Foreword

The Office of Health Technology Assessment (OHTA) evaluates the risks, benefits, and clinical effectiveness of new or unestablished medical technologies that are being considered for coverage under Medicare. These assessments are performed at the request of the Health Care Financing Administration (HCFA). They are the basis for recommendations to HCFA regarding coverage policy decisions under Medicare.

Questions about Medicare coverage for certain health care technologies are directed to HCFA by such interested parties as insurers, manufacturers, Medicare contractors, and practitioners. Those questions of a medical, scientific, or technical nature are formally referred to OHTA for assessment.

OHTA's assessment process includes a comprehensive review of the medical literature and emphasizes broad and open participation from within and outside the Federal Government. A range of expert advice is obtained by widely publicizing the plans for conducting the assessment through publication of an announcement in the Federal Register and solicitation of input from Federal agencies, medical specialty societies, insurers, and manufacturers. The involvement of these experts helps assure inclusion of the experienced and varying viewpoints needed to round out the data derived from individual scientific studies in the medical literature.

After OHTA receives information from experts and the scientific literature, the results are analyzed and synthesized into an assessment report. Each report represents a detailed analysis of the risks, clinical effectiveness, and uses of new or unestablished medical technologies considered for Medicare coverage. These Health Technology Assessment Reports form the basis for the Public Health Service recommendations to HCFA and are disseminated widely. Individual reports are available to the public once HCFA has made a coverage decision regarding the subject technology.

OHTA is one component of the Agency for Health Care Policy and Research (AHCPR), Public Health Service, Department of Health and Human Services.

• Thomas V. Holohan, M.D.
• Director
• Office of Health Technology Assessment
• J. Jarrett Clinton, M.D.
• Acting Administrator
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• Division of Information and Publications
• AHCPR
• 5600 Fishers Lane
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Introduction

Electrostimulation has been introduced as a technique for increasing salivary output in the treatment of patients with xerostomia (dry mouth) secondary to Sjogren's syndrome. The procedure uses an electrostimulation device (salivation electrostimulator) to increase salivary production from existing glandular tissue. The device delivers a small electrical stimulus to the mouth via a probe. The electrostimulation device consist of an electric control module, a connecting cord, and a hand-held stimulus probe with two metal electrodes. The device may be battery-powdered. Patients with residual salivary tissue in the oral and pharyngea regions who demonstrate a decrease in the flow rate of saliva are potential candidates for this procedure.

Xerostomia may be the result of Sjogren's syndrome, other diseases, medications, or radiation therapy to the head and neck. To determine that the xerostomia has resulted from Sjogren's syndrome, clinicians also confirm the presence of keratoconjunctivitis sicca (dry eye) and a positive lip biopsy with or without the presence of a connective tissue disease. It is estimated that more than one million people, mostly women, suffer from Sjogren's syndrome in the United States.(1)

Xerostomia is usually defined as a symptom that exists when saliva production is less than 0.1 mL/min (or 0.1 g/min). However, the symptom of xerostomia has been reported to appear when normal salivary output declines by approximately 50, regardless of the starting value. Normal saliva production has been estimated to be 600 mL/24h.(2) Patients with chronic xerostomia complain of a continual feeling of oral dryness and find it difficult to eat dry foods.(3) In addition to the subjective complaints, the patient with salivary gland dysfunction is susceptible to increased dental caries, oral pain, frequent infections, and difficulties in speaking, chewing, and swallowing.(4) Several tests are available for measuring salivary function. According to Fox et al, (5). evaluation of salivary gland function can be assessed by stimulated saliva collection and analysis. The biopsy of the salivary glands, usually obtained from the lower lip, is used to differentiate true Sjogren's syndrome from other forms of salivary gland dysfunction.

The approach to the treatment of this condition varies considerably. In some patients, xerostomia may be managed by sipping water frequently. Other patients stimulate salivary flow with sugarless mints or gum.(6) Salivary substitutes such as a carboxymethylcellulose-based artificial saliva have been used by some patients to supplement low quantities of salivary flow. Pharmacologic agents have been introduced to treat the oral dryness of salivary gland dysfunction in patients where unstimulated salivary flow was low or nonexistent but where some functional salivary gland tissue existed. Fox et al(4). reported that pilocarpine was effective for relieving xerostomia by increasing natural salivary function. The production of endogenous saliva is of greatest benefit to the patient both for its convenience and the importance of natural saliva to oral Recently, attempts to increase saliva production have utilized electrical stimulation. Preliminary investigations were reported by Weiss et al(7). in 1986.

This report will examine the published literature and other available evidence to evaluate the electrostimulation of salivary production and determine if there are xerostomic patients who would benefit from this procedure.

Background

Sjogren's syndrome is a chronic inflammatory and autoimmune disease in which the salivary and lacrimal glands undergo progressive destruction by lymphocytes and plasma cells resulting in decreased production of tears and saliva.(8) Sjogren's syndrome is seen predominantly in middle-aged and elderly women.(9). Females are involved 10 times more commonly than males. Secondary effects of xerostomia include impairment in the normal movement of lips and tongue, thereby hampering speech, mastication, and swallowing.(10) Additional signs include oral soreness, adherence of food to buccal surfaces, fissuring of the tongue, an altered sense of taste, and a marked increase in dental caries and infection. Soreness and redness of the mucosa are usually the result of candidal infection, which is found in approximately 70 of the Sjogren's syndrome patients.(11)

Complaints resulting from dryness of the mouth are varied and often describe the difficulties encountered in trying to eat dry foods without sufficient lubrication.(11) Many subjects require frequent ingestion of liquids. They may resort to carrying water bottles or hard candy.

The parotid gland enlarges in many patients secondary to cellular infiltration and ductal obstruction. Usually asymptomatic and self-limited, the enlargement can be recurrent and associated with pain or erythema. Focal infiltrates of lymphocytes are also found in the minor salivary glands of the lower lip. Biopsy provides histologic confirmation and quantification of the degree of infiltration.

The subjective impression of xerostomia, or oral dryness, may not reflect actual salivary gland capabilities.(12) Salivary flow rate estimation is a sensitive indicator of salivary gland function. A suction cup is used to obtain parotid saliva from the gland after the tongue is stimulated with citric acid. Although the parotid glands make the major contribution to the total salivary flow, the submandibular glands are the most consistently affected glands in patients with Sjogren's syndrome. Measurement of parotid function may result in false-normal values. In Sjogren's syndrome, measurement of the submandibular/sublingual secretions are a sensitive indicator of salivary gland hypofunction. According to Fox et al(12). alterations in submandibular/sublingual function have the greatest impact on the sensation of oral dryness.

Another useful technique for studying the salivary glands is lip biopsy. The technique is a sensitive and specific diagnostic procedure for Sjogren's syndrome. It is well tolerated and causes no disfigurement. The changes in the minor of the lower lip show a close correlation with those in the major salivary glands.(11) In addition to confirming the diagnosis, biopsy allows quantification of the degree of lymphocytic infiltration and tissue damage. Aggregates of lymphocytes within the acinar tissue are scored. An aggregate of 50 or more cells represents a focus. The number of foci within 4 mm(2). of glandular tissue is determined and constitutes the focus score. A focus score or more than 1 is characteristic of Sjogren's syndrome.(8)

Salivary scintigraphy, which measures the uptake, concentration, and excretion of technetium pertechnetate by the major salivary glands, is also a sensitive index of glandular function. However, it is expensive, requires exposure to a radionuclide, and has little advantage over the other two procedures.(8)

The symptoms of dry eyes and dry mouth in the absence of any drug treatment or other disorder likely to be causal suggest a diagnosis of Sjogren's (11). According to Talal(8). the diagnosis of Sjogren's syndrome is based upon the confirmed presence of two of the following three criteria: (1) a focus score of more than 1 in the labial salivary gland biopsy, (2) dry eye (keratoconjunctivitis sicca), and (3) an associated connective tissue or lymphoproliferative disorder. The triad of dry eyes, dry mouth, and a connective tissue or collagen disease, usually rheumatoid arthritis, is termed secondary Sjogren's syndrome.(11) Dry eyes and dry mouth in the absence of a collagen disease is referred to as primary Sjogren's syndrome. The use of diuretics, antihypertensive drugs, antihistamines, antipsychotics, and antidepressants may diminish lacrimal and salivary gland function.(13) Because the use of anticholinergic drugs as well as a number of other medications may be the single most frequent cause of xerostomia, it is essential to establish the presence of focal lymphoid infiltrates and autoimmunity in a patient suspected of having Sjogren's syndrome. Supportive serologic data would include the presence of antinuclear antibodies, an elevated erythrocyte sedimentation rate, and the presence of anti-SS-A and anti-SS-B antibodies.

Treatment of xerostomia is difficult and includes preventing caries, treating and retreating oral candidiasis, and attempting to relieve the symptoms of dry mouth by increasing fluid intake, replacing absent saliva with saliva substitutes, or stimulating the remaining glandular tissue to secrete. Patients presenting with milder stages of xerostomia may benefit from frequent small sips of water or other fluids such as fruit nectars, and this may be as effective as any other means of alleviating symptoms. Sialagogues such as vitamin C tablets, sugarless chewing gum, mints, or hard candies may offer temporary relief through masticatory or gustatory stimulation. For other patients, saliva substitutes may ameliorate symptoms and possibly increase salivary flow. Efforts at relieving the symptoms of chronic xerostomia through the use of salivary substitute and by stimulating salivary flow usually offer only temporary relief from dryness. Nevertheless, appropriate management of patients with xerostomia requires that those patients whose salivary flow can be increased by means of sialagogues be distinguished from those patients whose salivary flow cannot be stimulated, or whose flow is insufficiently stimulated.(14). Patient response can be tested with the use of a mechanical (paraffin chewing) or a gustatory (citric acid) stimulant.(15) The replacement of citric acid crystals or a 2 citric acid solution in the mouth will stimulate demonstrable salivary flow within a few minutes in responsive patients.(12,14)

Where stimulation of salivary flow by sialagogues has been ineffective, saliva substitutes have been applied symptomatically to alleviate mucosal discomfort and to aid oral functioning.(10) Artificial saliva substitutes usually contain carboxymethylcellulose with or without the presence of natural mucins. Carboxymethylcellulose is used to impart lubrication and viscosity. Saliva substitutes that contain natural mucins maintain a surface tension similar to that of natural saliva. Salts are added to artificial saliva to mimic the eletrolyte content of natural saliva.(15) According to Brastings, (16). mucin-containing salivas as preferred by patients because carboxymethylcellulose compounds seem to be uncomfortably sticky. Preparations containing mucin are considered to provide formulations that most closely resemble human saliva.(17) When applied using an atomizer, saliva substitutes wet the oral cavity for about 30 minutes.(18) In addition, intraoral reservoirs have been designed to allow continuous wetting of the oral surfaces. Recently, a denture with a palatal reservoir for artificial saliva has been constructed. This reservoir holds 2-3 cc of substitute and needs to be refilled every 2-5 hours.(16) Several saliva substitutes are available and appear to be most successful when used at night.(3)

Parasympathomimetic drugs have been used as pharmacologic sialagogues in the treatment of xerostomia. Fox et al(4). demonstrated that in persons with documented salivary gland disease who have some functional salivary gland tissue, an orally administered systemic agent is effective in relieving xerostomia and increasing salivary output. Orally administered pilocarpine increases the production of saliva by parotid and submandibular or sublingual glands and relieves the sensation of oral dryness. The investigators suggest that a sustained-release form of the drug may offer increased therapeutic benefit. Scully(11). recommends pyridostigmine because it is longer acting with fewer side effects than other pharmacologic agents. According to Vissink et al(14). the usefulness of pharmacologic sialagogues is limited because of their side effects and contraindications.

By application of the concept of electrically stimulating nerves to elicit a response, electrostimulation was developed for use in the oral cavity to stimulate the salivary reflex. Investigators have reported that electrostimulation increases salivary output and should be used to treat patients with xerostomia secondary to Sjogren's syndrome.(3,7) The cost of a battery-operated, hand-held stimulus probe that can provide electrical stimulation to the tongue and hard palate is approximately $1,500.

Rationale

Proponents of electrostimulation as a method to increase salivary production suggest that this procedure enhances the patient's ability to generate saliva by augmenting normal physiologic salivary reflexes. Salivary secretion is normally controlled by reflex stimulation with effector nerve impulses traveling along sympathetic as well as parasympathetic nerves to the glands. Sympathetic nerve stimulation produces a sparse viscous secretion, whereas the parasympathetic nerve stimulation produces a voluminous watery secretion.(19) The dual secretion (saliva) is a fluid mixture produced from paired major salivary glands (parotid, submandibular, and sublingual) and many smaller aggregations of minor salivary glands imbedded in the submucosa of the cheeks, lips, hard and soft palates, and tongue.

Proponents believe that xerostomia secondary to Sjogren's syndrome can be caused by interruption of the stimulus that elicits salivation at the effector site; such interruption results from loss of glandular tissue with replacement by round cell infiltration, scar, or fatty tissue. They postulate that an electronic device that touches the tongue and roof of the mouth simultaneously will stimulate tactile receptors, taste receptors, and intrinsic muscle mechanoreceptors within the mucosa of the dorsum of the tongue and the roof of the mouth. This produces electrical stimulation to the oral and pharyngeal afferent nervous system resulting in a reflex volley of efferent impulses to all residual salivary tissue, major and minor, in the oral pharyngeal regions causing salivation.

Review of Available Literature

It has long been known that the nerves to salivary glands control the secretion of saliva. According to Garrett(19). an experiment in 1850 by Ludwig demonstrated that electrical stimulation of the chordalingual nerve in the dog caused a copious secretion of submandibular saliva.

In 1986 Weiss et al(7). reported on the use of an electronic stimulator as a method for increasing salivary production. In this preliminary investigation, 9 of the 24 patients with a primary complaint of xerostomia has Sjogren's syndrome (diagnosed on the basis of medical history only). Following a visual examination of the oral cavity as well as a gloved finger test to determine the presence of moisture (any reflection was considered a sign of wetness), patients were administered a 3-minute stimulus to the tongue and roof of the mouth with the probe (electrodes) of the hand-held stimulator. The maximum voltage delivered by the device is 6 V with a current of 9 micro-A. Patient tolerance controls and determines the level of stimulation. Two subsequent stimulations of 3 minutes each were conducted at the same sitting by most of the patients (actual numbers not reported). Each stimulation procedure was followed by a subjective patient evaluation of improvement and a repeat clinical examination.

According to the investigators, prior to stimulation, seven of the nine patients with Sjogren's syndrome were considered to have slight amounts of moisture present, and the remaining two patients had "no moisture" present. Following stimulation, all nine patients reported subjective impressions of increased salivation as compared with prestimulation conditions. Clinical assessment was in agreement with the subjective patient evaluations. Weiss et al(7). reported that the electronic device stimulates residual salivary tissue in the oral and pharyngeal regions, producing increased salivation.

In 1988, Steller et al(3). conducted a study of electrical stimulation of salivary flow in patients with biopsy-proven Sjogren's syndrome. The response to an electrical stimulus applied to the tongue and hard palate was observed in a randomized, double-blind, 4-week study of 29 subjects with xerostomia secondary to Sjogren's syndrome. To be eligible to participate in the study, subjects had to have an unstimulated whole (total gland secretions) salivary flow rate of less than 0.2 g/min. Patients were randomly assigned to active or placebo devices, which they used for 3 minutes, three times a day for 4 weeks. Response to stimulation was assessed as whole saliva flow rates, which were measured at weeks 0, 2, and 4, both before and after stimulation with the device.

According to the investigators, there were no statistically significant differences between changes in prestimulation whole saliva flow rates or differences between the net changes in mean whole saliva flow rate (post-stimulation minus prestimulation flow) of the active and placebo groups at each visit. The investigators did find the changes in mean post stimulation whole saliva flow rates between subjects using active and placebo devices from weeks 0 to 4 of the study to be statistically significant. However, analysis of the results showed that the mean increase in the poststimulation flow rate of the active device group (13 subjects) was due mainly to the responses of three subjects who showed marked increases in their whole saliva flow rates during the study. The investigators noted that the initial salivary flow rates of these subjects were the highest in that group, and their labial salivary gland focus scores were among the lowest.

The investigators concluded that some Sjogren's syndrome patients with residual salivary flow show significant responses to electrical stimulation, but others with low or absent whole saliva flow rates do not respond. During the 4-week study period no change in the appearance of the oral mucosa was observed at the site of electrode placement, and no marked changes or patterns of variation in subjects' pulse and blood pressure were observed before or after the device was used.

Discussion

Xerostomia is a complaint of elderly individuals, particularly women.(6) Decreases in both quantity of saliva as well as composition cause a multitude of problems. In a healthy mouth, copious saliva containing essential electrolytes, glycoproteins, and antimicrobial enzymes continually lubricates and protects the oral mucosa, thus cleaning the mouth, regulating acidity, maintaining the integrity of the teeth, and destroying bacteria.

Currently, xerostomia is managed on the basis of subjective symptoms, evidence of reduction in salivary flow, and complications that result from dry mouth. To alleviate some of the problems resulting from salivary dysfunction, pharmacologic sialagogues such as pilocarpine and pyridostigmine as well as sialagogues that include sugarless chewing gum, mints, or candy are prescribed in order to stimulate more salivary flow.(18) Sialagogues are effective only if salivary gland function is present.

The preliminary investigation by Weiss et al(7). in 1986 demonstrated that a probe providing electrical stimulation applied to the tongue and hard palate of patients with xerostomia presumed secondary to Sjogren's syndrome produces a salivary response. The salivary response was obtained in the nine patients following a single session of one to three electrical stimulations of 3 minutes each. As a preliminary investigation, this study did not include a control group or any quantitative assessment of salivary response, duration of response, or long-term assessment of efficacy. Moreover, seven of the nine patients tested exhibited residual saliva production prior to treatment and may have been exhibiting a tactile response to the probe.

The only other published report determining whether an electrical stimulus applied to the tongue and hard palate could stimulate salivary flow in subjects with xerostomia secondary to Sjogren's syndrome is the randomized, double-blind, 4-week study reported by Steller et al in 1988.(3). The results of this short-term study indicate that some Sjogren's patients with residual salivary flow in an unstimulated state (<0.11 -0.20 g/2 min) show a significant response to electrical stimulation, but others with low (less than 0.11 g/2 min) or absent whole saliva rates do not respond or respond to a clinically insignificant degree. Only 3 of 13 patients using the active device showed a significant response (about 0.6 -1.0 g/2 min) in salivary production when compared with the responses of the placebo group. The whole saliva flow rates of the remaining 10 subjects in the active group remained below 0.25 g/2 min throughout the study and were not of the order of magnitude necessary to indicate a significant salivary response. Whole saliva flow rates of 10 subjects in the placebo group remained below 0.20 g/2 min throughout the study. It appears that additional studies with larger patient populations are needed to define specific degrees of salivary function or dysfunction that would respond to electrical stimulation. These studies could help to determine whether a single salivary response to electrostimulation or some other test such as lip biopsy focus score should be used to help identify those patients who may benefit from the technique.

Guidelines that would specify which types of Sjogren's patients with what degree of xerostomia and at what points in their clinical evaluation or management would benefit from electrostimulation cannot be developed without further clinical investigation. Long-term studies of well-characterized patient groups will also help to determine how long it take to achieve a response. According to some investigators, this should allow sufficient time to determine if any regeneration of the salivary gland parenchyma is achieved. In order to determine the effectiveness of electrical stimulation of salivary flow in Sjogren's patients, studies should include information regarding concomitant therapy (continued frequent water sipping or use of other sialagogues) and the duration of the salivary response so that it can be compared with the use of other therapies. Studies and subsequent management of Sjogren's patients with dry mouth should include quantitative assessment of salivary function (unstimulated and stimulated, whole and individual gland salivas), assessment of oral conditions for signs of salivary hypofunction, and subjective patient evaluations.

Salivary glands in patients who suffer from rheumatoid diseases show varying degrees of destruction. This damage is progressive and considered irreversible by some investigators.(17) The ability to induce secretion in individuals with these conditions will be inversely related to the glandular damage. The study by Stellar et al(3). shows that a device providing electrical stimulation to treat dry mouth in patients with Sjogren's syndrome appears to be effective after 4 weeks of study in only a small percentage of patients. These patients my represent a group with less advanced disease (lesser degree of lymphocytic infiltration) and a greater amount of functional salivary parenchyma. These individuals would likely respond equally well to mechanical, chemical, tactile, and pharmacologic means of salivary stimulation. Anything that enhances mastication will induce secretion. So, too, will salts an citric acid solutions. While all of these techniques are effective, their effects are transient; however, there have been no studies to demonstrate that electrical stimulation provides any advantage or is more effective than other existing techniques.

Successful treatment for dry mouth is recorded as both subjective and objective increases in saliva output. According to Fox et al, (5). patient complaints of xerostomia or oral dryness may not reflect actual salivary gland capabilities or function. Subjective assessments alone are not adequate fo diagnostic or therapeutic purposes. Although there is no fixed salivary level for intervention, xerostomia is generally associated with whole saliva flow rates of less than 0.1 mL/min. For some patients, a 50 reduction in salivary output leads to the subjective impression of dry mouth. However, the level of diminished salivary output where a patient becomes subject to increased risk of oral disease or dysfunction is not known. Moreover, there is a wide variability of "normal" salivary output. A 50& decline for one individual might still result in a flow rate greater than another individual's normal output. Some investigators feel than if the minor salivary glands can be stimulated to coat the mucosa with a thin layer of mucous, the sensation of dryness will be relieved. Even very small increases in saliva output may be beneficial in preventing or minimizing the oral effects of salivary dysfunction. Long-term clinical studies are needed to examine these issues.

Summary

Electrostimulation has been introduced as a technique for increasing salivary output in the treatment of patients with xerostomia (dry mouth) secondary to Sjogren's syndrome. The procedure uses an electrostimulation device (salivation electrostimulator) to increase salivary production from existing glandular tissue. The device delivers a low-voltage electrical stimulus to the mouth via a probe. Patients with residual salivary tissue in the oral and pharyngeal regions who demonstrate a decrease in the flow rate of saliva are potential candidates for this procedure.

It is estimated that more than one million people in the United States, predominantly middle-aged and elderly women, suffer from Sjogren's syndrome. Patients with chronic xerostomia complain of a continual feeling of oral dryness and have difficulty eating dry foods. These patients are susceptible to increased caries, oral pain, infection, and have difficulty speaking, chewing, and swallowing.

The approach to the treatment of xerostomia in Sjogren's patients is usually determined by the level of severity of the symptoms. Appropriate management of patients with xerostomia requires that those patients whose salivary flow can be increased by means of sialagogues be distinguished from those patients whose salivary flow is either unaffected or insufficiently stimulated. To alleviate some of the complications due to salivary dysfunction in those patients who respond to stimuli, pharmacologic sialagogues as well as sialagogues that include sugarless gums, mints and candies are prescribed in order to increase salivary flow.

Recently, electrostimulation via a hand-held stimulus probe has been introduced as a method of treatment in xerostomia secondary to Sjogren's syndrome. From the single published study as well as data provided to the FDA, it appears that an electrical stimulus applied to the tongue and hard palate (by a battery-operated device) may be useful in the management of salivary hypofuntion in certain patients. It appears, however, that there are insufficient data at the present time to determine the clinical utility of electrostimulation, to evaluate the long-term clinical effectiveness of this modality of salivary production, or to identify those xerostomic patients who would benefit from this procedure. Also, electrostimulation is not widely accepted as an effective method of treatment for xerostomia secondary to Sjogren's syndrome. The number of published studies is limited and other less expensive treatments are available. Further research of electrical stimulation of salivary flow is required to determine its role in the treatment of Sjogren's patients with xerostomia.

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2.

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3.

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Duxbury AJH, Thakker NS, Wastell DG A double-blind cross-over trial of a mucin-containing artificial saliva Br Dent J 1989 166:115–120. [PubMed: 2465774]

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[no authors listed] Summary of Safety and Effectiveness Data: Salivation Electro-Stimulation Device, (unpublished report) Food and Drug Administration. 1988.

AHCPR 91-0009