Comparative Study of the Efficacy and Safety Between Suburothelial and Trigonal Intravesical Botulinum Toxin A Injection in Treatment of Interstitial Cystitis Refractory to Conventional Treatment - A Prospective, Randomized, Clinical Trial

Introduction Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic disease of unknown etiology characterized by urgency frequency and suprapubic pain at full bladder. Current treatments are usually unsuccessful in completely eradicating bladder pain and increasing bladder capacity. Intravesical resiniferatoxin once was considered to be effective but this has not been shown in a large scale multiple center trial. Several oral medication such as pentosanpolysulphate (PPS), amitryptynine, cyclosporin have been tried but the therapeutic efficacy have been proven ineffective. Intravesical treatment with heparin, hyaluronic acid, chondroitin sulphate, bacillus Calmette-Guerin, dimethylsulphoxide, resiniferatoxin, or botulinum toxin A has been shown early effectiveness in some patients. However, the placebo effect should be weighed and randomized, double-blind trials should be undertaken to demonstrate the actual therapeutic effects of these therapeutic modalities.

Although botulinum toxin type A (BoNT-A) has been widely reported in its efficacy in the treatment of neurogenic and idiopathic detrusor overactivity (DO) with satisfactory results, there have only been few studies using BoNT-A in treatment of IC/PBS. In recent basic researches, BoNT-A has been shown to inhibit not only the release of acetylcholine and norepinephrine, but also that of nerve growth factor, adenosine triphosphate, substance P and calcitonin gene-related peptide from the nerve fibers and urothelium. In clinical experiments, BoNT-A has been shown to reduce DO, impaired bladder sensation, and decrease visceral pain in chronic inflammatory diseases. These results suggest that BoNT-A treatment can modulate sensory transmission as well as reduce detrusor contractility. Although BoNT-A injection seems promising in treating symptoms of IC/PBS, long term results did not provide successful outcome. The limited successful result is possibly due to inadequate distribution of BoNT-A delivered to the bladder wall, inadequate dose of toxin, or lacking of some promoting factors to enhance the therapeutic effect of BoNT-A. Repeated intravesical BoNT-A injections was recently performed in refractory IC/PBS and the therapeutic effects seems promising. About 70% of the patients with non-ulcer type IC/PBS may benefit from repeated BoNT-A injections every 6 months. Immunohistochemistry study also confirmed the reduction of inflammatory biomarkers and pro-apoptotic proteins such as Bax and Bad expressions after repeated BoNT-A injections.

Concerning the injection sites of BoNT-A for IC/BPS bladders, there is no consensus. Suburothelial injection and Trigonal injection have all been used in treatment of IC/BPS and the short-term and long-term results are equivalent. It is unmet to clarify which injection method is superior in clinical efficacy and patient safety. This study was designed in a randomized, double-blind trial to test the therapeutic effects and adverse events between intravesical BoNTA injection into suburothelium and trigone. The results of this study might provide clinical evidence for a better therapeutic regimen of BoNT-A in the treatment of IC/PBS.

Materials and Methods

A total of 60 patients with IC/PBS who have failed previous treatments for at least 6 months will be enrolled in this study. A diagnosis of IC/PBS has been established based on characteristic symptoms and cystoscopic findings of glomerulations, petechia, or mucosal fissures after hydrodistention. All patients have been treated with at least two types of treatment modalities including non-steroid anti-inflammatory drugs, oral PPS, intravesical instillation of heparin, hyaluronic acid, or tricyclic antidepressant for at least 6 months but the symptoms remained unchanged or relapsed. They will be investigated thoroughly on enrollment and will be excluded if not meeting the inclusion criteria of NIDDK. However, in this study the patients with Hunner's ulcer will not be included because previous study has shown that ulcer type IC/BPS does not respond to intravesical BoNT-A injection.