Which medication used to treat urinary incontinence strengthens the urinary sphincters and has anticholinergic action?

Standard Therapies

General measures to treat detrusor overactivity include the use of a voiding diary to understand the actual voiding habits and objectify the occurrence of frequency, urgency, and incontinent episodes. A diary should also include intake/output volumes to monitor for excess intake. A timed voiding regimen should be prescribed to gradually increase the time between voids.

Pelvic floor exercises (Kegel) to inhibit spontaneous bladder contractions are beneficial. This can be combined with biofeedback to provide visual and auditory clues to reinforce the teaching of pelvic floor exercises.

Cholinergic muscarinic receptor antagonists and musculotropic relaxant medications are mainstays in the therapy of overactive bladder. These agents work by blocking the action of acetylcholine, the neurotransmitter that triggers a detrusor contraction. Examples of such drugs include oxybutynin chloride, propantheline bromide, hyoscyamine sulfate, flavoxate hydrochloride, and tolterodine. All of these medications display typical anticholinergic side effects including dry mouth, constipation, and blurred vision.

Tricyclic antidepressants, such as amitriptyline and imipramine, block both central and peripheral cholinergic muscarinic receptors and inhibit the neuronal reuptake of monoamines, in particular norepinephrine and serotonin.

Surgical options to treat overactive bladder are reserved for those who fail to respond to pharmacotherapy. Augmentation cystoplasty is up to 90% effective for those with neurogenic bladders and hyperreflexia. Percutaneous and extradural sacral nerve stimulators have been successfully used to suppress urgency and frequency by modulating the neural input to the bladder.

Overactive bladder

OAB is a syndrome defined by the International Continence Society as “urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence in the absence of UTI or other obvious pathology” (Abrams et al., 2002). The diagnosis is made based upon the patient's self-reported symptoms of urinary urgency, frequency, nocturia, and/or urgency urinary incontinence. Whilst urgency is difficult to measure clinically, urinary frequency is defined as voiding more than eight times per day, nocturia in OAB as passing small amounts of urine several times overnight, and urgency urinary incontinence can be recorded using a diary (Gormley et al., 2015). There are several conditions that may result in these symptoms; however, in a subset of individuals with “idiopathic” OAB, the cause remains obscure despite extensive investigations.

Patients with OAB report considerable morbidity. They have significantly worse health-related quality of life, are less likely than individuals without OAB to be employed, and may report sexual dysfunction (Ergenoglu et al., 2013; Tang et al., 2014). Patients with urinary incontinence (wet OAB) are more severely affected than those without incontinence (dry OAB). Disease-specific and global quality-of-life scores are lower and patients are less productive, and have greater health resource allocation (Tang et al., 2014). OAB is a long-term problem for the majority of patients and is underreported and undertreated (Getsios et al., 2005; Ergenoglu et al., 2013).

OAB is associated with high levels of anxiety and depression (Matsuzaki et al., 2012; Matsumoto et al., 2013; Vrijens et al., 2015). A recent systematic review reported a positive association between depression and OAB in 26/35 studies, and between anxiety and OAB in 6/9 studies. There was strong evidence of OAB developing in patients who had depression, with an odds ratio 1.15–5.78, although it was not possible to assess causality (Vrijens et al., 2015). The occurrence of OAB symptoms is associated with worse quality-of-life scores, embarrassment, and social isolation (Wagg et al., 2007; Tang et al., 2014).

Anxiety in healthy individuals can cause increased urinary frequency and urgency. Charcot and contemporaries used the term “pollakiuria” to describe “frequent and repeated micturition which one experiences under the stress of an emotion” (Dejerine and Gauckler, 1913). Animal studies suggested that chronic stress in anxiety-prone animals resulted in bladder hyperalgesia, which may contribute to the pathogenesis of LUT symptoms in affective disorders (Lee et al., 2015).

There is limited literature exploring LUT symptoms in patients with pathologic anxiety disorders. In one longitudinal community study, anxiety appeared to have a causative role in the occurrence of urge incontinence (Perry et al., 2006). Females aged over 40 years old were asked through a community postal survey about anxiety and depression using the Hospital Anxiety and Depression scale, and urinary symptoms, and followed up for a year. It was observed that the presence of urge incontinence and urinary frequency predicted the development of anxiety and depression. Moreover, anxiety predicted urge incontinence, whereas depression did not. In contrast, stress incontinence did not predict either anxiety or depression (Perry et al., 2006).

Four randomized controlled trials demonstrated that successful treatment of OAB resulted in a significant improvement in patients’ affective symptoms (Vrijens et al., 2015). The relationship between depression, anxiety, and OAB is postulated to be due to altered serotonin and norepinephrine levels causing OAB. This is on the basis of animal models demonstrating that serotonin and norepinephrine have a modulatory effect on Onuf's nucleus, which prevents accidental voiding when abdominal pressure increases, that serotonin inhibits the parasympathetic voiding activity and stimulates sympathetic activity, and that frequency is reduced after administration of selective serotonin reuptake inhibitors (Redaelli et al., 2015).

An alternative mechanism is through the central effect of increased corticotropin-releasing factor, released due to dysregulation of the hypothalamic–pituitary–adrenal axis, causing both bladder and mood symptoms, as seen in rodent models (Wood et al., 2013).

Recently three studies investigated functional somatic syndrome comorbidities in OAB and found irritable-bowel syndrome (IBS) occurring in up to one-third of patients with OAB, with a background population rate of 20% (Matsumoto et al., 2013). Patients with fibromyalgia (FM) were significantly more likely to have OAB and more severe OAB symptoms correlated to more severe FM symptoms. There was a significant overlap between OAB and functional dyspepsia in population-based studies (Persson et al., 2015). A history of sexual abuse was found to be associated with urinary frequency, urgency, and nocturia in at least three studies (Davila et al., 2003; Fitzgerald et al., 2007; Link et al., 2007). Among these studies, one fulfilled the Bradford Hill criteria for causality (Link et al., 2007).

Overactive bladder

OAB is a symptom syndrome consisting of urinary urgency, usually accompanied by frequency and nocturia, with or without UUI, in the absence of a causative infection or pathologic conditions (Haab, 2014). The prevalence of OAB is approximately 11–19% in both men and women, and leads to a significant negative effect on a patient's health-related QoL. OAB is also associated with comorbidities such as UTI and an increased risk of falls (Haab, 2014). Neurogenic detrusor overactivity is a bladder dysfunction frequently observed in patients with conditions such as multiple sclerosis (MS) and spinal cord injury (SCI) (Nicholas et al., 2010; Haab, 2014). In these specific patients, increased storage pressure can put the upper urinary tract at risk of deterioration, and reducing this risk is a primary aim of therapy. Urinary incontinence is reported by approximately 50% of MS patients, and most SCI patients will develop some bladder dysfunction (Ruffion et al., 2013; Haab, 2014). Random-effect meta-analysis found the prevalence of urinary incontinence was 50.9% in patients with MS, 52.3% with SCI, 33.1% with Parkinson's disease, and 23.6% with stroke (Ruffion et al., 2013).

Several studies have suggested that women with wet OAB – defined as UUI associated with detrusor overactivity – complain of dissatisfaction, and poor QoL, and have high rates of sexual impairment (Quarto et al., 2007; Coyne et al., 2011; Hall et al., 2012; Tapia et al., 2013). Despite a significant heterogeneity in findings, the literature suggests that health-related QoL in patients with urinary incontinence due to neurogenic detrusor overactivity is worse than patients with urinary incontinence in general or those with the same underlying neurologic condition without urinary incontinence (Tapia et al., 2013).

In a urodynamic study of 118 sexually active women, individuals were separated into SUI, UUI, and MUI groups. Of these patients, MUI patients had the lowest (i.e., best) Pelvic organ prolapsed/urinary Incontinence Sexual Questionnaire (PISQ-12) scores, followed by patients with SUI. Patients with UUI and urodynamic evidence of detrusor overactivity had the highest (worst) PISQ-12 scores (Coksuer et al., 2011). Because women with dry OAB (i.e., without UUI) were not enrolled, the incremental sexual impairment of OAB alone versus OAB with UUI could not be determined from that specific study.

A relatively small cohort study from Korea using non-validated instruments for the assessment of sexual activity suggested that OAB and urinary incontinence (not otherwise specified) were both associated with worse SF; OAB emerged to be significantly more predictive of sexual problems than SUI (Kim et al., 2005). Similarly, in a population-based study from Taiwan in which women were invited to complete a translated version of the Bristol Female Urinary Tract Symptoms Questionnaire, findings suggested a progressively greater prevalence of interference in sexual life and a lowering of overall QoL in women with SUI, OAB, and MUI (Chen et al., 2003). In a study of women with urodynamically proven OAB or SUI, it was determined that women with OAB had generally poorer marital adjustment scores (as assessed by the Dyadic Adjustment Scale) and lower scores for overall sexual satisfaction (as assessed with the Derogatis Sexual Functioning Inventory) as compared to women with normal lower urinary tract function (Yip et al., 2003). There was no significant difference in sexual interest between women with OAB and healthy women. Interestingly, a trend towards similar relationships was noted in women with SUI, but the relationship was less robust; in this context, only scores regarding the global marital adjustment were significantly lower in women with urinary incontinence compared to those of women without urinary symptoms. Of note, the women in the OAB group were younger than those in the other two arms of the study (mean age 43 years versus 49 and 50 years, respectively); this may influence the importance and trouble ascribed to sexual symptoms in different groups (Yip et al., 2003).

The Epidemiology of Lower Urinary Tracts Symptoms (EpiLUTS) study, which includes a total of 14 400 men and women, showed that OAB negatively affects sexual enjoyment and activity in both sexes (Coyne et al., 2011). Moreover, the EpiLUTS study showed significant links between OAB and both lower desire and arousal scores in women, along with greater rates of erectile dysfunction and ejaculatory dysfunction in men. The authors reported that rates of decreased sexual enjoyment were 25% and 20% in incontinent and continent women suffering from OAB, respectively; in contrast, decreased sexual enjoyment was reported in only 2% of women with minimal or no urinary tract symptoms (Coyne et al., 2011).

Nilsson and coworkers (2011) investigated a relatively large cohort of sexually active women (n = 147), aged 18–74 years, with urinary incontinence and urgency using a dedicated semistructured instrument and the Bristol Female Lower Urinary Tract Symptoms questionnaire. Their findings showed that most women considered urinary incontinence and urgency per se as having a negative impact on their sexual life, which in turn was perceived as being very important in their lives. One-third of the women enrolled had urinary leakage during sexual activity. Half reported that sexual life was more or less spoiled due to their urinary incontinence or urgency and they were worried about having urinary leakage during intercourse, and almost two-thirds worried about odor and felt unattractive. Women's dissatisfaction with their sexual lives was strongly correlated to lack of satisfaction with psychologic health, orgasmic disability, and worry about urinary leakage during intercourse. As a whole, insufficient vaginal lubrication, lack of satisfaction with psychologic health, and ill health of partners were all significantly correlated with decreased sexual desire (Nilsson et al., 2011). Therefore, the authors outlined how a dialogue about SF in women with urinary symptoms should become an integral component in clinical management.

Introduction

The refractory overactive bladder represents one of the most challenging problems in urology as well as a clinical problem that significantly erodes patient quality of life. Symptoms include urinary frequency, urgency, urge incontinence, and nocturia. Urinary frequency is defined as voiding more than eight times in a 24 hour period. Many of the afflicted patients complain of the need to void more than once per hour, a practice which can be profoundly disruptive to daily activities. Nocturia is the interruption of sleep by the urge to void. Often, patients with overactive bladder will complain about sleepless nights punctuated by hourly trips to the bathroom. Urinary urgency is the extreme desire to void, which, if not heeded, may result in incontinence (urge incontinence) or pain. Urge incontinence is caused by an involuntary bladder contraction and has many etiologies, including neurologic disease, bladder outlet obstruction, and senile and idiopathic causes. Obviously, the embarrassment and social stigma of incontinence is the predominant symptom which these patients, many of them in their 40s to 60s, seek to correct.

Initial treatment for patients with overactive bladder without any remediable anatomic cause is anticholinergic therapy. For patients who are not candidates for, refractory to, or who cannot tolerate anticholinergic pharmacotherapy, options are limited. Augmentation cystoplasty, in which a piece of small or large intestine is used to enlarge the bladder, has traditionally been offered as a last resort. However, this is a major operation with significant potential short-term and long-term complications. As Leng and Chancellor point out, even without complications most patients are troubled by the need for lifelong intermittent bladder catheterization after such reconstructive procedures (Leng and Chancellor, 2005). Neuromodulation offers an alternative to patients who have failed more conservative treatments and may be considering irreversible surgical options.

Electrical stimulation has been used to treat a broad range of disorders of both bladder filling/storage and emptying/voiding, with varying degrees of success (Table 78.1). As illustrated in the table, the stimulation can be applied peripherally or centrally; acutely, subacutely, or chronically; and by nonimplantable or implantable electrodes – all depending on the purpose of the therapy. Since its graduation from experimental technique to proven clinical option in 1997, sacral neuromodulation has offered a minimally invasive solution with long-term efficacy and safety to this patient population as well as to patients with idiopathic, or non-obstructive, urinary retention. This chapter will focus on the application and clinical outcomes of neurostimulation and neuromodulation therapies for the treatment of voiding dysfunction.

Table 78.1. Potential applications of electrical stimulation in the treatment of voiding dysfunction

Adapted from A. Wein, Neuromuscular dysfunction of the lower urinary tract and its management, in P.C. Walsh et al. (2002) Campbell’s Urology, 8th edn (Philadelphia: Saunders), p. 981

PATIENTS WITH IRRITATIVE SYMPTOMS

As previously noted, overactive bladder (OAB) is common in men with both obstructed and unobstructed bladders. Although a complete diagnostic picture may be obtained by urodynamic tests on each patient, few units can afford the academic luxury of this purist approach; hence, trials of therapy are commonly practiced in elderly patients with the frequency urge syndrome (see Figure 86-9A).

Physiologic bladder contraction is mediated by a stimulation of postganglionic parasympathetic cholinergic receptors on detrusor smooth muscle, and of the forms of muscarinic receptor, the M3 subtype is thought to be the most important for bladder contraction.54 Hence, atropine and atropine-like agents will induce a lessening of the contraction wave with corresponding decrease in detected urgency by the patient.

Early descriptions of such pharmacologic agents55,56 and subsequent variations in release rate57 were precursors of a plethora of publications comparing efficacy, safety, and side-effect profiles.58–60 New-generation extended release (ER) preparations such as tolterodine ER and solifenacin have been studied, although only a minority of the patients were elderly men.61 Similar constraints applied to a systematic review of antimuscarinic therapy, and it is acknowledged that more studies are required to address urge problems in the elderly population.62

Despite these laudable efforts, many will be familiar with the statement about any treatment for overactive bladder: “one is always surprised when it works.”

Solifenacin

In an analysis of 1873 subjects with overactive bladder treated with placebo or solifenacin 5 or 10 mg/day, the main adverse effects were dose-related mild and moderate dry mouth (4.5%, 11%, and 29% respectively), constipation (3.6%, 6.4%, and 14%), and blurred vision (1.8%, 4.0%, and 4.6%); there were no differences in withdrawal rates between placebo and solifenacin (4.4%, 2.8%, 6.8%) [14].

In four 12-week, double-blind, phase III, international, multicenter, randomized, parallel-group studies of placebo or solifenacin 5 and 10 mg/day in 1045 elderly subjects with overactive bladder, the main adverse effects were dose-related dry mouth (4.5%, 14%, and 30% respectively), constipation (4.3%, 8.9%, and 17%), and urinary tract infections (3.1%, 3.6%, and 7.0%) [15]. Most of the adverse events were mild to moderate and did not result in treatment withdrawal.

Solifenacin (Vesicare)

Solifenacin is useful for treating contraction of overactive bladder with associated problems such as increased urination frequency and urge incontinence. Solifenacin is a competitive cholinergic receptor antagonist, selective for the M3 receptor subtype. The binding of acetylcholine to these receptors, particularly M3, plays a critical role in the contraction of smooth muscle. By preventing the binding of acetylcholine to these receptors, solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half-life, a once-a-day dose can offer 24-h control of the urinary bladder smooth muscle tone. The most common side effects of solifenacin are dry mouth, blurred vision and constipation. As with all anticholinergics, solifenacin may rarely cause hyperthermia due to decreased perspiration.

Future Modalities

SUMMARY

Anticholinergics are usually the gold standard used to treat overactive bladder (OAB). Side effects and lack of efficacy are the two main causes for considering alternative treatments. Until recently, invasive surgery (mainly bladder augmentation) was the only available treatment option for these intractable bladders. This chapter considers botulinum neurotoxin (BoNT) injection as an alternative treatment to surgery in patients with detrusor overactivity (DO) in whom anticholinergic therapy has failed.

There is convincing evidence that BoNT injection into the detrusor is a very effective method to treat urinary incontinence secondary to neurogenic detrusor overactivity (NDO) as well as to idiopathic detrusor overactivity (IDO). In both conditions, the duration of effect is at least 6 months. The overall success rate seems to be similar in both patient populations. For NDO, two evidence-based medicine level 1 studies are available; for IDO only evidence-based medicine level 3 or 4 studies have been published. Injection technique and outcome parameters vary from study to study, and standardization is required. Outcome following repeated injections has been the object of several publications: the efficacy remains as good as after the first injection, and there is no evidence of change in bladder compliance or detrusor fibrosis. However, long-term observation studies remain necessary to assess these last points. To date, there is no proposed clear ratio for Botox or Dysport for treatment of NDO or IDO. However, clinical experience using 200-300 units Botox or 500-750 units Dysport are comparable. The current BoNT/A (Botox versus Dysport) reported dose appears to be safe, and few side effects have been reported by using these toxins.

Managing the overactive bladder