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Advances in Medical Treatment for Urinary Incontinence
Dr. BC Tong
Geriatrician, PMH
Hon Treasurer, HKCS
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Urinary incontinence
• The complaint of any involuntary leakage of urine (which is objectively demonstrable and is a social or hygiene problem)
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bladder muscle
bladder
Urethra closed
Sphincter Muscles
Squeezed Shut
bladder muscle
bladder
Urethra open
Sphincter Muscles
Relaxed
urine urine
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Type Urge
Incontinence
Stress
Incontinence
Overflow
Incontinence
Functional
Incontinence
Cause Detrusor overactivity
Uninhibited bladder
contraction causing leakage of
moderate to large amounts of
urine
Reduced outlet resistance
Increase in intraabdominal
pressure, eg. coughing, sneezing,
laughing or other physical activity,
causing leakage of small to
moderate amount of urine
Increased outlet resistance
Detrusor underactivity
Distension of bladder causing
overflow leakage of small
amount of urine
Unrelated to lower urine
tract cause
Inability or unwillingness of
a normal continent elderly
to go to the toilet
Etiology Cystitis
Bladder stone/ neoplasm
CNS disorder
Spinal cord disease
Idiopathic
Obesity
Estrogen deficiency
Childbirth
Weakness and laxity of pelvic
floor muscles
Post-prostatectomy
Prostatic enlargement
Urethral stricture
Spinal cord disease
Faecal impaction
Diabetic neuropathy
Sacral nerve damage
Medication
Musulosketetal disorders
Impaired mental status
Unfamiliar environment
Depression
Hostility
Sedating medication
Use of physical restraints….
Mixed incontinence
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Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition.
Nat Rev Neurosci. 2008 Jun;9(6):453-66
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Acetylcholine
Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition.
Nat Rev Neurosci. 2008 Jun;9(6):453-66
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Noradrenalin
Noradrenalin
Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition.
Nat Rev Neurosci. 2008 Jun;9(6):453-66
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Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition.
Nat Rev Neurosci. 2008 Jun;9(6):453-66
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Management of urinary
incontinence
depends on causes
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4th International Consultation on Incontinence, 2008
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CAUSE OF URINARY
INCONTINENCE
Transient
Established
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Cause of transient incontinence
DI(A)PPERS
• Delirium• Infection, urinary• (Atrophic urethritis/ vaginitis)• Pharmaceutical• Psychological• Excessive urine output
– Large fluid intake– Diuretic agents: caffeinated beverages, alcohol– Metabolic caused: sugar, calcium
• Restricted mobility• Stool impaction
Resnick NM 1984
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Iatrogenic Incontinence
Effects Drug classes
Delirium, sedation Anticholinergics, antipsychotics, TCA, Anti-parkinsonic drugs, Sedative/hypnotics, nacroticanalgesics, alcohol
Cough ACEI
Polyuria Diuretics, alcohol
Bladder stimulation Caffeinated beverages
Bladder relaxation Anticholinergics, calcium channel blocker
Sphincter contraction Alpha-adrenergic agonist
Sphincter relaxation Alpha-adrenergic blockers
Constipation Anticholinergics, narcotic analgesics, calcium channel blockers etc
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Post hoc analyses identified an even greater likelihood of UI with peripheral alpha blockers when taken in
combination with loop diuretics (AR = 8.81; 95% CI = 1.78–43.53; p = .0076)
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Drugs Use in
Urinary Incontinence
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Drugs for overactive detrusor
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Andersson KE,. Chapple CR,et al.
Pharmacological treatment of overactive bladder: report from the
International Consultation on Incontinence
Current Opinion in Urology 2009, 19:380–394
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Anticholinergic/
anti-muscarinic agents
Acetylcholine
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• The use of anticholinergic drugs in the management of overactive bladder syndrome is well established when compared to placebo treatment.
• During initial treatment of overactive bladder syndrome there was more symptomatic improvement when
(a) anticholinergics were compared with bladder training alone, and
(b) anticholinergics combined with bladder training were compared with bladder training alone
Rai BP, Cody JD, Alhasso A, Stewart L.
Anticholinergic drugs versus non-drug active therapies for non-neurogenic overactive bladder syndrome in adults.
Cochrane Database Syst Rev. 2012 Dec 12;12:CD003193
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Buser N, Ivic S, Kessler TM, Kessels AG, Bachmann LM.
Efficacy and adverse events of antimuscarinics for treating overactive bladder: network meta-analyses.
Eur Urol. 2012 Dec;62(6):1040-60
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Kessler TM, Lucas, Bachmann LM, et al.
Adverse Event Assessment of Antimuscarinics for Treating Overactive Bladder: A Network Meta-Analytic Approach
PLoS One (2011) 6:e16718
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Buser N, Ivic S, Kessler TM, Kessels AG, Bachmann LM.
Efficacy and adverse events of antimuscarinics for treating overactive bladder: network meta-analyses.
Eur Urol. 2012 Dec;62(6):1040-60
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• For urgency incontinence, antimuscarinicmedications improved the clinical severity of incontinence relative to placebo
• Magnitude of treatment effects low: <200 cases of continence attributable to treatment per 1000 patients treated
• NNT to achieve complete continence in 1individual did not vary markedly across drugs – 9 for oxybutynin, 12 for tolterodine, 8 for
fesoterodine, 9 for solifenacin, and 9 for trospium
• Discontinuation of treatment because of adverse effects common– 1 woman for every 16 treated with oxybutynin, every
33 treated with fesoterodine, every 56 treated with trospium, and every 78 treated with solifenacin
Shamliyan T,Wyman J, Kane RL.
Nonsurgical Treatments for Urinary Incontinence in Adult Women: Diagnosis and Comparative Effectiveness.
Agency for Healthcare Research and Quality; April 2012.
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• Regardless of which specific antimuscarinic drug is studied, persistence rates are usually poor
• Considering all drugs together, median persistence rates were – 12.0 - 39.4% at 12 months– 8.0 - 15.0% at 18 months– 6.0 - 12.0% at 24 months– 0.0 (darifenacin) - 16.0% (trospium) at 36 months
• Mean reported medication possession rates were also low, with a mean of 0.37 at 12 months
• Risk factors for discontinuation: younger age group, use of oxybutynin and use of immediate release formulations
J Urol. 2014 Apr;191(4):1003-8
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Intradetrusor injections of botulinum toxin
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Onabotulinumtoxin A in Neurogenic Detrusor overactivity
Santos-Silva A, da Silva CM, Cruz F.
Botulinum toxin treatment for bladder dysfunction.
Int J Urol. 2013 Oct;20(10):956-62
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Santos-Silva A, da Silva CM, Cruz F.
Botulinum toxin treatment for bladder dysfunction.
Int J Urol. 2013 Oct;20(10):956-62
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Cruz F, Herschorn S, Aliotta P, et al.
Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor
overactivity: a randomised, double-blind, placebo-controlled trial.
Eur Urol. 2011 Oct;60(4):742-50
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Cruz F, Herschorn S, Aliotta P, et al.
Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor
overactivity: a randomised, double-blind, placebo-controlled trial.
Eur Urol. 2011 Oct;60(4):742-50
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Onabotulinumtoxin A in Idiopathic Detrusor overactivity
Cui Y, Zhou X, Zong H, Yan H, Zhang Y.
The efficacy and safety of onabotulinumtoxinA in treating idiopathic OAB: A systematic review and meta-analysis.
Neurourol Urodyn. 2014 Mar 28. [Epub ahead of print]
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Madersbacher S.
Onabotulinumtoxin A for idiopathic overactive bladder symptoms: many answers but more questions.
Eur Urol. 2013 Aug;64(2):257-9
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Novel drug: Selective Beta-3 adrenoceptor agonist
• Mirabegron
Noradrenalin
Bridgeman MB, Friia NJ, Taft C, Shah M.
Mirabegron: β3-adrenergic receptor agonist for the treatment of overactive bladder.
Ann Pharmacother. 2013 Jul-Aug;47(7-8):1029-38
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Phase II trial
(n = 85)
(n = 85)
(n = 88)
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Drugs for outflow obstruction
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Drugs for outflow obstruction
Alpha adrenergic blockerPrazocin (Minipress)
Terazocin (Hytrin)
Doxazocin (Cardura)
Alfuzosin (Xatral RS/XL)
Tamsulosin (Harnal)
5-alpha reductase inhibitorFinasteride (Proscar)
Dutasteride (Avodart)
Noradrenalin
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Drugs for BPH
• Alpha blocker has a more immediate action• Alfuzosin and Tamsulosin are better tolerated,
Tamsulosin has least effect on BP Eur Urol 1999;36:1-13
• Prostate volume predicts outcome of treatment with Finasteride- 40 ml Urology 1996;48: 398-405 Dutasteride is effective for prostate size >30 ml J Urol 2006; 176:1045-50
• Combination therapy NEJM 2003, 349;2387-98
– reduced the risk of overall clinical progression– Combination therapy and finasteride monotherapy reduced the long-
term risk of acute urinary retention and the need for invasive therapy – greater improvement in the AUA symptom score and the maximal
urinary flow rate than did either drug alone.
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Meredith PA
Cardiology 2001; 96(Suppl 1):19-24
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J. C. Nickel, S. Sander, T. D. Moon
Int J Clin Pract, October 2008, 62, 10, 1547–1559
dizziness, hypotension or syncope
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Intraoperative Floppy Iris syndrome
• Pooled OR after Tamsulosin use ~40 fold greater than that after Alfuzosin use. Alfuzosin>Terazosin>Doxazosin Opthalmology 2011;
118:730-735
• Iris fluttering, iris prolapse towards incision and progressive pupillary constriction leading to high rate of complication during cataract surgery Acta Opthal 2009; 87:704-8
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Combination treatment with Alpha-blocker plus Anti-cholinergic
• The sequential use of a-blockers and antimuscarinics seems to be the most appropriate approach
• use of antimuscarinics and a-blockers appears generally to be safe and efficacious
• Efficacy of antimuscarinics has been proven in different trials regarding different storage symptom end points, but not all end points regarding OAB reached significance.
• All the reported trials are of short duration (4–12 wk) and include only men with low postvoid residual urine volumes (<200 ml) at baseline .
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Expert Opin. Pharmacother. (2012) 13(14):2085-2096
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Expert Opin. Pharmacother. (2012) 13(14):2085-2096
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Expert Opin. Pharmacother. (2012) 13(14):2085-2096
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Expert Opin. Pharmacother. (2012) 13(14):2085-2096
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Drugs for stress incontinence
Alpha adrenergic agonists
Phenylpropanolamine
Ephedrine
Pseudoephedrin
Noradrenalin
Phenylpropanolamine hydrochloride (PPA)
FDA is taking steps to remove phenylpropanolamine
hydrochloride from all drug products due to the risk of
hemorrhagic stroke. FDA has significant concerns
because of the seriousness of stroke and the inability to
predict who is at risk.
[November 6, 2000 - Public Health Advisory - FDA
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Duloxetine Drugs 2004; 64(22):2567-73
• Serotonin and Norepinephrine reuptake inhibitor (SNRI)
• Block the reuptake of S and N at Onuf’s nucleus in sacral spinal cord, activating pudendal motor neuron causing an increase in urethral striated muscle tone and the force of contraction
• ? A central effect resulting in increase in bladder capacity
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Duloxetine, a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) for
the Treatment of Stress Urinary Incontinence: A Systematic Review.
European Urology 51 ( 2 0 0 7 ) 67–74
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Duloxetine, a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) for
the Treatment of Stress Urinary Incontinence: A Systematic Review.
European Urology 51 ( 2 0 0 7 ) 67–74
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Duloxetine, a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) for
the Treatment of Stress Urinary Incontinence: A Systematic Review.
European Urology 51 ( 2 0 0 7 ) 67–74
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Nausea is the most common side-effect. Other side-effects
reported were vomiting, constipation, headache, dry mouth,
fatigue, dizziness, and insomnia
Duloxetine, a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI) for
the Treatment of Stress Urinary Incontinence: A Systematic Review.
European Urology 51 ( 2 0 0 7 ) 67–74
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• Overall rate of improvement was 37%.
• 66% women discontinued therapy due to adverse effects or lack of efficacy
• Conclusion: In a non-trial situation duloxetine is poorly tolerated
BJOG 2007;114:543–547.
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• duloxetine hydrochloride reduced the clinical severity of incontinence but was not more likely to resolve incontinence (ie, result in continence) relative to placebo.
• Based on 24 published studies, the benefit-to-risk ratio of duloxetine was low:– improved incontinence severity in 75 to 140
women per 1000 treated, and
– 129 women per 1000 treated stopped using the medication due to adverse effects
Shamliyan T,Wyman J, Kane RL.
Nonsurgical Treatments for Urinary Incontinence in Adult Women: Diagnosis and
Comparative Effectiveness.
Agency for Healthcare Research and Quality; April 2012.
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Estrogen and UI
• Oral estrogen supplement: Subjective improvement without objective reduction of urine leaked Obstet Gynecol 83:12-8, 1994
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• Combined result of six trials of
systemic administration (of oral
systemic oestrogens) resulted in
worse incontinence than on
placebo (RR 1.32, 95% CI 1.17
to 1.48)
• Some evidence that oestrogens
used locally (for example
vaginal creams or pessaries)
may improve incontinence (RR
0.74, 95% CI 0.64 to 0.86).
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Drugs for underactive detrusor
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Drugs for underactive detrusor
Cholinergic agents
Distigmine (Ubetid)
Bethanechol (Urecholine)
Acetylcholine
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The currently available data show little if any
benefit of using parasympathomimetics agents in
preventing or treating underactive urinary bladder
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Requirements in achieving
continence
• Lower urinary tract function
• Mental function
• Mobility and dexterity
• Environment
• Motivation- both patients and cares
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Urological
Mental Neurological
Functional
Psychosocial
Iatrogenic
Environmental
Co-morbidities
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Thank you