Botulinum toxin

Schurch et al. 2005
Switzerland/France/
Belgium/USA
PEDro=8
RCT
N=59

Population:Mean age = 41 yrs; Gender: males = 61%; Severity of injury: AIS: A = 33, B = 10, C = 5, D = 4, E = 1.

Treatment:Participants were randomized in a 1:1:1 ratio into one of three groups: 300 U BTx-A, 200 U BTx-A, and placebo.  Patients received 3 vials of treatment depending on their group.

Outcome Measures:Incontinence episodes, maximum cystometric capacity, reflex detrusor volume and maximum detrusor pressure. Patients were followed up at 2, 6, 12, 18, and 24 weeks. 

1. Significant decrease was seen in:
   • Incontinence episodes for each BTx A group (p<0.05).
   • Maximum detrusor pressure for each BTx A group (p<0.023).
2. Significant increase was seen in:
   • Mean maximum cystometric capacity in each BTx-A group (p<0.020).
   • Mean reflex detrusor volume at 6 weeks in the 300 U BTx A group and at 24 weeks in the 200 U BTx A group (p<0.021).

Ehren et al. 2007
Sweden
PEDro=6
RCT
N=31

Population: Mean age = 36 yrs; Gender: males = 17, females = 14.

Treatment: Patients were randomly selected to receive intravesical injections of either 500 U of botulinum A toxin (BTx-A) or placebo.  Patients not experiencing any therapeutic effects of the injection were allowed to use a maximum of 2 tablets of tolterodine daily. 

Outcome Measures:Intake of tolterodine, bladder capacity, maximum detrusor pressure, leakage days. Patients were followed for 26 weeks.

1. Patients in the placebo group had a significantly higher intake of tolterodine tablets than the BTx-A group (p=0.003).
2. Cystometric bladder capacity was significantly higher in the BTx-A group than the placebo group at 6 (p<0.001) and 12 weeks (p=0.026); however, it was not significantly different at 26 weeks.
3. Maximum bladder pressure was significantly lower in the BTx-A group compared to the placebo group (p<0.01).
4. BTx-A group had significantly less leakage days than the placebo group (p<0.01).

Patki et al. 2006
UK
Downs & Black score=21
Pre-Post
N=37

Population:Mean age=39.4yrs; Gender: males=24, females=14; Level of injury: C=10, T=24, L=3; Severity of injury: complete=25, incomplete=12

Treatment:SCI patients with drug resistant NDO were administered 1000 U BTX-A into the detrusor muscle and followed.

Outcome Measures:MDP, incontinence, QoL.

1. Significant increase in mean MCC (p<0.001) was seen post BTX-A injection.
2. MDP decreased significantly post injection (p<0.001).
3. 3 months post injection, 76% had no unstable contractions on VCMG.
4. 69% of patients previously incontinent were continent post injection.
5. QoL questionnaire showed favorable response towards BTX-A injection in 86% of patients.
6. Symptoms began to recur at 8 weeks to 3 months.

Kuo 2006
Taiwan
Downs & Black score=21
Pre-Post
N=24

Population:SCL Mean Age=38.6yrs; Gender: males=11, females=1; CVA Mean Age=72.4yrs; Gender: males=6, females=6

Treatment:Patients with neurogenic detrusor overactivity were administered suburotheral BTX-A injection (200U) and assessed for efficacy.

Outcome Measures:Urinary retention, voiding pressure, bladder capacity, PVR, incontinence.

1. 4 SCL patients had urinary retention in the 1st post operative week.
2. Voiding pressure decreased significantly at 1 month compared to baseline in SCL patients (p=0.002).
3. From 1 month to 3 month followup an increase was seen in
   • IDC volume
   • Bladder capacity
   • PVR
4. From baseline to 3 month follow up:
   • A decrease in incontinence grade was seen
   • An increase in grade of difficulty urinating was seen.
5. 91.6% of SCL patients reported successful results at 3 months.

Tow et al. 2007
Singapore
Downs & Black score=21
Pre-Post
N=15

Population:Mean age = 49.9 yrs; Gender: males = 10, females = 5; Level of injury: paraplegic = 6; tetraplegic = 9; Severity of injury: complete = 11, incomplete = 4; Mean follow-up time = 7.1 yrs.

Treatment:300 units of botulinum toxin type A diluted in 30mL of normal saline solution.  30 injections of 1 ml each were given intramuscularly into the detrusor, sparing the trigone.  Patients were asked to reduce anticholinergic drugs after treatment. 

Outcome Measures:Mean number of leakages, maximal catheterisable volume, catheterisation frequency, mean reflex volume, mean cystometric bladder capacity, maximal detrusor pressure, mean duration of contraction. A post-treatment assessment was conducted 6 and 26 weeks after injection and a 3 day voiding diary was kept at 2 weeks and 6 weeks.

1. Mean number of leakages decreased significantly at 6 and 26 weeks post-injection (p<0.05).Catheterization frequency was significantly reduced 6 weeks post-injections (p=0.029) but not 26 weeks and 39 weeks post-injection.
2. Maximal catheterized volume increased at 6 weeks (p=0.003), 26 weeks (p=0.006), and 39 weeks (p=0.0296) post injection.
3. Mean reflex volume improved 6 weeks (p=0.0019) and 26 weeks (p=0.0172) post-injection.
4. Mean cystometric bladder capacity improved at 6 week post-injection (P=0.00007) and at 26 weeks post-injection (p=0.0117).
5. Maximal detrusor pressure decreased at 6 weeks (p=0.00007) and 26 weeks (p=0.0117) post-injection.
6. The duration of contraction showed no significant difference from pre-injection to 6 and 26 weeks post-injection.

Grosse et al. 2009
Germany
D&B=20
Case control
N=56
N_Dysport=28
N_Botox=28

Population:Dysport group (n=28): Mean age=36.8yrs; Gender: males=19, females=9; Type of injury: SCI=23, myelomeningocele=3, MS=2; Level of injury: paraplegia=24, tetraplegia=4; Severity of injury: incomplete=13, complete=15; Bladder management type: intermittent catheter=25, reflex voiding=3; Botox group (n=28): Mean age=37.4yrs; Gender: males=22, females=6; Type of injury: SCI=24, myelomeningocele=1, MS=1, central trauma=2; Level of injury: paraplegia=24, tetraplegia=4; Severity of injury: incomplete=12, complete=16; Bladder management type: intermittent catheter=26, reflex voiding=1, indwelling catheter=1

Treatment:Patients were retrospectively divided into two groups: Dysport group included those who had been previously been treated with Dysport (500 IU, 750 IU, or 1000 IU); Botox group consisted of patients previously treated with Botox (300 IU, 200 IU or 400 IU). The efficacy of both treatments was accessed.

Outcome Measures: Continence volume, medication use, dosage change, repeat injections

1. The Dysport and Botox group only differed significantly at 3 months for the continence volume, p=0.015.
2. No significant difference was seen in patients' medication use or dosage between the two groups.
3. 21 individuals in the Dysport group had repeat injects when their condition relapsed at about 13 months, while 26 Botox group individuals required a repeat injection at an average of 10 months.
4. Treatment failure (reinjection in less than 3 months) was seen in 5 Dysport group patients.

Schurch et al. 2000 Switzerland
Downs & Black=20
Pre-post
Initial N=21; Final N=19
 

Population: SCI: Age = 15-59 yrs; Gender: males = 14, females = 7.

Treatment:Outpatient botulinum-A toxin injection under cystoscopic control.

Outcome Measures:Continence level achieved, dose of anticholinergic medication, reflex volume, max detrusor pressure during voiding, detrusor compliance, max cystometric bladder capacity and patient satisfaction.

1. Significant increase in reflux volume, maximum cystometric bladder capacity (p<0.016).
2. Increase in post void residual urine volume. 
3. Non-significant voiding pressure change.
4. At the 6-wk followup complete continence was restored in 17 of 19 cases in which anticholinergic medication was markedly decreased or withdrawn.
5. Eleven patients at 16 & 36 wks follow-up continued to show bladder function improvement.

Akbar et al. 2007
Germany
Downs & Black score=19
Case series
N=44

Population: Mean age = 34.34 yrs; Gender: males = 10; females = 15; Level of injury: paraplegic = 15, tetraplegic = 10.

Treatment: BTx (Dysport) injected intramuscularly into 20 sites for pediatric patients and 40 sites for adults. Patients were re-injected when there was a substantial return to baseline measures.

Outcome Measures:Detrusor compliance, bladder capacity and detrusor pressure.  Follow-up was conducted every 3, 6, 9, and 12 months.

1. After 1, 2, and 3 injections significant improvement (p<0.001) in:
   • Detrusor compliance
   • Maximum detrusor pressure
   • Bladder capacity.
2. Prolonged efficacy of repeated injections in patients with neurogenic bladder function was seen over an average of 4.5 years.
3. No drug tolerance or changes in morphological appearance of the bladder was seen.
4. Side effects were seen in 3 patients receiving a dose of 1000 units Dysport, which was resolved by reducing the dose to 750 units.

Hajebrahimi et al. 2005
Canada
Downs & Black score=19
Pre-Post
N=10

Popluation:Mean age=41yrs; Gender: males =6, females=4;  Level of injury: tetraplegic=3, paraolegics=7; Severity of injury: complete=6, incomplete=4: AIS A=6, B=2, C=2.

Treatment:SCI patients with detrusor overactivity and failed to respond to anticholinergic medications were administered 400 U BTA injections into the bladder and followed.

Outcome Measures:Reflex capacity, MDP, satisfaction.

1. An increase of 63.08% was seen in average reflex capacity post injection, p<0.02.
2. A decrease in MDP of 15.52% was seen post injection however, this was not significant.
3. Patients reported 90% satisfaction rate.

Klaphajone et al. 2005
Thailand
Downs & Black score=19
Pre-Post
N=10

Population:Mean age=32.5yrs; Gender: males=6, females=4; Level of injury: C=1, T=9; Severity of injury: AIS A=7, B=2, C=1

Treatment: SCI patients with neurogenic detrusor overactivity were injected with 300 U BTX-A into the detrusor muscle.

Outcome Measures:Bladder compliance, functional bladder capacity, volume at first reflex, detrusor contraction, adverse events.

1. At 6 weeks post injection, significant increase was seen in mean bladder compliance (p=0.012), mean functional bladder capacity (p=0.008) and mean volume at first reflex (p=0.045).
2. Mean maximum detrusor contraction decreased significantly (p<0.001) 6 weeks post injection.
3. These effects lasted up till 16 weeks, with levels returning to baseline by week 36.
4. No adverse effects were seen.

Chen et al. 2010
Taiwan
Downs & Black score=19
Pre-Post
N=18

Population: Mean age=36.7yrs; males; Level of injury: C=13, T=5; AIS A=9, B=5, C=3, D=1.

Treatment:Patients were injected with 100U of BTX-A through the perineum into the external urethral sphincter.

Outcome Measures:Detrusor pressure, Detrusor leak point pressure, Pure pressure, iEMG, Static Pure pressure were taken at baseline and 4 weeks post injection. Post-void Residual (PVR) was measured at baseline, 1 month, 2, months, 4 months and 6 months post injection.

1. No signficant change was seen in detrusor pressure and detrusor leak point pressure post injection.
2. 1 month post injection, significant reduction was seen in:
   • Pure pressure, p=0.023
   • iEMG, p=0.008
   • Static pure pressure, p=0.012
3. Significant reducing in PVR was seen up to 6 months post injection, p<0.05.

Hori et al. 2009
UK
Downs & Black score=18
Case series
N=72

Population:Mean age=45.4yrs; Gender: males=43, females=29

Treatment:SCI patients who received BTX-A injections previously were evaluated for overall treatment satisfaction

Outcome Measures:Satisfaction.

1. 67% of patients previously receiving BTX-A injection for NDO remained on the treatment, while 33% discontinued treatment due to its ineffectiveness.
2. Decrease in dosage from 1000 IU to 750 IU resulted in a halt in episodes of muscular weakness in patients previously presenting.
3. 50-95% of patients were satisfied or very satisfied with BTX-A treatments with a mean satisfaction score of 6.2.
4. 43 of 48 patients still on BTX-A treatment reported losing BTX-A in the long term as an option.
5. Younger patients were more likely to consider a permanent surgical solution than older patients (p=0.02).

Reitz et al. 2004
Switzerland
Downs & Black =18
Case series
N=231 Initial
N=200 Final (167 with SCI)

Population:Neurogenic detrusor overactivity. Gender: males=131, females=69.

Treatment:Patients from 10 European medical centers who previously received 300 units of Botox were assessed.

Outcome Measures:Mean cystometric bladder capacity, reflex volume, bladder compliance, mean voiding pressure were assessed at 12 and 36 weeks post injection.

1. Significant improvement in mean cystometric bladder capacity, reflex volume, bladder compliance and mean voiding pressure was seen at about 12 weeks post injection (p<0.0001).
2. Complete continence was achieved in 132 of the 180 individuals with incontinence pretreatment.
3. At 36 week follow-up, improvements in mean cystometric bladder capacity (p<0.0001), reflex volume (p<0.01) and mean voiding pressure (p<0.0001) remained.

Giannantoni et al. 2009
Italy
Downs & Black = 17
Pre-Post
N=17

Population:Neurogenic detrusor overactivity; Mean age=39.7yrs; Gender: Males = 11, Female = 6; Severity of injury: AIS A=11, B=6; Levels of injury : T1–2=1, T4–5=3, T9–10=2, T11–12=7; C=4

Treatment:Patients who previously received intravesical Botulinum Neurotoxin for NDO were followed up after about 6 years.

Outcome Measures:Number of catheterizations; number of incontinence episodes, UDC first volume, UDC maximum pressure, maximum cystometric capacity, UTIs were measured at baseline, 4 months, 1yr, 3 yrs and 6 year follow ups.

1. A significant decrease was seen in daily incontinence episodes and mean catheterization 4 months post treatment (p<0.001).
2. Improvement in all outcomes were seen at the 6 year follow-up:
   • Number of catheterizations/day, p=0.01
   • Number of incontinence episodes/day, p=0.01
   • UDC first volume, p=0.001
   • UDC maximum pressure, p=0.01
   • Maximum cystometric capacity, p=0.001
   • UTIs/year=0.001
   • Mean QoL index increased significantly at 3 year and 6 year follow ups (p<0.001).

Capsaicin/resiniferatoxin

deSeze et al. 2004 France
PEDro=10
RCT
N=39

Population: SCI (N=18); MS (N=21); Mean age = 47 yrs; Gender: males = 17, females = 22; Level of injury: paraplegia = 14, tetraplegia = 4; Severity of injury: AIS: A, B; Bladder management method:  IC = 23, reflex or voluntary voiding = 8, suprapubic percussion = 2, spontaneous voiding = 14.

Treatment:100ml 100nMol/l resiniferatoxin (RTX) in 10% ethanol or 1mmol/l capsaicin (CAP) diluted in glucidic solvent.

Outcome Measures:Clinical: daily voids/catheterization, leakage episodes with urgency/ leakage delay. Urodynamic: max cystometric capacity [MCC]; max detrusor pressure [DPmax].  Day 30&60=general tolerability; Cystoscopy on day 60.

1. No significant difference between groups:  both resulted in clinical and urodynamical improvement at day 30
2. CAP attained statistical significance for increase in security delay (p<0.01) 
3. Trend to greater increase in MCC in CAP group
4. No difference in detrusor pressure. 
5. Persistent clinical improvement 94% vs 60% in favour of RTX but not significant. 
6. MCC improvement maintained at 90 days with 86% vs 68% in favour of CAP but not statistically significant. 
7. Duration of efficacy similar. 
8. Side effects similar between groups except clinically tolerable/brief suprapubic pain sig higher in CAP group (P<0.04). 
9. No cystoscopic pathological changes on day 60.

deSeze et al. 1998 France
PEDro=10
RCT
N=20

Population:  MS 12, SCI 8; Age = 20-66 yrs; Gender: males = 11, females = 9; Level of injury: paraplegia = 17, tetraplegia = 3; Severity of injury: complete = 6, incomplete = 14; Time since injury = 1-27 yrs.

Treatment:30mg capsaicin in 100ml 30% ethanol or 100ml 30% ethanol alone

Outcome Measures:Clinical: voiding diary. Urodynamic: max cystometric capacity [MCC]; max detrusor pressure [DPmax].

1. 30 days after instillation, results favoured capsaicin over placebo:
2. Decrease in 24h voiding freq (p=0.016); 
3. Decrease in 24h leakages (p=0.0008). 
4. Increase in MCC (p=0.01)
5. Decrease in MDP (p=0.07; not significant). 
6. Similar side effects in each group.

Kim et al. 2003
USA
PEDro=8
RCT
N=36

Population:SCI=20, MS=7, Other=9 with detrusor hyperreflexia and intractable UTIs despite previous anticholinergic drug use; Gender: males = 22, females = 14.

Treatment:Double-blind dose escalation of single instillation of 100 mL intravesical resineferatoxin (RTX 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, or 1.0 microM of RTX; n=4/group) or placebo (n = 8 ).

Outcome Measures:A visual analog pain scale (VAPS), bladder diary, mean cystometric bladder capacity (MCC) at wks 1, 3, 6 & 12 posttreatment, adverse events including autonomic dysreflexia (AD).

1. VAPS: min. to mild discomfort with values of 2.85 and 2.28 for the 0.5-microM and 1.0-microM RTX treatment groups.
2. No statistically significant changes in MCC or incontinence at lower doses.
3. MCC increased by 53% & 48% for the 0.5-microM & 1.0-microM RTX at 3 wks.
4. Incontinence decreased by 51.9% & 52.7% for the 0.5-microM & 1.0-microM RTX.
5. No long-term complications.
6. Intravesical RTX is well-tolerated but monitoring for AD required.

Silva et al. 2005
Portugal
PEDro=8
RCT
N=28

Population:Neurogenic detrusor overactivity. Mean age=38yrs; Gender: males=15, females=13

Treatment:Patients were randomly placed in a treatment group receiving 50nM resiniferatoxin or placebo group.

Outcome Measures:First detrusor contraction, maximal cystometric capacity. Measures were assessed 1 month and 1 week pre treatment and 1 and 3 months post treatment.

1. FDC and MCC increased significantly in the treatment group compared to the placebo group (p=0.03, p=0.02).
2. No significant difference was seen in FDC and MCC in the treatment group between month 1 post treatment and month 3.
3. Individuals in the RTX instillation group reported a nonsignficant increase in discomfort compared to the placebo. Otherwise similar side effects were seen between RTX and placebo.
4. A significant decrease in daily incontinence was seen in the treatment group (p=0.03).

George et al. 2007
India
Downs & Black score=20
Prospective controlled trial
N=18
 

Population: Age = 20-53 yrs; Gender: males = 17, females = 1.

Treatment:Oxybutynin, propantheline, and capsaicin solution were instilled intravesically.  Oxybutynin and propantheline were administered 3 times daily by a double blind method with a 6 day washout period between each drug.  Patients receiving propantheline or oxybutynin had urodynamic studies done before and 3 hours after the instillation of the third dose. The capsaicin instillation was not possible to blind and urodynamic studies were repeated 1 and 2 weeks after instillation of the drug.

Outcome Measures:Reflex volume, detrusor leak point pressure, cystometric capacity, and urine leak frequency.

1. Overall capsaicin treatment resulted in significant change in:
   • Reflex volume (p=0.018).
   • Cystometric capacity (p=0.0440).
   • Leak volume (p=0.000).
   • Leak frequency (p=0.009).
2. Pre and post responses between intravesical oxybutynin, propantheline and capsaicin showed significant differences at 2 weeks with respect to leak volume (p=0.017) and leak frequency (p=0.003).
3. Side effects included:
   • Increased thirst and dryness of mouth following intravesical oxybutynin in 2 patients.
   • Symptoms of autonomic dysreflexia in 2 patients following instillation of capsaicin.

Shin et al. 2006
Korea
Downs & Black score=20
Pre-Post
N=15

Population:Mean age = 27.2 yrs; Gender: males = 11, females = 4; Severity of injury: AIS: A = 10; B = 5.

Treatment:Conventional and ice provocative urodynamic studies were performed. Seven days later, 100 ml of resiniferatoxin solution (100 nM) diluted in 10% ethanol was instilled into the bladder at an infusion rate of 30 ml/min. 

Outcome Measures:Involuntary detrusor activity, reflex volume, maximal bladder capacity, compliance, maximal detrusor pressure, and reflex volume. Urodynamic changes were examined 30 days after the instillation.

1. Intravesical resiniferatoxin instillation resulted in a significant increased reflex volume ratio (p<0.05).
2. No significant change was found after intravesical resiniferatoxin instillation in:
   • Maximum bladder capacity.
   • Compliance
   • Maximal detrusor pressure.
3. Three cases showed complete suppression and 9 cases showed partial suppression of the unmyelinated C-fiber activities.

Das et al. 1996
USA
Downs & Black score=11
Case Series
Initial N=7; Final N=5

Population:Mixed group: Age = 23-52 yrs.

Treatment:Intravesical capsaicin treatment: 100uM, 500uM, 1mM, 2 mM

Outcome Measures:Improvement, bladder capacity.

1. Symptomatic improvement: 3/5 completers.
2. Mean urodynamic bladder capacity increased (p<0.05).

Dasgupta et al. 1998
UK
Downs & Black score=10
Post Test
N=20

Population:MS, SCI: Age = 40-70 yrs; Gender: males = 9, females = 11.

Treatment:Intravesical capsaicin.

Outcome Measures:Histopathological examination of bladder biopsies, urodynamics to assess bladder capacity, cystoscopy in 2 patients.

1. All biopsies were benign. Some reflected chronic inflammation (cystoscopy: 2 males with TM - transient inflammatory reaction to treatment).
2. Bladder capacity improvement at 6 weeks.

Nociception/orphanin phenylalanine glutamine

Lazzeri et al. 2003
Italy
PEDro=10
RCT
N=14

Population:SCI subjects with neurogenic detrusor overactivity: Mean Age (treatment) = 43.7 yrs; Mean age (placebo) = 41.4 yrs; Gender: males = 6, females = 8 (ratio 3:4 per group); Level of Injury: T4-L2; Cause of injury: trauma = 10, non-trauma = 4 (ratio 5:2 per group); Time since injury (treatment) = 8.7 yrs; Time since injury = 7.0 yrs.

Treatment:Evaluate the neuropeptide nociceptin/orphanin FQ (N/OFQ) vs placebo (randomized placebo-controlled, double-blind study).

Outcome Measures:Bladder capacity, volume threshold for the appearance of detrusor overactivity (DO), and maximal bladder pressure during involuntary bladder contractions.

1. N/OFQ resulted in sig increase in:
   • Capacity (p<0.001; 139 ± 48mL to 240 ± 61mL)
   • DO volume threshold  (p<0.01 84 ± 32mL to 201 ± 68mL).
2. N/OFQ resulted in a non-sig decrease in:
   • Max bladder pressure: 81 ± 25cm H20 to 66 ± 12cm H20.
3. No diff btwn N/OFG and Placebo in:
   • No phasic contractions or autonomic dysreflexia
   • Incomplete patients - no suprapubic or urethral sensation
   • Vital signs unchanged.
4. N/OFQ (but not placebo) elicits robust acute inhibitory effect on micturition reflex in patients with neurogenic bladder.

Lazzeri et al. 2006
Italy
PEDro=8
RCT
N=18

Population:Neurogenic detrusor overactivity. Treatment: Mean age=37.1yrs; Gender: males=4, females=5; Placebo: Mean age=44.9yrs; Gender: males=4, females=5

Treatment:SCI patients were randomly placed into the treatment group receiving 1 mg of nociceptin/orphanin FQ/day for 10 days or placebo.

Outcome Measures:Bladder pressure, Incontinence Episode Frequency (IEF), Voiding Diary – Bladder Capacity (VD-BC).

1. Post treatment, mean bladder pressure and IEF decreased significantly (p<0.05) in the treatment group; however, no such change was seen in the placebo group.
2. No significant difference was seen in the bladder capacity and VD-BC post treatment.