Overactive Urinary Bladder
Epidemiology, aetiology, pathophysiology
Narrative Review Article
Part 1
Prof. Dr. Semir. A. Salim. Al Samarrai
Overactive bladder is defined by the International Continence Society (ICS) as “urinary urgency, usually accompanied by frequency and nocturia, with or without (Urge Urinary Incontinence (UUI), in the absence of Urinary Tract Infection (UTI) or other obvious pathology” [1]. Overactive bladder is a chronic condition and can have debilitating effects on QoL. The hallmark urodynamic feature is Detrusor Overactivity (DO), although this may not be demonstrated in a large proportion of Overactive Bladder (OAB) patients, which may partly be due to failure to reproduce symptoms during urodynamic assessment. The EPidemiology of InContinence (EPIC) study was one of the largest population-based surveys of the prevalence of LUTS and OAB [2]. It was a cross-sectional telephone survey of adults aged > 18 years conducted in five countries, including Canada, Germany, Italy, Sweden and the UK. The study included > 19,000 participants and demonstrated an overall prevalence of OAB symptoms of 11.8% (10.8% in men and 12.8% in women). Other studies have reported prevalences of up to 30 to 40%, with rates generally increasing with age [3]. Various theories have been proposed to explain the pathophysiology of OAB, mainly relating to imbalances in inhibitory and excitatory neural pathways to the bladder and the urethra or sensitivity of bladder muscle receptors. However, no definite identifiable causes have been established.
Overactive bladder is generally classified into wet and dry, based on the presence or absence of associated Urinary Incontinence (UI).
Evaluation of symptoms of OAB follows the general pathway of evaluation of women with LUTS.
The Diaries are particularly helpful in establishing and quantifying symptoms of frequency, urgency and UI, and may be valuable in assessing change over time or response to treatment. Several observational studies have demonstrated a close correlation between data obtained from bladder diaries and standard symptom evaluation [4-7]. The optimum number of days required for bladder diaries appears to be based on a balance between accuracy and compliance. Diary duration of three to seven days is routinely used in the literature.
The Urodynamics is essential in establishing the presence of DO, but its absence does not preclude diagnosis of OAB, which is based on symptoms alone. A Cochrane review of seven RCTs showed that use of urodynamic tests increased the likelihood of prescribing drugs or avoiding surgery. However, there was no evidence that this influence on decision-making altered the clinical outcome of treatment [8]. A sub-analysis of an RCT comparing fesoterodine to placebo [9] showed that the urodynamic diagnosis of DO had no predictive value for treatment response.
A single report (SR) and meta-analysis indicated that the urinary tract nerve growth factor (Urinary NGF) and Brain-divided neurotrophic factor or abneurin are members of the neurotrophic family of growth factors were increased in female OAB patients as urinary biomarker compared to healthy controls, whereas no difference was found for the prostaglandins E2 (PGE2) level normalized to the concentration of the urinary creatine was elevated and higher in the BPH/OAB than in the BPH/non-groups [10]. The current data is inadequate to assess any other potential biomarkers, such as urinary malondialdehyde (UMDA), ATP, and cytokines, in the management of OAB in female patients. Further studies are needed to establish their potential as diagnostic and management tools in OAB women.
The conservative management of the overactive bladder has long been recommended as first in clinical practice, because they usually carry the lowest risk of harm. While this remains true for non-pharmacological conservative treatments [e.g., pelvic floor muscle training (PFMT)], increasing concerns regarding the adverse events of some pharmacological treatments used to treat LUTS (e.g., anticholinergic drugs), particularly regarding cognitive function, have emerged and patients should be fully counselled regarding this potential risk.
It is possible that improvement of associated disease may reduce the severity of the lower urinary tract symptoms (LUTS), especially in elderly patients, which are associated with multiple comorbid conditions including:
• cardiac failure;
• chronic renal failure;
• diabetes;
• chronic obstructive pulmonary disease;
• neurological disease;
• general cognitive impairment;
• sleep disturbances, e.g., sleep apnoea;
• depression;
• metabolic syndrome.
The Lifestyle factors that may be associated with UI include obesity, smoking, level of physical activity, regulation of bowel habit and fluid intake. Modification of these factors may improve symptoms of OAB.
The caffeine intake in many drinks contain caffeine are particularly coffee, tea and cola. Conflicting epidemiological evidence of urinary symptoms being aggravated by caffeine intake has focused on whether caffeine reduction improves LUTS [11, 12]. A scoping review of fourteen interventional and twelve observational studies reported that reduction in caffeine intake may reduce symptoms of urgency, but the certainty of evidence was low, with significant heterogeneity in study populations [13].
The fluid intake modification are particularly restriction, and is a strategy commonly used by people with OAB to relieve symptoms. Any advice on fluid intake given by HCPs should be based on 24-hour fluid intake and urine output measurements as retrieved from the bladder diary. From a general health point of view, it should be advised that fluid intake should be sufficient to avoid thirst and that an abnormally low or high 24-hour urine output should be investigated. The few RCTs that have been published provide inconsistent evidence [14-16]. In most studies, the instructions for fluid intake were individualised and it was difficult to assess participant adherence. All available studies were in women. An RCT showed that a reduction in fluid intake by 25% improved symptoms in patients with OAB but not UI [16]. Personalised fluid advice compared to generic advice made no difference to continence outcomes in people receiving anticholinergics for OAB, according to an RCT comparing drug therapy alone to drug therapy with behavioural advice [17]. Patients should be warned of the potential consequences of fluid restriction such as worsening of constipation or development of UTI.
The obesity and overweight have been identified as a risk factors for LUTS in many epidemiological studies [18, 19]. There is evidence that the prevalence of both UUI and SUI increases proportionately with body mass index [20]. However, the evidence base largely relates to obesity and SUI rather than UUI and OAB. Therefore, no definite inference can be drawn between obesity and the prevalence of OAB.
The smoking cessation is a general public health measure and has been shown to be weakly associated with improving urgency, frequency and UI [21, 22]. The effect of smoking cessation on LUTS was described as uncertain in a health technology assessment review [23].
The behavioural and physical therapies are approaches include bladder training (BT) and pelvic floor muscle training (PFMT) involves the contraction of the puborectal anal sphincter and external urethral muscles, and inhibition of the detrusor contraction. A SR on cognitive components of behavioural therapies for OAB concluded that they were neither well described nor rationalized. Cognitive strategies include mental distraction (the most common), relaxation and mindfulness practices [24].
The term prompted voiding implies that carers, rather than the patient, initiate the patient going to void with the aim of preventing or reducing UI. Timed voiding is defined as fixed, predetermined, time intervals between toileting, applicable for those with or without cognitive impairment. A Cochrane review of timed voiding reviewed two RCTs, finding inconsistent improvement in continence compared with standard care in cognitively impaired adults [25].
The bladder training is a programme of patient education along with a scheduled voiding regimen with gradually increasing intervals. Specific goals are to correct faulty patterns of frequent urination, improve control over bladder urgency, prolong voiding intervals, increase bladder capacity, reduce incontinent episodes and restore patient confidence in controlling bladder function. There have been three SRs on the effect of BT compared to standard care confirming that BT is more effective than no treatment in improving UUI [26, 23, 27]. The addition of BT to anticholinergic therapy did not improve UUI compared to anticholinergics alone but it did improve frequency and nocturia [28]. A review identified seven RCTs in which BT was compared to drug therapy alone and only showed a benefit for oxybutynin for cure or improvement of UUI [28].
The Pelvic floor muscle training has an immediate effect of PFM contraction and simultaneous inhibition of urgency, detrusor contraction and incontinence [29]. Intensive and regular strength training of the PFMs over time increases both PFM contraction strength and endurance, and changes the morphology of the pelvic floor, which may yield more effective inhibition of the detrusor and help to stabilize the proximal urethra and improve urethral function.
The electrical stimulations are methods of delivery of electrical stimulation (ES) and vary considerably. Electrical stimulation of the PFM can also be combined with other forms of conservative therapy; e.g., PFMT with and without biofeedback. A SR of the effect of ES included 51 trials with 3,443 adults with OAB symptoms [30], with quality of evidence ranging from very low to moderate. Moderate-quality evidence suggests that ES is more likely to improve OAB symptoms compared to sham control, no treatment or placebo. Moderate-quality evidence suggests that ES is more likely to improve OAB symptoms compared to anticholinergic therapy.
The posterior tibial nerve stimulation is an electrical stimulation of the posterior tibial nerve (PTNS) delivers electrical stimuli to the sacral micturition centre via the S2–S4 sacral plexus. Stimulation is percutaneous with a fine (34-G) needle, inserted just above the medial aspect of the ankle (P-PTNS). Transcutaneous stimulation is also available (T-PTNS) that delivers stimulation via surface electrodes that do not penetrate the skin. Treatment cycles typically consist of twelve weekly treatments of 30 minutes.
The reviewed studies included a SR, two twelve-week RCTs of P-PTNS compared with sham treatment [31-33], one comparing PTNS to tolterodine, and a three-year extension trial utilising a maintenance protocol in patients with UUI [34, 35]. The results of studies of PTNS in women with refractory UUI are consistent. These results suggest that PTNS improves UUI in women who do not have adequate improvement or cannot tolerate anti-muscarinic therapy. Improvements in voiding frequency, nocturia, urgency, incontinence episodes, cystometric capacity and compliance were described in the SR [33].
The transcutaneous posterior tibial nerve stimulation showed in a small RCT compared T-PTNS plus standard treatment (PFMT and BT) with PFMT and BT alone in older women [36]. Women in the T-TPNS group were more likely to achieve improvement at the end of therapy. A SR of thirteen trials (ten RCTs and three cohort studies) compared the efficacy of T-PTNS (duration four to twelve weeks) with sham treatment, anticholinergics, and exercise in treatment of adults with OAB symptoms [37]. Both P-PTNS and T-PTNS were more effective than BT alone. These two tibial nerve stimulation methods had similar clinical efficacy but with slight differences: TTNS had shorter preparation time, less discomfort level and higher patient satisfaction than PTNS [38].
The pharmacological management with anticholinergic (antimuscarinic) drugs are currently the mainstay of treatment for OAB. They differ in their pharmacological profiles, such as muscarinic receptor affinity and other modes of action and in their pharmacokinetic properties, such as lipid solubility and half-life. In general, a SR noted that the overall treatment effect of drugs is usually small but larger than that of placebo. Some RCTs have UI as an outcome rather than UUI. Dry mouth is the commonest adverse effect, although constipation, blurred vision, fatigue and cognitive dysfunction may occur with anticholinergic drugs [27]. Immediate-release (IR) anticholinergic preparations provide maximum dosage flexibility, including an off-label on-demand use. Immediate-release drugs have a greater risk of adverse effects than extended release (ER) formulations because of differing pharmacokinetics. Seven SRs of individual anticholinergic drugs vs. placebo have been reviewed [27, 39-44]. Most studies included patients with a mean age of 55–60 years. The evidence reviewed was consistent, indicating that ER and IR formulations of anticholinergics offer clinically significant short-term improvement of OAB compared to placebo.
The comparison of the efficacy and adverse effects of different anticholinergic agents are of interest for decision-making. A network meta-analysis revealed no clear best anticholinergic preparation for cure or improvement [45]. Darifenacin (40%), tolterodine IR and oxybutynin ER (13% each) appeared to score highest in indirect comparisons. Fesoterodine and oxybutynin IR were more effective than oxybutynin (transdermal) and tolterodine ER. There were no clinically significant differences between anticholinergics for voiding and UI outcomes. Another network meta-analysis of 53 RCTs compared the efficacy and tolerability of solifenacin 5 mg with other oral anticholinergics in the treatment of adults with OAB symptoms [46]. Solifenacin 5 mg/day was significantly more effective than tolterodine 4 mg/day for reducing UUI episodes, but significantly less effective than solifenacin 10 mg/day for reducing micturition episodes. Solifenacin 5 mg/day showed significantly lower risk of dry mouth compared with other anticholinergics. There were no significant differences for the risk of blurred vision or constipation. No single anticholinergic agent improved QoL more than another [41]. Dry mouth is the most prevalent adverse effect. Extended release formulations of short- and longer-acting drugs are associated with lower rates of dry mouth than IR preparations [41, 47].
The anticholinergic drugs versus conservative treatment of OAB patients is an important question. More than 100 RCTs and high-quality reviews are available [28, 41, 42, 49-51]. Most of these were independent studies. The main focus of the reviews was to compare the different drugs used to treat UUI. A SR with meta-analysis included RCTs combining anticholinergics with various non-invasive modalities including pregabalin, topical estrogenic, and physiotherapy. The review showed that these combinations were associated with significantly higher improvement in mean symptoms score on validated questionnaires (6 RCTs, MD: 0.55; 95% CI: 0.16-0.95), urgency episodes (4 RCTs, MD: 0.68; 95% Cl: 0.04-1.32) and UUI episodes (5 RCTs, MD: 1.18; 95% CI 0.18-2.17).
The Beta-3 adrenoceptors are the predominant beta receptors expressed on detrusor smooth muscle cells and their stimulation is thought to induce detrusor relaxation. Mirabegron was the first clinically available beta-3 agonist. Vibegron is another beta-3 agonist commercially available in some countries. Mirabegron has undergone evaluation in industry-sponsored phase II and III trials [52-55]. Three SRs assessing the clinical effectiveness of mirabegron [52, 53, 56] reported that mirabegron at doses of 25, 50 and 100 mg results in significantly greater reduction in UI episodes, urgency episodes and micturition frequency than placebo, with no difference in the rate of common adverse events [53]. The dry rates in most of these trials are 35–40% for placebo and 43–50% for mirabegron. In all trials the significant differences were consistent only for improvement but not for cure of UI. Similar improvements in the frequency of UI episodes and micturition frequency were found whether or not patients had previously tried anticholinergic agents. One SR showed that mirabegron is as efficacious as most anticholinergics in reducing UUI episodes [57]. The most common adverse events in the mirabegron groups were hypertension (7.3%), nasopharyngitis (3.4%) and UTI (3%), with the overall rate similar to that with placebo [52, 55, 58]. A SR with meta-analysis of data pooled from three RCTs comparing vibegron (75 mg or 100 mg) with placebo in 2120 patients with OAB revealed significant improvement of urgency episodes and UUI episodes and mean voided volume associated with vibegron [59].
• Fesoterodine: Pooled analyses of the RCTs of fesoterodine confirmed the efficacy of 8 mg but not 4 mg dose in patients aged > 75 years [60]. Adherence was lower in patients aged > 75 years but effects on mental status were not reported [61, 60, 62]. A more recent RCT showed efficacy of fesoterodine in vulnerable elderly people with no differences in cognitive function at twelve weeks [63].
• Mirabegron: Analysis of pooled data from three RCTs showed efficacy and safety of mirabegron in elderly patients [64].
The oestrogen treatment for UI has been tested using oral, transdermal and vaginal routes of administration. Vaginal (local) treatment is primarily used to treat symptoms of vaginal atrophy in postmenopausal women. Available evidence is related mainly to SUI, and although some reviews include participants with UUI, it is difficult to generalise the results to women with predominantly OAB/UUI. The association of LUTS with genitourinary syndrome of menopause (GSM) should be considered [65]. Genitourinary syndrome of menopause (GSM) is a new term that describes various menopausal symptoms and signs associated with physical changes of the vulva, vagina and LUT. These include mucosal pallor/erythema, loss of vaginal rugae, tissue fragility/fissures, vaginal petechiae, urethral mucosal prolapse, introital retraction and vaginal dryness. There is evidence from a SR to suggest benefit from vaginal oestrogen therapy in GSM [66]. All vaginal oestrogens demonstrated superiority in objective and subjective end points of GSM compared with placebo. Vaginal oestrogen showed superiority over vaginal lubricants and moisturisers for the improvement of objective clinical end points of vulvovaginal atrophy but not for subjective end points [66].
The surgical management include the bladder wall injection of botulinum toxin A Onabotulinum toxin A (onabotA; BOTOX®) 100 U is licenced in Europe to treat OAB with persistent or refractory UUI in adults of both sexes [67, 68]. Surgeons should be aware that other doses of onabotA and other formulations of botulinumtoxin A, abobotulinumtoxin A and incobotulinumtoxin A, are not licensed for use in OAB/UUI. Doses for onabotA are not transposable to the other brands of botulinumtoxin A. The continued efficacy of repeat injections is usual, but discontinuation rates may be high [69, 70]. The most important adverse events related to onabotA 100U injection detected in the regulatory trials were UTI and an increase in PVR volume that may require CISC [71].
Cohort studies have shown the effectiveness of bladder wall injections of onabotA in elderly and frail elderly people [72], although the success rate might be lower and the PVR volume (> 150 ml) higher in this group. The median time to request retreatment in the pooled analysis of the two RCTs was 24 weeks [68, 71]. Follow-up over 3.5 years showed consistent or increasing duration of effect for each subsequent treatment, with a median of 7.5 months. However, patients receiving onabotA were not only more likely to have cure of UUI (27% vs. 13%), but also had higher rates of urinary retention during the initial 2 months (5% vs. 0%) and of UTIs (33% vs. 13%). Patients taking anticholinergics were more likely to have dry mouth. These results are further strengthened by a 2017 SR and network meta-analysis including 65 RCTs of onabotulinum toxin A vs. oral therapies (anticholinergics and mirabegron) for OAB at twelve weeks [73].
The sacral nerve stimulation involves placing electrodes adjacent to the sacral nerve roots and delivering an electric current to the area via an attached battery implanted in the buttock, which delivers low-amplitude stimulation resulting in modulation of neural activity and stabilisation of bladder electrical activity through a mechanism that is, as yet, not fully understood. All randomised studies suffer from the limitation that patients cannot be blinded to the treatment allocation since all recruited patients have to respond to a test phase before randomisation. Forty-six per cent in the onabotulinum toxin A group and 26% in the SNS group had > 75% reduction in the number of episodes of UUI [74]. Two-year follow-up data from 87% of participants in this trial suggest no significant differences in treatment outcomes over 2 years, although satisfaction rates and treatment endorsement remain higher with onabotulinum toxin.
A recent SR evaluated the use of vaginal lasers in the treatment of OAB and evaluated short-term studies detailing minimal improvement [75].
The augmentation cystoplasty (also known as clam cystoplasty), a detubularised segment of bowel is inserted into the bivalved bladder wall. The distal ileum is the bowel segment most often used but any segment can be utilised if it has the appropriate mesenteric length. Most of the evidence pertaining to cystoplasty comes from patients with neuropathic bladder dysfunction. One study did not find any difference between bivalving the bladder in the sagittal or coronal plane [76, 77]. The procedure can be done, with equal success by open or robotic techniques, although the latter takes more time [78]. There are no RCTs comparing bladder augmentation to other treatments for patients with OAB/UUI. Most often, bladder augmentation is used to correct neurogenic DO, small capacity or low-compliant bladders caused by fibrosis, chronic infection such as tuberculosis, radiation, or chronic inflammation from interstitial cystitis. The largest case series of bladder augmentation in a mixed population of idiopathic and neurogenic UUI included 51 women [79]. Depending on the relative costs of onabotulinum toxin A and augmentation cystoplasty, the latter can be costeffective within 5 years if the complication rate is low and duration of effect of onabotulinum toxin A is < 5 months [80].
Detrusor myectomy (bladder auto-augmentation) Detrusor myectomy aims to increase bladder capacity and reduce storage pressure by incising or excising a portion of the detrusor muscle, to create a bladder mucosal bulge or pseudo-diverticulum. It was initially described as an alternative to bladder augmentation in children [81]. Two case series in adult patients with idiopathic and neurogenic bladder dysfunction demonstrated poor longterm results caused by fibrosis of the pseudo-diverticulum [82, 83]. This technique is rarely, if ever, used nowadays.
The urinary diversion remains a reconstructive option for patients with intractable UI after multiple pelvic procedures, radiotherapy or pelvic pathology leading to irreversible sphincteric incompetence or fistula formation. Patients may be offered irreversible urinary diversion surgery. Options include ileal conduit urinary diversion, orthotopic neobladder and heterotopic neobladder with Mitrofanoff continent catheterisable conduit. There is insufficient evidence to comment on which procedure leads to the most improved QoL. A small study comparing ileal with colonic conduits concluded that there are no differences in the relative risks (RR) of UUT infection and uretero-intestinal stenosis. However, no studies that have specifically examined these techniques for treatment of intractable OAB/UUI [76]. Therefore, careful consideration of which operation is undertaken depends on thorough preoperative counselling, access to stoma/continence nurses, as well as patient factors to allow for fully informed patient choice.
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Author Correspondence:
Prof. Dr. Semir A. Salim. Al Samarrai
Medical Director of Professor Al Samarrai Medical Center.
Dubai Healthcare City, Al-Razi Building 64, Block D, 2nd Floor, Suite 2018
E-mail: semiralsamarrai@hotmail.com
Tel: +97144233669
