Botulinum toxin, the most toxic naturally occurring substance, used in minute doses can be administered therapeutically. Botulinum toxin A (BTx-A) has been used for many disorders including strabismus, focal spasticity, hyperhydrosis, cosmetic disorders (wrinkles) and others.  A promising emerging use is for neurogenic detrusor overactivity treatment in individuals with SCI. The advantage of botulinum toxin over systemic administration of medications such as anti-cholinergics is the treatment of focal portions of the dysfunctional voiding process. Application of botulinum toxin focally to the detrusor directs the drug to the area of need and avoids systemic side effects. There are various types of botulinum toxin available, including various types of botulinum toxin type A. When evaluating the literature in this area, for example comparing Dysport to Botox, one must be very aware that although these medications are both botulinum toxin type A, they are very different and units cannot be compared or interchanged.

The use of capsaicin (CAP), a vanilloid, as a topical temporary analgesic is not uncommon as evidenced by over-the-counter ointments available for purchase in local pharmacies.  Localized and reversible antinociception by capsaicin is a result of induced C-fibre conduction and subsequent neuropeptide release inactivation (Dray 1992).  Although C-fibers are not involved in normal voiding, neuroplastic changes to C-fiber bladder afferent growth account for injury emergent C-fiber mediated voiding reflex (i.e., spinal detrusor hyperreflexia; (deGroat 1995)).  Resiniferatoxin (RTX) is another vanilloid which has been studied for its similar beneficial effects, with less irritation to the bladder and is thus better tolerated. By chemically decreasing C-fiber bladder afferent influence with intravesical vanilloids (i.e., CAP, RTX) bladder contractility is decreased and bladder capacity is increased (Evans 2005). 

Table: Toxin Therapy for SCI-Related Detrusor Overactivity

Discussion

Botulinum toxin

In 2005 Schurch et al., published the first multi-centre trial evaluating the efficacy of botulinum toxin A (Botox) injections into the detrusor muscle in people with SCI to reduce incontinence and increase bladder capacity. This landmark trial was the first published randomized, placebo controlled study to evaluate botulinum toxin for neurogenic overactive bladder. The study evaluated the effects of 200 IU, 300 IU, or placebo injected into the detrusor wall. The results revealed a significant decrease in incontinence by about half for both Botox groups, and a significant drop in maximum detrusor pressure. Baseline maximum detrusor pressures were 92.6cm H₂O and 77.0 cm H₂O in the 300 IU and 200 IU groups, respectively, and by 2 weeks had dropped to 41.0 cm H₂0 and 31.6 cm H₂0), respectively. Dramatic improvements were seen in cystometric capacity with baseline being 293 cc and 260cc in the 300 and 200 group respectively, and improving by 2 weeks to 479cc and 482 cc respectively. Mean reflex detrusor volume improved at 6 weeks in the 300 U BTx A group and at 24 weeks in the 200 U BTx A group (p<0.021). The significant improvements were mostly maintained out to 6 months, at which point the study follow-up was terminated - thus, the true duration of effect of the injection is unknown.

Ehren et al. (2007) studied a different form of botulinum toxin A, Dysport, using 500 IU in a placebo controlled study. These authors also found improved continence, cystometric capacity, and decreased pressures. In addition, concomitant anti-cholinergic use, tolterodine, was found to be less in the botulinum toxin group.

Schurch and colleagues (2000) were also the first group to publish a large prospective trial on the use of botulinum toxin for neurogenic detrusor overactivity to improve incontinence and increase bladder capacity.  This first trial was not placebo controlled, but given the impressive changes in objective measures such as urodynamic measures, it bears considerable significance. Pre-injection, the subjects had detrusor hyperreflexia and urge incontinence resistant to high-dose oral anticholinergic treatment and emptied their bladders by intermittent self-catheterization.  By 6 weeks post injection, ninety percent of subjects were continent between catheterizations in conjunction with markedly decreased or withdrawn anticholinergic drug administration.  Post-void residuals were significantly increased, which is the goal with people on intermittent catheterizations, and significant increases in cystometric bladder capacity as well as decreases in maximum detrusor voiding pressure were found.  Autonomic dysreflexic hypertensive crises were abolished in the 3 patients with a history of autonomic dysreflexia. This group reported that a dose of 300 units of Botox was required for successful treatment of detrusor overactivity lasting at least 9 months per injection. These results were amplified by a large scale study (n=200 - 167 with SCI) involving a retrospective case series design across 10 European centres (Reitz et al. 2004). This study showed significant improvements in a wide variety of urodynamic-related measures that were maintained for up to 36 weeks following a single procedure of botulinum toxin injections to the detrusor. Several smaller open-label studies have had similar promising results (Hajebraimi 2005, Klaphajone 2005, Patki 2006, Tow 2007, Akbar 2007, Kuo 2008, Grosse 2009, Giannantoni et al. 2009, Chen et al. 2010). In all of these studies, incontinence was reduced and bladder capacity increased with botulinum toxin. The unique aspects of each of these will be noted below.

Klaphajone (2005) addressed the question of low compliance bladders in people with SCI. People with poor bladder compliance had been excluded in previous large trials. In this open-label trial, the authors found that bladder compliance, bladder capacity, and reflex detrusor volume all increased and maximum detrusor pressure decreased. However, most of these effects were only seen out to 16 weeks and not to 36 weeks (or longer) as has been shown in other studies in people with compliant but spastic bladders. An evaluation between these two points of 16 weeks and 36 weeks would have been helpful to learn how long to expect effects to last in this type of neurogenic bladder.

Dysport, at 1000 IU, was similiarly found to have beneficial effects (Patki 2006) in an open-labelled trial of 37 people with SCI and drug resistant neurogenic detrusor overactivity. At mean follow up of 7 months the maximum cystometric capacity, maximal detrusor pressure, quality of life and incontinence were significantly improved, and 86% were able to stop anticholinergics.

Recently, Kuo (2006) evaluated the effects of suburothelial injections of botulinum toxin A instead of intradetrusor muscle injection, in hopes of reducing risk of urinary retention in those with neurogenic bladder dysfunction who continue to exhibit voiding dysfunction (frequency, urgency, and incontinence). The proposed mechanism for effect is addressing the afferent system with known effects on the P2X3 and TRYP V1 receptors, thus presumably decreasing the reflexic activity by targeting these receptors on the afferent loop. These subjects were not on intermittent catheterization at time of enrolment although perhaps some should have been as 58% of the people with SCI had baseline post-void residual values of >150ml at baseline. Only 8/24 of the subjects had SCI, and were incomplete or complete, with levels from C6 –S2. Similar beneficial effects to the other studies were seen, with 92% of subjects with SCI becoming continent, but post-void residual increased by 4 times the baseline value. Thus, although the goal of subendothelial injections was to reduce the degree of urinary retention, this goal was not achieved, and no additional benefits were seen over those seen in studies with intra-muscular injection. Head to head comparisons would be required to indicate which type of injection is better. Certainly one cannot conclude from this study that suburothelial injections protect against worsening urinary retention.

Tow et al. (2007) assessed Botox in an open-label fashion and added frequency of catheterizations to the outcomes. This was significantly improved at the 6 week point but not at 24 weeks. Other measures seen in the previous studies were similarly improved, but this study, as did the 2000 Schurch study, followed subjects for 9 months. Only the improvement in catheterized volumes was maintained to the 9 month mark, while most of the other improvements persisted only until the 6 month mark. This study was small (n=15) and not placebo controlled. Perhaps the reason for not reaching statistical significance for changes out to 9 months was small sample size, as Schurch et al. (2000) did find many of these same parameters attained significance at 9 months.

Giannantoni et al. (2009) prospectively followed 17 persons with motor complete SCI and bladder dysfunction due to neurogenic detrusor overactivity over a period of 6 years as they were treated with 300U of Botox with re-injections as required. In addition to the prolonged follow-up period, which showed continued effectiveness and minimal side effects associated with ongoing treatment, this investigation incorporated an assessment of incontinence-related quality of life. Improvements in this measure were maintained throughout the treatment period.

Akbar et al. (2007) used Dysport in an open-label fashion with the objective of reporting effects of repeated use of botulinum toxin to the detrusor. Some of these patients had systemic weakness after injections of 1000 IU, but when reducing the dose to 750 IU this side effect subsided. The subjects were reinjected with botulinum toxin when their symptoms returned or when urodynamic studies revealed a return to baseline. The repeat injections were 7.8-8.0 months apart for the first 3 injections, then 9 months for the subsequent injection, although fewer patients continued in the study to this point (11 as compared to 41 receiving 3 injections). Compliance, maximum detrusor pressure, and capacity all improved significantly with respect to baseline with all reinjections. All these numbers showed a slight gradual improvement with each subsequent injection, but statistical analysis was not performed to show if this modest improvement was significant.

Hori (2008) addressed patient satisfaction with detrusor injections of botulinum toxin A by way of a 5-minute questionnaire conducted via telephone. 90% of people who had botulinum toxin A injections for neurogenic detrusor overactivity stated they would consider staying on this treatment long-term. This group has had low annual withdrawal rate from this long-term treatment and a high annual new patient starting rate, prompting the authors to conclude that health care systems would be advised to incorporate this new treatment option as part of routine service provision.

A retrospective trial (Grosse 2009) compared the effects of Dysport (BTX-A) in doses 500-1000 IU to Botox in doses 200-400 IU. The different doses of Dysport had no difference at follow up of 3.8 months, and comparison of the Dysport group to the Botox group revealed no difference at 3 months. Although the effect lasted 9.5 months in the Dysport 500 group compared to 16.1 months in the Dysport 1000 group, this was not judged to be statistically significant, but seems to have clinical significance. The difference does raise the question of whether larger dosing may have longer lasting effects, and certainly has potential for future studies. Note in this study 9/28 in Dysport group did not respond compared to 7/28 in the Botox group. One subject who received Dysport 750 IU experienced transient hypoasthenia.

Capsaicin

deSeze et al. (1998) has provided level 1 evidence in support of the ability of CAP to improve bladder function (decrease frequency and leakages) by increasing bladder capacity.  These authors found that 30 days after instillation, CAP was superior to placebo in decreasing 24h voiding freq (p=0.016), decreasing 24h leakages (p=0.0008), increasing maximal cystometric capacity (p=0.01), and decreasing maximal detrusor pressure, although not significantly.  They found similar side effects in each group. This corroborates other small, non-RCT studies that also reported significant CAP-induced increases in bladder capacity (Das et al. 1996; Dasgupta et al. 1998).

George et al. (2007) reported use of a capsaicin one time instillation and reported that the “efficacy” of 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 capsaicin 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 patients following CAP. Although this study included blinded evaluations of oxybutynin vs propantheline instillation, CAP evaluations could not be blinded and therefore, discussion of oxybutynin vs propantheline results are undertaken separately. 

The Dasgupta group (1998) confirmed presence of metaplasia, dysplasia, flat carcinoma in situ.  However, papillary or solid invasive cancer were not detected after 5 years of follow-up.   Further surveillance is required up to 10 years when chemical carcinogenic morphologies typically present.

Resiniferotoxin

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.  There was also a statistically significant increase with CAP for the side effect, suprapubic pain, although it was clinically tolerable and brief (p<0.04).  The increase in persistent clinical improvements due to RTX over CAP at 90 days follow-up was not statistically significant.

The efficacy of RTX vs placebo was confirmed in an RCT conducted by Silva et al. (2005) where they found that RTX was responsible for significantly increased volume of first involuntary detrusor contraction (FDC; 143±95mL vs184±93mL; p=0.03), maximum cystometric capacity (MCC; 115±61mL vs 204±92mL; p=0.02), decreased urinary frequency (p=0.01) and incontinence (p=0.03) with similar side effects as compared to placebo. Kim et al. (2003) confirmed the improvements in SCI bladder function and further investigated the effect of dose (single 100 ml instillation of 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, 1.0 microM RTX or placebo).  Despite the small sample size in each dose category, MCC increased by 53% and 48% for the two highest dosages by 3 weeks post-treatment.  Similarly, incontinence episodes decreased by 51.9% and 52.7%. 

Nociception/orphanin phenylalanine glutamine

Nociception/orphanin phenylalanine glutamine (N/OFG) is a heptadecapeptide (Meunier et al. 1995; Reinscheid et al. 1995) that acts on sensory innvervation of the lower urinary tract in a similar fashion to CAP and RTX. It activates the G protein coupled receptor nociceptin orphan peptide and thus has an inhibitory effect on the micturition reflex in the rat (Lecci et al. 2000).  Following a successful preliminary human study, Lazzeri et al. (2003) confirmed that N/OFG versus placebo is responsible for a significant increase in bladder capacity (p<0.001) and threshold volume of detrusor overactivity (p<0.001), and a non-significant decrease of maximum bladder pressure of the dysfunctional neurogenic bladder. These results were verified in an additional small-scale RCT (n=18) of a 10 day course of N/OFG treatment vs placebo (saline). Statistically significant improvements to bladder capacity (assessed by daily voiding diary) and urine leakage episodes were seen in the treated group but not with placebo (Lazzeri et al. 2006). The authors conclude that this inhibition of the micturition reflex supports nociceptin orphan peptide receptor agonists as a possible new treatment for neurogenic bladders of SCI patients.

Conclusion

• Level 1 evidence based on two RCTs supports the use of Botox A injections into the detrusor muscle to provide targeted treatment for neurogenic detrusor overactivity and urge incontinence resistant to high-dose oral anticholinergic treatments with intermittent self-catheterization in SCI.  Numerous level 3 and 4 studies confirm the efficacy and safety. 
• Level 1 evidence supports the use of vanillanoid compounds such as capsaicin or resiniferatoxin to increase maximum bladder capacity and decrease urinary frequency and leakages in neurogenic detrusor overactivity of spinal origin.
• Level 4 evidence exists to suggest that intravesical capsaicin instillation in bladders of SCI individuals does not increase the rate of common bladder cancers after 5 years of use. 
• Level 1 evidence based on two small-scale RCTs supports the use of N/OFG, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

• Overall botulinum toxin for neurogenic detrusor overactivity in SCI is effective in reducing incontinence and excessive bladder pressure while improving bladder capacity for those resistant to, or intolerant of, oral anticholinergics.
• Capsaicin seems to have some clinical benefits but the side effects of pain and AD are concerning for clinical use. Resiniferotoxin seems to be tolerated much better and has similar improvements therapeutically. Pharmaceutical formulation difficulties make it unavailable for clinical use at present.