Duloxetine in the context of current needs and issues in treatment of women with stress urinary incontinence

Authors

  • L Cardozo

    Corresponding author
    1. King's College Hospital, London, UK
      Prof. L Cardozo, King's College Hospital, Urogynaecology Department, 8 Devonshire Place, London WIG 6HP, UK. Email lcardozo@compuserve.com
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Prof. L Cardozo, King's College Hospital, Urogynaecology Department, 8 Devonshire Place, London WIG 6HP, UK. Email lcardozo@compuserve.com

Introduction

Urinary incontinence (UI), the involuntary leakage of urine,1 is common, especially among women.2 UI mainly manifests as stress urinary incontinence (SUI), mixed urinary incontinence (MUI) or urge urinary incontinence (UUI).1 SUI has been defined as the complaint of involuntary leakage of urine upon effort or exertion, or on sneezing or coughing.1 SUI is the most prevalent type of UI in younger and middle-aged women.3

The symptom of SUI is not life-threatening, but it can disrupt a woman's life. Being most common among women who are at an age when they wish to lead an active working and social life, SUI is likely to be bothersome and to impair quality of life (QoL). Women with the symptom of SUI report a considerably negative impact on daily and social activities, self-perception, personality and confidence.4 Furthermore, SUI may jeopardise sexuality and sports activities.5,6 Being incontinent is also associated with feelings of depression and loneliness.7

Despite the often considerable impact of SUI on QoL, only one in three incontinent women consults a doctor concerning her incontinence (1Figure 1).8 Even among women who consider their incontinence moderately to extremely bothersome, only 56% had ever talked to a doctor about this problem.9 Reasons for not seeking treatment include embarrassment, lack of knowledge about treatment options and the common belief that incontinence constitutes an unavoidable part of ageing or following childbirth. In contrast, seeking treatment for UI is associated with the negative impact it has on QoL, lack of embarrassment, having spoken to others about UI, a positive attitude towards health care and willingness to take long-term medication (1Table 1).8,10

Figure 1.

Percentage of incontinent women who consulted a doctor about their UI problem.8

Table 1.  Predictors of help-seeking behaviour among women with UI. Multivariable analyses adjusted for age, UI duration and frequency, and women's perception of bother caused by their UI8
VariableComparatorReferenceAdjusted OR (95% CI)
Acceptability level of surgerySomeNot at all1.3 (1.0–1.6)
UI accidentYesNo1.4 (1.1–1.9)
Use of padsYesNo1.5 (1.2–2.0)
Embarrassment level in discussing UI with doctorNot at allSome1.7 (1.3–2.1)
Number of visits to doctor≥3/year0–2/year2.1 (1.6–2.9)
UI will get worse no matter what I doNoYes2.3 (1.3–4.1)
Spoken to others about UIYesNo3.5 (2.5–4.9)
Willingness to stay on medicationYesNo7.0 (4.2–11.8)

Unmet needs in the management of SUI

Even among incontinent women who seek help, only a minority actually receive treatment. A survey in 2004 showed that approximately 30% of incontinent women had consulted a doctor for their problem, only 5% were taking medication(s), 8% had undergone incontinence surgery and 50% used absorbent pads.3 Pad use was routinely recommended as a treatment for UI by family practitioners and internists in another study.11 This study reported that only 17% of the physicians were aware of clinical guidelines for treating UI.11 Diokno et al.9 reported that 23% of incontinent women who consulted a doctor were told that their symptoms were normal for their age and 7% of the women received no explanation, treatment or evaluation.9 Most women who consult a doctor indicate that they, and not the doctor, had to raise the issue of UI.10 Hence, doctors could play an important role in disclosing UI by proactively asking about possible urinary symptoms, especially in high-risk groups, and inform women about the possible treatment options for their incontinence problem.

Duloxetine in the context of current needs and issues in treatment of women with SUI

To date, SUI has been treated conservatively by means of pelvic floor muscle training (PFMT) and lifestyle interventions such as weight loss, regulating fluid intake and smoking cessation.12 Failure of conservative treatment options may result in doctor/patient discussions about surgical intervention. Until recently, pharmacological options have been limited to the off-label use of several medications including oestrogens, α-adrenergic receptor agonists, β-adrenergic antagonists, tricyclic antidepressants and anticholinergics. However, these medications have questionable efficacy and are often associated with adverse effects.13 The development of the relatively balanced serotonin and noradrenaline reuptake inhibitor (SNRI) duloxetine has increased the treatment options for SUI. Duloxetine is the only widely approved drug for SUI and is available in over 30 countries including many in Europe. Hence, duloxetine may help fill the gap in the management of SUI.

The subsequent papers in this issue provide more insight into duloxetine's mechanism of action, efficacy in various patient profiles and safety. Prof. Bernhard Schuessler explains duloxetine's mechanism of action in women with SUI. The concept of using an SNRI for SUI relies on insights into the neurourological control of the lower urinary tract. Animal studies have shown that serotonin (5-hydroxytryptamine [5-HT]) and noradrenaline (NA) in the sacral spinal cord facilitate rhabdosphincter (external urethral sphincter) activity and prevent urine leakage during the storage phase of the micturition cycle.14 Importantly, 5-HT and NA exert only a modulatory effect as they are not able to directly excite motor neurons. Glutamate is the key descending neurotransmitter that can be considered as the ‘on/off’ switch for the micturition reflex. During glutamate release, which occurs in the storage phase, duloxetine enhances rhabdosphincter activity, thereby strengthening sphincter closure. During the voiding stage, which occurs in the absence of glutamate, duloxetine allows relaxation of the rhabdosphincter, thereby allowing voiding. Although there is a paucity of data regarding the mechanism of action of duloxetine in humans, clinical trials suggest that duloxetine enhances urethral closure through neuromodulation of the rhabdosphincter. In addition, the efficacy of duloxetine in women with SUI has been proven in several randomised controlled trials.15–18

Subsequently, Dr. Robert Freeman discusses the initial management of SUI according to the revised guidelines of the International Consultation on Incontinence (ICI).12 These revised guidelines recommend complementing conservative therapy with appropriate drug therapy, i.e. an SNRI such as duloxetine for the initial management of women with the symptom of SUI.19 There is level 1 evidence giving duloxetine a grade A recommendation from the pharmacological committee of the third ICI, Monaco, 2004.19

PFMT as a first-line therapy for SUI comprises strength and skill training.20 Strength training is believed to improve urethral compression during activity and overall decreases the frequency of incontinence episodes with time. Skill training involves learning to contract the muscles during events that might cause urine leakage, reducing the amount of leakage. In contrast to strength training, effects are almost immediate.21 The efficacy of PFMT depends on motivation and compliance, but unfortunately, the latter is often poor in the long term, with few women continuing PFMT.22 The combination of PFMT and duloxetine might be helpful as the former can strengthen and support the pelvic floor, while the latter can improve sphincter function. A study in 2005 primarily comparing the effect of combined treatment of duloxetine and PFMT with sham treatment found that combination therapy was significantly better than no treatment for all outcomes, including incontinence frequency.23 In addition, combined treatment induced a significant reduction in pad use and significant improvements in QoL scores.23 Hence, combination therapy may produce additive benefits in the treatment of women with SUI.

Prof. Harold Drutz presents data on the efficacy of duloxetine in various patient profiles. Results from one phase II trial 17 and three phase III trials15–18 have shown duloxetine to be significantly more effective than placebo in reducing incontinence episode frequency (IEF) and improving QoL scores in women with moderate (defined as <14 incontinence episodes per week) as well as severe SUI (≥14 incontinence episodes per week). Pooled analysis showed that the women in the duloxetine-treated group achieved a 52% reduction in IEF against 33% for the women in the placebo group, as well as an improvement of 9.2 in mean total Incontinence Quality of Life (I-QOL) score as compared with 5.9 in women in the placebo group (P < 0.001).15–18 The efficacy of duloxetine did not depend on incontinence severity or previous treatment experience in contrast to the placebo response; a trend for a lower placebo response in women with more severe SUI and those who had undergone previous surgery or PFMT was observed.24 Another study assessed the efficacy of duloxetine in women with severe SUI (≥14 weekly incontinence episodes), who were on a waiting list for surgery.25 In line with the data from the other trials, duloxetine induced significant decreases in IEF as well as improvements in I-QOL score. In addition, a significant reduction in pad use was reported for duloxetine-treated women compared with women on placebo.25 Duloxetine was equally effective in women with and without intrinsic sphincter deficiency. All duloxetine responses were observed within 2 weeks. Importantly, 20% of the duloxetine-treated women indicated that they were no longer interested in SUI surgery.

Last, Prof. Martin Michel discusses the tolerability and safety profile of duloxetine and puts this into clinical perspective. Inhibition of 5-HT and NA reuptake is not only the basis of duloxetine's efficacy in SUI, but it is also the cause of its adverse effects. The most common adverse effect of duloxetine is nausea, which occurs in around 23% of women.15–18 However, nausea tends to be of mild to moderate intensity and resolves within 1 month in the majority of women. Other frequently reported adverse events comprise dry mouth, fatigue, insomnia, constipation, headache and dizziness occurring in 9–13% of women. These adverse events are consistent with duloxetine's receptor physiology and are typical for 5-HT reuptake inhibition.26,27 Most common adverse event-related treatment discontinuations were due to nausea, dizziness, fatigue and insomnia (1–6% of women).15–18 The fact that most women affected by nausea continued the study indicates that nausea is not perceived as a serious adverse event by most women. In addition, women counselling about potential transient nausea may improve treatment adherence. A dose-escalation study showed that some women may benefit from starting treatment at a dose of 20 mg twice daily for 2 weeks before increasing to the recommended dose of 40 mg twice daily.28 Dose escalation may decrease, although not eliminate, the risk of nausea and dizziness.

Studies have shown that duloxetine has not been associated with obstructive voiding symptoms nor with acute urinary retention requiring catheterisation.29 In addition, no serious cardiovascular effects have been reported when treating women with duloxetine.15,16,18,25,30 In contrast, older uptake inhibitors, such as tricyclic antidepressants, are known to cause cardiac arrhythmias, especially in high doses.31 Duloxetine is not associated with elevated moods such as mania in non-depressed women.32 In general, duloxetine has an adverse effect profile typical for an SNRI and is safe and well tolerated.

Conclusions

SUI is common in women and often has a negative impact on their QoL. Despite the bother caused by SUI, few women consult a doctor. This is mainly due to embarrassment, lack of knowledge about treatment options and fear of surgery. The fact that most women who consult a doctor have to initiate the discussion themselves highlights the importance of doctors proactively inquiring about urinary symptoms.

Until recently, available therapy for SUI was limited to conservative treatment options such as PFMT and lifestyle interventions. The development of the SNRI duloxetine has broadened treatment options to include safe and effective pharmacotherapy. Duloxetine has proven efficacy in a wide range of women with SUI, irrespective of underlying condition or previous treatment. The combination of duloxetine with PFMT may yield additive benefit compared with either treatment alone.

The most common adverse effect is nausea, which is consistent with duloxetine's mechanism of action. However, nausea is usually mild to moderate and, importantly, transient. Dose escalating may reduce, although not eliminate the risk of nausea and dizziness. Patient counselling may increase treatment compliance. Complementing duloxetine with PFMT may provide additional benefit compared with either treatment alone.

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