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Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex
Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat.
In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days.
Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.
Ketamine and neuroprotection. Clinical outlook.
As the mechanism of action of ketamine, particularly its non-competitive antagonism at the N-methyl-D-aspartate receptor (NMDA), has become better understood, the use of the drug as a neuroprotective agent has received increasing interest. Although the potential prometabolic effects of ketamine might be counterproductive to neuroprotection, the increase in intracranial pressure it has repeatedly been reported to produce does not appear to be relevant clinically under certain conditions, e.g. in patients with normocapnia and a stable blood pressure. Also, the drug has been shown to be anticonvulsant in clinically applied doses rather than epileptogenic, as was previously assumed. These insights have opened up entirely new perspectives for the use of ketamine as a neuroprotective agent. But as both in vitro and in vivo studies are inconclusive, the benefits of the drug are still controversial. In addition, the potential neurotoxicity attributed to extremely high ketamine doses is poorly understood. Consequently, well controlled animal experiments and studies in humans would be necessary to establish the role of ketamine and its more potent enantiomer S-(+)-ketamine in combination with other neuroprotective measures and to shed light on its true neuroprotective potential and its possible neuroregenerative effects.
Patient acceptance of dissociative anesthetics
Plastic Reconstructive Surgery
A prospective study was undertaken to evaluate the efficacy, safety, and patient acceptance of low-dose ketamine when used to diminish the pain of local anesthetic injections. The role of diazepam in preventing the untoward psychological effects of ketamine was also investigated. Our findings, derived from a postoperative questionnaire, reinforce the assertions of others, that ketamine is safe and effectively prevents pain in 85 percent of patients. While 13 percent of our patients hallucinated, most found the experience pleasant, and there were no "bad trips" or emergence reactions. Adequate premedication appears to be important in the successful use of ketamine. Whether sedation is augmented with diazepam or achieved with other medications does not appear to matter. A close supportive relationship with the surgeon and operating room personnel is probably as important as any pharmacologic manipulation in avoiding psychological mishap with low-dose ketamine.
Oral ketamine therapy in the treatment of postamputation stump pain
Acta Anaesthesiol Scand
BACKGROUND: Hyperactivity of N-methyl-D-aspartate (NMDA) receptors may be one of the factors in the maintenance of postamputation stump pain.
CASE REPORT: Ketamine-a clinical available NMDA receptor antagonist-was administered intravenously to a patient with established stump pain in a double-blind saline-controlled fashion. Following infusion stump pain was alleviated for 31 hours. Ketamine reduced the allodynic area and wind-up-like pain and increased pressure-pain thresholds. Treatment was started with ketamine 50 mg x 4 per day dissolved in juice. No side effects or development of tolerance were observed during a 3-month treatment period.
CONCLUSION: NMDA receptor antagonists may have a potential in the treatment of neuropathic pain, including stump pain.
Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery
Anesth Analg 1999 Jul;89(1):98-103
Small-dose ketamine may enhance the analgesic effect of opiates. We studied the effect of IV coadministration of small-dose ketamine 50-100 microg/kg with morphine 50 microg/kg on postoperative morphine requirements and pain in 140 patients undergoing outpatient surgery. Midazolam 1-2 mg was administered in the holding area. Anesthesia was induced with propofol 2-2.5 mg/kg and was maintained with desflurane in a nitrous oxide/oxygen mixture. Patients received morphine 50 microg/kg with placebo (Group 1, n = 35) or ketamine 50 microg/kg IV (Group 2, n = 35), 75 microg/kg IV (Group 3, n = 35), or 100 microg/kg IV (Group 4, n = 35) 15 min before the end of the operation. Pain and drowsiness were assessed using visual analog scales on arrival in the recovery room, then every 15 min until the time of discharge to phase 2 recovery (phase 1 recovery). Morphine consumption in Groups 3 and 4 was approximately 40% less than that in the control group (91+/-9 and 89+/-8 microg/kg vs. 145+/-9 microg/kg; P<0.05 for both). Pain scores in Groups 3 and 4 were approximately 35% less than those in the control group at all time periods (P<0.0001 for all). There was no significant group difference in drowsiness scores. Small-dose ketamine 75-100 microg/kg IV, enhanced morphine-induced analgesia after outpatient surgery. Simultaneous use of small doses of ketamine with morphine enhances the pain relief produced by morphine.
IMPLICATIONS: Simultaneous use of small doses of ketamine with morphine enhances the pain relief produced by morphine.
The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans
Anesthesiology 1999 Jun;90(6):1539-45
BACKGROUND: The (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity and is involved in the occurrence of secondary hyperalgesia. Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating secondary hyperalgesia in humans. Although it is disputed, the actions of ketamine have been ascribed not only to NMDA receptor antagonism, but also to opioid receptor agonism. A study therefore was designed in which the abolishment of a previously demonstrated effect of ketamine on secondary hyperalgesia was sought by pretreatment with naloxone.
METHODS: Twenty-five volunteers were subjected to three treatment regimens. A standardized first-degree burn injury was induced. On appearance of primary and secondary hyperalgesia, one of the following infusion schemes was applied in a randomized, double-blind, cross-over fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of placebo, succeeded by infusion of placebo. Heat-pain detection thresholds, magnitude of secondary hyperalgesia around the burn injury, and side effects were determined.
RESULTS: Ketamine reduced secondary hyperalgesia. Naloxone did not affect the action of ketamine. The magnitudes of side effects were equal if the subjects received ketamine, regardless of preceding infusion of naloxone.
CONCLUSIONS: In this experimental setting, opioid receptor blockade does not inhibit ketamine-induced reductions of secondary hyperalgesia.
Clinical experience with oral ketamine
J Pain Symptom Manage 1999 May;17(5):384-6
Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist used recently for analgesia in patients with chronic pain. Twenty one patients with chronic neuropathic pain were treated with oral ketamine starting at a divided dose of 100 mg/day and titrating upwards by 40 mg/day until efficacy was reached, or until side effects became limiting. A retrospective chart review was conducted to evaluate the analgesic efficacy and side effects of the treatment. Nine patients discontinued ketamine because of intolerable side effects, four patients experienced few or no side effects but had no discernible benefit, four others had equivocal responses. Four patients have continued oral ketamine for long periods. One patient has had no significant benefit or side effects but continues to use ketamine 500 mg/day and three people have used doses ranging from 100-240 mg day for over 1 year duration and have reported improvements in pain and decreased use of analgesics. The analgesic benefits of ketamine appeared to be most pronounced in, but not limited to, patients with pain histories of less than 5 years.
Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain
J Pharmacol Exp Ther 1999 May;289(2):1060-6
We examined the role of N-methyl-D-aspartate (NMDA) receptors in chronic (pathological) pain in humans by using the NMDA receptor antagonist ketamine as a probe. Thirty patients with neuropathic pain in the trigeminal area were given an i.m. injection of ketamine 0.4 mg/kg combined with midazolam 0.05 mg/kg. Pethidine 1.0 mg/kg served as a control. Three different response patterns were observed. Ketamine caused a long-term (6-24 h) analgesic effect partly dissociated from the mental side effects in 8 of the 26 patients who completed the study; these patients also had a slight analgesic effect of pethidine. In nine patients, ketamine caused a short-lasting (<2 h) analgesic effect closely associated with the mental side effects, whereas pethidine caused little or no analgesia. The remaining nine patients did not experience any reduction of pain after either drug in spite of characteristic side effects. One week after the i.m. challenge the patients received either 4.0 mg/kg ketamine hydrochloride or placebo capsules to be taken orally as a nightly dose for three consecutive nights. Five of the eight patients who had a long-term analgesic effect of the i.m. challenge reported decreased pain on days after ketamine. None of the others reported an analgesic effect. The phenomenon of long-term depression of pain in a subgroup of patients was thus confirmed when ketamine was given p.o. These findings indicate that NMDA receptors are involved in the perception and maintenance of pathological pain in some patients. In others, pain appears to be mediated by NMDA receptor-independent mechanisms. We suggest that NMDA receptor-independent transmission in central pain pathways may contribute to the reduced efficiency of analgesic drugs often seen in chronic pain states.
Low-dose ketamine in the management of opioid nonresponsive terminal cancer pain
J Pain Symptom Manage 1999 Apr;17(4):296-300
Two patients with far-advanced cancer, near death, who were experiencing excruciating and intractable pain that was poorly responsive to rapidly escalating doses of morphine and hydromorphone were treated with low-dose intravenous ketamine (0.1-0.2 mg/kg). This intervention eliminated the need for any further opioid use, providing profound analgesia and a sense of calm during the last hours and days of these patients' lives. These case reports add to the small but growing body of clinical literature suggesting that ketamine may have a significant place in the care of patients with pain that is poorly responsive to opioids, or who experience dose-limiting adverse effects, near the end of life. This is an important matter to disseminate in order to reassure the public that we do have the tools necessary to keep the promise that no one need die with uncontrolled pain. This therapeutic approach may also serve to reassure concerned physicians that their efforts to assure pain relief may not be misconstrued as hastening death.
Effect of ketamine on hypoxic-ischemic brain damage in newborn rats
Brain Res 1999 Feb 20;819(1-2):1-7
The present study tests the hypothesis that ketamine, a dissociative anesthetic known to be a non-competitive antagonist of the NMDA receptor, will attenuate hypoxic-ischemic damage in neonatal rat brain. Studies were performed in 7-day-old rat pups which were divided into four groups. Animals of the first group, neither ligated nor exposed to hypoxia, served as controls. The second group was exposed to hypoxic-ischemic conditions and sacrificed immediately afterwards. Animals of the third and fourth groups were treated either with saline or ketamine (20 mg/kg, i.p.) in four doses following hypoxia. Hypoxic-ischemic injury to the left cerebral hemisphere was induced by ligation of the left common carotid artery followed by 1 h of hypoxia with 8% oxygen. Measurements of high energy phosphates (ATP and phosphocreatine) and amino acids (glutamate and glutamine) and neuropathological evaluation of the hippocampal formation were used to assess the effects of hypoxia-ischemia. The combination of common carotid artery ligation and exposure to an hypoxic environment caused major alterations in the ipsilateral hemisphere. In contrast, minor alterations in amino acid concentrations were observed after the end of hypoxia in the contralateral hemisphere. These alterations were restored during the early recovery period. Post-treatment with ketamine was associated with partial restoration of energy stores and amino acid content of the left cerebral hemisphere. Limited attenuation of the damage to the hippocampal formation as demonstrated by a reduction in the number of damaged neurons was also observed. These findings demonstrate that systemically administered ketamine after hypoxia offers partial protection to the newborn rat brain against hypoxic-ischemic injury.
What is the optimal dose of intramuscular ketamine for pediatric sedation?
Acad Emerg Med 1999 Jan;6(1):21-6
OBJECTIVE: The optimal dose of i.m. ketamine for ED procedural sedation in children is not known. The authors wished to quantify the dose-response of ketamine with respect to sedation adequacy, time to discharge, and adverse effects in order to identify an optimal dose.
METHODS: The study was a consecutive case series of 1,022 children < or = 15 years of age given i.m. ketamine in the EDs of a university medical center and an affiliated county hospital over a nine-year period. Adequacy of sedation, time to discharge, and adverse effects were compared with dose administered.
RESULTS: Doses in the sample averaged 3.96+/-0.69 mg/kg, with a range of 0.48 to 9.09 mg/kg. Children judged to be adequately sedated received higher doses compared with those inadequately sedated (3.94+/-0.44 mg/kg vs 3.77+/-0.49 mg/kg, p=0.041), and a nonsignificant trend was noted toward uniformly adequate sedation with increasing dose (< or =91% at <4.00 mg/kg, 93% at 4.00-4.49 mg/kg, and 100% at > or = 4.50 mg/kg). No significant difference or trend in time to discharge or adverse effects was noted between the children receiving <4.00 mg/kg and those receiving > or = 4.00 mg/kg of ketamine, and the study had power (alpha=0.05, beta=0.20) to detect a 9-minute difference in times to discharge, a 3.3% difference in rates of airway complications, a 5.6% difference in rates of emesis, and a 12.3% difference in rates of recovery agitation.
CONCLUSION: Ketamine doses of 4 to 5 mg/kg i.m. produced adequate sedation in 93%-100% of children, suggesting that this dosing range may be optimal for ED procedural sedation. No difference in time to discharge or adverse effects was observed for lower or higher doses.
Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells
Anesthesiology 1999 Jan;90(1):174-82
BACKGROUND: The authors examined the interaction of ketamine with recombinant mu, kappa, and delta opioid receptors and recombinant orphan opioid receptors expressed in Chinese hamster ovary cells (CHO-mu, CHO-kappa, CHO-delta, and CHO(ORL1), respectively).
METHODS: CHO-mu, CHO-kappa, and CHO-delta membranes were incubated with the opioid receptor radioligand [3H]diprenorphine at room temperature. Ketamine (racemic, R(-) and S(+)) was included at concentrations covering the clinical range. CHO(ORL1) membranes were incubated with [125I]Tyr(14)nociceptin and racemic ketamine at room temperature. The effects of racemic ketamine and selective opioid receptor agonists (mu: [D-Ala2, MePhe4, Gly(ol)5] enkephalin (DAMGO); kappa: spiradoline or delta: [D-pen2, D-pen5] enkephalin (DPDPE)) on forskolin-stimulated cyclic adenosine monophosphate formation also were examined. Data are mean +/- SEM.
RESULTS: Racemic ketamine increased the radioligand equilibrium dissociation constant for [3H]diprenorphine from 85+/-5 to 273+/-11, 91+/-6 to 154+/-16, and 372+/-15 to 855+/-42 pM in CHO-mu, CHO-kappa, and CHO-delta, respectively. The concentration of radioligand bound at saturation was unaffected. In CHO-mu and CHO-kappa cells, racemic ketamine did not slow the rate of naloxone-induced [3H]diprenorphine dissociation. Ketamine and its isomers also displaced [3H]diprenorphine binding to mu, kappa, and delta receptors in a dose-dependent manner, with pKi values for racemic ketamine of 4.38+/-0.02, 4.55+/-0.04, and 3.57+/-0.02, respectively. S(+)-ketamine was two to three times more potent than R(-)-ketamine at mu and kappa receptors. Racemic ketamine displaced [125I]Tyr(14)nociceptin with an estimated affinity constant of 0.5 mM. Racemic ketamine inhibited the formation of cyclic adenosine monophosphate (naloxone insensitive) in a dose-dependent manner (concentration producing 50% inhibition approximately 2 mM) in all cell lines, including untransfected CHO cells. Ketamine (100 microM) reversed DAMGO (mu) and spiradoline (kappa) inhibition of formation of cyclic adenosine monophosphate.
CONCLUSIONS: Ketamine interacts stereoselectively with recombinant mu and kappa opioid receptors.
The clinical use of S-(+)-ketamine--a determination of its place
Anasthesiol Intensivmed Notfallmed Schmerzther 1998 Dec;33(12):764-70
The intravenous anaesthetic ketamine is a racemic mixture of two equimolar doses of enantiomers. After stereoselective separation, the right-handed S(+)-isomer is now clinically available. Since anaesthetic and analgesic pharmacological studies have shown that S(+)-ketamine is approximately two times as potent as racemic ketamine, the clinical effects of S(+)-ketamine were evaluated in comparison to ketamine-racemate at dose relation of 1:2 in several therapeutic investigations. The studies disclosed that both drugs caused a similar activation of the endocrine stress response and a comparable stimulation of the sympathoadrenergic system. However, application of S(+)-ketamine was associated with a remarkably smoother emergence period, a profound postoperative analgesia, a more rapid recovery of cerebral functions, and a greater preference by the study persons. The incidence of psychotomimetic phenomena appeared to be negligibly less after S(+)-ketamine in comparison to racemic ketamine, but their quality was described as far less unpleasant. Clinical use of S(+)-ketamine administered at one-half of the usual dose is thus not only associated with a reduction of undesirable adverse effects without altering ketamine's anaesthetic and analgesic potency, but also offers distinctive improvements due to the reduced drug load. Moreover, increasing experimental evidence supports a remarkable neuroprotective effect of S(+)-ketamine, which may become a promising drug for new therapeutic approaches to neuroprotection.
Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions
QJM 1998 Jul;91(7):493-503
We have previously shown that eating disorders are a compulsive behaviour disease, characterized by frequent recall of anorexic thoughts. Evidence suggests that memory is a neocortical neuronal network, excitation of which involves the hippocampus, with recall occurring by re-excitement of the same specific network. Excitement of the hippocampus by glutamate-NMDA receptors, leading to long-term potentiation (LTP), can be blocked by ketamine. Continuous block of LTP prevents new memory formation but does not affect previous memories. Opioid antagonists prevent loss of consciousness with ketamine but do not prevent the block of LTP. We used infusions of 20 mg per hour ketamine for 10 h with 20 mg twice daily nalmefene as opioid antagonist to treat 15 patients with a long history of eating disorder, all of whom were chronic and resistant to several other forms of treatment. Nine (responders) showed prolonged remission when treated with two to nine ketamine infusions at intervals of 5 days to 3 weeks. Clinical response was associated with a significant decrease in Compulsion score: before ketamine, mean +/- SE was 44.0 +/- 2.5; after ketamine, 27.0 +/- 3.5 (t test, p = 0.0016). In six patients (non-responders) the score was: before ketamine, 42.8 +/- 3.7; after ketamine, 44.8 +/- 3.1. There was no significant response to at least five ketamine treatments, perhaps because the compulsive drive was re-established too soon after the infusion, or because the dose of opioid antagonist, nalmefene, was too low.
The dehydrating action of ketamine on malignant breast tumors
Vopr Onkol 1998;44(4):395-7
The study has been concerned with the influence of the anesthetic drug--ketamine--on hydration processes in normal and tumor glandular tissues as well as the binding of labeled ouabain to tissues, to assay the levels of NaK molecules of ATFase on cell membrane. Cell hydration declined during their incubation with Tyrode's solution-based narcotic and subnarcotic doses of ketamine. Also, a sharp drop in the binding ability of 10(-8) M of 3H-ouabain was observed after tumor tissue incubation with ketamine, which served as another indicator of cell shrinkage. It is suggested that tumor cell hydration level is relatively high and subnarcotic doses of ketamine produce a discriminate effect on tumor tissue.
Mechanisms of action of ketamine
Anaesthesiol Reanim 1998;23(3):60-3
Racemic ketamine is a mixture of equal amounts of the two enantiomers (S)-ketamine and (R)-ketamine. The analgesic and anaesthetic potency of (S)-ketamine is about threefold superior to (R)-ketamine. Along with faster elimination, improved control of the anaesthetic state with reduced drug load is achieved. Pharmacokinetic properties of (S)-ketamine are generally comparable with the racemic mixture. The pharmacological profile of ketamine is characterized by the so-called "dissociative anaesthesic state" with profound analgesic and moderate hypnotic properties and by marked sympathomimetic reactions. Important adverse effects are hallucinations and hypersalivation. This pharmacological profile cannot be explained by a single mechanism. Analgesic, anaesthetic and sympathomimetic effects are mediated by different sites of action. N-methyl-D-aspartate (NMDA)-receptor antagonism is the most important neuropharmacological mechanism for the analgesic effects of ketamine. The same mechanism may be involved in the supposed neuroprotective potency of the substance. Effects on opiate receptors may contribute to the analgesic state as well as to dysphoric reactions. Sympathomimetic properties are mediated by enhanced central peripheral monoaminergic transmission. Inhibition of central and peripheral cholinergic transmission may contribute to the induction of anaesthetic state and hallucinations. Effects on neuromuscular transmission are unimportant. Local anaesthetic qualities are obvious as well, but are not responsible for systemic effects. At the different sites of action, qualitatively comparable effects of (S)- and (R)-ketamine were found, but significant quantitative differences are obvious as well.
Ketamine psychedelic therapy (KPT): a review of the results of ten years of research
J Psychoactive Drugs 1997 Apr-Jun;29(2):165-83
Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors' use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors' standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors' studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.