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Enhancing Bladder Volumes Pharmacologically – Capsaicin and Resiniferotoxin

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the main compound in hot peppers (e.g., red chili, jalapeños, and habaneros). It works as a temporary topical analgesic and is sold as an ointment world-wide and as a topical patch in Europe for allodynia. Capsaicin (CAP) induces localized and reversible anti-nociception from first C-fibre activation then subsequent neuropeptide release inactivation (Dray 1992). The initial C-fibre activation can be extremely painful and, in some individuals, intolerable. Although C-fibers are not involved prominently in normal voiding, neuroplastic changes to C-fiber bladder afferent expression after spinal cord injury account for an overactive C-fiber mediated voiding reflex (i.e., spinal detrusor hyperreflexia). Given the over-expression of C-fibers after SCI, the instillation of capsaicin into the bladder has been explored as a therapeutic approach. This, however, can be very painful and thus has not become clinically popular despite the initial work done in this area over 2 decades ago.

Resiniferatoxin (RTX) is an alternative vanilloid which has also been studied for its similar beneficial effects. Resiniferatoxin is less irritating to the bladder and is therefore better tolerated. By chemically reducing C-fiber bladder afferent influence with intravesical vanilloids (i.e., CAP, RTX), bladder contractility is decreased and bladder capacity is increased (Evans 2005). Unfortunately, despite the promising results presented below, it is not commercially available due to difficulty with formulation.

Table 3 Capsaicin

Author Year

Country
Research Design
Score
Total Sample Size

MethodsOutcome
Silva et al. 2005

Portugal

RCT

PEDro=8

N=28

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

Intervention: Individuals were randomly placed in a treatment group receiving 50nM resiniferatoxin or a placebo group.
Outcome Measures: First detrusor contraction (FDC), maximal cystometric capacity (MCC). 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 non-significant 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).

deSeze et al. 2004 France

RCT

PEDro=10

N=39

Population: SCI (n=18); MS (n=21); Mean age: 47 yr; 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.

Intervention: 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. Primary outcome measure: Maximum Cystometric Capacity (MCC).

1.     No significant difference between groups in MCC (p=0.4): both resulted in clinical and urodynamic improvement at d 90 (Improvement in MCC: 68% of RTX and 86% in CAP groups).

2.     Persistent clinical improvement 94% versus 60% in favour of RTX but the difference was not significant.

3.     Side effects were similar between groups except clinically tolerable/brief suprapubic pain significantly higher in CAP group (P<0.04).

Kim et al. 2003

USA

RCT

PEDro=8

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.

Intervention: Double-blind dose escalation of single instillation of 100mL intravesical resiniferatoxin (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 of RTX.

3.     However in higher doses (0.5-microM & 1.0-microM) of RTX, MCC increased by 53% & 48% respectively at 3 weeks.

4.     Incontinence decreased by 51.9% & 52.7% for the 0.5-microM & 1.0-microM RTX.

5.     Intravesical RTX is well-tolerated but monitoring for autonomic dysreflexia is required.

Petersen et al. 1999

Denmark

RCT crossover

PEDro=5

N=12

Population: Median age: 45 yr (range 28-68); Gender: males=6, females=6.

Intervention: Individuals were initially randomized to either an intraversical saline (100ml left in the bladder for 30 minutes) or intravesical capsaicin (100 ml 1mmol/L left in the bladder for 30 minutes) group; cross-over to the alternative treatment took place after 4 weeks.

Outcome Measures: Intravesical pressure during DH and bladder capacity, visual analogue scale (VAS).

1.     There were significant changes in the mean values of VAS scores during the study.

2.     VAS scores, mean volume and maximum pressure during DH was not significantly different between groups at follow-up.

3.     Bladder biopsies taken two weeks post treatment showed pronounced inflammation, superficial hemorrhage, and squamous epithelial metaplasia.

deSeze et al. 1998 France

RCT

PEDro=10

N=20

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

Intervention: 30 mg capsaicin in 100mL 30% ethanol or 100ml 30% ethanol alone

Outcome Measures: Clinical: voiding diary. Urodynamic: Maximum Cystometric Capacity (MCC), Maximum Detrusor Pressure (MDP).

30 d after instillation, results favoured capsaicin over placebo:

1.     Decrease in 24h voiding freq (p=0.016);

2.     Decrease in 24h leakages (p=0.0008).

3.     Increase in MCC (p=0.01)

4.     Decrease in MDP (p=0.07; not significant).

5.     Similar side effects in each group.

George et al. 2007

India

Prospective Controlled Trial

N=18

 

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

Intervention: Oxybutynin, propantheline, and capsaicin solution were instilled intravesically. Oxybutynin and propantheline were administered 3 times daily by a double blind method with a 6 d washout period between each drug. Individuals 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).

 

Shin et al. 2006

Korea

Pre-Post

N=15

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

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

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

1.     Intravesical RTX instillation resulted in a significant increased reflex volume ratio (p<0.05).

2.     No significant change was found after intravesical RTX 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.

Watanabe et al. 2004

Japan

Pre-Post

N=16

Population:

Group 1: Individuals with NDO from SCI (n=7) or transverse myelitis (n=1): Mean age: 30.9 yr (range19-53); Gender: males=6, females=2.

Group 2: Individuals with NDO from SCI (n=7) or cerebral palsy (n=1); Mean age: 28.1 yr (range 19-46); Gender: males=7, females=1.

Intervention: Intravesical resiniferatoxin (RTX) (30 mL of 500 nM in protocol 1, 100ml of 1um in protocol 2).

Outcome Measures: Incontinence, bladder capacity

1.     6/8 individuals (75%) reported improvements in their incontinence grades and symptoms.

2.     The mean bladder capacity increased significantly in both protocol groups (protocol 1: 138ml to 227.3ml, protocol 2:133.1ml to 247 ml, p<0.05).

 

Lazzeri et al. 1998

Italy

Pre-Post

N=7

Population: SCI individuals with detrusor hyperreflexia currently being treated with itnravesical instillation of capsaicin: Mean age: 32.85 yr (range 19-54); Gender: males=2, females=5

Intervention: Resiniferatoxin (RTX) saline solution (30ml at 10-5 M) instilled into the bladders of all individuals and left for 30 minutes.

Outcome Measures: Mean cystomanometric capacity (MCC); mean maximum bladder detrusor pressure (MDP), incontinence.

1.     15 days post-treatment: MCC significantly increased (190ml to 407.14 ml, p<0.01) and MDP decreased significantly.

2.     Four weeks after RTX instillation, MCC remained significantly increased from its baseline value (421.66 ml, p value).

3.     Incontinence was improved in 6/7 individuals (85.7%): improvements in their frequency, urgency and nocturia (n=3) or remained completely dry (n=3) post-treatment.

Dasgupta et al. 1998

UK

Post Test

N=20

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

Intervention: Intravesical capsaicin.

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

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.

Das et al. 1996

USA

Case Series

Ninitial=7; Nfinal=5

Population: Mixed group: Age range 23-52 yr.

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

Outcome Measures: Symptomatic improvement, bladder capacity.

1.     Symptomatic improvement: 3/5 completers.

2.     Mean urodynamic bladder capacity increased (p<0.05).

Discussion

DeSeze et al. (1998) has provided level 1b evidence in support of the ability of capsaicin (CAP) to improve bladder function. The authors found that CAP installation was effective in decreasing 24h voiding frequency (p=0.016), decreasing 24h leakages (p=0.0008) and increasing maximal cystometric capacity (p=0.01) 30-days after installation compared to placebo. This study offers support to other small, non-RCT studies that reported significant CAP-induced increases in bladder capacity (Das et al. 1996; Dasgupta et al. 1998). However, a small RCT cross-over study did not find differences in bladder improvement between individuals receiving CAP versus placebo (Petersen et al. 1999).

George et al. (2007) described the use of a one time instillation of CAP and reported that its “efficacy” for cystometric capacity was significant. However, when evaluating the data, it seems the significant difference was actually a significant decline in capacity at 3 hours (pre=224.6 cc, 3 hr post=139.6 cc, p=0.015) and a non-significant decline at 1 week (174.2 cc at 1 week, p=0.059). The authors claim that there was a marked, progressive and overall improvement following CAP except for leak point pressure. But the statistical results do not support this claim, and only leak volume was improved statistically at 2 weeks. Autonomic dysreflexia, a significant side effect, was reported in 2 individuals following CAP. Although this study included blinded evaluations of oxybutynin versus propantheline instillation, CAP evaluations could not be blinded and therefore, a discussion of oxybutynin versus propantheline results was undertaken separately.

Dasgupta et al. (1998) confirmed the presence of metaplasia, dysplasia, and flat carcinoma in situ after treatment with intravesical CAP. All biopsies were determined to be benign but some showed signs of chronic inflammation; this finding has been supported by a small cross-over RCT by Petersen et al. (1999). Dasgupta et al. (1998) reported that neither papillary nor solid invasive cancer was detected after 5 years of follow-up. Further surveillance is required up to 10 years when chemical carcinogenic morphologies typically present.

DeSeze et al. (2004) established that RTX was similarly effective in increasing bladder capacity when compared to CAP. CAP was significantly more effective at increasing urgency delay (p<0.01) but there was only a trend to greater maximum bladder capacity in favour of CAP. The increase in persistent clinical improvements due to RTX over CAP at 90 days follow-up was not statistically significant. Although there was also a statistically significant increase in suprapubic pain with CAP, it was clinically tolerable and brief (p<0.04).

Despite non-significant findings reported in a small non-RCT by Shin et al. (2006), the efficacy of RTX has been confirmed in one RCT (Silva et al. 2005) and two pre-post studies (Watanabe et al. 2004; Lazzeri et al. 1998). Compared to placebo, Silva et al. (2005) found that RTX was responsible for significantly increased volume of first involuntary detrusor contraction (p=0.03), maximum cystometric capacity (p=0.02), decreased urinary frequency (p=0.01) and incontinence (p=0.03) with similar side effects compared to placebo. Kim et al. (2003) confirmed the improvements in SCI bladder function and further investigated the effect of RTX dosing. Despite the small sample size in each dose category, maximum cystometric capacity at 3 weeks post-treatment increased by 53% and 48% for doses of 0.5 uM and 1.0 uM, respectively. Similarly, incontinence episodes decreased by 51.9% and 52.7%, respectively.

Conclusion

There is level 1a evidence (four RCTs; Silva et al. 2005; deSeze et al. 2004; Kim et al. 2003; deSeze et al. 1998) and three level 4 studies that the use of vanillanoid compounds (e.g., capsaicin, resiniferatoxin) increases maximum bladder capacity and decreases urinary frequency, leakages, and pressure in NDO of spinal origin.

There is level 4 evidence (from one post test study; Dasgupta et al. 1998) that intravesical capsaicin instillation in bladders of individuals with SCI does not increase the rate of common bladder cancers after 5 years of use.

Vanillanoid compounds such as capsaicin or resiniferatoxin increase maximum bladder capacity, and decrease urinary frequency, incontinence, and intradetrussor pressure in neurogenic detrusor overactivity.

Intravesical capsaicin instillation in bladders of individuals with SCI does not increase the rate of common bladder cancers after 5 years of use.