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Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity

  • Anesthetic Techniques in Pain Management (D Wang, Section Editor)
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A Correction to this article was published on 18 September 2021

This article has been updated

Abstract

Purpose of Review

While ketamine’s analgesia has mostly been attributed to antagonism of N-methyl-d-aspartate receptors, evidence suggests multiple other pathways are involved in its antidepressant and possibly analgesic activity. These mechanisms and ketamine’s role in the nociplastic pain paradigm are discussed. Animal studies demonstrating ketamine’s neurotoxicity have unclear human translatability and findings from key rodent and human studies are presented.

Recent Findings

Ketamine’s metabolites, and (2R,6R)-hydroxynorketamine in particular, may play a greater role in its clinical activity than previously believed. The activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the mammalian target of rapamycin by ketamine are mechanisms that are still being elucidated. Ketamine might work best in nociplastic pain, which involves altered pain processing.

Summary

While much is known about ketamine, new studies will continue to define its role in clinical medicine. Evidence supporting ketamine’s neurotoxicity in humans is lacking and should not impede future ketamine clinical trials.

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Authors and Affiliations

  1. Department of Anesthesiology, Sidney Kimmel Medical College at Thomas Jefferson University, 111 South 11th Street, Gibbon Building, 8290, Philadelphia, PA, 19107, USA

    Eric S. Schwenk, Alexander Olson, Marc C. Torjman & Eugene R. Viscusi

  2. Psychiatry & Pediatrics, Cooper Medical School of Rowan University, Camden, NJ, USA

    Basant Pradhan

  3. Department of Physical Medicine and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA

    Rohit Nalamasu

  4. NEMA Research, Inc., Naples, FL, USA

    Lucas Stolle & Joseph V. Pergolizzi

  5. Cooper Medical School, Rowan University, Camden, NJ, USA

    Irving W. Wainer

  6. Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA

    Michael Cirullo

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  1. Eric S. Schwenk
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Correspondence to Eric S. Schwenk.

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Conflict of Interest

Irving W. Wainer declares holding a patent assigned to U.S. Government, Department of Health and Human Services, National Institutes of Health, for which he may receive royalties.

Joseph Pergolizzi discloses the following relationships: Consultant/ Speaker, Owner, and Researcher for Spirify, US World Meds, Salix, Enalare, Scilex, Pfizer, Lilly, Teva, Taketa, Regeneron, BDSI, Bridge Therapeutics Grunenthal, and Neumentum. Specific to ketamine include present consultant to Spirify Pharma.

Marc Torjman reports a patient pending on the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain.

Basant Pradhan, Lucas Stolle, Eric Schwenk, Alexander Olson, Rohit Nalamasu, and Michael Cirullo declare no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Anesthetic Techniques in Pain Management

The original online version of this article was revised: The family name of Dr. Alexander Olson was misspelled.

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Schwenk, E.S., Pradhan, B., Nalamasu, R. et al. Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity. Curr Pain Headache Rep 25, 57 (2021). https://doi.org/10.1007/s11916-021-00977-w

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