Pharmacotherapy for Urinary Incontinence

Educational Objectives

The goals of this program are to improve diagnosis and management of urogynecologic conditions. After hearing and assimilating this program, the clinician will be better able to:

1. Evaluate the efficacy and safety of approved, off-label, and investigational pharmacologic agents for treatment of incontinence.

2. Describe plant- and bacterial-derived biologic agents under investigation for treatment of incontinence.

Summary

Overactive bladder (OAB): achieving normal bladder filling requires adequate compliance and sensation, and closed bladder outlet at rest; maintaining continence requires ability to compensate for increased intraabdominal pressure and absence of involuntary contractions of bladder

Pharmacologic agents: efficacy, tolerability, and safety paramount; convenience, understanding pharmacology, and affordability also important

Muscarinic receptors: responsible for control of bladder function; acetylcholine (ACh) released at neuromuscular junction and binds to M2 and M3 receptors in detrusor muscle (affects normal contraction and involuntary contractions); antimuscarinics weak or competitive agonists that block action of ACh at postganglionic site; M2 receptors most numerous in bladder; M3 receptors responsible for normal contraction; M2 receptors active in obstructive and neuropathic conditions; few drugs successfully treat OAB

Approved antimuscarinics: oxybutynin available in immediate-release (IR) and extended-release (ER) formulations, transdermal patch, and gel; tolterodine available in IR and ER forms, fesoterodine in ER, and trospium in IR and ER; others — solifenacin; darifenacin

Comparative data: differences in efficacy minor, but comparative trials scarce; some differences seen in tolerability, but safety profiles good; placebo effect evident in most trials studying frequency and urgency urinary incontinence (UUI); speaker finds difference between active drug and placebo to be more important measure than ratio of effect of active drug to placebo; per International Consultation on Incontinence (ICI), most compounds approved in United States supported by level 1 evidence; differences among compounds evident when examining tolerability (ie, for side effects of dry mouth, constipation, somnolence, and dizziness), receptor binding, and dosing

Other agents: drugs with mixed actions include propiverine, oxybutynin, and flavoxate (Urispas); serotonin-norepinephrine reuptake inhibitors imipramine and duloxetine used for stress incontinence (SUI), but weak evidence suggests efficacy in OAB and detrusor overactivity

Adherence to antimuscarinic therapy: poor; failure of medication to meet expectations most common reason given for stopping; other reasons include side effects and cost

Stress urinary incontinence (SUI): no medication currently approved; α-adrenergics — ephedrine and pseudoephedrine stimulate receptors in urethral smooth muscle; under stress, smooth muscle contributes ≈20% of intrinsic resistance of urethra and skeletal muscle contributes ≈75%, so agents that act on skeletal muscle preferred; side effects include increased blood pressure (BP) and increased peripheral vascular resistance (PVR); duloxetine — (Ariclaim, Cymbalta, Duzela) marketed in United States only as antidepressant, but approved elsewhere for SUI; in presence of glutamate, increases availability of serotonin and norepinephrine in Onuf nucleus and increases skeletal muscle activity in urethra without changing BP or PVR; 24% of patients in phase III trials had nausea and vomiting during first 6 wk of therapy, but later acclimated to drug; however, only 11% of patients became completely dry; imipramine — not approved for SUI, UUI, or mixed incontinence; inhibits reuptake of norepinephrine and serotonin and enhances effect of norepinephrine on smooth muscle; has both striated and smooth muscle effects; early data using 75-mg dose for SUI produced high rates of cure, but in later experience, clinical effectiveness closer to that of duloxetine; conclusions — per ICI, evidence of efficacy for duloxetine grade A, level 1; no good evidence for imipramine or clenbuterol; low-grade evidence available for α-adrenergics and estrogen

α3-agonists: phase II data available on mirabegron, solabegron, and another agent; agents stimulate β3 receptors in bladder but have few β1 and β2 effects, so BP and pulse unaffected; data show two-thirds reduction in UUI episodes, 20% to 26% reduction in urinary frequency, and 20% to 25% increase in voided volume; effects on systolic BP observed in few patients in phase II data for class, but not in phase III trial with mirabegron; 50-mg dose of mirabegron associated with small but significant changes in frequencies of incontinence and micturition and increases in voided volume, compared with placebo; low rates of constipation and dry mouth with β3-agonists may permit synergistic use with antimuscarinics

Future therapies: desmopressin (DDAVP) — effective for OAB; used off-label for nocturia; tachykinin receptor antagonists — NK-1 and NK-2 inhibitors expand bladder capacity and decrease frequency in animals but cause retinal changes in humans; potassium channel openers — promising in animal studies, but no human trials done yet; Bryophyllum pinnatum — plant-derived agent showed trend toward decrease in frequency of micturition in small study

Vanilloids: physiology — act on unmyelinated C-fibers; fibers normally quiescent, but activated in pathologic states in bladder; capsaicin — extract from red peppers; stimulates or burns at first, then desensitizes (produces numbness); intravesical capsaicin under anesthesia successfully controls bladder contractions in ≈50% of patients with neurogenic detrusor overactivity; in largest series, 44% of participants dry and 36% improved; drawbacks include inconsistencies in formulation and need for general or local anesthesia; resiniferatoxin — more potent but less painful than capsaicin; can be instilled in office; significant improvement in incontinence and increased bladder capacity seen in patients with OAB; initial trials in interstitial cystitis used solution of 10% alcohol that produced irritation of bladder

Botulinum toxin: efficacy — in patients with neurogenic detrusor overactivity unresponsive to antimuscarinics, 200-U and 300-U doses superior to placebo; in trials conducted in patients with OAB, 75% achieved 50% reduction in weekly incontinence episodes, ≈37% of patients completely dry, and maximum cystometric capacity increased; median duration of effect 10.5 mo in neurogenic patients; safety — rate of urinary tract infection (UTI) higher in patients on active treatment than placebo (24% vs 17%); among neurogenic patients not self-catheterizing, retention rate higher with active treatment (17% vs 3%); phase III OAB data — group receiving 100 U had greater mean reduction in incontinence episodes than placebo group (48% vs 12%), greater reduction in urinary frequency (17% vs 4%), and greater reductions in episodes of nocturia (20% vs 0%) and episodes of urgency (32% vs 10%); active treatment group had higher rates of retention (5% vs 0.5%) and UTI (16% vs 6%); more patients in active treatment arm achieved 50% reduction in episodes of incontinence (58% vs 38%) and complete dryness (23% vs 6.5)

Readings

Abramov Y et al: Transforming growth factor beta 1 gene expression during vaginal vs cutaneous surgical wound healing in the rabbit. Int Urogynecol J. 2012 Aug 8. [Epub ahead of print];Abrams P et al: Fourth International Consultation on Incontinence Recommendations of the International Scientific Committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn. 2010;29(1):213-40; Amrute KV, Badlani GH: The science behind biomaterials in female stress urinary incontinence surgery. ScientificWorldJournal. 2009;9:23-31; Benner JS et al: Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105(9):1276-82; Braekken IH et al: Can pelvic floor muscle training reverse pelvic organ prolapse and reduce prolapse symptoms? An assessor-blinded, randomized, controlled trial. Am J Obstet Gynecol. 2010;203(2):170.e1-7;Chapple CR et al: Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol. 2013;63(2):296-305; Davila GW: Nonsurgical outpatient therapies for the management of female stress urinary incontinence: long-term effectiveness and durability. Adv Urol. 2011;2011:176498; Duthie JB et al: Botulinum toxin injections for adults with overactive bladder syndrome. Cochrane Database Syst Rev. 2011;(12):CD005493; Fowler CJ et al: OnabotulinumtoxinA improves health-related quality of life in patients with urinary incontinence due to idiopathic overactive bladder: a 36-week, double-blind, placebo-controlled, randomized, dose-ranging trial. Eur Urol. 2012;62(1):148-57; Hay-Smith J et al: Comparisons of approaches to pelvic floor muscle training for urinary incontinence in women: an abridged Cochrane systematic review. Eur J Phys Rehabil Med. 2012;48(4):689-705; Jirschele K, Sand PK: Oxybutynin: past, present, and future. Int Urogynecol J. 2012 Sep 14. [Epub ahead of print]; Kanai A et al: Mechanisms of action of botulinum neurotoxins, β3-adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI-RS 2011. Neurourol Urodyn. 2012;31(3):300-8; Kuo R, Goldberg RP: Nongenetic factors associated with stress urinary incontinence. Obstet Gynecol. 2011;117(2 Pt 1):251-5; Lee HN et al: Pelvic floor muscle training using an extracorporeal biofeedback device for female stress urinary incontinence. Int Urogynecol J. 2012 Sep 2.8. [Epub ahead of print]; Sacco E, Bientinesi R: Mirabegron: a review of recent data and its prospects in the management of overactive bladder. Ther Adv Urol. 2012;4(6):315-24; Vij M et al: Emerging drugs for treatment of urinary incontinence. Expert Opin Emerg Drugs. 2010;15(2):299-308; Yurteri-Kaplan LA, Gutman RE: The use of biological materials in urogynecologic reconstruction: a systematic review. Plast Reconstr Surg. 2012;130(5 Suppl 2):242S-53S.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Sand is on the advisory board for Allergan, Astellas Pharma US, Ferring Pharmaceuticals, Merck & Co, Pfizer, Uroplasty Inc, and Watson Pharmaceuticals; receives grant/research support from Allergan, Boston Scientific, and EMKinetics; and is on the Speakers’ Bureaus for Allergan, Astellas Pharma US, Pfizer, and Watson Pharmaceuticals. The planning committee reported nothing to disclose. In this lecture, Dr. Sand presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Sand spoke at the 21st Annual Advances in Urogynecology and Reconstructive Pelvic Surgery, jointly sponsored by University of Chicago Pritzker School of Medicine and NorthShore University HealthSystem, and held June 14-16, 2012, in Chicago, IL. For information about upcoming CME courses sponsored by the University of Chicago Pritzker School of Medicine, please visit cme.uchicago.edu. The Audio-Digest Foundation thanks the speaker and the sponsors for their cooperation in the production of this issue.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

OB600601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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