|Year : 2010 | Volume
| Issue : 2 | Page : 270-278
Medical management of overactive bladder
Sarvpreet S Ubee1, Ramaswamy Manikandan2, Gurpreet Singh3
1 Department of Urology, Royal Liverpool University Hospital, Liverpool, United Kingdom
2 Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, United Kingdom
3 Southport District and General Hospital, Southport, United Kingdom
|Date of Web Publication||12-Jul-2010|
Sarvpreet S Ubee
Apartment 198, Spectrum, Blackfriars road, Salford
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Overactive bladder (OAB), as defined by the International Continence Society, is characterized by a symptom complex including urinary urgency with or without urge incontinence, usually associated with frequency and nocturia. OAB syndrome has an incidence reported from six European countries ranging between 12-17%, while in the United States; a study conducted by the National Overactive Bladder Evaluation program found the incidence at 17%. In Asia, the prevalence of OAB is reported at 53.1%. In about 75%, OAB symptoms are due to idiopathic detrusor activity; neurological disease, bladder outflow obstruction (BOO) intrinsic bladder pathology and other chronic pelvic floor disorders are implicated in the others. OAB can be diagnosed easily and managed effectively with both non-pharmacological and pharmacological therapies. The first-line treatments are lifestyle interventions, bladder training, pelvic floor muscle exercises and anticholinergic drugs. Antimuscarinics are the drug class of choice for OAB symptoms; with proven efficacy, and adverse event profiles that differ somewhat.
Keywords: Antimuscarinics, bladder training, overactive bladder
|How to cite this article:|
Ubee SS, Manikandan R, Singh G. Medical management of overactive bladder. Indian J Urol 2010;26:270-8
| Introduction|| |
Overactive bladder (OAB), as defined by the International Continence Society (ICS), is characterized by a symptom complex including urinary urgency with or without urge incontinence, usually associated with frequency and nocturia.  This is distinct from the urodynamic diagnosis of detrusor overactivity (DO); ICS defines this as an involuntary rise in detrusor pressure during filling of the bladder in a laboratory situation in a conscious co-operative patient. 
OAB syndrome has an incidence reported from six European countries ranging between 12-17%, while in the United States; a study conducted by the National Overactive Bladder Evaluation (NOBLE) program found the incidence at 17%. ,, In Asia, the prevalence of OAB is reported at 53.1%.  The prevalence of OAB increases with age.  Storage Lower Urinary Tract Symptoms (LUTS) comprise OAB and are extremely bothersome, especially with urge incontinence (UI) coexistent in 30% of patients. The etiology is unknown, and it is suggested that OAB symptoms could be either neurogenic or myogenic. The neurogenic theory suggests that damage to central inhibitory pathways or sensitization of afferent pathways in the bladder unmasks primitive voiding reflexes and trigger detrusor overactivity.  Myogenic theory proposes a partial denervation of the detrusor with an increased excitability and involuntary pressure rise.  A third, the autonomous bladder hypothesis has recently been proposed; this suggests that overactivity may be due to inappropriate activation or modulation of phasic activity. 
In about 75%, OAB symptoms are due to idiopathic detrusor activity (IDO); neurological disease, bladder outflow obstruction (BOO) intrinsic bladder pathology and other chronic pelvic floor disorders are implicated in the others.
| Assessment and Outcome Strategy|| |
OAB symptoms are subjective; with an unpredictable relationship to their bothersome index. Based on the history alone, clinicians tend to underestimate the impact of symptoms and patient completed assessment methods are essential.  Both subjective and objective assessment methods measure different aspects of a patient's clinical profile and should be interpreted as assessing a different outcome.  The overall patient experience can be better understood by identifying objective treatment endpoints; including changes in the quality of life, symptom bother, and patient satisfaction.
A wide range of tools have been developed for use in the clinical settings. Validated disease-specific quality of life questionnaires like the International Consultation on Incontinence (ICIQ) assess the level of bother; frequency-volume charts assess voiding and drinking patterns. A common method of objective assessment is the bladder diary, which records the voiding times, volumes, incontinence episodes, pad usage, fluid intake, degree of urgency and degree of incontinence. Synchronous pressure flow studies are mandatory for objective assessment. Reflex volumes, amplitude of involuntary detrusor contractions, bladder compliance and maximum cystometric capacity along with voiding detrusor pressures and maximum urinary flow rate are important urodynamic parameters.
| Initial Management - Guidelines|| |
ICS has guidelines subdividing management into initial (first line) and specialized (second line) therapy. Non-surgical treatment is the mainstay and should include lifestyle, including dietary modifications, bladder retraining and pelvic floor training with or without biofeedback; these are combined with pharmacotherapy with antimuscarinics as appropriate.
| Lifestyle Interventions Dietary and Fluid Modification|| |
Epidemiological evidence suggests that reducing bladder irritants such as acidic foods, alcohol, and caffeine may improve urinary incontinence.  A study of 4000 men examining the role of food and alcohol in the development of OAB symptoms found that alcohol had a protective effect; and of the foods, only potatoes appeared to have a detrimental effect on symptoms.  Another study of 6,424 women found that smoking, obesity and consumption of carbonated beverages were associated with OAB; alcohol did not make a difference. 
Research on the effect of caffeine has been conflicting; one of the studies showed a decrease in frequency with caffeine withdrawal and another did not show any statistically significant association between caffeine intake and urinary incontinence. ,
Many patients with OAB attempt to restrict their fluid intake, in a belief that it will reduce their incontinence episodes. However, dehydration and concentrated urine can act as a bladder irritant; studies have demonstrated a strong association between fluid intake and voided volume. , The association of fluid intake with incontinence episodes was weak, but decreasing evening fluid intake reduced nocturnal incontinence.
| Bladder Training|| |
The goal of bladder training is to break the cycle of urgency and frequency using consistent, incremental voiding schedules. To accomplish this, the brain must be trained to ignore the signals from the detrusor muscle. It is hypothesized that urinary urgency develops first and this leads to urinary frequency. As this cycle progresses, the patient develops a decreased bladder capacity, which will then lead to detrusor overactivity. ,
The patient fills in a bladder diary; recording the times of micturition, voided volumes, urgency and incontinence episodes, pad usage, and fluid intake. The duration of the diary can range from one to seven days, with a four-day diary as reliable as a seven-day diary.  A minimum of three days need recording, to give the frequency volume chart validity.  Using this data, the voiding and fluid intake habits are modified to increase the bladder capacity. Fantl et al. in a randomized clinical trial showed a 57% reduction in incontinence episodes in older women; there was, however, no objective improvement on urodynamic parameters post bladder training.  Quoted results vary from 26 to 90% and bladder training remains a valuable tool for treating urge incontinence as it weakens the urge-void response. ,
Pelvic floor muscle exercises and biofeedback
Pelvic floor muscle exercises (PFME), originally described by Kegel in 1948 for stress incontinence, may also reduce urge incontinence episodes.  In a study by Burgio et al. 197 women with urge incontinence were randomized in to three groups. Patients on PFME with biofeedback had an 80.7% reduction in incontinent episodes compared to a 68.5% and a 39.4% reduction in patients on medical therapy and placebo.  Three studies randomized patients with mixed incontinence to PFME, PFME with bladder training and control groups. The two groups utilizing PFME had improvement ranging from 54 to 74% in comparison to the control group. ,, Though most of the trials are on patients with mixed and stress incontinence, a Cochrane Meta-analysis concluded that PFME is valid first line therapy for urinary incontinence. 
Biofeedback ensures that with PFME, the right muscle groups are being exercised; and can vary from verbal feedback to vaginal or anal electromyography. A randomized study showed a 69.4, 63.1; and 58.5% reduction in incontinence with verbal feedback, anal myometry feedback and in controls, with the difference between the three groups not reaching statistical significance. 
Antimuscranics are established first line treatment options for OAB symptoms. In randomized controlled trials they are more effective than placebo as shown in a recent meta-analysis.  The level of recommendation is grade A in women and grade B in men with OAB.  Despite good efficacy antimuscarinics have significant side effects and compliance with treatment is at best average.
Acetylcholine activates muscarinic receptors on detrusor myocytes and is the main contractile transmitter in the bladder. Five subtypes, of Muscarinic receptors (M1-M5), encoded by 5 distinct genes are identified. In the human detrusor smooth muscle M2 and M3 subtypes predominate, with M3 as the most important for detrusor contraction.  Studies have shown that the M3 receptors work by mediating carbacol-induced contractions and it's suggested that transmembrane flux of Ca++ through nifedepine - sensitive calcium channels as well as activation of the Rho-kinase pathway and inhibition of potassium channel, may be implicated. It was demonstrated that the L-type calcium channel blocker nifedipine almost completely inhibited carbachol-induced detrusor contraction. ,
A functional role for the M2 receptor has not been definitely identified and the hypothesis is that; it opposes sympathetically mediated smooth muscle relaxation. 
It is suggested to reduce spontaneous activity in the resting detrusor muscle, thus decreasing the frequency and intensity of the detrusor contractions. , Yokoyama et al., in a study on rats showed that tolteradine exerted an inhibitory effect on the C-fiber afferent bladder nerves, thereby improving the bladder capacity.  In vitro and clinical studies have shown that the effects are due to its action on the storage phase. ,
Propantheline, methantheline, emepronium, diclomine, terodiline and oxybutynin are antimuscarinics historically used to treat OAB; of these oxybutynin remains in current use, the others discontinued due to lack of efficacy and/or poor tolerability.  Newer agents like propiverine, tolterodine, trospium, solifenacin and darifenacin along with oxybutynin have proven efficacy in patients with OAB.  These antimuscarinics are available in various formulations like immediate release, extended release and transdermal preparations. The extended-release form allows steady plasma concentrations for up to 24 hours and minimizes the peak and trough concentrations seen with conventional multiple-daily dosage form.  Transdermal delivery of oxybutynin decreases the associated side effects as it avoids the hepatic and gastrointestinal metabolism, producing less N-desethyloxybutynin, a metabolite, deemed responsible for side-effects such as dry mouth. 
These antimuscarinics have variable affinity to the muscarinic receptors sub-types. Oxybutynin and solifenacin are moderately selective for M3 relative to M2 receptors; and darifenacin is selective for M3 relative to M2, and to a lesser extent to the M1 receptors. The pharmacokinetics of the antimuscarinics varies considerably [Table 1].
Clinical efficacy of antimuscarinics
The number of antimuscarinics available is increasing and placebo-controlled, double-blind, randomized clinical trials have shown efficacy in OAB. ,,,,,, Head to head trials pitching one against the other show effectiveness in providing relief to different symptoms within the OAB spectrum. ,,,,,,,,,, Systematic meta-analysis, published in recent years, have reviewed placebo-controlled, as well as the active-controlled trails; and commented on the efficacy of antimuscarinics based on urgency, incontinence episodes, frequency of micturition, voided volume per micturition, impact on quality of life along with tolerability, and side effects. ,
Herbison et al. identified 64 potential trials, the 32 included were randomized placebo controlled trials published between January 1966 and January 2002.  Primary outcomes were patient's observations of cure or improvement in symptoms, number of leakages, and number of voids. Secondary outcomes were urodynamic measures and adverse events. Quality of life and economic outcomes were also considered. Weighted mean differences in: change in incontinence episodes per 24 hours, micturitions per 24 hours, and maximum cystometric capacity were calculated. Patients receiving antimuscarinics reported a weighted mean difference (vs. placebo) of 0.56 (95% CI − 0.93 to − 0.15) for a change in incontinence episodes and 0.59 (95% CI − 0.83 to − 0.36) for the change in micturitions per 24 hours.
The changes in maximum cystometric capacity at a weighted mean difference (95% CI) of + 54 mls (43-66), also favored active treatment. The volume at first bladder contraction had a weighted mean difference of 52.25 (95% CI 37.45 to 67.06). Although these were statistically significant differences and favored antimuscarinic treatment over placebo, the authors challenged the clinical significance of the efficacy quoted because the magnitude of improvement in these endpoints was small.
Chapple and colleagues did a systematic review to assess the efficacy, safety and tolerability of antimuscarinic treatments for OAB and also to consider the effects of antimuscarinics on quality of life (QoL); and to assess whether there are differences between individual antimuscarinics.  Data from 56 blinded, randomized, placebo and active-controlled trials of oral and transdermal antimuscarinics used to treat OAB was collected and compared, with, comparisons between individual antimuscarinics The weighted mean difference (95% CI) vs. placebo for the change in incontinence episodes per 24 hours was significant for oxybutynin immediate release (IR) (15.0 mg/day; − 0.72, − 1.09 to − 0.34), transdermal oxybutynin (− 0.55, − 1.05 to − 0.04), solifenacin (5 mg/day; − 0.66, − 1.13 to − 0.19; 10 mg/day, − 0.69, − 1.19 to − 0.19), tolterodine IR (4 mg/day, − 0.50, − 0.70 to − 0.30), and tolterodine extended release (ER 4mg/day) (− 0.73, − 0.93 to − 0.53). For changes in micturition frequency per 24 h, there were significant improvements vs. placebo for transdermal oxybutynin (− 0.55, − 1.03 to − 0.07), solifenacin (5 mg/day, − 0.99, − 1.52 to − 0.46; 10 mg/day, − 1.41, − 1.97 to − 0.85), tolterodine IR (2 mg/day, −0.68, − 1.15 to − 0.22; 4 mg/ day, − 0.67, − 0.92 to − 0.42), and tolterodine ER 4 mg/ day (− 0.73, − 0.96 to − 0.49).
Some evidence suggesting propiverine IR and ER might also reduce incontinence episodes and micturition frequency relative to placebo; was not suitable for inclusion in the meta-analysis. The changes in urgency episodes per 24 hours vs. placebo were significant for solifenacin (5 and 10 mg/day) and tolterodine ER. Improvements in volume voided per micturition were significant for oxybutynin IR (8.8-15.0 mg/day), transdermal oxybutynin, solifenacin (5 mg and 10 mg/day), tolterodine IR (2 mg and 4 mg/day), and tolterodine ER. The 'relative risk', (RR, 95% CI) for return to continence was significant for oxybutynin IR (5.0-7.5 mg/day; 3.53, 1.94-6.41), transdermal oxybutynin (1.75, 1.16-2.62), tolterodine ER (1.72, 1.14-2.58), and trospium (2.00, 1.40-2.86).
This suggests that patients who receive antimuscarinics are nearly twice as likely to return to continence compared with placebo. QoL data were available for transdermal oxybutynin, tolterodine IR (4 mg/day), tolterodine ER, and trospium. The meta-analysis revealed significant weighted mean differences vs placebo for 27 of 37 QoL domains.  A meta-analysis of three active-controlled studies of tolterodine ER and tolterodine IR revealed no significant differences in the change in QoL measures between active treatments. 
Evidence from the 24 active-controlled trials included in the meta-analysis, suggests that patients receiving solifenacin (5 or 10 mg/day) had up to one fewer urgency episodes per day than did those receiving tolterodine IR (4 mg/day). Solifenacin (10 mg/ day) was also associated with significantly fewer micturitions per 24 hours compared to tolterodine IR (4 mg/day). Oxybutynin ER (10 mg/day) was associated with approximately two fewer incontinence episodes per week with a greater percentage of patients returning to continence when compared with tolterodine ER (4 mg/day) Patients treated with oxybutynin IR (15 mg/ day) or solifenacin (5 and 10 mg/day) compared with patients receiving tolterodine IR (4 mg/day) had a significant increase in voided volumes. 
Fesoterodine is a newer non-selective agent that acts as a competitive muscarinic receptor antagonist. It is functionally a prodrug and hydrolyzed to its active metabolite 5 - hydroxymethyl tolterodine and available in 4 mg and 8 mg formulations. Its active metabolite is similar to that of tolterodine. In phase II and III trials, fesoterodine has shown efficacy in improving the symptoms of OAB in patients who were previously dissatisfied with tolterodine or tolterodine ER. ,,
Adverse effects and withdrawals
Dry mouth, constipation, headache, and blurred vision are frequent adverse effects in patients treated with oxybutynin, tolterodine, trospium, propiverine, darifenacin, and solifenacin in clinical trials. ,,,,,,,,,,,,,, In placebo- and active-controlled trials, the incidence of dry mouth in patients taking oxybutynin IR was 17-97%, oxybutynin ER 23-68%, transdermal oxybutynin 4-39%, propiverine IR 20-47%, propiverine ER 22%, tolterodine IR 8-50%, tolterodine ER 7-34%, trospium 3-41%, solifenacin 8-30%, and darifenacin 18-31%; a dry mouth is common and exceeded the combined incidence of constipation, headache, and abnormal vision. ,,,,,,,,,,,,,, Oxybutynin IR was found to be associated with a greater incidence of dry mouth compared with oxybutynin ER, oxybutynin transdermal, propiverine IR, tolterodine ER, tolterodine IR and trospium.  The Relative risk (95% CI) for dry mouth was significantly greater than placebo for patients receiving antimuscarinics with the exceptions of low dose oxybutynin IR (5.0-7.5 mg/day; 1.06, 0.90-1.29), transdermal oxybutynin (1.35, 0.67-2.72), and propiverine IR (45 mg/day; 3.00, 0.13-71.9).  Transdermal oxybutynin circumvents 'first-pass' metabolism and results in lower concentrations of the active metabolite N-desethyloxybutynin. This metabolite has a greater affinity for muscarinic receptors in the parotid gland and might contribute to dry mouth reported by many patients receiving oral oxybutynin. ,
Other reported adverse effects are blurred vision (with oxybutynin IR, propiverine IR and solifenacin); constipation (with darifenacin, solifenacin and trospium); dyspepsia (with darifenacin and oxybutynin IR); erythema and pruritus (with oxybutynin TDS); and urinary retention (with oxybutynin IR). Solifenacin 10 mg/day was associated with a higher incidence of blurred vision than tolterodine IR 4 mg/day; the risk of constipation was reduced by using oxybutynin transdermal in preference to oxybutynin IR, and tolterodine IR in preference to solifenacin nausea was less in patients treated with oxybutynin ER compared with oxybutynin IR; and the risk of vomiting was less for oxybutynin ER compared with tolterodine ER. With low incidence it is difficult to validate these differences.
There have been concerns raised with an increased risk of cardiac adverse events with antimuscarinics, particularly increases in heart rate and QT prolongation and induction of polymorphic ventricular tachycardia (torsade de pointes); however, at recommended therapeutic doses there is no evidence to substantiate this concern. ,,,
Withdrawal due to adverse events has been infrequent in placebo- and active-controlled trials of oral antimuscarinic. Herbison et al. reported that patients receiving placebo were equally likely to withdraw owing to adverse events as were those receiving antimuscarinics (RR 1.01, 95% CI, 0.78-1.31).  In the Chapple meta-analysis, the RR (95% CI) for all-cause withdrawals was significantly greater in patients receiving oxybutynin IR (8.8-15.0 mg/day, 1.40, 1.06-1.84) compared with placebo and the risk of all-cause withdrawal for patients receiving tolterodine ER (0.71, 0.51-0.99) was significantly less than placebo. 
The difference with other antimuscarinic agents and placebo did not reach statistical significance Tolterodine IR was found to cause fewer withdrawals due to adverse events than oxybutynin IR and; tolterodine ER caused fewer than both oxybutynin IR and transdermal oxybutynin. Literature supports the tolerability of antimuscarinics for the treatment of OAB symptoms with adverse event profiles dependent on muscarinic receptor subtype selectivity. In the clinical scenario, should the patient wish to discontinue treatment with one type of antimuscarinic, it is worth trying a different drug as this might be as effective and better tolerated.
Antimuscarinics in special conditions OAB with bladder outlet obstruction
There has been some concern that the inhibitory effect of antimuscarinics on detrusor muscle contraction could theoretically impair detrusor contractility and thus cause urinary retention in men with OAB symptoms secondary to BOO.
Athanasopoulos et al. reported on a randomized study of 50 men aged 52-80 years with mild to moderate bladder outlet obstruction and proven detrusor overactivity; comparing tamsulosin with a combination therapy of tamsulosin and tolterodine over a three-month period. There were no episodes of retention in the either group and the addition of tolterodine to tamsulosin is safe; patients with severe obstruction were excluded from this trial. 
Abrams et al. in a double-blind, placebo-controlled study, reported on the efficacy of antimuscarinics monotherapy in patients with symptoms of OAB and urodynamic evidence of DO and BOO.  A total of 222 men were recruited over 12-week and randomized 2:1 between treatments with tolterodine 2 mg twice daily or a placebo. Urodynamic parameters including change in Q max and detrusor pressure at Q max were comparable in the two groups, while volume to first detrusor contraction (reflex volume) and maximum cystometric capacity were significantly improved in men receiving tolterodine. A statistically significant increase in PVR (+33 mL vs. placebo) was not considered clinically significant; and micturition disorders led to withdrawals in one of 72 (1%) patients receiving placebo and three of 150 (2%) patients receiving tolterodine.
In a recent blinded randomized prospective trial, Kaplan et al. studied the efficacy of tolterodine ER and/or the alpha1-receptor antagonist tamsulosin in 879 men who met research criteria for both OAB and benign prostate hypertrophy.  A significantly greater proportion of patients receiving combined therapy (80%) reported treatment benefit by week 12 compared with placebo (62%), tamsulosin (71%), or tolterodine ER (65%). Combined therapy resulted in significant improvements in bladder diary variables (i.e. UUI, urgency, 24-hour micturition frequency, and nocturnal frequency) and the IPSS total and QoL scores vs. placebo. The incidence of AUR requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; placebo, 0%).
Recent evidence suggests that the incidence of acute retention in patients with bladder outlet obstruction and on antimuscarinics is low. However, their safety in patients with larger residues and over long term treatment needs to be established.
Antimuscarinics in elderly patients
Impairment of the cognitive function in the elderly with the use of antimuscarinic is of particular concern. All five muscarinic receptor subtypes have been identified in brain tissue and a decline in CNS cholinergic activity has been observed with normal ageing possibly due to a reduction in the density of functioning muscarinic receptors. A large-scale study by Staskin et al., in patients with OAB showed no significant differences in measures of sleepiness or CNS adverse effects between 20 mg trospium and placebo.  Trospium did not increase the daytime sleepiness or affect the alertness levels across the age groups.
Kay et al. studied the effects of darifenacin and oxybutynin on cognitive function of older patients.  150 patients 60 years or older were randomized to darifenacin, oxybutynin ER or placebo. At three weeks, darifenacin did not show any significant difference as compared to a placebo (mean difference = -0.06, P = 0.908) on the Name-Face Association test. Whereas oxybutynin ER resulted in memory impairment, with significant lower scores than placebo and darifenacin (mean differences = -1.30, P = 0.011 and -1.24, P = 0.022 respectively).
Although reports of hallucinations in elderly high-risk patients using tolterodine have been published, a causal relationship between tolterodine treatment and cognitive impairment needs to be established. , Higher-quality studies, such as randomized controlled trials, prospective epidemiological studies, and large case series, are required to determine if any causal relationship exists between antimuscarinic treatment and cognitive impairment.
Antimuscarinics in neuropathic bladder
Propiverine hydrochloride is one of the few drugs recommended for the treatment of detrusor overactivity by the International Consultation on Incontinence.  It comprises a neurotropic and a musculotropic mode of action, thus inducing antimuscarinic effects as well as effects on the calcium influx and calcium-homeostasis.  In a dosage-optimizing study of spinal cord injured adults, Mazur and coworkers recommended 15 mg propiverine thrice daily dose as being adequate in most patients.  Subsequently, Stohrer et al. proved the efficacy of propiverine (15 mg thrice daily) compared to placebo over a treatment period of 14 days by documenting urodynamic improvements. 
In a multicenter placebo-controlled double-blind study 61 patients with spinal cord injuries and detrusor hyperreflexia were treated with 20 mg trospium chloride twice daily over a period of 3 weeks. Pre- and post treatment urodynamic measurements demonstrated large improvements in maximum cystometric capacity (mean = 138.1 ml), decreased maximum detrusor pressure (mean = -37.8 cm H 2 O) and an increase in compliance (mean = 12.1 ml/cm H 2 O) in the treatment group. Significant difference for these parameters was reported with, no effect on maximum flow rate and residual urine. 
Currently only propiverine and trospium are licensed to be used for OAB in a neuropathic bladder but trials have been done to assess the efficacy of other anticholinergics in these patients. In patients with neurogenic detrusor overactivity, mainly due to traumatic spinal cord injury, a randomized controlled trial, comparing propiverine and oxybutynin, showed they were equally effective, both for the medical objective of lowering detrusor pressure and for the patient objective of achieving continence.  However, patients on propiverine showed fewer anticholinergic adverse events, especially dryness of the mouth.
| Future Trends|| |
The market with antimuscarinic pharmacotherapy is lucrative with many players in the industry constantly investigating newer molecules with greater efficacy and fewer side effects; the race to find the next blockbuster is on. Improved uroselectivity might be achieved through alterations in structure or route of administration.  New drug classes under investigation for OAB include α3-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors. However, clinical data, particularly comparing efficacy and safety is awaited before clinical use.
| Conclusions|| |
OAB syndrome is a very common condition that affects people of all ages and may cause a severe impact on quality of life. OAB can be diagnosed easily and managed effectively with both non-pharmacological and pharmacological therapies. The first-line treatments are lifestyle interventions, bladder training, pelvic floor muscle exercises and anticholinergic drugs. Antimuscarinics are the drug class of choice for OAB symptoms; with proven efficacy, and adverse event profiles that differ somewhat. Physicians can individualize OAB treatment by working with each patient to identify the most effective and best tolerated agent. Failure with one agent does not preclude usage of another and recently combinations of anticholinergics with improved efficacy and no increase in side-effects have been reported.
| References|| |
|1.||Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167-78. |
|2.||Milsom I, Abrams P, Cardozo L, Roberts RG, Thόroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87:760-6. |
|3.||Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, et al. Prevalence and burden of overactive bladder in the United States. World J Urol 2003;20:327-36. |
|4.||Yamanishi T, Chapple CR, Chess-Williams R. Which muscarinic receptor is important in the bladder? World J Urol 2001;19:299-306. |
|5.||Lapitan MC, Chye PL The epidemiology of overactive bladder among females in Asia: a questionnaire survey. Int Urogynecol J Pelvic Floor Dysfunct 2001;12:226-31 |
|6.||De Groat WC. A neurologic basis for the overactive bladder. Urology 1997;50:36-52. |
|7.||Brading AF. A myogenic basis for the overactive bladder. Urology 1997;50:57-67. |
|8.||Gillespie JI. Modulation of autonomous contractile activity in the isolated whole bladder of the guinea pig. BJU Int 2004;93:393-400. |
|9.||Litwin MS, Lubeck DP, Henning JM, Carroll PR. Differences in urologist and patient assessments of health related quality of life in men with prostate cancer: results of the CaPSURE database. J Urol 1998;159:1988-92. |
|10.||Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU Int 2007;100:987-06. |
|11.||Wyman JF. Management of urinary incontinence in adult ambulatory care populations. Annu Rev Nurs Res 2000;18:171-94. |
|12.||Dallosso HM, Matthews RJ, McGrother CW, Donaldson MM, Shaw C. The association of diet and other lifestyle factors with the onset of overactive bladder: a longitudinal study in men. Public Health Nutr 2004;7:885-91. |
|13.||Dallosso HM, McGrother CW, Matthews RJ, Donaldson MM. The association of diet and other lifestyle factors with overactive bladder and stress incontinence: a longitudinal study in women. BJU Int 2003;92:69-77. |
|14.||Edelstein BA, Keaton-Brasted C, Burg MM. Effects of caffeine withdrawal on nocturnal enuresis, insomnia, and behavior restraints. J Consult Clin Psychol 1984;52:857-62. |
|15.||Tomlinson BU, Dougherty MC, Pendergast JF, Boyington AR, Coffman MA, Pickens SM. Dietary caffeine, fluid intake and urinary incontinence in older rural women. Int Urogynecol J Pelvic Floor Dysfunct 1999;10:22-8. |
|16.||Wyman JF, Elswick RK, Wilson MS, Fantl AJ. Relationship of fluid intake to voluntary micturations and urinary incontinence in women. Neur Urodyn 1991;10:463-73. |
|17.||Griffiths DJ, McCracken PN, Harrison GM, Gromley EA. Relationship of fluid intake to involuntary micturations and urinary incontinence in geriatric populations. Neurourol Urodyn 1993;12:1-7. |
|18.||Jeffcoate TN, Francis WJ. Urgency incontinence in the female. Am J Obstet Gynecol 1966;94:604-18. |
|19.||Burgio KL. Current perspectives on management of urgency using bladder and behavioral training. J Am Acad Nurse Pract 2004;16:4-7. |
|20.||Schick E, Jolivet-Tremblay M, Dupont C, Bertrand PE, Tessier J. Frequency-volume chart: the minimum number of days required to obtain reliable results. Neurourol Urodyn 2003;22:92-6. |
|21.||Brown JS, McNaughton KS, Wyman JF, Burgio KL, Harkaway R, Bergner D, et al. Measurement characteristics of a voiding diary for use by men and women with overactive bladder. Urology 2003;61:802-9. |
|22.||Fantl JA, Wyman JF, McClish DK, Harkins SW, Elswick RK, Taylor JR, et al. Efficacy of bladder training in older women with urinary incontinence. JAMA 1991;265:609-13. |
|23.||Hu TW, Igou JF, Kaltreider DL, Yu LC, Rohner TJ, Dennis PJ, et al. A clinical trial of a behavioral therapy to reduce urinary incontinence in nursing homes. Outcome and implications. JAMA 1989;261:2656-62. |
|24.||Jarvis GJ, Millar DR. Controlled trial of bladder drill for detrusor instability. Br Med J 1980;281:1322-3. |
|25.||Kegel AH. Progressive resistance exercise in the functional restoration of the perineal muscles. Am J Obstet Gynecol 1948;56:238-48. |
|26.||Szonyi G, Collas DM, Ding YY, Malone-Lee JG. Oxybutynin with bladder retraining for detrusor instability in elderly people: a randomized controlled trial. Age Ageing 1995;24:287-91. |
|27.||Burns PA, Pranikoff K, Nochajski T, Desotelle P, Harwood MK. Treatment of stress incontinence with pelvic floor exercises and biofeedback. J Am Geriatr Socc 1990;38:341-4. |
|28.||O'Brien J, Austin M, Sethi P, O'Boyle P. Urinary incontinence: prevalence, need for treatment, and effectiveness of intervention by nurse. BMJ 1991;303:1308-12. |
|29.||Lagro-Janssen AL, Debruyne FM, Smits AJ, van Weel C. The effects of treatment of urinary incontinence in general practice. Fam Pract 1992;9:284-9. |
|30.||Hay-Smith EJ, Dumoulin C. Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women. Cochrane Database Syst Rev 2006;1:CD005654. |
|31.||Burgio KL, Goode PS, Locher JL, Umlauf MG, Roth DL, Richter HE, et al. Behavioral training with and without biofeedback in the treatment of urge incontinence in older women: a randomized controlled trial. JAMA 2002;288:2293-9. |
|32.||Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008;54:543-62. |
|33.||Abrams P, Andersson KE, Birder L. 4th International Consultation on Incontinence recommendations of the International Scientific community: Evaluation and treatment of Urinary incontinence, Pelvic Organ Prolapse and Faecal Incontinence, 4th ed. Paris, France: Health Publication Ltd; 2009. |
|34.||Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev 2004;56:581-631. |
|35.||Schneider T, Fetscher C, Krege S, Michel MC. Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther 2004;309:1148-53. |
|36.||Hegde SS, Choppin A, Bonhaus D, Briaud S, Loeb M, Moy TM, et al. Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 1997;120:1409-18. |
|37.||Andersson KE. Storage and voiding symptoms: pathophysiologic aspects. Urology 2003;62:3-10. |
|38.||Yokoyama O, Yusup A, Miwa Y, Oyama N, Aoki Y, Akino H. Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats. J Urol 2005;174:2032-6. |
|39.||Boy S, Schurch B, Nehring G, Knapp P, Karsentry G, Reitz A. The effect of tolterodine on sensations evoked by electrical stimulation and bladder filling sensations. Eur Urol Suppl 2006;5:223. |
|40.||Andersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004;3:46-53. |
|41.||Preik M, Albrecht D, O'Connell M, Hampel C, Anderson R. Effect of controlled-release delivery on the pharmacokinetics of oxybutynin at different dosages: severity-dependent treatment of the overactive bladder. BJU In 2004;94:821-7. |
|42.||Davila GW, Starkman JS, Dmochowski RR. Transdermal oxybutynin for overactive bladder. Urol Clin North Am 2006;33:455-63. |
|43.||Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS. Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence. OROS Oxybutynin Study Group. J Urol 1999;161:1809-12. |
|44.||Gleason DM, Susset J, White C, Munoz DR, Sand PK. Evaluation of a new once-daily formulation of oxbutynin for the treatment of urinary urge incontinence. Ditropan XL Study Group. Urology 1999;54:420-3. |
|45.||Chapple CR, Rechberger T, Al-Shukri S, Meffan P, Everaert K, Huang M, et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 2004;93:303-10. |
|46.||Chapple CR, Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, Warnack W, Drogendijk T, et al. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005;48:464-70. |
|47.||Cardozo L, Lisec M, Millard R, van Vierssen Trip O, Kuzmin I, Drogendijk TE, et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172:1919-24. |
|48.||Zinner N, Gittelman M, Harris R, Susset J, Kanelos A, Auerbach S. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol 2004;171:2311-5. |
|49.||Cardozo L, Dixon A. Increased warning time with darifenacin: a new concept in the management of urinary urgency. J Urol 2005;173:1214-8. |
|50.||Diokno AC, Appell RA, Sand PK, Dmochowski RR, Gburek BM, Klimberg IW, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003;78:687-95. |
|51.||Appell RA, Sand P, Dmochowski R, Anderson R, Zinner N, Lama D, et al. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study. Mayo Clin Proc 2001;76:358-63. |
|52.||Sussman D, Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). Curr Med Res Opin 2002;18:177-84. |
|53.||Haab F, Cardozo L, Chapple C, Ridder AM Long-term open-label solifenacin treatment associated with persistence with therapy in patients with overactive bladder syndrome. Eur Urol 2005;47:376-84. |
|54.||Karram MM, Toglia MR, Serels SR, Andoh M, Fakhoury A, Forero-Schwanhaeuser S. Treatment with solifenacin increases warning time and improves symptoms of overactive bladder: results from VENUS, a randomized, double-blind, placebo-controlled trial. Urology 2009;73:14-8. |
|55.||Cardozo L, Hessdφrfer E, Milani R, Araρσ P, Dewilde L, Slack M, et al. Solifenacin in the treatment of urgency and other symptoms of overactive bladder: results from a randomized, double-blind, placebo-controlled, rising-dose trial. BJU Int 2008;102:1120-7. |
|56.||Chapple CR, Abrams P. Comparison of darifenacin and oxybutynin in patients with overactive bladder: assessment of ambulatory urodynamics and impact on salivary flow. Eur Urol 2005;48:102-9. |
|57.||Zinner N, Tuttle J, Marks LEfficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder. World J Urol 2005;23:248-52. |
|58.||Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003;326:841-4. |
|59.||Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol 2005;48:5-26. |
|60.||Khullar V, Chapple C, Gabriel Z, Dooley JA. The effects of antimuscarinics on health-related quality of life in overactive bladder: a systematic review and meta-analysis. Urology 2006;68:38-48. |
|61.||Chapple C, Van Kerrebroeck P, Tubaro A, Haag-Molkenteller C, Forst HT, Massow U, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 2007;52:1204-12. |
|62.||Khullar V, Rovner ES, Dmochowski R, Nitti V, Wang J, Guan Z. Fesoterodine dose response in subjects with overactive bladder syndrome. Urology 2008;71:839-43. |
|63.||Wyndaele JJ, Goldfischer ER, Morrow JD, Gong J, Tseng LJ, Guan Z, et al. Effects of flexible-dose fesoterodine on overactive bladder symptoms and treatment satisfaction: an open-label study. Int J Clin Pract 2009;63:560-7. |
|64.||Yarker YE, Goa KL, Fitton A. Oxybutynin. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging 1995;6:243-62. |
|65.||Bang LM, Easthope SE, Perry CM. Transdermal oxybutynin: for overactive bladder. Drugs Aging 2003;20:857-64. |
|66.||Clemett D, Jarvis B. Tolterodine: a review of its use in the treatment of overactive bladder. Drugs Aging 2001;18:277-304. |
|67.||Rovner ES, Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review. Eur Urol 2002;41:6-14. |
|68.||Payne CK. Solifenacin in overactive bladder syndrome. Drugs 2006;66:175-90. |
|69.||Rovner ES. Trospium chloride in the management of overactive bladder. Drugs 2004;64:2433-46. |
|70.||Croom KF, Keating GM. Darifenacin: in the treatment of overactive bladder. Drugs Aging 2004;21:885-92. |
|71.||Madersbacher H, Mόrtz G. Efficacy, tolerability and safety profile of propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic). World J Urol 2001;19:324-35. |
|72.||Steers W, Corcos J, Foote J, Kralidis G. An investigation of dose titration with darifenacin, an M3-selective receptor antagonist. BJU Int 2005;95:580. |
|73.||Dorschner W, Stolzenburg JU, Griebenow R, Halaska M, Schubert G, Mόrtz G, et al. Efficacy and cardiac safety of propiverine in elderly patients - a double-blind, placebo-controlled clinical study. Eur Urol 2000;37:702-8. |
|74.||Athanasopoulos A, Gyftopoulos K, Giannitsas K, Fisfis J, Perimenis P, Barbalias G. Combination treatment with an alpha-blocker plus an anticholinergic for bladder outlet obstruction: a prospective, randomized, controlled study. J Urol 2003;169:2253-6. |
|75.||Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006;175:999-1004. |
|76.||Kaplan SA, Roehrborn CG, Rovner ES, Carlsson M, Bavendam T, Guan Z. Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial. JAMA 2006;296:2319-28. |
|77.||Staskin DR, Harnett MD. Effect of trospium chloride on somnolence and sleepiness in patients with overactive bladder. Curr Urol Rep 2004;5:423-6. |
|78.||Kay G, Crook T, Rekeda L, Lima R, Ebinger U, Arguinzoniz M, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol 2006;50:317-26. |
|79.||Womack KB, Heilman KM. Tolterodine and memory: dry but forgetful. Arch Neurol 2003;60:771-3. |
|80.||Tsao JW, Heilman KM. Transient memory impairment and hallucinations associated with tolterodine use. N Engl J Med 2003;349:2274-5. |
|81.||Andersson KE, Appell R, Cardozo L, Chapple C, Drutz H, Fourcroy J, et al. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A. Paris: Health Publication Ltd; 2005. P . 809-54. |
|82.||Madersbacher H, Mόrtz G. Efficacy, tolerability and safety profile of propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic). World J Urol 2001;19:324-35. |
|83.||Mazur D, Gφcking K, Wehnert J, Schubert G, Herfurth G, Alken RG. Clinical and urodynamic effects of oral propiverine therapy in neurogenic urinary incontinence. A multicenter study for optimizing dosage. Urologe A 1994;33:447-52. |
|84.||Stφhrer M, Madersbacher H, Richter R, Wehnert J, Dreikorn K. Efficacy and safety of propiverine in SCI-patients suffering from detrusor hyperreflexia--a double-blind, placebo-controlled clinical trial. Spinal Cord 1999;37:196-200. |
|85.||Stφhrer M, Bauer P, Giannetti BM, Richter R, Burgdφrfer H, Mόrtz G. Effect of trospium chloride on urodynamic parameters in patients with detrusor hyperreflexia due to spinal cord injuries. A multicentre placebo-controlled double-blind trial. Urol Int 1991;47:138-43. |
|86.||Stφhrer M, Mόrtz G, Kramer G, Schnabel F, Arnold EP, Wyndaele JJ Propiverine compared to oxybutynin in neurogenic detrusor overactivity--results of a randomized, double-blind, multicenter clinical study. Eur Urol 2007;51:235-42. |
|This article has been cited by|
||Twelve Months Follow-up of Injection of OnabotulinumtoxinA into Vesical Submucosa for Refractory Non-neurogenic Overactive Bladder
| ||Okamura, K. and Takei, M. and Nojiri, Y. and Otsuka, A. and Takamoto, H. and Maeda, Y. and Fujimura, T. and Yokoyama, T. and Gotoh, M. and Homma, Y. |
| ||LUTS: Lower Urinary Tract Symptoms. 2013; 5(2): 55-59 |
||Twelve Months Follow-up of Injection of OnabotulinumtoxinA into Vesical Submucosa for Refractory Non-neurogenic Overactive Bladder
| ||Kikuo OKAMURA,Mineo TAKEI,Yoshikatsu NOJIRI,Atsushi OTSUKA,Hitoshi TAKAMOTO,Yoshiko MAEDA,Tetsuya FUJIMURA,Teruhiko YOKOYAMA,Momokazu GOTOH,Yukio HOMMA |
| ||LUTS: Lower Urinary Tract Symptoms. 2013; 5(2): 55 |
|[Pubmed] | [DOI]|
||A comparative analisys of pelvic floor muscle strength in women with stress and urge urinary incontinence
| ||Gameiro, M.O. and Moreira, E.C. and Ferrari, R.S. and Kawano, P.R. and Padovani, C.R. and Amaro, J.L. |
| ||International Braz J Urol. 2012; 38(5): 661-666 |
||Botulinum toxin A submucosal injection for refractory non-neurogenic overactive bladder: Early outcomes
| ||Kikuo Okamura,Yoshikatsu Nojiri,Kaname Ameda,Takashige Namima,Masahito Suzuki,Katsumi Inoue,Takatoshi Ogawa,Momokazu Gotoh,Yukio Homma |
| ||International Journal of Urology. 2011; 18(6): 483 |
|[Pubmed] | [DOI]|
||Botulinum toxin A submucosal injection for refractory non-neurogenic overactive bladder: Early outcomes
| ||Okamura, K., Nojiri, Y., Ameda, K., Namima, T., Suzuki, M., Inoue, K., Ogawa, T., (...), Homma, Y. |
| ||International Journal of Urology. 2011; 18(6): 483-487 |