Abstract: In 1996, we published an editorial ‘Ketamine, mechanism(s) of action and unusual clinical uses’ in the British Journal of Anaesthesia.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar In that editorial, we described the pharmacology of ketamine including bronchodilator, anti-shock, and neuroprotective actions along with some unusual clinical applications. The editorial has been cited more than 130 times in total with around 10 citations every year, which implies that ketamine is still of interest to a wide audience. However, as ketamine anaesthesia is associated with cardiovascular hyperdynamics and disturbing emergence reactions, this agent is often avoided, despite the ease with which these adverse reactions can be prevented by pre-administration, co-administration of sedatives, or both such as benzodiazepines, propofol, dexmedetomidine, or droperidol. In the past 15 yr, ketamine has been reported to possess several new clinically beneficial properties such as potentiation of opioid analgesia, prevention of opioid-induced acute tolerance and spinal ischaemia, anti-inflammatory actions, preventive effects on recall and awareness during general anaesthesia, and anti-tumour actions. In this ‘update’ editorial, we have focused on these potential clinical advantages of ketamine. Ketamine per se produces antinociceptive actions via inhibition of N-methyl-d-aspartate (NMDA) receptors1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar and activation of descending inhibitory monoaminergic pain pathways. NMDA receptor-mediated spinal reflexes are intimately involved as the pharmacological basis for wind-up, which contributes to neuropathic pain. Ketamine prevents pain associated with wind-up.2Hughes AM Rhodes J Fisher G Sellers M Growcott JW Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy volunteers.Br J Clin Pharmacol. 2002; 53: 604-612Crossref PubMed Scopus (38) Google Scholar However, ketamine is rarely used as a sole analgesic agent for postoperative pain control as it produces psychotomimetic adverse reactions. Low-dose ketamine is often used as an adjuvant to opioid-induced analgesia. Ketamine even at non-analgesic doses has been reported to potentiate opioid analgesia in rodents. An investigation of subanalgesic doses of ketamine (30 mg kg−1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar i.p.) on analgesia induced by morphine (2.5, 5.0, and 7.5 mg kg−1, s.c.) using the tail-flick test in rats found that the combination of morphine and ketamine resulted in a dose-related increase in both intensity and duration of morphine antinociception.3Campos AR Santos FA Rao VS Ketamine-induced potentiation of morphine analgesia in rat tail-flick test: role of opioid-, alpha2-adrenoceptors and ATP-sensitive potassium channels.Biol Pharm Bull. 2006; 29: 86-89Crossref PubMed Scopus (28) Google Scholar This potentiation has also been reported clinically. A systematic review of randomized, controlled clinical trials of ketamine addition showed that ketamine reduced 24 h patient-controlled analgesia (PCA) morphine consumption and postoperative nausea or vomiting.4Bell RF Dahl JB Moore RA Kalso E Perioperative ketamine for acute postoperative pain.Cochrane Database Syst Rev. 2006; : CD004603PubMed Google Scholar In addition, they described that adverse effects were mild or absent. A recent review of randomized, double-blinded clinical trials of ketamine added to opioid in i.v. PCA for postoperative pain found that the ketamine–opioid combination could significantly reduce pain scores, cumulative morphine consumption, and postoperative desaturation in patients undergoing thoracic surgery, although this is less clear in orthopaedic or abdominal surgery.5Carstensen M Møller AM Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials.Br J Anaesth. 2010; 104: 401-406Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Ketamine may be useful as an efficient adjuvant analgesic in chronic pain or palliative care patients. Patients with uncontrolled severe pain receiving i.v. or epidural PCA obtained analgesia with ketamine.6Chazan S Ekstein MP Marouani N Weinbroum AA Ketamine for acute and subacute pain in opioid-tolerant patients.J Opioid Manag. 2008; 4: 173-180PubMed Google Scholar In a group of patients with intractable cancer pain, ketamine reduced the total daily dose of morphine required by 50% in 12 patients; eight patients were able to go home with a portable pump delivering morphine and ketamine.7Lossignol DA Obiols-Portis M Body JJ Successful use of ketamine for intractable cancer pain.Support Care Cancer. 2005; 13: 188-193Crossref PubMed Scopus (47) Google Scholar Although opioids are often used as sole analgesics during anaesthesia and for postoperative pain control, opioids have been reported to produce hyperalgesia and tolerance.8Christie MJ Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.Br J Pharmacol. 2008; 154: 384-396Crossref PubMed Scopus (308) Google Scholar These effects are particularly important in patients suffering from intractable severe pain caused by malignancy, trauma, or neuropathy. Tolerance and dependence result from long-term exposure, high-dose exposure, or both to opioids. Basic research suggests that receptor desensitization comprising loss of receptor function and internalization is involved.8Christie MJ Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.Br J Pharmacol. 2008; 154: 384-396Crossref PubMed Scopus (308) Google Scholar 9Whistler JL von Zastrow M Morphine-activated opioid receptors elude desensitization by β-arrestin.Proc Natl Acad Sci USA. 1998; 95: 9914-9919Crossref PubMed Scopus (318) Google Scholar Changes in opioid receptor conformation caused by agonist-induced receptor phosphorylation increase opioid receptor affinity for cytosolic β-arrestins. Interaction of β-arrestins with opioid receptors results in redistribution of opioid receptors from the plasma membrane to intracellular vesicles. This process has been defined as opioid receptor internalization.8Christie MJ Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.Br J Pharmacol. 2008; 154: 384-396Crossref PubMed Scopus (308) Google Scholar 9Whistler JL von Zastrow M Morphine-activated opioid receptors elude desensitization by β-arrestin.Proc Natl Acad Sci USA. 1998; 95: 9914-9919Crossref PubMed Scopus (318) Google Scholar β-Arrestin also desensitizes cells to opioid by functional uncoupling μ-opioid receptors.8Christie MJ Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.Br J Pharmacol. 2008; 154: 384-396Crossref PubMed Scopus (308) Google Scholar 9Whistler JL von Zastrow M Morphine-activated opioid receptors elude desensitization by β-arrestin.Proc Natl Acad Sci USA. 1998; 95: 9914-9919Crossref PubMed Scopus (318) Google Scholar It is important, however, to remember that these general processes are opioid-dependent. Noxious stimuli such as surgery may also produce opioid receptor internalization via NMDA receptor-mediated opioid release. Pretreatment with NMDA receptor antagonists (MK801, AP5, MRZ2/576, and MRZ2/596) significantly inhibited μ-opioid receptor internalization in neurones caused by laparotomy in guinea pigs.10Patierno S Zellalem W Ho A et al.N-Methyl-d-aspartate receptors mediate endogenous opioid release in enteric neurons after abdominal surgery.Gastroenterology. 2005; 128: 2009-2019Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In this context, ketamine is a non-competitive antagonist of the NMDA receptor.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar In addition, at clinically relevant concentrations, ketamine interacts with the phencyclidine (PCP)-binding site leading to a significant inhibition of NMDA receptor activity.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar This interaction with the PCP-binding site appears to be stereoselective with affinity (Ki) values of 3.2 and 1.1 μM for S(+)- and R(−)-ketamine, respectively, implying that subanaesthetic concentrations of ketamine inhibit the NMDA receptor via the PCP-binding site.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar It could therefore be predicted that ketamine could inhibit opioid receptor internalization. Indeed, ketamine prevents opioid-induced hyperalgesia and acute tolerance. In rats, fentanyl produced analgesia but also induced early (hours) and long-lasting hyperalgesia (days) and acute tolerance to the analgesic effects of morphine, but ketamine pretreatment completely prevented both hyperalgesia and tolerance.11Laulin JP Maurette P Corcuff JB Rivat C Chauvin M Simonnet G The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance.Anesth Analg. 2002; 94: 1263-1269Crossref PubMed Scopus (287) Google Scholar After systemic administration, ketamine is rapidly metabolized in the liver and lung to norketamine. Norketamine has been reported to have antinociceptive actions and to enhance morphine's antinociceptive action to thermal nociception, peripheral neuropathy, and tonic inflammatory pain and blocked tolerance.12Holtman Jr, JR Crooks PA Johnson-Hardy J Wala EP Interaction between morphine and norketamine enantiomers in rodent models of nociception.Pharmacol Biochem Behav. 2008; 90: 769-777Crossref PubMed Scopus (20) Google Scholar Therefore, we believe that norketamine could maintain (parent) potentiation of opioid analgesia and prevention of both hyperalgesia and tolerance. Subanaesthetic doses of ketamine potentiate opioid-analgesia via NMDA receptor block, but what about anaesthetic doses? Ketamine has been reported to interact with MOP(μ)-, DOP(δ)-, and KOP(κ)-opioid receptors.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar Clinical studies show that S(+)-ketamine produces two to three times more potent antinociception than R(−)-ketamine,1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar and in agreement with these clinical observations, S(+)-ketamine produces a two- to three-fold stereoselectivity (for binding not function) at μ- and κ- but not δ-receptor.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar 13Hirota K Okawa H Appadu BL Grandy DK Devi LA Lambert DG Stereoselective interaction of ketamine with recombinant μ, κ, and δ opioid receptors expressed in Chinese hamster ovary cells.Anesthesiology. 1999; 90: 174-182Crossref PubMed Scopus (99) Google Scholar Morphine, but not ketamine, analgesia can be reversed by microinjection of naloxone into the periaqueductal gray (PAG) region of the rat brain, which contains μ- but not κ-receptor.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar Moreover, microinjection of ketamine into the PAG did not produce analgesia but antagonized the effects of morphine. We previously found that anaesthetic concentrations of ketamine reversed both μ- and κ-opioid inhibition of the formation of cyclic adenosine monophosphate (as a marker of receptor activation) in Chinese hamster ovary cells expressing recombinant μ- and κ-opioid receptors, similar to naloxone.13Hirota K Okawa H Appadu BL Grandy DK Devi LA Lambert DG Stereoselective interaction of ketamine with recombinant μ, κ, and δ opioid receptors expressed in Chinese hamster ovary cells.Anesthesiology. 1999; 90: 174-182Crossref PubMed Scopus (99) Google Scholar These data suggest that anaesthetic concentrations of ketamine could exert antagonistic actions at both μ- and κ-opioid receptors. Therefore, high-dose ketamine may not be an appropriate addition to opioids. We have previously reported that i.v. ketamine14Hirota K Ishihara H Matsuki A Ketamine and the inhibition of albumin extravasation in chemical peritonitis in rat.Eur J Anaesthesiol. 2002; 19: 173-176Crossref PubMed Google Scholar inhibits albumin extravasation in a rat model of chemical peritonitis. Recently, the immunoinhibitory effects of ketamine were found to be partly due to inhibition of transcription factor activator protein-1 and nuclear factor-κB (NF-κB), which regulate the production of proinflammatory mediators.15Welters ID Hafer G Menzebach A et al.Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines.Anesth Analg. 2010; 110: 934-941Crossref PubMed Scopus (44) Google Scholar In vivo, a subanaesthetic dose of ketamine produced a dose-dependent decrease in mortality with a significant reduction in the production of tumour necrosis factor-α and interleukin (IL)-6 in septic rats.16Mazar J Rogachev B Shaked G et al.Involvement of adenosine in the anti-inflammatory action of ketamine.Anesthesiology. 2005; 102: 1174-1181Crossref PubMed Scopus (67) Google Scholar An anaesthetic dose of ketamine attenuated lipopolysaccharide-induced liver injury with a reduction in cyclooxygenase-2, inducible nitric oxide synthase protein, and NF-κB-binding activity.17Suliburk JW Helmer KS Gonzalez EA Robinson EK Mercer DW Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2.Surgery. 2005; 138: 134-140Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar These data clearly indicate that ketamine may exert anti-inflammatory actions in vivo. These anti-inflammatory effects of ketamine have also been found in clinical settings. A low dose of ketamine (0.25 mg kg−1) significantly suppressed intraoperative and postoperative increases in serum IL-6 in patients undergoing coronary artery bypass surgery (CABG) with cardiopulmonary bypass (CPB)18Roytblat L Talmor D Rachinsky M et al.Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass.Anesth Analg. 1998; 87: 266-271Crossref PubMed Google Scholar and significantly decreased superoxide production after on-pump CABG.19Zilberstein G Levy R Rachinsky M et al.Ketamine attenuates neutrophil activation after cardiopulmonary bypass.Anesth Analg. 2002; 95: 531-536PubMed Google Scholar Similarly, low-dose ketamine (0.5 mg kg−1) attenuated the increases in serum C-reactive protein, IL-6, and IL-10 after cardiac surgery with CPB.20Bartoc C Frumento RJ Jalbout M Bennett-Guerrero E Du E Nishanian E A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients.J Cardiothorac Vasc Anesth. 2006; 20: 217-222Abstract Full Text PDF PubMed Scopus (63) Google Scholar However, low-dose ketamine was not shown to have any anti-inflammatory effects in low-risk patients undergoing off-pump coronary artery bypass graft surgery.21Cho JE Shim JK Choi YS Kim DH Hong SW Kwak YL Effect of low-dose ketamine on inflammatory response in off-pump coronary artery bypass graft surgery.Br J Anaesth. 2009; 102: 23-28Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The link remains controversial. Errando and colleagues22Errando CL Sigl JC Robles M et al.Awareness with recall during general anaesthesia: a prospective observational evaluation of 4001 patients.Br J Anaesth. 2008; 101: 178-185Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar reported that the incidence of awareness with recall and dreaming during general anaesthesia were relatively high, 1.1% with propofol–total intravenous anaesthesia and 0.59% with balanced anaesthesia (i.v. agent induction with halogenated maintenance). Long-term potentiation (LTP or increased amplitude of excitatory post-synaptic potentials after high-frequency stimulation) of synaptic transmission in the hippocampal CA1 region contributes to learning and memory processes.23Lynch MA Long-term potentiation and memory.Physiol Rev. 2004; 84: 87-136Crossref PubMed Scopus (1441) Google Scholar As memories are thought to be encoded by synaptic modification in the hippocampus, LTP is considered as one of the major cellular mechanisms of learning and memory.23Lynch MA Long-term potentiation and memory.Physiol Rev. 2004; 84: 87-136Crossref PubMed Scopus (1441) Google Scholar A study of recall during spinal anaesthesia under propofol sedation (mean 4.2 mg kg−1 h−1) sufficient to maintain bispectral index 70 found that 56% of patients had recall.24Gonano C Meitner E Kettner SC Chiari A Marhofer P Effect of earplugs on propofol requirement and awareness with recall during spinal anesthesia.Minerva Anestesiol. 2010; 76: 504-508PubMed Google Scholar In contrast, several reports suggest that subanaesthetic doses of ketamine may inhibit LTP via NMDA receptor block.25Desmond NL Colbert CM Zhang DX Levy WB NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat.Brain Res. 1991; 552: 93-98Crossref PubMed Scopus (53) Google Scholar Indeed, clinical investigations26Rowland LM Astur RS Jung RE Bustillo JR Lauriello J Yeo RA Selective cognitive impairments associated with NMDA receptor blockade in humans.Neuropsychopharmacology. 2005; 30: 633-639Crossref PubMed Scopus (136) Google Scholar clearly show that subanaesthetic doses of ketamine impair memory and recall. A comparison of sedation quality during bronchoscopy between propofol–alfentanil (Group PA, n=138)- and propofol–ketamine (Group PK, n=138)-treated groups showed that recall was significantly lower in the PK group.27Hwang J Jeon Y Park HP Lim YJ Oh YS Comparison of alfentanil and ketamine in combination with propofol for patient-controlled sedation during fiberoptic bronchoscopy.Acta Anaesthesiol Scand. 2005; 49: 1334-1338Crossref PubMed Scopus (52) Google Scholar Although these reports support our hypothesis that the preventive effects of propofol on recall might be weak, further clinical studies are required. Although a variety of surgical procedures for malignancy are performed under general anaesthesia, it is unclear how anaesthetics affect the behaviour of malignant tumours. Uncontrolled cell proliferation, local invasion, and metastasis are responsible for the progression of malignant tumours. It has been reported that glutamate receptor subunits are expressed in a variety of tumour cells such as glioma, colorectal and gastric cancer, oral squamous cell carcinoma, prostate cancer, melanoma, and osteosarcoma.28Stepulak A Luksch H Gebhardt C et al.Expression of glutamate receptor subunits in human cancers.Histochem Cell Biol. 2009; 132: 435-445Crossref PubMed Scopus (145) Google Scholar In addition, glutamate and its receptors may regulate tumour growth as glutamate receptor antagonists limit proliferation.29Rzeski W Turski L Ikonomidou C Glutamate antagonists limit tumor growth.Proc Natl Acad Sci USA. 2001; 98: 6372-6377Crossref PubMed Scopus (215) Google Scholar NMDA receptor block has been reported to inhibit several tumour-related actions. The NMDA receptor antagonist MK801 inhibited extracellular signal-regulated kinase 1/2 pathway, an intracellular signalling cascade, and the proliferation of lung carcinoma cells.30Stepulak A Sifringer M Rzeski W et al.NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.Proc Natl Acad Sci USA. 2005; 102: 15605-15610Crossref PubMed Scopus (119) Google Scholar MK801 also improved the survival of mice with metastatic lung adenocarcinoma and slowed the growth of neuroblastoma and rhabdomyosarcoma in mice. The NMDA receptor antagonist AP5, or silencing the NMDA receptor NR2A subunit, suppresses cell proliferation due to cell cycle arrest at G1 phase in MKN45 gastric cancer cells.31Watanabe K Kanno T Oshima T Miwa H Tashiro C Nishizaki T The NMDA receptor NR2A subunit regulates proliferation of MKN45 human gastric cancer cells.Biochem Biophys Res Commun. 2008; 367: 487-490Crossref PubMed Scopus (48) Google Scholar It has been reported that most breast cancer cells expressed functional NMDA1 and NMDA2 receptors which play important roles in human breast cancer xenografts (e.g. Mc-f in mice).32North WG Gao G Memoli VA Pang RH Lynch L Breast cancer express functional NMDA receptors.Brest Cancer Res Tract. 2010; 122: 307-314Crossref PubMed Scopus (68) Google Scholar Moreover, daily administration of MK801 completely arrested the growth of the Mc-f-human mouse-xenograft. Accordingly, NMDA receptor antagonism with ketamine (which binds to the same site as MK801) should exert anti-tumour actions. Indeed, ketamine suppressed the proliferation of rat glioma (but not normal brain) cells and induced apoptosis (Niwa and colleagues, unpublished data). Clinical investigations are required to evaluate the anti-tumour effects of ketamine on postoperative outcome such as survival rate in patients undergoing tumour resection. As activation of NMDA receptors induces cerebral ischaemic damage, ketamine clearly has a neuroprotective potential. Indeed, experimental reports suggest neuroprotective effects of ketamine. Ketamine improved neuronal outcome from incomplete cerebral ischaemia in rats by a mechanism related to a decrease in plasma catecholamine levels, improved neurological outcome with a reduction in volume of haemorrhagic necrosis in head trauma rats, and attenuated damage in the caudoputamen of hypocapnic rats with chronic cerebral hypoperfusion.1Hirota K Lambert DG Ketamine: its mechanism(s) of action and unusual clinical uses.Br J Anaesth. 1996; 77: 441-444Abstract Full Text PDF PubMed Scopus (340) Google Scholar In the clinical setting, ketamine may also produce neuroprotective actions as several reports show that ketamine attenuated postoperative delirium and cognitive dysfunction in patients undergoing cardiac surgery.33Hudetz JA Pagel PS Neuroprotection by ketamine: a review of the experimental and clinical evidence.J Cardiothorac Vasc Anesth. 2010; 24: 131-142Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar However, it remains unclear whether ketamine could exert neuroprotective effects in other surgical groups who are not subjected to the stress of CPB. Several articles34Kakinohana M Kakinohana O Jun JH Marsala M Davison KJ Sugahara K The activation of spinal N-methyl-d-aspartate receptors may contribute to degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia.Anesth Analg. 2005; 100: 327-334Crossref PubMed Scopus (19) Google Scholar 35Kakinohana M Nakamura S Fuchigami T Davison KJ Marsala M Sugahara K Mu and delta, but not kappa, opioid agonists induce spastic paraparesis after a short period of spinal cord ischaemia in rats.Br J Anaesth. 2006; 96: 88-94Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar suggest that opioids worsen spinal ischaemia. Intrathecal administration of μ- and δ-, but not κ-opioid, receptor agonists increased spasticity in a dose-dependent manner after a short period of spinal cord ischaemia in rats.34Kakinohana M Kakinohana O Jun JH Marsala M Davison KJ Sugahara K The activation of spinal N-methyl-d-aspartate receptors may contribute to degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia.Anesth Analg. 2005; 100: 327-334Crossref PubMed Scopus (19) Google Scholar Although opioids such as morphine, fentanyl, and remifentanil are often used as analgesics for thoracoabdominal aortic aneurysm repair surgery, opioids may be involved in neuronal injury in the spinal cord after aortic cross-clamping as naloxone could attenuate neurological consequences of spinal injury in rats. NMDA receptor activation could contribute to this opioid-induced neurotoxicity.35Kakinohana M Nakamura S Fuchigami T Davison KJ Marsala M Sugahara K Mu and delta, but not kappa, opioid agonists induce spastic paraparesis after a short period of spinal cord ischaemia in rats.Br J Anaesth. 2006; 96: 88-94Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Ketamine might therefore attenuate opioid-induced degeneration of spinal motor neurones. We have introduced what we believe to be clinically important beneficial effects of ketamine. However, as most published clinical trials were of limited size, the data from these trials used to determine optimal dose and timing of administration are questionable. In addition, long-term follow-up data are lacking. Therefore, large clinical trials are required to address these issues. K.H. organized the 17th Japanese Society of Intravenous Anesthesia Meeting in 2010 that was partly supported by several Pharmaceutical companies including Daiichi Sankyo Co. Ltd who provides ketamine in Japan. The support was used for meeting running costs. In addition, K.H. has received a lecture fee from this company in the past 5 yr. D.G.L. is a Director on the Board of the British Journal of Anaesthesia.