Where Dysphagia Begins: Polypharmacy and Xerostomia

Abstract

Background

Xerostomia, the subjective sensation of dry mouth, contributes to dysarthria, dysphagia, and diminished quality of life. Polypharmacy is a known and modifiable risk factor for xerostomia. The objective of this study was to evaluate the prevalence of dry mouth, the relationship between dry mouth and other oral conditions, and the impact of polypharmacy on dry mouth.

Methods

This study was a retrospective cross-sectional study of all patients seen in fiscal year (FY) 2015 (October 1, 2014 to September 30, 2015) at the VA Palo Alto Health Care System (VAPAHCS), a tertiary care US Department of Veterans Affairs (VA) hospital. Patients diagnosed with xerostomia were identified using ICD-9 codes (527.7, 527.8, R68.2) and Systemized Nomenclature of Medicine Clinical Terms (SNOMED CT) codes (87715008, 78948009).

Results

Of all the patients seen at VAPAHCS during FY 2015, 138 had a diagnostic code for xerostomia; of those patients, 84 had at least 1 documented speech, dentition, or swallowing (SDS) problem, and 55 (39.9%) were taking ≥ 12 medications, more than twice as many patients as in any one of the other groups studied (0–2, 3–5, 6–8, and 9–11 medications taken). Although 4,971 total patients seen at VAPAHCS had documented SDS problems during FY 2015, of those patients only 77 (1.5%) had an additional recorded diagnosis of xerostomia.

Conclusions

Heightened physician awareness regarding the signs and symptoms of and risk factors for xerostomia is needed to improve health care providers’ ability to diagnose dry mouth. Polypharmacy also must be considered when developing new strategies for preventing and treating xerostomia.

Xerostomia, the subjective sensation of dry mouth, is a common problem developed by geriatric patients. In practice, xerostomia can impair swallowing, speech, and oral hygiene, and if left unchecked, symptoms such as dysphagia and dysarthria can diminish patients’ quality of life (QOL). Salivary gland hypofunction (SGH) is the objective measure of decreased saliva production, determined by sialometry. Although xerostomia and SGH can coexist, the 2 conditions are not necessarily related.^1–4 For this discussion, the term xerostomia will denote dry mouth with or without a concomitant diagnosis of SGH.

Xerostomia is seen in a wide variety of patients with varied comorbidities. It is commonly associated with Sjögren syndrome and head and neck irradiation. The diagnosis and treatment of xerostomia often involves rheumatologists, dentists, otolaryngologists, and oncologists. Additionally, most of the scientific literature about this topic exists in dental journals, such as the Journal of the American Dental Association and the British Dental Journal. Rarer still are studies in the veteran population.⁵

Faced with increasing time pressure to treat the many chronic diseases affecting aging veterans, health care providers (HCPs) tend to deprioritize diagnosing dry mouth. To that point, saliva is often not considered in the same category as other bodily fluids. According to Mandel, “It lacks the drama of blood, the sincerity of sweat… [and] the emotional appeal of tears.”⁶ In reality, saliva plays a critical role in the oral-digestive tract and in swallowing. It contains the first digestive enzymes in the gastrointestinal tract and is key for maintaining homeostasis in the oral cavity.⁷ Decreased saliva production results in difficulties with speech and mastication as well as problems of dysphagia, esophageal dysfunction, dysgeusia, nutritional compromises, new and recurrent dental caries, candidiasis, glossitis, impaired use of dentures, halitosis, and susceptibility to mucosal injury.^7,8 Problems with the production of saliva may lead to loss of QOL, such as enjoying a meal or conversing with others.⁴

Although xerostomia is often associated with advanced age, it is more often explained by the diseases that afflict geriatric patients and the arsenal of medications used to treat them.^2,9–16 Polypharmacy, the simultaneous use of multiple drugs by a single patient for ≥ 1 conditions, is an independent risk factor for xerostomia regardless of the types of medication taken.¹⁶ From 2005 to 2011, older adults in the US significantly increased their prescription medication use and dietary supplements. More than one-third of older adults used ≥ 5 prescription medications concurrently, and two-thirds of older adults used combinations of prescribed medications, over-the-counter medications, and dietary supplements.¹⁷ Several drug classes have the capacity to induce xerostomia, such as anti-hypertensives, antiulcer agents, anticholinergics, and antidepressants.^2,5,12 Prevalence of dry mouth also can range from 10% to 46%, and women typically are more medicated and symptomatic.^{2,3,9,13,14,16} Xerostomia can also lead to depression and even reduce patients’ will to live.¹⁸ Despite xerostomia’s prevalence and impact on QOL, few patients report it as their chief symptom, and few physicians attempt to treat it.¹⁹

In order to target polypharmacy as a cause of dry mouth, the objectives for this study were to evaluate (1) the prevalence of xerostomia; (2) the relationship between xerostomia and other oral conditions; and (3) the impact of polypharmacy on dry mouth in a veteran population.

METHODS

This is a retrospective cross-sectional study of all outpatient visits in fiscal year (FY) 2015 (October 1, 2014 to September 30, 2015) at the VA Palo Alto Health Care System (VAPAHCS), a tertiary care US Department of Veterans Affairs (VA) hospital. This study was approved by the Stanford University Institutional Review Board. All patients diagnosed with xerostomia in the 1-year study period were identified using ICD-9 diagnosis codes for dry mouth or disturbance of salivary gland secretion (527.7, 527.8, R68.2) and Systemized Nomenclature of Medicine Clinical Terms (SNOMED CT) codes covering dry mouth, xerostomia, aptyalism, absent salivary secretion, and disturbance of salivary secretion (87715008, 78948009). Data analysts in the VA Office of Business Analytics assisted in gathering data from the Veterans Information Systems and Technology Architecture (VistA) electronic health record.

The statistical analysis of that data was performed using Microsoft Excel. Age and gender distributions were determined for the patients. The relationship between xerostomia and the number and types of medications taken by patients also was examined. A previous Swedish study examining the link between dry mouth and quantities of medications used a scale ranging from 0 to ≥ 7 medications.¹⁶ The scale for this study was made wider to include the following groups: 0–2, 3–5, 6–8, 9–11, and ≥ 12 medications. Items that do not have xerogenic risks, such as medical supplies (eg, gloves, syringes, etc) and topical medications, were excluded from the analysis. Finally, the number of subjects with comorbid problems with speech, dentition, or swallowing (SDS) was recorded. Non-VA medications were included to capture any self- or externally prescribed xerogenic medications.

RESULTS

Of the patients seen at VAPAHCS during FY 2015, 138 had a diagnostic code for xerostomia, including 129 men (93.5%) and 9 women (6.5%). The average (SD) age of this xerostomia cohort was 69.3 (12.6) years, and the 3 most common age groups were 60 to 69 years (37.7%), 70 to 79 years (28.3%), and 80 to 89 years (13.0%) (Table 1). Of those 138 patients with a xerostomia diagnosis, a majority (84; 60.9%) had at least 1 documented SDS problem (Table 2). Conversely, during FY 2015, although 4,971 patients seen at VAPAHCS had documented SDS problems, only 77 (1.5%) had a recorded diagnosis of xerostomia.

TABLE 1.

Age Distribution of Patients With Xerostomia

Age Range, y	Patients, No. (%)
20–29	1 (0.7)
30–39	2 (1.4)
40–49	6 (4.3)
50–59	11 (8.0)
60–69	52 (37.7)
70–79	39 (28.3)
80–89	18 (13.0)
90–99	9 (6.5)

TABLE 2.

Patients With Xerostomia With ≥ 1 SDS Problem

Without SDS Problems, No. (%)	With SDS Problems, No. (%)
54 (39.1)	84 (60.9)

Abbreviation: SDS, speech, dentition, or swallowing.

Of the 138 patients with xerostomia, 55 (39.9%) were taking ≥ 12 medications, more than twice as many patients as in any of the other groups studied (0–2, 3–5, 6–8, and 9–11 medications taken) (Table 3). On average, each patient with xerostomia filled prescriptions for 10.4 (SD, 7.2) different drugs. In this cohort of 138 patients diagnosed with xerostomia, anti-hypertensive medications or analgesics were taken by > 50% of patients, while statins, psychiatric medications, antibiotics, proton pump inhibitors, or drugs known to have anticholinergic activity were taken by > 40%. Antihistamines, anticonvulsants, diuretics, or inhaled respiratory agents were used by > 20% of the patients in this cohort (Table 4).

TABLE 3.

Medications Taken by Patients With Xerostomia

Medications, No.	Patients, No. (%)
0–2	22 (15.9)
3–5	16 (11.6)
6–8	22 (15.9)
9–11	23 (16.7)
≥ 12	55 (39.9)

TABLE 4.

Most Commonly Prescribed Medication Classes^a

Medication Classes	Patients, No. (%)
Antihypertensives	81 (58.7)
Analgesics	74 (53.6)
Statins	67 (48.6)
Anticholinergicsb	65 (47.1)
Psychiatricc	65 (47.1)
Antibiotics	61 (44.2)
Proton pump inhibitors	58 (42.0)
Antidepressants	53 (38.4)
Antihistamines	49 (35.5)
Anticonvulsants	46 (33.3)
Antiplatelet agents	46 (33.3)
Constipation relief	44 (31.9)
Diuretics	42 (30.4)
Inhaled respiratory agents	40 (29.0)
α-1 blockers	39 (28.3)

^aPercentage of patients taking ≥ 1 medication from each class.

^bIncludes muscarinic antagonists, antihistamines (first generation), antispasmodics, antidepressants, antipsychotics, antiemetics, and antiparkinsonian agents known to display anticholinergic activity.

^cIncludes antidepressants, antianxiolytics, antipsychotics, and mood stabilizers.

Data on each individual medication were split into 2 categories: the percentage of patients that filled ≥ 1 prescription for that drug, and the total number of prescriptions filled and/or refilled for that drug (ie, including all fills and refills made by individual patients). The 5 most widely used medications in this cohort were omeprazole (39.1%), docusate sodium (29.7%), gabapentin (29.7%), aspirin (27.5%), and hydrocodone/acetaminophen (26.1%) (Table 5). The 5 prescriptions that were cumulatively most filled and/or refilled were omeprazole (128), sildenafil citrate (108), gabapentin (101), hydrocodone/acetaminophen (100), and oxycodone (92) (Table 6). Though sildenafil citrate and oxycodone were among the most-filled prescriptions, these were not included in Table 5 as neither was taken by > 15% of the patients studied. These prescriptions were filled multiple times by a small subset of patients.

TABLE 5.

Most Commonly Prescribed Medications

Medications	Patients, No. (%)
Omeprazole	54 (39.1)
Docusate sodium	41 (29.7)
Gabapentin	41 (29.7)
Aspirin	38 (27.5)
Hydrocodone/acetaminophen	36 (26.1)
Atorvastatin	33 (23.9)
Lisinopril	33 (23.9)
Artificial saliva spray	32 (23.2)
Amlodipine	28 (20.3)
Simvastatin	25 (18.1)
Tamsulosin	25 (18.1)
Loratadine	23 (16.7)
Acetaminophen	22 (15.9)
Albuterol	22 (15.9)
Levothyroxine	22 (15.9)
Chlorhexidinea	21 (15.2)
Hydrochlorothiazide	21 (15.2)
Trazodone	21 (15.2)

^aGermicidal mouthwash.

TABLE 6.

Most Frequently Filled Prescriptions

Medications	Prescriptions Filled, No.
Omeprazole, 20 mg (enteric-coated capsule)	128
Sildenafil citrate, 100 mg (tablet)	108
Gabapentin, 300 mg (capsule)	101
Hydrocodone/acetaminophen, 5 mg/325 mg (tablet)	100
Oxycodone hydrochloride, 5 mg (tablet)	92
Aspirin, 81 mg (enteric-coated tablet)	89
Artificial saliva spray	86
Docusate sodium, 250 mg (capsule)	77
Tamsulosin hydrochloide, 0.4 mg (capsule)	71
Hydrochlorothiazide, 25 mg (tablet)	63

Regarding treatment for dry mouth, artificial saliva spray was one of the most widely used (23.2%) and the seventh most-filled prescription within this cohort (86). The only other medication taken by > 15% of patients in a formulation other than a tablet or capsule was chlorhexidine, a germicidal mouthwash used to improve oral care.

Also, 30 (21.7%) patients with a documented xerostomia diagnosis had a history of substance misuse involving use of ≥ 1 of tobacco, alcohol, marijuana, or other illicit drugs.

DISCUSSION

Saliva is an essential component for the maintenance of normal oral health.^20,21 Decreased saliva production causes problems, including difficulties with speech, mastication, dysphagia, changes in taste, dental caries, impaired use of prostheses, recurrent infections, halitosis, deterioration of soft tissues, and compromised QOL.^22,23 Among patients with a diagnosed SDS abnormality who were seen at this facility during FY 2015, the prevalence of xerostomia was only 1.5%. However, the true prevalence and incidence of xerostomia among veterans is not known. Given the role of xerostomia as a common risk factor for SDS problems and the polypharmacy exhibited by those presented here with SDS problems, it is probable that xerostomia was underreported in this veteran cohort.

Additionally, although salivary acinar cells are known to atrophy with age, as is consistent with this xerostomia cohort’s average age (SD) of 69.3 (12.6) years, the development of dry mouth is a multifactorial process. The current scientific literature asserts that most salivary loss is due to local and systemic diseases, immunologic disorders, external radiation, and as was highlighted by this study, multiple prescription and nonprescription medications.^24–26

It has also been demonstrated previously that dry mouth complaints and low salivary flow rates are directly proportional to the number of medications taken by patients.^2,27–30 Polypharmacy is therefore an area of great interest, and ≥ 40 categories of xerogenic medications have been identified by investigators such as Sreebny and Schwartz.³¹ Among those, some of the most xerogenic medication classes include antihypertensives, antiulcer agents, anticholinergics, and antidepressants, are all very commonly consumed in this cohort of patients with dry mouth (58.7%, 42.0%, 47.1%, and 38.4%, respectively). The medication regimens within this cohort of veterans with xerostomia were prime examples of polypharmacy as each patient took an average (SD) of 10.4 (7.2) medications, 39.9% took ≥ 12, and 72.5% of patients with xerostomia were taking ≥ 6 prescription drugs during a 1-year period.

Given the dangers of polypharmacy, a more conservative approach to prescribing medications could feasibly help with preventing xerostomia and SGH. In practice, while clinicians try to avoid prescribing anticholinergics, antimuscarinics, and antihistaminergic drugs for geriatric patients, they are tasked with the complex management of medication adverse effects (AEs) when dealing with multiple health conditions. The clinicians’ primary responsibilities are to follow the standard of care and not to introduce unnecessary harm when managing patients, but they also must push for, stay abreast of, and conduct more basic research and clinical trials to inform, adjust, and improve our current standard.

Research into polypharmacy and its role in inducing dry mouth is ongoing. Twenty years ago, Thomson and colleagues identified reduced salivary flow in patients who used antianginals, thyroxine, diuretics, antidepressants, and medications for asthma, while only 5 years earlier Loesche and colleagues reported the role of antiulcer medications, such as proton pump inhibitors, in the development of xerostomia.^2,32 Within the past 5 years, Viljakainen and colleagues and Ohara and colleagues have echoed some of those findings by identifying associations between xerostomia and agents that impact digestive organs.^33,34 A strong association recently was identified between the use of antipsychotic drugs and xerostomia.³⁵ Additionally, when attributing xerostomia to polypharmacy, the interaction between medications is often overlooked in favor of considering the raw number of prescriptions taken. Whereas 1 medication alone may not have drying properties, combinations of medications might be more likely to induce xerostomia. Thomson and colleagues suggested such a situation regarding the interaction between thyroxine and diuretics.³⁶ Future studies should focus on identifying viable substitutes for existing medications that reduce risk for xerostomia without compromising the management of other serious conditions.

Treatment

Another pressing question for clinicians concerns artificial saliva. Although 23.2% of patients with dry mouth in this xerostomia cohort used artificial saliva, the efficacy of this treatment is still unproven. Saliva substitutes are often used by patients who cannot produce sufficient amounts of natural saliva. In practice, artificial saliva produces, at best, modest temporary improvement in dry mouth symptoms in up to 40% of patients. At worst, as put forth by the Cochrane Review, artificial saliva may be no better than placebo in treating dry mouth.^37,38 The volumes needed for symptom relief are large, ranging between 40 mL and 150 mL per day depending on the substitute’s composition. Saliva substitutes also must be reapplied throughout each day. This is particularly bothersome when patients must wake up repeatedly to reapply the treatment at night.³⁷ In short, these substances do not seem wholly effective in managing dry mouth, and other options must be made available to patients with refractory xerostomia when artificial saliva and lifestyle modifications fail.

For now, few alternatives exist. Chewing gums and lozenges help to stimulate salivary flow, as do muscarinic agonists like pilocarpine. Unfortunately, muscarinic agonists are seldom used due to cholinergic AEs. Humidifiers are effective in increasing nighttime moisture but are contraindicated in patients with dust mite allergies.³⁹ Reservoir-based devices with automated pumps funnel water and/or salivary substitutes from a fanny pack into patients’ mouths for lubrication.³⁷ Other more esoteric pharmacologic treatments include Dlimonene, yohimbine, and amifostine, which purportedly protect salivary progenitor cells, increase peripheral cholinergic activity, and protect salivary glands from free-radical damage during radiation treatment, respectively. Although these agents have shown some promise, D-limonene is difficult to administer given the high dosage required for treatment, yohimbine hasn’t been seriously investigated for improving salivary secretion since 1997, and amifostine isn’t used widely due to its AE profile despite its US Food and Drug Administration approval for prevention of xerostomia.³⁹

Substance Abuse

The impact of smoking on xerostomia remains controversial. Some studies report an association between active smoking and xerostomia; others suggest that the local irritant effect of tobacco smoke may increase salivary gland output.^40,41 The same may be true for chronic alcohol use as there are no epidemiologic studies showing a causal relationship between alcohol use and xerostomia. Studies with rats that are chronically exposed to ethanol have found increased salivary flow rates.⁴² In the xerostomia cohort presented here, 30 patients (21.7%) had a documented history of substance misuse. That percentage is likely underestimated, as substance misuse is often underreported, and frequent use may not always constitute misuse. Therefore, nicotine exposure, alcohol exposure, illicit drug use, and vaping all should be considered during the workup of a patient with xerostomia.

Limitations

It is common for medications to remain in a patient’s health record long after that patient stops taking them. Developing methods to track when patients discontinue their prescriptions will be essential for clearing up uncertainty in our data and in other similar studies. This study also did not account for patients’ medication adherence and the duration of exposure to medications and illicit substances. Furthermore, the results of this veteran study are not easily generalizable as this cohort is disproportionately male, of advanced age, and especially prone to exhibiting both substance use and psychiatric diagnoses relative to the general population. As described by Viljakainen and colleagues, risk factors for xerostomia include advanced age, female gender, low body mass index (BMI), malnutrition, and depressive symptoms, but because the demographic scope of this veteran population was narrow, it was not possible to discern the impact of, for example, gender.³³ Data on variables like BMI, malnutrition, and depressive symptoms were not available. For this study, xerostomia could only be considered as an all-or-nothing phenomenon because the dataset did not describe different levels of dry mouth severity (eg, mild, moderate, severe).

Additionally, past polypharmacy studies have acknowledged an inability to tell whether xerostomia is mainly due to medications or to underlying medical conditions. For example, for emphysema, β-adrenergic stimulation from bronchodilators could cause dry mouth by thickening saliva and decreasing salivary volume, but the pathophysiology and/or cardinal symptoms of emphysema, including chronic obstructive pulmonary disease-associated tachypnea, might contribute independently to dryness.

Though we can make inferences based on the medications taken by this cohort (eg, those taking antihypertensives have high blood pressure), this dataset did not explicitly detail comorbid conditions and ICD codes for chronic diseases that commonly arise with xerostomia. Those conditions, however, are of great clinical importance. Diabetes mellitus, HIV/AIDS, and, classically, Sjögren syndrome, all are known to cause dry mouth.⁴³ Identifying new conditions that co-occur with xerostomia would allow clinicians to describe the root causes of and risk factors for dry mouth and SDS conditions in greater detail. Patients with dry mouth without SDS problems in this dataset are of particular interest as closer examination of their medications and comorbid conditions could help us understand why some individuals and not others develop SDS problems. The subjects of how comorbidities contribute to dry mouth and how their influences can be judged independently from the effects of medications are of great interest to us and will be investigated rigorously in our future studies.

CONCLUSIONS

In this cohort, few patients with SDS problems had documentation of a concomitant xerostomia diagnosis. This could represent a true infrequency of dry mouth or more likely, an underrecognition by clinicians. Heightened physician awareness regarding the signs and symptoms of and risk factors for xerostomia is needed to improve providers’ ability to diagnose this condition.

In particular, polypharmacy should be a major consideration when evaluating patients for xerostomia. This continues to be an important area of research, and some of the latest data on polypharmacy among older patients were compiled in a recent meta-analysis by Tan and colleagues. The authors of that systematic review reiterated the significant association between salivary gland hypofunction and the number of medications taken by patients. They also advocated for the creation of a risk score for medication-induced dry mouth to aid in medication management.⁴⁴ Per their recommendations, it is now as crucial as ever to consider the numbers and types of medications taken by patients, to discontinue unnecessary prescriptions when possible, and to continue developing new strategies for preventing and treating xerostomia.