**5.2.1.3 Solifenacin**

Solifenacin is an antimuscarinic agent has potent selectivity for the M3 over the M2 receptor. (Chapple et al., 2006) In addition it has a higher affinity for the M3 receptor in smooth muscle than it does for the M3 receptor in the salivary gland. (Chapple et al., 2006). This M3 selectivity provides for an improved side effect profile. Solifenacin is administered at 5-10 mg daily for the treatment of OAB.

It has been proven efficacious in multiple trials in patients with OAB. (Cardozo et al., 2004; Cardozo et al., 2008; Chapple, 2005) Another recent study confirmed that solifenacin was significantly more effective in reducing the mean number of severe urgency episodes with or without incontinence per 24 hours, improved urgency symptoms and was well tolerated. Additionally, no cognitive impairment has been associated with this drug. (Kay et al., 2006)

#### **5.2.1.4 Trospium chloride**

Trospium chloride is a quaternary ammonium compound that is nonselective for the muscarinic receptor. It also has smooth muscle relaxant qualities. (Staskin et al., 2007) Trospium chloride is available in an IR formulation given 20 mg twice daily or an ER formula administered 60 mg daily. The uniqueness of this antimuscarinic is that it is renally cleared. Care should be used in the elderly and patients with renal impairment. The initial dosing in these patients she be the IR formulation 20 mg once daily. The ER formulation should not be used in patients with severe renal impairment. Because of poor bioavailability, trospium chloride must be taken on an empty stomach.

When compared to placebo, trospium chloride showed a greater decrease in the number of daily episodes of incontinence than patients who received placebo (from a mean of 2.9 to 1.0 with trospium and 1.6 with placebo). (Zinner et al., 2004) Side effects in the trospium chloride group included dry mouth (20 percent) and constipation (11 percent).

In a randomized trial utilizing the ER formulation (60 mg once daily) for patients with severe urge incontinence, patients' incontinence episodes decreased significantly compared to placebo. Adverse events were lower than reported for immediate-release trospium chloride (dry mouth 13 percent, constipation 8 percent). (Dmochowski et al., 2008)

#### **5.2.1.5 Fesoterodine**

Fesoterodine is given at a starting dose of 4 mg once daily, which can be increased to 8 mg. As with most of the anticholinergic drugs, the most common side effects are dry mouth and constipation.

Fesoterodine is metabolized to 5-hydroxymethyl tolterodine, (the active metabolite of tolterodine).

#### **5.2.1.6 Darifenacin**

174 Urinary Incontinence

controlled trial. (Chapple et al., 2005) The authors found that the flexible dose of solifenacin showed marked advantages over the single dose of tolterodine extended release. In a reanalysis comparing only the patients in the trial taking solifenacin 5 mg once daily with the patients in the tolterodine arm the authors found a more modest benefit. (Chapple et al., 2007) Solifenacin 5 mg once daily was superior for incontinence episodes and pad usage, but showed no difference in urge incontinence or dryness rates. Notably in both analyses, the main advantage for solifenacin was minimizing rates of dry mouth and constipation. However, there were slightly more withdrawals due to adverse events in the solifenacin

Solifenacin is an antimuscarinic agent has potent selectivity for the M3 over the M2 receptor. (Chapple et al., 2006) In addition it has a higher affinity for the M3 receptor in smooth muscle than it does for the M3 receptor in the salivary gland. (Chapple et al., 2006). This M3 selectivity provides for an improved side effect profile. Solifenacin is administered at 5-10

It has been proven efficacious in multiple trials in patients with OAB. (Cardozo et al., 2004; Cardozo et al., 2008; Chapple, 2005) Another recent study confirmed that solifenacin was significantly more effective in reducing the mean number of severe urgency episodes with or without incontinence per 24 hours, improved urgency symptoms and was well tolerated. Additionally, no cognitive impairment has been associated with this drug. (Kay et al., 2006)

Trospium chloride is a quaternary ammonium compound that is nonselective for the muscarinic receptor. It also has smooth muscle relaxant qualities. (Staskin et al., 2007) Trospium chloride is available in an IR formulation given 20 mg twice daily or an ER formula administered 60 mg daily. The uniqueness of this antimuscarinic is that it is renally cleared. Care should be used in the elderly and patients with renal impairment. The initial dosing in these patients she be the IR formulation 20 mg once daily. The ER formulation should not be used in patients with severe renal impairment. Because of poor

When compared to placebo, trospium chloride showed a greater decrease in the number of daily episodes of incontinence than patients who received placebo (from a mean of 2.9 to 1.0 with trospium and 1.6 with placebo). (Zinner et al., 2004) Side effects in the trospium

In a randomized trial utilizing the ER formulation (60 mg once daily) for patients with severe urge incontinence, patients' incontinence episodes decreased significantly compared to placebo. Adverse events were lower than reported for immediate-release trospium

Fesoterodine is given at a starting dose of 4 mg once daily, which can be increased to 8 mg. As with most of the anticholinergic drugs, the most common side effects are dry mouth and

bioavailability, trospium chloride must be taken on an empty stomach.

chloride group included dry mouth (20 percent) and constipation (11 percent).

chloride (dry mouth 13 percent, constipation 8 percent). (Dmochowski et al., 2008)

group.

**5.2.1.3 Solifenacin** 

mg daily for the treatment of OAB.

**5.2.1.4 Trospium chloride** 

**5.2.1.5 Fesoterodine** 

constipation.

Similar to solifenacin, the newer antimuscarinic drug darifenacin is more selective for M-3 muscarinic receptors in the bladder. Drifenacin is administered 7.5 mg daily and can be increased to 15 mg daily. In a randomized trial of darifenacin versus placebo, median incontinence episodes were show to significantly decrease with darifenacin. (Zinner et al., 2006) However, dry mouth and constipation rates were similar when compared to other anticholinergics (29% dry mouth and 18% constipation).

As noted above, the most common side effects associated with darifenacin are mild to moderate dry mouth and constipation. This drug has been studied in patients who were dissatisfied with prior OAB treatment with oxybutynin ER or tolterodine ER. The authors found significant improvements in OAB symptoms with darifenacin. (Zinner et al., 2008) Additionally, long-term studies have shown persistence of continuation with darifenacin therapy and well-maintained treatment benefits (over 2 years in duration). (Haab et al., 2006 & Hill et al., 2007)

Because of its' selectivity for the M3 receptor darifenacin minimizes the risk of side effects due to blockade of other muscarinic subtypes, such as M1 mediated cognitive impairment. (Foote et al., 2005) This is important in relation to the treatment of elderly populations who may be more susceptible to cognitive impairment and CNS effects.


Table 1. Commonly prescribed anticholinergic drugs for treatment of OAB

Diagnosis and Treatment of Overactive Bladder 177

Questionnaire. They did not discover clear differences between the two doses. Intravesical botulinum toxin has a variable duration of action, with loss of efficacy typically seen within one year. (Reitz et al., 2007) Based upon this limited data, it appears that there may be a role for the use of intravesical botulinum for patients with OAB, especially when other therapies fail. Finally, one of the bothersome adverse effects is urinary retention which can last up to three months after one injection. This, the clinician must have considerable knowledge and

In a recent literature review (Anger et al, 2010) the authors systematically reviewed the efficacy and safety of botulinum toxin in the management of overactive bladder. Based upon this review of three small randomized placebo controlled trials they found that patients treated with botulinum toxin-A had 3.88 fewer incontinence episodes per day (95% CI -6.15, -1.62). Patients also noted significant improvements in quality of life compared with placebo. In addition they found a 9-fold increased odds of increased post-void residual after botulinum toxin-A compared with placebo (8.55; 95% CI 3.22, 22.71). They concluded that "intravesical injection of botulinum toxin resulted in improvement in medication refractory

Since most patients do not achieve complete continence with behavioral therapy or anticholinergic therapies alone, many clinicians combine these two in the treatment of OAB. A combination of anticholinergic agents and behavioral interventions have been shown to be safe and effective in many studies. (Fantl et al., 1996; Gormley, 2002; Milne & Moore, 2006) Side affect profiles of most of the drugs used for OAB make long term adherence to

In a large study, Mattiasson et al (Mattiasson et al., 2003) showed additional benefit from bladder retraining when compared with tolterodine alone. Additionally, 76% of the patients on tolterodine and behavioral therapy noted improvement in their bladder symptoms compared to baseline as compared with 71% in the tolterodine group (Mattiasson et al.,

Combination therapy has been shown to be associated with significantly fewer incontinent episodes, an improved quality of life, and greater treatment satisfaction when compared to non-pharmacologic intervention alone or drug treatment alone. (Wyman et al., 1998) However, the authors found that the effects of each of the interventions were similar 3 months after treatment. They concluded that the nature of the treatment may not be as important as having a structured intervention program that includes education, counseling,

Finally, Chancellor et al ( Chancellor et al., 2008), in a more recent trial, compared the benefits of anticholinergic therapy alone against a combination of anticholinergic and behavioral therapy in 395 patients in a randomized controlled trial of flexible dose darifenacin (7.5 mg/day increased to 15 mg/day if required), with or without additional advice about dietary modification, timed voiding/bladder retraining, and pelvic floor training. No significant differences were observed between groups in OAB symptoms.

and frequent monitoring of the treatment. (Wyman et al., 1998)

skill in the judicious use of botulinum toxin.

overactive bladder symptoms".

**5.2.4 Combination therapies** 

therapy difficult.

2003)

#### **5.2.2 Antidepressants**

#### **5.2.2.1 Duloxetine**

Duloxetine is a serotonin noradrenaline re-uptake inhibitor that is approved by the Food and Drug Administration (FDA) for depression, but not for urinary incontinence. The mechanism of action is to significantly increase sphincteric muscle activity during the filling/storage phase of micturition. Although not approved for use in patients with OAB symptoms alone, it may have some efficacy. Steers et al (Steers et al., 2007) randomized 306 women to placebo or duloxetine over 12 weeks. Duloxetine showed significant benefit in 24 hour urinary frequency and incontinence episodes. It also improved condition-specific quality of life measures. However, no significant increase was observed in mean voided volume, suggesting that the benefits were mediated through an effect at the urethral rhabdosphincter, rather than any direct effect on detrusor contractility. Thus, duloxetine may be considered as an option for patients who cannot tolerate antimuscarinic drugs. However, duloxetine's primary efficacy is in the treatment of stress urinary incontinence.

#### **5.2.2.2 Imipramine**

Imipramine, an antidepressant, is the only drug in this category that has been widely used to treat the symptoms of OAB. It has multiple pharmacological effects, including systemic antimuscarinic actions and blockade of the reuptake of serotonin and noradrenaline, but its mode of action in the treatment of OAB is not clear. (Hunsballe & Djurhuus, 2001) Imipramine has shown a favorable therapeutic effect in the treatment of nocturnal enuresis in children with a success rate of 10–70% in controlled trials. (Glazener et al., 2003; Hunsballe & Djurhuus, 2001) However, there are no good quality randomized trials that prove the efficacy of imipramine in the treatment of OAB.

#### **5.2.3 Intravesical botulinum toxin**

Botulinum toxin is a neurotoxin that inhibits the release of acetylcholine from presynaptic cholinergic nerve endings. This inhibition results in a localized reversible chemical denervation, with decreased detrusor contractility. Although it is currently not FDAapproved for the treatment of OAB, it shows promise as an addition to the treatment arsenal. The most likely place for its use is for patients who fail oral therapies. Current data primarily address only patients with refractory detrusor overactivity. In the most recent Cochrane review, randomized trials of intravesical botulinum versus placebo reported results favoring botulinum toxin. (Duthie et al., 2007) The authors noted that there was significant improvement in incontinence episodes, bladder capacity, maximum detrusor pressure and quality of life. They concluded "Botulinum toxin injections into the bladder appeared to give few side effects or complications, but there were no long-term follow-up studies, and there could be rare side effects that have not been discovered yet." (Duthie et al., 2007)

As stated above, many questions remain regarding its use, including the optimal dose and site of injection, the appropriate population, and long-term safety. To address this issue, Schurch et al (Schurch et al., 2007) randomized 59 patients with neurogenic detrusor overactivity to intravesical botulinum A (200 or 300 U) or placebo. These investigators noted significant improvements when compared to placebo using the Incontinence Quality of Life

Duloxetine is a serotonin noradrenaline re-uptake inhibitor that is approved by the Food and Drug Administration (FDA) for depression, but not for urinary incontinence. The mechanism of action is to significantly increase sphincteric muscle activity during the filling/storage phase of micturition. Although not approved for use in patients with OAB symptoms alone, it may have some efficacy. Steers et al (Steers et al., 2007) randomized 306 women to placebo or duloxetine over 12 weeks. Duloxetine showed significant benefit in 24 hour urinary frequency and incontinence episodes. It also improved condition-specific quality of life measures. However, no significant increase was observed in mean voided volume, suggesting that the benefits were mediated through an effect at the urethral rhabdosphincter, rather than any direct effect on detrusor contractility. Thus, duloxetine may be considered as an option for patients who cannot tolerate antimuscarinic drugs. However, duloxetine's primary efficacy is in the treatment of stress urinary incontinence.

Imipramine, an antidepressant, is the only drug in this category that has been widely used to treat the symptoms of OAB. It has multiple pharmacological effects, including systemic antimuscarinic actions and blockade of the reuptake of serotonin and noradrenaline, but its mode of action in the treatment of OAB is not clear. (Hunsballe & Djurhuus, 2001) Imipramine has shown a favorable therapeutic effect in the treatment of nocturnal enuresis in children with a success rate of 10–70% in controlled trials. (Glazener et al., 2003; Hunsballe & Djurhuus, 2001) However, there are no good quality randomized trials that

Botulinum toxin is a neurotoxin that inhibits the release of acetylcholine from presynaptic cholinergic nerve endings. This inhibition results in a localized reversible chemical denervation, with decreased detrusor contractility. Although it is currently not FDAapproved for the treatment of OAB, it shows promise as an addition to the treatment arsenal. The most likely place for its use is for patients who fail oral therapies. Current data primarily address only patients with refractory detrusor overactivity. In the most recent Cochrane review, randomized trials of intravesical botulinum versus placebo reported results favoring botulinum toxin. (Duthie et al., 2007) The authors noted that there was significant improvement in incontinence episodes, bladder capacity, maximum detrusor pressure and quality of life. They concluded "Botulinum toxin injections into the bladder appeared to give few side effects or complications, but there were no long-term follow-up studies, and there could be rare side effects that have not been discovered yet." (Duthie et

As stated above, many questions remain regarding its use, including the optimal dose and site of injection, the appropriate population, and long-term safety. To address this issue, Schurch et al (Schurch et al., 2007) randomized 59 patients with neurogenic detrusor overactivity to intravesical botulinum A (200 or 300 U) or placebo. These investigators noted significant improvements when compared to placebo using the Incontinence Quality of Life

prove the efficacy of imipramine in the treatment of OAB.

**5.2.3 Intravesical botulinum toxin** 

**5.2.2 Antidepressants** 

**5.2.2.1 Duloxetine** 

**5.2.2.2 Imipramine** 

al., 2007)

Questionnaire. They did not discover clear differences between the two doses. Intravesical botulinum toxin has a variable duration of action, with loss of efficacy typically seen within one year. (Reitz et al., 2007) Based upon this limited data, it appears that there may be a role for the use of intravesical botulinum for patients with OAB, especially when other therapies fail. Finally, one of the bothersome adverse effects is urinary retention which can last up to three months after one injection. This, the clinician must have considerable knowledge and skill in the judicious use of botulinum toxin.

In a recent literature review (Anger et al, 2010) the authors systematically reviewed the efficacy and safety of botulinum toxin in the management of overactive bladder. Based upon this review of three small randomized placebo controlled trials they found that patients treated with botulinum toxin-A had 3.88 fewer incontinence episodes per day (95% CI -6.15, -1.62). Patients also noted significant improvements in quality of life compared with placebo. In addition they found a 9-fold increased odds of increased post-void residual after botulinum toxin-A compared with placebo (8.55; 95% CI 3.22, 22.71). They concluded that "intravesical injection of botulinum toxin resulted in improvement in medication refractory overactive bladder symptoms".

#### **5.2.4 Combination therapies**

Since most patients do not achieve complete continence with behavioral therapy or anticholinergic therapies alone, many clinicians combine these two in the treatment of OAB. A combination of anticholinergic agents and behavioral interventions have been shown to be safe and effective in many studies. (Fantl et al., 1996; Gormley, 2002; Milne & Moore, 2006) Side affect profiles of most of the drugs used for OAB make long term adherence to therapy difficult.

In a large study, Mattiasson et al (Mattiasson et al., 2003) showed additional benefit from bladder retraining when compared with tolterodine alone. Additionally, 76% of the patients on tolterodine and behavioral therapy noted improvement in their bladder symptoms compared to baseline as compared with 71% in the tolterodine group (Mattiasson et al., 2003)

Combination therapy has been shown to be associated with significantly fewer incontinent episodes, an improved quality of life, and greater treatment satisfaction when compared to non-pharmacologic intervention alone or drug treatment alone. (Wyman et al., 1998) However, the authors found that the effects of each of the interventions were similar 3 months after treatment. They concluded that the nature of the treatment may not be as important as having a structured intervention program that includes education, counseling, and frequent monitoring of the treatment. (Wyman et al., 1998)

Finally, Chancellor et al ( Chancellor et al., 2008), in a more recent trial, compared the benefits of anticholinergic therapy alone against a combination of anticholinergic and behavioral therapy in 395 patients in a randomized controlled trial of flexible dose darifenacin (7.5 mg/day increased to 15 mg/day if required), with or without additional advice about dietary modification, timed voiding/bladder retraining, and pelvic floor training. No significant differences were observed between groups in OAB symptoms.

Diagnosis and Treatment of Overactive Bladder 179

operating room allowing for placement of the lead with a test period of 1 to 2 weeks; full implantation can be performed under local or general anesthesia. Response is objectively

The test phase of the procedure consists of implantation of tined quadripolar leads, under intravenous (IV) sedation, local anaesthesia, or general anaesthesia. Under fluoroscopy with a C-arm the right or left S3 foramen is identified and the permanent tined lead is passed through the foramen needle. The lead is then tested for a response. Correct placement in the S3 foramina includes bellows contraction of the pelvic floor and plantar flexion of the great toe. Once the appropriate side and position is selected, the lead is connected to an external pulse generator and taped to the skin surface. A 7- to 14-day home test period is used to determine which patients meet criteria to have the IPG implanted. Patients who respond favorably and demonstrate a 50% symptom improvement from baseline have the permanent

The most common adverse events include lead migration, implant site pain, bowel dysfunction, and infection. Infection usually resolves with antibiotics and the lead adverse events can usually be corrected by reprogramming, reinforcing the lead, or inserting a new

There is now convincing evidence for the success of SNM for refractory OAB. Several studies including RCTs and long-term observational studies reported fair clinical response

In addition, percutaneous stimulation of the tibial nerve (PTNS) has shown promise in the treatment of patients with refractory urge incontinence. PTNS is a minimally invasive, office-based procedure that involves percutaneous placement of a 34-gauge (ga) needle over the medial malleolus of the ankle to provide stimulation of the posterior tibial nerve. The procedure is repeated in 30-minute treatment sessions over a period of 12 weeks. PTNS in patients with OAB has been shown to significantly reduce in symptoms and improvement in health-related quality of life. (Yoong et al, 2010) However, one multicenter randomized trial of 100 patients with OAB symptoms did not show a reduced rate of urinary frequency

when PTNS was compared to tolterodine extended release, 4mg daily. (Peters, 2009)

In general most patients with OAB symptoms can be treated with medical and behavioral therapies. Generally, augmentation cystoplasty is only considered when patients have small

Augmentation cystoplasty (AC) is a surgery where a portion of the bowel is removed and patched to the bisected bladder. This procedure increases bladder capacity and decreases bladder pressure caused by unstable detrusor contractions. Considered a procedure of last resort, the risks of the surgery include recurrent UTI's, renal or bladder infections, metabolic changes and mucus production. (Khastgir et al., 2003) reviewed outcomes associated with

evaluated by pre- and postvoiding diaries assessing various urinary parameters.

generator implanted. (Al-Shaiji et al, 2011)

between 64 and 88% of all patients (Leong et al, 2010).

**5.3.3 Percutaneous stimulation of the tibial nerve** 

volume bladders and are debilitated by their symptoms.

**5.4.1 Augmentation cystoplasty** 

lead contralaterally.

**5.4 Surgery** 
