Treatment of painful bladder syndrome/interstitial cystitis with botulinum toxin A: why isn't it effective in all patients?

Abstract

Botulinum toxin A (BTA) is currently used to treat a variety of painful disorders, including painful bladder syndrome/interstitial cystitis (PBS/IC). However, BTA is not consistently effective in all patients. This may be due to the disparity of causes of pain, but this may also relate to the processes by which BTA exerts anti-nociceptive effects. This review discusses mechanisms by which BTA may inhibit pain and studies of the use of BTA in PSB/IC patients. It is doubtful that any single treatment will effectively control pain in PBS/IC patients, and it is highly probable that multiple strategies will be required, both within individual patients and across the population of PBS/IC patients. The purpose of this review is to discuss those mechanisms by which BTA acts, with the intent that alternative strategies exploiting these mechanism, or work through alternative pathways, can be identified to more effectively treat pain in PBS/IC patients in the future.

Keywords: Painful bladder syndrome/interstitial cystitis (PBS/IC); botulinum toxin A (BTA); treatment.

Figure 1

BTA entry and mechanism of action. BTA binds with low affinity to polysialogangliosides on the surface of the cell, and with high affinity to synaptic vesicle protein SV2. After endocytosis, the light chain is cleaved and released into the cystosol, where it cleaves SNAP-25 thereby disrupting SNARE-dependent exocytosis of neurotransmitters and receptor trafficking to the plasma membrane. BTA decreases neurogenic inflammation by blocking NGF and neuropeptide (CGRP and SP) release from afferent nerves. It also disrupts receptor trafficking to the plasma membrane (TRPV1, P2X3). ATP, adenosine triphosphate; ACh, acetylcholine; CGRP, calcitonin gene-related peptide; SP, substance P; NGF, nerve growth factor; BTA, botulinum toxin A; SV2, synaptic vesicle protein 2.

Figure 2

BTA dampens afferent input. This occurs by both direct (blocking of ATP release in response to stretch), and indirect mechanisms (normalizing NO release, while preventing increased TRPV1/P2X3 receptor expression and NGF-mediated increase in excitability and innervation density). Increased NO release may act via myofibroblasts to attenuate afferent activity. However, the effects of BTA on NO release may be context-dependent, varying among LUT disorders. BTA, botulinum toxin A; NGF, nerve growth factor; ATP, adenosine triphosphate; ACh, acetylcholine; NO, nitric oxide.