Current Urology Reports

, Volume 14, Issue 3, pp 227–234

Botulinum Toxin—What Urologic Uses Does the Data Support?

Authors

    • Department of Uro-NeurologyUCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery
    • MRC Centre for Transplantation, King’s College London, King’s Health Partners, Department of UrologyGuy’s Hospital
  • M. S. Khan
    • MRC Centre for Transplantation, King’s College London, King’s Health Partners, Department of UrologyGuy’s Hospital
  • P. Dasgupta
    • MRC Centre for Transplantation, King’s College London, King’s Health Partners, Department of UrologyGuy’s Hospital
  • A. Sahai
    • MRC Centre for Transplantation, King’s College London, King’s Health Partners, Department of UrologyGuy’s Hospital
Female Urology (H Goldman, Section Editor)

DOI: 10.1007/s11934-013-0326-9

Cite this article as:
Seth, J., Khan, M.S., Dasgupta, P. et al. Curr Urol Rep (2013) 14: 227. doi:10.1007/s11934-013-0326-9

Abstract

Botulinum toxin-A (BTX-A) is well established in the management of various aspects of lower urinary tract dysfunction (LUTD). One formulation, OnabotulinumtoxinA has recently been licensed in many parts of the world for use in neurogenic detrusor overactivity (NDO), and in the US for idiopathic overactive bladder (OAB), in patient’s refractory to antimuscarinics. This review article looks at recent clinical publications that examine the use of BTX-A for the treatment of LUTD with a focus on OAB, detrusor overactivity (DO), benign prostatic hyperplasia (BPH) and Painful bladder syndrome / interstitial cystitis (PBS / IC). A literature review was conducted using the PubMed database and studies that were published within the time frame of January 2011 to present were included. Large randomised placebo controlled trials and a pooled analysis of patients with multiple sclerosis / spinal cord injury and NDO has suggested that BTX-A improved urinary incontinence (UI) episodes, urodynamic parameters and QoL in these patients. 200 U of OnabotulinumtoxinA appeared equivalent to 300 U. In patients with OAB, lower doses of 100 U OnabotulinumtoxinA, appear efficacious and with an acceptable adverse event profile. In one large phase III trial, de novo clean intermittent catheterisation rates were 6.1 %. Repeated injections in DO appear efficacious. Results from BPH studies are mixed, and the largest randomised study in this setting has shown significant improvements in a number of parameters for a variety of OnabotulinumtoxinA doses, but none of the doses were statistically better than placebo. Few studies have been conducted in PBS / IC and larger scale randomised placebo controlled trials are required to validate its use in this setting.

Keywords

Detrusor overactivityOveractive bladderPainful bladder syndromeInterstitial cystitisBenign prostatic hyperplasiaBotulinum toxin A

Introduction

The use of botulinum toxin-A (BTX-A) to treat overactive bladder (OAB) symptoms and detrusor overactivity (DO) is now commonplace and featured in the majority of continence guideline recommendations in patients refractory to conservative treatment and antimuscarinics [1, 2]. Publications that support its use continue to emerge. The two most common formulations used are Ona- and AbobotulinumtoxinA, previously known as Botox® and Dysport®, respectively. On the background of large phase III randomised controlled trials, licensing of OnabotulinumtoxinA at 200 U for the treatment of urge urinary incontinence (UUI) in patients with multiple sclerosis (MS) / spinal cord injury (SCI) and neurogenic detrusor overactivity (NDO) has been granted in many parts of the world. It was also recently approved by the FDA in the United States for patients with OAB. The purpose of this article is to review the most recent published evidence for its clinical use to treat lower urinary tract dysfunction (LUTD) in adults with a focus on bladder injections for OAB, DO and Painful bladder syndrome / interstitial cystitis (PBS / IC), and prostatic injections to treat benign prostatic hyperplasia (BPH).

Methods

Evidence was gathered through a PubMed search of publications in the English language, using the keywords botulinum toxin, bladder, detrusor, overactive bladder, painful bladder syndrome, interstitial cystitis and benign prostatic hyperplasia in various combinations, from January 2011 to January 2013. Included studies were limited to the adult population and studies assessing mechanism of action were excluded.

Results

Neurogenic Detrusor Overactivity

A recent phase III, multicentre, international, randomised, double blind placebo controlled trial involving 154 patients with MS and 121 with SCI, suffering with urinary incontinence (UI) and NDO has recently been reported [3•]. Patients were randomised into receiving OnabotulinumtoxinA at 200 U, 300 U or placebo, utilising a trigone sparing injection technique. At week 6, there were significant improvements in the number of weekly UI episodes, mean cystometric capacity (MCC), mean detrusor pressure at Qmax, and Quality of Life (QoL) scores. The median time for patients requesting retreatment in the placebo arm was at 13.1 weeks, and 42.1 weeks for the BTX-A arm. Most frequent adverse events included urinary retention and urinary tract infection (UTI). Increases seen in post-void residual (PVR) appeared to be dose related, with 12 %, 30 % and 42 % of patients from the placebo, 200 U and 300 U arms initiating clean intermittent catheterisation (CIC) after treatment [3•]. UTI rates were similar in all the treatment groups including placebo for patients with SCI, with rates at 20 %, 20 % and 22 % for placebo, 200 U and 300 U. For MS groups, it was higher in the BTX-A arms compared to placebo with rates of 16 %, 31 % and 35 % of patients affected for placebo, 200 U and 300 U [3•]. A second multicenter, double blind, randomised placebo-controlled trial in 416 patients with NDO secondary to MS (n = 227) or spinal cord injury (n = 189), showed significant improvements with 200 U and 300 U of OnabotulinumtoxinA [4•]. The results are summarised in Table 1. Median time to retreatment by patient request was at 256 and 254 days for the treatment arms, and 92 days for placebo. Rates of adverse events mirrored that of other studies, with the need for new onset catheterisation at 10 % for placebo, 35 % for 200 U and 42 % for 300 U [4•]. The data from these two pivotal studies were pooled, to provide a dataset from 691 patients with NDO [5]. Approximately 65 % of patients had no involuntary detrusor contraction on urodynamics at 6 weeks following treatment with OnabotulinumtoxinA. Improvements were seen in those despite persistent NDO in MCC, volume at first unstable contraction, and maximal detrusor pressure during filling cystometry. Bladder compliance also improved with OnabotulinumtoxinA treatment, and low baseline pre-treatment compliance did not affect clinical outcomes. BTX-A was well tolerated at both 200 U and 300 U, with no increased efficacy of 300 U over 200 U [5]. In a smaller Canadian study, 57 patients with antimuscarinic refractory NDO secondary to MS or SCI were randomised into 300 U of OnabotulinumtoxinA or placebo. Significant improvements were seen in the BTX-A arm, for UI episodes up to 36 weeks, and for urodynamic and QoL parameters [6].
Table 1

Mean +/− SD values for OnabotulinutoxinA and placebo in total, multiple sclerosis (MS) and spinal cord injury (SCI) populations and effect of urinary incontinence (UI), urodynamics and quality of life (QoL). Source [4•]

Parameter

TOTALS

TOTALS

TOTALS

MS

MS

MS

SCI

SCI

SCI

 

Placebo

200 U

300 U

Placebo

200 U

300 U

Placebo

200 U

300 U

No. pts

149

135

132

81

77

69

68

58

63

UI (No./wk):

         

Baseline

28.3 ± 15.8

32.3 ± 22.8

31.1 ± 17.0

30.3 ± 17.8

32.7 ± 22.2

31.3 ± 17.7

25.9 ± 12.8

31.6 ± 23.7

30.9 ± 16.5

Change from baseline

−8.8 ± 16.2

−21.0 ± 23.8*

−22.7 ± 17.1*

−11.5 ± 19

−20.4 ± 25.7

−23.8 ± 18.3*

−5.7 ± 11.2

−21.9 ± 21.1*

−21.5 ± 15.8*

MCC (ml):

         

Baseline

256 ± 144

252 ± 154

256 ± 145

243 ± 143

260 ± 161

251 ± 149

271 ± 145

242 ± 147

262 ± 142

Change from baseline

16 ± 127

151 ± 171*

168 ± 170*

−7.5 ± 118

142 ± 179*

162 ± 171*

45 ± 134

163 ± 160*

175 ± 169*

MDP at 1st IDC (cm H2O):

         

Baseline

50.9 ± 38.1

51.3 ± 34.7

47.1 ± 36.3

42.3 ± 30.9

43.6 ± 28.8

36.8 ± 28.2

61.1 ± 43.2

61.6 ± 39.1

58.4 ± 40.8

Change from baseline

−2.4 ± 43.4*

−35.1 ± 35.7*

−33.3 ± 37.8*

12.1 ± 42.3

−28.4 ± 31.9*

−29.0 ± 33.2*

−19.6 ± 38.5

−41.0 ± 38.4

−36.3 ± 41.4

I-QOL total summary score:

         

Baseline

35.1 ± 18.1

34.0 ± 18.0

32.2 ± 18.6

31.5 ± 17.2

33.5 ± 17.1

30.5 ± 18.6

39.4 ± 18.3

34.5 ± 19.4

34.1 ± 18.6

Change from baseline

10.8 ± 18.4

26.9 ± 26.8*

32.9 ± 23.9*

12.4 ± 18.9

28.0 ± 28.0*

38.3 ± 24.1*

8.9 ± 17.7

25.4 ± 25.2*

26.6 ± 22.2*

* p < 0.05 vs placebo

In a small open labelled study involving 71 patients with MS and NDO, 26 % patients failed treatment (no improvement in clinical or urodynamic parameters), and this was found to be associated with a longer duration of MS symptoms [7]. As a result, the authors concluded that BTX-A treatment should be considered soon after failure of antimuscarinics.

A recent study has investigated the effect of repeated OnabotulinumtoxinA injections in MS and SCI patients as part of an extension study of the phase III clinical trials mentioned above [8•]. Patients continued to receive their original treatment dose of either 200 or 300 U. A total of 387, 336, 241, 113, and 46 patients received one, two, three, four and five OnabotulinumtoxinA injections, respectively. The proportion of patients achieving ≥ 50 % and 100 % dryness by 6 weeks were 73–94 % and 36–55 % respectively, depending on treatment cycle. Continued improvements in QoL were observed after all cycles of OnabotulinumtoxinA treatment. The UTI rate was 20 % and 23.8 % in patients receiving 200 U and 300 U in their fifth cycle of treatment. Just over 40 % of naïve patients needed to start performing CIC at some point during treatment [8•]. Repeated injections have also shown to be efficacious in other cohorts of NDO patients (MS and SCI) [9, 10].

Whilst the majority of studies in patients with NDO involve patients with SCI and MS, one study examined patients with Parkinson’s disease and refractory NDO. Eight patients were treated with 100 U OnabotulinumtoxinA, and in all patients, a reduction was seen in day and night time frequency and UI episodes with associated improvements in QoL. This was also mirrored by improvements in urodynamic parameters at 6 months [11].

The results of a small, randomised, double blind, placebo controlled study focusing on treatment satisfaction and QoL after OnabotulinumtoxinA treatment in patients with MS and SCI has recently been reported [12]. In total, 92 patients received 200 U and 91 had 300 U of BTX-A. Mean improvements were seen in incontinence-QoL scores and overactive bladder-patient satisfaction with treatment questionnaire for the BTX-A treated group compared with that for the placebo group at 6 and 12 weeks.

Preservation of renal function in patients with SCI is of paramount importance. One study examined this in particular, by observing any effect of repeated OnabotulinumtoxinA injections (200 U) on the renal function of patients with SCI over a 24-month follow-up period [13]. This was analysed by video urodynamic and 99mTc-DTPA studies, which were performed at baseline and at every 3 months post-injection in 33 patients. Whilst urodynamic parameters improved with increased MCC and reduced intravesical pressures after 200 U, there was no significant improvement in GFR over this time period. Mean GFR decreased from 93.4 to 83.5 ml/min, with significant reductions in GFR seen in the patients whose bladder compliance increased by less than 10 cm H20, and in those whose detrusor pressure decreased by less than 10 cm H20 after BTX-A treatment [13].

Another study examined the effect of BTX-A on UTI in patients with SCI [14]. Forty-one male patients, who were a mean duration of 21.5 months since injury, all received 300 U OnabotulinumtoxinA. Urine cultures were collected before and 3 months after injection, although UTI’s were also recorded 6 months prior to and after injection. The definition of a UTI included patients with a symptomatic UTI with bacteruria. It was reported that the mean number of UTI’s significantly decreased from 1.39 episodes in the 6 months prior to injection to 0.78 episodes within 6 months post-treatment. This significant decrease was seen in the group of patients whose DO had been inhibited by injection (n = 17) and was not significant in those where DO persisted (n = 24). Mean detrusor filling pressures were also seen to decrease in the former group and not in those whose DO persisted. The mean number of catheterisations per 24 hours increased from 4.0 to 4.7 after injection, with an increase in the mean urine volume drained per catheterisation from 204.0 mls to 365.8 mls [14].

Overactive Bladder / Idiopathic Detrusor Overactivity

A large phase III, placebo controlled study was carried out involving 557 patients with OAB and urge urinary incontinence (UUI) who were refractory to antimuscarinic therapy and were treated with 100 U OnabotulinumtoxinA [15•]. Patients did not have to have IDO to be included. Outcome measures included measurement of daily UUI episodes, scoring on the treatment benefit response scale, and health related QoL scores. At 12 weeks post-treatment, significant improvements were seen for these measures in those that received BTX-A, with 22.9 % of BTX-A patients achieving continence versus 6.5 % in placebo. Some of the results are summarised in Table 2. De novo CIC rates in this population have traditionally been a concern but in this study was only required in 6.1 % . CIC was initiated for post-void residuals > 200 mL if symptomatic, or > 350 mL regardless of symptoms. UTI was the most common adverse event at 15.5 % [15•].
Table 2

Mean change from baseline (95 % CI) and the corresponding percent change from baseline in daily average episodes of micturition, urgency and nocturia and volume voided per micturition up to week 12 post-treatment. Source [15•]

Parameter

Placebo (N = 277)

OnabotA 100 U (N = 280)

Placebo (N = 277)

OnabotA 100 U (N = 280)

 

Mean change from baseline (95 % CI)

Mean change from baseline (95 % CI)

Mean percent change from baseline (%)

Mean percent change from baseline (%)

Micturition episodes/day

    

Week 2

–0.79 (–1.09, –0.48)

–1.58* (–1.95, –1.21)

5.9

–11.7

Week 6

–0.98 (–1.28, –0.67)

–1.96* (–2.30, –1.62)

1.1

–15.4

Week 12

–0.91 (–1.22, –0.59)

–2.15* (–2.50, –1.79)

4.1

–16.9

Urgency episodes/day

    

Week 2

–1.34 (–1.75, –0.93)

–2.83* (–3.33, –2.32)

-11.5

-28.4

Week 6

–1.45 (–1.89, –1.02)

–3.21* (–3.69, –2.74)

-13.3

-35.3

Week 12

–1.21 (–1.67, –0.76)

–2.93* (–3.43, –2.44)

-10.0

-31.6

Nocturia episodes/day

    

Week 2

–0.16 (–0.27, –0.05)

–0.40** (–0.54, –0.27)

5.4

-13.0

Week 6

–0.26 (–0.39, –0.14)

–0.48** (–0.61, –0.35)

1.6

-21.1

Week 12

–0.24 (–0.37, –0.11)

–0.45** (–0.60, –0.30)

0.2

-20.2

Volume voided/micturition, ml

    

Week 2

8.1 (1.2, 15.1)

19.7** (12.1, 27.2)

10.0

18.7

Week 6

9.0 (1.8, 16.1)

32.3* (23.8, 40.9)

10.0

30.0

Week 12

9.7 (2.5, 17.0)

41.1* (30.5, 51.8)

10.1

37.3

* p < 0.001 vs. placebo

** p ≤ 0.05 vs. placebo

BTX-A treatment has also been directly compared in a head to head study with antimuscarinic therapy [16]. In this double blind, placebo controlled randomised trial, 247 patients with UUI were randomised into either a daily antimuscarinic tablet (solifenacin / trospium chloride) and an intradetrusor injection of saline, or an intradetrusor injection of OnabotulinumtoxinA (100 U) and a daily oral placebo tablet. In both arms, significant improvements were seen at 6-month follow-up. Both groups had a reduction of incontinence episodes from 5.0 per day to 3.4 and 3.3 for antimuscarinics and BTX-A, respectively. The BTX-A arm had significantly higher rates of complete resolution of UUI than the antimuscarinic arm (27 % vs 13 %). QoL also improved in both groups, without significant differences between the two arms. The antimuscarinic group had a significantly higher rate of dry mouth, but had significantly lower CIC rates and UTI episodes [16].

Results of a multicenter, dose escalation, phase II, randomised, double blind, placebo-controlled trial of 313 patients with refractory idiopathic OAB have also been published recently [17]. Again, IDO was not a pre-requisite for inclusion. The results showed that for doses ≥ 100 U OnabotulinumtoxinA, there were significant improvements in I-QoL score from 2 weeks to 24 weeks, and in the majority of time points for the KHQ. Assessing urodynamic parameters in the same study, 76 % of patients had demonstrable DO at baseline and significant improvements were seen in MCC at 12 weeks with all doses, and for 150, 200, and 300 U at week 36 [18]. At 12 weeks, significantly fewer UUI episodes were seen for all doses compared with placebo. Doses above 150U were more commonly associated with raised PVR > 200 mls. Whether patients had DO or not did not affect outcomes.

A further double blind study of 240 women with refractory OAB and DO were recruited from eight centres in the UK, and were randomised to either 200 U OnabotulinumtoxinA or placebo [19]. At six months, significant improvements were seen in frequency, urgency and UI episodes, and 31 % of patients achieved continence compared to 12 % in the placebo arm. 31 % and 16 % of patients in the BTX-A arm developed UTI and the need for CIC compared to 12 % and 4 % in the placebo group, with one third of women achieving continence.

Long-term effects of the toxin are largely unknown with regards to continuing efficacy, antibody formation and its effects on bladder function. However, medium term efficacy and discontinuation rates have recently been reported in a prospective study of 100 patients who had repeated injections of OnabotulinumtoxinA to treat refractory IDO [20]. For those who had up to five injections, there was statistically significant improvement in OAB symptoms and QoL compared to baseline, with a mean inter-injection interval of 322 days. The main reasons for those who dropped out of treatment were poor efficacy in 13 %, and CIC related issues in 11 % [20]. Dropout rates were highest in the first 2 years following treatment and then very rare. Other studies have confirmed the efficacy of repeated injections in this patient population [21, 22]. However, in their retrospective study, Mohee et al. noted different outcomes with BTX-A, in a predominantly OAB / IDO population (although some patients with NDO were included) [23]. In 137 patients with at least 3 years of follow-up, approximately 60 % had discontinued treatment, mainly as a result of CIC related issues or UTI. Limitations include lack of antibiotic use and outcomes were based on patient reported factors as opposed to specific instruments or diaries and the retrospective nature of the study. Interestingly, many of the patients had reverted back to conservative treatments and antimuscarinic therapy to which they were initially refractory [23].

Technique of Injection

Injection technique is controversial, with different centres advocating different techniques depending on indication [24]. Depth, number, volume and location of injection have not been fully ascertained. However, a recent single centre randomised controlled trial in 22 patients assessed location of injection utilising AbobotulinumtoxinA at 500 U [25]. The trigone sparing group had 20 x 1 ml injections throughout the bladder avoiding the trigone, whilst the trigone including group had 5 x 1 ml injections into the trigone, and 15 x 1 ml injections throughout the remainder of the bladder. The overactive bladder symptom score (OABSS) was improved up to 26 weeks post-procedure, with significant improvements in favour of the trigone-including group. Mean PVR and CIC rates between the two groups were similar, and no patients developed vesico-uretric reflux (VUR) [25]. The main limitation of the study was the lack of inclusion of a trigone-only injection group.

A large open labelled study utilising AbobotulinumtoxinA at 500 U for 64 patients with NDO and 250 U for 170 patients with IDO has also confirmed that trigonal injection do not promote VUR [26]. Full continence was achieved in 80-93 %, and only seven patients, all with IDO, had to perform CIC. Duration of effect was lower than expected (4.9–5.7 months).

A small pilot study in patients with SCI examined for a difference between suburothelial and intradetrusor injection [27]. This involved 32 patients with SCI and NDO. Patients all received 300 U OnabotulinumtoxinA; however, group A received intradetrusor injections at 2–4 mm depth, which were visualised by ultrasound; no suburothelial blebs or bulking were seen with the injection. Group B received suburothelial injections, all of which demonstrated bulking of the urothelium with injection. Bladder diary and urodynamic parameters were compared before and 3 months after injection. There was no significant differences between group A and B; however, improvement of bladder compliance seemed to be better in the intradetrusor group; 21.57 to 52.14 ml/cmH20 compared to 17.94 to 34.49 in groups A and B, respectively [27].

Finally, Kuo, injected OnabotulinumtoxinA at 100 U and randomized IDO patients to bladder versus bladder and bladder base / trigone versus bladder base / trigone injections alone [28•]. No differences were found in OAB symptoms, urodynamics, dry rates or patient perception of bladder condition, regardless of the location of the injection.

Cost Effectiveness

The cost effectiveness of this treatment will depend on a number of factors based on individual countries healthcare systems. In the USA, a recent study compared OnabotulinumtoxinA 300 U (ten injections over 5 years) and augmentation cystoplasty using a decision analysis model, and demonstrated BTX-A treatment was less expensive over 5 years, costing $28,065, and was more cost-effective over 5 years if the effect lasted for > 5.1 months [29]. The model was based on a surgical complication rate of 40 %, but if this rate fell to < 14 %, augmentation cystoplasty was cheaper over the 5 years.

Using a Markov analytical model, sacral neuromodulation was compared to BTX-A over 5 years [30]. Success was defined as a 50 % reduction in UI episodes, daytime frequency or pad usage. The cost effectiveness analysis after a 5-year period showed 4.95 QALYs for neuromodulation compared to 4.72 for BTX. The 5-year costs were €25,780 for SNM and €19,353 for BTX. Sacral neuromodulation only became cost effective after 4 years. In this analysis, it was presumed both procedures were performed under general anaesthesia and OnabotulinumtoxinA 200 U was injected yearly. If the analysis factored in the BTX-A injections under local anaesthesia or when peripheral nerve evaluation or bilateral testing was used for neuromodulation, BTX-A injections were more cost effective.

Finally, another study using a Markov analytical model from Spain suggested sacral neuromodulation was the most cost effective at 10 years when compared to BTX-A or optimized medical therapy [31].

Benign Prostatic Hyperplasia

There has been a growing interest in recent years to explore the use of BTX-A in treating benign prostatic hyperplasia (BPH). The initial work by Maria et al. suggested BTX-A injected into the prostate may reduce AUA symptom scores, improve flow rates and reduce total prostate volume (TPV) and was better than placebo in the blinded part of the study (up to 2 months) [32]. Mechanism of action was thought to be related to selected denervation and atrophy of the gland. Treatment was reserved for those who were poor surgical candidates, who had failed oral medical therapy and who refused bladder outlet surgery.

Results from a multicenter, randomised phase II clinical, involving 134 men with BPH, showed that intraprostatic injection of 100 or 300 U of OnabotulinumtoxinA resulted in 30 % improvement in AUA symptom scores and/or improvement in urinary flow rate and no significant adverse events, from baseline to 3 months post-treatment [33]. An optimum dose was not discovered; however, it was felt that 100 U may have similar efficacy to 300 U, with reduced costs and adverse events, and so should be considered preferentially. Adverse events included UTI, pelvic pain, macroscopic haematuria, haematospermia and urinary retention. Serious adverse events were also noted in three patients who developed systemic urosepsis. However, the limitation with this study is the lack of a placebo-controlled arm.

Arnouk et al. performed a randomised study examining 34 patients after 100 or 200 U of intra-prostatic BTX-A. Significant improvements were seen for IPSS scores, maximum flow rate (Qmax) and PVR at both doses at 3 and 6 months. A reduction in prostate volume was only seen after 6 months in the 200 U arm. PSA reduction was seen at 3 and 6 months in those receiving 200 U, and only at 6 months for those with 100 U [34]. Rate of complications were similar amongst both groups.

A study of 15 patients by de Kort et al. also examined urodynamic parameters, along with histological effects after 200 U of BTX-A through transrectal intraprostatic injection. Although there were improvements in IPSS and IPSS QoL scores, from 22 to 13 and 5 to 2 respectively, and a reduced PVR from 170 to 80 mls, no change was seen in Qmax, PSA and prostate volume during 12 months of follow-up. Histologically, 37 % of pre-treatment biopsies and 64 % of post-treatment biopsies had some evidence of prostatitis [35]. Ten of these 15 patients eventually had a TURP for persistent symptoms, despite improvements in IPSS.

Sacco et al. evaluated 64 patients with BPH at 3 months, following 200 U of OnabotulinumtoxinA through a transperineal route [36]. Significant improvements were seen for IPSS and IPSS QoL scores, a 33 % increase in Qmax, and an 80 % reduction in PVR. The treatment was judged to be effective by 68 % of patients.

Another small study reported on ten patients with BPH and LUTS unresponsive to traditional medical therapy, who were poor surgical candidates and were treated with varying doses of transurethral BTX-A (100-300 U) depending on prostatic size [37]. After treatment, there were noted improvements in mean IPSS from 24.5 to 13.4, an increase in Qmax from 7.9 to 16.2 ml/s and reductions in TPV from 41.5 ml to 30.4 ml and mean PSA from 3.1 to 1.7 ng/ml. It was felt that the transurethral method of injection was a safe alternative method of delivery in this pilot study [37].

Most recently, Marberger et al. have published the results of the largest study of BTX-A and BPH [38•]. This multicenter randomised double blind placebo controlled phase II trial included men over the age of 50 years with an IPSS of 12 or over, a TPV of 30–100 mls, and a maximum flow rate of 5–15 ml/sec. Patients received either transperineal or transrectal injection of placebo (n = 94), BTX-A 100 U (n = 95), 200 U (n = 94), or 300 U (n = 97) into the transitional zone, with almost 100 patients in each arm. Interestingly, at 12 weeks, there were significant improvements from baseline in IPSS, Qmax, TPV and transition zone volume for all groups including placebo, with no significant improvement for BTX-A over placebo patients. In a subgroup analysis, it was observed that the patients who appeared to improve significantly more than the placebo group, were those who had prior treatment with a-blockers and who were treated with 200 U. The reason for the pronounced placebo effect in this study was largely unknown. No changes in PSA were seen in the treatment groups. BTX-A had no negative impact on sexual function measured with the IIEF-5 questionnaire.

Silva et al. specifically focused on the potential effects of transrectal intraprostatic BTX-A treatment on sexual function. This questionnaire-based study used the IIEF-5 quetionnaire, and assessed ejaculatory function and libido with the IIEF–Long Form. The patients comprised of 16 sexually active men with BPH, who each received 200 U of OnabotulinumtoxinA. There was no deterioration of any domain of sexual function at 6-month follow-up [39].

Painful Bladder Syndrome / Interstitial Cystitis

The European Society for the Study of Interstitial Cystitis proposed a definition as ‘chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder with at least one other urinary symptom such as persistent urge to void or urinary frequency’ [40]. The above description is to be considered in the absence of a current UTI or other identifiable cause. Previous non-randomised clinical trials have suggested intradetrusor BTX-A injections can provide a significant improvement in pain, frequency and symptom scores [41].

Only one level 1 evidence study has been published recently, examining the use of BTX-A for this condition. This study used an alternative approach to bladder injections and investigated the possibility of periurethral injection in blocking urethral visceral and somatic afferent fibres, and assessed whether this would be helpful in PBS / IC women [42]. No significant improvement in the pain scores or the other symptom scores assessed was demonstrated compared to the placebo group after 3 months [42].

A recent open labelled study assessed 67 patients with refractory PBS / IC who underwent 100 U injection of OnabotulinumtoxinA followed by cystodistension [43]. Significant improvements were seen in pain, frequency, global response assessment, interstitial cystitis problem indexes, interstitial cystitis symptom indexes, and O’Leary-Sant symptom score compared to baseline at 3 and 6 months.

A single centre study of 16 patients with PBS examined the use of four repeat intratrigonal injections of OnabotulinumtoxinA over a 4-year period. Each patient was injected with 100 U under general anaesthesia [44]. In this open labelled study, patients reported improvements in visual analogue pain scores, urinary frequency from bladder diary collection and QoL scores. Patients were followed up within the first month of injection, then at every 3 months post-injection. Symptom benefit lasted up to an average of 9.9 months, with no cases of voiding dysfunction, and five patients had experienced non-complicated UTIs. The lack of voiding dysfunction was felt to be due to the injections being limited to the trigone area.

Larger scale randomised placebo controlled trials with bladder injections in this area are needed to further validate the use of BTX-A for PBS /IC.

Conclusions

So what does the evidence support? Recent large scale randomised placebo controlled trials have validated the use of BTX-A in DO. For patients with NDO refractory to antimuscarinics, a license has been granted for the use of OnabotulinumtoxinA at 200 U. A large phase III study in those with OAB has shown significant benefit in favour of 100 U OnabotulinmtoxinA compared to placebo, with a low CIC rate of 6.1 %. This treatment indication was recently approved in the US by the FDA. UTI rates are still significant with BTX-A injections for DO. Repeated injections for OAB appear efficacious and dropout rates appear related to CIC issues, UTI or poor efficacy.

The largest study for BTX-A in the treatment of BPH has shown no benefit of the use of BTX-A over placebo. In a sub-analysis of the same study, there was significant improvement in IPSS scores in patients who received 200 U OnabotulinumtoxinA who had previously received alpha-blockers compared to placebo, and this patient population may need further study.

Further large scale randomised placebo controlled trials in PBS / IC are needed before firm conclusions can be made in this area.

Acknowledgments

JS acknowledges financial support from the InComb project and would like to acknowledge UCLH/UCL Institute of Neurology. AS, PD acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King’s College Hospital NHS Foundation Trust. They also acknowledge the support of the MRC Centre for Transplantation.

Disclosure

Dr. Jai Seth reported receiving a grant from The Urology Foundation. Dr. Seth has also received travel accommodations from Astellas and honoraria from Allergan.

Dr. Mohammad Shamim Khan reported receiving a grant and travel accommodations from Allergan.

Dr. Prokar Dasgupta reported receiving a grant from Allergan.

Dr. Arun Sahai reported receiving a grant from Allergan and honoraria from Allergan, Pfizer and Astellas for presentations. Dr. Sahai received travel accommodations from Allergan and Astellas. He has completed / is currently conducting trial work for AMS, Allergan, and Astellas.

Copyright information

© Springer Science+Business Media New York 2013