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KETAMINE INDUCED CYSTOPATHY KETAMINE INDUCED CYSTOPATHY Presentation Transcript

  • KETAMINE INDUCED CYSTOPATHY CASE CONFERENCE 2013. 07. 18 臨床藥學與藥物科技研究所 陳秋縈 指導老師 張育誌醫師 黃千惠藥師
  • Patient profile Name 林X榆 HT 163 cm Age 23 y/o BW 39.2 kg Gender female BMI 14.7 Drug Allergy NKDA Family History Not contribution Social History • Smoking (-) • Drinking (-) • Betel nut (-) • Drug abuse (-) 2 2011/ 10/06 • R’t flank pain and bilateral shoulder, L’t subcostal, bilateral hip, bilateral knee soreness • Diagnosis: muscle sprain  Diclofenac 25mg TID x 3 days ER
  • History of present illness-12/4 ER 3 2011/ 12/04 • R’t nasal bleeding this morning • Bil hydronephrosis (+), septal perforation(+) • Diagnosis: epistaxis, right  Fexofenadine 60mg BID Tranexamic acid 250 mg QID ER
  • History of present illness-12/10 ER 4 4 2011/ 12/10 • CC: 咳嗽, 上腹痛與腹脹感, 嘔吐多次 • Cough with whitish sputum, N/V(+), fever(-), sorethroat(-), general malaise(+), rhinorrhea(+) • PH: bil. Hydronephrosis • Diagnosis: 1. Common cold, r/o airway infection 2. CKD 3. Anemia  metochlopramide, strocain, desloratadine, cough mix Hb (g/dL) 8.7 WBC (/μL) 6.8 BUN (mg/dL) 83 MCV (fl) 85 Seg(%) 71 Crea(mg/dL) 7.85 According to patient’s statement: Past SCr baseline level: 5 mg/dL, lost of F/U 6 months ER
  • Hospital course 12/16-12/21 • CC: bilateral flank pain for one day with dysuria and hematuria • PE: T/P/R: 36.8/136/20, BP: 138/112 mmHg bilateral knocking tenderness (+) • Urine analysis 5 5 2011/ 12/16 | 12/21 Admission Urine 2011/12/16 SG 1.02 pH 6.5 LEU(/UL) 500 NIT Negative PRO(mg/dL) 100 GLU(mg/dL) Negative KET(mg/dL) Negative UBG(mg/dL) Normal BIL(mg/dL) Negative ERY(/UL) 200 RBC(/HPF) 189 WBC(/HPF) 2097 Urine 2011/12/16 Bacteria Negative Yeast Negative SQEP Negative Others Negative NSQEP Negative Hyaline Negative Cast(/LPF) Negative CAOX Negative Crystal(/HPF) Negative AMOR Negative Mucus Negative
  • Lab data 6 血液 2011/12/10 2011/12/16 WBC(10^3/μL) 6.8 8.6 RBC(10^6/μL) 3 Hb(g/dL) 8.7 9.1 Hct(%) 25.5 25.4 MCV(fl) 85 MCH(pg) 29.1 MCHC(g/dL) 34.2 RDW(%) 16.2 Reti(%) 1.18 Plt(10^3/μL) 610 589 Seg(%) 71.1 81 Eos(%) 1.2 1.2 Baso(%) 0.6 0.5 Mono(%) 9.2 4.2 Lymph(%) 17.9 13.1 2011/12/10 2011/12/16 BUN(mg/dL) 83 93 CREA(mg/dL) 7.85 7.65 eGFR 6 7 ALT(U/L) 10 BIL-T(mg/dL) 0.2 BIL-D(mg/dL) 0.1 LD(U/L) 87 ALBUMIN(g/dL) 4.1 CA(mg/dL) 8.5 P(mg/dL) 6.7 NA(mmol/L) 132 K(mmol/L) 4 CL(mmol/L) 95 Glucose (random) 130 IRON(ug/dL) 48 TIBC(ug/dL) 192 PTHi(pg/mL) 626.9
  • Past history Impression  Pyuria, suspected UTI  Acute on CKD, suspected ketamine related uropathy  Anemia, related to CKD  Admission 7 According to patient’s statement: • Ketamine abuse history 5#/day for 1 year many years ago, but quit now • Frequency, urgency, nocturia, and intermittent gross hematuria since 5 years ago • Bil hydronephrosis secondary to bil ureteral stricture was told - s/p D-J stenting at 2009 奇美醫院, no improvement after insertion and loss of follow up - Remove D-J at 2011/05 台南市立醫院 due to forgotten D-J with infection - SCr around 5 mg/dL at 2011/05
  • Hospital course 12/16-12/21 8 Medication • Cefuroxime 12/16-21 (UTI) • Amlodipine 5 mg QD (HTN 130-150/90-110 mmHg) • Ferall 1# BIDAC, epoetin 4000 IU QW (Anemia with CKD) • Calcium acetate 1334 mg TID (Hyperphosphatemia) • Tramadol 50 mg BID (Pain control) • 12/19 Echo: ₋ The urinary bladder is not distended and poorly studied ₋ Bilateral hydronephrosis, with some intraluminal echogenic material  contracted bladder (capacity <30 ml) • 12/20 U/C: (-) • 12/21 Stable condition discharge 8 2011/ 12/16 | 12/21 12/16 12/19 12/21 BUN(mg/dL) 93 89 116 CREA(mg/dL) 7.65 6.87 6.99 eGFR 7 7 7 Lost of F/U after discharge…
  • History of present illness 9 9 • Abdominal (epigastralgia) pain and L’t flank knocking pain • WBC: 10900/μL, seg: 84%, CRP 75.4 mg/L, Scr: 7.8 mg/dL UA: pyuria, WBC:1973, bacteria(-)  Suspect UTI • Urologist suggest PCN insertion for hydronephrosis with turbid content drainage  Patient refused, AAD 至奇美醫院 2012/ 02/06 • CC: abdominal pain and flank soreness, N/V (+) Impression: • Acute on CKD impending ESRD • UTI 2012/ 03/12 | 03/29 Hb (g/dL) 5.8 Electrolye Urine Analysis WBC (/μL) 12000 Na (mmol/L) 126 PRO(mg/dL) 100 Seg(%) 91.5 K (mmol/L) 2.2 RBC(/HPF) 11 BUN (mg/dL) 153 Mg 1.3 WBC(/HPF) 470 Crea(mg/dL) 8.72 Ca (mg/dL) 5.4 Bacteria Trace eGFR 6 P (mg/dL) 9.5 Albumin (g/dL) 4 Admission ER  Admission
  • Hospital course 3/12-3/29 10 • Cefazolin 1000 mg QD for UTI • PCN indwelling to rescue renal function 3/14 left PCN, 3/16 right PCN • Correct electrolyte imbalance • Urologist consultation for evaluation of neo-bladder reconstruction  keep PCN indwelling and monitor renal function closely 10 3/13 3/14 3/16 3/19 3/22 3/26 3/29 BUN(mg/dL) 153 125 88 79 95 92 CREA(mg/dL) 9.42 8.72 7.62 5.32 5.08 4.61 4.82 eGFR 5 6 7 10 11 12 11 CA(mg/dL) 5.4 5.4 7.7 8.6 8 8.6 P(mg/dL) 9.5 2.8 3 2.8 NA(mmol/L) 122 126 132 132 134 K(mmol/L) 7.2 2.2 4.7 3.8 4.1 MG(mg/dL) 1.1 1.4 1.9 1.6 2.1 Albumin(g/dL) 4 3.1 3.5 2012/ 03/12 | 03/29
  • Hospital course 3/12-2/29 11 • Bloody stool and drop Hb level to 6.9 g/dL • Sigmoidoscopy and panendoscopy: - Reflux esophagitis, grade A - Gastric ulcer - External hemorrhoid  Pantoprazole 40mg QD, Proctosedyl oinment 3/29 Clinical stable discharge and OPD follow up 11 Discharge medication • Amlodipine 5 mg QD • Calcitriol 0.25 mg QD • Calcium acetate 1334 mg TID • MgO 250 mg BID • Pantoprazole 40 mg QD • Sodium bicarbonate 600 mg BID 2012/ 03/12 | 03/29
  • Urine analysis 12 檢驗名稱 2011/12/16 2011/12/19 2012/2/6 2012/3/13 SG 1.02 1.02 1.02 1.015 pH 6.5 6.5 6.5 6 LEU(/UL) 500 500 500 500 NIT Negative Negative Negative Negative PRO(mg/dL) 100 100 30 100 GLU(mg/dL) Negative Negative Negative Negative KET(mg/dL) Negative Negative Negative Negative UBG(mg/dL) Normal Normal Normal Normal BIL(mg/dL) Negative Negative Negative Negative ERY(/UL) 200 200 80 80 RBC(/HPF) 189 129 15 11 WBC(/HPF) 2097 1181 1973 470 Bacteria Negative Trace Negative Trace Culture 2011/12/20 U/C (-) 2012/2/7 U/C (-), B/C (-) 2012/3/13 U/C (-)
  • Abdominal sonography-2012/02/17 13 Bilateral hydronephrosis, with some intraluminal echogenic material
  • 14 Antegrade pyelography- 2012/3/21 Suspect urolithiasis in bilateral upper third ureter with obstructive uropathy
  • 細胞學檢查報告-2012/3/15  Diagnosis: Urine cytospin smear: Negative for malignancy.  GROSS FINDING: The specimen measures 40 ml with a yellow-turbid appearance. There is one slide totally, which is a Papanicolaou stain. 15
  • Outline  Introduction of Ketamine  Ketamine induced cystopathy/cystitis  Presentation  Investigation  Management  Other chronic complications related to ketamine use  Summary 16
  • “ ” Introduction of ketamine 17
  • History of Ketamine  1962 First synthesized as a replacement for phencyclidine by Stevens in at Parke-Davies laboratories (now part of Pfizer)  1970 FDA approved ketamine for human use Introduced into the Vietnam war as battlefield anesthetic  Late 1970s and early 1980s “Emergence phenomena” led to increasing illicit use and withdrawn from mainstream anaesthetic use with humans 18 Common street names Special K, Kit-Kat, Cat Valium, K 褲子(取字母開頭諧音,與Ecstacy的衣服相似) 下面(相較於衣服(上面),取其相對)
  • Pharmacology of Ketamine  Multiple binding Sites  NMDA-receptor  Non competitive NMDA receptor antagonist that blocks glutamate  Bind to PCP binding site and prevents neuronal Ca2+ influx  S(+)-isomer showing 4 times greater affinity than R(-)-isomer  Norketamine is also an NMDA-R antagonist  Opioid Receptors: Weak agonist (µ > κ > δ)  GABA Receptors: Weak agonist, reduce GABA reuptake  Sympathomimetic agonist activity at ɑ1- and β2-adrenoceptors  Muscarinic Ach receptors: inhibitor, anticholinergic effect 19 J Pain Symptom Manage. 2011 Mar;41(3):640-9.
  • Physiological effect  Cardiovascular: tachycardia, hypertension  Respiratory: bronchodilation  Neurological: hallucinations, amnesia, mental clouding, loss of memory, impaired attention, out of body experiences (K-hole effect)  Gastrointestinal: nausea  Physical features: paralyzed feeling, numbness  Muscles: dystonia, convulsions 20 J Pain Symptom Manage. 2011 Mar;41(3):640-9. Emerg Health Threats J. 2011; 4: 10.3402
  • Pharmacokinetics 21 Emerg Health Threats J. 2011; 4: 10.3402 Micromedex Ketamine and its metabolites are renally excreted Can be detected in urine Half-life elimination: Alpha: 10-15 minutes; Beta: 2.5 hours Hepatic metabolism Major: CYP3A4 Minor: CYP2B6 &2C9 N-demethylation 33% activity Dehydrogenated Activity unspecified Hydroxylation
  • Drug interactions  Long-term use of ketamine leads to hepatic enzyme induction, including enzymes responsible for its own metabolism  The development of tolerance in recreational users abusing it in high doses  CYP3A4 Inhibitors (eg. Clarithromycin, ketoconazole) Increase plasma concentrations of ketamine  CNS depressants (eg. Tramadol, opiods, alcohol) Increased risk of respiratory depression, profound sedation, and coma  Tubocurarine, atracurium (Nimbex) Increased neuromuscular blockade  Theophylline May result in a lower seizure threshold 22 BJU Int. 2011;107:1881-4. J Pain Symptom Manage. 2011 Mar;41(3):640-9. Micromedex
  • Medical use of ketamine Originally – Dissociative anaesthetic Now- 3rd line Rx option for chronic and acute pain  General anaesthesia  Particularly paediatrics, veterinary anaesthesia and field medicine  Relative preservation of airway reflexes and haemodynamic stability  Analgesia/sedation (unlabeled use)  Particularly in neuropathic pain & complex regional pain syndrome  Treatment-resistant depression (unlabeled use) 23 Addiction. 2012 Jan;107(1):27-38.
  •  Study design: A randomized, placebo-controlled, double-blind crossover trial  Patient: 18 adults with treatment-resistant major depressive disorder - failure of at least 2 adequate antidepressant trials and - 21-item HAM-D score ≥ 18 after 2-week drug-free period  Intervention: IV infusion ketamine HCl 0.5 mg/kg vs. saline 50 mL over 40 minutes  Outcome: Changes in HAM-D score 24 Arch Gen Psychiatry. 2006 Aug;63(8):856-64.
  • Results  Ketamine significant improved depression scores compared to placebo from 110 minutes after injection through 7 days  In patient treated with ketamine  71% response at day 1  35% response at 1 week  29% remission at day 1  29% remission at 1 week 25 Arch Gen Psychiatry. 2006 Aug;63(8):856-64. * indicates P<.05; †, P<.01; ‡, P<.001 Response ( ≥ 50% decrease in HAM-D score) Remission ( HAM-D score ≤ 7)
  • Medical use of ketamine Treatment-resistant depression  Antidepressants typically take weeks to produce a response  Intravenous infusion of ketamine 0.5 mg/kg has rapid and profound short-term effect on reducing depression symptom in patients with treatment-resistant major depressive disorder  However, its long-term safety and effectiveness need to be evaluated 26 Arch Gen Psychiatry. 2006 Aug;63(8):856-64. Ann Pharmacother. 2012 Jan;46(1):117-23.
  • Recreational use of ketamine  Ketamine is fast becoming a popular recreational drug  Relatively cheap to other substance (NTD 1000-1200/g)  Easy accessibility  Absence of any physical withdrawal syndrome  Policy: 第三級管制藥品 (98.5 持有/施用: 1-5萬罰鍰, 4-8 h講習)  User’s acute experiences (Emergence phenomena)  Sense of melting into surroundings  Visual hallucinations  Spiritual and out of body experiences  K-hole (dissociative sensation): a near death experience, with the sensation of rising above one’s body, inner peace, and radiant light 27 Dose
  • 台灣地區精神醫療院所通報藥物濫用者 使用藥物之種類分布統計表 28 Ketamine MDMA 成長率 No.1 No.2
  • 台灣地區濫用藥物尿液檢驗統計圖 90年~102年3月
  • 2009 年 國民健康訪問暨藥物濫用調查 台灣地區12-64 歲族群 各種非法物質使用盛行率與人數推估 30 衛生署食品藥物管理局 ,衛生署國民健康局,財團法人國家衛生研究院
  • Route of abuse  Ketamine is water soluble, has a pKa of 7.5 and a high lipid solubility 10 times that of thiopental  Allows administration by many routes and rapidly crosses BBB  Injected: IV, IM  Orally  Bitter taste, slower onset of action  Extensive first-pass hepatic metabolism reduces its bioavailability  Snorting or inhaling 31 Emerg Health Threats J. 2011; 4: 10.3402
  • Nasal septum perforation and ketamine snorting  Clinical signs of drug use through nasal consumption: Nasal discharge, epistaxis, nasal septal perforation (occurs with cocaine, inhalants)  As with other substances, long-term nasal consumption cause chronic inflammation and necrosis of the nasal mucosa  In extreme cases, intense necrosis can result in an opening in the nasal septum  The sense of smell can also be damaged by chronic nasal consumption 32 Donald G. Barceloux. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants.
  • Chronic complications related to ketamine use  Ketamine-induced cystitis  Kidney dysfunction  ‘K-cramps’  Neuropsychological effects and neurotoxicity 33 Addiction. 2012 Jan;107(1):27-38.
  • Chronic complications pattern in ketamine abusers  From June 2008 to July 2011, 96 cases of chronic ketamine poisoning in Hong Kong  Duration of ketamine abuse: mean 8.6 years (SD 4.1 years); median:4 years  92 % presented with features of ketamine cystitis  66 % presented with chronic epigastric pain  42 % nasal problems (3 cases of septal perforation)  16 % psychiatric features 34 J Med Toxicol. 2012 Sep;8(3):267-70.
  • “ ” Ketamine induced cystopathy/cystitis 35
  • 36
  • Ketamine-induced ulcerative cystitis  First documented in 2007 37 Urology 2007: 69:810-812 Hong Kong Med J 2007; 13:S1-3 Urology 2007: 69:810-812 Described nine patients who were daily ketamine users • Severe dysuria, frequency, urgency and gross hematuria • Urine culture: sterile in all cases • CT scan: marked thickening of the bladder wall, a small capacity and perivesicular stranding consistent with severe inflammation • Cystoscopy: all patients had severe ulcerative cystitis • All these patients benefited from cessation of ketamine use and the addition of pentosan polysulfate (Elmiron)
  • Epidemiology  Prevalence data are difficult to obtain  Recent reports suggest that approximately 20–30% of ketamine abusers suffer from lower urinary tract symptoms (cystitis or bladder problems)  The presence of urinary symptoms were related to the dose and frequency of ketamine used:  38% of those reporting less than daily use  50% of those using <2g/day  75% using 2-5g/day  100% of those using >5g/day 38 Drug Alcohol Depend 2008;95: 219–29. Eur Urol Suppl 2009; 8: 170.
  • Presentation  Time of onset of lower urinary tract symptoms varies from a few days to a few years following the onset of abusive use  Symptoms are consistent with interstitial cystitis, ulcerative cystitis and lower urinary tract symptoms  Dysuria, haematuria, urgency and frequency, nocturia, urge incontinence, pelvic, bladder and urethral pain  Severe complications include intractable symptoms, renal impairment and hydronephrosis 39 BJU Int. 2012 Sep;110(6):E164-5.
  •  A study in Taiwan 11 patients with urinary tract symptoms and a history of ketamine abuse in recent years  mean age: 24 y/o, duration of drug abuse: 1-4 years 40 Int J Urol. 2009 Oct;16(10):826-9.
  • Ketamine and bladder damage Causal relationship  The possibility that other co-use substance (adulterant) is responsible for the major bladder damage? 1. As the use of adulterants would be expected to vary, ketamine appears to be the common factor 2. The low cost of ketamine mitigates against the need for, or regular use of adulterants 3. An animal model suggests a causal link 4. There are case reports in adult and paediatric patients using therapeutic ketamine 5. There is both a dose and time relationship 41 BJU Int. 2011 Jun;107(12):1881-4 Toxicol Lett. 2009 Dec 15;191(2-3):275-8. Toxicol Lett. 2009 Dec 15;191(2-3):275-8.
  • Bladder symptoms in pain care patients  A pain clinic reports the case of a pediatric pain patient developing bladder symptoms as a result of ketamine prescribed for pain 42 Urology. 2008 Jun;71(6):1232-3. • This 16 y/o female patient was being treated for complex regional pain syndrome (CRPS-Type1). After unsuccessful trials of multiple medications, oral ketamine was added to a regimen and she reported a significant decrease in her neuropathic pain. • After 9 days on ketamine 8mg/kg/day, she started to develop dysuria, frequency, urgency and incontinence. The urinalysis was normal and the urine culture was negative. Her symptoms decreased as the dosage was decreased and eventually resolved at 2mg/kg/day. • A few months later, the patient was again started on ketamine and the urinary symptoms reappeared at a dose of 5mg/kg/day. The symptoms again resolved when the dosage was reduced to 3mg/kg/day. A potential dose-related effect of the ketamine on the bladder mucosa
  • Possible mechanism of bladder damage (1)  The aetiopathological mechanism of disease development remains unknown  Ketamine and its metabolites are renally excreted and can be measured in high quantities in the urine of patients using ketamine  Conjugates (80%), dehydronorketamine (16.2%), ketamine (2.3%), norketamine (1.6%)  It is plausible that ketamine and its active metaboiltes can accumulate in the urine and induce significant bladder irritation 43 Urology 2007: 69:810-812
  • Possible mechanism of bladder damage (2)  A number of different theories have been proposed  Direct toxic effect of ketamine or its metabolites on bladder interstitial cells  Microvascular damage to the urinary tract leading to chronic ischaemia and fibrosis  Indirect effect of ketamine by causing an autoimmune reaction against the bladder urothelium and submucosa due to circulating ketamine or urinary ketamine and its metabolites  Unrecognized bacteriuria (less likely) 44 BJU Int. 2011 Jun;107(12):1881-4
  • Clinical investigation (1)  Urinalyses showed nonbacterial pyuria and sterile on culture  Renal impairment with raised serum creatinine was observed in many cases Imaging studies  Bladder wall thickness  Small capacity bladder  Perivesical inflammation  Papillary necrosis  Hydronephrosis (bilateral hydronephrosis in 50% of patients) 45
  • 46 Tzu Chi Med J 2008;20(2):144-146. A reduced cavity and irregular wall thickening in the urinary bladder IVP showed a contracted urinary bladder, narrowing of bilateral cystoureteral junctions, bilateral hydroureters and bilateral hydronephrosis
  • Ureteric wall thickening and enhancement were also observed in advanced cases 47 Clin Radiol. 2010 Oct;65(10):795-80 A 32 y/o man presented with dysuria, haematuria, and suprapubic pain with a 4 year history of ketamine use (4 g/day) Bilateral upper ureteric narrowing with associated mild bilateral hydronephrosis Marked thickening on the bladder wall Ureteric wall thickening and enhancement
  • Clinical investigation (2) Urodynamics  Detrusor over-activity and decreased bladder compliance  Small capacity bladder 48 BJU Int. 2008 Dec;102(11):1616-22. Cystometric bladder capacities in 47 patients who had a video-urodynamic study, showing that most of them had capacities of <150 mL
  • Clinical investigation (3) Cystoscopy  One or more of epithelial inflammation, neovascularisation, petechial (pinpoint) haemorrhages and erythematous bladder mucosa 49 BJU Int. 2008 Dec;102(11):1616-22. Two daily ketamine abusers who had been inhaling ketamine nasally for 4 years (A) and 7 years (B) There were varying degrees of inflammation and neovascularization, with petechial haemorrhages in more severely affected patients. 4 years 7 years
  • Clinical investigation (4) Histology  Denuded epithelium  Infiltration of tissues with eosinophils, lymphocytes, mast cells Immunohistochemistry  High expression of p53 (cell death)  High expression of Ki67 (cell growth)  Absence of CK20 expression (ca in situ) 50
  • 51 Urology 2007: 69:810-812
  • Management  There is no clearly defined treatment other than symptomatic treatment  Early diagnosis is essential to effectively manage ketamine- induced bladder pathology and prevent irreversible renal tract damage  Treatments reported in the literature are often those used for interstitial cystitis, but experience is lacking  Cessation of ketamine use  The only effective treatment modality to prevent deterioration of the renal function and indeed offer the possibility of symptom resolution  Full symptomatic resolution will not be achieved in more advanced cases (severely reduced bladder capacity and compliance and resultant hydronephrosis) 52 Int J Clin Pract. 2011 Jan;65(1):27-30.
  • Management-medications  Various treatment regimens include antibiotics, oral NSIADS, steroids, anticholinergic therapy have failed to provide significant and lasting improvement  Pentosan polysulfate (PPS, Elmiron®)  Use: Relief of bladder pain or discomfort due to interstitial cystitis  Dosage: oral 100 mg TID  Mechanism of Action  A low-molecular weight heparin-like compound  Supplement the glycos-amino-glycan (GAG) layer of the damaged urothelium  Adhere to the bladder wall mucosa where it may act as a buffer to protect the tissues from irritating substances in the urine  A case reported nine patients benefited from cessation of ketamine use and the addition of pentosan polysulfate (Elmiron®) 53 Int J Clin Pract. 2011 Jan;65(1):27-30.
  • Management  Intravesical instillations  Hyaluranic acid, pentosan polysulfate (Elmiron®)  Urethral indwelling catheters  Provide relief from the suprapubic pain, urgency and dysuria  Surgical interventions  Bladder augmentation  Neo-bladder construction (created from bowel) Potential risk: lead to re-absorption of ketamine or its metabolites  There are two reported cases of augmentation cystoplasty in the literature, but in both cases, ketamine abuse continued leading to continued symptoms, and disease progression to ureteric stricturing and renal failure 54 BJU Int 2008; 102: 1616–22 NDT Plus 2008; 1: 310–2. Int J Clin Pract. 2011 Jan;65(1):27-30.
  • “ ” Other chronic complications related to ketamine use 55
  • Kidney dysfunction  Frequent, high-dose ketamine use appears to be hydronephrosis secondary to urinary tract problems  Of 59 ‘ketamine bladder’ patients, 30 (51%) patients presented with hydronephrosis  Unilateral: 4 (7%), Bilateral: 26 (44%)  Cases of disease progression renal failure 56 BJU Int. 2008 Dec;102(11):1616-22 Addiction. 2012 Jan;107(1):27-38.
  • ‘K-cramps’  ‘K-cramps’—Severe gastric pain  Spontaneously reported in 33% of 90 ketamine users interviewed  Frequent ketamine users often report taking more ketamine to alleviate this pain and this can make attempts to quit using fail  The etiology of K-cramps remains unclear  Three small case reported the existence of  ‘Colicky’ upper gastric pain  Presented with abnormal liver function  Dilation of the common bile duct with a smooth tapered end, mimicking choledochal cysts 57 Addiction. 2012 Jan;107(1):27-38. Drug Alcohol Depend 2008; 95: 219–29.
  • Dilated common bile ducts mimicking choledochal cysts in ketamine abusers 58 Hong Kong Med J. 2009; 15:53-6. Case 1 Case 2 Case 3 Patient 21 y/o woman 27 y/o man 23 y/o man Ketamine history Once per 1-2 month for 18 months BIW for 2 years Once per week for 7 years Recent 3 months: everyday S/S Recurrent epigastric pain, especially after taking ketamine Recurrent epigastric pain Admission due to injuries Occasional colicky epigastric pain in the past few years Liver function test ALP: 122 IU/L ALT: 333 IU/L bilirubin: 14 µmol/L ALP: 137 IU/L ALT: 75 IU/L bilirubin: 7 µmol/L Normal Radiology Dilated common bile duct without obstruction Resolusion Yes (3 moths after cessation ) Yes (4 moths after cessation ) Unknown Hong Kong Med J. 2009; 15:53-6.
  • Clinical picture  Recurrent epigastric pain  Increase in that pain after taking ketamine; the pain would decrease when he temporarily ceased abusing the drug  Abnormal liver function  Mainly involved elevation in ALP and ALT levels, and a normal bilirubin level  Dilated common bile duct on imaging  Fusiform dilatation of the entire common hepatic and bile duct  No obstructive lesion was found  It resembles Todani’s type Ic choledochal cyst (diffuse fusiform dilatation of the common hepatic and bile duct)  Symptoms seem to be reversible on cessation of abuse 59 Hong Kong Med J. 2009; 15:53-6
  • Radiological features 60 Hong Kong Med J. 2009; 15:53-6. Case 1 MRCP taken after cessation of ketamine abuse for 3 months, showing resolution of biliary tree dilatation (Diameter: 4 mm) Case 1 ERCP showed a dilated common bile duct with a smooth tapered end (Diameter: 9 mm) Endoscopic Retrograde Cholangiopancreatogram (ERCP) Magnetic Resonance Cholangiopancreatogram (MRCP)
  • Etiology of dilated common bile ducts  Ketamine is metabolised in the liver and excreted in bile, we postulate that this may be the reason for the dilation of the common bile duct that we observed  The reason for the biliary tree dilatation is unknown  It is not clear whether it is caused by dysfunction in the sphincter of oddi or the formation of a benign biliary stricture  An animal study has shown that ketamine increases the flow resistance across the sphincter of oddi, via the activation of opiate receptors on the sphincter 61 Hong Kong Med J. 2009; 15:53-6
  • Other chronic complications related to ketamine use Cognitive impairment  Frequent ketamine users exhibit profound impairments in both short- and long-term memory  Few cognitive deficits seen in infrequent users Neurological Changes  White matter density reduction noted in frontal and parietal regions in ketamine addicts compared to controls 62 Am J Psychiatry 2005; 162: 2352–9. Psychopharmacology (Berl) 2006; 188: 408–24. Addiction. 2012 Jan;107(1):27-38.
  • Summary  In young adults presenting with severe irritative lower urinary tract symptoms, a positive history of ketamine abuse should be considered to have ketamine associated cystopathy  Secondary renal damage can occur in severe cases which might be irreversible  Currently, ketamine cessation is the only effective treatment modality  The outcome of treatment depends on the severity of the disease process 63
  • “ ” Thank you for your attention 64
  • Pain control  Analgesic treatment –  Mild - moderate pain: NSAID and acetaminophen– treatment of choice, (also consider nefopam)  Severe pain: opiods  Adrenergic antidepressants – (with analgesic properties)  Amitrptyline, imipramine: anticholinergic effect, H1 blockage  hydroxyzine 65
  • Radiological features (2) 66 Hong Kong Med J. 2009; 15:53-6 Case 3 A dilated common bile duct, measuring 11.2 mm in diameter Case 2 MRCP scan showed fusiform dilation of the common hepatic and bile duct
  • Antegrade pyelography-3/21  Suspect urolithiasis in upper third ureter with obstructive uropathy 67
  • 68 J Formos Med Assoc. 2011 Dec;110(12):787-91. Bladder mucosa pathology showed neutrophilic and lymphoplasma cell infiltration in bladder mucosa, which was consistent with chronic inflammation.
  • 69 Int J Urol. 2009 Oct;16(10):826-9. Urodynamic study of one patient showed detrusor overactivity with phasic contraction when filling the urinary bladder with about 90 mL of normal saline