Future Directions in Overactive Bladder Treatment

Transcription

1 Curr Bladder Dysfunct Rep (2011) 6:45 50 DOI /s Future Directions in Overactive Bladder Treatment Melissa R. Kaufman Published online: 6 November 2010 # Springer Science+Business Media, LLC 2010 Abstract Overactive bladder (OAB) remains a remarkably common urologic condition resulting in significant clinical and economic sequelae. Although likely underestimated, the overall prevalence of overactive bladder is projected to be between 15% and 38%. The mainstay of therapy for decades has revolved around anticholinergic pharmaceuticals. However, recent advances in bladder and urothelial physiology have dramatically expanded the treatment options available for OAB management. Herein we present an overview of several emerging options for OAB therapy and review the available literature regarding these therapies. Despite substantial investment into OAB treatment, we are witness to but the genesis of research on detrusor function and urothelial biology that will guide practitioner interventions in the coming decades. Immense opportunity exists for future evaluation of OAB pathophysiology to advance our knowledge regarding management of this multifactorial urologic disorder. Keywords Overactive bladder. Antimuscarinics. Afferent bladder signaling. β3 agonists. Botulinum toxin. Sacral neuromodulation Introduction Overactive bladder (OAB), defined by the International Continence Society as urgency, with or without urgency urinary incontinence, usually with frequency and nocturia in the absence of pathological or metabolic conditions M. R. Kaufman (*) Department of Urologic Surgery, Vanderbilt University Medical Center, A-1302 Medical Center North, Nashville, TN , USA melissa.kaufman@vanderbilt.edu that might be able to explain these symptoms [1], continues to generate substantial attention and debate in the urologic community. The economic and psychosocial sequelae of OAB are profound given estimates that more than 37 million individuals in the United States are affected [2]. Recent comprehensive, prevalence-based modeling analysis revealed an alarming outlay, with aggregate total OAB-attributable expenditures of 65.9 billion dollars in 2007 [3]. As a disease with increasing prevalence and morbidity in our aging population, the future global impact of OAB and its treatment on the infrastructure of the health care system is staggering, with these costs estimated to spiral upward to 82.6 billion dollars by With this immense burden of OAB disease, response from the research community and pharmaceutical and device industries has been intensive. Recent advances in our understanding of bladder neurophysiology and urothelial biology are shaping new frontiers for OAB therapies. However, the precise etiology of OAB is often an individualized affair, with endless combinations of neurologic and myogenic insults playing causative roles. The multifactorial nature of the OAB disease process has impacted the efficacy of our clinical interventions, and large percentages of patients are refractory to many first-line therapies. Herein we describe several novel modalities of treatment currently used for OAB symptoms, and future directions that may yield substantial alterations in the clinical approach to management of OAB patients in the coming decades. Anticholinergic Agents For decades, the mainstay of clinical therapy for OAB has revolved around permutations of oral antimuscarinic pharma-

2 46 Curr Bladder Dysfunct Rep (2011) 6:45 50 cologic agents [4 ]. These compounds have been presumed to exert their effect on reduction of patient storage urinary symptoms by increasing capacity and reducing urgency and frequency [5]. It has been commonly assumed that antimuscarinic agents provide efficacy by directly blocking efferent receptors on the detrusor to diminish pathologic contractility mediated by cholinergic parasympathetic nerves [6]. Curiously, in the dose range commonly used for antimuscarinic agent clinical efficacy, there is sparse evidence that a reduction in detrusor contractility is accomplished [7]. This observation has evolved into an explosion of high-quality research directed at elucidating the true mechanism of action of antimuscarinic agents that is currently focusing on afferent bladder signaling [8 ]. Aggressive investigations of alternative mechanisms of action for the antimuscarinic class are likely to yield substantial clinical insight in the coming years [9]. Current antimuscarinic agents are classified as tertiary or quaternary amines that differ in lipophilicity and additional molecular parameters affecting absorption and metabolism and, thus, side effect profiles [10]. Substantial effort by the pharmaceutical industry has been devoted to promoting bladder selectivity of currently available oral and transdermal agents. However, looking at these agents as a group, one of the major factors that continues to limit treatment compliance and efficacy is the presence of bothersome peripheral effects such as accommodation paralysis that result in blurry vision, constipation, tachycardia, altered cognition, and dry mouth [11, 12]. Emerging means of delivery of antimuscarinic compounds could theoretically eliminate some of the systemic absorption side effect profile. One such mode of delivery is intravesical administration of antimuscarinics [13]. Serum levels of the compound similar to those resulting from oral administration are achieved with a diminished side effect profile due to first-pass liver metabolism [14]. Several mechanisms of action have been proposed to account for intravesical oxybutynin efficacy, including direct antimuscarinic action, anesthetic effect, and systemic stimulation. Although this system has obvious and inherent barriers with regard to patient tolerability and persistence and remains an off-label, non US Food and Drug Administration approved use of the drug, future technologies that will enhance and promote long-term solutions for overcoming the urothelial barrier are emerging [15]. One tool on the horizon that has great promise is the use of liposome-based delivery systems [16]. Liposomes are spherical lipid vesicles with a lipophilic bilayer that can serve as efficient carriers for aqueous compounds entrapped in the interior. As we discuss in a subsequent section, liposome technology is currently under investigation to potentiate delivery of intravesical botulinum toxin to preclude the necessity for injection. β3 Agonists One of the predominant concerns with regard to the use of antimuscarinic agents, particularly in the context of OAB in conditions of relative bladder outlet obstruction, is the possibility of urinary retention due to decreases in detrusor contractility. Another proposed target for the management of pathologic detrusor contraction and OAB symptomatology are the β-adrenergic receptors (β-ars) of detrusor smooth muscle. During the normal urinary storage phase, β-ars mediate smooth muscle relaxation of the detrusor via adrenergic stimulation, providing an attractive theoretical target for OAB [17]. Unlike antimuscarinic agents, in animal models, β-ar agonists do not result in diminished detrusor contractility with voiding, thus reducing the clinical concern for use in patients with such conditions and benign prostatic hyperplasia [18, 19]. Molecular studies have established that the predominant β-ar in the human bladder is the β 3 -AR subtype [20]. This β 3 -AR likewise has been identified in the urothelium, indicating a potential role in sensory inhibition of OAB symptoms even in the absence of detrusor overactivity (DO) [21]. Currently, several β 3 -AR selective agonist agents are undergoing evaluation in phase 2 and phase 3 clinical trials, with promising results with regard to efficacy in OAB symptom abatement, and a side effect profile potentially more tolerable than that of traditional anticholinergic agents [22]. Vanilloid Receptor Agents Two members of the vanilloid family, capsaicin and resiniferatoxin, have been demonstrated to increase bladder capacity and decrease urge incontinence in OAB patients [23]. These ligands bind an ion channel receptor and may potentiate effect via functional desensitization of C-fiber afferent neurons, providing yet another intriguing pathway for OAB therapy [24]. In the treatment of neurogenic voiding dysfunction, several studies have demonstrated substantial benefits for both compounds; however, largescale, randomized trials are lacking [25, 26, 27 ]. Neurokinin-1 Receptor Antagonists Tachykinins, exemplified by substance P, are postulated to be involved in the pathophysiologic sensory signaling of OAB [28]. The receptor with the highest binding affinity for substance P is the neurokinin-1 (NK-1) receptor, which is present in high concentrations in tissues of the nervous system and the bladder epithelium [29]. Following initial proof-of-concept trials suggesting efficacy of this class in

3 Curr Bladder Dysfunct Rep (2011) 6: OAB therapy, a recent randomized, double-blind, multicenter, placebo-controlled trial of the NK-1 receptor antagonist serlopitant resulted in significant reduction in the primary end point of daily micturition [30, 31]. However, the secondary end points, including incontinence episodes and presence of adverse events such as dry mouth, did not demonstrate a dose response or superiority when compared with placebo or antimuscarinic control. These results may temper enthusiasm for use of NK-1 receptor antagonists as monotherapy, but they open avenues for exploration of combination treatments and decidedly the basic pathophysiologic mechanisms of OAB. Phosphodiesterase-5 Inhibitors Recognition of the comorbidity of the disease processes as well as the clinical benefit in lower urinary tract symptoms among men treated with phosphodiesterase-5 (PDE-5) inhibitors for erectile dysfunction spurred multiple studies to evaluate the efficacy of this class of pharmaceuticals in treating OAB symptomatology [32, 33]. Extensive knowledge regarding the physiologic mechanisms of PDE-5 inhibitors reveals shared pathways that provide a logical approach for use of these agents in conditions of detrusor dysfunction [34]. PDE-5 inhibitors potentiate muscle relaxation in the detrusor via generation of cyclic nucleotides and modulation of nitric oxide, making these compounds an attractive option for evaluation as an OAB therapeutic. Clinically significant findings from several randomized controlled trials demonstrated improvements in patient-reported lower urinary tract symptoms in men [35 37]. Curiously, none of these trials demonstrated significant changes with regard to the objective urinary flow rates, again calling into question our comprehension of how these agents may be acting in the detrusor or urothelium to manifest symptom relief. Additionally, studies of PDE-5 inhibitors in female OAB patients are lacking [27 ]. Additional Pharmacologic Agents Several targets within the central nervous system may be amenable to modification of dysfunction as manifested in OAB. Gabapentin, originally designated as an anticonvulsant, has provided symptom improvement in pilot studies among both neurogenic and antimuscarinic-refractory, nonneurogenic OAB patients [38]. In animal and human studies, tramadol, a common analgesic, has been demonstrated to inhibit DO and incontinence episodes [39, 40]. Intensive investigation of an incredible array of potential pharmacotherapies presents a staggering variety of mechanisms to address the OAB symptom complex. It is intriguing that eventually, many of these may be exploited and individualized for each patient as the diversity of pathophysiologic mechanism demands. Some of the general compounds currently under study include endothelin inhibitors, vitamin D3 receptor analogues, nitric oxide modulators, cyclooxygenase inhibitors, antidepressants, and hormonal agents [27, 40]. Botulinum Toxin Great excitement in the urologic community has been generated in recent years regarding the advent of intradetrusor injection of botulinum toxin for medicationrefractory OAB symptoms. Botulinum neurotoxins, secreted by the spore-forming obligate anaerobe Clostridium botulinum, are among the most potent naturally occurring neuromuscular blocking agents known. Although several formulations from various manufactures are available in the United States and Europe, the most commonly used subtype is botulinum toxin A (BTX-A). The clinical impact of BTX-A is at the level of neurotransmitter releases at the presynaptic cholinergic nerve terminal, which results in flaccid muscle paralysis [41]. Axonal regeneration limits durability of the response, with the clinical effect lasting 6 to 12 months. In addition to this direct efferent block of cholinergic signaling and detrusor contractility, just as with other agents previously discussed, there is an expanding appreciation of the afferent signaling impact of BTX-A, as well as modulation of many urothelial molecules [42]. A recent compilation of studies on the use of BTX-A in patients with idiopathic OAB with or without concomitant DO revealed substantial efficacy despite wide ranges in dose, injection technique, follow-up, concomitant antimuscarinic use, and outcomes measures [43, 44]. Questions with regard to optimal dosing, timing, and avoidance of the clinically significant complication of urinary retention remain to be investigated in large-scale trials. Liposomes recently have been used to deliver BTX-A via permeation of the urothelial barrier, as opposed to direct injection, expanding many avenues for expeditious and comfortable therapies to offer patients [45]. Sacral Neuromodulation Since 1997, sacral neuromodulation (SNM) has been a US Food and Drug Administration approved treatment for refractory urgency/frequency and urge urinary incontinence. Despite our limited conceptualization of what are likely to be myriad mechanisms of action of SNM, it has emerged as a commonly used step on the OAB treatment

4 48 Curr Bladder Dysfunct Rep (2011) 6:45 50 ladder. More than 50,000 implants have been placed for a variety of lower urinary tract symptoms, with multiple randomized controlled trials demonstrating substantial efficacy [46]. However, enthusiasm for the technology has been tempered by the need for surgical implantation; adverse events such as pain, lead migration, and infection; and a reoperation rate of 33% [47 49]. New frontiers with regard to SNM include a currently ongoing clinical trial involving a transcutaneous neurostimulator for the sacral nerve ( These devices hold promise to expand the utility of SNM without the associated morbidity of surgical implantation. Posterior Tibial Nerve Stimulation Peripheral neuromodulation involves percutaneous placement of a small gauge needle over the medial malleolus to provide stimulation of the posterior tibial nerve. Twelve weekly sessions of 30-minute stimulation are administered. A recent randomized, multicenter study was published comparing posterior tibial nerve stimulation (PTNS) with antimuscarinic therapy [50]. Results demonstrated equivalency with regard to subjective patient symptoms as well as objective measures in bladder diary variables. An equally compelling multicenter, double-blind, randomized controlled trial comparing the efficacy of PTNS with sham through 12 weeks of therapy revealed that PTNS yielded statistically significant improvement in outcome parameters when compared with sham controls [51]. Despite the limited follow-up in this study, these data provide level I evidence that PTNS is safe and effective in improving OAB. This therapy promises expansion with regard to a minimally invasive, office-based procedure. Bladder Augmentation General practice patterns usually reserve highly invasive surgical modalities for patients failing a loosely defined algorithm of more conservative and reversible alternatives. Augmentation cystoplasty, autoaugmentation, as well as urinary diversion remain viable options for the treatment of refractory, end-stage OAB disease associated with debilitating symptoms or organ compromise [48, 52, 53]. Gene Therapy Although primarily directed at afferent sensory nerves involved in painful bladder syndrome, exceptionally novel advances in the realm of gene therapy represent a significant advance that may be exploited for OAB treatment [54]. This recent study investigated the effect of targeted and localized expression of enkephalin in afferent bladder nerves via gene transfer using replication-defective herpes simplex virus vectors in a rat model of bladder hyperactivity and pain. Remarkably, the transgenic animals demonstrated improvement in bladder hyperactivity and visceral pain provoked by bladder irritation. Stem Cell Therapy Another potential factor in lower urinary tract symptom pathogenesis involves bladder ischemia secondary to endothelial dysfunction. Animal models of DO have been created via induced hyperlipidemia with feeding of ahigh-fatdiet[55]. The clinical correlate in the human population is beginning to be appreciated with investigations of the link between systemic cardiovascular pathology and OAB [56]. Adipose-derived stem cells (ADSCs) have generated substantial interest in the urologic literature in recent years as potential agents in the treatment of stress urinary incontinence via reconstitution of the external urethral sphincter [57, 58]. Novel application of ADSCs directed at reduction of this hyperlipidemiaassociated DO was performed in a rat model. Injection of autologous ADSCs resulted in a significant decrease in micturition frequency combined with anatomic changes in nerve and blood vessel density [59]. Regenerative medicinemayultimatelyholdthekeytoallowthedysfunctional detrusor to regain native sensory and motor components to ameliorate OAB symptoms. Conclusions Although new frontiers are continually being forged with regard to our therapeutic options for treatment of OAB, the true pathophysiologic mechanisms involved in the culmination of patient symptomatology remain elusive. A recent consortium of thought leaders reinforced the concepts that the diversity of the OAB patient population made prediction of outcomes and algorithmic approaches to therapy limited in resourcefulness and subject to vast inconsistencies [60, 61]. Advances in the realms of pharmaceuticals, neuromodulation, stem cell therapy, and even gene therapy promise to expand the urologist s armamentarium by providing foremost an increased sophistication with regard to our appreciation of OAB pathophysiology. Disclosure No potential conflict of interest relevant to this article was reported.

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