Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 1960 2023-05-16 02:14:31 |
2 format correct Meta information modification 1960 2023-05-16 05:21:05 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Riccardi, A.; Guarino, M.; Serra, S.; Spampinato, M.D.; Vanni, S.; Shiffer, D.; Voza, A.; Fabbri, A.; De Iaco, F. Drug Characteristics of Ketamine. Encyclopedia. Available online: https://encyclopedia.pub/entry/44337 (accessed on 13 April 2024).
Riccardi A, Guarino M, Serra S, Spampinato MD, Vanni S, Shiffer D, et al. Drug Characteristics of Ketamine. Encyclopedia. Available at: https://encyclopedia.pub/entry/44337. Accessed April 13, 2024.
Riccardi, Alessandro, Mario Guarino, Sossio Serra, Michele Domenico Spampinato, Simone Vanni, Dana Shiffer, Antonio Voza, Andrea Fabbri, Fabio De Iaco. "Drug Characteristics of Ketamine" Encyclopedia, https://encyclopedia.pub/entry/44337 (accessed April 13, 2024).
Riccardi, A., Guarino, M., Serra, S., Spampinato, M.D., Vanni, S., Shiffer, D., Voza, A., Fabbri, A., & De Iaco, F. (2023, May 16). Drug Characteristics of Ketamine. In Encyclopedia. https://encyclopedia.pub/entry/44337
Riccardi, Alessandro, et al. "Drug Characteristics of Ketamine." Encyclopedia. Web. 16 May, 2023.
Drug Characteristics of Ketamine
Edit

Pain is the leading cause of medical consultations and occurs in 50–70% of emergency department visits. To date, several drugs have been used to manage pain. The clinical use of ketamine began in the 1960s and it immediately emerged as a manageable and safe drug for sedation and anesthesia. 

ketamine pain dopamine

1. Pharmacokinetics

Ketamine is a highly lipophilic molecule with rapid distribution and immediate passage through the central nervous system. It has low plasma protein binding, ranging from 10% to 50%, an alpha half-life of 2–4 min and a beta half-life of 2–4 h [1][2][3]. Owing to its high liposolubility, it has a large volume of distribution, ranging from 160 to 550 litres [2]. The liver metabolizes ketamine via the cytochromes CYP 2B6 and CYP3A4, producing (R, S)-norketamine, which is converted to 6-hydroxynorketamine and 5,6-dehydronorketamine [4]. These metabolites have an extended half-life of up to 3 days and, according to various authors, provide prolonged analgesic and antidepressant effects, which will be discussed later [4][5][6][7]. Bioavailability and duration of action vary depending on the route of administration: with intravenous administration, bioavailability is 100% and maximum effect is achieved within 1–2 min [4][8][9]; with intramuscular administration, bioavailability is 93% and maximum effect is achieved within 5–10 min [4][8][9]; with oral administration, bioavailability is 16–29% and maximum effect is achieved within 20–120 min [4]. Intranasal administration shows a bioavailability of 35–50% [10][11][12], an analgesic effect with onset of action within 10 min, a time-to-peak effect of 10–14 min [13] and a duration of up to 60 min [14]. Oral administration of ketamine is considered less beneficial because of its lower bioavailability and significant hepatic first-pass effect [2][15]. As ketamine is one of the most commonly abused psychoactive substances worldwide, its oral route is not recommended because of its potential for abuse. The intranasal route of administration has been discussed in a separate section. Ketamine and its metabolites are excreted from the body mainly by the kidneys [4]. Women generally metabolize ketamine more rapidly (up to 20%) than men, whereas older people tend to metabolize it more slowly [4]. Ketamine is contraindicated during pregnancy and lactation [16][17]. Due to its short half-life, no dosage adjustment is required in patients with impaired renal function [18].
Owing to its pharmacokinetic properties, the intravenous route of administration is the most beneficial for acute pain. Ketamine has a faster onset of action than morphine but a shorter half-life [19].

2. Mechanism of Action

The main mechanism of action of ketamine is to block glutamatergic neurons via its antagonistic effect on NMDA receptors [1][3]. It does this by non-competitively blocking the opening of glutamatergic channels, mainly in the prefrontal cortex and hippocampus [4][20]. Ketamine also activates the prefrontal cortex via blockade of inhibitory interneurons, which is one of the mechanisms responsible for its psychomimetic effects [21]. The effect of ketamine on NMDA receptors is unique in that it acts as an open-channel blocker. It blocks the calcium channel only when it is open and has no effect on the closed resting channel [9]. However, the analgesic effects of ketamine are diverse and multifaceted, with effects on dopaminergic [22][23][24], adrenergic [25][26], serotoninergic [27], opioid [26][28] and cholinergic [14][29] receptors. Ketamine acts on the latter by stimulating the nicotinic pathway and inhibiting the muscarinic pathway by blocking M1 receptors, which explains the mydriasis and sialorrhea observed at dissociative doses [14][29]. In addition, ketamine acts on spinal GABA interneurons [30].
Ketamine modulates the reuptake of serotonin, dopamine, and norepinephrine and causes a paradoxical increase in glutamate with stimulation of the descending inhibitory pathways [4][24]. This broad and diverse spectrum of action is essential for its antidepressant effect, which is of particular interest for chronic and neuropathic pain [1]. The blockade of NMDA receptors by ketamine is involved in reducing spinal cord exhaustion, which is a major contributor to the development of chronic pain [20]. Severe pain activates NMDA receptors with hyperexcitability of spinal interneurons in the posterior horn, leading to spinal cord wind-up and central sensitisation [31]. The paradoxical increase in glutamate is essential for the stimulation of medullary GABA inhibitors [4] and for the stimulation of AMPA receptors, which are crucial for the control of depressive symptoms [4][32][33]. Ketamine blocks the NMDA-Rs of GABAergic interneurons, leading to a paradoxical increase in extracellular glutamate and activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr), which stimulates the mammalian target of rapamycin complex-1 (mTORC1) signalling pathway, particularly in cortical excitatory pyramidal neurons [34]. AMPA blockade inhibits the antidepressant effect of ketamine [35][36]. Ketamine also has an anti-inflammatory effect by lowering the levels of IL-6 and TNF-alpha [37]. Increased levels of dopamine in the prefrontal, frontal, nucleus striatum, and nucleus accumbens are other causes of psychomimetic symptoms triggered by ketamine, which can mimic schizophrenic symptoms [38][39]. Serotonin also plays an important role in pain modulation, and blockade of 5-HT2 receptors in mouse models reduces the analgesic effect of ketamine [40].
In the past, great importance was placed on the analgesic role of ketamine metabolites, but this has since been revised [6]. However, experimental evidence in animal models suggests that norketamine plays an essential role in hyperpolarizing the HCN channels in the spinal cord and hippocampus, which is particularly important for antidepressant modulation by ketamine [4][7]. However, in animal models, HCN receptors appear to be involved in the analgesic effects [41][42][43][44]. The action of ketamine on opioid receptors does not appear to have a direct analgesic effect but does have a modulatory effect. Direct intrathecal antagonism of mu and delta receptors (but not kappa receptors) blocks the analgesic effect of ketamine, which is not affected by the parenteral administration of naloxone [45]. The effects of ketamine are extensive and are still largely misunderstood. It acts on sigma-1 receptors, L-type voltage-gated calcium channels, and voltage-gated sodium channels, but their exact functions and possible roles in analgesia are not yet known [1][20].
Ketamine reduces the reuptake of catecholamines at the neuronal level, resulting in increased levels of norepinephrine, dopamine, and serotonin, thus increasing the catecholaminergic tone [2]. However, the effects of ketamine on the cardiovascular system remain unclear. For example, ketamine has a negative inotropic effect only in patients with catecholamine deficiency due to direct myocyte blockade, as seen in patients with severe trauma or intensive care [20]. The neuronal interaction of ketamine is even more complex; while ketamine has raised concerns about neuronal damage in animal models [46][47], there is evidence of a neuroprotective effect of ketamine in the presence of acute stress [48][49][50][51]. Indeed, ketamine has been shown to protect against hyperammonemia-induced lethality in acute portosystemic encephalopathy through nitric oxide- and glutamate-mediated neuroprotection, with reduced neuronal oedema [52][53][54][55][56][57]. A similar neuroprotective effect was observed in patients with super-refractory epilepsy [58]. The exact mechanism by which ketamine exerts its neuroprotective effects is not yet fully understood. However, it has been suggested to increase neuronal calcium while inhibiting calmodulin activation, NO synthase, and NO production from L-arginine, resulting in a neuroprotective effect [59].
Ketamine has a broad spectrum of actions and undeniable benefits for the protection of respiratory function. Unlike opiates, ketamine does not induce respiratory depression [1]. In addition, unlike natural opiates such as morphine, which can cause bronchosthenosis in asthmatics [60], ketamine acts as a bronchodilator [15][61][62].

3. Ketamine’s Antidepressant Action and Its Effect on Chronic Pain

There is an interesting link between pain and depression: functional and neuroimaging studies have shown that ketamine reduces the activity of the insular cortex and thalamus, which are normally activated by pain [16][63][64]. Although the effect of ketamine on NMDAR receptors has not been fully elucidated, some observations have suggested that these receptors play a crucial role in the context of depression and chronic pain. Specifically, ketamine increases neuronal calcium via NMDAr blockade, which causes a secondary decrease in NMDA-R receptors via gene depression, thereby increasing levels of brain-derived neurotrophic factor (BDNF), which are low in mouse models of induced depression and whose levels are increased by ketamine [65]. In addition, ketamine has been shown to decrease receptor affinity for substance P, a neurotransmitter that increases in chronic pain and is one of the mechanisms underlying the loss of medullary pain inhibition [66][67]. In addition, ketamine appears to block acetylcholine muscarinic receptors (m1ChRs), which may also play a role in modulating chronic pain. Studies suggest that agonists of these receptors may increase the pain threshold [29][68]. In addition, animal studies have suggested that ketamine may modulate astrocytic and glial responses that play a role in chronic neuropathic pain [69][70].
As mentioned in the Introduction, the exact analgesic effect of ketamine metabolites is not yet fully understood. However, some studies suggest that these metabolites have analgesic properties equivalent to one-third of the analgesic effect of ketamine [71][72] and tend to accumulate over longer infusion periods, resulting in a sustained analgesic effect over several days [73][74].
The relationship between ketamine, serine, depression and chronic pain is of great interest because NMDA-Rs require D-serine or glycine as co-agonists, especially in neurons in the limbic region involved in the development of depression and chronic pain. Serine racemase produces D-serine in medullary interneurons, and its level increases during neuropathic pain, leading to the activation of NO synthase. Ketamine may also interfere with this level [75][76].
However, it is worth noting that depression and chronic pain are closely linked [77], and a drug that can effectively treat both conditions would be ideal [78][79][80][81]. Indeed, ketamine appears to have a stronger analgesic effect in patients with chronic pain and depression [82]. The first observation of the antidepressant effects of ketamine dates to the 1970s. However, it took many years to gain acceptance in this field [4], and the first major study on this topic was conducted in 2000 [83].
The mechanisms underlying the effects of ketamine are not fully understood. However, there is evidence of a synergistic effect between ketamine and lithium as antidepressants [84]. The paradoxical increase in extraneuronal glutamate by ketamine appears to disinhibit pyramidal neurons, activate AMPAs and TORC1s, increase levels of GABA-B and BdNF, and inhibit glycogen synthase kinase 3 (GSK-3B) in the brain, and lithium also affects GSK-3B. As a result, these two drugs can act synergistically to produce enhanced antidepressant effects [84].

4. Synergistic Effects of Ketamine and Magnesium

The first observation of the analgesic effects of magnesium and ketamine dates to 1971 [85], and the relationship between magnesium and ketamine is intriguing. Magnesium binds to the NMDAR receptor channel at rest, whereas it does not bind when the channel is active [65]. Magnesium is the body’s NMDA receptor antagonist, and the binding site of ketamine to the same receptor is nearby [65]. The presence of magnesium increases the binding affinity of ketamine for NMDA receptors, and their association with analgesic purposes becomes even more interesting when one considers that brain magnesium levels are reduced in both depression and chronic pain [86]. The addition of 50 mg/kg magnesium to the analgesic ketamine bolus and 10 mg/kg/h magnesium to the ketamine infusion seems to enhance the analgesic efficacy of ketamine [87][88][89][90][91][92][93]. However, it is not yet known how long magnesium infusions should be administered. Magnesium also appears to improve haemodynamic stability [94].

5. Relationship between Ketamine and the Opioid System

As mentioned earlier, ketamine has a complex relationship with opioid receptors. By interacting with central and spinal opioid receptors and NMDA-R, it reduces opioid tolerance, opioid-induced hyperalgesia (OIH) and central sensitisation [2][17][31][95][96][97]. Although opiates reduce pain perception by activating mu receptors, they also activate NMDA receptors, leading to postsynaptic hyperexcitability, central tolerance, and sensitization. Ketamine has been shown to modulate and reduce these effects when combined with an NMDA antagonist such as MK-801 [21][98][99][100][101]. In addition, ketamine exerts a downstream effect by increasing opioid-induced phosphorylation of extracellular signal-regulated 1/2 kinase (ERK 1–2), so fewer opioids are required to achieve the desired therapeutic effect (opioid-sparing effect). This also helps reduce adverse events such as respiratory depression and vomiting [8][26][102][103][104][105][106][107].

6. Ketamine and Its Anti-Inflammatory Properties

Pain is an important inflammatory component, particularly in the postoperative setting [4]. Ketamine decreases IL-6, TNF alpha, CRP, and NO synthase levels. High levels of IL-6 are associated with poor postoperative outcomes [37]. Chronic postoperative pain can occur in up to 20% of all surgeries and 50–60% of surgeries involving nerve structures [108]. Postoperative neuropathic pain is caused by activated microglia in the spinal cord [21][37][108][109][110]. Therefore, the effect of ketamine on glial cells [69][70] can alleviate postoperative pain.

References

  1. Kohtala, S. Ketamine-50 years in use: From anesthesia to rapid antidepressant effects and neurobiological mechanisms. Pharmacol. Rep. 2021, 73, 323–345.
  2. Peltoniemi, M.A.; Hagelberg, N.M.; Olkkola, K.T.; Saari, T.I. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin. Pharmacokinet. 2016, 55, 1059–1077.
  3. De Iaco, F.; Gandolfo, E.; Guarino, M.; Riccardi, A.; Saggese, M.P.; Serra, S. Terapia Del Dolore in Urgenza E Sedazione Procedurale: Manuale SAU; Independently Published: Traverse, MI, USA, 2022; ISBN 979-8819663554.
  4. Zanos, P.; Moaddel, R.; Morris, P.J.; Riggs, L.M.; Highland, J.N.; Georgiou, P.; Pereira, E.F.R.; Albuquerque, E.X.; Thomas, C.J.; Zarate, C.A., Jr.; et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol. Rev. 2018, 70, 621–660, Erratum in Pharmacol. Rev. 2018, 70, 879.
  5. Olofsen, E.; Noppers, I.; Niesters, M.; Kharasch, E.; Aarts, L.; Sarton, E.; Dahan, A. Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers. Anesthesiology 2012, 117, 353–364.
  6. Schwenk, E.S.; Pradhan, B.; Nalamasu, R.; Stolle, L.; Wainer, I.W.; Cirullo, M.; Olson, A.; Pergolizzi, J.V.; Torjman, M.C.; Viscusi, E.R. Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity. Curr. Pain Headache Rep. 2021, 25, 57, Erratum in Curr. Pain Headache Rep. 2021, 25, 62.
  7. Shaffer, C.L.; Dutra, J.K.; Tseng, W.C.; Weber, M.L.; Bogart, L.J.; Hales, K.; Pang, J.; Volfson, D.; Am Ende, C.W.; Green, M.E.; et al. Pharmacological evaluation of clinically relevant concentrations of (2R,6R)-hydroxynorketamine. Neuropharmacology 2019, 153, 73–81.
  8. Davis, W.D.; Davis, K.A.; Hooper, K. The Use of Ketamine for the Management of Acute Pain in the Emergency Department. Adv. Emerg. Nurs. J. 2019, 41, 111–121.
  9. Nowacka, A.; Borczyk, M. Ketamine applications beyond anesthesia—A literature review. Eur. J. Pharmacol. 2019, 860, 172547.
  10. Malinovsky, J.M.; Servin, F.; Cozian, A.; Lepage, J.Y.; Pinaud, M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br. J. Anaesth. 1996, 77, 203–207.
  11. Miller, M.; Kruit, N.; Heldreich, C.; Ware, S.; Habig, K.; Reid, C.; Burns, B. Hemodynamic response after rapid sequence induction with ketamine in out-of-hospital patients at risk of shock as defined by the shock index. Ann. Emerg. Med. 2016, 68, 181–188.
  12. Nielsen, B.N.; Friis, S.M.; Rømsing, J.; Schmiegelow, K.; Anderson, B.J.; Ferreirós, N.; Labocha, S.; Henneberg, S. Intranasal sufentanil/ketamine analgesia in children. Paediatr. Anaesth. 2014, 24, 170–180.
  13. Huge, V.; Lauchart, M.; Magerl, W.; Schelling, G.; Beyer, A.; Thieme, D.; Azad, S.C. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur. J. Pain 2010, 14, 387–394.
  14. Carr, D.B.; Goudas, L.C.; Denman, W.T.; Brookoff, D.; Staats, P.S.; Brennen, L.; Green, G.; Albin, R.; Hamilton, D.; Rogers, M.C.; et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: A randomized, double-blind, placebo-controlled, crossover study. Pain 2004, 108, 17–27.
  15. Barrett, W.; Buxhoeveden, M.; Dhillon, S. Ketamine: A versatile tool for anesthesia and analgesia. Curr. Opin. Anaesthesiol. 2020, 33, 633–638.
  16. Sinner, B.; Graf, B.M. Ketamine; Handbook of Experimental Pharmacology; Springer: Berlin/Heidelberg, Germany, 2008; pp. 313–333.
  17. Pourmand, A.; Mazer-Amirshahi, M.; Royall, C.; Alhawas, R.; Shesser, R. Low dose ketamine use in the emergency department, a new direction in pain management. Am. J. Emerg. Med. 2017, 35, 918–921.
  18. Visser, E.; Schug, S.A. The role of ketamine in pain management. Biomed. Pharmacother. 2006, 60, 341–348.
  19. Ahern, T.L.; Herring, A.A.; Miller, S.; Frazee, B.W. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015, 16, 1402–1409.
  20. Cohen, S.P.; Liao, W.; Gupta, A.; Plunkett, A. Ketamine in pain management. Adv. Psychosom. Med. 2011, 30, 139–161.
  21. Subramanian, S.; Haroutounian, S.; Palanca, B.J.A.; Lenze, E.J. Ketamine as a therapeutic agent for depression and pain: Mechanisms and evidence. J. Neurol. Sci. 2022, 434, 120152.
  22. Marcus, D.J.; Bruchas, M.R. Where ketamine and dopamine collide. eLife 2021, 10, e70148.
  23. Kapur, S.; Seeman, P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol. Psychiatry. 2002, 7, 837–844.
  24. Seeman, P.; Guan, H.C.; Hirbec, H. Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Synapse 2009, 63, 698–704.
  25. Thurston, T.A.; Mathew, B.P. In vitro myocardial depression by ketamine or thiopental is dependent on the underlying beta-adrenergic tone. Acta Anaesthesiol. Scand. 1996, 40, 338–341.
  26. Gupta, A.; Devi, L.A.; Gomes, I. Potentiation of μ-opioid receptor-mediated signaling by ketamine. J. Neurochem. 2011, 119, 294–302.
  27. Aleksandrova, L.R.; Phillips, A.G. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends Pharmacol. Sci. 2021, 42, 929–942.
  28. Lee, E.N.; Lee, J.H. The Effects of Low-Dose Ketamine on Acute Pain in an Emergency Setting: A Systematic Review and Meta-Analysis. PLoS ONE 2016, 11, e0165461.
  29. Durieux, M.E. Inhibition by ketamine of muscarinic acetylcholine receptor function. Anesth. Analg. 1995, 81, 57–62.
  30. Gerhard, D.M.; Pothula, S.; Liu, R.J.; Wu, M.; Li, X.Y.; Girgenti, M.J.; Taylor, S.R.; Duman, C.H.; Delpire, E.; Picciotto, M.; et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J. Clin. Investig. 2020, 130, 1336–1349.
  31. Subramaniam, K.; Subramaniam, B.; Steinbrook, R.A. Ketamine as adjuvant analgesic to opioids: A quantitative and qualitative systematic review. Anesth. Analg. 2004, 99, 482–495.
  32. Matveychuk, D.; Thomas, R.K.; Swainson, J.; Khullar, A.; MacKay, M.A.; Baker, G.B.; Dursun, S.M. Ketamine as an antidepressant: Overview of its mechanisms of action and potential predictive biomarkers. Ther. Adv. Psychopharmacol. 2020, 10, 2045125320916657.
  33. Singh, N.S.; Zarate, C.A., Jr.; Moaddel, R.; Bernier, M.; Wainer, I.W. What is hydroxynorketamine and what can it bring to neurotherapeutics? Expert Rev. Neurother. 2014, 14, 1239–1242.
  34. Miller, O.H.; Moran, J.T.; Hall, B.J. Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: Direct inhibition and disinhibition. Neuropharmacology 2016, 100, 17–26.
  35. Zanos, P.; Moaddel, R.; Morris, P.J.; Georgiou, P.; Fischell, J.; Elmer, G.I.; Alkondon, M.; Yuan, P.; Pribut, H.J.; Singh, N.S.; et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016, 533, 481–486.
  36. Highland, J.N.; Zanos, P.; Riggs, L.M.; Georgiou, P.; Clark, S.M.; Morris, P.J.; Moaddel, R.; Thomas, C.J.; Zarate, C.A., Jr.; Pereira, E.F.R.; et al. Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. Pharmacol. Rev. 2021, 73, 763–791.
  37. Shaked, G.; Czeiger, D.; Dukhno, O.; Levy, I.; Artru, A.A.; Shapira, Y.; Douvdevani, A. Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats. Resuscitation 2004, 62, 237–242.
  38. Kokkinou, M.; Irvine, E.E.; Bonsall, D.R.; Natesan, S.; Wells, L.A.; Smith, M.; Glegola, J.; Paul, E.J.; Tossell, K.; Veronese, M.; et al. Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: A translational imaging study with ketamine. Mol. Psychiatry. 2021, 26, 2562–2576.
  39. Kokkinou, M.; Ashok, A.H.; Howes, O.D. The effects of ketamine on dopaminergic function: Meta-analysis and review of the implications for neuropsychiatric disorders. Mol. Psychiatry. 2018, 23, 59–69.
  40. Crisp, T.; Perrotti, J.M.; Smith, D.L.; Stafinsky, J.L.; Smith, D.J. The local monoaminergic dependency of spinal ketamine. Eur. J. Pharmacol. 1991, 194, 167–172.
  41. Takasu, K.; Ono, H.; Tanabe, M. Spinal hyperpolarization-activated cyclic nucleotide-gated cation channels at primary afferent terminals contribute to chronic pain. Pain 2010, 151, 87–96.
  42. Zhang, S.; You, Z.; Wang, S.; Yang, J.; Yang, L.; Sun, Y.; Mi, W.; Yang, L.; McCabe, M.F.; Shen, S.; et al. Neuropeptide S modulates the amygdaloidal HCN activities (Ih) in rats: Implication in chronic pain. Neuropharmacology 2016, 105, 420–433.
  43. Du, L.; Wang, S.J.; Cui, J.; He, W.J.; Ruan, H.Z. The role of HCN channels within the periaqueductal gray in neuropathic pain. Brain Res. 2013, 1500, 36–44.
  44. Du, L.; Wang, S.J.; Cui, J.; He, W.J.; Ruan, H.Z. Inhibition of HCN channels within the periaqueductal gray attenuates neuropathic pain in rats. Behav. Neurosci. 2013, 127, 325–329.
  45. Mikkelsen, S.; Ilkjaer, S.; Brennum, J.; Borgbjerg, F.M.; Dahl, J.B. The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans. Anesthesiology 1999, 90, 1539–1545.
  46. Olney, J.W.; Labruyere, J.; Price, M.T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989, 244, 1360–1362.
  47. Olney, J.W.; Labruyere, J.; Wang, G.; Wozniak, D.F.; Price, M.T.; Sesma, M.A. NMDA antagonist neurotoxicity: Mechanism and prevention. Science 1991, 254, 1515–1518.
  48. Yan, J.; Li, Y.R.; Zhang, Y.; Lu, Y.; Jiang, H. Repeated exposure to anesthetic ketamine can negatively impact neurodevelopment in infants: A prospective preliminary clinical study. J. Child Neurol. 2014, 29, 1333–1338.
  49. Church, J.; Zeman, S.; Lodge, D. The neuroprotective action of ketamine and MK-801 after transient cerebral ischemia in rats. Anesthesiology 1988, 69, 702–709.
  50. Spandou, E.; Karkavelas, G.; Soubasi, V.; Avgovstides-Savvopoulou, P.; Loizidis, T.; Guiba-Tziampiri, O. Effect of ketamine on hypoxic-ischemic brain damage in newborn rats. Brain Res. 1999, 819, 1–7.
  51. Wang, L.; Deng, B.; Yan, P.; Wu, H.; Li, C.; Zhu, H.; Du, J.; Hou, L. Neuroprotective effect of ketamine against TNF-α-induced necroptosis in hippocampal neurons. J. Cell. Mol. Med. 2021, 25, 3449–3459.
  52. Monfort, P.; Kosenko, E.; Erceg, S.; Canales, J.J.; Felipo, V. Molecular mechanism of acute ammonia toxicity: Role of NMDA receptors. Neurochem. Int. 2002, 41, 95–102.
  53. Chan, P.H.; Chu, L. Ketamine protects cultured astrocytes from glutamate-induced swelling. Brain Res. 1989, 487, 380–383.
  54. Rodrigo, R.; Cauli, O.; Boix, J.; ElMlili, N.; Agusti, A.; Felipo, V. Role of NMDA receptors in acute liver failure and ammonia toxicity: Therapeutical implications. Neurochem. Int. 2009, 55, 113–118.
  55. Cauli, O.; Rodrigo, R.; Boix, J.; Piedrafita, B.; Agusti, A.; Felipo, V. Acute liver failure-induced death of rats is delayed or prevented by blocking NMDA receptors in brain. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 295, G503–G511.
  56. Boscán, P.L.; Piña-Crespo, J.C.; Daló, N.L. Ketamine reduces lethality on the acute ammonia intoxication in mice. Investig. Clin. 1996, 37, 129–135.
  57. Romero, T.R.; Galdino, G.S.; Silva, G.C.; Resende, L.C.; Perez, A.C.; Côrtes, S.F.; Duarte, I.D. Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats. Anesth. Analg. 2011, 113, 1254–1259.
  58. Fujikawa, D.G. Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia 1995, 36, 186–195.
  59. Kamp, J.; Van Velzen, M.; Olofsen, E.; Boon, M.; Dahan, A.; Niesters, M. Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: An update of the most recent literature. Expert Opin. Drug Metab. Toxicol. 2019, 15, 1033–1041.
  60. Hlavaty, L.; Hansma, P.; Sung, L. Contribution of opiates in sudden asthma deaths. Am. J. Forensic Med. Pathol. 2015, 36, 49–52.
  61. Kurdi, M.S.; Theerth, K.A.; Deva, R.S. Ketamine: Current applications in anesthesia, pain, and critical care. Anesth. Essays Res. 2014, 8, 283–290.
  62. Rehder, K.J. Adjunct Therapies for Refractory Status Asthmaticus in Children. Respir. Care. 2017, 62, 849–865.
  63. Rogers, R.; Wise, R.G.; Painter, D.J.; Longe, S.E.; Tracey, I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology 2004, 100, 292–301.
  64. Sprenger, T.; Valet, M.; Woltmann, R.; Zimmer, C.; Freynhagen, R.; Kochs, E.F.; Tölle, T.R.; Wagner, K.J. Imaging pain modulation by subanesthetic S-(+)-ketamine. Anesth. Analg. 2006, 103, 729–737.
  65. Iacobucci, G.J.; Visnjevac, O.; Pourafkari, L.; Nader, N.D. Ketamine: An Update on Cellular and Subcellular Mechanisms with Implications for Clinical Practice. Pain Physician 2017, 20, E285–E301.
  66. Abbadie, C.; Brown, J.L.; Mantyh, P.W.; Basbaum, A.I. Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain. Neuroscience 1996, 70, 201–209.
  67. Okamoto, T.; Minami, K.; Uezono, Y.; Ogata, J.; Shiraishi, M.; Shigematsu, A.; Ueta, Y. The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes. Anesth. Analg. 2003, 97, 104–110.
  68. Bartolini, A.; Ghelardini, C.; Fantetti, L.; Malcangio, M.; Malmberg-Aiello, P.; Giotti, A. Role of muscarinic receptor subtypes in central antinociception. Br. J. Pharmacol. 1992, 105, 77–82.
  69. Culp, C.; Kim, H.K.; Abdi, S. Ketamine Use for Cancer and Chronic Pain Management. Front. Pharmacol. 2021, 11, 599721.
  70. Mika, J.; Osikowicz, M.; Rojewska, E.; Korostynski, M.; Wawrzczak-Bargiela, A.; Przewlocki, R.; Przewlocka, B. Differential activation of spinal microglial and astroglial cells in a mouse model of peripheral neuropathic pain. Eur. J. Pharmacol. 2009, 623, 65–72.
  71. Fanta, S.; Kinnunen, M.; Backman, J.T.; Kalso, E. Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing. Eur. J. Clin. Pharmacol. 2015, 71, 441–447.
  72. Niesters, M.; Martini, C.; Dahan, A. Ketamine for chronic pain: Risks and benefits. Br. J. Clin. Pharmacol. 2014, 77, 357–367.
  73. Sigtermans, M.J.; van Hilten, J.J.; Bauer, M.C.R.; Arbous, S.M.; Marinus, J.; Sarton, E.Y.; Dahan, A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain 2009, 145, 304–311.
  74. Sigtermans, M.; Dahan, A.; Mooren, R.; Bauer, M.; Kest, B.; Sarton, E.; Olofsen, E. S(+)-ketamine effect on experimental pain and cardiac output: A population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. Anesthesiology 2009, 111, 892–903.
  75. Lefèvre, Y.; Amadio, A.; Vincent, P.; Descheemaeker, A.; Oliet, S.H.; Dallel, R.; Voisin, D.L. Neuropathic pain depends upon D-serine co-activation of spinal NMDA receptors in rats. Neurosci. Lett. 2015, 603, 42–47.
  76. Choi, S.R.; Roh, D.H.; Yoon, S.Y.; Choi, H.S.; Kang, S.Y.; Han, H.J.; Beitz, A.J.; Lee, J.H. Astrocyte D-serine modulates the activation of neuronal NOS leading to the development of mechanical allodynia in peripheral neuropathy. Mol. Pain 2019, 15, 1744806919843046.
  77. Sheng, J.; Liu, S.; Wang, Y.; Cui, R.; Zhang, X. The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain. Neural. Plast. 2017, 2017, 9724371.
  78. Doan, L.V.; Wang, J. An Update on the Basic and Clinical Science of Ketamine Analgesia. Clin. J. Pain 2018, 34, 1077–1088.
  79. Nicholas, M.K.; Coulston, C.M.; Asghari, A.; Malhi, G.S. Depressive symptoms in patients with chronic pain. Med. J. Aust. 2009, 190, S66–S70.
  80. Lerman, S.F.; Rudich, Z.; Brill, S.; Shalev, H.; Shahar, G. Longitudinal associations between depression, anxiety, pain, and pain-related disability in chronic pain patients. Psychosom. Med. 2015, 77, 333–341.
  81. Wang, J.; Goffer, Y.; Xu, D.; Tukey, D.S.; Shamir, D.B.; Eberle, S.E.; Zou, A.H.; Blanck, T.J.; Ziff, E.B. A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology 2011, 115, 812–821.
  82. Zhou, Y.; Wang, C.; Lan, X.; Li, H.; Chao, Z.; Ning, Y. Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: Improvement by ketamine. J. Neuroinflammation 2021, 18, 200.
  83. Berman, R.M.; Cappiello, A.; Anand, A.; Oren, D.A.; Heninger, G.R.; Charney, D.S.; Krystal, J.H. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000, 47, 351–354.
  84. Scheuing, L.; Chiu, C.T.; Liao, H.M.; Chuang, D.M. Antidepressant mechanism of ketamine: Perspective from preclinical studies. Front. Neurosci. 2015, 9, 249.
  85. Weisman, H. Anesthesia for pediatric ophthalmology. Ann. Ophthalmol. 1971, 3, 229–232.
  86. Kotermanski, S.E.; Johnson, J.W. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J. Neurosci. 2009, 29, 2774–2779.
  87. Liu, H.T.; Hollmann, M.W.; Liu, W.H.; Hoenemann, C.W.; Durieux, M.E. Modulation of NMDA receptor function by ketamine and magnesium: Part I. Anesth. Analg. 2001, 92, 1173–1181.
  88. Hollmann, M.W.; Liu, H.T.; Hoenemann, C.W.; Liu, W.H.; Durieux, M.E. Modulation of NMDA receptor function by ketamine and magnesium. Part II: Interactions with volatile anesthetics. Anesth. Analg. 2001, 92, 1182–1191.
  89. Savic Vujovic, K.R.; Vuckovic, S.; Srebro, D.; Medic, B.; Stojanovic, R.; Vucetic, C.; Prostran, M. A synergistic interaction between magnesium sulphate and ketamine on the inhibition of acute nociception in rats. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 2503–2509.
  90. Varas, V.; Bertinelli, P.; Carrasco, P.; Souper, N.; Álvarez, P.; Danilla, S.; Egaña, J.I.; Penna, A.; Sepúlveda, S.; Arancibia, V.; et al. Intraoperative Ketamine and Magnesium Therapy to Control Postoperative Pain After Abdominoplasty and/or Liposuction: A Clinical Randomized Trial. J. Pain Res. 2020, 13, 2937–2946.
  91. Crosby, V.; Wilcock, A.; Corcoran, R. The safety and efficacy of a single dose (500 mg or 1 g) of intravenous magnesium sulfate in neuropathic pain poorly responsive to strong opioid analgesics in patients with cancer. J. Pain Symptom Manag. 2000, 19, 35–39.
  92. Begon, S.; Pickering, G.; Eschalier, A.; Dubray, C. Magnesium and MK-801 have a similar effect in two experimental models of neuropathic pain. Brain Res. 2000, 887, 436–439.
  93. Delage, N.; Morel, V.; Picard, P.; Marcaillou, F.; Pereira, B.; Pickering, G. Effect of ketamine combined with magnesium sulfate in neuropathic pain patients (KETAPAIN): Study protocol for a randomized controlled trial. Trials 2017, 18, 517.
  94. Forget, P.; Cata, J. Stable anesthesia with alternative to opioids: Are ketamine and magnesium helpful in stabilizing hemodynamics during surgery? A systematic review and meta-analyses of randomized controlled trials. Best Pr. Res. Clin. Anaesthesiol. 2017, 31, 523–531.
  95. Mak, P.; Broadbear, J.H.; Kolosov, A.; Goodchild, C.S. Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion (“Burst Ketamine”) in Diabetic Neuropathic Rats. Pain Med. 2015, 16, 1781–1793.
  96. Lilius, T.O.; Jokinen, V.; Neuvonen, M.S.; Niemi, M.; Kalso, E.A.; Rauhala, P.V. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat. Br. J. Pharmacol. 2015, 172, 2799–2813.
  97. Klein, T.; Magerl, W.; Nickel, U.; Hopf, H.C.; Sandkühler, J.; Treede, R.D. Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system. Neuropharmacology 2007, 52, 655–661.
  98. Mao, J.; Price, D.D.; Mayer, D.J. Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain 1995, 62, 259–274.
  99. Dickenson, A.H. NMDA receptor antagonists: Interactions with opioids. Acta Anaesthesiol. Scand. 1997, 41 Pt 2, 112–115.
  100. Laulin, J.P.; Maurette, P.; Corcuff, J.B.; Rivat, C.; Chauvin, M.; Simonnet, G. The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth. Analg. 2002, 94, 1263–1269.
  101. Trujillo, K.A.; Akil, H. Inhibition of opiate tolerance by non-competitive N-methyl-D-aspartate receptor antagonists. Brain Res. 1994, 633, 178–188.
  102. Riddell, J.M.; Trummel, J.M.; Onakpoya, I.J. Low-dose ketamine in painful orthopaedic surgery: A systematic review and meta-analysis. Br. J. Anaesth. 2019, 123, 325–334.
  103. Bi, Y.; Ye, Y.; Zhu, Y.; Ma, J.; Zhang, X.; Liu, B. The Effect of Ketamine on Acute and Chronic Wound Pain in Patients Undergoing Breast Surgery: A Meta-Analysis and Systematic Review. Pain Pract. 2021, 21, 316–332.
  104. Wang, L.; Johnston, B.; Kaushal, A.; Cheng, D.; Zhu, F.; Martin, J. Ketamine added to morphine or hydromorphone patient-controlled analgesia for acute postoperative pain in adults: A systematic review and meta-analysis of randomized trials. Can. J. Anaesth. 2016, 63, 311–325.
  105. Brinck, E.C.; Tiippana, E.; Heesen, M.; Bell, R.F.; Straube, S.; Moore, R.A.; Kontinen, V. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst. Rev. 2018, 12, CD012033.
  106. Gorlin, A.W.; Rosenfeld, D.M.; Ramakrishna, H. Intravenous sub-anesthetic ketamine for perioperative analgesia. J. Anaesthesiol. Clin. Pharmacol. 2016, 32, 160–167.
  107. Radvansky, B.M.; Shah, K.; Parikh, A.; Sifonios, A.N.; Le, V.; Eloy, J.D. Role of ketamine in acute postoperative pain management: A narrative review. Biomed Res. Int. 2015, 2015, 749837.
  108. Yu, M.; Shao, D.; Yang, R.; Feng, X.; Zhu, S.; Xu, J. Effects of ketamine on pulmonary inflammatory responses and survival in rats exposed to polymicrobial sepsis. J. Pharm. Pharm. Sci. 2007, 10, 434–442.
  109. Hayashi, Y.; Kawaji, K.; Sun, L.; Zhang, X.; Koyano, K.; Yokoyama, T.; Kohsaka, S.; Inoue, K.; Nakanishi, H. Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain. J. Neurosci. 2011, 31, 17370–17382.
  110. Watkins, L.R.; Milligan, E.D.; Maier, S.F. Glial activation: A driving force for pathological pain. Trends Neurosci. 2001, 24, 450–455.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , , , , ,
View Times: 280
Revisions: 2 times (View History)
Update Date: 16 May 2023
1000/1000