Recent advances in pharmacological management of urinary incontinence

Introduction

Urinary incontinence (UI), alone or as an overactive bladder (OAB) symptom, is a growing global health-care problem that increases in prevalence with age^1–3. UI is 1.5 times more common in women than men, affecting approximately 45% and 77% of adult males and females, respectively, in the US, the UK, and Sweden⁴. Both severity and frequency of UI significantly increase mortality among men and women⁵. An industry report recently predicted a 2.9% global market growth rate of pharmacological treatments for OAB from 2017 to 2022 and projected a total cost of USD $4.19 billion by the year 2020⁶. Despite its widespread prevalence and socioeconomic burden, incontinence therapy remains limited and often accompanied by significant adverse effects (AEs), low efficacy, and high discontinuation rates^7,8. In addition, there is surprisingly little information regarding biomarkers that can identify age-induced bladder dysfunction or patient response to treatment. There is a growing and pervasive need for pharmacologic therapies that are efficacious, safe, and tolerable. Efforts in the past three years have identified potential new targets in addition to combination therapies or adding a non-pharmacological intervention or both. This article will highlight advances within the last three years regarding current pharmacological treatments for both urge UI (UUI) and stress UI (SUI).

UI subtypes

Clinical and basic science has classified UI into subtypes based on pathophysiology and causal factors. The most bothersome subtype reported by women is UUI^4,9 whereas the most prevalent subtype is SUI^4,10. The pathophysiology underlying UUI is complex and based on altered physiological mechanisms controlling bladder storage and emptying. Causal factors have been focused on myogenic, neurogenic, and (more recently) sensory dysfunction (see review 11). SUI is urinary leakage due to increased abdominal pressure caused by sneezing, coughing, exercise, lifting, and position change. Its pathophysiology, compared with that of UUI, may be less complex and largely related to physical changes in structures forming or in relation to the lower urinary tract (for example, the pelvic floor muscles). A large proportion of women experience mixed urinary incontinence (MUI), which includes both UUI and SUI symptoms. Studies have reported MUI alone to affect 2–4 out of 10 women who are from 20 to more than 80 years old^4,9. Following clinical determination of urge or stress incontinence, a number of treatment regimens can be followed. Deciding on a treatment regimen is a multi-factorial decision process dictated in part by UI subtype and symptom severity.

Pharmacological management for urge incontinence

Anti-muscarinic (anti-cholinergic) drugs remain the most widely used treatment option for UUI and often are used in primary care in combination with behavioral and lifestyle changes, which can include pelvic floor muscle training exercises or reduction of caffeine intake or both. An unfavorable balance between efficacy and tolerability of anti-muscarinic agents, despite their widespread use, exists and has raised questions regarding the overall benefits derived from use of these agents. Furthermore, caution regarding use of anti-muscarinics is recommended in frail elderly patients because of an increased risk of cognitive impairment^12,13. Oxybutynin is the most widely prescribed anti-muscarinic for UUI¹⁴. Other drugs, such as β3-agonists and phosphodiesterase 5 (PDE5) inhibitors, are available and may have fewer unwanted AEs but have not been shown to be any more effective in improving storage lower urinary tract symptoms. Several advances are being made to reduce anti-cholinergic side effects primarily by creating receptor-selective agents, altering formulation or administration (or both), thus minimizing AEs caused by systemic antagonism of cholinergic receptors.

Currently licensed anti-muscarinics indicated for incontinence include orally prescribed oxybutynin, tolterodine, and trospium available as immediate release (IR) and extended release (ER) formulations. In addition, US Food and Drug Administration (FDA)-approved anti-muscarinics include fesoterodine, darifenacin, and solifenacin as oral IR formulations. Propiverine is an oral anti-muscarinic approved in Asia and recently in Canada and is awaiting FDA approval for the US¹¹. Oxybutynin is the most widely available anti-muscarinic in the US, where it is also available in oral ER and transdermal formulations¹³.

Transdermal formulations of oxybutynin and tolterodine were introduced in 2007 to avoid/minimize systemic AEs associated with oral treatments. A comparison study in 2017 involving 1,530 patients (more than 20 years old) with OAB assessed efficacy and toxicity at 12 weeks between the oxybutynin patch and oral propiverine (20 mg). The authors reported non-inferiority in terms of reducing the number of incontinence episodes (urge or total incontinence). While a greater incidence of AEs was reported with oxybutynin patch versus propiverine group (74.8% versus 64.9%), the incidence of dry mouth or constipation was reduced more than 50% compared with propiverine. The predominant AE associated with the patch, which affected 40.2% of patients, was dermatitis and was reportedly mild in the majority of cases; 26.7% of the affected group (10.7% total) continued treatment with topical steroidal treatment¹⁵. A phase 3 study assessed the efficacy and safety of once-daily applied oxybutynin transdermal gel 3% (OTG3%) (84 or 56 mg) or placebo in 624 adult patients with OAB-UUI. At 12 weeks, OTG3% 84 mg reduced the weekly number of incontinence episodes (urge and mixed) compared with placebo (difference from baseline, -20.4 versus -18.1, respectively). The study concluded that OTG3% 84 mg/day was well tolerated and effective in this adult population¹⁶. Lastly, a large meta-analysis in women with OAB found that long-acting oxybutynin formulations (oral, patch, and gel), compared with IR, were more effective, had a lower incidence of AEs, and were better tolerated¹⁷.

Little evidence is available to support the long-term use of anti-muscarinics. Besides the typical systemic effects which can include dry mouth, constipation, and blurry vision, increasing new evidence indicates that cumulative anti-muscarinic use is associated with an increase in incident dementia¹⁸ as well as mood disorders, including depression¹⁹. These findings support earlier reports of associated depression with short-term anti-muscarinic treatment²⁰. The new knowledge of incident dementia and mood disorders warrants careful consideration by clinicians and patients when considering treatment options for incontinence, particularly in elderly patients and those with neurobiological disease such as multiple sclerosis and Alzheimer’s disease. In the past three years, clinicians have created FORTA (Fit fOR The Aged), a clinical tool to help aid decision making regarding appropriateness of pharmacotherapies in elderly patients often being treated for multiple conditions²¹.

Pharmacological management for stress incontinence

SUI is the involuntary leakage of urine on exertion, sneezing, or coughing⁴⁹. In clinical practice, the most efficacious approach to reduce the number of incontinence episodes is to increase musculature tone in the pelvic region (pelvic floor muscles) with exercise^12,50. Although data supporting long-term use are limited, α1-AR antagonists have been used to increase urethral tone to ensure continued closure during episodes of increased pressure. Alternative drugs such as β2-AR agonists have been used in Japan for SUI treatment²³.

Studies report an increased risk of pelvic floor disorders after menopause and this may be linked to estrogen deficiency; thus, estrogen therapy may be beneficial in improving SUI in post-menopausal women. A meta-analysis of clinical trial data rated the evidence for efficacy of estrogen in reducing incontinence as low but well tolerated, much more so than alternative drugs for OAB/incontinence^51,52. The route of administration appears to be very important as recently concluded by a Cochrane review. The authors reported worsening of UI with systemic estrogen versus an improvement in UI when estrogen was applied locally⁵³. Conversely, the addition of vaginal estrogen to IR or ER tolterodine did not improve urinary symptoms more than tolterodine alone⁵¹. In addition, vaginal estrogen has been shown to normalize the microbiota and bladder function, making the case for preventive treatment^54,55. Current guidelines suggest the use of estrogen as an adjunct therapy⁵¹.

Duloxetine is a dual serotonin and noradrenaline reuptake inhibitor currently approved in Canada, the US, and Europe for depression. In 2004, duloxetine, under the trade name Yentreve, was approved and licensed in Europe as an add-on therapy for SUI⁵⁶. Despite reported efficacy in US and Canadian phase III trials^57,58, licensing in the US and Canada failed because of concerns over incident suicidality. The FDA reported a doubling in suicide attempts in women receiving the drug for SUI compared with that in the general population (see product information at: https://www.fda.gov/downloads/drugs/developmentapprovalprocess/developmentresources/ucm328101.pdf). An independent analysis of the dataset used by the European Medicines Agency to license duloxetine was performed by a Canadian research group specifically assessing psychological disturbances. The authors concluded that the risks outweighed the benefits, thus raising concerns regarding the rationale for duloxetine use for treatment of SUI^59,60. As of 2013, National Institute for Health and Care Excellence guidelines recommend duloxetine (Yentreve) as a second-line therapy in place of surgery for women with SUI, and counseling on expected AEs is advised⁶¹.

Conclusions

In terms of pharmacologic treatment for UI, many drugs exhibit poor efficacy and increased incidence of AEs. Alternative approaches such as the herbal medicine drug AOBO-001 have been introduced for OAB-incontinence and frequency in adults, and a phase II clinical trial is under way to study efficacy in adults with urge incontinence. There is a need for development of new therapeutic approaches, especially in terms of SUI, which have limited options. However, given the recent examples of off-target effects, one should carefully consider increased patient vulnerability to toxicity and AEs due to change in organ function which presents more opportunity for drug-disease interactions.