This Invited Commentary accompanies the following original articles:
Boenigk K, Echevarria GC, Nisimov E, et al. Low-dose ketamine infusion reduces postoperative hydromorphone requirements in opioid-tolerant patients following spinal fusion: A randomised controlled trial. Eur J Anaesthesiol 2019; 36:8–15.
Wang J, Echevarria GC, Doan L, et al. Effects of a single subanaesthetic dose of ketamine on pain and mood after laparoscopic bariatric surgery. A randomised, double-blind, placebo controlled study. Eur J Anaesthesiol 2019; 36:16–24.
The studies from Wang et al. 1 and Boenigk et al. 2 published in this issue of the Journal raise fundamental questions about the current position of ketamine within modern multimodal analgesia. 3
Synthesised in 1962 by Calvin Stevens, ketamine was first used in human experiments by Edward Domino and Guenter Corssen of the University of Michigan, who published the first clinical studies more than 50 years ago (1965). They described so-called dissociative anaesthesia, namely an electrophysiological and functional dissociation between thalamocortical and limbic systems. 4 From the outset, it was recognised that ketamine provided potent analgesia, but despite the fact that Sadove et al. 5 showed in 1971 that ‘subdissociative’ doses (0.44 mg kg−1) exhibited analgesic properties with only moderate adverse effects, psychomimetic effects and hallucinations were considered a problematic issue in the early 1970s, and were responsible for the subsequent fall of ketamine into relative oblivion (apart from unusual clinical settings such as shock, burns, cardiac tamponade or asthma).
The expansion of the use of remifentanil in the early 1990s changed the story. 6 Its short contextual half-life prompted a regular overdosage routine which was subsequently recognised as responsible for so-called opioid-induced hyperalgesia (OIH). The N-methyl-D-aspartate (NMDA) receptor involvement led to a triumphal comeback of ketamine as a NMDA blocking agent, 6 an action which was soon coined ‘antihyperalgesic’. 7
Nowadays, OIH and the so-called US opioid epidemic 8 which put the spotlight on the respiratory dangers of opioids have triggered a paradigm shift in the management of peri-operative pain. Some anaesthesiologists have dropped the obsolete concept of ‘high-dose fentanyl anaesthesia’ 9 for the promising one of ‘opioid-free anaesthesia’ (OFA). 10,11
In spite of a lack of reduction in the visual analogue pain scores, the study by Wang et al. 1 tells us a new thing: as well as being the ‘actor’ of dissociative anaesthesia, ketamine is also responsible for ‘dissociative analgesia’, that is, preclusion of emotional translation of nociceptive perception. This finding may be put in perspective with the blossoming of ketamine use as a fast antidepressant in patients with a high suicide risk 12 (a property known for more than 40 years 13 and rediscovered about 15 years ago), 14,15 and the recent development of innovative psychedelic therapeutics, including ketamine, in palliative medicine. 16
However, previous works had demonstrated the failure of single ketamine bolus doses to reduce postoperative pain. 17,18 Moreover, boluses of 1 mg kg−1 administered at induction of anaesthesia were clearly inefficient in the recent Prevention of Delirium and Complications Associated with Surgical Treatments trial, where neither pain intensity nor opioid use was diminished. 19 It must be kept in mind that following a bolus dose of 0.5 mg kg−1, ketamine concentration falls beneath 150 ng ml−1 after only 10 min, and less than 25 min after a bolus dose of 1 mg kg−1 (Fig. 1).
Ketamine is a ‘use-dependent’ drug: it blocks NMDA channels only if they have already been opened by intense or repeated noxious stimuli. This ‘foot in the door’ blockade 20 explains why administration prior to the start of surgery is of no peculiar interest. Moreover, the Boenigk et al. 2 study enlightens an interesting part of this fundamental concept: the fact that ketamine is much more efficient when the ‘door has been opened’ by prior use of opioids. We guess that the same happens when NMDA receptors are opened by intense nociceptive stimuli. Indeed, ketamine was shown 17 years ago to prevent chronic postoperative pain after major abdominal surgery, but to achieve this goal, it seems mandatory to use a continuous infusion of at least 0.25 mg kg−1 h−1. 21 Finally, Zakine et al. 22 showed that it could be even better to administer ketamine during the early postoperative days.
To conclude, we were told as early as 2005 that continuous administration of ketamine was mandatory for preventive analgesia. 23 Nearly 15 years of use have confirmed that small concentrations of ketamine are safe and have no propensity to trigger the adverse effects (cardiac, cerebral) attributed to hypnotic doses. 2 In the era of OFA, it may be time to consider the use of a continuous infusion of ketamine for noxious surgery or to diminish opioid exposure in endangered patients such as those with respiratory disease, obesity or obstructive sleep apnoea.
Acknowledgements relating to this article
Assistance with the commentary: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Comment from the Editor: this Invited Commentary was checked by the editors but was not sent for external peer review.
This article was checked and accepted by the Editors, but was not sent for external peer-review.
1. Wang J, Echevarria G, Doan L, et al. Effects of a single, subanaesthetic dose of ketamine on pain and mood after laparoscopic bariatric surgery: a randomised, double-blind, placebo controlled study. Eur J Anaesthesiol
2. Boenigk K, Echevarria GC, Nisimov E, et al. Low-dose ketamine infusion reduces postoperative hydromorphone requirements in opioid-tolerant patients following spinal fusion: a randomised controlled trial. Eur J Anaesthesiol
3. Moro ET, Feitosa IMPSS, de Oliveira RG, et al. Ketamine does not enhance the quality of recovery following laparoscopic cholecystectomy: a randomized controlled trial. Acta Anaesthesiol Scand
4. Mion G. Ketamine story. Past, present and future. Eur J Anaesthesiol
5. Sadove MS, Shulman M, Hatano S, et al. Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg
6. O'Shaughnessy CT, Lodge D. N
-methyl-D-aspartate receptor-mediated increase in intracellular calcium is reduced by ketamine and phencyclidine. Eur J Pharmacol
7. 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
8. Weisberg D, Stannard C. Lost in translation? Learning from the opioid epidemic in the USA. Anaesthesia
9. Lunn JK, Stanley TH, Eisele J, et al. High dose fentanyl anesthesia for coronary artery surgery: plasma fentanyl concentrations and influence of nitrous oxide on cardiovascular responses. Anesth Analg
10. Lavand’homme P, Steyaert A. Opioid-free anesthesia opioid side effects: tolerance and hyperalgesia. Best Pract Res Clin Anaesthesiol
11. Friedberg BL. Opioid free anesthesia with BIS/EMG monitored propofol-ketamine. Rev Esp Anestesiol Reanim
12. Zarate CA Jr, Niciu MJ. Ketamine for depression: evidence, challenges and promise. World Psychiatry
13. Sofia RD, Harakal JJ. Evaluation of ketamine HCl for antidepressant activity. Arch Int Pharmacodyn Ther
14. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry
15. Kudoh A, Takahira Y, Katagai H, et al. Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg
16. Okon T. Ketamine: an introduction for the pain and palliative medicine physician. Pain Physician
17. Faiz HR, Rahimzadeh P, Visnjevac O, et al. Intravenous acetaminophen is superior to ketamine for postoperative pain after abdominal hysterectomy: results of a prospective, randomized, double-blind, multicenter clinical trial. J Pain Res
18. Aubrun F, Gaillat C, Rosenthal D, et al. Effect of a low-dose ketamine regimen on pain, mood, cognitive function and memory after major gynaecological surgery: a randomised, double-blind, placebo-controlled trial. Eur J Anaesthesiol
19. Avidan MS, Maybrier HR, Abdallah AB, et al. PODCAST Research Group. Intraoperative ketamine for prevention of postoperative delirium or pain after major surgery in older adults: an international, multicentre, double-blind, randomised clinical trial. Lancet
20. Lester HA, Lavis LD, Dougherty DA. Ketamine inside neurons? Am J Psychiatry
21. De Kock M, Lavand’homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine? Pain
22. Zakine J, Samarcq D, Lorne E, et al. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study. Anesth Analg
23. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology