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Treatment of overactive bladder syndrome and detrusor overactivity
Reviews in Gynaecological Practice 5 (2005) 243–250 www.elsevier.com/locate/rigp
Treatment of overactive bladder syndrome and detrusor overactivity Hashim Hashim *, Paul Abrams Bristol Urological Institute, Southmead hospital, Westbury on Trym, Bristol BS10 5NB, UK Received 22 April 2005; accepted 18 July 2005 Available online 30 August 2005
Abstract The overactive bladder syndrome is a relatively new-term defined by the International Continence Society in 2002. Previous definitions were based on urodynamic diagnoses; however, the overactive bladder syndrome is a symptomatic diagnosis with urgency as the cornerstone symptom, thus allowing treatment to be initiated by primary care physicians before embarking on complex investigations. It affects millions of people worldwide and has considerable economic costs. Its aetiology is unknown but some people suggest that it may be a nerve-related problem while others suggest that it may be a muscle-related problem. The true cause probably lies somewhere between the two theories. With this in mind, treatment is aimed at relief of symptoms and improving quality of life. Conservative treatments combined with antimuscarinic drugs are the main treatment for overactive bladders. There are many antimuscarinics available, with several under development, which have different specificities for the muscarinic receptors. Other drugs have also been tried but with limited success. If conservative and oral medical treatments fail, the options include intravesical therapy, neuromodulation or major surgery. However, urodynamics are essential for patients referred for these treatments, which are mainly initiated by specialists rather than primary care physicians. The aim of this review is to give an overview of the overactive bladder and detrusor overactivity, their diagnosis and treatment options. # 2005 Elsevier B.V. All rights reserved. Keywords: Overactive bladder; Detrusor overactivity; Antimuscarinics; Neuromodulation
1. Definition and prevalence The International Continence Society defined the overactive bladder (OAB) as a syndrome consisting of urgency, with or without urge incontinence, usually with frequency and nocturia, if there is no proven infection or other obvious pathology [1]. Urgency is the complaint of a sudden compelling desire to pass urine, which is difficult to defer. Urgency urinary incontinence (UUI) is the complaint of involuntary leakage of urine accompanied by or immediately preceded by urgency. Increased daytime frequency is the complaint by the patient who considers that he/she voids too often by day. Nocturia is the complaint that the individual has to wake at night one or more times to void. Detrusor overactivity is an urodynamic observation characterised by involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked. * Corresponding author. Tel.: +44 117 959 5690; fax: +44 117 950 2229. E-mail address: [email protected] (H. Hashim). 1471-7697/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.rigp.2005.07.003
The above definition of OAB is based on a clinical diagnosis and compliments previous definitions, which were based on detrusor function during the filling phase of urodynamics. OAB is suggestive of urodynamically demonstrable detrusor overactivity (DO), where DO replaced the older term of detrusor instability, i.e. OAB is a clinical diagnosis while DO is an urodynamic diagnosis. Not all patients with OAB will have DO and equally some patients with DO may not have OAB. Prevalence of OAB increases with age but differs between the sexes. In Europe, it is about 16.6% (15.6% in men; 17.4% in women) [2], in USA, it is about 16.6% (16% in men; 16.9% in women) [3] while in Canada it is 18.1% (14.8% in men; 21.2% in women) [4]. 2. Quality of life and social costs OAB is a prevalent condition that can affect all aspects of quality of life (QoL) and with significant costs to society.
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Despite increasing number of campaigns to increase awareness, OAB remains to be under-reported, because many patients do not present to their general practitioner for several reasons [5] including patients being unaware of the treatment options, worried that cancer may be diagnosed or considering the problem as part of normal ageing. Economic costs of OAB and incontinence in the UK were estimated to be around £743 million for the year 2000. In the USA, it was about US$ 12.6 billion and US$ 19.5 billion for OAB and incontinence, respectively, for the year 2000. The costs of OAB are mainly direct ones and are comparable to that of asthma and osteoporosis [6]. The indirect and intangible costs are difficult to calculate but would definitely increase the total costs; for example, the increased risk of hip fractures secondary to falls, in patients who have to rush to the toilet because of urgency [7].
3. Aetiology of OAB Bladder filling and emptying are controlled by a complex interaction between the central and peripheral nervous systems as well as by local regulatory factors. Bladder disorders can, therefore, result from a problem at any level in the control mechanisms. During the bladder filling phase, which is when OAB symptoms occur, there is continuous and increasing afferent activity from the bladder. Three main theories have been proposed for the aetiology of OAB. The muscle-related theory suggests that changes in the smooth muscle leading to increased excitability and coupling between cells are a prerequisite for involuntary detrusor contractions [8]. This can happen with bladder outflow obstruction and ageing. The nerve-related theory suggests that damage to the nerves in the brain and spinal cord can result in changes that trigger DO [9]. In suprapontine lesions, such as stroke and Parkinson’s disease, there is a loss of inhibition of the micturition reflex leading to uninhibited DO. Spinal cord lesions, such as multiple sclerosis, above the lumbosacral region and below the level of the pons, results in DO mediated by the spinal reflex pathways and C-fibre afferents. The third theory is the autonomous bladder theory. It has been recently proposed and suggests that DO is generated by a network of myofibroblasts causing inappropriate activation and modulation of normal phasic activity in the bladder [10]. The true cause of OAB is still unknown and it is probably a mixture of the above theories as well as other that still have not been discovered.
to look for urogenital atrophy, leakage when coughing, strength of pelvic squeeze and pelvic organ prolapse using a Sim’s speculum with the patient lying in the left lateral position. The International Continence Society Pelvic Organ Prolapse Quantification (ICS POP-Q) test could be used when describing pelvic organ prolapse [11,12]. In simple terms, three types of POP are identified: anterior vaginal wall, posterior vaginal wall and apex of the vagina or vault prolapse. The hymen is used as a reference point to define the degree of prolapse and six specific vaginal sites are measured in centimetres from that reference point (Fig. 1) giving four degrees of prolapse. A simple neurological examination of the lower limbs should also be performed looking at tone, power, sensation and reflexes. Urinalysis using reagent strips should be done to exclude urinary tract infections, glucosuria and haematuria. A urine free flow rate and post-void residual urine needs to be done to look for any evidence of retention and incomplete bladder emptying. All patients with lower urinary tract symptoms should be asked to fill out a voiding diary, which could be a micturitiontime chart, a frequency–volume chart or a bladder diary [1]. Controversy exists about the number of days that a diary should be filled for. Recent evidence suggests that in women a 4-day diary will be sufficient in providing adequate information to aid diagnosis and treatment [13]. A voiding diary will give a better picture regarding symptoms and help in excluding conditions, such as global and nocturnal polyuria. The bladder diary is also an invaluable tool in assessing the treatment effects. Ideally, QoL should also be assessed before and after treatment, using a validated disease-specific questionnaire, e.g. KHQ, ICI-OABq and ICIQ [14–16]. Follow-up of the patient should be arranged after 1 week to analyse the bladder diary and QoL questionnaire. A preliminary diagnosis of OAB is then made and treatment initiated. In women, it is sometimes difficult to make an accurate diagnosis of OAB because more than half the women will have mixed symptoms of urgency and stress
4. Diagnosis of OAB A thorough history and examination forms the basis of an accurate diagnosis. This includes enquiry about urological, obstetric and gynaecological symptoms and examination of the abdomen and genitalia including a vaginal examination
Fig. 1. Six sites (points Aa, Ba, C, D, Bp and Ap), genital hiatus (gh), perineal body (pb) and total vaginal length (tvl), used for pelvic organ support quantification in the POP-Q. (Reprinted with permission from Health Publications Limited.)
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incontinence making diagnosis of OAB, based on symptoms alone, more difficult.
5. Treatment Since the true cause of OAB is still unknown, treatment is aimed at relief of symptoms rather than cure. There are five treatment options: (1) (2) (3) (4) (5)
conservative treatment; oral pharmacological treatment; intravesical therapy; neuromodulation; surgical treatment.
5.1. Conservative treatment Conservative management includes education about the condition, addressing risk factors for OAB, such as obesity and smoking, lifestyle interventions, bladder training and pelvic floor muscle exercises (PFME). Lifestyle interventions include manipulation of fluid input to restrict carbonated and caffeine-containing drinks [17] as well as limiting fluid input to about 1.5 L in 24 h. Results from a large epidemiological study seem to show a reduced risk of OAB with higher consumption of vegetables, bread, chicken, Vitamin D, protein and potassium [18,19]. In those who suffer with nocturia, advice should be given on elevating the legs during the afternoon, above the level of the heart to help drain any dependant oedema, avoid drinking or eating water-containing foods, such as fruits and vegetables, about 4 h before going to bed and emptying the bladder before going to sleep. Bladder training, supplemented by PFME (Kegel exercises), aims to improve control of involuntary detrusor contractions, increase bladder capacity and decrease micturition frequency [20]. This can be achieved by teaching the patient to void at regular intervals, and then increase the interval by 10 or 15 min each week, until they feel comfortable with their micturition frequency. If they get an involuntary contraction, they should tighten their pelvic floor to try to suppress the contraction. Biofeedback and/or electrical stimulation can be used as adjuncts to bladder training in patients who are unable to locate their pelvic floor muscles and are unable to contract them voluntarily [21]. Conservative treatment is safe, cheap and effective in reducing OAB symptoms but needs patient motivation as it can be time consuming. The best effect of conservative treatment seems to be when it is combined with oral pharmacotherapy [22]. 5.2. Oral pharmacotherapy Five different muscarinic receptor subtypes (M1–M5) have been identified in the human body, distributed
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throughout the organs, including the bladder. Acetylcholine (Ach) is the main neurotransmitter acting on these receptors and responsible for mediating detrusor contraction. Therefore, the use of antimuscarinic drugs would block the action of Ach at these receptors, throughout the body, including the bladder, causing a reduction in detrusor contraction. The M2 subtype makes up two thirds of the receptors in the bladder but it is the M3 receptors, which are mainly responsible for detrusor contraction, although they only make up a third of the receptors [23]. Blockade of the M3 receptors at other organs results in side effects including constipation (smooth muscle), dry mouth (salivary glands), blurred vision (eyes) and dizziness (brain). Blockage of the M2 receptors results in tachycardia. Antimuscarinics form the cornerstone of pharmacological management of OAB. They are more effective than placebo in reducing OAB symptoms but can be poorly tolerated due to side effects [24]. Five main antimuscarinics are currently available on the market: oxybutynin, tolterodine, propiverine, trospium and solifenacin. 5.2.1. Oxybutynin chloride Oxybutynin (OXY) is a tertiary antimuscarinic amine with musculotropic, smooth muscle-relaxant and local anaesthetic effects. It has a high affinity for M1 and M3 receptors in the bladder and parotid gland with 12 times more selectivity for M3 over M2 receptors [25]. OXY is available in two oral tablet formulations, immediate-release (OXY IR) and extended-release (OXY ER) and a topical transdermal patch formulation (OXY TD). OXY IR is administered three times per day. It is extensively metabolised in the liver to its active metabolite, N-desethyloxybutynin, which has similar properties to the parent compound and contributing to its side effect profile. OXY IR acts within 30–60 min and exerts its maximum effect within 3–6 h of administration. OXY ER, on the other hand, is administered once daily, with plasma concentration increasing within 4–6 h and maintained fairly constant over 24 h. It is as effective as OXY IR in reducing UUI but better tolerated with less dry mouth and constipation [26], resulting in improved compliance in taking the tablet. Oxybutynin has recently been marketed as a transdermal patch, thus avoiding first-pass metabolism and causing less antimuscarinic side effects compared to OXY IR. It reaches peak plasma concentration within 36 h and is applied twice weekly to the abdomen, hips or buttocks in an alternating manner to reduce skin irritation, pruritis and erythema. OXY TD is comparative to tolterodine extended-release in efficacy of reducing the average number of UUI episodes, increasing the voided volume and improving QoL [27]. 5.2.2. Tolterodine tartrate Tolterodine (TOLT) is a synthetic competitive antimuscarinic tertiary amine. Unlike OXY, TOLT has greater selectivity for the bladder over salivary glands but only four
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times selectivity for the M3 over M2 receptors [28]. It is administered orally in an immediate-release (TOLT IR) or extended-release (TOLT ER) form. TOLT, like OXY, undergoes extensive first-pass metabolism, but reaches peak serum concentrations within 1–2 h after administration of TOLT IR and 2–6 h after TOLT ER. TOLT IR is well tolerated, improves QoL, decreases urinary frequency and UUI episodes with an increase in volume voided/void when compared to placebo. TOLT IR is as effective as OXY IR in reducing frequency and UUI episodes and increasing voided volume/void in 24 h but causes less dry mouth and adverse events resulting in better tolerability and compliance [29]. Compared to OXY ER, TOLT IR causes similar frequencies of dry mouth and CNS side effects resulting in equal tolerability and discontinuation rates, but it is less effective in reducing micturition frequency and UUI episodes [30]. TOLT ER works after only 1 week of treatment with maximum benefit after 4 weeks. It has good tolerability and safety over a 12 months period and is more effective than TOLT IR in improving OAB symptoms of urinary frequency, urgency and UUI, resulting in decreased pad usage, improvement in mean voided volume/void and QoL, with less dry mouth [31]. In clinical trials, both TOLT ER and OXY ER, showed similar improvement in reducing UUI episodes. On the other hand, OXY ER was more effective at reducing micturition frequency and improving total dryness [32] but patients on TOLT ER had a better degree of perceived improvement in their bladder symptoms [33]. CNS side effects were similar between OXY ER and TOLT ER but dry mouth was significantly more common with OXY ER resulting in poorer tolerability. 5.2.3. Propiverine Propiverine is a tertiary antimuscarinic with calcium antagonistic effects [34]. It undergoes extensive first-pass metabolism, following oral administration, reaching peak plasma levels in about 2.5 h with a half-life of 11–14 h. It is eliminated in urine, bile and faeces. Compared to placebo, propiverine reduces urgency and frequency episodes, resulting in an increase in the mean volume voided/void. Improvement in clinical parameters and urodynamic parameters is comparable to TOLT IR and OXY IR, respectively [35,36]. Its tolerability is also comparable to TOLT IR but causes less dry mouth than OXY IR. It does not seem to improve QoL much more than placebo [37]. 5.2.4. Trospium chloride Trospium chloride (TCL) is a hydrophilic competitive quaternary antimuscarinic amine with equal selectivity to the M3 and M2 receptors [38]. It, theoretically, does not cross the blood brain barrier, resulting in less CNS side effects compared to the lipophilic tertiary antimuscarinics.
Following oral administration, TCL is poorly absorbed from the upper gastrointestinal tract, reaching peak plasma concentration after 4–6 h, of which 80% is excreted in the stool as the active parent compound. TCL helps with all OAB symptoms. It decreases urgency, frequency and UUI episodes, within 1 week, and nocturia within 4 weeks, of starting treatment [39]. It seems to be as effective as OXY IR and TOLT IR [40] in reducing frequency but more effective than TOLT IR in reducing UUI episodes and better tolerated than OXY IR. 5.2.5. Solifenacin succinate Solifenacin is the latest bladder-selective antimuscarinic to be launched. It is available in two doses, as once daily oral administrations, which are primarily cleared by hepatic metabolism with some urinary excretion. Solifenacin reaches peak plasma concentration in 3–8 h and has very good bioavailability because it has the longest half-life (45– 68 h) compared to all the other antimuscarinics. It is about 12 times more selective for the M3 over M2 receptor subtype [41] and is more selective towards the bladder over salivary glands compared to tolterodine, oxybutynin and darifenacin [42]. Solifenacin significantly reduces the mean number of all OAB symptoms per 24 h compared to placebo [43,44] for 1 year of administration, improving QoL [45] and suggesting it has good tolerability with a low discontinuation [46]. Side effects are antimuscarinic in nature. Pooling the results of four trials, it was found that both solifenacin and TOLT IR reduced frequency, urgency and UUI episodes significantly compared to placebo but only solifenacin significantly reduced nocturia [47]. These were not head-to-head trials, but recently, the STAR study was completed. Solifenacin was used in a flexible dose regimen with tolterodine XL as an active comparator in a double blind, double dummy, randomised controlled overactive bladder symptom trial. Solifenacin, with a flexible dosing regimen, showed superior efficacy to TOLT XL in reducing urgency, UUI and pads used and in increasing the volume voided per void. Solifenacin was not inferior to TOLT XL in improving nocturia or daytime frequency. Side effects were mainly mild to moderate and discontinuation rates were comparable in both groups [48]. 5.2.6. New antimuscarinics Darifenacin hydrobromide and fesoterodine are new antimuscarinics that have completed phase three trials and will be launched in the near future. Darifenacin, available in two oral doses of 7.5 and 15 mg, is a tertiary amine and is 59 times more selective for the M3 over M2 receptor subtype [49]. It has a rapid onset of action, reaching peak plasma concentration in about 7 h. In multicentre, double blind clinical trials, it caused significant median reduction, within 2 weeks of administration, in all OAB symptoms as well as increasing bladder capacity and
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warning time (time from the first sensation of urgency to voluntary micturition or incontinence), at both doses, compared to placebo [50,51]. Darifenacin is well tolerated and improves QoL. It seems to have long-term safety with no cardiac or CNS effects, especially in the elderly. Fesoterodine is a specific but non-subtype selective antimuscarinic that seems to be effective and well tolerated [52]. Following oral administration, it is extensively metabolised in the liver, reaching maximum plasma levels after about 5 h. Results of the phase III trials will be published in the near future.
7. What if conservative and medical treatment fails?
5.2.7. Other oral pharmacological agents Many pharmacological agents, such as flavoxate, imipramine and propantheline, have been used in the past and continue to be used, especially in developing countries for the treatment of OAB; however, the level of evidence available is not sufficient for them to be recommended for general use. This also applies for local vaginal oestrogens, which, in a meta-analysis, have been shown to be effective in relieving frequency, nocturia, urgency and incontinence episodes especially in postmenopausal women [53].
7.1. Intravesical pharmacotherapy
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If one drug fails to improve symptoms, assuming good patient compliance, then either another drug should be tried or the patient referred for urodynamics, and a specialist urological or urogynecological opinion, to establish a diagnosis. Once a diagnosis of DO is confirmed, the other available antimuscarinics should be tried especially the extended-release ones. Should these fail to relieve symptoms, available options include intravesical therapy, neuromodulation or surgery.
7.1.1. Oxybutynin chloride Intravesical OXY is another formulation of oxybutynin that offers an increase in bladder capacity and improvement in clinical symptoms. This route avoids liver metabolism, thus patients have less dry mouth than oral OXY. Its mode of action is uncertain but the local anaesthetic effect, on the bladder wall, of OXY may be important in temporarily desensitising afferent C-fibres. The intravesical route of administration is inconvenient and should be reserved for patients who do not respond to oral therapy and are already catheterised or perform intermittent self-catheterisation.
6. Which oral antimuscarinic to use? Essentially, all the antimuscarinics do the same job, but some do it better than others. Choice of one drug over the other is very difficult and is governed by many factors including drug availability, cost, tolerability, compliance and physician preference. Based on current evidence from clinical trials, OXY ER and TOLT ER are more efficacious with better tolerability and compliance than OXY IR and TOLT IR, but are more expensive. OXY TD, TCL and solifenacin improve symptoms of OAB with minimal CNS effects at a slightly lower cost than TOLT ER but more than OXY ER. It is, therefore, very difficult to recommend guidelines on drug prescription but OXY ER and TOLT ER should probably be used as first-line treatments, if available. OXY TDS, TCL and solifenacin, help increase the armamentarium of drugs available to treat OAB. TCL may be used in the elderly and in those who operate machinery as the first-line agent due to the reduced risk of CNS side effects. Following the publication of the STAR data, solifenacin may in the future be used as a first-line agent replacing TOLT ER and OXY ER but will probably be reserved for second-line treatment until health care providers obtain more clinical experience in using it. OXY TD will have a role in the treatment of OAB especially in patients who cannot swallow tablets or in patients who are on multiple drugs, especially elderly patients, thus reducing the risk of drug interactions. If none of the above drugs are available then propiverine, OXY IR or TOLT IR could be used.
7.1.2. Botulinum-A toxin Some urologists and urogynecologists have been using Botulinum-A toxin (BTA) as second-line treatment for neurogenic DO, with good results, as it selectively blocks release of Ach from nerve endings. BTA is effective in reducing UUI by allowing the bladder to hold and retain more urine [54]. BTA is injected into the bladder via a flexible cystoscope under local anaesthetic. Its effects usually last about 9 months; however, data is lacking on exact site and number of injections, optimal doses and concentrations to be used and long-term side effects. Its effect, compared to placebo, remains to be established in idiopathic DO by the use of randomised controlled trials. 7.1.3. Capsaicin and resiniferatoxin Capsaicin is a crystalline alkaloid and is the main active compound that causes the heat in chilli peppers. In the bladder, it acts on vanilloid receptors rendering the afferent C-fibres resistant to activation by natural stimuli. Only a small and very limited number of trials have been published looking at the effects of capsaicin on DO, and thus its use is mainly experimental. Side effects include pain, discomfort and burning sensation at the pubic-urethral level during instillation, autonomic dysreflexia and inflammatory reactions. Resiniferatoxin (RTX), an ultra-potent analogue of capsaicin, acts selectively on vanilloid receptor subtype-1 to desensitise unmyelinated afferent C-fibres. RTX is as effective as capsaicin in relieving clinical and urodynamic symptoms of neurogenic DO [55], with less bladder
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irritation; however, no trials have compared their effects to placebo. In idiopathic DO, RTX does not seem to provide any benefit over placebo in relief of OAB symptoms or improvement in urodynamic parameters [56]. Randomised placebo controlled trials are needed to look at its effect in patients with DO as well as determining the optimal dosage and intervals between treatments. 7.2. Neuromodulation Sacral nerve stimulation (SNS) [57] and percutaneous tibial nerve stimulation (PTNS) [58] are used for intractable OAB and DO and voiding difficulties. SNS is minimally invasive and involves implanting a neurostimulator in the buttock, which sends electric impulses to the sacral nerves to help control OAB symptoms. In PTNS, a needle electrode is inserted proximal to the medial malleolus, which stimulates the afferent nerve fibres of the tibial nerve modulating the sacral nerve plexus. Both SNS and PTNS increase bladder capacity and reduce frequency, UUI episodes and nocturia with improvement in QoL. The direct costs of SNS, including the device cost, hospitalisation costs and professional costs, are approximately £8000–£10000 per patient. These costs do not include the cost of surgical revision or replacement of the device. However, once the device is in place and calibrated appropriately, the cost associated with managing DO will decrease with an improvement in the QoL of patients. The devices normally last between 5 and 10 years. In the longterm, neuromodulation seems to be more cost-effective than, for example, using incontinence pads, and thus neuromodulation will probably help ‘bridge the gap’ between pharmacotherapy and major surgery. 7.3. Surgery Many surgical options exist but are reserved as a last resort for patients with DO, especially those with neurogenic DO. These include augmentation cystoplasty (aims to increase bladder capacity by augmenting the bladder with bowel), detrusor myectomy (removing the detrusor muscle resulting in a surgical diverticulum) and urinary diversion (bypasses the bladder). However, these procedures are not without complications including recurrent infections, stones, bowel obstruction and perforation, failure resulting in re-operation and about 10% of patients requiring intermittent self-catheterisation to empty the bladder. These procedures have now almost replaced the previous procedures of bladder hydrodistension, bladder denervation or transection, transvesical phenol injections and cystolysis, which did not produce good results with high recurrence and complication rates. So far, there are no prospective randomised controlled trials assessing any of these surgical procedures [11].
8. Conclusion OAB is a prevalent condition affecting millions of people worldwide causing significant economic costs. Unfortunately the precise cause of OAB is unknown and treatment is aimed at relieve of symptoms and improving QoL rather than cure. Conservative treatment including lifestyle interventions, bladder training and PFME should be combined with antimuscarinics to offer the best treatment combination. Many new drugs are currently undergoing research to look for new ways of treating OAB. If combination therapy fails and before any further treatment is initiated, the patient should be referred for urodynamics to confirm the diagnosis. In intractable OAB cases, intravesical therapy, neuromodulation and finally surgery could be tried. Practice points Take a thorough history and examination especially of lower urinary tract symptoms. Exclude other pathologies. Perform urinalysis, flow-rate and measure post-void residual urine. Ask the patient to complete a bladder diary and quality of life questionnaire. Treat with a combination of conservative and medical treatments. If treatment fails, refer to a specialist for urodynamics and further management. Research directions Large randomised controlled trials with long-term follow-up on many different aspects of conservative treatment. Large randomised controlled ‘head-to-head’ trials of different antimuscarinics. More long-term data on use of antimuscarinics and other treatments. Trials looking at the effects of antimuscarinics in the community rather than in the setting of clinical trials. Analysis of data looking at difference over placebo rather than difference over baseline. Basic science research into the cause of overactive bladder.
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[24] Andersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004;3(January (1)):46–53. [25] Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther 2004;310(September (3)):1255–65. [26] 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(6):809–12. [27] Dmochowski RR, Sand PK, Zinner NR, Gittelman MC, Davila GW, Sanders SW. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 2003;62(August (2)):237–42. [28] Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther 2004;310(September (3)):1255–65. [29] Abrams P, Freeman R, Anderstrom C, Mattiasson A. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998;81(6):801–10. [30] 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(April (4)):358–63. [31] Zinner NR, Mattiasson A, Stanton SL. Efficacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients. J Am Geriatr Soc 2002;50(5):799–807. [32] 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(June (6)):687–95. [33] Sussman D, Garely A. Treatment of overactive bladder with oncedaily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET). Curr Med Res Opin 2002;18(4):177–84. [34] Madersbacher H, Murtz G. Efficacy, tolerability and safety profile of propiverine in the treatment of the overactive bladder (non-neurogenic and neurogenic). World J Urol 2001;19(5):324–35. [35] Ju¨nemann KP, Halaska M, Rittstein T, Bruenjes R. Propiverine vs. tolterodine—efficacy and tolerability in patients with detrusor overactivity (Abstract 26). Neurourol Urodyn 2003;22(5):401. [36] Madersbacher H, Halaska M, Voigt R, Alloussi S, Hofner K. A placebo-controlled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU Int 1999;84(October (6)):646–51. [37] Juenemann K, Hessdoerfer E, Unamba-Oparah I, Berse M, Bruenjes R, Madersbacher H, et al. Propiverine hydrochloride immediate (IR) and extended release (ER): comparison of efficacy and tolerability in overactive bladder (Abstract 143). Neurourol Urodyn 2004;23(5– 6):599–600. [38] Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther 2004;310(3):1255–65. [39] 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(June (6 Pt 1)):2311–5. quiz.
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[40] Ju¨nemann KP, Al-Shukri S. Efficacy and tolerability of trospium chloride and tolterodine in 234 patients with urge-syndrome: a double-blind, placebo-controlled, multicentre trial (Abstract 85B). Neurourol Urodyn 2000;19:488–90. [41] Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther 2004;310(September (3)):1255–65. [42] Kobayashi S, Ikeda K, Miyata K. Comparison of in vitro selectivity profiles of solifenacin succinate (YM905) and current antimuscarinic drugs in bladder and salivary glands: a Ca2+ mobilization study in monkey cells. Life Sci 2004;74(7):843–53. [43] 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(3):303–10. [44] Cardozo L, Lisec M, Millard R, van Vierssen TO, 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(5 Pt 1):919–24. [45] Kelleher CJ, Cardozo L, Chapple CR, Haab F, Ridder AM. Improved quality of life in patients with overactive bladder symptoms treated with solifenacin. BJU Int 2005;95(1):81–5. [46] 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(March (3)):376–84. [47] Yamanouchi Pharma Ltd., Vesicare (solifenacin). Summary of product characteristics; 16 August 2004. [48] 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.
[49] Nelson CP, Gupta P, Napier CM, Nahorski SR, Challiss RA. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. J Pharmacol Exp Ther 2004;310(3):1255–65. [50] Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol 2004;45(4):420–9. [51] Khullar V. Darifenacin, an M3 selective receptor antagonist, reduces the frequency of nocturnal awakening, an important symptom of overactive bladder (Abstract 491). J Urol 2004;171(4 Suppl.):131. [52] Chapple C. Fesoterodine a new effective and well-tolerated antimuscarinic for the treatment of urgency-frequency syndrome: results of a phase 2 controlled study (Abstract 142). Neurourol Urodyn 2004;23(5–6):598–9. [53] Cardozo L, Lose G, McClish D, Versi E. A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder. Acta Obstet Gynecol Scand 2004;83(October (10)):892–7. [54] Smith CP, Nishiguchi J, O’Leary M, Yoshimura N, Chancellor MB. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005;65(1):37–41. [55] de SM, Wiart L, de Seze MP, Soyeur L, Dosque JP, Blajezewski S, et al. Intravesical capsaicin versus resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: a doubleblind, randomized, controlled study. J Urol 2004;171(January (1)):251–5. [56] Rios L, Mattos Jr D, Panhoca R, Srougi M, Bruschini H. Intravesical resiniferatoxin for the treatment of idiopatic detrusor overactivity in women: a randomized placebo controlled trial (Abstract 147). Neurourol Urodyn 2004;23(5–6):604–5. [57] Abrams P, Blaivas JG, Fowler CJ, Fourcroy JL, MacDiarmid SA, Siegel SW, et al. The role of neuromodulation in the management of urinary urge incontinence. BJU Int 2003;91(March (4)):355–9. [58] Govier FE, Litwiller S, Nitti V, Kreder Jr KJ, Rosenblatt P. Percutaneous afferent neuromodulation for the refractory overactive bladder: results of a multicenter study. J Urol 2001;165(4):1193–8.
Treatment of overactive bladder syndrome and detrusor overactivity Hashim Hashim *, Paul Abrams Bristol Urological Institute, Southmead hospital, Westbury on Trym, Bristol BS10 5NB, UK Received 22 April 2005; accepted 18 July 2005 Available online 30 August 2005
Abstract The overactive bladder syndrome is a relatively new-term defined by the International Continence Society in 2002. Previous definitions were based on urodynamic diagnoses; however, the overactive bladder syndrome is a symptomatic diagnosis with urgency as the cornerstone symptom, thus allowing treatment to be initiated by primary care physicians before embarking on complex investigations. It affects millions of people worldwide and has considerable economic costs. Its aetiology is unknown but some people suggest that it may be a nerve-related problem while others suggest that it may be a muscle-related problem. The true cause probably lies somewhere between the two theories. With this in mind, treatment is aimed at relief of symptoms and improving quality of life. Conservative treatments combined with antimuscarinic drugs are the main treatment for overactive bladders. There are many antimuscarinics available, with several under development, which have different specificities for the muscarinic receptors. Other drugs have also been tried but with limited success. If conservative and oral medical treatments fail, the options include intravesical therapy, neuromodulation or major surgery. However, urodynamics are essential for patients referred for these treatments, which are mainly initiated by specialists rather than primary care physicians. The aim of this review is to give an overview of the overactive bladder and detrusor overactivity, their diagnosis and treatment options. # 2005 Elsevier B.V. All rights reserved. Keywords: Overactive bladder; Detrusor overactivity; Antimuscarinics; Neuromodulation
1. Definition and prevalence The International Continence Society defined the overactive bladder (OAB) as a syndrome consisting of urgency, with or without urge incontinence, usually with frequency and nocturia, if there is no proven infection or other obvious pathology [1]. Urgency is the complaint of a sudden compelling desire to pass urine, which is difficult to defer. Urgency urinary incontinence (UUI) is the complaint of involuntary leakage of urine accompanied by or immediately preceded by urgency. Increased daytime frequency is the complaint by the patient who considers that he/she voids too often by day. Nocturia is the complaint that the individual has to wake at night one or more times to void. Detrusor overactivity is an urodynamic observation characterised by involuntary detrusor contractions during the filling phase, which may be spontaneous or provoked. * Corresponding author. Tel.: +44 117 959 5690; fax: +44 117 950 2229. E-mail address: [email protected] (H. Hashim). 1471-7697/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.rigp.2005.07.003
The above definition of OAB is based on a clinical diagnosis and compliments previous definitions, which were based on detrusor function during the filling phase of urodynamics. OAB is suggestive of urodynamically demonstrable detrusor overactivity (DO), where DO replaced the older term of detrusor instability, i.e. OAB is a clinical diagnosis while DO is an urodynamic diagnosis. Not all patients with OAB will have DO and equally some patients with DO may not have OAB. Prevalence of OAB increases with age but differs between the sexes. In Europe, it is about 16.6% (15.6% in men; 17.4% in women) [2], in USA, it is about 16.6% (16% in men; 16.9% in women) [3] while in Canada it is 18.1% (14.8% in men; 21.2% in women) [4]. 2. Quality of life and social costs OAB is a prevalent condition that can affect all aspects of quality of life (QoL) and with significant costs to society.
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Despite increasing number of campaigns to increase awareness, OAB remains to be under-reported, because many patients do not present to their general practitioner for several reasons [5] including patients being unaware of the treatment options, worried that cancer may be diagnosed or considering the problem as part of normal ageing. Economic costs of OAB and incontinence in the UK were estimated to be around £743 million for the year 2000. In the USA, it was about US$ 12.6 billion and US$ 19.5 billion for OAB and incontinence, respectively, for the year 2000. The costs of OAB are mainly direct ones and are comparable to that of asthma and osteoporosis [6]. The indirect and intangible costs are difficult to calculate but would definitely increase the total costs; for example, the increased risk of hip fractures secondary to falls, in patients who have to rush to the toilet because of urgency [7].
3. Aetiology of OAB Bladder filling and emptying are controlled by a complex interaction between the central and peripheral nervous systems as well as by local regulatory factors. Bladder disorders can, therefore, result from a problem at any level in the control mechanisms. During the bladder filling phase, which is when OAB symptoms occur, there is continuous and increasing afferent activity from the bladder. Three main theories have been proposed for the aetiology of OAB. The muscle-related theory suggests that changes in the smooth muscle leading to increased excitability and coupling between cells are a prerequisite for involuntary detrusor contractions [8]. This can happen with bladder outflow obstruction and ageing. The nerve-related theory suggests that damage to the nerves in the brain and spinal cord can result in changes that trigger DO [9]. In suprapontine lesions, such as stroke and Parkinson’s disease, there is a loss of inhibition of the micturition reflex leading to uninhibited DO. Spinal cord lesions, such as multiple sclerosis, above the lumbosacral region and below the level of the pons, results in DO mediated by the spinal reflex pathways and C-fibre afferents. The third theory is the autonomous bladder theory. It has been recently proposed and suggests that DO is generated by a network of myofibroblasts causing inappropriate activation and modulation of normal phasic activity in the bladder [10]. The true cause of OAB is still unknown and it is probably a mixture of the above theories as well as other that still have not been discovered.
to look for urogenital atrophy, leakage when coughing, strength of pelvic squeeze and pelvic organ prolapse using a Sim’s speculum with the patient lying in the left lateral position. The International Continence Society Pelvic Organ Prolapse Quantification (ICS POP-Q) test could be used when describing pelvic organ prolapse [11,12]. In simple terms, three types of POP are identified: anterior vaginal wall, posterior vaginal wall and apex of the vagina or vault prolapse. The hymen is used as a reference point to define the degree of prolapse and six specific vaginal sites are measured in centimetres from that reference point (Fig. 1) giving four degrees of prolapse. A simple neurological examination of the lower limbs should also be performed looking at tone, power, sensation and reflexes. Urinalysis using reagent strips should be done to exclude urinary tract infections, glucosuria and haematuria. A urine free flow rate and post-void residual urine needs to be done to look for any evidence of retention and incomplete bladder emptying. All patients with lower urinary tract symptoms should be asked to fill out a voiding diary, which could be a micturitiontime chart, a frequency–volume chart or a bladder diary [1]. Controversy exists about the number of days that a diary should be filled for. Recent evidence suggests that in women a 4-day diary will be sufficient in providing adequate information to aid diagnosis and treatment [13]. A voiding diary will give a better picture regarding symptoms and help in excluding conditions, such as global and nocturnal polyuria. The bladder diary is also an invaluable tool in assessing the treatment effects. Ideally, QoL should also be assessed before and after treatment, using a validated disease-specific questionnaire, e.g. KHQ, ICI-OABq and ICIQ [14–16]. Follow-up of the patient should be arranged after 1 week to analyse the bladder diary and QoL questionnaire. A preliminary diagnosis of OAB is then made and treatment initiated. In women, it is sometimes difficult to make an accurate diagnosis of OAB because more than half the women will have mixed symptoms of urgency and stress
4. Diagnosis of OAB A thorough history and examination forms the basis of an accurate diagnosis. This includes enquiry about urological, obstetric and gynaecological symptoms and examination of the abdomen and genitalia including a vaginal examination
Fig. 1. Six sites (points Aa, Ba, C, D, Bp and Ap), genital hiatus (gh), perineal body (pb) and total vaginal length (tvl), used for pelvic organ support quantification in the POP-Q. (Reprinted with permission from Health Publications Limited.)
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incontinence making diagnosis of OAB, based on symptoms alone, more difficult.
5. Treatment Since the true cause of OAB is still unknown, treatment is aimed at relief of symptoms rather than cure. There are five treatment options: (1) (2) (3) (4) (5)
conservative treatment; oral pharmacological treatment; intravesical therapy; neuromodulation; surgical treatment.
5.1. Conservative treatment Conservative management includes education about the condition, addressing risk factors for OAB, such as obesity and smoking, lifestyle interventions, bladder training and pelvic floor muscle exercises (PFME). Lifestyle interventions include manipulation of fluid input to restrict carbonated and caffeine-containing drinks [17] as well as limiting fluid input to about 1.5 L in 24 h. Results from a large epidemiological study seem to show a reduced risk of OAB with higher consumption of vegetables, bread, chicken, Vitamin D, protein and potassium [18,19]. In those who suffer with nocturia, advice should be given on elevating the legs during the afternoon, above the level of the heart to help drain any dependant oedema, avoid drinking or eating water-containing foods, such as fruits and vegetables, about 4 h before going to bed and emptying the bladder before going to sleep. Bladder training, supplemented by PFME (Kegel exercises), aims to improve control of involuntary detrusor contractions, increase bladder capacity and decrease micturition frequency [20]. This can be achieved by teaching the patient to void at regular intervals, and then increase the interval by 10 or 15 min each week, until they feel comfortable with their micturition frequency. If they get an involuntary contraction, they should tighten their pelvic floor to try to suppress the contraction. Biofeedback and/or electrical stimulation can be used as adjuncts to bladder training in patients who are unable to locate their pelvic floor muscles and are unable to contract them voluntarily [21]. Conservative treatment is safe, cheap and effective in reducing OAB symptoms but needs patient motivation as it can be time consuming. The best effect of conservative treatment seems to be when it is combined with oral pharmacotherapy [22]. 5.2. Oral pharmacotherapy Five different muscarinic receptor subtypes (M1–M5) have been identified in the human body, distributed
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throughout the organs, including the bladder. Acetylcholine (Ach) is the main neurotransmitter acting on these receptors and responsible for mediating detrusor contraction. Therefore, the use of antimuscarinic drugs would block the action of Ach at these receptors, throughout the body, including the bladder, causing a reduction in detrusor contraction. The M2 subtype makes up two thirds of the receptors in the bladder but it is the M3 receptors, which are mainly responsible for detrusor contraction, although they only make up a third of the receptors [23]. Blockade of the M3 receptors at other organs results in side effects including constipation (smooth muscle), dry mouth (salivary glands), blurred vision (eyes) and dizziness (brain). Blockage of the M2 receptors results in tachycardia. Antimuscarinics form the cornerstone of pharmacological management of OAB. They are more effective than placebo in reducing OAB symptoms but can be poorly tolerated due to side effects [24]. Five main antimuscarinics are currently available on the market: oxybutynin, tolterodine, propiverine, trospium and solifenacin. 5.2.1. Oxybutynin chloride Oxybutynin (OXY) is a tertiary antimuscarinic amine with musculotropic, smooth muscle-relaxant and local anaesthetic effects. It has a high affinity for M1 and M3 receptors in the bladder and parotid gland with 12 times more selectivity for M3 over M2 receptors [25]. OXY is available in two oral tablet formulations, immediate-release (OXY IR) and extended-release (OXY ER) and a topical transdermal patch formulation (OXY TD). OXY IR is administered three times per day. It is extensively metabolised in the liver to its active metabolite, N-desethyloxybutynin, which has similar properties to the parent compound and contributing to its side effect profile. OXY IR acts within 30–60 min and exerts its maximum effect within 3–6 h of administration. OXY ER, on the other hand, is administered once daily, with plasma concentration increasing within 4–6 h and maintained fairly constant over 24 h. It is as effective as OXY IR in reducing UUI but better tolerated with less dry mouth and constipation [26], resulting in improved compliance in taking the tablet. Oxybutynin has recently been marketed as a transdermal patch, thus avoiding first-pass metabolism and causing less antimuscarinic side effects compared to OXY IR. It reaches peak plasma concentration within 36 h and is applied twice weekly to the abdomen, hips or buttocks in an alternating manner to reduce skin irritation, pruritis and erythema. OXY TD is comparative to tolterodine extended-release in efficacy of reducing the average number of UUI episodes, increasing the voided volume and improving QoL [27]. 5.2.2. Tolterodine tartrate Tolterodine (TOLT) is a synthetic competitive antimuscarinic tertiary amine. Unlike OXY, TOLT has greater selectivity for the bladder over salivary glands but only four
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times selectivity for the M3 over M2 receptors [28]. It is administered orally in an immediate-release (TOLT IR) or extended-release (TOLT ER) form. TOLT, like OXY, undergoes extensive first-pass metabolism, but reaches peak serum concentrations within 1–2 h after administration of TOLT IR and 2–6 h after TOLT ER. TOLT IR is well tolerated, improves QoL, decreases urinary frequency and UUI episodes with an increase in volume voided/void when compared to placebo. TOLT IR is as effective as OXY IR in reducing frequency and UUI episodes and increasing voided volume/void in 24 h but causes less dry mouth and adverse events resulting in better tolerability and compliance [29]. Compared to OXY ER, TOLT IR causes similar frequencies of dry mouth and CNS side effects resulting in equal tolerability and discontinuation rates, but it is less effective in reducing micturition frequency and UUI episodes [30]. TOLT ER works after only 1 week of treatment with maximum benefit after 4 weeks. It has good tolerability and safety over a 12 months period and is more effective than TOLT IR in improving OAB symptoms of urinary frequency, urgency and UUI, resulting in decreased pad usage, improvement in mean voided volume/void and QoL, with less dry mouth [31]. In clinical trials, both TOLT ER and OXY ER, showed similar improvement in reducing UUI episodes. On the other hand, OXY ER was more effective at reducing micturition frequency and improving total dryness [32] but patients on TOLT ER had a better degree of perceived improvement in their bladder symptoms [33]. CNS side effects were similar between OXY ER and TOLT ER but dry mouth was significantly more common with OXY ER resulting in poorer tolerability. 5.2.3. Propiverine Propiverine is a tertiary antimuscarinic with calcium antagonistic effects [34]. It undergoes extensive first-pass metabolism, following oral administration, reaching peak plasma levels in about 2.5 h with a half-life of 11–14 h. It is eliminated in urine, bile and faeces. Compared to placebo, propiverine reduces urgency and frequency episodes, resulting in an increase in the mean volume voided/void. Improvement in clinical parameters and urodynamic parameters is comparable to TOLT IR and OXY IR, respectively [35,36]. Its tolerability is also comparable to TOLT IR but causes less dry mouth than OXY IR. It does not seem to improve QoL much more than placebo [37]. 5.2.4. Trospium chloride Trospium chloride (TCL) is a hydrophilic competitive quaternary antimuscarinic amine with equal selectivity to the M3 and M2 receptors [38]. It, theoretically, does not cross the blood brain barrier, resulting in less CNS side effects compared to the lipophilic tertiary antimuscarinics.
Following oral administration, TCL is poorly absorbed from the upper gastrointestinal tract, reaching peak plasma concentration after 4–6 h, of which 80% is excreted in the stool as the active parent compound. TCL helps with all OAB symptoms. It decreases urgency, frequency and UUI episodes, within 1 week, and nocturia within 4 weeks, of starting treatment [39]. It seems to be as effective as OXY IR and TOLT IR [40] in reducing frequency but more effective than TOLT IR in reducing UUI episodes and better tolerated than OXY IR. 5.2.5. Solifenacin succinate Solifenacin is the latest bladder-selective antimuscarinic to be launched. It is available in two doses, as once daily oral administrations, which are primarily cleared by hepatic metabolism with some urinary excretion. Solifenacin reaches peak plasma concentration in 3–8 h and has very good bioavailability because it has the longest half-life (45– 68 h) compared to all the other antimuscarinics. It is about 12 times more selective for the M3 over M2 receptor subtype [41] and is more selective towards the bladder over salivary glands compared to tolterodine, oxybutynin and darifenacin [42]. Solifenacin significantly reduces the mean number of all OAB symptoms per 24 h compared to placebo [43,44] for 1 year of administration, improving QoL [45] and suggesting it has good tolerability with a low discontinuation [46]. Side effects are antimuscarinic in nature. Pooling the results of four trials, it was found that both solifenacin and TOLT IR reduced frequency, urgency and UUI episodes significantly compared to placebo but only solifenacin significantly reduced nocturia [47]. These were not head-to-head trials, but recently, the STAR study was completed. Solifenacin was used in a flexible dose regimen with tolterodine XL as an active comparator in a double blind, double dummy, randomised controlled overactive bladder symptom trial. Solifenacin, with a flexible dosing regimen, showed superior efficacy to TOLT XL in reducing urgency, UUI and pads used and in increasing the volume voided per void. Solifenacin was not inferior to TOLT XL in improving nocturia or daytime frequency. Side effects were mainly mild to moderate and discontinuation rates were comparable in both groups [48]. 5.2.6. New antimuscarinics Darifenacin hydrobromide and fesoterodine are new antimuscarinics that have completed phase three trials and will be launched in the near future. Darifenacin, available in two oral doses of 7.5 and 15 mg, is a tertiary amine and is 59 times more selective for the M3 over M2 receptor subtype [49]. It has a rapid onset of action, reaching peak plasma concentration in about 7 h. In multicentre, double blind clinical trials, it caused significant median reduction, within 2 weeks of administration, in all OAB symptoms as well as increasing bladder capacity and
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warning time (time from the first sensation of urgency to voluntary micturition or incontinence), at both doses, compared to placebo [50,51]. Darifenacin is well tolerated and improves QoL. It seems to have long-term safety with no cardiac or CNS effects, especially in the elderly. Fesoterodine is a specific but non-subtype selective antimuscarinic that seems to be effective and well tolerated [52]. Following oral administration, it is extensively metabolised in the liver, reaching maximum plasma levels after about 5 h. Results of the phase III trials will be published in the near future.
7. What if conservative and medical treatment fails?
5.2.7. Other oral pharmacological agents Many pharmacological agents, such as flavoxate, imipramine and propantheline, have been used in the past and continue to be used, especially in developing countries for the treatment of OAB; however, the level of evidence available is not sufficient for them to be recommended for general use. This also applies for local vaginal oestrogens, which, in a meta-analysis, have been shown to be effective in relieving frequency, nocturia, urgency and incontinence episodes especially in postmenopausal women [53].
7.1. Intravesical pharmacotherapy
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If one drug fails to improve symptoms, assuming good patient compliance, then either another drug should be tried or the patient referred for urodynamics, and a specialist urological or urogynecological opinion, to establish a diagnosis. Once a diagnosis of DO is confirmed, the other available antimuscarinics should be tried especially the extended-release ones. Should these fail to relieve symptoms, available options include intravesical therapy, neuromodulation or surgery.
7.1.1. Oxybutynin chloride Intravesical OXY is another formulation of oxybutynin that offers an increase in bladder capacity and improvement in clinical symptoms. This route avoids liver metabolism, thus patients have less dry mouth than oral OXY. Its mode of action is uncertain but the local anaesthetic effect, on the bladder wall, of OXY may be important in temporarily desensitising afferent C-fibres. The intravesical route of administration is inconvenient and should be reserved for patients who do not respond to oral therapy and are already catheterised or perform intermittent self-catheterisation.
6. Which oral antimuscarinic to use? Essentially, all the antimuscarinics do the same job, but some do it better than others. Choice of one drug over the other is very difficult and is governed by many factors including drug availability, cost, tolerability, compliance and physician preference. Based on current evidence from clinical trials, OXY ER and TOLT ER are more efficacious with better tolerability and compliance than OXY IR and TOLT IR, but are more expensive. OXY TD, TCL and solifenacin improve symptoms of OAB with minimal CNS effects at a slightly lower cost than TOLT ER but more than OXY ER. It is, therefore, very difficult to recommend guidelines on drug prescription but OXY ER and TOLT ER should probably be used as first-line treatments, if available. OXY TDS, TCL and solifenacin, help increase the armamentarium of drugs available to treat OAB. TCL may be used in the elderly and in those who operate machinery as the first-line agent due to the reduced risk of CNS side effects. Following the publication of the STAR data, solifenacin may in the future be used as a first-line agent replacing TOLT ER and OXY ER but will probably be reserved for second-line treatment until health care providers obtain more clinical experience in using it. OXY TD will have a role in the treatment of OAB especially in patients who cannot swallow tablets or in patients who are on multiple drugs, especially elderly patients, thus reducing the risk of drug interactions. If none of the above drugs are available then propiverine, OXY IR or TOLT IR could be used.
7.1.2. Botulinum-A toxin Some urologists and urogynecologists have been using Botulinum-A toxin (BTA) as second-line treatment for neurogenic DO, with good results, as it selectively blocks release of Ach from nerve endings. BTA is effective in reducing UUI by allowing the bladder to hold and retain more urine [54]. BTA is injected into the bladder via a flexible cystoscope under local anaesthetic. Its effects usually last about 9 months; however, data is lacking on exact site and number of injections, optimal doses and concentrations to be used and long-term side effects. Its effect, compared to placebo, remains to be established in idiopathic DO by the use of randomised controlled trials. 7.1.3. Capsaicin and resiniferatoxin Capsaicin is a crystalline alkaloid and is the main active compound that causes the heat in chilli peppers. In the bladder, it acts on vanilloid receptors rendering the afferent C-fibres resistant to activation by natural stimuli. Only a small and very limited number of trials have been published looking at the effects of capsaicin on DO, and thus its use is mainly experimental. Side effects include pain, discomfort and burning sensation at the pubic-urethral level during instillation, autonomic dysreflexia and inflammatory reactions. Resiniferatoxin (RTX), an ultra-potent analogue of capsaicin, acts selectively on vanilloid receptor subtype-1 to desensitise unmyelinated afferent C-fibres. RTX is as effective as capsaicin in relieving clinical and urodynamic symptoms of neurogenic DO [55], with less bladder
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irritation; however, no trials have compared their effects to placebo. In idiopathic DO, RTX does not seem to provide any benefit over placebo in relief of OAB symptoms or improvement in urodynamic parameters [56]. Randomised placebo controlled trials are needed to look at its effect in patients with DO as well as determining the optimal dosage and intervals between treatments. 7.2. Neuromodulation Sacral nerve stimulation (SNS) [57] and percutaneous tibial nerve stimulation (PTNS) [58] are used for intractable OAB and DO and voiding difficulties. SNS is minimally invasive and involves implanting a neurostimulator in the buttock, which sends electric impulses to the sacral nerves to help control OAB symptoms. In PTNS, a needle electrode is inserted proximal to the medial malleolus, which stimulates the afferent nerve fibres of the tibial nerve modulating the sacral nerve plexus. Both SNS and PTNS increase bladder capacity and reduce frequency, UUI episodes and nocturia with improvement in QoL. The direct costs of SNS, including the device cost, hospitalisation costs and professional costs, are approximately £8000–£10000 per patient. These costs do not include the cost of surgical revision or replacement of the device. However, once the device is in place and calibrated appropriately, the cost associated with managing DO will decrease with an improvement in the QoL of patients. The devices normally last between 5 and 10 years. In the longterm, neuromodulation seems to be more cost-effective than, for example, using incontinence pads, and thus neuromodulation will probably help ‘bridge the gap’ between pharmacotherapy and major surgery. 7.3. Surgery Many surgical options exist but are reserved as a last resort for patients with DO, especially those with neurogenic DO. These include augmentation cystoplasty (aims to increase bladder capacity by augmenting the bladder with bowel), detrusor myectomy (removing the detrusor muscle resulting in a surgical diverticulum) and urinary diversion (bypasses the bladder). However, these procedures are not without complications including recurrent infections, stones, bowel obstruction and perforation, failure resulting in re-operation and about 10% of patients requiring intermittent self-catheterisation to empty the bladder. These procedures have now almost replaced the previous procedures of bladder hydrodistension, bladder denervation or transection, transvesical phenol injections and cystolysis, which did not produce good results with high recurrence and complication rates. So far, there are no prospective randomised controlled trials assessing any of these surgical procedures [11].
8. Conclusion OAB is a prevalent condition affecting millions of people worldwide causing significant economic costs. Unfortunately the precise cause of OAB is unknown and treatment is aimed at relieve of symptoms and improving QoL rather than cure. Conservative treatment including lifestyle interventions, bladder training and PFME should be combined with antimuscarinics to offer the best treatment combination. Many new drugs are currently undergoing research to look for new ways of treating OAB. If combination therapy fails and before any further treatment is initiated, the patient should be referred for urodynamics to confirm the diagnosis. In intractable OAB cases, intravesical therapy, neuromodulation and finally surgery could be tried. Practice points Take a thorough history and examination especially of lower urinary tract symptoms. Exclude other pathologies. Perform urinalysis, flow-rate and measure post-void residual urine. Ask the patient to complete a bladder diary and quality of life questionnaire. Treat with a combination of conservative and medical treatments. If treatment fails, refer to a specialist for urodynamics and further management. Research directions Large randomised controlled trials with long-term follow-up on many different aspects of conservative treatment. Large randomised controlled ‘head-to-head’ trials of different antimuscarinics. More long-term data on use of antimuscarinics and other treatments. Trials looking at the effects of antimuscarinics in the community rather than in the setting of clinical trials. Analysis of data looking at difference over placebo rather than difference over baseline. Basic science research into the cause of overactive bladder.
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