Recreational Ketamine Wood

2011 THE AUTHORS; BJU INTERNATIONAL 2011 BJU INTERNATIONAL Mini Reviews RECREATIONAL KETAMINE WOOD

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Recreational ketamine: from pleasure to pain BJUIBJU INTERNATIONAL Dan Wood*, Angela Cottrell†, Simon C. Baker‡, Jennifer Southgate‡, Maya Harris§, Simon Fulford§, Christopher Woodhouse* and David Gillatt† *Department of Urology, University College London Hospitals (UCLH), London †Bristol Urological Institute, Southmead Hospital, Bristol, ‡Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York, and §Department of Urology, James Cook University Hospital, Middlesbrough, UK Accepted for publication 28 October 2010

Ketamine has become increasingly What’s known on the subject? and What does the study add? recognized as a drug of recreational use. There is a very limited literature on the syndrome described in this review. The largest Individuals using signiﬁcant amounts have series comes from Hong Kong and includes 59 patients – this was largely a description of developed symptoms including a small the presenting problems and established the link between these symptoms and ketamine. painful bladder, ureteric obstruction, Prior to this much smaller case series (including one from the same group) were all that papillary necrosis and hepatic dysfunction. exists. The present paper examines the current literature on the relationship between An increasing number of UK urologists are reporting seeing these patients and we have ketamine use and these symptoms. Our formed a collaboration interested in understanding the pathology and establishing an own clinical experience and the data effective treatment pathway for these patients. This paper aims to consolidate this available clarify the causal relationship, knowledge. and further data help to elucidate the mechanism of damage. On the basis of for medical practitioners who encounter with an interest in the treatment of the continued work and development with patients with these symptoms to ask about condition. patients who are ketamine users we recreational drug use. Ketamine remains a suggest an assessment and treatment safe and effective drug to use under KEYWORDS regime that includes cessation of ketamine appropriate medical supervision. Patients use and adequate analgesia to overcome identiﬁed as suffering from this syndrome ketamine, painful bladder syndrome, lower symptoms. In conclusion, it is important will need to be referred to a urological unit urinary tract symptoms

INTRODUCTION dose noted in the series of patients The clinical syndrome includes a small, very encountered by our group is 20 g per day. The painful bladder, incontinence, upper tract Ketamine is a ‘dissociative anaesthetic’ that present review focuses on the urological obstruction, papillary necrosis and hepatic acts as a glutamatergic N-methyl-d-aspartate issues associated with sustained ketamine use dysfunction [7,8]. Before recognition of the antagonist. It was first synthesized in 1964 and presents evidence to establish a causal syndrome, many patients had been treated and it has had an excellent track record in relationship between ketamine toxicity and empirically for recurrent UTIs or painful anaesthesia and analgesia across both human the symptoms/clinical findings described in bladder syndrome and a lack of specific medical and veterinary fields [1,2]. In clinical patients. enquiry relating to substance abuse has practice, patients coming round from contributed to treatment failure. Cystoscopic ketamine-based anaesthesia have reported a Ketamine misuse is already a major problem inspection of the bladder frequently shows a variety of strange effects including ‘out of in Asia where significant quantities are denuded urothelium, which in the most body’ and ‘near-death’ experiences, delirium, manufactured by the generics pharmaceutical severe cases may slough off as intact sheets confusion, delusions and hallucinations. industry, providing a ready supply. Internet of cells. The mechanism of damage from This dissociative sensation (the ‘K Hole’) is searches and anecdotal discussions with users ketamine is not yet clear, but the effects, pleasurable to some and, combined with its indicate a number of perceived advantages, which are not specific to the bladder, are ready availability and low price (annecdotally including low rates of physical or most likely to result from direct toxicity of ‘cheaper than a night on alcohol’), has led to psychological addiction and minimal side ketamine or its metabolites. This is supported ketamine gaining in popularity as a effects. However, there is evidence of by a rudimentary mouse model based on recreational drug. Some ‘middle-class’ social cognitive impairment and long-term intraperitoneal ketamine injections [9] and circles use ketamine regularly at weekends, psychological effects as a result of prolonged by a few cases where patients given and the drug has been adopted by the party heavy use [4]. In addition, we have identified a therapeutic ketamine have experienced scene worldwide, leading to the emergence of cohort of patients who have developed a identical symptoms to those described by a mixed pattern of intermittent, daily and major urological syndrome that was originally recreational users. In addition, laboratory extremely high-dose users [3]. The highest reported in small case series [5,6]. research from our group has shown a

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specific interaction between ketamine and process. We have considered the possibility There is some suspicion in the field that differentiated human urothelium in vitro, that another substance is responsible for the metabolites of ketamine could be the toxic thus providing a direct link between major bladder damage, but that the sensation agents responsible for LUTS; however, at the ketamine and the clinical syndrome [Baker is masked by the anaesthetic properties of the time of writing, there is no direct evidence to et al., own unpublished data]. ketamine. Upon consideration, an adulterant support this hypothesis. effect seems highly unlikely for the following Because of the illegal nature of the drug, we reasons: As part of an audit of our histopathological may never know how many people use assessment of patients with ketamine- ketamine, or the precise correlation between 1. As the use of adulterants would be induced cystitis, we have found a difference in chronic high-dose intake and symptoms. expected to vary, ketamine appears to be the the number of mast cells compared with Previous studies have suggested that 20% of common factor. Although there is some equivalent tissues from patients with users may develop symptoms but there is no variation in the detailed pattern of disease interstitial cystitis. This may indicate consistent safe level or time frame for regular between different racial groups (e.g. emphasis differences in the underlying aetiopathology users [10]. Although it is difficult to obtain on upper tract manifestations in Asia [7]), of the two conditions and reflect the specific accurate data regarding the epidemiology of there is consistency in the use of ketamine immune-mediated response to ketamine or ketamine use, in 2007/2008, 0.9% of 16–24 and the development of symptoms. its metabolites, although at present the exact year olds questioned in the UK admitted to 2. The low cost of ketamine mitigates against mechanism remains unclear (C.White and ketamine use in the preceding year [11]. This the need for, or regular use of adulterants. A.Freeman, unpubl. data). figure rises in selected populations (e.g. police 3. An animal model suggests a causal link [9]. detainees in Taiwan) to 2% [12] and up to 4. There are case reports in adult and Developing our understanding of the 70% of ‘party drug’ users in Australia [3]. paediatric patients using therapeutic histopathology of the disease is critical, as David Nutt recently stated that Class C ‘may ketamine [13,14]. before the syndrome was recognized, the be the wrong class’ for ketamine, suggesting 5. There is both a dose and time relationship histological similarities to high grade the need for its status to be reviewed. [15]. dysplasia or malignant cystitis could have led Additionally, in 2009, the Home Office to a mistaken diagnosis of carcinoma in situ. suggested that the classification of ketamine On the basis of these considerations, we are The absence of a pattern of cytokeratin 20 should be reviewed after consideration of its convinced of the causal link between expression associated with carcinoma in situ pathological effects on the urinary tract ketamine use and damage to the urinary tract; [17] in patients with ketamine-induced (http://news.bbc.co.uk/newsbeat/10003110 however, the possibility of a synergistic effect cystitis appears to be an important (checked 31/12/10)). between either an adulterant or other distinguishing feature [18]. substances taken in tandem (e.g. alcohol, tobacco or other drugs) does need to be PATIENTS considered. TREATMENT REGIME Among the three clinical centres involved MECHANISM OF DAMAGE There is no evidence for a successful in our collaboration, we have seen treatment regime and at the outset of our approximately 60 patients; the majority are The possible mechanisms suggested by Chu collaboration, all groups were doing their best young (17–45 years at presentation) and et al. [7] for damage to the urinary tract can to treat patients who were presenting almost all are recreational users. We have be summarized as follows: with a previously unseen phenomenon. The developed four principal questions: urologists amongst us have all seen young 1. Direct toxic damage to the urinary tract by patients, at an end-stage in the disease 1. Is there a true causal relationship between ketamine and/or its metabolites. process, who have required cystectomy and ketamine and the LUTS? 2. Microvascular damage by ketamine and/or reconstruction. For those patients most 2. What is the mechanism(s) of damage? its metabolites. severely affected, suprapubic pain has been a 3. What is an effective and appropriate 3. Autoimmunity triggered by either major issue and unfortunately many patients treatment regime for such patients? circulating or urinary ketamine. have resorted to self-medication with 4. What support exists from other agencies 4. Unrecognized bacteriuria. ketamine itself as the most effective means of to educate about the harmful effects and to pain relief. reduce use? In vitro studies carried out by the scientists in our collaboration have shown compelling After our group met initially, we wrote to the CAUSAL RELATIONSHIP evidence of a direct interaction between President of BAUS suggesting a strategy for ketamine and the bladder urothelium, with evaluating these patients. We wrote: A reasonable question that has been raised in cell death observed at concentrations ≥1 mM, both written and verbal discussion is whether but with evidence of an intriguing receptor- Early investigation must rule out UTIs and it is ketamine itself that causes the symptoms. mediated component [Baker et al., own is fairly standard. Anyone who gives a It could be that other substances taken in unpublished data]. The nature of the receptor history of drug abuse should be placed in conjunction with ketamine, either knowingly activated by ketamine has yet to be identified contact with a local drug support service. or as an adulterant, are responsible or that as ketamine is renowned for its binding If ketamine is identified as a factor we there is another unrecognized disease promiscuity [16]. strongly recommend that renal function is

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assessed. In addition a CT urogram is an and for furthering enquiry into this emerging looking at patients, Miss Clare Taylor, Urology important investigation to understand the clinical phenomenon. SpR at UCLH for her help in looking after extent of disease. UCLH patients and Mr Alex Freeman for his In conclusion, the urological syndrome histopathological advice. A urine culture is mandatory in our clinical associated with ketamine use is severe. If drug practice and we routinely evaluate the upper cessation is achieved it may be, at least tracts with a CT urogram to rule out ureteric partially, reversible. The early syndrome may CONFLICT OF INTEREST stricture and use cystoscopy to assess bladder be present in casual or weekend users as capacity. episodes of cystitis treated empirically. Once a None declared. usage threshold is crossed, bladder pain (or It is clearly vital to ask the correct questions other symptoms) may drive further use to and failure to ask about recreational drug use suppress symptoms, leading to irreversible REFERENCES will result in this being overlooked in many damage and scarring. This is a concern of patients. We have all seen patients with ours, as the worst-affected patients have 1 Agarwal A, Gupta D, Kumar M, Dhiraaj symptoms compatible with these patients’ required major surgery, i.e. cystectomy and S, Tandon M, Singh PK. Ketamine for complaints and many have been treated with bladder reconstruction, with all its inherent treatment of catheter related bladder a variety of speculative therapies. Increasing risks. Such surgery should only be done after discomfort: a prospective, randomized, awareness of the urological effects of careful counselling and a sustained attempt placebo controlled and double blind recreational drugs should lead to more to stop ketamine use. study. Br J Anaesth 2006; 96: 587–9 doctors asking the questions that will help to 2 Naguib M, Adu-Gyamfi Y, Absood GH, identify and treat such syndromes [19]. Ketamine has been widely used for chronic Farag H, Gyasi HK. Epidural ketamine for pain and there is one report of ketamine- postoperative analgesia. Can Anaesth Soc Foremost in our treatment strategy is the induced cystitis in a paediatric patient [13]. J 1986; 33: 16–21. absolute requirement for a patient to stop There is also a report of disabling bladder 3 Degenhardt L, Copeland J, Dillon P. ketamine use. This may sound symptoms in patients receiving ketamine in Recent trends in the use of ‘club drugs’: straightforward, but in a context where the chronic pain and palliative care setting; an Australian review. Subst Use Misuse patients feel their only way of controlling the this suggests that the effect is not uniform 2005; 40: 1241–56 pain is with ketamine, it has proven to be and some individuals may be more susceptible 4 Morgan CJ, Muetzelfeldt L, Curran HV. difficult. It is not universally true, but many than others. However, most studies of Consequences of chronic ketamine self- of this patient population have been ketamine used for chronic pain were of short administration upon neurocognitive unreliable attendees at both outpatient and duration and involved lower doses than seen function and psychological wellbeing: a investigation appointments. in recreational use, so LUTS were not reported 1-year longitudinal study. Addiction 2010; [14]. Whilst somewhat rudimentary, a mouse 105: 121–33 Because ketamine is relatively cheap, it has model has gone some way to cementing the 5 Shahani R, Streutker C, Dickson B, little or no direct association with crime and link between ketamine and urinary tract Stewart RJ. Ketamine-associated hence drug support agencies and primary damage [9]. Laboratory research from our ulcerative cystitis: a new clinical entity. care trusts may not see ketamine users as a group shows a clear link between ketamine Urology 2007; 69: 810–2 high priority for rehabilitation. For these and damage to the urothelium; this, coupled 6 Chu PS, Kwok SC, Lam KM et al. ‘Street reasons, expecting someone to stop ketamine with disease manifestation and patterns of ketamine’-associated bladder use carries a significant risk of failure. In use, firmly establishes the causal link with dysfunction: a report of ten cases. Hong Bristol, the chronic pain team have worked ketamine. Kong Med J 2007; 13: 311–3 closely with the urology team and developed 7 Chu PS, Ma WK, Wong SC et al. The a strategy that includes buprenorphine We emphasize that, under medical destruction of the lower urinary tract by patches with cocodamol and amytriptiline at supervision, ketamine remains a very safe and ketamine abuse: a new syndrome? BJU Int night. This appears to offer reasonable useful drug in anaesthetic practice. However, 2008; 102: 1616–22 symptom control, allowing users to avoid there are significant side effects as a result of 8 Wong SW, Lee KF, Wong J, Ng WW, ketamine. misuse, with long-term consequences. We Cheung YS, Lai PB. Dilated common bile would urge all medical practitioners seeing ducts mimicking choledochal cysts in The involvement of drug support agencies is patients with these symptoms to ask about ketamine abusers. Hong Kong Med J 2009; important but can be difficult, particularly if recreational drug use and to consider 15: 53–6 patients are seeing a urologist out of their appropriate rehabilitation and support, along 9 Yeung LY, Rudd JA, Lam WP, Mak YT, residential area. As support is given by with referral to a urology department with a Yew DT. Mice are prone to kidney residential area, it is best organized by the GP specialized interest. pathology after prolonged ketamine once the diagnosis has been established. addiction. Toxicol Lett 2009; 191: 275–8 10 Muetzelfeldt L, Kamboj SK, Rees H, In some areas, drug support agencies have ACKNOWLEDGEMENTS Taylor J, Morgan CJ, Curran HV. Journey been extremely proactive in initiating contact through the K-hole: phenomenological with a local urology department. This has The authors acknowledge Mr Chris White, aspects of ketamine use. Drug Alcohol created a productive link both for patients Urology MSc Student at UCL for his audit Depend 2008; 95: 219–29

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11 Hoare J, Flatley J. National Crime Survey. clinical entity. Urology 69: 810-812, 2007). 17 Harnden P, Eardley I, Joyce AD, Drugs Misuse Declared: Findings from the Urology 2008; 71: 1232–3 Southgate J. Cytokeratin 20 as an British Crime Survey. England and Wales. 14 Storr TM, Quibell R. Can ketamine objective marker of urothelial dysplasia. October 2008. Available at: http:// prescribed for pain cause damage to the Br J Urol 1996; 78: 870–5 rds.homeofﬁce.gov.uk/rds/pdfs08/ urinary tract? Palliat Med 2009; 23: 670– 18 Oxley JD, Cottrell AM, Adams S, Gillatt hosb1308.pdf. Accessed December 2010 2 D. Ketamine cystitis as a mimic of 12 Lua AC, Lin HR, Tseng YT, Hu AR, Yeh 15 Cottrell A, Warren K, Ayres R, carcinoma in situ. Histopathology 2009; PC. Proﬁles of urine samples from Weinstock P, Kumar V, Gillatt D. 55: 705–8 participants at rave party in Taiwan: The destruction of the lower urinary 19 Coull N, O’Brien T. ‘Street urology’: prevalence of ketamine and MDMA abuse. tract by ketamine abuse: a new beyond the formulary. BJU Int 2009; 103: Forensic Sci Int 2003; 136: 47–51 syndrome? BJU Int 2008; 102: 1178–9; 721–2 13 Gregoire MC, MacLellan DL, Finley GA. author reply 1179 A pediatric case of ketamine-associated 16 Bergman SA. Ketamine: review of its Correspondence: Dan Wood, Department of cystitis (Letter-to-the-Editor RE: Shahani pharmacology and its use in pediatric Urology, University College London Hospitals R, Streutker C, Dickson B, et al: Ketamine- anesthesia. Anesth Prog 1999; 46: 10– (UCLH), London NW1 2PJ, UK. associated ulcerative cystitis: a new 20 e-mail: [email protected]