Managing Overactive Bladder in Primary care

Transcription

1 Dudley Robinson * MD FRCOG Linda Cardozo 2* MD FRCOG Consultant Urogynaecologist 2 Professor of Urogynaecology * Department of Urogynaecology, Kings College Hospital, London Correspondence: Dudley Robinson Kings College Hospital dudley.robinson@nhs. net Managing Overactive Bladder in Primary care bstract Overactive Bladder (OB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Whilst a number of women may be managed based on a clinical diagnosis alone urodynamic studies may be useful in those women with complex or refractory symptoms. In the first instance all women will benefit from a conservative approach using bladder retraining although a number will require antimuscarinic therapy. For those women with persistent symptoms following medical therapy referral to secondary care for alternative treatment modalities such as intravesical Botulinum toxin, neuromodulation or reconstructive surgery may be considered. This review, whilst giving an overview of the syndrome, will focus on a practical clinical approach to managing women with symptoms of OB in the primary care setting. Keywords Overactive Bladder, urgency, incontinence, medical management, surgical management. Introduction Overactive Bladder (OB) is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology. The aim of this review is to provide practical clinical advice regarding the investigation and management of women complaining of lower urinary tract symptoms suggestive of OB as well as providing an evidence based approach to treatment in primary care. Prevalence Epidemiological studies from North merica have reported a prevalence of OB in women of 6.9% and the prevalence increases with age rising to 30.9% in those over the age of 65 years. 2 Further prevalence data from Europe 3 also has shown the overall prevalence in men and women over the age of 40 years to be 6.6%. Frequency was the most commonly reported symptom (85%) whilst 54% complained of urgency and 36% urgency incontinence. Pathophysiology The symptoms of OB are due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle. These involuntary contractions are termed detrusor overactivity and are mediated by acetylcholine-induced stimulation of bladder muscarinic receptors. However OB is not synonymous with detrusor overactivity as the former is a symptom based diagnosis whilst the latter is a urodynamic diagnosis. It has been estimated that 64% of patients with OB have urodynamically proven detrusor overactivity and that 83% of patients with detrusor overactivity have symptoms suggestive of OB. 4 Hence the terms should not be considered synonymous. 98 Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

2 Clinical Presentation Overactive Bladder usually presents with a multiplicity of symptoms. Those most commonly seen are urgency, daytime frequency, nocturia, urgency incontinence, stress incontinence, nocturnal enuresis and often coital incontinence. However it is important to remember that there are numerous other causes of urgency and frequency Table. There are no specific clinical signs in women with overactive bladder but it is always important to look for vulval excoriation, urogenital atrophy, a urinary residual and demonstrable stress incontinence. pelvic examination is also important to exclude the presence of urogenital prolapse or a pelvic mass, both of which may mimic the symptoms of OB. Occasionally an underlying neurological lesion such as multiple sclerosis will be discovered by examining the cranial nerves in addition to S2, 3 and 4. Investigation Whilst Overactive Bladder (OB) is a symptomatic diagnosis all patients require a basic assessment in order to confirm the diagnosis as well as excluding any other underlying cause for lower urinary tract dysfunction Figure. Urine culture midstream specimen of urine should be sent for microscopy, culture and sensitivity in all cases of incontinence. Frequency/volume chart ll patients should complete a frequency/volume chart in order to evaluate their fluid intake and voiding pattern. s well as the number of voids and incontinence episodes, the mean volume voided over a 24-hour period can also be calculated as well as the diurnal and nocturnal volumes. nalysis of voiding diaries helps to make a diagnosis of OB as well as being useful in monitoring treatment. Quality of Life Quality of Life (QoL) is assessed by the use of questionnaires completed by the patient alone or as part of the consultation and allows the quantification of morbidity and the evaluation of treatment efficacy as well as being a measure of how lives are affected and coping strategies adopted. Generic questionnaires, such as the Short Form 36, are general measures of QoL and are therefore applicable to a wide range of populations and clinical conditions whilst disease-specific questionnaires, such as the Kings Health Questionnaire (KHQ) are designed to focus on lower urinary tract symptoms. Whilst QoL questionnaires are commonly used in the secondary care setting they may also be useful to assess bother in primary care. When Should I Refer? Whilst a number of women complaining of symptoms suggestive of OB may be managed effectively in primary Table : Common causes of frequency and urgency of micturition. Urological Urinary tract infection Detrusor overactivity Small-capacity bladder Interstitial cystitis Chronic urinary retention/chronic urinary residual Bladder mucosal lesion, e.g. papilloma Bladder calculus Urethral syndrome Urethral diverticulum Urethral obstruction Gynaecological Pregnancy Stress incontinence Cystocoele Pelvic mass, e.g. fibroids Previous pelvic surgery Radiation cystitis/fibrosis Postmenopausal urogenital atrophy Sexual Coitus Sexually transmitted disease Contraceptive diaphragm Medical Diuretic therapy Upper motor neurone lesion Impaired renal function Congestive cardiac failure (nocturia) Hypokalaemia Endocrine Diabetes mellitus Diabetes insipidus Hypothyroidism Psychological Excessive drinking Habit nxiety care on the basis of simple investigations those women with refractory or complex symptoms may benefit from further investigation Figure 2. In addition those women whose symptoms fail to improve with primary therapy may also benefit from further investigations to exclude Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

3 Figure : Initial ssessment of Urinary Incontinence (ICI Guidelines 2009). 7 other causes of lower urinary tract symptoms. ssessment in secondary care may involve urodynamic investigation and cystourethroscopy. Urodynamic Investigation Urodynamics is the term used to describe investigations that measure the ability of the bladder to store and expel urine. Urodynamic investigations include uroflowmetry, filling cystometry and pressure/flow voiding studies. Further investigation allows a urodynamic diagnosis of detrusor overactivity to be made whilst excluding many of the other causes of OB type symptoms. Cystourethroscopy lthough endoscopy is not helpful in diagnosing detrusor overactivity it may be used to exclude other causes for the symptoms associated with OB such as a bladder tumour or calculus. In addition cystourethroscopy should be considered in all women complaining of haematuria, painful bladder syndrome and recurrent incontinence. When Should I Refer Immediately? The majority of women presenting with OB will have a number of lower urinary tract symptoms although in those women who present with complex, or unusual, symptoms immediate referral to secondary care should be considered. Women who present with Red Flag symptoms such as recurrent lower urinary tract infections, bladder pain or haematuria should be referred immediately for further investigation Table 2. In addition those patients who complain of recurrent urinary symptoms following previous investigation and management may also benefit from prompt referral. Table 2: Red Flag Symptoms. Bladder pain Haematuria Recurrent lower urinary tract infection Recurrent incontinence Significant voiding symptoms Pelvic irradiation Radical pelvic surgery Failed Continence Surgery Suspected urinary tract fistula Conservative Management ll women with OB benefit from advice regarding simple measures which they can take to help alleviate their symptoms. Many patients drink too much and they should be told to reduce their fluid intake to between and.5 litres per day and to avoid tea, coffee and 200 Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

4 Figure 2: Specialised ssessment of Urinary Incontinence (ICI Guidelines 2009). 7 alcohol if these exacerbate their problem. In addition there is also increasing evidence to suggest that weight loss may improve symptoms of urinary incontinence. Concomitant medication should be reviewed and those drugs which affect bladder function, such as diuretics and α adrenreceptor antagonists, should be reviewed and if possible stopped. In women who complain of troublesome nocturia manipulating the timing of medication, such as diuretics, may be very effective in improving their symptoms. If there is co-existent urodynamic stress incontinence then pelvic floor exercises may also be helpful in addition to bladder retraining. Bladder Retraining Several behavioral interventions, such as bladder retraining have been successfully used to treat OB and have been shown to improve symptoms in up to 80% of women. Unfortunately, these types of therapy are time consuming and require the patient to be highly motivated. In addition, there is a high relapse rate and patients do not seem to respond as well on a second occasion. However, it is always appropriate to instruct patients with OB regarding the use of bladder drill and this may often be used as an adjunct to drug therapy. controlled trial of bladder drill in 60 consecutive incontinent women with idiopathic overactive bladder has previously been reported. Following inpatient treatment, 90% of the bladder retraining group were continent and 83.3% remained symptom free after 6 months. In the control group 23.2% were continent and symptom free due to the placebo effect. Despite the excellent early results it has been shown that up to 40% of patients relapse within 3 years. Given the current pressure on hospital beds very few units are now able to offer bladder retraining on an inpatient basis and is more often performed in the community or as an outpatient Table 3. meta-analysis has concluded that bladder retraining is more effective than placebo and medical therapy although there is insufficient evidence to support the effectiveness of electrical stimulation and too few studies to evaluate the effect of pelvic floor exercises and biofeedback in women with urinary urge incontinence. Nevertheless the National Institute of Clinical Excellence (NICE) 5 and International Consultation on Incontinence (ICI) 6 recommend that bladder retraining should be considered as first line treatment in all women with OB. Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

5 Table 3: Bladder Retraining Technique.. Exclude pathology. 2. Explain rationale to patient. 3. Instruct the patient to void every one-and-a-half hours during the day (either she waits or is incontinent). 4. When one-and-a-half hours is achieved, increase by half an hour and continue with 2-hourly voiding, etc. 5. llow a normal fluid intake (500ml/24h). 6. The patient keeps a fluid balance chart. 7. She meets a successful patient. 8. She receives encouragement from patients, nurses and doctors. Medical Management Whilst a conservative approach is justified initially drug therapy remains integral in the management of women with OB and there are a number of different agents available. Traditionally tolerability, compliance and persistence have limited the usefulness of many of the antimuscarinic agents although with the introduction of newer bladder selective drugs, once daily dosing and differing routes of administration it is possible that persistence with therapy may increase. There are now a number of different licensed antimuscarinic drugs available on the market within the UK. These have all been recently reviewed by the International Consultation on Incontinence Table 4 and all have Level evidence and a Grade recommendation. 7 The most recent systematic review and meta-analysis of 83 studies, including patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine and trospium), supports the efficacy of antimuscarinic therapy in the management of OB. Overall there was a significantly higher return to continence favouring active treatment over placebo; the pooled RR across different studies and different drugs being (p<0.0). ntimuscarinic therapy was also shown to be statistically significantly more effective in reduction of incontinence episodes per day, reduction in number of micturitions per day and reduction of urgency episodes per day. 8 subsequent Cochrane review of 6 trials including 956 patients was supportive of these findings with a significantly greater cure or improvement rate in the antimuscarinic group when compared to placebo (RR.39, 95%CI:.28-.5). Importantly there was also a significant improvement in QoL implying clinical, as well as statistical significance. 9 Overall the additional benefit of active treatment was about 5% more improved or cured which translates into a Number Needed to Treat (NNT) of seven. Whilst these data confirm the efficacy of antimuscarinic drugs the evidence comparing drugs with one another is less robust. The available evidence would suggest that extended release oxybutynin and tolterodine have superior efficacy to the immediate release preparations. In addition Table 4: Drugs used in the treatment of overactive bladder. ntimuscarinic drugs Darifenacin Fesoterodine Oxybutynin Propiverine Solifenacin Tolterodine Trospium Level of evidence Grade of recommendation ndersson KE, Chapple CR, Cardozo L, et al. Pharmacological treatment of urinary incontinence. In Incontinence, 4 th Edition Eds brams P, Cardozo L, Khoury S, Wein. Health Publication Ltd, Editions 2, Paris, France solifenacin has been shown to be non inferior to, and fesoterodine superior to tolterodine extended release. Should I use Bladder Retraining and ntimuscarinic Drugs together? ntimuscarinic therapy may be a useful addition to conservative therapy. In a Cochrane review of 3 trials including 770 patients symptomatic improvement was more common amongst those on antimuscarinic therapy compared to bladder retraining (RR 0.73; 95%CI ) and combination treatment was also associated with more improvement than bladder training alone (RR 0.55; 95% CI: ). Similarly there was a trend towards greater improvement with a combination of antimuscarinic therapy with bladder retraining compared to antimuscarinic therapy alone (RR 0.8; 95%CI: ) although this was not statistically significant. 0 What Should I Do fter Primary Drug Therapy Failure? fter conservative therapy antimuscarinic agents are the most commonly used agents in the management of OB although compliance and persistence rates continue to be poor. Lack of efficacy has been shown to be the primary reason why patients stop therapy with intolerable side effects being the second most common. Should efficacy be the main reason for stopping therapy then it would seem appropriate to try an alternative drug whilst if adverse effects are the main reason for discontinuation then an alternative route of administration may be useful. Before resorting to more invasive treatment options in the management of OB there are several different treatment approaches that should be considered. Make an accurate diagnosis OB is a symptom complex rather than a urodynamic diagnosis and there are many different causes of frequency and urgency. Consequently those patients who fail on primary therapy may benefit from further investigation with urodynamic studies in addition to excluding other gynaecological, urological and medical causes of lower urinary tract symptoms. 202 Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

6 Use a Holistic pproach There is considerable evidence to show that combination therapy with medication and conservative measures lead to a greater improvement in patient symptoms. Equally improving patient awareness and education should lead to an improvement in compliance with medication. re there any lternatives to ntimuscarinic Drugs? Many other drugs are used in the treatment of patients with OB although the levels of evidence supporting their usage varies. Using an alternative treatment approach may be helpful to groups of patients with troublesome OB symptoms that have not responded to conventional antimuscarinic therapy. Desmopressin, a synthetic vasopressin analogue has been used primarily in the treatment of nocturia and nocturnal enuresis in children and adults although has also been reported for the treatment of daytime urinary incontinence. There is a risk of hyponatreamia whilst using desmopressin and consequently a serum sodium should be checked prior to starting therapy and after five to seven days. Should the serum sodium level be dropping significantly then therapy should be stopped. lternatively Imipramine may be useful in those patients who complain of bladder pain and coital incontinence although care should be taken in the elderly. In addition newer agents remain under evaluation. lthough the use of calcium blocking agents and potassium channel opening drugs showed initial promise neither have proved to be useful in the clinical setting. Consequently the search for novel agents to treat OB continues and has recently focused on the use of neurokinin antagonists, vitamin D analogues and more recently the β adrenoceptor agonists. Is there a role for Vaginal Oestrogen therapy in Post Menopausal Women? Whilst all the evidence would now appear to suggest that systemic hormone replacement therapy is not beneficial in managing lower urinary tact symptoms there is some evidence to suggest that local oestrogen therapy may be beneficial in managing the symptoms associated with OB. Whether this is due to a true effect on the bladder or by simply reversing local atrophic changes remains unclear. More recently there has been some evidence regarding the synergistic use of vaginal oestrogen therapy with antimuscarinics in the management of postmenopausal women with OB although the results are contradictory. There is also some evidence, from one study, to suggest that local oestrogen therapy with an oestradiol releasing ring may be as beneficial as Oxybutynin. Consequently the currently available evidence would appear to suggest that vaginal oestrogens may be effective and there is certainly no evidence of harm. Referring to Secondary Care: Refractory OB Whilst the majority of patients with OB will respond to conservative therapy and drug treatment a minority will continue to complain of distressing lower urinary tract symptoms. In general these patients benefit from referral to primary care for further investigation and management. Once alternative pathology has been excluded they may benefit from more invasive therapy such as intravesical Botulinum Toxin, neuromodulation and perhaps reconstructive surgery. β 3 drenoceptor gonists β adrenoceptor agonists have been shown to promote bladder relaxation and to increase bladder capacity. Subsequently three subtypes of β adrenoceptors (β, β 2 and β 3 ) have been identified both in the detrusor muscle and also in the urothelium. β 3 adrenoceptor agonists induce bladder relaxation by the activation of adenyl cyclase with the subsequent formation of cyclic adenyl monophosphate (cmp) and have been shown to increase bladder capacity with no change in micturition pressure and residual urine volumes. Currently there are two β adrenoceptor agonists under investigation for the treatment of OB, mirabegron and solabegron. The evidence supporting the use of β 3 adrenceptor agonists would suggest that these drugs may offer an alternative to antimuscarinic therapy whilst at the same time offering a better side effect profile. In addition the introduction of a new class of drug may offer the possibility of combination therapy which may minimise adverse events whilst maximizing efficacy. Botulinum Toxin Intravesical Botulinum Toxin offers an alternative in those women with intractable OB although the effect is only temporary, lasting nine to twelve months, and there is a significant risk of voiding difficulties although these would appear to dose related. Whilst there are little long term data regarding the efficacy and complications associated with repeat injections the current evidence would suggest that repeat procedures are safe and remain effective. Botulinum Toxin may be administered either under general anesthetic with a rigid cystoscope or under local anaesthetic with a flexible cystoscope. Whilst it is not currently licensed in the UK for this indication there is widespread usage and an increasing amount of evidence to support safety and efficacy. Neuromodulation Neuromodulation may also be used in women with refractory symptoms and may be peripheral, central or cutaneous. Peripheral Neuromodulation Stimulation of the posterior tibial nerve in patients with urge incontinence was first reported in 983 and Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

7 has also been proposed for pelvic floor dysfunction. The tibial nerve is a mixed nerve containing L4-S3 fibres and originates from the same spinal cord segments as the innervation to the bladder and pelvic floor. Consequently peripheral neural modulation may have a role in the management of urinary symptoms. Stimulation of the posterior tibial nerve has been shown to be effective and the evidence would appear to suggest that it offers a similar improvement in QoL as treatment with antimuscarinic agents. prospective randomised multicentre North merican study has been reported comparing PTNS with tolterodine 4mg ER in 00 patients. Overall there was an improvement in 75% of patients with PTNS compared to 55.8% with tolterodine ER in addition to a significant improvement in QoL in both groups. Posterior tibial nerve stimulation is achieved by the temporary insertion of a needle in the lower leg posterior to the tibia and two finger widths above the medial malleolus. Treatment may be performed in the clinic setting and is weekly for the first 2 weeks and then maintenance therapy is generally monthly with each session lasting 30 minutes. Sacral Neuromodulation Stimulation of the dorsal sacral nerve root using a permanent implantable device in the S3 sacral foramen has been developed for use in patients with overactive bladder and neurogenic detrusor overactivity. The sacral nerves contain nerve fibres of the parasympathetic and sympathetic system providing innervation to the bladder as well as somatic fibres providing innervation to the muscles of the pelvic floor. The latter are larger in diameter and hence have a lower threshold of activation, meaning that the pelvic floor may be stimulated selectively without causing bladder activity. Prior to implantation temporary cutaneous sacral nerve stimulation is performed to check for a response and if successful, a permanent implant is inserted under general anaesthesia. Initial studies in patients with overactive bladder refractory to medical and behavioural therapy have demonstrated that after 3 years, 59% of 4 urinary urge incontinent patients showed greater than 50% reduction in incontinence episodes, with 46% of patients being completely dry. Whilst the efficacy of sacral neuromodulation is well documented revision rates have been reported to be up to 42% indicating that sacral neuromodulation may be associated with considerable long term morbidity. Whilst neuromodulation remains an invasive and expensive procedure, it does offer a useful alternative to medical and surgical therapies in patients with severe, intractable overactive bladder prior to considering reconstructive surgery although technical failure may often necessitate surgical revisions. Cutaneous Neuromodulation More recently a cutaneous sacral neuromodulation system has been developed which may offer a less invasive approach and early trials have demonstrated the device to be safe and efficacious. The cutaneous patch may be applied either by the patient or her physician and is changed weekly. t present the device is currently undergoing clinical evaluation and should be available early next year. Reconstructive Surgery Ultimately a small number of women who have failed to respond to medical therapy may benefit from reconstructive surgery and may be considered for an ileal diversion, clam cystoplasty or detrusor myectomy. However, reconstructive surgery is associated with high morbidity and long term complications and really should only be considered when all other treatment modalities have failed. Consequently the majority of these procedures are now only performed in specialist centres. Nice Guidelines The medical management of OB has just been reviewed by the National Institute for Health and Care Excellence (NICE CG 7) in October 203. 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 immediate release non-propriety oxybutynin, tolterodine or darifenacin should be offered to women with OB as first line drug treatment if bladder retraining has been ineffective. If first line drug therapy is not effective then the drug with the lowest acquisition cost should be used as second line therapy. Desmopressin may be considered specifically to reduce nocturia in women this is currently outside the marketing authorisation and hence informed consent must be obtained. In addition women should be counseled regarding the adverse effects of antimuscarinic drugs and seen initially after four weeks of therapy for review. If the treatment is effective then patients should be reviewed on an annual basis although the elderly should be seen every six months. When considering the role of oestrogens the recommendations are that systemic hormone replacement therapy should not be recommended although intravaginal oestrogens are recommended for the treatment of OB in postmenopausal women with urogenital atrophy. ll women who may benefit from invasive therapy should be reviewed in the multidisciplinary team meeting within secondary care. Botulinum Toxin may be offered in those women with proven detrusor overactivity on 204 Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):

8 urodynamic investigation although should be taught to self catheterise beforehand. If they are unable to self catheterise they should be offered percutaneous sacral nerve stimulation. Conversely percutaneous posterior tibial nerve stimulation should only be considered if the patient does not wish to have Botulinum Toxin or percutaneous sacral nerve stimulation. ugmentation cystoplasty should be reserved for those women who have failed conservative therapy and are able to self catheterise. In addition they should be warned regarding the long term metabolic risks and the small risk of malignancy. Ileal Conduit diversion should only be used in those women who have failed all conservative therapies and augmentation cystoplasty. Conclusions Overactive Bladder is a common and distressing condition which is known to have a significant effect on QoL. The clinical diagnosis of OB is often one of exclusion although urodynamic investigations are helpful in those women with refractory or unusual symptoms. The majority of women will benefit from conservative measures in the first instance although many will eventually require drug therapy. For those with refractory symptoms Botulinum Toxin and neuromodulation now offer effective alternatives to reconstructive surgery. Whilst the majority of women can be managed effectively in primary care it is important to consider referral to secondary care in those women who have severe or unusual symptoms or symptoms that have not responded to primary intervention. Conflict of Interest ll authors have no conflict of interest to declare. No extraneous funding was obtained. Clinical Practice Points Overactive Bladder is a common condition and the prevalence increases with age. OB is known to have a significant impact on QoL. OB is a symptomatic diagnosis whilst detrusor overactivity is a urodynamic diagnosis. The terms, although often used interchangeably are not synonymous. ll women require basic assessment to exclude urinary tract infection and voiding dysfunction. Urodynamic investigations may be useful in women with persistent symptoms. Conservative measures should be used as first line therapy prior to starting antimuscarinic therapy. Referral to secondary care should be considered if any of the Red Flag symptoms are present. Women with refractory OB may benefit from intravesical Botulinum Toxin or neuromodulation. Reconstructive surgery should be reserved for those women who have not responded to all other treatment modalities. References. Haylen BT, de Ridder D, Freeman RM, et al. n International Urogynaecological ssociation (IUG)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J 200; 2: Stewart WF, Corey R, Herzog R, et al. Prevalence of overactive bladder in women: results from the NOBLE program. Int Urogynaecol. J. 200; 2 (3): S Milsom I, brams P, Cardozo L, et al. How widespread are the symptoms of overactive bladder and how are they managed? population-based prevalence study. BJU Int. 200; 87(9): Hashim H, brams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol. 2006; 75: NICE Guideline 40. The Management of Urinary Incontinence in Women. Department of Health Hay-Smith J, Berghmans B, Burgio K, et al. dult Conservative Management. In Incontinence, 4 th Edition Eds brams P, Cardozo L, Khoury S, Wein. Health Publication Ltd, Editions 2, Paris, France brams P, Cardozo L, Khoury S, et al. Incontinence Health Publication Ltd, Editions 2, Paris, France. 8. Chapple CR, Khullar V, Gabriel Z, et al. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol 2008; 54(3): Nabi G, cody JD, Ellis G, et al. nticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database of Systematic Reviews 2006, Issue. rt No: CD DOI: 0.002/ pub2 0. lhasso, McKinlay J, Patrick K, et al. nticholinergic drugs versus non drug active therapies for overactive bladder syndrome in adults. Cochrane Database of Systematic Reviews 2006; Issue 4. rt No: CD DOI: 0.002/ CD00393.pub3.. Copyright 203 Rila Publications Ltd. Clinical Focus Primary Care 203, 7(3):