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][1,6,44]. Owing to its high liposolubility, it has a large volume of distribution, ranging from 160 to 550 litres ^[2][6]. 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][45]. 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][32,36,45,46]. 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][39,45,47]; with intramuscular administration, bioavailability is 93% and maximum effect is achieved within 5–10 min ^[4][8][9][39,45,47]; with oral administration, bioavailability is 16–29% and maximum effect is achieved within 20–120 min ^[4][45]. Intranasal administration shows a bioavailability of 35–50% ^[10][11][12][48,49,50], an analgesic effect with onset of action within 10 min, a time-to-peak effect of 10–14 min ^[13][51] and a duration of up to 60 min ^[14][52]. Oral administration of ketamine is considered less beneficial because of its lower bioavailability and significant hepatic first-pass effect ^[2][15][6,18]. 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][45]. Women generally metabolize ketamine more rapidly (up to 20%) than men, whereas older people tend to metabolize it more slowly ^[4][45]. Ketamine is contraindicated during pregnancy and lactation ^[16][17][11,24]. Due to its short half-life, no dosage adjustment is required in patients with impaired renal function ^[18][29].

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][53].

The main mechanism of action of ketamine is to block glutamatergic neurons via its antagonistic effect on NMDA receptors ^[1][3][1,44]. It does this by non-competitively blocking the opening of glutamatergic channels, mainly in the prefrontal cortex and hippocampus ^[4][20][4,45]. Ketamine also activates the prefrontal cortex via blockade of inhibitory interneurons, which is one of the mechanisms responsible for its psychomimetic effects ^[21][3]. 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][47]. However, the analgesic effects of ketamine are diverse and multifaceted, with effects on dopaminergic ^[22][23][24][54,55,56], adrenergic ^[25][26][57,58], serotoninergic ^[27][59], opioid ^[26][28][58,60] and cholinergic ^[14][29][52,61] 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][52,61]. In addition, ketamine acts on spinal GABA interneurons ^[30][62].

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][45,56]. 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][4]. Severe pain activates NMDA receptors with hyperexcitability of spinal interneurons in the posterior horn, leading to spinal cord wind-up and central sensitisation ^[31][63]. The paradoxical increase in glutamate is essential for the stimulation of medullary GABA inhibitors ^[4][45] and for the stimulation of AMPA receptors, which are crucial for the control of depressive symptoms ^[4][32][33][45,64,65]. 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][66]. AMPA blockade inhibits the antidepressant effect of ketamine ^[35][36][67,68]. Ketamine also has an anti-inflammatory effect by lowering the levels of IL-6 and TNF-alpha ^[37][69]. 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][70,71]. 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][72].

In the past, great importance was placed on the analgesic role of ketamine metabolites, but this has since been revised ^[6][36]. 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][45,46]. However, in animal models, HCN receptors appear to be involved in the analgesic effects ^{[41][42][43][44]}[73,74,75,76]. 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][77]. 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][1,4].

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][6]. 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][4]. The neuronal interaction of ketamine is even more complex; while ketamine has raised concerns about neuronal damage in animal models ^[46][47][78,79], there is evidence of a neuroprotective effect of ketamine in the presence of acute stress ^{[48][49][50][51]}[80,81,82,83]. 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]}[84,85,86,87,88,89]. A similar neuroprotective effect was observed in patients with super-refractory epilepsy ^[58][14]. 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][90].

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][91], ketamine acts as a bronchodilator ^[15][61][62][18,92,93].

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][11,94,95]. 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][96]. 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][97,98]. 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][61,99]. In addition, animal studies have suggested that ketamine may modulate astrocytic and glial responses that play a role in chronic neuropathic pain ^[69][70][100,101].

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][33,34] and tend to accumulate over longer infusion periods, resulting in a sustained analgesic effect over several days ^[73][74][102,103].

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][104,105].

However, it is worth noting that depression and chronic pain are closely linked ^[77][106], and a drug that can effectively treat both conditions would be ideal ^{[78][79][80][81]}[23,107,108,109]. Indeed, ketamine appears to have a stronger analgesic effect in patients with chronic pain and depression ^[82][110]. 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][45], and the first major study on this topic was conducted in 2000 ^[83][111].

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][112]. 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][112].

The first observation of the analgesic effects of magnesium and ketamine dates to 1971 ^[85][113], 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][96]. Magnesium is the body’s NMDA receptor antagonist, and the binding site of ketamine to the same receptor is nearby ^[65][96]. 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][114]. 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]}[115,116,117,118,119,120,121]. However, it is not yet known how long magnesium infusions should be administered. Magnesium also appears to improve haemodynamic stability ^[94][122].

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]}[6,24,63,123,124,125]. 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]}[3,126,127,128,129]. 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]}[39,58,130,131,132,133,134,135].

Pain is an important inflammatory component, particularly in the postoperative setting ^[4][45]. Ketamine decreases IL-6, TNF alpha, CRP, and NO synthase levels. High levels of IL-6 are associated with poor postoperative outcomes ^[37][69]. Chronic postoperative pain can occur in up to 20% of all surgeries and 50–60% of surgeries involving nerve structures ^[108][136]. Postoperative neuropathic pain is caused by activated microglia in the spinal cord ^{[21][37][108][109][110]}[3,69,136,137,138]. Therefore, the effect of ketamine on glial cells ^[69][70][100,101] can alleviate postoperative pain.