Xerostomia - Non-Pharmacological Treatment Modalities and Its Review

Introduction

In 1868, Bartley introduced the term "dry mouth". Later in 1889, Hutchinson coined the term "xerostomia". Xerostomia is a medical term for the individual complaint of dry mouth due to salivary gland hypofunction. It is a symptom of oral dryness that occurs when salivary flow is insufficient to remunerate fluid loss from the oral cavity.¹

The literature proposes that the two are not inescapably concurrent and their frequency may change. Rationally, xerostomia occurs because of reduced salivary flow, but both the subjective (xerostomia) and objective (salivary gland hypofunction) factors are known to occur independently of each other. In a systematic review, the prevalence of dry mouth ranged from 8 to 42, although the prevalence of salivary gland hypofunction ranged from 12 to 47.² The prevalence of both conditions is approximately 2% to 6%. There is a sex difference in xerostomia, where the reported prevalence of xerostomia is lower in men (10 – 26%) than in women (10 – 33%).^2,3

The triggers of xerostomia can be categorized into iatrogenic, developmental, systemic, or local factors. The most common reasons for dry mouth include xerogenic medications, radiation therapy for head and neck cancer, and systemic conditions, for instance, various connective tissue diseases. Irradiation of the malignant tumors of the head and causes damage to the salivary gland resulting in a dry mouth. Systemic conditions for example diabetes mellitus and chronic renal failure can result in dehydration and thus cause dry mouth. Other causes include sarcoidosis, hepatitis C virus infection, and Sjögren syndrome. Additionally, there are physiological causes of dry mouth, such as anxiety (due to sympathetic activity), mouth breathing, and salivary gland agenesis. More than one factor can be responsible for dry mouth in a patient (Table 1).⁴

The partial or total loss of saliva causes several oral consequences, demonstrating an uncomfortable feeling of dryness within the mouth and hence presenting several signs and symptoms primarily in the mucous membranes, tongue, lips, teeth, and salivary glands (Table 2).⁵

Non-Pharmacological Treatment Modalities

There are two treatment modalities for xerostomia, pharmacological and non-pharmacological. Pharmacological treatment offers only symptomatic relief, and symptoms reoccur after discontinuation of prescribed medications. Newer non-pharmacological interventions increase salivation and improve the symptoms related to xerostomia. In the last few years, non-pharmacological methods have been developed for the management of xerostomia to improve symptoms as compared to pharmacological methods.6,7 This review aims to present new developments for managing xerostomia.

1. Acupuncture

Acupuncture means “to puncture with a needle,” which is an important element of complementary medicine and has gained popularity in recent times as an available palliative intervention modality. Emerging reports are effective in treating xerostomia.

Acupuncture has been shown to increase salivary flow in healthy volunteers, in patients with Sjogren’s syndrome and with radiation-induced salivary gland injury.⁸ It involves the insertion of extremely thin solid needles into intradermal or subdermal loci for therapeutic relief of many symptoms by activating neurons in the parasympathetic and sympathetic nervous systems. Additionally, this treatment initiates the release of neuropeptides (vasodilator calcitonin gene-related peptide) with anti-inflammatory properties and trophic changes on the salivary gland resulting an increase in blood flow in the acini. Additional explanation for this is that acupuncture affects the blood flow locally in the proximity to the salivary gland and hence increases salivation.⁹ Figure 1 presents the basic steps of Acupuncture.

In a study involving 5 randomized controlled trials (with a total of 153 participants who had dry mouth following radiotherapy treatment), acupuncture was compared to placebo. Out of these trials, two reported outcome data suitable for meta-analysis. The collective estimation of these two trials, which included 70 participants, showed no significant difference in symptoms of dry mouth between the control and acupuncture groups. However, there was a slight increase in unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) towards the end of the treatment period (i.e., after 4 to 6 weeks) as reported in three trials with 71 participants. This advantage was found to persist even after the 12-month follow-up assessment in two trials comprising of 54 participants.^7-10

2. Electrical Stimulation

Electrical activity is necessary for the development, function, and survival of the neurons. Electrostimulation is a technique used to increase the salivary output in patients with xerostomia. Transcutaneous electrical nerve stimulation (TENS) is a physical and noninvasive method for electrical stimulation of nerves via electrodes applied to the skin.¹¹ It has been known that electrical stimulation (ES) may be a common rehabilitative approach for restoring the function of muscle and neural tissues. Cardioversion and defibrillation have also illustrated the huge therapeutic potential of ES. It can be aimed to produce saliva in salivary hypofunction.¹²

In ES, a handheld battery-operated device generates an electrical stimulus to the oral mucosa (dorsum surface of the tongue). Alternatively, a TENS device can be used by connecting electrodes to the skin. It has been proven that electrical impulses applied to one or more arms of the salivary reflex arch result in increased salivary gland secretion. Electrostimulation of the lingual nerve, stimulates the submandibular and sublingual glands to increase the flow of saliva.¹³

1st Generation

Neuro electro stimulation to increase salivary secretion led to the production of a device that causes salivary stimulation. The probe is applied to the intraoral mucosal surfaces between the tongue and the palate. It delivers a stimulating signal to sensory neurons of the mouth which induces salivation.

2nd Generation Devices

It is a removable intraoral appliance produced for individual patients by using their teeth-pattern molds. It is similar to a mouth guard and has a horseshoe-like shape that fits on the lower dentition. Electronic components are embedded inside the appliance for safe and contamination-free applications intraorally. A remote control helps the patient to communicate with the device and adjust its functions.

3rd Generation device (dental implant based)

It was developed for constant stimulation of the salivary glands in the form of neuroelectric-stimulating device which is implanted inside the oral cavity. An implant is positioned in the lower third molar region in close proximity to the lingual nerve, which on stimulation causes salivary secretion.¹⁴

Two randomized controlled trials (RCTs) were conducted with a total of 101 participants diagnosed with Sjogren's Syndrome. The studies compared the use of an electrostimulation device with a placebo device, but neither study reported the effect on dry mouth. One of the studies found no significant difference in the salivary flow rates of stimulated whole saliva (SWS) or unstimulated whole saliva (UWS) between the electrostimulation and placebo groups at the end of the 4-week treatment period.^11-13

3. Powered Toothbrushes

Dr. Philippe of Switzerland invented the first electric toothbrush called BROXODENT in 1954. The toothbrush operates at an audible range of 20-20,000 Hz per minute. A powered toothbrush can be powered by either AC or battery and typically features a handle containing a motor that provides mechanical movement to the toothbrush head with filaments that move rapidly. Table 3 presents the generations of powered toothbrushes.¹⁵

It is thought that there are four possible nerve pathways for sonic vibration to be involved in salivary stimulation.

1. First - sonic vibration may overcome medicationinduced inhibition of the salivary reflexes, thereby increasing the normal physiological reflexes.

2. Second - sonic vibrations cause “reflexive depolarization of the autonomic nerve endings within salivary glands”.

3. Third - vibration causes tactile stimulation of the nerve (trigeminal), and

4. Finally - vibration also induces stimulation of gustatory receptors.¹⁶

Sialitron is a saliva-stimulating system that is found to increase salivation within a period of three-minute electrostimulation. However, it is not currently available because of its cost-effectiveness for the general population; hence, its effect cannot be judged. Papas et al. in 2006, studied the outcome of powered toothbrushes Sonicare in the xerostomia population to stimulate salivation and found it to be useful. In the end, it is supposed that the use of Sonicare® toothbrush is useful in managing salivary hypofunction.¹⁷ A single study compared the stimulatory effect of powered and manual tooth brushing and found no significant difference in the results of UWS or SWS after brushing.6

4. Lasers

Photo biomodulation or low-level laser therapy has been widely used as the newest, non-invasive, and valuable tool for the reduction of xerostomia. Photo biomodulation exerts positive effects upon growth factors or cytokine release, and therefore may stimulate cell proliferation and differentiation; hence, its application to salivary glands can improve salivation.¹⁸

The advantages of photo biomodulationare include improved cell mitosis in the epithelium, an increase in salivary ducts, and stimulation of synthesis of protein in salivary (submandibular) glands. It also increases anti-apoptotic protein expression, calcium levels intracellularly, and blood circulation in the salivary glands which leads to salivary gland regeneration and improved functions. The most commonly used lasers are Ga-As laser and HeNe laser.¹⁹ Figure 2 presents the steps involved in Laser therapy.

A review of 25 articles revealed that low-level laser therapy (LLLT) has positive effects, including the significant enhancement of salivary secretion. The current literature suggests that LLLT can be safely and effectively utilized as an advanced treatment option to reduce symptoms of xerostomia. However, further in vivo, in vitro, and clinical studies are recommended to determine the optimal laser parameters that should be used.²⁰

5. Hyperbaric Oxygen Therapy (Hbot)

HBO therapy utilizes the basic physiologic principles of gases, their response underneath pressure, and more precisely, how oxygen will respond to pressure. The increased concentration of oxygen in a solution increases the diffusion gradient for its transport into deeper tissues, which is the foundation of HBOT and effects that alter tissue responses to diseases and injury. Nowadays it is a more advanced therapy and becomes further available to clinical practice.²¹

Approximately, 97% of oxygen is normally transported bound to haemoglobin (Hb), and only a small portion of it is transported in solute. The reason of using HBOT is used because of its ability to increase the O₂ from 3 ml/L at normal ATA up to 60 ml/L at 3 ATA of pure oxygen carried in the solute. Since O₂ is present in the solution,

1. it enters blocked areas that are not reached by red blood cells and

2. facilitates oxygenation of tissues with impaired Hb oxygen carriage.

HBOT can hence be useful in reinstating natural homeostasis in hypoxic tissues due to the following mechanism: -

1. inducing angiogenesis,

2. increasing O₂ tension,

3. collagen synthesis, and

4. stem cell recruitment.

Repair of vascular supply towards salivary gland dysfunction brought by radiotherapy enables the tissue regeneration, restoration of normal salivary flow, and thus improves the quality of life of these patients by governing the complications induced by hyposalivation.²²

A pilot study was conducted at the Copenhagen University Hospital to evaluate the effect of hyperbaric oxygen therapy (HBOT) on salivation in previously irradiated head and neck cancer patients, based on spontaneous and subjective reports of improvement in dry mouth. The study data indicated a significant decrease in hyposalivation and xerostomia among the evaluated patients. So far, seven studies (comprising 246 patients) have reported that HBOT induces longterm enhancement in subjective assessments of dry mouth. However, due to the limited number of randomized controlled clinical trials, the strength of these studies is somewhat constrained. Additionally, while other currently available therapies only provide short-term relief, HBOT has shown promising potential in providing long-term benefits.⁶

6. Gene Therapy

One of the key features of salivary gland dysfunction is the loss of functional water channels in the salivary gland epithelium. In order to restore this permeability and increase the production of saliva, the first study on salivary gland gene therapy was conducted in 1997. This method utilizes the human AQP1 gene to be administered into the submandibular gland of donor Wistar rats via recombinant adenovirus delivery (AdhAQP1). Preclinical studies in rats & pigs have demonstrated that gene therapy helps in recovering salivary gland dysfunction.²⁴

In the first published clinical trial, 11 patients who had been treated with radiotherapy were assessed previously following AdhAQP1 vector delivery to the parotid gland. Their response was good, there were only mild to moderate adverse effects and no deaths were reported. Five of the 11 subjects experienced a subjective improvement in their symptoms of xerostomia, indicating the success of gene therapy, its safety issues, and tolerance. Neutralisation of inflammatory mediators through gene therapy is also a therapeutic approach for patients with the Sjogren syndromic patients. Neutralisation of inflammatory mediators such as B-cell–activating factors and proliferation-inducing ligands in an animal model of Sjogren’s syndromic patients led to significantly reduced CD138+ inflammatory cells and a decrease in IgG and IgM levels in the salivary glands. In addition to replacing the missing components of the salivary glands, protective growth factors are administered via growth factors. Delivery of human keratinocyte growth factor (hKGF) via adenoviral vector was protective against IR-induced SMG dysfunction, and salivary flow, measured following pilocarpine stimulation, was similar in mice administered the AdLTR (2) EF1α-hKGF vector compared with nonirradiated control animals. Recent studies showed that transfer of the HKG-Factor (human keratinocyte growth gene) reduced post-irradiation xerostomia in a mouse model.²⁵

7. Transplantation of Salivary Gland Stem Cells

Cell transfer therapy with stem cells is a probable method for compensating lost parenchymal cells in damaged organs/ tissues. These cells have been widely used in regenerative medicine because they have self-renewal and multipotency functions; hence, they are proficient in generating daughter cells constituting an organ/tissue for their lifetime.²⁴

Stem cells can be classified as follows:

Tissue stem cells – these are organ-specific cells, that reside in a tissue and are capable of compensating for the lost cells by turn over with new cells in order to maintain tissue homeostasis. In addition, these stem cells can proliferate and supply new cells whenever a tissue is injured. They are located in a niche essential for maintaining stemness. They divide asymmetrically to develop new daughter cells:

1. one cell - original stem cell

2. the other cell - daughter cells that can differentiate into tissue cells.

Embryonic stem (ES) cells – which were initially established from the inner cell mass of blastocystsin 1981. These cells are pluripotent and can differentiate into three different germ layers:

1. ectoderm,

2. mesoderm

3. endoderm

These cells are a promising resource for regenerative medicine as they proliferate infinitely within a normal euploid karyotype under undifferentiated conditions.

Induced pluripotent stem cells (iPS) - Human iPS cells have been found to be an attractive cell source because they possess ES cell-like proliferative ability and pluripotency. The best thing about this is that it can be established from the patient’s own somatic cells.²⁶

Current clinical applications: Salivary gland regeneration by stem cells has never been useful in many clinical trials, although MSCs have been applied in numerous clinical trials. Adipose-tissue-derived stem cells (ADSCs) have been used for clinical trials of irradiation-induced salivary gland hypofunction in patients with cancer of the head and neck region. Phase I/II studies have been started to evaluate the safety and activity of cell therapy using ADSCs. Thus, although there have been very few clinical trials that use stem cells for the treatment of xerostomia, cell therapy using MSCs will be encouraged for the management of this xerostomic patients.²⁷

Mesenchymal stem cells infusion was performed in 24 patients with primary Sjögren’s syndrome. All patients showed improvement in symptoms after 2 weeks up to 6 months, with no reported side effects. The flow rate of saliva was seen to be increased within one year of follow-up. This research holds tremendous promise for the future of xerostomia, additional studies are required for the conclusion.^27,28

Conclusion

Upon encountering patients with dry mouth dentists face a problem that is difficult to treat. Treatment with pharmacological methods (lubricants, salivary substitutes or drugs) generates improvement; however, xerostomia reoccurs once the treatment is interrupted. Non-pharmacological methods such as acupuncture and electrostimulation have revealed positive results in reviews. Alternative treatments such as HBOT, LLLT provide promising results by promoting salivary flow. Finally, exciting new areas of regenerative medicine such as gene therapy, and stem cell transplantation are opening up new possibilities for xerostomia. While research is still focused on animal models, future applications in human clinical trials will be important in advancing the field of prevention and treatment of xerostomia.

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Conflicts of Interest

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