Medications That Cause Dry Mouth As an Adverse Effect in Older People

A Systematic Review and Metaanalysis

Edwin C. K. Tan, PhD; Duangjai Lexomboon, PhD; Gunilla Sandborgh-Englund, PhD; Ylva Haasum, PhD; Kristina Johnell, PhD

Disclosures

J Am Geriatr Soc. 2018;66(1):76-84. 

In This Article

Discussion

Summary of Evidence

Our systematic review found that medication use was significantly associated with xerostomia and salivary gland hypofunction in older individuals. Findings of the metaanalyses confirm that specific drugs, including those from therapeutic classes used for urinary incontinence, antidepressants, and psycholeptics are significantly associated with xerostomia. The risk was greatest in drugs used for urinary incontinence, for which the odds of xerostomia were almost 6 times as great as with placebo. Methodological limitations of current studies were related to sample selection, randomization, and blinding.

The most common ATC categories associated with xerostomia were agents acting on the genitourinary and nervous systems, with the most cited drugs being tolterodine (4 studies), duloxetine (4 studies), and oxybutynin (3 studies). This finding is reflected in a previous review.[4] Most of the drugs used for urinary incontinence are antimuscarinics and exert dry mouth through this antimuscarinic mechanism. Oxybutynin, tolterodine, and fesoterodine are nonselective antimuscarinic agents. Darifenacin and solifenacin are M3-selective receptor antagonists and may be more bladder-specific and less prone to causing anticholinergic side effects, such as dry mouth. Mirabegron, assessed in one study, is a beta-3 adrenergic receptor agonist and an alternative to antimuscarinic drugs. It is less likely to cause dry mouth, and this is reflected in our metaanalysis in that it was not significantly different from placebo.

Our metaanalysis of antidepressants included 3 classes of antidepressants: duloxetine, a selective serotonin and noradrenaline reuptake inhibitor (SSNRI); escitalopram, a selective serotonin-reuptake inhibitor (SSRI); and doxepin, a tricyclic antidepressant (TCA). TCAs enhance the actions of noradrenaline and serotonin by blocking their reuptake at the neuronal membrane, but they also block histaminic, α1-adrenergic, and muscarinic cholinergic receptors, resulting in adverse drug reactions such as dry mouth.[2] Although SSRIs and SNRIs can cause dry mouth, they are generally less likely to cause anticholinergic side effects than TCAs.[2]

Several psycholeptic medications, including particular antipsychotics, anxiolytics, and hypnotics, are also prone to causing dry mouth.[2] Quetiapine, an atypical antipsychotic, works through antagonism at D2 receptors in the mesolimbic pathway and 5HT2A receptors in the frontal cortex. Quetiapine also has a strong affinity for histaminergic and α1-adrenergic receptors, which may be responsible for dry mouth. Eszopiclone, a nonbenzodiazepine hypnotic, interacts with the gamma-aminobutyric acid-benzodiazepine receptor complex. The most common adverse effect of eszopiclone is unpleasant taste, although it may also produce dry mouth.

There were considerable differences in the magnitude of the likelihood of xerostomia between different drug classes. This is probably because of variations in the mechanism of actions between and within drug classes. The greatest likelihood of xerostomia was seen with drugs used for urinary frequency and incontinence (G04BD) (OR = 5.91), which is probably related to their antimuscarinic properties. This was equivalent to a 25% greater absolute risk of dry mouth and is clinically significant given that 1 in 4 individuals treated with a urological medication developed dry mouth. Orally administered immediate-release oxybutynin was associated with the greatest risk of dry mouth (56% absolute risk increase) of the drugs in the same therapeutic class. The second largest likelihood was seen with antidepressants (N06A) (OR = 4.74), which mainly consisted of antidepressants with fewer anticholinergic side effects. Lastly, the psycholeptics (N05) in our metaanalysis had the lowest likelihood of causing xerostomia (OR = 1.60), because they were newer agents with more selective receptor activity. Antidepressants and psycholeptics were associated with a 9% greater absolute risk of dry mouth, indicating that, for every 11 people treated, one would experience drug-induced dry mouth.

In our systematic review, a significant association was found between number of drugs and dry mouth in older people. These findings reflect the results of previous studies conducted in the general population and highlight the link between polypharmacy and dry mouth.[60]

To our knowledge, this is the first review to quantify the risk of medication-associated dry mouth in persons aged 60 and older. The odds ratio of xerostomia as a side effect of xerostomic drugs in our study would be expected to be higher than in younger individuals because salivary production declines with aging.[61] A Swedish study also reported a greater prevalence of xerostomia with older age in nonmedicated adults,[60] but there have been few other metaanalyses assessing the risk of dry mouth as a medication side effect in elderly adults.

Limitations

This systematic review and metaanalysis has some limitations. Although broad search strategies were implemented in a range of databases to ensure that all relevant studies were included, unpublished and non-English-language studies were not sought. Thus, the possibility of publication bias cannot be excluded. We limited the search from 1990 to 2016, so currently used medications with a strong association with dry mouth that were researched before this time were excluded. Common examples include older TCAs, potent diuretics, antihistamines, and various drugs acting on the central nervous system

Dry mouth is usually not a primary outcome of experimental studies; hence our search may have missed certain studies that did not report dry mouth as an adverse outcome in the title or abstract. Heterogeneity in the definitions and methods used to assess dry mouth across studies may have affected the ability to compare findings and draw conclusions. Xerostomia is a subjective phenomenon, and different people may have experienced and reported xerostomia differently. Currently, there is no criterion standard method of assessing xerostomia. There may have been differences in medication exposure between studies. Treatment dose, duration, and formulation were not assessed in this review. It is likely that these factors influence the severity of medication-induced xerostomia.[3] For ease of classification, we categorized drugs according to ATC codes, but inclusion of different drugs in each group, some of which may have different indications, may have differing effects on xerostomia. Most of the cross-sectional studies used self-reported drug use, which may underestimate total drug use. Additionally, the way drugs were classified into particular groups may have varied between studies. We addressed potential heterogeneity in sample characteristics and treatment effects in our metaanalyses by using random-effects models. Some included studies were of low methodological quality, and thus their findings should be interpreted with caution. Our systematic review included fewer studies than previous similar reviews,[4] which probably reflects our stricter inclusion criteria, including restricting the population to older people and the years of publication.

Implications

This review has implications for practitioners treating and managing older adults using drugs. Practitioners should carefully weigh the benefits of therapy against the potential risk of dry mouth, oral complications, and treatment discontinuation. This is particularly important in people with polypharmacy. Medications should be regularly monitored and reviewed to identify potential oral side effects of medications, and dose adjustment or change of therapy should be considered when needed. Based on the quantified risk, risk scores can be developed that may be a useful guide for practitioners not only in identifying individuals at risk of dry mouth, but also in evaluating the risk grade for dental health. This can provide information on how much the risk of dental complications is for elderly adults and aid in the development and implementation of preventive programs and comprehensive therapy plans. Future studies should be conducted to develop risk scores for dental health based on the use of different drug groups and numbers of drugs used. Additional factors such as dose, duration, and formulation of treatment should also be considered. The major consequences of medication-induced xerostomia, such as the development of dental caries and need for clinical intervention, should also be explored in future research.

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