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Quick Reference Guide for Clinicians
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Diagnosis and Management of Overactive Bladder

(Published March 2011)

Pharmacologic Treatment

  • Pharmacologic treatment can be combined with non-pharmacologic therapy.
  • Combined treatment with behavior modification and antimuscarinics has been shown to be more efficacious than either modality used alone.1

Combination therapy reduction in incontinence

Combination Therapy Reduction in Incontinence1

  • When non-pharmacologic and pharmacologic treatments fail, specialists can try other methods for treating OAB, such as botulinum toxin injections, neuromodulation, and surgery. These therapeutic modalities are not discussed in detail in this Quick Reference Guide.

Pharmacologic therapies

  • Four types of pharmacologic therapy are used to treat OAB:
    • Estrogen
    • Antimuscarinic drugs
      • Non-selective
      • Selective
    • Tricyclic antidepressants
    • Botulinum toxin (BOTOX®) injections

Estrogen

  • Local estrogen use is associated with overall subjective improvement in individuals with incontinence—fewer voids in 24 hours, fewer nocturnal voids, and less frequency and urgency.2
  • However, systemic estrogen therapy may worsen incontinence.2,3

Antimuscarinic drugs

  • The mainstays of medical treatment for OAB are the antimuscarinic agents, also referred to as anticholinergic drugs.
  • Antimuscarinic drugs inhibit involuntary detrusor contractions and thus reduce urgency (see sidebar).

Parasympathetic innervation

Parasympathetic innervation

  • Available antimuscarinic agents have similar efficacy and safety profiles.
  • The most important differences among these drugs relate to their side effects and tolerability.
  • Individual agents vary based on receptor selectivity and serum concentration of the active drug.
  • These agents can be divided into two basic groups:
    • Non-selective—have affinity for all muscarinic receptors
    • Selective—have relatively more affinity for M2 and M3 muscarinic receptors (see The Role of Muscarinic Receptors in OAB Pharmacologic Treatment)

The Role of Muscarinic Receptors in OAB Pharmacologic Treatment

The primary neurotransmitter located at nerve endings on the detrusor muscle of the bladder is acetylcholine. Acetylcholine stimulates muscarinic nerve endings, of which there are five subtypes, named M1 through M5. Only M2 and M3 are highly concentrated in the bladder. M2 is more prevalent, but the M3 receptors are responsible for detrusor contraction.

Antimuscarinic drugs block the parasympathetic muscarinic receptors and appear to exert their effects on OAB through M2 and M3 receptors by inhibiting involuntary detrusor contractions. The effects on these and other muscarinic receptors are responsible for the side effects associated with these agents.

Table 3. Side effects associated with receptor stimulation4-6
Muscarinic receptor subtype Side effects
M1 Impaired memory and cognition
M2 Prolongation of the QT interval, which can resultin cardiac arrhythmias and tachycardia
M3 Dry mouth, constipation, blurred vision
M4 Impaired cognition
M5 Receptor present in the hippocampus and otherareas of the brain, but stimulation-impairedcognition does not appear to be associatedwith M5 stimulation

Medication Dose Receptor Affinity Metabolism Side Effects
Dry mouth Constipation CNS
Oxybutynin IR 5mg TID M1, M2, M3, M4 Hepatic * * *
Oxybutynin ER 4mg QD M1, M2, M3, M4 Hepatic ** ** *
Oxybutynin patch 3.9mg BIW M1, M2, M3, M4 Hepatic, 2nd pass *** *** **
Oxybutynin Gel 1 gm QD M1, M2, M3, M4 Hepatic, 2nd pass *** *** **
Tolterodine LA 4mg QD M1, M2, M3, M5 Hepatic ** *** **
Trospium 20 mg BID M1, M2, M3, M4, M5 Renal *** * ***
Solifenacin 5/10mg QD M3 Hepatic ** * ***
Darifenacin 7.5/15 mg QD M3 Hepatic ** * ***
Fesoterodine 4/8 mg QD M1, M2, M3, M5 Hepatic * ** **
NOTE: * denotes least severe, ** somewhat severe, and *** most severe
Table used with permission from Jerry G. Blaivas, MD

Oxybutynin (Ditropan®)

  • First drug used for OAB
  • Approved 1975
  • Non-selective antimuscarinic agent
  • Extensive first-pass metabolism
  • Formulations:
    • Immediate release (IR) (Ditropan®)
      • Tabs: 5mg BID or TID; syrup 5mg/5ml
      • Onset 30-60 min, peak effects 3–6 hrs
      • Start at lower dose, increase gradually after 7 days
      • Max dose 30mg/day
    • Extended release (ER) (Ditropan® XL)
      • Tabs: 5mg, 10mg, 15mg QD
      • Better compliance, possibly fewer side effects
    • Transdermal (Oxytrol®)
      • 3.9mg/day 2x/wk
    • Gelnique®
      • Bypasses first-pass metabolism

Tolterodine (Detrol®)

  • Competitive muscarinic antagonist
  • More effective than placebo in relieving frequency, urgency, and urge incontinence in patients with OAB7
  • No effect on cognition compared with placebo
  • Formulations:
    • Immediate release (Detrol®)
      • Tabs: 1mg, 2mg BID
    • Extended release (Detrol® LA)
      • Tabs: 2mg, 4mg QD
      • Half-life 3 hrs

Summary: Oxybutynin versus Tolterodine

  • Both are equally effective at reducing urgency and urge incontinence.
  • Oxybutynin may be superior at decreasing frequency but is more commonly associated with dry mouth.8
  • Discontinuation rates are similar.
  • Both have adherence issues due to side effects.
  • Both improve quality of life.
  • No head-to-head trials have been conducted that compare the agents' effect on quality of life.

Trospium chloride (Sanctura®)

  • Peripheral, non-selective antimuscarinic agent
  • Does not cross blood-brain barrier
  • Potentially low CNS side effects
  • No cytochrome P450 metabolism
  • Perhaps fewer drug-to-drug interactions
  • Formulations:
    • Sanctura®
      • 20mg BID on empty stomach
    • Sanctura XR®
      • 60mg QD on empty stomach
      • No head-to-head trials versus extended-release forms
      • Dose reduced to 20mg QD in elderly or in patients with renal impairment

Solifenacin succinate (VESIcare®)

  • Competitive muscarinic receptor antagonist
  • More selective for M3 receptors
  • Formulations:
    • Tabs: 5mg, 10mg QD
  • Superior to placebo in reducing frequency, urgency, urge incontinence, and nocturia9,10
  • No QT effect, so potentially safe with heart disease
  • Superior to tolterodine IR 2mg BID in reducing urge and urge incontinence with less dry mouth11
  • Superior to tolterodine ER 4mg in decreasing urge, urge incontinence, and pad use12

Darifenacin (Enablex®)

  • Bladder-selective M3 receptor antagonist
  • Formulations:
    • Tabs: 7.5mg, 15mg QD
  • Superior to placebo in reducing frequency, urgency, urge incontinence13
  • Dry mouth and constipation more common than with placebo
  • No differences in memory versus placebo and oxybutynin ER14,15
  • High selectivity for the M3 receptor relative to the M1 receptor (9.3 times more affinity), which may minimize or avoid cognitive impairment16-18
  • No alteration of QT interval
  • Theoretically, risk of torsades de pointes is decreased; clinical relevance uncertain, potentially safe with heart disease
  • No renal dosing necessary

Fesoterodine fumarate (ToviazTM)

  • Competitive muscarinic receptor antagonist
  • Formulations:
    • Tabs: 4mg, 8mg QD
  • Superior to placebo in reducing the number of urge incontinence episodes and micturitions per 24 hours
  • No renal dosing in mild–moderate renal disease; avoid 8mg dose with severe renal disease
  • No QT interval prolongation
  • No comparative trials conducted

Summary: Cognitive side effects with antimuscarinic agents14

  • Oxybutynin adversely affects cognition.
  • Darifenacin, solifenacin, and tolterodine do not.
  • Fesoterodine and trospium probably do not.

Tricyclic antidepressants

  • Imipramine and amitryptiline are used.
  • Both drugs inhibit uptake of norepinephrine and serotonin.
  • Demonstrate anticholinergic and sympathomimetic (i.e., stimulation of sympathetic nervous system) effects.
  • Suppress detrusor contractions and increase outlet resistance by urethral contraction; both of these mechanisms of action promote urinary incontinence but can also cause urinary retention.
  • Effects are additive to those of antimuscarinic agents.
  • Not approved by Food and Drug Administration for OAB and should not be used for primary treatment.
  • Generally used in combination with antimuscarinic agents for patients with refractory OAB.

Guidance on drug selection

  • All antimuscarinic agents have approximately the same efficacy and side effect profile.
  • The incidence of side effects associated with a particular antimuscarinic agent varies based on:
    • Route of administration
    • Receptor specificity
    • Chemical structure
    • Metabolic breakdown pathways
  • Generally, controlled-release medications are associated with fewer adverse events.
  • If there is a concern about cognitive function, a selective M3 receptor blocker or one that does not have an affinity for crossing the blood-brain barrier is advisable.
  • For patients who have pre-existing constipation, non-selective antimuscarinics are preferable to M3 selective blockers because of the presence of M3 receptors in the bowel.
  • In patients with hepatic impairment, trospium or fesoterodine may be preferable because they are not processed by the CYP3a4 system. Avoid darifenacin in patients with severe hepatic impairment.
  • Specific guidance:
    • Begin with either tolterodine or oxybutynin.
    • If the patient has cognitive issues, use darifenacin (caution in patients with constipation ), tolterodine, or solifenacin.
    • Avoid in patients with hepatic impairment.
    • For second-line drugs, try non-generic agents.
    • If symptoms continue despite maximum dose of antimuscarinics for four weeks and the patient is tolerating the anticholinergic side effects, consider adding a tricyclic antidepressant. NOTE, however, that the side effects of this combination can be limiting.

Specialty treatments for refractory OAB

  • For patients with refractory OAB (i.e., no response to treatment for four to six weeks), referral to a specialist is prudent.
  • Specialty treatments include injections of botulinum toxin, neuromodulation, enterocystoplasty, and urinary diversion.
    • Botulinum toxin
      • Injections into bladder
      • 40%–80% success, but requires repeated injections every 6 to 9 months19
      • Relatively high incidence of temporary urinary retention requiring intermittent self-catheterization until the effects wear off
    • Neuromodulation20
      • Implantable electrical stimulation device
      • 56%– 90% success (using a primary outcome measure of a 50% decrease in OAB symptoms at 6 months)
      • Complications are minor.
    • Enterocystoplasty21-23
      • Major abdominal surgery: part of the intestine (the ileum or ileocecal segment) is detached from the rest of the bowel, reconfigured, and anastomosed to the bladder.
      • > 90% success
      • Afterward the patient may void normally, require intermittent self-catheterization, or wear an external appliance that collects the urine.
    • Urinary diversion21
      • Major abdominal surgery: a continent abdominal stoma may be created for intermittent catheterization.
      • Appropriate for patients with disabilities that make catheterizing through the urethra impractical.
      • > 90% success

Criteria for specialist referral

  • Patients with OAB should be referred to urologic or gynecologic specialists under the following circumstances:
    • Hematuria
    • Unclear diagnosis
    • Presence of voiding symptoms
    • Presence of pelvic organ prolapse
    • No response to therapy
    • Elevated post-void residual
    • Previous pelvic surgery
    • Bladder pain
    • Presence of neurologic disease

References

  1. Burgio KL, Locher JL, Goode PS. Combined behavioral and drug therapy for urge incontinence in older women. J Am Geriatr Soc. 2000;48(4):370–4.
  2. Cody JD, Richardson K, Moehrer B, et al. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev. 2009;(4):CD001405.
  3. Hendrix SL, Cochrane BB, Nygaard IE, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA. 2005;293(8):935–48.
  4. Hegde SS. Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol. 2006;147(Suppl 2):S80–7.
  5. Kay GG, Ebinger U. Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Int J Clin Pract. 2008;62(11):1792–800.
  6. Staskin DR, Zoltan E. Anticholinergics and central nervous system effects: are we confused? Rev Urol. 2007;9(4):191–6.
  7. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled analysis. Urology. 1997; 50(Suppl 6A):90–6.
  8. Diokno AC, Appell RA, Sand PK, et al.; OPERA Study Group.  Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003;78(6):687–95.
  9. Cardozo L, Castro-Diaz D, Gittelman M, et al. 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):512–9.
  10. Brubaker L, FitzGerald MP. Nocturnal polyuria and nocturia relief in patients treated with solifenacin for overactive bladder symptoms. Int Urogynecol J Pelvic Floor Dysfunct. 2007;18(7):737–41.
  11. Chapple CR, Rechberger T, Al-Shukri S, et al.; YM-905 Study Group. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int. 2004;93(3):303–10.
  12. Chapple C, Khullar V, Gabriel Z, Dooley JA. The effects of antimuscarinic treatments in overactive bladder: a systematic review and meta-analysis. Eur Urol. 2005;48(1):5–26.
  13. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol. 2004;45(4):420–9.
  14. Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol. 2005;173(2):493–8.
  15. Kay G, Crook T, Rekeda L, et al. Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects. Eur Urol. 2006;50(2):317–26.
  16. Napier C, Gupta P. Darifenacin is selective for the human recombinant M3 receptor subtype. Neurourol Urodyn. 2002;21:A445. (abstract)
  17. Kay GG, Wesnes KA. Pharmacodynamic effects of darifenacin, a muscarinic M3 selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers. BJU International. 2005;96(7):1055–62.
  18. Wesnes K, Lipton R, Kolodner K, Edgar C. Darifenacin, an M3 selective receptor antagonist for the treatment of overactive bladder, does not affect cognitive function in elderly volunteers. Eur Urol. 2004;3(2):131. (abstract)
  19. Karsenty G, Denys P, Amarenco G, De Seze M, Gamé X, Haab F, et al. Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/neurogenic overactive bladder: a systematic literature review. Eur Urol. 2008;53(2):275-87.
  20. Chartier-Kastler E. Sacral neuromodulation for treating the symptoms of overactive bladder syndrome and non-obstructive urinary retention: >10 years of clinical experience. BJU Int. 2008;101(4):417–23.
  21. Blaivas JG, Weiss JP, Desai P, et al. Long-term followup of augmentation enterocystoplasty and continent diversion in patients with benign disease. J Urol. 2005;173(5):1631–4;
  22. Flood HD, Malhotra SJ, O'Connell HE, et al. Long-term results and complications using augmentation cystoplasty in reconstructive urology. Neurourol Urodynam. 1995;14(4):297–309.
  23. Herschorn S, Hewitt RJ. Patient perspective of long term outcome of augmentation cystoplasty for neurogenic bladder. Urology. 1998;52(4):672–8.