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Keywords:

  • botulinum toxin;
  • neurogenic detrusor overactivity;
  • onabotulinum toxin A;
  • overactive bladder;
  • urinary incontinence

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

Botulinum toxin A is available under three different protein complexes that are not interchangeable until appropriate comparative studies are undertaken. The best studied for the treatment of urinary incontinence as a result of neurogenic detrusor overactivity and overactive bladder/idiopathic detrusor overactivity is onabotulinum toxin A. This brand is only approved for the treatment of urinary incontinence as a result of neurogenic detrusor overactivity at a dose of 200 U and idiopathic detrusor overactivity at a dose of 100 U. In patients with detrusor overactivity as a result of spinal cord injury or multiple sclerosis, 200 U of onabotulinum toxin A should be injected in 30 different sites above the trigone. It was shown to be highly effective in curing or decreasing urinary symptoms of incontinence, increasing quality of life, increasing bladder capacity and decreasing maximal detrusor pressure. This effect was independent of the concomitant use of oral anticholinergic drugs. Adverse events were mild, mainly urinary tract infections and high postvoid residual requiring clean intermittent catheterization. In patients with overactive bladder/idiopathic detrusor overactivity, 100 U of onabotulinum toxin A should be injected in 20 sites above the trigone. It markedly decreases urinary incontinence and improves quality of life. Frequency and urgency episodes are also decreased. Adverse events are mild, mainly urinary tract infections and urinary retention. The latter occurred in just 5% of the patients. Candidates for onabotulinum toxin A treatment should be warned that the effect of the toxin is transient and that repeated injections will be required to maintain the effect in the long term. There is no evidence that repeated injections will have a decreased efficacy.


Abbreviations & Acronyms
abobotA

abobotulinum toxin A

BoNT/A

botulinum toxin A

BPS/IC

bladder pain syndrome/interstitial cystitis

CIC

clean intermittent catheterization

DO

detrusor overactivity

EMEA

European Medicines Agency

FDA

Food and Drug Administration

GRA

global response assessment

ICPI

Interstitial Cystitis Problem Index

ICS

International Continence Society

ICSI

Interstitial Cystitis Symptom Index

IDO

idiopathic detrusor overactivity

incobotA

incobotulinum toxin A

I-QOL

incontinence quality of life

MCC

maximum cystometric capacity

MDP at 1st IDC

maximum detrusor pressure at first involuntary detrusor contraction

MS

multiple sclerosis

NDO

neurogenic detrusor overactivity

OAB

overactive bladder

OnabotA

onabotulinum toxin A

PdetmaxIDC

maximum detrusor pressure during first involuntary detrusor contraction

RCT

randomized controlled trials

SCI

spinal cord injury

TBS

Treatment Benefit Scale

UI

urinary incontinence

UTI

urinary tract infections

VAS

visual analog score

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

BoNT/A has been a good example of human creativity. From a lethal poison identified by Christian Kerner, a German physician, and considered in biological warfare, BoNT/A turned into one of the most promising and innovative therapeutic agents.

BoNT/A is, among the seven serotypes produced by Clostridium botulinum, the most relevant for clinical application. BoNT/A is available as a protein complex under at least four different commercial forms, Botox, Dysport, Xeomin and Prosigne. Although the toxin structure is very similar, associated proteins differ substantially, changing not only the molecular weight, but also the relative potency of each brand. Potency is expressed in units (U). However, the lack of appropriate dose conversion studies for the human lower urinary tract prevents the interchangeable use of the different brands. The FDA recognized the potential risk of considering botulinum toxin brands as identical agents and introduced non-proprietary names for each brand. OnabotA, abobotA and incobotA are the non-proprietary names for the toxins with the trade names of Botox, Dysport and Xeomin, respectively. Prosigne does not have a known non-proprietary name.

In the lower urinary tract, only onabotA received approval for urinary incontinence as a result of NDO, a process that started in 2011 after the successful conclusion of two large regulatory phase 3 trials.[1, 2] These studies were the final step of intense clinical research that started in 2000, when onabotA injections in the bladder of SCI patients were first suggested as an alternative treatment to NDO refractory to antimuscarinic drugs.[3, 4] Pivotal studies of onabotA in idiopathic detrusor overactivity have concluded with very positive preliminary reports (Nitti et al. Late Breaking News, AUA annual meeting 2012, and Chapple et al., non-discussed poster, ICS, 2012). FDA approved onabotA 100 U for the treatment of urinary incontinence as a result of OAB/IDO in January 2013, and a positive recommendation from the EMEA was already issued. In addition, bladder injections in patients with bladder pain syndrome/interstitial cystitis is another area under research for toxin application.

A recent systematic review of the literature regarding the use of botulinum toxin in the lower urinary tract identified good-quality studies that evaluated onabotA for all the aforementioned indications in adults; such was not the case with abobotA. Although this does not imply that onabotA is more effective than abobotA, it should be a consideration when counselling patients on the use of botulinum toxin in urological applications.[5]

Regulatory phase 3 trials with BoNT/A in adult NDO patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

The DIGNITY clinical research program (acronym for Double-blind InvestiGation of purified Neurotoxin complex In neurogenic deTrusor overactivitY) included two large pivotal phase 3 studies where efficacy and safety of onabotA in doses of 200 and 300 U were compared against a placebo in approximately 700 patients with NDO and urinary incontinence.[1, 2] Two main consequences came out from these studies. First, that 200 U and 300 U are more effective than placebo in controlling incontinence, without clinically relevant differences between the two doses, with an exception made to adverse events, which were more common with the higher dose. Second, health authorities in the USA and Europe approved onabotA 200 U to treat urinary incontinence in SCI and MS patients with NDO.

The design of the two studies was similar. Patients with NDO caused by MS (Expanded Disability Status Score ≤6.5) or SCI (below T1) who experienced at least 14 episodes of incontinence per week were randomized to receive 200 U and 300 U of onabotA or placebo (saline) in 30 bladder injections above the trigone. Patients had to be on CIC or be able and willing to do so. From week 12 onwards (84 days), patients could request a retreatment. Those that received placebo were re-randomized to receive onabotA, 200 U or 300U. The primary outcome measure was the change from baseline in 1-week episodes of urinary incontinence at week 6 after treatment. The secondary outcome measures included the change from baseline in MCC, PdetmaxIDC and quality of life using the I-QOL total score.

Both studies yielded similar findings in terms of primary and secondary outcomes.[1, 2] In the Cruz et al. study, the change from baseline in weekly incontinence episodes was −21.8 in onabotA 200 U, −19.4 with 300 U and −13.2 with placebo (P < 0.01), without relevant differences between the two doses. At the same time point, 7.6%, 38.0% and 39.6% of patients in the placebo, 200 U and 300 U onabotA groups, respectively, were fully continent in a 7-day bladder diary. A marked improvement was found in quality of life of patients treated with onabotA 200 U and 300 U over the placebo. In the study by Ginsberg et al., onabotA 200 U and 300 U were, likewise, more effective than the placebo in reducing the number of incontinence episodes, increasing the percentage of dry patients and improving quality of life. Again, no relevant differences were found between the two doses. A summary of these data can be seen in Table 1.

Table 1. Change from baseline in clinical and urodynamic data, at week 6
 Cruz et al.[1]Ginsberg et al.[2]
Week 6, 275 patientsWeek 6, 416 patients
Saline200 U300 USaline200 U300 U
  1. *P < 0.05. Reproduced from Cruz et al.[1] and Ginsberg et al.[2] with permission.

Incontinence episodes (n)−13.2−21.8*−19.4*−8.8−21*−22.7*
Fully continent (% of patients)7.60%38.00%*39.60%*0.00%36.00%*41.00%*
MCC mean ± (SD)6.5 ± 144.8157.0 ± 164.8*157.2 ± 185.2*16.0 ± 127151.0 ± 171*168.0 ± 170*
PdetmaxIDC, cmH2O (mean ± SD)6.4 ± 41.1−28.5 ± 47.8*−26.9 ± 33.2*−2.4 ± (43.4)−35.1 ± 35.7*−33.3 ± 37.8*
Patients with no detrusor contraction (%)17.40%64.40%*59.50%*19.00%64.00%*69.0%*
I-QOL score11.724.4*24.3*10.826.9*32.9*

In both studies, maximal detrusor pressure decreased and cystometric capacity increased significantly in the active groups when compared with the placebo, without relevant differences between the two doses (see Table 1).[1, 2]

The median time for saline-treated patients to request retreatment was approximately 90 days (84 days was the minimum time allowed per protocol for retreatment). This time was substantially higher, approximately 300 days for those treated with 200 U or 300 U of onabotA. Also in this parameter, no relevant differences were observed between the two doses.[1, 2]

The efficacy of onabotA 200 U and 300 U was also analyzed according to the etiology of NDO. No differences were found between SCI or MS patients in terms of improvement of urinary incontinence, although a more robust placebo effect was found in the MS population (Table 2).[1, 2]

Table 2. Clinical and urodynamic data of the subpopulations (multiple sclerosis and spinal cord injury) in the Cruz et al. and Ginsberg et al. studies
Ginsberg et al.[2]
 MSSCI
Saline200 U300 USaline200 U300 U
No. patients817769685863
Incontinence episodes (no. episodes)−11.5−20.4*−23.8*−5.7−21.9*−21.5*
MCC, mL (mean ± SD)−7.5 ± 118142 ± 179*162 ± 171*45 ± 134163 ± 160*175 ± 169*
MDP at 1st IDC, cmH2O (mean ± SD)12.1 ± 42.3−28.4 ± 31.9*−29.0 ± 33.2*−19.6 ± 38.5−41.0 ± 38.4*−36.3 ± 41.4*
Cruz et al.[1]
 MSSCI
Saline200 U300 USaline200 U300 U
  1. *P < 0.05. Reproduced from Cruz et al.[1] and Ginsberg et al.[2] with permission.

No. patients505351423940
Incontinence episodes (number of episodes)−18.1−25.9*−24.4*−7.5−16.1*−12.9*
MCC, mL (mean ± SD)28.4 ± 121.6159.2 ± 156.9*168.7 ± 179*−21.9 ± 167.8153.8 ± 177.7*140.6 ± 195.3*
MDP at 1st IDC, cmH2O (mean ± SD)8.8 ± 43.0−14.6 ± 36.0*−20.2 ± 22.9*3.2 ± 40.3−45.6 ± 56.0*−34.1 ± 41.1*

The most common adverse event of bladder injection of onabotA was UTI.[1, 2] It might, however, be recalled that urine culture was not mandatory for the diagnosis of UTI. In the SCI population, the majority of whom was carrying out CIC at baseline, the incidence was similar across all treatment groups (approximately 50% in the two studies). In the MS population, the picture was quite different, with a high incidence of UTI among patients treated with onabotA. In the study by Cruz et al., the UTI rate was 32% after saline, 58.5% after 200 U and 70% after 300 U.[1] In the study by Ginsberg et al., the incidence of UTI was 28%, 50% and 51% after saline, 200 U and 300 U onabotA doses, respectively.[2] The high incidence of UTI in MS patients treated with onabotA can be attributed to the increase of significant postvoid residuals and to the need of de novo CIC among these patients.[1, 2]

Botulinum toxin and antimuscarinic use

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

At the time of study entry, slightly more than 50% of the patients were taking antimuscarinic drugs (Table 3), indicating a very poor pharmacological control of NDO.[1, 2] For the purpose of the DIGNITY studies, patients off antimuscarinics could not initiate an antimuscarinic drug during the entire length of the study. Those taking antimuscarinics at baseline had to maintain the baseline dose unchanged.

Table 3. Anticholinergic users at baseline in reference studies
 Cruz et al.Ginsberg et al.
Saline200 U300 USaline200 U300 U
  1. Reproduced from Cruz et al.[1] and Ginsberg et al.[2] with permission.

Current anticholinergic user, n (%)57 (62.0)54 (58.7)51 (56.0)83 (56.0)66 (49)68 (52)

Similarly, significant reductions in UI episodes were observed after onabotA 200 U and 300U regardless of anticholinergic use (Table 4). The percentage of patients fully dry at week 6 was also similar among anticholinergic users and non-users. For patients treated with onabotA 200 U, dry rates were achieved for 36.7% for anticholinergic users and 37.4% for non-users (Sievert et al. oral poster, annual EAU congress, 2012, see Table 4). In what concerns urodynamic outcomes, similar increases in MCC and decreases in PdetmaxIDC were observed among anticholinergic users and non-users. The median time to patient request for retreatment in anticholinergic users and non-users treated with onabotA was also identical. Thus, the rationale to maintain chronic anticholinergic use after onabotA administration needs re-evaluation in a properly designed study.

Table 4. Continence rates among anticholinergic users and non-users treated with onabotA at 200 U and 300 U
 Anticholinergic usersAnticholinergic non-users
200 U300 U200 U300 U
  1. Results are presented as change from baseline. Data from Sievert et al. oral poster, annual EAU congress, 2012.

No. incontinence episodes−20.3−21−22.5−27.7
Dry rates %36.739.537.441.3
Increase in MCC (mL)157.2180.4149.3142.3

OnabotA 100 U in MS patients

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

The approved dose of onabotA in incontinent MS patients as a result of NDO is 200 U. However, the population of the two regulatory studies might not reflect the entire spectrum of the incontinent MS population. In fact, the two studies recruited only MS patients with at least two episodes of incontinence per day. As a consequence, the MS population treated with 200 U was a severely incontinent one, with a number of daily UI episodes ranging between four and five per day.[1, 2] Although the percentage of dry MS and SCI patients in a 7-day bladder diary was 36%,[2] a high percentage had to initiate CIC. Cruz et al.[1] found urinary retention in 30.2% and for Ginsberg et al.,[2] the number was 29%.

In an exploratory open labelled study, Mehnert et al. recruited 12 MS incontinent patients refractory to antimuscarinic drugs, but with a number of incontinence episodes marked inferior to that of regulatory studies, 3.8 in a 3-day bladder diary.[6] Treatment consisted of bladder injection of 100 U of onabotA diluted in 10 mL 0.9% saline and distributed over 10 injection sites at 1 mL each. A substantial reduction in the episodes of incontinence was observed, down to an average of one episode in a 3-day bladder diary. Although three patients required a catheter to empty the bladder, that study showed the possibility of using lower doses of onabotA than in MS patients with less severe forms of incontinence. Eventually, this might decrease the risk of CIC as noticed in IDO patients.[4, 7] An ongoing trial is investigating this possibility in MS patients with a minimum of incontinence episodes of two in a 3-day bladder diary.

OnabotA in IDO/OAB

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

The European Association of Urology Panel for Urinary Incontinence Guidelines has identified four RCT in which onabotA was investigated for the treatment of IDO/OAB in adults. All the studies using onabotA showed significant improvements at doses of 200 U.[8-11] Tincello et al. included 227 patients, which constitutes the largest RCT published in full version up to the moment.[11] In addition, the EAU Panel also indentified two dose-finding studies with onabotA: Domochwsky et al.[7] who compared a placebo and 50, 100, 150, 200 and 300 U, and Denys et al.[12] who compared a placebo against 50, 100 and 150 U. A new meta-analysis with all these studies, updating the previous meta-analysis by Mangera et al.[5] and the Cochrane review, yielded the following results: the odds ratio (95% CI) of becoming dry with onabotA versus placebo are 2.28 (0.95–5.49; P = 0.07) for 50 U, 4.39 (1.91–10.12; P = 0.0005) for 100 U, 4.96 (2.14–11.53; P = 0.0002) for 150 U, 4.34 (2.49–7.59, P < 0.00001) for 200 U and 7.05 (2.68–18.51, P < 0.0001) for 300 U. These results showed that 50 U had inferior efficacy than higher dosages. In the Dmochowski dose-finding study, the cure-dry rate at 12 weeks was 37.0% for 100 U and 50.9% for 200 U. However, the rate of de novo CIC was 9.1% for 100 U and 18.2% for 200 U.[7] Thus, 100 U seems to be the ideal dose for IDO/OAB.

Two large regulatory phase 3 RCT have now been concluded, in which onabotA 100 U was compared against a placebo in patients with OAB, and the results were communicated in the American Urological Association annual meeting in 2012,[13] and in the ICS meeting in 2012 (Chapple et al., non-discussed poster, ICS, 2012). Eligible patients were wet OAB patients refractory to oral antimuscarinics with at least three episodes of urgency urinary incontinence recorded in a 3-day bladder diary, eight micturition episodes per day and a postvoid residual less than 100 mL. Patients were randomized to receive 20 injections of 0.5 mL each above the trigone, containing 5 U per injection with a total of 100 U or only saline. The two studies randomized 557 patients for onabotA 100U and 548 patients for saline. Week 12 was the primary time-point, and two coprimary end-points were defined: change from baseline in the daily average frequency of UI episodes and the proportion of patients with a positive treatment response on the TBS (Table 5).

Table 5. Change from baseline at week 12 in incontinence episodes, urinary frequency and TBS in treated population versus placebo
 Nitti et al.[13]Chapple et al. 2012
OnabotA 100PlaceboOnabot 100Placebo
  1. Reproduced from Nitti[13] and Chapple studies (Chapple et al., non-discussed poster, ICS, 2012) with permission.

Incontinence−2.65−0.86−2.95−1.03
TBS (%)68.829.262.826.8
Frequency (daily micturition episodes)−2.15−0.91−2.55−0.83

In the Nitti et al. study, at week 12, there were three- to fourfold greater reductions from baseline in the mean daily frequency of UI episodes with onabotA 100 U versus placebo (–2.65 vs −0.87; P < 0.001), which corresponded to mean percent reductions from baseline of −47.9% with onabotA 100 U versus −12.5% with the placebo. Also, 57.5% of onabotA-treated patients achieved a 50% reduction in UI episodes versus 28.9% with placebo (P < 0.001); 22.9% of onabotA-treated patients were continent (100% reduction) compared with just 6.5% in the placebo group (P < 0.001). A higher proportion of onabotA-treated patients reported positive treatment response on the TBS versus placebo (60.8% vs 29.2%; P < 0.001). A decrease in daily micturition episodes from baseline at week 12 with onabotA versus placebo were −2.15 versus −0.91 (P < 0.001; Table 5).

In the Chapple et al. study (Chapple et al., non-discussed poster, ICS, 2012), there was a significant improvement of the number of incontinence episodes in a 3-day bladder diary (−2.95 vs 1.03, P < 0.001), and a significant improvement in TBS (62.8% vs 26.8%) in the onabotA and placebo groups, respectively. A decrease in the daily frequency (2.55 vs 0.83, P < 0.001) was observed in the onabotA compared with the placebo group. Adverse events were rare. The UTI rate was 20.4% in the onabotA and 5.2% in the placebo arm. The postvoid residual increase was 25.9 mL in the onabotA and 5.8 mL in the placebo arm. The percentage of patients that initiated CIC was 6.9% and 0.7% in the onabotA and placebo arm, respectively. Taking into consideration the data from these two regulatory trials, it is expected that onabotA 100 U will be soon approved for the treatment of IDO refractory to antimuscarinic drugs.

OnabotA injections in OAB have been recently compared against antimuscarinics, the standard initial pharmacotherapy in a double-blind, double-placebo–controlled, randomized trial. Women who had five or more episodes of urgency urinary incontinence in a 3-day bladder diary were recruited.[14] For a 6-month period, 247 participants were randomly assigned to solifenacin, 5 mg initially, with possible escalation to 10 mg (and if necessary with a switch to trospium XR, 60 mg) plus one intradetrusor injection of saline or one intradetrusor injection of 100 U of onabotA plus daily oral placebo. The baseline average urgency urinary incontinence was 5.0 per day. The mean reduction in episodes over the course of 6 months, in the anticholinergic and onabotA group, was similar at 3.4 and 3.3, respectively. Interestingly, the group receiving onabotA was more likely to have complete resolution of urgency urinary incontinence (27% vs 13%, P = 0.003). Patients on onabotA had higher rates of urinary retention during the initial 2 months (5% vs 0%), and more urinary tract infections (33% vs 13%). Patients on antimuscarinnics were more likely to have dry mouth.

Until now, onabotA has been considered an option for OAB/IDO patients refractory to antimuscarinics. This interesting study opens the door to the debate of how to initiate the treatment of OAB/IDO patients. Eventually, the preference of the patient for a dry status might be relevant criterion in the choice between the two treatments.

Other areas of research in OAB/IDO that are still undecided merit a comment. One is the issue of the injections sites. Although the regulatory trials have considered only bladder injections above the trigone, a pilot RCT compared supra-trigonal injections with injections above and in the trigone. Although the number of patients was small, just 22, the 11 that received trigonal and supra-trigonal injections had a greater symptomatic improvement and a longer duration of the effect.[15] The second is the adherence to the treatment. Dowson et al. reported in a cohort of 100 patients a rapid decline of the patients willing to receive repeated onabotA injections.[16] In fact, 25 patients abandoned the treatment after the first injection and more 12 after the second injection. Although these patients had received 200 U, de novo CIC, poor response and treatment invasiveness were pointed out as major reasons for discontinuation. The third aspect to be investigated is the effect of onabotA injections in men with IDO, as most of the OAB patients recruited in the aforementioned studies were women.

OnabotA injection for chronic bladder pain

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

OnabotA significantly inhibits the noxious sensory input from the bladder.[17, 18] Therefore, several small pilot studies were immediately carried out, none were placebo controlled, to explore the analgesic effects of onabotA in patients with chronic bladder pain as a result of BPS/IC. Unfortunately, conflicting results or weak and transient clinical improvements were reported.[19-21] A prospective, randomized study enrolled 67 patients with refractory BPS/IC. Of these, 44 patients received suburothelial injection of onabotA 100 U (n = 29) or 200 U (n = 15), followed by cystoscopic hydrodistension 2 weeks later. The control group (23 patients) only received hydrodistension. All patients remained on baseline pentosan polysulphate throughout the study.[22] A significant decrease of pain score in a 10-point visual analog pain scale was observed from baseline to 3 months within the groups that received onabotA 100 U (4.8–2.9) or 200 U (5.4–2.4). Patients in the hydrodistension only group had a non-significant decrease from 4.3 to 3.5. Comparisons between groups were not carried out.

In another prospective, non-randomized study, Chung et al. evaluated the efficacy of intravesical injection of 100 U of onabotA immediately followed by cystoscopic hydrodistention under intravenous general anesthesia for treatment of BPS/IC in 67 patients refractory to conventional treatment.[23] Patients were evaluated 6 months after onabotA treatment; a significant improvement compared with the baseline was shown for O'Leary-Sant ICSI and ICPI, VAS for pain, functional bladder capacity, and GRA. Results for baseline and 6 months after onabotA treatment were ICSI and ICPI (23.6 ± 5.9 vs 15.2 ± 8.5, P = 0.000), VAS (5.3 ± 2.2 vs 3.3 ± 2.4, P = 0.000), functional bladder capacity (136 ± 77.6 vs 180 ± 78.2, P = 0.000) and GRA (0.3 ± 0.8 vs 1.4 ± 1.0, P = 0.000). The authors concluded that intravesical onabotA injection appears to be a safe and effective therapeutic option for analgesia and increased bladder capacity for patients with BPS/IC.

Recently, in a prospective interventional study of 81 patients, Kuo evaluated the efficacy and safety of repeated intravesical onabotA injections for treatment of BPS/IC, and compared the success rates among patient groups receiving different injection numbers.[24] Intravesical injection of 100 U of onabotA was carried out in 81 patients every 6 months for up to four times or until patients' symptoms significantly improved. Patients who received a single injection served as active controls. Measured parameters included ICSI and ICPI, VAS for pain, voiding diary variables, urodynamic parameters, maximal bladder capacity under anesthesia, glomerulation grade, and global response assessment. Among the 81 patients, 20 received single injections, 19 received two injections, 12 received three injections and 30 received four injections. The mean scores of ICSI, ICPI, VAS, functional bladder capacity and daytime frequency all showed significant improvement after repeated onabotA treatment with different injections. Significantly better success rates were noted in patients who received four repeated injections (P = 0.0242) and three injections (P = 0.050), compared with those who received a single injection. However, there was no significant difference of long-term success rates among patients who received two, three and four injections.

Taking into consideration that most of the bladder nociceptors course in the trigone, Pinto et al. restricted 100 U onabotA injections to the trigone, in 10 sites (10 U/1 mL each). A total of 26 women with positive findings at cystoscopy and/or biopsy were enrolled.[25] All patients reported subjective improvement at 1- and 3-month follow up in pain, day and night-time voidings, O'Leary-Sant score, and quality of life. Treatment remained effective for 9 months. No cases of dysfunctional voiding were reported after trigonal injections of onabotA 100 U, and the UTI rate was 11.9%.[25] Retreatment was equally effective in all cases, with up to four re-injections with similar duration of the effect.[25, 26] At this moment, a well conducted placebo controlled RCT is necessary before making further statements regarding the utility of onabotA injections for controlling chronic bladder pain.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

OnabotA is an established and approved (by regulatory agencies – FDA and EMEA) treatment for incontinence in NDO for patients with MS and SCI, with great clinical and urodynamic improvement; it seems to be a promising treatment for patients with IDO, that has already been approved by the FDA and is pending approval by EMEA, and, in the future, might have a role in the treatment of BPS/IC.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References

Francisco Cruz is a consultant and investigator to Allergan. André Santos-Silva is an investigator to Allergan. Carlos Martins da Silva has no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Regulatory phase 3 trials with BoNT/A in adult NDO patients
  5. Botulinum toxin and antimuscarinic use
  6. OnabotA 100 U in MS patients
  7. OnabotA in IDO/OAB
  8. OnabotA injection for chronic bladder pain
  9. Conclusion
  10. Conflict of interest
  11. References
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