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Diagnosis and treatment of (dry )

Article in Odontology · August 2009 DOI: 10.1007/s10266-008-0099-7 · Source: PubMed

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REVIEW ARTICLE

Joel J. Napeñas · Michael T. Brennan · Philip C. Fox Diagnosis and treatment of xerostomia (dry mouth)

Received: November 14, 2008 / Accepted: December 18, 2008

Abstract Xerostomia (dry mouth) is a common complaint lases in aid in digestive function by breakdown of with widespread implications such as impaired quality of starch.2 life, oral pain, and numerous oral complications. There are The major salivary glands – the parotid, submandibular a variety of salivary and nonsalivary causes of xerostomia, and sublingual glands – account for over 90% of saliva the most frequent being medication side effects and sys- production. The remainder is produced by the minor sali- temic disorders. A systematic approach should be employed vary glands, located in the submucosa throughout the oro- to determine the etiology of this condition, with distinctions pharynx. The primary secretory cells, the acini, produce an made between patients with subjective complaints of xero- isotonic primary saliva, which is modifi ed by salt reabsorp- stomia alone and those with measurable dys- tion within the ductal system, resulting in a fi nal secreted function. Management is multidisciplinary and multimodal. saliva that is hypotonic with respect to plasma.3 There are This review summarizes the current literature on the etiol- two types of acinar cells: serous-type acinar cells produce a ogy, diagnosis, and complications of xerostomia, and on the watery fl uid, and mucous-type cells produce a more viscous management of patients with xerostomia. fl uid. Salivary fl ow is regulated by the autonomic nervous system, with the parasympathetic response primarily respon- Key words Saliva · Xerostomia · Dry mouth sible for stimulating fl ow and the sympathetic system involved in salivary protein production.4 Flow rate and sali- vary composition are dependent upon the type and length Introduction of stimulus, and the gland from which the saliva is secreted. Xerostomia is the subjective feeling of dry mouth, a Saliva is essential to the function and protection of the oral symptom that may or may not be accompanied by hyposali- cavity and contiguous gastrointestinal epithelium. Common vation, an objective decrease in salivary fl ow. Though the functions of the fl uid component of the salivary secretions most common symptom of hyposalivation is xerostomia, include cleansing and lubricating of oral soft and hard studies have shown that the former does not necessarily tissues, solubilization and bolus formation of food, facilita- guarantee the latter.5,6 However, patients that have a greater tion of taste perception, mastication and speech, and reten- than 50% reduction in salivary fl ow usually experience tion of removable prostheses. Bicarbonate and other buffers xerostomia.7 in saliva help maintain saliva’s physiologic pH at 6.5–7.4 and The prevalence of xerostomia and salivary gland hypo- protect against acidic challenges from bacterial cariogenic function is very diffi cult to determine with certainty owing pathogens.1 Glycoproteins such as , histatins, and to the limited number of epidemiological studies and differ- numerous other salivary components also have protective ences in how the two conditions have been defi ned. More- effects against harmful microorganisms. Amy- over, estimates are hard to obtain because the population experiencing these conditions is heterogeneous and the conditions have various causes. A systematic review pub- lished in 2006 found that the prevalence of self-reported J.J. Napeñas · M.T. Brennan · P.C. Fox xerostomia in population-based samples ranged from 0.9% Department of Oral Medicine, Carolinas Medical Center, Charlotte, 8 NC, USA to 64.8%. Another study estimated that 30% of the popula- tion aged 65 years or older suffered from these disorders.9 P.C. Fox (*) PC Fox Consulting, Via Monterione 29, 06038 Spello (PG), Italy Among patients with Sjögren’s syndrome and those having Tel. +1-301-979-9540 (U.S.); +39-340-948-4780 (Italy) received head and neck radiation for the treatment of e-mail: [email protected] cancer, the prevalence of xerostomia is nearly 100%.10,11 77

17–19 Causes of xerostomia cause neither hyposalivation nor xerostomia. Diuretics have been implicated in xerostomia but not hyposaliva- tion.20,21 Other classes of medications responsible for There are many causes of xerostomia, both salivary and hyposalivation due to anticholinergic effects are antispas- nonsalivary (Table 1). Nonsalivary causes include dehydra- modic drugs, which contain anticholinergic alkaloids, and tion, cognitive and neurologic alterations, oral sensory dys- some barbiturates.13 function, psychological disorders, and idiopathic causes.12 Sjögren’s syndrome (SS) is a chronic, autoimmune, Causes of xerostomia due to salivary gland dysfunction infl ammatory disorder characterized by lymphocytic infi l- can be categorized into autoimmune exocrinopathies (most tration of the exocrine glands in multiple sites, most com- notably Sjögren’s syndrome), medication side effects, radia- monly the lacrimal and salivary glands. It can occur alone tion-induced salivary gland dysfunction, and salivary gland (primary SS), or in conjunction with another autoimmune trauma. Other, less common causes that have been reported rheumatic disease (secondary SS). The estimated preva- include salivary gland tumors, infectious processes, endo- lence in the population is 0.6%, with the highest prevalence crine and renal disorders, dementia, cystic fi brosis, and in the fourth or fi fth decade of life.22 Ninety percent of amyloidosis.13 patients are women. The focal lymphocytic infi ltration of A distinction must be made between those medications the exocrine glands may lead to germinal center formation, that cause xerostomia and those that cause hyposalivation. production of antibodies, and focal .23 The patho- Though many medications have xerostomia as a side effect, genesis is not known, but is thought to be multifactorial in very few have been tested for objective changes in salivary nature. It is believed to involve an interplay of autoantibod- fl ow. Medications with anticholinergic activity presumably ies [e.g., SS-A (or anti-Ro) and SS-B (or anti-La)] and inhibit salivary secretion, and in most cases the effect is cytokines (e.g., B-cell activating factor, tumor necrosis reversed upon discontinuance of the drugs.14,15 Tricyclic factor) with multiple potential triggers.22 antidepressants are potent inhibitors of salivation that act Clinically, patients with SS most often present with a by binding to muscarinic–cholinergic receptors. Antihyper- complaint of dry eyes (keratoconjunctivitis sicca) and dry tensive medications are commonly cited for side effects of mouth; however, extraglandular manifestations may also xerostomia or hyposalivation. Whereas α-adrenergic agonist occur. Transient or chronic bilateral enlargement of the antagonists (e.g., clonidine, guanfacine, and methyldopa) parotid or submandibular glands is seen in 20%–30% of consistently cause hyposalivation,16 β-blockers and angio- patients in combination with hyposalivation and symptoms tensin-converting enzyme inhibitors have been shown to of fatigue and arthralgias.24 Other extraglandular manifesta-

Table 1. Causes of complaints of xerostomia Nonsalivary Dehydration Cognitive alteration Neurological dysfunction Oral sensory dysfunction Psychological Mouth breathing

Salivary (hyposalivation and/or altered salivary composition) Disease Sjögren’s syndrome Autoimmune disorders (e.g., systemic , rheumatoid arthritis, scleroderma, primary biliary cirrhosis) Diabetes mellitus Human immunodefi ciency Herpes virus family (e.g., cytomegalovirus, Epstein-Barr virus) Hepatitis C End-stage renal disease Treatment side effects Medications Tricyclic antidepressants Antihypertensive medications (e.g., diuretics, α-adrenergic agonist antagonists) Antispasmodic drugs Other Radiation therapy External beam radiation therapy (head and neck, mantle, whole body) Radioiodine therapy (131I) Salivary gland trauma Salivary gland tumor Nutritional defi ciencies, and/or eating disorders (anorexia/bulimia) 78 tions include vasculitis, thyroid insuffi ciency, interstitial persist for the remainder of the patient’s lifetime. Xero- pneumonia, and renal tubular acidosis.13 Diagnosis and stomia and hyposalivation may also occur after lower dose careful continuing follow-up of SS are essential, in particu- partial and whole-body irradiation for hematologic lar because the risk of developing non-Hodgkin lymphoma malignancies.43 in primary SS patients is over 18 times that in the general Older individuals experience xerostomia for a number of population.25,26 reasons, including the ones stated above. Salivary glands Secondary SS is seen in 25%–35% of rheumatoid arth- are known to undergo signifi cant histological changes with ritis patients.27,28 Systemic lupus erythematosus has been age, with secretory (acinar) components being replaced by associated with a decreased unstimulated whole saliva fl ow fi brous and adipose tissue.44 This phenomenon is most rate, a 75% incidence of oral complaints (e.g., xerostomia, evident in the submandibular glands, and less so in the pain), and secondary SS in one-third of patients.29–31 Primary minor and parotid glands, resulting in an overall decreased biliary cirrhosis is associated with xerostomia, as 70% of weight of the glands. However, it has been shown that clini- patients have a coexisting autoimmune disease such as SS cally signifi cant decreases in major salivary gland fl ow do and 90% exhibit focal sialadenitis.22,32 Fifteen percent of not occur in healthy older people,45 although age-related patients with scleroderma show lymphocytic infi ltrates, but changes in salivary electrolytes have been found, including there is no evidence of increased xerostomia or hyposaliva- decreased Na+ and increased K+ concentrations.46 Further, tion.33 Sarcoidosis patients can present with signs and symp- studies have shown increases with age in IgA, proline-rich toms highly suggestive of primary SS; therefore, they should proteins (which are involved in tooth remineralization), and be differentiated by a salivary gland biopsy, which will show the antimicrobial proteins lactoferrin and lysozyme.47,48 It granulomatous infl ammation rather than the lymphocytic has been shown that, in the absence of major medical prob- infi ltration found in SS. Although it has been reported that lems and medication use, such constituents remain stable in hepatitis C virus (HCV)-infected individuals have mild sial- the aged.49 Therefore, one cannot simply attribute changes adenitis, clinical evidence of hyposalivation, xerostomia, or in salivary quantity and quality to aging; rather, it is more dry eyes is often absent.34 There is confl icting evidence likely that such changes are due to the additive effects of about links between HCV and SS, and even though pres- medications and systemic disorders. ence of HCV is an exclusion criterion in the American– European classifi cation of SS, it is not thought to be a cause of SS. Xerostomia has been reported in people with diabe- tes mellitus, although no defi nitive association between this Diagnosis condition and hyposalivation has been established.35 Radiation therapy (RT) combined with surgery is the A systematic approach should be used to distinguish patients main therapy for head and neck cancers. Depending on with symptoms of xerostomia versus those with measurable the site and extension of primary tumors and the path of salivary gland hypofunction (Table 2). The chief complaint lymphatic spread, all or part of the major and minor sali- should be noted and explored in detail. Certain complaints vary glands are included within the radiation fi elds. Stan- are highly predictive of impaired salivary fl ow rates, whereas dard radiotherapy for advanced head and neck carcinomas others do not correlate with hyposalivation. Specifi cally, consists of fractionated doses of approximately 10 Gy per positive responses to any of the following complaints are week over 5–7 weeks. Salivary gland exposure to radiation associated signifi cantly with hyposalivation: oral dryness results in severe hypofunction and changes in saliva com- when eating; need to sip liquids to swallow dry foods; diffi - position. Glandular damage includes infl ammatory cell and culty swallowing (deglutition); and the perception of too lymphocytic infi ltration, degeneration, necrosis, atrophy, little saliva.5 Complaints that may or may not accompany fi brosis and duct dilatation, with damage primarily to decreased salivary fl ow include a feeling of dryness upon serous acinar cells.1 The severity of salivary gland damage awakening and at night; use of chewing gum, candies, or is dependent on the volume of glandular tissue in the radia- mints to stimulate salivary fl ow; and keeping a glass of water tion fi eld and the radiation dose. Profound salivary hypo- at the bedside. All these are common complaints but do not function is believed to occur when greater than 50% of reliably predict salivary gland hypofunction.5 Other symp- the volume is irradiated.36 Reversible toms are speech and eating diffi culties, which may compro- decreases in the salivary fl ow rate have been seen with mise nutritional status and cause problems in the patient’s doses as low as 2.25 Gy and as high as 20 Gy.37,38 A thresh- social life. Patients may have taste disturbances due to the old effect between reversible and irreversible salivary gland need for saliva to stimulate gustatory receptors and deliver damage has been suggested at a dose of 26 Gy.39 Parotid tastants to the buds.50 Other complaints include halitosis, glands receiving doses in excess of 60 Gy sustain perma- stomatodynia (burning mouth and tongue), and intolerance nent damage.40 An 80% reduction in both parotid and of acidic or spicy foods.51 Denture wearers may have more submandibular/sublingual fl ow rates occurs after the fi rst sore spots, and diffi culty in retention of prostheses. 2 weeks of RT, and deterioration toward undetectable Next, a thorough and complete medical history to iden- levels is seen at 6–8 weeks.41 Improvements in xerostomic tify conditions, treatments, and medications that may cause symptoms can occur a few months after therapy, despite xerostomia or hyposalivation should be obtained. This a continuing decline in salivation, suggesting adaptation.42 should be followed by a physical examination of oral hard However, xerostomia and salivary gland hypofunction and soft tissues to identify signs of hyposalivation, which 79

Table 2. Evaluation of salivary function History Focus on: Systemic or local diseases Trauma Medication list Symptom questions Predictive of hyposalivation (Fox et al., 1987)5 “Do you sip liquids to aid in swallowing dry foods?” “Does your mouth feel dry when eating a meal?” “Do you have diffi culties swallowing any foods?” “Does the amount of saliva in your mouth seem to be too little, too much, or you don’t notice it?” Physical examination Extraoral examination Major salivary glands Lymph nodes Intraoral examination Soft tissues Periodontium Dentition Measurement of salivary output Unstimulated whole saliva fl ow Stimulated whole saliva fl ow Ductal fl ow of major salivary glands (e.g., parotid, submandibular/sublingual) Sialochemical analyses Serum laboratory studies Complete blood count with differential Autoimmune markers (e.g., antinuclear antibody, anti-SS-A, anti-SS-B, rheumatoid factor) Serum immunoglobulins Erythrocyte sedimentation rate Salivary imaging Scintigraphy (99mTc) Ultrasonography Magnetic resonance imaging Plain fi lm Computed tomography Salivary biopsy Labial minor salivary gland Fine-needle aspiration Major salivary gland

may include dried and chapped , glossy or desiccated tions, and those with gingival recession that exposes more ; fi ssured, red, or depapillated tongue; and lack caries-prone root surfaces. of salivary pooling in the fl oor of mouth. The quantity and Enlarged salivary glands, unilateral or bilateral, may be quality of saliva should be examined, with a more viscous seen in patients with hyposalivation. Lack of salivary fl ow consistency indicative of salivary gland hypofunction. The may lead to bacterial or viral infection, although individuals examiner should try to express saliva from the four major with SS may experience swelling and sialadeniti without salivary gland ducts: the two parotid (Stensen’s) ducts in the infection. buccal mucosa adjacent to the upper fi rst molars, and the Measurement of salivary output is imperative to differ- two submandibular (Wharton’s) ducts on the fl oor of mouth. entiate between salivary and nonsalivary causes of xerosto- The presence of a cloudy or purulent discharge from the mia. A number of methods for measurement of unstimulated ducts may indicate an infection within the major salivary whole saliva (UWS) and stimulated whole saliva (SWS) glands. fl ow rates have been described that require no specialized of all varieties (e.g., pseudomembrane- equipment, are controlled and reproducible, and can be ous, erythematous, median rhomboid , and angular performed in any offi ce setting.52 Individualized collectors ) may be seen in patients with hyposalivation. It is can be used to get specialized measurements of salivary fl ow usually diagnosed on the basis of clinical fi ndings; however, from the major salivary glands. Salivary fl ow rates are useful it can be confi rmed microbiologically with a direct smear. for diagnosing autoimmune exocrinopathies; specifi cally, Dental caries are also frequently found in these patients, they are an objective criterion in the American–European especially in older adults, those with more dental restora- Classifi cation Criteria for diagnosis of SS.53 A UWS below 80 0.12–0.16 ml/min and a SWS fl ow rate below 0.5 ml/min, ence for CMC-based products over mucins.11 Attempts obtained using a standardized technique, are considered should be made in all patients to stimulate the remaining indicative of hyposalivation.52,54 Salivary function can also salivary function by using topical or systemic approaches. be measured by scintigraphy. 99mTechnetium pertechnetate Sugar-free candies and chewing that contain xylitol (Tc) is a gamma ray-emitting radionuclide that is taken up are intended to stimulate salivary fl ow and can provide by salivary glands after intravenous injection and then transient relief of xerostomia. Such products have been secreted. Measurement of uptake and secretion into the shown to have more positive effects than lubricants in post- oral cavity can determine the presence and extent of func- RT and hemodialysis patients.11,22 There is not suffi cient tional acinar tissue. Major gland function can be graded by clinical evidence to support the defi nitive recommendation applying a scoring system to the scans.55 of any single palliative product; therefore, it is best for the A number of other imaging techniques can aid in iden- patient to try several agents and select the one that gives tifying salivary gland abnormalities. Magnetic resonance greatest relief. Use of a humidifi er, particularly at the imaging, with its ability to visualize water-containing struc- bedside during sleep, can alleviate symptoms of xerostomia tures, can identify solid and cystic masses in the glands and and dry eyes and nasal passages. Patients can also make lymph nodes. Plain fi lms may also be useful in identifying adjustments in their diet to avoid dry or acidic foods, to salivary tumors. Sialography is a useful technique to visual- accompany dry foods with frequent sips of water, and to ize the anatomy of ducts, acinar integrity, calcifi cations, and avoid caffeine-containing or alcoholic beverages that cause some tumors.56 The gland anatomy is well delineated by dehydration and increase oral dryness symptoms. retrograde instillation of a radio-opaque fl uid through a Preventive care should be addressed next. Extra mea- major salivary gland duct orifi ce. Ultrasonography is an sures should be instituted to prevent oral complications effective and noninvasive means of identifying changes from low salivary output. This starts with frequent dental within the gland parenchyma and periglandular and intra- and oral evaluations, with examinations every 4–6 months and extraductal structures, particularly .57 and radiographs performed annually. To prevent dental Salivary gland biopsy provides a defi nitive diagnosis of caries, meticulous oral hygiene, a low-sugar diet, and regular glandular pathology. A labial minor salivary gland biopsy use of topical fl uoride are recommended. Daily use of is more readily and commonly performed than a biopsy of neutral pH sodium fl uoride is the most effective means the major salivary glands. In cases of suspected SS, the pres- of preventing rampant hyposalivation-induced caries.11 ence of focal, periductal lymphocytic infi ltration beyond a Fluorides and remineralizing solutions are available as var- graded threshold is the best criterion for defi nitive diagnosis nishes, dentifrices, gels, and rinses, which can be used with of the salivary component.58 Fine-needle aspiration of or without applicator trays. The specifi c preventive fl uoride enlarged major salivary glands followed by immunocyto- regimen should be determined by the dentist and patient by chemical analyses is useful for differentiating between a considering the extent of salivary gland hypofunction and benign polyclonal lymphocytic infi ltration and a malignant the caries rate. monoclonal infi ltration as found in lymphoma. Oral candidiasis is a common oral complication in xero- stomia and salivary gland hypofunction patients. A number of topical antifungal agents, in the form of rinses, ointments, pastilles, and troches, are effective therapeutics. Systemic Management antifungal therapy should be reserved for cases refractory to topical therapy, and for immunocompromised patients. After establishing a diagnosis, a step-wise management Denture users should prevent fungal colonization through approach should be implemented. This consists of alleviat- daily immersion of prostheses in benzoic acid, chlorhexi- ing symptoms, instituting preventive measures, treating oral dine 0.12% solution, or 1% sodium hypochlorite. Angular conditions, improving salivary function (if possible), and cheilitis can be treated with topical antifungal and anti- managing any underlying systemic conditions (Table 3). A infl ammatory agents. multidisciplinary approach among health-care providers is For xerostomic patients, or hyposalivation patients with required. an appreciable difference between UWS and SWS fl ow There are many palliative measures available to alleviate rates, systemic secretogogues may be of benefi t. Even in symptoms. Salivary substitutes and lubricants with moisten- patients with minimal salivary function, stimulation of ing properties are designed to provide prolonged mucosal secretion may be of benefi t, both for relieving dryness wetting.59 Products include “artifi cial” salivas, rinses, gels, symptoms and providing the protective effects of natural and sprays, which may contain carboxymethylcellulose saliva. Parasympathomimetics that are agonists for musca- (CMC), a mucopolysaccharide, glycerate polymer gel base, rinic receptors can stimulate salivary fl ow. Two parasympa- or natural mucins, singly or in combination. Toothpastes thomimetic drugs, pilocarpine and cevimeline, are approved are available that contain a synthetic detergent (sodium by the U.S. Food and Drug Administration for treatment lauryl sulfate) and an osmoprotectant (glycine betaine of xerostomia; pilocarpine is approved for SS- and RT- BET). In clinical studies of post-RT patients, these products induced xerostomia, and cevimeline for SS. Pilocarpine is a have collectively exhibited a mild effect on the subjective nonselective muscarinic agonist, whereas cevimeline has complaint of xerostomia but no effect on objective mea- specifi c affi nity for receptor subtypes not present in cardiac surements of hyposalivation. Patients express a mild prefer- and respiratory tissue. There is suffi cient evidence from 81

Table 3. Treatment of xerostomia, hyposalivation, and related oral complications Management of symptoms Diet and habit modifi cations Frequent and regular sips of water Avoidance of dry, hard, sticky, acidic foods Avoidance of excess caffeine and alcohol Salivary substitutes and lubricants Artifi cial saliva Rinses Gels Sprays Toothpastes Use of bedside humidifi er during sleeping hours Preventive measures Increased frequency of oral/dental evaluation Topical fl uoride application Varnish (0.5% NaF) Daily use of fl uoridated dentifrice Topical: over-the-counter (0.05% NaF); prescription (1.0% NaF, 0.4% SnF) Treatment of oral conditions Dental caries Restorative therapy, topical fl uoride Oral candidiasis Chlorhexidine (CHX) 0.12%: rinse, swish, and spit 10 ml twice daily Nystatin/triamcinolone ointment for : apply topically 4 times daily Clotrimazole troches: 10 mg dissolved orally 4–5 times daily for 10 days Systemic therapy for immunocompromised patients Denture antifungal treatment: soaking of denture for 30 min daily in CHX or 1% sodium hypochlorite Bacterial infections Systemic antibiotics for 7–10 days Ill or poor fi tting prostheses Denture adjustment Hard and soft reline Use of denture adhesives Implant-borne prostheses Increase salivary fl ow Sugar-free, xylitol-containing mints, candies, and gum Sialogogues Pilocarpine: 5–10 mg orally 3 times daily Cevimeline: 30 mg orally 3 times daily Acupuncture Manage underlying systemic conditions Multidisciplinary management with other health-care providers

randomized controlled clinical trials that oral forms of pilo- The xerostomic side effects of medications may be allevi- carpine and cevimeline both increase saliva fl ow rates and ated or reduced by substituting for the problem medications alleviate symptoms.22 Pilocarpine in the form of a mouth- similar drugs that have lesser side effects. For instance, wash, used orally for 1 min, was shown in one randomized selective serotonin reuptake inhibitors cause less xerosto- controlled trial with healthy patients to increase salivary mia than do tricyclic antidepressants.63 Moreover, altera- fl ow and affect subjective dryness as well.60 However, other tions in the timing or dosing schedule of medications, such topical forms of pilocarpine (e.g., spray, pastilles) did not as avoidance of medication doses at nighttime when salivary have the same benefi cial outcome in post-RT patients.61,62 fl ow is normally at its lowest, may minimize xerostomic Both drugs have side effects, including excessive sweating, effects. Multidisciplinary management of underlying sys- rhinitis, increased pancreatic secretion, and urinary and gas- temic conditions is imperative to reduce oral complications. trointestinal disturbances. Less common and more serious For instance, primary care providers should help diabetic adverse side effects of pilocarpine and cevimeline involve patients maintain good glycemic control. A rheumatologist the cardiovascular and respiratory systems. The use of pilo- may treat a patient with SS with other therapeutics involv- carpine and cevimeline is contraindicated in patients with ing cytokines or immunoregulators (e.g., rituximab or gastric ulcer, uncontrolled asthma, or hypertension, or in hydroxychloroquine) or with systemic steroids. Prominent patients on β-blockers. Acupuncture has been investigated complaints of xerostomia in patients with end-stage renal for treatment of hyposalivation and xerostomia, but the disease have been shown to improve following renal results are confl icting.22 transplantation.64 82

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