Ketamine (Drugs / Substance Abuse)

substance_abuse_300x300Ketamine is a drug used in human and veterinary medicine, primarily for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation. Like other drugs of its class, such as tiletamine and phencyclidine (PCP), ketamine induces a state referred to as “dissociative anesthesia” and is used as a recreational drug.Ketamine is effective in treating depression in patients with depression and bipolar disorder who have not responded to antidepressants. It produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to μ-opioid receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity – and to sigma receptors in rats.Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.

Medicinal Use

Indications for use as an anaesthetic:

      Pediatric anesthesia (as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and 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.[citation needed] Other ingredients found useful by pain specialists and their patients, as well as the compounding pharmacists who make the topical mixtures, include amitriptyline, cyclobenzaprine, clonidine, tramadol, gabapentin, baclofen, and mepivacaine and other longer-acting local anaesthetics (e.g. tetracaine, procaine).
  • Emergency surgery in field conditions in war zones;
  • To supplement spinal/epidural anesthesia/analgesia using low doses;

In medical settings, ketamine is usually injected intravenously or intramuscularly.Since it suppresses breathing much less than most other available anaesthetics, ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because it tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient’s fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. Research is ongoing in France, the Netherlands, Russia, Australia and the US into the drug’s usefulness in pain therapy, depression, and for the treatment of alcoholism and heroin addiction.

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. It may also be used as an intravenous coanalgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines.Ketamine is a coanalgesic, so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects. The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.

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. It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is also a potent analgesic and can be used in subanesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, “going into other worlds” or “seeing God” while anesthetized, and these unwanted psychological side effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS).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.

In some neurological intensive care units, ketamine has been used in cases of prolonged seizures. Some evidence indicates the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.

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.

Pain Management
The dissociative anesthetic effects of ketamine have also been applied for postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption, as well as reports of nausea following abdominal surgery.

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: 5-10 mg four times daily Increase dose in 5-10 mg increments
  • Usual dose range: 10-60 mg four times daily

Side Effects

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 recreational ketamine users and in animal models.

Neurological Effects
Chronic use of ketamine may lead to cognitive impairments, including memory problems. In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes in two small areas of the rat brain, which, however, has significant differences in metabolism from the human brain, so may not occur in humans.

The first large-scale, longitudinal study of ketamine users found that frequent ketamine users (at least 4 days/week, averaging 20 days/month) had increased depression and impaired memory by several measures, including verbal, short-term memory and visual memory. However, infrequent (1–4 days/month, averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.
Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and non-cell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal morphology and thus might lead to dysfunctions of neural networks.

More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time.Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month.

Urinary Tract Effects
According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.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. The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.

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.Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.

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. Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.

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

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

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. In Canada, ketamine is classified as a Schedule I narcotic, as of August 2005. In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician’s prescription. 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.

Recreational Use

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Ketamine sold illicitly comes either from diverted legitimate supplies and semilegitimate suppliers, or from theft of legitimate suppliers. It produces effects similar to phencyclidine (PCP) and dextromethorphan (DXM).

Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting, its hallucinatory effects lasting 60 minutes when insufflated or injected and up to two hours when ingested orally, the total experience lasting no more than a few hours. 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. At sufficiently high doses, users may experience what is called the “K-hole”, a state of extreme dissociation with visual and auditory hallucinations. John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. Both Moore and Turner died prematurely in a way that has been indirectly linked to the sedative properties of ketamine.