Xerostomia Update: Comprehensive and Systematic Diagnosis and Management

The ubiquitous oral health symptom of oral dryness, frequently referred to as xerostomia, can be attributed to salivary gland dysfunction and can have a negative impact on quality of life. Management is usually individualized for the specific patient and should be targeted at the underlying pathophysiology of the disease.

Mr. A was a 77-year-old male who presented to the dental office with a chief complaint of "dry mouth," along with ill-fitting dentures. His past medical history included a myocardial infarction 7 months previously and a history of depression. His current medication list included 50 mg of amitriptyline orally at bedtime, 50 mg of hydrochlorothiazide orally per day, 81 mg of aspirin orally per day, and 15 mg of ramipril orally per day.

Mr. A was an example of a very ordinary case that oral healthcare practitioners (OHCPs) may see many times in a day. As patients age, they tend to "collect" chronic diseases that are treated with multiple medications, and because many of these patients retain dentation into later life, they still require appointments to reinforce good oral hygiene. Despite the ordinariness of this type of case, the prudent practitioner should pay close attention to the patient's complaints, medical history, and pharmacologic history, because they all point to a high index of suspicion that the patient may be suffering from xerostomia. A dry maxillary gingiva seen on intraoperative examination could alert the clinician, but other factors help point to the root cause(s) of dry mouth, which could be due to the patient's advancing age, chronic diseases, medications being received to treat those diseases, or all those factors combined. Consideration of these factors and how to address them may be more successful in managing this type of patient's dry mouth than an operative approach.

It was recommended that Mr. A improve his oral hygiene with more regular tooth brushing and flossing. A particular dentifrice was suggested that has been shown to help manage symptoms, including relieving the discomfort of dry mouth, providing long-lasting moisturization and long-lasting lubrication, and not irritating dry-mouth tissues. It was also suggested that he apply a moisturizing gel under his denture. He was given an appointment in 3 months for follow-up.

Mrs. B was a 58-year-old female with a past medical history of seasonal allergic rhinitis. She had no known drug allergies and received only over-the-counter (OTC) antihistamines during her allergy season. Her chief complaint was a 2-month history of fatigue and general trouble sleeping at night; she also stated that she often woke up with a dry mouth and throat. Her eyes had been dry, tired, and red recently, but she attributed that to her poor sleep patterns. Mrs. B tried to consume up to seven pints a day of liquids (such as coffee, tea, water, juice, milk, and soda) and was very distressed by her severe dry mouth.

Mrs. B was also an example of an ordinary case that OHCPs may see many times in a day. Unlike Mr. A, she was not advanced in age, did not have any chronic diseases, and did not receive medications frequently. She had a similar chief complaint, however, and once again, if the prudent practitioner pays close attention to this type of patient's complaints, they all point to a high index of suspicion that the patient may be suffering from xerostomia. In this case the underlying pathophysiology was different, but her history of dry eyes and dry mouth (known as sicca complex), coupled with her age and sex, may have suggested a differential diagnosis of Sjögren's disease. Sjögren's is the second most common autoimmune disorder and has the highest incidence in causing dry mouth, decreased saliva production, and dry eyes, especially in middle-aged women. Consideration of these factors and appropriate referral to the patient's primary care provider for additional diagnostic workup may again be more successful in managing this type of patient's dry mouth than an operative approach.

Mrs. B was counseled on potential non-pharmacologic measures in helping prevent dry mouth (reducing intake of caffeinated beverages and alcohol, and a cool air humidifier at bedtime). It was also suggested that she try a saliva substitute moisturizing mouth spray throughout the day. In the meantime, a consultation with her primary prescriber to discuss working her up to confirm a potential diagnosis of Sjögren's was initiated, and she was given an appointment in 3 months for follow-up.

Etiology

OHCPs often refer to a patient's subjective complaint of dry mouth as xerostomia.^1-4Although the sensation of the amount or quality of saliva being produced is related to xerostomia, from a pathophysiologic perspective it is more appropriately diagnosed as salivary gland dysfunction. Salivary gland dysfunction is usually expressed as a reduced volume of saliva secretion (salivary gland hypofunction) or a change in salivary composition.^1,3,5 The differential diagnosis of salivary gland hypofunction, however, is not always an absolute indicator of the subjective reporting of xerostomia.^4,6,7

There are three major pairs of salivary glands that secrete saliva intermittently when stimulated. The parotid glands are the largest and produce 70% of total saliva output in the stimulated state. They are located anterior, but inferior, to the external auditory meatus and are innervated by sympathetic and parasympathetic divisions. The parotid ducts are also known as Stensen's ducts and exit opposing the maxillary second molar, delivering saliva to the oral cavity. These glands secrete a very serous, or watery, type of saliva that many people are familiar with when anticipating food, often referred to as the Pavlovian effect. In the unstimulated state, the parotid gland's contribution is just 30% of the total saliva output.⁸

The submandibular glands are the second largest pair of salivary glands and produce 30% of total saliva output in the stimulated state. Opposite to the parotid glands, in the unstimulated state they are responsible for 65% to 70% of total saliva output. The ducts carrying saliva from these glands are called Wharton's ducts, which exit on the floor of the mouth opposing the lingual surface of the tongue. Unlike the parotid glands, these glands are innervated by parasympathetic nerve endings and possess no sympathetic receptors. The parasympathetic fibers arrive through the facial and glossopharyngeal nerves and are an important target for some of the prescription medications used to treat xerostomia.⁸

The final and smallest pair of the major salivary glands are the sublingual glands. They produce less than 5% of total saliva output; this rate is relatively unchanged in either the stimulated or unstimulated state. Saliva is delivered by the ducts of Bartholin, and the glands are innervated by parasympathetic fibers, with little or no sympathetic influence. Additionally, hundreds of minor glands secrete saliva continuously in the unstimulated state.⁸

The most common quantifiable method to diagnose salivary gland dysfunction is a sialometry test. The definitive diagnosis of hyposalivation is when unstimulated salivary flow rates are less than 0.1 mL/min (0.7 mL/min under stimulation).⁹Although the subjective report of a dry mouth, xerostomia, is often associated with hyposalivation, normal salivary flow is frequently reported in many patients complaining of dry mouth.^10-12

Prevalence

Xerostomia symptoms range from mild oral discomfort to substantial oral disease that can negatively impact a patients' dietary intake, quality of life, and overall health.^13-17 Up to 50% of the population experiences dry mouth; factors such as patient age, gender, and medications play important roles in accurately diagnosing this complaint.^18-21 Correctly identifying and treating the underlying pathophysiology of xerostomia is vital to providing optimal and targeted oral healthcare. Early detection, effective prevention, and the treatment of oral sequelae related to xerostomia require focused management by both the patient and the OHCP. Although salivary stimulation and symptom relief encompass most of the historical treatment options, newer strategies and products are being studied, such as acupuncture and transcutaneous electrical nerve stimulation as alternative treatments, with varied results.^5,22-27This article presents a comprehensive, evidence-based, and practical approach to the successful management of xerostomia for the practicing oral healthcare professional.

The Function of Saliva

Saliva not only helps digestion by enabling the mastication and swallowing of food, it also has protective roles that include preventing tooth demineralization, cleansing the oral cavity, protecting oral tissue against physical and microbial insults, and maintaining a neutral pH (Table 1). A variety of immune and nonimmune salivary proteins inhibit the adherence and growth of bacteria and viruses that contribute to its antimicrobial characteristics.²⁸ Meanwhile, salivary proteins and mucins confer the coating and lubrication of oral tissues. Together these compounds protect the oral mucosa from chemical, microbial, and physical damage. Saliva also enables taste and speech through moisturization and lubrication. Furthermore, taste receptors on the tongue are stimulated by the materials saliva dissolves. When salivary glands do not function normally, patients experience difficulty swallowing (dysphagia) and an altered taste sensation (dysgeusia).^29-31 Saliva flow is also critical to the preservation of enamel. The pH buffering and presence of calcium and phosphate in saliva, along with the proteins that attach to and stabilize the surface pellicle, keep the pH of the oral cavity above the demineralization pH of 5.5. Causes of low saliva states include radiation treatment, medications, autoimmune diseases of salivary glands, and the diurnal variation everyone experiences when sleeping-patients should avoid eating sugary snacks or carbohydrates before going to bed and should always brush before sleep. The low saliva flow when sleeping coupled with these snacks further reduce the pH of the oral cavity below the pH of demineralization, leading to an increased risk of caries. Patients who suffer from gastroesophageal reflux disease can experience the same pathophysiology if they regurgitate any acidic gastric contents throughout the evening. Sleeping with additional pillows or raising the head of the bed may improve the management of these patients.

Assessment and Diagnosis of Xerostomia

Iatrogenic Causes

Salivary gland damage and hyposalivation are typically the result of medical treatment, whether it be pharmacologic or interventional.^19,32-35 After radiation therapy for head and neck cancer, salivary flow decreases significantly during the first week of treatment. The resultant fibrosis of the salivary glands and permanent loss of secretory ability can radically diminish the overall quality of life for the patient.^23,35,36The amount of damage is dependent on the total dose of radiation and the degree of irradiated tissue. Patients who undergo chemotherapy can also experience temporary xerostomia.^37,38

One of the most commonly cited causes of xerostomia and hyposalivation is systemic medication.^6,39-41 More than 500 medications are known to cause xerostomia, including many of the most common OTC and prescription classes of medications (Table 2).^3,30 Unfortunately, many illicit drugs also have this side effect, and the combination tends to be additive, if not synergistic.^42-47Patients who take multiple xerostomic drugs tend to have more severe xerostomic symptoms, and patients with salivary gland hypofunction are more vulnerable to the dry mouth side effects of drugs than patients with normal salivary gland function.^9-12

Most medications that cause dry mouth do not damage salivary glands, but their anticholinergic side effects decrease unstimulated salivary flow rates. In addition, some studies have shown differences in the prevalence of xerostomia based on gender (it is more common in women) and with increasing age.^19,39,48 One explanation for the increase in older patients is that they often take more xerogenic medications for chronic illnesses than younger patients, leading to a higher prevalence of xerostomia and an overall reduction of the unstimulated salivary flow rate in this population.^19,49

More recently there has been concern about illicit drug abuse as a significant confounder in poor oral health and the growing prevalence of xerostomia in the population because almost all illicit drugs cause dry mouth (cannabis, cocaine, narcotics, and methamphetamine are examples). In the case of methamphetamine, the precursors used to synthesize this drug either by the red phosphorus method (pseudoephedrine reduction method) or the Nazi method (anhydrous ammonia method) include many highly acidic and toxic compounds: pseudoephedrine, ephedrine, acetone, red phosphorus, denatured alcohol, battery acid, iodine, muriatic acid, Freon, anhydrous ammonia, drain cleaner, paint thinner, and sulfuric acid, among other adulterants.⁴² These toxic elements produce a highly addictive drug of abuse, resulting in the intraoral presentation of "meth mouth," which many OHCPs have wrongly attributed to the acidic precursors used to make this drug.⁴⁵Studies have shown that the ingredients used to make methamphetamine are most likely not responsible for the rapid destruction to dentition, however, because methamphetamine cannot lower the pH of the oral cavity below the pH for demineralization.^50-52 In addition, abusers who chose to only inject methamphetamine, versus smoking or snorting the drug, also present with meth mouth. Meth mouth may be a misnomer because of the presentation of decay on buccal and smooth surfaces, which is indicative of generalized drug-induced hyposalivation; methamphetamine-related dental destruction actually occurs from a perfect storm of rampant decay, decreased or nonexistent oral hygiene, a high intake of carbonated, sugary beverages, and significant bruxism.^42,45

Disease-Induced Causes

In addition to a complete pharmacologic history, a thorough medical history is the foundation for an accurate diagnosis and resultant treatment of the underlying cause of xerostomia in a patient. The history or presence of specific diseases may increase a patient's risk for developing dry mouth, or, much more commonly, dry mouth may be induced by medications used to treat these diseases. Common medical conditions associated with xerostomia include the following^21,41,53:

• Autoimmune and inflammatory conditions
(eg, Sjögren's disease, primary biliary
cirrhosis)

• Degenerative disease (eg, amyloidosis)

• Graft-versus-host disease

• Granulomatous disease (eg, sarcoidosis)

• Immunoglobulin G4-related sclerosing
disease

• Infections: human immunodeficiency

virus/acquired immune deficiency

syndrome (HIV/AIDS), hepatitis C

• Lymphoma

• Salivary gland aplasia or agenesis

Sjögren's, the second most common autoimmune disorder, has the highest incidence in causing dry mouth, decreased saliva production, and dry eyes (sicca complex).^24,54OHCPs are particularly aware of this autoimmune disease because it affects almost 5% of the population. One investigative group from the National Institutes of Health created a simple chairside questionnaire to identify these patients more concisely (Table 3).⁵⁵ This survey tool confirms a differential diagnosis of xerostomia, likely due to Sjögren's, a drug effect or infection, an obstruction to saliva flow (tumor, stone), or dehydration. Further objective criteria would then include at least two of the following for the actual diagnosis of xerostomia: (1) abnormal scintigraphy (salivary gland imaging studies) demonstrating decreased spontaneous secretion, decreased uptake, and/or decreased secretion after citrus stimulation; (2) lymphoplasmocytic infiltrate in an adequate biopsy of labial salivary glands (sialoadenitis); and (3) reduced unstimulated salivary flow, with ≤ 1.5 mL saliva collected in 15 minutes.

Psychological and neurologic disorders, dehydration, and mouth breathing can further add to the perception of dry mouth. Some psychiatric illnesses can affect the fight or flight reaction (sympathetic nervous system); these types of patients also tend to report xerostomia.^56-59

Management of Xerostomia

Recognizing and treating the underlying cause(s) of xerostomia are principal to providing targeted and optimal oral healthcare.¹⁹ Patients at risk for hyposalivation or xerostomia require frequent appointments with their OHCP, every 3 to 6 months, as a critical component for adherence and treatment success.^60,61 In addition, patients receiving medications that can induce salivary gland hypofunction should discuss with their primary provider whether decreasing the dosage of their medications or taking fewer xerostomic medications could be an alternative strategy.^62,63Management of the side effects of dry mouth may also require consideration.

Signs and Symptoms

Patients with xerostomia often have an atrophic and erythematous oral mucosa, peeling or cracked lips, and loss of tongue papillae. Traumatic lesions on the lateral borders and buccal mucosa of the tongue may also be visible. Removable dentures can become loose, leading to painful ulcerations, and patients frequently describe a continuous need to sip fluids immediately after waking from sleep and especially when eating.

Oral candidiasis and cervical or root surface caries are common in patients with dry mouth; these patients may have possible salivary gland infections and enlarged salivary glands. For these reasons, xerostomia treatment should be patient-specific because the solution is not the same for everyone; often a multimodal approach is required, including frequent consultation with the patient's physician, oncologist, or other healthcare providers, in addition to patient education.

Non-Drug Treatment

Smoking, including the use of e-cigarettes and vaping, has a strong association with xerostomia and should be minimized or stopped altogether.^43,64 Integrating a smoking-cessation program, including medication treatment if required, is paramount for successful dry mouth management.^64,65 Other lifestyle modifications, such as adequate hydration maintenance by frequently sucking on ice or sipping water, using a cold air humidifier at night, and sleeping on one's side to minimize mouth-breathing, help address the symptoms of xerostomia.^19,66 Avoiding or limiting the intake of alcohol, caffeine, acidic beverages, and foods (including some mouthwashes) also serve as non-drug treatments for the symptoms of xerostomia. Drinking whole or 2% milk with meals appears to have many of the chemical and physical properties of a good saliva substitute.⁶⁷ Besides the obvious benefit of providing moisture and lubrication from fat for the dehydrated mucosa, milk buffers oral acids, reduces enamel solubility, and contributes to enamel remineralization. Patients who cannot drink cow's milk may find similar benefit in almond or soy milk.

Nonprescription Treatment Options for Dry Mouth

Given the significant prevalence of xerostomia, there is an equally significant market of OTC products to treat dry mouth symptoms. These include saliva substitutes and stimulants in the form of sprays, gels, toothpastes, rinses, oral patches, chewing gums, and lozenges. These symptomatic treatments typically have one or more targets, such as increasing existing saliva flow, replacing lost secretions, controlling dental caries, or specific measures such as treatment of infections. Interestingly, despite the large selection of OTC medications, a recent meta-analysis and systematic review by the Cochrane group concluded that, "the use of these agents cannot be supported on the basis of current evidence."^23,68 Nevertheless, many these products are effective in patients when used in combination, and the benefits may be additive when used with proven, prescription therapies.³

A worksheet for patients of treatment options to report back on the success or lack of success in helping reduce dry mouth symptoms may be useful, especially in making recommendations to patients for palliative treatment. Often these diaries help improve patient compliance and medication adherence by requiring them to be engaged and accountable in their management and overall treatment success. In addition, patients should receive detailed information about the potential causes of dry mouth and the potential sequelae of impaired salivary secretion to help them in determining which products, or combination of products, may work best for their unique situation.

Prescription Treatment Options for Dry Mouth

Whereas previous systematic reviews and meta-analyses concluded a lack of efficacy of OTC treatment strategies for dry mouth, in evaluating 20 randomized, controlled clinical trials of more than 1,700 patients, prescription sialagogue medications, such as cevimeline and pilocarpine, consistently increased salivary flow and reduced the subjective symptoms of xerostomia.^23,68,69Cevimeline and pilocarpine are currently the only two prescription sialagogues approved in the United States for the treatment of xerostomia. Functional salivary gland tissue is required for these medications to be effective because both oral cevimeline and oral pilocarpine act as salivary gland stimulants. Cevimeline has a stronger affinity for M3 muscarinic receptors, whereas pilocarpine has both parasympathomimetic and muscarinic actions.^19,70-74 Cevimeline and pilocarpine offer similar benefits and have similar side-effect profiles, so the choice between therapies is typically dependent on individual patient factors: clinical response, cost, insurance limitations, convenience (dosing frequency), and drug availability.

Pilocarpine. Pilocarpine stimulates cholinergic receptors directly as a parasympathomimetic. This causes an increase in salivary flow and also causes secretions of other exocrine glands.^75,76Side effects most commonly experienced with pilocarpine are an extension of its parasympathetic effect, with hyperhidrosis (sweating) most commonly reported (up to 68% of patients).⁷⁷Other common side effects include chills (3% to 15%), flushing (8% to 13%), edema (≤ 5%), epistaxis (1% to 2%), and pruritus (1% to 2%). Pilocarpine is available in 5-mg and 7.5-mg tablets and is typically started as 5 mg orally four times daily. The dosage can be titrated up to 7.5 mg four times daily, if required, but the lowest effective maintenance dose should be used. Even a reduced dose of 2.5 mg to 3.75 mg three times daily or even 5 mg twice daily may still provide benefit for some patients.^75-77

Both pilocarpine and cevimeline are contraindicated in patients with a history of hypersensitivity, uncontrolled asthma, and narrow-angle glaucoma, and these medications should be used with caution for patients taking concomitant beta-blockers. A brief secretion of saliva is experienced by patients using pilocarpine but, due to the relatively short serum half-life (less than 1 hour) compared with cevimeline (4 to 6 hours), pilocarpine requires a higher frequency of administration.^78,79 Pilocarpine is usually half the price of cevimeline, so patients may opt for this more economical product over the convenience, yet higher expense, of cevimeline.

Many patients choose to take the eye drops form orally given the significant cost advantage over the tablets. In fact, at the usual starting dose of 5 mg four times per day, the cost savings can be even more significant (and the volume required to swallow, much less) by using a more concentrated solution: there are 5 mg in each mL of a 0.5% solution and 20 mg in each mL of a 2% solution; thus, only 0.25 mL (about five drops) would be required per dose of the more concentrated solution.^80,81

One recent trial showed that pilocarpine as an oral rinse increased salivary flow and relieved xerostomia symptoms with fewer side effects when used as a "swish and spit" strategy.⁸⁰ By dissolving three 5-mg tablets in 150 mL of water, patients would hold the rinse in their mouth for 2 minutes before expectorating it. This may be a strategy for patients trying to titrate the dose of pilocarpine while avoiding the systemic side effects of whole oral pilocarpine tablets. In this study, patients used up to 150 mL of the rinse per day.

Cevimeline. As a muscarinic-specific receptor agonist, cevimeline increases secretion of exocrine glands. Similar to pilocarpine, this results in the stimulation of salivary and sweat glands, while increasing the tone of the smooth muscle in the gastrointestinal tract (causing diarrhea) and urinary tract (causing urinary frequency).^79,82-84 Cevimeline is usually taken a half-hour before meals and is typically dosed as 30 mg three times per day. There is insufficient efficacy and safety data to support doses of more than 90 mg per day.^82,84

Conflicting information has found cevimeline to be better tolerated than pilocarpine because some studies show it causes less flushing (diaphoresis), whereas other investigators have found that it causes nausea and diarrhea more often.^84,85 In general the side-effect profiles are very similar and include excessive sweating, emesis, nausea, diarrhea, cutaneous vasodilation, and persistent hiccups in some patients.^77,81

Cevimeline has a longer receptor occupancy time and half-life than pilocarpine, allowing for dosing three times daily rather than four. This minor advantage could result in better patient adherence and therefore better outcomes, but the convenience may be outweighed for some patients by cevimeline's higher price. The dose of cevimeline and pilocarpine should be increased gradually when first starting therapy, beginning with just one dose daily for a week and tapering up the dose weekly after that. This helps to prevent a sudden onset of sweating and minimizes other potential side effects. To avoid gastric bloating and dyspepsia, taking these medications with food is also advantageous. A trial of at least 3 months' duration is necessary to see whether these medications are tolerated because the overall response is frequently delayed. If needed for nocturnal dryness, a fourth dose of cevimeline can be taken at bedtime. In patients who may be intolerant of the full dose due to side effects, similar to pilocarpine, lower doses of cevimeline have also been reported as being effective.⁸⁵ Lower doses can be extemporaneously prepared by dissolving the desired fraction of a 30-mg cevimeline capsule's content in water. Some patients may also use a "rinse-and-spit" regimen to minimize side effects and systemic absorption.^75,85

Future Trends

Currently available pharmacologic methods to manage xerostomia include stringent oral hygiene, the use of saliva substitutes and stimulants, dentifrices with fluoride, and sialagogic agents, but side effects can occur with many of these therapies. Clinical trials have shown that acupuncture may be effective in treating xerostomia without these adverse effects.⁸⁶ Although this strategy can be safely added to pharmacologic approaches, the practicality in contemporary clinical practice has not been completely elucidated. Likewise, salivary gland stem cell therapy could be an inexpensive and simple, nontraumatic, and individualized therapy for medically challenging cases such as xerostomia, but research into this strategy is still in its early stages.⁸⁷ A recent meta-analysis found that interferon alpha at 150 IU thrice daily is also effective in increasing salivary flow rates, with the additional advantage of disease modification in patients suffering from Sjögren's, given its immunomodulatory action.⁸⁸ Lastly, a systematic review that appraised 25 randomized, controlled trials involving 1,586 patients found complementary and alternative therapies such as herbal medicines had potential benefits for improving salivary function and reducing the severity of dry mouth in cancer patients. Unfortunately, relatively small sample sizes and methodologic limitations reduced the strength of the evidence.⁸⁹

Conclusions

Although the prevalence of xerostomia in the overall population is high, standard treatment guidelines do not exist. Management is usually individualized for the specific patient and should be targeted at the underlying pathophysiology of the disease. Therefore, accurately diagnosing xerostomia is critical for patients to receive the best treatment possible. No one solution is best for everyone; successful treatment often involves a multimodal approach.

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