The impetus for this talk was the increased utilization of ketamine for treatment-resistant depression (IV Ketamine can have a rapid antidepressant effect within 24 hours in patients with major depression) – and in the era of opioid addiction, a potential treatment for pain. Just recently, the FDA approved nasal spray of ketamine for treatment of depression – with limited availability.
Ketamine is an NMDA receptor antagonist, first used in 1965 in humans. It has analgesia and dissociative properties, and provides amnesia to pain. It has been used in palliative care medicine more often. It has a rapid onset and short duration of action. It is metabolized by the liver and excreted in the kidneys – hence its impact on the urinary tract.
Ketamine has been illegally used since the 1980s to provide an “out of body” / “near death” experience – and while it does not generate a physiologic dependence, it does cause psychologic dependence. This results in increased dosages and increased frequency of use.
She then commented on the Hong Kong epidemic experience. Starting in the 1980’s, ketamine began to be very actively used by the younger population. Over 2000 drug abusers per year were reported by the early 2000’s.
Dr. Chu first encountered this when a husband/wife pair presented to her clinic in December 2006 with severe pelvic pain, dysuria, and urinary urgency/frequency. Both had deteriorated renal function, and on cystoscopy, she noted an inflamed mucosa, biopsied for cystitis glandularis, and bilateral hydronephrosis. Impressively, despite being 25 and 23 years old respectively, their functional bladder capacities were 50 and 30 mL. After much digging into their history, he was a ketamine abuser for 7 years – and after his marriage, she began to use ketamine and had used it for 4 years.
They then completed a survey of ketamine users to assess lower urinary tract symptoms. They found that ~30% reported similar symptoms (despite being younger in age), and some were even diaper dependent. Urine cultures demonstrated sterile pyuria. They were often treated empirically with antibiotics multiple times by family physicians. They reported this phenomenon in the Hong Kong Journal of Medicine in 2007 – to help educate the lay practitioner about this new entity. Of the 10 cases they reported in that study, ~50% had bilateral hydronephrosis, most had altered renal function, and most were 20-30 years old.
Their study set off a slew of other studies from other countries (UK, Canada, Belgium, China, US) that reported similar findings. However, the study in the UK, which specifically looked at the effects in patients treated for palliative purposes helped identify the fact that it was ketamine itself (and not a contamination in the street formulation) that led to these effects.
The rest of her talk was primarily anecdotal:
- Bladder malignancies can present in ketamine abusers – two case reports, including a yolk sac tumor of the bladder and leiomyosarcoma, were reported. Both required cystectomy and both died within 3 years.
- Ketamine effect, by comparing ketamine users to non-users, appears to be on small and large vessels – specific ischemic damage to the bladder
- Ketamine-induced apoptosis has also been reported as a potential pathway to disease in urothelial tissue – by Simon Baker and colleagues
- In the kidney, evaluation of renal histology in ketamine users has identified loss of cell-to-cell adhesion in the proximal tubules, and she has seen sclerosed glomeruli on final pathology
She has worked with her anesthesia colleagues to develop a superior hypogastric nerve block in conjunction with RF ablation to help some patients with pain – but doesn’t work in all patients. In some patients, who have demonstrated the ability to abstain, she has worked on urinary tract reconstruction – including bladder augmentation, ureteral interposition, etc.
A pitfall with bladder augmentation cystoplasty is that, if the patient relapses, then the ketamine gets excreted in the urine and reabsorbed through the bowel mucosa – and increases blood concentration of ketamine. This can have serious consequences and lead to renal failure! So, it should only be done carefully in patients who have demonstrated commitment. Also, she reports having done gastric bladder augmentation – as this is less likely to reabsorb!
A recent mouse study may help make all of this moot however. Lee SW et al. demonstrated that injection of mesenchymal stem cells in mice with IVI ketamine helped improve outcomes – and may be an option in the future.1
However, her most important contribution is her work in changing Hong Kong legislation and efforts to combat the ketamine epidemic. Based on the work of urologists, penalties for ketamine use were increased and an effort was made to reach the public re: the effects of ketamine. She is happy to report that due to those efforts, in 2017, the number of reported ketamine users in Hong Kong have plummeted to almost zero.
This story highlights the importance of clinical research in conjunction with patient outreach and legislative efforts to impact population health and fight an epidemic!
Presented by: Peggy Chu, Tuen Mun Hospital, Hong Kong
Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois
1. Lee SW, Ryu CM, Shin JH, et al. The Therapeutic Effect of Human Embryonic Stem Cell-Derived Multipotent Mesenchymal Stem Cells on Chemical-Induced Cystitis in Rats. Int Neurourol J. 2018 Jan;22(Suppl 1):S34-45. doi: 10.5213/inj.1836014.007. Epub 2018 Jan 31.