of providing multi-target benefits to restore the homeostatic systems in cells and tissues, affected by metabolic impairments or protein/peptide dysregulation [108,109,110]. Consequently, additional clinical studies conducted more closely to the traditional herbal intake patterns are needed to clarify the capacity of medicinal herbs to alleviate dry mouth.

Regarding acupuncture, the results are conflicting, and there is insufficient scientific evidence to support its effectiveness in significantly increasing the salivary volume in dry mouth. Further scientific evidence is also needed to prove the efficacy of innovative therapies including electrostimulation, photobiomodulation, and hyperbaric therapy. Stem cell therapy, and gene therapy are promising platforms for investigating new therapeutic solutions.

5. Conclusions

In conclusion, many of the analyzed treatments show a stable relief of xerostomia.

Specifically, salivary substitutes and stimulants can increase WBS and reduce the VAS scores, regardless the cause of xerostomia; but in any case, the relief obtained by the topical therapy demonstrates stability after the suspension of the agents.

The use of TM for treating xerostomia needs to be further verified. In fact, the modifications to the traditional remedies as they were used in the trials, may have affected the efficacy of the herbs against the disease.

Regarding innovative therapies including acupuncture, electrostimulation, photobiomodulation, and hyperbaric therapy, they are interesting proposals, but further scientific evidence is required in the near future. We have similar considerations regarding stem cell therapy and gene therapy, which are promising platforms for investigating new therapeutic solutions.

Consequently, the management of xerostomia and its devastating complications remain a significant void in daily clinical practice.