Review
Nonanesthetic Effects of Ketamine: A Review Article

https://doi.org/10.1016/j.amjmed.2018.04.029Get rights and content

Abstract

Ketamine is considered a dissociative anesthetic medication, and it is commonly administered by a parenteral route. It works mainly by blocking the N-methyl-D-aspartate receptor. It inhibits the voltage-gated Na and K channels and serotonin and dopamine reuptake; also, it affects specific receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid A receptors. Ketamine appears to have particular mechanisms that are potentially involved during analgesic induction, including enhancing of descending inhibition and antiinflammatory effects. More recently, it has been shown that ketamine has potential in clinical practice for the management of chronic pain, cognitive function, depression, acute brain injury, and disorders of the immune system.

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)

  • HD-CC Rosenbrock et al.

    Effects of specific nicotinic acetylcholine receptor agonists on hippocampal long-term potentiation

    Alzheimers Dement

    (2011)
  • M Moosavi et al.

    The effect of sub-anesthetic and anesthetic ketamine on water maze memory acquisition, consolidation and retrieval

    Eur J Pharmacol

    (2012)
  • LM Monteggia et al.

    Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

    Curr Opin Neurobiol

    (2015)
  • FX Vollenweider et al.

    Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans

    J Psychiatr Res

    (2000)
  • CH Duman et al.

    Spine synapse remodeling in the pathophysiology and treatment of depression

    Neurosci Lett

    (2015)
  • R Yang et al.

    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

    (2017)
  • C Mock et al.

    Strengthening the prevention and care of injuries worldwide

    Lancet

    (2004)
  • Y Hijazi et al.

    Pharmacokinetics and haemodynamics of ketamine in intensive care patients with brain or spinal cord injury

    Br J Anaesth

    (2003)
  • B Beilin et al.

    Low-dose ketamine affects immune responses in humans during the early postoperative period

    Br J Anaesth

    (2007)
  • F-L Liu et al.

    Mechanisms of ketamine-induced immunosuppression

    Acta Anaesthesiologica Taiwanica

    (2012)
  • G Shaked et al.

    Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats

    Resuscitation

    (2004)
  • YS Shibakawa et al.

    Effects of ketamine and propofol on inflammatory responses of primary glial cell cultures stimulated with lipopolysaccharide

    Br J Anaesth

    (2005)
  • Z Liu et al.

    Ketamine attenuates high mobility group box-1-induced inflammatory responses in endothelial cells

    J Surg Res

    (2016)
  • B Sokol et al.

    HMGB1 level in cerebrospinal fluid as a marker of treatment outcome in patients with acute hydrocephalus following aneurysmal subarachnoid hemorrhage

    J Stroke Cerebrovasc Dis

    (2015)
  • G Hocking et al.

    Ketamine in chronic pain management: an evidence-based review

    Anesth Analg

    (2003)
  • JG Reves et al.

    Intravenous anesthetics

  • J Stone et al.

    Anaesthesia at a glance

    (2013)
  • A Agrawal et al.

    Intravenous ketamine for refractory bronchospasm precipitated by H1N1 infection

    Front Pediatr

    (2014)
  • D Garg et al.

    Subanaesthetic dose of ketamine in intractable asthma

    J Indian Med Assoc

    (2011)
  • A Kvarnstrom et al.

    The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain

    Acta Anaesthesiol Scand

    (2003)
  • PJ Christo et al.

    Post-herpetic neuralgia in older adults: evidence-based approaches to clinical management

    Drugs Aging

    (2007)
  • TC Brown et al.

    Ketamine: A new anaesthetic agent

    Aust N Z J Surg

    (1970)
  • DK Lim

    Ketamine associated psychedelic effects and dependence

    Singapore Med J

    (2003)
  • A Perel et al.

    Recurrent hallucinations following ketamine

    Anaesthesia

    (1976)
  • AR Powers et al.

    Ketamine-induced hallucinations

    Psychopathology

    (2015)
  • M Sigtermans et al.

    S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers

    Anesthesiology

    (2009)
  • DW Herd et al.

    Investigating the pharmacodynamics of ketamine in children

    Paediatr Anaesth

    (2008)
  • R Kohrs et al.

    Ketamine: teaching an old drug new tricks

    Anesth Analg

    (1998)
  • L Vutskits et al.

    Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro

    Toxicol Sci

    (2006)
  • R Schnoebel et al.

    Ketamine impairs excitability in superficial dorsal horn neurones by blocking sodium and voltage-gated potassium currents

    Br J Pharmacol

    (2005)
  • SF Grieco et al.

    Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3

    World J Biol Psychiatry

    (2017)
  • M Stenovec et al.

    Ketamine inhibits ATP-evoked exocytotic release of brain-derived neurotrophic factor from vesicles in cultured rat astrocytes

    Mol Neurobiol

    (2016)
  • 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 Research
      Citation 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 Disorders
      Citation 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, Seizure
      Citation 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 Surgery
      Citation 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.

    View all citing articles on Scopus

    Funding: None.

    Conflict of Interest: None.

    Author Roles: All authors had a role in writing the manuscript.

    View full text