Antimuscarinic drugs to treat overactive bladderBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e2130 (Published 27 March 2012) Cite this as: BMJ 2012;344:e2130
- Correspondence to: D Robinson
- Accepted 20 January 2012
A 45 year old woman presents to her general practitioner complaining of troublesome urinary symptoms increasingly affecting her quality of life. She is currently voiding more than 10 times a day and rising three times at night. In addition she notices a sudden urgent desire to void and on two occasions has leaked urine before reaching the toilet. She gives no history of urinary tract infection or haematuria. Her periods remain regular.
In the past she has had two vaginal deliveries, has no significant medical history, and is not taking any medication. Pelvic examination is unremarkable and urine analysis normal. Ultrasound examination shows no post-void residual urine.
Based on the history, clinical examination, and basic investigations you make a symptomatic diagnosis of overactive bladder. After discussing her bladder symptoms, you offer lifestyle advice including the moderation of fluids and reduction of caffeine intake. In addition you refer her for bladder retraining and start treatment with antimuscarinic drugs.
What is overactive bladder?
Overactive bladder is the term used to describe the symptom complex of urinary urgency, usually accompanied by frequency and nocturia, with or without urge urinary incontinence, in the absence of urinary tract infection or other obvious pathology.1
Epidemiological studies in North America have reported a prevalence of overactive bladder in women of 16.9%, and the prevalence increases with age—from 4.8% in women under 25 years to 30.9% in those aged over 65 years.2 Prevalence data from Europe are similar, with frequency the most commonly reported symptom (85%), and 54% reporting urgency and 36% urge incontinence.3
The symptoms of overactive bladder are most likely due to involuntary contractions of the detrusor muscle during the filling phase of the micturition cycle; abnormalities in afferent sensation may also play a role. Detrusor overactivity1 is mediated by acetylcholine induced stimulation of muscarinic receptors in the bladder, under the control of the parasympathetic nervous system. Although the cause of detrusor overactivity is unknown, there is evidence to support both neurogenic and myogenic causes.4 5 Antimuscarinic drugs used to treat overactive bladder (see box 1) act by blocking muscarinic receptors at the neuromuscular junction and thus prevent acetylcholine mediated bladder contraction.
Consequently, overactive bladder is a symptom based diagnosis, and detrusor overactivity can be diagnosed only after urodynamic investigation. The two terms are not synonymous: 64% of women with overactive bladder have urodynamically proved detrusor overactivity, while 83% of women with detrusor overactivity have symptoms suggestive of overactive bladder.6
Box 1: Antimuscarinic drugs used to treat overactive bladder
Based on level I evidence for all these drugs, the International Consultation on Incontinence has made grade A recommendations for their use in overactive bladder syndrome.7 (See box 2 for definitions of levels of evidence and recommendations)
How well do antimuscarinic drugs work?
Several antimuscarinic drugs are licensed and available in the UK. These have all been recently recommended by the International Consultation on Incontinence7 to treat overactive bladder syndrome (box 1) and all have level I evidence8 and a grade A recommendation (see box 2 for definitions).9
Levels of evidence
I—Systematic review of all relevant randomised controlled trials
IIA—One randomised controlled trial, with low probability of bias and high probability of causal relationship
IIB—One randomised controlled trial
IIIA—Well designed controlled trials (no randomisation)
IIIB—Cohort or case-control studies
IIIC—Multiple time series or dramatic results in uncontrolled experiments
IV—Expert opinion (traditional use)
Grades of recommendations
A—A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as level I directly applicable to the target population and showing overall consistency of results
B—A body of evidence including studies rated as level IIA directly applicable to the target population and showing overall consistency of results, or extrapolated evidence from studies rated as level I
C—A body of evidence including studies rated as IIB directly applicable to the target population and showing overall consistency of results, or extrapolated evidence from studies rated as level II
D—Evidence level III or IV, or extrapolated evidence from studies rated as II
The clinical effectiveness of antimuscarinic agents was first questioned in a systematic review of 32 randomised controlled trials including 6800 participants.10 Cure or improvement after treatment were all significantly in favour of antimuscarinic drugs (relative risk 1.41 (95% confidence interval 1.29 to 1.54), P<0.0001), although the differences from placebo were small and of questionable clinical significance. A subsequent Cochrane review of 61 randomised controlled trials including 11 956 patients was supportive of these findings, with a significantly greater cure or improvement rate in the antimuscarinic group compared with placebo (relative risk 1.39 (1.28 to 1.51)). Importantly, there was also a significant improvement in quality of life, implying clinical as well as statistical significance.11 The overall number needed to treat (NNT) was seven.
The most recent meta-analysis of 83 randomised controlled trials, including 30 699 patients and six different drugs (fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, and trospium), also supports the efficacy of antimuscarinic drugs in the treatment of overactive bladder. Overall there was a significantly higher return to continence with active treatment compared with placebo—the pooled relative risk across different studies and different drugs was 1.3–3.5 (P<0.01). Antimuscarinic therapy was also shown to be significantly more effective in reducing the daily number of incontinence episodes (pooled differences in mean change 0.4–1.1), micturitions (0.5–1.3), and urgency episodes (0.64–1.56).12
While these data confirm the efficacy of antimuscarinic drugs, the evidence for comparing different drugs is less robust. Some randomised controlled data suggest that extended release oxybutynin13 and tolterodine14 may have superior efficacy to the immediate release preparations15 In addition, solifenacin is as effective as extended release tolterodine,16 and fesoterodine is superior to it.17 However, the incidence of adverse effects increases with increasing dose.
How safe are antimuscarinic drugs?
Antimuscarinic drugs are associated with the common anticholinergic adverse effects of dry mouth, constipation, blurred vision, and somnolence. Although these are not life threatening, they may be associated with poor compliance or persistence with treatment. A recent systematic review of 149 papers found discontinuation rates of 43–83% in the first 30 days of treatment, and more than half of patients never refill the initial prescription.18 More serious adverse effects include cognitive and cardiac effects, specifically prolongation of the QT interval,19 though all the safety data suggest that routine electrocardiography is not required. A recent meta-analysis of prospective randomised trials investigating the effect of antimuscarinic drugs on the central nervous system found the incidence of adverse effects was poorly reported overall, and 77% of studies neither measured nor reported central nervous system outcomes.20 In those that did, dizziness was the most common adverse effect (oxybutynin 3%, propiverine 3.2%, tolterodine 1.8%, and placebo 1.6%), and confusion was found in <1% of cases. Small randomised studies have also shown no effect on cognition in elderly patients with solifenacin,21 darifenacin,22 and trospium chloride.23
What are the precautions?
Hepatic or renal impairment—As antimuscarinic drugs undergo both hepatic metabolism and renal excretion, the dose may need to be decreased in such patients
Elderly patients—A lower dose should be considered because of the risk of postural hypotension and cognitive impairment
Voiding dysfunction—In men there may be some concerns regarding the exacerbation of voiding difficulties, but this is only rarely reported in women, so post-void residual urine volumes need not be monitored routinely
Contraindications—Do not prescribe these drugs in patients with angle closure glaucoma, myasthenia gravis, severe ulcerative colitis, toxic megacolon, or intestinal obstruction because of their anticholinergic effects
Pregnancy—There is limited evidence for all antimuscarinic agents. Oxybutynin is generally felt to be safe if essential, but avoid darifenacin, fesoterodine, propiverine, tolterodine, solifenacin, and trospium
Drug interactions—Box 3 summarises possible interactions
Antimuscarinics may interact with drugs that compete for hepatic metabolism via cytochrome P450 and renal excretion,16 especially in patients with mild hepatic and renal impairment and in elderly patients, who may be receiving polypharmacy
Concomitant use of other drugs that have antimuscarinic effects may increase the risk of adverse effects.
Box 3: Antimuscarinic drug interactions
Antiarrythmics—Darifenacin and tolterodine may increase risk of arrythmias when given with antiarrythmics
Antifungals—Solifenacin and fesoterodine levels increased by itraconazole and ketoconazole. Avoid use of darifenacin and tolterodine with itraconazole and ketoconazole
Antipsychotics—Reduce the effect of haloperidol and phenothiazines
Antiretrovirals—Fesoterodine and solifenacin levels increased with antiretrovirals. Avoid darifenacin with antiretroviral agents
Domperidone—Antimuscarinics may antagonise the effects on gastric motility
Levodopa—Antimuscarinics may reduce absorption
Metoclopramide—Antimuscarinics may antagonise the effects on gastric motility
Phenothiazines—Antimuscarinics may increase risk of antimuscarinic side effects
Tricyclic antidepressants—May increase risk of antimuscarinic effects
From British National Formulary 2011;61
How cost effective are antimuscarinic drugs?
In a recent assessment of cost effectiveness of all antimuscarinic therapies within the UK National Health Service, solifenacin was associated with the highest quality adjusted life year (QALY) gain in terms of urinary urgency, frequency, and incontinence. Solifenacin was found to be more cost effective than fesoterodine, tolterodine, and propiverine, though not oxybutynin.24 A cost utility analysis comparing solifenacin and tolterodine found that solifenacin was less expensive and more effective than tolterodine: solifenacin was found to have an incremental cost of £8087 per QALY, and the one year costs were £509 with solifenacin compared with £526 for tolterodine.25
How are antimuscarinic drugs taken and monitored
All antimuscarinic drugs can be taken orally, and oxybutynin is also available as a transdermal preparation (gel and patch). Counsel patients on the adverse effects associated with antimuscarinic treatment (see box of tips for patients) and always review concomitant medication before starting treatment. Some patients may have sufficient improvement in their symptoms with conservative measures and be reluctant to take drugs. In general start at a low dose and titrate against efficacy and adverse effects. It is not necessary to monitor liver and renal function in patients with hepatic and renal impairment.
How do antimuscarinic drugs compare with conservative therapy and other drugs?
Antimuscarinic drugs may be a useful addition to non-drug therapy in the management of overactive bladder. In a Cochrane review of 13 trials including 1770 patients, symptomatic improvement was more common among those taking antimuscarinic drugs compared with bladder retraining (relative risk 0.73 (0.59 to 0.90)), and combination treatment was also associated with more improvement than bladder training alone (0.55 (0.32 to 0.93)). Similarly there was a trend towards greater improvement with a combination of antimuscarinic drugs with bladder retraining compared with antimuscarinics alone (relative risk 0.81 (0.61 to 1.06)), although this was not significant.26
Many other drugs are used to treat overactive bladder, but evidence for their effectiveness is variable (see table⇓).5 Of these, only desmopressin, a synthetic vasopressin analogue used primarily to treat nocturia and nocturnal enuresis, has level I evidence to support its use, although there are no comparative studies with antimuscarinic drugs.
Although the use of calcium blocking agents and potassium channel opening drugs showed initial promise, neither have proved to be useful in the clinical setting.27 28 The search for novel agents to treat overactive bladder continues and has recently focused on the use of neurokinin antagonists,29 vitamin D analogues,30 and β adrenoceptor agonists.31
Tips for patients
Overactive bladder is a common and distressing condition
Bladder retraining, lifestyle advice, and pelvic floor exercises should help to improve the symptoms of overactive bladder
Think about fluid intake and try to avoid caffeinated drinks, artificially sweetened carbonated drinks, and alcohol. Try not to drink too much (generally no more than 1.5 litres a day), and limit your fluid intake before bed
Your local continence advisory service will be able to provide you with tips for coping strategies and advice about containment products such as continence pads
Antimuscarinic drugs may be useful in addition to conservative measures when trying to control your bladder symptoms; these may be required long term as overactive bladder is a chronic condition
Antimuscarinic drugs may be associated with a dry mouth. Try sucking a sweet or chewing gum to increase salivation
Constipation may also be associated with taking antimuscarinic drugs: it may be necessary to alter your diet or consider laxatives
Cite this as: BMJ 2012;344:e2130
This is one of a series of occasional articles on therapeutics for common or serious conditions, covering new drugs and old drugs with important new indications or concerns. The series advisers are Robin Ferner, honorary professor of clinical pharmacology, University of Birmingham and Birmingham City Hospital, and Philip Routledge, professor of clinical pharmacology, Cardiff University. To suggest a topic for this series, please email us at email@example.com
Contributors: Both authors planned, wrote, and revised this review article. DR is the guarantor.
All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organisation for the submitted work. DR has worked as a consultant for Astellas, Pfizer, Gynaecare, and Ferring and has accepted payments for lecturing and expenses for meetings from Astellas, Pfizer, and Gynaecare. LC has worked as a consultant for Astellas, Pfizer, Merck, Teva, and Ethicon; has a research grant from Pfizer; and has accepted payments for lecturing and expenses for meetings from Astellas and Pfizer.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient consent not required (patient anonymised, dead, or hypothetical).