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Many patients report the subjective feeling of dry mouth, which oral healthcare practitioners (OHCPs) often refer to as xerostomia.1,2 In reality, though a disruption in the amount or quality of saliva being produced is related to patient-reported xerostomia, from a pathophysiological standpoint it may be more correctly diagnosed as salivary gland dysfunction. Salivary gland dysfunction routinely manifests as salivary gland hypofunction (a reduced volume of saliva secretion) or a change in salivary composition.3 The objective presentation of salivary gland hypofunction, however, is not an absolute indicator of the subjective reporting of xerostomia.4,5
The clinical method most often employed to diagnose salivary dysfunction is a sialometry test, and a definitive diagnosis of hyposalivation is made when unstimulated salivary flow rates are less than 0.1 mL/minute or 0.7 mL/minute under stimulation.6 Although xerostomia, defined as the subjective report of a dry mouth, is often associated with hyposalivation, many cases of xerostomia have been described in patients with a normala salivary flow.7-9 Xerostomia, therefore, is the subjective sensation of dry mouth, whereas hyposalivation is a pathological condition in which there is insufficient or decreased production of saliva. In many though not necessarily all cases, the subjective report of xerostomia may correlate with a decrease in the amount of saliva, while there may be instances where patients report xerostomia without hyposalivation, which could be because of alterations in salivary composition.2,4
Symptoms of dry mouth may range from mild oral discomfort to significant oral disease that can negatively impact a patient's health, dietary intake, and quality of life.10-14 Five percent to 46% of the population experiences xerostomia, and factors such as age, gender, systemic diseases, and medications play significant roles in correctly diagnosing this presentation.15-18Identifying and treating the underlying causes of dry mouth are paramount to providing optimal, targeted oral healthcare. Effective prevention, early detection, and treatment of the oral sequelae associated with dry mouth require aggressive management by both dentist and patient along with interdisciplinary care. While symptom relief and salivary stimulation comprise most of the contemporary treatment options, newer products and strategies are being investigated such as transcutaneous electrical nerve stimulation and acupuncture as alternative strategies with mixed results.3,19-24
This article presents a comprehensive, practical, and evidence-based approach to the current management of xerostomia for the practicing oral healthcare professional.
Normal Salivary Function
Saliva not only aids in digestion by facilitating oral processing and swallowing of food, but it also has protective functions that include cleansing the oral cavity, maintaining a neutral pH, preventing tooth demineralization, and protecting oral tissue against microbial and physical insults (Table 1). The various immune and non-immune salivary proteins that inhibit the adherence and growth of viruses and bacteria confer the antimicrobial properties of saliva,25 while the mucins and salivary proteins contribute to the lubrication and coating of oral tissues. These agents protect the oral mucosa and teeth from physical, chemical, and microbial damage. Saliva facilitates speech and taste through lubrication and moisture, and the dissolution of materials in saliva stimulates taste receptors on the tongue. Salivary gland hypofunction often results in dysgeusia (altered taste sensation) and dysphagia (difficulty swallowing).26,27
Physical Assessment and Diagnosis of Xerostomia
Disease-Induced Xerostomia
A thorough medical history is the cornerstone of a correct diagnosis and, subsequently, appropriate treatment of the underlying cause of xerostomia. The presence or history of particular diseases may put patients at risk for the development of dry mouth, or, much more commonly, xerostomia may be medication-induced (licit or illicit). Table 2 lists the most common medical conditions associated with xerostomia.18,28,29
Given that Sjögren's disease (Sicca) is the second most common autoimmune disorder, affecting from 0.06% to 4.8% of the population, OHCPs are particularly sensitive to this autoimmune illness given its propensity to cause decreased saliva production, dry mouth, and dry eyes (xerophthalmia).22,30 Moutsopoulos et al from the National Institutes of Health developed a concise, chairside questionnaire to help identify these patients more easily (Table 3).15,31 While the results of this survey confirm a differential diagnosis of xerostomia likely due to Sjögren's disease, dehydration, obstruction to saliva flow (stone, tumor, etc), or a drug effect or infection, further objective criteria for the diagnosis of xerostomia would then include at least two of the following: (1) reduced unstimulated salivary flow, with ≤1.5 mL saliva collected in 15 minutes; (2) lymphoplasmocytic infiltrate in an adequate biopsy of labial salivary glands (sialoadenitis); (3) abnormal salivary gland imaging studies (scintigraphy) demonstrating decreased uptake, decreased spontaneous secretion, and/or decreased secretion after citrus stimulation.
Other systemic diseases and comorbidities leading to xerostomia are diverse. They include Parkinson's disease, anxiety and depression, rheumatoid arthritis, scleroderma, and treatment for head and neck cancers.3,32-34
Iatrogenic Causes of Xerostomia
Hyposalivation and salivary gland damage most often are the result of medical treatment, whether it be interventional or pharmacological.15,35-38 Regarding radiation therapy for head and neck cancer, salivary flow decreases rapidly during the first week of treatment. The ensuing fibrosis of the salivary glands and permanent loss of secretory capacity may dramatically diminish the patient's overall quality of life.19,38,39 The degree of damage is dependent on the volume of tissue irradiated and the total dose of radiation. Patients undergoing chemotherapy may also experience transient xerostomia.40,41
Systemic medication use is one of the most frequently reported causes of hyposalivation and xerostomia.4,28,42,43 More than 500 drugs are known to cause dry mouth, including many of the most common over-the-counter (OTC) and prescribed classes of medications (Table 4).3,27Unfortunately, this effect is not just limited to licit medications, as many illicit drugs produce this consequence as well.44-49 Patients receiving multiple xerostomic medications tend to have more severe dry mouth symptoms, and patients with salivary gland hypofunction are more susceptible to the xerogenic side effects of medications than patients with normal salivary gland function.6-9
Most xerostomic medications do not damage salivary glands, but they do decrease unstimulated salivary flow rates typically because of their anticholinergic side effects. Some studies have shown differences in the prevalence of xerostomia between the sexes (occurring more so in females than males) and with increasing age.15,42,50 One possible explanation for the latter is that older individuals take many more xerogenic medications for chronic ailments than younger individuals, which may lead to an overall reduction of the unstimulated salivary flow rate.15,51
Mouth breathing, dehydration, and psychological or neurological disorders can add to the perception of xerostomia. Mood disorders may affect the sympathetic nervous system (fight or flight reaction), and such patients may experience oral dryness.52-55
Xerostomia Management
Identifying and treating the underlying cause(s) of dry mouth are paramount to providing optimal, targeted oral healthcare.15 In addition, management of xerostomic side effects may also require attention. Patients with dry mouth often have erythematous and atrophic oral mucosa, loss of tongue papillae, angular cheilitis, and peeling or cracked lips. Traumatic lesions may even be visible on the lateral borders and buccal mucosa of the tongue. Removable dentures may become loose, which could lead to painful ulcerations. Patients often describe a constant need to sip fluids, especially when eating or immediately upon awaking from sleep. Root surface or cervical caries and candidiasis are common in patients with xerostomia; these patients may have enlarged salivary glands and possibly salivary gland infection. Treatment for xerostomia should be patient-specific and often requires a multimodal approach that goes beyond patient education and includes frequent consultation with the patient's physician, oncologist, or other healthcare providers.
Prevention
In patients at risk for xerostomia or hyposalivation, frequent visits to their OHCP (usually every 3 to 6 months) is critical for treatment compliance and success.56,57 In addition, although evidence is lacking, patients using medications known to induce salivary gland hypofunction could consider taking less xerostomic medications or decreasing the dosage of their medications if an alternative is unavailable.58,59 Of course, any suggested change to a patient's medication should be discussed with the primary prescriber.
Smoking, including vaping and use of e-cigarettes, has a strong association with dry mouth and should be minimized or discontinued altogether.44,60 For patients who smoke, integrating smoking-cessation counseling and associated medication treatment is the cornerstone of successful xerostomia management.61 Other lifestyle modifications to help address oral dryness include adequate hydration maintenance by frequently sipping water, sucking on ice, or using a humidifier at night.15,62 Moreover, it is important to educate xerostomia patients regarding intake of sugar and other fermentable carbohydrates, which can increase caries risk, as well as other dietary issues such as limiting alcohol and caffeine consumption.56,57 An effective multimodal approach to managing xerostomia combines these important lifestyle changes with pharmacological interventions.
OTC Treatment Options
The high prevalence of xerostomia has produced a market for numerous OTC products for dry mouth. These include toothpastes, rinses, lozenges, sprays, gels, oral patches, and chewing gums. Despite the wide selection of OTC formulations, however, a recent systematic review and meta-analysis and a 2011 Cochrane review concluded that, "the use of these agents cannot be supported on the basis of current evidence."19,63 Regardless, some patients do find these products to be effective, and when used in conjunction with proven, prescription therapies the benefits may be additive.
Toothpastes-A bevy of toothpastes are marketed for dry mouth. OTC examples include: Biotène® Fresh Mint Original Fluoride Toothpaste (GlaxoSmithKline, gsk.com), ACT® Dry Mouth Toothpaste (Sanofi, sanofi.com), Hydris™ Dry Mouth Hydrating Toothpaste (Colgate, colgate.com), and Enamelon® Preventive Treatment Gel (Premier, premusa.com). Even more products are available via prescription, such as PreviDent® 5000 Dry Mouth (Colgate) and MI Paste® ONE (GC America, gcamerica.com). Commonalities of toothpastes designed for the relief of dry mouth are that they contain fluoride and may contain a sugar alcohol such as xylitol, they do not contain sodium lauryl sulfate (SLS), they are designed to soothe and moisturize oral tissues, and they are intended to be non-irritating.15,64
In 2003 Rantanen et al completed a crossover trial comparing three types of toothpaste: 1% SLS, a formulation containing 4% betaine (BET), and a third product containing both 1% SLS and 4% BET. The researchers found a statistically significant difference in mouth dryness relief in 44% of the BET toothpaste group compared to relief of symptoms in 22% and 18% of BET + SLS and SLS toothpaste groups, respectively.64 More recently, Jose et al evaluated the results from two randomized studies comparing the oral tolerance of three fluoride toothpaste formulations in a dry mouth population and found all formulations to offer potential alternatives to individuals with dry mouth equally compelling.65 Once again, there was no clear benefit of one product over another, but the authors reaffirmed the need for fluoride in a dry mouth toothpaste.
Similarly, a comparative study between a new preventive treatment gel containing 0.4% stannous fluoride compared to a marketed OTC artificial saliva gel product to relieve subject-perceived dry mouth symptoms in a self-reported dry mouth population showed each product performed equally well.66 Based on inter-patient variability and individual patient preferences the study generally recommended that patients should evaluate multiple products to determine which can provide favorable results.
Saliva substitutes-Saliva substitutes can be administered either as sprays, gels, or lozenges. No type of product has shown superiority over another in comparisons between formulations or in comparative trials to placebo.63 Products such as mucin sprays, mucoadhesive discs, mucin lozenges, carboxymethylcellulose sprays, xanthum gum-containing sprays, carbopol sprays, and even buffered prophylin gel have all failed to show clear superiority. While this reinforces the Cochrane database finding that, "the use of these agents cannot be supported on the basis of current evidence,"63 it does not necessarily rule out the benefit of these products in combination or in a multimodal approach to xerostomia treatment, especially when combined with prescription treatment options.
Saliva stimulants-The production of saliva is stimulated by the act of mastication. Therefore, sugar-free chewing gum, usually containing a sugar alcohol like xylitol, for patients with residual salivary function may be more helpful than salivary substitutes described above. There is still, however, insufficient evidence to substantiate that chewing gum is superior to other interventions in assuaging dry mouth symptoms.67 Other saliva stimulants in the form of lozenges, which are easy to administer, offer prolonged contact with the oral mucosa and may be gentler on the sensitive mouth in patients following recent radiotherapy.68 Lozenges also have the benefit of mechanical stimulation of saliva.69 Topical oral gels have also been formulated with the same endpoint in mind. In all of these cases, however, there is insufficient evidence to definitively confirm whether lozenges or oral gel formulations are effective treatments for dry mouth.
Prescription Treatment Options
Mercadante et al recently reviewed currently available interventions for the management of radiotherapy-induced xerostomia and hyposalivation.19 As mentioned earlier, this systematic review and meta-analysis concurred with prior reviews on the lack of efficacy of OTC treatment strategies for xerostomia.70 Based on their results from 20 randomized, controlled clinical trials involving 1732 participants, however, the prescription sialagogue medications pilocarpine and cevimeline were found to consistently reduce dry mouth symptoms and increase salivary flow.
Pilocarpine and cevimeline are the only two systemic sialagogues approved by the US Food and Drug Administration for the treatment of dry mouth. Their mechanism of action is dependent on the presence of functional salivary gland tissue, with oral pilocarpine acting as a parasympathomimetic with muscarinic action and cevimeline acting as a salivary gland stimulant with stronger affinity for M3 muscarinic receptors.15,71-74 Both pilocarpine and cevimeline offer similar benefits in patients with dry mouth.75 The choice between the two medications is largely determined by individual patient factors, including cost to the patient, individual clinical response, convenience, and regulatory or insurance limitations on drug availability. The following summaries differentiate these drugs further.
Pilocarpine-As a parasympathomimetic, pilocarpine directly stimulates cholinergic receptors causing secretions of the exocrine glands, including an increase in salivary flow.75,76 It is available in 5-mg and 7.5-mg tablets and is initially dosed as 5 mg four times daily. The dosage may be titrated up to 7.5 mg four times daily, if needed, but the lowest effective maintenance dose should be used. A reduced dose of 2.5 mg to 3.75 mg three times daily or even 5 mg twice daily may still provide benefit.77,78
Adverse reactions seen with orally administered pilocarpine are an exaggeration of its parasympathetic effect. Hyperhidrosis (sweating) is a frequent adverse effect reported in 29% to 68% of patients. Other common adverse effects include chills (3% to 15%), edema (≤5%), flushing (8% to 13%), epistaxis (1% to 2%), and pruritus (1% to 2%).79 Pilocarpine (and cevimeline) are contraindicated in patients with hypersensitivity, narrow-angle glaucoma, and uncontrolled asthma, and these agents should be used cautiously in patients taking beta-blockers. Patients using pilocarpine typically experience a brief spurt of saliva due to the relatively short serum half-life of this drug compared to cevimeline, given the higher frequency of administration, but pilocarpine typically is at least half the price of cevimeline.
During a shortage of pilocarpine tablets in 1990, many patients were switched to pilocarpine eye drops to be taken orally, as the eye drops were also used before the availability of the tablets.78,80 The gastrointestinal absorption of the ophthalmic solution appears to be similar to that of the tablets, and the medication appears to be equiefficacious when administered by this route. The cost can be significantly less as shown in at least one study where patients used four drops of 2% pilocarpine solution, swish and swallow, three times daily. In this study by Rhodus and Schuh, pilocarpine stimulated saliva production in more than 75% of patients.78 The volume of each dose depends on the concentration of the solution used. Because the usual dose is 5 mg four times per day, the amount of solution used should reflect this same dose. For example, there is 5 mg in each mL of a 0.5% solution. The cost savings will be greater if more concentrated pilocarpine solutions are used since there is 20 mg in each mL of a 2% solution; thus, only 0.25 mL, or about five drops, is required for each dose.
In one clinical trial pilocarpine oral rinse was also shown to increase salivary flow and relieve dry mouth symptoms with less side effects when compared to oral tablets.81 The oral solution was compounded by dissolving three 5-mg tablets in 150 mL of water. Patients held the rinse in their mouth for
2 minutes before expectorating it and were allowed to use up to 150 mL of the rinse per day. This may be an option for patients who wish to easily titrate the dose of pilocarpine and avoid the systemic side effects of oral pilocarpine tablets.
Cevimeline-Cevimeline is a muscarinic receptor agonist and has a specifically high binding affinity for muscarinic M3 receptors on lacrimal and salivary gland epithelium. As a muscarinic receptor agonist, cevimeline increases secretion of exocrine glands, such as salivary and sweat glands, and increases tone of the smooth muscle in the gastrointestinal tract and urinary tract similar to pilocarpine. Cevimeline is prescribed at a dose of 30 mg three times per day taken about a half-hour before meals. There is insufficient safety and efficacy information to support doses of more than 90 mg/day.82
Adverse effects of cevimeline are similar to those of pilocarpine and include excessive sweating, cutaneous vasodilation, emesis, nausea, diarrhea, and, in some patients, persistent hiccups. It has a longer half-life and receptor occupancy time than pilocarpine and requires dosing only three times daily rather than four, which may further improve patient compliance. Some studies have reported cevimeline is better tolerated than pilocarpine since it does cause less diaphoresis (flushing), but other studies have found that it causes gastrointestinal side effects (eg, nausea, diarrhea) more often.83,84
The dose of pilocarpine or cevimeline should be increased gradually when initiating therapy, starting with one dose daily for a week, which helps to prevent a sudden onset of sweating. Taking these medications with food to avoid dyspepsia and gastric bloating is also advantageous. Typically, a trial of at least 3 months' duration is necessary to see if these medications are tolerated because the response is frequently delayed. Cevimeline can be taken in a fourth dose at bedtime if needed for nocturnal dryness. Similar to pilocarpine, the effective use of lower doses of cevimeline in patients with poor tolerance of the full dose has been reported.76 A lower dose can be prepared by dissolving the desired fraction of a 30-mg capsule's contents in water. The desired fraction can be taken to achieve the preferred reduced dose, or the solution can be used in a "rinse-and-spit" regimen to minimize systemic absorption.76,85
Conclusions
Despite the significant prevalence of xerostomia in the general population, no standard treatment guidelines exist. Successful treatments are typically individualized for the specific patient and should target the underlying pathophysiology of the disease. Therefore, an accurate diagnosis of xerostomia causality is paramount in order to offer patients the best treatment possible. While many treatment options exist for the management of xerostomia and hyposalivation, ranging from the removal or reduction in dose of xerostomic agents to lifestyle changes that include smoking cessation, the recommendation of nonprescription, topical agents cannot be routinely made on the basis of current evidence. Only the prescription sialagogue medications pilocarpine and cevimeline have been found to consistently reduce dry mouth symptoms and increase salivary flow, although some patients may prefer a multimodal approach that combines the use of these agents with a topical treatment.
About the Authors
Mark Donaldson, ACPR, PHARMD
Associate Principal, Vizient Pharmacy Advisory Solutions, Irving, Texas; Clinical Professor, School of Pharmacy, University of Montana, Missoula, Montana; Clinical Assistant Professor, School of Dentistry, Oregon Health & Sciences University, Portland, Oregon; Adjunct Professor, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia; Fellow, American Society of Hospital Pharmacists; Fellow, American College of Healthcare Executives
Jason H. Goodchild, DMD
Director of Clinical Affairs, Premier Dental Products Co., Plymouth Meeting, Pennsylvania; Associate Clinical Professor, Department of Diagnostic Sciences, Creighton University School of Dentistry, Omaha, Nebraska; Adjunct Assistant Professor, Division of Oral Diagnosis, Department of Diagnostic Sciences, Rutgers School of Dental Medicine, Newark, New Jersey
Queries to the author regarding this course may be submitted to authorqueries@aegiscomm.com.
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