Current drug treatments for female urinary incontinence Tarang Majmudar MRCOG and Mark Slack MMed, FRCOG, FCOG(SA)

Transcription

1 Drug review Incontinence Current drug treatments for female urinary incontinence Tarang Majmudar MRCOG and Mark Slack MMed, FRCOG, FCOG(SA) Skyline Imaging Ltd Several new drug treatments are now marketed for incontinence with improved efficacy and reduced side-effects. Our Drug review discusses the range of drugs currently available to treat this condition, followed by a review of prescription data, sources of further information and the Datafile. The population of older people is increasing and with it are growing numbers of patients suffering from urinary incontinence. About 16 per cent of adults have symptoms of an overactive bladder, with prevalence rising to 35 per cent in those over 75 years. 1 Ever-increasing patient expectations put GPs under pressure to prescribe effective treatment without unwanted side-effects. Unfortunately, the majority of drugs available to treat bladder complaints are not organ specific and systemic side-effects limit their use. Recent advances in bladder pharmacotherapy, however, have improved both efficacy and tolerability. Overview of bladder function The bladder acts as both a storage and voiding organ. Continence is maintained by a combination of relaxation of the detrusor muscle and contraction of the urethral sphincter. Prescriber 5 December

2 pontine micturition centre cortical control anticholinergics antimuscarinics, eg oxybutynin antidepressants, eg imipramine Stress urinary incontinence The commonest type of storage problem is stress urinary incontinence (SUI). This is the involuntary loss of small amounts of urine in the presence of raised intra-abdominal pressure. It typically presents with leakage on laughing, coughing, exercise, etc, and is usually caused by weakening of the pelvic floor secondary to childbirth. S 2-4 pelvic nerve pudendal nerve S 2,S 3 (pelvic floor and external urethral sphincter) alpha-1 adrenergic innervation (rhabdosphincter) alpha-blockers may cause SUI Figure 1. Nerve pathways associated with incontinence. When the bladder is full, impulses pass to the pontine micturition centre, triggering the micturition reflex. Efferent impulses stimulate relaxation of the involuntary urethral sphincter and the pelvic floor, and the detrusor muscle contracts as a result of acetylcholine acting on muscarinic receptors. The micturition reflex can be inhibited by higher cortical control leading to urethral closure via the voluntary external urethral sphincter. Anticholinergic drugs block the action of acetylcholine on detrusor receptors. Duloxetine-mediated stimulation of alpha-1 adrenergic receptors treats SUI. When the bladder is full, afferent impulses pass to the pontine micturition centre and, if uninhibited, the micturition reflex commences. Efferent impulses stimulate relaxation of the involuntary urethral sphincter and the pelvic floor. The detrusor muscle is made to contract under the influence of acetylcholine acting on muscarinic receptors. Urethral pressure falls below bladder pressure and voiding begins. If the time or place for voiding is inappropriate the micturition reflex is inhibited by higher cortical control and voiding is deferred. In this situation the voluntary external urethral sphincter may be brought into play to enhance urethral closure and maintain continence (see Figure 1). Types of incontinence Bladder disorders requiring pharmacotherapy can be broadly divided into storage and voiding disorders. This review concentrates on problems of storage, as a complete discussion about voiding dysfunction is beyond the scope of this article. Urge incontinence The second commonest type of storage disorder is an overactive bladder or urge incontinence. This is urinary leakage accompanied by a very strong desire to pass urine and is usually associated with urinary frequency and nocturia. Overactive bladder results from detrusor contractions during bladder filling. The majority of cases are idiopathic, although there is an association with neurological disease and bladder outflow obstruction. Management of storage disorders As with any condition, initial assessment should include a thorough medical history and physical examination and urinalysis. A bladder diary charting fluid input, urine output and symptoms is helpful and should be completed for at least 48 hours. In the absence of significant neurological disease, previous incontinence surgery and other complicating factors, urodynamic investigations are unnecessary at this stage (see Table 1). Currently nonpharmacological management centres on dietary modification, pelvic floor exercises and bladder retraining (see Table 2). 2 Drugs used to treat urge incontinence Standard classification of drugs for this disorder is according to the drug type and action. Other distinguishing characteristics are the degree of selectivity they express and the mode of release in the body (see Table 3). The side-effects of the antimuscarinic group of drugs depend on the following characteristics: amine group, muscarinic receptor selectivity and speed of release. Quaternary amines, eg trospium chloride (Regurin), are less lipophilic than tertiary amines, eg tolterodine (Detrusitol), and as such have less penetration into the CNS. In older people, somnolence and cognitive impairment are recognised complications of anticholinergic therapy, and quaternary amines may reduce this. 3 It is believed that most smooth-muscle contraction, including that of the bladder, is mediated by muscarinic receptors. Five subtypes (M1-M5) have been 24 Prescriber 5 December

3 History frequency? nocturia? urgency/urge incontinence? stress incontinence? urinary flow? General examination abdominal pelvic neurological Voiding diary Urinalysis Table 1. Primary assessment of incontinence identified and the M3 subtype is prevalent in the bladder. Theoretically, subtype selectivity will treat the overactive bladder while minimally affecting other receptor subtypes in other parts of the body and so reduce the associated side-effects experienced with nonselective preparations. By changing the drugs to an extendedrelease capsule formulation the side-effect profile has been reduced without a reduction in efficacy. New routes of administration have been investigated and have demonstrated pleasing reductions in the side-effect profile. The only transdermal product available is oxybutynin (Kentera). It is known that calcium-channel blockers have an effect on bladder smooth muscle. Propiverine (Detrunorm) has antimuscarinic and calcium-channel blocking properties and is now available as an alternative to other drugs in the treatment of detrusor overactivity. Antidiuretic drugs decrease urine production. Desmopressin, a synthetic antidiuretic hormone (ADH) analogue used for treating nocturnal enuresis, has recently been used to control daytime frequency (unlicensed indication). Narrow-angle glaucoma is an absolute contraindication to all antimuscarinic drugs, although openangle glaucoma poses no problems. All antimuscarinics can precipitate oesophageal reflux and there is a risk of urinary retention in patients with poor detrusor function. Unfortunately, although there are many drugs used in the treatment of overactive bladder, most have not been fully evaluated in randomised, controlled trials. In many of these trials there is a high placebo response, and there have been difficulties demonstrating the differences between the drug and the placebo. 4 Antimuscarinic drugs Antimuscarinic drugs are the mainstay of treatment for urge incontinence. They relax the detrusor muscle and increase bladder capacity by diminishing unstable detrusor contractions. Unfortunately, many of the commonly-cited studies are of poor quality and the placebo effect is high, rising above 35 per cent in many trials. 5 Oxybutynin hydrochloride This is one of the oldest anticholinergics available. This tertiary amine blocks the muscarinic effects of acetylcholine and has some selectivity for the M1 and M3 muscarinic receptors. It also acts as a direct muscle relaxant and has local anaesthetic properties. Unfortunately, when administered as an immediate-release formulation its side-effect profile, which includes dry mouth, blurred vision, constipation and reflux, limits its use. Up to 80 per cent of patients will experience side-effects, with less than 20 per cent continuing treatment beyond six months. 6 This aside, the treatment is effective and useful as a short-term measure to gain symptom control when most needed, eg holidays and long journeys. Extended-release (ER) oxybutynin (Lyrinel XL) has the potential benefits of once-a-day administration and avoidance of fluctuations in serum levels. Efficacy is similar to immediate-release oxybutynin, but there appears to be up to a 40 per cent reduction in sideeffects. 7 The usual dose is mg per day. Patients taking immediate-release oxybutynin can be transferred to the nearest equivalent daily ER dose. The introduction of this drug has all but replaced the immediate-release formulations, where use should be reserved for the indications mentioned above. Transdermal oxybutynin is now available as a patch (see Figure 2), which releases oxybutynin at approximately 3.9mg per day. The patch should be applied twice weekly. It has a significantly better tolerability compared with the oral route of administration. Oral oxybutynin undergoes extensive GI and hepatic metabolism to a primary active metabolite n-desethyloxybutynin, which is present in the circulation 4-10 times higher than the parent compound. It is this metabolite that is primarily responsible for the anticholinergic side-effects. With transdermal administration, this metabolite though still present due to hepatic metabolism is present only at a very low concentration. A multicentre study comparing transdermal vs immediate-release oral oxybutynin has shown comparable efficacy between the two and a significantly improved side-effect profile for the transdermal delivery system. Dry mouth occurred in significantly fewer 26 Prescriber 5 December

4 patients in the transdermal (38 per cent) compared with the oral group (94 per cent). 8 Tolterodine tartrate is not receptor selective but is thought to have a greater affinity for bladder smooth muscle than for salivary gland smooth muscle. It has a similar efficacy to oxybutynin but is better tolerated, with side-effects being reported in 50 per cent of patients compared to 86 per cent taking oxybutynin. 9 Some patients report difficulty with reflux oesophagitis, which can lead to discontinuation. Extended-release tolterodine (Detrusitol XL), with its improved tolerability, is also available. 10 When ER oxybutynin (10mg once daily) and ER tolterodine (4mg once daily) were compared, the latter appeared to be better tolerated. ER tolterodine also appears to be marginally more efficacious, with 70 per cent of patients reporting an improvement in bladder symptoms over an eight-week period, compared to 60 per cent of patients taking ER oxybutynin. 11 In contrast another randomised, controlled trial (Overactive bladder: Performance of Extended Release Agents, OPERA) that compared ER oxybutynin and ER tolterodine in 71 USA centres has shown that both these formulations are equally effective in reduction of weekly and total urge incontinence episodes. In the oxybutynin group, urinary frequency was significantly lower and the percentage of women reporting no urge incontinence episodes was significantly higher compared with the tolterodine group. Dry mouth was more common with oxybutynin, but tolerability was otherwise comparable, with both groups having similar discontinuation of treatment rates. 12 A comparative study of ER tolterodine and transdermal oxybutynin has shown similar efficacy in improving symptoms and quality of life. Systemic anticholinergic side-effects occurred more frequently in the tolterodine group (dry mouth: 7.3 vs 4.1 per cent). Transdermal oxybutynin was, however, associated with application site reactions in some patients. 13 Trospium chloride is a quaternary ammonium compound with predominantly nonselective antimuscarinic effects. The usual dosage is 20mg twice daily Prescriber 5 December

5 Dietary reduce caffeine avoid excessive fluid intake Nonpharmacological bladder retraining pelvic floor exercises Pharmacological 1-month trial with anticholinergic if unsuccessful, try second-line anticholinergic Table 2. Primary management of incontinence includes bladder retraining as well as pharmacological treatment and, like oxybutynin, the most commonly reported side-effect is dry mouth. Because of its quaternary structure and low lipophilicity it has significantly less CNS side-effects than other antimuscarinic agents. Trospium has performed well in clinical trials. In placebo-controlled trials the drug has been found to cause significant improvement in symptoms and urodynamic parameters. 14, 15 In comparative studies with oxybutynin, both drugs showed comparable improvement in urodynamic parameters; however, trospium was better tolerated. 16, 17 In a comparative study with tolterodine, efficacy and safety of both were comparable. 18 While the available clinical data on trospium is relatively scarce, it appears to be a safe and effective drug, and should certainly be considered as an alternative therapy in patients who are unable to tolerate oxybutynin or tolterodine. Because of its low incidence of CNS side-effects it may be of advantage in older patients. Propiverine, a tertiary amine, acts as both an anticholinergic and a calcium-channel blocker. The recommended dose is 15mg once to three times daily, increasing to a maximum of four times daily depending on the response. Despite its relatively infrequent use it has been shown to be as efficacious as oxybutynin 19 and ER tolterodine, 20 with possibly a more favourable sideeffect profile over oxybutynin. It may be used as an alternative to first-line treatments. Further comparative studies are required to evaluate its potential fully. Detrunorm XL is a modified-release preparation of propiverine. The recommended dose is one 30mg capsule daily. Solifenacin succinate (Vesicare) is a new once-daily oral antimuscarinic agent that has functional selectivity for the bladder over other organs. In-vitro and in-vivo studies have indicated relative selectivity for the bladder compared with the salivary glands, which was greater than that demonstrated by tolterodine and oxybutynin. 21, 22 Solifenacin at doses of 5-10mg per day significantly improves all major symptoms of overactive bladder. Solifenacin at 10mg per day also decreases frequency of nocturia. Overall, solifenacin has a good tolerability profile and a low incidence of dry mouth, especially at the 5mg starting dose. 23 It is superior to tolterodine ER as regards efficacy in treating overactive bladder. Urgency episodes, urge incontinence and pad usage are significantly lower than with tolterodine, and the patient s overall perception of improvement is greater with solifenacin. The side-effects in both groups are low and comparable. 24 TCAs TCAs have been used successfully in the management of overactive bladder symptoms, especially nocturia. Imipramine is the most widely used, gaining popularity from its efficacy in the treatment of bedwetting in children. It has marked systemic anticholinergic properties and blocks the reuptake of serotonin and noradrenaline. It may be particularly useful in patients with refractory nocturia. It is customary to start at a dosage of 25mg once daily. Dosage can be increased to 150mg but increasing side-effects will usually limit the maximum dose to 50mg at night. 25 Its use as a stand-alone treatment is limited by side-effects but it can prove a useful adjunct at night for people who experience a partial improvement on newer anticholinergics but still complain about nocturia. Care is needed in older people, who are particularly susceptible to side-effects, commonly drowsiness and postural hypotension. Antidiuretic drugs (desmopressin/ddavp) DDAVP (1-deamino-8-D arginine vasopressin) is a long-acting synthetic analogue of the natural hormone vasopressin. It is available as a nasal spray and in tablet form, although only the nasal spray is licensed for treating nocturnal enuresis. It acts like ADH by increasing the permeability of the renal collecting ducts, but without the systemic effects of vasopressin on blood pressure. Studies have shown a 50 per cent reduction in urine production with this drug. By reducing nocturnal urine production it is useful in alleviating troublesome nocturia, and it has been used for treating nocturnal enuresis in children and adults. 26 It is safe for long-term use, but is contraindicated in patients with cardiac disease, hypertension and epilepsy. A multicentre placebo-controlled study using DDAVP has shown it to be safe and effective in the treatment of daytime urinary incontinence. 27 This is 28 Prescriber 5 December

6 currently an unlicensed indication but can prove very efficacious in carefully assessed patients. The major complication with this product is hyponatraemia, and it is essential to check the electrolytes four days after initiating therapy. The use of this agent should, for the time being, be limited to specialist clinics. Hormone replacement therapy Oestrogens were recommended for use in the treatment of incontinence as early as Despite the theoretical advantages of this treatment there seems to be little evidence that they are effective in the treatment of lower urinary tract dysfunction. 28 Obviously if the patient has marked urogenital atrophy, it would seem sensible to add a course of topical oestrogen to the treatment. This has been shown to be of use in preventing recurrent urinary tract infections. 29 Drugs used to treat stress incontinence Stress incontinence is the most common form of urinary incontinence. Until now, pelvic floor exercises have been the cornerstone of conservative treatment for SUI. Success rates have been fairly modest and continued success depends on patient perseverance. Consequently, relapse rates are very high. Surgery has much better success rates but it has been estimated that fewer than 5 per cent of women with the condition will undergo surgery. This may be related to concern over complications, risks or time lost from work or other activities. 30 Surgery can be associated with debilitating complications and therefore conservative therapy should always be offered ahead of an operation. Until recently, there had been no approved pharmacological option for the treatment of SUI. Several trials have now reported significant improvement in SUI with duloxetine (Yentreve). Duloxetine is a balanced dual serotonin (5-HT)-norepinephrine reuptake inhibitor. It increases bladder capacity and urethral sphincter activity. Duloxetine-mediated increase in urethral sphincter contraction is the underlying mechanism by which it prevents SUI. The normal final dosage is 40mg twice daily. By starting the patient on a dose of 20mg twice daily, the side-effect profile can be substantially reduced. Nausea is the commonest side-effect. It tends to be mild to moderate and usually resolves within a week to a month. However, it is also the commonest reason for discontinuing the treatment. There is no evidence that this drug causes voiding dysfunction. Phase III placebo-controlled trials worldwide have demonstrated significant improvement in incontinence episode frequency and quality of life scores Class of drug Antimuscarinic agents oxybutynin tolterodine trospium propiverine solifenacin TCAs imipramine Calcium-channel blockers flavoxate Antidiuretics desmopressin Mode of action inhibit bladder contractions by blocking the action of acetylcholine on detrusor muscarinic receptors selective M1- and M3-receptor antagonist antimuscarinic, direct muscle relaxant and local anaesthetic properties some tissue specificity greater affinity for detrusor muscle than salivary gland neither receptor nor tissue selective antimuscarinic and calcium-channel blocker antimuscarinic with bladder selectivity central and peripheral action anticholinergic activity blockade of reuptake of serotonin and noradrenaline alpha-adrenoceptor agonist mild antidiuretic properties inhibit bladder contractions by blocking the transmembrane influx of calcium ions calcium-channel blocker and local anaesthetic properties decrease in urine production increases glomerular reabsorption of water in the kidney Table 3. Mode of action of drugs used in urge incontinence within 12 weeks. 31, 32, 33 Duloxetine is equally efficacious in the treatment of severe SUI (incontinence episode frequency of >14 per week) as it is for moderate forms of SUI. 34 Iatrogenic SUI Drugs acting on the urethral sphincter can precipitate urinary incontinence. The most common occurrence is with the use of alpha-blockers in women with hypertension. Such drugs should be stopped and treatment with alternative therapies initiated before the patient is referred for investigation or treatment. Voiding disorders A failure to empty the bladder efficiently can lead to urinary retention, which ultimately may result in overflow incontinence. Such problems are associated with prostatic hypertrophy in men and are rarely seen in women, unless associated with previous incontinence surgery or neurological disease. continued on page 32 Prescriber 5 December

7 Figure 2. Kentera (transdermal oxybutynin) has similar efficacy to immediate-release oxybutynin but causes significantly less dry mouth; the patch should be applied twice weekly Drugs have little or no role in correcting voiding disorders in women, with the mainstay of treatment being the use of clean, intermittent self-catheterisation. Conclusion The cornerstones of treatment in primary care are bladder training, physiotherapy and pharmacotherapy. The ideal drug for the treatment of urinary incontinence has not yet been developed and adverse effects caused by the lack of lower urinary tract specificity result in many patients terminating current therapies prematurely. Extended-release anticholinergics have an improved side-effect profile. They are no more efficacious than their immediate-release counterparts but the improvement in quality of life associated with the reduced side-effect profile has improved their acceptability and, with it, compliance. Transdermal oxybutynin causes significantly less dryness of the mouth. Newer drugs like propiverine and solifenacin may be more efficacious and can be used as alternatives. All primary care practitioners should familiarise themselves with at least two of the newer drugs for the treatment of overactive bladder. This should include side-effect profile and dosage variation. Initiation of therapy should be accompanied by the introduction of dietary modification (reduction in caffeine intake) and bladder retraining. In choosing the initial drug there is no real evidence to support any of the newer drugs over each other. Response will differ from patient to patient, so if the first drug chosen is unsuccessful a better response may be achieved by changing to a different medication, even if it is from the same class of drug. If the second drug is also unsuccessful, the patient should be VM referred to a specialist team for investigation and management. Other instances where patients should be referred to a specialist are outlined in Table 4. Drug therapy for SUI has been licensed for use in moderate to severe cases, and clinical trials have demonstrated the efficacy of duloxetine. Furthermore, it has been shown that a combination of duloxetine and pelvic floor exercises is more effective than each of these interventions alone. With the numbers of people affected by these conditions it is important that the primary care teams have a pivotal role in the initial management. By doing this the limited secondary and tertiary services can be reserved for the worst affected. References 1. Milsom I, Abrams P, Cardozo L, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87: Wilson PD, Bo K, Bourcier A, et al. Conservative management of women (Committee 14). In: Abrams P, Cardozo L, Khouri S, et al, eds. Incontinence. Plymouth: Health Publication Ltd, Donnellan CA, Fook L, McDonald P, et al. Oxybutynin and cognitive dysfunction. BMJ 1997;315: Andersson KE, Appell R, Awad S, et al. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khouri S, eds. Incontinence. Plymouth: Health Publication Ltd; 2002: Herbison P, Hay-Smith J, Ellis G, et al. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003;326: Kelleher CJ, Cardozo LD, Khullar V, et al. A medium-term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol 1997;104: Birns J, Lukkari E, Malone-Lee JG. A randomised controlled trial comparing the efficiency of controlled-release oxybutynin tablets (10mg once daily) with conventional oxybutynin tablets (5mg twice daily) in patients whose symptoms were stabilized on 5mg twice daily of oxybutinin. BJU Int 2000;85: Davila GW, Daugherty CA, Sanders SW; Transdermal Oxybutynin Study Group. A short-term, multicenter, randomised double-blind dose titration study of the efficacy and anticholinergic side-effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary continence. J Urol2001;166: Abrams P, Freeman R, Anderstrom C, et al. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998;81: Van Kerrebroeck P, Kreder K, Jonas U, et al; Tolterodine Study Group. Tolterodine once-daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 32 Prescriber 5 December

8 Haematuria Recurrent proven urinary tract infections Sudden onset of severe urge symptoms Complicated history previous incontinence surgery associated prolapse neurological symptoms Failed pharmacotherapy Table 4. When to refer patients with incontinence 2001;57: Sussman D, Garely A. Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the Antimuscarinic Clinical Effectiveness Trial (ACET). Curr Med Res Opin 2002;18: Diokno AC, Appell RA, Sand PK, et al; OPERA Study Group. Prospective, randomised, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003;78: Dmochowski RR, Sand PK, Zinner NR, et al; Transdermal Oxybutynin Study Group. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology 2003;62: Cardozo L, Chapple CR, Toozs-Hobson P, et al. Efficacy of trospium chloride in patients with detrusor instability: a placebo-controlled, randomized, double-blind, multicentre clinical trial. BJU Int 2000;85: Zinner N, Gittelman M, Harris R, et al; Trospium Study Group. Trospium chloride improves overactive bladder symptoms: a multicentre phase III trial. J Urol 2004;171(6Pt1): Halaska M, Ralph G, Wiedemann A, et al. Controlled, double-blind, multicentre clinical trial to investigate longterm tolerability and efficacy of trospium chloride in patients with detrusor instability. World J Urol 2003;20: Madersbacher H, Stohrer M, Richter R, et al. Trospium chloride versus oxybutynin: a randomised, double-blind, multicentre trial in the treatment of detrusor hyperreflexia. Br J Urol 1995;75: Junemann KP, Al-Shukri S. Tolerability of trospium chloride and tolterodine in 234 patients with urge syndrome: a double-blind, placebo-controlled, multicentre clinical trial. Neurourol Urodyn 2000;19: (Abstract.) 19. Madersbacher H, Halaska M, Voigt R, et al. A placebocontrolled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU Int 1999;84: Junemann KP, Halaska M, Rittstein T, et al. Propiverine versus tolterodine: efficacy and tolerability in patients with overactive bladder. Eur Urol 2005;48(3): Hatanak T, Ukai M, Ohtake A, et al. In vitro tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary glands in rats and monkeys. International Continence Society Meeting, Florence, Italy 2003, abstract Ohtake A, Hanaka T, Ikeda K, et al. In vivo bladder selective profile of solifenacin succinate (YM905) over salivary gland in mice and rats. International Continence Society Meeting, Florence, Italy 2003, abstract Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. JUrol2004;172(5Pt1): Chapple CR, Martinez-Garcia R, Selvaggi L, et al; for the STAR study group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at treating overactive bladder syndrome: results of the STAR trial. Eur Urol 2005;48: Castleden CM, George CF, Renwick AG, et al. Imipramine a possible alternative to current therapy for urinary incontinence in the elderly. JUrol1981;125: Hilton P, Stanton SL. The use of desmopressin (DDAVP) in nocturnal urinary frequency in the female. Br J Urol 1982;54: Robinson D, Cardozo L, Akeson M, et al. Antidiuresis: a new concept in managing female daytime urinary incontinence. BJU Int 2004;93(7): Fantl JA, Bump RC, Robinson D, et al. Efficacy of estrogen supplementation in the treatment of urinary incontinence. The Continence Program for Women Research Group. Obstet Gynecol 1996;88: Cardozo L, Benness C, Abbott D. Low dose oestrogen prophylaxis for recurrent urinary tract infections in elderly women. Br J Obstet Gynaecol 1998;105: Brown JS, Waetjen LE, Subak LL, et al. Pelvic organ prolapse surgery in the United States, Am J Obstet Gynecol 2002;186: Dmochowski RR, Miklos JR, Norton PA, et al; Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. JUrol2003;170(4Pt1): Van Kerrebroeck P, Abrams P, Lange R, et al; Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. BJOG 2004;111: Millard RJ, Moore K, Rencken R, et al; Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. BJU Int 2004;93: Cardozo L, Drutz HP, Baygani SK, et al. Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Obstet Gynaecol 2004;104: Mr Majmudar is specialist registrar at Hinchingbrooke Hospital, Huntingdon, and Mr Slack is consultant gynaecologist at Addenbrooke s Hospital, Cambridge Prescriber 5 December

9 Prescription review GPs in England wrote 2.7 million scrips for drugs to treat urinary incontinence in the year to September 2006, at a total cost of 66.9 million. The market is dominated by oxybutynin (36 per cent of scrips, 19 per cent of spending) and tolterodine (45 per cent of scrips, 60 per cent of spending). Prescribing of solifenacin and duloxetine, introduced in the latter half of 2004, has increased gradually and accounted for 8 and 2 per cent of the total volume in the latest quarter respectively (see Figure 3). Total prescribing volume in this category has increased by over 40 per cent since the end of 2001 but spending has risen by 88 per cent. The number for scrips for oxybutynin has changed little but costs have risen by 50 per cent (see Figure 4). By contrast, scrips for tolterodine have increased by 67 per cent and spending by 84 per cent over the same period. Items (thousands) flavoxate oxybutynin propiverine tolterodine trospium duloxetine solifenacin Year by quarter Figure 3. Number of prescriptions for urinary incontinence drugs in England by quarter, Net ingredient cost ( million) 20 flavoxate oxybutynin propiverine tolterodine trospium duloxetine solifenacin Year by quarter Figure 4. Cost of drugs prescribed for urinary incontinence in England by quarter, Prescriber 5 December