Overactive bladder is a common and bothersome condition. Antimuscarinic agents, as a class, are the cornerstone of medical treatment of overactive bladder. They offer significant improvements in symptoms and patients’ quality of life. Antimuscarinics are generally well tolerated with mild and predictable side effects. Available antimuscarinics have small, yet statistically significant, differences in their efficacy and tolerability profiles. In clinical practice, finding the agent that offers the optimum balance of efficacy and side effects for an individual patient remains the major challenge.
Overactive bladder (OAB) is a lower urinary tract condition, characterized by symptoms of urgency, with or without urge incontinence, usually with frequency and nocturia. This symptom complex significantly affects patient’s quality of life. In most cases, the underlying pathophysiology is an involuntary detrusor contraction during the storage phase of the voiding cycle [
Normal bladder contraction during voiding involves stimulation of the muscarinic receptors on the detrusor muscle by acetylcholine (Ach). The role of Ach in the pathogenesis of involuntary contractions during the storage phase is elusive. Despite the fact that detrusor may contract spontaneously, as a result of the intrinsic activity of the myocyte or of small units of smooth muscle cells [
There are several subtypes of muscarinic receptors. The human detrusor contains mainly the M2 and M3 subtypes [
Oxybutynin [
The current literature on the efficacy and safety of antimuscarinics was reviewed by searching Medline/PubMed for relevant articles, published in English between 1980 and 2010.
Oxybutynin is the first antimuscarinic used for the treatment of OAB. In addition to its antimuscarinic action, oxybutynin in high doses exerts muscle-relaxant and local anaesthetic effects [
Oxybutynin is now available in oral, immediate (IR) and extended release (ER), as well as two transdermal formulations, a patch and a gel. An intravesical formulation of oxybutynin has also been studied [
Oxybutynin IR formulation was the fist that entered clinical practice. Despite its satisfactory efficacy, the substantial incidence of dry mouth, immediate release oxybutynin’s most common and bothersome side-effect, limited its tolerability. Newer formulations aimed at eliminating peaks in concentration of oxybutynin and its metabolites in order to reduce related side effects.
The ER formulation of oxybutynin provides a smooth plasma concentration profile over the 24-hour dosage interval, facilitating once-daily administration. Hence, given its overall efficacy/tolerability and dose flexibility, oxybutynin ER provides an alternative in the first line of pharmacotherapy for OAB [
The transdermal oxybutynin (OXY-TDS) formulation offers patients with urinary incontinence an effective, safe and well-tolerated option for managing the symptoms of overactive bladder [
Oxybutynin chloride topical gel (OTG) was approved in January 2009 by the US FDA. OTG was designed to provide steady plasma oxybutynin levels with daily application, favorably altering the circulating N-desethyloxybutynin metabolite to oxybutynin ratio, thus minimizing the antimuscarinic adverse effects of oral formulations. The use of a biocompatible delivery system also reduced the application-site skin reactions associated with other available forms of transdermal delivery. OTG represents an efficacious, safe, and convenient alternative to other oxybutynin formulations and oral antimuscarinics for the treatment of OAB [
Interestingly, all the above-mentioned oxybutynin formulations have been shown to be more efficacious than the IR oxybutynin [
Tolderodine is a widely prescribed antimuscarinic and, it was the first specifically developed to treat OAB. Tolterodine is not selective for any muscarinic receptor subtype, but it exhibits selectivity for the urinary bladder over salivary glands in vivo [
An IR formulation was available first, but an ER, administered once daily, formulation was later designed. Its efficacy and tolerability have been proved in a large number of trials [
Oxybutynin and tolterodine, the until relatively recent years most commonly prescribed antimuscarinics, have been shown to have similar efficacies in general OAB populations [
Propiverine, another muscarinic receptor antagonist, has also been demonstrated to inhibit L-type Ca++ channels in high concentrations [
Propiverine has similar efficacy to oxybutynin and tolterodine, similar tolerability and impact on quality of life to tolterodine, but a better tolerability profile than oxybutynin [
Propiverine and oxybutynin are efficacious in children with incontinence due to overactive bladder and propiverine is officially approved in certain countries for pediatric use. Alloussi et al. [
Darifenacin is the antimuscarinic with the highest M-3 receptor subtype selectivity. Long-term darifenacin treatment was associated with significant and clinically meaningful improvements in quality of life of patients with urge incontinence (“wet” OAB) over 2 years [
A pooled analysis of four randomized, placebo-control1ed, phase III studies of solifenacin in OAB patients without incontinence, showed a significant improvement of symptoms and voided volume after 12 weeks of treatment [
How does solifenacin compare to longer established antimuscarinics? One comparison of the “new” (solifenacin and darifenacin) and “old” antimuscarinic agents showed the two generations of treatment had similar efficacy [
Solifenacin is the first antimuscarinic to demonstrate significant warning-time improvement in a large OAB clinical trial conducted to evaluate warning time and diary variables in the same study population [
A relatively recent comprehensive review for solifenacin concluded that this agent was effective in the treatment of OAB with urge incontinence [
Trospium chloride is a quaternary ammonium compound. It does not cross the blood-brain barrier; therefore, no central nervous system adverse events are anticipated [
Fesoterodine is the newest antimuscarinic for the treatment of OAB. Fesoterodine is a prodrug. It is rapidly and extensively hydrolyzed by nonspecific esterases, thus bypassing the CYP system, to 5-hydroxymethyl tolderodine (5-HMT), which is also the active metabolite of tolderodine. Interestingly, as 5-HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases, the rate of fesoterodine hydrolyzation maybe more uniform and complete.
Initial data from phase 2 trials showed that fesoterodine was an effective and well-tolerated therapy for OAB [
In a posthoc analysis of pooled data from two clinical trials including 1,548 women with overactive bladder, fesoterodine 4 mg and 8 mg and tolderodine showed significant improvements in all bladder diary variables assessed and greater response rates versus placebo. Fesoterodine 8 mg was significantly more efficacious than fesoterodine 4 mg and tolderodine ER in improving UUI episodes and continence days per week [
Currently available antimuscarinics have all demonstrated their efficacy and safety in well-designed, controlled studies conducted during their clinical development. The significant placebo effect observed in OAB trials and the frequent treatment discontinuations in real-life practice have often raised doubts regarding the true efficacy and/or safety of this drug class. Systematic reviews and meta-analyses of existing data have tried to clarify uncertainties.
In 2003, Herbison et al. [
A 2005 systematic review of 52 randomized, controlled trials by Chapple et al. [
Differences in efficacy of antimuscarinics have often reached statistical significance in clinical trials. Nevertheless, the magnitude of these differences is not readily appreciated in everyday clinical practice and many clinicians consider drugs in this class as “comparable” in terms of efficacy. According to a meta-analysis by Novara et al. [
As far as safety is concerned, antimuscarinics, in general, are safe [
Slight differences in the safety profiles of existing antimuscarinic agents depend on their selectivity for specific muscarinic receptor subtypes, selectivity for the bladder compared to salivary glands, their lipophilicity and ability to cross the blood-brain barrier, as well as their pharmacokinetic properties.
Evidence from controlled trials [
In general, the extended release formulations are better tolerated than the immediate release ones. In cases that dry mouth is intolerable with the oral formulations, transdermal oxybutynin might bean alternative, but, unfortunately, application site reactions are common with the oxybutynin patch [
Central nervous system side effects are a concern when prescribing antimuscarinics for the treatment of OAB, particularly in vulnerable populations such as the elderly and CNS-compromised, neurogenic bladder patients. The evidence for cognitive impairment with oxybutynin is compelling [
The binding of muscarinic receptors in the heart may lead to cardiovascular adverse events and QT interval prolongation has been a concern with antimuscarinics. In a randomized, double-blind, placebo-controlled, crossover trial [
Despite acceptable rates of treatment discontinuation in clinical trials, real-life compliance, especially to long-term treatment, is low. For example, in a pharmacy dispensing records review for antimuscarinic agents from January 2003 to December 2006 conducted for the United States Military Health System National Capital Region, 35% of OAB patients did not refill a fully reimbursed prescription for antimuscarinics [
Low compliance to treatment can be due to inadequate drug efficacy, intolerable side effects, poor patient education and follow up, and cost issues. Among these reasons dry mouth is the most common [
Dose flexibility offers the advantage of an individually tailored treatment to achieve the optimum balance between efficacy and adverse events. A strategy based on patient-requested dose increases has been found to consistently improve overactive bladder symptoms. The impact of dose flexibility on clinical management of OAB has been examined in studies with solifenacin, darifenacin, and oxybutynin ER [
Despite the fact that differences in efficacy of antimuscarinics in clinical trials with large OAB populations are relatively small, an individual patient may benefit more from a particular drug than another. “Salvaging” nonresponders to one drug with another has been shown in several studies. Solifenacin, for example, has been shown to significantly improve bladder diary and validated quality-of-life outcomes in women with urge incontinence that failed to respond or were unable to tolerate oxybutynin IR [
The above studies, despite limitations in patient selection and overall design, suggest that switch between drugs is a reasonable approach in patient failing initial treatment.
A significant concern when antimuscarinics are considered in male patients with storage lower urinary tract symptoms (LUTS), suggestive of an overactive bladder, is the risk of urinary retention. This concern seems particularly relevant when voiding, benign prostate hyperplasia-related LUTS are present. The reality, nevertheless, is that antimuscarinics at clinically recommended doses have little effect on voiding pressures. Clinical experience has proved that concerns regarding acute urinary retention or increased residual volume are unfounded [
Antimuscarinic agents, as a class, are the cornerstone of medical treatment of overactive bladder. Accumulated evidence from clinical trials and meta-analyses has proved their efficacy and safety. Antimuscarinics offer significant improvements in symptoms of urge incontinence, urgency, frequency, and nocturia. This translates in substantial benefits in quality of life. Antimuscarinics are generally well tolerated with mild and predictable antimuscarinic side effects. The most common and bothersome of them, dry-mouth, not infrequently leads to treatment discontinuation.
Available antimuscarinics have small, yet statistically significant, differences in their efficacy and tolerability profiles. In general, the higher doses of drugs that offer dose flexibility have higher efficacy. Tolerability depends mainly on drug selectivity for the bladder over other organs, selectivity for muscarinic receptor subtypes and ability to penetrate the CNS. Given that there is no “cure” for OAB yet, finding the agent that offers the optimum balance of efficacy and side effects for an individual patient remains the major challenge in OAB treatment.
A. Athanasopoulos is or has been an investigator, lecturer and consultant for pharmaceutical companies producing or developing drugs for lower urinary tract symptoms (Pfizer, Astellas, Ucb, Lilly, Allergan, Bard, and Amgen). K. Giannitsas is or has been an investigator and lecturer for pharmaceutical companies producing or developing drugs for lower urinary tract symptoms (Pfizer, Astellas, Lilly, and Allergan).