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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 31  |  Issue : 3  |  Page : 91-98

Perspectives of medical treatment for overactive bladder


1 Department of Surgery, Division of Urology, Cardinal Tien Hospital, New Taipei, Taiwan
2 Department of Surgery, Division of Urology, Cardinal Tien Hospital; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan

Date of Submission16-Feb-2020
Date of Decision22-Mar-2020
Date of Acceptance07-Apr-2020
Date of Web Publication26-Jun-2020

Correspondence Address:
Chun-Hou Liao
School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_16_20

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  Abstract 


Overactive bladder (OAB) syndrome is a clinical symptom diagnosis. Treatment strategies are aimed at relieving symptoms. Because antimuscarinic drugs are applied for OAB, several targets of treatment about OAB had been found and newer treatments were also discovered. Besides, further studies about the potential advantages of combination therapy are proved to have increased efficacy and acceptable tolerability. Our study aims to update clinicians managing an OAB with an overview of the existing and newer medical therapies for OAB, including pharmacology, efficacy, side effects, and impact on the patient's quality of life. We review the most frequently used pharmacological therapies and new agents aimed at treating OAB. PubMed and Medline were explored for randomized controlled drug trials in adults with OAB, meta-analyses of medical therapy for OAB, and individual drug names, including the keywords efficacy, tolerability, quality of life, and compliance. In conclusion, newer antimuscarinic drugs focus on more selective muscarinic receptors with less side effects. Some β3-adrenoceptor (β-AR) agonists had also been approved in Japan, and Phase III study is ongoing in the USA. In addition to antimuscarinic drugs and β-AR agonists, several newer treatments, such as intravesical botulinum toxin injection and phosphodiesterase-5 inhibitors, were proved to improve OAB symptoms. The new targets of treatment should be the focus of future studies.

Keywords: Antimuscarinic treatment, overactive bladder syndrome, β3-adrenoceptor agonist


How to cite this article:
Lin CT, Chiang BJ, Liao CH. Perspectives of medical treatment for overactive bladder. Urol Sci 2020;31:91-8

How to cite this URL:
Lin CT, Chiang BJ, Liao CH. Perspectives of medical treatment for overactive bladder. Urol Sci [serial online] 2020 [cited 2020 Jul 12];31:91-8. Available from: http://www.e-urol-sci.com/text.asp?2020/31/3/91/287975




  Introduction Top


Overactive bladder (OAB) is one of the common lower urinary tract syndromes that has negative effects on people's quality of life worldwide. Its symptom complex includes urinary urgency, frequency, or nocturia, with or without urinary incontinence in the absence of urinary tract infection (UTI) or other bladder diseases.[1] This term was first proposed by Paul Abrams and Alan Wein in 1997 and formally adopted by the International Continence Society in 2002.[2] Although patients with OAB have symptoms, not all patients have abnormal urodynamic study such as phasic detrusor overactivity, low compliance, or a combination of both.[3] An estimated 20.1% of the 2018 worldwide population was affected by OAB and the frequency increases with age.[4]

OAB is a symptomatic diagnosis, but precise causes have not yet been identified. The following three hypothetical theories about OAB have been proposed: myogenic, neurogenic, and urotheliogenic factors.[5] The myogenic factor suggested that alterations of smooth muscle properties are necessary for the production of an involuntary detrusor contraction, leading to increased intravesical pressure. Changes of smooth muscle properties resulted in increased excitability and electrical coupling between cells. Local alterations of detrusor muscle properties in any part of the bladder will spread throughout the bladder wall, resulting in abnormal contraction of the entire bladder.[6],[7] The neurogenic factor, the second theory, suggests that damage to the central nervous system (CNS) or sensitization of peripheral afferent terminals in the bladder can unmask voiding reflexes triggering detrusor overactivity.[8] Damage to the brain induces detrusor overactivity by reducing suprapontine inhibition. The emergence of primitive spinal bladder reflexes triggered by C-fiber bladder afferent neurons is found in some patients with spinal cord injury. Sensitization of afferent innervations in the suburothelial layer of the bladder wall also resulted in detrusor overactivity.[9]

Dysregulation of bladder afferent activity leads to altered bladder efferent signaling, consequently causing impaired detrusor muscle. Oxidative stress has been demonstrated to activate capsaicin-sensitive C-fiber afferent pathways, thereby inducing detrusor overactivity. Developing afferent nerve blockers may be a new treatment for OAB. The third theory, urotheliogenic factors, is the relatively new hypothesis suggesting that the urothelium is not just a barrier, but also is an autonomous structure.[10] Transmitters released from the urothelium may change the excitability of afferent nerves.[11] During the bladder filling phase, there is autonomous function with nonmicturition contractions and phasic sensory activity.[12] These mechanisms can become modified in pathological conditions, causing excessive excitatory inputs or failure of inhibiting inputs, leading to detrusor overactivity.

Although the cause of OAB remains to be founded, current treatment involving conservative, pharmacological, and surgical interventions is developing. The first-line therapy of OAB is focused upon conservative and medical treatments. Due to developments in the pathophysiology study of OAB and many classes of medication having been proposed for OAB, this review addresses the current and future pharmacological management of the OAB syndrome.


  Antimuscarinic Treatment Top


Acetylcholine is the predominant peripheral neurotransmitter. Muscarinic receptors are widely distributed throughout the body.[13] Human bladder contractions are initiated via the interaction of acetylcholine and muscarinic receptors in the detrusor muscle. Among the five known muscarinic subtypes (M1 through M5), human voiding function appears to occur via parasympathetic activation of the M2 or M3 receptors. The M3 receptor is highly predominant in the human bladder.[14] Acetylcholine can inhibit sympathetically mediated bladder relaxation via M2 receptors.[15] Besides, muscarinic receptors are also found in the urothelial cell. Consequently, the detrusor muscle and urothelium may be the site of action of antimuscarinic drugs.[16]

Antimuscarinic drugs are the first-line treatment for OAB. Since the first antimuscarinic drug, oxybutynin, was approved for OAB, other antimuscarinic drugs and new dosage forms have been discovered. An update of a systematic review published in 2018 suggested that all the reviewed antimuscarinics were more effective than the placebo.[17] [Table 1] lists the common antimuscarinic drugs currently used to treat OAB.[18],[19] Although anticholinergic drugs are efficacious and safe, some side effects, such as dry mouth, constipation, gastroesophageal reflux, blurry vision, urinary retention, and cognitive effects, can also occur and affect drug compliance.
Table 1: Anticholinergic drugs for OAB

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Because some older patients with OAB are treated with cholinesterase inhibitors for dementia, the potential for adverse cognitive effects is a particular concern.[20] Among these antimuscarinic therapies, oxybutynin has more CNS effects.[21] Due to increased permeability of the blood–brain barrier in older adults, the intake of anticholinergic therapy may render individual patients more susceptible to antimuscarinic adverse CNS events.[22] As a result, more selective antimuscarinic therapy and newer agents should be tested, especially in older patients. A study has investigated the discontinuation rates of anticholinergic medications in women.[23] The discontinuation rate of antimuscarinic drugs reported in this study was 4.76 months after initial therapy use. In OAB treatment episodes, 58.8% discontinued treatment at 6 months, 77.2% by 1 year, and 92% by 3 years. Higher discontinuation rates and bothersome side effects on antimuscarinic therapy highlight the need for additional options.

The development of more selective muscarinic receptor antagonists and more organ selectivity to the bladder is ongoing. Imidafenacin (Uritos, Kyorin Pharmaceutical Co., Japan) is a new antimuscarinic drug approved in Japan in 2007 and Korea in 2013. In a placebo-controlled trial, the efficacy and safety of the treatment have been confirmed.[24] OAB episodes were reduced in a dose-dependent manner after 12 weeks of treatment.[24] Imidafenacin also has higher selectivity for M3 and M1 receptors than for the M2 receptor, whereas tolterodine and oxybutynin had no selectivity.

On the prejunctional nerve terminals, the M1 subtype is a facilitator of muscarinic receptors.[25] Imidafenacin inhibits bladder contraction by an M3 receptor antagonist and regulates acetylcholine release by mediating the M1 receptor.[26] Furthermore, imidafenacin also has a more selective inhibitory cholinergic reaction on the urinary bladder over the salivary gland.[26] Many studies are conducted to compare the clinical efficacy and safety of imidafenacin to other OAB medications. In a randomized, open-label, tolterodine-controlled, comparative multicentric study, imidafenacin was associated with a reduction in voiding frequency and urgency incontinence when compared to tolterodine.[27] The safety profiles were similar between these two study groups.[27]

Apart from imidafenacin, some novel potent antimuscarinic agents are also further developing. Tarafenacin (SVT-40776) is a highly selective antagonist for M3 receptors. The dose–response relationship for the efficacy and tolerability of tarafenacin had been confirmed in a Phase II study.[28] Afacifenacin (SMP-986), a new antimuscarinic drug, can be a nonselective muscarinic receptor antagonist, which inhibits the bladder afferent pathway through a sodium channel blocker. A Phase II trial of afacifenacin, carried out in Europe and the United States, has recently been completed.[29] The results have not yet been published. DA-8010, an experimental medical treatment synthesized by Dong-A ST Pharmaceutical Company (Yongin, Korea), was proved to be selective for urinary bladder over salivary gland. The muscarinic receptor binding assay of DA-8010 showed that the potency for bladder smooth muscle cells was 3.6-fold higher than that for salivary gland cells from mice.[30] A Phase II trial of DA-8010 is in progress.


  β 3-Adrenoceptor Agonist Top


β-adrenoceptors (β-ARs) are classified into three different subtypes: β1, β2, and β3; they are widely distributed in the body to mediate different physiological effects.[31] Since β3-ARs were first identified on the surface of both white and brown adipocytes in 1989, more studies have indicated that they are also expressed in the human heart, gall bladder, gastrointestinal tract, prostate, and urinary bladder detrusor.[32],[33] Nonselective β-agonists have an obvious effect on detrusor muscle relaxation and increasing bladder capacity.[34] Three β-AR subtypes (β1, β2, and β3) can be identified in the detrusor and urothelium. β3-AR revealed a predominant expression in the human detrusor muscle.

In a human bladder study, spontaneous contractile activity occurred during the bladder filling phase.[35] It is believed that the spontaneous contractile, phasic activity of the detrusor muscle during filling, can induce an afferent signal resulting in OAB. This spontaneous contractile can be decreased by stimulating the β3-ARs on the detrusor muscle.[36] In addition, β3-AR agonists have little effects on voiding contraction caused by muscarinic receptor, and it can increase bladder capacity without change in residual volume. This may be the reason why urine retention does not seem to be impaired by β3-AR agonists. As a result, β3-ARs are an attractive target for drug discovery.

Mirabegron, a β3-AR agonist approved by the US Food and Drug Administration (FDA) in 2012, has been confirmed to improve OAB patients' clinical condition.[37],[38] Several clinical trials and systematic reviews revealed that mirabegron can improve the mean number of micturition/24 h and the rate of continence and dry rate compared with placebo.[39],[40],[41] One study showed that patients with OAB and bladder outlet obstruction treated by mirabegron and an alpha-blocker had storage symptom improvement compared with alpha-blocker alone.[42] In a urodynamic study, mirabegron did not affect flow rate, detrusor pressure at maximum flow rate, or bladder contractile index.[43]

The common adverse events of mirabegron were hypertension (9%–11%), headache (4%), nasopharyngitis (3%–4%), and UTI (3%–6%), having similar frequency to that of placebo.[37],[40] In several randomized controlled trial and systematic reviews, mirabegron had similar improvement in efficacy.[44],[45] A study data indicated higher adherence and persistence among patients treated with mirabegron than with antimuscarinics.[46]

Because β3-AR agonists had the same effect on OAB and less side effects compared to antimuscarinics, many novel β3-AR agonists had been discovered [Table 2]. Vibegron (MK-4618/KRP-114V), a selective β3-AR approved in Japan in September 2018, showed pharmacological activityin vitro andin vivo in some studies.[47],[48]
Table 2: β3-Receptor Agonists for Overactive Bladder

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In a Phase III study of vibegron,[49] 1232 patients were randomized into four groups (vibegron 50 mg, vibegron 100 mg, placebo, and imidafenacin). The mean change of the number of micturition per day at 1 week was 2.08, 2.03, 1.21, and 2.06, respectively (P< 0.0001). Drug-related adverse event rates were 7.6%, 5.4%, 5.1%, and 10.3%, respectively. On quality of life assessment, vibegron can also significantly improved quality of life.[49] The efficacy of vibegron 50 mg or 100 mg once daily for 12 weeks was superior to that of placebo.[49]

Another novel β3-AR agonist, solabegron (GW427353), was discovered and developed. In a double-blind, randomized, placebo-controlled trial, solabegron 125 mg had statistically significant improvements in the percent change in incontinence episodes compared to the placebo.[50]


  Combination Therapy Top


Antimuscarinic agents are the first-line oral therapy for OAB, but a higher discontinuation rate is noted due to insufficient efficacy and bothersome adverse events. β3-AR agonist is a new class of pharmacotherapy for OAB.

According to the European Association of Urology and the American Urological Association guidelines, there is strong evidence of combination therapy for the treatment of OAB. Many trials were conducted on the efficacy and safety results in combination treatment with β3-AR agonist and antimuscarinics. In the SYNERGY study, OAB patients were divided into the following six groups: solifenacin (5 mg) plus mirabegron (25 mg), solifenacin (5 mg) plus mirabegron (50 mg), placebo, mirabegron (25 mg) monotherapy, mirabegron (50 mg) monotherapy, or solifenacin (5 mg) monotherapy.[51] All active treatment groups showed greater improvements in urinary incontinence episodes/24 h and the mean number of micturition per 24 h than placebo. Drug-related adverse events slightly increased in the combination therapy groups compared to monotherapies.[51] In the follow-up SYNERGY II trial,[52] the primary objective was to evaluate safety by measuring the treatment-emergent adverse events. The efficacy was also measured as the change from baseline to the end of treatment in the mean number of incontinence episodes and micturition per 24 h. There were 1829 OAB patients randomized to combination 5 mg solifenacin plus 50 mg mirabegron, solifenacin monotherapy, mirabegron monotherapy, or placebo. Treatment-emergent adverse events showed that dry mouth was the most commonly reported, more frequently in the combination group (49%) than in the mirabegron group (41%) or solifenacin group (44%). Combination therapy was statistically superior to mirabegron and solifenacin monotherapy for decreasing the number of incontinence episodes and micturition (all P < 0.05).[52] In the BESIDE trial,[53] solifenacin 5 mg plus mirabegron 50 mg was found to be superior to solifenacin 5 mg, with statistically significant improvements in daily incontinence (P< 0.001), daily micturition (P< 0.001), and incontinence noted in a 3-day diary (P< 0.014).[53] In the postmarketing, open-label study (MILAI study),[54] the safety and efficacy of mirabegron as an add-on therapy to solifenacin in patients with OAB were evaluated. OAB patients, who were treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks, were enrolled. The patients continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks.[54] An optional dose increase to 50 mg at week 8 was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. At the treatment end point, there were significant improvements in OAB symptoms with combination therapy with mirabegron and solifenacin.[54] Among these combination studies,[51],[52],[53],[54] significant improvement in OAB symptoms was observed. Combination treatment and add-on therapy with mirabegron and an antimuscarinic agent, such as solifenacin, may provide an attractive therapeutic option.


  Other Medications Top


Several newer pharmacotherapy or dosage forms are intended to relieve and alleviate the symptoms and need to be further discovered and developed. The efficacy of intravesical botulinum toxin injection for patients with OAB has been shown.[55] There is no standard dosage for the application of botulinum toxin injection. In some trials,[56],[57],[58],[59],[60],[61] 100–300 U Botox is injected at different sites of the bladder wall. Almost all patients with OAB in these trials showed significant improvements in OAB symptoms compared with placebo.[56],[57],[58],[59],[60],[61] Although intravesical botulinum toxin injection has benefits for patients with OAB, side effects, increased postvoid residual urine volume, and UTI remained to be resolved. A new dosage form of botulinum toxin, liposome-encapsulated onabotulinum toxin A, was revealed for patients with OAB.[62],[63] Liposomes are phospholipid bubbles filled with water that can carry the onabotulinum toxin A protein across the cell membrane. In a pilot study,[64] Kuo et al. stated that liposomes can be a vehicle for delivering botulinum toxin into the urothelium. Liposome-encapsulated onabotulinum toxin A can decrease OAB symptoms without increasing the risk of large postvoiding urine.[64] In a prospective randomized trial, lipo-botulinum toxin had a statistically significant decrease in micturition events (−4.64 for lipo-botulinum toxin vs. −0.19 for placebo; P = 0.0252) and urinary urgency (P = 0.0181) after 4 weeks of treatment.[65]

Phosphodiesterase-5 inhibitors (PDE5I), clinically used to treat erectile dysfunction, had been demonstrated to significantly improve male lower urinary tract symptoms (LUTS).[66],[67],[68],[69] In 2011, tadalafil 5 mg once daily was approved for male LUTS by the FDA and European Medicine Agency. In an animal model, PDE5I was effectively used as a urodynamic parameter.[70] The efficacy of daily low-dose sildenafil for treating interstitial cystitis was also demonstrated.[71] This finding suggests that PDE5I is a potential treatment for OAB. In a randomized, double-blind, placebo-controlled trial,[72] the frequency, incontinence, and urgency episodes significantly improved in the tadalafil treatment group as compared with the placebo group (P< 0.05). Although PDE5I has benefits for the OAB patient, further investigation involving a larger population and a longer follow-up period is needed.[72]

It has been hypothesized that afferent fibers (C and alpha-delta) and sensory neurons in the bladder are responsible for controlling detrusor activity.[73] Gabapentin is a ligand of the voltage-sensitive calcium channels involved in the activation of afferent fibers (C and alpha-delta).[73] In some studies,[74],[75],[76] gabapentin is effective in reducing OAB symptoms. Pregabalin is similar to gabapentin in its mechanism of action,[77] though pregabalin has higher bioavailability, more rapid adsorption, and greater potency.[78]

In preclinical studies, pregabalin resulted in increases in bladder capacity.[79],[80] Synergism effects were also observed in preclinical studies when combined with tolterodine.[81] In a Phase II study, pregabalin alone or in combination with tolterodine displayed a significant increase in mean voided volume per micturition after 4 weeks of treatment.[82]

Except for oral medication, some experimental drug delivery systems were also discovered. TAR-302-5018 is a trospium-releasing intravesical system placed into the bladder through an inserter. Trospium is gradually released during indwelling time. A Phase I study of TAR-302-5018 has been completed.[83] The results have not yet been published. URO-902 (hMaxi-K), a gene therapy using a plasmid vector, had been proved to result in overexpression of the human BK channel α-subunit which is a large-conductance Ca2+-activated K + channel expressed on bladder smooth-muscle cells and reduce bladder detrusor muscle excitability.[84] Phase I study of URO-902 stated that gene therapy may be a promising therapy and needs further investigation.[85] A Phase II study of URO-902 is in progress.


  Conclusion Top


OAB syndrome is a clinical symptom diagnosis that affects health-related quality of life. Owing to its unknown cause, treatment strategies are aimed at relieving symptoms, not at changing the pathology state. Anticholinergic treatment is the mainstay of medical treatment that had proven efficacy. Due to significant side effects, anticholinergic treatment needs to be carefully used, especially in the elderly. Some newer antimuscarinics with less drug-related side effects have been discovered. Considering mirabegron has been licensed since 2012, β3-AR agonists have been confirmed to improve clinical outcomes with less side effects compared to antimuscarinic treatment. Although there are several monotherapy options, many studies demonstrated the efficacy of combination therapy with antimuscarinic therapy and β3-AR agonists. The potential advantages of combination therapy for OAB are increased efficacy and acceptable tolerability. Several trials had investigated the efficacy and safety of PDE5I and pregabalin, but further study is needed. With the development of more pharmacotherapy and the discovery of pathophysiology, newer formulations or medications have been shown to have more efficacy and less drug-related side effects. A new target of treatment should be the focus of future studies.

Acknowledgments

The authors would like to thank Cardinal Tien Hospital who contributed to this study. This research was funded by Program CTH105A-2F01.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
Antimuscarinic T...
β 3
Combination Therapy
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