CPD: Overactive Bladder

60 Second Summary

Overactive bladder (OAB) is a common chronic condition associated with voiding dysfunction. The underlying OAB pathophysiology is overactivity of the detrusor muscle, which is a smooth muscle found in the wall of the bladder that contracts during urination.

Taking a clinical history is important, i.e. symptoms, aggravating/alleviating factors, 24 hour incontinence pad use. Physical examination of the genitourinary system, prostate assessment in men and vaginal examination in women should be performed.

There are multiple guidelines for management of OAB such as those from the National Institute for Health and Care Excellence (NICE), European Association of Urology (EAU) and American Urological Association (AUA), which are generally in agreement with each other in terms of the type of stepwise approach to use. This stepwise approach should be tailored to the patient’s needs: they do not necessarily need to go through every step in the set order.

AUTHOR: Donna Cosgrove PhD MPSI

Donna graduated with a BSc in Pharmacy from the Royal College of Surgeons in Ireland. She then returned to university to complete a MSc in Neuropharmacology. This led to a PhD investigating the genetics of schizophrenia, followed by a postdoctoral research position in the same area. Currently Donna works as a pharmacist in Galway, and as a clinical writer.

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Managing Symptoms of Overactive Bladder

Introduction

Overactive bladder (OAB) is a common chronic condition associated with voiding dysfunction. 1 The underlying OAB pathophysiology is overactivity of the detrusor muscle (Figure 1), which is a smooth muscle found in the wall of the bladder that contracts during urination. OAB is often (not always) linked to detrusor muscle overactivity on urodynamic evaluation. 2 It is defined by the International Continence Society as “urinary urgency, usually accompanied by increased daytime frequency and/or nocturia, with urinary incontinence (OAB-wet) or without (OAB-dry), in the absence of urinary tract infection or other detectable disease”. 3 Urinary urgency is the “complaint of a sudden, compelling desire to pass urine which is difficult to defer”. 4 Some women may also experience urine leakage during sex. 5 It is a very common condition, affecting 16.6% of people in Europe; and in the US, estimates suggest a prevalence of up to 43% in women and 27% in men over 40. It is more common in women, and with increasing age. 6 The prevalence of OAB Asian populations has been reported to be lower than that in other races in both men and women. The disorder reduces health-related quality of life (QoL) and results in a significant economic burden on society. 1

The following lifestyle changes and treatments may help with OAB: 5

• Losing weight if overweight

• Reduction in caffeine and liquid intake

• Pelvic floor exercises

• Bladder retraining

• Medication

• Surgery

• Botox

Because urinary urgency and incontinence symptoms can be difficult to objectively characterise for research and clinical purposes, many studies of OAB treatments have used other measures (number of daily micturitions or incontinence episodes) to enable quantification of treatment response. Although highly variable (depending on sleep, fluid intake, and medical conditions, among other things), up to seven micturition episodes during waking hours is considered normal.

When a patient presents with troublesome symptoms of daytime and nighttime urinary frequency and urgency, this commonly leads to a diagnosis of OAB. 4

OAB can be idiopathic or secondary to a neurological cause e.g. Multiple Sclerosis, Parkinson’s disease. 4 Idiopathic OAB can be due to an obstruction or have no obvious contributing pathology. Men are more likely to have OAB dry (without incontinence), and women are more likely to have wet (with incontinence). It is likely to be significantly underreported and therefore significantly undertreated. 2 The guidelines and treatments discussed here generally refer to idiopathic OAB, excluding the management of neurological OAB.

Figure 1. Overactive bladder 7

Diagnosis

Often, patients have been living with OAB symptoms for substantial lengths of time, only seeking treatment when symptoms become particularly problematic. Diagnosis of OAB is made based on symptoms of daytime urinary frequency and urgency, potentially occurring with urge incontinence (6). A simple 3-day voiding diary, completed by the patient, outlining voiding frequency, timing, and fluid intake can aid with quantifying frequency and nocturia. The identification of excessive or poorly timed fluid intake can guide behavioural recommendations. 2

Haematuria and infection should be ruled out (by dipstick urinalysis initially). Taking a clinical history is important, i.e. symptoms, aggravating/alleviating factors, 24 hour incontinence pad use. Physical examination of the genitourinary system, prostate assessment in men and vaginal examination in women should be performed. 6 Imaging is not required unless a urinary obstruction is suspected. Urodynamic testing, to evaluate bladder function, is a technique that involves passing a thin tube into the bladder and another one into the rectum to measure bladder activity and episodes of urinary incontinence. Patients often find this uncomfortable, and some people develop cystitis after the test. 8 Detrusor overactivity identified through urodynamic testing tends to be more common in men and those with wet OAB (69% men in cases of dry OAB compared to 44% women; 90% men in wet OAB compared to 58% women). 6

Urodynamic testing is an invasive procedure, and currently guidelines recommend that its use should be limited to those with refractory OAB. A clinical trial investigating the utility of urodynamics for advising on OAB treatment is ongoing. 8

Treatment

Initial OAB management is conservative, including: 2

• Optimising the management of any potential contributing medical conditions (constipation, UTI, diabetes, heart failure, sleep apnoea)

• Managing oral fluid intake overall and particularly in the evening. Consumption of diuretics like alcohol and caffeine should be minimised.

• Timed voiding

• Bladder retraining techniques

• Reduction of excessive body weight

• Smoking cessation

Unexpectedly, not all studies show that discontinuing caffeinated beverages leads to an improvement in symptoms, but this is still commonly recommended. Where possible, the use of prescription diuretics, a known cause of incontinence in the elderly, should be avoided.- Symptoms of OAB can also be significantly improved by limiting fluid intake by 25% (to up to 1.5 litres a day). Although pharmacotherapy is often more successful than behavioural, in all instances it is recommended that these be used in combination, as this is more effective than either one used in isolation.

Behavioural Therapy

These therapies aim to increase the interval between urine voiding times, reduce nocturia and urgency, and prevent incontinence by providing tools to patients to interrupt/inhibit detrusor contractions. 6 Compared with the recommended medications, especially antimuscarinics, behavioural therapy is associated with a lower risk of adverse events.

Pelvic floor training can be very effective, reducing leakage by 50- 80%, with up to 30% of patients becoming dry. Occasionally, a behavioural intervention and pharmacotherapy are used simultaneously to provide an additive effect for OAB treatment.

The following instructions describe briefly how to go about pelvic floor training: 9

• The patient should sit, stand or lie with your knees slightly apart. The pelvic floor muscles should be slowly tightened. They should try to lift and lift and squeeze as long as possible, followed by resting for 4 seconds. The contraction should be repeated, building up the strength to do 10 slow contractions at a time (holding for 10 seconds each) with rests of 4 seconds in between.

• The pelvic floor muscles also need to react quickly to sudden stresses from coughing, laughing or exercise that puts pressure on the bladder. Quick contractions should also be practised, i.e. drawing in the pelvic floor and holding just for one second before relaxing. People should aim to achieve a strong muscle tightening with up to ten quick contractions in succession.

These should be performed 3-4 times daily. It takes time for the exercises to strengthen the muscles: at least 3 months should be allowed before the muscles gain their full strength.

Bladder training in OAB helps control urgency through diverting attention, by e.g. performing mental arithmetic or pelvic floor muscle contractions, and/or relaxation e.g. with deep breathing activities, and gradually prolonging the voiding interval by 15 minutes. 1 Eventually, the patient may be able to void every three to four hours without the frequent urge to urinate.

There is currently no agreed or standardised definition, but bladder training includes the following:

• Patient education about the mechanism of bladder action and voiding function provide patients with a better understanding of their excretory function.

• Scheduled voiding at fixed voiding intervals while awake, progressively lengthening as successful control is achieved.

• Positive reinforcement through psychological support to patients, encouraging them to continue the practice.

Bladder training is occasionally combined with other therapies, such as pelvic floor muscle training and pharmacotherapy, for an additive effect. In clinical practice, bladder training and pelvic floor muscle training are prescribed in combination. Currently a Cochrane review (1) is being undertaken to assess the effects of bladder training for treating adults with OAB in more detail.

Initial Pharmacotherapy

Pharmacological treatments for OAB have traditionally included antimuscarinic medications as the first line choice. Oral oxybutynin was one of the first medications used, but subsequent formulations of anticholinergics have been developed to improve compliance through the use of extended release (ER) formulations and minimising the associated adverse effects. 2 Table 1 summarises some of the main medications available for treatment of OAB.

Antimuscarinics (available as transdermal and oral preparations) are still the first line treatment for OAB, and are effective in reducing major symptoms in 65-70% of patients. In some cases, the side effects of dry eyes and mouth, blurred vision and constipation may be an issue for patients; and central antimuscarinic effects like impaired cognition may contribute to adverse events in older people such as falls, cognitive impairment and delirium. These side effects reduce patient compliance. 6 Anticholinergics reduce the amplitude of bladder contractions which improves bladder capacity and involuntary detrusor contractions, meaning less urgency and frequency. 2

The use of the oxybutynin transdermal patch vs oral administration leads to fewer side effects. The most common adverse reactions from the patch were application site pruritus (16.1%), application site erythema (7.0%), dry mouth (7.0%), and constipation (2.1%). Dry mouth was the most common adverse event from oral ER oxybutynin (68% of patients).

Tolterodine is often better tolerated than oxybutynin, but should be used with caution if there is any known history of QT prolongation or with concomitant use of certain antiarrhythmics. The most common adverse events reported by patients receiving tolterodine ER were dry mouth (23%), headache (6%), constipation (6%), and abdominal pain (4%).

Fesoterodine has minimal effect on cognition, and the most common adverse event reported in trials was dry mouth, reported in 19% taking 4 mg daily, and 35% on 8 mg daily. Trials comparing fesoterodine to tolterodine demonstrated that fesoterodine was superior across multiple outcome measures (patient-reported cure or improvement, leakage episodes, frequency, urgency episodes). However, fesoterodine showed a comparatively higher risk of dry mouth, and withdrawal due to adverse effects.

Solifenacin is selective for M3 receptors. Although the 10 mg dose is more effective in OAB treatment, it has a higher rate of side effects. These include dry mouth (10.9% with 5 mg vs 27.6% with 10 mg), constipation (5.4% with 5 mg vs 13.4% with 10 mg), and blurred vision (3.8% with 5 mg vs 4.8% with 10 mg). A Cochrane review concluded that there were significantly less reports of dry mouth rates with solifenacin than with tolterodine ER, and better QoL improvements.

Trospium is equivalent to oxybutynin in terms of improvement of urinary outcomes. The two most common adverse reactions were dry mouth (20.1%) and constipation (5.8%). Dry mouth led to discontinuation in 1.9% of treated patients.

Mirabegron facilitates bladder detrusor relaxation through the alternative mechanism of beta 3 adrenoceptor agonist action. Detrusor relaxation is mediated mostly through noradrenaline action on beta 1, 2 and 3 receptors. The beta 3 receptor subclass is thought to be most important in mediating detrusor relaxation, and this receptor is preferentially expressed on urinary bladder tissues. Mirabegron causes a dose-dependent relaxation of the detrusor muscle, inhibiting overactivity. This mechanism of action means that there are no anticholinergic adverse effects. In theory there may be a risk of hypertension in patients taking mirabegron, but this has not been observed when treatment is compared to placebo. One large UK study found that persistence with and adherence to pharmacotherapy with mirabegron is higher than with the older antimuscarinic drugs used in OAB. 2, 6

Combination therapy of an antimuscarinic and beta agonist (e.g. solifenacin 5mg with mirabegron 25 or 50mg) can be considered if monotherapy does not work. This does not appear to cause any increase in adverse effects, but has been reported to significantly reduce incontinence and micturition when compared to monotherapy with each agent alone. The use of mirabegron along with solifenacin 5mg may offer more benefit than an increase in solifenacin dose to 10mg due to fewer adverse effects.

A novel selective beta 3 agonist, virabegron, has shown significant improvement in OAB symptoms in trials although is not yet approved for use in Ireland.

Injection of Botox (botulinum toxin A) into the bladder wall has, in clinical trials, shown significant improvement in symptoms for patients who have not responded to behavioural or conventional pharmacotherapy. The need for repeated administration every 6-9 months, risk of UTIs, and intermittent catheterisation for post voiding residuals at times may not be acceptable to some patients, however. 6

Additional Pharmacotherapy Treatments

Tricyclic Antidepressants (TCAs) are potent inhibitors of muscarinic, a-adrenergic, and histamine H1 receptors, and inhibit noradrenaline and serotonin reuptake at nerve terminals. They have been shown to reduce bladder contraction and increase the bladder volume required to initiate reflex voiding in animal studies. They may be considered as second or third line therapy in “off label” use.

Desmopressin is a synthetic form of the antidiuretic hormone vasopressin used for the treatment of nocturia and nocturnal enuresis in children and adults. The main risk of desmopressin treatment is hyponatremia.

Hormone Replacement Therapy (HRT) has shown a statistically significant improvement in symptoms of frequency, urgency and incontinence episodes, with both topical and oral formulations demonstrating these benefits. 2

Phosphodiesterase inhibitors (PDE1 and PDE5) have been observed to lead to improvements in urodynamic measures. PDE5 medications (sildenafil, tadalafil) are licensed in some countries for lower urinary tract symptoms and erectile dysfunction management in men, but not specifically in OAB.

Recent research has indicated that low dose tadalafil has been found to be effective in treating OAB in women but it is not licensed for this use. 6

In general, ER formulations of anticholinergics lead to better QoL improvements than immediate release formulations. Long term patient compliance may be an issue due to the requirement of long term therapy and occurrence of side effects. Treatment persistence was better with solifenacin than with other agents. 2

Non-Pharmacological Treatments

Sacral neuromodulation (SNM) is a process in which an electrode is placed in the sacral foramen to stimulate S3/S4 nerve roots. This is tested, and if symptoms improve, implanted. It has similar reported success rates to the use of Botox injections, ~69%.

Posterior tibial nerve stimulation (PTNS) involves electrical stimulation of the sacral micturition centres using a fine needle placed just above the medial ankle. It aims to alter the abnormal stimulation of the nerves that supply the bladder. No long term data (over 6 months) is yet available for this, although a 71-79.5% patient reported response to improvement has been observed. Treatment requires 12 sessions lasting about 30 minutes, usually once a week. There is at the moment no consensus regarding the use of PTNS among the clinical guidelines.

Augmentation cystoplasty, also known as bladder augmentation, is a type of surgery to make the bladder larger. This is generally a last resort. Intermittent catheterisation may be required after the procedure, but for some patients with severe intractable symptoms, this is preferable to the symptoms of OAB. 6

OAB is a syndrome with no cure, rather than a disease, and patient education about treatment, adherence and outcomes is important. The most up to date clinical guidelines should always be consulted to advise about the most current treatment recommendations. Pharmacists can play an important role in the management of OAB. Because of the accessibility of pharmacies, this can put pharmacists and pharmacy teams in a good position to recognise and advise OAB patients. 11 Pharmacists can further assist by providing additional evidence based information to patients about their therapy and other treatment options. Furthermore, at the point of dispensing and supply, pharmacists have an opportunity to further educate patients about treatment, provide advice on any side effects, and reinforce the need for longterm adherence, which is important for successful management of any chronic condition.

References

1. Funada, S., Yoshioka, T., Luo, Y., Sato, A., Akamatsu, S., & Watanabe, N. (2020). Bladder training for treating overactive bladder in adults. The Cochrane Database of Systematic Reviews, 2020(4).

2. Jayarajan, J., & Radomski, S. B. (2014). Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life. Research and reports in urology, 6, 1.

3. Haylen, B. T., De Ridder, D., Freeman, R. M., Swift, S. E.,

Berghmans, B., Lee, J., … & Schaer, G. N. (2010). An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourology and Urodynamics: Official Journal of the International Continence Society, 29(1), 4-20.

4. Lightner, D. J., Gomelsky, A., Souter, L., & Vasavada, S. P. (2019). Diagnosis and treatment of overactive bladder (nonneurogenic) in adults: AUA/SUFU guideline amendment 2019. The Journal of urology, 202(3), 558- 563.

5. Health Service Executive. (n.d.). Overactive Bladder/Urge Incontinence. Available https:// www.hse.ie/eng/services/list/2/ primarycare/community-fundedschemes/continence/public/urgeincontinence-leaflet.pdf

6. Fontaine, C., Papworth, E., Pascoe, J., & Hashim, H. (2021). Update on the management of overactive bladder. Therapeutic Advances in Urology, 13, 17562872211039034.

7. Bladder Health UK. (2022). Overactive Bladder. Available https://bladderhealthuk.org/page/ index/306

8. Abdel-Fattah, M., Chapple, C., Guerrero, K., Dixon, S., Cotterill, N., Ward, K., … & Norrie, J. (2021). Female Urgency, Trial of Urodynamics as Routine Evaluation (FUTURE study): a superiority randomised clinical trial to evaluate the effectiveness and cost-effectiveness of invasive urodynamic investigations in management of women with refractory overactive bladder symptoms. Trials, 22(1), 1-18.

9. Bladder and Bowel Foundation. (2008). Pelvic Floor Exercises For Women Available https:// www.nhs.uk/planners/ pregnancycareplanner/documents/ bandbf_pelvic_floor_women.pdf

10. Madhuvrata, P., Cody, J. D., Ellis, G., Herbison, G. P., & Hay- Smith, E. J. C. (2012). Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database of Systematic Reviews, (1).

11. Stewart, K., McGhan, W. F., Offerdahl, T., & Corey, R. (2002). Overactive bladder patients and the role of the pharmacist. Journal of the American Pharmaceutical Association (1996), 42(3), 469-478.