Ketamine*

Abstract

Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativebooks.com. The series editors welcome feedback on the articles ([email protected]). Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativebooks.com. The series editors welcome feedback on the articles ([email protected]). Specialist use only Off-label indication Continuous intravenous infusion Continuous subcutaneous infusion Cytochrome P450 Epidural N-methyl-D-aspartate Intramuscular Intravenous Per os, by mouth Per rectum Pro re nata, as required Quarta in die, four times daily Randomized controlled trial Sublingual ter in die, three times daily Water for injection Class: General anesthetic. Indications: Induction and maintenance of anesthesia; †pain unresponsive to standard treatments (postoperative, neuropathic, inflammatory, ischemic limb, myofascial and procedure-related).1Persson J. Hasselström J. Wiklund B. et al.The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans.Acta Anaesthesiol Scand. 1998; 42: 750-758Crossref PubMed Scopus (51) Google Scholar, 2Graven-Nielsen T. Aspegren Kendall S. Henriksson K.G. et al.Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients.Pain. 2000; 85: 483-491Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 3Visser E. Schug S.A. The role of ketamine in pain management.Biomed Pharmacother. 2006; 60: 341-348Crossref PubMed Scopus (186) Google Scholar Contraindications: Any situation in which an increase in blood pressure or intracranial pressure would constitute a hazard. Acute intermittent porphyria. The NMDA-glutamate receptor is a calcium channel closely involved in the development of central sensitization of dorsal horn neurons, which transmit pain signals (Figure).4Richens A. The basis of the treatment of epilepsy: neuropharmacology.in: Dam M. A practical approach to epilepsy. Pergamon Press, Oxford1991: 75-85Google Scholar At normal resting membrane potentials, the channel is blocked by magnesium and is inactive.5Mayer M.L. Westbrook G.L. Guthrie P.B. Voltage-dependent block for Mg2+ of NMDA responses in spinal cord neurones.Nature. 1984; 309: 261-263Crossref PubMed Scopus (2216) Google Scholar When the resting membrane potential is changed as a result of prolonged excitation, the channel unblocks and calcium moves into the cell. This results in neuronal hyperexcitability and consequently a reduction in opioid-responsiveness, hyperalgesia and allodynia. These effects are probably mediated by the intracellular formation of nitric oxide.6Elliott K. Minami N. Kolesnikov Y.A. Pasternak G.W. Inturrisi C.E. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids.Pain. 1994; 56: 69-75Abstract Full Text PDF PubMed Scopus (252) Google Scholar Ketamine is a dissociative anesthetic that has analgesic properties in subanesthetic doses.3Visser E. Schug S.A. The role of ketamine in pain management.Biomed Pharmacother. 2006; 60: 341-348Crossref PubMed Scopus (186) Google Scholar, 7Fallon M.T. Welsh J. The role of ketamine in pain control.Eur J Palliat Care. 1996; 3: 143-146Google Scholar Ketamine is the most potent NMDA-receptor-channel blocker available for clinical use, binding to the phencyclidine site when the channels are in the open activated state.8Øye I. Ketamine analgesia, NMDA receptors and the gates perception.Acta Anaesthesiol Scand. 1998; 42: 747-749Crossref PubMed Scopus (39) Google Scholar It also may bind to a second membrane-associated site, which decreases the frequency of channel opening.9Orser B.A. Pennefather P.S. MacDonald J.F. Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors.Anesthesiology. 1997; 86: 903-917Crossref PubMed Scopus (254) Google Scholar In some countries, both the racemic mixture and the S-enantiomer are commercially available for clinical use; in the USA, only the racemic mixture is marketed. Because of its greater affinity and selectivity for the NMDA-receptor, the S-enantiomer (parenterally) is about 4 times more potent an analgesic than the R-enantiomer, and twice as potent as the racemic mixture.10Øye I. Hustveit O. Maurset A. et al.The chiral forms of ketamine as probes for NMDA receptor function in humans.in: Kameyama T. Nabeshima T. Domino E.F. NMDA receptor related agents: Biochemistry, pharmacology and behavior. 1991. NPP Books, Ann Arbor1991: 381-389Google Scholar, 11White P.F. Ham J. Way W.L. Trevor A.J. Pharmacology of ketamine isomers in surgical patients.Anesthesiology. 1980; 52: 231-239Crossref PubMed Scopus (306) Google Scholar, 12Mathisen L.C. Skjelbred P. Skoglund L.A. Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain.Pain. 1995; 61: 215-220Abstract Full Text PDF PubMed Scopus (198) Google Scholar When equianalgesic doses are compared, the S-enantiomer is also associated with lower levels of undesirable effects, e.g., anxiety, tiredness, cognitive impairment.11White P.F. Ham J. Way W.L. Trevor A.J. Pharmacology of ketamine isomers in surgical patients.Anesthesiology. 1980; 52: 231-239Crossref PubMed Scopus (306) Google Scholar, 13Pfenninger E.G. Durieux M.E. Himmelseher S. Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers.Anesthesiology. 2002; 96: 357-366Crossref PubMed Scopus (123) Google Scholar However, no significant differences in efficacy or tolerability were found between the PO racemic mixture (median dose 320 mg/24 h), the S-enantiomer, or placebo in patients with cancer-related neuropathic pain.14Fallon M.T. Bray C. Boyd A. et al.A randomised, double-blind, placebo-controlled, parallel group study, comparing oral racemic ketamine and S-ketamine in the treatment of cancer-related neuropathic pain. [abstract].Palliat Med. 2008; 22: 440Crossref Scopus (9) Google Scholar Ketamine has other actions, some of which also may contribute to its analgesic effect. These include interactions with other calcium and sodium channels, dopamine receptors, cholinergic transmission, and noradrenergic and serotoninergic re-uptake (intact descending inhibitory pathways are necessary for analgesia), together with opioid-like and anti-inflammatory effects.15Meller S. Ketamine: relief from chronic pain through actions at the NMDA receptor?.Pain. 1996; 68: 435-436Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 16Kawasaki C. Kawasaki T. Ogata M. Nandate K. Shigematsu A. Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood.Can J Anaesth. 2001; 48: 819-823Crossref PubMed Scopus (52) Google Scholar Ketamine also appears to have a rapid antidepressant effect in patients with major depression.17Diazgranados N. Ibrahim L. Brutsche N.E. et al.A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.Arch Gen Psychiatry. 2010; 2010: 793-802Crossref Scopus (765) Google Scholar The analgesic effects of ketamine have been utilized in a wide range of clinical settings using various regimens and routes of administration. Postoperative analgesia: Two systematic reviews of 37 RCTs of subanesthetic doses of ketamine as an adjunct to opioid-based postoperative analgesia concluded that:•IV and ED ketamine reduce opioid requirements and possibly chronic post-surgical pain•CIVI (typically 120–600 microgram/kg/h) is best for surgery associated with high opioid requirements, although a single IV dose (typically 150 microgram–1 mg/kg) may suffice for minor surgery•adding ketamine to IV patient-controlled analgesia (PCA) is not effective.18Subramaniam K. Subramaniam B. Steinbrook R.A. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review.Anesth Analg. 2004; 99: 482-495Crossref PubMed Scopus (410) Google Scholar, 19Bell R.F. Dahl J.B. Moore R.A. Kalso E. Perioperative ketamine for acute postoperative pain.Cochrane Database Syst Rev. 2006; (CD004603. (Updated 2009))PubMed Google Scholar Chronic non-cancer pain: A review of subanesthetic doses of ketamine for chronic non-cancer pain (mostly neuropathic but also ischemic, fibromyalgia, post-whiplash, etc.) identified 29 RCTs and concluded that:•ketamine provides relief•undesirable effects can limit its use•because of a lack of data, long-term use should be restricted to a controlled trial.20Bell R.F. Ketamine for chronic non-cancer pain.Pain. 2009; 141: 210-214Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar There is RCT evidence of benefit in complex regional pain syndrome type 1.21Sigtermans M.J. van Hilten J.J. Bauer M.C. et al.Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1.Pain. 2009; 145: 304-311Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 22Schwartzman R.J. Alexander G.M. Grothusen J.R. et al.Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study.Pain. 2009; 147: 107-115Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar Cancer pain: A systematic review of ketamine as an adjunct to opioids in cancer pain found only two studies of sufficient quality,23Yang C.Y. Wong C.S. Chang J.Y. Ho S.T. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain.Can J Anaesth. 1996; 43: 379-383Crossref PubMed Scopus (184) Google Scholar, 24Mercadante S. Arcuri E. Tirelli W. Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.J Pain Symptom Manage. 2000; 20: 246-252Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar and concluded that there was insufficient robust evidence to reach a conclusion.20Bell R.F. Ketamine for chronic non-cancer pain.Pain. 2009; 141: 210-214Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Thus, in patients with cancer, evidence of ketamine's efficacy as an analgesic is mainly from case reports, retrospective surveys or uncontrolled studies in patients with refractory neuropathic, bone and mucositis-related pain.23Yang C.Y. Wong C.S. Chang J.Y. Ho S.T. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain.Can J Anaesth. 1996; 43: 379-383Crossref PubMed Scopus (184) Google Scholar, 24Mercadante S. Arcuri E. Tirelli W. Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.J Pain Symptom Manage. 2000; 20: 246-252Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 25Oshima E. Tei K. Kayazawa H. Urabe N. (1990) Continuous subcutaneous injection of ketamine for cancer pain.Can J Anaesth. 1990; 37: 385-392Crossref PubMed Scopus (50) Google Scholar, 26Cherry D.A. Plummer J.L. Gourlay G.K. Coates K.R. Odgers C.L. Ketamine as an adjunct to morphine in the treatment of pain.Pain. 1995; 62: 119-121Abstract Full Text PDF PubMed Scopus (51) Google Scholar, 27Luczack J. Dickenson A. Kotlinske-Lemieszek A. The role of ketamine, an NMDA receptor antagonist, in the management of pain.Progress in Palliative Care. 1995; 3: 127-134Google Scholar, 28Mercadante S. Ketamine in cancer pain: an update.Palliat Med. 1996; 10: 225-230PubMed Google Scholar, 29Bell R.F. Low-dose subcutaneous ketamine infusion and morphine tolerance.Pain. 1999; 83: 101-103Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 30Fitzgibbon E.J. Hall P. Schroder C. Seely J. Viola R. Low dose ketamine as an analgesic adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral ketamine.J Pain Symptom Manage. 2002; 23: 165-170Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 31Kannan T.R. Saxena A. Bhatnagar S. Barry A. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients.J Pain Symptom Manage. 2002; 23: 60-65Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 32Benítez-Rosario M.A. Feria M. Salinas-Martín A. Martínez-Castillo L.P. Martín-Ortega J.J. A retrospective comparison of the dose ratio between subcutaneous and oral ketamine.J Pain Symptom Manage. 2003; 25: 400-402Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 33Kotlinska-Lemieszek A. Luczak J. Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.J Pain Symptom Manage. 2004; 28: 100-102Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 34Fitzgibbon E.J. Viola R. Parenteral ketamine as an analgesic adjuvant for severe pain: development and retrospective audit of a protocol for a palliative care unit.J Palliat Med. 2005; 8: 49-57Crossref PubMed Scopus (48) Google Scholar, 35Jackson K. Ashby M. Howell D. et al.The effectiveness and adverse effects profile of "burst" ketamine in refractory cancer pain: the VCOG PM 1-00 study.J Pall Care. 2010; 26: 176-183PubMed Google Scholar, 36Lauretti G.R. Lima I.C. Reis M.P. Prado W.A. Pereira N.L. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy and amitriptyline for cancer pain management.Anesthesiology. 1999; 90: 1528-1533Crossref PubMed Scopus (156) Google Scholar, 37Jackson K. Ashby M. Martin P. et al."Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients.J Pain Symptom Manage. 2001; 22: 834-842Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 38Lossignol D.A. Obiols-Portis M. Body J.J. Successful use of ketamine for intractable cancer pain.Support Care Cancer. 2005; 13: 188-193Crossref PubMed Scopus (47) Google Scholar, 39James P.J. Howard R.F. Williams D.G. The addition of ketamine to a morphine nurse- or patient-controlled analgesia infusion (PCA/NCA) increases analgesic efficacy in children with mucositis pain.Paediatr Anaesth. 2010; 20: 805-811Crossref PubMed Scopus (20) Google Scholar Generally, ketamine is used in addition to morphine or an alternative strong opioid when further opioid increments have been ineffective or precluded by unacceptable undesirable effects. When used in this way, ketamine is generally administered PO or SC/CSCI.27Luczack J. Dickenson A. Kotlinske-Lemieszek A. The role of ketamine, an NMDA receptor antagonist, in the management of pain.Progress in Palliative Care. 1995; 3: 127-134Google Scholar, 33Kotlinska-Lemieszek A. Luczak J. Subanesthetic ketamine: an essential adjuvant for intractable cancer pain.J Pain Symptom Manage. 2004; 28: 100-102Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar It also can be administered IM, IV, SL, intranasally, PR and spinally (preservative-free formulation).24Mercadante S. Arcuri E. Tirelli W. Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.J Pain Symptom Manage. 2000; 20: 246-252Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 40Lin T.C. Wong C.S. Chen F.C. Lin S.Y. Ho S.T. Long-term epidural ketamine, morphine and bupivacaine attenuate reflex sympathetic dystrophy neuralgia.Can J Anaesth. 1998; 45: 175-177Crossref PubMed Scopus (35) Google Scholar, 41Haines D. Gaines S. N of 1 randomised controlled trials of oral ketamine in patients with chronic pain.Pain. 1999; 83: 283-287Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 42Batchelor G. Ketamine in neuropathic pain.The Pain Society Newsletter. 1999; 1: 19Google Scholar, 43Beltrutti D.P. Trompeo A.C. Di Santo S. The epidural and intrathecal administration of ketamine.Curr Rev Pain. 1999; 3: 458-472Crossref PubMed Google Scholar, 44Carr D.B. Goudas L.C. Denman W.T. et al.Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study.Pain. 2004; 108: 17-27Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 45Mercadante S. Arcuri E. Ferrera P. Villari P. Mangione S. Alternative treatments of breakthrough pain in patients receiving spinal analgesics for cancer pain.J Pain Symptom Manage. 2005; 30: 485-491Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar However, for spinal routes, concerns have been raised about the potential for neurotoxicity with long-term use.46Vranken J.H. Troost D. Wegener J.T. Kruis M.R. van der Vegt M.H. Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain.Pain. 2005; 117: 231-235Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Ketamine has been given by CIVI in adults and children in combination with opioids (fentanyl, morphine) ± midazolam to control intractable cancer pain and agitation.47Conway M. White N. Jean C.S. Zempsky W.T. Steven K. Use of continuous intravenous ketamine for end-stage cancer pain in children.J Pediatr Oncol Nurs. 2009; 26: 100-106Crossref PubMed Scopus (24) Google Scholar, 48Berger J.M. Ryan A. Vadivelu N. et al.Ketamine-fentanyl-midazolam infusion for the control of symptoms in terminal life care.Am J Hosp Palliat Care. 2000; 17: 127-132Crossref PubMed Scopus (19) Google Scholar, 49Enck R. A ketamine, fentanyl, and midazolam infusion for uncontrolled terminal pain and agitation.Am J Hosp Palliat Care. 2000; 17: 76-77Crossref PubMed Scopus (2) Google Scholar Miscellaneous: Ketamine can provide analgesia during painful procedures, e.g., change of burns dressings.50Richardson P. Mustard L. The management of pain in the burns unit.Burns. 2009; 35: 921-936Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Topical ketamine has been applied to the skin in various non-cancer pains,51Finch P.M. Knudsen L. Drummond P.D. Reduction of allodynia in patients with complex regional pain syndrome: a double-blind placebo-controlled trial of topical ketamine.Pain. 2009; 146: 18-25Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 52Gammaitoni A. Gallagher R.M. Welz-Bosna M. Topical ketamine gel: possible role in treating neuropathic pain.Pain Med. 2000; 1: 97-100Crossref PubMed Scopus (56) Google Scholar and used as an oral rinse in radiation-induced mucositits.53Slatkin N.E. Rhiner M. Topical ketamine in the treatment of mucositis pain.Pain Med. 2003; 4: 298-303Crossref PubMed Scopus (58) Google Scholar “Burst” ketamine: There is some evidence that short-term “burst” treatment with ketamine may have relatively long-term benefit in both cancer and non-cancer pain. For example, in patients taking regular strong opioids for ischemic limb pain, a single 4 h IV infusion of ketamine 600 microgram/kg reduced opioid requirements during a week of observation.54Mitchell A.C. Fallon M.T. A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial.Pain. 2002; 97: 275-281Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Ketamine 100 mg/24 h by CIVI for 2 days in a cancer patient, repeated a month later, reduced opioid requirements by 70%.55Mercadante S. Villari P. Ferrera P. Burst ketamine to reverse opioid tolerance in cancer pain.J Pain Symptom Manage. 2003; 25: 302-305Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar In several case series of cancer patients with severe intractable pain from various causes, “burst” ketamine 100–500 mg/24 h by CSCI for 3–5 days relieved pain in about 50% of patients.35Jackson K. Ashby M. Howell D. et al.The effectiveness and adverse effects profile of "burst" ketamine in refractory cancer pain: the VCOG PM 1-00 study.J Pall Care. 2010; 26: 176-183PubMed Google Scholar, 37Jackson K. Ashby M. Martin P. et al."Burst" ketamine for refractory cancer pain: an open-label audit of 39 patients.J Pain Symptom Manage. 2001; 22: 834-842Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 56Wilcock A. Burst ketamine in cancer patients.Data on file. 2005; Google Scholar Relief lasted from several days to one month, and occasionally for two months. In one study using this regimen, although there were no withdrawals, 1/4 of the patients experienced severe undesirable effects, such as sedation and confusion.35Jackson K. Ashby M. Howell D. et al.The effectiveness and adverse effects profile of "burst" ketamine in refractory cancer pain: the VCOG PM 1-00 study.J Pall Care. 2010; 26: 176-183PubMed Google Scholar There is increasing concern about the potential for urinary tract toxicity with ketamine (see Box A). Thus, in patients with a prognosis of months to years, it is probably best to first try a “burst” approach and limit the long-term regular use of ketamine to situations where this fails. Even then, after 2–3 weeks of satisfactory analgesia with regular ketamine, an attempt can be made to tail off the ketamine over several weeks. Although this may fail and the dose may need to be increased again, for some patients benefit persists without ketamine for weeks to months, or with a smaller maintenance dose.57Fallon M. Personal communication, 2010.Google ScholarBox AKetamine and urinary tract toxicityThe use of ketamine can cause urinary tract symptoms, e.g., frequency, urgency, urge incontinence, dysuria, and hematuria.69Chu P.S. Ma W.K. Wong S.C. et al.The destruction of the lower urinary tract by ketamine abuse: a new syndrome?.BJU Int. 2008; 102: 1616-1622Crossref PubMed Scopus (284) Google Scholar, 70Shahani R. Streutker C. Dickson B. Stewart R.J. Ketamine-associated ulcerative cystitis: a new clinical entity.Urology. 2007; 69: 810-812Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar The causal agent has not been determined, but direct irritation by ketamine and/or its metabolites is a possibility.Investigations have revealed interstitial cystitis, detrusor overactivity, decreased bladder capacity, vesico-ureteric reflux, hydronephrosis, papillary necrosis, and renal impairment. Irreversible damage leading to renal failure has occurred.The largest case series involved 59 people who had used “street” ketamine over a prolonged period (6 months–several years).69Chu P.S. Ma W.K. Wong S.C. et al.The destruction of the lower urinary tract by ketamine abuse: a new syndrome?.BJU Int. 2008; 102: 1616-1622Crossref PubMed Scopus (284) Google ScholarA small series of three chronic pain patients developed urinary symptoms after receiving ketamine PO 650–800 mg/24 h for 5–18 months.71Storr T.M. Quibell R. Can ketamine prescribed for pain cause damage to the urinary tract?.Palliat Med. 2009; 23: 670-672Crossref PubMed Scopus (39) Google Scholar However, urinary symptoms developed after only 9 days in a 16 year-old receiving ketamine PO 8 mg/kg/24 h.72Grégoire M.C. MacLellan D.L. Finley G.A. A pediatric case of ketamine-associated cystitis.Urology. 2008; 71: 1232-1233Abstract Full Text Full Text PDF PubMed Scopus (47) Google ScholarThus, when patients on ketamine experience urinary symptoms with no evidence of bacterial infection, practitioners should consider discontinuing the ketamine and seeking the advice of a urologist.Symptoms generally settle several weeks after stopping ketamine; ideally this should be done gradually to avoid worsening pain (see Dose and Use).73Mitchell A.C. Generalized hyperalgesia and allodynia following abrupt cessation of subcutaneous ketamine infusion.Palliat Med. 1999; 13: 427-428Crossref PubMed Scopus (18) Google Scholar The use of ketamine can cause urinary tract symptoms, e.g., frequency, urgency, urge incontinence, dysuria, and hematuria.69Chu P.S. Ma W.K. Wong S.C. et al.The destruction of the lower urinary tract by ketamine abuse: a new syndrome?.BJU Int. 2008; 102: 1616-1622Crossref PubMed Scopus (284) Google Scholar, 70Shahani R. Streutker C. Dickson B. Stewart R.J. Ketamine-associated ulcerative cystitis: a new clinical entity.Urology. 2007; 69: 810-812Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar The causal agent has not been determined, but direct irritation by ketamine and/or its metabolites is a possibility. Investigations have revealed interstitial cystitis, detrusor overactivity, decreased bladder capacity, vesico-ureteric reflux, hydronephrosis, papillary necrosis, and renal impairment. Irreversible damage leading to renal failure has occurred. The largest case series involved 59 people who had used “street” ketamine over a prolonged period (6 months–several years).69Chu P.S. Ma W.K. Wong S.C. et al.The destruction of the lower urinary tract by ketamine abuse: a new syndrome?.BJU Int. 2008; 102: 1616-1622Crossref PubMed Scopus (284) Google Scholar A small series of three chronic pain patients developed urinary symptoms after receiving ketamine PO 650–800 mg/24 h for 5–18 months.71Storr T.M. Quibell R. Can ketamine prescribed for pain cause damage to the urinary tract?.Palliat Med. 2009; 23: 670-672Crossref PubMed Scopus (39) Google Scholar However, urinary symptoms developed after only 9 days in a 16 year-old receiving ketamine PO 8 mg/kg/24 h.72Grégoire M.C. MacLellan D.L. Finley G.A. A pediatric case of ketamine-associated cystitis.Urology. 2008; 71: 1232-1233Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Thus, when patients on ketamine experience urinary symptoms with no evidence of bacterial infection, practitioners should consider discontinuing the ketamine and seeking the advice of a urologist. Symptoms generally settle several weeks after stopping ketamine; ideally this should be done gradually to avoid worsening pain (see Dose and Use).73Mitchell A.C. Generalized hyperalgesia and allodynia following abrupt cessation of subcutaneous ketamine infusion.Palliat Med. 1999; 13: 427-428Crossref PubMed Scopus (18) Google Scholar PO ketamine undergoes extensive first-pass hepatic metabolism mainly to norketamine (via CYP3A4).58Hijazi Y. Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes.Drug Metab Dispos. 2002; 30: 853-858Crossref PubMed Scopus (242) Google Scholar As an anesthetic, norketamine is about 1/3 as potent as parenteral ketamine. However, as an analgesic, it is equipotent. The maximum blood concentration of norketamine is greater after PO administration than after an injection,59Clements J.A. Nimmo W.S. Grant I.S. Bioavailability, pharmacokinetics and analgesic activity of ketamine in humans.J Pharm Sci. 1982; 71: 539-542Crossref PubMed Scopus (234) Google Scholar and in chronic use norketamine may be the main analgesic agent. Ketamine causes tachycardia and intracranial hypertension. After anesthetic use, most patients experience vivid dreams, misperceptions, hallucinations and alterations in body image and mood as emergent (psychotomimetic) phenomena, i.e., as the effects of a bolus dose wear off. These occur to a lesser extent with the subanesthetic analgesic doses given PO or CSCI, and generally can be controlled by concurrent administration of a benzodiazepine (e.g., diazepam, midazolam) or haloperidol.24Mercadante S. Arcuri E. Tirelli W. Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study.J Pain Symptom Manage. 2000; 20: 246-252Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 60Hughes A. Crosby V. Wilcock A. Corcoran R. Ketamine.CME Bulletin Palliat Med. 1999; 1: 53Google Scholar, 61Giannini A.J. Underwood N.A. Condon M. (2000) Acute ketamine intoxication treated by haloperidol: a preliminary study.Am J Ther. 2000; 7: 389-391Crossref PubMed Scopus (39) Google Scholar Subanesthetic doses of ketamine are associated with impaired attention, memory and judgement, and it is used as a pharmacological model for acute schizophrenia.3Visser E. Schug S.A. The role of ketamine in pain management.Biomed Pharmacother. 2006; 60: 341-348Crossref PubMed Scopus (186) Google Scholar Less than 10% of ketamine is excreted unchanged, half in the feces and half renally. Norketamine is excreted renally. Long-term use of ketamine leads to hepatic enzyme induction and enhanced ketamine metabolism. Bioavailability: 93% IM; 45% nasal; 30% SL; 30% PR; and 20% PO.62Chong C.C. Schug S. Page-Sharp M. Ilett K. Bioavailability of ketamine after oral or sublingual administration. [abstract].Pain Med. 2006; 7: 469Crossref Google Scholar, 63Yanagihara Y. Ohtani M. Kariya S. et al.Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.Biopharm Drug Dispos. 2003; 24: 37-43Crossref PubMed Scopus (128) Google Scholar Onset of action: 5 min IM; 15–30 min SC; 30 min PO. Time to peak plasma concentration: no data SC; 30 min PO; 1 h norketamine.64Grant I.S. Nimmo W.S. Clements J.A. Pharmacokinetics and analgesic effects of IM and oral ketamine.Br J Anaesth. 1981; 53: 805-810Crossref PubMed Scopus (268)