Management of Overactive Bladder Syndrome

OVERACTIVE BLADDER

Overactive bladder (OAB) is the term used to describe the symptom complex of urgency with or without urge incontinence, usually with frequency and nocturia, in the absence of urinary tract infection or any other obvious cause.¹

The symptoms of OAB are as a result of involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity¹ and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors.² It has been estimated that 64% of patients with OAB have urodynamically proven detrusor overactivity and that 83% of patients with detrusor overactivity have symptoms suggestive of OAB.³

DETRUSOR OVERACTIVITY

Detrusor overactivity is defined as ‘a urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked’. The detrusor is shown objectively to contract (either spontaneously or with provocation) during bladder filling whilst the subject is attempting to inhibit micturition.¹ Detrusor overactivity is a urodynamic diagnosis and usually presents with symptoms of frequency, urgency, urge incontinence, nocturia, nocturnal enuresis and sometimes incontinence at orgasm.

Epidemiological studies have reported the overall prevalence of OAB in women to be 16.9% suggesting that there could be 17.5 million women in the USA who suffer from the condition. The prevalence increases with age, from 4.8% in women under 25 years to 30.9% in those over the age of 65 years.⁴ This is supported by prevalence data from Europe in which 16,776 interviews were conducted in a population-based survey.⁵ The overall prevalence of OAB in individuals 40 years and above was 16.6% and increased with age. Frequency was the most commonly reported symptom (85%), whilst 54% complained of urgency and 36% urge incontinence. When considering management 60% had consulted a physician, although only 27% were currently receiving treatment.

More recently, a further population-based survey of lower urinary tract symptoms in Canada, Germany, Italy, Sweden and the UK has reported on 19,165 men and women over the age of 18 years.⁶ Overall 11.8 % were found to complain of symptoms suggestive of OAB and 64.3% reported at least one urinary symptom. Nocturia was the most prevalent lower urinary tract symptom being reported by 48.6% of men and 54.5% of women.

These prevalence data derived from the EPIC study have also been used to investigate the economic impact of OAB.⁷ Overall the estimated average direct cost of OAB per patient ranged between $262 in Spain to $619 in Sweden. The estimated total direct cost for OAB per country was found to range from $333 million in Sweden and 1.2 billion in Germany, and the total annual direct cost in these six Western countries was estimated to be $3.9 billion. In addition nursing home costs were estimated at $4.7 billion per year, whilst work absenteeism related to OAB costs around $1.1 billion per year.

There is also considerable evidence demonstrating a significant impact of OAB on work productivity. A population-based cross-sectional internet survey has been reported involving 2876 men and 2820 women in the US.⁸ Overall those men and women complaining of OAB wet reported the lowest levels of work productivity and the highest levels of daily work interference. Storage symptoms associated with OAB were most consistently associated with work productivity outcomes, although there was also a significant association with other storage and voiding phase lower urinary tract symptoms.

Molecular cloning studies have revealed five distinct genes for muscarinic acetylcholine receptors in rats and humans, and it has been shown that there are five receptor subtypes (M₁–M₅). In the human bladder there are M₂ and M₃ receptors, and the latter is thought to cause a direct smooth muscle contraction. Whilst the role of the M₂ receptor has not yet been clarified, it may oppose sympathetically mediated smooth muscle relaxation. In general it is thought that the M₃ receptor is responsible for the normal micturition contraction, although in certain disease states, such as neurogenic bladder dysfunction, the M₂ receptors may become more important in mediating detrusor contractions. 

PATHOPHYSIOLOGY

A detrusor contraction is initiated in the rostral pons. Efferent pathways emerge from the sacral spinal cord as the pelvic parasympathetic nerves (S2, S3, S4) and run forwards to the bladder. Whilst preganglionic neurotransmission is predominantly mediated by acetylcholine acting on nicotinic receptors, transmission may also be modulated by adrenergic, muscarinic, purinergic and peptidergic presynaptic receptors.

Acetylcholine is released by the postganglionic nerves at the neuromuscular junction and results in a co-ordinated detrusor contraction mediated through muscarinic receptors. However, adenosine triphosphate (ATP) also has a role⁹ mediated through non-adrenergic, non-cholinergic receptors (NANC).

Conversely, sympathetic innervation is from the hypogastric and pelvic nerves acting on β-adrenoreceptors causing relaxation of the detrusor muscle. Thus a balance between sympathetic and parasympathetic stimulation is required for normal detrusor function.

OUTFLOW OBSTRUCTION HYPOTHESIS

The association of detrusor overactivity with outflow obstruction has been recognized for some time,¹⁰ although is more important in men than women.

Outflow obstruction may lead to partial denervation and morphological studies have demonstrated a reduction in acetylcholine esterase staining nerves in obstructed human bladder.¹¹ In addition pharmacological studies have shown that muscle strips from patients with detrusor overactivity exhibit supersensitivity to acetylcholine.¹²

In addition outflow obstruction may alter the contraction properties of the detrusor muscle¹³ leading to changes in cell to cell propagation of electrical activity and this in turn may lead to a higher incidence of instability of membrane potential.¹⁴ These findings suggest that individual cells are more irritable when synchronous activation is damaged.

Outflow obstruction has also been shown to lead to the facilitation of the spinal reflex¹⁵ mediated by C-fibers with increased expression of nerve growth factor (NGF) and tachykinins.¹⁶ The latter have been shown to have an effect on spinal and supraspinal control of the bladder via neurokinin receptors.¹⁷

NEUROGENIC HYPOTHESIS

The pathophysiology of detrusor overactivity remains unclear. In vitro studies have shown that the detrusor muscle in cases of idiopathic detrusor overactivity contracts more than normal detrusor muscle. These detrusor contractions are not nerve mediated and can be inhibited by the neuropeptide vasoactive intestinal polypeptide.¹⁸ Other studies have shown that increased α-adrenergic activity causes increased detrusor contractility.¹⁹

There is evidence to suggest that the pathophysiology of idiopathic and obstructive overactive bladder is different. From animal and human studies on obstructive overactivity, it would seem that the detrusor develops postjunctional supersensitivity, possibly owing to partial denervation,²⁰ with reduced sensitivity to electrical stimulation of its nerve supply but a greater sensitivity to stimulation with acetylcholine²¹ If outflow obstruction is relieved, the detrusor can return to normal behavior and reinnervation may occur.²²

URETHRAL REFLEX

Relaxation of the urethra is known to precede contraction of the detrusor in a proportion of women with detrusor overactivity.²³ This may represent primary pathology in the urethra which triggers a detrusor contraction or may merely be part of a complex sequence of events which originate elsewhere. It has been postulated that incompetence of the bladder neck, allowing passage of urine into the proximal urethra, may result in an uninhibited contraction of the detrusor. However, Sutherst and Brown²⁴ were unable to provoke a detrusor contraction in 50 women by rapidly infusing saline into the posterior urethra using modified urodynamic equipment.

MYOGENIC HYPOTHESIS

Brading and Turner²⁵ have suggested that the common feature in all cases of detrusor overactivity is partial denervation of the detrusor which may be responsible for altering the properties of the smooth muscle, leading to increased excitability and increased ability of activity to spread between cells, resulting in co-ordinated myogenic contractions of the whole detrusor.²⁶ They dispute the concept of neurogenic detrusor overactivity, that is, increased motor activity to the detrusor, as the underlying mechanism in detrusor overactivity, proposing that there is a fundamental abnormality at the level of the bladder wall with evidence of altered spontaneous contractile activity consistent with increased electrical coupling of cells, a patchy denervation of the detrusor and a supersensitivity to potassium.²⁷ Charlton et al.²⁸ suggest that the primary defect in the idiopathic and neuropathic bladders is a loss of nerves accompanied by hypertrophy of the cells and an increased production of elastin and collagen within the muscle fascicles.

UROTHELIAL AFFERENT HYPOTHESIS

More recently the role of afferent activation in the urothelium and suburothelial myofibroblasts has been investigated as a factor in the pathophysiology of detrusor overactivity. C-fiber afferents are known to have nerve endings in the suburothelial layer of the bladder wall as well as in the urothelium. Studies have revealed that ATP is released from the urothelium by bladder distension²⁹ and this may lead to activation of purinergic receptors on afferent nerve terminals which in turn evokes a neuronal discharge leading to bladder contraction.

In addition prostanoids³⁰ and nitric oxide³¹ are synthesized locally in the urothelium and are also released by bladder distension. It is probable that a cascade of stimulatory (ATP, prostanoids, tachykinins) and inhibitory (nitric oxide) mediators are involved in the activation of sensory pathways during bladder filling.³² The role of C-fibers in the pathophysiology of detrusor contractions is also supported by the use of intravesical vanilloids (capsaicin and resiniferatoxin) in patients with idiopathic detrusor overactivity and hypersensitivity disorders.³³

SYMPTOMS

OAB usually presents with a multiplicity of symptoms. Those most commonly seen are urgency, daytime frequency, nocturia, urgency incontinence, stress incontinence, nocturnal enuresis and often coital incontinence. However, it is important to remember that there are numerous other causes of urgency and frequency (Table 1) and these should be excluded before making a definitive diagnosis of OAB. This is particularly important in women who have recurrent symptoms, or who have failed primary therapy.

Table 1 Common causes of frequency and urgency of micturition

SIGNS

Although there are no specific clinical signs in women with OAB it is important to look for vulval excoriation, urogenital atrophy, a urinary residual and stress incontinence. In addition, in those women with refractory symptoms an underlying neurological lesion such as multiple sclerosis should be excluded by examining the cranial nerves and S2, 3 and 4 outflow.

Whilst OAB is a symptomatic diagnosis, all patients require a basic assessment in order to confirm the diagnosis as well as excluding any other underlying cause for lower urinary tract dysfunction. A midstream specimen of urine should be sent for microscopy, culture and sensitivity in all cases of incontinence. In addition patients should be encouraged to complete a frequency/volume chart in order to evaluate their fluid intake and voiding pattern. As well as the number of voids and incontinence episodes, the mean volume voided over a 24-hour period can also be calculated as well as the diurnal and nocturnal volumes. This is helpful in supporting the diagnosis of OAB and can be useful in excluding other causes of urinary symptoms such as nocturnal or global polyuria.

URODYNAMIC INVESTIGATIONS

Whilst a number of women complaining of symptoms suggestive of OAB may be managed on the basis of simple investigations, urodynamic investigations are integral in the investigation of women with refractory or complex symptoms in order to make an accurate diagnosis prior to embarking on more invasive, or perhaps irreversible, therapy.

Simple urodynamic investigations include uroflowmetry, filling cystometry and pressure/flow voiding studies. In addition those women with a neurological history, or who have had previous pelvic surgery, may benefit from videocystourethrography which allows simultaneous screening of the lower urinary tract during filling cystometry and voiding studies.

CYSTOURETHROSCOPY

Although endoscopy is not helpful in diagnosing detrusor overactivity it may be used to exclude other causes for the symptoms associated with OAB such as a bladder tumor or calculus. In addition cystourethroscopy should be considered in all women complaining of hematuria, painful bladder syndrome and refractory OAB.

The treatment options for OAB can be divided into conservative, pharmacological, neuromodulation and surgical options.

CONSERVATIVE MANAGEMENT

Conservative measures include advice regarding fluid intake. It may be that simply cutting down on the volume of fluid consumed throughout the day or altering the times at which drinks are taken will be enough to reduce the symptoms and improve quality of life. Women should be advised to consume between 1 L and 1.5 L in any 24-hour period. It is not advisable to restrict fluid intake severely, as a low urine output together with frequent voiding can lead to a reduction in the bladder’s functional capacity. Caffeine and alcohol are known to irritate the bladder, and women should be advised to try to avoid caffeine-based drinks or substitute them with decaffeinated drinks.

Bladder retraining

The principles of bladder retraining are based on the ability to suppress urinary urge and to extend the intervals between voiding. The regimen is generally initiated at set voiding intervals and the patient is not allowed to void between these predetermined times, even if she is incontinent. When she remains dry, the time interval is lengthened. This continues until a suitable time span is achieved, usually around 3–4 hours. Cure rates using bladder retraining alone and no pharmacological agents have been reported between 44% and 90%.³⁴ Many professionals advise the combined use of pelvic floor exercises with bladder retraining, as this can help suppress the symptom of urinary urgency.

PHARMACOLOGICAL MANAGEMENT

Drug therapy has an important role in the management of women with urinary symptoms caused by OAB, although there are none which specifically act on the bladder and urethra which do not have systemic effects. The large number of drugs available is indicative of the fact that none is ideal and it is often their systemic adverse effects which limit their use in terms of efficacy and compliance. The pharmacology of drugs and recommendations for usage has recently been reviewed by the 5th International Consultation on Incontinence (ICI) (Table 2).³⁵

Table 2 Drugs used in the treatment of overactive bladder³⁵

Antimuscarinic drugs

The detrusor is innervated by the parasympathetic nervous system (pelvic nerve), the sympathetic nervous system (hypogastric nerve) and by non-cholinergic, non-adrenergic neurones. The motor supply arises from S2, 3 and 4 and is conveyed by the pelvic nerve. The neurotransmitter at the neuromuscular junction is acetylcholine, which acts upon muscarinic receptors. Antimuscarinic drugs should therefore be of use in the treatment of detrusor overactivity. Atropine is the classic non-selective anticholinergic drug with antimuscarinic activity; however, its non-specific mode of action makes it unacceptable for clinical use because of the high incidence of side-effects. All antimuscarinic agents produce competitive blockade of acetylcholine receptors at postganglionic parasympathetic receptor sites. They all, to a lesser or greater extent, have the typical side-effects of dry mouth, blurred vision, tachycardia, drowsiness and constipation. Unfortunately, virtually all the drugs which are truly beneficial in the management of OAB produce these unwanted systemic side-effects.

Tolterodine

Tolterodine is a competitive muscarinic receptor antagonist with relative functional selectivity for bladder muscarinic receptors. Whilst it shows no specificity for receptor subtypes, it does target the bladder muscarinic receptors rather than those in the salivary glands. Several randomized, double-blind, placebo-controlled trials have demonstrated a significant reduction in incontinent episodes and micturition frequency,³⁶ whilst the incidence of adverse effects has been shown to be no different to placebo. When compared to oxybutynin in a randomized double-blind placebo-controlled parallel group study, it was found to be equally efficacious and to have a lower incidence of side-effects, notably dry mouth.³⁷  

Tolterodine has also been developed as an extended release once daily preparation. A double-blind multicenter trial of 1235 women has compared extended release tolterodine to immediate release tolterodine and placebo. Whilst both formulations were found to reduce the mean number of urge incontinence episodes per week, the extended release preparation was found to be significantly more effective.³⁸

Extended release (ER) oxybutynin and ER tolterodine have also been compared. In the OPERA (Overactive bladder: Performance of Extended Release Agents) study, which involved 71 centers in the US, improvements in episodes of urge incontinence were similar for the two drugs, although oxybutynin ER was significantly more effective than tolterodine ER in reducing frequency of micturition.³⁹

In summary, the available evidence would suggest that tolterodine is as effective as oxybutynin, although since it has fewer adverse effects patient tolerability and compliance are improved.

Trospium chloride

Trospium chloride is a quaternary ammonium compound which is non-selective for muscarinic receptor subtypes and shows low biological availability. It crosses the blood–brain barrier to a limited extent and hence would appear to have few cognitive effects.⁴⁰ A placebo-controlled, randomized, double-blind multicenter trial has shown trospium to increase cystometric capacity and bladder volume at first unstable contraction, leading to significant clinical improvement without an increase in adverse effects over placebo.⁴¹ When compared to oxybutynin it has been found to have comparable efficacy, although was associated with a lower incidence of dry mouth and patient withdrawal.⁴² At present trospium chloride would appear to be equally effective as oxybutynin, although it may be associated with fewer adverse effects.

Solifenacin

Solifenacin is a potent M₃ receptor antagonist that has selectivity for the M₃ receptors over M₂ receptors and has much higher potency against M₃ receptors in smooth muscle than it does against M₃ receptors in salivary glands.

The clinical efficacy of solifenacin has been assessed in a multicenter, randomized, double-blind, parallel group, placebo-controlled study of solifenacin 5 mg and 10 mg once daily in patients with overactive bladder.⁴³ The primary efficacy analysis showed a statistically significant reduction of the micturition frequency following treatment with both 5 mg and 10 mg doses when compared with placebo, although the largest effect was with the higher dose. The most frequently reported adverse events leading to discontinuation were dry mouth and constipation. These were also found to be dose related.

In order to assess the long-term safety and efficacy of solifenacin a multicenter open label long-term follow-up study has been reported. This was essentially an extension of two previous double-blind placebo-controlled studies in 1637 patients.⁴⁴ Overall the efficacy of solifenacin was maintained in the extension study with a sustained improvement in symptoms of urgency, urge incontinence, frequency and nocturia over the 12-month study period. The most commonly reported adverse events were dry mouth (20.5%), constipation (9.2%) and blurred vision (6.6%) and were the primary reason for discontinuation in 4.7% of patients.

Solifenacin has also been compared with tolterodine ER in the Solifenacin (flexible dosing) od and Tolterodine ER as an Active comparator in a Randomized trial (STAR).⁴⁵ This was a prospective double-blind, double dummy, two-arm, parallel-group, 12-week study of 1200 patients with the primary aim of demonstrating non-inferiority of solifenacin to tolterodine ER. Solifenacin was non-inferior to tolterodine ER with respect to change from baseline in the mean number of micturitions per 24 hours. In addition solifenacin resulted in a statistically significant improvement in urgency, urge incontinence and overall incontinence when compared with tolterodine ER. The most commonly reported adverse events were dry mouth constipation and blurred vision, and were mostly mild to moderate in severity. The number of patients discontinuing medication was similar in both treatment arms (3.5% in the solifenacin arm versus 3.0% in the tolterodine arm).

Darifenacin

Darifenacin is a tertiary amine with moderate lipophilicity and is a highly selective M₃ receptor antagonist which has been found to have a 5-fold higher affinity for the human M₃ receptor relative to the M₁ receptor.

A review of the pooled darifenacin data from the three phase III, multicenter, double-blind clinical trials in patients with OAB has been reported in 1059 patients.⁴⁶ Darifenacin resulted in a dose-related significant reduction in median number of incontinence episodes per week. Significant decreases in the frequency and severity of urgency, micturition frequency, and number of incontinence episodes resulting in a change of clothing or pads were also apparent, along with an increase in bladder capacity. Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth and constipation, although together these resulted in few discontinuations. The incidence of central nervous system and cardiovascular adverse events were comparable to placebo.

Fesoterodine

Fesoterodine is a novel derivative of 3,3-diphenylpropyl-amine which is a potent antimuscarinic agent that has more recently been developed for the management of OAB. A phase II dose finding study was conducted in 728 patients in Europe and South Africa.⁴⁷ Fesoterodine 4 mg, 8 mg and 12 mg were all found to show significantly greater decreases in micturition frequency than placebo. The most commonly reported side effect was dry mouth with an incidence of 25% in the 4 mg group rising to 34% in the 12 mg group. Discontinuation rates were 6% and 12%, respectively. Subsequently a phase III randomized placebo-controlled trial has been reported comparing fesoterodine 4 mg and 8 mg with tolterodine ER 4 mg in patients complaining of OAB in 1135 patients at 150 sites throughout Australia, New Zealand, South Africa and Europe.⁴⁸ Both doses of fesoterodine demonstrated significant improvements over placebo in reduction of daytime frequency and number of urge incontinence episodes per day and were found to be superior to tolterodine. The current evidence from two large phase IV studies would support these findings and suggest that fesoterodine may offer some advantages over tolterodine in terms of efficacy and flexible dosing regimens.^{49, 50} 

Drugs that have a mixed action

Oxybutynin

Oxybutynin is a tertiary amine that undergoes extensive first-pass metabolism to an active metabolite, N-desmethyl oxybutynin which occurs in high concentrations and is thought to be responsible for a significant part of the action of the parent drug. It has a mixed action consisting of both an antimuscarinic and a direct muscle relaxant effect in addition to local anaesthetic properties. Oxybutynin has been shown to have a high affinity for muscarinic receptors in the bladder and has a higher affinity for  M₁  and M₃ receptors over M₂.

The effectiveness of oxybutynin in the management of patients with detrusor overactivity is well documented. A double-blind placebo-controlled trial found oxybutynin to be significantly better than placebo in improving lower urinary tract symptoms, although 80% of patients complained of significant adverse effects, principally dry mouth or dry skin.⁵¹

The antimuscarinic adverse effects of oxybutynin are well documented and are often dose limiting, with 10–23% of women discontinuing medication.⁵² Using an intravesical route of administration higher local levels of oxybutynin can be achieved whilst limiting the systemic adverse effects. Intravesical administration of oxybutynin is an effective and useful alternative for patients with neurogenic detrusor overactivity who need to self-catheterize or who suffer from 'bypassing' an indwelling catheter.

In order to improve tolerability a controlled-release oxybutynin preparation using an osmotic system (OROS) has been developed which has been shown to have comparable efficacy when compared with immediate release oxybutynin, although are associated with fewer adverse effects.⁵³ In order to maximize efficacy and minimize adverse effects alternative delivery systems are currently under evaluation. An oxybutynin transdermal delivery system has recently been developed and compared with extended release tolterodine in 361 patients with mixed urinary incontinence. Both agents significantly reduced incontinence episodes, increased volume voided and lead to an improvement in quality of life when compared to placebo. The most common adverse event in the oxybutynin patch arm was application site pruritis in 14%, although the incidence of dry mouth was reduced to 4.1% compared to 7.3% in the tolterodine arm.⁵⁴

A large prospective multicenter, randomized, double-blind placebo-controlled study has been reported investigating the use of oxybutynin gel in the management of overactive bladder in 704 patients.⁵⁵ Overall there was a significant reduction in urge incontinence episodes in the gel arm compared to placebo, a significant reduction in daytime frequency and increase in volume voided. When considering adverse events dry mouth was more common in the treatment arm when compared to placebo (6.9% vs 2.8%) and skin site reactions were infrequent in both arms at 5.4% and 1.0%, respectively. Consequently oxybutynin gel may represent an important development over the oxybutynin patch in terms of patient acceptability.

In summary, the efficacy of oxybutynin is well documented, although very often its clinical usefulness is limited by adverse effects. Alternative routes and methods of administration may produce better patient acceptability and compliance.

Propiverine

Propiverine has both antimuscarinic and calcium channel-blocking actions. Open studies have demonstrated a beneficial effect in patients with overactive bladder⁵⁶ and neurogenic detrusor overactivity.⁵⁷ Dry mouth was experienced by 37% in the treatment group as opposed to 8% in those taking placebo, with dropout rates being 7% and 4.5%, respectively. Overall propiverine was found to have comparable efficacy to oxybutynin but was better tolerated in terms of adverse effects.

More recently propiverine ER has been introduced and been shown to be as effective as the immediate release preparation in the management of overactive bladder.⁵⁸

β₃-adrenoceptor agonists

β-adrenoceptor agonists have been shown to be effective in the management of OAB and mirabegron⁵⁹ has been recently been launched in the UK. β₃-adrenoceptor agonists induce bladder relaxation by the activation of adenyl cyclase with the subsequent formation of cyclic adenyl monophosphate (cAMP) and have been shown to increase bladder capacity with no change in micturition pressure and residual urine volumes.⁶⁰ β₃-adrenceptor agonists may offer an alternative to antimuscarinic therapy whilst at the same time offering a better side effect profile.⁶¹ In addition the introduction of a new class of drug may offer the possibility of combination therapy which may minimize adverse events whilst maximizing efficacy.

Tricyclic antidepressants

These drugs have a complex pharmacological action. Imipramine has antimuscarinic, antihistamine and local anesthetic properties. It may increase outlet resistance by peripheral blockage of noradrenaline uptake and it also acts as a sedative. The side-effects are antimuscarinic, together with tremor and fatigue. Imipramine is particularly useful for the treatment of nocturia and nocturnal enuresis. In light of relatively poor evidence and the serious adverse effects associated with tricyclic antidepressants their role in detrusor overactivity remains of uncertain benefit, although they are often useful in patients complaining of nocturia or bladder pain.

Antidiuretic agents

Desmopressin

Desmopressin (1-desamino-8-D-arginine vasopressin; DDAVP), a synthetic vasopressin, has been shown to reduce nocturnal urine production by up to 50%. It can be used for children or adults with nocturia or nocturnal enuresis,⁶² but must be avoided in patients with hypertension, ischemic heart disease or congestive cardiac failure. There is good evidence to show that it is safe to use in the long term and may be given orally or as buccal preparation. Desmopressin has also been used as a ‘designer drug’ for daytime incontinence⁶³ and also in the treatment of overactive bladder.⁶⁴

Desmopressin is safe for long-term use, however, the drug should be used with care in the elderly owing to the risk of hyponatremia and the current recommendations are that serum sodium should be checked in the first week following the start of treatment.

Estrogen in the management of overactive bladder

Whilst the effect of estrogens on lower urinary tract function remain controversial, there is evidence to show that estrogen deficiency may increase the risk of developing OAB following the menopause. Animal data would suggest that estrogen might inhibit the function of Rho-kinase in bladder smooth muscle, and hence effect smooth muscle contraction, whilst having no effect on its expression. Consequently estrogen deprivation following the menopause may lead to the development of OAB symptoms.⁶⁵Evidence from in vitro studies has demonstrated that ovariectomized rats showed a significant decrease in voided volume and an increase in 24-hour frequency with an increase in basal and stretch induced acetylcholine release. Conversely there was a reduction in acetylcholine release from nerve fibers. This may explain why there is a decrease in detrusor contractility following the menopause with a corresponding increase in the development of OAB symptoms. Interestingly estrogen replacement therapy reversed these changes.⁶⁶

Based on these finding estrogen replacement following the menopause may lead to an improvement in physiological voiding function, whilst at the same time reducing the risk of developing symptoms of overactive bladder. Given the concerns regarding the use of systemic estrogen replacement therapy, the vaginal route of administration may offer a better treatment approach.

Estrogens have been used in the treatment of urinary urgency and urgency incontinence for many years although there have been few controlled trials to confirm their efficacy. A double-blind placebo-controlled crossover study using oral estriol in 34 postmenopausal women produced subjective improvement in symptoms,⁶⁷ although a double-blind multicenter study of the use of estriol in postmenopausal women complaining of urgency has failed to confirm these findings.⁶⁸

There is some evidence to show that vaginal 17β-estradiol tablets (Vagifem) therapy may be useful in managing the symptoms of OAB and, in particular, in improving the symptom of urgency.⁶⁹ A further double-blind, randomized, placebo-controlled trial has shown lower urinary tract symptoms of frequency, urgency, urgency and stress incontinence to be significantly improved, although there was no objective urodynamic assessment performed.⁷⁰ However, some of the subjective improvement in these symptoms may simply represent local estrogenic effects reversing urogenital atrophy rather than a direct effect on lower urinary tract function.

In a review of 10 randomized placebo-controlled trials estrogen was found to be superior to placebo when considering symptoms of urgency incontinence, frequency and nocturia, although vaginal estrogen administration was found to be superior to placebo for the symptom of urgency.⁷¹ Consequently the implications of these findings are that exogenous estrogen therapy, particularly using the vaginal route of administration may be useful in the management of OAB.

Intravesical therapy

Capsaicin

This is the pungent ingredient found in red chillies and is a neurotoxin of substance P-containing (C) nerve fibers. Patients with neurogenic detrusor overactivity secondary to multiple sclerosis appear to have abnormal C-fiber sensory innervation of the detrusor, which leads to premature activation of the holding reflex arc during bladder filling. Intravesical application of capsaicin dissolved in 30% alcohol solution can be effective for up to 6 months. The effects are variable⁷² and the long-term safety of this treatment has not yet been evaluated.

Resiniferatoxin

This is a phorbol-related diterpene isolated from the cactus and is a potent analogue of capsaicin that appears to have similar efficacy but with fewer side-effects of pain and burning during intravesical instillation. It is 1000 times more potent than capsaicin at stimulating bladder activity. As with capsaicin, the currently available evidence does not support the routine clinical use of the agents, although they may prove to have a role as an intravesical preparation in neurological patients with neurogenic detrusor overactivity.

Botulinum toxin

The use of intravesical botulinum toxin type A (onobotulinumtoxin) was first described in the management of patients with neurogenic detrusor overactivity,⁷³ although there is now considerable evidence to support its usage in patients with idiopathic detrusor overactivity as well.

A randomized double-blind placebo-controlled trial of onobotulinumtoxin 200 IU has demonstrated a significantly greater improvement in urgency episodes, incontinence episodes and urinary frequency with onobotulinumtoxin when compared to placebo. The commonest side-effects were urinary tract infection in 31% of patients and voiding dysfunction necessitating self catherization in 16% of cases.⁷⁴

These results are supported by a large phase III randomized double-blind placebo-controlled trial of onobotulinumtoxin 100 IU in 557 patients with idiopathic OAB. There was a significantly greater decrease in incontinence episodes with onobotulinumtoxin when compared to placebo (−2.65 vs −0.87, p <0.001) and incontinence resolved in 22.9% vs 6.5% of patients, respectively. Once again urinary tract infection was the most commonly reported adverse event, although the rate of urinary retention was found to be reduced to 5.4% with the lower dose of onobotulinumtoxin. ⁷⁵

The efficacy of onabotulinumtoxin 100 IU has also been compared to antimuscarinic therapy (solifenacin 5 mg escalating to 10 mg and trospium chloride 60 mg) in a randomized double-blind placebo-controlled trial in 249 women. There was no difference between groups in the mean reduction of urgency incontinence episodes between the antimuscarinic arm and the onobotulinumtoxin arm (3.4 vs 3.3; p = 0.81) and resolution of incontinence was reported by 13% and 27% of the women, respectively (p = 0.003). Whilst QoL improved in both groups, the antimuscarinic group had a higher rate of dry mouth (46% vs. 31%, p = 0.02) but lower rates of self catheterization at 2 months (0% vs. 5%, p = 0.01) and urinary tract infections (13% vs. 33%, p <0.001).⁷⁶

Consequently onobotulinumtoxin may be effective in managing women with refractory OAB symptoms and may be administered either under general anesthetic with a rigid cystoscope or under local anesthetic with a flexible cystoscope. Botulinum toxin type A (Botox^®) is currently licensed in the UK for the treatment of neurogenic detrusor overactivity and idiopathic OAB.

NEUROMODULATION

Sacral neuromodulation

Stimulation of the dorsal sacral nerve root using a permanent implantable device in the S3 sacral foramen has been developed for use in patients with OAB and neurogenic detrusor overactivity. The sacral nerves contain nerve fibers of the parasympathetic and sympathetic system providing innervation to the bladder as well as somatic fibers providing innervation to the muscles of the pelvic floor. The latter are larger in diameter and hence have a lower threshold of activation, meaning that the pelvic floor may be stimulated selectively without causing bladder activity.

Prior to implantation temporary cutaneous sacral nerve stimulation is performed to check for a response and if successful, a permanent implant is inserted under general anesthesia. Initial studies in patients with OAB refractory to medical and behavioral therapy have demonstrated that after 3 years, 59% of 41 urinary urge incontinent patients showed greater than 50% reduction in incontinence episodes, with 46% of patients being completely dry.⁷⁷

Whilst neuromodulation remains an invasive and expensive procedure, it does offer a useful alternative to medical and surgical therapies in patients with severe, intractable overactive bladder prior to considering reconstructive surgery, although technical failure may often necessitate surgical revisions.

Peripheral neuromodulation

Stimulation of the posterior tibial nerve in patients with urge incontinence was first reported in 1983⁷⁸ and has also been proposed for pelvic floor dysfunction.⁷⁹ The tibial nerve is a mixed nerve containing L4–S3 fibers and originates from the same spinal cord segments as the innervation to the bladder and pelvic floor. Consequently peripheral neural modulation may have a role in the management of urinary symptoms.

Posterior tibial nerve stimulation is performed by the insertion of a needle in the lower leg posterior to the tibia and two finger widths above the medial malleolus. Treatment is performed in the outpatient setting weekly for the first 12 weeks and then monthly maintenance therapy with each session lasting 30 minutes.

In a prospective multicenter study, 35 patients with urge incontinence underwent 12 weekly sessions of posterior tibial nerve stimulation (PTNS) with 70% of patients reporting a greater than 50% reduction in urinary symptoms and 46% being completely cured.⁸⁰ In addition, a randomized trial of posterior tibial nerve stimulation versus sham stimulation has demonstrated improvement in 54.5% of the active arm compared to 20.9% in the sham arm.⁸¹

More recently a prospective randomized multicenter North American study has been reported comparing PTNS with tolterodine 4 mg ER in 100 patients. Overall there was an improvement in 75% of patients with PTNS compared to 55.8% with tolterodine ER and there was a significant improvement in QoL in both groups.⁸² Furthermore a recent systematic review and meta-analysis has reported a subjective success rate of 61.4% (95% CI 57.5–71.8) and objective success rate of 60.6% (95% CI 49.2–74.7) and also demonstrated similar efficacy to antimuscarinic therapy.⁸³

Consequently peripheral neuromodulation may offer an alternative therapeutic option for those patients with intractable overactive bladder who have failed to respond to medical therapy.

Approximately 10% of women with OAB remain refractory to medical and behavioral therapy and may be considered for surgery. Various different surgical techniques have been developed, although currently augmentation is the most commonly performed technique using a clam cystoplasty or auto-augmentation using detrusor myectomy.

CLAM CYSTOPLASTY

In the clam cystoplasty⁸⁴ the bladder is bisected almost completely and a patch of gut (usually ileum) equal in length to the circumference of the bisected bladder (about 25 cm) is sewn in place. This often cures the symptoms of OAB by converting a high-pressure system into a low-pressure system, although inefficient voiding may result. Patients have to learn to strain to void or may have to resort to clean intermittent self-catheterization, sometimes permanently. In addition, mucus retention in the bladder may be a problem and chronic exposure of the ileal mucosa to urine may lead to malignant change.

DETRUSOR MYECTOMY

Detrusor myectomy offers an alternative to clam cystoplasty by increasing functional bladder capacity without the complications of bowel interposition. In this procedure the whole thickness of the detrusor muscle is excised from the dome of the bladder, thereby creating a large bladder diverticulum with no intrinsic contractility.⁸⁵ Whilst there is a reduction in episodes of incontinence, there is little improvement in functional capacity and thus frequency remains problematic.⁸⁶

URINARY DIVERSION

As a last resort, for those women with severe OAB or neurogenic detrusor overactivity who cannot manage clean intermittent catheterization, it may be more appropriate to perform a urinary diversion. Usually this will utilize an ileal conduit to create an incontinent abdominal stoma for urinary diversion. An alternative is to form a continent diversion using the appendix (Mitrofanoff) or ileum (Koch pouch) which may then be drained using self-catheterization. 

The medical management of OAB has recently been reviewed by the National Institute for Health and Care Excellence (NICE). ⁸⁷

• Patients should be counselled regarding caffeine and fluid intake.
• Those who are overweight (BMI >30) should be encouraged to lose weight.
• Pelvic floor muscle training (PFMT) lasting for a minimum of 3 months should be offered to all women with mixed incontinence.
  
• Bladder retraining lasting for a minimum of 6 weeks should be offered to all women with mixed or urge incontinence.
• In those women who do not achieve satisfactory benefit from bladder retraining alone the combination of an antimuscarinic agent, in addition to bladder retraining should be considered.
• Immediate release non-propriety oxybutynin, tolterodine or darifenacin should be offered to women with OAB or mixed urinary incontinence as first-line drug treatment if bladder retraining has been ineffective.
• If first-line therapy is not well tolerated, the drug with the lowest acquisition cost should be used as second-line therapy. Transdermal oxybutynin and mirabegron may also be used in patients who have had significant adverse effects with antimuscarinics. In addition women should be counselled regarding the adverse effects of antimuscarinic drugs.
• A medication review should be performed at 4 weeks. If there is clinical improvement, then treatment should continue. If there is lack of efficacy or troublesome side-effects, then an alternative drug should be prescribed.
• Patients on medication should be followed up at 12 months. Those over the age of 75 years should be followed up at 6 months.
• Referral to secondary care should be considered if symptoms do not improve with primary or secondary therapy.
• Systemic hormone replacement therapy should not be recommended, although intravaginal estrogens are recommended for the treatment of OAB in postmenopausal women with urogenital atrophy.
• Patients referred to secondary care should be investigated with urodynamic investigations and their medical management discussed at a multidisciplinary team meeting (MDT).
• Patients who are happy to self catheterize, have been taught how to do so, and have a diagnosis of detrusor overactivity, should be offered botulinum toxin.
• Sacral neuromodulation may be offered to patients who are unable to self catheterize or who have failed on botulinum toxin.
• Posterior tibial nerve stimulation should be considered in women when botulinum toxin or sacral neuromodulation are not appropriate.
• If conservative measures fail, those patients who are able to self catheterize should be offered augmentation cystoplasty. Those who are unable to self catheterize should be offered a urinary diversion.

Overactive bladder is a common and distressing condition which is known to have a significant effect on QoL. The clinical diagnosis of OAB is often one of exclusion, although urodynamic investigations are helpful in those women with refractory or unusual symptoms. The majority of women will benefit from conservative measures in the first instance, although many will eventually require drug therapy. Whilst antimuscarinic drugs are currently integral in the medical management of OAB, new drugs remain under development and β3-agonists may offer an alternative mode of treatment for those women who have persistent symptoms or intolerable adverse effects. In addition a different approach to drug therapy, by tailoring medication to the individual patient, may also improve compliance and acceptability. For those women with refractory symptoms who fail to derive sufficient benefit with medical therapy, alternative treatment approaches with botulinum toxin and neuromodulation now offer effective alternatives to reconstructive surgery.