The successful and effective use of ketamine to induce anesthesia in human subjects was first described in a 1966 clinical study by Corssen and Domino.1 At the time, it was a chemical labeled CI-581. The phencyclidine derivative was approved for anesthesia four years later by the FDA under the brand name Ketalar.2 Since then, evidence supporting its use in humans to treat a variety of pain and psychiatric conditions has grown substantially. Because of this, use of ketamine in various dosage forms has expanded, often by those with little training in anesthesiology, which is a concerning conundrum given its wide range of clinical effects.
Ketamine chemically is an arylcycloakylamine that was synthesized from phencyclidine in 1956 by the Parke Davis Company.3 The chemical itself exists as a racemic mixture of two isomers, S(+) and R(-), both with primary affinity and potency toward its main target the N-methyl-D-aspartate (NMDA) receptor, which seems to be responsible for the majority of ketamine’s effects.4 Interestingly, it appears that the S(+) isomer inhibits NMDA receptors with about 3 to 4 times greater anesthetic potency than the R(-) isomer,4 though the R(-) isomer has shown to be more potent when used as an antidepressant in mouse studies.5 Nevertheless, what makes ketamine’s ability to antagonize NMDA receptors unique is that it does so non-competitively and allosterically through open-channel blockade that causes reductions in channel opening frequency, allowing for a relatively slow off-rate.6,7
In addition to its actions on NMDA receptors, ketamine has several additional molecular mechanisms that contribute to its various effects throughout the human body. It has been shown to antagonize alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, antagonize L-type calcium channels, potentiate and augment delta- and mu-opioid receptor function, increase release of various aminergic neuromodulators including dopamine and noradrenaline, and reduce cholinergic neuromodulation.6,7 From an analgesic perspective, it is thought that several of the above mechanisms are involved in its efficacy, especially as many of the above result in neuronal membrane potential stabilization and can allow for inhibition of various descending pain pathways.7
Regarding ketamine’s rapid and sustained antidepressant effects, it again appears that several of its underlying mechanisms likely contribute. However, the primary mediator may potentially be its antagonism of NMDA receptors, as this then is able to promote AMPA receptor activation directly, compared to monoaminergic antidepressants, which promote AMPA receptor activation indirectly and gradually.11 This thought process has much to do with potential and theoretical depression pathophysiological models, some of which implicate abnormalities in glutamatergic transmission may play a significant role.11
Although ketamine is a racemic mixture, it is soluble in both water and lipid solvents and thus can be administered in a multitude of routes of administration including intravenously (IV), intramuscularly (IM), orally, nasally, rectally, subcutaneously, and epidurally. However, ketamine undergoes extensive first-pass metabolism, which is why oral and rectal formulations of ketamine have shown to allow for much lower bioavailabilities (17% to 29% and 11% to 25%, respectively)14-16 compared to their intravenous and intramuscular counterparts (100% and 93%, respectively). This, of course, is why ketamine has been traditionally used in intravenous and intramuscular settings, though increasing efforts have been made to optimize alternative dosage forms.
Dosing of ketamine is what has really garnered much attention, as it appears ketamine’s differential effects are somewhat dose dependent. For example, general anesthesia is generally achieved through repeated administration of IV or IM doses between 0.5 mg/Kg to 1 mg/kg.20 Analgesia, on the other hand, has been shown to be achieved at subanesthetic doses (0.2 mg/kg to 0.8 mg/kg IV; 2 mg/kg to 4 mg/kg IM).6,7
Although ketamine has been used to induce anesthesia for greater than half a century, its use intraoperatively to reduce intra- and post-operative pain, as well as its use in chronic pain has garnered significant interest.
From an analgesic perspective, overall data on ketamine efficacy is still relatively conflicting in the chronic, non-cancer pain population, and its effectiveness specifically in chronic pain may depend on specific pain pathologies and syndromes.21-27 For example and not surprisingly, ketamine has shown to be effective in the treatment of several pain conditions with underlying neuropathic and central sensitization components including CRPS type 1, postherpetic neuralgia, and neuropathies associated from peripheral nerve damage.26,27 This efficacy primarily has to do with the various cellular mechanisms involved in the development and sustainment of neuronal damage including upregulation of NMDA receptors particularly within dorsal horn synapses,28 which can also be a primary mediator of central sensitization.
A more recent meta-analysis of trials assessing efficacy of ketamine infusions in chronic pain conditions by Orhurhu et al was published in 2019.27 Interestingly, this meta-analysis included seven studies that met criteria, where three studied ketamine use in non-neuropathic pain.27 Per this meta-analysis, six of the seven studies found that the lowest pain score rating occurred between 48 hours and 2 weeks after initial treatment of the ketamine infusion, another indication of potential delayed anti-nociceptive effects, and further analysis of the data from those six studies showed that ketamine allowed for a significant reduction in pain scores compared to standard or control comparative treatments.27 Importantly, Salas et al was the one study included in the meta-analysis that showed no benefit from ketamine use in patients with refractory cancer pain.29
The data presented above support the general consensus guidelines around the use of intravenous ketamine infusions for chronic pain published in 2018 and supported by the American Society of Regional Anesthesia and Pain Medicine (ASRA), the American Academy of Pain Medicine (AAPM), and the American Society of Anesthesiologists.31 Essentially, these groups found that although the evidence put forth supports the use of ketamine for chronic pain, the level of evidence varies by condition and dose, and studies have generally been prone to a variety of flaws and inherent biases.31 It is also absolutely agreed that use of ketamine by a variety of different clinicians and the rise of various ketamine clinics that are run by those not trained in anesthesiology may represent a variety of dangers with use. Best practice would dictate that use of intravenous ketamine should be at least overseen by those trained in anesthesiology or skilled in airway management and hemodynamic resuscitation.
Ketamine, and its recently approved S(+) enantiomer esketamine nasal spray, have been increasingly used in those with depression and/or other mental health disorders. This has to do with ketamine’s ability to produce potent and rapid antidepressant effects in patients, as evidenced by several trials over the past decades and first shown by Berman et al in 2000.32
Interestingly, the body of evidence around ketamine infusions specifically for treatment of depression has really found benefit when studied in the short term.33 Even more intriguingly, although there have not been any trials to date directly comparing esketamine with intravenous ketamine use in depression, a comparative meta-analysis conducted by Bahji et al in 2021 found that after analysis of 24 trials assessing either racemic ketamine or esketamine in patients with unipolar or bipolar major depression, racemic ketamine actually demonstrated greater overall response (Rate Ratio = 3.01 vs RR = 1.38) and remission rates (RR = 3.7 vs RR = 1.47).33 Both ketamine and esketamine have additionally shown significant, potent, and rapid anti-suicidal effects, allowing for a potential role in patients living from moderate to severe depression with acute suicidality.33
Perhaps the greatest consideration when it comes to the use of ketamine has to do with its side effect potential. Even at relatively low IV doses, ketamine can still be associated with symptoms of dissociation and psychotic symptoms including hallucinations and delirium, in which these effects are noted to be secondary to its NMDA blockade.6 Importantly, this is another potential difference between ketamine and other NMDA blocking drugs, given these psychotomimetic effects seem to depend on the relative trapping ability of these drugs.6 Hypnosis or the loss of responsiveness to the outside world (otherwise known as its anesthetic effects) is generally produced at much greater concentrations (up to 2000 ng/mL) and is also dependent on its NMDA antagonism.6
Other potential effects of ketamine include cardiovascular (can directly relax vascular smooth muscle, sympathetically mediate vasoconstriction, and act as a myocardial depressant) and pulmonary where it actually produces positive effects by allowing for higher flow and respiratory rates, despite its actions on opioid receptors.6,39 Other dose-dependent side effects can include dizziness, nausea, vomiting, hypersalivation, and hyperreflexia.39 Of course, there is certainly a propensity of relative euphoria and abuse as well.
Ketamine use has been increasing and expanding ever since its creation more than 60 years ago. Although it is still only FDA-approved for anesthesia, which has unfortunately limited third-party and insurance coverage when used for other conditions, a significant amount of evidence has shown its utility for the treatment of specific chronic pain conditions (potentially more so in those associated with central sensitization) and depression. Its modulation of NMDA receptors is relatively unique, and its effects on other cellular mediators allows for its drastic range of effects. These all add to ketamine’s potential usefulness to treat a variety of conditions, though because of its risks, it should be limited to those with significant experience with it and should be used cautiously in patient populations.
- Corssen G, Domino EF. Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Anal. 1966;45:29-40.
- Ketalar. FDA. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process Accessed March 2021.
- Maddox VH, Godefroi EF, Parcell RF. The synthesis of phencyclidine and other 1-arylcyclohexylamines. J Med Chem. 1965;8:230-235.
- White PF, Schuttler J, Shafer A, et al. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57(2):197-203. doi:10.1093/bja/57.2.197
- Zhang JC, Li SX, Hashimoto K. R(-)-ketamine shows greater potency and longer lasting antidepressant effects than S(+)-ketamine. Pharmacol Biochem Behav.2014;116:137-141. doi:10.1016/j.pbb.2013.11.033
- Sleigh J, Harvey M, Voss L, Denny B. Ketamine – More mechanisms of action than just NMDA blockade. Trends Anaesth. Crit. Care. 2014;4:76–81. doi: 10.1016/j.tacc.2014.03.002
- Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):257-267. doi:10.1111/bcp.12094
- Sarton E, Teppema LJ, Olievier C, et al. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Anesth Analg. 2001;93(6):1495-5000. doi:10.1097/00000539-200112000-00031
- Shikanai H, Hiraide S, Kamiyama H, et al. Subanalgesic ketamine enhances morphine-induced antinociceptive activity without cortical dysfunction in rats. J Anesth. 2014;28(3):390-398. doi:10.1007/s00540-013-1722-5
- Gupta A, Devi LA, Gomes I. Potentiation of mu-opioid receptor-mediated signaling by ketamine. J Neurochem. 2011;119(2):294-302. doi:10.1111/j.1471-4159.2011.07361.x
- Maeng S, Zarate CA Jr. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep. 2007;9(6):467-474. doi:10.1007/s11920-007-0063-1
- Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205-1215. doi:10.1176/appi.ajp.2018.18020138
- Zhang K, Hashimoto K. Lack of opioid system in the antidepressant actions of ketamine. Biol Psychiatry. 2019;85:e25-e27. doi:10.1016/j.biopsych.2018.11.006
- Chong C, Schug SA, Page-Sharp M, et al. Development of a sublingual/oral formulation of ketamine for use in neuropathic pain: Preliminary findings from a three-way randomized, crossover study. Clin Drug Investig. 2009;29(5):317-324. doi:10.2165/00044011-200929050-00004
- Rolan P, Lim S, Sunderland V, et al. The absolute bioavailability of racemic ketamine from a novel sublingual formulation. Br J Clin Pharmacol. 2014;77(6):1011-1016. doi:10.1111/bcp.12264
- Malinovsky JM, Servin F, Cozian A, et al. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203-207. doi:10.1093/bja/77.2.203
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- Domino EF, Domino SE, Smith RE, et al. Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther. 1984;36(5):645-653. doi: 10.1038/clpt.1984.235
- Eide PK, Jorum E, Stubhaug A, et al. Relief of post-herpetic neuralgia with the N-methyl- D‐aspartic acid receptor antagonist ketamine: a double‐blind, cross‐over comparison with morphine and placebo. Pain 1994;58:347–354. doi: 10.1016/0304-3959(94)90129-5
- Rabben T, Oye I. Interindividual differences in the analgesic response to ketamine in chronic orofacial pain. Eur J Pain. 2001;5(3):233-240. doi: 10.1053/eujp.2001.0232
- Kvarnstrom A, Karlsten R, Quiding H, Emanuelsson BM, Gordh T. The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain. Acta Anaesthesiol Scand 2003;47:868–877. doi: 10.1034/j.1399-6576.2003.00187.x
- Sigtermans MJ, van Hilten JJ, Bauer MCR, et al. Ketamine produces effective and long-term pain relief in patients with complex regional pain syndrome type 1. Pain. 2009;145:304-311. doi:10.1016/j.pain.2009.06.023
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- Michelet D, Brasher C, Horlin AL, et al. Ketamine for chronic non-cancer pain: A meta-analysis and trial sequential analysis of randomized controlled trials. Eur J Pain. 2018;22(4):632-646. doi:10.1002/ejp.1153
- Orhurhu V, Orhurhu MS, Bhatia A, Cohen SP. Ketamine infusions for chronic pain: A systematic review and meta-analysis of randomized controlled trials. Anesth Analg. 2019;129(1):241-254. doi:10.1213/ANE.0000000000004185
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- Cohen SP, Bhatia A, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):521-546. doi:10.1097/AAP.0000000000000808
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