Inhaled Nebulised S(+)-Ketamine for Postoperative Analgesia

Introduction

Since first described in 1965 1, the phencyclidine derivative ketamine [(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone] has gained widespread use as an anaesthetic, sedative and analgesic. 2 There is some evidence that ketamine might possess antidepressant effects as well. 3 In anaesthetic dosages, ketamine produces dissociative anaesthesia with low respiratory or circulatory depressive effects. Therefore it is the optimal anaesthetic e.g. in haemodynamically compromised patients or when minimal respiratory depression is desirable during induction of anaesthesia, e.g. in emergency care. 2 Despite this, adverse psychomimetic effects such as hallucinations and initially observed effects on intracranial pressure (ICP) have limited the use of ketamine without additional sedation or in patients with neurological injury. 4 Increasing evidence, however, supports the notion that - during controlled ventilation - ketamine can be safely used in patients with neurotrauma 5 and that the adverse psychometric side effects are less pronounced with the S(+)-enantiomer. 6,7

Both chiral forms of ketamine modulate nociception mainly via inhibition of N-methyl-D-aspartate (NMDA)-receptor activation. 8 Analgesic effect is also related to modulation of signalling via nitric oxide (NO) synthase inhibition 4,9, monoamine 10,11 and muscarinic 12 neurotransmission, and µ-, δ- and κ-opiate receptor agonism 13.

S(+)-ketamine has been observed to exert analgesic effect two-to-four times that of racemic ketamine 17 or the R(-)-isomer 18 alone. Although observations regarding unwanted psychometric effects with equianalgetic dosages of the S(+)-enantiomer and racemic ketamine are in favour of S(+)-ketamine 6,7 or controversial 17,18, it would seem that the superior potency 17 and shorter duration of effect 19 of the S(+)-ketamine allows for easier dosing and titration.

Ketamine has been administrated via the intravenous, intramuscular, subcutaneous, rectal, oral, transdermal, intranasal, sublingual, transmucosal, epidural, intrathecal, and intra-articular routes. 20-30 Following intravenous administration, bioavailability is 90 % and peak anaesthetic effect is observed in 1 to 5 minutes. 2 Parenteral administration results in more effective analgesia due to avoidance of first-pass metabolism in the liver to the less potent norketamine, but, on the other hand, oral administration may result in less psychometric side effects as norketamine does not exert hallucinogenic properties. 2 Pharmacokinetic properties of inhaled ketamine have not been studied officially, but one of our researchers has tested nebulized ketamine on himself with repeated painful stimulus and monitoring applied. Based on this experiment, analgesic effect is roughly estimated to begin in 3 minutes.