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  • Shipped in plain packaging                                                                                                              Ketamine is a dissociative anesthetic developed in 1963 to replace PCP and currently used in human anesthesia and veterinary medicine. Much of the ketamine sold on the street has been diverted from veterinarians’ offices. Ketamine’s chemical structure and mechanism of action are similar to those of PCP.
  •  WIKIPEDIAKetamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.[2] At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity[3] – and to sigma receptors in rats.[4] Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.[5] Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as “dissociative anesthesia[6] and is used as a recreational drug.
    Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.[7] Ketamine is primarily used 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. It has been shown to be effective in treating depression in patients with bipolar disorder who have not responded to anti-depressants.[8] In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.[9] It is also a popular anesthetic in veterinary medicine.
    Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[10]
    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.[11]

    Medicinal use

    One 10ml vial of 1000mg Ketamine

    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 endotracheal intubation);
  • Asthmatics or patients with chronic obstructive airway disease;
  • As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. 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, and mepivicaine and other longer-acting local anaesthetics.
  • In emergency medicine if entrapped patient is suffering severe trauma;[12]
  • Emergency surgery in field conditions in war zones;
  • To supplement spinal / epidural anesthesia / analgesia utilizing low doses;
  • To improve bipolar depression. [13]

In medical settings, ketamine is usually injected intravenously or intramuscularly.[14] Since it suppresses breathing much less than most other available anaesthetics,[15] ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine 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. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression suppression, and for the treatment of alcoholism[16] and heroin addiction.[17]

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. 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. 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.[18] It may also be used as an intravenous co-analgesic together 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 counter-acting 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 co-analgesic, and 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 is, however, particularly useful for pain caused by cancer.[20]

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.[21] 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 sub-anesthetic 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.[19]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.[22] 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.[23]

In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.[24]

Pain Management
The dissociative anesthetic effects of ketamine have also been applied within the realm of 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 when pain is controlled.
• Starting dose: 5-10mg four times daily.
• Increase dose in 5-10mg increments.
• Usual dose range: 10mg-60mg four times daily.
Subcutaneous ketamine infusion
• Starting dose: 50-150mg/24 hours.
• Review daily; increase dose in 50-100mg increments.
• Usual dose range: 50mg- 600mg/24 hours
Converting from a 24 hour SC ketamine infusion to oral ketamine
• Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine.
• Titrate dose in 5-10mg increments.
• Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.[26]

Adverse effects

Short term

Up to 40% of patients may experience adverse effects with continuous subcutaneous infusion (adverse effects are less common upon oral administration). These include:[27]

Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.[27]

Long term

Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in ketamine abusers.[28]

Neurological effects

Main article: Olney’s lesions

Chronic use of ketamine may lead to cognitive impairments including memory problems.[29] In 1989, psychiatry professor John Olney reported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.[30][31][32]

The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.[33]

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 that 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 morphology and thus might lead to dysfunctions of neural networks.[34][35]

There is a long list of medicines that could counteract these potential toxic effects[dubiousdiscuss], including clonidine, anticholinergics, benzodiazepines, barbiturates and risperidone, which are also highly addictive.[31][32][36]

Urinary tract effects

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[37] 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][37] The pathogenesis of papillary necrosis has been investigated in mice, and it has been suggested that mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence is a possible mechanism.[38]

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.[37] 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.[37] Both hyaluronic acid instillation and combined pentosan polysulphate 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 polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[37]

Case reports of hepato-toxicity 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 that liver enzymes have to be monitored during such treatment.[39]

Drug interactions

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.

Mechanism of action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the PCP site within the NMDA channel to inhibit calcium influx. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[40] NMDAR antagonism effects 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.[41] Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.[42]

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 noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.[27][43]

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[41]

  • 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 effects bronchodilation.

Pharmacokinetics

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubility.[44] When administered orally, Ketamine undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) iso-enzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[45] 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.[46] 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.[44][47] 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][45] Peak plasma concentrations are reached within 1 minute intravenously, 5–15 minutes intramuscularly, and 30 minutes orally.[47] Ketamine’s duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4–6 hours 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.[48][49] 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 further heating the reaction product in decalin, a ring expansion rearrangement occurs, causing formation of ketamine.

Ketamine synthesis.svg

History

Medical use

Ketamine was developed in 1965 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.[50] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.[50] These investigations demonstrated that ketamine’s shorter duration of action and lesser psychomimetic profile made it favorable over PCP as a “dissociative” anesthetic.[51] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.

Nonmedical use

Nonmedical use of ketamine was documented in the early 1970s in underground literature (see 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.[52] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[53][54][55][56][57] 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;[57] in addition, reports of ketamine being sold as “ecstasy” are common.[58] The use of ketamine as part of a “post-clubbing experience” has also been documented.[59] Ketamine’s rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[57]

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.[60] In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[46][61] In Canada ketamine is classified as a Schedule I narcotic, as of August 2005.[62] In Hong Kong, as of the year 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.[63] 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.[46]

International brand names

Brand names for ketamine vary internationally:[64]

  • 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, UY, YE, ZA)
  • Ketalin (MX)
  • Ketamax (PH)
  • Ketamin-S (+) (PY)
  • Ketanest (NL, HR, PL, DE)
  • 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)

Recreational use

Ketamine poured onto glass and left to dry.

Ketamine sold illicitly comes either from diverted legitimate supplies and semi-legitimate 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 sixty minutes when insufflated or injected and up to two hours when ingested, the total experience lasting no more than a couple of hours.[65] 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.[66] At sufficiently high doses, users may experience what is called the “K-hole“, a state of dissociation whose effects are thought to mimic the phenomenology of schizophrenia.[67] John C. Lilly,[68] Marcia Moore[69] and D. M. Turner[70] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. (Both Moore[71] and Turner[72] died prematurely in a way that has been linked to their ketamine use.)

Research

Antidepressant use

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was pain management. It was not possible to quantify to what degree depression recovery was secondary to the patient’s recovery from CRPS.

One trial administered a short-term ketamine regimen to patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients’ normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients demonstrated significant, long-term improvement.[73] Another small study found that ketamine significantly improved treatment-resistant major depression within hours of injection.[74] The improvement lasted up to one week after the single dose.[75] These patients were previously treatment resistant, having tried an average of six other treatments that failed. 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.”

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist.[76] Those findings of Zarate et al. corroborate earlier findings by Berman et al..[77] However Zarate et al. do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

These findings are corroborated by Liebrenz et al., who successfully, according to an attending doctor, treated a patient with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al. who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.[78][79]

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.[80]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[81] 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 it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[82] 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.

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 be necessary to produce a rapid onset of antidepressant action in rats.[83]

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.[84][85] 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.

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 out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out 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. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.[86][87]

Krupitsky and Kolp summarized their work to date in 2007.[88]

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 subanesthetic ketamine infusion of 0.5 mg/kg·h. 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. There were no differences in effects on outcome after 4 months.[17]

 

Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.[2] At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity[3] – and to sigma receptors in rats.[4] Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.[5] Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as “dissociative anesthesia[6] and is used as a recreational drug.

Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.[7] Ketamine is primarily used 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. It has been shown to be effective in treating depression in patients with bipolar disorder who have not responded to anti-depressants.[8] In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.[9] It is also a popular anesthetic in veterinary medicine.

Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[10]

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.[11]

Medicinal use

One 10ml vial of 1000mg Ketamine

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 endotracheal intubation);
  • Asthmatics or patients with chronic obstructive airway disease;
  • As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. 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, and mepivicaine and other longer-acting local anaesthetics.
  • In emergency medicine if entrapped patient is suffering severe trauma;[12]
  • Emergency surgery in field conditions in war zones;
  • To supplement spinal / epidural anesthesia / analgesia utilizing low doses;
  • To improve bipolar depression. [13]

In medical settings, ketamine is usually injected intravenously or intramuscularly.[14] Since it suppresses breathing much less than most other available anaesthetics,[15] ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine 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. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression suppression, and for the treatment of alcoholism[16] and heroin addiction.[17]

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. 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. 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.[18] It may also be used as an intravenous co-analgesic together 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 counter-acting 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 co-analgesic, and 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 is, however, particularly useful for pain caused by cancer.[20]

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.[21] 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 sub-anesthetic 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.[19]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.[22] 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.[23]

In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.[24]

Pain Management
The dissociative anesthetic effects of ketamine have also been applied within the realm of 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 when pain is controlled.
• Starting dose: 5-10mg four times daily.
• Increase dose in 5-10mg increments.
• Usual dose range: 10mg-60mg four times daily.
Subcutaneous ketamine infusion
• Starting dose: 50-150mg/24 hours.
• Review daily; increase dose in 50-100mg increments.
• Usual dose range: 50mg- 600mg/24 hours
Converting from a 24 hour SC ketamine infusion to oral ketamine
• Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine.
• Titrate dose in 5-10mg increments.
• Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.[26]

Adverse effects

Short term

Up to 40% of patients may experience adverse effects with continuous subcutaneous infusion (adverse effects are less common upon oral administration). These include:[27]

Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.[27]

Long term

Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in ketamine abusers.[28]

Neurological effects

Main article: Olney’s lesions

Chronic use of ketamine may lead to cognitive impairments including memory problems.[29] In 1989, psychiatry professor John Olney reported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.[30][31][32]

The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.[33]

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 that 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 morphology and thus might lead to dysfunctions of neural networks.[34][35]

There is a long list of medicines that could counteract these potential toxic effects[dubiousdiscuss], including clonidine, anticholinergics, benzodiazepines, barbiturates and risperidone, which are also highly addictive.[31][32][36]

Urinary tract effects

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[37] 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][37] The pathogenesis of papillary necrosis has been investigated in mice, and it has been suggested that mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence is a possible mechanism.[38]

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.[37] 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.[37] Both hyaluronic acid instillation and combined pentosan polysulphate 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 polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[37]

Case reports of hepato-toxicity 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 that liver enzymes have to be monitored during such treatment.[39]

Drug interactions

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.

Mechanism of action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the PCP site within the NMDA channel to inhibit calcium influx. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[40] NMDAR antagonism effects 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.[41] Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.[42]

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 noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.[27][43]

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[41]

  • 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 effects bronchodilation.

Pharmacokinetics

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubility.[44] When administered orally, Ketamine undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) iso-enzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[45] 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.[46] 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.[44][47] 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][45] Peak plasma concentrations are reached within 1 minute intravenously, 5–15 minutes intramuscularly, and 30 minutes orally.[47] Ketamine’s duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4–6 hours 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.[48][49] 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 further heating the reaction product in decalin, a ring expansion rearrangement occurs, causing formation of ketamine.

Ketamine synthesis.svg

History

Medical use

Ketamine was developed in 1965 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.[50] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.[50] These investigations demonstrated that ketamine’s shorter duration of action and lesser psychomimetic profile made it favorable over PCP as a “dissociative” anesthetic.[51] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.

Nonmedical use

Nonmedical use of ketamine was documented in the early 1970s in underground literature (see 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.[52] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[53][54][55][56][57] 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;[57] in addition, reports of ketamine being sold as “ecstasy” are common.[58] The use of ketamine as part of a “post-clubbing experience” has also been documented.[59] Ketamine’s rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[57]

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.[60] In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[46][61] In Canada ketamine is classified as a Schedule I narcotic, as of August 2005.[62] In Hong Kong, as of the year 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.[63] 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.[46]

International brand names

Brand names for ketamine vary internationally:[64]

  • 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, UY, YE, ZA)
  • Ketalin (MX)
  • Ketamax (PH)
  • Ketamin-S (+) (PY)
  • Ketanest (NL, HR, PL, DE)
  • 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)

Recreational use

Ketamine poured onto glass and left to dry.

Ketamine sold illicitly comes either from diverted legitimate supplies and semi-legitimate 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 sixty minutes when insufflated or injected and up to two hours when ingested, the total experience lasting no more than a couple of hours.[65] 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.[66] At sufficiently high doses, users may experience what is called the “K-hole“, a state of dissociation whose effects are thought to mimic the phenomenology of schizophrenia.[67] John C. Lilly,[68] Marcia Moore[69] and D. M. Turner[70] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. (Both Moore[71] and Turner[72] died prematurely in a way that has been linked to their ketamine use.)

Research

Antidepressant use

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was pain management. It was not possible to quantify to what degree depression recovery was secondary to the patient’s recovery from CRPS.

One trial administered a short-term ketamine regimen to patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients’ normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients demonstrated significant, long-term improvement.[73] Another small study found that ketamine significantly improved treatment-resistant major depression within hours of injection.[74] The improvement lasted up to one week after the single dose.[75] These patients were previously treatment resistant, having tried an average of six other treatments that failed. 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.”

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist.[76] Those findings of Zarate et al. corroborate earlier findings by Berman et al..[77] However Zarate et al. do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

These findings are corroborated by Liebrenz et al., who successfully, according to an attending doctor, treated a patient with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al. who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.[78][79]

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.[80]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[81] 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 it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[82] 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.

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 be necessary to produce a rapid onset of antidepressant action in rats.[83]

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.[84][85] 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.

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 out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out 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. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.[86][87]

Krupitsky and Kolp summarized their work to date in 2007.[88]

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 subanesthetic ketamine infusion of 0.5 mg/kg·h. 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. There were no differences in effects on outcome after 4 months.[17]

 

 

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  • Shipped in plain packaging                                                                                                              Ketamine is a dissociative anesthetic developed in 1963 to replace PCP and currently used in human anesthesia and veterinary medicine. Much of the ketamine sold on the street has been diverted from veterinarians’ offices. Ketamine’s chemical structure and mechanism of action are similar to those of PCP.
  •  WIKIPEDIAKetamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.[2] At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity[3] – and to sigma receptors in rats.[4] Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.[5] Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as “dissociative anesthesia[6] and is used as a recreational drug.
    Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.[7] Ketamine is primarily used 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. It has been shown to be effective in treating depression in patients with bipolar disorder who have not responded to anti-depressants.[8] In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.[9] It is also a popular anesthetic in veterinary medicine.
    Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[10]
    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.[11]

    Medicinal use

    One 10ml vial of 1000mg Ketamine

    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 endotracheal intubation);
  • Asthmatics or patients with chronic obstructive airway disease;
  • As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. 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, and mepivicaine and other longer-acting local anaesthetics.
  • In emergency medicine if entrapped patient is suffering severe trauma;[12]
  • Emergency surgery in field conditions in war zones;
  • To supplement spinal / epidural anesthesia / analgesia utilizing low doses;
  • To improve bipolar depression. [13]

In medical settings, ketamine is usually injected intravenously or intramuscularly.[14] Since it suppresses breathing much less than most other available anaesthetics,[15] ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine 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. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression suppression, and for the treatment of alcoholism[16] and heroin addiction.[17]

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. 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. 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.[18] It may also be used as an intravenous co-analgesic together 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 counter-acting 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 co-analgesic, and 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 is, however, particularly useful for pain caused by cancer.[20]

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.[21] 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 sub-anesthetic 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.[19]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.[22] 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.[23]

In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.[24]

Pain Management
The dissociative anesthetic effects of ketamine have also been applied within the realm of 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 when pain is controlled.
• Starting dose: 5-10mg four times daily.
• Increase dose in 5-10mg increments.
• Usual dose range: 10mg-60mg four times daily.
Subcutaneous ketamine infusion
• Starting dose: 50-150mg/24 hours.
• Review daily; increase dose in 50-100mg increments.
• Usual dose range: 50mg- 600mg/24 hours
Converting from a 24 hour SC ketamine infusion to oral ketamine
• Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine.
• Titrate dose in 5-10mg increments.
• Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.[26]

Adverse effects

Short term

Up to 40% of patients may experience adverse effects with continuous subcutaneous infusion (adverse effects are less common upon oral administration). These include:[27]

Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.[27]

Long term

Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in ketamine abusers.[28]

Neurological effects

Main article: Olney’s lesions

Chronic use of ketamine may lead to cognitive impairments including memory problems.[29] In 1989, psychiatry professor John Olney reported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.[30][31][32]

The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.[33]

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 that 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 morphology and thus might lead to dysfunctions of neural networks.[34][35]

There is a long list of medicines that could counteract these potential toxic effects[dubiousdiscuss], including clonidine, anticholinergics, benzodiazepines, barbiturates and risperidone, which are also highly addictive.[31][32][36]

Urinary tract effects

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[37] 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][37] The pathogenesis of papillary necrosis has been investigated in mice, and it has been suggested that mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence is a possible mechanism.[38]

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.[37] 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.[37] Both hyaluronic acid instillation and combined pentosan polysulphate 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 polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[37]

Case reports of hepato-toxicity 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 that liver enzymes have to be monitored during such treatment.[39]

Drug interactions

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.

Mechanism of action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the PCP site within the NMDA channel to inhibit calcium influx. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[40] NMDAR antagonism effects 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.[41] Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.[42]

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 noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.[27][43]

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[41]

  • 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 effects bronchodilation.

Pharmacokinetics

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubility.[44] When administered orally, Ketamine undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) iso-enzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[45] 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.[46] 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.[44][47] 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][45] Peak plasma concentrations are reached within 1 minute intravenously, 5–15 minutes intramuscularly, and 30 minutes orally.[47] Ketamine’s duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4–6 hours 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.[48][49] 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 further heating the reaction product in decalin, a ring expansion rearrangement occurs, causing formation of ketamine.

Ketamine synthesis.svg

History

Medical use

Ketamine was developed in 1965 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.[50] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.[50] These investigations demonstrated that ketamine’s shorter duration of action and lesser psychomimetic profile made it favorable over PCP as a “dissociative” anesthetic.[51] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.

Nonmedical use

Nonmedical use of ketamine was documented in the early 1970s in underground literature (see 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.[52] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[53][54][55][56][57] 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;[57] in addition, reports of ketamine being sold as “ecstasy” are common.[58] The use of ketamine as part of a “post-clubbing experience” has also been documented.[59] Ketamine’s rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[57]

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.[60] In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[46][61] In Canada ketamine is classified as a Schedule I narcotic, as of August 2005.[62] In Hong Kong, as of the year 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.[63] 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.[46]

International brand names

Brand names for ketamine vary internationally:[64]

  • 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, UY, YE, ZA)
  • Ketalin (MX)
  • Ketamax (PH)
  • Ketamin-S (+) (PY)
  • Ketanest (NL, HR, PL, DE)
  • 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)

Recreational use

Ketamine poured onto glass and left to dry.

Ketamine sold illicitly comes either from diverted legitimate supplies and semi-legitimate 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 sixty minutes when insufflated or injected and up to two hours when ingested, the total experience lasting no more than a couple of hours.[65] 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.[66] At sufficiently high doses, users may experience what is called the “K-hole“, a state of dissociation whose effects are thought to mimic the phenomenology of schizophrenia.[67] John C. Lilly,[68] Marcia Moore[69] and D. M. Turner[70] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. (Both Moore[71] and Turner[72] died prematurely in a way that has been linked to their ketamine use.)

Research

Antidepressant use

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was pain management. It was not possible to quantify to what degree depression recovery was secondary to the patient’s recovery from CRPS.

One trial administered a short-term ketamine regimen to patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients’ normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients demonstrated significant, long-term improvement.[73] Another small study found that ketamine significantly improved treatment-resistant major depression within hours of injection.[74] The improvement lasted up to one week after the single dose.[75] These patients were previously treatment resistant, having tried an average of six other treatments that failed. 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.”

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist.[76] Those findings of Zarate et al. corroborate earlier findings by Berman et al..[77] However Zarate et al. do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

These findings are corroborated by Liebrenz et al., who successfully, according to an attending doctor, treated a patient with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al. who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.[78][79]

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.[80]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[81] 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 it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[82] 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.

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 be necessary to produce a rapid onset of antidepressant action in rats.[83]

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.[84][85] 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.

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 out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out 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. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.[86][87]

Krupitsky and Kolp summarized their work to date in 2007.[88]

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 subanesthetic ketamine infusion of 0.5 mg/kg·h. 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. There were no differences in effects on outcome after 4 months.[17]

 

Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.[2] At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity[3] – and to sigma receptors in rats.[4] Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.[5] Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as “dissociative anesthesia[6] and is used as a recreational drug.

Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.[7] Ketamine is primarily used 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. It has been shown to be effective in treating depression in patients with bipolar disorder who have not responded to anti-depressants.[8] In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.[9] It is also a popular anesthetic in veterinary medicine.

Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.[10]

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.[11]

Medicinal use

One 10ml vial of 1000mg Ketamine

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 endotracheal intubation);
  • Asthmatics or patients with chronic obstructive airway disease;
  • As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. 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, and mepivicaine and other longer-acting local anaesthetics.
  • In emergency medicine if entrapped patient is suffering severe trauma;[12]
  • Emergency surgery in field conditions in war zones;
  • To supplement spinal / epidural anesthesia / analgesia utilizing low doses;
  • To improve bipolar depression. [13]

In medical settings, ketamine is usually injected intravenously or intramuscularly.[14] Since it suppresses breathing much less than most other available anaesthetics,[15] ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine 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. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression suppression, and for the treatment of alcoholism[16] and heroin addiction.[17]

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. 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. 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.[18] It may also be used as an intravenous co-analgesic together 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 counter-acting 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 co-analgesic, and 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 is, however, particularly useful for pain caused by cancer.[20]

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.[21] 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 sub-anesthetic 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.[19]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.[22] 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.[23]

In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.[24]

Pain Management
The dissociative anesthetic effects of ketamine have also been applied within the realm of 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 when pain is controlled.
• Starting dose: 5-10mg four times daily.
• Increase dose in 5-10mg increments.
• Usual dose range: 10mg-60mg four times daily.
Subcutaneous ketamine infusion
• Starting dose: 50-150mg/24 hours.
• Review daily; increase dose in 50-100mg increments.
• Usual dose range: 50mg- 600mg/24 hours
Converting from a 24 hour SC ketamine infusion to oral ketamine
• Oral ketamine is more potent than SC ketamine (due to liver metabolism). Many patients require a dose reduction of 25-50% when changing to oral ketamine.
• Titrate dose in 5-10mg increments.
• Some specialists stop the SC infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.[26]

Adverse effects

Short term

Up to 40% of patients may experience adverse effects with continuous subcutaneous infusion (adverse effects are less common upon oral administration). These include:[27]

Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.[27]

Long term

Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in ketamine abusers.[28]

Neurological effects

Main article: Olney’s lesions

Chronic use of ketamine may lead to cognitive impairments including memory problems.[29] In 1989, psychiatry professor John Olney reported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.[30][31][32]

The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.[33]

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 that 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 morphology and thus might lead to dysfunctions of neural networks.[34][35]

There is a long list of medicines that could counteract these potential toxic effects[dubiousdiscuss], including clonidine, anticholinergics, benzodiazepines, barbiturates and risperidone, which are also highly addictive.[31][32][36]

Urinary tract effects

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[37] 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][37] The pathogenesis of papillary necrosis has been investigated in mice, and it has been suggested that mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence is a possible mechanism.[38]

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.[37] 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.[37] Both hyaluronic acid instillation and combined pentosan polysulphate 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 polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[37]

Case reports of hepato-toxicity 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 that liver enzymes have to be monitored during such treatment.[39]

Drug interactions

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.

Mechanism of action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the PCP site within the NMDA channel to inhibit calcium influx. The S(+) and R(-) stereoisomers bind with different affinities: Ki = 3200 and 1100 nM, respectively.[40] NMDAR antagonism effects 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.[41] Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.[42]

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 noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.[27][43]

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:[41]

  • 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 effects bronchodilation.

Pharmacokinetics

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubility.[44] When administered orally, Ketamine undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) iso-enzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[45] 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.[46] 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.[44][47] 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][45] Peak plasma concentrations are reached within 1 minute intravenously, 5–15 minutes intramuscularly, and 30 minutes orally.[47] Ketamine’s duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4–6 hours 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.[48][49] 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 further heating the reaction product in decalin, a ring expansion rearrangement occurs, causing formation of ketamine.

Ketamine synthesis.svg

History

Medical use

Ketamine was developed in 1965 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.[50] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.[50] These investigations demonstrated that ketamine’s shorter duration of action and lesser psychomimetic profile made it favorable over PCP as a “dissociative” anesthetic.[51] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.

Nonmedical use

Nonmedical use of ketamine was documented in the early 1970s in underground literature (see 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.[52] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[53][54][55][56][57] 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;[57] in addition, reports of ketamine being sold as “ecstasy” are common.[58] The use of ketamine as part of a “post-clubbing experience” has also been documented.[59] Ketamine’s rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[57]

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.[60] In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[46][61] In Canada ketamine is classified as a Schedule I narcotic, as of August 2005.[62] In Hong Kong, as of the year 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.[63] 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.[46]

International brand names

Brand names for ketamine vary internationally:[64]

  • 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, UY, YE, ZA)
  • Ketalin (MX)
  • Ketamax (PH)
  • Ketamin-S (+) (PY)
  • Ketanest (NL, HR, PL, DE)
  • 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)

Recreational use

Ketamine poured onto glass and left to dry.

Ketamine sold illicitly comes either from diverted legitimate supplies and semi-legitimate 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 sixty minutes when insufflated or injected and up to two hours when ingested, the total experience lasting no more than a couple of hours.[65] 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.[66] At sufficiently high doses, users may experience what is called the “K-hole“, a state of dissociation whose effects are thought to mimic the phenomenology of schizophrenia.[67] John C. Lilly,[68] Marcia Moore[69] and D. M. Turner[70] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. (Both Moore[71] and Turner[72] died prematurely in a way that has been linked to their ketamine use.)

Research

Antidepressant use

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was pain management. It was not possible to quantify to what degree depression recovery was secondary to the patient’s recovery from CRPS.

One trial administered a short-term ketamine regimen to patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients’ normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients demonstrated significant, long-term improvement.[73] Another small study found that ketamine significantly improved treatment-resistant major depression within hours of injection.[74] The improvement lasted up to one week after the single dose.[75] These patients were previously treatment resistant, having tried an average of six other treatments that failed. 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.”

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist.[76] Those findings of Zarate et al. corroborate earlier findings by Berman et al..[77] However Zarate et al. do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

These findings are corroborated by Liebrenz et al., who successfully, according to an attending doctor, treated a patient with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al. who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.[78][79]

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.[80]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.[81] 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 it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.[82] 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.

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 be necessary to produce a rapid onset of antidepressant action in rats.[83]

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.[84][85] 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.

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 out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out 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. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.[86][87]

Krupitsky and Kolp summarized their work to date in 2007.[88]

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 subanesthetic ketamine infusion of 0.5 mg/kg·h. 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. There were no differences in effects on outcome after 4 months.[17]

 

 

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