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In medical settings, ketamine is usually injected [[Intravenous therapy|intravenously]] or [[Intramuscular injection|intramuscularly]].<ref name="lankenau">{{Cite journal|author=Lankenau SE, Sanders B, Bloom JJ, ''et al.'' |title=First injection of ketamine among young injection drug users (IDUs) in three U.S. cities |journal=Drug and Alcohol Dependence |volume=87 |issue=2–3 |pages=183–93 |date=March 2007 |pmid=16979848 |pmc=1852477 |doi=10.1016/j.drugalcdep.2006.08.015}}</ref> |
In medical settings, ketamine is usually injected [[Intravenous therapy|intravenously]] or [[Intramuscular injection|intramuscularly]].<ref name="lankenau">{{Cite journal|author=Lankenau SE, Sanders B, Bloom JJ, ''et al.'' |title=First injection of ketamine among young injection drug users (IDUs) in three U.S. cities |journal=Drug and Alcohol Dependence |volume=87 |issue=2–3 |pages=183–93 |date=March 2007 |pmid=16979848 |pmc=1852477 |doi=10.1016/j.drugalcdep.2006.08.015}}</ref> |
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Since it suppresses breathing much less than most other available anaesthetics,<ref name="heshmati">{{Cite journal|author=Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A |title=Use of ketamine in severe status asthmaticus in intensive care unit |journal=Iranian Journal of Allergy, Asthma, and Immunology |volume=2 |issue=4 |pages=175–80 |date=December 2003 |pmid=17301376 |doi=}}</ref> ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable [[Mechanical ventilation|ventilation]] equipment is not available. Ketamine tends to increase [[heart rate]] and blood pressure. Because it tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient's fluid volume status is unknown (''e.g.'', from traffic accidents). Ketamine can be used in [[podiatry]] and other minor surgery, and occasionally for the treatment of [[migraine]]. Research is ongoing in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression,<ref>{{Cite journal|author=Zarate CA Jr, et al |title=Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial |journal=Biological Psychiatry|volume=71 |issue=11 |pages=939–46 |date=January 2012 |pmid=22297150 |pmc=22297150|doi=10.1016/j.biopsych.2011.12.010|first2=Nancy E.|first3=Lobna|first4=Jose|first5=Nancy|first6=Anibal|first7=Jessica|first8=Craig A.|first9=Victoria|first10=David A.}}</ref> and for the treatment of [[alcoholism]]<ref>{{Cite journal|author=Krystal JH, Madonick S, Perry E, ''et al.'' |title=Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism |journal=Neuropsychopharmacology |volume=31 |issue=8 |pages=1793–800 |date=August 2006 |pmid=16395307 |doi=10.1038/sj.npp.1300994}}</ref> and [[heroin]] [[Substance use disorder|addiction]].<ref name="jovaisa">{{Cite journal|author=Jovaisa T, Laurinenas G, Vosylius S, Sipylaite J, Badaras R, Ivaskevicius J |title=Effects of ketamine on precipitated opiate withdrawal |journal=Medicina |volume=42 |issue=8 |pages=625–34 |year=2006 |pmid=16963828 |url=http://medicina.kmu.lt/0608/0608-03e.htm}}</ref> |
Since it suppresses breathing much less than most other available anaesthetics,<ref name="heshmati">{{Cite journal|author=Heshmati F, Zeinali MB, Noroozinia H, Abbacivash R, Mahoori A |title=Use of ketamine in severe status asthmaticus in intensive care unit |journal=Iranian Journal of Allergy, Asthma, and Immunology |volume=2 |issue=4 |pages=175–80 |date=December 2003 |pmid=17301376 |doi=}}</ref> ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable [[Mechanical ventilation|ventilation]] equipment is not available. |
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Ketamine is frequently used in severely injured patients. It is the drug of choice for patients with head injury who are at risk of [[hypotension]].{{cn}} Hypotension is extremely dangerous in patients with severe head injury and ketamine is anaesthetic agent least likely to precipitate hypotension. For years medical myth has held that ketamine was dangerous in patients with head injury over concerns that it might transiently increase the pressure inside the skull. This small transient effect is completely outweighed by the devastation caused by hypotension in severely head injured patients. AirMedical services and Paramedics are using this drug with increasing frequency.{{cn}} |
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Ketamine tends to increase [[heart rate]] and blood pressure. Because it tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient's fluid volume status is unknown (''e.g.'', from traffic accidents). Ketamine can be used in [[podiatry]] and other minor surgery, and occasionally for the treatment of [[migraine]]. Research is ongoing in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression,<ref>{{Cite journal|author=Zarate CA Jr, et al |title=Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial |journal=Biological Psychiatry|volume=71 |issue=11 |pages=939–46 |date=January 2012 |pmid=22297150 |pmc=22297150|doi=10.1016/j.biopsych.2011.12.010|first2=Nancy E.|first3=Lobna|first4=Jose|first5=Nancy|first6=Anibal|first7=Jessica|first8=Craig A.|first9=Victoria|first10=David A.}}</ref> and for the treatment of [[alcoholism]]<ref>{{Cite journal|author=Krystal JH, Madonick S, Perry E, ''et al.'' |title=Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism |journal=Neuropsychopharmacology |volume=31 |issue=8 |pages=1793–800 |date=August 2006 |pmid=16395307 |doi=10.1038/sj.npp.1300994}}</ref> and [[heroin]] [[Substance use disorder|addiction]].<ref name="jovaisa">{{Cite journal|author=Jovaisa T, Laurinenas G, Vosylius S, Sipylaite J, Badaras R, Ivaskevicius J |title=Effects of ketamine on precipitated opiate withdrawal |journal=Medicina |volume=42 |issue=8 |pages=625–34 |year=2006 |pmid=16963828 |url=http://medicina.kmu.lt/0608/0608-03e.htm}}</ref> |
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In [[veterinary anesthesia]], ketamine is often used for its anesthetic and [[analgesic]] effects on cats, dogs, [[rabbit]]s, [[rat]]s, and other small animals. It is an important part of the "[[rodent cocktail]]" a mixture of drugs used for anesthetizing rodents.{{citation needed|date=March 2014}} Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent [[pain wind-up]]. Ketamine is used to manage pain among large animals, though it has less effect on [[bovine]]s.{{citation needed|date=March 2014}} It is the primary intravenous [[anesthetic]] agent used in equine surgery, often in conjunction with [[detomidine]] and [[thiopental]], or sometimes [[guaifenesin]]. |
In [[veterinary anesthesia]], ketamine is often used for its anesthetic and [[analgesic]] effects on cats, dogs, [[rabbit]]s, [[rat]]s, and other small animals. It is an important part of the "[[rodent cocktail]]" a mixture of drugs used for anesthetizing rodents.{{citation needed|date=March 2014}} Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent [[pain wind-up]]. Ketamine is used to manage pain among large animals, though it has less effect on [[bovine]]s.{{citation needed|date=March 2014}} It is the primary intravenous [[anesthetic]] agent used in equine surgery, often in conjunction with [[detomidine]] and [[thiopental]], or sometimes [[guaifenesin]]. |
Revision as of 14:10, 21 March 2014
Clinical data | |
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AHFS/Drugs.com | Consumer Drug Information |
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Dependence liability | Moderate |
Routes of administration | IV, IM, Insufflated, oral, topical |
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Pharmacokinetic data | |
Metabolism | Hepatic, primarily by CYP3A4[1] |
Elimination half-life | 2.5–3 hours. |
Excretion | renal (>90%) |
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KEGG | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.027.095 |
Chemical and physical data | |
Formula | C13H16ClNO |
Molar mass | 237.725 g/mol g·mol−1 |
3D model (JSmol) | |
Melting point | 262 °C (504 °F) |
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Ketamine is a drug used in human and veterinary medicine, primarily for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.[2] Like other drugs of its class, such as tiletamine and phencyclidine (PCP), ketamine induces a state referred to as "dissociative anesthesia"[3] and is used as a recreational drug.
Ketamine can be effective in treating depression in patients with depression and bipolar disorder who have not responded to antidepressants.[4] It produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.[5]
Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.[6] At high, fully anesthetic level doses, ketamine has also been found to bind to μ-opioid receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity[7] – and to sigma receptors in rats.[8] Ketamine also interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels,[9] and it inhibits hyperpolarization-activated cyclic nucleotide–modulated (HCN1) cation channels.[10]
Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[11]
Medical use
Indications for use as an anaesthetic:
- Pediatric anesthesia, as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and tracheal intubation;
- Asthmatics or patients with chronic obstructive airway disease;
- As part of a cream, gel, or liquid (only available from compounding pharmacies as it is not a branded product, specific formulation and ratios are specified by the prescribing physician) for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% lidocaine, and 10% ketamine.[citation needed] Other ingredients found useful by pain specialists and their patients, as well as the compounding pharmacists who make the topical mixtures, include amitriptyline, cyclobenzaprine, clonidine, tramadol, gabapentin, baclofen, and mepivacaine and other longer-acting local anaesthetics (e.g. tetracaine, procaine).
- Emergency surgery in field conditions in war zones;
- To supplement spinal or epidural anesthesia/analgesia using low doses;
In medical settings, ketamine is usually injected intravenously or intramuscularly.[12] Since it suppresses breathing much less than most other available anaesthetics,[13] ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available.
Ketamine is frequently used in severely injured patients. It is the drug of choice for patients with head injury who are at risk of hypotension.[citation needed] Hypotension is extremely dangerous in patients with severe head injury and ketamine is anaesthetic agent least likely to precipitate hypotension. For years medical myth has held that ketamine was dangerous in patients with head injury over concerns that it might transiently increase the pressure inside the skull. This small transient effect is completely outweighed by the devastation caused by hypotension in severely head injured patients. AirMedical services and Paramedics are using this drug with increasing frequency.[citation needed]
Ketamine tends to increase heart rate and blood pressure. Because it tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient's fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. Research is ongoing in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression,[14] and for the treatment of alcoholism[15] and heroin addiction.[16]
In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. It is an important part of the "rodent cocktail" a mixture of drugs used for anesthetizing rodents.[citation needed] Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. Ketamine is used to manage pain among large animals, though it has less effect on bovines.[citation needed] It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.
Ketamine may be used in small doses (0.1–0.5 mg/kg·h) as a local anesthetic, particularly for the treatment of pain associated with movement and neuropathic pain.[17] It may also be used as an intravenous coanalgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines.[18] Ketamine is a coanalgesic, so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects.[18] The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.[19]
The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system.[20] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is also a potent analgesic and can be used in subanesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, "going into other worlds" or "seeing God" while anesthetized, and these unwanted psychological side effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.[18]
Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS).[21] Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore, nurses administering ketamine to patients with CRPS should do so only in a setting where a trained physician is available if needed to assess potential adverse effects on patients.[22]
In some neurological intensive care units, ketamine has been used in cases of prolonged seizures. Some evidence indicates the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.[23]
Ketamine is a "core" medicine in the World Health Organization's "Essential Drugs List", a list of minimum medical needs for a basic healthcare system.[24]
Pain
The dissociative anesthetic effects of ketamine have also been applied for postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption, as well as reports of nausea following abdominal surgery.[25]
Oral ketamine
- Ketamine can be started using the oral route, or patients may be changed from a subcutaneous infusion once pain is controlled.
- Bioavailability of oral ketamine hydrochloride is approximately 20%
Converting from a 24-hour subcutaneous ketamine infusion to oral ketamine
- Oral ketamine is easily broken down by bile acids and thus has a low bioavailability (~20%). Oftentimes lozenges or "gummies" for sublingual or buccal absorption prepared by a compounding pharmacy are used to combat this issue.
- Some specialists stop the subcutaneous infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.[26]
Side effects
Short term
Up to 40% of patients may experience side effects with continuous subcutaneous infusion (side effects are less common upon oral administration). These include:[27]
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Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.[27]
As discussed below, current research suggests that acute ketamine exposure does not cause significant neurotoxicity.
Long term
Because ketamine is not administered chronically in a typical clinical setting, long-term effects are primarily reported and investigated in recreational ketamine users and in animal models.[28]
Neurological effects
In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain, which, however, has significant differences in metabolism from the human brain, so may not occur in humans.[29][30][31][32] Indeed, a review published in 2009 found no evidence of ketamine-induced neuron death in humans.[33]
The first large-scale, longitudinal study of ketamine users found that current frequent ketamine users (at least 4 days/week, averaging 20 days/month) had increased depression and impaired memory by several measures, including verbal, short-term memory and visual memory. However, current infrequent (1–4 days/month, averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.[34]
Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and non-cell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.[35][36]
More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time.[37] Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month.[37] A study conducted on rhesus monkeys found that a 24-hour intravenous infusion of ketamine caused signs of brain damage in 5-day-old but not 35-day-old animals.[38]
The acute effects of ketamine cause cognitive impairment including reduced vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.[39]
Urinary tract effects
According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[40] Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.[28][40] The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.[41]
The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract.[40] Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.[28] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.[28]
Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension.[40] Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[40]
Case reports of hepatotoxicity in chronic pain management
In case reports of three patients treated with (S)-(+)-ketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.[42]
Interactions
Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI anti-depressants, MAOIs. Increase blood pressure, increased heart rate, palpitations and arrhythmias may be potential effects. Ketamine alone additionally increases intracranial pressure (ICP)
Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.[citation needed]
Mechanism of action
Central nervous system
Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. It appears to inhibit the receptor by binding both in the open channel and at an allosteric site.[43] The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[44] NMDAR antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.[27] Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia.[45] It also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.[46]
Ketamine also interacts with a host of other receptors to effect analgesia. It blocks voltage-sensitive calcium channels and depresses sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenaline and serotonin uptake inhibitor, which are involved in descending antinociceptive pathways.[27][47]
Peripheral systems
Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[45]
- Cardiovascular: Ketamine inhibits reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
- Gastrointestinal: Inhibition of neuronal uptake and increased serotonergic activity are thought to underly nausea and vomiting.
- Respiratory: Induced catecholamine release and stimulation of β2 adrenergic receptors causes bronchodilation.
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skeletal formula of (R)-ketamine -
ball-and-stick model of (R)-ketamine -
skeletal formula of (S)-ketamine -
ball-and-stick model of (S)-ketamine
Pharmacokinetics
Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[48] When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[49] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.[50] As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration.[48][51] Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are as follows: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.[27][49] Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.[51] Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.[27]
Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.[27]
Synthesis
Ketamine is synthesized from 2-chlorobenzonitrile, which reacts with the Grignard reagent cyclopentylmagnesium bromide to give 1-(2-chlorobenzoyl)cyclopentane.[52][53] The next step is bromination using bromine to the corresponding bromoketone, which upon reaction with an aqueous solution of methylamine forms the methylimino derivative. During this reaction, a simultaneous hydrolysis of the tertiary bromine atom occurs. On heating the reaction product in decalin, a ring-expansion rearrangement occurs, forming ketamine.
History
Medical use
Ketamine was originally developed in 1962 as a derivative of phencyclidine (PCP), which was synthesized in 1926, a feat made possible by the discovery of a new organic Grignard reaction by Parke-Davis scientist Harold Maddox.[54] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.[54] These investigations demonstrated that ketamine's shorter duration of action and lesser psychotomimetic profile made it favorable over PCP as a "dissociative" anesthetic.[55] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.[56]
Nonmedical use
Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.[56] Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication.[57] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[58][59][60][61][62] However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;[62] in addition, reports of ketamine being sold as "ecstasy" are common.[63] The use of ketamine as part of a "post-clubbing experience" has also been documented.[64] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[62] Related to its purported ability to cause confusion and amnesiac effects, ketamine can leave users vulnerable to drug-facilitated sexual assault.[65]
Society and culture
Legal status
The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.[66]
In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[50][67] On 10 December 2013 the UK ACMD recommended that the government reclassify ketamine to become a Class B drug,[68] and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".[69][70]
The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice said that the issue of its recheduling for medical and veterinary would be addressed "separately to allow for a period of consultation."[69]
In Canada, ketamine is classified as a Schedule I narcotic, as of August 2005.[71] In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.[72] By 2002, ketamine was classified as schedule III in Taiwan; given the recent rise in prevalence in East Asia; however, rescheduling into schedule I or II is being considered.[50]
In December 2013 the government of India added ketamine to Schedule X of the Drug and Cosmetics Act, adding restrictions on who can buy or sell it.[73]
International brand names
Brand names for ketamine vary internationally:[74]
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Recreational use
Ketamine sold illicitly comes either from diverted legitimate supplies and semilegitimate suppliers, or from theft of legitimate suppliers. It produces effects similar to phencyclidine (PCP) and dextromethorphan (DXM).
Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting, its hallucinatory effects lasting 60 minutes when insufflated or injected and up to two hours when ingested orally, the total experience lasting no more than a few hours.[75] At subanesthetic doses, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization.[76] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.[77] John C. Lilly,[78] Marcia Moore[79] and D. M. Turner[80] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. Both Moore and Turner died prematurely in a way that has been indirectly linked to the sedative properties of ketamine.[81]
Research
Antidepressant use
Animal studies
Some research in rodents has attributed the effects of ketamine to being an NMDA receptor antagonist,[43] which increases the activity of the AMPA receptor, and this boost in AMPA activity may be crucial for ketamine’s rapid antidepressant actions.[82] NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system is an emerging target for antidepressant drug discovery and development.[83][84][85]
Acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. The increase of hippocampal BDNF protein levels induced by ketamine might also be necessary to produce a rapid onset of antidepressant action in rats.[86]
Human studies
Research on the antidepressant effects of ketamine infusions at subanaesthetic doses has consistently shown rapid (4 to 72 hours) responses from single doses, with substantial improvement in mood in the majority of patients and remission in some. However, these effects are often short-lived, and attempts to prolong the antidepressant effect with repeated doses and extended ("maintenance") treatment have resulted in only modest success.[87]
When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, some patients were observed in the early 2000s to make a significant recovery from depression. This recovery was not formally documented, as the primary concern was pain management and it was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS.[88] This led the investigators to conduct a study in two patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients demonstrated significant, long-term improvement.[88]
A randomized placebo-controlled study in 18 patients conducted at the US NIH and published in 2006, found ketamine significantly improved treatment-resistant major depression within hours of injection that lasted up to one week after the single dose.[89] NIMH director Dr. Thomas Insel remarked:"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."[90]
A 2013 two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression found that 64% of the patients responded after 24 hours according to the Montgomery–Åsberg Depression Rating Scale compared to 28% responding to midazolam.[91]
Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[92] Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in the active group as compared with the control. The group receiving ketamine also had significantly lower postoperative pain.
Epilepsy
Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[93] Ketamine was well tolerated and prolonged seizure duration overall, but particularly in those who had a seizure duration shorter than 25 seconds with methohexital at the maximum available stimulus intensity. Ketamine also increased midictal EEG slow-wave amplitude. Thus, a switch to ketamine may be useful when eliciting a robust seizure is difficult. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.
Treatment of addiction
The Russian doctor Evgeny Krupitsky (Clinical Director of Research for the Saint Petersburg Regional Center for Research in Addiction and Psychopharmacology) has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.[94][95] This method involved psychotherapy, controlled ketamine use, and group therapy, and resulted in 60 of the 86 alcoholic males selected for the study remaining fully abstinent through one year of treatment. For heroin addiction, the same researcher reached the conclusion that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence from heroin during one year without any adverse reactions. In a recently published study, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups.[citation needed]
Participants in the first group received two addiction counseling sessions followed by two KPT sessions (with a single IM injection of 2 mg/kg ketamine), with sessions scheduled on a monthly interval (multiple KPT group). Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. Three sessions of ketamine-assisted psychotherapy were found to be more effective than a single session for the treatment of heroin addiction.[96][97]
Krupitsky and Kolp summarized their work to date in 2007.[98]
Jovaisa et al. from Lithuania demonstrated attenuation of opiate withdrawal symptoms with ketamine. A total of 58 opiate-dependent patients were enrolled in a randomized, placebo-controlled, double-blind study. Patients underwent rapid opiate antagonist induction under general anesthesia. Prior to opiate antagonist induction, patients were given either placebo (normal saline) or a subanesthetic ketamine infusion of 0.5 mg/kg·h. The ketamine group presented better control of withdrawal symptoms, which lasted beyond ketamine infusion itself. Significant differences between ketamine and control groups were noted in anesthetic and early postanesthetic phases. No differences in effects on outcome after four months were observed.[16]
Complex regional pain syndrome
Ketamine is being used as an experimental and controversial treatment for complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD). CRPS/RSD is a severe chronic pain condition characterized by sensory, autonomic, motor, and dystrophic signs and symptoms. The pain in CRPS is continuous, worsens over time, and is usually disproportionate to the severity and duration of the inciting event. The hypothesis is that ketamine manipulates NMDA receptors which might reboot aberrant brain activity. One treatment modality is a low-dose ketamine infusion of between 25 and 90 mg per day, over five days, either in hospital or as an outpatient, called the awake technique. Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine (awake technique) in the CRPS patient concluded, "A four-hour ketamine infusion escalated from 40–80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation".[99]
Case notes of 33 patients whose CRPS pain was treated by the inpatient administration of a continuous subanesthetic intravenous infusion of ketamine were reviewed at Mackay Base Hospital, Queensland, Australia. A total of 33 patients with diagnoses of CRPS who had undergone ketamine treatment at least once were identified. Due to relapse, 12 of 33 patients received a second course of therapy, and two of 33 patients received a third. There was complete pain relief in 25 (76%), partial relief in six (18%), and no relief in two (6%) patients.
The degree of relief obtained following repeat therapy (N=12) appeared even better, as all 12 patients who received second courses of treatment experienced complete relief of their CRPS pain. The duration of relief was also impressive, as was the difference between the duration of relief obtained after the first and after the second courses of therapy. In this respect, following the first course of therapy, 54% of 33 individuals remained pain-free for three months or more and 31% remained pain free for six months or more. After the second infusion, 58% of 12 patients experienced relief for a year or more, while almost 33% remained pain free for over three years. The most frequent side effect observed in patients receiving this treatment was a feeling of inebriation. Hallucinations occurred in six patients. Less-frequent side effects also included complaints of light-headedness, dizziness, and nausea. In four patients, an alteration in hepatic enzyme profile was noted; the infusion was terminated and the abnormality resolved thereafter. No long-term side effects were noted.[99] This procedure has only recently been allowed in the United States for the treatment of CRPS.
A second treatment modality consists of putting the patient into a medically induced coma and giving an extremely high dosage of ketamine, typically between 600 and 900 mg.[100] This version, previously done in Germany and Mexico, is now currently only preformed in the United States.[101] According to Dr Schwartzman, 14 of 41 patients in the coma-induced ketamine experiments were completely cured. "We haven't cured the original injury", he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone." He added, "No one ever cured it before... In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."[100]
In Tuebingen, Germany, Dr Kiefer treated a patient who presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury. Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm. Her pain was unmanageable with all standard therapies. As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3–5 mg/kg·h) doses in conjunction with midazolam over a period of five days. On the second day, edema and discoloration began to resolve and increased spontaneous movement was noted. On day six, symptoms completely resolved and infusions were tapered. The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms. The patient has maintained this complete remission from CRPS for eight years now. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within a month of treatment.[102]
Fear of harm
According to a recent report on NPR,[103] Demitri Papolos uses ketamine to treat children with "fear of harm" profile, a condition characterized by: sleep disturbances including frequent and terrifying nightmares; an extreme reaction when anyone tries to control their behavior; and overheating, especially at night. Although "fear of harm" profile has been lumped in with bipolar disorder over the recent decades that understanding is emerging about these concerns, "fear of harm" may be related to an overly-sensitive "flight-or-fight" reaction, which classical bipolar disorder is not.
See also
- Acamprosate
- Arylcyclohexylamine
- Esketamine
- Dissociative
- NMDA receptor
- Methoxetamine
- Phencyclidine
- Dextromethorphan
- K-hole
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The combined effects can leave the user vulnerable to particular forms of crime, especially "date rape".
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Minister writes to Les Iversen, chair of the ACMD, accepting the council's recommendation to reclassify ketamine as a Class B drug and announcing the intention to consult on its scheduling.
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External links
- Ketamine Advocacy Network: Ketamine for the treatment of major & bipolar depression
- The Merck Manual: Ketamine
- Ketamine on RxList
- DEA: Ketamine Fact Sheet
- Center for Substance Abuse Research: Ketamine