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Combination and Novel Pharmacologic Agents for OAB - Beyond the Abstract

Overactive bladder (OAB) is a common bothersome condition defined by the International Continence Society as “urinary urgency, usually with urinary frequency and nocturia, with or without urgency incontinence” in the absence of urinary tract infection (UTI).1 More than 16% of adults in the United States suffer from this condition according to telephone surveys conducted by the National Overactive Bladder Evaluation (NOBLE) Program in 2001.2 Besides the estimated cost of about $750 per year per person, OAB contributes to a substantial decline in quality of life including higher rates of depression, decreased social functioning, and a decline in quality of sleep.

There are many available treatments for OAB, and the American Urologic Association (AUA) and the Society of Urodynamics, Female Pelvic Medicine, and Urogenital Reconstruction (SUFU) have developed clinical care pathways to guide physicians in management of OAB. The AUA/SUFU pathway consists of three stages of therapy. First-line therapy involves behavioral therapies such as urge suppression, dietary modification, or pelvic floor training for a period of 4-8 weeks. Second-line treatment involves pharmacotherapy with antimuscarinics or Beta-3 agonists for a period of at least 4-8 weeks. Finally, patients without satisfactory resolution of symptoms can be offered third-line advanced therapies such as sacral neuromodulation (SNM), chemodenervation (e.g. Botox), or percutaneous tibial nerve stimulation (PTNS).

Despite many OAB treatment options, complete resolution is rarely achieved. There is an approximate 70% discontinuation rate of OAB medication at 6 months,3-5 and only 9% of women with OAB continue with medical management at 1 year.6 Furthermore, only 5-10% of patients subsequently progress to third-line treatment options.7 Among patients eligible for third-line therapies, up to 13% may not choose an advanced therapy due to invasiveness of the procedure, frequent follow-up requirements, or possible adverse outcomes.8 Novel and combined therapies could serve as an option to fill the gap of patients discontinuing second-line therapies or those dissatisfied with third-line options.

The etiology of OAB can guide therapy. OAB may be caused by dysfunction of neural, muscular, and/or urothelial systems. The myogenic hypothesis posits that OAB symptoms are a result of detrusor overactivity during the filling phase of urodynamics. The urotheliogenic hypothesis attributes urgency to aberrant sensory function of the urothelium. Finally, the neurogenic hypothesis emphasizes the role of dysfunctional integration of afferent sensory signals with supraspinal inhibitory control of the micturition reflex. While monotherapies targeting these pathways have shown to be effective, recent studies have demonstrated improved efficacy when combining therapeutic agents with conflicting reports of increased side effects.

Combined oral agents target the myogenic hypothesis of OAB with agents that offer broad coverage of one receptor target or agents that target two distinct receptors in the myogenic pathway. Combined anticholinergic agents (such as trospium and solifenacin or tolterodine) aim to diversify the muscarinic receptors targeted. When incorporated with cyclic therapy, combined anticholinergics have demonstrated compliance as high as 80% at one year.9 On the other hand, combining anticholinergics with a beta-3 agonist (solifenacin and mirabegron) nearly doubled the decrease in episodes of urge incontinence when compared to either therapy alone. However, this benefit was associated with higher incidence of adverse events, such as retention, though they were mild or moderate in severity.10

Combining second-line oral agents with third-line advanced therapies aims to treat OAB by targeting more than one pathway. Anticholinergics combined with PTNS resulted in significantly improved urgency and urgency urinary incontinence compared to either monotherapy in a randomized control trial of 105 women.11 Combining anticholinergics with SNM resulted in subjectively reported improvements in a retrospective review of patients who either restarted anticholinergic therapy after SNM or were on the medication while undergoing SNM.12 There have been no studies investigating the combination of anticholinergics with intradetrusor Botox nor the combination of beta-3 agonists with any of the third-line advanced therapies. Future studies should investigate whether these therapies can produce synergistic effects as others have.

New generation anticholinergic or beta-3 agonist agents entering the market may improve compliance with treatment with greater receptor selectivity and decreased adverse outcomes. Imidafenacin is an anticholinergic with high bladder selectivity, thereby decreasing incidence of dry mouth, constipation, and other anticholinergic side effects. When compared to other anticholinergics, Imidafenacin showed improved efficacy in decreasing nocturia and had similar effects on voids, urgency, urgency incontinence episodes, and incontinence episodes. With a significantly lower incidence of dry mouth, constipation, and withdrawal from medication, Imidafenacin may improve compliance with second-line therapies.13 Novel beta-3 agonists such as solabegron, ritobegron, and vibegron have shown promising results in animal studies and early clinical trials but have not been compared to already established second-line therapies.

Novel agents in oral therapy may target the urothelial or neurogenic pathway of OAB. One target is P2X receptors on nerve fibers, which detect the level of ATP released from the urothelium with bladder stretching. The role of these receptors in sensing and initiating micturition has been demonstrated in knockout mice models.14 Another target is the transient receptor potential (TRP) channels, which have been implicated in neurogenic lower urinary tract dysfunction. Though agonistic agents (capsaicin and resiniferatoxin) have been used to desensitize TRP channels, they have been associated with hyperthermia and reduced heat sensation leading to burn injuries.15 Newer agents targeting these channels more specifically may prove to become a new therapy in OAB. Finally, gabapentin is a neuromodulator that has long been used in neurologic and psychologic conditions. Its use in OAB showed comparable improvements in micturition and urgency episodes as solifenacin with superiority over solifenacin in mean nocturia episodes.16

Agents targeting less commonly accepted hypotheses of OAB are on the horizon. Amiloride, an inhibitor of epithelial sodium channels (ENaC), has been shown to normalize the intercontaction interval, which may be reduced in patients with OAB.17 Sildenafil, a phosphodiesterase-inhibitor, has been shown to promote relaxation of detrusor muscle via cGMP, cAMP, and potassium channel signaling pathways.18 Finally, Nicorandil, a vasodilatory drug, may act as an agent to decrease theoretical ischemia that may induce OAB.19

The pathogenesis of OAB remains complex and not fully understood. While proposed hypotheses have led to effective treatments and guidelines, compliance rates remain low and overall burden remains high. Additionally, no single therapy has been found to be curative or effective for all patients. Recent studies have demonstrated promising results when combining agents and proposed new agents that target pathways under investigation. Given the complex etiology of OAB, further research may elucidate the pathogenesis of this condition and greatly enhance its treatment.

Written by: Arshia Aalami Harandi, MS, & Whitney Clearwater, MD, MPH, Albert Einstein College of Medicine, Bronx, New York, USA

References:

  1. Haylen BT, de Ridder D, Freeman RM, et al. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Int Urogynecol J. 2010;21(1):5-26.
  2. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20(6):327-336.
  3. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105(9):1276-1282.
  4. Yeaw J, Benner JS, Walt JG, Sian S, Smith DB. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm. 2009;15(9):728-740.
  5. Chancellor MB, Migliaccio-Walle K, Bramley TJ, Chaudhari SL, Corbell C, Globe D. Long-term patterns of use and treatment failure with anticholinergic agents for overactive bladder. Clin Ther. 2013;35(11):1744-1751.
  6. Lifshitz K, Mintz, I., Shenhar, C., Yossepowitch, O., Baniel, J., Shtabholtz, Y., Aharony, S. A0442 - Persistence of overactive bladder pharmacological treatment in women as reflected from large-scale real-world data of prescription claims: A retrospective cohort study (2010-2020). European Urology. 2022;81:S660-S661.
  7. Amundsen CL, Richter HE, Menefee SA, et al. OnabotulinumtoxinA vs Sacral Neuromodulation on Refractory Urgency Urinary Incontinence in Women: A Randomized Clinical Trial. Jama. 2016;316(13):1366-1374.
  8. SUFU 2022 Abstracts Issue of Neurourology and Urodynamics. Neurourol Urodyn. 2022;41 Suppl 1:S5-s254.
  9. Kosilov K, Loparev S, Iwanowskaya M, Kosilova L. Effectiveness of combined high-dosed trospium and solifenacin depending on severity of OAB symptoms in elderly men and women under cyclic therapy. Cent European J Urol. 2014;67(1):43-48.
  10. Herschorn S, Chapple CR, Abrams P, et al. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study). BJU Int. 2017;120(4):562-575.
  11. Vecchioli-Scaldazza C, Morosetti C. Effectiveness and durability of solifenacin versus percutaneous tibial nerve stimulation versus their combination for the treatment of women with overactive bladder syndrome: a randomized controlled study with a follow-up of ten months. Int Braz J Urol. 2018;44(1):102-108.
  12. George E, Lane F, Noblett K. Use of combined anticholinergic medication and sacral neuromodulation in the treatment of refractory overactive bladder. Female Pelvic Med Reconstr Surg. 2011;17(2):97-99.
  13. Wu JP, Peng L, Zeng X, Li H, Shen H, Luo DY. Is imidafenacin an alternative to current antimuscarinic drugs for patients with overactive bladder syndrome? Int Urogynecol J. 2021;32(5):1117-1127.
  14. Hao Y, Wang L, Chen H, et al. Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function. JCI Insight. 2019;4(16).
  15. Andersson KE. Agents in early development for treatment of bladder dysfunction - promise of drugs acting at TRP channels? Expert Opin Investig Drugs. 2019;28(9):749-755.
  16. Chua ME, See MCt, Esmeňa EB, Balingit JC, Morales ML, Jr. Efficacy and Safety of Gabapentin in Comparison to Solifenacin Succinate in Adult Overactive Bladder Treatment. Low Urin Tract Symptoms. 2018;10(2):135-142.
  17. Yamamoto S, Hotta Y, Maeda K, et al. Mineralocorticoid receptor stimulation induces urinary storage dysfunction via upregulation of epithelial sodium channel expression in the rat urinary bladder epithelium. J Pharmacol Sci. 2016;130(4):219-225.
  18. Oger S, Behr-Roussel D, Gorny D, et al. Signalling pathways involved in sildenafil-induced relaxation of human bladder dome smooth muscle. Br J Pharmacol. 2010;160(5):1135-1143.
  19. Saito M, Ohmasa F, Tsounapi P, et al. Nicorandil ameliorates hypertension-related bladder dysfunction in the rat. Neurourol Urodyn. 2012;31(5):695-701.

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