Treating Overactive Bladder in the Elderly: Side-Effect Profiles of
Anticholinergic Drugs
Adonis Hijaz, MD; Raymond Rackley, MD
Introduction
The International Continence Society has defined the overactive bladder (OAB) syndrome as disturbance
of bladder function that leads to "urgency, with or without urge incontinence, usually with frequency and
nocturia." According to 2 population-based studies, one in the United States and one in Europe, the
overall prevalence of OAB is approximately 17%.[1,2] In both studies the prevalence was found to increase
with age -- 31% of women and 42% of men older than 75 years are affected.[1] Anticholinergic therapy is
the first line of medical therapy for the OAB syndrome. With an aging population and a higher prevalence
of OAB in the elderly, understanding the interaction of aging and anticholinergics in the treatment of OAB
is increasingly important. The purpose of this article is to provide an overview of the different
anticholinergics available for managing OAB. We will focus specifically on the side effects of these
medications that are of most concern in the elderly and we will discuss how the individual drugs in this
class of anticholinergics differ with respect to these effects.
Pharmacologic Considerations
There are 5 types of muscarinic receptor, classified as M1-5.[3] The muscarinic subclasses of cholinergic
receptors found in the human detrusor muscle are mostly of the M2 and M3 subtypes. Despite the
predominance of the M2 receptors (66%), the M3 receptors are mainly responsible for normal micturition
contraction. M3 receptors are also located in the parotid gland and in the gastrointestinal tract. [4]
Among the medications approved by the US Food and Drug Administration for treating the symptom
complex of OAB are oxybutynin, tolterodine, and 3 more recently approved drugs, trospium, solifenacin,
and darifenacin. All current anticholinergic drugs lack true specificity for the muscarinic receptors in the
target bladder organ, even though some have claims of functional bladder selectivity/specificity over other
end-organs, such as the salivary gland. Moreover, except for darifenacin, which is the first M3-selective
agent, all of the above are nonselective to the muscarinic receptor subtype. [5]
The Safety and Tolerability of Anticholinergic Drugs in the Elderly
The major concern of clinicians prescribing anticholinergics for the treatment of OAB in the
elderly patient is the side-effect profile. Observed central nervous system (CNS) side effects (eg,
cognitive effects, which are M1-mediated) and cardiac effects (eg, tachycardia, which is M2mediated) are the 2 main issues. Dry mouth and constipation continue to play a role in the
patient's compliance with the medication, but are not as great a concern since they do not affect
the patient's overall mental and physical health and possibly his/her independent status. The
cholinergic system is a major neuromodulatory neurotransmitter system in core regions of the
brain affecting learning and memory functions. All 5 subtypes of muscarinic receptors are located
at the postsynaptic level of the central cholinergic synapse. Studies investigating the depressant
effects that these drugs have on the CNS have shown that antimuscarinic agents have the
potential to cause impairment of CNS functioning. CNS dysfunction may manifest as changes in
memory, disruption of sleep, hallucinations, confusion, and delirium.
When prescribing an anticholinergic drug to an elderly patient, several safety issues should be
considered. First, anticholinergic effects have been identified in many drugs other than those that
are traditionally known to have major anticholinergic effects.[6] Second, many elderly patients are
receiving more than 1 drug with anticholinergic effects. Blazer and colleagues[7] reported that
over 1 year, 59% of the sampled elderly nursing home residents received 1 or more drugs with
anticholinergic properties. Third, it is the total burden of anticholinergic agents that determines
the development of side effects.[6] Therefore, reviewing the medication list of the elderly for the
total anticholinergic burden when faced with an adverse effect or when prescribing an
anticholinergic for OAB is essential to the safety of the patient.
The incidence and intensity of CNS side effects of anticholinergics is determined by 2 factors: the
ability of the drug to pass the blood-brain barrier and the affinity of the drug for the muscarinic
receptor subtypes present in the CNS. The ability of the drug to cross the blood-brain barrier
depends on its structure (lipophilicity, electrical charge, and molecular size). Small lipophilic,
noncharged molecules and compounds pass the blood-brain barrier more readily than do large,
charged compounds.[8,9]
CNS Effects of Anticholinergic Treatment for OAB
There are a number of clinical case reports of neuropsychological or cognitive adverse effects with the
immediate-release (IR) formulations of oxybutynin and tolterodine. However, when we reviewed the
literature from the major clinical trials on safety and tolerability of anticholinergics currently approved for
OAB, we found that CNS adverse effects were rarely observed and were limited to minor effects such as
dizziness, headache, etc. But the clinical trials were structured to capture adverse effects reported by the
patient and not to test for specific CNS adverse effects such as cognitive changes. In addition, these
studies included a relatively small number of elderly patients with limited cognitive or CNS reserve. As
outlined below, few trials specifically studied the effect of anticholinergic side effects on the elderly or
specifically assessed CNS changes with anticholinergics through cognitive testing.
Postmarketing Reports of CNS Adverse Events
Four cases of neuropsychological adverse events including psychosis, hallucination, and confusion have
been reported with oxybutynin-IR in elderly patients with Parkinson's disease who are cognitively
impaired.[10] Moreover, there were 3 cases in which tolterodine intake resulted in acute delirium in patients
taking an acetylcholinesterase inhibitor for the treatment of dementia.[11] Womack[12] reported a case of
memory loss and abnormal memory test results that improved when tolterodine therapy was discontinued
in a nonelderly working person.
CNS Effects Reported in Clinical Trials and Retrospective Analyses
Malone-Lee and coworkers[13] studied the safety and tolerability of tolterodine-IR 1 and 2 mg twice daily in
an elderly population (> 65 years). The study was placebo-controlled and involved 175 elderly patients
(mean age, 75 years) with OAB syndrome. The reported CNS adverse effects (headache, dizziness)
were comparable in the tolterodine and placebo groups. Moreover, there were no cardiac or retention
adverse effects in the treatment groups.
Analyzing data from the OPERA (Overactive bladder: Performance of Extended-Release Agents) trial,
Chu and coworkers[14] looked at the CNS effects of the extended-release (ER) formulations of oxybutynin
and tolterodine. They found that neither agent elicited clinically problematic CNS adverse events. Of the
CNS adverse events judged to be possibly or probably treatment-related, only dizziness (2.6%) and
insomnia (1.3%) in the oxybutynin-ER group and only somnolence (2.0%) and dizziness (1.8%) in the
tolterodine-ER group were reported for more than 1% of either group. CNS adverse events led to early
discontinuation by 1.5% of participants taking oxybutynin-ER and 0.5% of participants taking tolterodineER. It is worth mentioning that only 15% of the OPERA population were over 75 years of age. The study
authors do not present a comparative analysis of these CNS side effects in this subpopulation, especially
because the study was limited by the lack of a placebo arm. However, they concluded that the clinical
data indicated a low rate of adverse CNS effects associated with either formulation and suggested that
the use of either may be particularly appropriate for the elderly.
In a pooled analysis of a number of phase 3 trials on darifenacin, the incidence of nervous system
adverse effects (peripheral and/or CNS events) reported by patients taking 7.5 mg or 15 mg of
darifenacin was comparable to that of placebo.[15] The most common nervous system adverse effects
were dizziness (darifenacin 7.5 mg, 0.9%; 15 mg, 2.1%; vs placebo, 1.3%) and somnolence (0.3% and
0.9% vs 0.8%, respectively).
Foote[16] carried out an evaluation of the efficacy, tolerability, and safety of darifenacin in the subgroup of
older patients from a pooled analysis of 3 phase 3, multicenter, randomized, double-blind clinical trials in
patients with OAB. Patients aged 65 years or older with OAB symptoms received up to 12 weeks of oral
treatment with darifenacin 7.5 mg or 15 mg once daily or with matching placebo. Safety endpoints
included withdrawal rates and treatment-related adverse events. Treatment with darifenacin in patients 65
years or older was associated with a dose-related, significant improvement of all major symptoms of
OAB, and there were no CNS or cardiovascular safety concerns.
In 2 large phase 3 clinical trials of solifenacin there were no reports of CNS side effects. The leading side
effects in these studies were dry mouth, constipation, and blurred vision. [17,18] Furthermore, Zinner[19]
reported no CNS side effects in a phase 3 trial of trospium.
Studies Designed to Assess Specific CNS Effects
Sleep. Diefenbach and colleagues[20] conducted a randomized, double-blind, crossover study of the
effects of oxybutynin-IR, tolterodine-IR, trospium chloride, and placebo on sleep in healthy young
volunteers. They found that oxybutynin influenced sleep structure, which was reflected by REM
suppression and mild sedation, while subjective parameters and psychometric tests remained unaffected.
In a second study involving healthy volunteers aged 50 years and older, Diefenbach and coworkers[21]
showed that there was a 14.2% reduction in median REM sleep duration in subjects receiving oxybutynin
(P = .002) and 15.2% in those receiving tolterodine (P = .012) compared with placebo. REM duration in
subjects receiving trospium chloride did not differ significantly from placebo. The study authors also
assessed cognitive function 1 hour after administration of the drugs using the number-combination test,
which evaluates information-processing capacity and working velocity, and the d2 test of attention for
assessing individual sustained attention and concentration. Although oxybutynin and tolterodine were
associated with a small but significant reduction in REM sleep compared with trospium, no decrements in
cognitive function at 1 hour after dosing were noted, and no longer-term effects were tested in this limited
study design.
Quantitative electroencephalogram. Todorova and coworkers[22] conducted a single-blinded, parallel
study in 64 young healthy male volunteers to evaluate the potential CNS side effects of oxybutynin,
tolterodine, and trospium chloride in comparison to placebo. A quantitative electroencephalogram (EEG)
was recorded at baseline and at 4 hours after intake of trial medications. Patients receiving oxybutynin
had a significant change in the EEG activity; however, the global subjective evaluation of drug tolerability
by volunteers was comparable among all of the treatment groups.
Cognitive function. Katz and colleagues[23] carried out a randomized, cross-over study in 12 volunteers
to evaluate the cognitive effects of oxybutynin and to compare these effects with those in subjects
receiving placebo and a positive control (diphenhydramine). They found that oxybutynin-IR resulted in a
decline in 7 of 15 cognitive measurements in healthy elderly subjects compared with diphenhydramine,
which was associated with declines in 5 of the 15 measures.
Herberg and Fusgen[24] evaluated the effect of trospium, oxybutynin, and propiverine on traffic-related
performance with regard to safety (precision of visual orientation, concentration, vigilance, motor
coordination, and reaction in a stress situation). Healthy volunteers took the anticholinergics for a period
of 7 days. None of the 3 medications caused deterioration in the volunteers' functional capacity. Trospium
was found to be superior to oxybutynin and propiverine in the vigilance test at the start of the treatment
and to propiverine at the end of the medication phase. The vigilance test is particularly relevant for the
elderly patients whose vigilance is impaired as a result of their age.
In a double-blind, 3-period, crossover study, Lipton and coworkers [25] tested 129 volunteers 65 years or
older with no/mild cognitive impairment. Subjects were randomized to receive 3 or 5 treatments, namely
darifenacin controlled-release (3.75, 7.5, or 15 mg once daily), darifenacin immediate release (5 mg 3
times daily), or matching placebo for 14 days. Cognitive function was tested at baseline and at treatment
end. For the memory scanning sensitivity, speed of choice reaction time, and word recognition sensitivity,
there was no statistically significant difference for darifenacin vs placebo. Darifenacin was not associated
with a change in alertness, contentment, or calmness. The study authors concluded that the battery of
tests examining attention, vigilance, memory, and reaction time revealed no difference in cognitive
performance in subjects treated with darifenacin and placebo. The lack of cognitive impairment with
darifenacin may be explained by its relatively low affinity to the M1 receptors, coupled with its active
transport out of the brain as a substrate of the P-glycoprotein efflux transporter.[23]
Conclusion
The current literature on anticholinergics contains case reports on cognitive and neuropsychological
adverse effects of IR forms of oxybutynin and tolterodine in elderly patients with specific medical
conditions. In most of the phase 3 studies on oxybutynin-ER, tolterodine-ER, darifenacin, solifenacin, and
trospium, there were no reports of serious CNS side effects. However, formal cognitive testing was not
carried out in these studies. Studies that were designed to assess the CNS effects of anticholinergics
revealed a significant effect on REM sleep and EEG with oxybutynin-IR in healthy volunteers, yet there
were no associated cognitive changes. In studies of darifenacin, trospium, propiverine, and oxybutynin-IR
that were primarily designed to study cognitive effects, it appears that darifenacin and trospium had no
negative cognitive effects. In one study, oxybutynin was associated with a decline in some cognitive
function measures in the healthy elderly, but this study had a small sample size. The CNS cognitive
safety of anticholinergics in the elderly will need to be further addressed in trials with placebo and
hopefully a positive drug control.
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