Glasgow Meeting - May 2003

Michael G. Irwin, MB ChB, FRCA, FHKAM Associate Professor and Head, Department of Anaesthesiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong

Ketamine was first synthesised in 1963 as a safer derivative of phencyclidine and gained initial popularity as a reasonably simple sole drug technique because of its relative lack of cardio respiratory depressant effects and ability to produce profound analgesia ("dissociative anaesthesia"). Its evaluation coincided with the Vietnam War where it was commonly used as a field anaesthetic. It soon became apparent, however, that recovery could be slow and accompanied by hallucinations and dysphoria. As a result, its use was diminished to emergency anaesthesia (shock, asthma), short painful procedures e.g. burns dressings and occasionally paediatrics where it was perceived to have fewer adverse effects. A better understanding of the basic science of anaesthesia and pain, particularly in relation to the role of N-methyl-d-aspartate (NMDA) receptors, has rekindled an interest in ketamine and potentially expanded its therapeutic indications. Non competitive NMDA glutamate receptor antagonism appears to be the primary target for ketamine although it also reduces pre-synaptic glutamate release, antagonises acetyl choline receptors, and has a weak affinity for opioid receptors and possibly GABAA receptors.1 Other actions such as inhibition of serotonin and dopamine reuptake, inhibition of nerve growth factor and inhibition of voltage gated Na and K channels have also been demonstrated. The drug is a racemic mixture of the isomers R(-)-ketamine and S(+)-ketamine.2 The S(+) isomer is 3 to 4 times as potent as an analgesic with a faster clearance than R(-), although they both have a similar affinity for cholinergic receptors. The use of the S(+) single isomer form results in a faster recovery of cognitive function and a lower incidence of psychomimetic side effects. The primary pharmacodynamic effects of ketamine are very well known and familiar to most anaesthetists. Recent research has focused on new clinical uses of the drug, often in lower doses as a supplement to conventional anaesthetic and analgesic techniques in an attempt to improve the efficacy of these techniques while minimising ketamine related side effects.3,4 NMDA antagonism attenuates central sensitisation after tissue injury or inflammation, reduces secondary hyperalgesia and prevent the growth of new pain pathways (inhibition of c-fos-oncogene induction).5A number of randomised controlled trials (RCTs) suggest that ketamine has pre emptive analgesic and opioid sparing effects in doses as low as 0.15 mg/kg.6 It also appears to reduce acute opioid tolerance, and even improve postoperative mood without cognitive impairment. There are few RCTs of long term administration of ketamine for neuropathic pain, although it has been efficacious in single dose studies and case reports.

Glutamate signalling may have an important role in the neuronal injury cascade which suggests that ketamine may be an appropriate therapy in the treatment of acute cerebral ischaemia/hypoxia. S(+)-ketamine may also have neuroregenerative properties. However, in vivo effects are variable and there is not enough clinical evidence to support its routine use as a neuroprotective drug.7 Preservative free S(+)-ketamine in a dose of 0.25 – 0.5 mg/kg has been shown to improve the quality and duration of epidural and intrathecal local anaesthesia with no differences in sedation or times to micturition.8 Studies have also demonstrated a significant reduction by ketamine in leukocyte activation during hypoxia or sepsis.9 It has also been suggested recently that ketamine anaesthesia may reduce albumin extravasation in inflammatory tissues.10 Increasing scientific data, particularly in relation to sub-anaesthetic doses in acute pain management, and the recent introduction of the S(+) enantiomer have increased our knowledge and, therefore, the clinical indications for ketamine. A recent postal questionnaire of paediatric anaesthetists in the UK indicated that 32% already use ketamine as a multimodal adjuvant to caudal local anaesthesia and it is likely that such techniques will gain in popularity.11

1. Bergman SA. Ketamine: review of its pharmacology and its use in pediatric anesthesia. Anesth Prog 1999; 46: 10-20.

2. Weiskopf RB, Nau C, Strichartz GR. Drug chirality in anesthesia. Anesthesiology 2002;97: 497-502.

3. Gehling M, Tryba M. New aspects of ketamine in post operative pain management. Acute Pain 1998; 1: 22-34.

4. 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; 82:111-125.

5. Sang CN. NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage 2000; 19: 21-25.

6. Stubhaug A, Breivik H, Eide PK, et al. Mapping of punctate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997; 41: 1124-1132.

7. Kohrs R, Durieux ME. Ketamine: Teaching an old drug new tricks. Anesth Analg 1998; 87: 1186-93.

8. Koinig H, Marhofer P, Krenn CG, et al. Analgesic effects of caudal and intramuscular S(+)-ketamine in children. Anesthesiology 2000; 93: 976-980.

9. Zahler S, Heindl B, Becker BF. Ketamine does not inhibit inflammatory responses of cultured human endothelial cells but reduces chemotactic activation of neutrophils. Acta Anaesthesiol Scand 1999; 43: 1011-1016.

10. Hirota K, Ishihara H, Matsuki A. Ketamine and the inhibition of albumin extravasation in chemical peritonitis in rat. Eur J Anaesthesiol 2002; 19: 173-6.

11. Sanders JC. Paediatric regional anaesthesia, a survey of practice in the United Kingdom. Br J Anaesth 2002; 89: 707–10.