Nonanesthetic Effects of Ketamine: A Review Article

This review (2018) examines (preliminary) evidence of the medical benefits of the non-anesthetic effects of ketamine, as well as supporting evidence of the effectiveness and tolerability of ketamine for improving pain conditions, depression, memory function in Alzheimer’s disease, and brain damage after stroke. It also examines underlying mechanisms that exert these effects by stimulating or blocking certain neuroreceptor pathways.

Abstract

“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.”

Authors: Jabril Eldufani, Alireza Nekoui & Gilbert Blaise

Summary

Ketamine is considered a dissociative anesthetic medication and is commonly administered by a parenteral route. It works by blocking the N-methyl-D-aspartate receptor and affects specific receptors, including a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid A receptors.

INTRODUCTION

Ketamine has been used as an anesthetic medication since 1970. It is thought to modulate N-methyl-D-aspartate, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid-A receptors, and inhibit voltage-gated Na and K channels, serotonin and dopamine reuptake.

Ketamine has been used to treat chronic pain, cognitive function, depression, acute brain injury, and immune system disorders since 1965.

PHARMACOLOGY

Ketamine can rapidly pass the blood-brain barrier and has a quick onset of analgesic effect. It may also inhibit dopamine reuptake and the nitric oxide pathway.

CHRONIC PAIN

Ketamine is administered to treat various diseases that cause chronic refractory pain, particularly those that have a neuropathic component. Ketamine works by inhibiting the N-methyl-D-aspartate receptor, but other mechanisms are also involved.

Ketamine can be used to treat chronic pain by blocking the N-methyl-D-aspartate receptor and enhancing the descending inhibition pathway, especially in patients with chronic neuropathic pain.

Ketamine is superior to opioids at reducing neuropathic pain, but it can additively and synergistically interact with opioids through the descending inhibitory pathway.

COGNITIVE FUNCTION

Ketamine is an amnestic medication that impairs working memory and reduces the encoding of information into episodic memory. Ketamine-induced memory loss is self-resolving, but the effects on memory function from long-term use of low-dose ketamine are poorly reported.

Ketamine may protect cognitive function by reducing postoperative cognitive dysfunction in non-head trauma patients and by reducing the incidence of postoperative delirium.

DEMENTIA AND ALZHEIMER’S DISEASE

Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist, which is used to improve the symptoms of Alzheimer’s disease. It also plays an important role in psychic phenomena by inhibiting nicotinic and muscarinic receptors.

Ketamine blocks the N-methyl-D-aspartate receptor, which is responsible for ketamine’s most essential pharmacologic properties. The N-methyl-D-aspartate receptor is present on nearly all the neural cells of the central nervous system, particularly in the structures implicated in nociception.

A single subanesthetic dose of ketamine increases lipid peroxidation and protein damage in the hippocampus, which is a significant structure for memory function of humans and spatial memory of rodents. Ketamine can affect memory acquisition and retrieval but does not reduce memory consolidation.

DEPRESSION

Ketamine is a high-affinity N-methyl-D-aspartate receptor antagonist, which also binds to opioid m and sigma receptors. Ketamine has active and rapid antidepressant properties, so it is suggested for treatment-resistant depression (TRD).

Several studies have shown that ketamine can interact with several cellular signaling pathways involved in major depressive disorder. However, there is no current research available for addressing the long-term effect of a single-injection of ketamine on brain circuitry in major depressive disorder.

Ketamine has shown antidepressant effects in patients with major depressive disorder and in several animal models of depression. It works by expressing serine/threonine protein kinase, which modulates cell growth, proliferation, motility, survival, and protein synthesis.

Ketamine’s effects on depression are dose-dependent, and the highest dose achieved vast improvements. Ketamine may also reduce suicidality and alleviate posttraumatic stress disorder symptoms.

ACUTE BRAIN INJURY

The occurrence of traumatic brain injury is high, and the treatment is aimed at alleviating secondary damage, which occurs within hours to days after an acute brain insult.

Ketamine has been shown to reduce cell injury in cell cultures and reduce the size of focal ischemia and hemorrhagic necrosis in experimental head injury models. Ketamine also has antiglutamatergic impacts that may have a role in the management of delayed cerebral ischemia after subarachnoid hemorrhage and cerebral vasospasm.

IMMUNE SYSTEM

Ketamine reduces tissue necrosis factor a, interleukins, and nitric oxide production, which could affect macrophage-mediated immunity. Ketamine also inhibits messenger ribonucleic acid syntheses by lipopolysaccharide-activated macrophages.

Ketamine has both analgesic and neuroprotective effects, because it regulates the inhibition of tumor necrosis factor a, interleukin-6, and proinflammatory cytokine activities in both peripheral immune cells and glial cells in the CNS.

CONCLUSION

Ketamine’s mechanisms of action have been studied for its antidepressive effects, antiinflammatory effects, and chronic pain management and cognitive function. It is also used for enhancing memory function in Alzheimer’s patients.