Overactive bladder (OAB) is a common condition, defined as a new term by the International Continence Control Society (ICS) in September 2001, characterized by urinary urgency with or without urge incontinence, often accompanied by frequency and nocturia [1]. The Clinical Guidelines for Overactive Bladder Disorder of the Urology Control Group of the Chinese Medical Association Urology Branch defines OAB as a syndrome consisting of urinary frequency, urgency, and urge incontinence, which can occur individually or in any compound form [2]. In some patients during urodynamic examination, during the bladder storage phase, involuntary contraction of the bladder forcing muscles occurs, causing an increase in intravesical pressure, called detrusor overactivity (DAI) [3]. The two are both related and distinct.
I. Epidemiology
OAB is not an endemic disease in a specific cultural context. Because OAB is often confused with urinary incontinence and different physicians use different diagnostic criteria, the incidence or prevalence summarized varies widely [4]. However, it has also been suggested that the prevalence is approximately the same in different countries. In France, Italy, Sweden, the United Kingdom, and Spain, its prevalence is 11% to 22%. And it is estimated that about 17% of adults in Europe and the United States suffer from this disease. The number of people affected worldwide is around 50-100 million [3] [5]. Slightly more women than men suffer from the disease, and its incidence increases with age [6]. There is no epidemiological data on this disease in China, although a survey conducted by the Institute of Urology of Peking University in Beijing showed that the incidence of urge incontinence in men over 50 years of age was 16.4%, and the incidence of mixed and urge incontinence in women over 18 years of age was 40.4% [7]. Proper management of OAB will certainly reduce the incidence of urinary incontinence and thus improve the quality of life of patients.
II. etiology
The symptoms of OAB are due to involuntary contraction of the detrusor muscle during bladder filling [8], and its etiology is still not well understood; it may be due to damage to the central inhibitory efferent pathway, the peripheral sensory afferent pathway or the bladder muscle itself, which can be present individually or in combination [9].
In pontocerebral suprachiasmatic nerves, which mainly inhibit the voiding reflex, lesions here often result in insufficient inhibition, with a 75% to 100% incidence of detrusor hyperreflexia, usually without detrusor external sphincter synergism, whereas pontocerebral-sacral medullary lesions tend to show detrusor hyperreflexia plus detrusor external sphincter synergism [10]. Hyperreflexia of the detrusor muscle has also been reported in peripheral neuropathies of the sacral medulla, such as diabetes mellitus, which may be related to the multifocal nature of the lesion [10]. In addition the incidence of unstable bladder due to bladder outlet obstruction is as high as 50% to 80%, which causes increased excitability of the detrusor muscle and OAB symptoms through nerve and muscle changes in the bladder wall eventually.
III. Diagnosis
Applying the definition of ICS or urogenital control group, OAB is an empirical diagnosis. It is important to take a careful history, including typical symptoms and associated symptoms. History taking should cover the history of diagnosis and treatment and outcome of medical, neurological and genitourinary related diseases. A detailed voiding diary with a targeted questionnaire is also required.
The physical examination focuses on the abdomen, pelvis, rectum, and nervous system. Routine urinalysis is mandatory, and if positive, further bacteriological and cytological tests are required. For post-void residual urine determination and urodynamic tests are applied selectively according to the patient’s condition. The diagnosis of overactive bladder can be made after exclusion of pathological conditions such as infection, stones, and carcinoma in situ of the bladder.
IV. Treatment
Once a patient is diagnosed as possibly having OAB, the need for treatment is carefully considered to understand whether the patient has a requirement for treatment. The initial treatment is therefore determined around the question of how much the patient’s symptoms are affecting his or her quality of life.
Since OAB is a symptomatic diagnosis, its treatment can only relieve the symptoms rather than target the cause, and a cure is not possible. Current treatment includes behavior modification, medication, neuromodulation, and surgery.
(i) Behavior modification
Behavior modification includes patient health education, timely or delayed urination, bladder training, pelvic floor exercises, etc. Patients are taught how the lower urinary tract “works” so that they are aware of coping strategies. A voiding diary not only enhances the patient’s awareness of self-prevention, but also gives the physician a clear picture of when symptoms occur and their severity, so that he or she can teach the patient simple dietary controls and develop methods for regular or preventive voiding and bladder training. In addition, pelvic floor exercises can enhance the strength of the pelvic floor muscles, which can produce a strong inhibition of involuntary detrusor contractions. In recent years, the application of biofeedback to pelvic floor muscle physiotherapy has been effective in restoring the function of the lower urinary tract in a way that is difficult to obtain with other treatments. Lisa Lin et al. applied a pelvic biofeedback electrical stimulation device manufactured by Laborie Canada for the treatment of OAB and found its efficacy to be comparable to that of tolterodine [11], although the role of this method remains highly controversial. Behavior modification therapy has been reported to result in more than 50% improvement in the occurrence of urinary incontinence [12], and combined with pharmacological treatment resulted in an average 84.3% reduction in incontinence [13].
(ii) Pharmacological treatment
The goal of pharmacological treatment is to increase bladder capacity, prolong alert time, and eliminate urgency without interfering with the ability of the bladder to empty. The drugs currently used to treat OAB are (1) targeting parasympathetic efferent nerves and acting on cholinergic receptors on the detrusor muscle, including cholinesterase inhibitors. For example, atropine, probenecid, oxybutynin, tolterodine, darifenacin, trasylcholine, soliferacin, etc. (2) Drugs acting on sensory afferent nerves of the bladder: Capsaicin and Resiniferatoxin RTX. (3) Inhibit the release of acetylcholine from parasympathetic cholinergic nerve terminals: botulinum toxin A. (4) Drugs that act on the central nervous system.
Studies have found that different subtypes of muscarinic receptors (M receptors) are widely distributed in the body. They play different physiological roles in different sites. For example, M1 receptors in the brain and salivary glands are associated with cognition and saliva production [14][15]. M2 receptors in the cardiovascular system have an important role in the regulation of heart rate and cardiac output [16]. M5 receptors in the eye are associated with the contraction of the ciliary muscle [17] [18]. In the bladder tissue contains mainly M2 and M3 receptors, the density of M2 receptors is much greater than M3 receptors (about 4:1), while functionally M3 receptors are more important, mediating directly the contraction of the bladder forceps, the role of M2 receptors is not fully understood [19]. Antimuscarinic drugs can bind to some or all of these receptors in vivo with different affinities, which not only improve the symptoms of OAB but also cause many side effects such as dry mouth, constipation, cognitive deficits, tachycardia, and blurred vision [18], thus limiting the long-term use of such drugs. Therefore, several improvements have been made to these drugs in order to reduce side effects, improve tolerability, and obtain maximum efficacy. (1) Improving the dosage form by changing from the common rapid-release type of the drug to a sustained-release dosage form, so that the concentration of the drug rises slowly in the body and remains stable. (2) Change the route of drug delivery: such as oxybutynin transdermal permeation, intravesical administration, etc. (3) Improve the selective affinity of the drug with M3 receptors in the bladder, with reduced or no affinity for M receptors in other organs, such as the new drug darifenacin, which is a selective inhibitor of M3 receptors. In conclusion, as M receptor blockers continue to improve, their side effects will gradually decrease, and the patient’s compliance and efficacy of drug treatment will improve.
Early on it was found that after spinal cord transection in animals, the normally C-type bladder afferent fiber-induced spinal urinary reflex shifted from an inactive state to an active one, which was reversed by intravesical infusion of capsaicin [20]. This observation and many subsequent studies led to the use of capsaicin in the treatment of OAB. Capsaicin is an active ingredient extracted from red peppers that specifically blocks unmyelinated nerve afferent fibers in the bladder by depleting neuropeptides (e.g., substance P), desensitizing C-neurons, decreasing bladder sensory function, and attenuating the voiding reflex caused by bladder dilation. It is used to treat neurogenic bladder detrusor reflex hyperactivity without blocking the normal detrusor reflex. However, intravesical infusion of capsaicin can trigger an acute inflammatory response and even spasmodic pain and a burning sensation over the pubic bone affecting its use. In recent years, the development of rhodopsin (RTX), which is 1000 times hotter than capsaicin, is used in small concentrations, with mild side effects, and patients are willing to accept it.
Botulinum toxin A is a neurotoxin produced by Clostridium botulinum that paralyzes muscles by inhibiting the release of acetylcholine from cholinergic nerve endings at the neuromuscular junction. The application of botulinum toxin in patients with synergistic dysfunction of the detrusor-urethral sphincter relaxes the external urethral sphincter and improves bladder emptying in patients [21]. Recent studies have shown that botulinum toxin A is also able to relax the detrusor muscle and reduce detrusor overactivity in patients with spinal cord injury [22]. Therefore, the application of botulinum toxin A forced urinary muscle injection is effective in relaxing neurogenic forced urinary muscle overactivity.
The pathophysiology of OAB involves the peripheral and central nervous system, and many central diseases are associated with OAB, such as stroke, spinal cord injury, Parkinson’s syndrome, and multiple sclerosis. Most of the drugs used to treat OAB act at peripheral sites and mainly affect afferent and efferent neurotransmitters or the detrusor muscle itself. Because many central transmitter/transmitter systems are involved in voiding control, new targets for drug intervention may be found centrally. GABA, glutamate, opioids, 5hydroxytryptamine, norepinephrine, and dopamine receptors are known to affect voiding function, and a few drugs identified, such as orthoclopromide, promethazine, and duloxetine, act in the central nervous system for the treatment of voiding disorders. It is then possible that drugs affecting all of these systems could be developed for the treatment of OAB. Some studies have now demonstrated that this is possible [23].
(iii) Neuromodulation therapy
If non-invasive behavior modification and medication fail, then it is important to consider whether to increase the dose of medication, change medication, add other medications or treatments, or otherwise opt for a neuromodulation approach.
Sacral nerve stimulation for OAB has made great progress in recent years. The application of electrical stimulation of the sacral nerve roots (S3) causes excitation of the afferent nerves in the pubic area and of course may excite other afferent and efferent nerve fibers, modulating sensory and/or motor functions and restoring sacral reflex balance and coordination, thus improving the symptoms of OAB [24] [25]. Sacral neuromodulation therapy is still in its early stages and there are no reliable indications for its indications and prediction of its effectiveness; when a patient decides on sacral nerve stimulation therapy, the site of the sacral nerve is first selected transdermally, followed by an individualized in vitro stimulation test, and only after successful implantation of the sacral nerve stimulation system permanently. The available data report that this method is more effective in the treatment of urge incontinence [5]. The current stimulation system has been developed as a “dual simulator”, i.e., it inhibits the contraction of the detrusor muscle in the “on” state and triggers voiding in the “off” state. With the continuous improvement of this treatment system and the accumulation of clinical experience, it is believed that more OAB patients will benefit from this treatment.
(iv) Surgery
Patients with chronic non-responsive OAB and recalcitrant OAB may be treated surgically, including cystoneurotomy, bladder wall muscle dissection, bladder dilatation, bladder enlargement, pelvic nerve dissection, sacral nerve rhizotomy and urinary diversion.
Cystoneurotomy is actually a denervation and destruction of postganglionic parasympathetic fibers, a technically demanding method with a recurrence rate of up to 100% at 18-24 months postoperatively according to current experience [26]. Therefore it has been rarely applied. Expanded cystoplasty is also less commonly used because of the risk of complicating bladder emptying failure, and other surgical methods are also mainly used for spastic bladder after spinal cord injury; in conclusion, surgical methods for OAB are the last choice and have a more limited application.
V. Outlook
OAB is a symptomatic diagnosis based on the presence of urinary urgency, with or without urinary incontinence, often accompanied by frequent and nocturnal urination. Its treatment is comprehensive including behavioral, pharmacological and neuromodulation, and surgical. Future treatment will focus on improvements in pharmacologic and surgical approaches, and the development of effective and well-tolerated medications is a common desire of pharmacologists, urologists, and patients.
Non-pharmacological treatments for OAB also include emerging tissue engineering, where there is scaffold on which bladder tissue is cultured for cystoplasty, which can greatly simplify the surgical procedure without the need for anastomosis. There is also interest in gene therapy aimed at reversing some of the reversible changes in the nerves and thus restoring bladder function, which has been increasingly recognized and the research devoted to it will continue to increase due to the serious impact of OAB on the quality of life of patients.