Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.54 no.5 Campinas Sept./Oct. 2004
Ketamine and preemptive analgesia*
Cetamina y analgesia preemptiva
Caio Márcio Barros de Oliveira, M.D.I; Rioko Kimiko Sakata, TSA, M.D.II; Adriana Machado Issy, M.D.II; João Batista Santos Garcia, TSA, M.D.III
Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da UNIFESP
IIProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP EPM
IIIProfessor Adjunto da Disciplina de Anestesiologia da UFMA
BACKAGROUND AND OBJECTIVES:
Since the finding that ketamine blocks NMDA receptors in the neurons of spinal
dorsal horn, it has been used to inhibit or decrease central sensitization triggered
by nociceptive stimulations. This study aimed at presenting pharmacological
aspects of racemic ketamine and its levogyrous compound, as well as its usefulness
for preemptive analgesia.
CONTENTS: Current preemptive analgesia concepts, pharmacological aspects of ketamine and its levogyrous compound, as well as experimental and clinical trials on ketamine and its use in preemptive analgesia are presented.
CONCLUSIONS: The efficacy of ketamine in inhibiting or decreasing central sensitization triggered by nociceptive stimulations is not totally confirmed, probably due to different study and statistical analysis methods.
Key Words: ANALGESIA, Preemptive, ANESTHETICS, Venous: ketamine
JUSTIFICATIVA Y OBJETIVOS:
Desde la descubierta de que la cetamina bloquea los receptores NMDA en los
neuronios del cuerno dorsal de la médula, ella ha sido usada para inhibir
o reducir la sensibilización central provocada por estímulos nociceptivos.
Así, este trabajo tiene por finalidad mostrar aspectos farmacológicos
de la cetamina racemica y de su compuesto levogiro y su empleo en la analgesia
CONTENIDO: Se presentan conceptos actuales sobre analgesia preemptiva, aspectos farmacológicos de la cetamina y su derivado levogiro, bien como estudios experimentales y clínicos sobre la cetamina y su uso en analgesia preemptiva.
CONCLUSIONES: Aun no está totalmente comprobada la eficacia de la cetamina en inhibir o reducir la sensibilización central provocada por estímulos nociceptivos. Probablemente eso se deba al uso de diferentes métodos de estudio y de análisis estadística.
Central sensitization has been studied in several experimental animal models by Woolf 1. Wall 2, pioneer in using the term "preemptive analgesia", has observed decreased central changes when opioids and local anesthetics were administered alone or in association before surgical incision, with decreased postoperative pain.
Studies have shown that general anesthesia promotes decreased peripheral painful impulses transmission to central nervous system, however is unable to totally inhibit them 3. So, nociceptive stimulations promote central sensitization, responsible for increased postoperative pain and analgesic consumption. Postoperative pain depends not only on surgical incision, but also on factors such as: surgery type and length, tissue injury extension and nature, drugs pharmacological activity, and additional intra and postoperative analgesia 4,5.
Preemptive analgesia aims at blocking or decreasing central sensitization and pathological pain, which is different from physiological pain for being excessively severe and induced by non-painful stimulations 6,7.
Kissin 8 has recently reported that, for adequate preemptive analgesia approach, it is critical to evaluate analgesic efficacy of a treatment and its immediate postoperative duration. For this reason, it is possible that several studies have failed in showing a preemptive effect.
Some preemptive analgesia definitions are used by different authors, making difficult the evaluation and comparison of results. Preemptive analgesia is defined in different ways: 1 - that induced before surgical stimulation; 2 - that preventing surgical incision-induced central sensitization; 3 - that preventing the establishment of central sensitization by surgical incision and postoperative inflammatory processes.
The first definition may lead to a false conclusion, because analgesia should be enough to block afferent impulses, and not be simply administered before incision.
The second concept expresses preemptive analgesia in a strict sense, considering only intraoperative nociceptive phenomena. The difference among study groups would be only with regard to agents administration timing (before or after incision). Authors who do not believe in preemptive analgesia effectiveness in general adopt this concept in their studies, which is inadequate because it excludes central neuroplasticity induced by immediate postoperative period inflammatory reaction.
The third definition is more complete and encompasses central sensitization promoted both by surgical injury and inflammatory process, involving intra and immediate postoperative periods. According to surgical nature, there is predominance of surgical stimulation or of inflammatory stimulation on neuroplasticity.
A review of the literature about postoperative analgesia has shown that preventive approach, that is, applied to any surgical procedure moment, is more adequate than preemptive approach for decreasing postoperative pain and analgesic consumption 4. For such, NMDA receptor antagonists have been considered the most effective drugs.
This study aimed at presenting pharmacological aspects of racemic ketamine and its levogyrous compound, in addition to its usefulness for preemptive analgesia.
KETAMINE - PHARMACOLOGICAL ASPECTS
Ketamine, 2-(o-chlorophenyl)-2-(methylamine)-cycloexa- none, was synthesized in 1963 by Stevens, and was used for the first time in humans in 1965, by Corssen and Domino. This liposoluble phencyclidine with molecular weight of 238 daltons and pKa of 7.5 9-13 may be clinically used in the racemic form or as levogyrous isomer S (+) ketamine).
S (+) ketamine is considered 3 to 4 times more potent than the dextrogyrous isomer (R- ketamine) for pain relief and, in equianalgesic doses produces less psychic changes and agitation than racemic and dextrogyrous forms 14-21. S(+) ketamine is twice as potent as the racemic form to prevent spinal cord central sensitization 22.
This agent has 93% bioavailability 23 and 186 minutes plasma half-life 24. For being highly liposoluble, it has a large distribution volume of approximately 3 L.kg-1. Ketamine is metabolized by liver microsomal enzymes through N-demethylation, forming norketamine. This, in turn, is hydroxilated into hydroxynorketamine. These products are conjugated to hydrosoluble glycuronide products excreted by the urine 25,26. Its plasma clearance is also relatively high, varying 890 to 1227 mL.min-1, corresponding to a short excretion half-life of 2 to 3 hours 24,27.
Although being administered through different routes (intravenous, muscular, oral, rectal and nasal), intravenous and muscular routes are most commonly used in the clinical practice because therapeutic plasma concentration is more rapidly reached 28.
After intravenous administration, maximum ketamine effects are observed in 30 to 60 seconds, and distribution half-life is relatively short (11 to 16 minutes).
Ketamine is rapidly absorbed after muscular administration, with absorption half-life of 2 to 17 minutes 24.
Ketamine acts on several receptors, including nicotinic 29, muscarinic 30, µ, d and k opioids 30-32 and changes central and peripheral nervous system sodium channels 29, monoaminergic channels and frequency-dependent calcium channels 33. Ketamine also blocks, in a non-competitive manner, NMDA receptors and the highest its dose, the highest its affinity for such receptors 34-39. S(+) ketamine has higher affinity for NMDA receptors as compared to the racemic form, in addition to being twice as potent in preventing spinal central sensitization 22.
As to cardiovascular system, ketamine increases blood pressure, heart rate and cardiac output. Equipotent S(+) ketamine dose, although lower than the racemic mixture, leads to similar hemodynamic changes 40.
There is minor respiratory system effect, and apnea after anesthetic ketamine doses (intravenous 2 mg.kg-1) is very uncommon 41.
This drug has dissociative effect and patients seem cataleptic, remaining with eyes open and maintaining several reflexes although not safely protective 41.
Ketamine-induced amnesia is less pronounced as compared to benzodiazepines. After its administration, pupils are moderately dilated and there is nystagmus. Tearing and salivation are common.
Ketamine increases brain metabolism and blood flow, as well as intracranial pressure. It produces undesirable psychological effects, especially in the postoperative period, called emergency reactions. Most common are: nightmares, extracorporeal experiences (sensation of leaving the body) and illusions. The incidence of these effects varies 5% to more than 30% after anesthetic induction doses. Age and gender are some of the factors associated to these changes. Individuals with history of psychiatric disease have more frequent episodes. High intravenous ketamine doses (> 2 mg.kg-1), at high infusion rates (> 40 mg.min-1), cause more psychomimetic effects 25.
Ketamine plays an important rote in Anesthesiology for its bronchodilator and sympathomimetic properties. Currently, ketamine-induced psychic effects are still major obstacles for its comprehensive clinical use 42.
This drug may be used in patients with respiratory or cardiovascular system disorders, except for ischemic cardiomyopathy. It may be used in patients with chronic obstructive pulmonary disease and bronchial hyper-reactivity 43. It depresses myocardium when there is catecholamine reserves depletion in hypovolemic patients 44.
Since ketamine preserves heart rate and right atrial pressure through its effects on sympathetic nervous system, it has been used for anesthetic induction in patients with cardiac tamponade, restrictive pericarditis and congenital heart disease with proneness for right to left blood flow bypass 45.
The association of ketamine and diazepam or midazolam is used in continuous infusion to induce anesthesia in patients with valve or ischemic myocardial disease 46.
Psychomimetic reactions in children are less intense and frequent as compared to adults 47 and ketamine has been used for radiotherapy, radiological evaluations, dental treatments 48 and heart catheterization. When there is high pulmonary vascular resistance, ketamine may worsen the situation 49.
Recommended anesthetic induction doses are bolus 0.5 to 2 mg.kg-1, and 30 to 90 µg.kg-1.min-1 for maintenance. Muscular dose is 4 to 6 mg.kg-1.
Oral 3 to 10 mg.kg-1 ketamine induces sedation in 20 to 45 minutes. In comparing three different racemic ketamine doses as single oral agent, 8 mg.kg-1 has been considered the most effective for children, however recovery has been delayed 50. The association of barbiturates or benzodiazepines and antisyalogogues decreases ketamine dose 25. It seems to be no difference between racemic ketamine alone or associated with midazolam in post-anesthetic recovery time of children submitted to general anesthesia with sevoflurane 51.
Rectal S(+) ketamine as preanesthetic medication in children has been less effective and has promoted higher incidence of side effects as compared to midazolam 52.
Ketamine has been associated to regional anesthesia both in adults and children and intravenous 0.5 mg.kg-1 ketamine with 0.15 mg.kg-1 diazepam has not produced so many side effects 53.
KETAMINE AND CENTRAL SENSITIZATION
Although in clinical use for more than 30 years, ketamines property of blocking nociceptive stimulation-induced central sensitization was only discovered in the 90s 54,55.
Initially, it was thought that ketamine analgesic effects were mediated by its interaction with opioid receptors, however, subanesthetic doses 38 and non-reversion of analgesia by naloxone, an opioid antagonist 56, made this hypothesis improbable.
In low doses, ketamine inhibits, in competitive and non-competitive manner, NMDA (N-methyl-D-aspartate) receptors ion channels of the postsynaptic membrane of neurons of spinal dorsal horn. At this site, there are two binding points for ketamine: one within the receptor channel (which will decrease channel opening time) and the other in the receptors hydrophobic portion (which will decrease channel opening frequency) 28,42,57,58.
Ketamine dose is considered low when below 2 mg.kg-1 in muscular bolus, below 1 mg.kg-1 in intravenous or epidural bolus, and < 20 µg.kg-1.min-1 in continuous infusion 22,28,39,59-62.
Repetitive amyelic C fibers activity triggers central sensitization, characterized by increased spontaneous neuronal activation, decreased threshold or increased responsiveness to afferent impulses, prolonged discharges after repeated stimulations and peripheral receptive fields expansion of dorsal horn neurons 63,64.
With afferent impulses in enough frequencies or intensities, there is neuropeptides release (P substance, neurokinin A, somatostatin and peptide genetically related to calcitonin) and of excitatory aminoacids (glutamate and aspartate). These substances generate slow (produced by amyelic C fibers) and fast (produced by A d fibers of low excitability threshold) excitatory pre-synaptic potentials 57.
Rapid excitatory postsynaptic potentials generate short lasting ion currents to inside the cell and are mediated by glutamate action via AMPA receptors (alpha-amino-3-hydroxy-5- methyl-4-isoxasolpropionic), bound to sodium ion channel and metabothropic receptors, bound to membrane G protein and C phospholipase, which are known as non-NMDA receptors (N-methyl-D-aspartate).
Slow excitatory postsynaptic potentials are mostly generated by the action of glutamate on NMDA receptors and substance P and neurokinin A (tachykinins) action on neurokinin-1 (NK1) and neurokinin-2 (NK2) receptors, respectively, which are coupled to G protein and located in spinal dorsal horn 57,65-68.
Since slow potentials duration is long, there is build up during repetitive afferent fibers stimulation, producing prolonged postsynaptic depolarization and leading to progressive increase in discharging frequency. This phenomenon is known as wind up and is associated to NMDA receptors activation. For this activation to occur, there must be glutamate binding to these receptors and tachykinins modulating action, leading to channel unblocking by magnesium shift inside it (frequency-dependent effect) with consequent entrance of calcium in the neuron. With this, NMDA receptor is activated and the result is amplification and prolongation of responses implied in hyperalgesia 57,69,70.
Tachykinins play a major role in potentiating NMDA receptors-mediated changes. Tachykinins binding to receptors promotes diacylglycerol (DAG) increase and inositol 1,4,5-triphosphate (IP3) formation. In the presence of phosphatidylserine and calcium, DAG activates proteinokinase C (PKC) with proteins phosphorilation.
NMDA receptors phosphorilation promotes changes in magnesium ion binding, helping calcium entrance in the cell. There is higher proteinokinase C activation with increased intracellular calcium. IP3 may promote intracellular vesicles calcium release with further PKC activation. This calcium increase inside the cell through a frequency-dependent mechanism is also related to neurokinin receptors 70,71, promotes nitric oxide synthetase (NOS) and protoncogenes transcription (genes regulating DNA transcriptional process). NOS generates nitric oxide (NO) which, acting as a second messenger via cGMP, activates proteinokinases responsible for ion channels phosphorilation and activation. NO spreads in retrograde manner to the presynaptic terminal where it stimulates further glutamate release 71,72.
C-fos and c-jun protoncogenes are expressed in spinal dorsal horn after painful stimulations conducted by A d and C fibers, producing transcription protein (Fos). This acts on pre-prodinorphin and pre-proencephalin genes generating dinorphin and encephalin. Encephalin has antinociceptive effects decreasing neurplasticity and hyperalgesia, while dinorphin promotes direct neuronal excitation (causing hyperalgesia) and antinociception (by a negative feedback mechanism).
Protoncogenes also activate transcription of Messenger RNA controller of protein synthesis, such as glutamate receptors (increasing their density in the membrane and making neuron more sensitive to this neurotransmitter), ion channels (increasing their excitability) and enzymes such as phosphorilases and proteinokinases. These changes are long-lasting and possibly permanent, making such neurons hypersensitive for long periods 70,73.
This way, ketamine may be important in central sensitization modulation. Its administration before painful stimulation would then have a preemptive effect 63,69,73-76.
KETAMINE AND POSTOPERATIVE PAIN
Since the finding that ketamine could decrease central sensitivity through its NMDA receptor antagonist effect, several experimental and clinical studies have been performed with this drug for postoperative pain relief. Most studies are difficult to interpret due to problems with the method or the statistical analysis of data 28. Studies have used different administration routes and low dose ketamine as single agent or associated to other analgesics.
Ketamine has been tested in animals and human volunteers through different methods. Intravenous racemic ketamine decreases formalin-induced central stimulation in cats with spinal cord sectioned at the encephalic trunk, with best results when administered before formalin injection 81. Using visceral stimulation in rats, a study has shown antinociceptive effects of 4 mg.kg-1 epidural or 10 mg.kg-1 intravenous racemic ketamine doses 77. Some authors 78,79 have observed marked decrease in neuropathic pain induced in rats with epidural racemic ketamine. Also in rats, racemic ketamine has decreased peripheral hyperalgesia triggered by thermal stimulation 80.
In volunteers submitted to burns, racemic ketamine decreases central sensitization both by intravenous 82,83 and subcutaneous 84 routes. This effect has not been observed with oral administration 85.
Intravenous ketamine decreases acute pain intensity caused by experimental electric stimulation 86,87. There has been increased pain threshold in volunteers submitted to dental pulp A d nervous fibers stimulation after intravenous ketamine, without analgesic difference between S(+) and R(-) enantiomers 88.
Attenuation of hyperalgesia triggered by carrageenam injection in rear paws of rats has been observed after epidural S(+) ketamine 89. Through the same administration route, S(+) ketamine has promoted analgesic effects in rats submitted to thermal stimulations 90. S(+) ketamine has also potentiated morphine and dexmedetomidine analgesic effects 91, as well as of epidural endomorphine-1 92 in rats submitted to thermal stimulations.
Intravenously, S(+) ketamine has promoted more prolonged secondary hyperalgesia inhibition in volunteers submitted to electric stimulation 93. It has also reversed hyperalgesia after remifentanil infusion withdrawal 94.
Different administration routes have been used for clinical trials with racemic ketamine or its levogyrous component, in low doses, alone or associated to other analgesic drugs.
Oral racemic ketamine analgesic efficacy has been evaluated in children submitted to lip laceration repair 95,96, but there has been inadequate postoperative analgesic effect.
Muscular ketamine doses varying 0.1 mg.kg-1 to 1 mg.kg-1 have been evaluated 98. Ketamine has been used in bolus injection 20,99-101 or according to request of patients submitted to different surgical procedures 98, Studies with ketamine, both as single agent 28,101 or in association with opioids 102, have shown analgesic effects.
Results have indicated that 0.5 to 1 mg.kg-1 bolus racemic ketamine, have been effective and with twice the analgesic potency as compared to meperidine, however less potent than morphine 102. Administered before tonsillectomy in children, ketamine has promoted increased analgesic effect of the association of morphine and paracetamol, with decreased additional analgesic consumption and satisfactory swallowing in the postoperative period 97.
Ketamine associated to opioids provides more prolonged analgesia as compared to the single use of one of the drugs 100. In low doses, ketamine does not promote hemodynamic or respiratory depressing effects, being psychomimetic effects or sedation also uncommon. Low dose subcutaneous ketamine (1.7 µg.kg-1) after abdominal surgery has not triggered side effects and has promoted postoperative analgesia equivalent to 2 mg.h-1 morphine infusion 103. Subcutaneous ketamine, however, may cause significant inflammatory reaction at injection site 104.
Intravenous ketamine has been used in bolus37,105, bolus followed by continuous infusion 39,62,106-108, continuous infusion alone or associated to opioid or benzodiazepine 62,109-112 and in patient-controlled analgesia PCA) 113-117.
Intravenous racemic ketamine analgesic efficacy depends on infusion dose, on initial dose and on the association of opioids. Bolus ketamine doses above 300 µg.kg-1 promote effective and short duration pain relief 37. In doses below 4 µg.kg-1.min-1, there has been no effect on postoperative pain or morphine consumption 37, with anti-hyperalgesic effects with 1 to 6 µg.kg-1.min-1 107,110.
Several studies have shown that low dose ketamine was safe, being potent opioid adjuvant both in pain relief quality and decreased postoperative opioid consumption 39,62,100,113,118-120. After testing different combinations of morphine and racemic ketamine in patient-controlled intravenous analgesia (PCA), a study has observed that 1:1 ratio of this solution promotes the best analgesic effect with less side effects in patients submitted to hip or spinal surgeries 117. However, other studies were unable to show this benefit in other surgical procedures 121-123 with R(-) ketamine 124 or other racemic ketamine doses 112,114.
Potentiation of opioid effects with intravenous racemic ketamine has not been observed in children during appendicectomy 115, similar to other study after tonsillectomy 125, in disagreement with the positive result mentioned 97.
Due to low intravenous ketamine therapeutic index, it is interesting to associate it to other agents for postoperative pain relief, according to some authors 42,126.
Spinally, racemic ketamine may be used alone or associated to local anesthetic or opioids. After injection, ketamine is rapidly absorbed from the epidural space to systemic circulation with 77% ± 22% bioavailability.
Sacral epidural racemic ketamine has promoted adequate postoperative analgesia in children submitted to orchipexy 60 or inguinal herniorrhaphy 127. When administered alone by lumbar epidural route in adults, ketamine has not promoted effective postoperative analgesia 28,128, unless if used in high doses 129. On the other hand, it has promoted better pain relief when epidurally injected in low dose associated to morphine or local anesthetics 130-135. Sandler et al. 136, in editorial, have called the attention for the promising use of epidural racemic ketamine associated to other analgesic agents.
Sub-anesthetic epidural ketamine doses have promoted satisfactory analgesic effects in patients submitted to hip or knee arthroplasty 130,131. This effect has not been observed in a different study 137. Tan et al. 138 have obtained effective postoperative analgesia in patients submitted to lower abdominal surgeries with ketamine associated to morphine in epidural PCA. Results were also favorable in upper abdominal surgeries with the association of epidural ketamine and morphine, with decreased intraoperative opioid consumption 134,139,140. Epidural ketamine administered before incision has promoted satisfactory post-hysterectomy pain control 133.
Racemic ketamine and its levogyrous compound, even without preservatives, may be associated to spinal neurotoxicity and should not be spinally injected, especially in high doses 130,136,141-143, although chlorobutanol (preservative) is considered the major culprit 144,145. There are evidences that spinal ketamine continuous infusion is related to histopathologic findings of spinal cord vacuolization 146,147.
On the other hand, there are studies with sacral epidural racemic ketamine 60 or S(+) ketamine 21,61,148,149 in children, or lumbar epidural in adults 120,130 which have not reported neurotoxicity, being especially recommended preservative-free ketamine 150.
Clinical trials with S(+) ketamine have been recently published. Marhofer et al. 61 have reported that 1 mg.kg-1 sacral epidural levoketamine has promoted intra and postoperative analgesia equivalent to 0.25% bupivacaine with epinephrine in the same volume in children submitted to inguinal herniorrhaphy. Also studying this surgery in children, Koinig et al. 21 have observed that sacral epidural S(+) ketamine has induced more effective intra and postoperative analgesia as compared to muscular ketamine, in spite of lower serum ketamine levels after sacral administration, suggesting local analgesic effect.
Sacral epidural S(+) ketamine prolongs 0.125% bupivacaine analgesia in children submitted to brief surgeries 151. For similar pediatric procedures, S(+) ketamine has induced more prolonged analgesia as compared to the association of clonidine and bupivacaine in sacral epidural anesthesia 152, observing better results with the association of both drugs to local anesthetics 148.
Sub-anesthetic S(+) ketamine doses with epidural ropivacaine before incision have promoted better analgesic effect as compared to local anesthetics alone, in patients submitted to total knee replacement 153.
On the other hand, no long lasting analgesia or opioid effects potentiation has been shown with intravenous levoketamine before induction in patients submitted to anterior cruciate ligament injury repair 22, but these authors have used continuous intraoperative remifentanil, which could have inhibited central neuroplasticity in both studied groups. In addition, remifentanil may promote hyperalgesia and acute tolerance in the immediate postoperative period, thus interfering with S(+) ketamine preemptive effect 154,155.
Due to differences in preemptive analgesia concepts, ketamine doses, administration timing with regard to surgical incision, surgery types and statistical analysis, it is difficult to evaluate and confirm the clinical efficacy of ketamine in decreasing post-surgical stimulation central sensitization. Although S(+) ketamine being more potent than racemic ketamine, there are few studies justifying its superiority in central sensitization blockade. So, further studies are necessary to evaluate the importance of ketamine in preemptive analgesia.
01. Woolf CJ - Evidence for a central component of post-injury pain hypersensitivity. Nature, 1983;306:686-688. [ Links ]
02. Wall PD - The prevention of postoperative pain. Pain, 1988;33:289-290. [ Links ]
03. Katz J - Pre-emptive analgesia: importance of timing. Can J Anaesth, 2001;48:105-114. [ Links ]
04. Katz J, McCartney CJL - Current status of pre-emptive analgesia. Curr Opin Anaesthesiol, 2002;15:435-441. [ Links ]
05. Aida S, Baba H, Yamakura T et al - The effectiveness of preemptive analgesia varies according to the type of surgery: a randomized, double-blind study. Anesth Analg, 1999;89:711-716. [ Links ]
06. McQuay HJ - Preemptive analgesia. Br J Anaesth, 1992;69:1-3. [ Links ]
07. Kissin I - Preemptive analgesia. Anesthesiology, 2000;93: 1138-1143. [ Links ]
08. Kissin I - Study design to demonstrate clinical value of preemptive analgesia: is the commonly used approach valid? Reg Anesth Pain Med, 2002;27:242-244. [ Links ]
09. Stevens CL - Belgium Pat 634,208, Merck Index, 1963;903. [ Links ]
10. Corssen G, Domino EF - Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg, 1966;45: 29-40. [ Links ]
11. Cohen ML, Trevor AJ - On the cerebral accumulation of ketamine and the relationship between metabolism of the drug and its pharmacological effects. J Pharmacol Exp Ther, 1974;189:351-358. [ Links ]
12. Silvay G - Ketamine. Mt Sinai J Med, 1983;50:300-304. [ Links ]
13. Reich DL, Silvay G - Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth, 1989;36:186-197. [ Links ]
14. Marietta MP, Way WL, Castagnole Jr N et al - On the pharmacology of the ketamine enantiomorphs in the rat. J Pharmacol Exp Ther, 1977;202:157-165. [ Links ]
15. Ryder S, Way WL, Trevor AJ - Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol, 1978;49:15-23. [ Links ]
16. White PF, Ham J, Way WL et al - Pharmacology of ketamine isomers in surgical patients. Anesthesiology, 1980;52:231-239. [ Links ]
17. White PF, Schuttler J, Shafer A et al - Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth, 1985;57:197-203. [ Links ]
18. Oye I, Paulsen O, Maurset A - Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther, 1992;260:1209-1213. [ Links ]
19. Schuttler J - S(+)-ketamine. The beginning of a new ketamine era? Anaesthesist, 1992;41:585-587. [ Links ]
20. Mathisen LC, Skjelbred P, Skoglund LA et al - Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain, 1995;61:215-220. [ Links ]
21. Koinig H, Marhofer P, Krenn CG et al - Analgesics effects of caudal and intramuscular S(+)-ketamine in children. Anesthesiology, 2000;93:976-980. [ Links ]
22. Jaksch W, Lang S, Reichhalter R et al - Perioperative small-dose S(+)-ketamine has no incremental beneficial effects on postoperative pain when standard-practice opioid infusions are used. Anesth Analg, 2002;94:981-986. [ Links ]
23. Grant IS, Nimmo WS, Clements JA - Lack of effect of ketamine analgesia on gastric emptying in man. Br J Anaesth, 1981;53:1321-1323. [ Links ]
24. Clements JA, Nimmo WS - Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth, 1981;53:27-30. [ Links ]
25. White PF, Way WL, Trevor AJ - Ketamine - its pharmacology and therapeutic uses. Anesthesiology, 1982;56:119-136. [ Links ]
26. Corssen G, Reves JG, Stanley TH - Dissociative Anesthesia, em: Corssen G - Intravenous Anesthesia and Analgesia. Philadelphia: Lea and Febiger, 1988;99. [ Links ]
27. Idvall J, Ahlgren I, Aronsen KR - Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth, 1979;51:1167-1173. [ Links ]
28. Schmid RL, Sandler AN, Katz J - Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain, 1999;82: 111-125. [ Links ]
29. Scheller M, Bufler J, Hertle I et al - Ketamine blocks currents through mammalian nicotinic acetylcholine receptor channels by interaction with both the open and the closed state. Anesth Analg, 1996;83:830-836. [ Links ]
30. Hustveit O, Maurset A, Oye I - Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol, 1995;77:355-359. [ Links ]
31. Smith DJ, Pekoe GM, Martin LL et al - The interaction of ketamine with the opiate receptor. Life Sci, 1980;26:789-795. [ Links ]
32. Finck AD, Ngai SH - Opiate receptor mediation of ketamine analgesia. Anesthesiology, 1982;56:291-297. [ Links ]
33. Hirota K, Lambert DG - Ketamine: its mechanism(s) of action and unusual clinical uses. Br J Anaesth, 1996;77:441-444. [ Links ]
34. Smith DJ, Azzaro AJ, Saldivar SB - Properties of the optical isomers and metabolites of ketamine on the high affinity transport and catabolism of monoamines. Neuropharmacology, 1981;20:391-396. [ Links ]
35. Pekoe GM, Smith DJ - The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain, 1982;12:57-73. [ Links ]
36. Howe JR, Wang JY, Yaksh TL - Selective antagonism of the antinociceptive effect of intrathecally applied alpha adrenergic agonists by intrathecal prazocin and intrathecal yohimbine. J Pharmacol Exp Ther, 1983;224:552-558. [ Links ]
37. Maurset A, Skoglund LA, Hustveit O et al - Comparison of ketamine and pethidine in experimental and postoperative pain. Pain, 1989;36:37-41. [ Links ]
38. Eide PK, Stubhaug A, Breivik H et al - Ketamine: relief from chronic pain through actions at the NMDA receptor. Pain, 1998;72:289-291. [ Links ]
39. Suzuki M, Tsueda K, Lansing PS et al - Small-dose ketamine enhances Morphine-induced analgesia after outpatient surgery. Anesth Analg, 1999;89:98-103. [ Links ]
40. Doenicke A, Kugler J, Mayer M et al - Ketamine racemate or S(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings. Anaesthesist, 1992;41:610-618. [ Links ]
41. Raeder JC, Stenseth LB - Ketamine: a new look at an old drug. Curr Opin Anaesthesiol, 2000;13:463-468. [ Links ]
42. Fisher K, Coderre TJ, Hagen NA - Targeting the N-methyl-D-aspartate receptor for chronic pain mangement. Preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage, 2000;20:358-373. [ Links ]
43. Corssen G, Reves JG, Carter JR - Neuroleptanesthesia, dissociative anesthesia and hemorrhage. Int Anesthesiol Clin, 1974;12:145-161. [ Links ]
44. Van der Linden P, Gilbart E, Engelman E - Comparison of halothane, isoflurane, alfentanil, and ketamine in experimental septic shock. Anesth Analg, 1990;70:608-617. [ Links ]
45. Kingston HG, Bretherton KW, Holloway AM - A comparison between ketamine and diazepam as induction agents for pericardectomy. Anesth Intensive Care, 1978;6:66-70. [ Links ]
46. Hatano S, Keane DM, Boggs RE et al - Diazepam-ketamine anaesthesia for open heart surgery a "micro-mini" drip administration technique. Can J Anesth, 1976;23:648-656. [ Links ]
47. Sussman DR - A comparative evaluation of ketamine anesthesia in children and adults. Anesthesiology, 1974;40:459-464. [ Links ]
48. Okamoto GU, Duperon DF, Jedrychowski JR - Clinical evaluation of the effects of ketamine sedation on pediatric dental patients. J Clin Pediatr Dent, 1992;16:253-257. [ Links ]
49. Wolfe RR, Loehr JP, Schaffer MS - Hemodynamic effects of ketamine, hypoxia and hyperoxia in children with surgically treated congenital heart disease residing greater than or equal to 1,200 meters above sea level. Am J Cardiol, 1991;67:84-87. [ Links ]
50. Turhanoglu S, Kararmaz A, Özyilmaz MA et al - Effects of different doses of oral ketamine for premedication of children. Eur J Anaesthesiol, 2003;20:56-60. [ Links ]
51. Trabold B, Rzepecki A, Sauer K et al - A comparison of two different doses of ketamine with midazolam and midazolam alone as oral preanaesthetic medication on recovery after sevoflurane anaesthesia in children. Paediatr Anaesth, 2002;12:690-693. [ Links ]
52. Koinig H, Marhofer P - S(+)-ketamine in paediatric anaesthesia. Paediatr Anaesth, 2003;13:185-187. [ Links ]
53. Korttila K, Levanen J - Untoward effects of ketamine combined with diazepam for supplementing conduction anaesthesia in young and middle-aged adults. Acta Anaesthesiol Scand, 1978;22:640-648. [ Links ]
54. Mao J, Price DD, Hayes RL - Differential role of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy. Brain Res, 1992;598:271-278. [ Links ]
55. Qian J, Brown SD, Carlton SM - Systemic ketamine attenuates nociceptive behaviors in a rat model of peripheral neuropathy. Brain Res, 1996;715:51-62. [ Links ]
56. Mikkelsen S, Ilkjaer S, Brennum J - The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans. Anesthesiology, 1999;90:1539-1545. [ Links ]
57. Dickenson AH - Spinal cord pharmacology of pain. Br J Anaesth, 1995;75:193-200. [ Links ]
58. Orser BA, Pennefather PS, MacDonald JF - Multiple mechanisms of ketamine blockade of N-methyl-D-aspartate receptors. Anesthesiology, 1997;86:903-917. [ Links ]
59. Naguib M, Adu-Gyamfi Y, Absood GH et al - Epidural ketamine for postoperative analgesia. Can Anaesth Soc J, 1986;33:16-21. [ Links ]
60. Semple D, Findlow D, Aldridge LM et al - The optimal dose of ketamine for caudal epidural blockade in children. Anaesthesia, 1996;51:1170-1172. [ Links ]
61. Marhofer P, Krenn CG, Plochl W et al - S(+)-ketamine for caudal block in paediatric anaesthesia. Br J Anaesth, 2000;84:341-345. [ Links ]
62. Aida S, Yamakura T, Baba H et al - Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology, 2000;92:1624-1630. [ Links ]
63. Dickenson AH, Sullivan AF - Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology, 1987;26:1235-1238. [ Links ]
64. Cohen RH, Perl ER - Contributions of arachidonic acid derivates and substance P to the sensitization of cutaneos nociceptors. J Neurophysiol, 1990;64:457-464. [ Links ]
65. Woolf CJ - Recent advance in the pathophysiology of acute pain. Br J Anaesth, 1989;63:139-146. [ Links ]
66. Woolf CJ - Somatic pain - pathogenesis and prevention. Br J Anaesth, 1995;75:169-176. [ Links ]
67. Woolf CJ, Chong MS - Preemptive analgesia - treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg, 1993;77:362-379. [ Links ]
68. Gozzani JL - Analgesia Pós-Operatória, em: Manica J - Anestesiologia - Princípios e Técnicas. Porto Alegre: Artes Médicas, 1997;763-769. [ Links ]
69. Woolf CJ, Thompson SW - The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain, 1991;44:293-299. [ Links ]
70. Coderre TJ, Katz J, Vaccarino AL et al - Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain, 1993;52:259-285. [ Links ]
71. Urban L, Thompson SW, Dray A - Modulation of spinal excitability: co-operation between neurokinin and excitatory amino acid neurotransmitters. Trends Neurosci, 1994;17:432-438. [ Links ]
72. Schuman EM, Madison DV - Nitric oxide and synaptic function. Annu Rev Neurosci, 1994;17:153-183. [ Links ]
73. Munglani R, Hunt SP - Molecular biology of pain. Br J Anaesth, 1995;75:186-192. [ Links ]
74. Gogas KR, Presley RW, Levine JD et al - The antinociceptive action of supraspinal opioids results from an increase in descending inhibitory control: correlation of nociceptive behavior and C-fos expression. Neuroscience, 1991;42:617-628. [ Links ]
75. Ren K - Wind-up and the NMDA receptor: from animal studies to humans. Pain, 1994;59:157-158. [ Links ]
76. Yashpal K, Mason P, McKenna JE et al - Comparison of the effect of treatment with intrathecal lidocaine given before and after formalin on both nociception and Fos expression in the spinal cord dorsal horn. Anesthesiology, 1998;88:157-164. [ Links ]
77. Alam S, Saito Y, Kosaka Y - Antinociceptive effects of epidural and intravenous ketamine to somatic and visceral stimuli in rats. Can J Anaesth, 1996;43:408-413. [ Links ]
78. Hartrick CT, Wise JJ, Patterson JS - Preemptive intrathecal ketamine delays mechanical hyperalgesia in the neuropathic rat. Anesth Analg, 1998;86:557-560. [ Links ]
79. Burton AW, Lee DH, Saab C et al - Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Reg Anesth Pain Med, 1999;24:208-213. [ Links ]
80. Oatway M, Reid A, Sawynok J - Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg, 2003;97:168-173. [ Links ]
81. Nagasaka H, Nakamura S, Mizumoto Y et al - Effects of ketamine on formalin-induced activity in the spinal dorsal horn of spinal cord-transected cats: differences in response to intravenous ketamine administered before and after formalin. Acta Anaesthesiol Scand, 2000;44:953-958. [ Links ]
82. Ilkjaer S, Petersen KL, Brennum J et al - Effect of systemic N-methyl-D aspartate receptor antagonist (ketamine) on primary and secundary hyperalgesia in humans. Br J Anaesth, 1996;76:829-834. [ Links ]
83. Warncke T, Stubhaug A, Jorum E - Preinjury treatment with morphine or ketamine inhibits the development of experimentally induced secondary hyperalgesia in man. Pain, 2000;86:293-303. [ Links ]
84. Pedersen JL, Galle TS, Kehlet H - Peripheral analgesic effects of ketamine in acute inflammatory pain. Anesthesiology, 1998;89:58-66. [ Links ]
85. Mikkelsen S, Jorgensen H, Larsen PS et al - Effect of oral ketamine on secondary hyperalgesia, thermal and mechanical pain thresholds, and sedation in humans. Reg Anesth Pain Med, 2000;25:452-458. [ Links ]
86. Smith DC, Mader TJ, Smithline HA - Low dose intravenous ketamine as an analgesic: a pilot study using an experimental model of acute pain. Am J Emerg Med, 2001;19:531-532. [ Links ]
87. Bossard AE, Guirimand F, Fletcher D et al - Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain, 2002;98:47-57. [ Links ]
88. Rabben T - Effects of the NMDA receptor antagonist ketamine in electrically induced Ad-fiber pain. Methods Find Exp Clin Pharmacol, 2000;22:185-189. [ Links ]
89. Klimscha W, Horvath G, Szikszay M et al - Antinociceptive effect of the S(+)-enantiomer of ketamine on carrageenam hyperalgesia after intrathecal administration in rats. Anesth Analg, 1998;86:561-565. [ Links ]
90. Horvath G, Joo G, Klimscha W et al - The interaction of S(+)-ketamine with dexmedetomidine after intrathecal administration in rats. Eur J Anaesthesiol, 2000;17:176-177. [ Links ]
91. Joo G, Horvath G, Klimscha W et al - The effects of ketamine and its enantiomers on the morphine- or dexmedetomidine-induced antinociception after intrathecal administration in rats. Anesthesiology, 2000;93:231-241. [ Links ]
92. Horvath G, Joo G, Dobos I et al - The synergistic antinociceptive interactions of endomorphin-1 with dexmedetomidine and/or S(+)-ketamine in rats. Anesth Analg, 2001;93:1018-1024. [ Links ]
93. Koppert W, Dern S, Sittl R et al - A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine and lidocaine. Anesthesiology, 2001;95:395-402. [ Links ]
94. Koppert W, Sittl R, Scheuber K et al - Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology, 2003;99:152-159. [ Links ]
95. Abrams R, Morrison JE, Villasenor A et al - Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog, 1993;40:63-66. [ Links ]
96. Hollman GA, Perloff WH - Efficacy of oral ketamine for providing sedation and analgesia to children requiring laceration repair. Pediatr Emerg Care, 1995;11:399. [ Links ]
97. Elhakim M, Khalafallah Z, El-Fattah HA et al - Ketamine reduces swallowing-evoked pain after paediatric tonsillectomy. Acta Anaesthesiol Scand, 2003;47:604-609. [ Links ]
98. Dich-Nielsen JO, Svendsen LB, Berthelsen P - Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand, 1992;36:583-587. [ Links ]
99. Sadove MS, Shulman M, Hatano S et al - Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg, 1971;50:452-457. [ Links ]
100. Parkhouse J, Marriott G - Postoperative analgesia with ketamine and pethidine. Anaesthesia, 1977;32:285-289. [ Links ]
101. Marcus RJ, Victoria BA, Rushman SC et al - Comparison of ketamine and morphine for analgesia after tonsillectomy in children. Br J Anaesth, 2000;84:739-742. [ Links ]
102. Hagelin A, Lundberg D - Ketamine for postoperative analgesia after upper abdominal surgery. Clin Ther, 1981;4:229-233. [ Links ]
103. Bhattacharya A, Gurnani A, Sharma PK et al - Subcutaneous infusion of ketamine and morphine for relief of postoperative pain: a double-blind comparative study. Ann Acad Med Singapore, 1994;23:456-459. [ Links ]
104. Eide K, Stubhaug A, Oye I et al - Continuous subcutaneous administration of the N-methyl-D-aspartatic acid (NMDA) receptor antagonist ketamine in the treatment of post-herpetic neuralgia. Pain, 1995;61:221-228. [ Links ]
105. Kee WD, Khaw KS, Ma ML et al - Postoperative analgesic requirement after cesarean section: a comparison of anesthetic induction with ketamine or thiopental. Anesth Analg, 1997;85:1294-1298. [ Links ]
106. Owen H, Reekie RM, Clements JA et al - Analgesia from morphine and ketamine. A comparison of infusions of morphine and ketamine for postoperative analgesia. Anaesthesia, 1987;42:1051-1056. [ Links ]
107. Jahangir SM, Islam F, Aziz L - Ketamine infusion for postoperative analgesia in asthmatics: a comparison with intermittent meperidine. Anesth Analg, 1993;76:45-49. [ Links ]
108. Fu ES, Miguel R, Scharf JE - Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg, 1997;84:1086-1090. [ Links ]
109. Edwards ND, Fletcher A, Cole JR et al - Combined infusions of morphine and ketamine for postoperative pain in elderly patients. Anaesthesia, 1993;48:124-127. [ Links ]
110. Stubhaug A, Breivik H, Eide PK et al - Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand, 1997;41:1124-1132. [ Links ]
111. Wilder-Smith OH, Arendt-Nielsen L, Gaumann D et al - Sensory changes and pain after abdominal hysterectomy: a comparison of anesthetic supplementation with fentanyl versus magnesium or ketamine. Anesth Analg, 1998;86:95-101. [ Links ]
112. Holthusen H, Backhaus P, Boeminghaus F et al - Preemptive analgesia: no relevant advantage of preoperative compared with postoperative intravenous administration of morphine, ketamine and clonidine in patients undergoing transperitoneal tumor nephrectomy. Reg Anesth Pain Med, 2002;27:249-253. [ Links ]
113. Javery KB, Ussery TW, Steger H et al - Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth, 1996;43:212-215. [ Links ]
114. Reeves M, Lindholm DE, Myles PS et al - Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: a double-blinded, randomized controlled trial. Anesth Analg, 2001;93:116-120. [ Links ]
115. Dix P, Martindale S, Stoddart PA - Double-blind randomized placebo-controlled trial of the effect of ketamine on postoperative morphine consumption in children following appendicectomy. Paediatr Anaesth, 2003;13:422-426. [ Links ]
116. Unlugenç H, Ozalevli M, Guler T et al - Postoperative pain management with intravenous patient-controlled morphine: comparison of the effect of adding magnesium or ketamine. Eur J Anaesthesiol, 2003;20:416-421. [ Links ]
117. Sveticic G, Gentilini A, Eichenberger U et al - Combinations of morphine with ketamine for patient-controlled analgesia: a new optimization method. Anesthesiology, 2003;98:1195-1205. [ Links ]
118. Menigaux C, Fletcher D, Dupont X et al - The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg, 2000;90:129-135. [ Links ]
119. Menigaux C, Guignard B, Fletcher D et al - Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg, 2001;93:606-612. [ Links ]
120. De Kock M, Lavandhomme P, Waterloos H - "Balanced analgesia" in the perioperative period: is there a place for ketamine? Pain, 2001;92:373-380. [ Links ]
121. Adam F, Libier M, Oszustowicz T et al - Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg, 1999;89:444-447. [ Links ]
122. Heinke W, Grimm D - Preemptive effects caused by co-analgesia with ketamine in gynecological laparotomies? Anaesthesiol Reanim, 1999;24:60-64. [ Links ]
123. Dahl V, Ernoe PE, Steen T et al - Does ketamine have preemptive effects in women undergoing abdominal hysterectomy procedures? Anesth Analg, 2000;90:1419-1422. [ Links ]
124. Mathisen LC, Aasbo V, Raeder J - Lack of pre-emptive analgesic effect of (R)-ketamine in laparoscopic cholecystectomy. Acta Anaesthesiol Scand, 1999;43:220-224. [ Links ]
125. OFlaherty J, Lin C - Does ketamine or magnesium affect posttonsillectomy pain in children? Paediatr Anaesth, 2003;13:413-421. [ Links ]
126. Sang CN - NMDA-receptor antagonists in neuropathic pain: experimental methods to clinical trials. J Pain Symptom Manage, 2000;19:(Suppl1):S21-S25. [ Links ]
127. Moiniche S, Kehlet H, Dahl JB - A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology, 2002;96:725-741. [ Links ]
128. Peat SJ, Bras P, Hanna MH - A double-blind comparison of epidural ketamine and diamorphine for postoperative analgesia. Anaesthesia, 1989;44:555-558. [ Links ]
129. Gebhardt B - Epidural and intrathecal administration of ketamine - pharmacology and clinical results. Anaesthesist, 1994;43:S34-S40. [ Links ]
130. Wong CS, Liaw WJ, Tung CS et al - Ketamine potentiates analgesic effect of morphine in postoperative epidural pain control. Reg Anesth, 1996;21:534-541. [ Links ]
131. Wong CS, Lu CC, Cherng CH et al - Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement. Can J Anaesth, 1997;44:31-37. [ Links ]
132. Chia YY, Liu K, Liu YC et al - Adding ketamine in a multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg, 1998;86: 1245-1249. [ Links ]
133. Abdel-Ghaffar ME, Abdulatif M, Al-Ghamdi A et al - Epidural ketamine reduces post-operative epidural PCA consumption of fentanyl/bupivacaine. Can J Anaesth, 1998;45:103-109. [ Links ]
134. Wu CT, Yeh CC, Yu JC et al - Pre-incisional epidural ketamine, morphine and bupivacaine combined with epidural and general anaesthesia provides pre-emptive analgesia for upper abdominal surgery. Acta Anaesthesiol Scand, 2000;44:63-68. [ Links ]
135. Taura P, Fuster J, Blasi A et al - Postoperative pain relief after hepatic resection in cirrhotic patients: the efficacy of a single small dose of ketamine plus morphine epidurally. Anesth Analg, 2003;96:475-480. [ Links ]
136. Sandler AN, Schmid R, Katz J - Epidural ketamine for postoperative analgesia. Can J Anaesth, 1998;45:99-102. [ Links ]
137. Weir PS, Fee JPH - Double-blind comparison of extradural block with three bupivacaine-ketamine mixtures in knee arthroplasty. Br J Anaesth, 1998;80:299-301. [ Links ]
138. Tan PH, Kuo MC, Kao PF et al - Patient-controlled epidural analgesia with morphine plus ketamine for post-operative pain relief. Eur J Anaesthesiol, 1999;16:820-825. [ Links ]
139. Subramaniam B, Subramaniam K, Pawar DK et al - Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra and postoperative opioid-sparing effect. Anesth Analg, 2001;93:1321-1326. [ Links ]
140. Subramaniam K, Subramaniam B, Pawar DK et al - Evaluation of the safety and efficacy of epidural ketamine combined with morphine for postoperative analgesia after major upper abdominal surgery. J Clin Anesth, 2001;13:339-344. [ Links ]
141. Rawal N - Spinal antinociception: clinical aspects. Ann Med, 1995;27:263-268. [ Links ]
142. Yaksh TL - Epidural ketamine: a useful, mechanistically novel adjuvant for epidural morphine? Reg Anesth, 1996;21:508-513. [ Links ]
143. Eisenach JC, Yaksh TL - Epidural ketamine in healthy children - whats the point? Anesth Analg, 2003;96:626-627. [ Links ]
144. Malinovsky JM, Lepage JY, Cozian A et al - Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology, 1993;78:109-115. [ Links ]
145. Borgbjerg FM, Svensson BA, Frigast C et al - Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and electron microscopic examination. Anesth Analg, 1994;79:105-111. [ Links ]
146. Karpinski N, Dunn J, Hansen L et al - Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain, 1997;73:103-105. [ Links ]
147. Stotz M, Oehen HP, Gerber H - Histological findings after long-term infusion of intrathecal ketamine for chronic pain: a case report. J Pain Symptom Manage, 1999;18:223-228. [ Links ]
148. Hager H, Marhofer P, Sitzwohl C et al - Caudal clonidine prolongs analgesia from caudal S(+)-ketamine in children. Anesth Analg, 2002;94:1169-1172. [ Links ]
149. Marhofer P, Semsroth M - Epidural ketamine in healthy children - whats the point? Anesth Analg, 2003;96:626-627. [ Links ]
150. Lima J, Beggs S, Howard R - Neural toxicity of ketamine and other NMDA antagonists. Pain, 2000;88:311-312. [ Links ]
151. Weber F, Wulf H - Caudal bupivacaine and S(+)-ketamine for postoperative analgesia in children. Paediatr Anaesth, 2003;13:244-248. [ Links ]
152. De Negri P, Ivani G, Visconti C et al - How to prolong postoperative analgesia after caudal anaesthesia with ropivacaine in children: S-ketamine versus clonidine. Paediatr Anaesth, 2001;11:679-683. [ Links ]
153. Himmelseher S, Ziegler-Pithamitsis D, Argiriadou H et al - Small-dose S(+)-ketamine reduces postoperative pain when applied with ropivacaine in epidural anesthesia for total knee arthroplasty. Anesth Analg, 2001;92:1290-1295. [ Links ]
154. Guignard B, Bossard AE, Coste C et al - Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology, 2000;93:409-417. [ Links ]
155. Luginbuhl M, Gerber A, Schnider T et al - Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg, 2003;96: 726-732. [ Links ]
Dra. Rioko Kimiko Sakata
Rua Três de Maio, 61/51 Vila Clementino
04044-020 São Paulo, Brazil
Submitted for publication October 13, 2003
Accepted for publication February 11, 2004
* Received from Disciplina de Anestesiologia, Dor e Terapia Intensiva de Universidade Federal do Estado de São Paulo, Escola Paulista de Medicina (UNIFESP EPM), São Paulo, SP