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Addressing the Barriers to Effective Overactive Bladder Management Through Medication Therapy Management
Introduction
Overactive bladder (OAB) is a symptom complex that includes urinary urgency with or
without urge incontinence, urinating frequency (i.e., voiding 8 or more times in a 24-hour
period) and nocturia (i.e., awaking 2 or more times per night to void), in the absence of
urinary tract infection (UTI) or other obvious pathology.1,2
OAB is a syndrome, and syndromes represent a group of signs and symptoms that
occur together and characterize a particular anomaly; but this designation does not
imply a particular etiology.3 The pathogenesis of a syndrome is typically multifactorial
and, thus, highly individual in nature. Examples of other medical syndromes include
irritable bowel, cognitive impairment, gait disturbance, and falling, none of which have
exactly the same pathology when analyzing from one patient to another.
When one considers OAB, urinary incontinence (UI) and nocturia are important
components of the syndrome. The medications used to treat OAB are also used to treat
urge UI, which is a component of many forms of lower urinary tract symptoms (LUTS),
including benign prostatic hypertrophy (BPH). For this activity, the definition of OAB will
include UI. The individualized and multifactorial nature of OAB makes treatment
success both a challenge and an opportunity for improvement through the
personalization of care.
Pharmacists encounter OAB often in their patient panels. An estimate by a pharmacy
media and marketing company found that the OAB consumer represents 51 million
people in the United States, with 6 per day reaching every retail pharmacy. Over-the-counter (OTC) products to treat adult UI ranked third as the most frequently purchased
OTC products.4 Pharmacists have a key position in the community setting to play a
major role in supporting improved OAB treatment outcomes through medication therapy
management (MTM) services.
Prevalence and Costs Associated With OAB
The overall prevalence of OAB in the general population is estimated to be 9% to 17%
for men and 20% to 30% for women.5,6 Among older adults, the prevalence jumps to
more than 25% for community dwelling men and more than 55% for community dwelling
women older than 65 years of age.7 These estimates will trend higher when considering
those who are more frail or who have been institutionalized longer.7 The average annual
cost associated with OAB is estimated to be $1950 per capita and the total national cost
was estimated to be $72.2 billion in 2015.8 With the aging population, the total costs are
expected to increase by 25% from 2007 to 2020.8 The direct costs associated with OAB
include doctors' consults, prescriptions, and other medications, pads, diapers, dry
cleaning, laundry, and fees for those who must be institutionalized. Also, there are
indirect costs, including the cost of a caregiver, lost productivity, and diminished quality
of life (QoL).
9 OAB is also associated with
morbidity and correlated with an increased risk of
hospitalization and nursing home
placement.10 Persons living with unsuccessfully treated OAB have lower work productivity, poorer mental health, poorer sleep quality,
and a higher rate of depression.9 Additionally, OAB, especially in older women, has
been associated with higher risk of falls and sustaining a fracture than those without
OAB; those with more severe urinary symptoms and those with more physical
limitations are more severely affected.10
Many people living with OAB experience barriers to seeking professional help. It is
estimated that a very small fraction of patients who have OAB actually seek medical
evaluation.11 OAB is more prevalent in women than in men, and women who experience
OAB symptoms cite several reasons for not seeking help from a doctor, including not
knowing the doctor well enough, worry about costs, and physician gender being a man.12
Guidelines and Evidence
Terminology References to the terms non-neurogenic OAB and neurogenic OAB appear throughout
this manuscript. The latter refers to patients with underlying neurological disease.
Neurologic diseases can often damage the central of peripheral pathways that are
involved in control of the lower urinary tract. These diseases can be spinal (e.g., spinal
cord injury, spinal stenosis, spina bifida, and intervertebral disc disease), peripheral
(e.g., diabetes mellitus, herpes zoster), supraspinal (e.g., Parkinson's disease, cerebral
palsy, cardiovascular accident, dementia) or mixed. There are exceptions to these
categorizations and combined lesions can be difficult to identify and relate to lower
urinary tract dysfunction.13 Persons with neurogenic lower urinary tract dysfunction
should have close urodynamic monitoring because of the potentially elevated risk of
upper urinary tract and renal damage caused by highly elevated bladder pressure.14
The term non-neurogenic (or idiopathic) OAB refers to cases where the exact etiology
may be unclear.
Terminology is important to familiarize yourself with when studying the literature
regarding OAB and can be useful in clinical practice. However, in terms of the day-to-day management of OAB medications, the terminology is not as significant. Please refer
to the glossary accompanying this monograph for terminology reference. Some of the
medication treatments found in the American Urological Association/Society of
Urodynamic Female Pelvic Medicine & Urogenital Reconstruction (AUA/SUFU)
guideline on non-neurogenic OAB are also applicable to neurogenic lower urinary track
dysfunction and can be found in the guidelines published by the European Association
of Urology (EAU).15
Recommendations The AUA, in May of 2015, published the Diagnosis and Treatment of Overactive
Bladder (Non-Neurogenic) in Adults: AUA/SUFU Guideline , which is an amendment to
their 2012 guideline and includes an updated review of the literature from 2012 to 2014.
The focus of the update was on mirabegron, peripheral tibial nerve stimulation (PTNS),
sacral neuromodulation (SNS), and intravesical injections of botulinum toxin, and
emerging therapies since the 2012 AUA guideline on non-neurogenic OAB was
released. The amendment emphasizes that OAB symptoms are rarely cured, but the
symptoms and burden on QoL can be ameliorated.1 The guidelines update states the
importance of recognizing that OAB is a symptom complex that may compromise QoL,
but generally does not affect survival. A treatment plan should weight the risks and
reversibility of adverse effects with the potential benefit to the patient.
Efficacy and Expected Outcomes of Treatment
1 It stands to reason
that if most syndromes are multifactorial, defining a
clear algorithm that leads to successful treatment
for all patients with OAB through clinical studies is
challenging. In addition to differences across
studies, interindividual patient variability regarding factors contributing to OAB syndrome within studies would make the strength of
evidence a challenge.
Identifying strong evidence for successful single intervention or a universal treatment for
OAB is further challenged by the high treatment failure rate with regard to OAB
medications. A study looking at medication use persistence among individuals with
several types of chronic diseases who had been treated with oral therapies, including
cardiovascular disease, diabetes, and osteoporosis, found that OAB medication use
persistence was determined to be the lowest of the categories studied.16
Another study looking at insurance claims data from 103,250 patients (mean age of 58.7 years) over a 3-year period, the longest study period evaluating treatment
persistence to date, found that 92% of patients failed initial treatment with
anticholinergic therapy. A high percentage of patients (86%) were treatment
discontinuations, as opposed to switching to another anticholinergic therapy (5.8%), and
33% only filled 1 prescription, which indicated failure within the first 30 days. More than
one-half of patients discontinued anticholinergic treatment by the end of 2 years and
most discontinuations occurred within the first 6 months. It was also found that only 48%
of patients demonstrated a medication possession rate higher than 80%, indicating that
adherence to anticholinergic treatment is poor.17 Other studies have examined
anticholinergic OAB treatment failure rates and found similarly high rates of treatment
failure and, also, that extended-release (ER) forms of anticholinergics seem to have
improved persistence rates when compared with immediate-release formulations
(IR).1,18 Anticholinergic side effects are known to be more severe with IR dosage forms
and, thus, considered a factor for higher rates of discontinuation of use. Convenience of
dose with ER forms is also thought to impact adherence positively.19 The other aspect
attributed to low persistence and adherence rates is failed expectations of efficacy. It is
suggested that interventions to promote realistic expectations about treatment efficacy
might enhance adherence.20 Often, the realistic expectations of patients being treated
for OAB are not met because it is challenging to overcome the many factors that
compose OAB syndrome. Some patients expect success after treatment with a single oral medication or intervention and this unrealistic expectation can define treatment
failure for those patients. The pharmacist can play a significant role in improving health
literacy with regard to the impact of OAB medications by supporting realistic efficacy
expectations and helping with the management of side effects, as well as recognizing
the need for complementary modes of intervention, such as behavioral therapy.
AUA Guidelines
Table 1 1 but the highly individualized nature of OAB syndrome contributes to the
difficulty encountered while gathering definitive evidence regarding any treatment.
Understanding the mechanisms and factors contributing to OAB, along with efficacy and
safety considerations for lifestyle, functional outcomes, and pharmacologic
interventions, can enable the clinician to help achieve improved outcomes.
1
AUA/SUFU = American Urological Association/Society of Urodynamic Female Pelvic Medicine & Urogenital Reconstruction; IR = immediate release; ER = extended release
After obtaining a complete and thorough medical and family history from the patient,
physical and behavioral therapies are the first-line interventions, with or without
concurrent pharmacologic management.1 Behavioral therapies have been shown to
reduce leakage by 50% to 80% for older adults, with 10% to 30% achieving
continence.21 Behavioral treatments improve continence by teaching skills to empower
the patient with self-management through exercise (e.g., pelvic floor muscle strength
training and Kegel exercises), bladder control strategies, self-monitoring (e.g., bladder
diaries, electronic applications), scheduled and delayed voiding, caffeine reduction (i.e.,
direct urinary irritant), fluid management, weight loss, and other strategies.22,23 The clinician can help explain and coach behavioral therapy and follow-up with online
resources, such as the National Association for Continence (www.nafc.org), a nonprofit
organization that provides resources for patients, caregivers, and health care professionals. Within the NAFC Web site, patients can find a downloadable bladder
diary with instructions and an OAB treatment tracker that asks a series of questions to
develop a document for patients to discuss OAB with their provider more accurately,
along with forums and blogs. The National Institutes of Health (NIH) MedlinePlus Web
site has additional patient education resources about OAB and links to many other
online tools, including handouts on Kegel exercises in Spanish.22
Combining behavioral therapy with pharmacological treatments shows promise of being
a method to help adherence and persistence for a pharmacological treatment that
typically has a high treatment failure rate. A study by Wyman and colleagues evaluated
therapy persistence related to the addition of behavioral therapy to OAB pharmacologic
treatments for patients who were dissatisfied with prior pharmacologic treatment alone.
The participants received tolterodine ER and a self-administered behavioral intervention
for the first 8 weeks, which included a focused 2-page educational pamphlet that clinical
staff reviewed with the patients. If, after 8 weeks patients continued to express
dissatisfaction with their OAB treatment, they would receive individualized behavioral
interventions for the remaining 8 weeks. None of the participants required the
individualized behavioral intervention. The investigators conducted cognitive debriefing
interviews at 7 and 10 months after the conclusion of the 16 weeks. One-third of the
participants remained on the study medication for 7 to 10 months after completing the
16-week open-label trial phase.23 They assessed participants' treatment expectations
and experiences. Of the 15 participants, 12 attributed dissatisfaction with prior
antimuscarinics to lack of efficacy. With regard to information from the self-administered
behavioral therapy educational pamphlet, the participants acquired more positive
perceptions of the value of behavioral therapy. Many participants indicated that they
were not previously aware of the potential efficacy of muscle strengthening exercises
and that the voiding diary provided valuable feedback and an awareness of the impact
of medication and behavioral interventions on decreasing number of daily voids. Most
studies investigating the efficacy of OAB medications are of 12-week duration and the
treatment failure rate is high, despite the short duration of treatment.24 The Wyman
study illustrates the impact that behavioral treatment has on extending adherence to pharmacological treatment. It is easy to see why behavioral treatments rank high on the
AUA guidelines as an approach to the management of OAB.23
If the first-line behavioral approach fails, then second-line treatment involves the use of
antimuscarinic agents or beta-3 adrenergic agonists. Note that the second-line
recommendations still highlight behavioral therapy.
Neuroanatomy and Pathophysiology of the Lower Urinary Tract (LUT)
The pathophysiology of OAB is incompletely characterized and the clinical
understanding is evolving with time. OAB pathophysiology is highly individualized and
micturition is a complex physiological process that requires multiple systems work
efficiently and in a coordinated fashion. One must have intact cognition, neurological
function, intact neurotransmitter function, and normal receptor function, as well as
sufficient cultural and societal support for normal micturition to occur.
Normal function involves spinal reflex mechanisms that activate sympathetic and
somatic pathways to the urethral outlet and tonic inhibitory systems in the brain. The
tonic inhibitory system suppresses the parasympathetic system that is responsible for
the outflow of urine from the bladder, which is the default state in sympathetic tone that
fosters urine storage. In normal function, the bladder fills with pressure lower than
urethral resistance. With increased bladder filling pressure, afferent signaling to the
brain triggers parasympathetic tone (acetylcholine release) and decreased sympathetic
tone (noradrenaline release); urethral resistance is lowered and phasic contraction of
the detrusor muscle to empty the bladder results in urination.25 The voluntary control of
the bladder requires complex interactions between the autonomic system and somatic
sensorimotor pathways.25 Additionally, there is a strong psychosocial component to
micturition. There appears to be signaling from the pons to the sacral cord, allowing the
voiding reflex pathway an on or off mode that can be overridden whenever the bladder
reaches a critical level; thus, in individuals with spinal cord injuries, OAB and
incontinence is common because of the interruption of this pathway at the sacral cord
level. In continent individuals, the decision to void is strictly under voluntary control. The decision to void is an aspect of human behavior and is based on multiple factors, such
as emotional state, appreciation of the social environment, and knowledge of the extent
to which one's bladder content remains comfortable. The higher brain centers (i.e.,
prefrontal cortex) can suppress the excitatory signals to the cell group in the brain stem
specific for micturition.26 These are factors that have to be taken into consideration
when helping patients with realistic expectations for the outcome of OAB treatment.
In Figure 1 , the basic physiological control of the LUT is illustrated.
NE = norepinephrine; M = muscarinic receptor; SNS = sympathetic nervous system; PSNS = parasympathetic nervous system; Ach = acetylcholine
The major inhibitory mechanism is activation of beta-3 adrenergic receptors (B3ARs) in
the detrusor muscle and the epithelium and the activation of alpha-adrenergic receptors
(alpha ARs) in the urethra and bladder neck epithelium.26,27
The major excitatory mechanism is the cholinergic system, which mainly activates M3
receptors in the detrusor muscle, causing contraction, and the M2 receptors, to a lesser
extent. Nitric oxide released by parasympathetic nerves cause an inhibitory effect to the
urethral smooth muscle.26
Figure 1
25,30
Active Pathway Other Influences on LUT Function
Glutamate
Excitatory neurotransmitter in pathways controlling the LUT.
5HT (Serotonin)
Deficit associated with low voiding volume and unstable bladder contractions. More than 50% of patients with urge urinary incontinence (UUI) have depression; a very low % of stress urinary incontinence (UI) patients have depression, which supports pathological studies implicating 5HT deficiency is a factor in OAB.
Dopamine (D1,D2)
D1 receptors seem to have a role in suppressing bladder activity. D2 receptors seem to facilitate voiding.
Gamma-Aminobutyric acid (GABA) and enkephalin
Inhibit voiding in animal models.
Gabapentin
Inhibits C-fiber nerve tissues. C fiber sensitivity (in the dorsal root ganglia) can increase after spinal cord injury.
Bladder Outlet Obstruction
Urethral obstruction is associated with increased acetylcholine responsiveness and can increase NGF.
Nerve Growth Factor (NGF)
NGF response to dorsal and pelvic plexus nerve damage. NGF causes unstable detrusor contractions.
Metabolic Syndrome
Autonomic hyperactivity is associated with hypertension, hyperinsulinemia, and obesity.
Pelvic Floor
Pelvic floor weakness caused by childbirth, sarcopenia, or surgery can cause LUTS.
Pharmacist's Approach to MTM of OAB Syndrome
OAB is a complex syndrome which makes it difficult to manage successfully in the 15
minute office visit or bedside consult.31,32
The pharmacist is a member of the health care team that is very able to offer consistent
support for patients living with OAB syndrome. Therefore, an essential part of successful MTM for OAB patients is using this opportunity to apply comprehensive
understanding of OAB pathophysiology, assessment, treatment options, monitoring,
patient experience, and point of view to help coach patients toward successful MTM for
OAB.
The impact of OAB on patients, society, and the pathophysiology basics have been described; the recommended assessment and pharmacologic properties of OAB treatments will be explored in the next section.
Assessment
A mnemonic to help clinicians remember the various categories of assessment during
the treatment of OAB is DIAPPERS, an acronym that represents the following: d elirium,
i nfection, a trophic vaginitis and urethritis, p harmacological agents, p sychiatric
conditions, e xcessive urinary output, r estricted mobility, and s tool impaction. In
summary, the clinician should assess the possible transient causes of OAB, as well as
possible chronic conditions that can exacerbate OAB and other factors.32
Most of the conditions in Table 3
32
Transient OAB/UI
Chronic Conditions
Other
UTI Vaginitis Fecal impaction Hypercalcemia Delirium
- CHF
- Caffeine
33
ACE inhibitors
• Stress incontinence as the result of cough
Sedative hypnotics
• Inhibition of the central control of micturition
Calcium Channel Blockers
• Impaired detrusor contractility, fluid retention, nocturnal diuresis, overflow incontinence
IV fluids
• Large volume IVs
Diuretics, caffeine, EtOH, cholinesterase inhibitors • Urge incontinence as the result of uncontrolled bladder contractions/high urine flow stimulation of contractions
Alpha-blocking agents
• Stress incontinence caused by urinary sphincter relaxation (women)
Alpha and beta agonists
• Urinary retention caused by urinary sphincter contraction
Anticholinergics, antidepressants, antipsychotics, sedative hypnotics, antihistamines, EtOH, Anticholinergic anti-parkinsonian agents, anti-diarrheal agents
• Nervous system depressants; urinary retention caused by decreased bladder contractions
OAB = overactive bladder; ACE = angiotensin-converting enzyme; EtOH = ethyl alcohol; IV = intravenous
OTC = over-the-counter; MTM = medication therapy management; HTN = hypertension; HCTZ = hydrochlorothiazide; LUTS = lower urinary tract symptoms; IU = international units
Choosing an OAB Medication
Linking assessment of the LUT pathology to appropriate individualized treatment can improve
the reported treatment failure rates for OAB medications. Awareness of pharmacology and
toxicology improves individual titration of dose and selection of treatment.
The 2 classes of medication listed in the AUA guidelines for the treatment of OAB,
antimuscarinics and beta-3 adrenergic receptor agonists, have been established for efficacy.
The goal of treatment with these medications is to choose an agent that would fit the clinical
assessment best, with the lowest side effect profile for the individual patient. Another goal is to
help the patient persist with treatment beyond the typical time to treatment failure of about 5
months and the pharmacist, through MTM services, can play a large role in helping patients with
behavioral therapies, monitoring for side effects, and the assessment of medications that may
work against the efficacy of OAB treatment.17
Pharmacists also play a major role in assessing the appropriateness of therapy through MTM
services. For example, many patients can tolerate an anticholinergic medication for treatment of
a transient case of OAB that may have been caused by a UTI, but daily use thereafter would be
inappropriate if the underlying condition is no longer present. Other considerations include
assessing the risk versus the benefits of OAB medication use with respect to the impact on
other comorbidities and a patient's tolerance of side effects. Commonly, it is important to
minimize constipation, dry mouth, and cardiac and cognitive side effects, especially for older
adults.
The use of OAB medications to treat older adults with multiple comorbidities presents
heightened tolerability challenges. Goals of care for older adults with complex comorbidities
often include optimization of QoL and the assessment of the risks versus benefits of treatment,
which may be counterintuitive given the conventional prescribing information. Therefore, it helps
to understand that highly individualized goals of care and QoL considerations that may lead to
seemingly inappropriate use, when actually, the choice may have been intentional. For
example, the prescribing information for the antimuscarinic (anticholinergic) medications will
warn these medications are contraindicated for those with urinary retention. However, a patient
with obstructive overflow incontinence and urgency might benefit from the use of an antimuscarinic for the treatment of OAB symptoms (e.g., recall that obstruction can increase
sensitivity to acetylcholine and lead to urgency). Occasionally, a urology specialist will use an
antimuscarinic medication to treat obstructive overflow incontinence in conservative doses, off-label, to successfully manage OAB symptoms involving bladder spasticity despite the risk of
post void urine residual. It all depends on the individual patient and their circumstances.20 This
is where it will be necessary for the clinical pharmacist MTM services to synthesize and
integrate varying principles in OAB management for individualized treatment options.
Antimuscarinic Medications
Antimuscarinic (or anticholinergic) medications have been the mainstay in the treatment of OAB
for decades because originally they were the only approved pharmacologic treatment option for
symptom relief.34 The first antimuscarinic approved for the treatment of bladder conditions was
flavoxate (Urispas) in 1970.35
In 1975, oxybutynin (Ditropan) was approved for the treatment of bladder conditions. These
agents were different than the previous antispasmodic, anticholinergic agents, such as
papaverine, because they had little or no effect on blood vessel smooth muscle. These 2 agents
stand apart from the other antimuscarinic medications for the treatment of OAB because they
have moderate antihistaminic effects, some local anesthetic, and mild analgesic effects.21 The
newer antimuscarinic agents for the treatment of OAB are more specific to the muscarinic
receptor; also, oxybutynin has an active metabolite. Around the 1990s, newly approved
antimuscarinic agents were designed to target muscarinic receptors and, possibly, avoid the
side effects that made oxybutynin troublesome. Oxybutynin causes marked anticholinergic
effects throughout the body and the newer agents were designed to decrease effect on the
brain (confusion and somnolence), gut (constipation), mouth (dry mouth), and cardiovascular
system (tachycardia).28,36
Awareness of muscarinic receptor distribution throughout the body can help the clinician
anticipate side effects. Table 4 ).
27-29
The newer antimuscarinic bladder medications that were developed subsequent to oxybutynin
were also designed to try to avoid the cognitive effects of crossing the blood-brain barrier.
Therefore, the various agents were designed to be either positively charged (water soluble) and
not be able to cross the blood-brain barrier or remain lipophilic and have higher affinity for the
muscarinic receptors that work in the bladder and less affinity for the receptors associated with
side effects, such as the M1 or M5. The blood-brain barrier allows lipophilic agents into the brain
readily (i.e., psychoactive medications, opioids), but not charged moieties, such as quaternary
amines.28,35,36
Of the antimuscarinic agents for the treatment of OAB, trospium (Sanctura) is a quaternary
amine and, theoretically, should not cross the blood-brain barrier.37 In frail older adult patients,
the blood brain-barrier becomes somewhat porous and possibly charged; therefore, water-soluble drugs that are not intended to cross into the brain (i.e., drugs specifically designed to
stay out of the brain) sometimes enter through the blood-brain barrier and cause confusion or
other psychological effects. According the American Geriatrics Society 2015 Updated Beers
Criteria for Potentially Inappropriate Medication Use in Older Adults (Beers Criteria),
antimuscarinic bladder medications are considered strongly anticholinergic and are listed as
potentially inappropriate medications (PIMs) for older adults.38 The Beers Criteria expert panel
derived this determination from strong evidence demonstrating that this class of medication is
as strongly anticholinergic as atropine; thus, it is strongly recommended that antimuscarinic
agents are used with caution in older adult patients, with careful consideration of the risks
versus the benefits of therapy.38
When comparing agents in the antimuscarinic bladder medication group, consideration of
lipophilicity (e.g., the ability to cross the blood-brain barrier), M receptor selectivity, renal
adjustment, and hepatic metabolism are helpful when selecting an appropriate medication
based on the individual patient.
Hepatic Metabolism: Tolterodine (Detrol) should be avoided for the treatment of patients with
comorbid hepatic impairment. It is a potent cytochrome P450 (CYP) 3A4 inhibitor; therefore, it
should be used with caution in patients taking other medications metabolized through the
CYP3A4 system, such as mirabegron.39 Darifenacin (Enablex) and solifenacin (Vesicare)
should be dosed conservatively for those with moderate hepatic impairment.39
Lipophilicity and M Receptor Selectivity: Darifenacin (Enablex) is the most selective;
but, also, the most likely to cross the blood-brain barrier. According to clinical studies, it
has demonstrated less cognitive impairment and drowsiness with use.40
39,41,42
*All muscarinic antagonists have some cross receptor activity, even if designed not to.
39
Adverse Events: Predictability With Antimuscarinic Agents 39,42 Urinary tract infection, which is a concern
whenever there is post-void residual and less movement of urine out of the bladder (i.e.,
the result of the relaxation of detrusor muscle or any cause) occurs at a rate of
approximately 5%, except with the use of tolterodine and trospium, which occurs in
approximately 1% of patients.18,39
Beta-3 Adrenergic Receptor Agonists
The beta-3 adrenergic receptor agonists (B3ARs) were developed recently and
represent an alternative to antimuscarinic medications for OAB therapy. Currently there
is only 1 agent on the market, mirabegron (Myrbetriq). B3ARs are located throughout
the body, including in adipose, genital, cardiac, and respiratory tissues, as well as in
skeletal muscles.
The mechanism of action of the B3AR agonists in OAB therapy involves the B3
receptor, which is found throughout the detrusor muscle of the bladder and bladder
epithelium. When activated, the B3 receptor relaxes the detrusor muscle and, as
described earlier when discussing the physiology of the LUT system, the sympathetic
nervous system influence is increased, leading to greater bladder storage capacity.
Thus, the muscarinic antagonists slow the activation of the bladder system to urinate
and the B3 agonists support the storage of urine. Another bladder effect of the B3ARs, as
determined through pharmacological studies, includes an increased bladder capacity
with little effect on micturition pressure or post-void residual urine volume, which is in
contract to the volumetric effects and mituration pressure effects of the antimuscarinics.
This has possible implications for improved therapy in persons with obstruction and
OAB where post void residual and urine stream flow are important factors.44
Pharmacokinetically, mirabegron may produce clinically relevant interactions with
CYP2D6 substrate and CYP3A4 inhibitors; a substrate of CYP2D6, such as
desipramine could have an extended half-life when used concomitantly with
mirabegron.18 Also, a strong inhibitor of CYP3A4, such as ketoconazole, can supress
the clearance of mirabegron.45 Mirabegron is lipophilic and food impacts its absorption.
A high-fat meal might decrease the area under the curve (AUC) by 15% to 17% and a
low fat meal might decrease AUC by 51% to 75%. Mirabegron can increase digoxin
AUC by 29%.44
The side effect profile for mirabegron is considerably different than that of
antimuscarinic agents.46 Noted side effects are increased blood pressure and heart rate,
nasopharyngitis, headache, and urinary tract infection. In a safety and tolerability study,
mirabegron 50 mg was associated with a placebo-adjusted mean blood pressure
increase of 0.4 to 0.6 mmg Hg (P = 0.05) and, approximately, a 1 beat-per-minute
increase in pulse rate (P = 0.05), which were both reversible upon discontinuation.46,47
There is less incidence of dry mouth with the use of mirabegron than there is with the
use of antimuscarinics, but a higher incidence of palpitations and dizziness.47,48
The usual daily dose of mirabegron for the treatment of OAB is 25 mg once daily and
may be increased to 50 mg once daily, as tolerated. For patients with severe renal
impairment (i.e., having a calculated Creatinine Clearance (CrCl) of 15 to 29 mL/min
according to the Cockcroft-Gault Equation), mirabegron should be administered at a
maximum daily dose of 25 mg daily. Mirabegron use should be avoided in patients with
end-stage renal disease or a CrCl below 15 mL/min.35 The safety of mirabegron at
therapeutic doses is comparable with that of antimuscarinic agents.47 No
contraindications have been listed per the U.S. Food and Drug Administration (FDA)
drug monograph thus far.35
Efficacy of Mirabegron: The United Kingdom National Health Service (NHS) The
National Institute for Health and Care Excellence (NICE) technology appraisal guidance
review group looked at 22 studies for the outcome of micturition episodes per 24 hours
and found no difference among the users of mirabegron 50 mg daily and any of the
other active treatements assessed (anticholinergics).49 Mirabegron has equal efficacy to
antimuscarinics per the International Continence Society (ICS) panel.50
Combination Therapy
The current Trial Comparing Combination Treatment (Solifenacin Plus Mirabegron) With
One Treatment Alone (Solifenacin) (BESIDE) was recently completed and results are in
process. The study compared solifenacin–mirabegron combination therapy (i.e.,
solifenacin 5 mg and mirabegron 25 mg) with solifenacin monotherapy (i.e., 5 mg or 10
mg). Data presented at the AUA annual meeting of 2015 highlighted that the
combination therapy seemed to have fewer side effects. Dry mouth was noticeably
improved for patients using combination therapy than for those using solifenacin 10 mg
monotherapy. They also found that the combination group had a decrease in mean daily
incontinence episodes compared with the monotherapy groups taking 5 mg of
solifenacin, which was not different from that of the monotherapy group taking 10 mg of
solifenacin.51,52
The ultimate place mirabegron will hold in the treatment of OAB has yet to be
elucidated. Combination therapy with select anticholinergic agents shows promise and
works to utilized lower doses of medication from each class to optimize mechanistic
synergy. Another possible use may be for patients with benign prostatic hyperplasia
(BPH) because mirabegron and B3ARs appear to be less likely to increase the potential
for post-void residual urinary retention than anticholinergic agents.44,47
Other Medications Used for the Treatment of OAB Syndrome
As discussed earlier, it is difficult to disentangle OAB from other etiologies that also lead
to LUTS. Therefore, the assessment of OAB MTM must include recogniton of other
conditions and medicaitons that coexist with, or as part of, OAB syndrome. Please
review Table 6
38,42,53
BPH, Urinary Obstruction, and OAB
OAB accompanies BPH at times because of the physiologic changes that occur in the LUT when obstruction is present. Obstruction can be caused by scar tissue, surgery,
renal calculi, enlargement of the prostate gland aroud the urethra, as well as other
causes.25 The case of OAB accompanied by urinary obstruction presents a particular
clinical management challenge and selection of an inappropriate treatment intervention
may result in worsening of symptoms rather than improvement. The use of
anticholinergic medications to calm the hyperactivity of the detrusor muscle must be
balanced with the risk of worsening an already inadequate volume of post-void residual
urine that results from the blocked urinary outlet and, thus, worse incomplete bladder
emptying with micturition. The medications used for outlet obstruction typically target the
alpha receptor on the external urethral rhabdosphincter to help loosen the tightness of
this muscle on the urethra to allow maximal urinary flow.
The alpha antagonists used for the treatment of BPH and other obstruction-related
LUTS are tamsulosin (Flomax), Alfuzosin (Uroxatral), and Silodosin (Rapaflo). These
alpha-adrenergic receptor antagonists are preferred because of their selectivity for
bladder and prostate alpha receptors. The nonselective alpha receptor blockers (i.e.,
doxasosin [Cardura] terazosin [Hytrin], prazosin [Minipress]) work systemically and
have the risk for causing hypotension. The nonselective alpha-adrenergic antagonists
are on the Beers Criteria of PIMs for older adults.38
Recall that activation of the alpha receptor at the bladder neck obstructs or slows the
flow of urine.28 Duloxetine is used to treat stress incontinence because it has strong
norepinephrine properties that tighten up the rhabdosphincter and the serotonin aspect
is thought to help calm bladder vesicle overactivity in patients with depression.
Pharmacological models also implicate that serotonin receptors, located in the
supraspinal area, may be involved in the control of urination.39,54
Regarding the case study previously discussed in this activity, a woman showed signs
of having urinary incontinence, possibly caused by an obstruction, and symptoms of
increased post-void residual urine worsened with the use of the oxybutynin OTC patch.
In her case, the possible removal of the duloxetine, which she received to treat her stress incontinence, would be worth investigating. Another therapeutic strategy, if
removal of duloxetine fails to improve her OAB and incontinence, would be to attempt
treatment with alpha-receptor blockers to maximize urine flow around her obstruction.
This would hopefully create complete voiding with no residual urine and prevent
overflow incontinence. Often when a woman is prescribed an alpha-adrenergic
antagonist for the treatment of LUTS, the rest of the health care team may be
concerned because there is a lack of evidence for the use of this agent to treat women
with OAB; however, there are several studies regarding the sucessful use of alpha-adrenergic-antagonists for the treatment of women with obstructive LUTS.53,55
Conclusion
The sucessful management of OAB syndrome is both individualistic and complex.
Among health care providers, pharmacists are in the best position in the community
pharmacy to consult with patients beyond the typical office visit. Pharmacists provide an
approachable and unrushed environment for the patient living with OAB to explore the
various contributing factors that can lead to urinary symptoms. Expertise in
pharmacology is clearly a requirement for the sucessful management and selection of
treatment. The high treatment failure rate that results from poor adherence and patients
having unrealistic expectations of treatment efficacy is something that MTM services
can impact; MTM services can temper patient expectations and provide education to
improve health literacy about this disorder, as well as help the patient to sucessfully
avoid or tolerate the side effects that accompany pharmacologic treatment. There are
multiple areas in which pharmacists can provide support to patients through MTM
services, includinhg the following: the comprehensive medication profile review to
identify potentially reversible drug causes; education about the use of incontinence aids,
such as pads, and other helpful OTC products; and education about lifetyle
modifications to help patients live comfortably and sucessfully manage OAB symptoms.
Lastly, the pharmacist can serve as a patient advocate with interdiciplinary health care
team members, patients' families, and support services for patients living with OAB.
The Pharmacist's Role in Managing OAB
Glossary
Please click here for the glossary.
References
Gormley EA, Lightner DJ, Faraday M, et al; and the American Urological Association,
Society of Urodynamics Female Pelvic Medicine. Diagnosis and treatment of overactive
bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015;193(5):1572-1580.
Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological
Association (IUGA)/International Continence Society (ICS) joint report on the
terminology for female pelvic floor dysfunction. Int Urogynecol J. 2010;21(1):5-26.
Mosby's Medical Dictionary, 8th edition. (2009). Syndrome . http://medical-dictionary.thefreedictionary.com/syndrome. Accessed January 30, 2016.
Media REM. rx-edge.com. 2013. http://www.rx-edge.com/media-kit/pdfs/Consumer_Profile_OAB.pdf. Accessed February 24, 2016.
Coyne KS, Sexton CC, Bell JA, et al. The prevalence of lower urinary tract symptoms
(LUTS) and overactive bladder (OAB) by racial/ethnic group and age: results from OAB-POLL. Neurourol Urodyn. 2013;32(3):230-237.
Coyne KS, Sexton CC, Thompson CL, et al. The prevalence of lower urinary tract
symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of
LUTS (EpiLUTS) study. BJU Int. 2009;104(3):352-360.
Centers for Disease Control and Prevention (CDC), U.S. Department of Health and
Human Services (HHS), National Center for Health Statistics. Vital and Health Statistics. Prevalence of Incontinence Among Older Americans . June 2014. CDC Web site.
http://www.cdc.gov/nchs/data/series/sr_03/sr03_036.pdf. Accessed February 8, 2016.
Coyne KS, Wein A, Nicholson S, et al. Economic burden of urgency urinary incontinence
in the United States: a systematic review. J Manag Care Pharm. 2014;20(2):130-140.
Bartoli S, Aguzzi G, Tarricone R. Impact on quality of life of urinary incontinence and
overactive bladder: a systematic literature review. Urology. 2010;75(3):491-500.
Foley AL, Loharuka S, Barrett JA, et al. Association between the Geriatric Giants of
urinary incontinence and falls in older people using data from the Leicestershire MRC
Incontinence Study. Age Ageing. 2012;41(1):35-40.
El-Azab AS, Shaaban OM. Measuring the barriers against seeking consultation for urinary
incontinence among Middle Eastern women. BMC Womens Health. 2010;10:3.
Heit M, Blackwell L, Kelly S. Measuring barriers to incontinence care seeking. Neurourol
Urodyn. 2008;27(3):174-178.
Kennelly MJ, Devoe WB. Overactive bladder: pharmacologic treatments in the neurogenic
population. Rev Urol. 2008;10(3):182-191.
Nambiar A, Lucas M. Chapter 4: Guidelines for the diagnosis and treatment of overactive
bladder (OAB) and neurogenic detrusor overactivity (NDO). Neurourol Urodyn. 2014;33
(Suppl 3):S21-S25.
Pannek J, Blok B, Castro-Diaz D, et al; for the European Association of Urology (EAU).
Guidline on Neurogenic Lower Urinary Tract Dysfunction. Uroweb Web site.
http://uroweb.org/wp-content/uploads/20_Neurogenic-LUTD_LR.pdf. Accessed January
21, 2016
Yeaw J, Benner JS, Walt JG, et al. Comparing adherence and persistence across 6 chronic
medication classes. J Manag Care Pharm . 2009;15(9):728-740.
Chancellor MB, Migliaccio-Walle K, Bramley TJ, et al. Long-term patterns of use and
treatment failure with anticholinergic agents for overactive bladder. Clin Ther. 2013;35(11):1744-1751.
Chapple CR, Khullar V, Gabriel Z, et al. The effects of antimuscarinic treatments in
overactive bladder: an update of a systematic review and meta-analysis. Eur Urol .
2008;54(3):543-562
D'Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among
extended-release and immediate-release overactive bladder medications in a regional
managed care plan. J Manag Care Pharm. 2008;14(3):291-301.
Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing
overactive bladder medication. BJU Int. 2010;105(9):1276-1282.
Markland AD, Vaughan CP, Johnson TM, 2nd, et al. Incontinence. Med Clin North Am. 2011;95(3):539-554, x-xi.
National Institutes of Health (NIH), U.S. National Library of Medicine (NLM). Overactive
Bladder . Medline Plus Web
site. https://www.nlm.nih.gov/medlineplus/overactivebladder.html#cat69. Accessed
January 21, 2016.
Wyman JF, Harding G, Klutke C, et al. Contributors to satisfaction with combined drug
and behavioral therapy for overactive bladder in subjects dissatisfied with prior drug
treatment. J Wound Ostomy Continence Nurs. 2010;37(2):199-205.
Hsiao SM, Liao CH, Lin HH, Kuo HC. Duration of antimuscarinic administration for
treatment of overactive bladder before which one can assess efficacy: an analysis of
predictive factors. Int Neurourol J. 2015;19(3):171-177.
Chapple C. Chapter 2: Pathophysiology of neurogenic detrusor overactivity and the
symptom complex of "overactive bladder". Neurourol Urodyn. 2014;33(Suppl 3):S6-S13.
Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci.
20 08;9(6):453-466.
Ursino MG, Vasina V, Raschi E, et al. The beta3-adrenoceptor as a therapeutic target:
current perspectives. Pharmacol Res. 2009;59(4):221-234.
Waller DG, Sampson T. Medical Pharmacology and Therapeutics, 4th Edition . Saunders Ltd.
15:225-231. 2014.
Hanna-Mitchell AT, Kashyap M, Chan WV, et al. Pathophysiology of idiopathic overactive
bladder and the success of treatment: a systematic review from ICI-RS 2013. Neurourol
Urodyn. 2014;33(5):611-617.
Meng E, Lin WY, Lee WC, Chuang YC. Pathophysiology of overactive bladder. Low Urin
Tract Symptoms. 2012;4(Suppl 1):48-55.
Tai-Seale M, McGuire T. Time is up: increasing shadow price of time in primary-care office
visits. Health Econ. 2012;21(4):457-476.
Radomski SB, Barkin J. Medical management of overactive bladder. Can J Urol. 2012;19(Suppl 1):2-9.
Tsakiris P, Oelke M, Michel MC. Drug-induced urinary incontinence. Drugs Aging. 2008;25(7):541-549.
Chapple C. Antimuscarinics in men with lower urinary tract symptoms suggestive of
bladder outlet obstruction due to benign prostatic hyperplasia. Curr Opin Urol. 2010;20(1):43-48.
Package labeling: a. Myrbetriq (mirabegron) oral extended-release tablets [prescribing information]. Northbrook, Illinois: Astellas Pharma US, Inc. 2015. b. Flavoxate hydrochloride oral tablets [prescribing information]. Epic Pharma, LLC
(per DailyMed), Laurelton, NY, 2015. c. Flomax (tamsulosin hydrochloride) oral capsules [prescribing information].
Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2008. d. Rapaflo (silodosin) oral capsule [prescribing information]. Parsippany, NJ: Watson
Pharma, Inc a wholly-owned subsidiary of Actavis Pharma, Inc. 2013. e. Uroxatral (alfuzosin HCl) oral extended-release tablets [prescribing information].
Bridgewater, NJ: sanofi-aventis U.S. LLC. 2007. f. Myrbetriq (mirabegron) oral extended-release tablets [prescribing information].
Northbrook, Illinois: Astellas Pharma US, Inc. 2015.
Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: their distribution and
function in body systems, and the implications for treating overactive bladder. Br J
Pharmacol. 2006;148(5):565-578.
Schladitz-Keil G, Spahn H, Mutschler E. Determination of the bioavailability of the
quaternary compound trospium chloride in man from urinary excretion data. Arzneimittelforschung. 1986;36(6):984-987.
American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American
Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication
Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.
Hesch K. Agents for treatment of overactive bladder: a therapeutic class review. Proc (Bayl
Univ Med Cent). 2007;20(3):307-314.
Callegari E, Malhotra B, Bungay P, et al. A comprehensive non-clinical evaluation of the
CNS penetration of potentail antimuscarinic agents for the treatment of overactive
bladder. Brit Jour of Clin Pharmacology. 2011; 72(2) 235-246.
Cvijic S, Langguth P. Improvement of trospium-specific absorption models for fasted and
fed states in humans. Biopharm Drug Dispos. 2014;35(9):553-558.
Geoffrion R; for the Society of Obstetricians and Gynaecologists of Canada. Treatments
for overactive bladder: focus on pharmacotherapy. J Obstet Gynaecol Can. 2012;34(11):1092-1101.
Madhuvrata P, Cody JD, Ellis G, et al. Which anticholinergic drug for overactive bladder
symptoms in adults. Cochrane Database Syst Rev. 2012;1:CD005429.
Caremel R, Loutochin O, Corcos J. What do we know and not know about mirabegron, a
novel ß3 agonist, in the treatment of overactive bladder? Int Urogynecol J. 2014;25(2):165-170.
Krauwinkel W, Dickinson J, Schaddelee M, et al. The effect of mirabegron, a potent and
selective ß3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates
desipramine and metoprolol. Eur J Drug Metab Pharmacokinet. 2014;39(1):43-52.
Igawa Y, Aizawa N, Homma Y. Beta3-adrenoreceptor agonists: possible role in the
treatment of overactive bladder. Korean J Urol. 2010;51:811-818.
Nitti VW, Chapple CR, Walters C, et al. Safety and tolerability of the ß3-adrenoceptor
agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled
analysis of three 12-week randomised Phase III trials and of a 1-year randomised Phase III
trial. Int J Clin Pract. 2014;68(8):972-985.
Rosa GM, Ferrero S, Nitti VW, et al. Cardiovascular Safety of ß3-adrenoceptor Agonists
for the Treatment of Patients with Overactive Bladder Syndrome. Eur Urol. 2016;69(2):311-323.
United Kingdom National Health Service National Institute for Health and Care
Excellence NICE technology appraisal guidance. Mirabegron for treating symptoms of
OAB. https://www.nice.org.uk/guidance/TA290/chapter/4-Consideration-of-the-evidence. Accessed January 21, 2016.
Gras, J. (2012). Mirabegron for the treatment of overactive bladder. Drugs Today (Barc). 48(1):25-32.
Astellas news release: http://newsroom.astellas.us/2015-05-17-Mirabegron-As-Add-On-Treatment-To-Solifenacin-Therapy-Demonstrated-Superior-Results-To-Solifenacin-Monotherapy-In-BESIDE-Trial accessed January 27,2016.
Drake M, Izmir AA, Athanasiou S, et al. Efficacy and safety of mirabegron add-on
treatment to solifenacin in incontinent OAB subjects with an inadequate response to
initial 4-week solifenacin monotherapy. Abstract PII-LBA9: Presented at the American
Urological Association (AUA) 2015 Annual Meeting. May 17,
2015. http://www.medscape.com/viewarticle/845564. Accessed January 29, 2016
Vlachopoulos C, Oelke M, Maggi M, et al. Impact of cardiovascular risk factors and related
comorbid conditions and medical therapy reported at baseline on the treatment response
to tadalafil 5 mg once-daily in men with lower urinary tract symptoms associated with
benign prostatic hyperplasia: an integrated analysis of four randomised, double-blind,
placebo-controlled, clinical trials. Int J Clin Pract. 2015;69(12):1496-1507.
Andersson K, Wein AJ. Pharmacology of the Lower Urinary Tract: Basis for Current and
Future Treatments of Urinary Incontinence. Pharmacological Reviews. 2004; 56 (4) 581-631.53. 55. Athanasopoulos A, Gyftopoulos K, Giannitsas K, Perimenis P. Effect of
alfuzosin on female primary bladder neck obstruction. Int Urogynecol. J Pelvic Floor Dysfunct. 2009;20(2):217-222.
Athanasopoulos A, Gyftopoulos K, Giannitsas K, Perimenis P. Effect of alfuzosin on
female primary bladder neck obstruction. Int Urogynecol. J Pelvic Floor Dysfunct. 2009;20(2):217-222.
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