Ketamine is a medication primarily used for starting and maintaining anesthesia. It induces dissociative anesthesia, a trance-like state providing pain relief, sedation, and amnesia. The distinguishing features of ketamine anesthesia are preserved breathing and airway reflexes, stimulated heart function with increased blood pressure, and moderate bronchodilation. At lower, sub-anesthetic doses, ketamine is a promising agent for pain and treatment-resistant depression. However, the antidepressant action of a single administration of ketamine wanes with time, and the effects of repeated use have not been sufficiently studied.
Psychiatric side effects are frequent as well as raised blood pressure and nausea. Liver and urinary toxicity are common among regular users of high doses of ketamine for recreational purposes. Ketamine is an NMDA receptor antagonist, and that accounts for most of its actions except the antidepressive effect, the mechanism of which is a matter of much research and debate.
The use of ketamine in anesthesia reflects its characteristics. It is a drug of choice for short-term procedures when muscle relaxation is not required. The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. It suppresses breathing much less than most other available anesthetics. When used at anesthetic doses, ketamine usually stimulates rather than depresses the circulatory system. Protective airway reflexes are preserved, and it is sometimes possible to administer ketamine anesthesia without protective measures to the airways.Psychotomimetic effects limit the acceptance of ketamine; however, they can be counteracted by administering benzodiazepines or propofol.
Ketamine is frequently used in severely injured people and appears to be safe in this group. It has been widely used for emergency surgery in field conditions in war zones, for example, during the Vietnam War. A 2011 clinical practice guideline supports the use of ketamine as a sedative in emergency medicine, including during physically painful procedures. It is the drug of choice for people in traumatic shock who are at risk of hypotension.Low blood pressure is harmful in people with severe head injury, and ketamine is least likely to cause low blood pressure and often even able to prevent it.
Ketamine is an option in children, as the sole anesthetic for minor procedures or as an induction agent followed by neuromuscular blocker and tracheal intubation In particular, children with cyanotic heart disease and neuromuscular disorders are good candidates for ketamine anesthesia.
Ketamine infusions are used for acute pain treatment in emergency departments and in the perioperative period in individuals with refractory pain. The doses are lower than those used for anesthesia; they are usually referred to as sub-anesthetic doses. Adjunctive to morphine or on its own, ketamine reduces morphine use, pain level, nausea, and vomiting after surgery. Ketamine is likely to be most beneficial for surgical patients when severe post-operative pain is expected and for opioid-tolerant patients.
Ketamine is especially useful in the prehospital setting, due to its effectiveness and low risk of respiratory depression.
Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain. It may also prevent opioid-induced hyperalgesia and postanesthetic shivering.
For chronic pain, ketamine is used as an intravenous analgesic, particularly, if the pain is neuropathic. It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. In multiple clinical trials, ketamine infusions delivered short-term pain relief in neuropathic pain diagnoses, pain after traumatic spine injury, fibromyalgia, and complex regional pain syndrome (CRPS). However, the 2018 consensus guidelines on chronic pain concluded that, overall, there is only weak evidence in favor of ketamine use in spinal injury pain, moderate evidence in favor of ketamine for CRPS, and weak or no evidence for ketamine in mixed neuropathic pain, fibromyalgia, and cancer pain. In particular, only for CRPS there is evidence of medium to longer term pain relief.
Ketamine is a robust and rapid-acting antidepressant, albeit its effect is transient. Intravenous ketamine infusion in treatment resistant depression results in improved mood within 4 hours reaching the peak at 24 hours. The effect is diminished at 7 days, and most patients relapse within 10 days, although for a significant minority the improvement may last 30 days and longer. The main challenge with ketamine treatment is what to do when the anti-depressive action expires. The maintenance therapy with ketamine (from twice a week to once in two weeks) appears to be a promising option, although the evidence to firmly recommend it is insufficient. Ketamine may also decrease suicidal thoughts for up to three days after the injection. Ketamine may be effective for bipolar depression, but the data on its use is scarce.
It has been shown that a single dose of iv ketamine results in a response rate over 60% as early as 4.5 h after the dose (with a sustained effect after 24 h) and over 40% after 7 days.
Although there are only few pilot studies studying the optimal dose, increasing evidence suggests that 0.5 mg/kg dose injected over 40 minutes gives an optimal outcome.
Ketamine has not been approved for use as an antidepressant, but the Canadian Network for Mood and
Anxiety Treatments recommends it as a third line treatment for depression. One of the enantiomers of ketamine, esketamine, has been approved as a nasal spray for treatment-resistant depression in the United States and elsewhere (see Esketamine#Depression). Intravenous infusion of ketamine has never been directly compared with intranasal esketamine, but a comparative meta-analysis of clinical trials indicates the superiority of intravenous ketamine, which has greater overall response and remission rates, and a lower number of dropouts.
Ketamine is sometimes used in the treatment of status epilepticus that has failed to adequately respond to standard treatments, although only limited evidence (case studies and no randomized controlled trials) exists in its favor.
At anesthetic doses, 10-20% of adults (1-2% of children) experience adverse psychiatric reactions that occur during emergence from anesthesia, ranging from dreams and dysphoria to hallucinations and emergence delirium. These can be counteracted by pretreating with a benzodiazepine or propofol. Ketamine anesthesia commonly causes tonic-clonic movements (greater than 10% of people) and rarely hypertonia. Vomiting can be expected in 5-15% of the patients; pre-treatment with propofol mitigates it as well.Laryngospasm occurs only rarely with ketamine. Ketamine, generally, stimulates breathing; however, in the first 2-3 minutes of a high-dose rapid intravenous injection it may cause a transient respiratory depression.
At lower sub-anesthetic doses, psychiatric side effects are prominent. A majority of patients feel strange, spacey, woozy or floating, or have visual distortions or numbness. Also very frequent (20-50%) are difficulty speaking, confusion, euphoria, drowsiness, and difficulty concentrating. The symptoms of psychosis such as going into a hole, disappearing, feeling melting, experiencing colors and hallucinations are described by 6-10% of people. Dizziness, blurred vision, dry mouth, hypertension, nausea, increased/decreased body temperature, or feeling flushed are the common (>10%) non-psychiatric side effects. All these adverse effects are most pronounced by the end of the injection, dramatically reduced 40 min after, and completely disappear within 4 hours after the injection.
Liver toxicity of ketamine also involves higher doses and repeated administration. In a group of chronic high dose ketamine users, the frequency of liver injury was reported to be about 10%. There are case reports of increased liver enzymes involving ketamine treatment of chronic pain.
Dependence and tolerance
Although the incidence of ketamine dependence is unknown, some people who regularly use ketamine develop ketamine dependence. Animal experiments also confirm the risk of misuse. Additionally, the rapid onset of effects following insufflation may increase the drug's recreational use potential. The short duration of effects promotes bingeing. Ketamine tolerance rapidly develops, even with repeated medical use, prompting the use of higher doses. Some daily users reported withdrawal symptoms, primarily anxiety, shaking, sweating, and palpitations, following the attempts to stop. Cognitive deficits as well as increased dissociation and delusion symptoms were observed in frequent recreational users of ketamine.
Clinical observations suggest that benzodiazepines may diminish the antidepressant effects of ketamine. Ketamine is frequently used to treat resistant depression as an add-on to a variety of antidepressants. Hence, it appears most conventional antidepressants can be safely combined with ketamine.
Whether ketamine is an agonist of D2 receptors is controversial. Early research by Philip Seeman's group found ketamine to be a D2 partial agonist with the potency similar to that of its NMDA receptor antagonism. However, later studies by different researchers found the affinity of ketamine of >10 ?M for the regular human and rat D2 receptors, Moreover, whereas D2 receptor agonists like bromocriptine are able to rapidly and powerfully suppress prolactinsecretion, subanesthetic doses of ketamine have not been found to do this in humans and in fact have been found to dose-dependently increase prolactin levels.Imaging studies have shown mixed results on inhibition of striatal [11C] raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect. However, changes in [11C] raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D2 receptor.
Relationships between levels and effects
Dissociation and psychotomimetic effects are reported in patients treated with ketamine at plasma concentrations of around 100 to 250 ng/mL (0.42-1.1 ?M). The typical intravenous antidepressant dosage of ketamine used to treat depression is low and results in maximal plasma concentrations of 70 to 200 ng/mL (0.29-0.84 ?M). At similar plasma concentrations (70 to 160 ng/mL; 0.29-0.67 ?M) it also shows analgesic effects. In 1-5 minutes after inducing anesthesia by a rapid intravenous injection of ketamine, its plasma concentration reaches as high as 60-110 ?M. When the anesthesia was maintained using nitrous oxide together with continuous injection of ketamine, the ketamine concentration stabilized at about 9.3 ?M. In an experiment with purely ketamine anesthesia, patients began to awaken once the plasma level of ketamine decreased to about 2,600 ng/mL (11 ?M) and became oriented in place and time when the level was down to 1,000 ng/mL (4 ?M). In a single-case study, the concentration of ketamine in cerebrospinal fluid, a proxy for the brain concentration, during anesthesia varied between 2.8 and 6.5 ?M and was about 40% lower than in plasma.
Ketamine can be absorbed by many different routes due to both its water and lipid solubility. Intravenous ketamine bioavailability is 100% by definition, intramuscular injection bioavailability is slightly lower at 93%, and epidural bioavailability is 77%. Subcutaneous bioavailability has never been measured but is presumed to be high. Among the less invasive routes, intranasal has the highest bioavailability (45-50%) and oral - the lowest (16-20%). Sublingual and rectal bioavailabilities are intermediate at about 25-50%.
After an intravenous injection of tritium-labelled ketamine, 91% of the radioactivity is recovered from urine and 3% from the feces. The medication is excreted mostly in the form of metabolites, with only 2% remaining unchanged. Conjugated hydroxylated derivatives of ketamine (80%) followed by dehydronorketamine (16%) are the most prevalent metabolites detected in urine.
2-chlorobenzonitrile is reacted with the Grignard reagent cyclopentylmagnesium bromide to give (2-chlorophenyl)(cyclopentyl)methanone. This is then brominated using bromine to form the corresponding bromoketone, which is then reacted with methylamine in an aqueous solution to form the methylimino derivative, 1-(2-Chloro-N-methylbenzimidoyl)cyclopentanol, with hydrolysis of the tertiary bromine atom. This final intermediate is then heated in decalin or another suitable high-boiling solvent, upon which a ring-expansion rearrangement occurs, forming ketamine.
In chemical structure, ketamine is an arylcyclohexylamine derivative. Ketamine is a chiral compound. The more active enantiomer, esketamine (S-ketamine), is also available for medical use under the brand name Ketanest S, while the less active enantiomer, arketamine (R-ketamine), has never been marketed as an enantiopure drug for clinical use.
Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5-5.0 mg/L in persons receiving the drug therapeutically (during general anesthesia), 1-2 mg/L in those arrested for impaired driving and 3-20 mg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine drug use monitoring purposes. The presence of norketamine, a pharmacologically-active metabolite, is useful for confirmation of ketamine ingestion.
Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of Chemistry at Wayne State University and a Parke-Davis consultant. It was known by the developmental code name CI-581. After promising preclinical research in animals, ketamine was tested in human prisoners in 1964. These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as an anesthetic. The researchers were going to call the state of ketamine anesthesia "dreaming" but Parke-Davis did not like it. Hearing about this problem and about the "disconnected" appearance of the patients, the wife of one of the pharmacologists working on ketamine, Edward Domino, suggested "dissociative anesthesia". Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.
The discovery of antidepressive action of ketamine in 2000 has been described as the single most important advance in the treatment of depression in over 50 years. It has sparked interest in NMDA receptor antagonists for depression, and has shifted the direction of antidepressant research and development.
At subanesthetic doses ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world that is known as depersonalization and derealization. At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation with visual and auditory hallucinations.John C. Lilly, Marcia Moore, D. M. Turner, and David Woodard (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. Turner died prematurely due to drowning during presumed unsupervised ketamine use. In 2006 the Russian edition of Adam Parfrey's Apocalypse Culture II was banned and destroyed by authorities owing to its inclusion of an essay by Woodard about the entheogenic use of, and psychonautic experiences with, ketamine.
Recreational ketamine use has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005-2013. They include accidental poisonings, drownings, traffic accidents, and suicides. The majority of deaths were among young people. Because of its ability to cause confusion and amnesia, ketamine has been used for date rape.
Russian doctor Evgeny Krupitsky has claimed to have obtained encouraging results by using ketamine as part of a treatment for alcohol use disorder, which combines psychedelic and aversive techniques. Krupitsky and Kolp summarized their work to date in 2007.
In veterinary anaesthesia, ketamine is often used for its anaesthetic and analgesic effects on cats, dogs,rabbits, rats, and other small animals. It is frequently used in induction and anaesthetic maintenance in horses. It is an important part of the "rodent cocktail", a mixture of drugs used for anaesthetising rodents. Veterinarians often use ketamine with sedative drugs to produce balanced anaesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. Ketamine is also used to manage pain among large animals. It is the primary intravenous anaesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.
Ketamine appears not to produce sedation or anaesthesia in snails. Instead, it appears to have an excitatory effect.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 374-375. ISBN978-0-07-148127-4. Phencyclidine (PCP or angel dust) and ketamine (also known as special K) are structurally related drugs... their reinforcing properties and risks related to compulsive abuse
^Hijazi Y, Boulieu R (July 2002). "Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes". Drug Metabolism and Disposition. 30 (7): 853-8. doi:10.1124/dmd.30.7.853. PMID12065445. S2CID15787750.
^ abcdMarcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H, Richard-Devantoy S, Beauchamp S (December 2020). "A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 - January 2019". J Affect Disord. 277: 831-841. doi:10.1016/j.jad.2020.09.007. PMID33065824. S2CID223557698.
^Adams HA (December 1997). "[S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation]" [S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation]. Der Anaesthesist (in German). 46 (12): 1081-7. doi:10.1007/s001010050510. PMID9451493.
^Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NG, Hohl CM (January 2015). "The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review". Annals of Emergency Medicine. 65 (1): 43-51.e2. doi:10.1016/j.annemergmed.2014.06.018. PMID25064742.
^Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, Kraus C, Kadriu B, Zarate CA, Park LT (February 2020). "Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression". J Affect Disord. 263: 568-575. doi:10.1016/j.jad.2019.11.028. PMID31791675.
^ abcdCastellani D, Pirola GM, Gubbiotti M, Rubilotta E, Gudaru K, Gregori A, Dellabella M (April 2020). "What urologists need to know about ketamine-induced uropathy: A systematic review". Neurourol Urodyn. 39 (4): 1049-1062. doi:10.1002/nau.24341. PMID32212278. S2CID214643776.
^Handa F, Tanaka M, Nishikawa T, Toyooka H (February 2000). "Effects of oral clonidine premedication on side effects of intravenous ketamine anesthesia: a randomized, double-blind, placebo-controlled study". J Clin Anesth. 12 (1): 19-24. doi:10.1016/s0952-8180(99)00131-2. PMID10773503.
^ abPeltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI (September 2016). "Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy". Clin Pharmacokinet. 55 (9): 1059-77. doi:10.1007/s40262-016-0383-6. PMID27028535. S2CID5078489.
^ abJordan S, Chen R, Fernalld R, Johnson J, Regardie K, Kambayashi J, et al. (July 2006). "In vitro biochemical evidence that the psychotomimetics phencyclidine, ketamine and dizocilpine (MK-801) are inactive at cloned human and rat dopamine D2 receptors". European Journal of Pharmacology. 540 (1-3): 53-6. doi:10.1016/j.ejphar.2006.04.026. PMID16730695.
^ abcdefYamakura T, Chavez-Noriega LE, Harris RA (April 2000). "Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine". Anesthesiology. 92 (4): 1144-53. doi:10.1097/00000542-200004000-00033. PMID10754635. S2CID23651917.
^ abBartova L, Vogl SE, Stamenkovic M, Praschak-Rieder N, Naderi-Heiden A, Kasper S, Willeit M (November 2015). "Combination of intravenous S-ketamine and oral tranylcypromine in treatment-resistant depression: A report of two cases". European Neuropsychopharmacology. 25 (11): 2183-4. doi:10.1016/j.euroneuro.2015.07.021. PMID26302763. S2CID39039021.
^Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE (February 1982). "Plasma levels of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay". Anesth Analg. 61 (2): 87-92. doi:10.1213/00000539-198202000-00004. PMID7198883. S2CID27596215.
BE 634208, Stevens, Calvin L., "Procédé de production d'aminocétones", issued 1963-07-15.
^Krüger AD (1998). "[Current aspects of using ketamine in childhood]". Anaesthesiologie und Reanimation (in German). 23 (3): 64-71. PMID9707751.
^Chankvetadze B, Burjanadze N, Breitkreutz J, Bergander K, Bergenthal D, Kataeva O, Fröhlich R, Luftmann H, Blaschke G (2002). "Mechanistic study on the opposite migration order of the enantiomers of ketamine with ?- and ?-cyclodextrin in capillary electrophoresis". Journal of Separation Science. 25 (15-17): 1155-1166. doi:10.1002/1615-9314(20021101)25:15/17<1155::AID-JSSC1155>3.0.CO;2-M.
^Feng N, Vollenweider FX, Minder EI, Rentsch K, Grampp T, Vonderschmitt DJ. Development of a gas chromatography-mass spectrometry method for determination of ketamine in plasma and its application to human samples. Ther. Drug Monit. 17: 95-100, 1995.
^Parkin MC, Turfus SC, Smith NW, Halket JM, Braithwaite RA, Elliott SP, Osselton MD, Cowan DA, Kicman AT. Detection of ketamine and its metabolites in urine by ultra high pressure liquid chromatography-tandem mass spectrometry. J. Chrom. B 876: 137-142, 2008.
^R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 806-808.
^Lamont LA (November 2008). "Adjunctive analgesic therapy in veterinary medicine". The Veterinary Clinics of North America. Small Animal Practice. 38 (6): 1187-203, v. doi:10.1016/j.cvsm.2008.06.002. PMID18954680.
^Stunkard JA, Miller JC (September 1974). "An outline guide to general anesthesia in exotic species". Veterinary Medicine, Small Animal Clinician. 69 (9): 1181-6. PMID4604091.