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a general anesthetic and tranquilizer (not a barbiturate) that is administered intravenously or intramuscularly; used mainly by veterinarians or for minor surgery with geriatric or pediatric patients; taken in large doses it causes hallucinations similar to those associated with the use of PCP (同)ketamine_hydrochloride, Ketalar

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/09/29 11:13:31」(JST)

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Ketamine (INN) is a medication with many uses. It is used in medical procedures with humans and other animals. It is mainly for starting and maintaining general anesthesia. Other uses include sedation in intensive care, as a pain killer (particularly in emergency medicine and persons with potentially compromised respiration and/or allergies to opiate and barbiturate analgesics), as treatment of bronchospasm, and as a treatment for complex regional pain syndrome.

Respiratory function is unchanged with the administration of ketamine, which makes it a valuable anaesthetic.^[2] Potential complications include agitation.

Pharmacologically, ketamine is classified as an NMDA receptor antagonist, but it also acts at numerous other sites (including opioid receptors and monoamine transporters).^[3] Like other drugs in its class, such as tiletamine and phencyclidine (PCP), it is classified as a dissociative agent.^[4] The state it induces is described as a "trancelike cataleptic state of 'sensory isolation' [which] is characterized by potent analgesia, sedation, and amnesia while maintaining cardiovascular stability and preserving spontaneous respirations and protective airway reflexes."^[5]

Ketamine was first developed in 1962.^[6] It is on the World Health Organization's List of Essential Medicines, a list of essential medicines that should be available in a health system.^[7] Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Its use as a recreational drug has resulted in several high-profile deaths.^[8]

1 Use
- 1.1 Anesthesia
- 1.2 Pain
- 1.3 Depression
- 1.4 Recreational use
- 1.5 Administration
2 Side effects
- 2.1 Neurological effects
- 2.2 Urinary tract effects
- 2.3 Case reports of hepatotoxicity in chronic pain management
- 2.4 Interactions
3 Pharmacology
- 3.1 Pharmacodynamics
  - 3.1.1 Effects in central nervous system
  - 3.1.2 Effects in peripheral systems
- 3.2 Pharmacokinetics
4 Chemistry
- 4.1 Structure
5 History
- 5.1 Medical use
- 5.2 Nonmedical use
6 Society and culture
- 6.1 Legal status
- 6.2 International brand names
- 6.3 Pop culture
7 Research
- 7.1 Treatment of addiction
8 Veterinary medicine
9 See also
10 References
11 External links

Use

One 10-ml vial of 1000 mg of ketamine

Anesthesia

Uses as an anaesthetic:

Anesthesia in children, as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and tracheal intubation
Asthmatics or people with chronic obstructive airway disease
As a sedative for physically or emotionally painful procedures in emergency departments^[5]
Emergency surgery in field conditions in war zones
To supplement spinal or epidural anesthesia/analgesia using low doses

Since it suppresses breathing much less than most other available anaesthetics,^[9] ketamine is used in 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 people. A 2011 clinical practice guideline supports the use of ketamine as a dissociative sedative in emergency medicine.^[5] It is the drug of choice for patients in traumatic shock who are at risk of hypotension.^[10] Low blood pressure is harmful in people with severe head injury^[11] and ketamine is least likely to cause hypotension, often even able to prevent it.^[12]^[13]

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.^[14] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways.^{[citation needed]} Ketamine is considered relatively safe because protective airway reflexes are preserved.^[15]

Ketamine is used as a bronchodilator in the treatment of severe asthma.^[16] However, evidence of clinical benefit is limited.^[16]^[17]

Pain

Ketamine is also used for postoperative pain management. Low doses of ketamine reduces morphine use and nausea and vomiting after surgery.^[18]

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.^[19] 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.^[19] The combination of ketamine with an opioid may be useful for pain caused by cancer, as suggested in animal models.^[20] A review article in 2013 concluded, "despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain".^[21]

Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS).^[22] A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.^[23] Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some people have included hallucinations, dizziness, lightheadedness, and nausea. Therefore, the administration of ketamine to people with CRPS should only be done by medical personnel who are appropriately licensed and trained if needed to assess potential adverse effects on patients.^[24]

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. People 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 administration of a sedative such as a benzodiazepine.^[19]

Depression

Ketamine has been clinically tested for treatment-resistant bipolar depression, major depressive disorder, and people in a suicidal crisis in emergency rooms, and is being used this way off-label.^[25]^[26]^[27] The drug is given by a single intravenous infusion at doses less than those used in anesthesia, and preliminary data have indicated it produces a rapid (within 2 hours) and relatively sustained (about 1–2 weeks long) significant reduction in symptoms in some patients.^[28] Initial studies with ketamine have sparked scientific and clinical interest due to its rapid onset,^[29] and because it appears to work by blocking NMDA receptors for glutamate, a different mechanism from most modern antidepressants that operate on other targets.^[26]^[30]

Recreational use

Ketamine poured onto glass and left to dry

Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting. It takes effect within about 10 minutes,^[31] while its hallucinogenic effects last 60 minutes when insufflated or injected and up to two hours when ingested orally. The total experience lasts no more than a few hours.^[32]

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.^[33] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.^[34] John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with ketamine.^[35] Both Moore and Turner died prematurely during presumed unsupervised ketamine use.^[8]

Administration

In medical settings, ketamine is usually injected intravenously or intramuscularly.^[36]

Ketamine can be started using the oral route, or people may be changed from a subcutaneous infusion once pain is controlled. Bioavailability of oral ketamine hydrochloride is around 20%

Oral ketamine is easily broken down by bile acids, thus has a low bioavailability (about 20%). Often, 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.^[37]

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. 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).

Side effects

These include:^[38]

Cardiovascular: Arrythmias, bradycardia or tachycardia, hyper- or hypotension
Central nervous system: Ketamine is traditionally avoided in people with or at risk of intracranial hypertension (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.^[39]
Dermatologic: Transient erythema, transient morbilliform rash
Gastrointestinal: Anorexia, nausea, increased salivation, vomiting
Local: Pain or exanthema of the injection site
Neuromuscular and skeletal: Increased skeletal muscle tone (tonic-clonic movements)
Ocular: Diplopia, increased intraocular pressure, nystagmus
Respiratory: Airway obstruction, apnea, increased bronchial secretions, respiratory depression, laryngospasm
Other: Anaphylaxis, dependence, emergence reaction

Emergence reactions manifest as vivid dreams, hallucinations, and delirium and occur in 10 to 20% of patients at anesthetic doses.^[40] These reactions are less common in patients less than 15 years old and greater than 65 years old and when administered intramuscularly. Emergence reactions can occur up to 24 hours postoperatively. The chance of this occurring can be reduced by minimizing stimulation to the patient during recovery and pretreating with a benzodiazepine. If given a benzodiazepine, a lower dose of ketamine than normal should be given. Patients who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.^[38]

Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of patients.^[41]

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.^[42]

The first large-scale, longitudinal study of ketamine users found current frequent (averaging 20 days/month) ketamine users had increased depression and impaired memory by several measures, including verbal, short-term memory, and visual memory. Current infrequent (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.^[43]

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 noncell-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.^[44]^[45]

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.^[46] 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.^[46] A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.^[47] Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.^[48]

The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.^[49]

Urinary tract effects

A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine abuse.^[50] 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.^[50]^[51] 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.^[52]

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 g/day reported symptoms of the lower urinary tract.^[50] Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.^[51] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.^[51]

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.^[50] 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.^[50]

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.^[53]

Interactions

Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI antidepressants, and MAOIs. Increase blood pressure and heart rate, palpitations, and arrhythmias may be potential effects.

Ketamine may increase the effects of other sedatives, including, but not limited to: alcohols,^[54] benzodiazepines,^[55] opioids,^[56] and barbiturates.^[57]

Pharmacology

Pharmacodynamics

Ketamine acts primarily as an antagonist of the NMDA receptor, and this action accounts for most of its effects.^[3] However, the complete pharmacology of ketamine is more complex, and it is known to directly interact with a variety of other sites to varying degrees.^[3] Known actions of ketamine include:

Non-competitive antagonist of the NMDA receptor (NMDAR)^[3]^[58]
Negative allosteric modulator of the nACh receptor^[3]
Weak agonist of the μ-opioid and κ-opioid receptors (10- and 20-fold less affinity relative to NMDAR, respectively),^[3] and very weak agonist of the δ-opioid receptor^[3]
Agonist of the sigma receptor^[3]^[59] and D₂ receptor^[60]
Weak mACh receptor antagonist (10- to 20-fold less affinity relative to NMDAR)^[3]
Inhibitor of the reuptake of serotonin, dopamine, and norepinephrine^[3]
Voltage-gated sodium channel and L-type calcium channel blocker,^[3]^[61] and HCN1 cation channel blocker^[62]
Inhibitor of nitric oxide synthase^[3]^[59]

Ketamine appears to inhibit the NMDAR by binding both in the open channel and at an allosteric site.^[63] The S(+) and R(-) stereoisomers bind with different affinities: K_i = 3200 and 1100 nM, respectively.^[64]

Effects in central nervous system

NMDAR antagonism is responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects of ketamine, although activation of κ-opioid receptors and possibly sigma and mACh receptors may also contribute to its psychotomimetic properties.^[3] Dopamine reuptake inhibition is likely to underlie the euphoria the drug produces, although an additional involvement of μ-opioid receptor activation cannot be excluded.^[3] NMDAR antagonism is responsible for the rapid antidepressant effects of ketamine at lower doses.^[65]

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.^[41] Inhibition of nitric oxide synthase lowers the production of nitric oxide – a neurotransmitter involved in pain perception, hence further contributing to analgesia.^[66] The action of ketamine at sigma and μ-opioid receptors is relatively weak, and evidence is mixed as to whether the latter is of significance to its analgesic effects.^[3]^[67]

Ketamine also interacts with a host of other targets to cause analgesia. In particular, it blocks voltage-dependent calcium channels and sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it inhibits the reuptake of serotonin and norepinephrine, which are involved in descending antinociceptive pathways.^[41]^[68]

Effects in peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:^[66]

Cardiovascular: Ketamine inhibits the reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
Gastrointestinal: Serotonin reuptake inhibition is thought to underlie nausea and vomiting.^[3]
Respiratory: Catecholamine elevation and stimulation of β₂ adrenergic receptors causes bronchodilation.

Pharmacokinetics

Ketamine is absorbable by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.^[66] 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.^[69] 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.^[70] 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.^[66]^[71] Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are: 93% intramuscularly, 25–50% intranasally, 30% sublingually, and 30% rectally.^[41]^[69] Peak plasma concentrations are reached within a minute intravenously, 5–15 min intramuscularly, and 30 min orally.^[71] Ketamine's duration of action in a clinical setting is 30 min to 2 h intramuscularly and 4–6 h orally.^[41]

Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.^[41]

Chemistry

Structure

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.^[72]

Skeletal formula of (R)-ketamine
Ball-and-stick model of (R)-ketamine
Skeletal formula of (S)-ketamine
Ball-and-stick model of (S)-ketamine

History

Medical use

Ketamine vials

Ketamine was first synthesized in 1962 by Calvin Stevens, a Parke Davis consultant conducting research on alpha-hydroxyimine rearrangements.^[73] After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964.^[73]^[74] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over PCP as a dissociative anesthetic.^[75] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.^[76]

Nonmedical use

Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.^[76] 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.^[77] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.^[78] 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;^[79] in addition, there are reports of ketamine being sold as "ecstasy".^[80] The use of ketamine as part of a "postclubbing experience" has also been documented.^[81] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.^[79] Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies.^[73] Much of the ketamine diverted for nonmedical use originates in China and India.^[73]

Related to its ability to cause confusion and amnesiac effects, ketamine can leave users vulnerable to date rape.^[31]^[76]

Society and culture

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.^[7]

Legal status

The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.^[82]

In the United Kingdom, it became labeled a Class C drug on 1 January 2006.^[70]^[83] On 10 December 2013 the UK Advisory Council on the Misuse of Drugs (ACMD) recommended that the government reclassify ketamine to become a Class B drug,^[84] 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".^[85]^[86]

The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary would be addressed "separately to allow for a period of consultation."^[85]

In Canada, ketamine is classified as a Schedule I narcotic, since 2005.^[87] 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.^[88]^[89] By 2002, ketamine was classified as class III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.^[70]^[90]

In December 2013, the government of India, in response to rising abuse and the use of ketamine as a date rape drug, has added it to Schedule X of the Drug and Cosmetics Act requiring a special license for sale and maintenance of records of all sales for two years.^[91]^[92]

International brand names

Brand names for ketamine vary internationally:^[38]

Anesject (ID)
Brevinaze (ZA)
Calypsol (AE, BB, BG, BH, BM, BS, BZ, CY, CZ, EG, GY, HU, IL, IQ, IR, JM, JO, KW, LB, LY, OM, PK, PL, PR, QA, RU, SA, SR, SY, TH, TT, YE)
Ivanes (ID)
Kanox (MY)
Keiran (VE)
Ketacor (PH)
Ketalar (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CY, DK, EG, ES, FI, FR, GB, GR, GY, HK, HN, ID, IE, IL, IN, IQ, IR, IT, JM, JO, KW, LB, LU, LY, MY, NL, NO, OM, PE, PT, QA, SA, SE, SR, SY, TR, TT, TW, US, UY, YE, ZA)
Ketalin (MX)
Ketamax (PH)
Ketamin-S (+) (PY)
Ketanest (NL, HR, PL, DE, AT)
Ketashort (CO)
Ketava (MY)
Ketazol (PH)
Ketmin (IN)
Ketalor (ES)
Narkamon (DE, PL)
Paard (BE)
Soon-Soon (TW)
Tekam (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE)
Velonarcon (PL)

Pop culture

Ketamine was referenced in several episodes of the television show House. It was first mentioned in the finale of the second season, "No Reason",^[93]^[94] and was responsible for temporarily relieving House's leg pain.^[95]

Research

Treatment of addiction

Russian doctor Evgeny Krupitsky has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.^[96]^[97] Krupitsky and Kolp summarized their work to date in 2007.^[98]

Veterinary medicine

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.

References

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^ ^a ^b ^c Elia, N; Tramèr, MR (January 2005). "Ketamine and postoperative pain: A quantitative systematic review of randomised trials". Pain 113 (1): 61–70. doi:10.1016/j.pain.2004.09.036. PMID 15621365.
^ Saito, O; Aoe, T; Kozikowski, A; Sarva, J et al. (September 2006). "Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain". Canadian Journal of Anesthesia 53 (9): 891–8. doi:10.1007/BF03022832. PMID 16960267.
^ Bredlau, AL; Thakur, R; Korones, DN; Dworkin, RH (October 2013). "Ketamine for pain in adults and children with cancer: A systematic review and synthesis of the literature". Pain Medicine 14 (10): 1505–17. doi:10.1111/pme.12182. PMID 23915253.
^ Correll, GE; Maleki, J; Gracely, EJ; Muir, JJ; Harbut, RE (September 2004). "Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel therapeutic approach to complex regional pain syndrome". Pain Medicine 5 (3): 263–75. doi:10.1111/j.1526-4637.2004.04043.x. PMID 15367304.
^ O'Connell, NE; Wand, BM; McAuley, J; Marston, L et al. (2013). "Interventions for treating pain and disability in adults with complex regional pain syndrome". Pain, Palliative and Supportive Care Group. Cochrane Database of Systematic Reviews 4 (4): Art. No. CD009416. doi:10.1002/14651858.CD009416.pub2. PMID 23633371.
^ "Severe Pain Relief may be Possible with a Common Anesthetic Drug" (Press release). Blackwell Publishing. 1 October 2004. Archived from the original on 2008-12-16. Retrieved 13 December 2009. ^{[unreliable medical source?]}
^ *Gary Stix for Scientific American. September 11, 2013 From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment, Part 1
- Gary Stix for Scientific American. September 12, 2013 Is Ketamine Right for You? Off-Label Prescriptions for Depression Pick Up in Small Clinics, Part 2
- Gary Stix for Scientific American. September 13, 2013 Ketamine, a Darling of the Club Scene, Inspires Development of Next-Generation Antidepressants, Part 3
^ ^a ^b Caddy C et al. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014 Apr;4(2):75-99. doi: 10.1177/2045125313507739. Review. PMID 24688759 PMC 3952483
^ Tondo L et al. Options for pharmacological treatment of refractory bipolar depression. Curr Psychiatry Rep. 2014 Feb;16(2):431. doi: 10.1007/s11920-013-0431-y. Review. PMID 24425269
^ ECRI Institute, under contract to AHRQ. December 2013 AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report. Priority Area 05: Depression and Other Mental Health Disorders
^ National Institute of Mental Health (7 August 2006). "Experimental Medication Kicks Depression in Hours Instead of Weeks". NIH News (Press release). National Institutes of Health; Dept. of Health and Human Services; United States. "National Institute of Mental Health director Thomas Insel said, "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.""
^ Naughton, M; Clarke, G; O'Leary, OF; Cryan, JF; Dinan, TG (Mar 2014). "A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action.". Journal of Affective Disorders 156: 24–35. doi:10.1016/j.jad.2013.11.014. PMID 24388038.
^ ^a ^b "Do you know... Ketamine". Knowledge Exchange. Toronto: Centre for Addiction and Mental Health. 2003. Archived from the original on 2014-04-07. Retrieved 27 July 2014.
^ Giannini, AJ; Loiselle, RH; Giannini, MC; Price, WA (1985). "Phencyclidine and the dissociatives". Psychiatric Medicine 3 (3): 197–217. PMID 2893430.
^ Giannini, AJ; Underwood, NA; Condon, M (November 2000). "Acute ketamine intoxication treated by haloperidol: A preliminary study". American Journal of Therapeutics 7 (6): 389–91. doi:10.1097/00045391-200007060-00008. PMID 11304647.
^ Giannini, AJ (1999). Drug Abuse. Los Angeles: Health Information Press. p. 104. ISBN 1885987110.
^ References for recreational use in literature:
- Lilly, John Cunningham (1997). The Scientist: A Metaphysical Autobiography. Berkeley, CA: Ronin. pp. 144–. ISBN 0914171720.
- Kelly, Kit (2001). The Little Book of Ketamine. Ronin. pp. 23, 40–45, 46–51, ibid. ISBN 9781579511210.
- Alltounian, Howard Sunny; Moore, Marcia (1978). Journeys Into the Bright World. Rockport, MA: Para Research. ISBN 9780914918127.
- Palmer, Cynthia; Horowitz, Michael (2000). Sisters of the Extreme: Women Writing on the Drug Experience. Inner Traditions. pp. 254–8, ibid. ISBN 9780892817573.
- Turner, D.M. (1994). The Essential Psychedelic Guide. San Francisco: Panther Press. ISBN 0964263610.
^ Lankenau, SE; Sanders, B; Bloom, JJ; Hathazi, D et al. (March 2007). "First injection of ketamine among young injection drug users (IDUs) in three U.S. cities". Drug and Alcohol Dependence 87 (2–3): 183–93. doi:10.1016/j.drugalcdep.2006.08.015. PMC 1852477. PMID 16979848.
^ "Ketamine in Palliative Care". Palliative Care Guidelines. Edinburgh: NHS Lothian, NHS Scotland, Health and Social Care Directorates, Scotland. August 2013 [August 2010]. Archived from the original on 2013-10-29.
^ ^a ^b ^c Merck Manual; Drug Information Provided by Lexi-Comp. Last full review/revision May 2014 Ketamine
^ Wang, Xin; Ding, Xibing; Tong, Yao; Zong, Jiaying; Zhao, Xiang; Ren, Hao; Li, Quan (24 May 2014). "Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials". Journal of Anesthesia: 7. doi:10.1007/s00540-014-1845-3.
^ Strayer, RJ; Nelson, LS (2008). "Adverse events associated with ketamine for procedural sedation in adults". American Journal of Emergency Medicine 26 (9): 985–1028. doi:10.1016/j.ajem.2007.12.005. PMID 19091264.
^ ^a ^b ^c ^d ^e ^f Quibell, R; Prommer, EE; Mihalyo, M; Twycross, R et al. (March 2011). "Ketamine*". Journal of Pain and Symptom Management (Therapeutic Review) 41 (3): 640–9. doi:10.1016/j.jpainsymman.2011.01.001. PMID 21419322.
^ Neurological effects of ketamine introduction references:
- Olney, JW; Labruyere, J; Price, MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263.
- Anderson, Cliff (June 2003). "The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid. ^{[unreliable medical source?]}
- Tryba, M; Gehling, M (October 2002). "Clonidine - A potent analgesic adjuvant". Current Opinion in Anaesthesiology 15 (5): 511–7. doi:10.1097/00001503-200210000-00007. PMID 17019247.
- Dong, C; Anand, KJS (June 2013). "Developmental neurotoxicity of ketamine in pediatric clinical use". Toxicology Letters 220 (1): 53–60. doi:10.1016/j.toxlet.2013.03.030. PMID 23566897.
^ Morgan, CJA; Muetzelfeldt, L; Curran, HV (2009). "Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: A 1-year longitudinal study". Addiction 105 (1): 121–33. doi:10.1111/j.1360-0443.2009.02761.x. PMID 19919593.
^ Vutskits, L; Gascon, E; Potter, G; Tassonyi, E et al. (May 2007). "Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture". Toxicology 234 (3): 216–26. doi:10.1016/j.tox.2007.03.004. PMID 17418473.
^ Hargreaves, RJ; Hill, RG; Iversen, LL (1994). "Neuroprotective NMDA Antagonists: The Controversy Over Their Potential for Adverse Effects on Cortical Neuronal Morphology". In Ito, U; Baethmann, A et al. Brain Edema IX: Proceedings of the Ninth International Symposium Tokyo, May 16–19, 1993. Acta Neurochirurgica Supplement. Suppl 60. pp. 15–9. ISBN 9783709193365. doi:10.1007/978-3-7091-9334-1_4. PMID: 7976530.
^ ^a ^b Sun, L; LI, Q; Li, Q; Zhang, Y et al. (November 2012). "Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys". Addiction Biology: 185–94. doi:10.1111/adb.12004. PMID 23145560.
^ Slikker, W; Zou, X; Hotchkiss, CE; Divine, RL et al. (2007). "Ketamine-induced neuronal cell death in the perinatal rhesus monkey". Toxicological Sciences 98 (1): 145–58. doi:10.1093/toxsci/kfm084. PMID 17426105.
^ Patel, P; Sun, L (April 2009). "Update on neonatal anesthetic neurotoxicity: Insight into molecular mechanisms and relevance to humans". Anesthesiology (commentary) 110 (4): 703–8. doi:10.1097/ALN.0b013e31819c42a4. PMC 2737718. PMID 19276968.
^ Krystal, JH; Karper, LP; Seibyl, JP; Freeman, GK et al. (March 1994). "Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses". Archives of General Psychiatry 51 (3): 199–214. doi:10.1001/archpsyc.1994.03950030035004. PMID 8122957.
^ ^a ^b ^c ^d ^e Middela, S; Pearce, I (January 2011). "Ketamine-induced vesicopathy: A literature review". International Journal of Clinical Practice 65 (1): 27–30. doi:10.1111/j.1742-1241.2010.02502.x. PMID 21155941.
^ ^a ^b ^c Morgan, CJA; Curran, HV; Independent Scientific Committee on Drugs (ISCD) (January 2012). "Ketamine use: A review". Addiction 107 (1): 27–38. doi:10.1111/j.1360-0443.2011.03576.x. PMID 21777321.
^ Yeung, LY; Rudd, JA; Lam, WP; Mak, YT et al. (December 2009). "Mice are prone to kidney pathology after prolonged ketamine addiction". Toxicology Letters 191 (2–3): 275–8. doi:10.1016/j.toxlet.2009.09.006. PMID 19766175.
^ Sear, JW (2011). "Ketamine hepato-toxicity in chronic pain management: Another example of unexpected toxicity or a predicted result from previous clinical and pre-clinical data?". Pain (commentary) 152 (9): 1946–7. doi:10.1016/j.pain.2011.04.031. PMID 21555186.
^ Hui, TW; Short, TG; Hong, W; Suen, T et al. (March 1995). "Additive interactions between propofol and ketamine when used for anesthesia induction in female atients". Anesthesiology 82 (3): 641–8. doi:10.1097/00000542-199503000-00005. PMID 7879932.
^ Hong, W; Short, TG; Hui, TW (December 1993). "Hypnotic and anesthetic interactions between ketamine and midazolam in female patients". Anesthesiology 79 (6): 1227–32. doi:10.1097/00000542-199312000-00013. PMID 8267198.
^ Akhavanakbari, G; Mohamadian, A; Entezariasl, M (April 2014). "Evaluation the effects of adding ketamine to morphine in intravenous patient-controlled analgesia after orthopedic surgery". Perspectives in Clinical Research 5 (2): 85–7. doi:10.4103/2229-3485.128028. PMC 3980550. PMID 24741486.
^ Eker, HE; Yalcin Cok, O; Aribogan, A; Arslan, G (October 2011). "Children on phenobarbital monotherapy requires more sedatives during MRI". Pediatric Anesthesia 21 (10): 998–1002. doi:10.1111/j.1460-9592.2011.03606.x. PMID 21564387.
^ Harrison, NL; Simmonds, MA (February 1985). "Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex". British Journal of Pharmacology 84 (2): 381–91. doi:10.1111/j.1476-5381.1985.tb12922.x. PMC 1987274. PMID 2858237.
^ ^a ^b Narita, M; Yoshizawa, K; Aoki, K; Takagi, M et al. (September 2001). "A putative sigma1 receptor antagonist NE-100 attenuates the discriminative stimulus effects of ketamine in rats". Addiction Biology 6 (4): 373–6. doi:10.1080/13556210020077091. PMID 11900615.
^ Seeman, P; Guan, HC; Hirbec, H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse 63 (8): 698–704. doi:10.1002/syn.20647. PMID 19391150.
^ Pharmaceutical Society of Australia; The Royal Australian College of General Practitioners; Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (2011). "2.1.1 IV General Anaesthetics". Australian Medicines Handbook 2011 (12th ed.). Adelaide: Australian Medicines Handbook Pty Ltd. p. 13. ISBN 9780980579048.
^ Chen, X; Shu, S; Bayliss, DA (2009). "HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine". Journal of Neuroscience 29 (3): 600–9. doi:10.1523/JNEUROSCI.3481-08.2009. PMC 2744993. PMID 19158287.
^ Orser, BA; Pennefather, PS; MacDonald, JF (1997). "Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors". Anesthesiology 86 (4): 903–17. doi:10.1097/00000542-199704000-00021. PMID 9105235.
^ Hirota, K; Lambert, DG (October 1996). "Ketamine: Its mechanism(s) of action and unusual clinical uses". British Journal of Anaesthesia 77 (4): 441–4. doi:10.1093/bja/77.4.441. PMID 8942324.
^ Browne, CA; Lucki, I (2013). "Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants". Frontiers in Pharmacology 4: 161. doi:10.3389/fphar.2013.00161. PMC 3873522. PMID 24409146.
^ ^a ^b ^c ^d Aroni, F; Iacovidou, N; Dontas, I; Pourzitaki, C et al. (August 2009). "Pharmacological aspects and potential new clinical applications of ketamine: Reevaluation of an old drug". Journal of Clinical Pharmacology 49 (8): 957–64. doi:10.1177/0091270009337941. PMID 19546251.
^ Rowland, LM (July 2005). "Subanesthetic ketamine: How it alters physiology and behavior in humans". Aviation, Space, and Environmental Medicine 76 (Suppl 7): C52–8. PMID 16018330.
^ Meller, ST (December 1996). "Ketamine: Relief from chronic pain through actions at the NMDA receptor?". Pain (correspondence) 68 (2–3): 435–6. doi:10.1016/S0304-3959(96)03167-3. PMID 9121834.
^ ^a ^b Sinner, B; Graf, BM (2008). "Ketamine". In Schüttler, J; Schwilden, H. Modern Anesthetics. Handbook of Experimental Pharmacology 182. pp. 313–33. ISBN 9783540728139. doi:10.1007/978-3-540-74806-9_15. PMID: 18175098.
^ ^a ^b ^c Li, JH; Vicknasingam, B; Cheung, YW; Zhou, W et al. (2011). "To use or not to use: An update on licit and illicit ketamine use". Substance Abuse and Rehabilitation 2 (1): 11–20. doi:10.2147/SAR.S15458. PMC 3846302. PMID 24474851.
^ ^a ^b Haas, DA; Harper, DG (1992). "Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia". Anesthesia Progress 39 (3): 61–8. PMC 2148758. PMID 1308374.
^ Krüger, AD (1998). "[Current aspects of using ketamine in childhood]". Anaesthesiologie und Reanimation (in German) 23 (3): 64–71. PMID 9707751.
^ ^a ^b ^c ^d Morris, H; Wallach, J (July 2014). "From PCP to MXE: A comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis 6 (7-8): 614–32. doi:10.1002/dta.1620. PMID 24678061.
^ Domino, EF (September 2010). "Taming the ketamine tiger". Anesthesiology 113 (3): 678–84. doi:10.1097/ALN.0b013e3181ed09a2 (inactive 2014-08-02). PMID 20693870.
^ Corssen, G; Domino, EF (January–February 1966). "Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581". Anesthesia & Analgesia 45 (1): 29–40. doi:10.1213/00000539-196601000-00007. PMID 5325977.
^ ^a ^b ^c "Ketamine". Center for Substance Abuse Research (CESAR); University of Maryland, College Park. 29 October 2013. Archived from the original on 2013-11-12. Retrieved 27 July 2014.
^ History of non-medical use in literature references:
- Alltounian & Moore 1978
- Palmer & Horowitz 2000
- Kelly 2001
^ Increased non-medical use references:
- Awuonda, M (13 July 1996). "Swedes alarmed at ketamine misuse". The Lancet 348 (9020): 122. doi:10.1016/S0140-6736(05)64628-4.
- Curran, HV; Morgan, C (April 2000). "Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later". Addiction 95 (4): 575–90. doi:10.1046/j.1360-0443.2000.9545759.x. PMID 10829333.
- Gahlinger, PM (1 June 2004). "Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine". American Family Physician 69 (11): 2619–26. PMID 15202696.
- Jansen, KL (6 March 1993). "Non-medical use of ketamine". BMJ 306 (6878): 601–2. doi:10.1136/bmj.306.6878.601. PMC 1676978. PMID 8461808.
- Joe-Laider & Hunt 2008
^ ^a ^b Joe-Laidler, K; Hunt, G (1 June 2008). "Sit down to float: The cultural meaning of ketamine use in Hong Kong". Addiction Research & Theory 16 (3): 259–71. doi:10.1080/16066350801983673. PMC 2744071. PMID 19759834.
^ Ketamine sold as "ecstasy" references:
- Tanner-Smith, EE (July 2006). "Pharmacological content of tablets sold as "ecstasy": Results from an online testing service". Drug and Alcohol Dependence 83 (3): 247–54. doi:10.1016/j.drugalcdep.2005.11.016. PMID 16364567.
- Copeland, J; Dillon, P (2005). "The health and psycho-social consequences of ketamine use". International Journal of Drug Policy 16 (2): 122–31. doi:10.1016/j.drugpo.2004.12.003.
- Measham, Fiona; Parker, Howard; Aldridge, Judith (2001). Dancing on Drugs: Risk, Health and Hedonism in the British Club Scene. London: Free Association Books. ISBN 9781853435126. ^{[verification needed]}^{[page needed]}
^ Moore, K; Measham, F (2006). "Ketamine use: Minimising problems and maximising pleasure". Drugs and Alcohol Today 6 (3): 29–32. doi:10.1108/17459265200600047.
^ Marshall, Donnie R.; (Deputy Administrator); Drug Enforcement Administration; Dept. of Justice, United States (13 July 1999). "Schedules of Controlled Substances: Placement of Ketamine into Schedule III [21 CFR Part 1308. Final Rule 99-17803]". Rules and Regulations. Federal Register 64 (133): 37673–5.
^ "Club 'horse' drug to be outlawed". BBC News. 28 December 2005. Archived from the original on 2009-09-03. Retrieved 7 May 2010.
^ Advisory Council on the Misuse of Drugs (ACMD); Baker, Norman (10 December 2013), Ketamine: A review of use and harm (Policy paper), Crown copyright; Open Government Licence, retrieved 22 January 2014.
^ ^a ^b Baker, Norman; (Minister for Crime Prevention); Home Office; United Kingdom (12 February 2014), Response to ACMD recommendation on ketamine (Correspondence to Les Iverson [chair of]; Advisory Council on the Misuse of Drugs), Crown copyright; Open Government Licence, retrieved 21 February 2014.
^ Dixon, Hayley (12 February 2014). "Party drug ketamine to be upgraded to Class B". The Daily Telegraph. Retrieved 2 August 2014.
^ Legal status of ketamine in Canada references:
- Controlled Drugs and Substances Act (S.C. 1996 c.19) Schedule I § 14. "Statutes of Canada (S.C.)". Justice Laws Website. Government of Canada. 12 June 2014. Retrieved 2 August 2014.
- "Order Amending Schedule I to the Controlled Drugs and Substances Act". Canada Gazette Part II 139 (19). 21 September 2005. p. 2130. Retrieved 2 August 2014.
- "Status of ketamine under CDSA". Canadian Society of Customs Brokers. 2 May 2005. Retrieved 2 August 2014.
^ "Government to tighten control on Ketamine", info.gov.hk (press release) (Government of the Hong Kong Special Administrative), 22 November 2000, archived from the original on 2013-06-26, retrieved 2 August 2014
^ Ho Wai-kin, Victor (2011). Criminal Law in Hong Kong. Kluwer Law International. p. 33. ISBN 9789041133069.
^ Chang, Rich (4 December 2012). "Ketamine to be made a class-two drug: Official". Taipei Times. p. 3.
^ "Ketamine drug brought under 'Schedule X' to curb abuse". The Times of India. 7 January 2014. Retrieved 2 August 2014.
^ Deb Roy, Sumitra (30 December 2013). "Govt makes notorious 'date rape' drug ketamine harder to buy or sell". The Times of India. Archived from the original on 2013-12-30.
^ "No Reason". House, M.D.. Season 2. Episode 24. 23 May 2006. Fox.
^ "No Reason (TV episode)" at the Internet Movie Database House, M.D. (2006).
^ Wild, Diane Kristine (24 May 2006). "House Season Finale - 'No Reason'". Blogcritics. Retrieved 30 April 2014.
^ Krupitsky, EM; Grineko, AYa; Berkaliev, TN; Paley, AI et al. (1992). "The combination of psychedelic and aversive approaches in alcoholism treatment". Alcoholism Treatment Quarterly 9 (1): 99–105. doi:10.1300/J020V09N01_09.
^ Krupitsky, EM; Grinenko, AY (1997). "Ketamine psychedelic therapy (KPT): A review of the results of ten years of research". Journal of Psychoactive Drugs 29 (2): 165–83. doi:10.1080/02791072.1997.10400185. PMID 9250944.
^ Krupitsky, Evgeny; Kolp, Eli. "Ch. 6: Ketamine Psychedelic Psychotherapy". In Winkelman, Michael J.; Roberts, Thomas B. Psychedelic Medicine: New Evidence for Hallucinogens as Treatments. Vol. 2. Westport, CT: Praeger. ISBN 9780275990237.

External links

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UpToDate Contents

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1. 手術室外での小児への迅速導入気管挿管（RSI）：鎮静薬と筋弛緩薬 rapid sequence intubation rsi outside of the operating room in children medications for sedation and paralysis
2. ケタミン中毒 ketamine poisoning
3. 成人における選択的脊椎手術のための麻酔 anesthesia for elective spine surgery in adults
4. 手術室外での成人への鎮静処置 procedural sedation in adults outside the operating room
5. 小児に対する手術室外での鎮静処置に使用する薬剤 pharmacologic agents for pediatric procedural sedation outside of the operating room

English Journal

Sex-specific alterations in behavioral and cognitive functions in a "three hit" animal model of schizophrenia.

Kekesi G1, Petrovszki Z2, Benedek G3, Horvath G4.
Behavioural brain research.Behav Brain Res.2015 May 1;284:85-93. doi: 10.1016/j.bbr.2015.02.015. Epub 2015 Feb 16.
Whereas schizophrenia affects both human sexes, there are known sex-dependent disparities. We developed a chronic animal model that shows some schizophrenia-related deficits in rats by applying selective breeding after subchronic ketamine administration connected with postweaning social isolation (c
PMID 25698594

Drug development in schizophrenia: are glutamatergic targets still worth aiming at?

Goff DC1.
Current opinion in psychiatry.Curr Opin Psychiatry.2015 May;28(3):207-15. doi: 10.1097/YCO.0000000000000152.
PURPOSE OF REVIEW: The ketamine model has dominated drug discovery in schizophrenia over the past decade, supported by genetic and postmortem evidence implicating glutamatergic transmission. This review assesses recent successes and disappointments of glutamatergic agents and identifies promising ne
PMID 25710242

The effect of KETODEX on the incidence and severity of emergence agitation in children undergoing adenotonsillectomy using sevoflurane based-anesthesia.

Hadi SM1, Saleh AJ1, Tang YZ1, Daoud A2, Mei X1, Ouyang W3.
International journal of pediatric otorhinolaryngology.Int J Pediatr Otorhinolaryngol.2015 May;79(5):671-6. doi: 10.1016/j.ijporl.2015.02.012. Epub 2015 Feb 19.
BACKGROUND: Postoperative emergency agitation (EA) is a common problem often observed in children undergoing general anesthesia. The purpose of this study was to evaluate whether a bolus of intraoperative low-dose ketamine followed by dexmedetomidine i.v. could reduce the incidence of EA in children
PMID 25770644

Comparison of hollow fiber liquid-phase microextraction and ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction for the determination of drugs of abuse in biological samples by gas chromatography-mass spectrometry.

Meng L1, Zhang W2, Meng P3, Zhu B4, Zheng K4.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2015 May 1;989:46-53. doi: 10.1016/j.jchromb.2015.02.039. Epub 2015 Mar 9.
Two microextraction techniques based on hollow fiber liquid-phase microextraction (HF-LPME) and ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction (UA-LDS-DLLME) had been applied for the determination of drugs of abuse (methamphetamine, amphetamine, 3,4-methylenedioxyme
PMID 25801996

Japanese Journal

ケタミン麻酔による夢の検討

盛岡赤十字病院紀要 = Medical Journal of Japanese Red Cross Morioka Hospital 27(１), 1-7, 2018-07-31
NAID 120006503399

うつ病治療に対する(R)-ketamineの可能性と将来展望 (特集多様化するうつ病治療の選択肢と薬物療法の位置付け)

臨床精神薬理 21(7), 919-924, 2018-07
NAID 40021630551

精神科領域の用語解説 (R)-ketamine(Arketamine)

分子精神医学 18(2), 100-102, 2018-04
NAID 40021563522

(R)-ケタミンvs.(S)-ケタミン (特集中枢薬の新たなイノベーション)

臨床精神医学 = Japanese journal of clinical psychiatry 47(3), 269-274, 2018-03
NAID 40021491534

Related Pictures

★リンクテーブル★

リンク元	「ケタミン」
拡張検索	「ketamine hydrochloride」

「ケタミン」

Ketamine
Systematic (IUPAC) name
	(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
AHFS/Drugs.com	Consumer Drug Information
Licence data	US FDA:link
Pregnancy cat.	AU: B3; US: C;
Legal status	AU: Controlled (S8); CA: Schedule I; UK: CD; US: Schedule III;
Dependence; liability	Moderate
Routes	IV, IM, Insufflated, oral, topical
Pharmacokinetic data
Metabolism	Hepatic, primarily by CYP3A4
Half-life	2.5–3 hours
Excretion	renal (>90%)
Identifiers
CAS number	6740-88-1
ATC code	N01AX03
PubChem	CID 3821
DrugBank	DB01221
ChemSpider	3689
UNII	690G0D6V8H
KEGG	D08098
ChEBI	CHEBI:6121
ChEMBL	CHEMBL742
Chemical data
Formula	C13H16ClNO
Mol. mass	237.725 g/mol
	SMILES CNC1(C2=CC=CC=C2Cl)CCCCC1=O;
	InChI InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3 ; Key:YQEZLKZALYSWHR-UHFFFAOYSA-N ;
Physical data
Melt. point	262 °C (504 °F)
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　　[★]

英: ketamine
化: 塩酸ケタミン ketamine hydrochloride
商: ケタラール Ketalar

分類

全身麻酔薬

静脈麻酔薬

解離性静脈麻酔薬

概念

中枢神経に作用して、意識消失、鎮痛作用をもたらす
大脳皮質や視床を抑制する(体性知覚抑制)
大脳辺縁系・網様体賦活系は活性化(向精神作用)
そのため、覚醒時に不快な夢や幻覚を伴う
呼吸抑制が弱い(小児検査麻酔にも筋肉内注射で使用される)
血圧を上昇させることから、ハイリスク患者の麻酔導入や喘息患者の麻酔導入で使用される
カタレプシ様。目は半開き。→独特の顔貌を呈する
○：注射できる(筋肉注射)。呼吸抑制がない。強力な鎮痛作用
×：精神症状出現。唾液分泌亢進。血圧↑。心拍↑。肺動脈圧↑。脳内圧↑。

薬理作用

催眠作用、鎮痛作用

注意

頭蓋内圧が上昇するため、脳外科の手術には推奨されない

相互作用

添付文書

ケタラール静注用５０ｍｇ／ケタラール静注用２００ｍｇ

http://www.info.pmda.go.jp/go/pack/1119400A1031_3_07/1119400A1031_3_07?view=body

「ketamine hydrochloride」

　　[★]

塩酸ケタミン

関: ketamine

[1] 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. PMID 12065445.

[2] Mankikian, B; Cantineau, JP; Sartene, R; Clergue, F et al. (November 1986). "Ventilatory and chest wall mechanics during ketamine anesthesia in humans". Anesthesiology 65 (5): 492–9. doi:10.1097/00000542-198611000-00007. PMID 3777478.

[pmid9806706-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p Kohrs, R; Durieux, ME (November 1998). "Ketamine: Teaching an old drug new tricks". Anesthesia & Analgesia 87 (5): 1186–93. doi:10.1213/00000539-199811000-00039. PMID 9806706.

[4] Bergman, SA (1999). "Ketamine: Review of its pharmacology and its use in pediatric anesthesia". Anesthesia Progress 46 (1): 10–20. PMC 2148883. PMID 10551055.

[GreenRoback2011-5] Green, SM; Roback, MG; Kennedy, RM; Krauss, B (2011). "Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update". Annals of Emergency Medicine 57 (5): 449–61. doi:10.1016/j.annemergmed.2010.11.030. PMID 21256625.

[6] "Ketamine - CESAR". Center for substance abuse research. University of Maryland. Retrieved 26 September 2014.

[WHOMedList-7] WHO Model List of Essential Medicines (18th ed.). World Health Organization. October 2013 [April 2013]. p. 1 [p. 5 of pdf]. Retrieved 22 April 2014.

[Jansen2001-8] Jansen, Karl (2001). Ketamine: Dreams and Realities. Multidisciplinary Association for Psychedelic Studies. pp. 50, 89. ISBN 0966001931.

[heshmati-9] Heshmati, F; Zeinali, MB; Noroozinia, H; Abbacivash, R et al. (December 2003). "Use of ketamine in severe status asthmaticus in intensive care unit". Iranian Journal of Allergy, Asthma, and Immunology 2 (4): 175–80. PMID 17301376.

[10] Nickson, Chris (7 August 2013). "Intubation, Hypotension and Shock". Life in the Fastlane (blog). Critical Care Compendium. Retrieved 10 April 2014. ^{[unreliable medical source?]}

[11] Manley, G; Knudson, MM; Morabito, D; Damron, S et al. (2001). "Hypotension, hypoxia, and head injury: Frequency, duration, and consequences". Archives of Surgery 136 (10): 1118–23. doi:10.1001/archsurg.136.10.1118. PMID 11585502.

[12] Hemmingsen, C; Nielsen, JE (1991). "Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia". Acta Anaesthesiologica Scandinavica 35 (8): 755–7. doi:10.1111/j.1399-6576.1991.tb03385.x. PMID 1763596.

[13] Wong, DHW; Jenkins, LC (1975). "The cardiovascular effects of ketamine in hypotensive states". Canadian Anaesthetists' Society Journal 22 (3): 339–48. doi:10.1007/BF03004843. PMID 1139377.

[14] Adams, HA (December 1997). "S-(+)-ketamin kreislaufinteraktionen bei totaler intravenöser anästhesie und analgosedierung" [S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation]. Der Anaesthesist (in German) 46 (12): 1081–7. doi:10.1007/s001010050510. PMID 9451493.

[WongLee2014-15] Wong, JJM; Lee, JH; Turner, DA; Rehder, KJ (2014). "A review of the use of adjunctive therapies in severe acute asthma exacerbation in critically ill children". Expert Review of Respiratory Medicine 8 (4): 423–41. doi:10.1586/17476348.2014.915752. PMID 24993063.

[Goyal-16] Goyal, S; Agrawal, A (May 2013). "Ketamine in status asthmaticus: A review". Indian Journal of Critical Care Medicine 17 (3): 154–61. doi:10.4103/0972-5229.117048. PMC 3777369. PMID 24082612.

[17] Jat, KR; Chawla, D (November 2012). "Ketamine for management of acute exacerbations of asthma in children". Airways Group. Cochrane Database of Systematic Reviews 11 (11): Art. No. CD009293. doi:10.1002/14651858.CD009293.pub2. PMID 23152273.

[18] Bell, RF; Dahl, JB; Moore, RA; Kalso, EA (25 January 2006). "Perioperative ketamine for acute postoperative pain". Pain, Palliative and Supportive Care Group. Cochrane Database of Systematic Reviews (1): CD004603. doi:10.1002/14651858.CD004603.pub2. PMID 16437490.

[elia-19] Elia, N; Tramèr, MR (January 2005). "Ketamine and postoperative pain: A quantitative systematic review of randomised trials". Pain 113 (1): 61–70. doi:10.1016/j.pain.2004.09.036. PMID 15621365.

[20] Saito, O; Aoe, T; Kozikowski, A; Sarva, J et al. (September 2006). "Ketamine and N-acetylaspartylglutamate peptidase inhibitor exert analgesia in bone cancer pain". Canadian Journal of Anesthesia 53 (9): 891–8. doi:10.1007/BF03022832. PMID 16960267.

[21] Bredlau, AL; Thakur, R; Korones, DN; Dworkin, RH (October 2013). "Ketamine for pain in adults and children with cancer: A systematic review and synthesis of the literature". Pain Medicine 14 (10): 1505–17. doi:10.1111/pme.12182. PMID 23915253.

[22] Correll, GE; Maleki, J; Gracely, EJ; Muir, JJ; Harbut, RE (September 2004). "Subanesthetic ketamine infusion therapy: A retrospective analysis of a novel therapeutic approach to complex regional pain syndrome". Pain Medicine 5 (3): 263–75. doi:10.1111/j.1526-4637.2004.04043.x. PMID 15367304.

[OConnellWand2013-23] O'Connell, NE; Wand, BM; McAuley, J; Marston, L et al. (2013). "Interventions for treating pain and disability in adults with complex regional pain syndrome". Pain, Palliative and Supportive Care Group. Cochrane Database of Systematic Reviews 4 (4): Art. No. CD009416. doi:10.1002/14651858.CD009416.pub2. PMID 23633371.

[24] "Severe Pain Relief may be Possible with a Common Anesthetic Drug" (Press release). Blackwell Publishing. 1 October 2004. Archived from the original on 2008-12-16. Retrieved 13 December 2009. ^{[unreliable medical source?]}

[25] *Gary Stix for Scientific American. September 11, 2013 From Club to Clinic: Physicians Push Off-Label Ketamine as Rapid Depression Treatment, Part 1

Gary Stix for Scientific American. September 12, 2013 Is Ketamine Right for You? Off-Label Prescriptions for Depression Pick Up in Small Clinics, Part 2

Gary Stix for Scientific American. September 13, 2013 Ketamine, a Darling of the Club Scene, Inspires Development of Next-Generation Antidepressants, Part 3

[26] Gary Stix for Scientific American. September 12, 2013 Is Ketamine Right for You? Off-Label Prescriptions for Depression Pick Up in Small Clinics, Part 2

[27] Gary Stix for Scientific American. September 13, 2013 Ketamine, a Darling of the Club Scene, Inspires Development of Next-Generation Antidepressants, Part 3

[Caddy2010-26] Caddy C et al. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014 Apr;4(2):75-99. doi: 10.1177/2045125313507739. Review. PMID 24688759 PMC 3952483

[27] Tondo L et al. Options for pharmacological treatment of refractory bipolar depression. Curr Psychiatry Rep. 2014 Feb;16(2):431. doi: 10.1007/s11920-013-0431-y. Review. PMID 24425269

[28] ECRI Institute, under contract to AHRQ. December 2013 AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report. Priority Area 05: Depression and Other Mental Health Disorders

[29] National Institute of Mental Health (7 August 2006). "Experimental Medication Kicks Depression in Hours Instead of Weeks". NIH News (Press release). National Institutes of Health; Dept. of Health and Human Services; United States. "National Institute of Mental Health director Thomas Insel said, "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.""

[30] Naughton, M; Clarke, G; O'Leary, OF; Cryan, JF; Dinan, TG (Mar 2014). "A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action.". Journal of Affective Disorders 156: 24–35. doi:10.1016/j.jad.2013.11.014. PMID 24388038.

[CAMHDYK-31] "Do you know... Ketamine". Knowledge Exchange. Toronto: Centre for Addiction and Mental Health. 2003. Archived from the original on 2014-04-07. Retrieved 27 July 2014.

[32] Giannini, AJ; Loiselle, RH; Giannini, MC; Price, WA (1985). "Phencyclidine and the dissociatives". Psychiatric Medicine 3 (3): 197–217. PMID 2893430.

[Giannini2000-33] Giannini, AJ; Underwood, NA; Condon, M (November 2000). "Acute ketamine intoxication treated by haloperidol: A preliminary study". American Journal of Therapeutics 7 (6): 389–91. doi:10.1097/00045391-200007060-00008. PMID 11304647.

[34] Giannini, AJ (1999). Drug Abuse. Los Angeles: Health Information Press. p. 104. ISBN 1885987110.

[RecreationalLiterature-35] References for recreational use in literature:

Lilly, John Cunningham (1997). The Scientist: A Metaphysical Autobiography. Berkeley, CA: Ronin. pp. 144–. ISBN 0914171720.

Kelly, Kit (2001). The Little Book of Ketamine. Ronin. pp. 23, 40–45, 46–51, ibid. ISBN 9781579511210.

Alltounian, Howard Sunny; Moore, Marcia (1978). Journeys Into the Bright World. Rockport, MA: Para Research. ISBN 9780914918127.

Palmer, Cynthia; Horowitz, Michael (2000). Sisters of the Extreme: Women Writing on the Drug Experience. Inner Traditions. pp. 254–8, ibid. ISBN 9780892817573.

Turner, D.M. (1994). The Essential Psychedelic Guide. San Francisco: Panther Press. ISBN 0964263610.

[38] Lilly, John Cunningham (1997). The Scientist: A Metaphysical Autobiography. Berkeley, CA: Ronin. pp. 144–. ISBN 0914171720.

[39] Kelly, Kit (2001). The Little Book of Ketamine. Ronin. pp. 23, 40–45, 46–51, ibid. ISBN 9781579511210.

[40] Alltounian, Howard Sunny; Moore, Marcia (1978). Journeys Into the Bright World. Rockport, MA: Para Research. ISBN 9780914918127.

[41] Palmer, Cynthia; Horowitz, Michael (2000). Sisters of the Extreme: Women Writing on the Drug Experience. Inner Traditions. pp. 254–8, ibid. ISBN 9780892817573.

[42] Turner, D.M. (1994). The Essential Psychedelic Guide. San Francisco: Panther Press. ISBN 0964263610.

[lankenau-36] Lankenau, SE; Sanders, B; Bloom, JJ; Hathazi, D et al. (March 2007). "First injection of ketamine among young injection drug users (IDUs) in three U.S. cities". Drug and Alcohol Dependence 87 (2–3): 183–93. doi:10.1016/j.drugalcdep.2006.08.015. PMC 1852477. PMID 16979848.

[37] "Ketamine in Palliative Care". Palliative Care Guidelines. Edinburgh: NHS Lothian, NHS Scotland, Health and Social Care Directorates, Scotland. August 2013 [August 2010]. Archived from the original on 2013-10-29.

[MerckManual-38] Merck Manual; Drug Information Provided by Lexi-Comp. Last full review/revision May 2014 Ketamine

[39] Wang, Xin; Ding, Xibing; Tong, Yao; Zong, Jiaying; Zhao, Xiang; Ren, Hao; Li, Quan (24 May 2014). "Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials". Journal of Anesthesia: 7. doi:10.1007/s00540-014-1845-3.

[StrayerNelson2008-40] Strayer, RJ; Nelson, LS (2008). "Adverse events associated with ketamine for procedural sedation in adults". American Journal of Emergency Medicine 26 (9): 985–1028. doi:10.1016/j.ajem.2007.12.005. PMID 19091264.

[Quibell2011-41] ^ ^a ^b ^c ^d ^e ^f Quibell, R; Prommer, EE; Mihalyo, M; Twycross, R et al. (March 2011). "Ketamine*". Journal of Pain and Symptom Management (Therapeutic Review) 41 (3): 640–9. doi:10.1016/j.jpainsymman.2011.01.001. PMID 21419322.

[NeurologicalEffects-42] Neurological effects of ketamine introduction references:

Olney, JW; Labruyere, J; Price, MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263.

Anderson, Cliff (June 2003). "The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid. ^{[unreliable medical source?]}

Tryba, M; Gehling, M (October 2002). "Clonidine - A potent analgesic adjuvant". Current Opinion in Anaesthesiology 15 (5): 511–7. doi:10.1097/00001503-200210000-00007. PMID 17019247.

Dong, C; Anand, KJS (June 2013). "Developmental neurotoxicity of ketamine in pediatric clinical use". Toxicology Letters 220 (1): 53–60. doi:10.1016/j.toxlet.2013.03.030. PMID 23566897.

[50] Olney, JW; Labruyere, J; Price, MT (June 1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263.

[51] Anderson, Cliff (June 2003). "The Bad News Isn't In: A Look at Evidence for Specific Mechanisms of Dissociative-Induced Brain Damage and Cognitive Impairment". Erowid. ^{[unreliable medical source?]}

[52] Tryba, M; Gehling, M (October 2002). "Clonidine - A potent analgesic adjuvant". Current Opinion in Anaesthesiology 15 (5): 511–7. doi:10.1097/00001503-200210000-00007. PMID 17019247.

[53] Dong, C; Anand, KJS (June 2013). "Developmental neurotoxicity of ketamine in pediatric clinical use". Toxicology Letters 220 (1): 53–60. doi:10.1016/j.toxlet.2013.03.030. PMID 23566897.

[Morgan2009-43] Morgan, CJA; Muetzelfeldt, L; Curran, HV (2009). "Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: A 1-year longitudinal study". Addiction 105 (1): 121–33. doi:10.1111/j.1360-0443.2009.02761.x. PMID 19919593.

[44] Vutskits, L; Gascon, E; Potter, G; Tassonyi, E et al. (May 2007). "Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture". Toxicology 234 (3): 216–26. doi:10.1016/j.tox.2007.03.004. PMID 17418473.

[45] Hargreaves, RJ; Hill, RG; Iversen, LL (1994). "Neuroprotective NMDA Antagonists: The Controversy Over Their Potential for Adverse Effects on Cortical Neuronal Morphology". In Ito, U; Baethmann, A et al. Brain Edema IX: Proceedings of the Ninth International Symposium Tokyo, May 16–19, 1993. Acta Neurochirurgica Supplement. Suppl 60. pp. 15–9. ISBN 9783709193365. doi:10.1007/978-3-7091-9334-1_4. PMID: 7976530.

[SunLi2012-46] Sun, L; LI, Q; Li, Q; Zhang, Y et al. (November 2012). "Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys". Addiction Biology: 185–94. doi:10.1111/adb.12004. PMID 23145560.

[47] Slikker, W; Zou, X; Hotchkiss, CE; Divine, RL et al. (2007). "Ketamine-induced neuronal cell death in the perinatal rhesus monkey". Toxicological Sciences 98 (1): 145–58. doi:10.1093/toxsci/kfm084. PMID 17426105.

[48] Patel, P; Sun, L (April 2009). "Update on neonatal anesthetic neurotoxicity: Insight into molecular mechanisms and relevance to humans". Anesthesiology (commentary) 110 (4): 703–8. doi:10.1097/ALN.0b013e31819c42a4. PMC 2737718. PMID 19276968.

[49] Krystal, JH; Karper, LP; Seibyl, JP; Freeman, GK et al. (March 1994). "Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses". Archives of General Psychiatry 51 (3): 199–214. doi:10.1001/archpsyc.1994.03950030035004. PMID 8122957.

[Middela2011-50] Middela, S; Pearce, I (January 2011). "Ketamine-induced vesicopathy: A literature review". International Journal of Clinical Practice 65 (1): 27–30. doi:10.1111/j.1742-1241.2010.02502.x. PMID 21155941.

[morgan11-51] Morgan, CJA; Curran, HV; Independent Scientific Committee on Drugs (ISCD) (January 2012). "Ketamine use: A review". Addiction 107 (1): 27–38. doi:10.1111/j.1360-0443.2011.03576.x. PMID 21777321.

[52] Yeung, LY; Rudd, JA; Lam, WP; Mak, YT et al. (December 2009). "Mice are prone to kidney pathology after prolonged ketamine addiction". Toxicology Letters 191 (2–3): 275–8. doi:10.1016/j.toxlet.2009.09.006. PMID 19766175.

[53] Sear, JW (2011). "Ketamine hepato-toxicity in chronic pain management: Another example of unexpected toxicity or a predicted result from previous clinical and pre-clinical data?". Pain (commentary) 152 (9): 1946–7. doi:10.1016/j.pain.2011.04.031. PMID 21555186.

[propofol-54] Hui, TW; Short, TG; Hong, W; Suen, T et al. (March 1995). "Additive interactions between propofol and ketamine when used for anesthesia induction in female atients". Anesthesiology 82 (3): 641–8. doi:10.1097/00000542-199503000-00005. PMID 7879932.

[midazolam-55] Hong, W; Short, TG; Hui, TW (December 1993). "Hypnotic and anesthetic interactions between ketamine and midazolam in female patients". Anesthesiology 79 (6): 1227–32. doi:10.1097/00000542-199312000-00013. PMID 8267198.

[Akhavanakbari2014-56] Akhavanakbari, G; Mohamadian, A; Entezariasl, M (April 2014). "Evaluation the effects of adding ketamine to morphine in intravenous patient-controlled analgesia after orthopedic surgery". Perspectives in Clinical Research 5 (2): 85–7. doi:10.4103/2229-3485.128028. PMC 3980550. PMID 24741486.

[EkerYalcin2011-57] Eker, HE; Yalcin Cok, O; Aribogan, A; Arslan, G (October 2011). "Children on phenobarbital monotherapy requires more sedatives during MRI". Pediatric Anesthesia 21 (10): 998–1002. doi:10.1111/j.1460-9592.2011.03606.x. PMID 21564387.

[harrison-58] Harrison, NL; Simmonds, MA (February 1985). "Quantitative studies on some antagonists of N-methyl D-aspartate in slices of rat cerebral cortex". British Journal of Pharmacology 84 (2): 381–91. doi:10.1111/j.1476-5381.1985.tb12922.x. PMC 1987274. PMID 2858237.

[ReferenceA-59] Narita, M; Yoshizawa, K; Aoki, K; Takagi, M et al. (September 2001). "A putative sigma1 receptor antagonist NE-100 attenuates the discriminative stimulus effects of ketamine in rats". Addiction Biology 6 (4): 373–6. doi:10.1080/13556210020077091. PMID 11900615.

[pmid19391150-60] Seeman, P; Guan, HC; Hirbec, H (August 2009). "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse 63 (8): 698–704. doi:10.1002/syn.20647. PMID 19391150.

[61] Pharmaceutical Society of Australia; The Royal Australian College of General Practitioners; Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (2011). "2.1.1 IV General Anaesthetics". Australian Medicines Handbook 2011 (12th ed.). Adelaide: Australian Medicines Handbook Pty Ltd. p. 13. ISBN 9780980579048.

[ChenShu2009-62] Chen, X; Shu, S; Bayliss, DA (2009). "HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine". Journal of Neuroscience 29 (3): 600–9. doi:10.1523/JNEUROSCI.3481-08.2009. PMC 2744993. PMID 19158287.

[Orser-63] Orser, BA; Pennefather, PS; MacDonald, JF (1997). "Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors". Anesthesiology 86 (4): 903–17. doi:10.1097/00000542-199704000-00021. PMID 9105235.

[hirota-64] Hirota, K; Lambert, DG (October 1996). "Ketamine: Its mechanism(s) of action and unusual clinical uses". British Journal of Anaesthesia 77 (4): 441–4. doi:10.1093/bja/77.4.441. PMID 8942324.

[pmid24409146-65] Browne, CA; Lucki, I (2013). "Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants". Frontiers in Pharmacology 4: 161. doi:10.3389/fphar.2013.00161. PMC 3873522. PMID 24409146.

[aroni-66] Aroni, F; Iacovidou, N; Dontas, I; Pourzitaki, C et al. (August 2009). "Pharmacological aspects and potential new clinical applications of ketamine: Reevaluation of an old drug". Journal of Clinical Pharmacology 49 (8): 957–64. doi:10.1177/0091270009337941. PMID 19546251.

[rowland-67] Rowland, LM (July 2005). "Subanesthetic ketamine: How it alters physiology and behavior in humans". Aviation, Space, and Environmental Medicine 76 (Suppl 7): C52–8. PMID 16018330.

[meller-68] Meller, ST (December 1996). "Ketamine: Relief from chronic pain through actions at the NMDA receptor?". Pain (correspondence) 68 (2–3): 435–6. doi:10.1016/S0304-3959(96)03167-3. PMID 9121834.

[sinner-69] Sinner, B; Graf, BM (2008). "Ketamine". In Schüttler, J; Schwilden, H. Modern Anesthetics. Handbook of Experimental Pharmacology 182. pp. 313–33. ISBN 9783540728139. doi:10.1007/978-3-540-74806-9_15. PMID: 18175098.

[heng2011-70] Li, JH; Vicknasingam, B; Cheung, YW; Zhou, W et al. (2011). "To use or not to use: An update on licit and illicit ketamine use". Substance Abuse and Rehabilitation 2 (1): 11–20. doi:10.2147/SAR.S15458. PMC 3846302. PMID 24474851.

[haas-71] Haas, DA; Harper, DG (1992). "Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia". Anesthesia Progress 39 (3): 61–8. PMC 2148758. PMID 1308374.

[Kruger1998-72] Krüger, AD (1998). "[Current aspects of using ketamine in childhood]". Anaesthesiologie und Reanimation (in German) 23 (3): 64–71. PMID 9707751.

[Morris-73] Morris, H; Wallach, J (July 2014). "From PCP to MXE: A comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis 6 (7-8): 614–32. doi:10.1002/dta.1620. PMID 24678061.

[domino-74] Domino, EF (September 2010). "Taming the ketamine tiger". Anesthesiology 113 (3): 678–84. doi:10.1097/ALN.0b013e3181ed09a2 (inactive 2014-08-02). PMID 20693870.

[75] Corssen, G; Domino, EF (January–February 1966). "Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581". Anesthesia & Analgesia 45 (1): 29–40. doi:10.1213/00000539-196601000-00007. PMID 5325977.

[CESAR-76] "Ketamine". Center for Substance Abuse Research (CESAR); University of Maryland, College Park. 29 October 2013. Archived from the original on 2013-11-12. Retrieved 27 July 2014.

[HistoryLiterature-77] History of non-medical use in literature references:

Alltounian & Moore 1978

Palmer & Horowitz 2000

Kelly 2001

[89] Alltounian & Moore 1978

[90] Palmer & Horowitz 2000

[91] Kelly 2001

[KetamineRave-78] Increased non-medical use references:

Awuonda, M (13 July 1996). "Swedes alarmed at ketamine misuse". The Lancet 348 (9020): 122. doi:10.1016/S0140-6736(05)64628-4.

Curran, HV; Morgan, C (April 2000). "Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later". Addiction 95 (4): 575–90. doi:10.1046/j.1360-0443.2000.9545759.x. PMID 10829333.

Gahlinger, PM (1 June 2004). "Club drugs: MDMA, gamma-hydroxybutyrate (GHB), Rohypnol, and ketamine". American Family Physician 69 (11): 2619–26. PMID 15202696.

Jansen, KL (6 March 1993). "Non-medical use of ketamine". BMJ 306 (6878): 601–2. doi:10.1136/bmj.306.6878.601. PMC 1676978. PMID 8461808.

Joe-Laider & Hunt 2008

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