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REVIEW ARTICLE |
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| Year : 2001 | Volume
: 17
| Issue : 2 | Page : 84-96 |
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Changing concepts in the diagnosis and management of overactive bladder
Hari Siva Gurunadha Rao Tunuguntla, Perinchery Narayan
North Florida Urology Research Institute, Gainesville, FL, USA
Correspondence Address:
Hari Siva Gurunadha Rao Tunuguntla
1624, S.W. 40th Terrace, Apt # D Gainesville, FL 32607
USA
 Source of Support: None, Conflict of Interest: None  | Check |
Keywords: Overactive Bladder; Alpha Adrenergic Receptors; Detrusor; Incontinence; Behavioral Therapy; Acetylcholine; Oxybutynin; Tolterodine.
How to cite this article:
Tunuguntla HG, Narayan P. Changing concepts in the diagnosis and management of overactive bladder. Indian J Urol 2001;17:84-96 |
Overactive Bladder (OAB) is defined as urinary urgency (a strong and sudden desire to void) and frequency (increased number of micturitions), with or without urge incontinence (loss of urine associated with urgency if involuntary contraction of the detrusor is not suppressed), in the absence of local pathologic or metabolic factors that would account for these systoms. This definition is practical, easily understood and is based on clinical symptoms. This definition is also useful for FDA drug studies in which the patients are enrolled based on symptoms and voiding diaries rather than urodynamics.
OAB is characterized by involuntary contractions of the bladder muscle (detrusor) occurring during the bladder's filling phase.
Approximately one half of those with this condition do not have incontinence. However, their quality of life (physical and social functioning, vitality, emotional role limitations) is affected due to urge and frequency of voiding. OAB has a greater impact on social functioning and emotional role limitations than congestive heart failure (a condition considered as especially debilitating). Even in the areas of physical status, the impact of OAB is roughly equivalent. The condition often follows a chronic course, often necessitating lifelong treatment. When compared with diabetes, congestive heart failure, major depression, and multiple sclerosis, conditions known for their effect on quality of life, the impact of OAB is comparable and sometimes even greater.
Prevalence and Statistics
The risk of developing OAB increases with age. In people over age 75. OAB prevalence ranges from 30% to 40%. In the United States, this disorder ranks among the 10 most common chronic conditions and is more common than diabetes and peptic ulcers. An estimated 17 to 53 million Americans have symptoms due to overactive bladder. 60 per cent of patients have urgency and frequency without urge incontinence. An estimated 17% (range, 10-35%) of adults have one or more symptoms of overactive bladder and the incidence increases with advancing age. Over one half of nursing home residents are estimated to have OAB with or without urge incontinence. [1],[2],[3]
Incontinence is 5 times more common in woman than in men. 24 per cent of woman suffer from stress urinary incontinence and 6% from urge incontinence. Symptoms of OAB are twice as common in women as in men. Quality of life is much more impaired in urge incontinence but only 15% of such patients consult a doctor. Symptoms of OAB negatively affect the quality of interpersonal and sexual relationships, sexual interest, and frequency of sexual activity. They can be associated with loss of sleep due to the need to urinate frequently during the night. [4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16]
Urinary incontinence and OAB impose a financial burden on individuals, families, and healthcare organizations and accounted for $28.9 billion healthcare cost in the year 1998. [6]
Etiology [17],[18]
The following causes are considered to be responsible for the development of overactive bladder: neurologic disease/ injury, local bladder/urethral irritation; bladder outlet obstruction; medications; aging and idiopathic causes.
Pathogenesis and Risk Factors [17],[18],[19],[20],[21],[22]
Primary structural and functional changes in smooth muscle and innervation (afferent and efferent; neuromuscular junction) of the bladder result in symptoms of overactive bladder [Table - 1]. Alteration in the threshold of afferent sympathetic nerves innervating the bladder with or without increased activity of C-fiber-mediated sacral reflex arc have been identified in this condition.
Voiding is mediated by 2 pathways: supraspinal and spinal `A' delta-fibers (small myelinated afferent fibers) pass through a pontine center and form the afferent loop of the spinobulbospinal micturition reflex pathway (dominant reflex). The other pathway consists of longer latency response mediated by `C' fibers (non-myelinated).
Efferent nerves in the bladder and muscarinic receptors are responsible for normal voiding. Cholinergic receptors in the lower urinary tract are of 2 types, muscarinic (located in the smooth muscle of the bladder and are the primary mediators of detrusor contraction) and nicotinic (located in striated muscle, such as the urethral sphincter and enhance tone). The muscarinic receptors in the bladder are of 5 types: M1-M5. The majority (80%) of these receptors are nonfunctional M2 receptors. Only the M3 receptors are functional in bladder emptying.
Alpha adrenergic receptors are located in the bladder and urethra and are thought to induce contraction of the urethral smooth muscle. Beta adrenergic receptors are located in the bladder and urethra and are thought to facilitate the relaxation of the bladder.
The neuropeptide, serotonin is inhibitory to the bladder. Diminished synthesis of serotonin in those with depression can result in the symptoms. This also explains why women are more prone to this condition (depression is more common in women). Up to 60% of women with urge and mixed incontinence have been found to have depressive symptoms in addition.
Vanilloid Sensitive pathway: capsaicin-sensitive afferent nerve fibers ('C' fibers) (small, non-myelinated neurons innervating the vanilloid receptors that are initially stimulated and later desensitized by capsaicin, the active ingredient of the hot chilli pepper, Capsicum annuum) are present in the bladder and may be responsible for symptoms of overactive bladder. Altough these fibers constitute the bulk (70%) of the efferent nerve fibers of the bladder, they do not play a role in normal urination but become active in conditions such as spinal cord injury or bladder inflammation.
Vanilloid receptors and pathway normally transmit pain and temperature sensation to the central nervous system and trigger homeostatic reflexes regulating the function of autonomic nervous system (e.g., microcirculation). These nerve fibers contain the tachykinin substance P along with other neuropeptides such as calcitonin gene related peptide (CGRP), which result in mast cell activation, lymphocyte activation and vasodilatation on release. Capsaicin can stimulate release of nitric oxide (NO) from the sensory nerve fibers in the bladder and result in pain, hyperreflexia and other symptoms associated with overactive bladder.
Sensitization of the 2nd order neurons following the activation of afferent neurons in the dorsal horn of the spinal cord is another mechanism suggested to explain the symptoms.
Symptoms of overactive bladder commonly occur in patients with bladder outlet obstruction due to BPH or neurovesical dysfunction.
Hypertension is an important risk factor for the development of symptoms of overactive bladder, especially in those with LUTS due to BPH.
Nitric Oxide (NO) and Bladder Overactivity
The nonadrenergic, noncholinergic (NANC) neurotransmission has recently been identified to have a role in the development of symptoms in patients with overactive bladder. NO is produced from L-arginine by NO synthase (NOS). NO activates guanylate cyclase resulting in the formation of cyclic guanosine monophosphate (cGMP) from guanosine 5'-triphosphate. cGMP acts on ion channels, phosphodiesterase and protein kinase enzymes in the cell resulting in smooth muscle relaxation. Lower urinary tract has adrenergic innervation and plays an active role in voiding. Disturbance in the L-arginine-NO-cGMP pathway has also been suggested to result in symptoms of overactive bladder.
Relationship between Overactive Bladder, Urge Incontinence, Stress Incontinence and Mixed Incontinence
Tranditionally urine loss accompanied by urgency resulting from abnormal bladder contractions is considered as urge incontinence whereas urine loss resulting from sudden increased intra-abdominal pressure (e.g., laugh, sneeze) is considered as stress incontinence. Mixed incontinence is a combination of both [Figure - 1]. It has now been recongnized that frequency and urgency can occur with or without involuntary leakage of urine (urge incontinence) and this condition is considered as overactive bladder (OAB). Stress incontinence is not a part of OAB. Mixed incontinence is now considered as a combination of OAB and stress incontinence.
Symptoms [23],[24],[25],[26],[27],[28],[29]
The symptoms of overactive bladder are due to involuntary contractions of the detrusor muscle during bladder filling. Most of the patients with this condition present with increased frequency and urgency of urination and nocturia. Some of them may have urge incontinence or mixed (urge and stress) incontinence.
Depending on the symptoms, patients with overactive bladder can be divided into the following 3 groups:
1. those with frequency and urgency;
2. those with frequency, urgency and urge incontinence
and;
3. those with mixed incontinence.
Overactive Bladder and BPH [26],[27],[28]
The prevalence of LUTS, BPH and overactive bladder increases with age. BPH is causally related to overactive bladder in men having both the conditions. The symptoms of overactive bladder may increase even in those with stable bladder outlet obstruction due to BPH. Symptoms improve/disappear in 2/3 of BPH men following surgical treatment such as TURP.
Diagnosis
The primary care physician should be the first point of contact for patients within the healthcare system. Primary care physicians are uniquely situated to screen for bladder symptoms.
A practical approach to diagnose OAB includes medical history, screening questions, physical examination and urinalysis.
A thorough medical history reveals bladder control symptoms [Table - 2] and identify examinations and / or procedures that may have bearing on the patient's present status. The physician should focus on medical, neurologic, and genitourinary status; review voiding patterns and medication; and administer a mental status examination, if appropriate. The patient's general physical appearance and demeanor should be assessed, especially if the patient is elderly.
A simple screening question is, "Do you have bladder problems that are bothersome, or do you ever leak urine?.
A bladder diary can be kept by the patient for a few days for a complete and accurate picture of symptoms. Bladder diaries are inexpensive and involve patients in their own health care. The patient should note the times of toilet use and roughly how much urine is passed, instances when accidental leakage of urine occurs, and information about fluid intake. Sometimes the patient's fluid intake is quite high, which may be responsible for their `excessive' urine output. The physician or support staff should give the patient careful instruction on how to complete the diary.
Urinalysis will indicate hematuria [bladder cancer, stone disease, urinary tract infection (UTI)], pyuria (UTI), bacteriuria (UTI), glucosuria (diabetes), and proteinuria (diabetes).
Symptoms of OAB should be differentiated from those due to BPH, prolapse of the uterus, pelvic floor dysfunction, stress incontinence, UTI, interstitial cystitis, diabetes mellitus and neurogenic bladder disease [Figure - 2],[Figure - 3],[Figure - 4]. A diagnosis of stress incontinence does not rule out OAB, since some patients may have both stress incontinence and OAB (mixed incontinence). OAB includes the symptoms of frequency and urgency, with or without urge incontinence.
The AHCPR (Agency for Health Care Policy and Research) guidelines for evaluation are aimed at identifying treatable causes or associated conditions such as urinary tract infection, bladder cancer, pelvic prolapse, spinal cord injury, peripheral neuropathy and depression. It may also occur in those with stress incontinence and bladder outlet obstruction (e.g., BPH). The work-up includes history, physical examination and urinalysis in all patients.
As assessment of strength of pelvic floor muscles helps in treatment planning. Measurement of post-void residual urine is useful in both men and women with bladder outlet obstruction.
A Voiding Diary helps to guide treatment and acts as a baseline to assess the efficacy of treatment.
Urodynamic assessment is indicated in the following patients:
1. Patients not responding to conservative treatment
2. Those with known neurologic disease/injury
3. Presence of significant postvoid residual urine and
4. Those with stress incontinence.
The specific types of urodynamic abnormalities identified include Detrusor Hyper-reflexia ± Impaired Contractility; Detrusor Hyper-reflexia + Dyssynergia; Detrusor Instability; Urgency/Frequency and Stress Incontinence.
Treatment [30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46]
An estimated 62% of patients with overactive bladder and urge incontinence wear pads and 8% do not get any treatment. Only 26% and 28% are treated with pelvic floor re-education or drugs, respectively and surgery is performed in 6%.
The clinician should reassure patients that urinary symptoms are not uncommon and that they are readily treatable with medications, behavioral therapy, exercise, and sometimes surgery. Treatment for overactive bladder is of 2 types: conservative or surgical.
A. Conservative Treatment includes: 1. Behavioral Therapy; 2. Pelvic Floor Exercises; 3. Electrical Stimulation; 4. Biofeedback; 5. Drug Therapy (Muscarinic Receptor Antagonists); 6. Intravesical Treatment with Capsaicin/ Resiniferatoxin.
B. Surgical Treatment includes: 1. Denervation; 2. Augmentation Cystoplasty; and 3. Autoaugmentation (by open surgery and laparoscopic autoaugmentation).
Behavioral and pelvic floor therapy are the initial forms of therapy which may be curative in some patients.
Bladder Training & Behavioral Therapy [38],[39]
Bladder Training: In this form of treatment, the patient is educated on the purpose and use of the bladder diary. The Bladder Diary is useful to monitor fluid intake and urine output and helps in the evaluation of training progress. The clinician should reinforce the need to practise delayed voiding and adhere to a strict schedule of voluntary voiding. Approximately 15% of patients have been reported to achieve complete resolution of symptoms by this treatment in a pooled analysis of 11 studies involving 698 patients. One half of patients experienced symptom reduction of 50-75% in a randomized, controlled trial.
Bladder training is a time and labor-intensive treatment. The patient should have an appropriate level of cognitive functioning to participate in this form of therapy.
Behavioral Therapy: In this the patient is educated about the condition and is advised to develop strategies to minimize or eliminate the incontinence and other symptoms (Cognitive Therapy). This includes information regarding normal bladder function, examination of individual function with a voiding diary, micturition charts and measures such as timed voiding, fluid-dietary management and urge inhibition to `retrain' the bladder.
Behavioral therapy options include diet, bladder training and pelvic floor rehabilitation (which includes Kegel exercises, biofeedback and electrostimulation). Fluid restriction (Dietary Therapy) and Timed Voiding, Delayed Voiding, Urge Inhibition and Reinforcement have been found to be useful in symptom relief. Dietary approaches include management of fluid intake and restricted consumption of irritating food, drugs, and beverages containing caffeine and alcohol.
Although behavioral therapy has been found to improve symptoms in >50% of patients, its long-term efficacy of behavioral strategies has yet to be determined [Table - 3],[Table - 4].
Pelvic Floor Rehabilitation: These were first described in 1948 by Kegel, who reported a cure rate of 84%, irrespective of the type of incontinence (urge, stress or mixed). In this Physical Therapy (electrical stimulation or pelvic floor muscle [PFM] training with or without biofeedback) is used and is effective in those with weak levator muscles.
Pelvic floor rehabilitation strengthens muscles in the pelvis supporting the bladder or uterus, improve urethral closure, and decrease detrusor instability so that the patient can learn to inhibit unstable contractions and/or urge incontinence. Rehabilitation is achieved through Kegel exercises, which squeeze the urinary sphincter. Rapid, active contractions can inhibit an unstable contraction. Small vaginal weights (cones held inside the vagina) are sometimes used as an adjunct to Kegel exercises.
Physical therapy inhibits detrusor muscle contraction by voluntary contraction of PFMs at the same time as the urge to void and prevents sudden falls in urethral pressure. Patients use the PFMs to decrease leakage (in the presence of urgency) and to learn to inhibit the urge completely.
Although results of this therapy are promising, randomized controlled trials are necessary to study the efficacy of PFM training (with or without pharmacotherapy).
Extracorporeal Magnetic Innervation (ExMI TM ) (The Neo Control® Pelvic Floor Therapy System):
This is a non-invasive treatment for urinary incontinence (stress, urge and mixed) and utilizes extracorporeal magnetic innervation (ExMI TM ) technology for pelvic floor stimulation. This can be given in the office setting and is based on magnetic induction of pelvic floor muscles. This device was cleared by the US FDA for the treatment of urinary incontinence in women.
Each treatment session last for 20 to 30 minutes. During the treatment the patients sit in the treatment chair. The pulsing magnetic fields generated by the treatment head penetrates the tissues of the perineum including all nerves and muscles of pelvic floor. The PFMs contract in response to each pulse. The frequency and strength of contractions can be set to a standard to improve the tone and function of the muscles resulting in improved awareness of the pelvic floor, better control of urinary function and improved quality of life. The treatment protocol includes 2 sessions per week for eight weeks or more, depending on the patient's pelvic floor muscle strength at diagnosis.
Electrical Stimulation: Electrostimulation [42],[43] (ES) is used to alter lower urinary tract function by stimulating the somatic/sacral autonomic nerves. This is an effective and well-tolerated treatment and acts by neuromodulation affecting the neural signaling that controls continence. Electrical stimulation causes hypertrophy of skeletal muscle fibers by the recruitment of faster-conducting motor units (normally recruited during voluntary activity).
Two types of ES, long-term r chronic (5-10 Hz, <20 mA) and acute maximal (50-100 Hz, >25 mA), have been used to treat detrusor instability.
The treatment is administered by non-implantable and implantable methods. Direct sacral stimulation is also commonly used. The treatment is advised twice weekly or twice daily depending on the severity of symptoms.
Vaginal electrical stimulators relieve the symptoms in approximately 50% of patients. Multiple sessions of nonimplanted stimulation (thigh stimulation, anal stimulation) and direct pelvic muscle stimulation are also used. This treatment has been found to improve urge-to-leak time.
Occasional side effects of this treatment include local discomfort and irritation. This treatment is contraindicated in those with pacemakers or other forms of implanted electrical devices.
Decrease in the rate of urine leaks, nocturia, pad count, total voids have been reported by a twice daily regimen. Approximately 41 % of the treated patients have shown >50% improvement of symptoms and 28% of patients are cured. The reported cure rate is 8% with improvement in 38% of treated patients.[42],[43]
Biofeedback: This is a form of learning or re-education in which the participant is restrained within a closed feedback loop. The patient is educated regarding the normally unconscious physiologic processes such as visual, auditory or tactile signals. Biofeedback is useful in children. Objective responses are recorded on a polygraph trace and shown to the patient.
Biofeedback can be an effective adjuvant therappy to pelvic floor rehabilitation. The devices used to train patients to strengthen the pelvic floor muscles and prevent/ minimize urine leakage include vaginal/anal probes and surfaces electrodes.
Biofeedback-assisted behavioral treatment has been found to be more effective than either oxybutynin or placebo in the treatment of urge and mixed urinary incontinence in older women. For success, the patient should be well motivated and intelligent. Although this form of treatment is time-consuming, the advantages include reduced morbidity and side effects associated with other type of treatment such as pharmacotherapy. This can also be used in combination with drug therapy.
Electromyographic Biofeedback: This is a form of biofeedback using the EMG activity of the urethral/anal sphincter of the pelvic floor. Stein and associates reported success rates of 36% and 43% in patients with stress and urge incontinence, respectively, using transvaginal/ transrectal EMG biofeedback.
Pharmacotherapy [47],[48],[49],[50],[51],[52],[53],[54],[55],[56]
The 1996 AHCPR Practice Guidelines recommend anticholinergics as first-line pharmacotherapy for OAB. Drug therapy is indicated for patients with reduced bladder capacity. Anticholinergic agents are the mainstay of treatment and are often combined with behavioral therapy and PFM exercises [Table - 5].
Rationale: Acetylcholine induced stimulation of postganglionic muscarinic receptors on detrusor smooth muscle is involved in normal and involuntary bladder contractions. In addition to their antispasmodic effect on the bladder and diminishing the frequency of uninhibited contractions, anticholinergics can increase total bladder capacity and delay the initial urge to void. Anti-muscarinic agents are, therefore, effective in the treatment of overactive bladder.
The bladder contains M2 and M3 subtypes of muscarinic receptors [mainly (80%) M2] [Table - 6].Muscarinic receptors in the bladder smooth muscle cells are stimulated by cholinergic nerves resulting in bladder contraction. 5 types of muscarinic receptors are identified: M1 to M5 (only M1-M4 occur in the human body; M1: in neural tissue; M2: in cardiac muscle; M3: in exocrine glands; M4: in brain and lungs). The detrusor contains both M2 (80%) and M3 (20%) receptors. M2 receptors regulate bladder relaxation, whereas M3 receptors are responsible for detrusor contraction. Muscarinic receptor activity is dynamic and changes according to the associated condition (spinal cord injury, bladder outlet obstruction).
In postmenopausal women estrogen replacement is used with alpha-adrenergic agents for mixed incontinence to produce possible synergic effects at the bladder outlet and urethra.
The downside of the anticholinergic agents is their treatment-limiting adverse effects such as dry mouth, constipation and blurred vision. The commonly used agents include oxybutynin and tolerodine.
Oxybutynin [48],[49] (Ditropan a ): Oxybutynin is the agent of choice for patients with overactive bladder according to the 1996 AHCPR guidelines. This is a musculotropic relaxant with moderate anticholinergic activity and local anesthetic properties. This agent has 10-fold higher selectivity for M3 over M2 receptors which is responsible for its efficacy and adverse effects. Its side-effects are responsible for poor patient compliance resulting in therapy discontinuation.
Oxybutynin is used in a dose of 5-15 mg 3 times daily. The available forms of this agent include oxybutynin immediate release (IR) (Ditropan), and oxybutynin extended release (ER) (Ditropan XL) formulations. In 4 placebocontrolled trials (N-151), oxybutynin IR resulted in an overall improvement versus placebo, producing significant decreases in frequency and urgency and significant increases in voided volume in 2 trials. Oxbutynin ER is once-daily treatment for OAB.
Dry mouth (50%) is the most important side-effect of oxybutynin resulting in discontinuation of treatment in 27% of patients. Oxybutynin ER produces dry mouth in 68% of treated patients (25%, moderate to severe). The other side-effects include constipation (15%), and blurred vision. In addition, this agent is associated with CNS adverse effects such as somnolence and dizziness, which have implications for elderly patients who are prone to falls and injuries.
The new approaches to improve the tolerability of oxybutynin include intravesical instillation, extended release oral preparations [Long-acting oxybutynin (Ditropan XL)] and rectal suppositories. Although intravesical therapy with oxybutynin is free of side-effects, this form of treatment is not acceptable to the majority of patients.
Long-acting oxybutynin (Ditropan XL) is available since January 1999 and has efficacy equivalent to the immediate-release preparation. A steady plasma drug level is obtained during a 24-hour period with this agent. Preliminary studies have reported better patient compliance with this agent with few side-effects. Approximately 4050% of patients with urge incontinence achieve continence with Ditropan XL. The agent is started in a dose of 5 mg per day and increased according to the response.
S-oxybutynin is the modified form aimed at reducing the side-effects (by reduced blockade of muscarinic receptors) of oxybutynin.
Tissue and subtype-selective antimuscarinic agents with improved tolerability have recently been developed to counter the side-effects of oxybutynin. These include the bladder-selective agent, tolterodine (Detrol® and the subtype selective (M3 receptors) agent, Darifenacin.
Tolterodine [50] (Detrol®): This agent was approved by the US FDA in March 1998. This is a muscarinic receptor antagonist with higher specificity for the M2 receptors and is useful to improve frequency, urgency and urge incontinence. The agent is used in a dose of 2 mg twice daily, which can be reduced to 1 mg twice daily depending on the response. The clinical response is seen within one week of beginning treatment with tolterodine. Due to its reduced activity on M3 receptors, adverse effects such as dry mouth are less common (3%). Tolterodine has been shown to reduce frequency by 20%.
This agent has minimal CNS, GI or cardiovascular sideeffects. The CNS side-effects of tolterodine (including cognitive changes) were comparable to placebo. Nonserious cardiac adverse events (mild EKG abnormalities) were more common with placebo therapy (6%) than with tolterodine (3%). There were no serious cardiac adverse events or any clinically significant alterations in laboratory parameters. Comparative clinical trials have shown that fewer patients on tolterodine required dose reduction or discontinuation of treatment due to the adverse effects such as dry mouth.
The efficacy of tolterodine is equivalent to that of oxybutynin but with improved tolerability and is currently the best alternative for long-term treatment of patients with overactive bladder.
Tolterodine is metabolized in the liver by cytochrome system (CYP2D6) to an active metabolite (DDO1) which is partly responsible for its clinical activity.
The efficacy of oxybutynin in a dose of 5 mg 3 times daily is equivalent to 2 mg twice daily tolterodine. Both the agents require 8-12 weeks of treatment before maximal effect is noted. 85 per cent of the effect is reached within 4 weeks after beginning the treatment. Pooled results demonstrated a significant decrease from baseline in number of incontinence episodes per 24 hour period for both tolterodine 2 mg and oxybutynin IR 5 mg over placebo. The reduction of mean daily incontinence episodes for tolterodine and oxybutynin IR ranged from 40-60% below the baseline mean.
In pooled studies, dry mouth was experienced by 16% of patients in the placebo group, 40% of patients in the tolterodine group, and 78% of patients in the oxybutynin IR group.
At a dose of 2 mg twice daily, tolterodine was found to increase voided volume and residual urine volume by 66 and 48 ml, respectively; reduce frequency by 20% and the mean number of incontinence episodes per 24 hours by 50%.
In 3 placebo-controlled 12-week studies using Detrol® encompassing 516 patients (399 patients treated with 2 mg twice daily of Detrol® and 177 treated with placebo) with overactive bladder with frequency. urgency and urge incontinence, tolterodine was found to result in greater decrease in micturition frequency (p<0.001), significant increases (p<0.001) in average volume voided per micturition and incontinence episodes per 24 hours compared to placebo.
In a prospective study of 28 patients with increased frequency (>8 times/day), urgency/urge incontinence (>I time/day) who were treated with 1-2 mg twice daily, frequency, nocturia and leakage episodes were reported to decrease significantly, whereas average urine volume per day and average voided volume did not change. No EKG / biochemical abnormalities were reported in treated patients during a mean follow-up of 9.4 months. This longterm study concluded that tolterodine is effective and well tolerated with excellent long-term compliance (no dropout in >9 months follow-up) and quality of life.
Children with detrusor hyperreflexia have also been found to tolerate tolterodine better than oxybutynin.
Tolterodine (Detrol®) is currently the best alternative for long-term treatemnt of patients with overactive bladder.
Cost data show that tolterodine 2 mg bid is priced comparably with oxybutynin ER and IR. The daily cost to the patient using oxybutynin IR (5 mg tid) is $2.77 (brand) and $1.18 (generic). The comparable costs for those using oxybutynin ER (5 mg qd) and tolterodine (2 mg bid) include $2.46 and $2.95. The daily cost in patients using 15 mg qd of oxybutynin ER is $3.14.
Darifenacin: This is a subtype-selective antimuscarinic agent and is a selective inhibitor of M3 muscarinic receptors in the bladder without systemic adverse effects (which are due to blockade of M 1 and M2 receptors) and is currently undergoing trials. This agent is used in a single oral dose of 10 mg daily and was found to be effective in a small placebocontrolled study.
Blockade of M3 receptors, however, is associated with blurred vision and constipation.
Other Drugs: The other agent which have been found to be effective in overactive bladder include inhibitors of serotonin and norepinephrine re-uptake such as mipramine, duloxetine, alpha-1-adrenoceptor antagonists, prostaglandin synthase inhibitors, potassium channel openers, prostaglandins, selective and nonselective inhibitors of cyclo-oxygenase and those acting on the beta-3-adrenergic receptors in the bladder detrusor muscle and agents inhibiting bladder afferent nerve transmission and their receptors.
Propantheline: This is no longer used because of the necessity for frequent dosing and side-effects.
Tricyclic antidepressants (imipramine) are used to treat both OAB and stress incontinence. However, the 1996 AHCPR guidelines caution that this class of drugs should be used only after careful evaluation of the patient. These agents have CNS side-effects, may cause postural hypotension, and can produce cardiac arrhythmias.
Beneficial effects have also been found with indomethacin and flurbiprofen. Certain centrally acting drugs affecting dopamine and GABA mechanism are also being studied in patients with overactive bladder. Only future research can elucidate the role of these agents in overactive bladder.
Intravesical Therapy with Vanilloids: These are mostly used in those with overactive bladder due to neurogenic disorders with detrusor hyperreflexia plus bladder empyting disorder(s). Patients with residual urine are advised self intermittent clean catheterization (SICC) in addition. Two types of agents are used:
1. intravesical agents that block pelvic nerve-detrusor smooth muscle cholinergic transmission (oxybutynin);
2. agents that block the afferent arm of the micturition reflex (local anesthetics such as lignocaine, bupivacaine; capsaicin and resiniferatoxin).
Capsaicin: 80 per cent of patients with spinal cord disease (e.g., multiple sclerosis) and detrusor hyperreflexia have been shown to respond to intravesical capsaicin. The agent results in a semipermanent neurotoxic effect on the afferent C-fibers in the bladder. The major disadvantage of capsaicin is bladder pain during instillation.
Resiniferatoxin (RTX) is an extract from the latex of Euphorhia resinifera and has been found to be useful in preliminary studies for patients with overactive bladder. This is instilled in the bladder with 10% ethanol or saline. Compared to Capsaicin, this is nonirritant to the bladder (treatment is less painful) and results in long-lasting desensitization of bladder afferent C-fibers. Preliminary studies have reported a 77% response rate with this agent.
Sacral Neuromodulation with permanent implants: This is a minimally invasive treatment option for patients with intractable symptoms of overactive bladder (frequency, urgency and urge incontinence) (especially due to neurovesical dysfunction) not responding to other conservative options. The treatment involves reflex inhibition of the bladder by S3 nerve root stimulation. This is effective in both children and adults with a short-term response rate of 80%.
Functional magnetic stimulation (FMS) to a maximum of 5 seconds above the S3 level and electrical stimulation for 30 seconds (in FMS failures) were reported to yield a response rate of 80% in nonobstructed patients with overactive bladder. This treatment is useful in both children and adults.
Denervation Techniques: Bladder denervation is aimed at achieving a low pressure bladder and restoration of urinary continence in patients with complete suprasacral spinal cord lesions. The bladder can be denervated at central (sacral nerves) or peripheral (pelvic nerves) levels or in the bladder. Denervation targets sensory or motor nerves to weaken/interrupt the detrusor reflex arc.
Bladder denervation can be achieved in a reversible (sacral nerve anesthesia, spinal anesthesia) or irreversible (subarachnoid alcohol/phenol injection, open surgical denervation, anterior sacral root rhizotomy, posterior sacral root rhizotomy, combined anterior and posterior sacral root rhizotomy, peripheral denervation, transvaginal denervation, bladder transection and hyperbaric bladder distension) manner.
Central denervation involves the sacral roots S3 and S4 which contain parasympathetic fibers to the bladder and somatic fibers to the pelvic floor.
Peripheral denervation is accomplished by perivesical dissection of the pelvic nerves (by abdominal/transvaginal approach).
Sacral de-afferentiation of the bladder (by dorsal sacral root rhizotomy of S2-S5) has been found to be effective for patients with spinal cord injuries and detrusor hyperreflexia, functional low compliance and reflex incontinence.
Although denervatin techniques have a high initial success rate in symptom relief and control of incontinence, the relapse rate within 18 months is very high (almost 100%). Currently, denervation techniques have limited applicability.
Surgical Treatment
This is used as a last resort in patients with severe symptoms not responding to conservative measures and is aimed at increasing functional bladder capacity and decrease maximum detrusor pressure at capacity (end filling pressure) which result in relief of symptoms.
Surgery has been found to be highly effective in those with detrusor hyperreflexia due to neurogenic bladder dysfunction. Bladder capacity is increased by Clam Augmentation Cystoplasty which utilizes different intestinal segments such as ileum/sigmoid colon. The complications associated with incorporation of bowel segments such as bladder stones, metabolic acidosis, electrolyte abnormalities can now be avoided by Autoaugmentation (open surgical/laparoscopic) or by using de-epithelialized bowel segments/urotheliumlined tissue (tissue engineering technique).
Bladder autoaugmentation achieves peripheral bladder denervation and involves removal of detrusor muscle down to the mucosa over a wide section of bladder dome and has resulted in symptom relief with voiding in 50% of patients over 7 years. Others require intermittent catheterization for bladder emptying.
Treatment of Overactive Bladder in Children
This includes measures such as physiotherapy, biofeed back, bladder training, pelvic floor muscle exercises (Kegel's exercises), neuromuscular electrical stimulation and drug therapy (oral/intravesical oxybutynin).
Complications
Patients with severe symptoms due to overactive bladder can develop intractable frequency and incontinence, deterioration of renal function, poor compliance during filling and high pressure phasic detrusor contractions (in those with neurovesical dysfunction).
The future treatment of OAB promises improved recognition and diagnosis as a result of consensus on a symptom-based definition. Improved treatment will also result from continued advances in the development of management strategies combining behavioral and drug therapies.
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]
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