Management of Salivary Gland Hypofunction


1. Preventive Therapy

  • Use of topical fluorides to control dental caries (dosage chosen and frequency of application should be determined based on severity of salivary dysfunction and rate of caries development)
  • Maintain oral hygiene -- more frequent dental visits to maintain optimal dental health
  • Diet -- avoid cariogenic foods and beverages and brush immediately after meals; avoid alcohol and caffeine as they can increase oral dryness, regular use of fresh, light acidic fruits, slices of cold cucumber and tomato or thin slices of cold apples are recommended. Fruit juices, however, are not recommended as they are often too acidic and have a strong taste.
  • Remineralizing solutions to alleviate some of the effects of loss or normal salivation
(Nieuw Amerongen & Veerman, 2003, p.229) (Valdez & Fox, 1993, p.274)


2. Symptomatic (palliative) Therapy

  • Take sips of water throughout the day to help moisten oral cavity, hydrate the mucosa and clear debris from the mouth
  • Take water with meals to make chewing and forming of food bolus easier (also eases swallowing and improves taste perception)
  • Increase in environmental humidity : eg. Use room humidifiers , particularly at night (will lessen discomfort markedly)
  • use of oral rinses, mouthwashes, and gels for dry mouth patients
  • AVOID products containing alcohol, sugar or strong flavourings that may irritate sensitive dry mucosa
  • Frequent use of products containing aloe vera or vitamin E
Table 1 Palliative oral care for xerostomia patients: mouthwashes and saliva substitutes
Home-made mouthwashes Commercial mouthwashes Saliva substitutes
  • Saline
  • Bicarbonate
  • Glycerol
  • Lemon
  • Biotene
  • Oral Balance
  • Zendium
  • Glandosane
  • Saliva Orthana
  • Xialine

(Nieuw Amerongen & Veerman, 2003, p.229)

3. Local and Topical Therapies
Table 1. Salivary enhancement therapies (Fox, 2004, p.242)
Local/topical secretagogues Systemic secretagogues
  • Gustatory stimulation
  • Masticatory stimulation
  • Oral rinses, gels, mouthwashes, toothpaste
  • Artificial saliva
  • Anhydrous crystalline maltose
  • Mucin spray
  • Humidifiers
  • Acupuncture
  • Pilocarpine HCl
  • Cevimeline HCl
  • Interferon Aplha
  • Bromhexine
  • Anethole trithione
  • Traditional Asian mixtures
  • Essential fatty acids (Evening primrose oil)
  • LongoVital® (Vitamin supplementation)
  • Yohimbine
  • Infliximab
  • Bethanechol
  • Carbacholine
  • Corticosteroids
  • Hydroxychloroquine
  • Electrostimulation


Masticatory Stimulation & Gustatory Stimulation
  • Chewing results in a significant increase in saliva output.
  • Salivation is also responsive to taste, especially sourness and bitterness.
  • A combination of gustatory and masticatory stimulation can hence increase salivation.
    • Sugar-free gums e.g. xylitol gums, lozenges (e.g. Salix®, Bentasil), candies or mints is a common form of palliative therapy for xerostomia.
    • Some chewing gums such as V6 (Stimorol) and Freedent (Wrigley) are able to buffer dietary acids.
    • Vitamin C tablets can also be used. Due to its bitter acidic taste, citric acid and a sweetener are often added. However, it is not recommended for frequent usage due to the corrosive effect of citric acid on enamel even though citric acid provides an additional gustatory stimulus.
    • But they may be inconvenient and patients may not comply with treatment.
    • Frequent ingestion of sugar-free liquids could be an alternative for these patients.
(Porter, Scully, and Hegarty, 2004, p.35) (Fox, 2004, p.242) (Nieuw Amerongen & Veerman, 2003, p.229) (Valdez & Fox, 1993, p.274)


Agents
  • Artificial salivas (severe cases)
    • Duration of effect is short because they are removed from the mouth during swallowing.
    • Lack the protective roles of saliva.
    • Hydrate and lubricate oral tissues.
    • Some saliva substitutes have a remineralizing effect on dentin and enamel due to its calcium and phosphate content, e.g. milk, certain prescribed artificial salivas.
    • Intraoral devices containing the saliva substitute can be used to slowly release the lubricant.
  • Oral rinses (Biotene) and gels (Oralbalance), flavoured mouthwashes, toothpastes
    • Using Biotene mouthwash in conjunction with Biotene toothpaste has been shown to be even more effective because it contains an enzyme lactoperoxidase that kills bacteria, such as the Candida species that cause Candidiasis.
    • Using topical fluorides to control caries.
    • Some are unsuitable because they cause demineralising of teeth e.g. lemon-based salivary substitutes that can erode enamel.
  • Mucin Spray
    • Useful against radiation-induced xerostomia, particularly in elderly patients.

    (Porter, Scully, & Hegarty, 2004, p.35) (Sandra F. Cassolato, Robert S. Turnbull, p.71)
Management of Salivary Gland Hypofunction - CariologyManagement of Salivary Gland Hypofunction - Cariology
(www.anglianpharma.com) (http://www.dentist.net/images/biotene-oralbalance-liquid.jpg)


4. Systemic Therapies

Cholinergic agonists

Pilocarpine HCL:
  • Pilocarpine is a parasympathomimetic (anti-cholinergic) agent with mild ß-adrenergic stimulating properties.
  • Pilocarpine is a parasympathetic agonist of acetylcholine muscarinic M3 receptors that binds unselectively to muscarinic receptors and thus stimulates salivary glands.
Used for the management of the following:
1. Xerostomia secondary to radiation-induced salivary gland damage
2. Xerostomia due to Sjögren’s syndrome
3. Potentially beneficial in limiting drug-induced xerostomia

Advantages

  • "Clinical trials have consistently demonstrated that at doses of 5–10 mg 3 or 4 times daily, pilocarpine can significantly improve symptoms of dry mouth and increase salivary output." (Fox, 204, p.243)
  • Duration of effect -- Maximum stimulation of salivary glands approximately 1 h after dosing pilocarpine. Secretion above baseline salivary output are found for 3–4 hrs.
  • The drug of choice for the treatment of radiation-induced xerostomia, dry mouth and dry eyes in patients with Sjögren’s syndrome.
Disadvantages

  • Side effects such as sweating, nausea, flushing and urinary frequency are common. However, they are often mild or moderate and of relatively short duration.
  • Stimulate the smooth muscle contraction, affecting gastrointestinal and urinary tracts, gall bladder, bile ducts, and bronchi.
  • Pilocarpine should not be used on patients with uncontrolled asthma, narrow-angle glaucoma or acute iritis.
  • Caution is advised for patients with cardiovascular disease, controlled asthma, chronic bronchitis, chronic obstructive pulmonary disease. This is especially so when pilocarpine is used together with ß-adrenergic antagonists or drugs with anti-cholinergic effects.
  • Adverse effects are rare, with no tachyphylaxis (a rapid decrease in the response to a drug after repeated doses over a short period of time) or problems with drug-to-drug interactions.
  • Refer to (http://www.drugs.com/pro/pilocarpine.html) for information on the extensive usage and side effects on different categories of patients.
Xerostomia secondary to radiation-induced salivary gland damage

Brachytherapy (source of irradiation is placed close to the surface of the body or within a body cavity) of tumors in head and neck can destroy salivary gland acinar. Serious xerostomia caused by direct radiation towards major salivary glands.
  • Intravenous administration of Amifostine before irradiation may lessen the severity of radiation-induced xerostomia.
  • Oral administration of Pilocarpine after irradiation may lessen the severity of radiation-induced xerostomia.
  • Pilocarpine enhances the function of minor salivary glands that are more resistant to radiation damage compared to major salivary glands. However, it cannot enhance the function of completely damaged glands.
  • Due to their location away from the direction of brachytherapy, minor mucous salivary glands may escape the full dose of radiation.
(Porter, Scully, and Hegarty, 2004, p.37-38) (Fox, 2004, p.243-244) (H.Mese & R.Matsuo, 2007, p.719-720) (Sandra F. Cassolato, Robert S. Turnbull, p.72-73)
    Cevimeline HCL:
    • Another parasympathomimetic agent (an acetylcholine analogue)
    • Cholinergic agonists.
    • Cevimeline have a high selective affinity for M3 subtype muscarinic receptors, the predominant receptor subtype in the salivary glands.
    • Low affinity for equivalent M2 receptors on cardiac and lung tissue.
    • At doses of 30 mg 3 times daily, cevimeline was shown to significantly improve symptoms of dry mouth and increase salivary output in patients with Sjögren’s syndrome.
    • A drug of choice for patients with Sjögren’s syndrome
    • Cevimeline has a similar pharmacological profile to pilocarpine, with differences in duration and time for onset. (Table 1)
    • Very similar to pilocarpine in terms of safety in usage and adverse effects.
    • Adverse effects on the central nervous system includes increased heart rate and blood pressure, chills, headache and dizziness.
    • Possible cardiovascular and pulmonary side effects limit the routine usage of these cholinergic agonists.
    Physiology
    • They are readily absorbed in the gastrointestinal tract, reach peak concentrations within approximately 1 hour for Pilocarpine and slightly longer for Cevimeline.
    • It is metabolized in the liver and excreted principally by the kidneys (half-life approximately 1 hour for Pilocarpine and 5 hours for Cevimeline).
    • Increases exocrine gland secretion (e.g. salivary and sweat glands)
    • Due to its cholinergic actions, may result in adverse side effects.
    (Porter, Scully, and Hegarty, 2004, p.38) (Fox, 2004, p.243) (H.Mese & R.Matsuo, 2007, p.719)


    Table 1: Comparison of pharmacokinetics and frequency of side effects associated with pilocarpine and cevimeline
    (H.Mese & R.Matsuo, 2007, p.720)

    Pilocarpine Cevimeline
    Parameter
    Dosage 5 mg q.i.d. 30 mg t.i.d.
    Time to peak plasma concentration (h) 1.25–1.47 1.53–2.86
    Mean elimination half-life (h) 0.76 5 ± 1
    Frequency (%) of side effects
    Excessive sweating 40 18.7
    Nausea 9 13.8
    Rhinitis 7 11.2
    Diarrhoea 6 10.3
    Flushing 9 0.3
    Urinary frequency 10 0.9


    Anethole Trithione

    • No cholinergic action, but upregulates muscarinic receptors on the postsynaptic membrane hence enhancing the potential for cholinergic stimulation.
    • The mechanisms responsible for salivary stimulation may relate to upregulation of substance P and α-calcitonin gene-related peptide by the drug.
    • Increase salivation in individuals with mild dysfunction.
    • Ineffective in more severe cases such as in Sjögren’s syndrome.
    • A synergistic effect possible between anethole trithione and pilocarpine in treatment for radiation-induced xerostomia but not in primary Sjögren’s syndrome.
    (Fox, 2004, p.244)

    Bethanechol
    • Has both muscarinic and nicotinic agonist actions.
    • Potential usage for drug-induced xerostomia.
    • Bethanechol was found to increase the unstimulated and stimulated salivary flow rates of patients with radiation-induced xerostomia.
    • Adverse effects, which may include nausea and diarrhoea, are infrequent.
    (Porter, Scully & Hegarty, 2004, p.38)

    Immunologically active agents

    Sjögren’s syndrome is an autoimmune disorder characterized by a destructive T-lymphocyte response and the release of a range of cytokines. Thus, modulating these responses will reduce damage to salivary glands.

    Interferon α:

    • Intramuscular and parenteral (a route of administration that involves the piercing of skin or mucous membrane) interferon α increases the lacrimal and salivary flow of patients with primary and secondary Sjögren’s syndrome.
    • Systemic interferons α on the other hand commonly results in a wide range of adverse effects.
    • Can be a high-dose injectable or a low-dose lozenge.
    • The injectable IFN-α is a recombinant protein, while the lozenge is a natural (cell line-derived) IFN-α.
    • The low-dose lozenge treatment showed improvement to minor salivary glands, reducing inflammation and increasing healthy acini on Sjögren’s syndrome patients after 6 months of treatment.
    • Side effects and adverse events were minimal.
    (Porter, Scully & Hegarty, 2004, p.39) (Fox, 2004, p.244)




    5. Therapies directed at an underlying systemic cause

    • Highly active antiretroviral therapy may reduce the salivary gland enlargement of HIV-related salivary gland disease.
    (Porter, Scully & Hegarty, 2004, p.40)



    6. Therapies that require further studies
    Acupuncture
    • Applying needles to specific locations which are often in close to the oral cavity.
    • At least two neuropeptides (vasoactive intestinal peptide and calcitonin gene-related peptide) are increased in saliva following acupuncture treatments.
    • It is possible that these neuropeptides could stimulate salivary functions.
    • Acupuncture remains a possible approach that requires further study.
    (Fox, 2004, p.244)
    Anhydrous crystalline maltose
    • Lonzenges containing anhydrous crystalline maltose has been used in recent clinical trials as a treatment for dry mouth in Sjögren’s syndrome with visible benefits.
    (Fox, 2004, p.243)
    Others (e.g. Bromhexine, Carbacholine, Pyridostigmine)
    • Conflicting data on the precise benefits.
    • Requires further clinical trials.
    • Minimal to non-existent effects.
    Humidifiers
    • Found to have minimal benefit
    (Porter, Scully & Hegarty, 2004, p.36)


    Future Directions for Saliva-Enhancing

    • Secretagogues with fewer side effects, longer effective duration and greater potency.
    • Small-molecule drugs that are specifically directed to other receptors on salivary cells other than the muscarinic receptor, hence reducing side effects.
    • Gene therapeutic techniques for salivary cell growth and repair.
    • Salivary transplantation
    • Artificial salivary gland
    (Fox, 2004, p.244-245)

    Oral Health Care in Patients with Xerostomia

    Table: Summary of oral care in patients with xerostomia (Porter, Scully, and Hegarty, 2004, p.35)

    Oral hygiene Plaque control, oral hygiene instruction, dietary advice, chlorhexidine mouthwash or fluoride mouthwash daily (0.05%) to minimize the risk of caries.
    Dentures Should fit well.
    Implant-retained.
    Provide instructions on denture hygiene.
    Antifungals Nystatin pastilles, amphotericin lozenges, miconazole gel
    Topical saliva substitutes Sugar-free gum and candies; oral moisturizers
    Systemic therapies Pilocarpine, cevimeline, and others

    DENTURES

    • The tongue adheres to and dislodges the denture, causing decreased retention of prosthesis resulting in abrasions, sore spots, ulceration and irritation
    • An implant-supported denture may be successful but expensive.
    • Dentures with reservoirs or chambers for artificial saliva for continuous delivery of saliva. But they should not be worn during meals.
    • Removable dental prostheses should be treated by soaking in anti-fungal medication.

    Reduced saliva causes an overgrowth of Candida albicans (fungus). This may be worsened by the use of dentures, smoking and diabetes.
    Angular cheilitis (inflammatory lesion at the labial commissure, or corner of the mouth that manifests as deep cracks or splits) can be treated with nystatin ointment or clotrimazole cream (both antifungal drugs).

    Management of Salivary Gland Hypofunction - Cariology
    Oral Candidiasis
    (http://medical-dictionary.thefreedictionary.com/candidiasis)

    Management of Salivary Gland Hypofunction - Cariology
    Angular Cheilitis
    (http://www.doctorspiller.com/aids.htm)
    1. Recurrent oral candidiasis can be treated with topical anti-fungal medications.

    2. Oral rinses with anti-fungal medications such as nystatin and fluconazole are effective in the treatment of oral candidiasis and for relieving oral discomfort.

    (Cassolato & Turnbull, p.70) (Valdez & Fox, 1993, p.275)

    References:
    1. Philip C. Fox. (2004). Salivary Enhancement Therapies. Caries Research, 38, 241-246.
    2. C.Dawes. (2004). How Much Saliva is Enough for Avoidance of Xerostomia? Caries Research, 38, 236-240.
    3. H.Mese, R.Matsuo. (2007). Salivary secretion, taste and hyposalivation. Journal of Oral Rehabilitation, 34, 711-723.
    4. S. R. Porter, C. Scully, A. M. Hegarty. (2004). An update of the etiology and management of xerostomia. Oral Medicine, Vol. 97, No. 1.
    5. Sandra F. Cassolato, Robert S. Turnbull. Xerostomia: Clinical Aspects and Treatment. Original Articles, Vol 20, No.2.
    6. A. V. Nieuw Amerongen, E. C. I. Veerman. (2003). Current therapies for xerostomia and salivary gland hypofunction associated with cancer therapies. Support Care Cancer, 11, 226-231.
    7. Ingrid H. Valdez and Philip C. Fox. (1993). Diagnosis and Management of Salivary Dysfunction. Critical Reviews in Oral Biology & Medicine, 4, 271-277.
    8. Drugs.com. (2009). Pilocarpine. Retrieved August 25,2009 from http://www.drugs.com/pro/pilocarpine.html
    9. Drugs.com. (2009). Cevimeline Hydrochloride. Retrieved August 25,2009 from http://www.drugs.com/ppa/cevimeline-hydrochloride.html

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