6.2.1 Lifestyle Changes/Behaviour Modification

Adequate fluid intake is required to eliminate irritants from the bladder. Under-hydration decreases the functional capacity of the bladder and may play a role in the development of UTIs, while excessive fluid intake can trigger incontinence and symptoms that could be misinterpreted as OAB (i.e. increased daytime frequency, nocturia and persisting desire to void). Fluid intake should be regulated to 6- to 8-ounce glasses or 30 cc/kg body weight per day, with a 1500 mL/day minimum—unless contraindicated by a prior medical condition [6]. Aging is associated with an increase in nocturia and chronic medical conditions (notably congestive cardiac failure, obstructive sleep apnoea and diuretic use); along with evening/night-time fluid consumption, these are all causes of nocturnal polyuria. Patients who develop oedema of the lower extremities may elevate their legs on a stool during the day to stimulate natural diuresis in the evening and hence reduce the amount of voiding during the night—though in reality, the difference this actually makes tends to be marginal. The patient should be advised to reduce his/her fluid intake after 6 pm (or approximately 4 h before usual bedtime) and shift the intake towards the morning and afternoon, to decrease the nocturia precipitated by fluid intake.

The consumption of caffeine-containing beverages , foods and medications are felt to have an impact, as the caffeine causes a significant bladder response, leading to storage symptoms. Alcohol provides a diuretic effect and its use can increase urinary frequency—if taken during evening hours, this may contribute to nocturia. It is therefore recommended that patients eliminate the possible products on a one-by-one basis to assess if symptoms decrease or resolve. Patients with storage LUTS and incontinence should avoid excessive caffeine intake (e.g. no more than 200 mg/day, equivalent to 2 cups) as it has been shown to reduce urinary symptoms and urine leakage [7].

Studies of women who have suffered severe chronic constipation (defined as less than three stools per week) and straining during defecation may manifest a change in pelvic floor neurological function relevant to storage LUTS, UI and OAB. Self-care practices that promote bowel regularity should be an integral part of a treatment care plan, such as addition of dietary fibre, increased fluid intake (which has to be balanced against the points above), regular exercise and external stimulation [8].

Smoking indirectly increases the incidence of urinary urgency and UI due to its effect on coughing and development of associated co-morbid conditions [9]. Coughing leads to increased intra-abdominal pressure and subsequent downward pressure on the pelvic floor, causing likely repeated stretch injury to the muscle and innervation. In conjunction, the effects of nicotine and tobacco products (potentially having possible anti-oestrogenic hormonal effects) may play a role in the worsening of individual symptoms.

The link between obesity and stress UI (SUI) and mixed UI appears to be multifactorial. Increases in intra-abdominal pressure on the bladder due to central obesity, as well as greater urethral mobility, appear to play a role in SUI. Furthermore, weight gain may impair blood flow and innervation to the bladder. Accordingly, weight loss is advocated in the treatment of UI.

6.2.2 Bladder Retraining

Several techniques are employed to improve symptoms and decrease rates of UI. The Cochrane Collaboration have reviewed publications for toileting programmes including habit training, timed voiding and prompted voiding. Most of the systematic reviews were based on the context of elderly patients within a care-home setting [6]. Bladder retraining has 3 main outcomes: (1) Improved bladder overactivity by controlling urgency and decreasing frequency; (2) Increased bladder capacity and (3) Reduced urgency incontinence episodes. It is felt that retraining improves cortical inhibition of detrusor contractions, facilitates cortical reinforcement of urethral closure during bladder filling, strengthens pelvic striated muscles and alters behaviours that affect continence [10].

The bladder training programme is done mainly on an outpatient basis. The initial voiding interval is determined by a pre-completed bladder diary, normally beginning with only a short deferral of voiding (a few minutes) and only during daytime hours, and steadily increasing the intervals in small realistic increments. The goal is for the patient to learn to inhibit urgency sensations by resisting or relaxing when they first start to get the sensation. Methods to resist or inhibit the urgency sensation include slow deep breathing to consciously relax the bladder, or six deliberate pelvic muscle contractions of 2–3 seconds duration. The final goal is that the patient will develop a normal voiding pattern [11], or (more likely) ability to reach voiding frequency and urgency severity that does not dominate their everyday life.

6.2.3 Pelvic Floor Muscle Training (PFMT)

There are two types of striated skeletal fibres that make up the pelvic floor muscles (PFM) which are under voluntary control and respond to the prescribed exercise regime. Type I (80%) are slow-twitch muscle fibres which improve muscle endurance by generating a slow, sustained but less-intense contraction to maintain a general level of pelvic support and urethral closure pressure. Type II (20%) are fast-twitch fibres which cause strong and forceful muscle contractions, build pelvic floor muscle strength and help in times of sudden increases in intra-abdominal pressure by contributing to urethral closure. The role of PFMT is to develop the technique of producing a voluntary pelvic floor contraction which will help to increase pressure in the urethra, inhibit detrusor contraction and control leakage of urine. The proposed mechanism of action is threefold: (a) increased urethral closure pressure; (b) lifting of the endopelvic fascia towards the pubic symphysis due to mechanical pressure increase and (c) a pelvic muscle ‘reflex’ contraction that precedes increased bladder pressure and may inhibit OAB [12].

Clinicians and specialist physiotherapists should assess the tone of the PFM by vaginal examination. Low muscle tone is the impaired ability to isolate and contract the PFM in the presence of atrophic, weak muscles, while high muscle tone refers to hypertonic, spastic PFM with impairment of muscle isolation, contraction and relaxation [14]. They then need to provide specific instructions on the location of the PFM, and how to focus on contracting it specifically [15], checking by physical examination that the patient has comprehended the instruction and can do it. The type of instruction used can be exemplified by: ‘Try to imagine the control of passing gas or pinching off a stool by tightening the ring of muscles around the anus without tensing the additional muscles of the legs, buttocks or abdomen. A closing and lifting sensation should be felt’.

It is equally important to control both muscle tightening and relaxing, to contract-relax for the same amount of time, and to relax completely between each muscle contraction. The patient should be encouraged to apply a concentrated effort with each PFM contraction, as greater intensity of contraction is associated with improvement in PFM strength. Figure 6.1 shows an example of instructions which can be given to patients to direct their exercise regime [6].

The long-term efficacy of PFMT ranges from 48 to 81% improvement rates [11].

A drawback, and perhaps the reason for hesitation on the part of the public, is that PFMT and other behavioural changes take time and effort—as many as 16 weeks for initial improvements and a lifelong commitment to ongoing maintenance. In addition, ineffective self-management can result in lack of improvement and frustration. Therapies and prevention technologies that provide feedback (i.e. biofeedback) can help women understand whether they are doing PFMT correctly.

6.2.4 Biofeedback

Biofeedback is the technique by which information regarding PFM contractions and relaxations is displayed in a format intuitively understandable to the patient, so they can adjust muscle action to gain confident appreciation of the activity. It uses either electromyography (EMG) or manometric pressure measurement. A common error in contraction of the PFM is collateral recruitment, when an additional (non-relevant) muscle group is contracting at the same time, which may in turn mask the strength of the PFM contraction. For example, it is very common for women to contract the gluteal muscles when trying to contract the PFM. Ongoing biofeedback visits are necessary until recruitment no longer happens.

There are different methods of EMG measurement which have been used: vaginal sensor, anal sensor, surface skin electrodes and needle electrodes. The baseline and follow-up EMG recordings measure short/quick contractions and sustained muscle contractions, as well as the relaxation phase. The ability to relax following a PFM contraction is important to gain control and co-ordination of the muscles [16].

6.5.1 TRP Channels

Cation channels of the TRP (Transient Receptor Potential) superfamily can be considered as universal cellular sensors, due to their ability to respond to a wide range of local signals, including physical stimuli (temperature, stretch) and a variety of endogenous and exogenous chemical ligands [2, 3]. In recent years, research using TRP channel-deficient mice and specific TRP channel (ant)agonists has revealed that several members of the TRP superfamily can act as sensors in the urothelium and bladder wall [2, 4, 17–19]. For example, TRPV1 (vanilloid 1) and TRPV4 (vanilloid 4) have been implicated in sensing bladder stretch [4, 17, 20], TRPV1 and TRPA1 (ankyrin 1) may act as sensors of chemical irritants and TRPM8 (melastatin 8), known as a cold sensor in the skin, is implicated in acute cold-induced urinary urgency [21]. Moreover, altered TRP channel expression and function have been linked to bladder dysfunction in various animal models of bladder disease [22]. These findings raise the possibility that TRP channels may be targeted pharmacologically to modulate the sensory function of urothelium and bladder wall, and could thereby alleviate storage LUTS in some patients. However, confining the drug effects to the lower urinary tract is a challenge that considerably limits their development for this indication. 

The only clinical application of TRP modulation used in patients with LUTS so far is the well-characterized intravesical TRPV1 desensitization using capsaicin or the 1000-fold more potent TRPV1-agonist resiniferatoxin [23, 24]. Intravesical resiniferatoxin instillation inactivates bladder afferent C fibres, resulting in reduced bladder pain in patients with bladder pain syndrome and increased maximum cystometric capacity in patients with detrusor overactivity [24]. These are not used in current practice but provide a valuable point of principle.

Other potential therapeutic targets for treating storage LUTS include TRPV4 and TRPM8, which are both expressed in the urothelium, and TRPV4 also is present in detrusor smooth muscle. Mice lacking TRPV4 exhibit a decrease in voiding frequency, with increased non-voiding contractions, and systemic administration of the TRPV4 antagonist HC-067047 also results in decreased voiding frequency with larger bladder capacities [4, 25]. The latter effect is seen both in healthy mice and in mice with cyclophosphamide-induced cystitis [4]. This makes TRPV4 antagonist a putative clinical candidate, but side effects would limit the dosing due to a widespread expression of TRPV4 in other organs (notably the nervous system, vascular endothelium and airway epithelium) [26].

Patients with idiopathic detrusor overactivity have an increase in density of suburothelial TRPM8-immunoreactive nerve fibres, and this density correlates with frequency scores [27]. Administration of a TRPM8-antagonist increases bladder capacity in rats [28]. Use of TRPM8 antagonist to treat increased frequency and (cold-exacerbated) urgency should be investigated further [18].

6.5.2 Degenerin/Epithelial Na⁺ Channels

The Degenerin/Epithelial sodium channels (Deg/ENaC) are mechanosensitive ion channels, and previous research has shown that they play a key role in the mechanosensory signalling of the bladder [29]. This cationic channel family, which was discovered in the 1990s, is characterized by amiloride sensitivity. They can be activated by either ligands and/or mechanical stimuli, or they may be constitutively active. The Deg/ENaC channels are divided into subfamilies and can be found in both vertebrates and non-vertebrates. In mammals, the following three groups are described: Epithelial Na channel (ENaC), acid-sensing ion channels 5-(ASIC) and brain–liver–intestine sodium channel/human intestine sodium channel (BLINaC/hINaC) [30]. One can notice some similarities when comparing the general characteristics of the DEG/ENaC family to the TRP channel family.

The ENaCs were first described to play a crucial role in sodium absorption in a wide variety of epithelia, such as secretory glands, respiratory airways, kidney, distal colon and peripheral nervous system [29]. They are expressed in the mammalian urinary tract epithelia and suburothelial nerve fibres; in the bladder epithelium, they are implicated in mechanosensory transduction by controlling stretch-evoked ATP release. Therefore, the Degenerin/Epithelial sodium channels are a potential pharmacological target for storage LUTS.

Proving this hypothesis appeared rather challenging. The in vivo research was conducted mostly on animals. However, it has been shown that there is a marked difference in expression level of ENaCs in human bladder under normal conditions versus the rodent bladder. Furthermore, these very low expression levels in humans under normal conditions seemed to be subject to changes in pathological situations. For example, a marked upregulation of ENaC expression was shown when comparing tissue from bladder epithelium of patients with detrusor overactivity caused by bladder outlet obstruction versus healthy controls. The research group concluded that ENaCs might be implicated in the mechanosensory transduction in the bladder afferent pathways [31]. Another group found that the expression of ENaCs and ASICs was highly upregulated in spinal cord injury patients with detrusor overactivity. They even conclude that this expression level could correlate significantly with their storage urinary symptoms [32]. Needless to say, these are very strong conclusions based on small populations, and this variance in expression complicates the implementation of a generalized disease model.

Another path that has been investigated are the ASICs, a subgroup of neuronal ENaCs. They were reported to be highly expressed in the urothelium and suburothelial nerve plexus. Upregulation of these channels or an increase in intra-bladder pressure during bladder filling may trigger afferent signalling [33]. They may be involved in nociception in various pathological conditions such as bladder pain syndrome and bladder inflammation [34]. Consequently, multiple research groups have defined ENaC/ASIC ion channels to be possible novel targets for the pharmacological treatment of inflammatory and overactive bladder conditions [29, 35].

To our knowledge, to this date, no large clinical trials have been reported in humans testing experimental drugs targeting members of the Deg/ENaC family. Some research teams are focusing on the effect of amiloride, an antagonist of ENaCs. One group has found that the induction of voiding frequency caused by fludrocortisone could be reversed by giving an intravesical infusion of amiloride. They conclude that upregulation of ENaC could play a role in storage dysfunction [36]. Furthermore, the antagonist amiloride was also shown to attenuate pain, induced by an intradermal acid infusion, but did not inhibit pain caused by capsaicin (TRPV1 agonist). This was investigated more extensively than the effect on bladder dysfunction, but due to some conflicting results and an incomplete physiological knowledge of ASICs, until now no drugs are developed and clinically tested [37].

6.5.3 Big Potassium Channels

Relaxation and contraction of the detrusor muscle allows the bladder to store urine or empty the bladder at appropriate times. In detrusor smooth muscle cells, three major subtypes of potassium channels are represented. These channels play a key role in maintaining the resting membrane potential and action potentials of the detrusor muscle. One of the most pathologically and physiologically important potassium channels are the large-conductance voltage- and Ca²⁺-activated K⁺ (BK) channels [38]. These so-called Big Potassium channels are widely expressed in mammalian tissues and cell types such as neurons, smooth and skeletal muscle and exocrine cells. They are positioned on membrane surfaces such as the plasma membrane, mitochondrial membranes and the nuclear membrane [39]. As these channels can be activated by both Ca²⁺ and membrane depolarization, they have the ability to integrate changes in intracellular calcium and membrane potential. This makes the BK channels an important negative feedback system to limit membrane depolarization and intracellular Ca²⁺ concentrations. Therefore, they are essential for the control of detrusor smooth muscle cell tone and detrusor contraction [40, 41]. For this reason, BK channels and their regulatory mechanisms could serve as novel targets for pharmacotherapeutic interventions or genetic therapies for OAB [42]. Thus far, three approaches to modulate BK channels have been explored. These include the use of BK channel openers, modulation of BK channel regulatory mechanisms and BK channel gene therapy.

Extensive in vitro and in vivo research in both animals and humans shows that positive modulation of BK channels by small molecules, the so-called channel openers, can reduce detrusor contractility without compromising normal voiding functions [41]. These BK channel openers have a certain selectivity for smooth muscle cell BK channels. As these BK channels, however, are also expressed in other smooth muscle cells, selective BK channel openers may, for example, also have vascular effects. Consequently, further investigation concerning new BK openers with improved selectivity is needed [38]. BK channel regulatory mechanisms provide another approach to targeting BK channels. One example of this approach is the selective β3-agonist mirabegron, which was successfully introduced into clinical practice in 2012. Other potential BK channel regulatory mechanism targets are PDE1 and PDE4. These enzymes have an essential part in regulation of cellular cAMP levels in detrusor smooth muscle cells. Modulation of these regulatory mechanisms, instead of direct activation of BK channels by selective BK channel openers, could be a better option for treatment of storage LUTS with possibly lower risk of adverse effects [38]. BK channel gene therapy is another potential therapeutic approach for LUTS treatment. According to the FDA, human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. A phase I multicentre study reported that the recombinant BK channel α-subunit gene can be directly and locally instilled in the human bladder to create a detrusor muscle cell-specific, long-lasting effect without significant transfer-related side effects. This transfer, however, needs to be repeated every 6 months, as the DNA does not integrate into the chromosome of the cells [38]. Another perspective is that BK channels may play an important role in bladder afferent nerve activity and urothelial function [41]. Unlike the role of BK channels in the detrusor smooth muscle cells, the physiological function of BK channels in the urothelium is still being investigated. A recent study, however, confirmed the presence of BK channels on mouse urothelial umbrella cells [43].

We can conclude that the BK channel embodies a promising opportunity for pharmacotherapeutic treatment of storage LUTS. The pathophysiological role of these channels in regulation of detrusor smooth muscle cells, however, needs to be understood better to better correlate basic research with clinical practice.

6.6.1 Comparisons of Onabotulinum Toxin A with Other Treatments

The Anticholinergic Versus Botulinum Toxin A Comparison Trial (ABC trial) [59] randomized 249 women with OAB who had 5 or more episodes of urgency urinary incontinence in a 3-day bladder diary. For a 6-month period, participants were randomly assigned to intradetrusor injection of 100 U of onabotulinum toxin A plus daily oral placebo, or daily oral anticholinergic medication (solifenacin 5 mg initially, with possible escalation to 10 mg and, if necessary, subsequent switch to trospium XR 60 mg) plus intradetrusor injection of saline. Complete continence was reported more commonly in the onabotulinum toxin A than in the anticholinergic group, at 27% vs 13% (p = 0.003), respectively. The toxin group had higher rates of catheter use at 2 months (5% vs. 0%) and UTI (33% vs. 13%) than the anticholinergic group. The latter on the other hand had a higher rate of dry mouth (46% vs. 31%) [59]. In a similar study, researchers randomized patients with OAB and urinary incontinence to receive onabotulinum toxin A 100 U injection plus oral placebo (n = 145), or oral solifenacin plus placebo injection (n = 151) or double placebo (n = 60), for 12 weeks. At week 12, mean reduction from baseline in urinary incontinence episodes/day was significantly greater with either onabotulinum toxin A (−3.2) or solifenacin (−2.6) versus placebo (−1.3; P < 0.001 for both). The proportion of patients with 100% reduction in urinary incontinence episodes at week 12 was 33% for onabotulinum toxin A and 24% for solifenacin [60]. Overall, a metanalysis confirmed that onabotulinum toxin A injections are more effective than any oral therapy (antimuscarinics, beta 3 agonists) to cure urgency incontinence [61].

The Rosetta study compared onabotulinum toxin A 200 U bladder injections against SNM (interStim) in refractory OAB patients [62]. A significantly greater number of patients experienced a complete resolution (20% vs 4%) of UUI episodes with onabotulinum toxin A 200 U treatment than with SNM InterStim at 6 months. However, these differences had faded away at 2 years follow-up. The cure rates were identical, 5% in both groups, although the satisfaction rate remained higher among patients treated with onabotulinum toxin A injections. In the onabotulinum A arm 72% asked for a second injection, while in the SNM 58% required reprogramming of the device. UTI and CIC were more common in the Onabotulinum toxin A arm [62].

6.6.2 Economic Aspects and Patient Preferences

Economic aspects of onabotulinum toxin A are a concern, due to the price of the drug and the need for repeated cystoscopies. For OAB/idiopathic detrusor overactivity, an assessment of costs from a US payer perspective extending up to 3 years was made for 3 interventions; sacral neuromodulation, onabotulinum toxin A and augmentation cystoplasty in patients refractory to antimuscarinics. The initial treatment cost was $22,226, $1,313, and $10,252 for sacral neuromodulation, onabotulinum toxin A and augmentation cystoplasty, respectively. Three years after initiating treatment, the cumulative cost was $26,269, $7651 and $14,337, respectively. Sensitivity analyses revealed that sacral neuromodulation persisted as the costliest intervention [63].

In a survey of 50 OAB patients, with a mean age of 61 years, 74% preferred onabotulinum toxin A and 26% chose SNM as first treatment option. In those who preferred onabotulinum toxin A, 54% disliked the thought of a foreign body in the back, 46% chose the option due to a shorter waiting list and 43% made the choice based on the quicker onset of benefit. In the SNM group 62% were averse to the potential need for repeated injections and 46% chose SNM to avoid the risk of urinary retention associated with the toxin [64].