Low-Energy Shock Wave Plus Intravesical Instillation of Botulinum Toxin A for Interstitial Cystitis/Bladder Pain Syndrome: Pathophysiology and Preliminary Result of a Novel Minimally Invasive Treatment

Abstract

Low-energy shock wave (LESW) therapy is known to facilitate tissue regeneration with analgesic and anti-inflammatory effects. LESW treatment has been demonstrated to be effective in treating chronic prostatitis and pelvic pain syndrome as well as overactive bladder, and it has a potential effect on interstitial cystitis/bladder pain syndrome (IC/BPS) in humans. LESW reduces pain behavior, downregulates nerve growth factor expression, and suppresses bladder overactivity by decreasing the expression of inflammatory proteins. Previous rat IC models have shown that LESW can increase urothelial permeability, facilitate intravesical delivery of botulinum toxin A (BoNT-A), and block acetic acid-induced hyperactive bladder, suggesting that LESW might be a potential therapeutic module for relieving bladder inflammatory conditions, such as bladder oversensitivity, IC/BPS, and overactive bladder. A recent clinical trial showed that LESW monotherapy was associated with a significant reduction in pain scores and IC symptoms. BoNT-A detrusor injection or liposome-encapsulated BoNT-A instillation could also inhibit inflammation and improve IC symptoms. However, BoNT-A injection requires anesthesia and certain complications might occur. Our preliminary study using LESW plus intravesical BoNT-A instillation every week demonstrated an improvement in global response assessment without any adverse events. Moreover, an immunohistochemistry study revealed the presence of cleaved SNAP25 protein in the suburothelium of IC bladder tissue, indicating that BoNT-A could penetrate across the urothelial barrier after application of LESW. These results provide evidence for the efficacy and safety of this novel IC/BPS treatment by LESW plus BoNT-A instillation, without anesthesia, and no bladder injection. This article reviews the current evidence on LESW and LESW plus intravesical therapeutic agents on bladder disorders and the pathophysiology and pharmacological mechanism of this novel, minimally invasive treatment model for IC/BPS.

Stress-Induced Changes in Trophic Factor Expression in the Rodent Urinary Bladder: Possible Links With Angiogenesis

“…Immature angiogenesis, leading to fragile vessels and potential areas of ischemia, has previously been reported in IC/BPS and is linked to an increase in VEGF expression [ 21 , 39 ]. Previous research has suggested that increased VEGF expression in IC/BPS might be caused by hypoxia in the bladder [ 55 , 56 ], but our data did not show evidence of hypoxia in WAS rats. This might indicate that NGF-induced mast cell activation plays a more prominent role in the increased release of VEGF [ 37 ].…”

Clinical Application of Botulinum Neurotoxin in Lower-Urinary-Tract Diseases and Dysfunctions: Where Are We Now and What More Can We Do?

“…These results provide evidence for the future treatment and safety of this novel treatment modality for patients with IC/BPS using LESW plus Botox instillation without bladder injection under anesthesia injection [32].…”

“…A prior immunohistochemistry study revealed the presence of cleaved SNAP-25 protein in the IC bladder suburothelium, suggesting that Botox molecules could be carried across the urothelial cell membrane with the assistance of LESW. These results provide evidence of the efficacy and safety of this novel treatment using LESW plus Botox instillation without anesthesia or bladder injection [ 32 ].…”

“…Using LESW to increase urothelial permeability and facilitate the penetration of Botox intravesical instillation showed an early promising effect and the presence of cleaved SNAP-25 protein in the suburothelium [ 28 ]. These results provide evidence for the future treatment and safety of this novel treatment modality for patients with IC/BPS using LESW plus Botox instillation without bladder injection under anesthesia injection [ 32 ].…”

“…LESW was shown to be effective for temporarily increasing tissue permeability and the intravesical delivery of Botox for the treatment of OAB in animal studies and in a human clinical trial [ 31 ]. Our preliminary study using LESW and intravesical BoNT-A instillation every week in OAB patients also demonstrated an improvement in the Global Response Assessment without any adverse events [ 32 ]. A prior immunohistochemistry study revealed the presence of cleaved SNAP-25 protein in the IC bladder suburothelium, suggesting that Botox molecules could be carried across the urothelial cell membrane with the assistance of LESW.…”