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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).

Although QoL scales vary, it has been well-documented that the impact of OAB on QoL is a serious issue that has not been adequately addressed. A study looking at 287 studies of the impact of OAB on QoL found that emotional disturbance and social isolation are the domains most affected and social embarrassment, avoidance, and limiting behavior are most common.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

The AUA/SUFU guideline publication states that methodical differences across studies challenge any interpretation of the OAB literature related to epidemiology and treatment and that most OAB studies exclude patients with neurological OAB.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 summarizes the recommendations of the AUA guidelines on non-neurogenic OAB treatment. The overall strength of evidence supporting these treatments is not impressive,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.

Table 1. AUA/SUFU Guideline Amendment Diagnosis and Treatment of Overactive Bladder (Non-Neurogenic) in Adults1
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 helps to explain the mechanism of action involved with the pharmacological agents used to treat OAB. Beta-3 adrenergic agonists increase urine storage, while muscarinic antagonists diminish detrusor overactivity; alpha blockers help relax the urethral epithelium and the external sphincter muscle of the urethra, and medications that stimulate norepinephrine release can help tighten the urethra through activation of urethral epithelium and external urethral sphincter muscles (useful in obstructive and stress incontinence.)

Table 2. Additional Pathways That Can Affect Lower Urinary Tract (LUT) Function25,30
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.

Figure 2. Pharmacist's Role in MTM Services 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: delirium, infection, atrophic vaginitis and urethritis, pharmacological agents, psychiatric conditions, excessive urinary output, restricted mobility, and stool 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 are not altered by the pharmacological agents recommended for the treatment of OAB; therefore, when overlooked, these conditions can lead to treatment failure despite the type of pharmacological treatment.

Table 3: Assessment of conditions impacting OAB32
Transient OAB/UI Chronic Conditions Other
UTI Vaginitis Fecal impaction Hypercalcemia Delirium - CHF
- Venous insufficiency -Sleep disorders -Diabetes mellitus
- Abnormal arginine
- vasopressin function
- Impaired mobility (Parkinson's disease, osteoporosis, muscle weakness)
- Psychological (i.e., depression)		 - Caffeine
- Alcohol
- Polydipsia
- Bowel habits
- Constipation
- Childbirth (weakened pelvic floor muscles)
- History of urethral sling placement (can leave scaring and obstruction).

Table 3. Medications Implicated in OAB33
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).

Table 4. Muscarinic Receptor Distribution Throughout the Human Body27-29

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

Table 5: Relative Lipophilicity and M Receptor Selectivity of Antimuscarinic Treatments for Overactive Bladder39,41,42
*All muscarinic antagonists have some cross receptor activity, even if designed not to.

Table 5. Renal Adjustments: Antimuscarinic Agents Have Renal Dose Adjustment Cautions39

Adverse Events: Predictability With Antimuscarinic Agents

The adverse drug events (ADEs) profiles for individual patients can be unpredictable during treatment with antimuscarinic agents. Oxybutynin stands out as an antimuscarinic medication with a higher risk for adverse events during treatment for OAB. That said, the transdermal patch, the gel, and the ER form are not as high risk for ADEs as the IR oral formulation. The reported average antimuscarinic OAB class incidence of side effects include the following: dry mouth occurs about 20%, except with oxybutynin when it may be as high as 60%; constipation occurs about 10%; blurred vision occurs more than 1%, except trospium which is more than 0.5%; drowsiness occurs more than 3%, except oxybutynin which is 12%; urinary retention occurs 1.2% to 1.4%, except oxybutynin which is approximately 5%.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 for highlights of other oral medication classes utilized to treat OAB and LUTS.

Table 6. Other Medications Used in the Treatment of OAB Syndrome38,42,53

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.

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