ReviewNonanesthetic Effects of Ketamine: A Review Article
Introduction
Since 1970, ketamine has been clinically used as an anesthetic medication.1 It is thought to modulate N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid-A receptors.1, 2 Its ability to inhibit the voltage-gated Na and K channels, and serotonin and dopamine reuptake might be useful in some clinical conditions, such as managing chronic pain, depression, acute brain injury, etc.1, 3 Ketamine has been used in clinical practice in different medical specialties.4, 5 It produces a wide variety of pharmacologic effects, including sedation, analgesia, bronchodilation, and sympathetic nervous system stimulation.4, 6,7 Anesthesiologists and pain specialists have begun to use ketamine in subanesthetic doses for the long-term treatment of chronic refractory pain, particularly neuropathic pains, such as complex regional pain syndrome, postherpetic neuralgia, and diabetic neuropathic pain.4, 8,9
The pharmacologic and anesthetic properties of ketamine have been identified since 1965.10 Ketamine is known as a dissociative anesthetic agent that produces strong analgesia and amnesia.10, 11 In addition, it elicits a variety of side effects, such as the induction of psychedelic conditions leading to hallucinations and excitation symptoms.12, 13 In this review, we will discuss the relevant literature on the potential benefits and risks of ketamine use in pathologic conditions, including managing chronic pain, cognitive function, depression, acute brain injury, and immune system disorders.
Section snippets
Pharmacology
Ketamine can rapidly pass the blood-brain barrier and therefore has a quick onset of analgesic effect.14, 15 Ketamine potentially produces an analgesic effect at several sites of the nervous system, both centrally and peripherally.16, 17, 18 New research shows that ketamine has inhibitory effects on voltage-gated Na and K channels and serotonin receptors, and it inhibits dopamine reuptake.19, 20, 21 The mechanism of action of ketamine is thought to involve an interaction between
Chronic Pain
Ketamine is administered to treat various diseases that cause chronic refractory pain, particularly those that have a neuropathic component.24 It has recently been reported that a low intravenous dose of ketamine produces potent analgesia in neuropathic pain conditions, presumably by inhibition of the N-methyl-D-aspartate receptor.24 However, it appears that particular mechanisms are potentially involved, including enhancing of the descending inhibition and antiinflammatory effects.25 In
Cognitive Function
Analysis of cognitive and memory functions during short-term ketamine infusion has demonstrated impairment of working memory and reduction in the encoding of information into episodic memory.27 In contrast to other amnestic medications, ketamine impairs semantic memory in some patients.27 After the termination of short duration and single ketamine infusions, memory function reverts to a healthy state, which possibly indicates that ketamine-induced memory loss is self-resolving.27 However, the
Dementia and Alzheimer's Disease
Ketamine is known as a noncompetitive N-methyl-D-aspartate receptor antagonist.16, 38,39 Therefore administration of ketamine and other N-methyl-D-aspartate receptor antagonists, such as memantine, is used to improve the symptoms of Alzheimer's disease.40 Some studies have revealed (the excitotoxic hypothesis) that there are glutamatergic hyperactivity receptors in Alzheimer's disease. Neuronal and astroglial glutamate transporter dysfunction in Alzheimer's disease may lead to excess glutamate
Depression
Antidepressant actions in animal models have been demonstrated with ketamine, as have rapid antidepressant effects in human studies.49, 50 Ketamine is a high-affinity N-methyl-D-aspartate receptor antagonist, which also binds to opioid µ and sigma receptors.51 Ketamine was reported to regulate dopamine transmission and reuptake.52, 53 Treatment-resistant depression affects more than 1% of individuals in the United States and nearly 30% of all depressed patients.54 Ketamine has active and rapid
Acute Brain Injury
The occurrence of traumatic brain injury is high; incidence is increased in developing countries and exceeds that of the developed world.63 Therapeutic strategy for reducing traumatic brain injury or stroke after ischemia or trauma is well defined.63 The treatment is aimed at alleviating secondary damage, which occurs within hours to days after an acute brain insult.63 Neuroscientists and clinicians have struggled to identify the cause and consequences of this secondary damage.64 Successful
Immune System
Ketamine reduces tissue necrosis factor α, interleukins, and nitric oxide production, all of which play vital roles during the inflammatory process, and the inhibition of these activities could affect macrophage-mediated immunity.74 The potential mechanism of ketamine-induced immunosuppression was studied to evaluate effects in macrophages, tissue necrosis factor α, interleukin-1β, and interleukin-6 messenger ribonucleic acid syntheses, and it was found that ketamine inhibited messenger
Conclusion
Much research has been conducted on ketamine's mechanisms of action; specifically those related to its antidepressive effects, antiinflammatory effects, and chronic pain management and cognitive function. Further study is needed for testing long-term efficacy and safety of ketamine in nonanesthetic clinical practice for managing major resistant depression, enhancing memory function in Alzheimer's patients, and reducing brain damage after stroke. This review provides evidence of the medical
References (84)
- et al.
Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1
Pain
(2009) - et al.
Is ketamine effective for the management of acute asthma exacerbations in children?
Ann Emerg Med
(2014) - et al.
Pathogenesis of pain
Semin Pediatr Neurol
(2016) - et al.
Ketamine inhibits nitric oxide production in mouse-activated macrophage-like cells
Br J Anaesth
(1996) - et al.
Analgesia for anesthetized patients
Top Companion Anim Med
(2010) - et al.
Mechanisms of ketamine-induced immunosuppression
Acta Anaesthesiol Taiwan
(2012) - et al.
The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complexregional pain syndrome
Arch Clin Neuropsychol
(2007) - et al.
Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications
Neuroscience
(2013) - et al.
Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex
J Psychiatr Res
(2017) - et al.
Physostigmine antagonizes ketamine-induced noradrenaline release from the medial prefrontal cortex in rats
Brain Res
(1999)
Effects of specific nicotinic acetylcholine receptor agonists on hippocampal long-term potentiation
Alzheimers Dement
The effect of sub-anesthetic and anesthetic ketamine on water maze memory acquisition, consolidation and retrieval
Eur J Pharmacol
Antidepressant actions of ketamine: from molecular mechanisms to clinical practice
Curr Opin Neurobiol
Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans
J Psychiatr Res
Spine synapse remodeling in the pathophysiology and treatment of depression
Neurosci Lett
WY-14643, a selective agonist of peroxisome proliferator-activated receptor-alpha, ameliorates lipopolysaccharide-induced depressive-like behaviors by preventing neuroinflammation and oxido-nitrosative stress in mice
Pharmacol Biochem Behav
Strengthening the prevention and care of injuries worldwide
Lancet
Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury
Br J Anaesth
Low-dose ketamine affects immune responses in humans during the early postoperative period
Br J Anaesth
Mechanisms of ketamine-induced immunosuppression
Acta Anaesthesiologica Taiwanica
Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats
Resuscitation
Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide
Br J Anaesth
Ketamine attenuates high mobility group box-1-induced inflammatory responses in endothelial cells
J Surg Res
HMGB1 level in cerebrospinal fluid as a marker of treatment outcome in patients with acute hydrocephalus following aneurysmal subarachnoid hemorrhage
J Stroke Cerebrovasc Dis
Ketamine in chronic pain management: an evidence-based review
Anesth Analg
Intravenous anesthetics
Anaesthesia at a glance
Intravenous ketamine for refractory bronchospasm precipitated by H1N1 infection
Front Pediatr
Subanaesthetic dose of ketamine in intractable asthma
J Indian Med Assoc
The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain
Acta Anaesthesiol Scand
Post-herpetic neuralgia in older adults: evidence-based approaches to clinical management
Drugs Aging
Ketamine: A new anaesthetic agent
Aust N Z J Surg
Ketamine associated psychedelic effects and dependence
Singapore Med J
Recurrent hallucinations following ketamine
Anaesthesia
Ketamine-induced hallucinations
Psychopathology
S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers
Anesthesiology
Investigating the pharmacodynamics of ketamine in children
Paediatr Anaesth
Ketamine: teaching an old drug new tricks
Anesth Analg
Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro
Toxicol Sci
Ketamine impairs excitability in superficial dorsal horn neurones by blocking sodium and voltage-gated potassium currents
Br J Pharmacol
Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3
World J Biol Psychiatry
Ketamine inhibits ATP-evoked exocytotic release of brain-derived neurotrophic factor from vesicles in cultured rat astrocytes
Mol Neurobiol
Cited by (21)
Schizophrenia-like endurable behavioral and neuroadaptive changes induced by ketamine administration involve Angiotensin II AT<inf>1</inf> receptor
2022, Behavioural Brain ResearchCitation Excerpt :Indeed, it might reverse the social withdrawal observed in animals treated with repeated ketamine administration. The contrasting effects of this psychotropic seem to depend on the dose used and/or the administration schedule [66–71] and this work adds new evidence that will help to elucidate the wide spectrum of ketamine effects and uses. On the other hand, our results support a key role for angII in the endurable schizophrenia-like behavioral and neuroadaptive changes.
Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies
2020, Journal of Affective DisordersCitation Excerpt :Moreover, an increasing amount of studies are revealing the potential antidepressant effect of N-methyl-d-aspartate (NMDA) receptors antagonist, such as ketamine, with consistent evidence of efficacy and a short latency of antidepressant activity onset (Amidfar et al., 2019). In humans, ketamine has traditionally been used as an anesthetic agent (Eldufani et al., 2018) and only in the last two decades research focused on the potential antidepressant properties of low-dose ketamine administered in treatment refractory mood disorders (Mathew et al., 2012; Murrough, 2012). Specifically, ketamine is a high-affinity, noncompetitive NMDA glutamate receptor antagonist that was found to exert an antidepressant effect, which occurs as early as 40 min from the administration and usually lasts 7 days, in treatment resistant major depression (TRD) patients, therefore representing a new therapeutic option for depressed patients (aan het Rot et al., 2010; Mathew et al., 2010; Zarate et al., 2006).
Novel drugs and early polypharmacotherapy in status epilepticus
2019, SeizureCitation Excerpt :Currently, ketamine is the only intravenous NMDA receptor antagonist available in most countries. Ketamine also interacts with other receptors (opioid, monoaminergic, muscarinic and nicotinic receptors), ion channels (L-calcium and sodium channels), and modulates some cytokines (IL-1, 6, 8, 10; TNF-α), which confers some anti-inflammatory properties to this drug [77,78]. Most human studies assessing the efficacy of ketamine in RSE and SRSE are small retrospective series or isolated cases focused on a late use of this drug when the patient is already on polytherapy, which limits any conclusions about efficacy [79–93].
Ketamine Mitigates Neurobehavioral Deficits in a Canine Model of Hypothermic Circulatory Arrest
2023, Seminars in Thoracic and Cardiovascular SurgeryCitation Excerpt :Indeed, despite many years of research, no pharmacologic intervention has proven to consistently and safely protect against HCA-induced neurologic dysfunction. We therefore sought to utilize ketamine, another NMDA receptor antagonist that is clinically approved for use in anesthesia, sedation, pain control, and treatment of depression, as a potential therapeutic that acts on the same pathway but with a better side effect profile.14 We hypothesized that ketamine would provide neuroprotection following a 90-minute period of HCA in our well-established canine model, as measured by daily neurobehavioral deficit scoring, cerebrospinal fluid (CSF) biomarker assay, and brain histopathology.
Antinociceptive and adverse effects of morphine:ketamine mixtures in rats
2024, Behavioural Pharmacology
Funding: None.
Conflict of Interest: None.
Author Roles: All authors had a role in writing the manuscript.