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Nonanesthetic Effects of Ketamine: A Review Article

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.

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, 6,7Anesthesiologists 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.


Ketamine can rapidly pass the blood-brain barrier and therefore has a quick onset of analgesic effect.14, 15Ketamine 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 N-methyl-D-aspartate receptors, the nitric oxide pathway, and opioid receptors.22, 23

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.24However, it appears that particular mechanisms are potentially involved, including enhancing of the descending inhibition and antiinflammatory effects.25 In chronic pain conditions, prolonged nociceptive stimulation leads to activation and upregulation of the N-methyl-D-aspartate receptors at the dorsal horn synapses, resulting in enhancing and amplifying pain signals to the brain.26 This phenomenon would be a significant factor in the process of perseverance and eventual chronification of pain.27, 28

More recently, research has shown that N-methyl-D-aspartate receptor antagonists, such as ketamine, can halt the excessive barrage of nociceptive input to the brain and therefore are possible alternatives to existing therapies of chronic pain syndromes.27, 29 Also, there are other effects of ketamine that might contribute to its analgesic behavior by enhancing the descending inhibition pathway, especially in patients with chronic neuropathic pain.29Indeed, ketamine could prevent the occurrence of chronic pain conditions, such as that experienced in the postsurgical period after lower limb amputation.28 To achieve adequate management of chronic pain, it is preferred to use a multimodal approach to different medications.27, 28

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-Jabril Eldufani, MD, MSc, Alireza Nekoui, MD, MSc, Gilbert Blaise, MD, PhD

This article originally appeared in the December issue of The American Journal of Medicine.

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