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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.

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References

  1. Domino EF. Taming the ketamine tiger. 1965. Anesthesiology. 2010;113:678–84.

    PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  3. Bhutta AT. Ketamine: a controversial drug for neonates. Semin Perinatol. 2007;31:303–8.

    Article  PubMed  Google Scholar 

  4. Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;182:313–33.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google Scholar 

  11. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71:539–42.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  16. White PF, Johnston RR, Pudwill CR. Interaction of ketamine and halothane in rats. Anesthesiology. 1975;42:179–86.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  21. Adams HA, Werner C. From the racemate to the eutomer: (S)-ketamine. Renaissance of a substance? Anaesthesist. 1997;46:1026–42.

    Article  CAS  PubMed  Google Scholar 

  22. Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19:370–80.

    Article  CAS  PubMed  Google Scholar 

  23. White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980;52:231–9.

    Article  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  26. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012;11:CD003351.

  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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure. 2015;30:14–20.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  45. Kharasch ED, Labroo R. Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology. 1992;77:1201–7.

    Article  CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  PubMed  Google Scholar 

  49. Herd DW, Anderson BJ, Keene NA, Holford NHG. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18:36–42.

    Article  PubMed  Google 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.

    Article  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  58. Mould DR, Upton RN. Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacomet Syst Pharmacol. 2012;1:e6.

    Article  CAS  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Traynelis SF, Cull-Candy SG. Proton inhibition of N-methyl-d-aspartate receptors in cerebellar neurons. Nature. 1990;345:347–50.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  CAS  Google Scholar 

  64. Orser BA, Pennefather PS, MacDonald JF. Multiple mechanisms of ketamine blockade of N-methyl-d-aspartate receptors. Anesthesiology. 1997;86:903–17.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  68. Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain. 2000;4:5–15.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  70. Finck AD, Samaniego E, Ngai SH. Morphine tolerance decreases the analgesic effects of ketamine in mice. Anesthesiology. 1988;68:397–400.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  74. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87:1186–93.

    CAS  PubMed  Google Scholar 

  75. Levänen J, Mäkelä ML, Scheinin H. Dexmedetomidine premedication attenuates ketamine-induced cardiostimulatory effects and postanesthetic delirium. Anesthesiology. 1995;82:1117–25.

    Article  PubMed  Google 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).

    Article  CAS  PubMed  Google Scholar 

  77. Shafer SL, Siegel LC, Cooke JE, Scott JC. Testing computer-controlled infusion pumps by simulation. Anesthesiology. 1988;68:261–6.

    Article  CAS  PubMed  Google Scholar 

  78. Flood P, Krasowski MD. Intravenous anesthetics differentially modulate ligand-gated ion channels. Anesthesiology. 2000;92:1418–25.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  81. Toro-Matos A, Rendon-Platas AM, Avila-Valdez E, Villarreal-Guzman RA. Physostigmine antagonizes ketamine. Anesth Analg. 1980;59:764–7.

    Article  CAS  PubMed  Google Scholar 

  82. Hamilton-Davies C, Bailie R, Restall J. Physostigmine in recovery from anaesthesia. Anaesthesia. 1995;50:456–8.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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).

    Article  CAS  PubMed  Google 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.

  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.

  87. Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth. 1981;53:27–30.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  99. Elia N, Tramèr MR. Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain. 2005;113:61–70.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  103. Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;CD004603.

  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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  CAS  Google 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.

    Article  CAS  PubMed  Google 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).

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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).

    CAS  PubMed  Google 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.

    CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  PubMed  Google Scholar 

  117. Hodgson PS, Neal JM, Pollock JE, Liu SS. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg. 1999;88:797–809.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  PubMed  Google Scholar 

  120. Koerner IP, Brambrink AM. Brain protection by anesthetic agents. Curr Opin Anaesthesiol. 2006;19:481–6.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Proescholdt M, Heimann A, Kempski O. Neuroprotection of S(+) ketamine isomer in global forebrain ischemia. Brain Res. 2001;904:245–51.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  127. Himmelseher S, Durieux ME. Revising a dogma: ketamine for patients with neurological injury? Anesth. Analg. 2005;101:524–34 (table of contents).

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  129. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet (London, England). 2006;367:1618–25.

    Article  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  134. Bell RF. Ketamine for chronic non-cancer pain. Pain. 2009;141:210–4.

    Article  CAS  PubMed  Google Scholar 

  135. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77:357–67.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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;146:18–25

    Article  CAS  PubMed  Google 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.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Bell RF. Ketamine for chronic noncancer pain: concerns regarding toxicity. Curr Opin Support Palliat Care. 2012;6:183–7.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  158. Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract. 2014;27:582–6.

    Article  PubMed  Google 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.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Perioperative Services, Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku and Turku University Hospital, Hämeentie 11, PO Box 52, 20520, Turku, Finland

    Marko A. Peltoniemi, Nora M. Hagelberg & Teijo I. Saari

  2. Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 4, PO Box 340, 00029, Helsinki, Finland

    Klaus T. Olkkola

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  1. Marko A. Peltoniemi
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  2. Nora M. Hagelberg
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  3. Klaus T. Olkkola
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  4. Teijo I. Saari
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Correspondence to Marko A. Peltoniemi.

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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.

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Peltoniemi, M.A., Hagelberg, N.M., Olkkola, K.T. et al. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet 55, 1059–1077 (2016). https://doi.org/10.1007/s40262-016-0383-6

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