EUROPEAN UROLOGY 59 (2011) 356358

available at www.sciencedirect.com journal homepage: www.europeanurology.com

Editorial
Referring to the article published on pp. 377386 of this issue

Antimuscarinic Treatment for Overactive Bladder Symptoms: An All-time Classic, Yet Still a Clinical and Basic Challenge
Apostolos Apostolidis *
2nd Department of Urology, Aristotle University of Thessaloniki, Greece

1.

Introduction

It has been a fascinating decade for antimuscarinics. Their clinical efficacy has been challenged and reinstated. New, efficacious extended-release formulations have broadened the therapeutic resources of physicians treating overactive bladder (OAB) sufferers. The mechanism of action has been revisited, and paradigm shifts have expanded clinical use indications. As knowledge about this class of drugs increases, more demanding questions arise, and research at the intersection of clinical and basic science is needed for robust answers. 2. The clinical challenge

Because the placebo effect in OAB studies appears to be overwhelming, reaching 4050% in some cases, a systematic review introduced the need for clinically significant statistical data on the use of antimuscarinics [1]. Consequent meta-analyses individually compared each antimuscarinic and placebo or active controls; reviewed data from more contemporary studies, including those that assessed the efficacy of newer agents, allowing discernment of within-class differences in efficacy; and reinstated the notion that antimuscarinics are clinically effective [2]. Aside from clinical studies, however, clinical practice creates scepticism: Only a small fraction of OAB patients continue on antimuscarinics in the long term, and inadequate efficacy is described as one of the main reasons for treatment discontinuation [3]. Patients expectations for treatment, inadequate physicianpatient interaction, and titration and follow-up issues may certainly interfere with

such findings, but other factors also could account for these unfavourable reports. Mechanistic aspects appear to be involved in a number of issues that remain unaddressed: Why do patients with similar symptom severity respond differently to similar doses of the same antimuscarinic? If antimuscarinics are more or less equally efficacious, why do different antimuscarinics produce different clinical responses in the same patient? Receptor selectivity and plasticity as well as the brain control of bladder function [4] and the dynamic nature of the OAB syndrome [5] may be the links to the missing information required to answer these queries. Additional factors may include a possible wearingoff effect or, conversely, conflicting patient reports concerning the time of onset of the beneficial effect both at the beginning of treatment and at the restart after a treatment-free period. More recently, the European Association of Urology guidelines have included antimuscarinics with or without the concomitant use of an a-blocker in the treatment of male, primarily storage, lower urinary tract symptoms (LUTS), based on a high level of published evidence [6]. At the same time, cautious prescription was advised in men with bladder outlet obstruction, although no cut-off was proposed for clinically significant obstruction, although such a cut-off would ensure safer use in such cases. Previous publications reported conclusions that antimuscarinics, even when used as monotherapy in men with benign prostatic hyperplasia or OAB, do not affect the flow rate or the detrusor voiding pressure significantly [7] and have the same low incidence of retention as does placebo treatment or combination therapy with an a-blocker [8]. However, treatment with an antimuscarinic (tolterodine) for up to 3 mo was found to be associated with reductions in both

DOI of original article: 10.1016/j.eururo.2010.11.040 * Papageorgiou General Hospital, 2nd Department of Urology, Ring road, Nea Efkarpia, 56403 Thessaloniki, Greece. Tel. +30 2310 991476/+30 2313 323712; Fax: +30 2310 683141/+30 2313 323697. E-mail address: zefxis@yahoo.co.uk.
0302-2838/$ see back matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2010.12.022

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detrusor contractility (median 5% drop in Bladder Contractility Index) and voiding efficiency (median 7% decrease) combined with an increase in postvoid residual in men with various degrees of urodynamic obstruction [7]. These urodynamic changes suggest a limited detrusor effect and were not considered to be clinically meaningful. 3. The basic challenge: mechanism of action

These findings are in agreement with the novel notion that antimuscarinics administered for OAB and detrusor overactivity (DO) do not act by blocking the detrusor muscarinic acetylcholine (ACh) receptors but actually exert their beneficial effect during the storage phase without interfering with the voiding contraction when used in therapeutic doses [9]. Revisiting the mechanism of action of antimuscarinics has been the consequence of a paradigm shift concerning the bladder afferent pathways and, in particular, the role of the urothelium. Because the bladder urothelium has been found to express a large range of receptors and neurotrophic factors and to release ACh, adenosine triphosphate, nitric oxide, tachykinins, and prostaglandins, the older notion that it serves as a plain protective barrier has been superseded by the view that it is a sensory organ. Suburothelial sensory nerves and closely apposed interstitial cells and/or myofibroblasts express the target receptors for urothelially released agents. A functional syncitium has been proposed that comprises complex interactions between the urothelial and suburothelial structures and is activated by bladder distension but also by spontaneous myogenic contractions. An increasing body of preclinical and clinical evidence supports the effect of antimuscarinics on the bladder afferent pathways [9]. It is intriguing that for such widely used drugs, relevantly little is known about the target of action. Literature on muscarinic receptors in health is generally in agreement about the expression and role of muscarinic receptors, at least in the detrusor, but research data are still largely based on animal experiments. Conflicting results exist regarding the expression of muscarinic receptors in human bladder disease states. Concerns have been raised regarding the specificity and diversity of antibodies used to characterise the structural localisation of muscarinic receptors [10]. In addition, the role of muscarinic receptors has been studied mainly in the detrusor; their role in the human bladder urothelium and suburothelium remains largely speculative. Although the distribution of muscarinic receptors in the human urothelium and suburothelium has only recently been addressed with conflicting reports [9,11], functional studies investigating the role of urothelial and suburothelial muscarinic receptors in OAB/DO are scarce [9]. Binding studies of the commercially used antimuscarinics to the bladder urothelium and suburothelium also would be required to support the direct effect of the drugs on the afferent pathways and to signify the functionality of receptors. Possibly as a result of the acknowledged efficacy of antimuscarinics in several randomised controlled studies, receptor selectivity as well as uroselectivity have been

considered mostly in association with the side-effect profile of antimuscarinics. Because the functionally predominant receptor in detrusor contraction is the M3 muscarinic ACh receptor, it has been the main research focus. However, only darifenacin is considered to be relatively M3 specific, whereas the remaining antimuscarinics show some selectivity over two receptors (oxybutinin, solifenacin) or none (trospium, propiverine, tolterodine, fesoterodine), with diverse affinity. Directly comparative studies between antimuscarinics are largely missing, and receptor selectivity has been left unstudied in terms of diversity of response to treatment between different patients as well as variance of response of the same patient to different antimuscarinics. Another issue that needs to be addressed is muscarinic receptor plasticity and its possible association with bladder disease states and their treatment. Animal studies have provided relevant evidence, but whether human bladder muscarinic receptors are susceptible to similar mechanisms of regulation of their expression via changes in the release of ACh remains to be proven. Nevertheless, it has been proposed as a complementary mechanism to aging and alterations of receptor excitability [9]; this could explain the changes in muscarinic receptor levels found in OAB/DO as well as the effect of treatment [11]. The short- and longterm effects of antimuscarinic treatment on the bladder are certainly of interest to both physicians and their patients, especially because there is no clear answer to patient queries about the need for continuous long-term or intermittent treatment. All five muscarinic receptor subtypes have been detected in the human prostate, although cultures of stromal and epithelial cells produced different results in receptor messenger RNA expression. In vitro and clinical evidence supports a role for muscarinic receptors in prostatic growth rather than prostatic contraction, with most studies showing a significantly higher density of muscarinic receptors in the epithelium compared to the stroma [12]. The expression of muscarinic receptors has been reported to be quantitatively similar in men with small asymptomatic and enlarged symptomatic prostates or in normal, hyperplastic epithelium and in well- to moderately differentiated carcinoma [13]. As the use of antimuscarinics rapidly expands for the treatment of male LUTS, can a prostatic effect of antimuscarinics be excluded? 4. Conclusions

In summary, antimuscarinics and their targets in the lower urinary tract still represent a challenge in terms of clinical practice as well as clinical and basic research. The design of clinical studies so far seems to complement patients limited adherence to treatment in terms of longevity, but OAB is a dynamic condition and physicians need information adjusted to both the nature of the syndrome and patients expectations and queries. As the older notion about the mechanism of action of antimuscarinics has been swept away by both preclinical and clinical findings, the demand for novel research focusing on the effect of

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EUROPEAN UROLOGY 59 (2011) 356358

antimuscarinics and the role and changes of their target receptors in the bladder as a whole has become a pressing reality.
Conicts of interest: Apostolos Apostolidis is an investigator for Allergan, Pharmaserve-Lilly, and GSK; has received honoraria and travel awards from Astellas, Pzer, and Pharmaserve-Lilly; consults for Astellas and Allergan; and has a research grant from Pzer.

[6] Oelke M, Bachmann A, Descazeaud A, et al. Guidelines on conservative treatment of non-neurogenic male LUTS. European Association of Urology Web site. http://www.uroweb.org/gls/pdf/BPH%202010. pdf. [7] Abrams P, Kaplan S, De Koning Gans HJ, Millard R. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006;175:9991004, discussion 1004. [8] Roehrborn CG, Kaplan SA, Jones JS, Wang JT, Bavendam T, Guan Z. Tolterodine extended release with or without tamsulosin in men with lower urinary tract symptoms including overactive bladder symptoms: effects of prostate size. Eur Urol 2009;55:47281. [9] Andersson K-E. Antimuscarinic mechanisms and the overactive detrusor: an update. Eur Urol 2011;59:37786. [10] Pradidarcheep W, Stallen J, Labruyere WT, Dabhoiwala NF, Michel MC, Lamers WH. Lack of specicity of commercially available antisera against muscarinergic and adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol 2009;379:397402. [11] Datta SN, Roosen A, Pullen A, et al. Immunohistochemical expression of muscarinic receptors in the urothelium and suburothelium of neurogenic and idiopathic overactive human bladders, and changes with botulinum neurotoxin administration. J Urol 2010; 184:257885. [12] Hedlund H, Andersson KE, Larsson B. Alpha-adrenoceptors and muscarinic receptors in the isolated human prostate. J Urol 1985;134:12918. [13] Witte LPW, Chapple CR, de la Rosette JJMCH, Michel MC. Cholinergic innervation and muscarinic receptors in the human prostate. Eur Urol 2008;54:32634.

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