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. 2009 Jun;1(2):71–83. doi: 10.1177/1756287209103937

Prospective pharmacologic therapies for the overactive bladder

Karl-Erik Andersson 1,✉
PMCID: PMC3126054  PMID: 21789056

Abstract

Lower urinary tract symptoms (LUTS), overactive bladder syndrome (OAB) and detrusor overactivity (DO) are all conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are first-line treatment–they often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium, the spontaneous myocyte activity during bladder filling, and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of LUTS/OAB/DO pathophysiology. There may be several new possibilities to treat LUTS/OAB/DO. β3-AR agonists (YM178), PDE 5 inhibitors (sildenafil, tadalafil, vardenafil), vitamin D analogs (elocalcitol), combinations (α1-AR antagonist + antimuscarinic), and drugs with a central mode of action (tramadol, aprepitant) all have Randomized controlled trial (RCT) documented efficacy. Which of these therapeutic principles will be developed to clinically useful treatments remains to be established.

Keywords: incontinence, detrusor overactivity, drug treatment

Introduction

The search for new pharmacologic therapies to treat voiding disorders, including the overactive bladder (OAB) syndrome has been intensive. Many new drugs aimed at micturition control have been suggested and discussed, and current research has revealed a number of peripheral and central mechanisms involved in the regulation of both normal and dysfunctional micturition [Drake 2008; Sacco et al. 2008; Yoshimura et al. 2008; Andersson 2007; Colli et al. 2007]. Some of these mechanisms may be realistic targets for drugs, but there is a difficulty in separating such mechanisms from ‘dead ends’. Signals obtained in preclinical models must be critically analysed and not interpreted based on wishful thinking, keeping in mind the large number of steps between a preclinical signal and a drug candidate. Some drugs, representing different principles, for which there is a reasonable rationale for use, and for which proof of principle studies have been positive, are the focus of this review. In addition, some interesting future research directions are briefly discussed.

An extensive evaluation and discussion of current OAB therapies was recently performed by the 4th International Consultation on Incontinence [Andersson et al. in press; Tables 1 and 2].

Table 1.

Oxford guidelines (modified), 4th International Consultation on Incontinence, Paris, July, 2008.

Levels of evidence
 Level 1: Systematic reviews, meta-analyses, good quality randomized controlled clinical trials (RCTs)
 Level 2: RCTs, good quality prospective cohort studies
 Level 3: Case-control studies, case series
 Level 4: Expert opinion
Grades of recommendation
 Grade A: Based on level 1 evidence (highly recommended)
 Grade B: Consistent level 2 or 3 evidence (recommended)
 Grade C: Level 4 studies or ”majority evidence” (optional)
 Grade D: Evidence inconsistent/inconclusive (no recommendation possible) or the evidence indicates that the drug should not be recommended
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Table 2.

Drugs used in the treatment of OAB/DO. Assessments according to the Oxford system (modified), 4th International Consultation on Incontinence, Paris, July, 2008.

Level of evidence Grade of recommendation
Antimuscarinic drugs
 Tolterodine 1 A
 Trospium 1 A
 Solifenacin 1 A
 Darifenacin 1 A
 Fesoterodine 1 A
 Propantheline 2 B
 Atropine, hyoscyamine 3 C
Drugs acting on membrane channels
 Calcium antagonists 2 D
 K-Channel openers 2 D
Drugs with mixed actions
 Oxybutynin 1 A
 Propiverine 1 A
 Dicyclomine 3 C
 Flavoxate 2 D
Antidepressants
 Imipramine 3 C
 Duloxetine 2 C
Alpha-AR antagonists
 Alfuzosin 3 C
 Doxazosin 3 C
 Prazosin 3 C
 Terazosin 3 C
 Tamsulosin 3 C
Beta-AR antagonists
 Terbutaline (beta 2) 3 C
 Salbutamol (beta 2) 3 C
 YM-178 (beta 3) 2 B
PDE-5 Inhibitors+
 (Sildenafil, Taladafil, Vardenafil) 2 B
COX-inhibitors
 Indomethacin 2 C
 Flurbiprofen 2 C
Toxins
 Botulinum toxin (neurogenic)*** 2 A
 Botulinum toxin (idiopathic)*** 3 B
 Capsaicin (neurogenic)** 2 C
 Resiniferatoxin (neurogenic)** 2 C
Other drugs
 Baclofen** 3 C
Hormones
 Estrogen 2 C
 Desmopressin# 1 A
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+(male LUTS/OAB); *intrathecal; **intravesical; ***bladder wall; #nocturia (nocturnal polyuria), caution hyponatremia, especially in the elderly!

Background

OAB is common and has a multifactorial pathophysiology, implying that it is difficult to conceive that one drug or drug principle would be effective (enough) in all patients with OAB symptoms (Figure 1). Irwin et al. [2006], studying 19,000 adult men and women, found that the prevalence in both men and women was around 12% and that it increases with age. The OAB syndrome has often been assumed to be caused by detrusor overactivity (DO), even if this not always seems to be the case [Aschkenazi et al. 2007; Hashim and Abrams 2004; Digesu et al. 2003; Hyman et al. 2001]. Irrespective of the pathophysiology, the goal of treatment of idiopathic OAB symptoms with and without DO is to obtain symptom relief without interfering with the emptying ability. Although our understanding regarding bladder function has increased during recent years, the detrusor muscle and its functional regulation still provide considerable research challenges. The detrusor muscle itself has for many years been the target for drug treatment. However, depression of detrusor contractility, resulting in a reduced ability to empty the bladder, has not produced any success in the treatment of voiding dysfunction and focus has changed to other bladder structures/mechanisms, such as urothelial signaling and afferent nerves as targets for intervention [Birder and de Groat 2007; Andersson 2002]. There is also an emerging interest for drugs acting in the central nervous system [Andersson and Pehrson 2003].

Figure 1.

Figure 1

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Pathophysiology of the overactive bladder.

β3-Adrenoceptor (AR) agonists

It has been known for a long time that β-adrenoceptor (AR) agonists can inhibit bladder contractions [Andersson, 1993], but the principle was considered therapeutically uninteresting for OAB/DO treatment because of cardiac side effects. The three defined β-AR subtypes (β1, β2, and β3) have been identified in the detrusor of most species [Michel and Vrydag, 2006; Andersson and Arner, 2004]. Also the human urothelium contains all three receptor subtypes [Otsuka et al. 2008], but in both detrusor and urothelium there is a predominant expression of β3-AR mRNA [Michel and Vrydag, 2006; Nomiya and Yamaguchi, 2003] and there is convincing evidence from both normal and neurogenic bladders that these receptors are functionally active [Leon et al. 2008; Badawi et al. 2007; Biers et al. 2006; Michel and Vrydag, 2006; Igawa et al. 2001; Morita et al. 2000; Fujumura et al. 1999; Igawa et al. 1999; Takeda et al. 1999]. The human detrusor also contains β2-ARs, and most probably both receptor subtypes are involved in the physiological effects (relaxation) of noradrenaline in this structure [Michel and Vrydag, 2006; Andersson and Arner 2004].

The generally accepted mechanism, by which β-ARs induce detrusor relaxation in most species, is activation of adenylyl cyclase with the subsequent formation of cAMP. However, there is evidence suggesting that in the bladder K+ channels, particularly BKca channels, may be more important in β-AR mediated relaxation than cAMP [Frazier et al. 2008; Frazier et al. 2005; Uchida et al. 2005; Hudman et al. 2000].

The in vivo effects of β3-AR agonists on bladder function have been studied in several animal models. It has been shown that compared with other agents (including antimuscarinics), β3-AR agonists increase bladder capacity with no change in micturition pressure and residual volume [Kaidoh et al. 2002; Takeda et al. 2002; Woods et al. 2001; Fujimura et al. 1999]. For example, Hicks et al. [2007] studied the effects of the selective β3-AR agonist, GW427353, in the anesthetized dog and found that the drug evoked an increase in bladder capacity under conditions of acid evoked bladder hyperactivity, without affecting voiding.

A number of β3-AR selective agonists are currently being evaluated as potential treatment for OAB in humans including GW427353 and YM178 [Colli et al. 2007]. Takasu et al. [2007] reported that the selective β3-AR agonist, YM187, mediated muscle relaxation in human bladder strips. Chapple et al. [2008] reported the results of a placebo controlled clinical trial with this drug in patients with OAB. The primary efficacy analysis showed a statistically significant reduction in mean micturition frequency, compared to placebo. With respect to secondary variables YM178 was significantly superior to placebo concerning mean volume voided per micturition, mean number of incontinence episodes, nocturia episodes, urgency incontinence episodes, and urgency episodes per 24 hours. The drug was well tolerated, and the most commonly reported side effects were headache and gastrointestinal adverse effects. The results of this well-conducted proof of concept study showed that the principle of β3-AR agonism may be useful for treatment of patients with OAB.

The positive effects of β3-AR agonists on DO in several animal models were obtained without affecting the ability to empty the bladder, and this was obviously also the case in the patient study of Chapple et al. [2008]. This would mean that β3-AR agonists do not interfere with the voiding contraction. Thus, the basic requirement of an OAB drug – elimination of symptoms and involuntary bladder contractions without effects on emptying – seems to be fulfilled. However, to show that β3-AR agonists offer a viable therapeutic alternative or complement to current treatments of OAB/DO requires further well designed RCTs.

Phosphodiesterase (PDE) inhibitors

It is generally considered that drugs acting through the NO/cGMP system preferably relax the smooth muscle of the bladder outflow region [Andersson and Arner, 2004], whereas drugs stimulating the generation of cAMP relax both the detrusor and the outflow region [Andersson and Arner, 2004; Andersson, 1999]. Providing that drugs producing relaxation of LUT smooth muscle would be effective in the treatment of OAB/DO, use of PDE inhibitors to enhance the cAMP- and cGMP-mediated relaxation of detrusor, prostate and urethral smooth muscle should then be a logical approach (Andersson, 2007). There should be no lack of alternatives since there are presently 11 PDE families, some of which preferentially hydrolyse either cAMP or cGMP [Andersson, 2007]. Uckert et al. [2001] investigating human bladder tissue, found messenger RNA for PDEs 1A, 1B, 2A, 4A, 4B, 5A, 7A, 8A, and 9A; most of these PDEs preferably inhibit the breakdown of cAMP. Truss et al. [2001; 2000] presented clinical data with vinpocetine (a low affinity inhibitor of PDE 1) in patients with urgency/urgency incontinence or low compliance bladders. However, vinpocetine only caused statistically significant results for one parameter [Truss et al. 2001]. Studies with other PDE 1 inhibitors than vinpocetin (which may not be an optimal drug for elucidation the principle) do not seem to have been performed.

PDE 4 (which also preferably hydrolyses cAMP) has been implicated in the control of bladder smooth muscle tone. PDE 4 inhibitors reduced the in vitro contractile response of guinea pig [Longhurst et al. 1997] and rat [Kaiho et al. 2008; Nishiguchi et al. 2007] bladder strips, and also suppressed rhythmic bladder contractions of the isolated guinea pig bladder [Gillespie 2004]. Previous experiences with selective PDE 4 inhibitors showed emesis to be a dose-limiting effect [Giembycz 2005]. If this side action can be avoided, PDE 4 inhibition seems to be a promising approach.

The observation that patients treated for erectile dysfunction with PDE 5 inhibitors had an improvement of their LUTS, has sparked a new interest in also using these drugs for treatment of LUTS and OAB. After the report in an open study [Sairam et al. 2002] that treatment with sildenafil appeared to improve urinary symptom scores in men with ED and LUTS, this observation has been confirmed in several well designed and conducted RCTs [Stief et al. 2008; McVary et al. 2007 a, b].

The mechanism behind the beneficial effect of the PDE 5 inhibitors on LUTS/OAB and their site(s) of action largely remain to be elucidated. The drugs obviously do not interfere with the emptying ability of the bladder, and thus do not reduce the contractility of the detrusor muscle in response to parasympathetic (mainly cholinergic) activation. Like the β3-AR agonists, the PDE 5 inhibitors seem to act mainly during bladder filling. If the main site of action were the smooth muscles of the outflow region (and the effect relaxation), an increase in flow rate should be expected. Such an effect was not found in the trials referred to. However, there are several other structures in the LUT that may be involved, including those in the urothelial signaling pathway (urothelium, interstital cells, and suburothelial afferent nerves).

The beneficial effects of PDE 5 inhibitors have so far been demonstrated in male LUTS/OAB. Ongoing trials will reveal whether or not these drugs are therapeutic OAB/DO alternative in females.

Vitamin D3 receptor analogues

Crescioli et al. [2005] demonstrated that rat and human bladders expressed receptors for vitamin D3. In a rat model of partial bladder outflow obstruction, Schröder et al. [2006] showed that an analogue of vitamin D3, elocalcitol (BXL-628), at non-hypercalcemic doses, reduced both frequency and amplitude of non-voiding contractions (Figure 2). Drug treatment did not prevent bladder hypertrophy, but reduced the damage to the bladder smooth muscle which occurs with increasing bladder weight in this model. The mechanism of action for the effects has not been clarified. Analogues of vitamin D3 have been shown to inhibit BPH cell proliferation and to counteract the mitogenic activity of potent growth factors for BPH cells [Crescioli et al. 2004; 2003; 2002]. However, elocalcitol was also shown to have an inhibitory effect on the RhoA/Rho kinase pathway [Morelli et al. 2007]. Upregulation of this pathway has been associated with bladder changes associated with diabetes, outflow obstruction, and DO [Christ and Andersson, 2007; Peters et al. 2006].

Figure 2.

Figure 2

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Effects of a β3-adrenoceptor agonist (YM-178) on urgency episodes (≥3)/24 h in patients with overactive bladder. Mean change from baseline to endpoint. Chapple et al. EAU 2008, poster presentation.

In an RCT enrolling 120 female patients with OAB, where the primary endpoint was an increase in the mean volume voided, treatment with elocalcitol produced a significant increase versus placebo was demonstrated [Colli et al. 2007]. The side effect profile of the drug is attractive–compared to placebo no adverse effects were demonstrated [Colli et al. 2007]. Irrespective of whether or not inhibition of the RhoA/Rho kinase pathway is the main mechanism by which elocalcitol (and vitamin D3 receptor agonists?) affects bladder function, it remains to be established if the drug (monotherapy or in combination) will be a useful alternative for the treatment of OAB/DO.

Centrally acting drugs

Many parts of the brain seem to be activated during storage and voiding [Fowler et al. 2008; Griffiths and Tadic 2008; Griffiths 2007], and there is increasing interest in drugs modulating the micturition reflex by a central action [Andersson and Pehrson 2003]. Several drugs used for pain treatment also affect micturition; morphine and some antiepileptic drugs being a few examples. However, central nervous mechanisms have so far not been preferred targets for drugs aimed to treat OAB, since selective actions may be difficult to obtain. Holstege [2005], reviewing some of the central mechanisms involved in micturition, including the periaqueductal gray (PAG) and the pontine micturition center (PMC), suggested that ‘the problem in OAB or urgency-incontinence is at the level of the PAG or PMC and their connections, and possible treatments for this condition should target the micturition pathways at that level.’

Gabapentin

Gabapentin is one of the new first-generation antiepileptic drugs that expanded its use into a broad range of neurologic and psychiatric disorders [Striano and Striano 2008]. It was originally designed as an anticonvulsant GABA (γ-aminobutyric acid) mimetic capable of crossing the blood-brain barrier [Maneuf et al. 2003]. The effects of gabapentin, however, do not appear to be mediated through interaction with GABA receptors, and its mechanism of action remains controversial [Maneuf et al. 2003]. It has been suggested that it acts by binding to a subunit of the α2δ unit of voltage dependent calcium channels [Striano and Striano 2008; Gee et al. 1996]. Gabapentin is also widely used not only for seizures and neuropathic pain, but for many other indications, such as anxiety and sleep disorders, because of its apparent lack of toxicity.

Carbone et al. [2006] reported on the effect of gabapentin on neurogenic DO. They found a positive effect on symptoms and significant improvement in urodynamic parameters, and suggested that the effects of the drug should be explored in further controlled studies in both neurogenic and non-neurogenic DO. Kim et al. [2004] studied the effects of gabapentin in patients with OAB and nocturia not responding to antimuscarinics. They found that 14 out of 31 patients improved with oral gabapentin. The drug was generally well-tolerated, and the authors suggested that it can be considered in selective patients when conventional modalities have failed. It is possible that gabapentin and other α2δ ligands (e.g., pregabalin and analogs) will offer new therapeutic alternatives.

Tramadol

Tramadol is a well-known analgesic drug [Grond and Sablotzski 2004]. By itself, it is a weak μ-receptor agonist, but it is metabolized to several different compounds, some of them almost as effective as morphine at the μ-receptor. However, the drug (metabolites) also inhibits serotonin (5-HT) and noradrenaline reuptake [Grond and Sablotzski 2004]. This profile is of particular interest, since both μ-receptor agonism and amine reuptake inhibition may be useful principles for treatment of LUTS/OAB/DO, as shown in a placobo controlled study with duloxetine [Steers et al. 2007].

In rats, tramadol abolished experimentally induced DO caused by cerebral infarction [Pehrson et al. 2003]. Tramadol also inhibited DO induced by apomorphine in rats [Pehrson and Andersson 2003; Figure 3] – a crude model of bladder dysfunction in Parkinson's disease. Singh et al. [2008] gave tramadol epidurally and found the drug to increase bladder capacity and compliance, and to delay filling sensations without ill effects on voiding. Safarinejad and Hosseini [2006] evaluated in a double-blind placebo-controlled randomized study, the efficacy and safety of tramadol in patients with idiopathic DO. A total of 76 patients 18 years of age or older were given 100 mg tramadol sustained release every 12 h for 12 weeks. Clinical evaluation was performed at baseline and every 2 weeks during treatment. Tramadol significantly reduced the number of incontinence periods and induced significant improvements in urodynamic parameters. The main adverse effect was nausea. It was concluded that in patients with non-neurogenic DO, tramadol provided beneficial clinical and urodynamic effects. Even if tramadol may not be the best suitable drug for treatment of OAB/DO (as judged from the side effect profile from pain treatment–constipation, nausea, dizziness and somnolence; Mongin 2007), the study proofs the principle of modulating micturition via the μ-receptor.

Figure 4.

Figure 4

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Effects of 100 µg kg–1 apomorphine given subcutaneously (s.c.) to female rat pretreated with intravenous saline (A) or 5 mg kg–1 tramadol intravenously (i.v.) (B). Upper tracings show bladder pressure. Lower tracings show voided volume. Pehrson and Andersson, 2003.

Figure 3.

Figure 3

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Effects of elocalcitol (BXL-628) on frequency and amplitude of spontaneous, non-voiding contractions in sham-operated vehicle (SV) and drug-treated rats (SD) compared to obstructed vehicle (BV) and drug-treated (BD) rats. Schröder et al. 2006.

NK1-receptor antagonists

The main endogenous tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), and their preferred receptors, NK1, NK2, and NK3, respectively, have been demonstrated in various CNS regions, including those involved in micturition control [Covenas et al. 2003; Saffroy et al. 2003; Lecci and Maggi 2001]. NK1 receptor expressing neurons in the dorsal horn of the spinal cord may play an important role in DO, and tachykinin involvement via NK1 receptors in the micturition reflex induced by bladder filling has been demonstrated [Ishizuka et al. 1994] in normal rats and more clearly in rats with bladder hypertrophy secondary to BOO. Capsaicin-induced detrusor overactivity was reduced by blocking NK1 receptor-expressing neurons in the spinal cord, using intrathecally administered substance P-saponin conjugate [Seki et al. 2005]. Furthermore, blockade of spinal NK1 receptor could suppress detrusor activity induced by dopamine receptor (L-DOPA) stimulation [Ishizuka et al. 1995].

In conscious rats undergoing continuous cystometry, antagonists of both NK1 and NK2 receptors inhibited micturition, decreasing micturition pressure and increasing bladder capacity at low doses, and inducing dribbling incontinence at high doses. This was most conspicuous in animals with outflow obstruction [Gu et al. 2000]. Intracerebroventricular administration of NK1 and NK2 receptor antagonists to awake rats suppressed detrusor activity induced by dopamine receptor (L-DOPA) stimulation [Ishizuka et al. 2000]. Taken together, available information suggests that spinal and supraspinal NK1 and NK2 receptors may be involved in micturition control.

Aprepitant, an NK-1 receptor antagonist used for treatment of chemotherapy-induced nausea and vomiting [Massaro and Lenz 2005], significantly improved symptoms of OAB in postmenopausal women with a history of urgency incontinence or mixed incontinence (with predominantly urgency urinary incontinence), as shown in a well designed pilot RCT [Green et al. 2006]. The primary end point was percent change from baseline in average daily micturitions assessed by a voiding diary. Secondary end points included average daily total urinary incontinence and urgency incontinence episodes, and urgency episodes. Aprepitant significantly decreased the average daily number of micturitions compared with placebo at 8 weeks. The average daily number of urgency episodes was also significantly reduced compared to placebo, and so were the average daily number of urgency incontinence and total urinary incontinence episodes, although the difference was not statistically significant. Aprepitant was generally well-tolerated and the incidence of side effects, including dry mouth, was low. The results of this initial proof of concept study suggest that NK-1 receptor antagonism holds promise as a potential treatment approach for OAB.

Alternative strategies – combinations

Combining the current α1-adrenoceptor antagonists with other agents might theoretically provide improved symptom relief. One such example is the combination of α1-adrenoceptor antagonists with 5 alpha reductase inhibitors, which has proven to improve clinical outcomes and reduce the incidence of BPH and LUTS progression measured as symptom worsening, retention or progression to surgery [Roehrborn et al. 2008; McConnell et al. 2003]. Other combinations have also been tested with varying degrees of success. Traditionally muscarinic receptor antagonists have been contradicted in patients with BPH due to fears of urinary retention. However, this dogma has been questioned and several studies have been performed in which α1-adrenoceptor antagonists are combined with muscarinic receptor antagonists with promising results [Rovner et al. 2008; McVary, 2007; Kaplan et al. 2006; Novara et al. 2006; Ruggieri et al. 2005; Lee et al. 2005; 2004; Athanasopoulus et al. 2003]. Speculatively, several other combinations can be suggested [Andersson, 2008].

Future directions

The endocannabinoid system has received widespread attention as a pharmacotherapeutic target to modulate physiological and pathophysiological conditions also in the bladder. Hiragata et al. [2007] showed that ajulemic acid, a mixed CB1/CB2 receptor agonist, can suppress normal bladder activity and urinary frequency induced by bladder nociceptive stimuli. The inhibitory effects were inhibited by AM251, a selective CB1 receptor antagonist. These findings suggest that cannabinoid receptor agonists may have a potential as therapeutic agents in DO.

An exciting finding is that TRPV1 receptor antagonists have potentially useful effects on micturition in animal model [Cruz et al. 2008]. Two other TRPs may also have a role in bladder function. TRPA1 receptors were shown to be expressed in C-fiber afferents as well as urothelium and interstitial cells, both in the bladder and urethra, and also to affect micturition [Gratzke et al. 2008; Streng et al. 2008; Du et al. 2007]. Of interest is the finding that hydrogen sulfide, which may be formed endogenously during infection/inflammation, is an activator of TRPA1. Another member of the TRP family, the TRPV4 receptor (channel), can be activated by hypo-osmolarity, heat or certain lipid compounds, and seems to be expressed mainly by urothelial cells. In mice deletion of this channel results in impaired voiding responses [Gevaert et al. 2007] and intravesical instillation of a TRPV4 agonist in the rat triggered a novel voiding reflex, which could regulate the late phase of contraction [Birder et al. 2007]. In the conscious ewe, TRPV4 may also be involved in a urethra to bladder reflex, proposed to facilitate bladder emptying [Combrisson et al. 2007]. The roles of TRPA1 and TRPV4 in the normal and pathological bladder have to be established. Whether or not antagonists of these receptors could be potential targets for drugs aimed for treatment of LUTS/OAB/DO can only be speculated on.

Conclusions

There may be several new possibilities to treat LUTS/OAB/DO. β3-AR agonists (YM178), PDE 5 inhibitors (sildenafil, tadalafil, vardenafil), vitamin D analogs (elocalcitol), combinations (α1-AR antagonist + antimuscarinic), and drugs with a central mode of action (tramadol, aprepitant) all have RCT documented efficacy. Which of these therapeutic principles will be developed to clinically useful treatments remains to be established.

Conflict of interest statement

The author consults for Astellas, Novartis, Procter & Gamble, Pfizer, BioXell and Sanofi-Aventis.

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