New approaches in the pharmacological treatment of stress urinary incontinence

Stress urinary incontinence (SUI) is a common condition among women of all ages which leads to significant bother and has a negative impact on the quality of life (QoL) of the affected individuals and their families [1,2]. The bothersome symptoms of SUI may restrict physical activities and impair social and sexual activities and relationships. However, many women with SUI suffer in silence [3,4]. This is probably due to the fact that patients experience SUI as a highly embarrassing condition and are ashamed to admit that they are suffering from it. In addition, many patients may attribute the symptoms to aging and/or are afraid of surgery and believe that this is the only treatment option available. Lack of a globally developed or widely approved pharmacological therapy that may fill the current gap in treatment options between conservative treatment on one hand and surgery on the other may also contribute to this barrier to seek treatment. In this regard, healthcare professionals should encourage help-seeking behavior of women suffering from SUI and educate them on the available treatment options. The purpose of the present supplement is, therefore, to review the epidemiology, etiology and management of women presenting with SUI symptoms, with a special focus on new pharmacological treatment approaches. The International Continence Society (ICS) has defined SUI at four different levels: as a symptom, sign, urodynamic observation and condition [5]. The symptom of SUI is defined as the patient's complaint of involuntary leakage of urine on effort or exertion, or on sneezing or coughing. The sign of SUI is defined as the observation of involuntary leakage from the urethra, synchronous with exertion/effort, or sneezing or coughing. This can be objectively demonstrated by the physician during for instance a cough or pad stress test. The urodynamic observation of SUI is the involuntary leakage of urine during increased abdominal pressure in the absence of involuntary detrusor contractions (IDCs) during filling cystometry. The condition of SUI is defined by the presence of urodynamic observations associated with characteristic symptoms or signs of SUI. In this supplement, Oscar Contreras Ortiz reviews the current literature on the prevalence of urinary incontinence (UI) according to the three main types of UI: SUI, urge urinary incontinence (UUI) and mixed urinary incontinence (MUI) [6]. It appears that UI is approximately two to four times more prevalent in women than men and that in women the reported prevalence of UI varies considerably across studies (range 11–72%) [6]. In a recent literature review of 35 worldwide studies surveying approximately 230 000 people, the author and his co-workers confirmed that UI is almost three times more common in women than in men and that in women the prevalence ranges between 5 and 58% [4]. This wide range in prevalence rates is probably mainly due to different definitions of UI (from ‘any loss of urine in a 12-month period’ to ‘two or more wetting episodes in the past month’), different populations studied (e.g. different age groups or different settings (community-based vs. institutionalized)) and/or different methods of data collection (posted questionnaires vs. personal interviews). The literature review, however, shows that on average one in every four women has UI [4]. This was confirmed in the EPINCONT study involving 27 936 women living in a county in Norway [1]. This study also showed that SUI is the most prevalent type of incontinence (occurring in 50% of all incontinent women) followed by MUI (36%) and UUI (11%) [1]. The literature review confirmed that most women (82%) suffer from SUI with or without additional urge symptoms (Fig. 1) [4]. It appears that whereas SUI is the most prevalent type in young and middle-aged women, MUI becomes more prevalent in older women due to the fact that the occurrence of urge symptoms increases with age (Fig. 2) [1,6]. Prevalence of UI by type of incontinence in women [4]. Four percent of the incontinent women had another type of incontinence other than SUI, MUI or UUI. Prevalence of UI by type of incontinence and by age in women. Reproduced by permission of Elsevier from Ref. [4]. Approximately half of all women with UI are slightly bothered and one third moderately to severely bothered [1,2,6]. Despite this, only one in every four incontinent women seeks medical advice [3,4,6] and often there is a delay of one year or longer before they first consult a physician [3,6,7]. In the studies included in the literature review, 50% of patients reported that UI affected their QoL at least slightly but 77% of these patients did not seek help [3]. There are two main causes of SUI: bladder neck/urethral hypermobility and intrinsic sphincter deficiency (ISD). In many women, SUI is caused by a combination of both. Due to weakening of the extrinsic support of the proximal urethra, the bladder neck and/or urethra descends outside the intra-abdominal cavity during stress activities (exercising, coughing, sneezing). As a consequence the urethra cannot sufficiently compress and the increased intra-abdominal pressure overrides intra-urethral pressure which leads to urine leakage. In patients with ISD, the intrinsic urethral sphincter mechanism and its nerve supply is damaged and can, therefore, not maintain an adequate urethral tone when stress activities increase intra-abdominal pressure. The etiology of (S)UI is still poorly understood. The available evidence on potential risk factors for the development of (S)UI such as age, pregnancy/childbirth/parity, obesity, smoking, chronic cough, constipation, menopause/estrogen deficiency and previous hysterectomy has also been reviewed by Oscar Contreras Ortiz [6]. It appears that the most studied risk factors with sufficient proof are age, pregnancy/childbirth/parity and obesity. As indicated by Peter Dwyer in this supplement, a major first step in the diagnosis and management of women presenting with incontinence is to distinguish between SUI and UUI as both types of incontinence require different treatment [8]. This differentiation is in first instance based on the patient's symptoms/complaints. Whereas incontinence associated with vigorous exercise, coughing, sneezing or laughing suggests the presence of SUI, incontinence accompanied or immediately preceded by urgency (e.g. during hand washing or key in the door) is suggestive of UUI. A bladder diary may be of help in assessing the type and frequency of symptoms as well as the circumstances causing urine leakage. A diagnosis of SUI becomes more likely when urine leakage can be observed during a cough and/or pad stress test; the weight of the pad is, moreover, indicative for the amount/severity of leakage. If SUI is confirmed by these methods, it does not seem to be essential to initially perform urodynamic studies for demonstrating urodynamic evidence of SUI. This is because these are invasive and the correlation between urodynamic findings and the symptoms of UI is in general poor, in particular in patients with MUI symptoms [8–10]. It is instead proposed to first test whether the patient responds to life style interventions (e.g. fluid management, weight loss, stop smoking), non-invasive conservative treatment such as pelvic floor muscle training (PFMT) and/or to pharmacological therapy for SUI. The major drawbacks of PFMT are the facts that it takes some time before the patient may experience the benefit and that in many patients compliance decreases over time. Unfortunately there are currently no globally developed or widely approved pharmacological treatments available (see Table 1) [11]. Some drugs are used off-label [i.e. α1-adrenoceptor (AR) agonists, tricyclic antidepressants (TCAs) and estrogens], but with no evidence of efficacy from randomized, controlled trials (RCTs). Furthermore, they can be associated with significant and sometimes serious side effects such as hypertension, cardiac arrhythmias and hemorrhagic stroke with the non-selective α-AR agonist phenylpropanolamine (PPA) and increased risk of cardiovascular disease and breast and endometrial cancer with estrogens. Patients with SUI who fail conservative and/or pharmacological treatment or patients with severe SUI in whom surgery is planned, should first undergo urodynamic studies. If during bladder filling increased intra-abdominal pressure (e.g. due to coughing) is not accompanied by IDCs, urodynamic stress incontinence is confirmed and one can proceed with surgery. There are three main types of surgical interventions available with increasing rates of invasiveness and increasing rates of associated effectiveness and complications (such as de novo detrusor overactivity and voiding dysfunction): urethral bulking agents (or injectables), sub-urethral sling procedures and colposuspensions. Urethral bulking agents are most suitable for patients with ISD; the glutaraldehyde cross-linked bovine (GAX)-collagen has been studied most intensively [12]. Of the sub-urethral sling procedures, the classical slings are indicated for patients with ISD and the less invasive tension-free vaginal tape (TVT) for patients with hypermobility [12]. Colposuspensions are still considered to be the gold standard surgical intervention for patients with hypermobility although high efficacy rates are also accompanied with increased invasiveness and complications rates. There is currently lack of consensus as to which surgical procedure is the best. This is due to the facts that the scientific evidence is weak as most data are derived from case series and that the methodological quality of many studies is poor with no consistency in efficacy and safety variables and definition of outcomes (e.g. different definitions of cure or success) used [13,14]. This makes comparison of the results from different studies with different surgical procedures very difficult. For more information on European guidelines for the initial diagnosis and treatment of UI in women, with emphasis on the International Consultation on Incontinence guidelines, the paper by Lars Viktrup and colleagues in this supplement provides an excellent overview [15]. It is clear that there is a need for a globally developed and widely approved pharmacological treatment option that has been proven to be effective and safe in well-designed, adequately powered RCTs. A pharmacological treatment designed to fill the treatment gap between PFMT on one hand (which requires long-term exercising and a highly motivated patient) and surgery (which is invasive and associated with intra- and post-operative complications for which patients are often afraid) on the other hand. One of such treatments may be the potent and balanced dual serotonin and norepinephrine (or noradrenaline) reuptake inhibitor (SNRI) duloxetine [16]. As outlined in this supplement by Karl Thor [17], the neurotransmitters serotonin and norepinephrine are believed to potentiate the effect of glutamate in Onuf's nucleus in the sacral spinal cord on stimulating the efferent activity of the pudendal nerve during bladder filling. This causes stimulation of nicotinic receptors in the striated urethral sphincter (or rhabdosphincter) and increased contraction of this sphincter thereby overriding increased intra-abdominal pressure during stress activities. By inhibiting the reuptake of serotonin and norepinephrine, duloxetine increases the concentration of these two neurotransmitters in the synaptic cleft in the CNS. It has been shown that this increases bladder capacity and induces an eight-fold increase in electromyography (i.e. rhabdosphincter) activity in an in vivo cat irritated bladder model [17,18]. That these effects are beneficial in women with SUI is demonstrated in the review in this supplement by Kate Moore on duloxetine's efficacy and safety in RCTs [19]. In phase two and phase three clinical trials almost 2000 patients were treated with placebo or duloxetine 80 mg/day (40 mg twice daily) for 12 weeks. Duloxetine provided a very fast (maximal effects within 1–2 weeks) increase in incontinence episode frequency and incontinence-related QoL, independent of incontinence severity at baseline. This was associated with an increase in mean time between voids and these effects were highly appreciated by the patients. The most common adverse event was nausea but this is experienced soon after start of therapy (usually within days), of mild to moderate intensity and transient as it resolves in most patients within 1–4 weeks. It, therefore, seems that duloxetine is a very promising new pharmacological treatment approach for women suffering from SUI.

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