Drug Therapy for an Overactive Bladder

“…a commonly reported problem with antimuscarinic medication is the intolerability due to side effects. These include dry mouth, constipation, blurred vision and cognitive impairment, especially in the elderly.”

Overactive bladder syndrome (OAB) is defined as 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 [1]. OAB has been shown to affect between 17 and 36% of adult women in Europe and USA [2–4]. Involuntary contraction of the detrusor muscle is termed detrusor overactivity (DO) and is the presumed underlying cause of OAB [1]. The mechanisms involved in the OAB symptom complex are multifactorial but the mainstay of medical management of OAB focuses on the treatment of DO without any underlying cause, ‘idiopathic DO’. OAB has a significant effect on quality of life and has been shown to increase the risk of falls, fractures, urinary tract and skin infections [5]. The NICE has recommended that the first-line treatment of OAB should be conservative management with lifestyle advice and bladder training. If a woman does not achieve satisfactory symptom relief after 6 weeks of conservative management alone, she may benefit from drug therapy [6].

The drug management of OAB is based upon understanding of the micturition reflex [7]. During bladder filling, sympathetic stimulation is predominant, with activation of β-adrenergic receptors, via fibers of the hypogastric plexus, suppressing contraction of the detrusor muscle in the bladder [8,9]. To facilitate voiding, acetylcholine is released from parasympathetic postganglionic nerves, mediated by muscarinic receptors, which leads to detrusor contraction and bladder emptying.

Until recently, the medical treatment of OAB has focused on antimuscarinic drugs, also known as anticholinergics, such as Oxybutynin, which block acetylcholine-mediated involuntary detrusor contractions. Compared with placebo, antimuscarinics have shown a statistically significant improvement in patient-reported qualitative and quantitative sensations of cure or improvement [10]. However, a commonly reported problem with antimuscarinic medication is the intolerability due to side effects. These include dry mouth, constipation, blurred vision and cognitive impairment, especially in the elderly [11]. Selective blockade of the M2 and M3 muscarinic receptor subtypes reduces the side effect profile.

As a result of significant side effects, patient persistence with treatment is generally poor with 50% of patients not requesting a repeat prescription following their initial trial of OAB medication. Adherence to treatment at 12 months was found to be just 14–35%, whereas persistence with oral hypoglycemic agents for diabetes was 66% over the same period [11,12]. There has been some improvement with newer more selective and extended release anticholinergic preparations. There are currently seven different antimuscarinic drugs for the treatment of OAB available in the UK: oxybutynin, tolterodine, propiverine, solifenacin, trospium, darifenacin and fesoterodine. These drugs are available in differing doses, duration of release and means of administration. The latest Cochrane review assessed 86 randomized trials including 31,249 adults with OAB or DO to assess which anticholinergic was best. Compared with oxybutnin, tolterodine had similar efficacy but less risk of dry mouth (relative risk [RR]: 0.65). Most available studies reported newer antimuscarinic therapy in direct comparison with tolterodine and found:

• Transdermal oxybutynin had similar levels of dry mouth compared with extended-release tolterodine but some patients withdrew from the trial because of transdermal patch skin reactions;

• Fesoterodine 8 mg and solifenacin 5 mg showed higher rate of cure or improvement (RR: 1.25 and RR: 1.11, respectively);

• Fesoterodine 8 mg had higher risks of dry mouth (RR: 1.80) and withdrawal due to adverse events (RR: 1.45) [13].

Comorbities must be taken into account when offering OAB therapy, for example, women with poor voiding function may be at higher risk of urinary retention with antimuscarinics. Similarly, the age and overall health of the patient must be considered. It is recommended that oxybutynin (immediate release) is avoided in ‘frail older women’ in view of the effect on cognitive function. A number of cohort studies have recently published data correlating an increased likelihood of Alzheimer's disease or dementia in those who have undergone cumulative anticholinergic exposure (odds ratio [OR]: 1.54; 95% CI: 1.21–1.96; p < 0.001) [14]. Worryingly, community prescribed medication, including antihistamines (chlorpheniramine), antiemetics (promethazine) and antidepressants (paroxetine) may already deliver women a high anticholinergic burden. Trospium chloride, a quaternary amine, crosses the blood–brain barrier to a much smaller degree as does darifenacin, a much larger molecule than oxybutynin. Both of these drugs not only cross the blood–brain barrier less readily, but are actively transported out of the CNS [15]. This has been correlated into clinical practice with three randomized controlled trials (RCTs) with a total of 205 patients, showing no significant cognitive effect with darifenacin compared with placebo or oxybutynin extended release [16–18]. A much smaller RCT with just 12 patients showed that solifenacin had no effect on cognitive function [19]. In view of the spectrum of side effects, it is recommended that a patient is started on the lowest recommended antimuscarinic dose and then titrated up if her symptoms demand it [6].

In view of the problem with compliance, recent research has concentrated on newer classes of drug therapy and considered alternative pathways within the micturition reflex. During bladder filling, the activation of β-adrenergic receptors suppresses detrusor muscle contraction [7,9], Stimulation of β3 adrenergic receptors results in detrusor relaxation, thus increasing bladder capacity and reducing OAB symptoms. Mirabegron, ritobegron and solabegron are β3 adrenoreceptor agonists. The latter two are in differing phases of research while mirabegron is available in many countries. Mirabegron was approved by the US FDA for the treatment of OAB in June 2012 and by NICE in June 2013. It is also licensed in Japan, Europe and Canada.

Meta-analysis of six RCTs comprising of about 6500 patients showed that mirabegron was more effective than placebo in treating OAB. Mirabegron was as effective as tolterodine in reducing the number of incontinence episodes and mean number of micturitions per 24 h but had a significantly lower adverse reaction rate [20].

In a multinational study to test the safety, tolerability and efficacy of mirabegron for up to 1 year of use, about 2500 patients were randomized to receive mirabegron or tolterodine once daily for 12 months [21]. Fewer patients taking mirabegron reported dry mouth (up to 2.8%) than tolterodine (8.6%). Serious adverse effects were reported in up to 6.2 and 5.4% of patients, respectively. Mirabegron was found to minimally raise mean blood pressure over the study period by up to 0.4 mmHg compared with a similar minimal increase of 0.5 mmHg with tolterodine.

Low dose local (vaginal) estrogens are also useful in the management of OAB in postmenopausal women. A recent Cochrane review found intravaginal estrogen to be an effective treatment of OAB symptoms in postmenopausal women (RR: 0.74; 95% CI: 0.64–0.86) with around one to two fewer voids per 24 h, less frequency and urgency [22]. Systemic HRT, however, increased OAB symptoms.

It is important to routinely offer a face-to-face or telephone review 4 weeks after the start of each new OAB drug treatment. If there is no or suboptimal improvement or intolerable adverse effects, women should escalate the dose or utilize an alternative OAB drug and be reviewed again 4 weeks later [6]. All women on long-term OAB drug treatment should be reviewed annually (or every 6 months if over 75 years of age) in primary care.

Research continues in the field of OAB drug therapy with studies looking into new routes of administration for existing drugs, new combination treatments and even completely new drugs. A Phase II study detailed the outcomes of 1306 patients who were randomized to receive combinations of solifenacin/mirabegron compared with solifenacin 5 mg monotherapy and placebo. Combination therapy with solifenacin/mirabegron significantly improved mean volume voided, micturition frequency and urgency compared with solifenacin 5 nig monotherapy [23]. Other novel concepts are also being investigated such as the antinicotinic drug dexmecamylamine (TC-5214). TC-5214 is a potent inhibitor of the a3 nAchR subtype which is found in urothelium and regulates bladder smooth muscle contraction. The results of a large Phase IIb double-blind, placebo-controlled, randomized, parallel group trial are eagerly awaited.

For patients with refractory OAB, neuromodulation or intravesical injections of botulinum toxin A can be considered. After these management options, more complex surgical options are required to be considered such as urinary diversion or augmentation cystoplasty. These treatment modalities are beyond the scope of this commentary so will not be discussed further here.

Conclusion

Antimuscarinic medications are currently the mainstay of OAB drug therapy and have been shown to be highly effective. Antimuscarinics have a significant side-effect profile and thus poor compliance. More recently, studies have shown higher cumulative anticholinergic usage as an increased risk of Alzheimer's disease and dementia. Due to these issues, other treatments have been sought and recently, the β3 adrenergic receptor agonist, mirabegron, has been successfully launched and integrated into existing care pathways. With many research programs to establish new better OAB treatment regimens underway, there is potential for effective and tolerable long-term treatment of OAB to exist in the near future.