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Urologic applications of botulinum toxin
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Ashley King, MD
Adrienne Quirouet, MD
Courtenay K. Moore, MD

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum1 and is the most poisonous naturally occurring toxin known.2 Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),1 but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.3 Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.4

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

  • It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.5
  • In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.6
  • It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.6,7
  • It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.3

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.8 From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.9

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.10 In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.10 At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.15

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al14 found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al13 reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,14 these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al13 they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al16 found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.16

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al17 used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).17 They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

 

 

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.18 The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.19 Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale22 at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%20 and 24.1%21 of patients) and urinary retention requiring self-catheterization (5.4%20 and 6.9%21).

The largest study to date of anticholinergic therapy vs botulinum toxin injection23 in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.23

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).23

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder24 to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.25

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.26

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),27 of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al28 and de Sèze et al29 also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al30 reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.30

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.25 In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

 

 

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).31

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.6 In animal studies,32 botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al33 performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.33

Abbott et al34 evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al35 injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,35 and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor36 compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.36

Pinto et al37 treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.37

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.38 The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.35 The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.2 The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.2 Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.2

Repeat injections can cause an immune response in up to 5% of patients.6 Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.6 In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.39

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

References
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  12. Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007; 41:335–340.
  13. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol 2012; 187:2131–2139.
  14. Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol 2011; 60:742–750.
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  17. Carlson JJ, Hansen RN, Dmochowski RR, Globe DR, Colayco DC, Sullivan SD. Estimating the cost-effectiveness of onabotulinumtoxinA for neurogenic detrusor overactivity in the United States. Clin Ther 2013; 35:414–424.
  18. Abrams P, Cardozo L, Fall M, et al; Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61:37–49.
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  36. Kuo HC, Chancellor MB. Comparison of intravesical botulinum toxin type A injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. BJU Int 2009: 104:657–661.
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  38. Rovner E. Chapter 6: Practical aspects of administration of onabotulinumtoxinA. Neurourol Urodyn 2014; 33(suppl 3):S32–S37.
  39. Schulte-Baukloh H, Herholz J, Bigalke H, Miller K, Knispel HH. Results of a BoNT/A antibody study in children and adolescents after onabotulinumtoxin A (Botox®) detrusor injection. Urol Int 2011; 87:434–438.
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Author and Disclosure Information

Ashley King, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Cleveland Clinic

Adrienne Quirouet, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Cleveland Clinic

Courtenay K. Moore, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute; Fellowship Director, Female Pelvic Medicine and Reconstructive Surgery; Assistant Professor of Urology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Courtenay K. Moore, MD, Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Q10-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Moore has disclosed receiving fees for consulting for Allergan.

Issue
Cleveland Clinic Journal of Medicine - 82(7)
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Cleveland Clinic Journal of Medicine
Topics
Geriatrics
Neurology
Women's Health
Drug Therapy
Nephrology
Page Number
456-464
Legacy Keywords
botulinum toxin, Botox, neurogenic detrusor overactivity, overactive bladder, detrusor external sphincter dyssynergia, incontinence, urgency, multiple sclerosis, Ashley King, Adrienne Quirouet, Courtenay Moore
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Author(s)
Ashley King, MD
Adrienne Quirouet, MD
Courtenay K. Moore, MD
Author(s)
Ashley King, MD
Adrienne Quirouet, MD
Courtenay K. Moore, MD
Author and Disclosure Information

Ashley King, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Cleveland Clinic

Adrienne Quirouet, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Cleveland Clinic

Courtenay K. Moore, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute; Fellowship Director, Female Pelvic Medicine and Reconstructive Surgery; Assistant Professor of Urology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Courtenay K. Moore, MD, Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Q10-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Moore has disclosed receiving fees for consulting for Allergan.

Author and Disclosure Information

Ashley King, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Cleveland Clinic

Adrienne Quirouet, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Cleveland Clinic

Courtenay K. Moore, MD
Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute; Fellowship Director, Female Pelvic Medicine and Reconstructive Surgery; Assistant Professor of Urology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Courtenay K. Moore, MD, Female Pelvic Medicine and Reconstructive Surgery, Glickman Urological Institute, Q10-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]

Dr. Moore has disclosed receiving fees for consulting for Allergan.

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Overactive bladder: Evaluation and management in primary care
Nocturia in the elderly: A wake-up call

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum1 and is the most poisonous naturally occurring toxin known.2 Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),1 but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.3 Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.4

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

  • It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.5
  • In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.6
  • It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.6,7
  • It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.3

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.8 From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.9

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.10 In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.10 At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.15

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al14 found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al13 reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,14 these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al13 they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al16 found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.16

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al17 used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).17 They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

 

 

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.18 The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.19 Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale22 at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%20 and 24.1%21 of patients) and urinary retention requiring self-catheterization (5.4%20 and 6.9%21).

The largest study to date of anticholinergic therapy vs botulinum toxin injection23 in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.23

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).23

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder24 to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.25

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.26

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),27 of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al28 and de Sèze et al29 also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al30 reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.30

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.25 In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

 

 

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).31

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.6 In animal studies,32 botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al33 performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.33

Abbott et al34 evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al35 injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,35 and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor36 compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.36

Pinto et al37 treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.37

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.38 The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.35 The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.2 The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.2 Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.2

Repeat injections can cause an immune response in up to 5% of patients.6 Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.6 In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.39

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

Patients with loss of bladder control experience discomfort, embarrassment, personal care and health issues, and, often, significant pain, all with a decidedly negative impact on quality of life. Although some patients may find lifestyle modifications, drug therapy, and self-catheterization acceptable and effective, there is a clear need for more options.

Botulinum toxin, or onabotulinumtoxinA, is currently approved by the US Food and Drug Administration (FDA) for neurogenic detrusor overactivity and overactive bladder refractory to drug therapy. Studies so far have shown botulinum toxin injection to be safe and effective for these conditions, and these results have led to interest in off-label uses, eg, for detrusor external sphincter dyssynergia (DESD), motor and sensory urgency, and painful bladder syndrome/interstitial cystitis (Table 1).

Although more data from clinical trials are needed, botulinum toxin injection offers patients a much-needed treatment option.

HOW BOTULINUM TOXIN WORKS

Seven serotypes identified

Discovered in 1897, botulinum toxin is a neurotoxin produced by the gram-positive, rod-shaped anaerobic bacterium Clostridium botulinum1 and is the most poisonous naturally occurring toxin known.2 Seven immunologically distinct antigenic serotypes have been identified (A, B, C1, D, E, F, and G),1 but only types A and B are available for clinical use.

Most research into potential therapeutic uses has focused on type A, which has the longest duration of action, a clinical advantage.3 Recently, work has been done to further characterize other serotypes and to isolate additional variants of botulinum toxin. For example, serotype E, the predominant serotype associated with foodborne botulism, is being studied in an effort to prevent future outbreaks.4

Our discussion focuses on clinical uses of the serotype A botulinum toxin preparation, which we will refer to simply as botulinum toxin.

Studies exploring how it works

Botulinum toxin exerts its effects by binding to peripheral cholinergic terminals, inhibiting release of acetylcholine at the neuromuscular junction. Flaccid paralysis ensues as a result.

Results of animal studies have shed additional light on the specific actions of botulinum toxin A:

  • It may alter levels of nerve growth factor and transient receptor potential vanilloid 1 in rats, and this may provide an additional mechanism of reducing bladder detrusor overactivity.5
  • In addition to blocking acetylcholine release from motor neurons, it inhibits the release of neurotransmitters involved in bladder sensory afferent pathways.6
  • It inhibits the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.6,7
  • It promotes apoptosis in prostatic tissue; however, this effect has not been shown in the bladder.3

The time necessary to recover function after botulinum toxin paralysis depends on the subtype of botulinum toxin as well as on the type of nerve terminal. Chemodenervation lasts from 3 to 6 months when the toxin is injected into the neuromuscular junction of skeletal muscle, and considerably longer (up to 1 year) when injected into the autonomic neurons of smooth muscle.2,6

TREATMENT OF NEUROGENIC DETRUSOR OVERACTIVITY

Neurogenic detrusor overactivity involves involuntary contractions of the bladder resulting from spinal cord injury, multiple sclerosis, and other neurologic conditions. An estimated 273,000 people in the United States have a spinal cord injury, and 81% of them have urologic symptoms ranging from areflexia to overactivity.8 From 75% to 100% of patients with multiple sclerosis have urologic symptoms, and detrusor overactivity is the most common.9

Detrusor overactivity can cause urinary urgency, urinary frequency, and urgency incontinence, significantly affecting quality of life and leading to skin breakdown, sacral ulcerations, and challenges with personal care.

Anticholinergic drugs have been the mainstay of therapy. If drug therapy failed, the next option was reconstructive surgery, often augmentation cystoplasty. Thus, botulinum toxin injection is an important advance in treatment options.

Studies that showed effectiveness

Botulinum toxin for neurogenic detrusor overactivity was first studied by Schurch et al.10 In their study, 200 U or 300 U was injected into the trigone of 21 patients with spinal cord injury and urgency incontinence managed with intermittent self-catheterization.10 At 6 weeks after injection, 17 of the 19 patients seen at follow-up visits were completely continent. Urodynamic evaluation revealed significant increases in maximum cystometric capacity and in volume at first involuntary detrusor contraction, and a decrease in detrusor voiding pressure. Of the 11 patients available for follow-up at 16 and 36 weeks, improvements in measures of incontinence and urodynamic function persisted.

In addition, two small randomized controlled trials11,12 showed significant increases in cystometric bladder capacity, significant improvement in quality-of-life measures, and reduction in episodes of urgency incontinence.

In 2011 and 2012, two multicenter double-blind randomized controlled trials reported on patients with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity inadequately managed with drug therapy. The patients were randomized to botulinum toxin injection (200 U or 300 U) or placebo injection.13,14 The primary end point for both studies was the change from baseline in episodes of urinary incontinence per week at week 6. Secondary end points were maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and score on the Incontinence Quality of Life scale.15

In both studies, the mean number of urinary incontinence episodes per week was 33 at baseline. At week 6, Cruz et al14 found that patients who received botulinum toxin injection had significantly fewer episodes per week (21.8 fewer with 200 U, 19.4 fewer with 300 U) than those in the placebo group, who had 13.2 fewer episodes per week (P < .01). Ginsberg et al13 reported decreases in the mean number of episodes of urinary incontinence of 21, 23, and 9 episodes per week in the 200 U, 300 U, and placebo groups, respectively (P < .001). The patients who received botulinum toxin had statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and Incontinence Quality of Life scores compared with placebo (P < .001). Thirty-eight percent of patients in the treatment group were fully continent.13,14

Safety and adverse effects

The most frequently reported adverse events were urinary tract infection (24% of patients)13,14 and urinary retention requiring initiation of clean intermittent catheterization. In the study by Cruz et al,14 these were reported in 30% with 200 U, 42% with 300 U, and 12% with placebo, while in the study by Ginsberg et al13 they were reported in 35% with 200 U, 42% with 300 U, and 10% with placebo.

In a study of long-term safety and efficacy of botulinum toxin injection in patients with neurogenic detrusor overactivity, Kennelly et al16 found that patients undergoing repeat injections had sustained reductions in episodes of incontinence and increases in the maximum cystometric capacity and quality of life scores, with no increase in adverse events over time.16

But is it cost-effective?

While botulinum toxin injection may be safe and effective for neurogenic detrusor overactivity, is it cost-effective?

Carlson et al17 used a Markov State Transition model to assess the cost of refractory neurogenic detrusor overactivity in patients receiving botulinum toxin vs best supportive care (incontinence pads, medications, intermittent self-catheterization).17 They found that the injections were more expensive than supportive care but were cost-effective when considering the reduction in episodes of incontinence, the reduced need for incontinence products, and improvement in measures of quality of life.

What the evidence indicates

Trials of botulinum toxin injection for neurogenic detrusor overactivity have shown that it improves continence, maximum cystometric capacity, detrusor pressures, and quality of life. The main adverse effects are urinary tract infection and urinary retention requiring intermittent self-catheterization.

Although many patients with this condition are already self-catheterizing, the physician must discuss this before botulinum toxin therapy to ensure that the patient or a family member is able to perform catheterization. Studies have shown that patients have an increase in urinary tract infections after botulinum injections. But in these studies, a urinary tract infection was defined as 100,000 colony-forming units or the presence of leukocytosis with or without symptoms. It is important to remember that patients on intermittent catheterization have bacteriuria and should be treated only for symptomatic, not asymptomatic, bacteriuria.

 

 

TREATMENT OF IDIOPATHIC OVERACTIVE BLADDER

Patients with idiopathic overactive bladder have urinary urgency accompanied by urgency incontinence, nocturia, or urinary frequency.18 The prevalence of this condition has been reported to range from 1.7% to 13.3% in men age 30 and older and 7% to 30.3% in women of similar ages. About one-third of women with overactive bladder also have detrusor overactivity.19 Overactive bladder presents a significant economic and medical burden on the healthcare system, as well as having a negative impact on quality of life.

The FDA approved botulinum toxin injection for treatment of idiopathic overactive bladder in January 2013.

Evidence of effectiveness

Two multicenter randomized controlled trials20,21 of botulinum toxin 100 U enrolled patients age 18 and older who had more than three episodes of urinary urgency incontinence in a 3-day period or more than eight micturitions per day inadequately managed by anticholinergic drug therapy. Primary end points were the change from baseline in the number of episodes of urinary incontinence per day and the proportion of patients with a positive response on the Treatment Benefit Scale22 at week 12. Secondary end points included episodes of urinary urgency incontinence, micturition, urgency, and nocturia, and scores on health-related quality of life questionnaires (Incontinence Quality of Life scale, King’s Health Questionnaire).

In both studies, patients receiving botulinum toxin had significantly fewer episodes of incontinence compared with placebo (−2.65 vs −0.87; P < .001 and −2.95 vs −1.03; P < .001).20,21 Reductions from baseline in all other symptoms of overactive bladder, a positive treatment response on the treatment benefit scale, and improvements in quality-of-life scores were also significantly greater with botulinum toxin injection than with placebo (P ≤ .01).

As in the studies of neurogenic detrusor overactivity, the most common adverse effects were urinary tract infection (occurring in 15.5%20 and 24.1%21 of patients) and urinary retention requiring self-catheterization (5.4%20 and 6.9%21).

The largest study to date of anticholinergic therapy vs botulinum toxin injection23 in women with urinary urgency incontinence, published in 2012, studied nearly 250 women who had five or more episodes of idiopathic urgency incontinence in a 3-day period. They were randomized either to daily oral therapy (solifenacin 5 mg with possible escalation to 10 mg and, if necessary, a subsequent switch to extended-release trospium 60 mg) plus one intradetrusor injection of saline, or to a daily oral placebo plus one injection of botulinum toxin 100 U.23

The dropout rate was low in both groups, with 93% of patients in both groups completing the 6-month protocol. Women experienced a mean reduction in urgency incontinence episodes of 3.4 per day (baseline 5) in the anticholinergic group vs 3.3 episodes in the botulinum toxin group (P = .81). However, more patients achieved complete resolution of urinary urgency incontinence in the botulinum toxin group than in the anticholinergic therapy group (27% vs 13%; P = .003). Quality of life improved in both groups without a significant difference between the groups. The botulinum toxin group had higher rates of initiation of self-catheterization (5% vs 0%, P = .01) and urinary tract infection (33% vs 13%, P < .001).23

Botulinum toxin as a third-line therapy

In May 2014, the American Urological Association updated its guidelines on idiopathic overactive bladder24 to include botulinum toxin injection as standard third-line therapy for patients in whom behavioral and medical management (ie, anticholinergics and beta-3-agonists) failed.

Interpreting the evidence to date

Overall, studies in idiopathic overactive bladder have shown a reduction in episodes of urgency incontinence and other symptoms, with some data also demonstrating a corresponding improvement in quality of life.

As in neurogenic detrusor overactivity, the main risks associated with botulinum toxin injection are urinary tract infection and the need to initiate self-catheterization. Although 94% of patients studied did not require self-catheterization after injection, the patient’s ability to perform self-catheterization should be determined before proceeding with botulinum toxin injections.

DETRUSOR EXTERNAL SPHINCTER DYSSYNERGIA

Botulinum toxin has been used not only to improve bladder storage but also to facilitate bladder emptying, as in patients with DESD, a lack of coordination between the bladder and the urinary sphincter. Normal voiding involves relaxation of the urinary sphincter and contraction of the bladder; in DESD the sphincter contracts and works against the bladder’s ability to empty. This leads not only to difficulty emptying the bladder but also to elevated bladder pressure, which can cause renal damage if untreated.

DESD can be seen after injury between the pontine micturition center, which coordinates activity between the bladder and the sphincter, and the caudal spinal cord. This can occur in spinal cord injury, multiple sclerosis, myelomeningocele, and transverse myelitis and can cause significant morbidity for the patient.

Treatment options include drug therapy, injection of botulinum toxin into the sphincter, clean intermittent catheterization, indwelling catheterization, urethral stenting, sphincterotomy, and reconstructive surgery such as urinary diversion.25

The goals of therapy are to avoid the need for clean intermittent catheterization in patients who have difficulty with manual dexterity, and to avoid the need for surgical procedures such as sphincterotomy and urinary diversion. The efficacy of urethral stenting is low, and medical management can be limited.26

DESD leads to difficulty emptying the bladder, elevated bladder pressure, and, if untreated, renal damage

In the first published report on botulinum toxin for DESD (in 1988),27 of 11 patients with spinal cord injury and DESD who received botulinum toxin injected into the external urethral sphincter, 10 showed signs of sphincter denervation on electromyography and reductions in urethral pressure profiles and postvoid residual volumes. Schurch et al28 and de Sèze et al29 also reported reductions in postvoid residual volume and maximal urethral pressures in patients with spinal cord injury and DESD.

In 2005, Gallien et al30 reported what is still the largest multicenter randomized controlled trial of botulinum toxin injection in DESD. Eighty-six patients with multiple sclerosis, DESD, and chronic urinary retention were randomized to receive either a single transperineal botulinum toxin injection of 100 U plus the alpha-1-blocker alfuzosin, or a placebo injection plus alfuzosin. Botulinum toxin treatment was associated with significantly increased voided volumes and reduced premicturition and maximal detrusor pressures, but no significant decrease in postvoid residual volume.30

More study needed

Despite these findings, a Cochrane Review concluded that, given the limited experience with intrasphincteric injection of botulinum toxin, data from larger randomized controlled trials are needed before making definitive recommendations.25 In the meantime, the clinician must weigh the low morbidity of the procedure against the limited options in the treatment of these patients.

 

 

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).31

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.6 In animal studies,32 botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al33 performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.33

Abbott et al34 evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al35 injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,35 and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor36 compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.36

Pinto et al37 treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.37

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.38 The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.35 The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.2 The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.2 Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.2

Repeat injections can cause an immune response in up to 5% of patients.6 Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.6 In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.39

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.

References
  1. Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Eur Urol 2003; 44:165–174.
  2. Sahai A, Khan M, Fowler CJ, Dasgupta P. Botulinum toxin for the treatment of lower urinary tract symptoms: a review. Neurourol Urodyn 2005; 24:2–12.
  3. Cruz F. Targets for botulinum toxin in the lower urinary tract. Neurourol Urodyn 2014; 33:31–38.
  4. Weedmark KA, Lambert DL, Mabon P, et al. Two novel toxin variants revealed by whole-genome sequencing of 175 Clostridium botulinum type E strains. Appl Environ Microbiol 2014; 80:6334–6345.
  5. Ha US, Park EY, Kim JC. Effect of botulinum toxin on expression of nerve growth factor and transient receptor potential vanilloid 1 in urothelium and detrusor muscle of rats with bladder outlet obstruction-induced detrusor overactivity. Urology 2011; 78:721.e1–721.e6
  6. Frenkl TL, Rackley RR. Injectable neuromodulatory agents: botulinum toxin therapy. Urol Clin North Am 2005; 32:89–99.
  7. Ikeda Y, Zabbarova IV, Birder LA, et al. Botulinum neurotoxin serotype A suppresses neurotransmitter release from afferent as well as efferent nerves in the urinary bladder. Eur Urol 2012; 62:1157–1164.
  8. Goldmark E, Niver B, Ginsberg DA. Neurogenic bladder: from diagnosis to management. Curr Urol Rep 2014; 15:448.
  9. Andersson KE. Current and future drugs for treatment of MS-associated bladder dysfunction. Ann Phys Rehabil Med 2014; 57:321–328.
  10. Schurch B, Stöhrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164:692–697.
  11. Schurch B, de Sèze M, Denys P, et al; Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005; 174:196–200.
  12. Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007; 41:335–340.
  13. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol 2012; 187:2131–2139.
  14. Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol 2011; 60:742–750.
  15. Wagner TH, Patrick DL, Bavendam TG, Martin ML, Buesching DP. Quality of life of persons with urinary incontinence: development of a new measure. Urology 1996: 47:67–71.
  16. Kennelly M, Dmochowski R, Ethans K, et al. Long-term efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: an interim analysis. Urology 2013; 81:491–497.
  17. Carlson JJ, Hansen RN, Dmochowski RR, Globe DR, Colayco DC, Sullivan SD. Estimating the cost-effectiveness of onabotulinumtoxinA for neurogenic detrusor overactivity in the United States. Clin Ther 2013; 35:414–424.
  18. Abrams P, Cardozo L, Fall M, et al; Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61:37–49.
  19. Milsom I, Coyne KS, Nicholson S, Kvasz M, Chen CI, Wein AJ. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur Urol 2014; 65:79–95.
  20. Nitti VW, Dmochowski R, Herschorn S, et al; EMBARK Study Group. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol 2013; 189:2186–2193.
  21. Chapple C, Sievert KD, MacDiarmid S, et al. OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled trial. Eur Urol 2013; 64:249–256.
  22. Colman S, Chapple C, Nitti V, Haag-Molkenteller C, Hastedt C, Massow U. Validation of Treatment Benefit Scale for assessing subjective outcomes in treatment of overactive bladder. Urology 2008; 72:803–807.
  23. Visco AG, Brubaker L, Richter HE, et al; Pelvic Floor Disorders Network. Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. N Engl J Med 2012; 367:1803–1813.
  24. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. www.auanet.org/education/guidelines/overactive-bladder.cfm. Accessed June 11, 2015.
  25. Utomo E, Groen J, Blok BF. Surgical management of functional bladder outlet obstruction in adults with neurogenic bladder dysfunction. Cochrane Database Syst Rev 2014; 5:CD004927.
  26. Mahfouz W, Corcos J. Management of detrusor external sphincter dyssynergia in neurogenic bladder. Eur J Phys Rehabil Med 2011; 47:639–650.
  27. Dykstra DD, Sidi AA, Scott AB, Pagel JM, Goldish GD. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol 1988; 139:919–922.
  28. Schurch B, Hauri D, Rodic B, Curt A, Meyer M, Rossier AB. Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients. J Urol 1996; 155:1023–1029.
  29. de Sèze M, Petit H, Gallien, de Sèze MP, Joseph PA, Mazaux JM, Barat M. Botulinum a toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease. Eur Urol 2002; 42:56–62.
  30. Gallien P, Reymann JM, Amarenco G, Nicolas B, de Sèze M, Bellissant E. Placebo controlled, randomised, double blind study of the effects of botulinum A toxin on detrusor sphincter dyssynergia in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2005; 76:1670–1676.
  31. Hanno PM, Burks DA, Clemens JQ, et al; Interstitial Cystitis Guidelines Panel of the American Urological Association Education and Research, Inc. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol 2011; 185:2162–2170.
  32. Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 2004; 172:1529–1532.
  33. Zermann DH, Ishigooka M, Schubert J, Schmidt RA. Perisphincteric injection of botulinum toxin type A. A treatment option for patients with chronic prostatic pain? Eur Urol 2000; 38:393–399.
  34. Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol 2006; 108:915–923.
  35. Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin A has antinociceptive effects in treating interstitial cystitis. Urology 2004; 64:871–875.
  36. Kuo HC, Chancellor MB. Comparison of intravesical botulinum toxin type A injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. BJU Int 2009: 104:657–661.
  37. Pinto R, Lopes T, Silva J, Silva C, Dinis P, Cruz F. Persistent therapeutic effect of repeated injections of onabotulinum toxin a in refractory bladder pain syndrome/interstitial cystitis. J Urol 2013; 189:548–553.
  38. Rovner E. Chapter 6: Practical aspects of administration of onabotulinumtoxinA. Neurourol Urodyn 2014; 33(suppl 3):S32–S37.
  39. Schulte-Baukloh H, Herholz J, Bigalke H, Miller K, Knispel HH. Results of a BoNT/A antibody study in children and adolescents after onabotulinumtoxin A (Botox®) detrusor injection. Urol Int 2011; 87:434–438.
References
  1. Leippold T, Reitz A, Schurch B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Eur Urol 2003; 44:165–174.
  2. Sahai A, Khan M, Fowler CJ, Dasgupta P. Botulinum toxin for the treatment of lower urinary tract symptoms: a review. Neurourol Urodyn 2005; 24:2–12.
  3. Cruz F. Targets for botulinum toxin in the lower urinary tract. Neurourol Urodyn 2014; 33:31–38.
  4. Weedmark KA, Lambert DL, Mabon P, et al. Two novel toxin variants revealed by whole-genome sequencing of 175 Clostridium botulinum type E strains. Appl Environ Microbiol 2014; 80:6334–6345.
  5. Ha US, Park EY, Kim JC. Effect of botulinum toxin on expression of nerve growth factor and transient receptor potential vanilloid 1 in urothelium and detrusor muscle of rats with bladder outlet obstruction-induced detrusor overactivity. Urology 2011; 78:721.e1–721.e6
  6. Frenkl TL, Rackley RR. Injectable neuromodulatory agents: botulinum toxin therapy. Urol Clin North Am 2005; 32:89–99.
  7. Ikeda Y, Zabbarova IV, Birder LA, et al. Botulinum neurotoxin serotype A suppresses neurotransmitter release from afferent as well as efferent nerves in the urinary bladder. Eur Urol 2012; 62:1157–1164.
  8. Goldmark E, Niver B, Ginsberg DA. Neurogenic bladder: from diagnosis to management. Curr Urol Rep 2014; 15:448.
  9. Andersson KE. Current and future drugs for treatment of MS-associated bladder dysfunction. Ann Phys Rehabil Med 2014; 57:321–328.
  10. Schurch B, Stöhrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164:692–697.
  11. Schurch B, de Sèze M, Denys P, et al; Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005; 174:196–200.
  12. Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality of life in patients with neurogenic detrusor overactivity: a randomised, placebo-controlled, double-blind study. Scand J Urol Nephrol 2007; 41:335–340.
  13. Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. J Urol 2012; 187:2131–2139.
  14. Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial. Eur Urol 2011; 60:742–750.
  15. Wagner TH, Patrick DL, Bavendam TG, Martin ML, Buesching DP. Quality of life of persons with urinary incontinence: development of a new measure. Urology 1996: 47:67–71.
  16. Kennelly M, Dmochowski R, Ethans K, et al. Long-term efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: an interim analysis. Urology 2013; 81:491–497.
  17. Carlson JJ, Hansen RN, Dmochowski RR, Globe DR, Colayco DC, Sullivan SD. Estimating the cost-effectiveness of onabotulinumtoxinA for neurogenic detrusor overactivity in the United States. Clin Ther 2013; 35:414–424.
  18. Abrams P, Cardozo L, Fall M, et al; Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61:37–49.
  19. Milsom I, Coyne KS, Nicholson S, Kvasz M, Chen CI, Wein AJ. Global prevalence and economic burden of urgency urinary incontinence: a systematic review. Eur Urol 2014; 65:79–95.
  20. Nitti VW, Dmochowski R, Herschorn S, et al; EMBARK Study Group. OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial. J Urol 2013; 189:2186–2193.
  21. Chapple C, Sievert KD, MacDiarmid S, et al. OnabotulinumtoxinA 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebo-controlled trial. Eur Urol 2013; 64:249–256.
  22. Colman S, Chapple C, Nitti V, Haag-Molkenteller C, Hastedt C, Massow U. Validation of Treatment Benefit Scale for assessing subjective outcomes in treatment of overactive bladder. Urology 2008; 72:803–807.
  23. Visco AG, Brubaker L, Richter HE, et al; Pelvic Floor Disorders Network. Anticholinergic therapy vs onabotulinumtoxinA for urgency urinary incontinence. N Engl J Med 2012; 367:1803–1813.
  24. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU Guideline. www.auanet.org/education/guidelines/overactive-bladder.cfm. Accessed June 11, 2015.
  25. Utomo E, Groen J, Blok BF. Surgical management of functional bladder outlet obstruction in adults with neurogenic bladder dysfunction. Cochrane Database Syst Rev 2014; 5:CD004927.
  26. Mahfouz W, Corcos J. Management of detrusor external sphincter dyssynergia in neurogenic bladder. Eur J Phys Rehabil Med 2011; 47:639–650.
  27. Dykstra DD, Sidi AA, Scott AB, Pagel JM, Goldish GD. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol 1988; 139:919–922.
  28. Schurch B, Hauri D, Rodic B, Curt A, Meyer M, Rossier AB. Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: a prospective study in 24 spinal cord injury patients. J Urol 1996; 155:1023–1029.
  29. de Sèze M, Petit H, Gallien, de Sèze MP, Joseph PA, Mazaux JM, Barat M. Botulinum a toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease. Eur Urol 2002; 42:56–62.
  30. Gallien P, Reymann JM, Amarenco G, Nicolas B, de Sèze M, Bellissant E. Placebo controlled, randomised, double blind study of the effects of botulinum A toxin on detrusor sphincter dyssynergia in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2005; 76:1670–1676.
  31. Hanno PM, Burks DA, Clemens JQ, et al; Interstitial Cystitis Guidelines Panel of the American Urological Association Education and Research, Inc. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol 2011; 185:2162–2170.
  32. Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 2004; 172:1529–1532.
  33. Zermann DH, Ishigooka M, Schubert J, Schmidt RA. Perisphincteric injection of botulinum toxin type A. A treatment option for patients with chronic prostatic pain? Eur Urol 2000; 38:393–399.
  34. Abbott JA, Jarvis SK, Lyons SD, Thomson A, Vancaille TG. Botulinum toxin type A for chronic pain and pelvic floor spasm in women: a randomized controlled trial. Obstet Gynecol 2006; 108:915–923.
  35. Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin A has antinociceptive effects in treating interstitial cystitis. Urology 2004; 64:871–875.
  36. Kuo HC, Chancellor MB. Comparison of intravesical botulinum toxin type A injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. BJU Int 2009: 104:657–661.
  37. Pinto R, Lopes T, Silva J, Silva C, Dinis P, Cruz F. Persistent therapeutic effect of repeated injections of onabotulinum toxin a in refractory bladder pain syndrome/interstitial cystitis. J Urol 2013; 189:548–553.
  38. Rovner E. Chapter 6: Practical aspects of administration of onabotulinumtoxinA. Neurourol Urodyn 2014; 33(suppl 3):S32–S37.
  39. Schulte-Baukloh H, Herholz J, Bigalke H, Miller K, Knispel HH. Results of a BoNT/A antibody study in children and adolescents after onabotulinumtoxin A (Botox®) detrusor injection. Urol Int 2011; 87:434–438.
Issue
Cleveland Clinic Journal of Medicine - 82(7)
Issue
Cleveland Clinic Journal of Medicine - 82(7)
Page Number
456-464
Page Number
456-464
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Cleveland Clinic Journal of Medicine
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Cleveland Clinic Journal of Medicine
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Geriatrics
Neurology
Women's Health
Drug Therapy
Nephrology
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Urologic applications of botulinum toxin
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Urologic applications of botulinum toxin
Legacy Keywords
botulinum toxin, Botox, neurogenic detrusor overactivity, overactive bladder, detrusor external sphincter dyssynergia, incontinence, urgency, multiple sclerosis, Ashley King, Adrienne Quirouet, Courtenay Moore
Legacy Keywords
botulinum toxin, Botox, neurogenic detrusor overactivity, overactive bladder, detrusor external sphincter dyssynergia, incontinence, urgency, multiple sclerosis, Ashley King, Adrienne Quirouet, Courtenay Moore
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Inside the Article

KEY POINTS

  • Anticholinergic drugs have been the first-line therapy for neurogenic detrusor overactivity. If drug therapy failed, the next option was reconstructive surgery such as cystoplasty. Botulinum toxin injection may be an option in select patients.
  • Urinary tract infection and urinary retention requiring intermittent self-catheterization are the most common adverse events of botulinum toxin injection in trials of patients with neurogenic detrusor overactivity or idiopathic overactive bladder.
  • Small studies have shown that botulinum toxin injection for painful bladder syndrome/interstitial cystitis can improve pain, urinary frequency, and quality of life. But larger randomized controlled trials are needed.
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