Therapeutic Strategies for Dry Mouth Management with Emphasis on Electrostimulation as a Treatment Option
Objectives. Xerostomia is a subjective sensation of dry mouth. It is commonly associated with salivary gland hypofunction. Both changes in the composition of the saliva and a reduction in the quantity secreted may be an objective finding of dry mouth. Although there are no currently available cures for the conditions resulting in dry mouth, there are several treatment options that give hope for patients who suffer from xerostomia. Individuals with some residual salivary gland function, which are contraindicated to pharmacological therapies, would benefit the most from identifying novel, alternative effective methods for stimulating production of saliva. The aim of this study was to give an overview of the latest and most relevant data related to treatment modalities for the management of dry mouth conditions. Data Resources and Study Selection. The present review was prepared by searching the National Library of Medicine database using the relevant medical terms and their combinations. A total of thirty-three studies met the inclusion criteria. Data were extracted by one author and verified by another. Conclusion. A number of patients showed positive treatment outcomes, and the adverse effects of both electrical stimulation (ES) and acupuncture have been reported as mild and transient. In patients who have undergone radiotherapy, acupuncture is shown to increase salivation. However, in patients with Sjogren’s syndrome, the effects of ES devices seem to be elusive. Moreover, due to the instability of the findings in relation to longevity of clinical effect, patient satisfaction, quality of life, and clinical effectiveness of such treatments, the results remain vague.
1. Saliva and Oral Implications
The multiple functions of saliva, which are linked to its specific components and fluid characteristics, are crucial for maintaining the hypotonic environment; remineralization of dental enamel; control of the composition of oral microflora with its antibacterial, antiviral, and antifungal properties; mastication and swallowing; digestion of food; articulation of speech; and many other functions [1–4]. Approximately 0.6 L of saliva is excreted daily by major and minor salivary glands [5, 6].
The secretion of salivary components is dependent upon the autonomic nervous system and regulated by several reflexes. The masticatory and gustatory afferent impulses, and thermoreceptive, olfactory, nociceptive, and psychic stimuli influence activation of the salivary gland cells [7–9]. These afferent sensory impulses are transmitted to the salivation center in the brainstem (parasympathetic), to the upper thoracic segments of the spinal cord (sympathetic), and to higher brain structures, which may react with both inhibitory and excitatory efferent signals to the salivatory nuclei and thereby salivary glands .
Furthermore, the function of salivary glands is under the influence of many stimuli and factors, which can affect the flow, volume, and composition of saliva. It has been shown that the expression of aquaporin 5 and of specific clock genes involved in the regulation of circadian rhythms is subject to diurnal pattern in gene expression in mouse submandibular gland cells . Thus, it is suggested that the molecular underpinnings orchestrating normal salivary secretion may be influenced by the circadian clock, which also may play a role in different pathologies of salivary glands . The size of the glands and the level of hydration of the body are other factors related to salivary flow rates [13–16].
From the clinical aspect, both changes in the composition of saliva and a reduction in the quantity secreted may be an objective finding of dry mouth [17, 18]. Dry mouth is a common problem in the general population with a prevalence between 10% and 33%, being more common in females [19, 20]. Although xerostomia more frequently affects the elderly, it may also be present in young adults [21, 22]. The subjective sensation of dry mouth in the older population may probably be attributed to other factors than age-related degenerative changes . The higher prevalence of chronic conditions and the resultant general “polypharmacy” with wide use of various anticholinergic medications are considered as important factors [20, 24]. Several medications, including commonly prescribed preparations, such as those used to treat hypertension, epilepsy, and depression, are reported to cause dry mouth through different mechanisms [20, 24].
In general, causes of xerostomia can be divided into two main groups: nonsalivary and salivary . Nonsalivary causes of oral dryness may include dehydration, anxiety, mouth breathing, and neurological dysfunction , whereas the salivary causes of dry mouth are associated with pathological changes in salivary glands. A number of patients with systemic autoimmune diseases such as Sjogren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and sarcoidosis suffer from dry mouth [25, 26]. Exocrine glands in those patients become infiltrated with immune cells, predominantly CD4+ lymphocytes T-cells. The lymphocytes further induce the production of different cytokines that alter saliva secretion . Simultaneously, an increased activity of certain matrix metalloproteinase, with a decrease in production of tissue inhibitors of such proteolytic enzymes, is found in those patients . Disturbance of saliva production is also reported in patients with diabetes mellitus, obesity, hypertension, chronic kidney disease and chronic heart failure [29–34]. Common in those patients is increased predisposition to oxidative stress. Products of oxidation can aggregate and accumulate in the salivary glands leading to damage of secretory cells and increase in the formation of reactive oxygen species. This may enhance local oxidative stress even more [35–37].
A noteworthy correlation was found between salivary gland hypofunction, followed by xerostomia and patients suffering from dementia [38, 39]. One plausible explanation is that neurological centers orchestrating function of salivary glands are impaired in those patients. However, this field requires more research in order to draw affirmative conclusions.
Xerostomia was reported in majority of COVID-19 patients. Since the virus has neuropathic and mucotropic effects on the salivary gland tissues, it is hypothesized that it alternates the structure and function of the gland at some point. As xerostomia occurs prior to other common symptoms of infection, this information could be used as an early diagnostic mark .
Since the treatment of chronic diseases becomes more effective and the life expectancy increases, it is also reasonable to assume that the number of people living with xerostomia will be higher [20, 23]. Dry mouth conditions may impact the quality of life in several ways. This includes difficulties with speech, chewing, and swallowing of food, due to the dehydrated mucosa . Taste sensation can be impaired and tenderness of the oral mucosa and gums makes the wearing of dentures difficult. Infections in salivary glands, oral candidiasis, and increased incidence of root caries have been reported [18, 43, 44]. A positive correlation between xerostomia and/or hyposalivation and caries activity in a population of younger adult patients has been shown recently . Patients with subjective sensation of dry mouth complain of burning mouth syndrome . Furthermore, psychological discomfort and impaired sleep may be another consequence. Finally, majority of patients can feel stigmatized, as their condition is often not taken seriously by others. This leads to social withdrawal and diminished self-esteem . Effective treatment of patients with dry mouth is therefore important in order to improve the quality of life of sufferers, and, in addition, from both a patient and public health perspective it is of outmost importance to treat dry mouth symptoms and minimize potentially painful oral infections and costly tooth loss.
Since xerostomia may affect the quality of life in individuals, the main aim of this study was therefore to provide an overview of the latest and most relevant findings related to treatment modalities for the management of dry mouth conditions.
2. Data resources and Study Selection
Data collected from the National Library of Medicine database were used in this study. The search was conducted with the different combinations of the following terms: (“dry mouth” OR “xerostomia” OR “hyposalivation”) AND (“treatment”) AND (“electrical stimulation” OR “electrotherapy” OR “acupuncture”) in an attempt to reveal relevant publications. The search was performed without restriction with regard to the language and study design. Selection criteria included articles published from 1981 to the present year. Primary search yielded 187 studies. All authors thereafter reviewed the titles and abstracts of the selected articles. Eventually, duplicates were excluded. Articles were also rejected if they were clearly unqualified. In case where updated versions of the paper were found, older versions were rejected. The authors then reviewed the remaining articles to determine their eligibility. Finally, thirty-three studies were accessed.
2.1. Current Treatment Options
Although there are no currently available cures for the conditions resulting in dry mouth, different treatment options give hope for patients who suffer from xerostomia. The most commonly used approaches are the use of salivary substitutes and increased fluid intake, which aim to treat the symptoms. Some individuals may manage the problems associated with dry mouth through optimal handling of the underlying conditions . For patients with milder symptoms, frequent sips of water and sucking of ice chips may result in sufficient relief . It is recommended to reduce/avoid the consumption of alcoholic drinks, caffeine, and smoking as they additionally dehydrate the oral mucosa [47, 48]. Topical application of oral rehydrating agents acts directly on the surface of the oral mucosa and may provide short-term relief . It has been shown that the use of oral moisturizers and toothpastes result in significant improvements in whole unstimulated salivary flow rate, a decrease in colonization with Candida, and a subjective improvement of xerostomia in patients with primary Sjogren’s syndrome and subjects that had undergone radiotherapy for head and neck cancer [49, 50]. It is important to note that the utility of artificial saliva products is to some extent limited in xerostomia treatment, due to the different composition of artificial saliva compared to human saliva with respect to pH values, osmolality, and electrical conductivity .
The symptomatic treatment of xerostomia by means of topical medications stimulating saliva production or increased fluid intake may be sufficient for patients with some degree of preserved salivary gland function . However, in patients with permanent destruction of salivary acini, in addition to palliative therapy, other forms of both local and systemic treatment may be necessary in order to induce secretions from the remaining salivary gland tissue. The two most common systemic agents are pilocarpine and cevimeline, which both act as the agonist for the muscarinic receptors on the surface of the salivary cells . Several clinical studies have demonstrated that the use of pilocarpine results in significant improvement in symptoms associated with xerostomia [53–55]. However, since it is a cholinergic agent, it is associated with several side effects like increased sweating and lacrimation, frequent urination, nausea, headache, rhinitis, and gastrointestinal disturbances . Cevimeline is an analog of acetylcholine and gives the same amount of relief from symptoms of dry mouth as pilocarpine. However, due to its high affinity to the M3 sub-receptor type, which is specific to the salivary gland tissue, it has fewer side effects compared to pilocarpine . Bethanechol and anethole trithione are other drugs that exert their function via the parasympathetic system and have been shown to have some effect on dry mouth symptoms . A study conducted on head and neck radiation therapy patients treated with either bethanechol or pilocarpine suggested that both medications have nearly the same effect on saliva production . It is also worth mentioning another medicine, amifostine, currently the only medicine used in an attempt to prevent xerostomia in radiation therapy patients, due to its ability to scavenge free radicals .
Gene therapy in the treatment of dry mouth is based on delivery of genes into the salivary glands. Although it may become a therapeutic strategy for radiation-induced salivary hypofunction in the future, current therapies are primarily experimental, with most studies performed in animal models . One clinical trial employing gene delivery to salivary gland in head and neck irradiated participants studied gene transfer utilizing the first-generation serotype 5, adenoviral (Ad5) vector coding for human aquaporin-1 (hAQP1) . AQP1, expressed in the myoepithelial and endothelial cells of the human [61, 62], is a water channel protein that facilitates fluid transfer by an osmotic gradient . Delivery of AdhAQP1 vector to a single parotid gland was found to be safe and the results demonstrated that the transfer of the hAQP1 cDNA increased the flow in parotid gland and relieved symptoms in a subset of patients . The improvements in these patients persisted for several years after the one-time treatment. At present, there are two ongoing clinical trials evaluating the delivery of aquaporin-1 (AQP1) via adeno-associated viral vector 2 (AAV2) to the parotid gland in human patients with radiation-induced salivary gland hypofunction [65, 66]. Both studies are in phase 1 with the estimated study completion in 2022.
Another potential approach in regeneration of salivary gland tissue is the use of stem cells. Although clinical trials are mostly in its early phases, the obtained results in radiation-induced xerostomic patients seem to be promising . The stem cells used in dry mouth treatment are mainly mesenchymal/stromal cells harvested from umbilical cord blood, bone marrow, or adipose tissue [68–71]. However, due to their potential to metastasize to other tissues, the long-term safety of these cells is yet to be investigated.
The quality of life of a patient suffering from radiation-induced xerostomia may be significantly reduced. Therefore, the use of low-power laser light for analgesive and anti-inflammatory effect has been suggested. The laser light that is transformed into energy for the cells improves microcirculation, glandular cell proliferation, cellular respiration, ATP production, protein synthesis, and intracellular calcium levels . Having in mind that this technique is noninvasive and noncostly, it could be used in xerostomia treatment.
Intraglandular administration of botulinum toxin prior to radiation treatment is another promising approach in the treatment of radiation-induced xerostomia. Although the mechanism of action is not yet clear, it is suggested that botulinum toxin reduces nerve stimulation and saliva production, thereby reducing the sensitivity of glandular cells to radiation. However, agreements for the use of this technique are still in the establishment phase [73, 74].
2.2. Electrical Stimulation as a means for Treating Dry Mouth
Electrical activity is essential for the development, function, and survival of neurons . Already in 1791, Luigi Galvani`s animal experiments demonstrated that the application of electrical current resulted in contractions in the muscles of frog legs. Since then, it has been known that electrical stimulation (ES) may be a common rehabilitative strategy to restore function in muscle and neural tissues. Cardioversion and defibrillation further illustrate the huge therapeutic potential of ES in medicine, and evolving research has provided evidence that ES of the eye may be a promising therapy for either preserving or restoring vision in several retinal and optic nerve diseases .
Electrostimulation of the salivary glands and acupuncture aim to increase the production of saliva. In ES, a hand-held battery-operated device is used to provide an electrical stimulus to the hard palate or dorsum of the tongue. Alternatively, a transcutaneous electrical nerve stimulation (TENS) device may be utilized by connecting the electrodes to the skin and may be used either in clinical setting or in the patient’s home. Acupuncture and ES have been shown to exert both clinical and biological effect with regard to the treatment of dry mouth [44, 77]. It has been demonstrated that application of electrical impulses to one or more arms of the salivary reflex arch may result in increased secretion of saliva . ES of the lingual nerve, i.e., the efferent trigeminal fibers, may stimulate the sublingual and submandibular glands to increase salivation . Regarding acupuncture, it is suggested to induce physiological effects such as increased peripheral blood flow and stimulation of the autonomic nervous system, which in turn may lead to increased production of saliva .
The beneficial effects of noninvasive ES in patients with xerostomia due to Sjögren’s syndrome and radiation therapy have been reported previously, which sparked a research interest in the effects of ES in clinical studies for treating dry mouth . The methods include therapies such as acupuncture and acupuncture-like TENS , both of which focus on specific points in and around the head and neck region and aim to stimulate the parasympathetic innervation of salivary glands. The first study on acupuncture for the treatment of xerostomia was reported in 1981 , and since then, many studies using this method have reported an increase in salivary flow rate in both healthy and diseased patients (Table 1). Blom and collaborators showed that the effects of acupuncture resulted in relief for patients who have undergone head and neck radiation therapy and in individuals with Sjogren’s syndrome. The study also demonstrated that the relief reported by the patients continued for up to six months posttreatment . Another study reported that the use of acupuncture in patients with xerostomia increased the amount of calcitonin gene-related peptide in saliva , a protein known to positively affect the salivary flow and provide beneficial trophic effects on the oral mucosa. Three other controlled trials studied the therapeutic efficacy of acupuncture in patients that exhibited radiation-induced xerostomia [84, 90, 96]; however, they all exhibited the high risk of bias due to the overall poor reporting of blinding and randomization. A single-blinded study showed no significant difference in salivary flow in the active acupuncture group compared with control patients (sham acupuncture) after six weeks of twice-a-week acupuncture treatment . Furthermore, Simcock et al. investigated the effects of eight weeks of once-a-week acupuncture compared to the effects of the use of artificial saliva, and they reported an improvement in xerostomia symptoms in acupuncture patients compared to controls . However, in this study, the magnitude of the improvement, as well as clinical significance, was indistinct. No statistical difference in salivary flow between individuals randomized to twelve weeks of real or sham acupuncture was also reported by Blom et al. in 1996 . A recent study from 2019, a randomized clinical trial, found that true acupuncture resulted in significantly fewer and less severe symptoms one year after treatment vs standard care control and sham acupuncture in radiation-induced xerostomia patients, although authors reported inconsistence in results with sham acupuncture and suggested further research to confirm their findings clinically .
Acupuncture-like TENS perform the same objective as acupuncture without using the needles and has been shown to be effective. Wong and colleagues utilized a method termed Codetron to deliver electric nerve stimulation twice a week for six weeks to patients with symptomatic xerostomia resulting from radiation therapy . They evaluated the residual salivary function and the results demonstrated statistically significant improvements in both subjective complaints of dry mouth and salivary flow rates for up to six months after treatment . Another study investigated the effects of twelve weeks of acupuncture-like TENS (twice per week for a total of 24 sessions of 20 min each) versus pilocarpine and showed no significant difference in salivary flow or xerostomia-related quality of life scale score between the groups . However, this study lacked the detailed information regarding the blinding, sequence generation, and allocation concealment.
3. Conclusion and Future Perspectives
Xerostomia, a symptom of dry mouth, is a condition that at present has no definitive means for treatment. Several inductive and palliative treatment approaches appear to be effective for reducing the morbidity associated with xerostomia. Most of the available treatment options are quite simply transient and are not considered to be an optimal treatment option. The present review has its limitations. The studies included in the work were reported between 1981 and 2021 and the patient population has changed during this time. Furthermore, the radiotherapy modalities have also progressed, where patients included in the most recent studies receive lower radiation dosage to salivary tissues.
So far, there is poor evidence on the effects of any of the interventions included in this review on patients with xerostomia. A number of patients with xerostomia show some indications of positive outcomes of these treatments, and the adverse effects of both ES and acupuncture have been reported as mild and transient. In patients who have undergone radiotherapy, the acupuncture is shown to increase salivation. However, in patients with Sjogren’s syndrome, the effects of ES devices seem to be elusive. Moreover, due to the instability of the findings in relation to longevity of clinical effect, patient satisfaction, quality of life, and the clinical effectiveness of such treatments, the results remain unclear. Further well-designed and conducted double-blind studies are warranted in order to understand the benefits of these treatment modalities (Figure 1).
|TENS:||Transcutaneous electrical nerve stimulation|
|SFR:||Salivary flow rate|
|ALTENS:||Acupuncture-like transcutaneous electrical nerve stimulation|
|VAS:||Visual analog scale|
|SSF:||Stimulated salivary flow|
|SPSF:||Self‐perception of salivary flow|
|QL:||Quality of life|
|XeQoLS:||Xerostomia-related quality-of-life scale|
|WSP:||Whole salivary production|
|MFR:||Months from randomization|
|IFCS:||Interferential current stimulation|
|LI4:||Large intestine 4|
|CV24:||Conception vessel 24|
|NMES:||Neuromuscular electrical stimulation.|
Conflicts of Interest
The authors declare no conflicts of interest.
AT, AM, MH, TPU, and AS equally contributed to the conception, design, data acquisition, and interpretation, and drafted and critically revised the manuscript. All authors gave their final approval and agreed to be accountable for any aspect of the present review.
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