Acute and chronic pain remains a significant health problem worldwide. The aging of the population has led to an increased number of individuals experiencing both acute injuries and chronic diseases that cause pain. Ketamine was originally developed by Craig Newlands and later synthesized by Calvin Stevens in 1962. It is a derivative of phenylcyclidine in order to produce a safer and more manageable drug. Recently there has been an increased interest about it especially in emergency medicine, acute and chronic pain and psychiatry. It is an analgesic imperative to maintain a balance between the adequate treatment of pain and preventing opiate dependence in the population.

It is a ‘dissociative anesthetic,’ which refers to the fact that simultaneously different areas of the brain are either activated, such as the hippocampus and frontal cortex, or suppressed, such as the thalamus, and therefore the various areas of the brain are ‘dissociated’ from each other. It rapidly induces general anesthesia while preserving the patient’s protective reflexes and vital functions besides its sympathomimetic effect. However, its psychomimetic effects have limited its use. Research in 1965 demonstrated its analgesic effect in subdissociative doses during painful procedures in children. In 1971, the analgesic effect of ketamine was further confirmed when it was observed that patients who underwent anesthesia with ketamine required less opioid medication and experienced better pain management.

It is highy lipophilic with a distribution half-life of 10 min, onset time of 30 s, short duration of action after a bolus dose, large volume of distribution (160-550 litres) and it is least protein bound(10-50%). 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. These metabolites have an extended half-life of up to 3 days and, according to various authors, provide prolonged analgesic and antidepressant effects. Bioavailability and duration of action vary depending on the route of administration: with intravenous administration, bioavailability is 100%. It is eliminated mainly in the urine (elimination half-life of 1,5-3 h) Women generally metabolize ketamine more rapidly (up to 20%) than men, whereas older people tend to metabolize it more slowly. It is contraindicated during pregnancy and lactation. Due to its short half-life, no dosage adjustment is required in patients with impaired renal function.

It has the ability to produce different effects depending on the dosage and this property is unique among drugs. Low-dose ketamine has been shown to have an opioid-sparing effect and has been shown to reduce opioid tolerance. In addition to its role as an analgesic in acute pain, it can reduce hyperalgesia and allodynia in chronic pain.

The main mechanism of action of ketamine is to block glutamatergic neurons via its antagonistic effect on NMDA receptors. It does this by non-competitively blocking the opening of glutamatergic channels, mainly in the prefrontal cortex and hippocampus. Ketamine also activates the prefrontal cortex via blockade of inhibitory interneurons, which is one of the mechanisms responsible for its psychomimetic effects. The effect of ketamine on NMDA receptors is unique in that it acts as an open-channel blocker. It blocks the calcium channels only when they are open and has no effect on the closed resting channel.

However, the analgesic effects of ketamine are diverse and multifaceted. It modulates the reuptake of serotonin, dopamine and norepinephrine and causes a paradoxical increase in glutamate with stimulation of the descending inhibitory pathways with effects on dopaminergic, adrenergic, serotoninergic, opioid and cholinergic receptors by stimulating the nicotinic pathway and inhibiting the muscarinic pathway by blocking M1 receptors. Ketamine also acts on spinal GABA interneurons.

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. Severe pain activates NMDA receptors with hyperexcitability of spinal interneurons in the posterior horn, leading to spinal cord wind-up and central sensitisation. The paradoxical increase in glutamate is essential for the stimulation of medullary GABA inhibitors and for the stimulation of AMPA receptors, which are crucial for the control of depressive symptoms. Ketamine blocks the NMDA-Rs of GABAergic interneurons, leading to a paradoxical increase in extra- cellular 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. Ketamine also has an anti-inflammatory effect by lowering the levels of IL-6 and TNF-alpha.

In the past, great importance was placed on the analgesic role of ketamine metabolites, but this has since been revised. However, experimental evidence in animal models suggests that norketamine plays an essential role in hyperpolarizing the Hyperpolarization-activated cyclic nucleotide-gated channels(HCN) in the spinal cord and hippocampus, which is particularly important for antidepressant modulation by ketamine. However, in animal models, HCN receptors appear to be involved in the analgesic effect. 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. 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.

Concerning 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. Although the effect of ketamine on NMDA-R 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 NMDA-R 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. 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. 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. In addition, animal studies have suggested that ketamine may modulate astrocytic and glial responses that also play a role in chronic neuropathic pain.

It appears to have a stronger analgesic effect in patients with chronic pain and depression because it may interfere with the production of D-serine or glycine which are required by NMDA receptors in the medullary interneurons as co-agonists, especially in neurons in the limbic region involved in the development of depression and chronic pain. D-serine in medullary interneurons, increases during neuropathic pain, leading to the activation of NO synthase.

Ketamine interacts with central and spinal opioid receptors and NMDA-R. Opiates reduce pain perception by activating mu receptors, but they activate NMDA receptors, leading to postsynaptic hyperexcitability, central tolerance, and sensitization. Ketamine has been shown to modulate and reduce these effects. It also 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.

Ketamine is indicated for managing acute pain in patients with severe pain that is not responsive to standard opioid analgesics. It can be used safely in head injuries as it does not increase intracranial pressure. It is particularly useful in major surgery and especially when the nervous system is involved. Due to differences in the surgical setting, procedures, timing of administration and dosages, meta-analyses are difficult to compare, and a large study with 8000 participants has not yet been completed.

In a recent systematic review, low-dose ketamine was comparable to morphine in analgesic effectiveness within 60 minutes of administration, with comparable safety profiles, when used in the emergency department.

In 2018 the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists published the following consensus guidelines for the use of ketamine in the management of acute and chronic pain:

1. When used for perioperative analgesia, ketamine bolus dose should not exceed 0.35 mg/kg, and infusion rate should not exceed 1 mg/kg/hr in non-intensive care settings. It should be avoided in patients with severe or uncontrolled cardiovascular disease, severe liver disease, increased intracranial pressure, elevated intraocular pressure, pregnancy, and underlying psychiatric disease associated with psychosis. Evidence supporting patient-controlled analgesia (PCA) with ketamine as the sole analgesic agent postoperatively is limited.

2. For chronic regional pain syndromes (CRPS), there is moderate certainty evidence supporting the use of ketamine infusions for analgesia, which has been shown to provide pain relief for up to 12 weeks. For fibromyalgia, cancer pain, ischemic pain, migraine headache, and low-back pain, there is weak or no evidence to support the use of ketamine infusion for immediate pain relief.

3. Oral ketamine is associated with high abuse potential and should be cautiously prescribed. Follow-up therapy (after intravenous ketamine infusion) with intra-nasal ketamine for breakthrough pain is supported by moderate certainty evidence and can be used in the appropriate population.

4. For palliative therapies and the treatment of neoplastic pain, the evidence is still limited, as it is for the treatment of headache, but there is evidence of considerable interest.

The optimal analgesic dosage of ketamine varies widely in the literature, ranging from 0.15 to 0.5 mg/kg. However, doses above 0.3 mg/kg can lead to psychomimetic symptoms, and 0.5 mg/kg is considered a subdissociative dose and is associated with a higher rate of adverse events. As a result, many authors define safe and effective analgesic dosing as 0.15–0.3 mg/kg bolus, 0.15–0.3 mg/kg/h continuous infusion, 0.5–1 mg/kg intramuscular administration, and 1 mg/kg intranasal administration. Oral administration of ketamine is not standardized, but doses of 0.5 mg/kg every 12 h are considered effective. Other possible routes of administration include transdermal (25 mg/24 h), subcutaneous (0.05–0.15 mg/kg/h), and rectal (10 mg/kg).

The administration method can be tailored to the clinical setting: Continuous infusion administration (up to 100 hours) takes advantage of the increased levels of ketamine metabolites and their analgesic and antidepressant properties. Infusions (up to 100 h) resulted in a sustained analgesic response of 4 to 8 weeks, while infusions of 12 to 24 h resulted in a reduced but stable response of 7 to 10 days.

Ketamine is an excellent drug for the treatment of severe pain in acute cases, but also has remarkable benefits in chronic pain infusions. Unfortunately, there is currently no clinical evidence to predict individual patient responses. Identifying clinical factors that can predict a patient’s response to ketamine will help clinicians determine the most appropriate treatment option. So rigorous research is still needed.

Given the opioid crisis, such studies are more urgent than ever. Future research should also investigate ketamine enantiomers and the development of molecules with more targeted analgesic effects and fewer psychomimetic side effects. Nevertheless, all healthcare providers involved in the treatment of acute, chronic, neuropathic, or neoplastic pain need to be aware of this treatment option and be able to manage its unique side effects.

References

1. Alessandro Riccardi, et al. Narrative review: low-dose ketamine for pain management. Review. J. Clin. Med. 2023; 12 :3256. https://doi.org/10.3390/jcm12093256

2. Orhurhu VJ, Roberts JS, Ly N, et al. Ketamine in acute and chronic pain management. Stat Pearls https://www.ncbi.nlm.nih.gov/books/about/copyright/

3. Eric S Schwen. Ketamine in the past, present, and future: mechanisms, metabolites, and toxicity. https://ww w.ncbi.nlm.nih.gov/books/about/copyright/

4. Kohtala S. Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanism. Pharmacol Rep. 2021;73(2):323–345. Published online 2021 Feb 20. doi: 10.1007/s43440-021-00232-4