Review Anticholinergic drugs for overactive bladder: a review of the literature and practical guide

Transcription

1 The Obstetrician & Gynaecologist /toag ;9:9 14 Review Review Anticholinergic drugs for overactive bladder: a review of the literature and practical guide Authors Nalini Munjuluri / William Wong / Wai Yoong Key content: Overactive bladder syndrome is a highly prevalent symptom complex that can be extremely distressing to women. It is associated with co-morbidities and reduced quality of life. Treatment involves behavioural therapy, physiotherapy and pharmacotherapy. There is robust and convincing evidence that anticholinergic agents are effective drug treatments. Possible adverse effects include disruption of cognitive function, dry mouth, constipation and blurred vision. Learning objectives: To know about the pharmacokinetics and pharmacodynamics of anticholinergic medications. To be able to prescribe them appropriately. To know about the differences in effectiveness between the newer anticholinergic drugs. Ethical issues: How much information should women be given about possible adverse effects? Keywords anticholinergic / antimuscarinic / overactive bladder / urge incontinence Please cite this article as: Munjuluri N, Wong W, Yoong W. Anticholinergic drugs for overactive bladder: a review of the literature and practical guide. The Obstetrician & Gynaecologist 2007;9:9 14. Author details Nalini Munjuluri MRCOG Specialist Registrar in Obstetrics and Gynaecology Department of Obstetrics and Gynaecology North Middlesex University Hospital London N18 1QX William Wong M Pharm MRPharm Senior Medical Informations Pharmacist North Middlesex University Hospital London N18 1QX Wai Yoong MD MRCOG Consultant in Obstetrics and Gynaecology Department of Obstetrics and Gynaecology North Middlesex University Hospital London N18 1QX wai.yoong@nmh.nhs.uk (Corresponding author) 9

2 Review 2007;9:9 14 The Obstetrician & Gynaecologist Figure 1 Neurological control of the filling and voiding phases of micturition Introduction Overactive bladder syndrome (OABS) is characterised by urgency, with or without urge incontinence, increased frequency of micturition ( 8 voids/day) and nocturia in the absence of another identifiable metabolic or pathological process affecting the lower urinary tract. 1 A population based study 2 suggests that around onesixth of adults over the age of 18 years report symptoms of OABS and the prevalence of these symptoms increases with age. One-third of them also have associated urge urinary incontinence. OABS is a highly prevalent condition that can be extremely distressing to women. It may be associated with co-morbidities such as urinary tract infections and sleep disturbances. Women with urge urinary incontinence are more likely to be depressed than those with stress urinary incontinence. 3 The elderly are also at increased risk of falls and fractures from rushing to the toilet. Common daily activities such as shopping, travel and physical exercise and personal relationships are often avoided because of fear of embarrassment. Many incontinent women develop coping mechanisms such as toilet mapping, frequent voiding and fluid restriction. As OABS has a negative impact on quality of life, there is a necessity for increased awareness, early diagnosis and appropriate treatment for this condition. This paper reviews the current anticholinergic pharmacotherapy, which is the mainstay of treatment for this condition. English language articles cited in MEDLINE from 1995 to 2006 were selected. Normal control of micturition Figure 1 demonstrates the neurological control of the filling and voiding phases, which is important in understanding the role of pharmacological agents. The bladder wall is lined with smooth (detrusor) muscle fibres interspersed with connective tissue. The internal urinary sphincter consists of the Brain Pons Parasympathetic S2,3,4 Bladder bladder neck and the proximal urethra itself. The bladder outlet consists of the internal sphincter and its surrounding striated musculature and is supported by the pelvic floor muscles. The periurethral striated muscle fibres and striated fibres around the internal sphincter constitute the external sphincter. The sympathetic nerves arise in the lateral horns of the spinal segments T1-L2. The parasympathetic innervation is from the S2, S3 and S4 spinal segments. The somatic motor innervation to the external urethral sphincter also arises from the S2, S3 and S4 spinal segments. This column of cells is called Onuf s nucleus. The control of micturition also comes from higher centres, including the brain stem (pons) and cerebral cortex. In the normal bladder, the detrusor and the interspersed connective tissue allow bladder filling during the storage phase with little or no change in the bladder pressure. 4 Sympathetic nerves, activated by the stretching urothelium, reduce the parasympathetic input and directly inhibit detrusor contractions. The sympathetic pathway also maintains tonic contraction of the urethral sphincters, thereby preserving continence. 5 The ultimate coordination of voiding is under control of the pontine micturition centre. When the bladder is full and it is socially convenient, the urethral sphincter and the pelvic floor relax and the bladder neck descends. This occurs early in the micturition phase. Simultaneously the intrinsic striated muscle of the urethra relaxes leading to a fall in intraurethral pressure. A few seconds later, the inhibitory input from the cerebral cortex on the sacral micturition centre is reduced allowing a rapid parasympathetic discharge. The detrusor muscle contracts as a response to this parasympathetic discharge. The intravesical pressure rises and when it is greater than the intraurethral pressure, voiding is initiated. 6 Treatment of OABS Treatment comprises patient education, bladder training, pelvic floor exercises and pharmacotherapy. Anticholinergic drugs remain the mainstay of pharmacotherapy. Other drugs used include imipramine, 7 desmopressin, 8 estrogens, 9 botulinum toxin 10 and intravesical vanilloids, such as capsaicin 11 and resiniferatoxin. 12 Thoracic Lumbar Sacral Sympathetic Onuf's nucleus Detrusor Internal sphincter External sphincter Pudendal nerve Anticholinergic (antimuscarinic) drugs Pharmacotherapy for OABS is based on inhibiting the action of acetylcholine, which stimulates detrusor contraction via muscarinic receptors. Five subtypes of muscarinic receptors within the 10

3 The Obstetrician & Gynaecologist 2007;9:9 14 Review Evidence level Drug Commercial names Cost Selectivity for efficacy Routes of delivery Oxybutynin Non proprietary IR 3.40 for 2.5 mg 56 tablet Selective, predominantly 1A Oral, transdermal, elixir Cystrin pack, 9.15 for 3 mg 56 tablet M1 and M3 Ditropan pack Kentera ER 6.20 Lyrinel XL Tolterodine Detrusitol IR 5.60 Non-selective 1 A Oral only ER Propiverine Detrunorm Non-selective 1 A Oral only Trospium Regurin Non-selective 1 A Oral only Solifenacin Vesicare Selective, predominantly M3 1 A Oral only Darifenacin In trials N/A Selective, predominantly M3 1 A Oral only ER extended release; IR immediate release Table 1 Commercial preparations of anticholinergics showing selectivity and levels of evidence of efficacy parasympathetic system have been identified. M2 and M3 receptors account for two-thirds and onethird, respectively, of the identifiable receptors in the bladder. M2 is the most common receptor within the bladder but M3 is more active in detrusor function. 13 M1 receptors are most abundant in the cerebral cortex and hippocampus. Inhibition of these receptors in the brain disrupts cognitive functions such as learning and memory. Non-selective anticholinergics also interfere with muscarinic function in other organ systems such as the eye and salivary glands. Broadly speaking, most anticholinergics relieve symptoms and have similar efficacy. 14 Adverse effects vary depending on receptor selectivity, peak serum levels and the route of delivery. Table 1 lists the selectivity, levels of evidence available for their efficacy and commercial preparations of anticholinergics. 15 Oxybutynin The highest affinity of oxybutynin is to M1 and M3 receptors. Most studies suggest that it reduces incontinence episodes by 55 83%. Adverse effects such as dry mouth, constipation and blurred vision are dose dependent and lead to discontinuation in up to 25% of patients. 16 Extended release (ER) preparations have fewer adverse effects but are of similar efficacy to immediate release (IR) preparations. 17 The transdermal route is comparable to IR preparations with a better adverse effect profile. The main adverse effect is pruritus at the site, which has been reported in 14% of patients. 18 Tolterodine Though non-selective, tolterodine appears to target bladder over salivary gland receptors. A pooled analysis of four studies between 1996 and 1998, which evaluated IR formulations of tolterodine (2 mg twice daily), oxybutynin (5 mg three times daily) and placebo found reductions in micturition frequency of 2.3, 2.0 and 1.4 per 24 hours, respectively. 19 Urge urinary incontinence episodes were also reduced. Adverse effects, particularly dry mouth, were more common with oxybutynin compared with tolterodine (78% versus 40%). Although tolterodine was deemed more efficacious, the clinical differences in outcome measures may not be that significant. Tolterodine ER was more effective than the IR preparation and had fewer reports of dry mouth. 20 The OPERA study 21 was a multicentre randomised controlled trial comparing tolterodine ER 4 mg (n = 399) and oxybutynin ER 10 mg (n 391). It showed similar reductions in mean weekly urge incontinence episodes. The frequency of micturition was significantly lower (28.4 versus 25.2) in the oxybutynin ER group. Both drugs had comparable tolerability except for a higher incidence of dry mouth with oxybutynin. The number of women discontinuing the study medication was similar in both groups. Trospium chloride This is an atropine derivative with predominantly antimuscarinic effects. It has a low incidence of central nervous system adverse effects because of its low solubility across the blood brain barrier. One randomised controlled trial 22 showed that urodynamic parameters were improved by 30% with trospium chloride compared with placebo. The frequency of adverse effects was similar in both groups. Trospium was shown to have similar efficacy to oxybutynin IR. However, those taking trospium reported a lower incidence of dry mouth (4% versus 23%) and were less likely to withdraw (6% versus 16%). 23, 24 Trospium has also been shown to have a similar efficacy and adverse effect profile to tolterodine IR. 25 Propiverine Propiverine has combined anticholinergic and calcium channel blocking actions and is the most commonly used drug for OABS in Germany, Austria and Japan. A multicentre randomised double blind placebo controlled trial 26 (n 366) compared propiverine IR against oxybutynin IR and a placebo. Both drugs were equally effective at increasing the maximum cystometric capacity and bladder volume at first desire. However, the incidence of dry mouth was lower with propiverine. There appears to be no significant difference in efficacy between IR and ER propiverine preparations. 27 Solifenacin This is a recent, once-daily antimuscarinic drug which has been shown to improve all the major symptoms of OABS. 28 When compared with placebo and tolterodine IR preparation in subjects, patients on solifenacin reported 11

4 Review 2007;9:9 14 The Obstetrician & Gynaecologist Table 2 Anticholinergic drugs used for OABS and drugs that can potentiate their adverse effects statistically significant reductions in the number of urgency episodes. Dry mouth was reported in 18.6% of patients with tolterodine, 14% with 5 mg of solifenacin and 21.3% with 10 mg of solifenacin. 29 The STAR trial 30 was a prospective, double blind study comparing 5 mg of solifenacin with 4 mg of tolterodine ER. After 4 weeks of treatment patients on solifenacin had the option to request an increase in dosage. This was not possible for those on tolterodine as the maximum dose is 4 mg. Primary efficacy analysis in this trial suggested that the reductions in the mean number of micturitions per 24 hours was comparable. When secondary end points were assessed, the solifenacin group had superior baseline to end point improvements in urgency, urge incontinence and overall incontinence compared with patients receiving tolterodine ER. The percentage of subjects discontinuing study medication due to adverse events was low and comparable for the two treatments. However, at the time of dose increase higher numbers of patients on solifenacin reported dry mouth and constipation. Darifenacin Darifenacin is a highly selective M3 receptor antagonist. A pooled analysis of phase III trials (n 1 059) reported significant reductions in the number of incontinence and urgency episodes and an increase in bladder capacity. Dry mouth and constipation were common adverse events. The discontinuation rate was higher in treatment groups compared with placebo. 31 As expected from its receptor selectivity, neurological and cardiac adverse effects were relatively uncommon and comparable to placebo. A randomised controlled trial of darifenacin versus oxybutynin IR reported that both active agents significantly reduced incontinence episodes and urgency episodes compared with placebo, with dry mouth being less frequent in the darifenacin group. 32 Adverse effects of anticholinergics The most common adverse effect is dry mouth, with a prevalence of about 30%. Oxybutynin IR is associated with more severe and frequent dry mouth episodes compared with other preparations, Anticholinergic agents Anti-emetics Drugs used for Parkinson s disease Antispasmodics Mydriatics/cyclopegics Drugs that can potentiate their adverse effects Anti-arrhythmics Antidepressants Antidiarrhoeal agents Antihistamines Antipsychotics Muscle relaxants while tolterodine ER seems to have the best tolerability profile. 33 Other adverse effects include constipation, blurred vision, nausea and vomiting, difficulty in micturition, palpitations, skin reactions, angioedema, arrhythmias and tachycardia. Effects on the central nervous system (CNS) such as disorientation, hallucination and convulsion can also occur. Anticholinergics may reduce sweating, leading to hyperthermia and fainting in hot environments. As other drugs with anticholinergic activity can potentiate these adverse effects (Table 2), the clinician has to be vigilant particularly in the elderly, in whom polypharmacy is common. Cautions Antimuscarinic drugs require caution in women with autonomic neuropathy, hiatus hernia and hepatic and renal impairment. They can worsen hyperthyroidism, coronary artery disease, congestive heart failure and arrhythmias. Contraindications Myasthenia gravis, glaucoma, significant bladder outflow obstruction or urinary retention, severe ulcerative colitis and gastrointestinal obstruction are contraindications to anticholinergic use. The role of IR preparations In a Cochrane Review, Hay-Smith, et al. 34 concluded that there were no statistically significant differences for cure/improvement, leakage episodes or micturition frequency in 24 hours between ER and IR regimens although, admittedly, the numbers in the study were low. Overall, ER preparations are associated with fewer adverse effects, particularly dry mouth, and may thus be preferable, although the discontinuation rates caused by adverse events were similar between the two formulations. In the current economic climate cost may be a factor in deciding between ER and IR preparations. Tolterodine ER compared with oxybutynin ER The OPERA study 21 compared tolterodine ER with oxybutynin ER and concluded that the latter significantly reduced micturition frequency in women but was also more commonly associated with mild dry mouth. Other end points were similar in the two groups: in particular, both drugs had comparable discontinuation rates. Solifenacin and darifenacin compared with other anticholinergics Chapple et al. 29 noted a statistically significant reduction in the number of urgency episodes with solifenacin 5 mg and 10 mg compared with Table 3 Likelihood of selected antimuscarinic agents crossing the blood brain barrier. 35 (With permission from Excerpta Medica, Inc.) TDS three times daily Agents likely to cross the blood brain barrier Agents unlikely to cross the blood brain barrier Drug Oral oxybutynin Oxybutynin TDS Darifenacin Tolterodine Trospium Lipophilicity Soluble Soluble Slight Very slight Low solubility Molecular weight Low Low High High High Polarity Neutral Neutral Positive Positive High 12

5 The Obstetrician & Gynaecologist 2007;9:9 14 Review tolterodine IR. Dry mouth was more common with solifenacin 10 mg. Subsequently, the STAR trial 30 showed that solifenacin showed a statistically superior improvement in secondary end points than tolterodine ER, although the significance of the results in everyday clinical practice is uncertain. Solifenacin has, so far, not been compared with oxybutynin. Darifenacin was shown to have equal efficacy and a similar adverse effects profile to oxybutynin IR. 32 The use of anticholinergics in nocturia Nocturia is a common and troublesome symptom which can be caused by medical conditions such as renal failure, hypercalcaemia and diabetes. Desmopressin, an analogue of antidiuretic hormone, is effective. It can, however, cause fluid overload and hyponatraemia. 8 Imipramine, a tricyclic antidepressant with anticholinergic effects, is beneficial. 7 Anticholinergic use in the elderly It is worrying that up to 32% of the elderly use two or more drugs with anticholinergic effects. 35 Those that spare M1 receptors have a lower impact on central nervous system function. The extent to which anticholinergics impair CNS function is proportional to their ability to cross the blood brain barrier, as shown in Table 3. Oxybutynin, a lipophilic molecule with neutral polarity, is the one most likely to cross the blood brain barrier. Despite this, it is still widely used to treat OABS in older patients because of the low cost. Newer agents such as tolterodine and darifenacin have low lipophilicity and are thought to be more suitable for older patients. Tolterodine IR and oxybutynin IR have a similar efficacy but the former has fewer adverse effects in patients over 50 years of age. 36 Trospium is the least likely to impair CNS function based on neuropsychological and coordination tests. 35 The role of combination therapy The authors have not found any evidence recommending or cautioning combined therapy using anticholinergics and other medication such as imipramine, although it would seem logical to combine the two in women with nocturia. Conclusions There is robust and convincing evidence that anticholinergic agents are effective drug treatments. However, many studies, although well designed and executed, have involved the older IR preparations, which may not be relevant any more. The newer, once-daily preparations such as solifenacin have comparable efficacy to oxybutynin. However, up to 25% of patients who start IR preparations 37 and 3% of patients who commence ER preparations 16 discontinue therapy because of adverse effects, therefore compliance is low. One recent European study 2 suggests that only 27% of people with OABS were receiving medication for their symptoms. The clinician needs to modify drug treatment according to the adverse effects experienced by their patients. References 1 Abrams P, Cardozo L, Magnus F, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function; report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21: doi: /nau Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001;87: doi: /j x x 3 Zorn BH, Montgomery H, Pieper K, Gray M, Steers WD. Urinary incontinence and depression. J Urol 1999;162:82 4. doi: / Abrams P. Describing bladder storage function: overactive bladder syndrome and detrusor overactivity. Urology 2003;62 Suppl 2: doi: /j.urology de GroatWC. The urothelium in overactive bladder: passive bystander or active participant? Urology 2004;64 Suppl 1:7 11. doi: /j.urology Hilton P. Anatomy and physiology of the lower urinary tract and the pathophysiology of urinary incontinence and sensory disorders of the lower urinary tract. In: Smith ARB, editor. Urogynaecology: The Investigation and Management of Urinary Incontinence in Women. London: RCOG Press; Hunsballe JM, Rittig S, Pedersen EB, Olesen OV, Djurhuus JC. Single dose imipramine reduces nocturnal urine output in patients with nocturnal enuresis and nocturnal polyuria. J Urol 1997;158: doi: /s (01) Lose G, Lalos O, Freeman RM, van Kerrebroeck P. Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double-blind placebo-controlled study in women. Am J Obstet Gynecol 2003;189: doi: /s (03) Robinson D, Cardozo LD. The role of estrogens in female lower urinary tract dysfunction. Urology 2003;62(S1), doi: /s (03) Rapp DE, Lucioni A, Katz EE, O Connor RC, Gerber GS, Bales GT. Use of botulinum A toxin for the treatment of refractory overactive bladder symptoms: an initial experience. Urology 2004;63: doi: /j. urology de Seze M, Wiart L, de Seze M, Soyeur L, Dosque J, Blajezewski S, et al. Intravesical capsaicin versus resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: a double blind randomized controlled study. J Urol 2004;171: doi: /01.ju d4 12 Kuo HC. Multiple intravesical instillation of low-dose resiniferatoxin is effective in the treatment of detrusor overactivity refractory to anticholinergics. BJU Int 2005;95: doi: /j X x 13 Toozs-Hobson P, Elnaqa A. Detrusor overactivity an update. BJOG 2004;111 (S1): Herbison P, Hay-Smith J, Ellis G, Moore K. Effectiveness of anticholinergic drugs compared with placebo in the treatment of overactive bladder: systematic review. BMJ 2003;326: doi: /bmj Napier C, Gupta P. Darifenacin is selective for the human recombinant M 3 receptor subtype. International Continence Society 32nd Annual Meeting, August 2002, Heidelberg, Germany. Abstract Versi E. Appell R, Mobley D, Patton W, Saltzstein D. Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. The Ditropan XLStudy Group. Obstet Gynecol 2000;95(5): doi: /s (99) Barkin J, Corcos J, Radomski S, Jammal MP, Miceli PC, Reiz JL, et al. Uromax study group: a randomized, double-blind, parallel-group comparison of controlled and immediate-release oxybutynin chloride in urge urinary incontinence. Clin Ther 2004;26: doi: /s (04) Dmochowski RR, Davilla GW, Zinner NR, Gittelman MC, Saltzstein DR, Lyttle S, et al. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary incontinence. J Urol 2002;168: doi: /s (05) Clemett D, Jarvis B. Tolterodine: a review of its use in the treatment of overactive bladder. Drugs Aging 2001;18: doi: / Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A; Tolterodine Study Group. Tolterodine once daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001;57: Diokno AC, Appell RA, Sand P, Dmochowski R, Gburek BM, Klimberg IW, et al. Prospective, randomized, 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(6): Cardozo L, Chapple CR, Toozs-Hobson P, Grosse-Freese M, Bulitta M, LehmacherW, et al. Efficacy of trospium chloride in patients with detrusor instability: a placebo-controlled, randomized, double-blind, multicentre 13

6 Review 2007;9:9 14 The Obstetrician & Gynaecologist clinical trial. BJU Int 2000;85: doi: /j x x 23 Madersbacher H, Stohrer M, Richter R, Burgdorfer H, Hachen HJ, MurtzG. Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in the treatment of detrusor hyper-reflexia. BrJ Urol 1995;75: Halaska M, Ralph G, Wiedemann A, Primus G, Ballering-Bruhl B, Hofner K, Jonas U. Controlled, double-blind, multicentre clinical trial to investigate long-term tolerability and efficacy of trospium chloride in patients with detrusor instability. World J Urol 2003;20: Singh-Franco D, Machado C, Tuteja S, Zapantis A. Trospium chloride for the treatment of overactive bladder with urge incontinence. Clin Ther 2005;27: doi: /j.clinthera Madersbacher H, Halaska M, Voigt R, Alloussi S, Hofner K. A placebocontrolled, multicentre study comparing the tolerability and efficacy of propiverine and oxybutynin in patients with urgency and urge incontinence. BJU Int 1999;84: doi: /j x x 27 Juenemann K, Hessdoerfer E, Unamba-Oparah I, Berse M, Bruenjes R, Madersbacher H, Gramatte T. Propiverine hydrochloride immediate release (IR) and extended release (ER): comparison of efficacy and tolerability in patients with overactive bladder. International Continence Society, 34th Annual Meeting, Paris, France, Abstract Cardozo L, Lisec M, Millard R, van Vierssen Trip O, Kuzmin I, Drogendijk TE, et al. Randomised, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172: doi: /01.ju Chapple CR, RechbergerT, Al-Shukri S, Meffan P, Everaert K, Huang M, et al. YM-905Study Group. Randomized, double-blind placebo and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 2004;93: doi: /j x x 30 Chapple CR, Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, WarnackW, DrogendijkT, 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: doi: /j.eururo Chapple C, Steers W, Norton P, Millard R, Kralidis G, Glavind K, et al. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. BJU Int 2005;95: doi: /j x x 32 Zinner N, Tuttle J, Marks L. Efficacy and tolerability of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), compared with oxybutynin in the treatment of patients with overactive bladder. World J Urol 2005;23: doi: /s Chapple C, KhullarV, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. EurUro 2005;48:5 26. doi: /j.eururo Hay Smith J, Herbison P, Ellis G, Morris A. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database Syst Rev 2005;(3): CD Kay GG, Granville LJ. Antimuscarinic agents: implications and concerns in the management of overactive bladder in the elderly. Clin Ther 2005;27: Malone-Lee J, Shaffu B, Anand C, Powell C. Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol 2001;165: doi: /s (05) Abrams P, Freeman R, Anderstrom C, Mattiasson A. Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. BrJ Urol 1998;81: Editor s Note This article was accepted by The Obstetrician & Gynaecologist before publication of the National Institute for Health and Clinical Excellence (NICE) Guideline on urinary incontinence in October Reference is made to recommendations for antimuscarinic drugs: Immediate release non-proprietary oxybutynin should be offered to women with OAB [overactive bladder syndrome] or mixed UI [urinary incontinence] as first-line [antimuscarinic] drug treatment, if bladder training has been ineffective. If immediate release oxybutynin is not well tolerated, darifenacin, solifenacin, tolterodine, trospium or an extended release or transdermal formulation of oxybutynin should be considered as alternatives. Women should be counselled about the adverse effects of antimuscarinic drugs. An early treatment review should be undertaken following any change in antimuscarinic drug therapy. Propiverine should be considered as an option to treat frequency of urination in women with OAB, but is not recommended for the treatment of UI. Flavoxate, propantheline and imipramine should not be used for the treatment of UI or OAB in women. The recommendation for non-proprietary oxybutinin as a first line drug treatment is based on the cost effectiveness of this agent. NICE acknowledges the possible criticism that this approach (drug choice based on cost effectiveness) does not sufficiently take into account the differences between drugs and formulations in terms of their adverse effects and tolerability profile. References 1 National Institute forhealth and Clinical Excellence. Urinary Incontinence: the Management of Urinary Incontinence in Women. NICEClinical Guideline 40. London: NICE; [ Robin Ashe FRCOG 14