Disclosure Recent Advances in the Management of Overactive Bladder (OAB) Astellas Regional Advisory Board Honorarium for talk Dharm Singh, MD, FACS Chief of Urology Campbellton Regional Hospital, New Brunswick Learning Objectives Definition Pathophysiology of OAB Diagnosis and treatments of OAB Recent advances in OAB Overactive Bladder: Definition ICS Standardization Committee Definition: Urgency, with or without urge, usually with frequency and nocturia can be described as the overactive bladder syndrome.. Abrams et al. Neurourology and Urodynamics 2002; 21:167-178 Overactive Bladder Symptom complex Frequency (>8/day) Nocturia (>2) Urgency +/ Urge Frequently associated with other conditions EPIDEMIOLOGY / PREVALENCE Rovner and Wein. Clinical Geriatrics, 2002
NOBLE: US Prevalence of Overactive Bladder National Overactive BLadder Evaluation Program 40 OAB 16.6% of adult population 33.3 million adults Men and women have similar prevalences Overall, 16.6% had symptoms of an overactive bladder Prevalence of overactive bladder increased with age Prevalence (%) 35 30 25 20 15 10 Men Women 5 US Population 200 million adults Stewart W et al. Prevalence of OAB in the US: results from the NOBLE program. Poster presented at WHO/ICI; July, 2001; Paris, France. 0 18 24 25 34 35 44 45 54 55 64 65 74 75+ Age (years) Stewart W et al. Prevalence of OAB in the US: results from the NOBLE program. Poster presented at WHO/ICI; July, 2001; Paris, France. Prevalence of Overactive Bladder: Incontinent versus Continent Prevalence of Overactive Bladder in Europe OAB 12.2 million (6.1% of the population) 37% Incontinent 63% Continent OAB with UI, 45% had mixed symptoms (UI plus SI) 16776 telephone interviews in 6 countries (France, Germany, Italy, Spain, Sweden, UK) Respondents aged 40 74 19% reported bladder symptoms 16.6% reported symptoms of OAB 15.6% in men 17.4% in women Of 1916 people with symptoms of OAB 60% had consulted a doctor 27% were currently on medication 21.2 million (10.5% of the adult population) Stewart W et al. Prevalence of OAB in the US: results from the NOBLE program. Poster presented at WHO/ICI; July, 2001; Paris, France. Milsom I et al. BJU Int. 2001;87:760-766. Prevalence is similar in men and women Women with OAB have more than men (9.3% vs 2.6%) Frequency is commonest symptoms (85%) followed by Urgency (54%) and UI (36%) Millions 40 35 30 25 20 15 10 5 0 Chronic sinusitis* Prevalence of Chronic Conditions Arthritis* Hay fever/ Allergic rhinitis* Heart disease* High cholesterol* Asthma* Chronic bronchitis* OAB Incontinence Diabetes* Ulcer* *National Center for Health Statistics. Vital health stat. 10;1994. Stewart W et al. Prevalence of OAB in the US: results from the NOBLE program.
Economic Costs of Overactive Bladder in 2000 Cost of Overactive Bladder Community $9.17 billion Based on Noble Study Total economic costs $12.02 billion Institutional $2.85 billion Expected to increase with shifting demographics Therapy for urge not curative Reimbursement for work up, medications, products variable Patient pays a large amount Hu T et al. Urology 2003; 61:1123-1128. Kobelt. Urology, 1997; Sand et al. Obstet Gynecol, 2001 Quality of Life significantly impairs QoL and reduces quality of sleep Frequent urination and the need to interrupt activities may affect the person s work and ability to trave odor, uncleanliness, and leakage during sexual activity may lead individuals to refrain from intimacy Overactive Bladder: A Disabling and Chronic Condition Coping behaviors Defensive voiding Toilet mapping Use of pads and diapers Restricted fluid intake Wearing dark and baggy clothes Canadian estimates 10% of US statistics 3 million people with OAB $1.8 billion Similar impact on HRQOL Diagnosis
A Hidden Condition Many patients self manage by voiding frequently, reducing fluid intake, and wearing pads Nearly half of patients are symptomatic for >3 years before seeking treatment Be proactive Ask about it 59% of patients do not seek help because they believe no effective treatment is available 73% of patients who seek treatment are currently not on medication Milsom I et al. BJU Int. 2001;87:760-766. What is Overactive Bladder? A medical condition characterized by Urgency with or without urgency Usually with frequency and nocturia Symptoms are suggestive of detrusor activity in the filling phase A widespread, often overlooked, and treatable condition Overactive Bladder: A Disorder of Filling and Holding Filling/Holding disorders Bladder related Urgency, frequency, +/ urge hypersensitivity Outlet related stress intrinsic sphincter dysfunction Emptying/Voiding disorders Bladder related neurologic, myogenic, psychogenic, idiopathic Outlet related prostatic obstruction bladder neck contracture urethral stricture or compression sphincter dyssynergia Abrams et al. Neurourology and Urodynamics 2002; 21:167-178 Milsom I et al. BJU Int. 2001;87:760-766. A Practical Approach to Diagnosing Overactive Bladder Many patients can be evaluated based on history, physical examination, and urinalysis Postvoid residual urine if necessary Specialized tests are not normally required to be part of the basic evaluation urodynamics cystoscopy imaging History Onset, nature, duration, severity, and bothersome Medical, Surgical, OBGYN history Social: smoking, alcohol, fluid intake Bladder diary: time, volume, episodes, pad usage Medications
A Practical Approach to Diagnosing Overactive Bladder (cont.) Medications That May Affect an Overactive Bladder Postvoid residual (PVR) should be done on the following patients Non mobile elderly Presence of neurological disease History suggestive of outflow obstruction Significant hesitancy and straining to void Feeling of incomplete emptying Previous lower urinary tract surgery Palpable bladder Diuretics Antidepressants Antihypertensives Hypnotics Analgesics Narcotics Sedatives OTC sleep aids and cold remedies Antipsychotics Herbal remedies Differential Diagnosis Prostatic Outflow Obstruction Bladder Prolapse Pelvic Floor Dysfunction Frequency related to Diabetes, Renal Disease, or Overdrinking Interstitial Cystitis GU Malignancy Urinary Tract Infection Neuropathic Lower Urinary Tract Urge urine loss accompanied by urgency resulting from abnormal bladder contractions Stress urine loss resulting from sudden increased intraabdominal pressure (eg, laugh, cough, sneeze) Differential Diagnosis: Types of Urinary Incontinence Mixed symptoms combination of stress and urge Sudden increase in intra-abdominal pressure Uninhibited detrusor contractions Urethral pressure Symptom Assessment Symptoms Overactive bladder Stress Mixed symptoms Urgency (strong, sudden desire to void) Yes No Yes Frequency with urgency (>8 times/24 h) Yes No Yes Leakage during physical activity, eg, coughing, sneezing, lifting, etc. No Yes Yes Amount of urinary leakage with each episode of Ability to reach the toilet in time following an urge to void May be large Small Variable (if present) Variable Yes Variable Waking to pass urine at night Usually Seldom Maybe Pathophysiology Adapted from Abrams P, Wein AJ. The Overactive Bladder A Widespread and Treatable Condition. 1998.
Multifactorial in etiology and pathophysiology Overactivity of detrusor muscles: Neurogenic, Myogenic and Idiopathic in origin Acetylcholine binds to M3 receptor activates phospholipase. This causes the release of calcium from the sarcoplasmic reticulum and contraction of the bladder smooth muscle. Increased sensitivity to stimulation by muscarinic receptors may lead to OAB. Leakage of acetylcholine from the parasympathetic nerve terminal may lead to micromotion of the detrusor, which may activate sensory afferent fibers, leading to the sensation of urgency. Possible Pharmacologic Mechanisms for Treatment of Overactive Bladder Although other pharmacologic mechanisms are theoretically attractive and some show promise in animal models, strong clinical proof of concept is lacking for all but the antimuscarinics Distribution of Muscarinic Receptors Muscarinic Receptor Subtypes Iris/ciliary body Lacrimal gland Salivary glands Heart Gallbladder Stomach Colon Uroselectivity Having desired effects on target muscarinic receptors in the bladder with minimal effects on muscarinic receptors in other organs of the parasympathetic nervous system M 1 : M 2 : M 3 : M 4 : M 5 : Cerebral cortex, hippocampus, glands, sympathetic ganglia Hindbrain, heart, smooth muscle Cerebral cortex, glands (eg, salivary), heart, smooth muscle Basal forebrain, striatum Substantia nigra Bladder Abrams P, Wein AJ. The Overactive Bladder A Widespread and Treatable Condition. 1998. Chapple CR. Urology. 2000;55:33-46. Caulfield M et al. Pharmacol Rev. 1998;50:279-290. Muscarinic Receptors in the Bladder Human bladder smooth muscle contains primarily M 2 (80%) and M 3 (20%) subtypes Activation of M 3 receptors evokes direct smooth muscle contraction (primary stimulus for bladder contraction) Stimulation of M 2 receptors may reverse sympathetically mediated smooth muscle relaxation Chapple CR. Urology. 2000;55:33-46. Muscarinic and Antimuscarinic Effects Accepted doctrine: Muscarinic receptor activation is responsible for bladder contraction Inhibition of muscarinic receptors is treatment for overactive bladder
Antimuscarinic Therapy: Mechanisms of Action Stabilizing effect on bladder (detrusor) muscle Increases bladder capacity Treatment options Diminishes frequency of involuntary bladder contractions Delays initial urge to void Does not change warning time Treatment Options Behavioral Therapy Behavioral therapy Medication Combined therapy 1 Minimally invasive therapy Surgery Patients should implement the following program at home: Regular pelvic floor muscle exercises Specified voiding schedule aimed at avoiding emergencies Reduce fluid intake to about 1.5 litres per day Avoid caffeine and alcohol 1. Burgio KL et al. J Am Geriatr Soc. 2000;48:370-374. Behavioral Therapy Bladder training Pelvic floor exercise Biofeedback Pelvic floor electrical stimulation Medications for Overactive Bladder Hyoscyamine sulfate Propantheline bromide Imipramine Oxybutynin (Ditropan) Tolterodine (Detrol) Solifenacin (Vesicare) Fesoterodine (Toviaz) Darifenacin (Enablex) Mirabegron (Myrbetriq)
Potential for Cognitive Side Effects Some anticholinergic agents have been associated with CNS side effects 1 Factors limiting access to the CNS: lipid solubility 2 electrical charge 2 neutral penetrates better than charged molecule size/bulkiness of the molecule 3 CNS Side Effects of Anticholinergics Drugs from several therapeutic classes (eg, antihistamines, antispasmodics, and antipsychotics) cause cognitive and memory impairment Acetylcholine is a pivotal mediator of short term memory and cognition Some anticholinergic agents that cross the bloodbrain barrier (BBB) disrupt memory and cognition 1. Katz IR et al. J Am Geriatr Soc. 1998; 46:8-13. 2. Goodman and Gilman s The Pharmacological Basis of Therapeutics, 1996. 3. Pardridge WM. J Neurochem. 1998;70:1781-1792. Anticholinergic Agents for Overactive Bladder: Potential Passage Across the BBB Tolterodine Oxybutynin + Low lipophilicity Relatively bulky molecular structure High lipophilicity Relatively small molecular structure Vasculature BBB + + + + + + + + + CNS In a study of 64 healthy volunteers in 4 groups Placebo, tolterodine, trospium, oxybutynin Measurement of EEG activity after administration Tolterodine, and trospium showed minimal EEG changes Oxybutynin showed measurable changes Todorova A et al. J Clin Pharmacol. 2001;41:636-644. Todorova A et al. J Clin Pharmacol. 2001;41:636-644. Combination Therapy Conclusions Percent reductions in episodes after 8 weeks Drug therapy alone (N = 18) Switched to behavioral (N =18) P-value 59.1% 77.1%.109 Behavioral therapy alone (N = 8) Drug therapy added (N = 8) 57.5% 88.5% 0.034 Drug therapy alone (N = 27) Behavioral therapy added (N = 27) 72.7% 84.3% 0.001 Combination therapy is more effective than either therapy alone 29% of patients randomized to oxybutynin alone chose to discontinue drug therapy and crossed over to behavioral therapy alone because of: unwanted side effects unwillingness to continue long term drug therapy Drugs such as tolterodine with fewer side effects may encourage patients to choose combination therapy Burgio KL et al. J Am Geriatr Soc. 2000;48:370-374. Burgio et al. J Am Geriatr Soc. 2000;48:370-374.
Basic evaluation Recent Advances In The Management of Overactive Bladder Newer Medication: Mirabegron Screening Evaluation Cause Bladder cause Patient with: bladder symptoms high risk History (risk factors, bladder record), DIAPPERS, physical examination, urinalysis, PVR (if indicated) Non Bladder Cause Evaluate /treat Polyuria Glucosuria Beta3 adrenoceptor agonist Compared to placebo, It decreases urgency and episodes. Has different side effects profile, less dry mouth Diagnosis Overactive Bladder urge Mixed Stress Overflow, Unconscious, or Continuous Functional Transient cause CHF Management Behavioural/lifestyle modification, education Pelvic, +/- bladder training Medications Treat reversible conditions Timed voiding Toileting Evaluate, treat reversible cause Follow-up Condition successfully managed? Yes Patient Satisfied No Specialist referral No Condition successfully managed? Yes Patient Satisfied Herschorn S, Drutz H, Frydrych S, et al. Pharmacia advisory board, 2000 Newer Medication: Mirabegron Useful for 1 st line treatment, not tolerable to antimuscarinic, contraindications to antimuscarinic (eg: narrow angle glaucoma) Doses: 25 and 50 mg, daily Incidents of hypertension so BP should be monitored Management of Refractory Overactive Bladder Minimally invasive procedures Intravesical instillation therapy botulinum toxin injection (Botox) Surgery neuromodulation bladder myectomy bladder augmentation urinary diversion Intradetrusor Botox Used for refractory OAB Usually 100U is used Significant decrease in frequency and Side effect: Urinary Retention, Hematuria May be repeated after 9 12 months
Conclusions Overactive bladder is a highly prevalent, morbid, and costly problem Identification, workup, and initial treatment of patients is straightforward Behavioural modification is of benefit alone and in combination with pharmacologic therapy Anticholinergics are the mainstay of pharmacologic treatment Conclusions Newer and long acting preparations may provide better clinical effectiveness Bladder selective agents and different drug delivery systems may yield better results Pharmacologic agents affecting other pathways are in development Thank You