Regional Anesthesia and Acute Pain ManagementRegional Anesthesia and Acute Pain ManagementРегионарная анестезия и лечение острой боли1993-65082687-1394Eco-Vector67792310.17816/RA677923OGYGVCReviewsНаучные обзорыReview ArticleKetamine: History, Contemporary Perspective, and New Opportunities. A Narrative ReviewКетамин: история, современный взгляд и новые возможности: нарративный обзорhttps://orcid.org/0000-0003-1272-13505720-4209LinkovaTatiana V.ЛиньковаТатьяна Викторовна
Russian Federation

MD, Cand. Sci. (Medicine)

канд. мед. наук

linkovat@gmail.comhttps://orcid.org/0000-0001-9973-02113210-5074DiordievAndrey V.ДиордиевАндрей Викторович
Russian Federation

MD, Dr. Sci. (Medicine), Professor

д-р мед. наук, профессор

avddoc@mail.ruhttps://orcid.org/0009-0004-4347-25318412-4628PanovaMarina S.ПановаМарина Сергеевна
Russian Federation
panova_ms@bk.ruhttps://orcid.org/0000-0003-3143-50691620-0503IakovlevaEkaterina S.ЯковлеваЕкатерина Сергеевна
Russian Federation

MD, Cand. Sci. (Medicine)

iakovlevadoc@gmail.comhttps://orcid.org/0000-0001-9850-67794284-4702AfukovIvan I.АфуковИван Игоревич
Russian Federation

MD, Cand. Sci. (Medicine)

afukovdoc@yandex.ruhttps://orcid.org/0009-0002-2425-89732632-1265ShagurinRoman V.ШагуринРоман Валерьевич
Russian Federation

MD

roman.sharugin@yandex.ruhttps://orcid.org/0009-0001-7684-78363369-1107IvaninaElina S.ИванинаЭлина Сергеевна
Russian Federation

MD

ivanina.eli@yandex.ruScientific and Practical Center for Child PsychoneurologyНаучно-практический центр детской психоневрологииScientific and Practical Center for Child PsychoneurologyНаучно-практический центр детской психоневрологииThe Russian National Research Medical University named after N.I. PirogovРоссийский национальный исследовательский медицинский университет имени Н.И. ПироговаChildren’s City Clinical Hospital No. 9Детская городская клиническая больница № 9 имени Г.Н. СперанскогоClinical and Research Institute of Emergency Pediatric Surgery and Trauma — Dr. Roshal’s ClinicНаучно-исследовательский институт неотложной детской хирургии и травматологии — Клиника доктора Рошаля12102025061120251931841993103202515082025Copyright ©; 2025, Eco-VectorCopyright ©; 2025, Эко-Вектор2025Eco-VectorЭко-Векторhttps://creativecommons.org/licenses/by-nc-nd/4.0/https://rjraap.com/1993-6508/article/view/677923

Ketamine, an N-methyl-D-aspartate receptor antagonist, developed more than 60 years ago as an anesthetic, has experienced a varied history but remains relevant in modern global medical practice. Over the past several decades, it has revealed new potential extending far beyond anesthesia. There is growing interest in the use of subdissociative doses of ketamine to treat various types of acute and chronic pain and depression. Its efficacy is similar to that of opioids, with a low incidence of transient adverse effects. Ketamine can be administered via multiple routes and is nearing the status of an ideal analgesic for the prehospital setting because of its favorable safety profile. In patients with severe trauma, ketamine is likely the optimal analgesic, as it provides hemodynamic stability without an increase in intracranial pressure. Ketamine is particularly useful in patients with opioid dependence, opioid tolerance, or opioid-induced hyperalgesia. The discovery of its multiple molecular targets and related effects enables the use of this unique agent in many areas of clinical and experimental medicine, including anesthesiology, emergency medicine, intensive care, pain management, psychiatry, research on the neurobiological basis of consciousness, and modeling of pathological mental states.

This article presents the history of ketamine development and reviews current understanding of its mechanisms of action, methods, and areas of application.

Антагонист NMDA-рецепторов кетамин, созданный более 60 лет назад в качестве анестетика и переживший исторические взлёты и падения, остаётся актуальным в современной мировой медицинской практике. В течение нескольких последних десятилетий он заново раскрывает свой потенциал, значительно выходя за рамки анестезии. Всё более актуальной темой становится использование кетамина в суб-диссоциативных дозах для лечения различных видов острой и хронической боли и депрессии. Он сравним по эффективности с опиоидами и имеет незначительное количество быстро преходящих побочных эффектов. Кетамин можно вводить множеством способов; он приближается к званию идеального анальгетика для догоспитального этапа благодаря своему профилю безопасности. У пациентов с тяжёлой травмой кетамин, вероятно, является лучшим анальгетиком, так как обеспечивает гемодинамическую стабильность и не повышает внутричерепное давление. Кетамин чрезвычайно полезен у пациентов с опиоидной зависимостью, толерантностью к опиоидам, опиоид-индуцированной гипералгезией. Раскрытие многообразных мишеней и связанных с ними эффектов кетамина позволяют использовать уникальные свойства препарата во многих областях клинической и экспериментальной медицины, включая анестезиологическую практику, неотложную помощь, интенсивную терапию, лечение боли, психиатрию, изучение нейробиологических основ сознания, моделирование патологических состояний психики.

В статье представлены история создания кетамина и обзор современных представлений о механизмах действия, способах и сферах его применения.

ketamineanalgesiaNMDA receptor antagonistsneuropathic painкетаминаналгезияблокада NMDAлечение нейропатической болиMion G. History of anaesthesia: The ketamine story — past, present and future. Eur J Anaesthesiol. 2017;34(9):571–575. doi: 10.1097/EJA.0000000000000638McCarthy DA, Chen G, Kaump DH, Ensor C. General Anesthetic and Other Pharmacological Properties of 2-(O-Chlorophenyl)-2-Methylamino Cyclohexanone HCl (CI-581). J. New Drug. 1965;5(1):21–33. doi: 10.1002/j.1552-4604.1965.tb00219.xDomino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–291. doi: 10.1002/cpt196563279Domino EF. Taming the ketamine tiger. Anesthesiology. 2010;113(3):678–684. doi: 10.1097/ALN.0b013e3181ed09a2Li L, Vlisides PE. Ketamine: 50 Years of Modulating the Mind. Front Hum Neurosci. 2016;10:612. doi: 10.3389/fnhum.2016.00612Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg. 1971;50(3):452–457. doi: 10.1213/00000539-197105000-00037White PF, Way WL, Trevor AJ. Ketamine — its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119–136. doi: 10.1097/00000542-198202000-00007Jansen K. Near death experience and the NMDA receptor. BMJ. 1989;298(6689):1708. doi: 10.1136/bmj.298.6689.1708-b 11Watkins JC, Jane DE. The glutamate story. Br J Pharmacol. 2006;147 Suppl 1(Suppl 1):S100–S108. doi: 10.1038/sj.bjp.0706444Collingridge G. Synaptic plasticity. The role of NMDA receptors in learning and memory. Nature. 1987;330(6149):604–605. doi: 10.1038/330604a0Riccardi A, Guarino M, Serra S, et al. Narrative Review: Low-Dose Ketamine for Pain Management. J Clin Med. 2023;12(9):3256. doi: 10.3390/jcm12093256Sinner B, Graf BM. Ketamine. Handb Exp Pharmacol. 2008;(182):313–333. doi: 10.1007/978-3-540-74806-9_15Simonini A, Brogi E, Cascella M, Vittori A. Advantages of ketamine in pediatric anesthesia. Open Med (Wars). 2022;17(1):1134–1147. doi: 10.1515/med-2022-0509Wang X, Lin C, Lan L, Liu J. Perioperative intravenous S-ketamine for acute postoperative pain in adults: A systematic review and meta-analysis. J Clin Anesth. 2021;68:110071. doi: 10.1016/j.jclinane.2020.110071Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet. 2016;55(9):1059–1077. doi: 10.1007/s40262-016-0383-6Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versatile tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020;33(5):633–638. doi: 10.1097/ACO.0000000000000916Zanos P, Moaddel R, Morris PJ, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev. 2018;70(3):621–660. doi: 10.1124/pr.117.015198Pourmand A, Mazer-Amirshahi M, Royall C, Alhawas R, Shesser R. Low dose ketamine use in the emergency department, a new direction in pain management. Am J Emerg Med. 2017;35(6):918–921. doi: 10.1016/j.ajem.2017.03.005Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006;60(7):341–348. doi: 10.1016/j.biopha.2006.06.021Cohen 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.0000000000000808Schwenk ES, Pradhan B, Nalamasu R, et al. Ketamine in the Past, Present, and Future: Mechanisms, Metabolites, and Toxicity. Curr Pain Headache Rep. 2021;25(9):57. doi: 10.1007/s11916-021-00977-wIacobucci GJ, Visnjevac O, Pourafkari L, Nader ND. Ketamine: An Update on Cellular and Subcellular Mechanisms with Implications for Clinical Practice. Pain Physician. 2017;20(2):E285–E301. doi: 10.36076/ppj.2017.e301Forget P, Cata J. Stable anesthesia with alternative to opioids: Are ketamine and magnesium helpful in stabilizing hemodynamics during surgery? A systematic review and meta-analyses of randomized controlled trials. Best Pract Res Clin Anaesthesiol. 2017;31(4):523–531. doi: 10.1016/j.bpa.2017.07.001Cohen SP, Liao W, Gupta A, Plunkett A. Ketamine in pain management. Adv Psychosom Med. 2011;30:139–161. doi: 10.1159/000324071Mendell LM. The Path to Discovery of Windup and Central Sensitization. Front Pain Res (Lausanne). 2022;3:833104. doi: 10.3389/fpain.2022.833104Savić Vujović K, Jotić A, Medić B, et al. Ketamine, an Old-New Drug: Uses and Abuses. Pharmaceuticals (Basel). 2023;17(1):16. doi: 10.3390/ph17010016Highland JN, Zanos P, Riggs LM, et al. Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. Pharmacol Rev. 2021;73(2):763–791. doi: 10.1124/pharmrev.120.000149Pacheco Dda F, Romero TR, Duarte ID. Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Res. 2014;1562:69–75. doi: 10.1016/j.brainres.2014.03.026Culp C, Kim HK, Abdi S. Ketamine Use for Cancer and Chronic Pain Management. Front Pharmacol. 2021;11:599721. doi: 10.3389/fphar.2020.599721Zhou C, Liang P, Liu J, et al. HCN1 Channels Contribute to the Effects of Amnesia and Hypnosis but not Immobility of Volatile Anesthetics. Anesth Analg. 2015;121(3):661–666. doi: 10.1213/ANE.0000000000000830Hallikeri SV, Sinha R, Ray BR, et al. Effect of Low-dose Ketamine on Inflammatory Markers, Perioperative Analgesia, and Chronic Pain in Patients Undergoing Laparoscopic Inguinal Hernia Surgery: A Prospective, Randomized, Double-blind, Comparative Study. Turk J Anaesthesiol Reanim. 2024;52(6):231–239. doi: 10.4274/TJAR.2024.241771Shaked G, Czeiger D, Dukhno O, et al. Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of Gram-negative bacterial sepsis in rats. Resuscitation. 2004;62(2):237–242. doi: 10.1016/j.resuscitation.2004.02.015Volkov SG, Vereshagin EI, Lebedeva MN. Neuroprotection by ketamine. Modern Problems of Science and Education. 2022;(3):152. doi: 10.17513/spno.31809 EDN: WGRFVGGoyal S, Agrawal A. Ketamine in status asthmaticus: A review. Indian J Crit Care Med. 2013;17(3):154–161. doi: 10.4103/0972-5229.117048Gao L, Han J, Bai J, et al. Nicotinic Acetylcholine Receptors are Associated with Ketamine-induced Neuronal Apoptosis in the Developing Rat Retina. Neuroscience. 2018;376:1–12. doi: 10.1016/j.neuroscience.2018.01.057Leung LS, Luo T. Cholinergic Modulation of General Anesthesia. Curr Neuropharmacol. 2021;19(11):1925–1936. doi: 10.2174/1570159X19666210421095504Pitsikas N. The nicotinic α7 receptor agonist GTS-21 but not the nicotinic α4β2 receptor agonist ABT-418 attenuate the disrupting effects of anesthetic ketamine on recognition memory in rats. Behav Brain Res. 2020;393:112778. doi: 10.1016/j.bbr.2020.112778Watson N, Eglen RM. Effects of muscarinic M2 and M3 receptor stimulation and antagonism on responses to isoprenaline of guinea-pig trachea in vitro. Br J Pharmacol. 1994;112(1):179–187. doi: 10.1111/j.1476-5381.1994.tb13049.xZakharov DV, Kokareva DD. Syalorrhea as a multidisciplinary problem. The review of possible causes and therapeutic solutions. Nervnye bolezni. 2023;(1):32–38. doi: 10.24412/2226-0757-2023-12842 EDN: YXUUJLProctor GB, Carpenter GH. Salivary secretion: mechanism and neural regulation. Monogr Oral Sci. 2014;24:14–29. doi: 10.1159/000358781Elverdin JC, Kaniucki MO, Stefano FJ, Perec CJ. Physiological role of alpha-adrenoceptors in salivary secretion. Acta Odontol Latinoam. 1990;5(1):31–38.Brown L, Christian-Kopp S, Sherwin TS, et al. Adjunctive atropine is unnecessary during ketamine sedation in children. Acad Emerg Med. 2008;15(4):314–318. doi: 10.1111/j.1553-2712.2008.00074.xLu J, Nelson LE, Franks N, et al. Role of endogenous sleep-wake and analgesic systems in anesthesia. J Comp Neurol. 2008;508(4):648–662. doi: 10.1002/cne.21685Pal D, Hambrecht-Wiedbusch VS, Silverstein BH, Mashour GA. Electroencephalographic coherence and cortical acetylcholine during ketamine-induced unconsciousness. British Journal of Anaesthesia. 2015;114(6):979–989. doi: 10.1093/bja/aev095Kushikata T, Yoshida H, Kudo M, et al. Role of coerulean noradrenergic neurones in general anaesthesia in rats. Br J Anaesth. 2011;107(6):924–929. doi: 10.1093/bja/aer303Kubota T, Anzawa N, Hirota K, Yoshida H, Kushikata T, Matsuki A. Effects of ketamine and pentobarbital on noradrenaline release from the medial prefrontal cortex in rats. Can J Anaesth. 1999;46(4):388–392. doi: 10.1007/BF03013235Lydic R, Baghdoyan HA. Ketamine and MK-801 decrease acetylcholine release in the pontine reticular formation, slow breathing, and disrupt sleep. Sleep. 2002;25(6):615–620. doi: 10.1093/sleep/25.6.615Lee U, Ku S, Noh G, et al. Disruption of frontal-parietal communication by ketamine, propofol, and sevoflurane. Anesthesiology. 2013;118(6):1264–1275. doi: 10.1097/ALN.0b013e31829103f5Blain-Moraes S, Lee U, Ku S, Noh G, Mashour GA. Electroencephalographic effects of ketamine on power, cross-frequency coupling, and connectivity in the alpha bandwidth. Front Syst Neurosci. 2014;8:114. doi: 10.3389/fnsys.2014.00114Bonhomme V, Vanhaudenhuyse A, Demertzi A, et al. Resting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers. Anesthesiology. 2016;125(5):873–888. doi: 10.1097/ALN.0000000000001275Schroeder KE, Irwin ZT, Gaidica M, et al. Disruption of corticocortical information transfer during ketamine anesthesia in the primate brain. Neuroimage. 2016;134:459–465. doi: 10.1016/j.neuroimage.2016.04.039Wong JJ, O’Daly O, Mehta MA, et al. Ketamine modulates subgenual cingulate connectivity with the memory-related neural circuit-a mechanism of relevance to resistant depression? PeerJ. 2016;4:e1710. doi: 10.7717/peerj.1710Muthukumaraswamy SD, Shaw AD, Jackson LE, et al. Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans. J Neurosci. 2015;35(33):11694–11706. doi: 10.1523/JNEUROSCI.0903-15.2015Traber DL, Wilson RD, Priano LL. Differentiation of the Cardiovascular Effects of CI-581. Anesthesia & Analgesia. 1968;47(6):769–778. doi: 10.1213/00000539-196811000-00025Eikermann M, Grosse-Sundrup M, Zaremba S, et al. Ketamine activates breathing and abolishes the coupling between loss of consciousness and upper airway dilator muscle dysfunction. Anesthesiology. 2012;116(1):35–46. doi: 10.1097/ALN.0b013e31823d010aHlavaty L, Hansma P, Sung L. Contribution of opiates in sudden asthma deaths. Am J Forensic Med Pathol. 2015;36(1):49–52. doi: 10.1097/PAF.0000000000000138Rehder KJ. Adjunct Therapies for Refractory Status Asthmaticus in Children. Respir Care. 2017;62(6):849–865. doi: 10.4187/respcare.05174Green SM, Roback MG, Krauss B. Laryngospasm during emergency department ketamine sedation: a case-control study. Pediatr Emerg Care. 2010;26(11):798–802. doi: 10.1097/PEC.0b013e3181fa8737Shapiro HM, Wyte SR, Harris AB. Ketamine anaesthesia in patients with intracranial pathology. Br J Anaesth. 1972;44(11):1200–1204. doi: 10.1093/bja/44.11.1200Rueda Carrillo L, Garcia KA, Yalcin N, Shah M. Ketamine and Its Emergence in the Field of Neurology. Cureus. 2022;14(7):e27389. doi: 10.7759/cureus.27389Alkhachroum A, Der-Nigoghossian CA, Mathews E, et al. Ketamine to treat super-refractory status epilepticus. Neurology. 2020;95(16):e2286–e2294. doi: 10.1212/WNL.0000000000010611Andropoulos DB. Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagn Ther. 2018;43(1):1–11. doi: 10.1159/000475928Choudhury D, Autry AE, Tolias KF, Krishnan V. Ketamine: Neuroprotective or Neurotoxic? Front Neurosci. 2021;15:672526. doi: 10.3389/fnins.2021.672526Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science. 1989;244(4910):1360–1362. doi: 10.1126/science.2660263Olney JW, Labruyere J, Wang G, et al. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991;254(5037):1515–1518. doi: 10.1126/science.1835799Laws JC, Vance EH, Betters KA, et al. Acute Effects of Ketamine on Intracranial Pressure in Children With Severe Traumatic Brain Injury. Crit Care Med. 2023;51(5):563–572. doi: 10.1097/CCM.0000000000005806Hertle DN, Dreier JP, Woitzik J, et al. Effect of analgesics and sedatives on the occurrence of spreading depolarizations accompanying acute brain injury. Brain. 2012;135(Pt 8):2390–2398. doi: 10.1093/brain/aws152Wang L, Deng B, Yan P, et al. Neuroprotective effect of ketamine against TNF-α-induced necroptosis in hippocampal neurons. J Cell Mol Med. 2021;25(7):3449–3459. doi: 10.1111/jcmm.16426Rodrigo R, Cauli O, Boix J, et al. Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int. 2009;55(1-3):113–118. doi: 10.1016/j.neuint.2009.01.007Beaudrie-Nunn AN, Wieruszewski ED, Woods EJ, et al. Efficacy of analgesic and sub-dissociative dose ketamine for acute pain in the emergency department. Am J Emerg Med. 2023;70:133–139. doi: 10.1016/j.ajem.2023.05.026Ahern TL, Herring AA, Miller S, Frazee BW. Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain. Pain Med. 2015;16(7):1402–1409. doi: 10.1111/pme.12705Mailis A, Taenzer P. Evidence-based guideline for neuropathic pain interventional treatments: spinal cord stimulation, intravenous infusions, epidural injections and nerve blocks. Pain Res Manag. 2012;17(3):150–158. doi: 10.1155/2012/794325Schwenk ES, Viscusi ER, Buvanendran A, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management 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):456–466. doi: 10.1097/AAP.0000000000000806Nowacka A, Borczyk M. Ketamine applications beyond anesthesia — A literature review. Eur J Pharmacol. 2019;860:172547. doi: 10.1016/j.ejphar.2019.172547Subdissociative-Dose Ketamine for Analgesia. Ann Emerg Med. 2018;71(3):e35. doi: 10.1016/j.annemergmed.2018.01.026Davis WD, Davis KA, Hooper K. The Use of Ketamine for the Management of Acute Pain in the Emergency Department. Adv Emerg Nurs J. 2019;41(2):111–121. doi: 10.1097/TME.0000000000000238Duhaime MJ, Wolfson AB. Ketamine Versus Opioids for Acute Pain in the Emergency Department. Acad Emerg Med. 2020;27(8):781–782. doi: 10.1111/acem.13976Balzer N, McLeod SL, Walsh C, Grewal K. Low-dose Ketamine For Acute Pain Control in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med. 2021;28(4):444–454. doi: 10.1111/acem.14159Li X, Hua GC, Peng F. Efficacy of intranasal ketamine for acute pain management in adults: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25(8):3286–3295. doi: 10.26355/eurrev_202104_25738Oliveira J E Silva L, Lee JY, Bellolio F, et al. Intranasal ketamine for acute pain management in children: A systematic review and meta-analysis. Am J Emerg Med. 2020;38(9):1860–1866. doi: 10.1016/j.ajem.2020.05.094Yousefifard M, Askarian-Amiri S, Rafiei Alavi SN, et al. The Efficacy of Ketamine Administration in Prehospital Pain Management of Trauma Patients; a Systematic Review and Meta-Analysis. Arch Acad Emerg Med. 2019;8(1):e1.Gorlin AW, Rosenfeld DM, Ramakrishna H. Intravenous sub-anesthetic ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol. 2016;32(2):160–167. doi: 10.4103/0970-9185.182085Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):357–367. doi: 10.1111/bcp.12094Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain. 2009;147(1-3):107–115. doi: 10.1016/j.pain.2009.08.015Voute M, Riant T, Amodéo JM, et al. Ketamine in chronic pain: A Delphi survey. Eur J Pain. 2022;26(4):873–887. doi: 10.1002/ejp.1914Jiao J, Fan J, Zhang Y, Chen L. Efficacy and Safety of Ketamine to Treat Cancer Pain in Adult Patients: A Systematic Review. J Pain Symptom Manage. 2024;67(3):e185–e210. doi: 10.1016/j.jpainsymman.2023.11.004Chah N, Jones M, Milord S, et al. Efficacy of ketamine in the treatment of migraines and other unspecified primary headache disorders compared to placebo and other interventions: a systematic review. J Dent Anesth Pain Med. 2021;21(5):413–429. doi: 10.17245/jdapm.2021.21.5.413Kuki I, Inoue T, Fukuoka M, et al. Efficacy and safety of ketamine for pediatric and adolescent super-refractory status epilepticus and the effect of cerebral inflammatory conditions. J Neurol Sci. 2024;459:122950. doi: 10.1016/j.jns.2024.122950Wang HZ, Wang LY, Liang HH, et al. Effect of caudal ketamine on minimum local anesthetic concentration of ropivacaine in children: a prospective randomized trial. BMC Anesthesiol. 2020;20(1):144. doi: 10.1186/s12871-020-01058-yIbrahim L, Diazgranados N, Luckenbaugh DA, et al. Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(4):1155–1159. doi: 10.1016/j.pnpbp.2011.03.019Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134–1142. doi: 10.1176/appi.ajp.2013.13030392Murrough JW, Soleimani L, DeWilde KE, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015;45(16):3571–3580. doi: 10.1017/S0033291715001506Donoghue AC, Roback MG, Cullen KR. Remission From Behavioral Dysregulation in a Child With PTSD After Receiving Procedural Ketamine. Pediatrics. 2015;136(3):e694–696. doi: 10.1542/peds.2014-4152Kokkinou M, Irvine EE, Bonsall DR, et al. Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Mol Psychiatry. 2021;26(6):2562–2576. doi: 10.1038/s41380-020-0740-6Subramanian S, Haroutounian S, Palanca BJA, Lenze EJ. Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence. J Neurol Sci. 2022;434:120152. doi: 10.1016/j.jns.2022.120152Noppers IM, Niesters M, Aarts LPHJ, et al. Drug-induced liver injury following a repeated course of ketamine treatment for chronic pain in CRPS type 1 patients: a report of 3 cases. Pain. 2011;152(9):2173–2178. doi: 10.1016/j.pain.2011.03.026Morgan CJ, Curran HV. Ketamine use: a review. Addiction. 2012;107(1):27–38. doi: 10.1111/j.1360-0443.2011.03576.xStoker AD, Rosenfeld DM, Buras MR, et al. Evaluation of Clinical Factors Associated with Adverse Drug Events in Patients Receiving Sub-Anesthetic Ketamine Infusions. J Pain Res. 2019;12:3413–3421. doi: 10.2147/JPR.S217005Blonk MI, Koder BG, van den Bemt PM, Huygen FJ. Use of oral ketamine in chronic pain management: a review. Eur J Pain. 2010;14(5):466–472. doi: 10.1016/j.ejpain.2009.09.005Harvey M, Sleigh J, Voss L, et al. Development of Rapidly Metabolized and Ultra-Short-Acting Ketamine Analogs. Anesth Analg. 2015;121(4):925–933. doi: 10.1213/ANE.0000000000000719