Hypothesis / aims of study
Ketamine has been used clinically as an anaesthetic agent in human and veterinary medicine for several decades. The dissociative symptoms, ease of use, fast onset and short half-life, and low costs made ketamine an appealing recreational drug, with a strong increase in recreational use in the past decade. In the Netherlands, the amount of people using ketamine as a recreational drug has more than doubled in the last 5 years, with a total estimated amount of 30,000 people using it on a regular basis.[1]
Less known to its users, ketamine abuse can lead to inflammation of the bladder (ketamine-induced cystitis) and upper urinary tract. Patients experience severe lower urinary tract symptoms (LUTS), including debilitating pain and gross haematuria. The consequential decrease in bladder compliance and thickening of the bladder wall can cause ureteral obstruction and eventually the development of renal insufficiency. The upper tract itself may also be involved in the inflammatory process.
An international guideline or disease management protocol does not yet exist. In this study, we describe our experiences with the first dedicated outpatient clinic for ketamine uropathy in the Netherlands, in which we manage patients according to a standard diagnosis and treatment protocol.
The aim of this study is to describe the experiences from our clinic and the first clinical outcomes.
Study design, materials and methods
In this prospective cohort study all new patients who visited our dedicated outpatient clinic for ketamine uropathy between January 2022 and December 2022 were included. Patients were referred to our clinic by their general practitioner or addiction specialist after reporting LUTS along their ketamine abuse. Figure 1 shows the flow-chart of our standard ketamine uropathy diagnosis and disease management protocol.
The protocol was designed based on the limited current knowledge on the disease course and pathophysiology of ketamine uropathy.
Next to a general assessment of LUTS, the priority in the diagnostic evaluation is to exclude the presence of upper urinary tract involvement and LUT risk factors for development of renal insufficiency. Further diagnostic evaluation is tailored to the patient based on this assessment.
Regardless of further diagnostics, all patients are counselled about the risks of ketamine on urinary tract function and the absolute necessity to abstain from ketamine in order to decrease symptoms and to avoid further disease progression. Patients are prescribed analgesics and anti-inflammatories (if no renal insufficiency) combined with antimuscarinics and/or a beta-3-adreno receptor agonist.
Patients are re-evaluated three months after treatment start. Patients succeeding in ketamine abstinence, but with ongoing LUTS, received further diagnostic tests prior to treatment escalation with intravesical glycosaminoglycan-therapy, botulinum toxin and/or laser coagulation of bladder ulcers.
Results
Since the start of our dedicated outpatient clinic for ketamine uropathy, we have evaluated and treated 36 new patients. Patient characteristics are presented in figure 2.
All 36 patients were counselled about the importance of ketamine abstinence and received a prescription for analgesics and bladder relaxants. Five patients did not attend the 3 month evaluation and were considered lost to follow-up.
Of the 31 remaining patients, four (13%) had hydronephrosis on ultrasound or CT urography. Blood tests revealed renal insufficiency in two patients. Renography in 3 patients showed (partial) bilateral upper tract obstruction. Video-urodynamic study in 1 patient showed a reduced bladder compliance without vesico-ureteral reflux. The patients with renal insufficiency received upper urinary tract drainage with nephrostomy and remain in follow-up.
After 3 months, 26 patients (72%) succeeded in ketamine abstinence. Of these patients, 17 (65%) experienced a (partial) resolution of their symptoms and did not require treatment continuation with analgesics, anti-inflammatories and bladder relaxants. Six (23%) patients also experienced partial symptom resolution, but preferred treatment continuation. Only three patients (12%) remained symptomatic despite ketamine abstinence. Cystoscopy showed bladder ulcers in all three patients and urodynamics showed detrusor overactivity in two of them. They were treated with laser coagulation of bladder ulcers and botulinum toxin in case of detrusor overactivity. Further follow-up has been planned.
The 5 patients who failed to abstain from ketamine all asked further guidance, help and supporting medication.
Interpretation of results
In this prospective cohort study we present the results of the first dedicated outpatient clinic for ketamine uropathy in the Netherlands, where patients are approached by a standard diagnosis and treatment protocol. Recent studies suggest that treatment of ketamine uropathy should be tailored to the patient, based on their individuality as well as on the specific symptoms and findings.[2,3] To our knowledge this is the first standard protocol combining both diagnostic evaluation and subsequent tailored treatment for patients suffering from ketamine uropathy.
The keystone in the treatment of ketamine uropathy is complete cessation of ketamine abuse. Our results show that over 65% of the patients who successfully abstain from ketamine, experience (partial) resolution of their symptoms and do not desire further support by medication within 3 months of follow-up. Furthermore, only 12% remained symptomatic despite ketamine abstinence and they had clear underlying conditions on cystoscopy / video-urodynamics explaining the persisting symptoms. In comparison, none of the patients who continued ketamine abuse had a decrease in symptoms. Ketamine abstinence is very difficult to achieve because of the addictive nature of the drug, combined with its analgesic effect. Therefore, most patients experience a short-term increase in symptoms after ceasing ketamine use. The combination of analgesics, anti-inflammatories and bladder relaxants, as offered upon cessation of ketamine abuse in our protocol, are aimed at symptom relief and hence to increase success chance of sustained abstinence. Furthermore, we believe that the multidisciplinary approach of our clinic, combining the expertise of a urologist to treat and control the urinary tract, and the expertise of addiction specialists to aid in abstinence, is a unique strength which may further increase the success rate of treatment of ketamine uropathy .
It is worrying that 13% of our patients also had upper tract dilatation and two patients (6%) even had renal insufficiency. As illustrated in our protocol, next to immediate cessation of ketamine, these patients require a different, more aggressive treatment approach aimed to preserve (remaining) renal function. Furthermore, these patients typically have advanced LUT dysfunction which, if irreversible, may require them to have a urinary diversion with or without cystectomy. Longer follow-up will reveal whether our patients with renal insufficiency fully recover.