Background
Lower Urinary Tract Symptoms (LUTS) have a high prevalence affecting up to 90% of men over 80 years [
1]. The term LUTS comprises a large group of symptoms usually divided into storage LUTS (daytime urinary frequency, nocturia, urgency, urinary incontinence), voiding LUTS (slow stream, splitting or spraying, intermittency, hesitancy, straining, terminal dribble), and post micturition LUTS (sensation of incomplete emptying, post-micturition dribble) [
2].
In men, LUTS may be associated with benign prostatic obstruction (BPO) typically resulting from benign prostatic hyperplasia (BPH) or benign prostatic enlargement (BPE) [
3]. Approximately half of men with histological BPH develop BPE but only 25–50% of these men have LUTS [
4,
5].
OAB and storage LUTS are defined as the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urinary incontinence, in absence of urinary tract infection or other urethro-vesical dysfunctions [
2]. Storage LUTS are generally a chronic condition, with a prevalence ranging from 10% to 26% [
6,
7]. Male storage symptoms could be caused by bladder dysfunction (like detrusor overactivity or detrusor impaired contractility), BPO (often caused by BPE) or by a combination of both bladder dysfunction and BPO [
8,
9]. In that scenario, the role of targeted therapies appears crucial. In order to obtain clinical relief of storage LUTS, an extensive counseling of patients is mandatory to evaluate all the possible treatments and their expected results since the lack of efficacy and the presence of bothering adverse events (AEs) can reduce compliance.
Behavioral therapies should be offered as first line treatment for all patients with storage LUTS. Their goal is to relieve bladder symptoms by changing voiding habits (bladder training, delayed voiding) or by improving control of urge suppression and urethral occlusion (PFMT). Nevertheless the gold standards of pharmacological therapy are antimuscarinic agents such as oxybutynin, tolterodine, fesoterodine, darifenacin, solifenacin, or trospium [
10].
Antimuscarinics (m-cholinoceptor antagonists) especially block specific receptors at the level of the bladder (M
2 and M
3 receptors on smooth muscle cells of the detrusor) in a more or less selective manner, thereby reducing involuntary bladder contractions or altering contraction thresholds. Antimuscarinics act mainly during the urinary storage phase and decrease the activity of afferent bladder nerves [
11] resulting in decreased urgency and increased bladder capacity. However, muscarinic receptors are also found in other parts of the body, including the brain, heart, gut, salivary glands, and tear ducts. First marketed antimuscarinics were limited by adverse effects, resulting in poor patient compliance and discontinuation of treatment [
12].
Oxybutynin was the first antimuscarinic agent, used since the mid-70s, for the treatment of overactive bladder (OAB)/bladder storage symptoms [
13]. Oxybutynin immediate release (IR) has proven efficacy for the condition [
14]. However, it has a significant incidence of peripheral anti-muscarinic adverse events such as dry mouth, constipation, tachycardia, paralysis of accommodation and central nervous system side effects (cognitive dysfunction or delirium), resulting in poor compliance and early discontinuation of therapy in a large number of patients [
12,
13].
More than fifteen years ago, tolterodine was developed with the aim of obtaining a better efficacy/adverse event profile and improving the compliance of patients compared to other antimuscarinic drugs. It is lesser lipid (soluble) than oxybutynin and crosses the blood–brain barrier to a lesser extent. Tolterodine is non-selective with respect to the muscarinic receptor sub-types but, as shown by data obtained from animals and healthy volunteers in the first clinical trials, showed a greater, more rapid and longer lasting effect on the bladder than on salivary glands
in vivo [
15‐
17].
Patient tolerability represents a fundamental parameter for the administration of antimuscarinic agents. Given the established role of frequency-dose and patient compliance and its potential effect on tolerability and efficacy, an extended release (ER) formulation was developed for several antimuscarinics. In a large systematic review and meta-analysis [
18], all the comparisons among IR (drug intake 2–3 times/day) and ER formulations (drug intake once/day) showed advantages for the latter, either in terms of efficacy or safety.
Few studies investigated the effects of antimuscarinic drugs on male patients with bladder outlet obstruction and OAB/bladder storage symptoms and the results of the use of antimuscarinic agents as monotherapy were conflicting. Starting in 1994, the approach of combination therapy with α-blockers and antimuscarinics has become increasingly popular [
19]. Earliest report of Athanasopoulos et al. [
20] on the effects of tolterodine 2 mg twice daily combined with tamsulosin 0.4 mg once daily compared with tamsulosin alone in 25 patients showed a better QoL only in the combination therapy group with no acute urinary retention. As a result, there has been a growing interest on the use of antimuscarinics in male LUTS/BPH.
Antimuscarinics have been increasingly used in clinical practice - with caution and regular re-evaluation - in particular for selected patients with moderate to severe LUTS who have predominant bladder storage symptoms and do not have elevated post-void residual urine volumes [
21,
22]. In the present review we analyzed in detail the mechanism of action of tolterodine ER and its overall safety and efficacy in the treatment of male bladder storage LUTS.
Methods
A wide Medline search was performed including the combination of following search terms: “LUTS”, “BPH”, “OAB”, “antimuscarinic”, “tolterodine”, “tolterodine ER”. No temporary limits were adopted. IPSS, IPSS storage sub-score and IPSS QoL (International Prostate Symptom Score) were the validated efficacy outcomes. In addition, the numbers of urgency episodes/24 h, urgency incontinence episodes/24 h, incontinence episodes/24 h and pad use were considered. We also evaluated the most common adverse events (AEs) reported for tolterodine ER in selected studies.
Conclusions
Tolterodine is an effective muscarinic receptor antagonist, with a receptor affinity comparable to oxybutynin in the bladder, and a remarkably lower affinity than oxybutynin in the parotid gland. Immediate-release tablets 2 mg twice daily and extended-release tablets 4 mg once daily have a comparable pharmacokinetic profile.
Tolterodine ER resulted effective in reducing frequency urgency and nocturia and urinary leakage in patients with OAB/storage LUTS. Dry mouth and constipation are the most frequently reported adverse events. The good safety profile, which allow to minimize treatment withdrew, and the adequate effectiveness in the management of storage LUTS, are the strengths of Tolterodine ER.
Further RTCs are needed to identify the best candidates for the treatment with tolterodine ER and to tailor promising combination therapies with other drugs currently available for male LUTS.
Competing interests
No sources of funding were used to assist in the preparation of this article. Dr Gacci has received Support for travel to meetings for the study, manuscript preparation or other purposes and payment for lectures from GSK, Eli Lilly, MEnarini, Pfizer, Bayer. Dr Novara has been advisory board member or speaker for Astellas, GlaxoSmithKleine, Lilly, Menarini, Nycomed, Pfizer Inc., Pierre Fabre, and Recordati. Dr Oelke has worked on the advisory board for Eli-Lilly and Company, and has received payment for lectures from Eli-Lilly and Company, Pfizer and Bayer. Drs De Nunzio, Tubaro, Schiavina, Brunocilla, Sebastianelli, Salvi, Gravas, Carini and Serni have no competing interest to declare.
Authors' contributions
Study concept and design: MG. Acquisition of data: AS, MS. Analysis and interpretation of data: MG, GN, CDN, MO. Drafting of the manuscript: MG, CDN, MO, RS, EB. Critical revision of the manuscript for important intellectual content: MC, SG, SS, AT. All authors read and approved the final manuscript.