Dysphagia Risk in Patients Prescribed Rivastigmine: A Systematic Analysis of FDA Adverse Event Reporting System

Abstract

Background:

Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer’s disease (AD) treatment.

Objective:

The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS).

Methods:

The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration.

Results:

When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50–70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events.

Conclusion:

Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase.

Keywords

Exelon FAERS FDA patch pharmacovigilance pneumonia swallow transdermal

INTRODUCTION

Alzheimer’s disease (AD) is a slowly progressing neurodegenerative condition that leads to gradual decline in short-term and long-term memory, cognitive processing, and motor skills [1, 2]. Pathologically, AD is characterized by an accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles derived from the microtubule-associated protein tau [1 , 4]. In most cases of the disease, AD pathology originates in the basal forebrain region of the brain, particularly in the hippocampus [1].

Two small molecule therapeutic classes are currently available for AD treatment: N-methyl-D-aspartate receptor (NMDAR) antagonists (Memantine) and acetylcholinesterase (AChE) inhibitors [5]. Memantine is a non-competitive antagonist molecule that selectively binds to NMDA glutamate channels and modulates excessive NMDA receptor (NMDAR) activity in order to inhibit excitotoxicity and protect against neuronal degeneration [6, 7]. The second class of therapeutic agents, AChE inhibitors, includes rivastigmine (Exelon), donepezil (Aricept), and galantamine (Razadyne) [5]. The decline in cognitive function, as characterized by lapses in short and long-term memory, is induced by the shrinkage of hippocampal volume, a decrease in acetylcholine-mediated neuronal stimulation, and neuronal degeneration [1]. Thus, AChE inhibitors may help to alleviate some degree of cognitive decline that is associated with the progression of AD pathology by preserving and maintaining acetylcholine stimulation. Acetylcholine is largely synthesized in the basal forebrain and is mediated by the enzyme choline acetyltransferase, of which promotes the conversion of choline and acetyl-CoA into acetylcholine [5]. The acetylcholine that is generated is subsequently transported into synaptic vesicles by vesicular acetylcholine transporter and then is released into the synaptic cleft via calcium-mediated depolarization of the synaptic vesicles [8]. In standard physiological conditions, stimulation of nicotinic and muscarinic acetylcholine receptors on cholinergic neuron is rapidly terminated by AChE-mediated hydrolysis of acetylcholine from the bound receptor [5]. Hydrolysis of acetylcholine generates acetate and choline, which can be recycled in presynaptic cells to generate new molecules of acetylcholine [5]. Thus, AChE inhibitors such as rivastigmine counteract, at least to some extent, the perturbations in cholinergic signaling induced by neuron damage and allow for enhanced memory and synaptic function.

In contrast to the other commonly administered therapeutic agents used in AD treatment, rivastigmine may be administered in oral form or in the form of a transdermal patch [9]. Doses for the capsule, of which is usually prescribed to patients with mild to moderate cases of the disease, range from 3–12 mg/day while the prescribed dose for the transdermal patch, which is primarily authorized for individuals with moderate to severe cases of AD, ranges from 4.6–13.3 mg/day [9].

Patients prescribed rivastigmine frequently report adverse drug reports such as vomiting, malaise, sleep disruption, increased aggression, and pneumonia [10]. In AD patients, dysphagia becomes increasingly common as the severity of the disease increases [11]. Dysphagia is characterized by the abnormal difficulty of passing a food bolus, or in some instances liquids, from the oropharynx to the stomach [12]. There are two main types of dysphagia that are categorized by localization of impairment and include oropharyngeal dysphagia, sometimes referred to as high dysphagia, and esophageal dysphagia, of which is sometimes referred to as low dysphagia [13]. With regards to AD, oropharyngeal dysphagia, which is characterized by impaired entry of food particles from the oral cavity to the esophagus resulting in an increase in difficulty for swallowing initiation, accounts for approximately 80% of all clinically diagnosed cases of dysphagia [14]. A normal swallowing response during the oropharyngeal stage is carried out by a complex interplay of reflexes triggered by inputs derived from the vagal, trigeminal, and glossopharyngeal nerves [13]. Rivastigmine and other AChE inhibitors have been shown to innervate the vagus nerve, which plays a key role in the regulation of the parasympathetic nervous system and involuntary mechanisms such as swallowing and digestion, through improved cholinergic signaling [15].

As we previously reported, rivastigmine was associated with an increased risk of pneumonia in patients relative to patients prescribed galantamine, donepezil, and memantine, and we postulated that overstimulation of the vagus nerve due to prolonged cholinergic signaling was, at least in part, responsible for this elevated risk [16]. Because of the close association between aspiration pneumonia and dysphagia in AD patients, we next wanted to observe whether rivastigmine use was concurrently associated with an increase in dysphagia risk. To our knowledge, there is currently no systematic comparative analysis that has assessed whether different AD therapeutics are associated with differential risks in dysphagia diagnosis. Data utilized in this study was derived from the FDA Adverse Event Reporting System (FAERS), the largest open-access data repository in the world that contains reported adverse drug event submitted by medical professionals, patients, and drug manufacturers [3, 16]. For this study, we conducted a comprehensive analysis to assess the association between the use of prescribed AD therapeutics and the reported frequency of dysphagia. In particular, we compared the frequency of reported dysphagia cases in individuals that were prescribed rivastigmine with patients prescribed galantamine, memantine, and donepezil. In addition, dysphagia frequency among patients prescribed rivastigmine were compared to drugs previously reported to cause dysphagia which served as positive controls. Finally, possible confounders including age, sex, dosage, and administration route were assessed for the association between rivastigmine use and dysphagia risk. In addition, the association between dysphagia and pneumonia was also evaluated.

MATERIAL AND METHODS

The public FAERS dashboard [17] was utilized to search and download FDA FAERS records. These records from the FAERS dashboard contain the following information: drug information, drug adverse events, patient outcome for the reported adverse event, patient demographic information (such as patient sex, age, and body weight), source of the reported adverse event, reporting dates, and the indications for use.

Drug adverse events that were suspected to be related to a drug of interest were extracted from the FAERS dashboard by inputting the generic name of the drug (for instance rivastigmine) and known brand names (such as Exelon or Exelon patch). The possible salts of the drug such as rivastigmine tartrate were also included in searching. The “suspect product names” or “suspect product active ingredients” of a record that contains those generic or brand names of the drug (or salt of the drug) will be outputted from FAERS dashboard.

Most of FAERS records are directly from patients reported to FDA, a pharmaceutical company, or a health professional. There are also some indirect records extracted from publications. Those records were excluded in this study for three reasons. First, these reports are generally reported to FDA by multiple companies which will cause 2∼10 duplicated copies of the same patients. These duplicated records will subsequently cause false positives in further calculation. Second, the reports from different companies may be inconsistent because different people have different understandings for the same publication or report. Third, these records are only about 2∼3% of the total cases in FAERS. Excluding those records will have little effect on the final conclusions.

A disproportionality analysis was conducted to compare the risk of dysphagia among the group of interest (experimental group) and the control group. The reporting odds ratio (ROR) for this comparison was then calculated. A lower bound value greater than 1.0 for the 95% confidence interval was indicative of a statistically significant higher likelihood of reporting dysphagia in the experimental group than in the control group. In addition, possible confounders including sex, age, dosage, and administration route were assessed using RORs as to their effects on the association between rivastigmine use and dysphagia risk. For dosage and administration route, only data from 2012 4th quarter to 2020 4th quarter were investigated because these records have clean structural information in the FAERS database.

Adverse events of rivastigmine use including nausea, vomiting, diarrhea, and dizziness were associated with reported pneumonia cases. A lift value >1 was used as the cutoff for a significant association. Data analysis was performed using R statistical software. The following formulas were used in order to calculate the lift as well as the confidence and support values. $\begin{matrix} Support ({X} \to {Y}) = \\ \frac{Number of reports containing both X and Y}{Total number of reports} \end{matrix}$ $\begin{matrix} Confidence ({X} \to {Y}) = \\ \frac{Number of reports containing both X and Y}{Number of reports containing X} \end{matrix}$ $Lift ({X} \to {Y}) = \frac{Support}{Support (X) * Support (Y)}$

RESULTS

The temporal and geographic distribution of reported dysphagia cases in patients prescribed rivastigmine

As of the end of 2020, there were 299 patients prescribed rivastigmine who had reported dysphagia as an adverse event to the FAERS database. The temporal distribution of these cases in patients are presented in Fig. 1. The frequency of reported dysphagia cases peaked from 2011 to 2017, of which the highest number of reports occurred in 2014 with approximately 40 cases. In general, the number of dysphagia reports increased between 2000 and 2014 and then slowly decreased from 2018 to 2020.

Fig. 1

The temporal distribution of dysphagia cases reported to the FAERS database for patients prescribed rivastigmine from 2000 to 2020. The number of reported dysphagia cases peaked between 2011 and 2017, with the most reports occurring in 2014.

Figure 2 presents the global geographic distribution of those dysphagia cases reports between 2000 and 2020. Approximately 50% of all reported dysphagia cases stemmed from Brazil. In addition, the United States, Japan, Mexico, France, and Canada also had a significant proportion of dysphagia reports. Thus, the temporal and geographic distribution of these dysphagia case reports suggests that dysphagia is a consistently globally observed adverse event in patients prescribed rivastigmine.

Fig. 2

The geographic distribution of cases reported to the FAERS database by patients prescribed rivastigmine.

Comparing the frequency of reported dysphagia in patients prescribed rivastigmine to those in patients taking other drugs

Dysphagia frequency was first compared between patients prescribed rivastigmine to individuals taking a series of positive controls including botulinum A toxin (a neuromuscular blocker), clozapine (an anti-psychotic drug), and penicillamine (immunosuppressive drug). These drugs were selected as positive controls as they have previously been shown to be associated with dysphagia risk [18 –21]. As shown in Table 1, individuals that used the neuromuscular blocker botulinum toxin A were approximately 66% more likely (ROR = 1.66; p < 0.0001) to report dysphagia as an adverse event compared to patients prescribed rivastigmine. Comparatively, individuals that used clozapine were 63% (ROR = 0.37; p < 0.0001) less likely to report dysphagia as an adverse event to the FAERS database while there was no statistically significant difference (ROR = 1.15; p = 0.45) in reported dysphagia cases in individuals prescribed penicillamine relative to individuals prescribed rivastigmine.

Table 1

The comparisons in reported dysphagia cases between individuals prescribed rivastigmine with those individuals that took other drugs (including a positive control, or another AD drug for treatment)

Drugs	Searching terms in FAERS	With	Without	ROR* (95% CI), p
	Dashboard	Dysphagia	Dysphagia
Rivastigmine	Exelon; Exelon Patch; Rivastigmine; Rivastigmine Tartrate; Rivastigmine Transdermal System	299	14,620
Positive controls
Botulinum A toxin	Botulinum Toxin type A; Botox; Botox Cosmetic	1,423	41,998	1.66 (1.46∼1.88), p < 0.0001
Clozapine	Clozapine; Versacloz; FazaClo; Clozaril	686	89,893	0.37 (0.32∼0.42), p < 0.0001
Penicillamine	Penicillamine; Penicillamine Hydrochloride; Penicillamine D-Penicillamine; Depen; Cuprimine	32	1,357	1.15 (0.80∼1.67), p = 0.45
AD drugs
Memantine	Memantine; Memantine Hydrochloride; Namenda; Namenda Xr	95	10,161	0.46 (0.36∼0.58), p < 0.0001
Galantamine	Galantamine; Galantamine Hydrobromide; Galantamine Hydrobromide Oral Solution; Galantamine hydrochloride; Galantamine∖Galantamine Hydrobromide; Razadyne; Razadyne Er	57	3,969	0.70 (0.53∼0.93), p = 0.0152
Donepezil	Donepezil; Donepezil Hydrochloride; Donepezil Hydrochloride 5Mg; Donepezil Hydrochloride 10Mg; Donepezil Hydrochloride Odt; Aricept; Aricept Odt	92	11360	0.40 (0.31∼0.50), p < 0.0001

ROR, reporting odds ratio; CI, confidence interval.

In addition, the frequency of dysphagia reports was compared between patients prescribed rivastigmine and patients that were prescribed another therapeutic for AD treatment. Patients that were prescribed the NMDAR antagonist memantine were 54% less likely (ROR = 0.46; p < 0.0001) to report dysphagia as an adverse event relative to patients that were instead prescribed rivastigmine. In addition, individuals that were prescribed galantamine or donepezil were 30% (ROR = 0.70; p = 0.0152) and 60% (ROR = 0.40; p < 0.0001) less likely respectively to report dysphagia as an adverse event to the FAERS database than patients prescribed rivastigmine. These results suggest that patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed any other AD therapeutics.

The severity of reported dysphagia cases

The severity of reported dysphagia cases and the classification of clinical outcomes were assessed in patients prescribed rivastigmine for treatment. As defined by the FDA, a serious outcome is defined as having at least one of these events in the case report: hospitalization, life-threatening, disability, death, congenital anomaly, or other serious medical event. Of the 299 patients that reported dysphagia as an adverse event, 293 were classified as being in serious condition. When compared to patients without dysphagia. Patients with dysphagia were 5.27 times more likely (ROR = 5.27; p = 0.0001) to be in serious clinical condition (Table 2).

Table 2

The severity of dysphagia cases in patients prescribed rivastigmine. Patients that developed dysphagia after being prescribed rivastigmine had a 5.27-fold greater likelihood (ROR = 5.27; p = 0.0001) of having a clinically serious outcome than patients prescribed rivastigmine that ultimately did not go on to have a dysphagia diagnosis

	Serious	Non-Serious	ROR (95% CI), p
Without Dysphagia	13,194	1,426
With Dysphagia	293	6	5.27 (2.35∼11.87),
			p = 0.0001

ROR, reporting odds ratio; CI, confidence interval.

In Table 3, the clinical outcomes for the patients that were prescribed rivastigmine and reported a dysphagia diagnosis are presented. Of the 299 reported instances of dysphagia, 161 patients were hospitalized (53.85%), 103 individuals died (34.44%), and 16 were in life-threatening condition (5.35%). Among patients that did not report a dysphagia event, 4,843 (33.12%) were hospitalized, 4,186 (28.63%) died, and 509 (3.48%) were in life-threatening condition. These findings suggest that individuals that reported dysphagia as an adverse drug event after rivastigmine use were significantly more likely to be hospitalized than rivastigmine users that did not report dysphagia.

Table 3

Clinical outcomes for individuals prescribed rivastigmine

	With Dysphagia	Without Dysphagia
Hospitalized	161 (53.85%)	4,843 (33.12%)
Death	103 (34.44%)	4,186 (28.63%)
Life-Threatening	16 (5.35%)	509 (3.48%)
Total Cases	299	14,620

ROR, reporting odds ratio; CI, confidence interval.

Age difference in the risk of dysphagia

To further assess possible age differences in dysphagia risk, patient age groups were partitioned into 3 groups, 50≤ age ≤70 years old, 70<age ≤80 years old, and age >80 years old. As shown in Table 4, patients prescribed rivastigmine in the 70<age ≤80 demographic were 88% more likely to report dysphagia as an adverse event to the FAERS database than the 50≤ age ≤70 demographic group (ROR = 1.88; p = 0.045). In addition, patients in the >80 age demographic were 122% more likely than individuals in the 50≤ age ≤70 demographic to report dysphagia as an adverse event after taking rivastigmine (ROR = 2.22; p = 0.0091). This suggests dysphagia risk rose as age increased in rivastigmine users.

Table 4

Age difference in the risk of dysphagia for individuals prescribed rivastigmine. Patients in the age between 70–80 age group were 88% more likely (ROR = 1.88; p = 0.045) to report dysphagia as an adverse event after rivastigmine use than the 50≤ Age ≤70 group. Patients in the age >80 group were 122% more likely (ROR = 2.22; p = 0.0091) to report dysphagia as an adverse event after rivastigmine use than the 50≤ Age ≤70 group

	With Dysphagia	Without Dysphagia	ROR (95% CI), p
50≤ Age ≤70	12	1014
70<Age ≤80	65	2917	1.88 (1.01∼3.50),
			p = 0.045
Age >80	112	4261	2.22 (1.22∼4.04),
			p = 0.0091

ROR, reporting odds ratio; CI, confidence interval.

Sex difference in the risk of dysphagia

Sex was assessed as a possible confounder for the association between rivastigmine use and dysphagia. As shown in Table 5, 163 females that were prescribed rivastigmine reported dysphagia as an adverse event while 123 males that were prescribed rivastigmine for AD treatment reported dysphagia as an adverse event. No statistically significant difference (ROR = 1.06; p = 0.66) in dysphagia likelihood was observed between males and females.

Table 5

Sex difference in the risk of dysphagia for individuals prescribed rivastigmine. No statistically significant difference in reporting dysphagia as an adverse event after being prescribed rivastigmine was identified between females and males (ROR = 1.06; p = 0.66)

Group	With Dysphagia	Without Dysphagia	ROR (95% CI), p
Female	163	8081
Male	123	5780	1.06 (0.83∼1.34),
			p = 0.66

ROR, reporting odds ratio; CI, confidence interval.

Administration route difference in the risk of dysphagia

Next, the administration route for rivastigmine use was assessed with regards to its possible confounding effects of the association between rivastigmine use and likelihood of dysphagia. Patients prescribed the transdermal rivastigmine patch were utilized as the control and were compared to patients administered rivastigmine in its oral form. Here, patients from 2012 4th quarter to 2020 4th quarter were investigated because these records have clean structural information on dosage and administration route in FAERS database. Out of the 7,305 patients prescribed the transdermal rivastigmine patch, 126 individuals reported dysphagia as an adverse event. For patients prescribed the capsule form of rivastigmine, 28 individuals reported dysphagia as an adverse event (ROR = 2.07; p = 0.0006). Thus, patients prescribed the oral form of rivastigmine were significantly more likely to report dysphagia as an adverse event than patients prescribed the transdermal patch (Table 6).

Table 6

Dysphagia occurrences in patients prescribed different administration route of rivastigmine. The table presents the role of the administration route of rivastigmine in the reporting of dysphagia as an adverse event by patients from 2012 4th quarter to 2020 4th quarter. The records which route information contains keywords “transdermal”, “topical”, “cutaneous”, or “intradermal” will be included in the transdermal group. The records which route information contains keywords “oral”, “capsule”, or “tablet” will be included in the oral group.

Group	With Dysphagia	Without Dysphagia	ROR (95% CI), p
Transdermal	126	7,179
Oral	28	771	2.07 (1.36∼3.14),
			p = 0.0006

ROR, reporting odds ratio; CI, confidence interval.

The dosage effect

The dosage of administration for rivastigmine was also assessed as a possible confounder in the association between rivastigmine use and the likelihood of dysphagia occurrence in patients from 2012 4th quarter to 2020 4th quarter. When compared to patients that were prescribed a <5 mg oral dose of rivastigmine, no statistically significant difference in the likelihood of reporting dysphagia was observed in patients prescribed either a 5–10 mg dose (ROR = 0.99; p = 0.96) or a dose ≥10 mg (ROR = 1.60; p = 0.12) (Table 7).

Table 7

Dysphagia occurrences in patients prescribed different dosages of rivastigmine. For all cases, no statistically significant association in dysphagia diagnosis was observed among patients prescribed a 5–10 mg dose (ROR = 0.99; p = 0.96) or a dose ≥10 mg (ROR = 1.60; p = 0.12) compared with the patients whose dosages are less than 5 mg

Dosage (mg)	With Dysphagia	Without Dysphagia	ROR (95% CI), p
Dosage <5 mg	41	2,195
10 mg > Dosage	31	1,682	0.99 (0.62∼1.58),
≥5 mg			p = 0.96
Dosage ≥10 mg	16	537	1.60 (0.89∼2.86),
			p = 0.12

ROR, reporting odds ratio; CI, confidence interval.

The association between dysphagia and pneumonia

Finally, the association rule algorithm was utilized to assess symptom patterns as to whether dysphagia occurred more frequently alongside pneumonia when compared to other commonly reported adverse drug events of rivastigmine use including death, fall, vomiting, malaise, cerebrovascular accidents, drug ineffective, confusional state, and nausea. Ten association rules were developed and presented in Table 8. A lift greater than 1 is indicative of a stronger than expected coupling of variables. For symptom patterns, 66 cases reported both pneumonia and dysphagia. Dysphagia had the largest lift values with pneumonia (lift = 3.57). Thus, dysphagia showed significantly greater association with pneumonia than other of commonly reported adverse events.

Table 8

Association between Dysphagia and Pneumonia. The association rule for {dysphagia, pneumonia} was the most significant (lift = 3.57) and thus, pneumonia and dysphagia had a strong association that exceeded the expected frequency

Association Rules	Count	Support	Confidence	Coverage	Lift
{Dysphagia = 1} -> {Pneumonia = 1}	66	0.0044	0.22	0.02	3.57
{Death = 1} -> {Pneumonia = 1}	60	0.0040	0.029	0.14	0.46
{Dementia alzheimer’s type = 1} -> {Pneumonia = 1}	55	0.0037	0.094	0.039	1.53
{Fall = 1} -> {Pneumonia = 1}	45	0.0030	0.044	0.069	0.70
{Vomiting = 1} -> {Pneumonia = 1}	44	0.0029	0.048	0.061	0.78
{Malaise = 1} -> {Pneumonia = 1}	37	0.0025	0.057	0.043	0.93
{Cerebrovascular accident = 1} -> {Pneumonia = 1}	32	0.0021	0.057	0.038	0.92
{Drug ineffective = 1} -> {Pneumonia = 1}	26	0.0017	0.049	0.035	0.80
{Confusional state = 1} -> {Pneumonia = 1}	23	0.0015	0.027	0.052	0.48
{Nausea = 1} -> {Pneumonia = 1}	19	0.0013	0.025	0.051	0.40

DISCUSSION

In this study, we systematically assessed the association between the dysphagia reports and rivastigmine usage. The number of reported dysphagia cases by individuals prescribed rivastigmine was compared with the frequency of dysphagia cases for individuals prescribed one of several positive controls including penicillamine, botulinum toxin A, and clozapine. Previous reports have indicated elevated dysphagia risk in patients that are administered these therapeutics [18 –21]. Dysphagia risk for rivastigmine-prescribed patients was comparable to the dysphagia likelihood observed in patients administered the immunosuppressant drug penicillamine and greater than the observed risk in patients administered clozapine. Conversely, the likelihood of dysphagia was higher in patients administered botulinum toxin A. In addition, we compared the risk of dysphagia as an adverse event for rivastigmine users relative to those prescribed other small-molecule therapeutics for AD treatment. Our findings showed that individuals prescribed rivastigmine had the highest risk of dysphagia compared to patients prescribed either galantamine, donepezil, or memantine.

Patients that reported dysphagia as an adverse event after taking rivastigmine were also significantly more likely to be hospitalized. Despite the high proportion of hospitalization, it cannot be soundly concluded that dysphagia plays a causative role in the elevated hospitalization rates. It is possible that dysphagia may occur after admission into the clinical setting and is not the cause for hospitalization. Another possibility is that dysphagia may be more readily diagnosed in the hospital setting and that many cases of mild dysphagia that would go unnoticed are subsequently identified.

Elevated dysphagia risk was observed with respect to an increase in patient age. Individuals in the 70–80 age demographic were 88% more likely to report dysphagia as an adverse event after taking rivastigmine than patients in the 50–70 age demographic. In addition, individuals older than 80 years of age were 122% more likely to report dysphagia as an adverse event after being prescribed rivastigmine than patients between the ages of 50 and 70. As an individual’s age extends beyond 65 years of age, the likelihood of AD diagnosis increases. Furthermore, individuals aged 80 and older are more likely to be in the later stages of AD pathology, of which are characterized by impaired breathing, impaired swallowing, loss of appetite, and lack of appetite [22].

Possible dosage effects were also assessed in patients prescribed rivastigmine. Although the ROR value (ROR = 1.60) is higher in the high dosage group than the low dosage group, no statistically significant difference in dysphagia risk was observed between them (p = 0.12). The lack of significance may be due to a rather small sample size and the statistical power of the experiment to detect a statistically significant difference being too low. Duplicate reports as well as individuals that took multiple rivastigmine dosage range were removed to isolate the effects of a particular dose on the likelihood of dysphagia occurring. As a result, the sample sizes were somewhat small for each dose, particularly the ≥10 mg dose group which had only 16 cases. Further testing with additional data reports will help to draw a more convincing conclusion as to whether the dosage of rivastigmine plays a significant role in dysphagia risk.

Finally, route of administration was assessed as a possible covariate with regards to dysphagia risk. Patients that took rivastigmine orally were 107% more likely to report dysphagia as an adverse event when compared to patients prescribed the transdermal patch. This significant difference in dysphagia may be due to the differences in the maximum concentration of rivastigmine in the blood stream (C_max) and the time in which it takes for the maximum concentration to be reached (T_max) between the capsule and transdermal patch [23]. The C_max is lower for the transdermal patch and the T_max is reduced when compared to the capsule form [23]. This may increase patient tolerability in those that are taking the transdermal patch while patients taking rivastigmine orally may be more at risk of gastrointestinal distress and vomiting, of which may increase the risk of dysphagia and aspiration pneumonia [23]. However, as was the case with the dose response assessment, the sample size is rather small. This is because many duplicate reports as well as reports for individuals that had taken both the capsule form and used the transdermal patch were excluded from the analysis. Thus, additional data needs to be collected to validate the presented conclusion of increased dysphagia risk in those taking rivastigmine orally.

Our results indicated that pneumonia is strongly associated with dysphagia in patients prescribed rivastigmine. It has been previously shown by us and other research groups that pneumonia, particularly aspiration pneumonia, was more strongly associated with rivastigmine use than other AD therapeutics [16, 24]. Dysphagia typically precedes pneumonia diagnosis and are closely related as impaired swallowing greatly increases the risk of food particles and gastric contents entering the lower respiratory tract [24]. Thus, it is reasonable to expect that similar mechanisms are to yield this observed elevated risk in both pneumonia and dysphagia in patients that are prescribed rivastigmine.

When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. AChE inhibitors are thought to stifle the progressive cognitive decline associated with later stages of AD through the inhibition of AChE and the subsequent enhancement of cholinergic signaling [25]. While acetylcholine-mediated signaling is an essential component of the parasympathetic nervous system, of which regulates muscle contraction required for breathing and swallowing as well as blood pressure, excessive cholinergic signaling induces a physiological state of cholinergic crisis [24]. Prolonged AChR binding of acetylcholine leads to an overstimulation of motor neurons and prevents muscles from relaxing after polarization and contraction [7]. Unlike the AChE inhibitors galantamine and donepezil, rivastigmine is thought to have higher selectivity to tissues of the central nervous system, particularly the hippocampus, the site of memory formation, and the medulla oblongata [26]. This may be a consequence of rivastigmine’s increased selectivity for the monomeric G1 isoform of AChE, which localizes to several regions of the brain that are severely impacted by AD pathology including the hippocampus, cerebral cortex, and medulla oblongata, the latter of which regulates autonomic processes including breathing, swallowing, salivation, and heart rate [27]. Degeneration or overstimulation of motor neurons in the medulla oblongata, particularly the large vagus nerve which extends from the brain stem through the thorax into the abdomen, leads to significant autonomic dysfunction including impaired swallowing, hindered breathing, gastrointestinal distress, and impaired coughing [24]. Thus, rivastigmine may induce a cholinergic crisis through suppression of AChE activity and promote disruption of autonomic processes (Fig. 3).

Fig. 3

The proposed mechanism for the rivastigmine-mediated dysphagia risk. CNS: central nervous system.

An additional distinguishing feature between rivastigmine and the other AChE inhibitors used for AD treatment is its additional ability to inhibit butyrylcholinesterase, a non-specific cholinesterase that can dissociate acetylcholine and other molecules such as the anesthetic succinylcholine from the acetylcholine receptor [28]. In a physiologically healthy brain devoid of AD pathology, AChE is highly expressed in the brain while butyrylcholinesterase is predominantly expressed in the peripheral nervous system [28]. However, as AD pathology worsens, the balance in expression is shifted in favor of butyrylcholinesterase upregulation as AChE levels decline [29]. Thus, this inherent compensatory mechanism, which is thought to slow neuronal degeneration and protect against autonomic dysfunction by limiting the occurrence of a cholinergic crisis, is also inhibited by rivastigmine use and may provide explanation for the observed elevated frequency of dysphagia when compared to those prescribed a different AD therapeutic [29].

Despite these promising results, some limitations exist in this study. First, cases of dysphagia may be largely underreported or not thought of as a possible adverse drug event, especially if the instances of dysphagia are mild. Because of this, the sample sizes used in this study are somewhat small and there were not many reports from individuals that were only prescribed rivastigmine. As a result, we cannot definitively conclude that the observed elevated dysphagia prevalence is entirely due to rivastigmine use as drug-drug interaction effects may be present [30, 31]. Thus, more data needs to be collected, particularly for patients only prescribed rivastigmine, to further assess the association between rivastigmine use and subsequent dysphagia occurrence. Future research will focus on investigating possible interactions between rivastigmine and other drugs using the FAERS database [32].

Conclusion

Dysphagia is commonly reported by patients prescribed rivastigmine, an AChE inhibitor. The dysphagia risk in individuals prescribed rivastigmine was similar to individuals prescribed penicillamine but significantly higher than users of clozapine. When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. This statistically significant difference may be due to the dual inhibition of both AChE and butyrylcholinesterase by rivastigmine, the latter of which galantamine and donepezil do not target.

Individuals that reported dysphagia as an adverse drug event after rivastigmine use were significantly more likely to be associated with serious outcomes than rivastigmine users that did not report dysphagia. There is no significant sex difference in the risk of dysphagia in rivastigmine users. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients younger than 50–70 years of age. The oral administration is about 2 times higher than transdermal patch. However, the dosage effect is not statistically significant with current data. The preferential localization of rivastigmine to the central nervous system may disrupt cholinergic signaling in areas of the brain responsible for autonomic function regulation such as the medulla oblongata as well as impair mechanisms designed to compensate a decrease in AChE activity, resulting in prolonged flaccid paralysis of muscles required for swallowing and an increase in dysphagia risk. Future studies will identify possible dysphagia-related drug-drug interactions with rivastigmine.

Footnotes

ACKNOWLEDGMENTS

This research was funded by a National Institutes of Health grant (1R03AG070536-01) to Feng Cheng.

Authors’ disclosures available online ().

References

Setti

, Hunsberger

, Reed

(2017) Alterations in hippocampal activity and Alzheimer’s disease. Transl Issues Psychol Sci 3, 348–356.

Morris

, Armbruster

, Silva

, Widell

, Cheng

(2020) The association between the usage of non-steroidal anti-inflammatory drugs and cognitive status: Analysis of longitudinal and cross-sectional studies from the Global Alzheimer’s Association Interactive Network and transcriptomic data. Brain Sci 10, 961.

Morris

, Luboff

, Jose

, Eckhoff

, Bu

, Pham

, Rohlsen-Neal

, Cheng

(2021) Bradycardia due to donepezil in adults: Systematic analysis of FDA adverse event reporting system. J Alzheimers Dis 81, 297–307.

Eckhoff

, Morris

, Zuluaga

, Polsky

, Cheng

(2021) The association between tau protein level in cerebrospinal fluid and cognitive status: A large-scale analysis of GAAIN database. Brain Sci 11, 861.

Ferreira-Vieira

, Guimaraes

, Silva

, Ribeiro

(2016) Alzheimer’s disease: Targeting the cholinergic system. Curr Neuropharmacol 14, 101–115.

Johnson

, Kotermanski

(2006) Mechanism of action of memantine. Curr Opin Pharmacol 6, 61–67.

Dominguez

, Chin

, Chen

, Wu

(2011) Management of moderate to severe Alzheimer’s disease: Focus on memantine. Taiwan J Obstet Gynecol 50, 415–423.

Abdrakhmanov

, Petrov

, Grigoryev

, Zefirov

(2013) Depolarization-induced calcium-independent synaptic vesicle exo- and endocytosis at frog motor nerve terminals. Acta Naturae 5, 77–82.

Patel

, Gupta

GuptaV(2021) Rivastigmine. In StatPearls, Treasure Island, FL.

10.

Szeto

, Lewis

(2016) Current treatment options for Alzheimer’s disease and Parkinson’s disease dementia. Curr Neuropharmacol 14, 326–338.

11.

Akuzawa

, Yoshii

, Ono

, Kuwako

, Osaki

, Osawa

, Jingu

, Watanabe

, Saito

(2019) Predictors of discontinuance of oral feeding in patients with advanced Alzheimer dementia and aspiration pneumonia in Japan: A single-center, retrospective observational study. Alzheimer Dis Assoc Disord 33, 339–345.

12.

Chilukuri

, Odufalu

, Hachem

(2018) Dysphagia. Mo Med 115, 206–210.

13.

Milewska

, Grabarczyk

, Dabrowska-Bender

, Jamroz

, Dziewulska

, Staniszewska

, Panczyk

, Szostak-Wegierek

(2020) The prevalence and types of oral- and pharyngeal-stage dysphagia in patients with demyelinating diseases based on subjective assessment by the study subjects. Mult Scler Relat Disord 37, 101484.

14.

O’Rourke

, Vickers

, Upton

, Chan

(2014) Swallowing and oropharyngeal dysphagia. Clin Med (Lond) 14, 196–199.

15.

Chang

, Chavan

, Pavlov

(2019) Cholinergic control ofinflammation, metabolic dysfunction, and cognitive impairment inobesity-associated disorders: Mechanisms and novel therapeuticopportunities. Front Neurosci 13, 263.

16.

Morris

, Umeukeje

, Bu

, Cheng

(2021) The association betweenuse of rivastigmine and pneumonia: Systematicanalysis of FDA Adverse event reporting system. J AlzheimersDis 83, 1061–1071.

17.

FDA FAERS, https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.

18.

Flanagan

, Lally

, Gee

, Lyon

, Every-Palmer

(2020) Clozapine in the treatment of refractory schizophrenia: A practical guide for healthcare professionals. Br Med Bull 135, 73–89.

19.

Stoschus

, Allescher

(1993) Drug-induced dysphagia. Dysphagia 8, 154–159.

20.

Koshiishi

, Koinuma

, Takagi

, Nakamura

(2020) Pharmacological considerations in antipsychotic drug selection for prevention of drug-induced dysphagia. Pharmazie 75, 595–598.

21.

O’Neill

, Remington

(2003) Drug-induced esophageal injuries and dysphagia. Ann Pharmacother 37, 1675–1684.

22.

Ahmad

, Dar

(2018) Classification of Alzheimer’s disease stages: An approach using PCA-based algorithm. Am J Alzheimers Dis Other Demen 33, 433–439.

23.

Sadowsky

, Micca

, Grossberg

, Velting

(2014) Rivastigmine from capsules to patch: Therapeutic advances in the management of Alzheimer’s disease and Parkinson’s disease dementia. Prim Care Companion CNS Disord 16, 10.4088/PCC.14r01654.

24.

Benghanem

, Mazeraud

, Azabou

, Chhor

, Shinotsuka

, Claassen

, Rohaut

, Sharshar

(2020) Brainstem dysfunction in critically ill patients. Crit Care 24, 5.

25.

Matsuda

, Hisatsune

(2017) Cholinergic modification of neurogenesis and gliosis improves the memory of AbetaPPswe/PSEN1dE9 Alzheimer’s disease model mice fed a high-fat diet. J Alzheimers Dis 56, 1–23.

26.

Onor

, Trevisiol

, Aguglia

(2007) Rivastigmine in the treatment of Alzheimer’s disease: An update. Clin Interv Aging 2, 17–32.

27.

Zhao

, Tang

(2002) Effects of huperzine A onacetylcholinesterase isoforms in vitro: Comparison with tacrine,donepezil, rivastigmine and physostigmine.. Eur J Pharmacol 455, 101–107.

28.

Soliday

, Conley

, Henker

(2010) Pseudocholinesterase deficiency: A comprehensive review of genetic, acquired, and drug influences. AANA J 78, 313–320.

29.

Nordberg

, Ballard

, Bullock

, Darreh-Shori

, Somogyi

(2013) A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer’s disease. Prim Care Companion CNS Disord 15, PCC.12r01412.

30.

, Shen

, Pietsch

, Nagar

, Fadli

, Huang

, Tu

, Cheng

(2015) A novel algorithm for analyzing drug-drug interactions from MEDLINE literature. Sci Rep 5, 17357.

31.

, Figler

, Huang

, Tu

, Wang

, Cheng

(2017) Characterization of the mechanism of drug-drug interactions from PubMed using MeSH terms. PLoS One 12, e0173548.

32.

Pham

, Cheng

, Ramachandran

(2019) A comparison study of algorithms to detect drug-adverse event associations: Frequentist, Bayesian, and machine-learning approaches. Drug Saf 42, 743–750.