Overactive Bladder and Urge Incontinence in Men: Current Opinions, Medical, and Surgical Management 臺大泌尿部 姜宜妮醫師

LUTS (Lower Urinary Tract Symptoms): Voiding and Storage Symptoms Irritative symtoms of BPH - storage symptom F requency U rgency N octuria Obstructive symptoms -voiding symptoms Weak urinary stream I ntermittency S train to begin urination sensation of not Emptying bladder completely 40歲以上常有各種排尿症狀，包括儲尿症狀和排尿症狀 Urinary Incontinence Any involuntary leakage of urine Urge Incontinence: associated with urgency Stress Incontinence: associated with stress Standardisation and Terminology Committees IUGA and ICS, Joint IUGA / ICS Working Group on Female Terminology. Haylen et al. Neurourol Urodyn. 2010;29(1):4-20.

Multifactorial Etiology 造成排尿症狀的原因有很多，以男性來說，最常見的還是攝護腺問題，因攝護腺肥大這個病理變化，引發攝護腺造成的尿路阻塞，但除了攝護腺之外，膀胱本身的問題overactive bladder 和detrusor overactivity，也會造成問題 Speakman MJ. Eur Urol Suppl 2008;7:680–689 Chapple CR et al. Eur Urol 2006;49:651–659

Most men have BOTH voiding and storage symptoms 14,139 men ≥40 years old; 71% reported LUTS; 45.7% with storage symptoms 大於40歲的男性，71%有下尿路症狀，45.7%有儲尿症狀，OAB 7-27% MALE, 9-43%

Storage Symptoms Urgency, frequency, urge incontinence Age has an impact, not gender 40-60% nursing home admissions Responses to muscarinic antagonists decrease with age Decreased number of muscarinic receptors in aging heart and parotid gland 豬,老鼠,人 muscarinic receptor減少，夜尿在下堂課討論 Michel MC, Schneider T, Krege S, Goepel M. Does gender or age affect the efficacy and safety of tolterodine? The Journal of urology. 2002 Sep

Overactive Bladder Treatment 1st Line Therapy Behaviral Therapy 2nd Line Therapy Antimuscarinics Beta-3 Agonist 3rd Line Therapy Intradetrusor onabotulinum toxin A Peripheral tibial nerve stimulation (PTNS) Sacral modulation (SNS) Rare, Augmentation cystoplasty, urinary diversion 2014 AUA Guideline on Overactive Bladder

Pharmacological Options Pharmacological treatment α1-Adrenoceptor antagonists (α1-blockers) 5α-Reductase inhibitors Muscarinic receptor antagonists Phosphodiesterase 5 inhibitors Vasopressin analogue-desmopressin Beta-3 agonists Surgical treatment Intradetrusor onabotulinum toxin A 85% with mild LUTS do not need management at one year EAU Guideline on the Management of Non-Neurogenic Male Lower Urinary Tract Symptoms, including BPO, 2014

Behavior Modification Reduction of fluid intake at specific times Aimed at reducing frequency Avoidance of alcohol and caffeine Double void Bladder retraining Hold on with sensory urgency Reviewing medication especially diuretics Constipation treatment

α1- Adrenergic Receptor Distribution & Function Primary subtype expressed in the prostate. Regulates contraction of the smooth muscle in the prostate, bladder base and neck, urethra, seminal vesicles, and vas deferens.1-5 α1B Primary subtype expressed in the blood vessels. Regulates contraction of arterial blood vessels in response to postural redistribution of blood volume.4-7 α1D Primary subtype expressed in the bladder, spinal cord, and nasal passages. Thought to play a role in bladder symptoms and nasal secretions.1,6 To date, three distinct α1-adrenergic receptor subtypes have been cloned and characterized: α1A, α1B, and α1D. The three receptor subtypes, although related, are structurally distinct.1 The α1-adrenergic receptors are distributed in many tissues throughout the body. In prostate tissue, particularly BPH prostate tissue, the α1A receptor subtype predominates.2 In the peripheral vasculature, the α1B receptors predominate.3 The primary subtype in the bladder, spinal cord,1 and nasal passages are α1D receptors.4 The receptor subtypes also have distinct functional roles. In general, prostate smooth muscle contraction is regulated by α1A adrenergic receptors,5 whereas contraction of the arterial blood vessels is regulated primarily by α1B receptor subtypes.6 The exact role of α1D receptors has not been established, but they are thought to regulate nasal secretions4 and to play a role in bladder symptoms.1 1. Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193-199. 2. Nasu K, Moriyama N, Kawabe K, et al. Quantification and distribution of α1-adrenoceptor subtype mRNAs in human prostate: comparison of benign hypertrophied tissue and nonhypertrophied tissue. Br J Pharmacol. 1996;119:797-803. 3. Murata S, Taniguchi T, Takahashi M, et al. Tissue selectivity of KMD-3213, an alpha(1)- adrenoceptor antagonist, in human prostate and vasculature. J Urol. 2000;164:578-583. 4. Stafford-Smith M, Bartz R, Wilson K, et al. Alpha-adrenergic mRNA subtype expression in the human nasal turbinate. Can J Anesth. 2007;54:549-555. 5. Kaplan SA. Use of alpha-adrenergic inhibitors in treatment of benign prostatic hyperplasia and implications of sexual function. Urology. 2004;63:428-434. 6. Townsend SA, Jung AS, Hoe YSG, et al. Critical role for the α-1B adrenergic receptor at the sympathetic neuroeffector junction. Hypertension. 2004;44:776-782. Schwinn DA, et al. Int J Urol. 2008;15:193-199. Kaplan SA. Urology. 2004;63:428-434. Nasu K, et al. Br J Pharmacol. 1996;119:797-803. Murata S, et al. J Urol. 2000;164:578-583. Carbone DJ, et al. Int J Impotence Res. 2003;15:299-306. Stafford-Smith M, et al. Can J Anesth. 2007;54:549-555. Townsend SA, et al. Hypertension. 2004;44:776-782.

α1-Blockers and Overactive Bladder Alpha1 Blocker First line agent of LUTS/BPH in AUA Guideline Tamsulosin OCAS (oral controlled absorption system) 0.4mg QD Tamsulosin MR (modified release) 0.2mg QD Alfuzosin XL (prolonged release) 10mg QD Silodosin 4mg BID Doxazosin 2-8mg QD Terazosin 5-10mg QD Alpha-1A blocker: less asthenia, dizziness, and orthostatic hypotension Improve urinary flow Increase Qmax 15-30% IPSS improve 30-45% 目前最常用於治療男性下尿路症狀的還是alpha-blocker，雖然主要是改善FLOW，但可能對其他也有幫忙 Marberger M. Medical management of lower urinary tract symptoms in men with benign prostatic enlargement. Advances in therapy. 2013

Antimuscarinic Mechanism Detrusor is innervated by parasympathetic nerves Muscarinic receptors, M1-M5 smooth muscle, bladder urothelial cells, salivary glands, peripheral or central nervous system Detrusor: M2, M3 predominant M2: more numerous M3: more important in bladder contractions

Antimuscarinics Considerations of antimuscarinics initiation Post-void residual urine (PVR)<150ml Caution in patients with PVR>250-300ml Caution in narrow-angle glaucoma,impaired gastric emptying Benefit: prostate volume<30ml, Qmax>10ml/sec Significantly reduce symptoms in PSA<1.3ng/ml Predominantly with storage symptoms Side effects: dry mouth (16%), constipation (4%), micturition difficulties (2%), nasopharyngitis (3%), dizziness (5%) Similar efficacy and adverse event profile Regular evaluation of PVR and IPSS 不會好，不能完全停藥

Antimuscarinics Efficacy差不多

Overactive Bladder: Antimuscarinics and their current challenges OAB is defined by the International Continence Society as: Urgency, with or without urgency incontinence usually with increased daytime frequency and nocturia in the absense of proven infection or other obvious pathology Antimuscarinics are the mainstay of pharmacotherapy for OAB However, persistence with antimuscarinics can be a challenge Patients may stop medication either due to an insufficient response to treatment or intolerable side effects Long-term, optimizing medication tolerability Once daily better Extended release better: ER v.s. IR 1. Abrams P, et al. Neurourol Urodyn 2009;28(4):287; 2. Milsom I, et al. BJU Int 2001;87(9):760–6; 3. Wein AJ, et al. J Urol 2006;175(3 Pt 2):S5–10; 4. Wagg et al. BJU Int 2012;110(11):1767-74.; 5. Sears CL, et al. J Urol 2010;183(3):1077–81; 6. Sexton CC, et al Int J Clin Res 2011;65:567–85.

Combination: Alpha-blocker and Antimuscarinic agents Kaplan SA, McCammon K, Fincher R, Fakhoury A, He W. Safety and tolerability of solifenacin add-on therapy to alpha-blocker treated men with residual urgency and frequency. The Journal of urology. 2013

Combination: Alpha-blocker and Antimuscarinic agents 45 year-old or older men, 12 weeks 8 or more micturitions per day Decreased frequency: -1.05 v.s. -0.67 Decreaed urgency: -2.18 v.s. -1.10 Urinary retention 1.4% Urgency 次數會減少

Beta-3 Agonist Nerve pathways in normal bladder control Mode of action of OAB treatments Betmiga™ works via a different receptor pathway from antimuscarinic agents. Antimuscarinics are thought to interfere with the action of acetylcholine on bladder smooth muscle (parasympathetic pathway) and inhibit involuntary contractions (i.e. delay voiding). By contrast, Betmiga™ is a potent and selective β3-adrenoceptor agonist, that increases relaxation of bladder smooth muscle via adrenergic receptors (sympathetic pathway) increasing storage volume and the time interval between voids. Reference Chu FM, Dmochowski R. Am J Med 2006;119(3 Suppl 1):3–8. Adapted from Chu FM, Dmochowski R. Am J Med 2006;119(3 Suppl 1):3–8.

Beta-3 Agonist Betmiga (Mirabegron) promotes urine storage through potent and selective agonism of the β3-AR Incidence of AEs of antimuscarinics, such as dry mouth and constipation, was comparable with placebo Cardiovascular effects, comparable with placebo An alternative choice All antimuscarinics and Mirabegron have similar efficacy to reduce frequency and incontinence episodes (Except Solifenacin 5-10mg, more effective) 當吃別的沒效，可以考慮換過來 2014 AUA Guideline on Overactive Bladder

PDE5-Is Phosphodiesterase Type 5 inhibitors Increased blood perfusion in the lower urinary tract Reduce moderate to severe (storage and voiding LUTS) in men with/without erectile dysfunction In comparison with placebo, Tadalafil (Cialis) 5mg QD IPSS reduction 22-37% Qmax increase 2.4ml/sec 4.7-6.6 IPSS point reduction v.s. 2.1-4.4 IPSS point TUA Male LUTS Guideline

Third-Line Options Failed behavioral and pharmacologic therapy Onabolinumtoxin A Peripheral tibial nerve stimulation Sacral neuromodulation CNS必須 整合感覺和運動神經放電，因此藉由電刺激做調整，SACRAL NERVE是直接植入，PTNS則是刺激小腿內側的神經，用電極片或細針 Sacral nerve stimulation (SNS) by the InterStim (Medtronic, Minneapolis, MN) procedure is performed in two stages: stage I, a clinical trial of a temporary or permanent lead for external stimulation; and stage II, implantation of a subcutaneous implantable pulse generator (IPG).unilateral lead at S3, external pulse generator and worn by the patient for several days. Lead migrationA fine needle electrode is inserted into the lower, inner aspect of the leg Campbell-Walsh Urology 2012 AUA Guideline 2014

Surgical Interventions OnabotulinumtoxinA in Refractory Overactive Bladder Third-line treatment In patients with failed behavioral therapy and oral medications (antimuscarinics and β3 agonists) Must inform possible side effects Urinary retention (8.9%) Gross hematuria (17.9%) UTI (7.1%) Dry mouth (19.6%) Dysphagia (5.4%) Impaired vision (5.4%) Eyelid weakness (8.9%) Arm weakness (8.9%) Leg weakness (7.1%) Cox L, Cameron AP. OnabotulinumtoxinA for the treatment of overactive bladder. Research and reports in urology. 2014 2014 AUA Guideline of Overactive Bladder

Intradetrusor Onabotulinum Toxin Intradetrusor onabotulinum toxin 100U Improvements 60-65% Urgency episodes Urinary incontinence episodes Symptom score Quality of life Flynn(2009): reduction in nocturia (0.5) and pad (2.2) 6 weeks after Duration of symptom relief 6-12 months Range 100-300U Cox L, Cameron AP. OnabotulinumtoxinA for the treatment of overactive bladder. Research and reports in urology. 2014

Conclusion Male urgency, frequency, and urge incontinence 1st line: behavioral therapy 2nd line Alpha-1 blocker Antimuscarinic agents Combination treatment An alpha-1 blocker and An antimuscarinic agent in patients with Failed monotherapy Men who may have bladder outlet obstruction New: Beta-3 agonist Optional: 5α-Reductase inhibitors, PDE5-inhibitors 3rd line Intradetrusor injection of 100U onabotulinumtoxinA 其他的combination仍未有確定的資訊m+m. m+b

Thank You for Your Attention