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The Present and Future Treatment of Overactive Bladder Syndrome

Manhan Vu, DO; Peter K. Sand, MD

Pharmacologic options for treatment of overactive bladder syndrome have expanded recently to include a variety of administration routes. Nonpharmacologic options such as behavior therapy and electrical stimulation are popular alternatives to drug therapy, while injectables and acupuncture are on the horizon.

Overactive bladder syndrome (OAB) is a chronic and debilitating condition defined by the presence of urgency, usually accompanied by urinary frequency, nocturia, and urge urinary incontinence (UUI). Affecting more than 11 million women in the United States, OAB is commonly caused by detrusor overactivity. The physical and psychological impact of OAB has been well documented; it can cause depression, recurrent urinary tract infections, falls, and fractures, as well as a negative effect on work productivity and sexual function.1-3 This article reviews current therapies for the treatment of OAB and discusses therapeutic options in development.

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Pharmacotherapy


Oral Antimuscarinics

Anticholinergic drugs are weak agonists that inhibit acetylcholine from binding to muscarinic receptors. There are 5 subtypes of muscarinic receptors: M1, M2, M3, M4, and M5. While these receptors can be found throughout the body, the bladder primarily has M2 and M3 receptors within the detrusor and on the urothelial surface. These selective antimuscarinics target M2 and M3 receptors to inhibit involuntary detrusor contractions.

First-generation antimuscarinics include oxybutynin and tolterodine. Oxybutynin has been approved by the FDA in oral immediate-release, extended-release, and transdermal formulations available as a patch and a gel.

Oxybutynin immediate-release (oxy-IR) is a tertiary amine that binds to M2 and M3 receptors to decrease mean urge urinary incontinence episodes by 50% or more in 60% to 80% of subjects, but due to side effects, such as dry mouth, two-thirds of patients in a 2-year prospective study stopped taking the medication.4-6 The active metabolite, N-desethyloxybutynin (N-DEO), which is derived via first-pass metabolism, is the puta-tive agent believed to be responsible for the systemic anticholinergic side effects. The extended-release form of oxybutynin (oxy-ER) offers a more convenient once-a-day dosing regimen, has fewer medication-related side effects due to its lower and more stable plasma levels, and has diminished N-DEO levels when compared to oxy-IR.7

Tolterodine tartrate immediate-release and extended-release (ER) have both been shown to effectively reduce OAB symptoms. In a double-blinded, randomized, placebo-controlled trial of 1,529 patients, the extended- and immediate-release formulations reduced UUI by a median 71% and 60%, respectively, compared to placebo (33%).8 In a 12-month open-label study, there was an 83% median reduction in incontinence and 21% reduction in urinary frequency with tolterodine-ER 4 mg. However, 9.9% of patients withdrew from the study, including 1.8% due to dry mouth.9 Because of prolongation of the Q-T corrected (QTc) interval in subjects taking tolterodine at higher than approved doses, the FDA has placed a precaution in the package insert recommending that the medication be used with caution in patients with cardiovascular disease and in conjunction with medications that may reduce its metabolism.

The other FDA-approved antimuscarinic medications include trospium chloride, darifenacin hydrobromide, and solifenacin succinate. Trospium chloride is available in both immediate-release and extended-release formulations. Trospium, which has a high affinity for M2 and M3 receptors, is hydrophilic, limiting its absorption in the gastrointestinal tract, and therefore requires ingestion on an empty stomach. Due to its hydrophilicity, size, and polarity, trospium likely has limited access to the central nervous system (CNS), as suggested by very low rates of CNS adverse events that are often lower than placebo in some trials.10 The rate of dry mouth is 21% for the immediate-release formulation, which is similar to the extended-release formulations of oxybutynin and tolterodine. In a randomized, double-blinded, placebo-controlled trial of 523 patients, mean urinary frequency and incontinence episodes decreased by 20% and 71%.11 Trospium also compared favorably to oxy-IR in a randomized trial of 95 patients with spinal cord injury and detrusor hyperreflexia.12

The extended-release formulation of trospium has been shown to have equal efficacy to the immediate-release formulation, but with lower rates of dry mouth (10.7%) and constipation. It has a serum half-life of about 35 hours and offers the advantage of once-daily dosing. In phase III trials, the extended-release formulation has been shown to have a dry rate of 35% on a 3-day bladder diary in subjects who had a mean of more than 4 incontinence episodes a day.

In a series of large randomized, double-blind, placebo-controlled studies, darifenacin hydrobromide, an M3 selective receptor antagonist, reduced incontinence episodes by at least 50% in two-thirds of the patients.13 Additionally, darifenacin appears to have a reduced CNS side-effect profile, possibly due to its relatively high affinity for M3 over M1 receptors in the CNS. Dizziness and asthenia were reported in 2.1% and 2.7% of patients, respectively, in phase III trials, and a randomized cross-over study of 129 elderly patients showed that darifenacin did not affect cognitive function more than did placebo. This CNS safety in the elderly may be countered by the greater risk of constipation with darifenacin.

Solifenacin succinate is a well-absorbed antimuscarinic medication that has slightly greater affinity for M3 than M2 receptors. In a pooled analysis of phase III trials, subjects having at least 6 urgency episodes a day had a cure rate of 42% with solifenacin 5 mg compared to 29% with placebo. Additionally, 71% to 79% of patients reported a reduction of incontinence episodes by at least one-half.14 In a double-blind, double-dummy, randomized study, extended-release tolterodine and solifenacin were equally effectively in reducing nocturia and frequency, but solifenacin was better at improving incontinence episodes.15 Due to its potential effect on prolonging the QTc interval at 3 times the highest dose, the medication has package insert labeling cautioning against its use in patients with cardiovascular disease and with medications that might reduce its metabolism. However, a postmarketing surveillance study of 4,450 patients revealed no clinically significant effects on heart rate, blood pressure, or ECG findings.16

Transdermal Medications

Oral antimuscarinics may be associated with dry mouth and/or constipation, which may lead to the discontinuation of the drug. In a small phase IIIb trial, transdermal oxybutynin was as efficacious as oral tolterodine-ER but with a substantial decrease in the incidence of dry mouth (4.1% vs 9.6%).17 The transdermal patch produces lower steady-state plasma levels of the parent compound and avoids most of the cytochrome P-450 (3A4) first-pass metabolism within the gastrointestinal tract and liver. Consequently, there is a decrease of N-DEO, which is the putative cause of these antimuscarinic side effects.18 Patient compliance may benefit from the improved therapeutic index and the ease of twice-weekly application. The most common side effect is local irritation of the skin. The FDA has recently approved a transdermal oxybutynin gel. Data from phase III trials show that it appears to be as efficacious as the patch but with fewer application site reactions.


Other Medications

Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been effective in the treatment of mixed urinary incontinence. It is approved throughout most of Europe for treatment of stress urinary incontinence (SUI). One study found it to resolve SUI in 11% of patients compared to 6% taking a placebo in phase III US trials, but the drug was approved for depression and not SUI in the United States.19 Duloxetine is believed to treat SUI by increasing urethral skeletal muscle activity through activation of Onuf’s nucleus in the spinal cord, and it also improves OAB. A randomized placebo-controlled study showed significant improvement in quality of life, urinary frequency, and incontinence. The most common side effects were nausea (31%) and dry mouth (16%).20

Dicyclomine is a medication for irritable bowel syndrome that has both antispasmodic and antimuscarinic properties. Side effects, such as cognitive impairment, and the lack of good studies comparing dicyclomine to placebo or other more tolerable medications for OAB have led to the use of more selective antimuscarinics. Hyoscyamine is another agent used principally as an antispasmodic for the treatment of irritable bowel syndrome; it also has antimuscarinic effects, but there are limited studies on its benefit in OAB. Imipramine and synthetic desmopressin are other off-label treatments for OAB. Imipramine, a tricyclic antidepressant, and desmopressin have been especially effective in the treatment of nocturia and nocturnal enuresis. Imipramine has a complex mechanism of action and may be not be safe in the elderly. When prescribing desmopressin it is important to monitor electrolytes, since it can be associated with hyponatremia as early as 3 days after initiating therapy. (Desmopressin can be used to concentrate the urine at night or episodically during the day.) The risk of hyponatremia increases with age; there is an 8% risk in those older than 65. Imipramine probably affects serotonergic receptors in the brain and spinal cord to treat detrusor overactivity, although the exact mechanism is not understood.

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Behavioral Therapy

Behavior modification can be a highly effective treatment whether used alone or in combination with pharmacotherapy.21 Timed voiding strategies are free of side effects and any inherent costs. Prompted voiding or scheduled voiding regimens can provide significant reduction of urinary incontinence when patients are prompted to void at regular intervals. This is particularly helpful for institutionalized patients to avoid incontinence episodes. Bladder drill is a technique where patients contract their levators to suppress their urgency and void at predetermined times that may be progressively lengthened. By contracting their levators, they initiate the vesicoinhibitory reflexes to suppress involuntary detrusor contractions as they would at the termination of voluntary micturition. Bladder drill is an effective therapy with a 78% to 82% cure rate.22 Biofeedback has also proved useful in treating detrusor overactivity and OAB. Patients monitor detrusor pressures during bladder filling and are taught to effectively extinguish detrusor contractions by contracting their levators. Unlike Kegel exercises for the treatment of SUI, the goal here is not strength but to isolate contraction of the levator ani and periurethral skeletal muscles. With dedicated, motivated patients, behavioral therapy is a cost effective treatment.

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Electrical Stimulation/ Neuromodulation

Pelvic floor electrical stimulation (PFES) has been shown effectively to treat OAB and SUI in controlled trials.23 PFES has been used since 1878 when it was first applied to patients with acontractile detrusors and urinary retention. PFES can help strengthen the pelvic floor musculature but probably works by activating the vesicoinhibitory reflexes to control detrusor overactivity in approximately 50% of patients. In a sham-controlled trial, researchers found that 82% of study patients were cured of OAB symptoms versus 32% in the placebo group.24

Stimulation of the sacral nerves (SNS) was approved by the FDA in 1997 for treatment of refractory UUI, urgency, frequency, and nonobstructive retention. SNS is thought to work by resetting the afferent inputs that stimulate the “guarding” micturition reflex, but this remains poorly understood. In one trial, 59% of patients had a 50% or greater improvement of their urinary incontinence, and 46% of patients were completely dry after 3 years. Fifty-six percent reported 50% or greater improvement in frequency, and 70% with urinary retention had significant improvement in their postvoid residuals.25

Peripheral nerve stimulation has become an increasingly popular alternative to pharmacotherapy. The pudendal nerve can be stimulated using a microstimulator such as the Bion implant or a pudendal quadripolar electrode lead connected to an implantable pulse generator. A small prospective randomized trial comparing SNS to pudendal nerve stimulation with a tined quadripolar lead (Interstim) demonstrated higher rates of improvement in symptoms with pudendal stimulation (51%) versus SNS (37%).26

Posterior tibial nerve stimulation activates a mixture of somatic and motor nerve fibers originating from L4 to S3 to theoretically inhibit the nociceptive spinothalamic tract neurons and reduces or eliminates detrusor overactivity. However, the exact mechanism of action is not clear. Weekly stimulation for 30 minutes has resulted in improvement of diurnal and nocturnal frequency after 10 to 12 weeks. One study showed a 60% reduction of incontinence episodes and 23% reduction in frequency.27 Peripheral nerve stimulation offers a potentially effective and minimally invasive treatment with results comparable to SNS.

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Instillations/Injectables


Botulinum

Botulinum toxin A (BTX-A) has been used successfully to treat idiopathic OAB with an 11-month interval between injections.28 The toxin is thought to block the release of the neurotransmitters such as acetylcholine and cause paralysis of muscles by preventing vesicular fusion to the cell membrane. Other proposed mechanisms of action include inhibition of adenosine triphosphate release and alteration of afferent input by acting on the urothelium. In a retrospective European study of 200 patients with neurogenic detrusor overactivity, there was a significant decrease in mean voiding pressures.29 For patients with idiopathic detrusor overactivity refractory to antimuscarinic medications, one investigator injected 100 units of BTX-A at 30 sites within the bladder and after 4 weeks showed resolution of urinary urgency and incontinence in 72% and 74% of patients, respectively.30 Botulinum toxin appears to be an effective treatment for OAB.


Vanilloids

Originating from plants in the pepper family, both capsaicin and resiniferatoxin target the vanilloid receptor type 1, which is found in the capsaicin-sensitive, unmyelinated sensory fibers of the bladder. It is believed that vanilloids desensitize C fibers that may initiate involuntary bladder contractions. In small, uncontrolled studies, the instillation of capsaicin and resiniferatoxin have increased bladder capacity and reduced UUI in refractory OAB. Although equally efficacious, resiniferatoxin appears to cause less pain during instillation than capsaicin, but their optimal concentration and long-term safety need further evaluation.31

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Acupuncture

Acupuncture has improved urinary urgency and frequency and maximum cystometric capacities in several trials. In the first prospective sham-controlled trial to assess the efficacy of acupuncture, researchers found that acupuncture at SP-6 worked significantly better than the control point (ST-36) in resolving UUI and affecting urodynamic parameters.32 In a larger, randomized, sham-controlled study, investigators reproduced these earlier positive outcomes. The treatment group showed an improvement in urinary urgency and frequency, whereas the placebo group did not. There was a significant decrease in incontinence in both groups (59% and 40%, respectively).33 It does appear that acupuncture could have a role in the treatment of OAB.

Dr Vu reports no actual or potential conflicts of interest in relation to this article. Dr Sand reports that he is an advisor and lecturer for Allergan, Astellas Pharma US, Pfizer, GlaxoSmithKline, Ortho-McNeil, and Watson Pharmaceuticals.

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Drugs Mentioned in This Article

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Manhan Vu, DO, is a Fellow, Division of Female Pelvic Medicine and Reconstuctive Surgery, and Peter K. Sand, MD, is Director, Evanston Continence Center, and Director, Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics and Gynecology, both at NorthShore University HealthSystem, Evanston, IL.

References

  1. Sand PK, Appell R. Disruptive effects of overactive bladder and urge urinary incontinence in younger women. Am J Med. 2006;119(3 Suppl 1):16-23.
  2. Coyne KS, Sexton CC, Irwin DE, Kopp ZS, Kelleher CJ, Milsom I. The impact of overactive bladder, incontinence and other lower urinary tract symptoms on quality of life, work productivity, sexuality and emotional well-being in men and women: results from the EPIC study. BJU Int. 2008;101(11):1388-1395.
  3. Brown JS, McGhan WF, Chokroverty S. Comorbidities associated with overactive bladder. Am J Manag Care. 2000;6(11 Suppl):S574-S579.
  4. Yoshimura N, Chancellor MB. Current and future pharmacological treatment for overactive bladder. J Urol. 2002;168(5):1897-1913.
  5. Andersson KE, Appel R, Awad S. Pharmacological treatment of urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. 2nd ed. Plymouth, UK: Health Publications; 2002:481-511.
  6. Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A medium-term analysis of the subjective efficacy and treatment for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol. 1997;104(9): 988-993.
  7. Sathyan G, Chancellor MB, Gupta SK. Effect of OROS controlled-release delivery on the pharmacokinetics and pharmacodynamics of oxybutynin chloride. Br J Clin Pharmacol. 2001;52(4):409-417.
  8. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A; Tolterodine Study Group. Tolterodine once daily: superior efficacy and tolerability in the treatment of the overactive bladder. Urology. 2001;57(3):414-421.
  9. Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended-release tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41(6): 588-595.
  10. Pietzko A, Dimpfel W, Schwantes U, Topmeier P. Influences of trospium chloride and oxybutynin on quantitative EEG in healthy volunteers. Eur J Clin Pharmacol. 1994;47(4):337-343.
  11. Zinner N, Gittelman M, Harris R, et al. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol. 2004;171(6 Pt 1): 2311-2315.
  12. Madersbacher H, Stöhrer M, Richter R, Burgdörfer H, Hachen HJ, Mürtz G. Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in treatment of detrusor hyper-reflexia. Br J Urol. 1995; 75(4):452-456.
  13. Abrams P, Lheritier K, Steel M. Approaches for determining the efficacy of treatment of OAB: assessment of responder rates with darifenacin in a pooled analysis of phase III studies. Poster presented at: XXth EAU Congress; March 16-20, 2005; Istanbul, Turkey.
  14. Cardozo L, Castro-Diaz D, Gittelman M, Ridder A, Huang M. Reductions in overactive bladder-related incontinence from pooled analysis of phase III trials evaluating treatment with solifenacin. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(5):512-519.
  15. Milsom I. Can best practice get better? Refining best practice in overactive bladder: STAR study results unveiled (Solifenacin in a flexible dose regimen with Tolterodine as an Active comparator in a double-blind, double-dummy, Randomized overactive bladder symptom trial). Presented at XXth EAU Congress; March 16-20, 2005; Istanbul, Turkey.
  16. Michel MC, Wetterrauer U, Vogel M, de la Rosette JJ. Cardiovascular safety and overall tolerability of solifenacin in routine clinical use: a 12-week, open-label, post-marketing surveillance study. Drug Saf. 2008; 31(6):505-514.
  17. Dmochowski RR, Sand PK, Zinner NR, et al. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology. 2003;62(2):237-242.
  18. Waldeck K, Larsson B, Andersson KE. Comparison of oxybutynin and its active metobolite, N-desethyl-oxybutynin, in the human detrusor and parotid gland. J Urol. 1997;157(3):1093-1097.
  19. Dmochowski RR, Miklos JR, Norton PA, Zinner NR, Yalcin I, Bump RC; Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol. 2003;170(4 Pt 1):1259-1263.
  20. Steers WD, Herschorn S, Kreder KJ, et al; Duloxetine OAB Study Group. Duloxetine compared with placebo for treating women with symptoms of overactive bladder. BJU Int. 2007;100(2):337-345.
  21. Hadley EC. Bladder training and related therapies for urinary incontinence in older people. JAMA. 1986; 256(3): 372-379.
  22. Frewen W. Role of bladder training in the treatment of the unstable bladder in the female. Urol Clin North Am. 1979;6(1):273-277.
  23. Siegel SW, Richardson DA, Miller KL, et al. Pelvic floor electrical stimulation for the treatment of urge and mixed urinary incontinence in women. Urology. 1997; 50(6):934-940.
  24. Yamanishi T, Yasuda K, Sakakibara R, Hattori T, Suda S. Randomized, double-blind study of electrical stimulation for urinary incontinence due to detrusor overactivity. Urology. 2000;55(3):353-357.
  25. Siegel SW, Catanzaro F, Dijkema HE, et al. Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention. Urology. 2000;56(6 Suppl 1):87-91.
  26. Stöhrer M, Kramer G, Goepel M, Löchner-Ernst D, Kruse D, Rübben H. Bladder autoaugmentation in adult patients with neurogenic voiding dysfunction. Spinal Cord. 1997; 35(7):456-462.
  27. Vandoninck V, van Balken MR, Finazzi Agrò E, et al. Percutaneous tibial nerve stimulation in the treatment of overactive bladder: urodynamic data. Neurourol Urodyn. 2003;22(3):227-232.
  28. Grosse J, Kramer G, Stöhrer M. Success of repeat detrusor injections of botulinum A toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol. 2005;47(5):653-659.
  29. Reitz A, Stöhrer M, Kramer G, et al. European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol. 2004;45(4):510-515.
  30. Schmid DM, Sauermann P, Werner M, et al. Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol. 2006;176(1):177-185.
  31. de Sèze M, Wiart L, de Sèze M. Efficacy and tolerance of intravesical instillation of capsaicin and resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: a double-blind controlled study: preliminary results. Neurourol Urodyn. 2002;21:41-42.
  32. Chang PL. Urodynamic studies in acupuncture for women with frequency, urgency, and dysuria. J Urol. 1988;140(3):563-566.
  33. Emmons SL, Otto L. Acupuncture for overactive bladder: a randomized controlled trial. Obstet Gynecol. 2005; 106(1):138-143.
 

 

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