Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Explain the diagnostic criteria of overactive bladder (OAB).

2. Describe various treatment options for OAB.

3. Differentiate risks of medications prescribed for OAB and explain patient selection for use of trospium, mirabegron, or vibegron before urogynecology referral.

Overactive bladder (OAB) is a symptomatic condition characterized by urinary urgency, with or without incontinence, and is often associated with nocturia and increased frequency.1 OAB is highly prevalent in the US adult population, affecting women and men similarly (16.9% and 16%, respectively). The prevalence of symptom type and severity, however, significantly differs by sex, with women noting urgency incontinence more frequently than men: 19.1% in women aged 65 to 74 years and 8.2% in men aged 65 to 74 years.2 In women older than 65 years, the prevalence of OAB increases from 16% to 30%.3 The hallmark physiologic abnormality responsible for OAB is detrusor overactivity, a diagnosis made clinically with evaluation of symptoms, or through urodynamic testing showing involuntary detrusor contraction during filling cystometrogram. Compared with matched controls, OAB, with and without urgency incontinence, is associated with significantly lower quality-of-life scores, higher depression scores, and a poorer quality of sleep and can be debilitating to patients.2-4

Initial management of OAB includes lifestyle modifications, such as pelvic floor exercises, weight loss, bladder retraining, and fluid restriction.3 Second-line management has historically relied heavily on oral anticholinergic medications. Recent data have emerged showing a significant association between long-term use of anticholinergic medication and increased risk of cognitive impairment and dementia.5-10 Given these new data, a focus on alternative oral medication treatments has emerged, including use of selective M2/M3 antagonists such as trospium and [beta]-3 adrenergic agonists mirabegron and vibegron.11-13 The American Geriatrics Society recently updated the Beers Criteria to include anticholinergic medications as a risk factor for dementia.14 As the risk of developing both OAB and dementia increases with age, it is important to consider alternative therapies to mitigate this risk. Our aim is to increase awareness among general practitioners of the association between specific OAB anticholinergic medication and dementia and to provide alternative oral medication treatment options for OAB.

Methods

We performed a comprehensive PubMed and NCBI search for studies of medication treatment of OAB using the search terms anticholinergics, dementia, OAB, mirabegron, trospium, and antimuscarinics. The search was limited to articles published since 2000 and included landmark publications on the association of anticholinergic use and cognitive impairment and dementia. We synthesized the findings of these studies to create a guide for providers to prescribe safe and effective oral medication for patients with OAB.

Results

History and Mechanism of Anticholinergics

For many years the only pharmacologic agent available to treat OAB was anticholinergic drugs, beginning with the use of oxybutynin in the 1970s.15 Anticholinergic receptors are present throughout the entire body. M1/M2, which are important for higher cognitive function, are present in the brain, and M2/M3 are the primary receptors present in the bladder.13 Anticholinergic medication used for the treatment of OAB will bind to all muscarinic receptors throughout the body, thereby leading to unintended affects.13 There are 2 specific types of anticholinergics used for OAB, tertiary or quaternary amines. Tertiary amines are neutral charge, smaller, and lipophilic, theoretically allowing crossing of the blood-brain barrier with the ability to bind to brain receptors. Alternatively, quaternary amines are positively charged, less lipophilic, and hydrophilic, theoretically preventing penetration of the blood-brain barrier.13

Dementia and Anticholinergic Burden

In recent years, there has been increased evidence showing a significantly increased risk for all-cause incident dementia and Alzheimer disease, with a higher cumulative dose-response relationship of anticholinergic medications.5,7,8,10,12,13,16,17

Studies comparing central nervous system penetration among anticholinergics demonstrate significant penetration with oxybutynin, tolterodine, and solifenacin, whereas poor penetration was seen with darifenacin, fesoterodine, and trospium chloride.17 Darifenacin and solifenacin are more selective toward M3 over M1, whereas oxybutynin and tolterodine are less selective, suggesting the latter are more likely to exert central nervous system side effects.18 However, a case-control study by Matta et al9 showed there was an increased odds of developing dementia in those taking solifenacin and darifenacin in the 6 months before diagnosis of dementia and those taking solifenacin, darifenacin, tolterodine, or fesoterodine in the year before diagnosis of dementia compared with those receiving mirabegron.9 This association was not found with trospium or oxybutynin, which they attribute to protopathic bias.

The most recent Cochrane review by Taylor-Rowan et al19 in 2021 showed a consistent association between risk of future dementia and use of anticholinergic medication. The review was unable to determine a causal role; however, anticholinergics can potentially double an individual's risk for developing dementia.19

Duration and cumulation of anticholinergic therapy and association with dementia is a point of interest. Recent evidence shows an increased risk of dementia in patients taking anticholinergics for greater than or equal to 3 months.7-10 A meta-analysis by Dmochowski et al10 calculates an increased risk of dementia by 46% with use of anticholinergics for greater than or equal to 3 months compared with nonuse. OAB anticholinergic use for more than 3 months (ie, darifenacin, fesoterodine, flavoxate, oxybutynin, solifenacin, tolterodine, propiverine, and trospium) was associated with an increased risk of dementia with odds ratios (ORs) ranging from 1.21 to 1.358 and 1.35 to 1.65.7 Notably, the risk of dementia from bladder anticholinergics was higher than the overall risk across all other anticholinergic agents, excluding antipsychotics, with increasing daily doses associated with higher odds of dementia [adjusted OR 1.65; 95% confidence interval (CI) 1.65-1.75] at the highest daily dose of anticholinergics.7 Anticholinergics with a higher Anticholinergic Burden Score of 2 or 3 (as defined by total daily dose of anticholinergics with higher scores indicating higher total daily doses) had a dose response relationship (adjusted OR 1.57; 95% CI 1.18-2.09; and adjusted OR 1.31; 95% CI 1.22-1.41, respectively), with higher daily doses associated with a higher odds of dementia.8

The association of anticholinergics for OAB and cognitive decline is also seen in anticholinergic treatment for depression, Parkinson disease, psychosis, and epilepsy.5-8,10 Among the various anticholinergic medications, bladder antimuscarinics (OR 1.65; 95% CI 1.65-1.75) demonstrate the most significant increase in risk.7 The increased risk of dementia may persist after discontinuation of anticholinergics, as patients who have taken anticholinergics in the past have a similar risk of dementia as those who are currently taking anticholinergics.13

Management

All patients with OAB can benefit from initial lifestyle modifications such as weight loss, caffeine reduction, reduction in fluid intake by 25% to 50%, and bladder retraining.1,3 A Cochrane review of 23 trials showed symptomatic improvement among patients who used anticholinergic therapy compared with bladder training alone (risk ratio 0.57; 95% CI 0.38-0.88).20 After initiating a conservative approach, including lifestyle modifications and bladder retraining, medication management still remains a central aspect of managing OAB.

Trospium Chloride

Anticholinergic therapy has been shown to be statistically more effective in reduction of micturition episodes per day, incontinence episodes per day, and reduction of urgency episodes per day.21 Medication management of OAB is an effective treatment, especially when combined with first-line behavioral modifications.20 In an effort to reduce negative cognitive effects of anticholinergics, newer selective agents, such as trospium chloride (a quaternary amine), should be considered an effective, first-line medical treatment option for OAB.11,13 In a study by Staskin et al,22 12 patients with OAB with a mean age of 68 years without dementia were given trospium chloride for 10 days and cerebral spinal fluid was tested at 0, 5, and 24 hours after administration. Trospium chloride was present in plasma, however was undetectable in cerebrospinal fluid, and neurocognitive assessments found no significant effect on learning or recall.22 In a multicenter phase III trial, trospium was well tolerated, improved quality of life, and was found to decrease the total number of voids, incontinence episodes, daily micturition, and severity of urge symptoms.23,24 Patients who took trospium chloride 20 mg twice a day experienced effect after 1 through 12 weeks, with the most common side effects being dry mouth and constipation, without other significant adverse events.24 In a randomized phase III noninferiority trial conducted in Germany in 2009, trospium chloride was shown to be noninferior to oxybutynin hydrochloride, and, thus, a great alternative treatment to oxybutynin.25

Mirabegron and Vibegron

Mirabegron and vibegron are [beta]-3 adrenergic agonists rather than anticholinergics, and bind to [beta]-3 receptors in the bladder wall, causing bladder relaxation as the bladder fills.1,11,13 Mirabegron is FDA approved for the treatment of OAB and has been found to significantly decrease incontinence episodes and urinary frequency while increasing bladder capacity.1,12,13 Mirabegron is an effective alternative to anticholinergics allowing avoidance of the common side effects seen with anticholinergics (dry mouth and dry eyes) and avoids contributing to anticholinergic load.11,12 In 1 randomized controlled trial, mirabegron (100 mg) had similar efficacy as tolterodine XR (4 mg) at 12 weeks.11 Mirabegron is overall well tolerated, with the most common side effects being hypertension, urinary tract infection, diarrhea, and constipation.11,12 Mirabegron should therefore be avoided in patients with uncontrolled hypertension, chronic kidney disease stages 3 to 5, or liver disease.

Refractory Cases

OAB cases refractory to behavioral modifications and oral medications should be referred to a specialist in bladder care. Third-line treatments can be considered, including intradetrusor botulinum toxin injections,26 percutaneous tibial nerve stimulation, and sacral neuromodulation.

Discussion

Data have shown a strong association between anticholinergic use and development of dementia. Higher cumulative use of anticholinergic medications is associated with increased risk of dementia. The data reviewed in this article show a significant association between increased dementia risk and multiple anticholinergic drug types including antidepressants, antiparkinson drugs, antipsychotics, bladder anticholinergics, and antiepileptics. Given the age of the population affected by OAB and the association between anticholinergic load and cognitive decline, it is pertinent to find alternative treatment options for OAB. It is also imperative to assess what other medications used by this patient population may contribute to their anticholinergic load or burden. Oxybutynin has historically been the most common oral medication for OAB treatment; however, there are many alternative, safer treatments now available. Anticholinergics such as trospium chloride with different molecular properties from other anticholinergics and [beta]-3 agonists, such as mirabegron and vibegron, have been shown to be effective treatment medication options for OAB. They avoid crossing the blood-brain barrier and therefore do not add to anticholinergic burden, thus decreasing the risk for cognitive decline.

Limitations

This review included multiple meta-analysis, case-control, prospective studies and review articles and lacked weighing of evidence by study design. Our comprehensive review may have missed some of the data available on the role of anticholinergics and risk of dementia: however, we aimed to show the most robust and recent data in an effort to create a guideline for practitioners prescribing oral OAB treatment.

Conclusion

OAB is a common problem, greatly affecting quality of life. Anticholinergic medications have long been the most commonly used medication for OAB. Recent data have shown significant associations between the use of anticholinergic medications and increased risk of cognitive impairment and dementia. We strongly recommend prescribing mirabegron or vibegron, or trospium as initial medication management for OAB. If symptoms persist despite medication management, patients should be referred to specialists for alternative options.

Practice Pearls

* OAB is a highly prevalent condition (16%-30%), for which all patients should be screened at their annual examinations.

* Initial management of OAB should consist of lifestyle modifications including weight loss, pelvic floor therapy, and fluid restriction.

* When behavioral therapy fails, caution should be used in prescribing anticholinergics to treat OAB, as some have been shown to be associated with increased risk for dementia. Careful counseling should be given to patients if anticholinergics are prescribed including a discussion of the risks of dementia and cognitive impairment balanced against the possible symptomatic benefits.

* Mirabegron or trospium should be considered first-line medications to treat OAB due to decreased risk of dementia compared with alternative antimuscarinics.

REFERENCES