ReviewNew drug treatments for urinary incontinence
Introduction
Urinary incontinence, the ‘complaint of any involuntary leakage of urine’ [1] is a common and distressing condition known to adversely affect quality of life (QoL) [2] which is often under-reported and under treated.
The prevalence of urinary incontinence has been reported in a large epidemiological study of 27,936 women from Norway [3]. Overall 25% of women reported urinary incontinence of which 7% felt it to be significant and the prevalence was found to increase with age. When considering the type of incontinence, 50% of women complained of stress, 11% urge and 36% mixed incontinence.
Whilst a conservative approach to the management of urinary incontinence is justified in almost all cases drug therapy remains integral in women complaining of overactive bladder (OAB) and has more recently become a treatment option in women with bothersome stress urinary incontinence.
The aim of this paper is to provide a comprehensive overview of the medical management of women with urinary incontinence.
Section snippets
Overactive bladder
Overactive bladder (OAB) is the term used to describe the symptom complex of urgency with, or without urge incontinence, usually with frequency and nocturia [1]. Epidemiological studies have reported the overall prevalence of OAB in women to be 16.9% suggesting that there could be 17.5 million women in the United States of America who suffer from the condition. The prevalence increases with age, being 4.8% in women under 25 years to 30.9% in those over the age of 65 years [4]. This is supported
Oxybutynin
Oxybutynin is a tertiary amine that undergoes extensive first-pass metabolism to an active metabolite, N-desmethyl oxybutynin [8] which occurs in high concentrations [9] and is thought to be responsible for a significant part of the action of the parent drug. It has a mixed action consisting of both an antimuscarinic and a direct muscle relaxant effect in addition to local anaesthetic properties.
The effectiveness of oxybutynin in the management of patients with detrusor overactivity is well
Tolterodine
Tolterodine is a competitive muscarinic receptor antagonist with relative functional selectivity for bladder muscarinic receptors [20] and whilst it shows no specificity for receptor subtypes it does appear to target the bladder over the salivary glands [21]. The drug is metabolised in the liver to the 5-hydroxymethyl derivative which is an active metabolite having a similar pharmacokinetic profile and is thought to significantly contribute to the therapeutic effect [22].
Several randomised,
Imipramine
Imipramine has been shown to have systemic anticholinergic effects [58] and blocks the re-uptake of serotonin. Some authorities have found a significant effect in the treatment of patients with detrusor overactivity [59] although others report little effect [60]. In light of this evidence and the serious adverse effects associated with tricyclic anti-depressants their role in detrusor overactivity remains of uncertain benefit although they are often useful in patients complaining of nocturia or
Desmopressin
Desmopressin (1-desamino-8-d-arginine vasopressin; DDAVP) is a synthetic vasopressin analogue. It has strong anti-diuretic effects without altering blood pressure. The drug has been used primarily in the treatment of nocturia and nocturnal enuresis in children [61] and adults [62]. More recently nasal desmopressin has been reported as a ‘designer drug’ for the treatment of daytime urinary incontinence [63]. Desmopressin is safe for long term use, however the drug should be used with care in the
NICE guidelines
The medical management of OAB has recently been reviewed in the UK by the National Institute for Health and Clinical Excellence (NICE) [64]. In the first instance bladder retraining lasting for a minimum of 6 weeks should be offered to all women with mixed or urge incontinence. In those women who do not achieve satisfactory benefit from bladder retraining alone the combination of an antimuscarinic agent, in addition to bladder retraining should be considered.
When considering drug therapy
Stress urinary incontinence
The term urinary stress incontinence may be used to describe the symptom or sign of urinary leakage on coughing or exertion but should not be regarded as a diagnosis. A diagnosis of urodynamic stress incontinence (USI) may only be made after urodynamic investigation and this is defined as the involuntary leakage of urine during increased abdominal pressure in the absence of a detrusor contraction [1].
Whilst various agents such as α1 adrenoceptor agonists, oestrogens and tricyclic
Duloxetine
Duloxetine is a potent and balanced serotonin (5-hydroxytryptamine) and noradrenaline reuptake inhibitor (SNRI) which enhances urethral striated sphincter activity via a centrally mediated pathway [65]. The efficacy and safety of duloxetine (20 mg, 40 mg, 80 mg) has been evaluated in a double-blind randomised parallel group placebo-controlled phase II dose finding study in 48 centres in the United States involving 553 women with stress incontinence [66]. Duloxetine was associated with significant
Oestrogens in the management of incontinence
Oestrogen preparations have been used for many years in the treatment of urinary incontinence [70], [71] although their precise role remains controversial. Many of the studies performed have been uncontrolled observational series examining the use of a wide range of different preparations, doses and routes of administration. The inconsistent use of progestogens is also a further confounding factor making interpretation of the results difficult.
Systemic oestrogen therapy
The role of systemic oestrogen replacement therapy in the prevention of ischaemic heart disease was assessed in the 4-year randomized Heart and Estrogen/progestin Replacement Study (HERS) [72] involving 2763 postmenopausal women younger than 80 years with intact uteri and ischaemic heart disease. In the study 55% of women reported at least one episode of urinary incontinence each week, and were randomly assigned to oral conjugated oestrogen plus medroxyprogesterone acetate or placebo daily.
Oestrogens in the management of stress urinary incontinence
Oral oestrogens have been reported to increase the maximum urethral pressures and lead to symptomatic improvement in 65–70% of women [76], [77] although other work has not confirmed this [78], [79]. In addition two placebo-controlled studies have been performed examining the use of oral oestrogens in the treatment of urodynamic stress incontinence in postmenopausal women. Neither conjugated equine oestrogens and medroxyprogesterone [80], or unopposed oestradiol valerate [81] showed a
Oestrogens in the management of overactive bladder
Oestrogens have been used in the treatment of urinary urgency and urge incontinence for many years although there have been few controlled trials to confirm their efficacy. A double-blind placebo-controlled crossover study using oral oestriol in 34 postmenopausal women produced subjective improvement in 8 women with mixed incontinence and 12 with urge incontinence [83]. However, a double-blind multicentre study of the use of oestriol (3 mg/d) in postmenopausal women complaining of urgency has
Oestrogen therapy—Cochrane review
The most recent meta-analysis of the effect of oestrogen therapy on the lower urinary tract has been performed by the Cochrane group [90]. Overall 33 trials were identified, including 19 313 incontinent women (1262 involved in trials of local administration) of which 9417 received oestrogen therapy.
Overall systemic administration (of unopposed oral oestrogens) resulted in worse incontinence than on placebo (RR 1.32; 95% CI: 1.17–1.48) although this result is heavily influenced by the weight of
Conclusion
Pharmacological therapy, in addition to bladder retraining remains important in the management of women with symptoms of the overactive bladder and has a more limited role in women with stress urinary incontinence. Whilst tolerability has previously limited compliance the development of long acting agents with an improved adverse event profile has improved this substantially. The development of new M3 specific and bladder selective muscarinic antagonists may also further improve efficacy and
Contributor
Linda Cardozo wrote the manuscript, edited and proof read prior to submission.
Competing interest
Dudley Robinson—Consultancy Fees and Speaker Honoraria: Astellas, Ferring, Pfizer, Uroplasty, Gynaecare, Novo Nordisk, SEP. Research: Astellas, Pfizer, Allergan, Plethora. Linda Cardozo—Consultancy Fees and Speaker Honoraria: Astellas, Pfizer, Rotapharm, Schering-Plough, SEP. Research: Astellas, Pfizer, Allergan, Plethora.
Provenance and peer review
Commissioned and externally peer reviewed.
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