Botulinum toxin for detrusor overactivity and symptoms of overactive bladder: where we are now and where we are going

REVIEWwww.nature.com/clinicalpractice/uro

Botulinum toxin for detrusor overactivity and symptoms of overactive bladder: where we are now and where we are goingArun Sahai, Mohammad S Khan, Norman Gregson, Kenneth Smith and Prokar Dasgupta* on behalf of the GKT Botulinum Study Group

INTRODUCTIONBotulinum toxin (BTX) injections have become used by urologists around the world as off-label therapy for many types of lower urinary tract dysfunction. Urethral injections into the external sphincter have been used to treat detrusor external sphincter dyssynergia and various types of voiding dysfunction; pros-tatic injections have been employed to improve symptoms in patients with benign prostatic hypertrophy and prostatitis.1,2 Intradetrusor injections of BTX as a second-line option for treating detrusor overactivity (DO) refractory to standard anticholinergic therapies have, however, shown the most promising results.

RESULTS FROM RANDOMIZED, PLACEBO-CONTROLLED TRIALSNeurogenic detrusor overactivitySchurch et al.3 were the first to report a double-blind trial of BTX in patients with neurogenic DO. Fifty-nine patients were randomized to receive 200 U or 300 U botulinum toxin-A (BTX-A; BOTOX®, Allergan Inc, Irvine, CA) or placebo. Most of the patients had spinal cord injury; all were refractory to anti cholinergics and performed clean intermittent self- catheterization (CISC). Follow-up safety and efficacy evaluations were done at 2, 6, 12, 18 and 24 weeks. The number of incontinence episodes per day, the primary end point of the trial, decreased significantly from base-line (by approximately 50%) at all time points (P <0.05) except at 12 and 18 weeks in the 200 U group. Yet, when compared with placebo, improvements only reached signifi cance in the 300 U group at 2 weeks (P = 0.015) and 6 weeks (P = 0.047) and in the 200 U group at 24 weeks (P = 0.019).

In addition, objective urodynamic parameters were improved in the BTX-A treated patients (Table 1). Approximately 55% of BTX-A treated patients did not experience DO for at least one post-treatment time point, compared with 10% in the placebo group. Patients receiving BTX-A

Botulinum toxin (BTX) treatment for overactive bladder and detrusor overactivity is becoming increasingly recognized as an excellent therapeutic option for treating patients refractory to anticholinergic agents. Results from open-label studies have suggested that this therapy is effective in neurogenic and idiopathic detrusor overactivity, yet validating evidence from randomized, placebo-controlled trials has been unavailable. The exact mechanism of action of BTX in the bladder is controversial, although evidence suggests that apart from preventing the presynaptic release of acetylcholine from the parasympathetic innervation to the bladder, it might have an effect on sensory mechanisms. The latter hypothesis could in part explain its effect on symptoms such as urgency. The purpose of this Review is to present the results of randomized, placebo-controlled trials in which BTX treatment for detrusor overactivity was investigated. Also the evidence supporting its potential dual mechanism of action in the bladder will be considered. In addition, the various techniques of administration of BTX are discussed and avenues for further research suggested.

KEYWORDS botulinum toxin, detrusor overactivity, overactive bladder, technique of administration

A Sahai is a Specialist Registrar in Urology, MS Khan is a Consultant Urological Surgeon, N Gregson is an Honorary Senior Research Fellow in Neuroimmunology, K Smith is a Professor of Neurophysiology, and P Dasgupta is Consultant Urological Surgeon in the Departments of Urology and Clinical Neurosciences, Guy’s Hospital and Guy’s, King’s and St Thomas’ School of Medicine, London, UK.

Correspondence*Department of Urology, 1st floor Thomas Guy House, Guy’s Hospital, London SE1 9RT, UK [email protected]

Received 20 September 2006 Accepted 8 May 2007

www.nature.com/clinicalpracticedoi:10.1038/ncpuro0839

REVIEW CRITERIAA PubMed search was done to select articles on which to base this Review. The search terms used were “botulinum toxin”, “bladder”, “detrusor”, “neurogenic/idiopathic detrusor overactivity”, “afferent”, “dorsal root ganglion”, and “pain”. We selected relevant articles from those published between 1997 and 2006 in English. In addition, we manually searched for abstracts from international urology meetings held between 2005 and 2006.

SUMMARY

JULY 2007 VOL 4 NO 7 NATURE CLINICAL PRACTICE UROLOGY 379

ncpuro_2006_221.indd 379ncpuro_2006_221.indd 379 19/6/07 6:28:50 pm19/6/07 6:28:50 pm

REVIEW

380 NATURE CLINICAL PRACTICE UROLOGY SAHAI ET AL. JULY 2007 VOL 4 NO 7

www.nature.com/clinicalpractice/uro

at either dose showed significant improve-ments (P ≤0.002) in quality of life as assessed by the Incontinence Quality of Life (I-QOL) questionnaire. The most commonly reported side effect was urinary tract infection (UTI) in 22% of patients. The authors concluded that treatment with 200 U and 300 U of BTX-A was equally effica cious. Anticholinergic use remained similar throughout the study, contrary to previous observations.4

Provisional results (up to 3 months) from another double-blind trial in patients with multiple sclerosis and concomitant neuro genic DO were presented by Finney and colleagues.5 Patients received a dose of 500 U of Dysport® (Ipsen, Ltd, Slough, UK), an alternative prepa-ration of BTX-A. Significant reductions in

pad weights and use of anti cholinergics were observed (P <0.05), and, although there were trends towards reductions in frequency, nocturia, and urgency incontinence episodes, differences between the study therapy and placebo groups did not reach significance.

Another trial recruited 31 patients with neurogenic DO who were refractory to anti-cholinergics and who were performing CISC.6 Patients were randomized to receive either 500 U Dysport® or placebo injected over 25 sites. Twenty-seven patients completed the study (BTX-A n = 17; placebo n = 10). Concomitant anticholinergic use was signifi-cantly greater in the placebo group during the first 6 weeks. Significant benefits with regards to urodynamic parameters (maximum cystometric capacity and maximum detrusor pressures) were observed in favor of BTX-A, although this effect was not sustained at 6 months.

Idiopathic detrusor overactivityRandomized, placebo-controlled trials in idio-pathic DO have been conducted to investigate the safety and efficacy of BTX-A7 and botu-linum toxin-B (BTX-B).8 In our department we randomly assigned patients with idiopathic DO who were refractory to anticholinergics either 200 U of BTX-A (BOTOX®) or placebo, administered by flexible cystoscopy under local anesthetic.7 Data from 34 patients were analyzed (BTX-A n = 16; placebo n = 18). The primary end point of maximum cystometric capacity increased significantly in the BTX-A group compared with placebo. Furthermore, improvements in overactive bladder symp-toms, additional urodynamic parameters, and quality of life (assessed by the Urogenital Distress Inventory-6 and Incontinence Impact Questionnaire-7 instruments) were demon-strated in patients in the BTX-A group compared with those in the placebo group (Table 2). Four weeks after treatment, continence was restored in 2 (12.5%) of 16 patients in the placebo group and 8 (50.0%) of 16 in the BTX-A group. By 12 weeks, all patients in the placebo group were again incontinent. Data from the open-label extension study (following unblinding at 12 weeks) suggested that the beneficial effects of BTX-A continued for a minimum of 24 weeks; in the BTX-A group, 50% of patients remained continent at 12 and 24 weeks. Six patients, all in the BTX-A group, had symptomatic

Table 1 Summary of results from a double-blind, randomized, placebo-controlled trial of botulinum toxin-A in patients with neurogenic detrusor overactivity.3

Variable and time point

Mean (SD) changes from baseline

300 U BTX-A (n = 19) 200 U BTX-A (n = 19) Placebo (n = 21)

Incontinence episodes

Baseline 2.8 (1.86) 1.9 (1.78) 3.0 (3.29)

2 weeks –1.3 (1.39)a –1.0 (1.67)b –0.2 (1.02)

6 weeks –1.5 (2.33)a –0.9 (1.84)b –0.2 (1.45)

12 weeks –1.2 (1.66)b –0.9 (2.14) –0.3 (1.46)

18 weeks –1.2 (1.16)b –0.8 (2.75) –0.3 (1.59)

24 weeks –0.9 (1.34)b –1.1 (1.92)a –0.1 (1.09)

Maximum cystometric capacity (ml)

Baseline 293.6 260.2 254.6

2 weeks 479.6 (186.1)a,b 482.5 (215.8)a,b 282.0 (27.4)

6 weeks 462.7 (169.1)a,b 448.8 (182.1)a 299.6 (45.0)

24 weeks 398.2 (92.9)b 440.9 (174.2)a,b 301.0 (41.6)

Reflex detrusor volume (ml)

Baseline 254.8 169.1 202.4

2 weeks 198.1 (8.6) 306.9 (135.3)b 206.7 (4.3)

6 weeks 268.5 (96.0)b 234.2 (47.3) 244.6 (42.6)

24 weeks 305.4 (72.4) 327.4 (144.6)a,b 226.4 (23.5)

Maximum detrusor pressure during bladder contraction (cm H20)

Baseline 92.6 77.0 79.1

2 weeks 41.0 (–66.3)a,b 31.6 (–52.9)a,b 71.4 (–7.7)

6 weeks 45.9 (–62.2) 40.1 (–44.4)a,b 69.0 (–10.1)

24 weeks 55.2 (–35.5)a,b 48.8 (–38.7)a,b 80.6 (–1.4)

aStatistically significant within-group changes from baseline and versus placebo. bStatistically significant changes versus placebo. Abbreviation: BTX-A, botulinum toxin-A.


REVIEW

JULY 2007 VOL 4 NO 7 SAHAI ET AL. NATURE CLINICAL PRACTICE UROLOGY 381


Table 2 Summary of results from a double-blind randomized placebo controlled trial of botulinum toxin-A in patients with idiopathic detrusor overactivity.8

Variable and time point

Mean (SD) value Difference between means (95% Cl)

P value

BTX–A Placebo

Frequency

Baseline 15.44 14.33 NS

4 weeks 7.93 (–7.51) 13.30 (–1.03) –5.37 (–8.82 to –3.78) <0.0001

12 weeks 9.25 (–6.19) 13.19 (–1.14) –3.94 (–7.05 to –1.55) 0.0033

Urgency

Baseline 11.69 7.31 0.0008

4 weeks 2.48 (–9.21) 6.02 (–1.29) –3.54 (–6.56 to –1.30) 0.0047

12 weeks 3.50 (–8.19) 6.39 (–0.92) –2.89 (–6.84 to 0.50) 0.0878

Urgency incontinence


4 weeks 1.90 (–3.08) 3.17 (–0.74) –1.27 (–3.79 to –0.23) 0.0284

12 weeks 1.48 (–3.50) 3.20 (–0.71) –1.72 (–3.78 to –0.63) 0.0076

Maximum cystometric capacity (ml)


4 weeks 313.25 (131.44) 168.56 (–29.50) 144.69 (100.95 to 215.75) <0.0001

12 weeks 263.88 (82.06) 168.17 (–29.89) 95.71 (47.47 to 172.45) 0.0011

Maximum detrusor pressure during bladder contraction (cm H20)


4 weeks 34.69 (–50.38) 75.22 (–3.44) –40.53 (–61.48 to –28.99) <0.0001

12 weeks 43.81 (–41.25) 78.67 (–0.00) –34.86 (–55.12 to –24.16) <0.0001

Postvoid residual (cm H2O)


4 weeks 96.13 (+52.06) 31.39 (+8.89) 64.74 (7.30 to 94.18) 0.0235

12 weeks 51.19 (+7.13) 22.50 (–0.00) 28.69 (–24.20 to 58.31) 0.4056

Reflex detrusor volume (ml)


4 weeks 217.32 (+93.07) 100.89 (–21.64) 116.43 (62.77 to 169.23) 0.0001

12 weeks 147.33 (+23.08) 93.11 (–29.42) 54.22 (7.60 to 99.25) 0.0238

Incontinence Impact Questionnaire short form


4 weeks 6.00 (–12.31) 10.67 (–4.11) –4.67 (–10.99 to –0.78) 0.0253

12 weeks 7.94 (–10.38) 15.39 (+0.61) –7.45 (–13.92 to –2.50) 0.0063

Urogenital Distress Inventory short form


4 weeks 5.60 (–5.15) 9.00 (–0.50) –3.40 (–6.17 to –2.08) 0.0003

12 weeks 5.13 (–5.63) 10.00 (+0.50) –4.87 (–7.83 to –2.96) <0.0001

Abbreviations: BTX-A, botulinum toxin-A; NS, not significant.


REVIEW



residual volumes >150 ml at follow-up and were taught CISC.

The first double-blind, crossover trial to test the efficacy and safety of BTX-B (Myobloc®, Solstice Neurosciences Inc., San Diego, CA) randomly assigned 17 patients with idiopathic DO and 3 with neurogenic DO to receive either 5,000 U of BTX-B or placebo.8 Significant improvements were observed in average voided volume, urinary frequency, inconti-nence episodes, and quality of life assessed by the King’s Health Questionnaire, but the effects seemed to last for only 6 weeks. CISC was required in two patients. Adverse effects included constipation (n = 2), dry mouth (n = 2) and general malaise (n = 1). Although effective in treating DO symptoms, the bene-ficial effects of BTX-B may not be long-lasting enough to merit use over BTX-A.

Clinical management and safetyThe goals of treatment for idiopathic DO patients are different from those for neurogenic DO. Many patients with neurogenic DO are already performing CISC or have a long-term catheter in place. In these patients a high dose of BTX can be given to prevent high detrusor pressures from being generated. Given that 1 U of BOTOX® is approximately equivalent to 3 U of Dysport®,9 and 200–300 U BOTOX® is the optimum dose for treatment of neuro-genic DO, a dose of Dysport® of approximately 750 U could potentially result in better efficacy than the randomized controlled trial results previously discussed for 500 U Dysport®.

In the idiopathic DO population, patients rarely perform CISC and the aim is to produce significant improvement in symptoms and quality of life with minimal voiding dysfunc-tion. The optimum dose of BTX-A in this setting needs further evaluation. Although notable improvements in symptoms are seen with 200 U BTX-A, the rate of CISC is a potential concern. Dose escalation studies are currently underway, and emerging data suggest that 100 U are adequate in some patients whilst minimizing incomplete bladder emptying.10 In our experience, however, not all patients will benefit from low doses, and some patients with idiopathic DO and detrusor pressures during filling cystometry higher than 110 mmHg might require doses of more than 200 U BOTOX® to demonstrate perceptible beneficial effects.11 The use of BTX-B should be reserved

for patients in whom BTX-A treatment fails, or who develop antibodies to BTX-A.

In general, the safety profile of BTX injec-tions for treating DO is excellent. Distal muscle weakness, albeit temporary, has been reported following BTX injections and is probably related to high doses of BTX-A and possibly injec-tion outside of the bladder leading to systemic absorption.12–14 Long-term safety data are still required. Evidence in a neurogenic DO popula-tion seems to suggest that the efficacy achieved with the first injection is sustained for repeated injections; drug resistance does not seem to develop.15

Additional concerns regarding histological change and long-term fibrosis following BTX injections have been addressed.16,17 Hafekamp et al.17 reported a lack of structural changes following BTX injections in patients with neurogenic DO. Contrary to reports of BTX effects on striated muscle, very little axonal sprouting was observed following treatment. Comperat and colleagues16 showed no differ-ences in inflammation and edema between bladder tissue samples collected at cystec-tomy from patients who had received BTX injections within the past year and controls. Interestingly, those who had received BTX had less fibrosis of the bladder wall than those who had not, although assessment was based on the researchers’ own grading scale (mild fibrosis defined as occupying <20% of muscle fibers, submucosa, or both; important fibrosis defined as occupying >20%).

ALTERNATIVE MECHANISMS OF ACTION AND NEW THERAPEUTIC DIRECTIONSAlthough the mechanism of BTX uptake by neurons has been known for many years, the acceptor molecule responsible for toxin binding and internalization has now been identified as the SV2 receptor.18 The initial use of BTX-A to treat DO was based on its ability to bind to peripheral cholinergic terminals and inhibit acetylcholine release at the neuromuscular junction.19 This process has been summarized elsewhere.20 A consensus, however, seems to be forming that BTX affects afferent pathways; henceforth an alternative hypothesis of a dual mechanism of action has been proposed.21 The bladder afferent neuronal receptors impli-cated include vanilloid, purinergic (P2X), and neurokinin receptors, and receptors for nerve growth factor.21 The neurotransmitters acting


REVIEW



at these receptors, namely ATP, substance P, neurokinin A, nitric oxide and calcitonin gene-related peptide (CGRP) are believed to have important roles in modulating the sensory afferent nerves in the human detrusor, especially in diseased bladder states, such as DO.22

In a rat model of chronic spinal cord injury and neurogenic DO, BTX-A significantly reduced the abnormal distension-evoked urothelial release of ATP.23 BTX-A also signifi cantly reduced the evoked release of CGRP in isolated rat blad-ders compared with that in controls.24 In a rat bladder pain model, following acetic acid instil-lation a significant improvement was observed in the interval between detrusor contractions in those who had received BTX-A at day 7 (P <0.05), along with reduced CGRP release from the bladder.25 The toxin has also been shown to reduce ATP and capsaicin-induced DO in an animal rat model.26

Apostolidis et al.21 have proposed that the primary peripheral effect of BTX-A involves the inhibition of acetylcholine, ATP, and substance P release, as well as the down-regulation of the expression of vanilloid and P2X receptors (Figure 1). Studies of bladder biopsies taken at 4 weeks and 16 weeks following BTX-A injections have shown a reduced expres-sion of TRPV1 and P2X3 in the suburothelium of patients with neurogenic or idiopathic DO.27 These sensory receptors are upregulated in both DO subtypes, but levels normalize within 16 weeks of administration of 200 U or 300 U BTX-A. In particular, the reduced expression of P2X3 correlates well with the reduction in urgency observed, the symptom most likely to trouble the patient.

Further evidence in support of the afferent mechanism of action of BTX-A comes from a proposed antinociceptive effect separate from its neuromuscular action. Welch and colleagues found that neurotransmitter release from rat dorsal root ganglia was inhibited by various isoforms of BTX.28 Another group reported an inhibitory effect of BTX upon the release of radioactive-labeled glutamate from rat dorsal root ganglia.29 In vivo studies have shown that pretreatment with BTX significantly reduced pain in a formalin-induced inflammatory rat model at 5 and 12 days after injection.30 This effect was also associated with a reduction in glutamate release from primary afferent terminals and c-fos expression (c-fos is usually expressed upon neuronal stimulation) when

compared with controls. Potentially, the reduc-tion in the release of peripheral pain media-tors such as glutamate could block peripheral sensitization, indirectly resulting in reduced central sensitization.31 Additional supporting clinical evidence was reported by Jankovic and Schwartz, in patients with cervical dystonia.32 They documented that pain improved soon after injection of BTX but before a reduction in muscle spasm could be detected, implying that a mechanism other than flaccid paralysis of the muscle, caused by the toxin, is involved.

If afferent mechanisms are important to the pathophysiology of DO, the excellent thera-peutic efficacy of BTX might be owing to its dual mechanism of action. Preliminary reports from small studies using BTX for interstitial cystitis and sensory urgency have been published, but the data need to be validated in larger clinical trials. Moreover, further research with BTX might lead to a better understanding of the physiological involvement of the urothelium and suburothelium in afferent mechanisms.

TECHNIQUES FOR BOTULINUM TOXIN ADMINISTRATIONVarious techniques for BTX administration have been reviewed.33 BTX-A for neurogenic DO therapy was originally administered under general or spinal anesthesia. The technique employed a rigid cystoscope and a flexible injection needle, and was trigone sparing as there were potential concerns of vesicoureteric reflux.19 Less invasive techniques have since been introduced that can be administered under local anesthesia,34,35 by use of a flex-ible cystoscope, and which can be performed on an outpatient basis. Smith and colleagues35 advocate injecting the trigone and bladder base as this area contains dense sensory innerva-tion. Furthermore, within their small study of patients with idiopathic DO, the authors found this technique useful in preventing elevated postvoid residual urine volume following therapy.35 Patients might, however, perceive trigonal injections as painful under local anes-thetic. The same researchers did not formally assess for reflux while performing this tech-nique, but no patients in their series developed pyelonephritis.36 A recommendation has been made that injections should be performed when the bladder is relatively full, although not completely full to prevent backflow of toxin, and that adding indigo carmine to the injection


REVIEW



mixture could be a useful adjunct for new prac-titioners to confirm placement of the toxin into the bladder.37

Number, depth, and volume of BTX injec-tions have been topics of much debate among uro logists. Karsenty et al. presented data comparing regimens of 30 and 10 injections of 300 U BTX-A in a population with neuro-genic DO. The researchers concluded that the lower number of injections did not affect effi-cacy or safety.38 The exact location of the toxin following injection was a potential concern.

Yet a recent MRI study found that with rigid cysto scopy approximately 13% of the injected volume was located in the extraperitoneal fat outside the bladder and between one-quarter or one-third of the total bladder wall volume was covered following 10 or 30 injections of toxin, respectively.39 Afferent mechanisms might have an important part in the mecha-nism of action of BTX and, therefore, targeted injections into the suburothelium might be beneficial. These types of injections raise a suburothelial bleb; however, most clinicians

Urine(pH changes, temperature changes, mechanical stretch)

TRPV1TRPV1TRPV1

TRPV1

M2

P2Y

P2YNK1NK1

M3M3

M3

M3

P2X3P2X3

P2X3

P2X3P2X3

M2

M2

M2

M2

M2

TRPV1

TRPV1

TRPV1

NGF NGF

SPATP/ACh

ACh

ACh

ACh

SP

SP

ATP

ATPbl

det

mf

ATP

Figure 1 A schematic diagram of identifiable ultrastructural components of the human bladder wall. The known or proposed locations of receptors and release sites for neuropeptides and growth factors involved in bladder mechanosensation are shown. All connections identified by arrows are thought to be upregulated in detrusor overactivity and might be reduced with the peripheral afferent desensitization that arises after injections of botulinum toxin-A. The thin solid arrows indicate the proposed pathways in which vesicular ATP release from the urothelium activates urothelial or suburothelial receptors (P2X3–P2Y) or potentiates the response of urothelial, suburothelial, or both receptors (TRPV1) to irritative stimuli. The thin dashed arrows indicate proposed pathways in which vesicular acetylcholine release from the urothelium or suburothelial nerves activates suburothelial or detrusor muscle muscarinic acetylcholine receptors. Thick dashed arrows highlight proposed pathways whereby suburothelially released substance P acts on neurokinin 1 receptors on the myofibroblast cell layer or potentiates the activation of TRPV1–P2X3 receptors in suburothelial afferents (Substance P is also known to affect the expression of NGF and vice versa). Finally, thick solid arrows show where NGF is thought to affect the expression of urothelial or suburothelial TRPV1, or both. Permission obtained from Elsevier Ltd © Apostolidis A et al. (2006) Eur Urol 49: 644–650. Abbreviations: ACh, acetylcholine; bl, basal lamina of urothelium; det, detrusor muscle; mf, myofibroblast layer; NGF, nerve growth factor; NK1, neurokinin 1; P2X/P2Y, purinergic receptors; SP, substance P; TRPV1, transient receptor potential vanilloid 1.


REVIEW



experienced with BTX-A injections feel that the efficacy of the therapy is not noticeably affected whether blebs are formed or not. No study findings yet suggest that one technique is better than another. As larger clinical trials and technique comparison studies are done, however, it is hoped that methods and instru-mentation used will become more standard-ized worldwide. Alternative modes of delivery, such as intravesical instillation of BTX or long-acting preparations, might also become avail-able. Studies in animal models have shown that pretreatment with protamine sulfate makes the urothelium sufficiently permeable for intra-vesically administered BTX to be absorbed and to produce an effect.25,40

CONCLUSIONSBTX-A injections into the bladder are emerging as effective therapy for treating patients with overactive bladder and DO. Long-awaited evidence from placebo-controlled, rando mized trials has proven the treatment’s efficacy in both neurogenic and idiopathic DO. Long-term safety data are still required, but early evidence for neurogenic DO seems to suggest that bene-ficial effects are sustained over the course of repeated injections. Most patients need injec-tions approximately once yearly. If longer-acting forms of BTX-A become available, it might be possible to increase the intervals between injections. With emerging evidence of the SV2 receptor being the acceptor molecule that BTX binds to, the future might allow for even better targeted therapy for patients.

KEY POINTS■ Botulinum toxin is becoming established as

an excellent second-line therapeutic option in patients with refractory overactive bladder

■ Evidence from small, randomized, placebo-controlled trials indicates that botulinum toxin is an effective treatment for both neurogenic and idiopathic detrusor overactivity

■ Evidence suggests that botulinum toxin affects sensory neuronal pathways in the bladder, which leads to inhibition of the release of various neurotransmitters and downregulation in the expression of vanilloid and purinergic receptors

■ Currently, injection techniques of botulinum toxin vary worldwide but no conclusive data are available to support one method over another

References1 Karsenty G et al. (2006) Injection of botulinum toxin

type A in the urethral sphincter to treat lower urinary tract dysfunction: a review of indications, techniques and results. Can J Urol 13: 3027–3033

2 Chuang YC et al. (2006) The potential and promise of using botulinum toxin in the prostate gland. BJU Int 98: 28–32

3 Schurch B et al. (2005) 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 174: 196–200

4 Popat R et al. (2005) A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-A toxin. J Urol 174: 984–989

5 Finney SM et al. (2006) A double-blind, placebo controlled study investigating efficacy of botulinum toxin type A (Dysport) in MS related overactive bladder syndrome (OAB): Provisional 12-week clinical results [abstract]. BJU Int 97: 31–32

6 Ehren I et al. (2006) Treatment with botulinum toxin A in neurogenic bladder dysfunction—a randomised double-blind study with Dysport [abstract]. Eur Urol 5 (Suppl): 299

7 Sahai A et al. Efficacy of botulinum toxin-A in treating idiopathic detrusor overactivity: results from a single center, randomised, double blind, placebo controlled trial. J Urol (in press)

8 Ghei M et al. (2005) Effects of botulinum toxin B on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial. J Urol 174: 1873–1877

9 Odergren T et al. (1998) A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment of cervical dystonia. J Neurol Neurosurg Psychiatry 64: 6–12

10 Schmid DM et al. (2006) Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol 176: 177–185

11 Sahai A et al. (2006) Urodynamic assessment of poor responders following intra-detrusor injections of botulinum toxin A for overactive bladder [abstract]. J Endourol 20 (Suppl 1): A60

12 Patki PS et al. (2006) Botulinum toxin-type A in the treatment of drug-resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU Int 98: 77–82

13 Ruffion A et al. (2006) What is the optimum dose of type A botulinum toxin for treating neurogenic bladder overactivity? BJU Int 97: 1030–1034

14 Wyndaele JJ and Van Dromme SA (2002) Muscular weakness as side effect of botulinum toxin injection for neurogenic detrusor overactivity. Spinal Cord 40: 599–600

15 Grosse J et al. (2005) Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 47: 653–659

16 Comperat E et al. (2006) Histologic features in the urinary bladder wall affected from neurogenic overactivity—a comparison of inflammation, oedema and fibrosis with and without injection of botulinum toxin type A. Eur Urol 50: 1058–1064

17 Haferkamp A et al. (2004) Lack of ultrastructural detrusor changes following endoscopic injection of botulinum toxin type a in overactive neurogenic bladder. Eur Urol 46: 784–791


REVIEW



18 Dong M et al. (2006) SV2 is the protein receptor for botulinum neurotoxin A. Science 312: 592–596

19 Schurch B et al. (2000) Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 164: 692–697

20 Sahai A et al. (2005) Botulinum toxin for the treatment of lower urinary tract symptoms: a review. Neurourol Urodyn 24: 2–12

21 Apostolidis A et al. (2006) Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol 49: 644–650

22 Smet PJ et al. (1997) Distribution and colocalization of calcitonin gene-related peptide, tachykinins, and vasoactive intestinal peptide in normal and idiopathic unstable human urinary bladder. Lab Invest 77: 37–49

23 Khera M et al. (2004) Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 45: 987–993

24 Rapp DE et al. (2006) Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol 175: 1138–1142

25 Chuang YC et al. (2004) Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 172: 1529–1532

26 Atiemo H et al. (2005) Effect of botulinum toxin on detrusor overactivity induced by intravesical adenosine triphosphate and capsaicin in a rat model. Urology 65: 622–626

27 Apostolidis A et al. (2005) Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 174: 977–982

28 Welch MJ et al. (2000) Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 38: 245–258

29 Purkiss JR et al. (1998) A method for the measurement of [3H]-glutamate release from cultured dorsal root ganglion neurons. Biochem Soc Trans 26: S108

30 Cui M et al. (2004) Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 107: 125–133

31 Aoki KR (2005) Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 26: 785–793

32 Jankovic J and Schwartz K (1990) Botulinum toxin injections for cervical dystonia. Neurology 40: 277–280

33 Sahai A et al. (2006) Techniques for the intradetrusor administration of botulinum toxin. BJU Int 97: 675–678

34 Harper M et al. (2003) A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 92: 325–326

35 Smith CP and Chancellor MB (2005) Simplified bladder botulinum-toxin delivery technique using flexible cystoscope and 10 sites of injection. J Endourol 19: 880–882

36 Smith CP et al. (2005) Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 65: 37–41

37 Schulte-Baukloh H and Knispel HH (2005) A minimally invasive technique for outpatient local anaesthetic administration of intradetrusor botulinum toxin in intractable detrusor overactivity. BJU Int 95: 454

38 Karsenty G et al. (2005) Botulinum toxin-A (BTA) in the treatment of neurogenic detrusor overactivity incontinence (NDOI)—a prospective randomized study to compare 30 vs 10 injection sites [abstract]. Neurourol Urodyn 24: 5–6

39 Boy S et al. (2006) Botulinum toxin injections into the bladder wall—a morphological evaluation of the injection technique using magnetic resonance imaging [abstract]. Eur Urol 5 (Suppl): 299

40 Khera M et al. (2005) In vivo effects of botulinum toxin A on visceral sensory function in chronic spinal cord-injured rats. Urology 66: 208–212

AcknowledgmentsThe GKT Botulinum Study Group is composed of Mr Arun Sahai, Mr Mohammad Shamim Khan, Mr Prokar Dasgupta, Professor Kenneth Smith, Dr Norman Gregson, Dr Yue Sun, and Professor Richard Hughes.

Competing interests A Sahai, MS Khan and P Dasgupta declared relationships with the following company: Allergan, Inc. See the article online for details. N Gregson and K Smith declared they have no competing interests.


Documents

Botulinum toxin for detrusor overactivity and symptoms of overactive bladder: where we are now and where we are going