Ketamine cystitis is a growing global problem afflicting predominantly young patients and exposing them to significant risk of bladder damage with unknown long-term consequences. To-date, there has been little research into the pathology of ketamine cystitis and as a result, the mechanism(s) of the bladder pain and damage remain unknown. This histological study observed expansion of the basal NGFR+ labelling, stromal nerve hyperplasia and the occurrence of superficial neuroma-like lesions which likely contribute to the extreme bladder pain experienced by ketamine cystitis patients.
The discovery of numerous fine NFP+ nerve fibres throughout the stroma of ketamine cystitis tissues is unusual and to our knowledge has not been previously described. The presence of nerve hyperplasia in ketamine cystitis tissue in conjunction with urothelial damage leading to stromal urine exposure may help to account for the extreme pain experienced by ketamine cystitis patients. Understanding the mechanism of pain in ketamine cystitis is critical to developing effective new treatment strategies since at present, many ketamine users self-manage their pain with increased ketamine use. The current lack of effective clinical pain management for these patients is a key obstacle to cessation of use [2]. In neuropathic bladders, there have been reports of nerve hyperplasia invading the urothelium [13]; however, no NFP+ fibres were observed within the urothelium in this study. In the small group of IC patients studied here only a single sample contained visible NFP+ fibres in the lamina propria. That this NFP+ IC patient may have been an undisclosed ketamine user cannot be ruled out; however, the potential utility of NFP as a biomarker for an IC subgroup with similarities of pathogenesis to ketamine cystitis warrants further investigation. Based on current knowledge, the discovery of NFP+ fibres in the bladder stroma may be a useful, if not unequivocal, clinical biomarker of ketamine cystitis in patients who have non-bacterial cystitis, but do not provide a history of drug use.
A further novel, and apparently unique, feature of ketamine cystitis reported here is the appearance of large peripheral nerve fascicles in the lamina propria, with a predominant Schwannian and perineural component, and some resemblance to a Morton’s neuroma. These lesions appear to arise as a hyperplastic/reactive response and may be consequential to interstitial regeneration following ketamine damage. At present, it is unclear how these changes relate to the degree of pain experienced in these patients; however, they appeared in nearly all (20/21) urology-referred ketamine cystitis patients in this study and were not seen in the other bladder pathologies studied as controls.
The cause of peripheral nerve fascicle hyperplasia in ketamine cystitis tissues remains unknown; however, chronic ketamine users (of at least 4 times/week) have on average twice the serum concentration of brain-derived neurotrophic factor (BDNF) when compared with a control group [14]. Further study of ketamine cystitis will need to address whether the cause of nerve fascicle hyperplasia is the direct action of ketamine and/or its metabolites; or alternatively, whether circulating BDNF could be the causative agent.
The role of NGFR in the urothelium remains an interesting unknown; however, in RP/IDO/SUI tissues it is most commonly confined to basal urothelial cells. The expansion of NGFR+ might be indicative of a general dedifferentiation of the tissues; however, no change was noted for other basal markers (eg CK5) and there was no disruption of differentiation markers such as uroplakin 3a (data not shown). Previous studies have reported increased Ki67 indices in ketamine cystitis urothelium [7] and interpreted with the supra-basal NGFR+ expansion reported here, this might suggest changes in the epithelium towards a regenerative wound-healing phenotype. This concept is consistent with the widespread urothelial damage observed in ketamine cystitis and retention of uroplakin labelling suggests the urothelium retains a functional barrier in areas where it remains full-thickness. During cystoscopy of one patient the urothelium was observed desquamating from the basement membrane as large sheets, which was consistent with finding histologically that areas of intact full-thickness urothelium were directly adjacent to areas of absent urothelium. Whether the mechanism of urothelial loss relates to direct toxicity of ketamine or the action of a metabolite requires further study.
Whilst ketamine was originally described as a NMDA receptor antagonist, this is a gross oversimplification of its binding promiscuity, which includes activity against β-adrenergic, sigma, and muscarinic receptors [15]. Recent interest in using ketamine as a rapid-onset anti-depressant and pressure to drive derivatives to market quickly (reviewed [16]), make understanding the mechanism of ketamine cystitis an urgent clinical problem to avoid side-effects in future therapeutics.