Current management of refractory overactive bladder

Overactive bladder (OAB) is a common condition affecting one‐sixth to one‐fifth of the global population. The treatment of refractory OAB remains a challenge for urologists. Current treatment options include the use of combination therapy with antimuscarinic agents and beta‐3 adrenoceptor agonists, and treating underlying curable disorders. Intravesical botulinum toxin type A (BoNT‐A) injection, percutaneous tibial nerve stimulation, and sacral nerve stimulation are third‐line management therapies suggested by the American Urological Association/Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction (AUA/SUFU) guidelines. In rare cases, more invasive surgical interventions can be considered after explaining the benefits and risks to the patients. Augmentation cystoplasty has a high success rate; however, it has also been associated with a high complication rate. In contrast, detrusor myomectomy is an easy procedure, but the treatment outcome remains controversial. Liposome‐encapsulated BoNT‐A is administered via bladder instillation, and promising results have been obtained in preliminary studies. More therapies are currently being investigated, and transient receptor potential vanilloid 1 antagonists may be new type of medication. Radiofrequency ablation and other targets for neuromodulation have also been studied; however, more evidence is needed to confirm their efficacy.     

Botulinum Toxin A Injections for Non-neurogenic Overactive Bladder

Intravesical botulinum toxin A (BoNT-A) injection is effective and has been approved in the treatment of overactive bladder (OAB) syndrome in patients who are refractory or intolerable to antimuscarinic therapy. Intravesical BoNT-A injection increases bladder capacity, decreases detrusor pressure, and reduces the urgency sensation in OAB patients. Although clinical experiences have demonstrated a dose-dependent therapeutic effect of BoNT-A, the adverse events such as acute urinary retention, voiding difficulty, large post-void residual, and subsequent urinary tract infection remain problematic and increase with higher doses in frail elderly patients. Currently, 100 U of onabotulinumtoxinA has been approved by many countries for the treatment of patients with non-neurogenic OAB. The duration of therapeutic effect is around 6 to 9 months and usually remains the same after repeat treatments. The injection sites can involve the bladder wall with or without sparing the trigone. Gathered experience has also shown that BoNT-A injection is also effective in the treatment of OAB symptoms in children and in patients with stroke or Parkinson’s disease. Before BoNT-A injection, physicians should learn the injection technique and inform the potential adverse events to patients who desire this treatment.     

Upregulation of Angiotensin II Receptor and Connexin 43 in Increased Suburothelial Myofibroblasts in the Rat Inflammatory Bladder

Objectives: Signaling pathways in suburothelial layer are involved in the bladder sensory response. The expression of angiotensin II type 1 (AT1) receptors and connexin 43 (Cx43) in suburothelial myofibroblasts was investigated in an acute bladder inflammation model. Methods: Adult female Wistar rats underwent urethral catheterization and received 0.2 mL intravesical infusion of 0.4 M HCl to establish acute bladder inflammation model or 0.2 mL of sterile saline as control (n = 10 rats/group). Eight days after treatment, cystometry was performed. Suburothelial myofibroblasts were also collected and subjected to immunohistochemical staining to examine AT1 receptor and Cx43 expression. Results: Eight days after treatment with HCl to induce acute bladder inflammation, the frequency and basal pressure of the bladder was significantly increased compared with those in control rats. The number of suburothelial myofibroblasts was significantly increased in acute bladder inflammation rats, as was the expression of AT1 receptor and Cx43. Conclusion: These results suggest that the increased number of suburothelial myofibroblasts, upregulation of AT1 receptor and Cx43 expression may be associated with the pathogenesis of hyperactivation of bladder sensory signaling pathways in acute inflammatory bladder.     

Overactive bladder--pharmacological aspects

The micturition reflex can be initiated by contraction or distension of detrusor smooth muscle cells, or by signals from the urothelium. It has been shown that bladder distension causes release of ATP from the urothelium, and that ATP can activate P2X3 receptors on suburothelial afferent nerve terminals to evoke a neural discharge. However, most probably the activation of afferent fibres during bladder filling involves not only ATP, but a cascade of inhibitory and stimulatory transmitters/mediators. These mechanisms may be targets for future drugs. Both in the normal and functionally disturbed bladder, muscarinic receptor stimulation produces the main part of detrusor contraction, but evidence is accumulating that in disease states, such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, interstitial cystitis, and also in the ageing bladder, a non-cholinergic activation via purinergic receptors may occur. If this component of activation is responsible not only for part of the bladder contractions, but also for the symptoms of the overactive bladder, it should be considered an important target for therapeutic interventions. Drags blocking different P2X receptor subtypes, or counteracting bladder contraction via other mechanisms, e.g. beta3-adrenoceptor stimulation, may be developed for treatment of the overactive bladder.     

Alternative therapies for overactive bladder: Cannabis and urge incontinence

Current drug therapies for overactive bladder (OAB) can produce variable outcomes and bothersome side effects, resulting in poor compliance. In patients with neurogenic detrusor overactivity and urge incontinence, evidence of a beneficial effect with oral cannabinoids is emerging. The rationale for their use was the discovery of cannabinoid receptors (CB1 and CB2), with CB1 receptors at various sites, including the brain and bladder, although the distribution of CB2 receptors is more limited. Cannabinoids also bind to vanilloid receptors, which have been the basis for intravesical therapies, such as capsaicin and resiniferatoxin. However, the use of capsaicin is limited by its pungency, whereas resiniferatoxin is limited by difficulties in delivery. Cannabinoids appear to work at several levels centrally and peripherally on detrusor smooth muscle, suggesting that they might produce similar effects in patients with neurogenic and nonneurogenic OAB. Large clinical trials of cannabinoids without psychotropic effects are required.     

Pathophysiology of refractory overactive bladder

Overactive bladder (OAB) is a common condition. The International Continence Society defines OAB as a symptom complex characterized by urgency with or without urge incontinence, usually with frequency and nocturia. The first‐line treatment for OAB includes behavioral therapy, such as caffeine reduction, fluid intake modification, weight reduction, bladder training, and pelvic floor muscle training, as well as treatment with antimuscarinic or β₃‐adrenoceptor agonist medications. However, less than half of all cases achieve satisfactory outcomes following first‐line treatment. Second‐line therapy considered if satisfactory responses are not achieved after 8 to 12 weeks treatment with first‐line therapy include intradetrusor botulinum toxin injection, neuromodulation, and surgical treatment. Patients with refractory OAB may have more severe symptoms or underlying pathophysiologies that were not resolved by the initial medication. The pathophysiologies of refractory OAB include occult neurogenic bladder, undetected bladder outlet obstruction, urethral‐related OAB, urothelial dysfunction with aging, chronic bladder ischemia, chronic bladder inflammation, central sensitization, and autonomic dysfunction. This article discusses the possible pathophysiologies of refractory OAB.     

Antimuscarinic drugs for overactive bladder and their potential effects on cognitive function in older patients

Antimuscarinic agents are the predominant pharmacological treatment for patients with overactive bladder (OAB). These drugs are thought to act primarily through antagonism at muscarinic M3 receptors located at neuromuscular junctions in the human bladder detrusor muscle. Several of these drugs have been shown to be efficacious in ameliorating the symptoms of OAB in older patients, but most currently available agents lack selectivity for the M3 receptor subtype, and interaction with other muscarinic receptor subtypes throughout the body may adversely affect a variety of physiological functions and result in unwanted side effects, including cognitive dysfunction. With the recent availability of antimuscarinic agents that show increased selectivity for M3 receptors relative to other muscarinic subtypes, an invitational expert panel meeting was convened to review not only the mechanisms by which antimuscarinic agents could affect cognitive function, but also the published literature on cognitive adverse events. A review of the literature shows that the cholinergic system in the central nervous system (CNS) exerts a major influence on cognitive processes, in particular memory via M1 cholinergic receptors. In addition, recent evidence suggests a role for M2 receptors in mediating cognitive function. Thus, cognitive dysfunction (including memory loss) during treatment with nonselective antimuscarinic agents for OAB is of growing concern, particularly in older patients and those with mild cognitive impairment or dementia. Increased blood-brain barrier permeability, which can occur with advanced age and certain comorbidities, may also facilitate CNS access of antimuscarinic agents (regardless of their physiochemical properties) and add to antimuscarinic burden. On the basis of available evidence, antimuscarinic agents with selectivity for M3 over M1 and M2 receptors, limited CNS penetration, or both may therefore offer a favorable balance of efficacy in treating OAB together with a reduced risk of adverse cognitive events in the older population.     

Pharmacologic management of overactive bladder

Overactive bladder (OAB) is a prevalent and costly condition that can affect any age group. Typical symptoms include urinary urgency, frequency, incontinence and nocturia. OAB occurs as a result of abnormal contractions of the bladder detrusor muscle caused by the stimulation of certain muscarinic receptors. Therefore, antimuscarinic agents have long been considered the mainstay of pharmacologic treatment for OAB. Currently, there are five such agents approved for the management of OAB in the United States: oxybutynin, tolterodine, trospium, solifenacin and darifenacin. This article summarizes the efficacy, contraindications, precautions, dosing and common side effects of these agents. All available clinical trials on trospium, solifenacin and darifenacin were reviewed to determine its place in therapy.     

Difficult Urination Does Not Affect the Successful Outcome after 100U OnabotulinumtoxinA Intravesical Injection in Patients with Idiopathic Detrusor Overactivity

Objectives: Intravesical injection of onabotulinumtoxinA (i.e. Botox) provides effective treatment for overactive bladder. However, treatment‐related adverse events (AEs) remain problems. This study investigated the effect of AEs after onabotulinumtoxinA injection on the success rate for idiopathic detrusor overactivity (IDO). Methods: A total of 174 patients who received the first single intravesical onabotulinumtoxinA 100U injection for refractory IDO were included. The onabotulinumtoxinA related AEs including acute urinary retention (AUR), large postvoid residual (PVR, ≥150 mL), difficult urination, urinary tract infection, gross hematuria and general weakness were recorded. The success rate was determined based on patient perception of bladder condition improved by two scales. The short‐term (3 months) and long‐term (up to 24 months) success rates were analyzed according to the occurrence of these AEs. Results: A successful outcome was reported by 138 (79.3%) patients at 3 months. AUR occurred in 12 (6.9%) patients, large PVR developed in 81 (46.6%) and 73 (42%) needed straining to void. Gross hematuria occurred in 17 (9.8%) patients, urinary tract infection developed in 27 (15.5%) and general weakness was noted in 6 (3.4%). The occurrence of AUR did not affect the therapeutic results. Patients having large PVR and difficult urination had a significantly higher success rate at 3 months. Long‐term success rates up to 24 months showed no significant difference between patients with and without AEs. Conclusions: AEs after intravesical 100U onabotulinumtoxinA for IDO were frequently encountered. However, the occurrence of AUR, large PVR or difficult urination did not affect the final therapeutic outcome.     

Muscarinic Receptor Binding of Imidafenacin in the Human Bladder Mucosa and Detrusor and Parotid Gland

Objectives: The current study aimed to characterize comparatively the binding of imidafenacin to muscarinic receptors in the human bladder mucosa and detrusor muscle and parotid gland. Methods: The muscarinic receptor in homogenates of human tissues (bladder mucosa and detrusor muscle and parotid gland) was measured using a radioligand binding assay with [N‐methyl‐³H]scopolamine methyl chloride ([³H]NMS). Results: Imidafenacin competed with [³H]NMS for binding sites in the bladder mucosa and detrusor muscle and parotid gland, and its affinity was significantly (2.6–8.7 times) higher than that of oxybutynin. Also, the affinity of imidafenacin for muscarinic receptors was approximately two‐fold higher in the parotid gland than bladder tissue. The affinity of imidafenacin in the mucosa was similar to that in the detrusor muscle, suggesting that this agent exhibits therapeutic effects by blocking muscarinic receptors in the mucosa as well as detrusor muscle. Scatchard analysis revealed that imidafenacin increased significantly (approximately four‐fold) K_d values for [³H]NMS binding in the human detrusor muscle and parotid gland, with little effect on B_max values. This observation indicates that imidafenacin binds to the muscarinic receptors in human tissues in a competitive and reversible manner. Conclusion: Imidafenacin binds to muscarinic receptors in the human bladder mucosa and detrusor muscle and parotid gland with high affinity. This agent was considered to exhibit therapeutic effects on the lower urinary tract symptoms due to an overactive bladder by blocking muscarinic receptors in the urothelium as well as detrusor muscle.     

Intravesical strategies to manage the neurogenic bladder

Intravesical therapy with botulinum toxin type A (BTX-A) and vanilloids (capsaicin and resiniferatoxin) are actively investigated as potential treatments for lower urinary tract symptoms refractory to conventional therapy in patients with neurogenic detrusor overactivity. BTX-A cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in afferent and efferent nerve endings, impeding the fusion of synaptic vesicles with the neuronal membrane necessary for the release of neurotransmitters. Vanilloids desensitize the transient receptor potential vanilloid type 1 receptor and inactivate C-fibers. BTX-A intradetrusor injections are extremely effective for treating urinary incontinence, provide adequate protection of the upper urinary tract, and improve quality of life in patients with neurogenic detrusor overactivity. Therefore, BTX-A is currently the mainstay of intravesical therapy. However, despite promising results overall, the administration of these compounds, including BTX-A, remains an experimental procedure requiring further clinical studies.     

The Overactive Bladder: New Concepts of Etiology and Treatment

Overactive bladder (OAB) is a disorder characterized by urinary urgency. In the past, the pathophysiology and treatment of OAB focused on the parasympathetic efferent innervation of detrusor smooth muscle cells. However, recent evidence has provided a clearer understanding of the neurological, chemical, and functional physiology of the bladder and how it relates to the pathophysiology of OAB. Urothelial cells, sensory neurons, and interstitial cells of Cajal have secretory and receptor functions that play an important role in bladder function and dysfunction. As we learn more about bladder function and the mechanism of current OAB treatments, newer forms of therapy are emerging. These include neuromodulation, botulinum toxin, and the development of new drugs based on the pathophysiology of OAB.     

Muscarinic receptors: What we know

An understanding of muscarinic receptors is tantamount to an understanding of overactive bladder and detrusor over-activity. The M₃ muscarinic receptor subtype is responsible for detrusor smooth muscle contraction, and it exerts an exocrine function in the salivary glands. Alterations in the receptor’s response to acetylcholine as a result of injury may lead to hypersensitivity and overactivity. Muscarinic receptor immunoreactivity and myofibroblast activity have been identified in the urothelium. Additionally, activation of muscarinic receptors in the urothelium may modulate afferent sensory function. Newer research implicates the M₁ receptor as responsible for significant cognitive adverse effects. Recent drug development has focused on greater selectivity for the M₃ receptor and avoidance of central muscarinic receptors. Growing knowledge of the nuances of receptor-ligand behavior and interaction between muscarinic receptor subtypes may provide novel targets for future drug development, improve efficacy, and reduce bothersome side effects.     

Modulation of Bladder Afferent Activity by Propiverine and its Active Metabolites (M‐1 and M‐2) in Rats

Objectives: To evaluate the effects of propiverine and its active metabolites (M‐1 and M‐2) on bladder function through modulation of afferent activity in rats. Methods: Cystometry was performed in urethane anesthetized female rats. We examined the effects of intravesical administration of propiverine, M‐1 and M‐2 on bladder overactivity induced by oxotremorine‐M (Oxo‐M; non‐selective mAChR agonist). Results: Intravesical administration of Oxo‐M (200 µM) elicited bladder overactivity as evidenced by decreased intercontraction interval (ICI) and pressure threshold (PT) without changing maximum voiding pressure or baseline pressure. These effects were blocked by intravesical administration of propiverine (30 µM) or M‐2 (300 µM). Intravesical administration of M‐1 (30 µM) alone increased ICI and PT, but did not prevent Oxo‐M‐induced decreases in ICI and PT. Conclusion: These results suggest that propiverine and M‐2 have anticholinergic effects on bladder afferent activity and that M‐1 has an inhibitory effect through the mechanism other than muscarinic receptor modulation. Thus, clinical benefits of propiverine in patients with overactive bladder could be mediated by multiple actions of propiverine and its active metabolites.     

Physiopathology of overactive bladder syndrome

The pathophysiology of OAB is complex, multifactorial and still largely unknown. Several pathophysiological mechanisms have been highlighted that may play a different role in different patient groups. There are now experimental evidences that support both the myogenic and neurogenic hypothesis, but in recent years the "integrative" hypothesis has been gaining more and more acceptance, where a disruption in the multiple interactions between different cell types (neurons, urothelium, interstitial cells, myocytes) and network functions represent a central element of lower urinary tract dysfunctions. Of utmost importance, a disorder in the urothelial sensory function and in the urothelial/suburothelial non-neural cholinergic system, favored by age and comorbidities, appears to be crucial for the development of the OAB. Neuroplastic and detrusor changes in OAB are broadly similar to those observed in bladders exposed to outlet obstruction, neuropathies, inflammation or aging, and may be driven by a common urothelial dysfunction. Several signaling substances and their receptors were found to be involved in central pathways of bidirectional communication between the different cell types in the bladder, and were shown to be modified in several animal models of OAB as well as in human models, indicating new potential therapeutic targets.     

Management of overactive bladder

Many people are affected by urinary urgency, which can be highly bothersome. Urgency is the cornerstone symptom of overactive bladder (OAB), commonly occurring in conjunction with urinary frequency and nocturia. Once other medical causes of similar symptoms have been excluded, first-line OAB management comprises fluid intake advice and bladder training, supplemented by antimuscarinic drugs if necessary. Urodynamic confirmation of the diagnosis is required for OAB patients whose symptoms are refractory to first-line interventions. If patients are severely bothered by OAB despite optimization of medical treatment, they may proceed to invasive treatments, including neuromodulation, enterocystoplasty, detrusor myectomy, or urinary diversion. Our burgeoning understanding of the complex cellular, neural and integrative physiology of the bladder offers new insights into the causative mechanisms of OAB, and reasons why patients sometimes fail to respond to treatment. Study of sensory information pathways in the lower urinary tract has led to identification of the urothelium, afferent nerves and interstitial cells as key cellular elements in OAB. In-depth knowledge of the hierarchy of central nervous system control is lacking, but functional imaging is beginning to elucidate the challenges that lie ahead. New treatments under investigation include botulinum neurotoxin-A injection, oral β(3)-adrenergic agonists, and novel modalities for nerve stimulation. The subjective nature of urinary urgency, the lack of animal models and the multifactorial pathophysiology of OAB present significant challenges to effective clinical management.     

Therapeutic effects of Choreito,a traditional Japanese (Kampo) medicine,on detrusor overactivity induced by acetic acid in rats

Choreito (CRT), a traditional Japanese (Kampo) medicine, is widely used for the treatment of overactive bladder (OAB) and other lower urinary tract symptoms in Japan. This study aimed to identify the effects and therapeutic mechanism of CRT on the improvement of detrusor overactivity (DO) using an experimental rat model. Forty‐five female Sprague‐Dawley rats were equally divided into three groups: intravesical saline instillation with normal food (normal group), intravesical acetic acid (AA) instillation with normal food (AA group), and intravesical AA instillation with CRT (AA with CRT group). To induce a decrease in bladder capacity, instillation of 0.2% AA was used based on prior studies. Cystometric investigation was employed to clarify the effects of AA and CRT. Microcirculation was performed using a laser blood flowmeter, and the localization of hypoxia‐inducible factor 1α (HIF1α) was assessed by immunohistochemistry. The bladder capacities of the normal, AA, and AA with CRT groups were 1.2 ± 0.3 mL, 0.4 ± 0.1 mL, and 0.8 ± 0.1 mL, respectively. CRT significantly attenuated AA irritation of the urinary bladder and exerted protective effects on basal pressure, micturition pressure, micturition interval, and micturition volume. Furthermore, CRT could prevent the excess blood flow and edematous change under the urothelium induced by intravesical AA instillation. No obvious changes in immunohistochemical HIF1α staining were observed among the groups. CRT attenuated DO induced by intravesical AA instillation in a rat experimental model. CRT might impart therapeutic effects on OAB via the mitigation of urothelial damage and regulation of excess blood flow.     

Pharmacodynamics of Overactive Bladder Drugs: Shifting the Curve

Understanding the role of pharmacodynamics in determining a drug’s effect helps prescribing physicians choose the most appropriate agent and regimen to achieve the optimal balance of beneficial and adverse effects. The pharmacodynamic profile describes how a drug exerts its effects on the body, whether by physical, chemical, or enzymatic activity, or through receptor interaction at a cellular level. Drug–receptor binding results in biologic and physiologic effects, while the nature of binding defines the drug activity and dose–response relationship. Muscarinic receptor antagonists (antimuscarinics) are used in the treatment of overactive bladder. Antimuscarinics competitively block acetylcholine binding to muscarinic receptors in the detrusor smooth muscle and urothelium/suburothelium of the bladder. To make pharmacodynamic principles more relevant to the clinical urologist, this review summarizes clinical pharmacodynamic concepts, using the current antimuscarinics prescribed for overactive bladder and other urologic disorders as examples.     

Intravesical therapy for overactive bladder

Overactive bladder and urgency incontinence are common conditions generally treated with oral anticholinergic therapy. Despite the development of new antimuscarinic agents, many patients do not tolerate or fail to respond to oral therapy. Intravesical instillation therapy can provide an alternative method of managing bladder overactivity. Intravesical instillation of anticholinergics such as oxybutynin and atropine can achieve cholinergic blockade without producing systemic side effects. Botulinum A toxin injected directly into the detrusor has been shown in preliminary studies to increase bladder capacity and decrease uncontrolled bladder contractility for up to 6 months. Intravesical local anesthetics such as lidocaine and bupivacaine block the conduction of unmyelinated C fibers and when administered into the bladder, lead to an increase in functional bladder capacity. Intravesical capsaicin and resiniferatoxin also affect afferent innervation by blocking C-fiber afferents, leading to decreased bladder contractility and increased bladder capacity. Intravesical instillation therapy can provide an alternative treatment for the management of overactive bladder.     

Does the Technique or Pattern Matter When Injecting OnabotulinumtoxinA?

OnabotulinumtoxinA (BTX-A) is a treatment option for patients with neurogenic detrusor overactivity (NDO) or idiopathic overactive bladder (OAB) inadequately controlled with or intolerant to oral medications. The currently approved dosing is 100 U for OAB and 200 U for NDO which is commonly injected into the detrusor muscle via 20–30 trigone-sparing sites. Growing evidence suggests that the efficacy of BTX-A may be maintained with fewer injection sites, varying injection depth, and differing injection locations. This review focuses on the recent literature regarding various BTX-A injection techniques for the treatment of NDO and OAB.