Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy
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Abstract
Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-d-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(−)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.
Keywords
Ketamine NMDA Receptor Complex Regional Pain Syndrome Racemate Opioid ConsumptionNotes
Compliance with Ethical Standards
No funding was received for the conduct of this study. Marko A. Peltoniemi, Nora M. Hagelberg, Klaus T. Olkkola and Teijo I. Saari have no conflicts of interest that are directly relevant to the content of this study.
References
- 1.Domino EF. Taming the ketamine tiger. 1965. Anesthesiology. 2010;113:678–84.PubMedGoogle Scholar
- 2.Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–91.PubMedCrossRefGoogle Scholar
- 3.Bhutta AT. Ketamine: a controversial drug for neonates. Semin Perinatol. 2007;31:303–8.PubMedCrossRefGoogle Scholar
- 4.Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;182:313–33.PubMedCrossRefGoogle Scholar
- 5.Weber F, Wulf H, Gruber M, Biallas R. S-ketamine and s-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children. Paediatr Anaesth. 2004;14:983–8.PubMedCrossRefGoogle Scholar
- 6.Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous MS, Marinus J, Sarton EY, et al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain. 2009;145:304–11.PubMedCrossRefGoogle Scholar
- 7.Chong C, Schug SA, Page-Sharp M, Jenkins B, Ilett KF. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: preliminary findings from a three-way randomized, crossover study. Clin Drug Investig. 2009;29:317–24.PubMedCrossRefGoogle Scholar
- 8.Huge V, Lauchart M, Magerl W, Schelling G, Beyer A, Thieme D, et al. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. 2010;14:387–94.PubMedCrossRefGoogle Scholar
- 9.Riediger C, Haschke M, Bitter C, Fabbro T, Schaeren S, Urwyler A, et al. The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study. J Pain Res. 2015;8:87–94.PubMedPubMedCentralGoogle Scholar
- 10.Grant IS, Nimmo WS, Clements JA. Pharmacokinetics and analgesic effects of i.m. and oral ketamine. Br J Anaesth. 1981;53:805–10.PubMedCrossRefGoogle Scholar
- 11.Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71:539–42.PubMedCrossRefGoogle Scholar
- 12.Yanagihara Y, Ohtani M, Kariya S, Uchino K, Hiraishi T, Ashizawa N, et al. Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers. Biopharm Drug Dispos. 2003;24:37–43.PubMedCrossRefGoogle Scholar
- 13.Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Kurkinen KJ, Neuvonen PJ, et al. Rifampicin has a profound effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketamine. Basic Clin Pharmacol Toxicol. 2012;111:325–32.PubMedCrossRefGoogle Scholar
- 14.Fanta S, Kinnunen M, Backman JT, Kalso E. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur J Clin Pharmacol. 2015;71:441–7.PubMedCrossRefGoogle Scholar
- 15.Hagelberg NM, Peltoniemi MA, Saari TI, Kurkinen KJ, Laine K, Neuvonen PJ, et al. Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine. Eur J Pain. 2010;14:625–9.PubMedCrossRefGoogle Scholar
- 16.White PF, Johnston RR, Pudwill CR. Interaction of ketamine and halothane in rats. Anesthesiology. 1975;42:179–86.PubMedCrossRefGoogle Scholar
- 17.Leung LY, Baillie TA. Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J Med Chem. 1986;29:2396–9.PubMedCrossRefGoogle Scholar
- 18.Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol. 1997;333:99–104.PubMedCrossRefGoogle Scholar
- 19.Holtman JR, Crooks PA, Johnson-Hardy JK, Hojomat M, Kleven M, Wala EP. Effects of norketamine enantiomers in rodent models of persistent pain. Pharmacol Biochem Behav. 2008;90:676–85.PubMedCrossRefGoogle Scholar
- 20.Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anesth. 2011;58:911–23.PubMedCrossRefGoogle Scholar
- 21.Adams HA, Werner C. From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance? Anaesthesist. 1997;46:1026–42.PubMedCrossRefGoogle Scholar
- 22.Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19:370–80.PubMedCrossRefGoogle Scholar
- 23.White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980;52:231–9.PubMedCrossRefGoogle Scholar
- 24.Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-d-aspartate receptors. J Pharmacol Exp Ther. 1992;260:1209–13.PubMedGoogle Scholar
- 25.Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW, Zbinden AM. Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth. 1996;77:625–31.PubMedCrossRefGoogle Scholar
- 26.Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012;11:CD003351.Google Scholar
- 27.Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49:1405–28.PubMedCrossRefGoogle Scholar
- 28.Abdallah CG, Averill LA, Krystal JH. Ketamine as a promising prototype for a new generation of rapid-acting antidepressants. Ann N Y Acad Sci. 2015;1344:66–77.PubMedPubMedCentralCrossRefGoogle Scholar
- 29.Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure. 2015;30:14–20.PubMedCrossRefGoogle Scholar
- 30.Dayton PG, Stiller RL, Cook DR, Perel JM. The binding of ketamine to plasma proteins: emphasis on human plasma. Eur J Clin Pharmacol. 1983;24:825–31.PubMedCrossRefGoogle Scholar
- 31.Hijazi Y, Bodonian C, Bolon M, Salord F, Boulieu R. Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury. Br J Anaesth. 2003;90:155–60.PubMedCrossRefGoogle Scholar
- 32.Geisslinger G, Hering W, Thomann P, Knoll R, Kamp HD, Brune K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br J Anaesth. 1993;70:666–71.PubMedCrossRefGoogle Scholar
- 33.Dahan A, Olofsenl E, Sigtermans M, Noppers I, Niesters M, Aarts L, et al. Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain. Eur J Pain. 2011;15:258–67.PubMedCrossRefGoogle Scholar
- 34.Sigtermans M, Dahan A, Mooren R, Bauer M, Kest B, Sarton E, et al. S(+)-ketamine effect on experimental pain and cardiac output. Anesthesiology. 2009;111:892–903.PubMedCrossRefGoogle Scholar
- 35.Persson J, Hasselström J, Maurset A, Oye I, Svensson JO, Almqvist O, et al. Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity. Eur J Clin Pharmacol. 2002;57:869–75.PubMedCrossRefGoogle Scholar
- 36.White PF, Schüttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57:197–203.PubMedCrossRefGoogle Scholar
- 37.White M, de Graaff P, Renshof B, van Kan E, Dzoljic M. Pharmacokinetics of S(+) ketamine derived from target controlled infusion. Br J Anaesth. 2006;96:330–4.PubMedCrossRefGoogle Scholar
- 38.Schüttler J, Stanski DR, White PF, Trevor AJ, Horai Y, Verotta D, et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. J Pharmacokinet Biopharm. 1987;15:241–53.PubMedCrossRefGoogle Scholar
- 39.Ihmsen H, Geisslinger G, Schüttler J. Stereoselective pharmacokinetics of ketamine: R(−)-ketamine inhibits the elimination of S(+)-ketamine. Clin Pharmacol Ther. 2001;70:431–8.PubMedCrossRefGoogle Scholar
- 40.Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Neuvonen PJ, Olkkola KT. St John’s wort greatly decreases the plasma concentrations of oral S-ketamine. Fundam Clin Pharmacol. 2012;26:743–50.PubMedCrossRefGoogle Scholar
- 41.Peltoniemi MA, Saari TI, Hagelberg NM, Laine K, Neuvonen PJ, Olkkola KT. S-ketamine concentrations are greatly increased by grapefruit juice. Eur J Clin Pharmacol. 2012;68:979–86.PubMedCrossRefGoogle Scholar
- 42.Peltoniemi MA, Saari TI, Hagelberg NM, Reponen P, Turpeinen M, Laine K, et al. Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. Clin Pharmacol Ther. 2011;90:296–302.PubMedCrossRefGoogle Scholar
- 43.Woolf TF, Adams JD. Biotransformation of ketamine, (Z)-6-hydroxyketamine, and (E)-6-hydroxyketamine by rat, rabbit, and human liver microsomal preparations. Xenobiotica. 1987;17:839–47.PubMedCrossRefGoogle Scholar
- 44.Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002;30:853–8.PubMedCrossRefGoogle Scholar
- 45.Kharasch ED, Labroo R. Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology. 1992;77:1201–7.PubMedCrossRefGoogle Scholar
- 46.Yanagihara Y, Kariya S, Ohtani M, Uchino K, Aoyama T, Yamamura Y, et al. Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2001;29:887–90.PubMedGoogle Scholar
- 47.Noppers I, Olofsen E, Niesters M, Aarts L, Mooren R, Dahan A, et al. Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology. 2011;114:1435–45.PubMedPubMedCentralCrossRefGoogle Scholar
- 48.Herd D, Anderson BJ. Ketamine disposition in children presenting for procedural sedation and analgesia in a children’s emergency department. Paediatr Anaesth. 2007;17:622–9.PubMedCrossRefGoogle Scholar
- 49.Herd DW, Anderson BJ, Keene NA, Holford NHG. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18:36–42.PubMedCrossRefGoogle Scholar
- 50.Herd DW, Anderson BJ, Holford NHG. Modeling the norketamine metabolite in children and the implications for analgesia. Pediatr Anesth. 2007;17:831–40.CrossRefGoogle Scholar
- 51.Dallimore D, Herd DW, Short T, Anderson BJ. Dosing ketamine for pediatric procedural sedation in the emergency department. Pediatr Emerg Care. 2008;24:529–33.PubMedCrossRefGoogle Scholar
- 52.Brunette KEJ, Anderson BJ, Thomas J, Wiesner L, Herd DW, Schulein S. Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures. Paediatr Anaesth. 2011;21:653–62.PubMedCrossRefGoogle Scholar
- 53.Elkomy MH, Drover DR, Hammer GB, Galinkin JL, Ramamoorthy C. Population pharmacokinetics of ketamine in children with heart disease. Int J Pharm. 2015;478:223–31.PubMedCrossRefGoogle Scholar
- 54.Olofsen E, Noppers I, Niesters M, Kharasch E, Aarts L, Sarton E, et al. Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers. Anesthesiology. 2012;117:353–64.PubMedPubMedCentralCrossRefGoogle Scholar
- 55.Zhao X, Venkata SLV, Moaddel R, Luckenbaugh DA, Brutsche NE, Ibrahim L, et al. Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression. Br J Clin Pharmacol. 2012;74:304–14.PubMedPubMedCentralCrossRefGoogle Scholar
- 56.Absalom AR, Lee M, Menon DK, Sharar SR, De Smet T, Halliday J, et al. Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers. Br J Anaesth. 2007;98:615–23.PubMedCrossRefGoogle Scholar
- 57.Jamsen KM, McLeay SC, Barras M, Green B. Reporting a population pharmacokinetic–pharmacodynamic study: a journal’s perspective. Clin Pharmacokinet. 2014;53:111–22.PubMedCrossRefGoogle Scholar
- 58.Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacomet Syst Pharmacol. 2012;1:e6.CrossRefGoogle Scholar
- 59.Kleinloog D, Uit den Boogaard A, Dahan A, Mooren R, Klaassen E, Stevens J, et al. Optimizing the glutamatergic challenge model for psychosis, using S+-ketamine to induce psychomimetic symptoms in healthy volunteers. J Psychopharmacol. 2015;29:401–13.PubMedCrossRefGoogle Scholar
- 60.Lodge D, Anis NA. Effects of ketamine and three other anaesthetics on spinal reflexes and inhibitions in the cat. Br J Anaesth. 1984;56:1143–51.PubMedCrossRefGoogle Scholar
- 61.Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79:565–75.PubMedPubMedCentralCrossRefGoogle Scholar
- 62.Traynelis SF, Cull-Candy SG. Proton inhibition of N-methyl-d-aspartate receptors in cerebellar neurons. Nature. 1990;345:347–50.PubMedCrossRefGoogle Scholar
- 63.Fan W, Huang F, Wu Z, Zhu X, Li D, He H. The role of nitric oxide in orofacial pain. Nitric Oxide. 2012;26:32–7.PubMedCrossRefGoogle Scholar
- 64.Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-d-aspartate receptors. Anesthesiology. 1997;86:903–17.PubMedCrossRefGoogle Scholar
- 65.Pelissier T, Laurido C, Kramer V, Hernández A, Paeile C. Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats. Eur J Pharmacol. 2003;477:23–8.PubMedCrossRefGoogle Scholar
- 66.Petersen-Felix S, Arendt-Nielsen L, Bak P, Roth D, Fischer M, Bjerring P, et al. Analgesic effect in humans of subanaesthetic isoflurane concentrations evaluated by experimentally induced pain. Br J Anaesth. 1995;75:55–60.PubMedCrossRefGoogle Scholar
- 67.Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manage. 2000;19:S2–6.PubMedCrossRefGoogle Scholar
- 68.Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain. 2000;4:5–15.PubMedCrossRefGoogle Scholar
- 69.Smith DJ, Bouchal RL, deSanctis CA, Monroe PJ, Amedro JB, Perrotti JM, et al. Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology. 1987;26:1253–60.PubMedCrossRefGoogle Scholar
- 70.Finck AD, Samaniego E, Ngai SH. Morphine tolerance decreases the analgesic effects of ketamine in mice. Anesthesiology. 1988;68:397–400.PubMedCrossRefGoogle Scholar
- 71.Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol. 1995;77:355–9.PubMedCrossRefGoogle Scholar
- 72.Mikkelsen S, Ilkjaer S, Brennum J, Borgbjerg FM, Dahl JB. The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans. Anesthesiology. 1999;90:1539–45.PubMedCrossRefGoogle Scholar
- 73.Nishimura M, Sato K, Okada T, Yoshiya I, Schloss P, Shimada S, et al. Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology. 1998;88:768–74.PubMedCrossRefGoogle Scholar
- 74.Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87:1186–93.PubMedGoogle Scholar
- 75.Levänen J, Mäkelä ML, Scheinin H. Dexmedetomidine premedication attenuates ketamine-induced cardiostimulatory effects and postanesthetic delirium. Anesthesiology. 1995;82:1117–25.PubMedCrossRefGoogle Scholar
- 76.Salmi E, Långsjö JW, Aalto S, Någren K, Metsähonkala L, Kaisti KK, et al. Subanesthetic ketamine does not affect 11C-flumazenil binding in humans. Anesth. Analg. 2005;101:722–5 (table of contents).PubMedCrossRefGoogle Scholar
- 77.Shafer SL, Siegel LC, Cooke JE, Scott JC. Testing computer-controlled infusion pumps by simulation. Anesthesiology. 1988;68:261–6.PubMedCrossRefGoogle Scholar
- 78.Flood P, Krasowski MD. Intravenous anesthetics differentially modulate ligand-gated ion channels. Anesthesiology. 2000;92:1418–25.PubMedCrossRefGoogle Scholar
- 79.Kornhuber J, Mack-Burkhardt F, Kornhuber ME, Riederer P. [3H]MK-801 binding sites in post-mortem human frontal cortex. Eur J Pharmacol. 1989;162:483–90.PubMedCrossRefGoogle Scholar
- 80.Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol Psychiatry. 2002;7:837–44.PubMedCrossRefGoogle Scholar
- 81.Toro-Matos A, Rendon-Platas AM, Avila-Valdez E, Villarreal-Guzman RA. Physostigmine antagonizes ketamine. Anesth Analg. 1980;59:764–7.PubMedCrossRefGoogle Scholar
- 82.Hamilton-Davies C, Bailie R, Restall J. Physostigmine in recovery from anaesthesia. Anaesthesia. 1995;50:456–8.PubMedCrossRefGoogle Scholar
- 83.Drummond JC, Brebner J, Galloon S, Young PS. A randomized evaluation of the reversal of ketamine by physostigmine. Can Anaesth Soc J. 1979;26:288–95.PubMedCrossRefGoogle Scholar
- 84.Haeseler G, Tetzlaff D, Bufler J, Dengler R, Münte S, Hecker H, et al. Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(−)-ketamine. Anesth Analg. 2003;96:1019–26 (table of contents).PubMedCrossRefGoogle Scholar
- 85.Servin FS, Sear JW. Pharmacokinetics of intravenous anesthetics. In: Evers AS, Maze M, Kharasch ED, editors. Anesthetic pharmacology: basic principles and clinical practice. Cambridge: Cambridge University Press; 2011.Google Scholar
- 86.Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88:82–8.Google Scholar
- 87.Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth. 1981;53:27–30.PubMedCrossRefGoogle Scholar
- 88.Leung A, Wallace MS, Ridgeway B, Yaksh T. Concentration–effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain. 2001;91:177–87.PubMedCrossRefGoogle Scholar
- 89.Himmelseher S, Pfenninger E. The clinical use of S-(+)-ketamine–a determination of its place. Anasthesiol Intensivmed Notfallmed Schmerzther. 1998;33:764–70.PubMedCrossRefGoogle Scholar
- 90.Mathisen LC, Skjelbred P, Skoglund LA, Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain. 1995;61:215–20.PubMedCrossRefGoogle Scholar
- 91.Green SM, Krauss B. Ketamine is a safe, effective, and appropriate technique for emergency department paediatric procedural sedation. Emerg Med J. 2004;21:271–2.PubMedPubMedCentralCrossRefGoogle Scholar
- 92.Freye E, Sundermann S, Wilder-Smith OH. No inhibition of gastro-intestinal propulsion after propofol- or propofol/ketamine-N2O/O2 anaesthesia. A comparison of gastro-caecal transit after isoflurane anaesthesia. Acta Anaesthesiol Scand. 1998;42:664–9.PubMedCrossRefGoogle Scholar
- 93.Jennings PA, Cameron P, Bernard S, Walker T, Jolley D, Fitzgerald M, et al. Morphine and ketamine is superior to morphine alone for out-of-hospital trauma analgesia: a randomized controlled trial. Ann Emerg Med. 2012;59:497–503.PubMedCrossRefGoogle Scholar
- 94.Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015;33:197–201.PubMedCrossRefGoogle Scholar
- 95.Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014;21:1193–202.PubMedCrossRefGoogle Scholar
- 96.Richebé P, Julien M, Brulotte V. Potential strategies for preventing chronic postoperative pain: a practical approach: continuing professional development. Anaesth: Can J; 2015.Google Scholar
- 97.Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82:111–25.PubMedCrossRefGoogle Scholar
- 98.Jouguelet-Lacoste J, La Colla L, Schilling D, Chelly JE. The use of intravenous infusion or single dose of low-dose ketamine for postoperative analgesia: a review of the current literature. Pain Med. 2015;16:383–403.PubMedCrossRefGoogle Scholar
- 99.Elia N, Tramèr MR. Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain. 2005;113:61–70.PubMedCrossRefGoogle Scholar
- 100.Weinbroum AA. Non-opioid IV adjuvants in the perioperative period: pharmacological and clinical aspects of ketamine and gabapentinoids. Pharmacol Res. 2012;65:411–29.PubMedCrossRefGoogle Scholar
- 101.Ilkjaer S, Nikolajsen L, Hansen TM, Wernberg M, Brennum J, Dahl JB. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth. 1998;81:707–12.PubMedCrossRefGoogle Scholar
- 102.Mathisen LC, Aasbø V, Raeder J. Lack of pre-emptive analgesic effect of (R)-ketamine in laparoscopic cholecystectomy. Acta Anaesthesiol Scand. 1999;43:220–4.PubMedCrossRefGoogle Scholar
- 103.Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;CD004603.Google Scholar
- 104.Hans P, Dewandre P-Y, Brichant JF, Bonhomme V. Comparative effects of ketamine on bispectral index and spectral entropy of the electroencephalogram under sevoflurane anaesthesia. Br J Anaesth. 2005;94:336–40.PubMedCrossRefGoogle Scholar
- 105.Neuhäuser C, Preiss V, Feurer M-K, Müller M, Scholz S, Kwapisz M, et al. Comparison of S-(+)-ketamine- with sufentanil-based anaesthesia for elective coronary artery bypass graft surgery: effect on troponin T levels. Br J Anaesth. 2008;100:765–71.PubMedCrossRefGoogle Scholar
- 106.Sprung J, Schuetz SM, Stewart RW, Moravec CS. Effects of ketamine on the contractility of failing and nonfailing human heart muscles in vitro. Anesthesiology. 1998;88:1202–10.PubMedCrossRefGoogle Scholar
- 107.Lahtinen P, Kokki H, Hakala T, Hynynen M. S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery. Anesth Analg. 2004;99:1295–301 (table of contents).PubMedCrossRefGoogle Scholar
- 108.Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. Special articles: 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Anesth Analg. 2012;114:11–45.PubMedCrossRefGoogle Scholar
- 109.Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg. 1999;89:665–9.PubMedGoogle Scholar
- 110.Szekely A, Heindl B, Zahler S, Conzen PF, Becker BF. S(+)-ketamine, but not R(−)-ketamine, reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts. Anesth Analg. 1999;88:1017–24.PubMedCrossRefGoogle Scholar
- 111.Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L, Shapira Y, et al. Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth Analg. 2002;95:531–6 (table of contents).PubMedGoogle Scholar
- 112.Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, et al. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg. 1998;87:266–71.PubMedGoogle Scholar
- 113.Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991;254:1515–8.PubMedCrossRefGoogle Scholar
- 114.Hayashi H, Dikkes P, Soriano SG. Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain. Paediatr Anaesth. 2002;12:770–4.PubMedCrossRefGoogle Scholar
- 115.Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol. 2000;130:1692–8.PubMedPubMedCentralCrossRefGoogle Scholar
- 116.Yan J, Jiang H. Dual effects of ketamine: neurotoxicity versus neuroprotection in anesthesia for the developing brain. J Neurosurg Anesthesiol. 2014;26:155–60.PubMedCrossRefGoogle Scholar
- 117.Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg. 1999;88:797–809.PubMedCrossRefGoogle Scholar
- 118.Bai X, Yan Y, Canfield S, Muravyeva MY, Kikuchi C, Zaja I, et al. Ketamine enhances human neural stem cell proliferation and induces neuronal apoptosis via reactive oxygen species-mediated mitochondrial pathway. Anesth Analg. 2013;116:869–80.PubMedPubMedCentralCrossRefGoogle Scholar
- 119.Yan J, Li Y, Zhang Y, Lu Y, Jiang H. Repeated exposure to anesthetic ketamine can negatively impact neurodevelopment in infants: a prospective preliminary clinical study. J Child Neurol. 2014;29:1333–8.PubMedCrossRefGoogle Scholar
- 120.Koerner IP, Brambrink AM. Brain protection by anesthetic agents. Curr Opin Anaesthesiol. 2006;19:481–6.PubMedCrossRefGoogle Scholar
- 121.Sanders RD, Hassell J, Davidson AJ, Robertson NJ, Ma D. Impact of anaesthetics and surgery on neurodevelopment: an update. Br J Anaesth. 2013;110:i53–72.PubMedPubMedCentralCrossRefGoogle Scholar
- 122.Proescholdt M, Heimann A, Kempski O. Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res. 2001;904:245–51.PubMedCrossRefGoogle Scholar
- 123.Hudetz JA, Pagel PS. Neuroprotection by ketamine: a review of the experimental and clinical evidence. J Cardiothorac Vasc Anesth. 2010;24:131–42.PubMedCrossRefGoogle Scholar
- 124.Långsjö JW, Maksimow A, Salmi E, Kaisti K, Aalto S, Oikonen V, et al. S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans. Anesthesiology. 2005;103:258–68.PubMedCrossRefGoogle Scholar
- 125.Långsjö JW, Kaisti KK, Aalto S, Hinkka S, Aantaa R, Oikonen V, et al. Effects of subanesthetic doses of ketamine on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology. 2003;99:614–23.PubMedCrossRefGoogle Scholar
- 126.Långsjö JW, Salmi E, Kaisti KK, Aalto S, Hinkka S, Aantaa R, et al. Effects of subanesthetic ketamine on regional cerebral glucose metabolism in humans. Anesthesiology. 2004;100:1065–71.PubMedCrossRefGoogle Scholar
- 127.Himmelseher S, Durieux ME. Revising a dogma: ketamine for patients with neurological injury? Anesth. Analg. 2005;101:524–34 (table of contents).PubMedCrossRefGoogle Scholar
- 128.Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on ICP in traumatic brain injury. Neurocrit Care. 2014;21:163–73.PubMedCrossRefGoogle Scholar
- 129.Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet (London, England). 2006;367:1618–25.CrossRefGoogle Scholar
- 130.McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain. Acta Anaesthesiol Scand. 2014;58:1199–213.PubMedCrossRefGoogle Scholar
- 131.Humble SR, Dalton AJ, Li L. A systematic review of therapeutic interventions to reduce acute and chronic post-surgical pain after amputation, thoracotomy or mastectomy. Eur J Pain. 2015;19:451–65.PubMedCrossRefGoogle Scholar
- 132.Tena B, Gomar C, Rios J. Perioperative epidural or intravenous ketamine does not improve the effectiveness of thoracic epidural analgesia for acute and chronic pain after thoracotomy. Clin J Pain. 2014;30:490–500.PubMedCrossRefGoogle Scholar
- 133.Hu J, Liao Q, Zhang F, Tong J, Ouyang W. Chronic postthoracotomy pain and perioperative ketamine infusion. J Pain Palliat Care Pharmacother. 2014;28:117–21.PubMedCrossRefGoogle Scholar
- 134.Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009;141:210–4.PubMedCrossRefGoogle Scholar
- 135.Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77:357–67.PubMedPubMedCentralCrossRefGoogle Scholar
- 136.Niesters M, Aarts L, Sarton E, Dahan A. Influence of ketamine and morphine on descending pain modulation in chronic pain patients: a randomized placebo-controlled cross-over proof-of-concept study. Br J Anaesth. 2013;110:1010–6.PubMedCrossRefGoogle Scholar
- 137.Niesters M, Dahan A, Swartjes M, Noppers I, Fillingim RB, Aarts L, et al. Effect of ketamine on endogenous pain modulation in healthy volunteers. Pain. 2011;152:656–63.PubMedCrossRefGoogle Scholar
- 138.Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147:107–15.PubMedCrossRefGoogle Scholar
- 139.Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in patients with complex regional pain syndrome: a double-blind placebo-controlled trial of topical ketamine. Pain 2009;146:18–25PubMedCrossRefGoogle Scholar
- 140.Gewandter JS, Mohile SG, Heckler CE, Ryan JL, Kirshner JJ, Flynn PJ, et al. A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer. 2014;22:1807–14.PubMedPubMedCentralCrossRefGoogle Scholar
- 141.Bell RF. Ketamine for chronic noncancer pain: concerns regarding toxicity. Curr Opin Support Palliat Care. 2012;6:183–7.PubMedCrossRefGoogle Scholar
- 142.Hardy J, Quinn S, Fazekas B, Plummer J, Eckermann S, Agar M, et al. Randomized, double-blind, placebo-controlled study to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. J Clin Oncol. 2012;30:3611–7.PubMedCrossRefGoogle Scholar
- 143.Rivosecchi RM, Rice MJ, Smithburger PL, Buckley MS, Coons JC, Kane-Gill SL. An evidence based systematic review of remifentanil associated opioid-induced hyperalgesia. Expert Opin Drug Saf. 2014;13:587–603.PubMedCrossRefGoogle Scholar
- 144.Scheuing L, Chiu C-T, Liao H-M, Chuang D-M. Antidepressant mechanism of ketamine: perspective from preclinical studies. Front Neurosci. 2015;9:249.PubMedPubMedCentralCrossRefGoogle Scholar
- 145.Segmiller F, Rüther T, Linhardt A, Padberg F, Berger M, Pogarell O, et al. Repeated S-ketamine infusions in therapy resistant depression: a case series. J Clin Pharmacol. 2013;53:996–8.PubMedCrossRefGoogle Scholar
- 146.Liu R-J, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology. 2013;38:2268–77.PubMedPubMedCentralCrossRefGoogle Scholar
- 147.Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.PubMedCrossRefGoogle Scholar
- 148.aan het Rot M, Collins K, Murrough JW, Perez AM, Reich DL, Charney DS, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139–45.PubMedCrossRefGoogle Scholar
- 149.Zhang J-C, Li S-X, Hashimoto K. R(−)-ketamine shows greater potency and longer lasting antidepressant effects than S(+)-ketamine. Pharmacol Biochem Behav. 2014;116:137–41.PubMedCrossRefGoogle Scholar
- 150.Kranaster L, Kammerer-Ciernioch J, Hoyer C, Sartorius A. Clinically favourable effects of ketamine as an anaesthetic for electroconvulsive therapy: a retrospective study. Eur Arch Psychiatry Clin Neurosci. 2011;261:575–82.PubMedCrossRefGoogle Scholar
- 151.Rolan P, Lim S, Sunderland V, Liu Y, Molnar V. The absolute bioavailability of racemic ketamine from a novel sublingual formulation. Br J Clin Pharmacol. 2014;77:1011–6.PubMedCrossRefGoogle Scholar
- 152.Fitzgibbon D, Morgan D, Dockter D, Barry C, Kharasch ED. Initial pharmacokinetic, safety and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients. Pain. 2003;106:309–15.PubMedCrossRefGoogle Scholar
- 153.Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L, 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;108:17–27.PubMedCrossRefGoogle Scholar
- 154.Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77:203–7.PubMedCrossRefGoogle Scholar
- 155.Winstock AR, Mitcheson L, Gillatt DA, Cottrell AM. The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int. 2012;110:1762–6.PubMedCrossRefGoogle Scholar
- 156.Jhang J-F, Hsu Y-H, Kuo H-C. Possible pathophysiology of ketamine-related cystitis and associated treatment strategies. Int J Urol. 2015;22:816–25.PubMedCrossRefGoogle Scholar
- 157.Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, et al. Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain. 2010;133:2115–22.PubMedCrossRefGoogle Scholar
- 158.Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract. 2014;27:582–6.PubMedCrossRefGoogle Scholar
- 159.Brown L, Christian-Kopp S, Sherwin TS, Khan A, Barcega B, Denmark TK, et al. Adjunctive atropine is unnecessary during ketamine sedation in children. Acad Emerg Med. 2008;15:314–8.PubMedCrossRefGoogle Scholar