Xerostomia is "a subjective sensation of oral dryness." These symptoms might present as dry mouth, difficulty swallowing or dry oral mucosa/skin.  There are numerous causes of xerostomia; the most common cause is medication side effects, followed by Sjogren syndrome (SS) and radiotherapy and other autoimmune diseases in no particular order. Irrespective of a specific etiology, the patient's primary complaint is dry mouth. Because it is such a debilitating condition without any specific treatment, there are major psychosocial factors that come into play, ranging from mild anxiety to major depressive disorder (MDD).
To find a cure or treatment of xerostomia, one needs to learn about salivary gland anatomy. The three major salivary glands responsible for saliva production are parotid gland, submandibular gland, and sublingual gland. The anatomy of all three glands is quite similar, consisting of a duct that opens into the oral cavity. Hyposalivation due to radiation shows fibrosis while hyposalivation due to an autoimmune disease could show an infiltrate of B and T-cells, leading to gland destruction.
Xerostomia has multiple etiologies. The commonest cause of xerostomia is due to the adverse effect of prescription and over the counter medications. Many medications have been implicated including but not limited to diuretics such as furosemide, anticholinergic, antihistamine, antihypertensive, antidiarrheal and antidepressant medications and treatment of head and neck cancers with radiation and or chemotherapy. Autoimmune systemic disorders such as Sjogren syndrome (although very well known but a rare cause), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), thyroid disease and primary biliary cirrhosis (PBC) all have implications as potential causes. Patients with a history of mouth breathing, dehydration, poorly controlled diabetes, nerve damage from head or neck injury, end-stage renal disease (ESRD), graft versus host disease (GVHD), HIV/AIDS also complain of dry mouth. Xerostomia is a common complaint in older patients, which is likely due to the higher use of medications in these patients and a higher incidence of comorbid conditions.
There is no concrete evidence about which sex gets affected the most. In 1996, a statistically significant study based in Sweden concluded that 21.3% of men and 27.3% of women reported xerostomia. According to a study in 2006, the prevalence of xerostomia ranged from 0.9% to 64.8%. The majority of data collected for these studies was in Scandinavia (most patients age greater than 50, the rest being over 18). In contrast, 100% of patients who received radiation for head and neck cancer or diagnosed with Sjogren syndrome complain of xerostomia.
The prevalence of xerostomia is increasing due to the increasing aging population. Age by itself is not a cause of xerostomia, but older patients tend to be on multiple medications and have a higher incidence of comorbid conditions.
All major and minor salivary glands have nerve supplies, and upon stimulation, salivatory nuclei in the medulla generate an efferent response. The efferent nerve impulses release acetylcholine (ACh), which works on muscarinic receptors (specifically M3 receptors), which then stimulates salivary glands to produce saliva. The stimulation that causes salivary production ranges from smelling to chewing. Histologically, major salivary glands are made up of salivary acini and ducts, which produce two types of fluids, serous and mucinous. Pathology arises when there is a dysfunction of gland innervation, or the gland itself.
Because so many drugs carry associations with xerostomia, it is imperative to check the medication list before conducting an extensive workup. Some of the medications that have strong correlations to xerostomia include atropine, scopolamine, phentermine, methyldopa, clonidine, furosemide, timolol, and numerous more. The majority of these medications act on the central nervous system (CNS) or at the neuroglandular junction.  Since the secretory cells receive nerve supply from muscarinic M1 and M3 receptors, alpha1- and beta1-adrenergic receptors, and specific peptidergic receptors that are involved in the initiation of salivary secretion, xerostomia is caused by either suppressing the CNS from producing ACh or by occupying the muscarinic/ adrenergic receptors.
In Sjogren syndrome, chronic lymphocytic infiltration and inflammation of acinar cells lead to exocrine fibrosis resulting in non-functional glands. Initially, only CD4+ lymphocytes were believed to be involved in the pathophysiology of Sjogren syndrome. However, new data also suggests the involvement of B-cells. Sjogren syndrome is more common in females, with an average age of around 50 to 60 years. It is unusual for Sjogren to present after the age of 65 and dry mouth after this age is more commonly attributable to age-related exocrine atrophy. The presence of anti-SSA (Ro) or anti-SSB (La) antibodies can help make the diagnosis of Sjogren syndrome. Sjogren syndrome, as explained earlier, is an autoimmune condition that is characterized by chronic lymphocytic infiltration, which causes eventual fibrosis of salivary glands. Management usually includes immunosuppressants.
The reason radiation causes xerostomia is that the oral cavity, lymph nodes, and salivary glands happen are in the radiation field when head and neck cancer patients are receiving treatment. Although the tissues of salivary glands have a low mitotic index which should make them quite stable and typically radiation-resistant, studies have shown a decline in salivary gland function proportional to the radiation dose. Acinar atrophy and chronic inflammation are considered hallmarks of radiation-induced xerostomia. This dose-dependent radiation causes a secretory dysfunction of the gland. Fibrosis mostly presents as periductal and intralobular, but the structure of the ducts remains intact.
Xerostomia, regardless of etiology, has similar signs and symptoms. Functional alterations include difficulty chewing, swallowing, speaking, and decreased taste sensation. Lack of and/or decrease in salivary production leaves one more susceptible to gingival disease, dental caries, periodontal disease, halitosis, and plaque formation. The objective changes that might be visible are cracked and dry lips, and lack of saliva on the floor of the mouth.  Some morphological changes that might be visible include atrophy of filiform papilla and erythematous mucosa in the posterior half of the tongue. Dry eyes, skin, and throat could also accompany dry mouth when radiation-induced or due to a condition like Sjogren syndrome.
Xerostomia is a clinical diagnosis primarily made based on history and physical examination. If needed, there are numerous techniques employed to evaluate hyposalivation.
1) Sialometry: The normal stimulated salivary flow rate is between 1.5 to -2.0 mL/min, while the unstimulated flow rate ranges from 0.3 to 0.4 mL/min. A diagnosis of hyposalivation is if stimulated salivary flow is less than 0.5 to 0.7 mL/min or unstimulated flow of under 0.1 mL/min.
2) Sialography: An Imaging technique that can be used to identify salivary stones or masses. Three-dimensional (3D) MR sialography looks to be a promising diagnostic approach in patients with radiation exposure as the salivary gland flow can be visualized.  A small trial on 3D MR sialography in pre and post-radiation patients has shown promise. Imaging performed at 6 weeks pre-radiation and 6 months post-radiation showed a decrease in salivary flow.
3) Biopsy: If a systemic cause such as sarcoidosis, amyloidosis, or a salivary mass is suspected, a biopsy of a salivary gland may be necessary. Further management then depends on biopsy results.
The main goal of management is symptomatic relief. The underlying cause should be treated if possible, such as the alleviation of nasal congestion leading to mouth breathing. Correction of dehydration and increasing fluid intake are important. Local measures such as the use of artificial saliva as sprays, lozenges, and gels may be used before meals and as needed. Frequent sips of water, chewing sugar-free gum or sucking on sugar-free candy, avoiding caffeine, tobacco, alcohol and dry or hard to chew foods may help. Consider the treatment of underlying candidiasis, which can be a consequence of dry mouth. Educate the patient regarding regular oral hygiene and dental care.
If xerostomia is medication-induced, the medication should either be stopped or substituted with another with less xerostomic effects if possible. Sialogogue drugs, specifically pilocarpine and cevimeline, are the two main FDA approved medications for the management of dry mouth. Both medications work on muscarinic receptors and induce salivation. Pilocarpine is given orally with normal dosing of 5 to 10 mg three times a day. Cevimeline is administered as 30 mg three times a day. Either agent is tried up to 3 months to ascertain efficacy. These medications do require some residual salivary gland function as it stimulates the patent gland to secrete saliva. The application of topical physostigmine has also been a therapy option in the treatment of xerostomia. Physostigmine is a cholinesterase inhibitor, thus increasing the amount of acetylcholine available to stimulate salivary glands. It increases the production of saliva by stimulating mucin-producing glands. A gel containing 1.8 mg of physostigmine may provide relief for about 120 minutes. Additionally, malic acid has demonstrated some benefit if xerostomia is drug-induced. Anethole trithionate (cholagogue-bile secretion stimulant) is another drug that has proven to be beneficial for xerostomia.
Patients presenting with primary complain of dry mouth should be evaluated for a variety of conditions known for causing sicca symptoms. These conditions include primary Sjogren syndrome, idiopathic sicca syndrome, other autoimmune diseases, and drug-induced sicca syndrome. Other disorders might need to be ruled out and require separate specific management. These include sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease, chronic hepatitis C (HCV) or HIV, GVHD, ESRD and head and neck radiation therapy.
The underlying cause of dry mouth determines prognosis. Almost all patients will benefit from symptomatic treatment. Clinicians can address a temporary etiology such as dehydration, medication-induced salivary hypofunction, use of substances such as caffeine, smoking, and alcohol with good results. For chronic and irreversible causes such as Sjogren syndrome and head and neck cancer post-irradiation, the symptom tends to be persistent.
The role of saliva is to provide lubrication and keep the oral cavity moist and clean, which helps protect the oral mucosa from mechanical injury. Salivary amylase helps to initiate the digestive process. Mucin and immunoglobulin in saliva protect the oral mucosa from microbial infection. Xerostomia can adversely affect oral intake leading to poor nutrition. Lack of saliva contributes to periodontal disease, gingival inflammation, bleeding, dental caries, and halitosis and can also lead to fungal infections and accelerated enamel erosion. Chronic discomfort from dry mouth can contribute to symptoms of anxiety and depression.
Patients should be encouraged to openly communicate with physicians if they have any symptoms of dry mouth or halitosis. Considering the debilitating nature of the disease, patients should be encouraged to try preventative measures, which include and are not limited to:
Sipping water, chewing gum (preferably sugar-free), using a humidifier, cutting back on alcohol, coffee, tobacco, sugary drinks, and candy and keeping cracked mucosal areas moist. Patients should also be encouraged to regularly follow up with their dentist (at least twice a year), incorporate flossing and using fluoride toothpaste. Providing appropriate therapy in time will help patients with their mental health, decrease anxiety and depression, maintain a better quality of life and well being.
Xerostomia has many causes, including medications and radiation. Despite being a common disorder, its diagnosis usually gets delayed, and the treatment is not satisfactory. For this reason, an interprofessional team is the best management strategy.
The most important thing is the recognition of the symptoms of xerostomia and taking action. A simple history and physical exam can help with the diagnosis. It is crucial that healthcare professional reviews the patient's medication list. Anti-hypertensives, Parkinson drugs, diuretics, and many others have all have implications as a cause of xerostomia. If a medication is the suspected cause and alteration of regimen is straightforward, it should merit consideration and a mutual decision made regarding ongoing therapy. A pharmacy consult is often necessary to discuss alternative regimens and to avoid drug-drug interactions.
Patients with Sjogren disease usually have poor results with present-day treatments. The constant dry mouth also leads to dental cavities and a poor quality of life. The dentist and rheumatologist should be involved in the care of these complex patients, and report their findings back to the entire interprofessional healthcare team.
The key is for the primary care providers, specialists, nurses, and pharmacist to provide interdisciplinary education of the patient on oral hydration and to avoid triggers like tobacco and certain medications. If medications are involved in treatment, the pharmacist should verify all dosing, perform medication reconciliation, and report any concerns to the nursing staff, who can inform the treating physicians. Nursing can check progress or lack thereof in treatment, and report to the team regarding therapy and lifestyle compliance.
Finally, patients should understand that there are several intra-oral appliances and electrical therapies available, but none of these work reliably, and most have not had testing in clinical trials. It is essential for the patient to speak to a clinician before investing in these therapies.
Because it can have both benign and pathological etiologies, xerostomia requires an interprofessional team approach, including physicians, specialists, dentists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]
For benign and medication causes of xerostomia, the outcomes are good, but for patients with radiation-induced xerostomia and Sjogren disease, the outcomes are poor.
|||Tanasiewicz M,Hildebrandt T,Obersztyn I, Xerostomia of Various Etiologies: A Review of the Literature. Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2016 Jan-Feb; [PubMed PMID: 26935515]|
|||Holmberg KV,Hoffman MP, Anatomy, biogenesis and regeneration of salivary glands. Monographs in oral science. 2014; [PubMed PMID: 24862590]|
|||Mortazavi H,Baharvand M,Movahhedian A,Mohammadi M,Khodadoustan A, Xerostomia due to systemic disease: a review of 20 conditions and mechanisms. Annals of medical and health sciences research. 2014 Jul; [PubMed PMID: 25221694]|
|||Nederfors T, Xerostomia: prevalence and pharmacotherapy. With special reference to beta-adrenoceptor antagonists. Swedish dental journal. Supplement. 1996; [PubMed PMID: 8813731]|
|||Orellana MF,Lagravère MO,Boychuk DG,Major PW,Flores-Mir C, Prevalence of xerostomia in population-based samples: a systematic review. Journal of public health dentistry. 2006 Spring; [PubMed PMID: 16711637]|
|||Anil S,Vellappally S,Hashem M,Preethanath RS,Patil S,Samaranayake LP, Xerostomia in geriatric patients: a burgeoning global concern. Journal of investigative and clinical dentistry. 2016 Feb; [PubMed PMID: 25175324]|
|||Wolff A,Joshi RK,Ekström J,Aframian D,Pedersen AM,Proctor G,Narayana N,Villa A,Sia YW,Aliko A,McGowan R,Kerr AR,Jensen SB,Vissink A,Dawes C, A Guide to Medications Inducing Salivary Gland Dysfunction, Xerostomia, and Subjective Sialorrhea: A Systematic Review Sponsored by the World Workshop on Oral Medicine VI. Drugs in R&D. 2017 Mar [PubMed PMID: 27853957]|
|||Al-Hashimi I, Xerostomia secondary to Sjögren's syndrome in the elderly: recognition and management. Drugs [PubMed PMID: 16323968]|
|||Delli K,Spijkervet FK,Kroese FG,Bootsma H,Vissink A, Xerostomia. Monographs in oral science. 2014; [PubMed PMID: 24862599]|
|||Gil-Montoya JA,Silvestre FJ,Barrios R,Silvestre-Rangil J, Treatment of xerostomia and hyposalivation in the elderly: A systematic review. Medicina oral, patologia oral y cirugia bucal. 2016 May 1; [PubMed PMID: 27031061]|
|||Villa A,Connell CL,Abati S, Diagnosis and management of xerostomia and hyposalivation. Therapeutics and clinical risk management. 2015; [PubMed PMID: 25653532]|
|||Alsakran Altamimi M, Update knowledge of dry mouth- A guideline for dentists. African health sciences. 2014 Sep; [PubMed PMID: 25352896]|
|||Astreinidou E,Roesink JM,Raaijmakers CP,Bartels LW,Witkamp TD,Lagendijk JJ,Terhaard CH, 3D MR sialography as a tool to investigate radiation-induced xerostomia: feasibility study. International journal of radiation oncology, biology, physics. 2007 Aug 1; [PubMed PMID: 17482767]|
|||Guchelaar HJ,Vermes A,Meerwaldt JH, Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 1997 Jul; [PubMed PMID: 9257424]|
|||Khosravani N,Birkhed D,Ekström J, The cholinesterase inhibitor physostigmine for the local treatment of dry mouth: a randomized study. European journal of oral sciences. 2009 Jun; [PubMed PMID: 19583746]|
|||Hamada T,Nakane T,Kimura T,Arisawa K,Yoneda K,Yamamoto T,Osaki T, Treatment of xerostomia with the bile secretion-stimulating drug anethole trithione: a clinical trial. The American journal of the medical sciences. 1999 Sep; [PubMed PMID: 10487404]|
|||Cornec D,Saraux A,Jousse-Joulin S,Pers JO,Boisramé-Gastrin S,Renaudineau Y,Gauvin Y,Roguedas-Contios AM,Genestet S,Chastaing M,Cochener B,Devauchelle-Pensec V, The Differential Diagnosis of Dry Eyes, Dry Mouth, and Parotidomegaly: A Comprehensive Review. Clinical reviews in allergy [PubMed PMID: 24952023]|
|||Barbe AG, Medication-Induced Xerostomia and Hyposalivation in the Elderly: Culprits, Complications, and Management. Drugs [PubMed PMID: 30187289]|