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.
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 (from 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.
