Faculty Disclosure

Dr. Iglesia has no relevant conflicts to disclose.

Objectives

• Develop effective treatment plans for women with overactive bladder.

• Describe how to communicate realistic goals of overactive bladder treatment with patients.

• Review how to minimize medication side effects in treatment plans for women with overactive bladder.

• Describe the efficacy and safety of new and emerging therapies for women with overactive bladder.

Urinary Incontinence (UI):Prevalence

• 13 million Americans• Gender– Female: 10%-55%– Male: 2%-5%

• Prevalence and severity increase with age

• Seen in over 50% of nursing home patients

Changing the Face of UI

Stereotype Reality

For illustrative purposes only. Not indicative of population distribution.

Prevalence of Any UIBy Age and Severity

Minassian VA, et al. Obstet Gynecol. 2008;111(2 Pt 1):324-331.

Minassian VA, et al. Obstet Gynecol. 2008;111(2 Pt 1):324-331.

Prevalence of Urge UIBy Age and Severity

Patient Case: Background (1)

• Mrs. D is a 48-year-old, perimenopausal, White female.

• Approximately one month ago, she began experiencing urgency, frequency, and occasional urge urinary incontinence (UI).

• In the past 6 months she has gained nearly 25 lbs, which she attributes to perimenopause. She now has a BMI of 28.5.

Patient Case: Background (2)

• She has noticed a significant decline in sexual desire and satisfaction since the onset of her bladder problems.

• She feels anxious and is nervous that she will embarrass herself in public.

• She takes HCTZ and propranolol for hypertension, and SSRI for mild depression.

Defining Overactive Bladder

• Urinary urgency, with or without urge incontinence, usually with urinary frequency and nocturia, in the absence of pathologic or metabolic factors that would explain these symptoms

The International Continence Society defines OAB as:

National Association for Continence (2008) www.nafc.org

Therefore, ask about URGENCY

Major Types of Urinary Incontinence

Stress

Urge Overflow Transient Functional

OAB in the United StatesIncontinent Versus Continent: NOBLE

Stewart WF, et al. World J Urol. 2003;20(6):327-336.

37%Incontinent

63%Continent

12.2 million (6.1% of the population)

21.2 million (10.5% of the adult population)

OAB

33.3million(>16% of pop.)

Functional Incontinence: Causes(AKA Transient or Reversible Incontinence)

• Patient-related• Environmental-related• Disease-related• Medication-related

• Delirium• Infection• Atrophy• Pharmacologic• Psychologic• Endocrinologic• Restricted mobility• Stool impaction

“DIAPPERS”Mnemonic

Physical• Limitations or

cessation of physical activities

Qualityof Life

Sexual• Avoidance of sexual

contact and intimacy

Occupational• Absence from work• Decreased

productivity

Social• Reduction in social

interaction• Limit and plan travel

around toilet accessibilityDomestic• Require specialized

underwear, bedding• Special precautions with

clothing

Psychological• Guilt/depression• Loss of self-esteem• Fear of:

– Being a burden– Lack of bladder

control– Urine odor

Tubaro A. Urology. 2004;64(6 suppl 1):2-6.

Impact on Quality of Life:The Silent Sufferers

Lower Urinary Tract Function

• Bladder and urethral functions– Storage– Micturition

• These functions are controlled by the central nervous system (CNS) through reflexes that coordinate the activity of:– Bladder (smooth muscle)– Urethra (smooth and striated muscles)– Pelvic floor muscles

Lower Urinary Tract Innervation

+M3

Pelvic Nerve(Parasympathetic) ACh

+N

Pudendal Nerve(Somatic) ACh

-3

+1 Hypogastric Nerve

(Sympathetic) NE

Acetylcholine (ACh)

SYM

ON

Spinal Relay Neuron

Hypogastric Nerve

Pudendal Nerve

Pelvic Nerve

+ 1

+ M2,3

Inhibition

Storage ReflexMicturition Reflex

Bladder

Rhabdosphincter

Periaqueductal Gray

PAR

Pontine Micturition

Center

- ß3

+N+N

NeuroUrology

Spinal Reflex

Initial Assessment

• Medical history

• Screening questions

• Urinalysis

• Physical examination

Evaluation and Management

• Urinalysis

• Simple pelvic examination

Patient Case: Continued

• Based on her assessment, you learned she suffers from constipation and has tried to increase her water intake to address that issue.

• With further questioning, she also reports that she has been getting up to urinate at least 4 times a night. – Is it nocturia or nocturnal polyuria?

Screening: Intake/Output Diary

Nocturia vs Nocturnal Polyuria

• Assessed with simple 24-hour urine collection

• Common causes: Sleep apnea, CHF, diabetes mellitus

• Sleep apnea– Most under-recognized cause of nocturnal

polyuria– Treatment with CPAP significantly reduces

nocturic frequency

Fitzgerald MP, et al. Am J Obstet Gynecol. 2006;194(5):1399-1403.

Drugs That Cause OAB-Like Symptoms

Ouslander JG. New Engl J Med. 2004;350(8):786-799.

• Alpha-adrenergic receptor agonists• Tricyclic antidepressants• Psychotropics (sedatives, hypnotics)• Cholinesterase inhibitors• Narcotic analgesics, opioids • Calcium channel blockers• Diuretics• Methylxanthines • NSAIDS

Patient Case: Management

• Change HTN medication• Eliminate caffeine• Decrease fluid consumption• Manage constipation• Lose weight

Behavioral Interventions• Behavioral Training Techniques– Pelvic floor muscle (PFM) training

• Physical therapy (PT)• Kegel exercises

– Bladder training: • Biofeedback• Timed voiding

• Behavioral Modification– Lifestyle modifications: Eliminating bladder irritants from

diet, managing fluid intake, weight control, monitoring bowel regularity, smoking cessation, and patient education

Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.

Pelvic Muscle Rehabilitation

Pelvic PT and Exercise Adherence Study

• Less than ¼ of women continued exercises.

• No difference in rate of subsequent SUI surgery in women who had intensive pelvic PT vs those who did not.

• Marked benefit of initial therapy not maintained 15 years later.

Bo K, et al. Obstet Gynecol. 2005;105(5 Pt 1):999-1005.

Pelvic Floor Muscle (PFM) Training(Kegel Exercises)

• Rationale: strong and fast PFM contraction increases urethral pressure and prevents leakage during sudden increase in abdominal pressure

• Recommendation:– 3 sets of 8-12 slow-velocity maximum voluntary

contractions, sustained for 6-8 seconds, performed 3-4 times a week for at least 15-20 weeks

• Effectiveness: depends upon type of exercise, frequency, intensity, and duration of training

Weighted Vaginal Cones

Pessary for Incontinence: Useful for Stress, Not Urge

Pessary in position

Behavioral Modification

• Elimination of bladder irritants from diet– Eliminate stimulants, such as caffeine and over-the-

counter prescription medication with caffeine. – Evidence suggests aspartame and other artificial

sweeteners may contribute to OAB symptoms.

• Smoking cessation– Smoking may cause chronic coughing, which in turn

may increase the intra-abdominal pressure and cause UI.

– Smoking cessation education should be offered, stressing the relationship between smoking and UI.

Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.

Behavioral Modification (cont)• Management of fluid intake

– When is too much, too much?– When is too little, not enough?

• Management of bowel regularity– Avoid constipation– Increase dietary fiber– Engage in regular exercise– Establish regular defecation plan

• Weight control– First-line option for treatment of UI for obese clients– Goal should be set to decrease BMI to <30 kg/m2

Wyman J, et al. Int J Clin Pract. 2009;63(8):1177-1191.

Patient Case

• Mrs. D eliminates caffeine from her diet; reduces her HTN medication; and tries do Kegel exercises regularly.

• She is still experiencing some leaking and continued, though less frequent, night urgencies.

• You suggest trying a pharmacologic agent.

Drugs for OABHave I got the pill for you?

Heading CE. Curr Opin CPNS Inves Drugs. 2000;3:321-325. Napier C, et al. Proc ICS. 2002:445. Abstract.

*Animal models.

1.33.6

12 12.3

59.2

0

10

20

30

40

50

60

Trospium Tolterodine Solifenacin Oxybutynin Darifenacin

Inhi

bitio

n Co

nsta

nt R

atio

(Ki)

for

Mus

carin

ic R

ecep

tor S

ubty

pes* M3 selective

Primarily M3 selectiveNonselective

(M3/M2)

Receptor Selectivity

Muscarinic Receptor Distribution and Potential Adverse Events

With Antagonist Use

• M2 reverses sympathetically mediated smooth muscle relaxation• M3 causes detrusor contraction

Potential AEsTissue Distribution

EyeM3

Decreased lacrimation Decreased accommodation

Salivary glandsM3

Xerostomia (dry mouth)

HeartM2-M3

Cardiovascular

BrainM1-M5

Decreased cognitive functionShort-term memory lossAltered sleep cycle

IntestineM3

Constipation

Urinary retention BladderM2-M3

Abrams P, et al. Br J Pharmacol. 2006;148(5):565-578.

M-3 Selective Antagonists

• Solifenacin

• Darifenacin

STAR Trial: N=1200

• 12-week, European, prospective, randomized, double-blind, double-dummy, 2-arm, parallel-group trial

• Dose titration regimen of solifenacin (5 mg or 10 mg qd) or a single dose of tolterodine LA 4 mg qd

• Primary objective: Non-inferiority study

• Primary endpoint: Micturition frequency

• Secondary endpoints: Incontinence episodes, urge incontinence episodes, urgency, volume voided, and tolerability

Chapple CR, et al. Eur Urol. 2005;48(3):464-470.

EndpointSolifenacin

(pooled 5 mg/10 mg)

Tolterodine(4 mg qd) P value

PRIMARY (non-inferiority) [PPS]*

Micturition frequency/24 h –2.45 –2.24 .004

SECONDARY (FAS)†

Urgency episodes/24 h –2.85 –2.42 .035

Incontinence episodes/24 h –1.60 –1.11 .006

Nocturia episodes –0.71 –0.63 .730

Urge incontinence episodes/24 h –1.42 –0.83 <.01

Mean volume voided (mL/void) 38.00 31.00 .01

Patients dry (%) 59.00 49.00 .006

Pads/24 h –1.72 –1.19 .0023

Perception of bladder condition –1.51 –1.33 .0061

STAR Trial Reported Endpoints

*Per protocol set. †Full analysis set.

(n=525) (n=524)

(n=578) (n=599)

Chapple CR, et al. Eur Urol, 2005:48(3):464-470.

Darifenacin

• Bladder selectivity (marginal) in animal studies: Not more than tolterodine or oxybutynin in guinea pigs

• Multicenter, placebo-controlled RCT (n=561)

• Reduction in incontinent episodes:– 67.7% Darifenacin 7.5 mg (P = .010)

– 72.8% Darifenacin 15 mg (P = .017)

– 55.9% Placebo

– No reductions in nocturia

Haab F, et al. Eur Urol. 2004;45(4):420-429.

Darifenacin and Warning Time?

Difference in Medians at Week 2 = 4.3 minutes (P = .003)

n=32 n=35

Cardozo L, et al. J Urol. 2005;173:1214-1218.

• Quaternary amine• Used in Europe for 20 years: Many studies• Efficacy not different from standard agents• Poor bioavailability• RCT in US (phase 3, N=523):*– 20 mg bid– Urge UI: 59% drug vs 44% placebo– Nocturnal frequency decreased by week 4– Side effects: Dry mouth 21.8%

Non-Selective Muscarinic Antagonists:

Trospium

*Zinner N, et al. J Urol. 2004;171(6 Pt 1):2311-2315.

Reasons for Nonadherence

Adapted from: BCG analysis, Harris interactive 10,000 Patient Survey, 2002.

Tailor Therapy to Each Patient to Improve Adherence

• Does it fit into their schedule? Do they need reminders to take?

• Cost: Have you reviewed formularies, copayments, availability of generics?

• Do they understand how long it might take to work? Is it working for them?

• Can you reduce potentiality of side effects?

Side Effects

• Dry mouth (higher than M2 agents)

• Constipation (higher than M2 agents)

• Blurred vision

• Exacerbation of gastroesophageal reflux

• Cardiac changes

• Urinary retention

CNS Considerations in the Treatment of Overactive Bladder:

Passive Diffusion Across the BBB

Lipophilicity Diffusion

Charge/polarity, hydrogen bonding Diffusion

Molecular “bulkiness” Diffusion

Pardridge WM. J Neurochem. 1998;70:1781-1792. Habgood MD, et al. Cell Mol Neurobiol. 2000;20:231-253.

Vasculature CNSBBB

-+ --+

---++

+

+-

+

BBB: blood-brain barrier

Effect of Darifenacin and Oxybutynin ER on Memory in Older Subjects

• 3-week, randomized, double-blind, double-dummy, parallel-group, placebo-controlled, multicenter study

• 150 healthy volunteers ‑ age range 60–83 (12.7% ≥75 years)‑ 62% female

• 2-week screening to assess eligibility• Active treatments administered according to US

prescribing information• Computerized battery of cognitive function tests

assessed effect of each drug at end of weeks 1, 2, & 3

Kay GG, et al. Eur Urol. 2006;50:317-326.

Primary Endpoint: Delayed Memory Recall in

The Name-Face Association Test

*P < .05 vs placebo; †P < .05 vs darifenacin (ANCOVA, adjusted for baseline score, age, and sex)Patient (n) numbers reflect baseline values

Score for accuracy(least square mean)

* *† †

Kay GG, et al. Eur Urol. 2006;50:317-326.Reprinted with permission from Elsevier

Week

Mea

n Sc

ore

for d

elay

ed re

call

Nam

e-Fa

ce A

ssoc

iatio

n Te

st

Placebo (n=50)Oxybutynin ER (n=49)Darifenacin (n=46)

Self-Rated Memory Assessment (MAC-S)

MAC-S score(least square mean)

Patient (n) numbers reflect baseline values

Placebo (n=50)Oxybutynin ER (n=49)Darifenacin (n=46)

Kay GG, et al. Eur Urol. 2006;50:317-326. Novartis Pharmaceuticals. Data on File

Alternative Therapies/Treatments

• Botulinum

• InterStim Therapy

• Tension-Free Vaginal Tape- only for mixed UI

InterStim Therapy

Tension-Free Vaginal Tape

Treatment for OAB:Never Surgery

• Mixed UI may be managed with mid-urethral slings, but efficacy is lower than pure SUI

Conclusions

• UI is common.

• Most women go untreated.

• Highly efficacious therapies exist.

• Encourage women to be proactive about treating quality-of-life conditions.