By: Pallak Sharma, PharmD Candidate c/o 2022 and Mia Cord-Cruz, PharmD Candidate c/o 2022

              Ketamine (Ketalar®) is currently approved by the Food and Drug Administration (FDA) for use as a general anesthetic, with additional indications listed within its package insert.¹ Ketamine is a highly abused “street drug”, especially in China. To demonstrate, in Hong Kong it has remained atop the list for most commonly abused psychotropic drugs since 2001. Between the years 2004 and 2013, ketamine was the most abused psychotropic drug with a peak of over 5000 abusers in 2009, according to the Hong Kong Central Registry of Drug Abuse Sixty-third Report. A small-scale survey conducted by a psychotropic substance rehabilitation center in Hong Kong reported that lower urinary tract symptoms (LUTS) were experienced in approximately 30% of ketamine abusers.² Prior to these small-scale surveys, cystitis induced from ketamine was a less commonly known adverse event, being that most patients who abuse ketamine also abuse other substances, and may not seek medical care until severe symptoms are present .²

The onset of ketamine cystitis results from ketamine abuse and it is rarely associated with the medically prescribed use of ketamine. The onset of LUTS can occur within a few days to a few years after ketamine use, and it is unclear if this is a dose-dependent adverse event.³  Researchers from Hong Kong have concluded that the exact prevalence of ketamine cystitis is difficult to quantify being that most patients who abuse ketamine allow symptoms to become more severe before seeking care.²

Ketamine is produced as a racemic mixture of the (R) and (S) enantiomers. A pharmacologic review explains that the (S) enantiomer of ketamine (esketamine) is more potent than the (R) enantiomer. When ketamine is used as a street drug, it is generally crushed in order to snort the drug for faster onset of its effects. According to studies conducted on the ketamine metabolites, (S)-ketamine contributes to illusions and alterations in hearing, vision, and proprioception whereas (R)-ketamine contributes to feelings of relaxation and “well-being”. The (S)-enantiomer, especially, caused acute psychotic reactions whereas the (R)-enantiomer did not. When ketamine is abused, the most common route of administration is nasal insufflation. This route provides an onset of feeling “high” ranging between 5 and 10 minutes and lasting between 40 and 75 minutes. It is reported that ketamine induces a highly dissociative experience marked by an altered state of consciousness and sensory detachment at peak levels of intake. Some users describe this as being comparable to a near-death experience.⁴

Racemic ketamine [(R,S)-KET] is initially metabolized via nitrogen demethylation to norketamine [(R,S)-norKET], primarily by enzymes CYP2B6 and CYP3A4. Norketamine can then be further metabolized to form dehydronorketamine (DHNK) or the hydroxynorketamines (HNKs). Another metabolic pathway of ketamine is the direct hydroxylation of ketamine to 6-hydroxyketamine (HK). Approximately 80% of ketamine is excreted as the glucuronic acid-labile conjugates of HK and HNK which are eliminated in urine and bile.⁴

The exact pathophysiology of ketamine cystitis is unknown, however, there are four proposed mechanisms that attempt to explain the urinary tract damage. These mechanisms were determined through retrospective analysis of 59 patients who abused ketamine, who were referred to the urology units of Princess Margaret and Tuen Mun Hospital, located in Hong Kong, from March 2000 to December 2007. The clinical presentations, pelvic pain and urgency/frequency scores, video-urodynamic studies, cystoscopy and radiological findings, and histological features of bladder biopsies of these 59 patients were gathered to propose these mechanisms.

The first proposed mechanism involves the direct effect of high concentrations of ketamine or its metabolites on bladder interstitial tissues. This may result in chronic submucosal inflammation. The inflammation could cause severe dysuria and diminished bladder capacity via submucosal edema, vascular ectasia, fibrosis, detrusor muscle inflammation, and fibrosis. Individuals who abuse chronic high doses of ketamine may even exhibit papillary necrosis due to irreversible toxicity effects on the papillary medullary interstitial cells. The damage to these cells can result in chronic renal insufficiency via interstitial fibrosis and structural damage. This is the same model used to explain aspirin-induced nephropathy.⁵

The second proposed mechanism involves microvascular changes in the bladder and possibly in the kidneys, induced by ketamine and/or ketamine metabolites. These microvascular changes may cause endothelial cell injury of microvessels which may lead to either compromised intrinsic microcirculation or decreased microvascular density in the sub-endothelium. This proposed mechanism is supported by cystoscopic findings of neovascularization. Severe suprapubic pain and dysuria (pain on urination) may be accounted for by bladder ischemia during bladder filling. When bladder ischemia is present, interstitial fibrosis and diminished bladder capacity can occur over time. Micro-angiopathy or capillary sclerosis in the renal medulla resulting in hypoperfusion of the papilla can be induced by papillary necrosis. Papillary necrosis induced by diabetes or analgesic nephropathy may exhibit similar pathophysiology to papillary necrosis seen in ketamine cystitis.⁵

The third proposed mechanism entails an indirect effect of ketamine. An autoimmune reaction against the bladder urothelium and submucosa, due to circulating ketamine or urinary ketamine and its metabolites, may result in ketamine cystitis. This autoimmune reaction may explain raised erythrocyte sedimentation rate (ESR) and the complements (C3/C4) found in some patients. Vascular congestion, submucosal edema, and scarring result from the autoimmune-mediated reaction. This may lead to diminished bladder capacity and poor compliance (the ability of the bladder to accommodate large volumes of urine).⁵

The final proposed mechanism of ketamine cystitis is bacterial infection. However, it is stated that a bacterial infection is an unlikely cause for ketamine cystitis and papillary necrosis since the patients studied did not present with bacterial cystitis. Of all of the patients studied, only two patients subsequently had a positive bacterial culture due to a concomitant bacterial urinary tract infection. No patients showed improvement with antibiotic treatments.⁵

Risk factors of ketamine cystitis are difficult to determine being that this unique condition has not been well studied and its exact mechanism is still unclear. However, a 2020 systematic review detailing ketamine-induced uropathy provides some potential insight regarding risk factors. The epidemiologic studies that were conducted revealed common trends and characteristics that are related to risk factors. It was determined that urologic injury may be dose-related, and may be related to an increased frequency of use and long-term abuse. Ketamine that is insufflated, or snorted, appeared to result in the development of more severe symptoms than smoking would cause. This systematic review also highlights that concomitant use of other substances is common in 35% of users, and these substances commonly include cocaine, heroin, cannabis, ecstasy, and alcohol.⁶ Of note, ketamine cystitis is commonly seen in younger patients (16-35 years old), as it coincides with the general age of patients who abuse ketamine.⁷

Across databases, such as UpToDate⁸, Micromedex⁹, and AHFS Essentials located within Lexicomp¹⁰, general urologic injury and cystitis are listed as adverse effects of chronic ketamine abuse. AHFS Essentials also references cystitis as a potential risk of long-term exposure that should be considered when undergoing ketamine infusion therapy for mood disorders.¹⁰ The drug monograph for esketamine (Spravato ®) found on UpToDate and Lexicomp lists ulcerative and interstitial cystitis under warnings and precautions. Further discussion reveals that ulcerative cystitis cases have been reported in individuals with long-term off-label use or misuse/abuse of ketamine.^8,10 Lexicomp also states that while clinical trials have shown higher rates of LUTS, they had not shown any cases of esketamine-related interstitial cystitis in patients treated for up to one year.¹⁰

There are various treatment modalities that can be employed for the management of ketamine cystitis, ranging from complete cessation of ketamine to pharmacologic interventions to even surgical interventions. These treatment modalities have been developed through trials of therapy with each unique patient case. It is important to note that the treatment of ketamine-associated cystitis depends on the severity of the disease. In all cases, the first-line, and mainstay, of treatment begins with ketamine cessation. In mild cases, cessation alone may even be sufficient.⁶  

Since ketamine cystitis is rare, and the mechanism of injury is still being investigated, treatment modalities focus on symptom management. First-line medications include a trial of non-steroidal anti-inflammatory drugs (ex: diclofenac) and anticholinergic agents (ex: solifenacin), followed by tramadol in the case of a partial response to these initial agents.⁶ One study showed that high dose antimuscarinics (oxybutynin 10mg by mouth three times daily or tolterodine 4mg by mouth twice daily) had no response.⁵ A separate study demonstrated that anti-inflammatory agents or corticosteroids may only achieve a partial response and are not curative.¹¹ Second-line options include re-epithelization, intravesical injection, bladder hydrodistension, or oral pentosan polysulfate sodium (Elmiron®).⁶ Pentosan polysulfate appears to adhere to the bladder wall mucosa where it may act as a buffer to protect the tissues from irritating substances in the urine which may play a role in treating interstitial cystitis. Pentosan polysulfate sodium is standardly dosed at 100 mg by mouth three times daily for cases of cystitis.¹² Surgery is also an available option as a last-line treatment for patients with late-phase disease after failing all other options. Surgical options include partial cystectomy, reconstruction, and augmentation enterocystoplasty. These procedures are performed in order to reduce inflammation and preserve micturition, as well as to improve bladder capacity and decrease pressure. However, relapse in ketamine use will more often than not result in symptom relapse.⁶

Published case reports support the current treatment recommendations for ketamine cystitis. Shahani et al was the first article published regarding ketamine-associated ulcerative cystitis. One case provided details of a 28-year-old male who presented with a six-month history of urinary symptoms that began shortly after the daily use of ketamine. The patient was unresponsive to both antibiotic and steroid therapy, while cessation of ketamine reduced some, but not all symptoms. This article also mentions the case of a 25-year-old female presenting with a two-year history of urinary symptoms associated with initial ketamine use. Here, ketamine cessation was successful in that the patient had marked improvements in symptoms. Another patient, a 17-year-old male, presented with recurrent episodes of urinary symptoms over the span of several months associated with ketamine use. However, in this case, discontinuation of ketamine had no effect and pentosan polysulfate therapy was needed to relieve irritative symptoms.¹³ Another case report involved a 52-year-old man presenting with a 10-year history of urinary symptoms and approximately 30 years of ketamine abuse. Interstitial cystitis was suspected and following the cessation of ketamine for six months and hydrodistension of the bladder, his symptoms improved gradually.¹⁴ For reference, hydrodistension is a procedure by which the bladder is filled with water in order to determine the diagnosis of any urinary symptoms.¹⁷ A final case report detailed a 25-year-old male with a four-year history of ketamine abuse presenting with refractory dysuria, gross hematuria, and frequent urination who was diagnosed with ketamine-associated ulcerative cystitis. An antibiotic course did not provide any improvement nor did treatment with pentosan polysulfate sodium, an antihistamine, or a corticosteroid. This patient required augmenting enterocystoplasty for his severe, disabling frequent urination.¹⁵ Enterocystoplasty, otherwise known as bladder augmentation, is a surgical procedure during which a portion of the intestine is excised, then attached to the bladder in an effort to enlarge the bladder and alleviate urinary symptoms.

A small randomized control trial found that the use of botulinum toxin A injections in combination with bladder hydrodistension was an effective form of management for ketamine cystitis. In this study, thirty-six patients (30 males and 6 females) between ages 19-38 with ketamine-associated cystitis were treated with intravesical botulinum toxin A injection (dose: 200UI) combined with bladder hydrodistension. All patients failed to achieve symptomatic relief with previous antimuscarinic and/or antibiotic therapy prior to the trial. All subjects had a history of ketamine abuse ranging from 1-5 years. In order to quantify any improvements in symptomatology, urodynamic testing, the O’Leary-Sant interstitial cystitis symptom index (ICSI), and problem index (ICP) were used to evaluate both baseline and post-treatment values. There were significant improvements (p-value <0.001) in many urinary symptoms from baseline to one-month post-treatment including nocturia, interval between micturition, void volume, maximum flow rate, and bladder capacity. There was also a notable decrease from baseline in ICSI and ICP following 1 month of post-treatment.¹⁶

Though the exact mechanism of ketamine cystitis is unknown, available literature suggests that it is most likely not caused by a bacterial infection. Therefore, the use of antibiotics is not a recommended treatment method. Available treatments focus on symptomatic management rather than disease cure. NSAIDs, anticholinergics, and opioids are the first modalities recommended for symptomatic relief, followed by more invasive means in the case of treatment failure. That being said, it has often been reported that symptoms typically resolve upon discontinuation of ketamine use and reappear with relapse.  Due to the variable presentations of ketamine cystitis and unknown pathophysiology, it is essential for healthcare clinicians to recognize the various symptoms associated with ketamine cystitis and utilize different treatment modalities for patients experiencing this unique drug-associated adverse event.

References:

1. KETALAR (ketamine hydrochloride) injection, for intravenous or intramuscular use, CIII. Package Insert. Chestnut Ridge, NY: Par Pharmaceutical; 2020.
2. Ma W-K, Chu PS-K. Burden of ketamine cystitis in Chinese society. Urol Sci. 2015;26(3):167-173.
3. Tsai TH, Cha TL, Lin CM, et al. Ketamine cystitis: Its urological impact and management. Int J Urol. 2009;16(10):826-829.
4. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms [published correction appears in Pharmacol Rev. 2018 Oct;70(4):879]. Pharmacol Rev. 2018;70(3):621-660. doi:10.1124/pr.117.015198
5. Chu PS, Ma WK, Wong SC, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome?. BJU Int. 2008;102(11):1616-1622. doi:10.1111/j.1464-410X.2008.07920.x
6. Castellani D, Pirola GM, Gubbiotti M, et al. What urologists need to know about ketamine-induced uropathy: A systematic review. Neurourol Urodyn. 2020;39(4):1049-1062. doi:10.1002/nau.24341
7. Middela S, Pearce I. Ketamine-induced vesicopathy: a literature review. Int J Clin Pract. 2011;65(1):27-30.
8. Hoffman R. Ketamine Poisoning. In: Post TW, ed. UpToDate. UpToDate; 2021. Accessed August 27, 2021. https://www.uptodate.com/contents/ketamine-poisoning
9. Ketamine. Micromedex Solutions. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. Accessed August 27, 2021.
10. Ketamine. Lexi-Drugs. Hudson, OH: Lexicomp, 2021. http://online.lexi.com/. Accessed August 27,2021.
11. Tsai TH, Cha TL, Lin CM, et al. Ketamine-associated bladder dysfunction. Int J Urol. 2009;16(10):826-829.
12. Pentosan Polysulfate Sodium. Lexi-Drugs. Hudson, OH: Lexicomp, 2021. http://online.lexi.com/. Accessed August 27,2021.
13. Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007 May;69(5):810-2.
14. Nomiya A, Nishimatsu H, Homma Y. Interstitial cystitis symptoms associated with ketamine abuse: the first Japanese case. Int J Urol. 2011 Oct;18(10):735.
15. Chiew YW, Yang CS. Disabling frequent urination in a young adult. Ketamine-associated ulcerative cystitis. Kidney Int. 2009;76(1):123-124.
16. Zeng J, Lai H, Zheng D, et al. Effective treatment of ketamine-associated cystitis with botulinum toxin type a injection combined with bladder hydrodistention. J Int Med Res. 2017;45(2):792-797.
17. Understanding hydrodistention with cystoscopy. Saint Luke’s Health System. https://www.saintlukeskc.org/health-library/understanding-hydrodistention-cystoscopy#:~:text=Hydrodistention%20is%20a%20procedure%20that,provider%20see%20inside%20your%20bladder. Accessed August 27, 2021.
18. Cystoplasty (bladder augmentation). Cleveland Clinic. https://my.clevelandclinic.org/health/treatments/15846-augmentation-cystoplasty-bladder-augmentation. Accessed August 27, 2021.

Published by Rho Chi Post