Although the majority of cholinergic receptors found in the human detrusor muscle (inset) are of the M2 subtype,
the M3 receptors are mainly responsible for normal micturition contraction. Most of the approved agents for overactive bladder
target these M3 receptors.
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SANDIP VASAVADA, MD, Co-Section Head, Section of Voiding Dysfunction
and Female Urology, Glickman Urological Institute, The Cleveland Clinic Foundation, Cleveland, Ohio.
RAYMOND R. RACKLEY, MD, Professor and Co-Section Head, Section of Voiding Dysfunction and Female Urology, The Cleveland Clinic Lerner College of
Medicine at Case Western Reserve University, and the Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland,
Ohio.
As defined at a recent International Continence Society (ICS) meeting, overactive bladder (OAB) syndrome encompasses disturbance
of bladder function that leads to urgency, with or without urge incontinence, and voiding frequency, including nocturia. This
review on the pharmacologic therapies available for OAB syndrome is organized around this definition, which includes a symptom
complex thought to be primarily of bladder origin (urgency and voiding frequency) with or without a secondary sign (urge incontinence)
typically related to the interaction of the bladder and surrounding structures of the pelvis (nerves and pelvic floor muscles).
The symptom complex of OAB may also be influenced by systemic health problems associated with nonbladder causes of frequency
and nocturia, referred to as secondary or nonprimary OAB. This primer focuses on current and future pharmacologic interventions
for primary OAB.
Based on the ICS definition of the OAB symptom complex, approximately 1 out of 6 adults has an overactive bladder that may
have a profound, clinically significant impact on his or her health and quality of life.1-3 The first-line pharmacologic treatment of primary OAB has traditionally involved the use of anticholinergic agents with
various muscarinic-receptor affinities.
Current drug therapies
TABLE 1. Agents approved for treatment of overactive bladder
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The cholinergic receptors found in the human detrusor muscle fall mainly into the M2 and M3 subtypes. Despite the predominance of M2 receptors, the M3 receptors are mainly responsible for normal micturition contraction. The role of the M2 receptors in bladder function has not been completely established but is thought to functionally oppose sympathetic-mediated
detrusor relaxation. Clinically, anticholinergic agents—specifically, antimuscarinic agents—depress both voluntary and involuntary
bladder contractions through direct effects on bladder smooth muscle and possibly efferent motor and afferent sensory nerve
interactions. In patients with involuntary contractions, antimuscarinic drugs increase the volume before the first contraction,
decrease the amplitude of this abnormal contraction, and increase total bladder capacity. All current anticholinergic drugs
lack true specificity for only the muscarinic receptors in the bladder, even though some manufacturers have made claims of
functional bladder selectivity/specificity over other end-organs, such as the salivary gland.4,5 FDA-approved medications for treating the symptom complex of OAB are listed in Table 1.
For clinical comparison and the following discussion, the agents are grouped according to their M3 receptor affinities—nonselective, primarily M3-selective, and M3-selective (see Figure 1).6,7 Of the FDA-approved agents for OAB, trospium (Sanctura) and tolterodine (Detrol, Detrol LA) are considered to be nonselective
receptor affinity agents for antimuscarinic activity.
FIGURE 1
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Trospium
Recently approved for use in the United States, this agent has a reduced probability of crossing a normal blood-brain barrier.
With a low biological availability of 5% and a half-life of 12 to 18 hours, the dosage is 20 mg/d bid, and the drug must be
taken 1 hour before meals. This agent is not highly metabolized and, for the most part, is renally excreted in an unchanged
form; however, for the same pharmacokinetic reasons that this drug does not cross a normal blood-brain barrier, it also will
not have a desired direct effect on bladder muscle or urothelium from its mere presence in the urine.
In a randomized, placebo-controlled trial, trospium, 20 mg/d bid, significantly reduced the number of daily urge incontinence
episodes by 60% compared with 44% for placebo.8 It significantly increased average volume per void and decreased average urge severity and daytime voiding frequency. These
findings paralleled an improved patient-perceived quality of life (see "A brief word on research methodologies and study limitations").
Dry mouth and constipation occurred in 21.8% and 9.5%, respectively, of the patients given trospium compared with 6.5% and
3.8%, respectively, of the patients in the placebo group.8 These symptoms occurred early and tended to resolve with continuing treatment. The overall discontinuation rate was identical
for both groups at 16.4%, while adverse events leading to discontinuation occurred in 8.8% of the trospium group versus 5.7%
of the placebo group. The cardiovascular effect of increased basal heart rate (primarily M2-receptor mediated) for patients on trospium compared with placebo appears to be unique to trospium's M2-receptor affinity.
Tolterodine
This agent has a major active metabolite, 5-hydroxymethyl tolterodine, with a similar pharmacologic profile to that of the
parent compound. The drug is rapidly absorbed and has a half-life of 2 to 3 hours, similar to that of its active metabolite.
Due to a low lipophilic affinity, this molecule has limited propensity to penetrate the normal CNS, which may explain the
low frequency of cognitive side effects associated with its use in patients with a normal blood-brain barrier. Tolterodine
is available also as an extended-release formulation that allows daily dosing and shows advantages over the immediate-release
form in efficacy and tolerability.9
Solifenacin (Vesicare)
Three agents currently used for treatment of OAB, solifenacin, oxybutynin (Ditropan, Ditropan XL, Oxytrol) and darifenacin
(Enablex), show various degrees of M3-receptor selectivity. Solifenacin is a long-acting muscarinic-receptor antagonist that has a primarily M3-receptor selective affinity. In a multicenter, randomized, placebo-controlled clinical trial, solifenacin significantly reduced
the number of urge episodes in 51% and 52% of subjects, respectively.10 This effect was also seen for episodes of urge incontinence.
Dry mouth was reported in 7.7% of patients receiving 5 mg of solifenacin and in 23% receiving 10 mg, versus 2.3% receiving
placebo.10 Constipation was experienced by 2% of patients taking placebo and by 3.7% and 9.1% of those taking the 5-mg and 10-mg
doses of solifenacin, respectively. No significant CNS or cardiac adverse events were identified.
Oxybutynin
The effects of oxybutynin include an antimuscarinic and direct muscle-relaxant effect, as well as a local anesthetic action.
Considered to be primarily M3-receptor selective, oxybutynin is easily absorbed but undergoes extensive first-pass metabolism, with a plasma half-life
of 2 hours and a wide variation in effects among patients. Oral and transdermal extended-release formulations allow once daily
oral dosing or twice-weekly skin application and both have shown advantages over the generic immediate-release form.9,11
The Overactive Bladder: Performance of Extended Release Agents (OPERA) randomized trial compared oral extended-release formulations
of oxybutynin, 10 mg/d, and tolterodine, 4 mg/d, in 790 women with OAB who were treated for 12 weeks.12 Improvements in the number of weekly urge incontinence episodes were similar for oxybutynin and tolterodine (391 and 399,
respectively). However, the oxybutynin group had a significantly greater reduction in micturition frequency than the tolterodine
group. The most frequently reported adverse event, dry mouth, was more common in the oxybutynin group, reported by 29.7% of
women taking this agent compared with 22.3% of those taking tolterodine.
The oxybutynin transdermal patch was introduced to avoid the first-pass effect and to decrease side effects from the immediate-
and extended-release preparations of oral oxybutynin. In a multicenter, placebo-controlled 12-week trial, 361 previously treated
patients with urge or mixed urinary incontinence were randomized to receive transdermal oxybutynin, 3.9 mg/d; extended-release
tolterodine, 4 mg/d; or placebo.13 When compared with placebo, both transdermal oxybutynin and extended-release tolterodine significantly reduced the number
of weekly incontinence episodes as well as daily urinary frequency and increased average voided volume. These changes were
associated with a significant improvement in quality of life. The most common adverse event for the transdermal formulation
was localized application site pruritus (14% versus 4% for placebo). The incidence of dry mouth for transdermal oxybutynin
was 4.1% compared with 7.3% for tolterodine and 1.7% for placebo.
Darifenacin
Of the currently available OAB agents, this one has the greatest M3-receptor affinity. Oral controlled-release darifenacin, 3.75 mg, 7.5 mg, and 15 mg, was compared with placebo in a 12-week
randomized, double-blind trial.14 Darifenacin, 3.75 mg, did not reduce the occurrence of urgency or incontinence episodes significantly; however, both
the 7.5- and 15-mg doses significantly reduced the number of urgency episodes per 24 hours by a median of 2 episodes, equivalent
to a 29% reduction from baseline. A statistically significant reduction in the number of weekly incontinence episodes was
observed at the higher doses.
A dose-related increase in side effects was observed with darifenacin, with dry mouth being reported in 13.2%, 18.8%, and
31.3% of patients taking 3.75 mg, 7.5 mg, and 15 mg, respectively.14 Overall, constipation was reported by 14% of the subjects, but the majority of the occurrences were described as mild by
the patients. Discontinuation rates due to constipation were similar to placebo, and darifenacin showed no significant CNS
adverse events or cardiac adverse events in this study.
This article was written by Drs Rackley and Vasavada and edited by Julia M. Russell.
Dr Vasavada discloses relationships with Novartis and Pfizer.
Dr Rackley discloses relationships with Pfizer, Novartis, Astellas, and Allergan.
REFERENCES
1. Wagner TH, Hu TW, Bentkover J, et al. Health-related consequences of overactive bladder. Am J Manag Care. 2002;8(19 suppl):S598-S607.
2. Brown JS, McGhan WF, Chokroverty S. Comorbidities associated with overactive bladder. Am J Manag Care. 2000;6(11 suppl):S574-S579.
3. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-336.
4. Eglen RM, Hedge SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev. 1996;48:531-565.
5. Nilvebrant L, Andersson KE, Gillberg PG, et al. Tolterodine—a new bladder-selective antimuscarinic agent. Eur J Pharmacol. 1997;327:195-207.
6. Napier C, Gupta P. Darifenacin is selective for the human recombinant M3 receptor subtype. Presented at the 32nd Annual
Meeting of the International Continence Society, Heidelberg, Germany, August 28-30, 2002. Abstract 445.
7. Corrigan C. The eotaxins in asthma and allergic inflammation: implications for therapy. Curr Opin Invest Drugs. 2000;1:321-328.
8. Zinner N, Gittelman M, Harris R, et al. Trospium chloride improves overactive bladder symptoms: a multicenter phase III
trial. J Urol. 2004;171 (6 pt 1):2311-2315.
9. Rovner ES, Wein AJ. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive
bladder: a review. Eur Urol. 2002;41:6-14.
10. Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic
agent solifenacin succinate in patients with overactive bladder. J Urol. 2004;172(5 pt 1):1919-1924.
11. Dmochowski RR, Davila GW, Zinner NR, et al. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed
urinary incontinence.
J Urol. 2002;168:580-586.
12. Diokno AC, Appell RA, Sand PK, et al. Prospective, randomized, double-blind study of the efficacy and tolerability of
the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003;78:687-695.
13. Dmochowski RR, Sand PK, Zinner NR, et al. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine
versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology. 2003;62:237-242.
14. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol. 2004;45:420-429; discussion 429.
Drugs mentioned in this article
Baclofen (Lioresal)
Botulinum toxin A (Botox)
Botulinum toxin B (Myobloc)
Darifenacin (Enablex)
Gabapentin (Neurontin)
Morphine
Nociceptin/orphanin FQ*
Oxybutynin (Ditropan, Ditropan-XL)
Oxybutynin, transdermal patch (Oxytrol)
Solifenacin (Vesicare)
Tolterodine (Detrol, Detrol LA)
Tramadol (Ultram)
Trospium (Sanctura)
*Investigational use.
On the horizon: The future of drug therapy for OAB
In addition to the available antimuscarinic agents previously discussed, other pharmacologic treatments show promise in the
treatment of the overactive bladder (OAB) symptom complex. Botulinum toxin A (Botox) and B (Myobloc), tramadol (Ultram), baclofen
(Lioresal), and gabapentin (Neurontin) have not been approved by the FDA for use in OAB.
Botulinum toxin injections
Botulinum toxins achieve their paralyzing effects by inhibiting the release of acetylcholine from the motor nerve into the
neuromuscular junction. Without acetylcholine release, muscles are unable to contract. After an IM injection of botulinum
toxin, temporary chemodenervation and muscle relaxation can be achieved. There is also evidence that botulinum toxin A decreases
the afferent signals from the bladder, thereby directly reducing the neural activity that results in sensory and muscle overactivity.
Opioid receptor agonists
For years, the clinical observation that morphine can increase bladder capacity or block detrusor contractions has served
as a proof of concept for development of its use in primary OAB. Tramadol, a weak opioid-receptor agonist used to treat pain,
functions as an inhibitor of serotonin and noradrenalin reuptake. In a rat model, this drug increases bladder capacity and
abolishes apomorphine-induced or cerebral infarct-induced detrusor overactivity.1-3 These observations suggest a potential clinical role for tramadol in controlling detrusor overactivity.
Serotonin mechanisms
Recent work has established that the lumbosacral autonomic nuclei, as well as the somatic motor nuclei (Onuf's nuclei),
receive a dense serotonergic input from the raphe nuclei. This descending pathway is an inhibitory circuit, with serotonin
acting as a key neurotransmitter. Electrical stimulation of 5-HT-containing neurons in the caudal raphe nucleus causes inhibition
of detrusor contractions.
Gamma-aminobutyric acid (GABA)
Experiments using both conscious and anesthetized rats demonstrated that exogenous GABA, muscimol (a GABAA-receptor agonist),
and the GABAB-receptor agonist baclofen administered intravenously, intrathecally, or intracerebroventricularly inhibit micturition.4,5 In a pilot study of gabapentin on neurogenic detrusor overactivity, investigators found a positive effect on symptoms and
significant improvement in urodynamic parameters after treatment and suggested that the effects of the drug on detrusor overactivity
should be explored further in controlled studies.6
Noradrenaline-mediated therapies
In the human detrusor, the most important beta-adrenoceptor (beta-AR) for bladder relaxation is the beta3-AR. This partially explains why analyses of the clinical effects of selective beta2-AR agonists in detrusor overactivity have been controversial and largely inconclusive.7 The beta3-AR appears to be a potential target for drugs aimed at treating OAB and detrusor overactivity. No published proof-of-concept
studies, however, have been performed in humans to confirm whether this is an effective principle for the treatment of OAB.
Nociceptin/orphanin FQ
Animal studies have demonstrated that the drug exerts an inhibitory effect on the micturition reflex in rats. A preliminary,
noncontrolled, nonrandomized study in humans showed that nociceptin/orphanin FQ produced a clear acute inhibitory effect on
the micturition reflex in patients with neurogenic incontinence but not in normal subjects.8 Investigators have suggested that nociceptin/orphanin FQ receptor agonists are potentially effective new drugs for the
treatment of neurogenic urinary incontinence.9
1. Pandita RK, Pehrson R, Christoph T, et al. Actions of tramadol on micturition in awake, freely moving rats. Br J Pharmacol. 2003;139:741-748.
2. Pehrson R, Stenman E, Andersson KE. Effects of tramadol on rat detrusor overactivity induced by experimental cerebral infarction.
Eur Urol. 2003;44:495-499.
3. Pehrson R, Andersson KE. Tramadol inhibits rat detrusor overactivity caused by dopamine receptor stimulation. J Urol. 2003;170:272-275.
4. Pehrson R, Lehmann A, Andersson KE. Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin
induced detrusor overactivity in female rats. J Urol. 2002;168:2700-2705.
5. Maggi CA, Santicioli P, Giuliani S, et al. The effects of baclofen on spinal and supraspinal micturition reflexes in rats.
Naunyn Schmiedebergs Arch Pharmacoll. 1987;336:197-203.
6. Carbone A, Tubaro A, Morello P, et al. The effect of gabapentin on neurogenic detrusor overactivity, a pilot study. Eur Urol. 2003;2(suppl):141. Abstract 555.
7. Andersson KE, Appell R, Awad S. Pharmacological treatment of urinary incontinence. In: Abrams P, Khoury S, Wein A, eds.
Incontinence. Proceedings of the 2nd International Consultation on Incontinence. London: Plymbridge Distributors, Ltd. 2002;1:479-511.
8. Lazzeri M, Calo G, Spinelli M, et al. Urodynamic and clinical evidence of acute inhibitory effects of intravesical nociceptin/orphanin
FQ on detrusor overactivity in humans: a pilot study. J Urol. 2001;166:2237-2240.
9. Lazzeri M, Calo G, Spinelli M, et al. Urodynamic effects of intravesical nociceptin/orphanin FQ in neurogenic detrusor
overactivity: a randomized, placebo-controlled, double-blind study. Urology. 2003;61:946-950.
A brief word on research methodologies and study limitations
A recent meta-analysis reported that antimuscarinic drugs produce significant improvements in overactive bladder (OAB) symptoms
compared with placebo, but the benefits are of limited clinical significance.1 This primarily biostatistical work proposed that the rationale for the use of antimuscarinic drugs in the management
of OAB should be re-examined and the results of treatment discussed. It is important to note that this review was limited
to randomized controlled trials on nonselective antimuscarinic drugs for non-neurogenic urge incontinent patients using only
patient self-reports of voiding diary outcomes. Furthermore, this meta-analysis does not include comparative outcome measures
of patients' perceptions or changes in quality of life (QOL).
Of course, no single measure or measurement tool can fully express or quantitate the overall outcome of an OAB intervention
in the structured clinical setting of a randomized controlled trial. The most common primary end points in OAB trials have
been easily measured variables of frequency and urge incontinence episodes that are obtained by patients using self-reporting
voiding diaries.
Certainly the limitations of a voiding diary as an instrument for patient self-reporting may be argued, but it is a practical
and cost-effective tool for measuring OAB symptoms. While the symptom of urgency is difficult to clinically describe and challenging
to assess as a primary end point, the presence and severity of this leading symptom used in defining the OAB condition are
relevant variables to measure, using the patient's perspective, as seen in more recent drug trials.
To date, few trials report outcomes for all the symptoms that comprise the OAB symptom complex, despite the fact that inclusion
criteria for all currently published, randomized, placebo-controlled trials are limited to patients with all 3 symptoms. Only
1 trial currently measures the outcomes of all 3 of these symptoms and includes QOL measures as well.2 Without significantly increasing the cost of their research, investigators must begin performing OAB trials that measure
all 3 facets of the OAB "wet" symptom complex—urgency, voiding frequency, and urge incontinence—patients' QOL scores, and
patients' self-reports of global perception of outcome. With this information, clinicians will be able to correlate objective
outcomes with patients' perceptions and QOL scores.
1. Herbison P, Hay-Smith J, Ellis G, et al. Effectiveness of anticholinergic drugs compared with placebo in the treatment
of overactive bladder: systematic review. BMJ. 2003;326:841-844.
2. Zinner N, Gittelman M, Harris R, et al. Trospium chloride improves overactive bladder symptoms: a multicenter phase III
trial. J Urol. 2004;171(6 pt 1):2311-2315.
