Share this article on:

History of anaesthesia: The ketamine story – past, present and future

Mion, Georges

European Journal of Anaesthesiology: September 2017 - Volume 34 - Issue 9 - p 571–575
doi: 10.1097/EJA.0000000000000638
Editorials

From the Department Anaesthesia, Cochin Hospital, Paris, France

Correspondence to Prof. Georges Mion, Département d’Anesthésie-Réanimation, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France Tel: +33 660 246 440; e-mail: mion.georges@bbox.fr

The history of ketamine begins in the 1950s at Parke-Davis and Company's laboratories in Detroit, Michigan, USA. At that time, Parke-Davis were searching among cyclohexylamines for an ‘ideal’ anaesthetic agent with analgesic properties.

Maddox, a chemist, discovered a process which led to the synthesis of phencyclidine or PCP [N-(1-phenyl-cyclohexyl)-piperidine] on 26 March 1956.1,2 Parke-Davis pharmacologist, Dr Chen, received the compound CI-395 (Fig. 1) from Maddox on 11 September 1958. Chen and, in the same period, Dr Domino,1 began to study the experimental effects of the drug on animals. Phencyclidine created potent analgesia in animals: laparotomies were performed in monkeys without pain, but the animals were in a cataleptic state with their eyes open, and muscle relaxation was of poor quality. Chen3 defined catalepsy as a ‘characteristic akinetic state with a loss of orthostatic reflexes but without impairment of consciousness, in which the extremities appear to be paralysed by motor and sensory failure’.

Parke-Davis then investigated the potential of phencyclidine as a human anaesthetic under the trade name of Sernyl (Parkes-Davis). In 1958, the first human trials of PCP (Sernyl) were published by Dr Greifenstein (1915 to 1997), professor of anaesthesiology at the Wayne State University, Detroit. PCP caused increases in blood pressure, respiratory rate and minute volume, with conservation of corneal and laryngeal reflexes. The presence of nystagmus and increased salivation were noted. These studies revealed genuine narcosis, with a cataleptic state, potent amnesia and analgesia produced by ketamine anaesthesia.4 Greifenstein and John Stirling Meyer, head of neurology at Wayne State University, concluded that phencyclidine produced a ‘centrally mediated’ sensory deprivation syndrome.1

Surgical incision, and in 30 patients of Greifenstein's series, the complete operation, could be performed under Sernyl alone. But Sernyl was unsatisfactory for surgery in 13 patients, five of whom suffered severe excitation. Ten of the 64 patients were unmanageable in the postoperative period, and some had a very prolonged postoperative recovery (3 to 18 h). It was immediately observed that in no instances did the electroencephalographic (EEG) trace resemble that obtained following the administration of a barbiturate, nor did it resemble the pattern of sleep.4

Johnstone and Evans published their clinical experience in the British Journal of Anaesthesia in 1959.5 They stated that ‘Sernyl was undoubtedly the most potent general analgesic agent which had been used in clinical medicine’. It had the unique advantage over other sedatives and analgesics that it did not cause depression of cardiovascular and respiratory function, nor depression of pharyngeal and laryngeal reflexes, and could be used safely in elderly patients. However, the usefulness of the drug was limited by the excitation which sometimes persisted for more than 12 h after a single dose. The authors spoke of psychotic reactions.5

With growing clinical knowledge, it became clear that phencyclidine was not suitable for human anaesthesia. Eticyclidine, CI-400 or PCE (N-ethyl-1-phenyl-cyclo-hexylamine; Fig. 2), was developed by Parke-Davis in the late 1950s,6 but, because of frequent hallucinations and the concomitant discovery of ketamine, it was not used extensively in clinical practice. The molecule induced a state of catatonia with generalised rigidity and had, like PCP, neither respiratory nor circulatory depressant effects. In 1960, Collins et al. analysed the provided state of consciousness as a kind of trance resulting in a ‘dissociation’ from the environment. On the EEG, delta waves appeared to be related to the analgesic effect. They supposed that the mechanism could possibly be a direct cortical dissociation, or a block of the thalamus or thalamocortical paths.7 PCE was placed into the Schedule I list of illegal drugs in the 1970s.

Dr Cal Bratton, head of pharmaceutical research at Parke-Davis, promoted further synthesis of related compounds in the hope of reducing PCP side-effects.1 Calvin Lee Stevens PhD (1923 to 2014) was a chemical consultant to Parke-Davis. He was a professor of organic chemistry at Wayne State University (Detroit, Michigan). Stevens now decided to synthesise a unique series of phencyclidine derivatives in his laboratory. Drs Chen and McCarthy and others,8 screened these in animals, especially monkeys.

One of the agents, synthesised in 1962 by Calvin Stevens, produced excellent anaesthesia and was short-acting. It was selected for human trials as CI-581 [2-(O-chloro-phenyl)-2-methyl-amino cyclohexanone],1 and because it was a ketone together with an amine, was named ketamine (Fig. 3). Surprisingly, McCarthy et al.8 described it in 1965 as being a compound with cataleptic, analgesic and anaesthetic action but without hypnotic properties.

One day in early 1964, Domino was contacted by Parke-Davis to study CI-581 in humans. As he was not an anaesthesiologist, he called his colleague Dr Corssen, a professor in anaesthesiology at the University of Michigan, who was interested in intravenous anaesthetics. Dr Corssen (1916 to 1990), who had been a war hero in the Wehrmacht during World War II, emigrated to the United States after the war and practised anaesthesiology and pain medicine. The first human administration was conducted by Corssen and Domino on 3 August 1964, to volunteer prisoners at the Jackson Prison in the state of Michigan.9 The incidence of adverse effects was one in three. Corssen and Domino observed that patients described their feeling of floating in outer space and having no feelings in the limbs.1 Domino et al.10 published the first clinical studies in 1965. They had ‘a good deal of discussion’ about how they would publish the data. The term ‘schizophrenomimetic’ would probably have nipped in the bud the future of the new molecule, and the three researchers were about to coin the term ‘dreaming’ to describe the peculiar anaesthetic state, when fortunately, as Domino spoke to his wife Toni of the fact that patients seemed to be ‘disconnected’, she suggested the term ‘dissociative anaesthetic’.1 So was ketamine finally characterised.11 Dissociative anaesthesia was later described as the electrophysiological and functional dissociation between thalamocortical and limbic systems.

Domino et al., continued to research and publish on ketamine,12–15 and the literature soon had contributions from German,16–18 Italian,19 Brazilian,20 Japanese21 and Danish22 teams. Ketamine arrived in France in 1970 after the 1968 publication by Lassner in ‘Les Cahiers d’Anesthésiologie’.23 The teams of Vourc’h et al.24 and Gauthier-Lafaye et al.25 published the first French clinical trials. Ketamine provided potent analgesia but was less potent and of considerably shorter duration of action than PCP, particularly with regard to psychic problematic effects. The introduction of ketamine in Britain in late 1969 had been described as a ‘disaster’ from which the drug never recovered.9 In 1970, hallucinations were considered so unpleasant that patient acceptance was much lower than with the barbiturates.26

Ketamine began as a veterinary anaesthetic when it was patented in Belgium in 1963. After being patented by Parke-Davis for human and animal use in 1966, ketamine became available by prescription in 1969 in the form of ketamine hydrochloride, under the name of Ketalar. It was officially approved for human consumption by the United States Food and Drug Administration in 1970 and, because of its sympathomimetic properties and its wide margin of safety, was administered as a field anaesthetic to soldiers during the Vietnam war.

The analgesic properties of the molecule were at that time a major argument for its development. Soon, chlorpromazine,27 diazepam28 or droperidol29 were proposed to limit the emergence excitement, which remained a real problem for procedures in which ketamine was used as an induction agent.30 Gorringe et al.31 warned in 1970 about the necessity to inject the induction dose in no less than 60 s and to avoid useless stimulation during emergence. In 1971, Sadove et al.32 demonstrated that ‘subdissociative’ doses (0.44 mg kg−1) of ketamine possessed analgesic properties with moderate side effects.

In subsequent years, many works clarified ketamine handling, such as intramuscular administration,33 its pharmacokinetics34–37 and that of its isomers,38 and its indications of choice (shock,39 asthma, emergency and crisis situations, burns, obstetrics, analgesia, etc.) as well as controversies regarding raised intracranial pressure40,41 or epilepsy.42 White et al.,43 one of the first to study ketamine isomers in man, published a shining review in Anesthesiology in 1982.44

Concerns over the so-called psychedelic effects of ketamine and the arrival of new intravenous hypnotics such as propofol prompted a marked decrease in the use of ketamine in the affluent world. Moreover, ketamine abuse45 appeared during the Vietnam war and on the East Coast of the United States and increased from 1978 onwards following the publication of two books; Marcia Moore's (1928 to 1979) ‘Journeys into the Bright World’ and John Lily's (1915 to 2001) ‘The Scientist’ put forward the authors’ psychedelic experiences. Because of this abuse, ketamine was placed among the class III substances of the US Controlled Substances Act in 1999. An interesting collateral effect of the psychedelic properties of ketamine, especially the induction of near-death experiences,46 was the development of a therapeutic use of ketamine in palliative medicine.47 In his book ‘Ketamine: Dreams and Realities’, Dr Jansen PhD, an English psychiatrist, suggested that under medical supervision, the drug's potent healing powers could be used to treat certain mental distresses (the so-called KPT: Ketamine Psychedelic Therapy).

Over the past 20 years numerous studies have revolutionised the field of ketamine knowledge. In 1980 Collingridge48 discovered that activation of the glutamate N-methyl-D-aspartate calcium channel (NMDA receptor) was responsible for induction of synaptic plasticity, and in 1986 Morris showed that NMDA receptor blockade induced inability to form a spatial memory in rodents. The discovery of the NMDA receptor and its noncompetitive inhibition by ketamine,49 first observed by David Lodge's team at the beginning of the 1980s,50 prompted large advances in the pathophysiology of hyperalgesia,51 schizophrenia52 and mental functioning.53 It became evident that memory, thinking and consciousness were the result of synaptic plasticity and of the fine tuning of glutamatergic influences via NMDA receptor-mediated phenomena.

In the early 1990s, with the arrival of remifentanil,54 the grail of high-dose opioid anaesthesia was close to being achieved. On the contrary, the high plasma concentrations of opioid allowed by the very short contextual half-life prompted an unexpected problem of opioid-induced hyperalgesia.55 The cause of this was not immediately recognised, and it was thought that in the immediate postoperative period, patients only suffered from a decrease of opioid analgesia. The active research in the field of NMDA receptor blockade led to decisive progress in the understanding of this phenomenon.56 In fact, it was demonstrated that opioids, together with eliciting a potent analgesia through μ-receptors, were able to open NMDA receptors in a dose-dependent manner and to trigger opioid-induced hyperalgesia.57 This led to a paradigm shift in the management of perioperative and other categories of pain, particularly chronic pain,58 and to a comeback of ketamine, as an NMDA receptor blocking agent and a so-called antihyperalgesic drug.59

Ketamine is now being used to manage treatment-resistant depression.60 Indeed, 25 years before the first randomised controlled trials of ketamine in depression by Berman et al.61 and by Kudoh et al.62 demonstrated that low-dose ketamine improves the postoperative state of depressed patients, Sofia had experimentally observed that ketamine possessed an antidepressant activity.63 As, contrary to ordinary antidepressants, ketamine does not act within weeks, but within only a few hours, it has been proposed as a potential fast antidepressant in patients with high suicidal risk.64

Today, the interest in ketamine continues. Its value and safety in anaesthetic and analgesic management have been demonstrated in thousands of patients, and after more than 50 years, ketamine makes a true clinical comeback in the affluent world. In the less affluent world, and since the Vietnam war 40 years ago, it has remained a crucial sole anaesthetic agent enabling surgery to be performed where, without it, nothing would be possible.65

During the 2000s, ketamine acquired the original position of an antihyperalgesic drug with a rightful place in the modern multimodal analgesic armamentarium.66 In the near future, its chemistry could change. In addition to the possible spreading of S-(+)-ketamine use, new ultra-short-acting ketamine analogues67 or even antagonists68 may become available. Could this be the definite end of half a century of emergence problems?

Back to Top | Article Outline

Acknowledgements relating to this article

Assistance with the Editorial: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Comment from the Editor: this Editorial is part of the ‘History of Anaesthesia’ series that is edited by Dr David Wilkinson.

Back to Top | Article Outline

References

1. Domino EF. Taming the ketamine tiger. 1965. Anesthesiology 2010; 113:678–684.
2. Maddox VH, Godefroi EF, Parcell RF. The synthesis of phencyclidine and other 1-arylcyclohexylamines. J Med Chem 1965; 8:230–235.
3. Chen G. Evaluation of phencyclidine-type cataleptic activity. Arch Int Pharmacodyn Ther 1965; 157:193–201.
4. Greifenstein FE, De Vault M, Yoshitake J, et al. A study of a I-aryl cyclo hexyl amine for anesthesia. Anesth Analg 1958; 37:283–294.
5. Johnstone M, Evans V, Baigel S. Sernyl (CI-395) in clinical anaesthesia. Br J Anaesth 1959; 31:433–439.
6. Lear E, Suntay R, Pallin IM, et al. Cyclohexamine (CI-400). A new intravenous agent. Anesthesiology 1959; 20:330–335.
7. Collins VJ, Gorospe CA, Rovenstine EA. Intravenous nonbarbiturate nonnarcotic analgesics: preliminary studies. I. Cyclohexylamines. Anesth Analg 1960; 39:302–306.
8. McCarthy DA, Chen G, Kaump DH, et al. General anesthetic and other pharmacological properties of 2-(O-chlorophenyl)-2-methylamino cyclohexanone HCl (CI 581). J New Drugs 1965; 5:21–33.
9. Dundee JW. Twenty-five years of ketamine. A report of an international meeting. Anaesthesia 1990; 45:159–160.
10. Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther 1965; 6:279–291.
11. Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 1966; 45:29–40.
12. Corssen G, Miyasaka M, Domino EF. Changing concepts in pain control during surgery: dissociative anesthesia with CI-581. A progress report. Anesth Analg 1968; 47:746–759.
13. Stanley V, Hunt J, Willis KW, et al. Cardiovascular and respiratory function with CI-581. Anesth Analg 1968; 47:760–768.
14. Miyasaka M, Domino EF. Neural mechanisms of ketamine-induced anesthesia. Int J Neuropharmacol 1968; 7:557–573.
15. Corssen G, Domino EF, Bree RL. Electroencephalographic effects of ketamine anesthesia in children. Anesth Analg 1969; 48:141–147.
16. Kreuscher H, Gauch H. The effect of phencyclidine derivatives ketamine (CI 581) on the cardiovascular system of the man. Anaesthesist 1967; 16:229–233.
17. Podlesch I, Zindler M. First experience with the phencyclidine derivative ketamine (CI-581), a new intravenous and intramuscular anesthetic. Anaesthesist 1967; 16:299–303.
18. Langrehr D, Alai P, Andjelković J, et al. On anesthesia using ketamine (CI-581): report of 1st experience in 500 cases. Anaesthesist 1967; 16:308–318.
19. Maritano M, Vergano F, Zaccagna CA, et al. Our experience with CI-581. Minerva Anestesiol 1969; 35:937–946.
20. Teuteberg HW, Nolte H. Ketamine, a new intravenous anesthetic with increased analgesic properties. Rev Bras Anestesiol 1969; 19:459–469.
21. Shibuya T, Horibe M, Sasaki Y, et al. Pharmacological study on 2-(O-chlorophenyl)-2-methylamino-cyclohexanone HC1 (CI-581), especially the effect on the central nervous system. Zasshi Tokyo Ika Daigaku 1969; 27:249–256.
22. Holten Jensen AM, Egebo K, Hansen A, et al. Ketalar (CI-581): a new short-acting anesthetic. Nord Med 1970; 84:1074–1077.
23. Lassner J. A new anesthetic, cyclohexylamine (C.I.-581 or ketamine). Remarks on its psychic effects. Cah Anesthesiol 1968; 16:1005–1012.
24. Conseiller C, Levante A, Vourc’h G. Ketamine, a new anesthetic agent. Anesth Analg (Paris) 1970; 27:1–28.
25. Mangeney F, Muhlmann-Weill M, Gauthier-Lafaye JP. Ketalar anesthesia; personal experience in 400 cases. Anesth Analg (Paris) 1971; 28:903–944.
26. Knox JW, Bovill JG, Clarke RS, et al. Clinical studies of induction agents. XXXVI: Ketamine. Br J Anaesth 1970; 42:875–885.
27. Erbguth PH, Reiman B, Klein RL. The influence of chlorpromazine, diazepam, and droperidol on emergence from ketamine. Anesth Analg 1972; 51:693–700.
28. Muhlmann-Weill M, Mangeney F, Gauthier-Lafaye JP. Ketamine-diazepam association in anesthesia. Anesth Analg (Paris) 1972; 29:355–363.
29. Sadove MS, Hatano S, Zahed B, et al. Clinical study of droperidol in the prevention of the side effects of ketamine anesthesia: a preliminary report. Anesth Analg 1971; 50:388–393.
30. Dundee JW, Knox JW, Black GW, et al. Ketamine as an induction agent in anaesthetics. Lancet 1970; 1:1370–1371.
31. Gorringe JA, Danchin J, Evans DP, et al. Ketamine. Lancet 1970; 2:149.
32. Sadove MS, Shulman M, Hatano S, et al. Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg 1971; 50:452–457.
33. Phillips LA, Seruvatu SG, Rika PN, et al. Anaesthesia for the surgeon-anaesthetist in difficult situations: the use of intramuscular 2(O-chlorophenyl)-2 methylamino cyclohexanone HCl (Parke Davis CI-581, Ketamine). Anaesthesia 1970; 25:36–45.
34. Idwall J, Ahlgren I, Aronsen KR, et al. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth 1979; 51:1167–1173.
35. Clements JA, Nimmo WS. The pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 1981; 53:27–30.
36. Domino EF, Domino SE, Smith RE, et al. Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther 1984; 36:645–653.
37. Absalom AR, Lee M, Menon DK, 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; 98:615–623.
38. Marietta MP, Way WL, Castagnoli N Jr, et al. On the pharmacology of the ketamine enantiomorphs in the rat. J Pharmacol Exp Ther 1977; 202:157–165.
39. McGown RG. A technique of anaesthesia in haemorrhagic shock. Anaesthesia 1975; 30:616–623.
40. Adams HA, Hempelmann G. 20 years of ketamine – a backward look. Anaesthesist 1990; 39:71–76.
41. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989; 36:186–197.
42. Winters WD. Epilepsy or anesthesia with ketamine. Anesthesiology 1972; 36:309–312.
43. White PF, Ham J, Way WL, et al. Pharmacology of ketamine isomers in surgical patients. Anesthesiology 1980; 52:231–239.
44. White PF, Way WL, Trevor AJ. Ketamine – its pharmacology and therapeutic uses. Anesthesiology 1982; 56:119–136.
45. Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs 2000; 32:419–433.
46. Jansen K. Near death experience and the NMDA receptor. BMJ 1989; 298:1708.
47. Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician 2007; 10:493–500.
48. Collingridge G. Synaptic plasticity. The role of NMDA receptors in learning and memory. Nature 1987; 330:604–605.
49. Davies SN, Alford ST, Coan EJ, et al. Ketamine blocks an NMDA receptor-mediated component of synaptic transmission in rat hippocampus in a voltage-dependent manner. Neurosci Lett 1988; 92:213–217.
50. Anis N, Berry SC, Burton NR, et al. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 1983; 79:565–575.
51. Ilkjaer S, Petersen KL, Brennum J, et al. Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 1996; 76:829–834.
52. Wachtel H, Turski L. Glutamate: a new target in schizophrenia? Trends Pharmacol Sci 1990; 11:219–220.
53. Micallef J, Guillermain Y, Tardieu S, et al. Effects of subanesthetic doses of ketamine on sensorimotor information processing in healthy subjects. Clin Neuropharmacol 2002; 25:101–106.
54. James MK, Feldman PL, Schuster SV, et al. Opioid receptor activity of GI 87084B, a novel ultra-short acting analgesic, in isolated tissues. J Pharmacol Exp Ther 1991; 259:712–718.
55. Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg 2001; 93:204–209.
56. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86:1307–1311.
57. Yu EH, Tran DH, Lam SW, et al. Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia 2016; 71:1347–1362.
58. Kristensen JD, Gordh T. Modulation of NMDA receptor function for pain treatment. 1997; Philadelphia, USA: Lippincott-Raven Publishers, 943–952.
59. Kissin I, Bright CA, Bradley EL Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg 2000; 91:1483–1488.
60. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63:856–864.
61. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47:351–354.
62. Kudoh A, Takahira Y, Katagai H, et al. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg 2002; 95:114–118.
63. Sofia RD, Harakal JJ. Evaluation of ketamine HCl for antidepressant activity. Arch Int Pharmacodyn Ther 1975; 214:68–74.
64. Zarate CA Jr, Niciu MJ. Ketamine for depression: evidence, challenges and promise. World Psychiatry 2015; 14:348–350.
65. Green SM, Clem KJ, Rothrock SG. Ketamine safety profile in the developing world: survey of practitioners. Acad Emerg Med 1996; 3:598–604.
66. Raeder JC, Stenseth LB. Ketamine: a new look at an old drug. Curr Opin Anaesthesiol 2000; 13:463–468.
67. Harvey M, Sleigh J, Voss L, et al. Development of rapidly metabolized and ultra-short-acting ketamine analogs. Anesth Analg 2015; 121:925–933.
68. Diaz-Gil D, Haerter F, Falcinelli S, et al. A novel strategy to reverse general anesthesia by scavenging with the acyclic cucurbit[n]uril-type molecular container calabadion 2. Anesthesiology 2016; 125:333–345.
© 2017 European Society of Anaesthesiology