Low S(+) ketamine doses: a review

Abstracts

JUSTIFICATIVA E OBJETIVOS: A utilização, em baixas doses, de cetamina e de seus isômeros apresenta perspectivas promissoras em anestesia e na analgesia pós-operatória. O objetivo desse trabalho foi revisar as propriedades do uso de baixas doses de cetamina que justifiquem seu uso em anestesia e em analgesia pós-operatória. CONTEÚDO: Vários artigos da literatura sugerem que a cetamina apresenta propriedades de analgesia preemptiva e preventiva em relação à dor pós-operatória, diminuindo o consumo de opióides e melhorando a satisfação dos pacientes. Os fenômenos de tolerância e de hiperalgesia induzidos pela utilização de opióides podem ser atenuados pelo uso da cetamina em baixas doses. Ela diminui o consumo de anestésicos inalatórios e possivelmente apresenta propriedades que podem ser interessantes na proteção da célula nervosa isquêmica. Efeitos promissores, como a neuroproteção e a melhora de resultados, em longo prazo, necessitam de mais estudos. CONCLUSÕES: Em baixas doses a S(+) cetamina apresenta, na maioria dos estudos, efeito preventivo, diminuindo a sensibilização do SNC, a tolerância e a hiperalgesia induzida por opióides, o consumo de anestésicos, o uso de analgésicos e a incidência de efeitos adversos pós-operatórios.

ANESTÉSICOS; COMPLICAÇÕES; DOR

REVIEW ARTICLE

Low S(+) ketamine doses: a review^*

S(+) cetamina en bajas dosis: actualización

Ana Luft, M.D.^I; Florentino Fernandes Mendes, TSA, M.D.^II

^IAnestesiologista

^IIMestre em Farmacologia pela FFFCMPA, Doutor em Medicina pela FMSCSP

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Low doses of ketamine or isomers are promising possibilities for anesthesia and postoperative analgesia. This study aimed at reviewing major properties of low ketamine doses, which may justify their use in anesthesia and postoperative analgesia.

CONTENTS: Literature suggests that ketamine induces preemptive and preventive postoperative pain relief, decreasing opioid consumption and improving patients' satisfaction. Opioid-induced tolerance and hyperalgesia may be minimized with low ketamine doses. Ketamine decreases inhalational anesthetic consumption and may protect ischemic nervous cells. Promising effects, such as neuroprotection and improvement of long-term outcomes, require further studies.

CONCLUSIONS: Most studies with low S(+) ketamine doses have shown preventive effects, decreasing central nervous system sensitization, opioid-induced tolerance and hyperalgesia, anesthetic and analgesic consumption, and the incidence of postoperative adverse effects.

Key Words: ANESTHETICS: ketamine; COMPLICATIONS, Postoperative; PAIN, Treatment

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La utilización, en bajas dosis, de cetamina y de sus isómeros presenta perspectivas promisorias en anestesia y en la analgesia pos-operatoria. El objetivo de ese trabajo es revisar las propiedades del uso de bajas dosis de cetamina que justifiquen su uso en anestesia y en analgesia pos-operatoria.

CONTENIDO: Varios artículos de la literatura sugieren que la cetamina presenta propiedades de analgesia preemptiva y preventiva con relación al dolor pos-operatorio, disminuyendo el consumo de opioides y mejorando la satisfacción de los pacientes. Los fenómenos de tolerancia y de hiperalgesia inducidos por la utilización de opioides pueden ser atenuados por el uso de la cetamina en bajas dosis. Ella diminuye el consumo de anestésicos inhalatorios y posiblemente presenta propiedades que pueden ser interesantes en la protección de la célula nerviosa isquémica. Efectos promisorios, como la neuroprotección y la mejora de resultados a largo plazo, necesitan más estudios.

CONCLUSIONES: En bajas dosis la S(+) cetamina presenta, en la mayoría de los estudios, efecto preventivo, disminuyendo la sensibilización del SNC, la tolerancia y a hiperalgesia inducida por opioides, el consumo de anestésicos, el uso de analgésicos y la incidencia de efectos adversos pos-operatorios.

INTRODUCTION

Ketamine was introduced approximately 30 years ago to be a single anesthetic agent able to promote analgesia, amnesia, unconsciousness and immobility ¹, but due to its major side effects it was not widely accepted. Recent studies on mechanisms of action, neuronal and analgesic effects have motivated its revaluation to broaden its application. In addition, the introduction of S(+) ketamine isomer, which could promote less adverse effects as compared to the racemic mixture ^2-4, has once more aroused the interest for this drug.

CLINICAL PHARMACOLOGY

Ketamine is available as racemic mixture associated to benzethonium chloride or chlorbutanol, or as S(+) ketamine ^4,5. Major pharmacokinetic properties are short distribution and excretion half-lives - alpha excretion phase takes 5 to 10 minutes and beta excretion half-life is 2 to 3 hours ⁶. Ketamine is metabolized in the liver by the P450 cytochrome system and its major metabolite, norketamine ⁷, has one third to one fifth of original drug potency ^5,6, being related to prolonged analgesic effects ⁶. Drug is excreted by kidneys ¹.

Classic analgesic effects are better described as resulting from dose-dependent central nervous system (CNS) depression determining the so-called dissociative effect characterized by deep analgesia and amnesia, but not necessarily by unconsciousness ^4-6,8. Although patients are not asleep, there is indifference with the environment. Suggested mechanisms for this catalepsy include electrophysiological inhibition of thalamic pathways and limbic system stimulation ^6,8.

Ketamine respiratory effects are in general beneficial. It is bronchodilator ⁹, promotes minor respiratory depression ¹⁰ and airway protecting reflexes are partially preserved ¹¹. Ketamine increases blood pressure and heart rate ². There are reports on increased pulmonary artery pressure, especially in patients with previous heart disease ^1,8 and care is suggested when giving ketamine to patients with coronary disease or right heart failure ^4,12.

Ketamine interacts with multiple binding areas, including NMDA and non-NMDA glutamate receptors; nicotinic, cholinergic muscarinic, monoaminergic and opioids receptors.

NMDA RECEPTOR

This is an inotropic receptor activated by glutamate, the most abundant CNS excitatory neurotransmitter ¹³. The channel is patent to calcium and, in a lesser degree, to sodium and potassium. Simultaneous binding of glutamate with glycine, a co-agonist, is mandatory to activate the receptor. Magnesium blocks in a current-dependent manner the channel at rest, and opening is only seen after simultaneous depolarization and agonist binding ¹³. NMDA receptors are post-synaptic areas of ketamine action to decrease CNS stimulation ¹⁴. Ketamine binds to phencyclidine receptor ⁴ in the NMDA channel and inhibits channel activation by glutamate in a non-competitive manner. S(+) enantiomer has three to four times more affinity for the receptor as compared to R(-), reflecting the observed differences in analgesic and anesthetic potency ¹⁵. There are evidences suggesting the importance of NMDA receptor in inducing and maintaining central sensitization during painful situations ^13,16,17.

NON-NMDA GLUTAMATE RECEPTOR

These are selectively activated by quisqualate, AMPA or cainate. These receptors are probably inhibited by ketamine through the glutamate/NO/GMPc system ¹⁸.

OPIOID RECEPTOR

Ketamine has agonist action on opioid receptors coupled to G protein, with mild analgesic effects. Ketamine psychomimetic effects may be explained by the interaction with kappa opioid receptor since kappa agonists produce similar effects. S(+) ketamine has two to four times more strongly bound to kappa receptors as compared to R(-) ketamine. Ketamine affinity for this receptor is 10 to 20 times lower than for NMDA receptors, suggesting that this interaction is of minor importance. This is confirmed by the fact that naloxone does not revert ketamine analgesic effects ^7,19.

CHOLINERGIC AND ADRENERGIC RECEPTORS

Acetylcholine nicotinic and muscarinic receptors are affected by ketamine. In clinical concentrations, ketamine inhibits acetylcholine release mediated by NMDA receptor. Post-synaptic inhibition of nicotinic receptors has no clinical significance. Muscarinic receptors are also inhibited and S(+) ketamine has twice more affinity for muscarinic receptors as compared to R(-) ¹⁹. Ketamine affinity for this receptor is 10 to 20 times lower as compared to NMDA receptors ²⁰. Behavioral adverse effects may be related to cholinergic transmission inhibition ^5,7. R(-) ketamine inhibits neuronal norepinephrine uptake and S(+) ketamine additionally inhibits extra neuronal uptake producing prolonged synaptic response and increased norepinephrine transfer to circulation ²¹. Dopamine and 5-HT uptake is inhibited, which could lead to increased central dopaminergic activity ¹.

S(+) KETAMINE

In 1992, the Food and Drugs Administration has warned that the separation of stereoisomers was not receiving adequate attention for the commercial development of drugs. Notwithstanding technical difficulties and high costs, the focus on this horizon could open new therapeutic possibilities. Animal studies have shown that S(+) ketamine has approximately four times more affinity for phencyclidine binding area in the NMDA receptor as compared to R(-) ketamine ^2,6. Increased affinity for the receptor, combined with similar pharmacokinets, suggests that S(+) ketamine could be a clinically interesting drug ^1,3. In rats and mice, S(+) ketamine has 1.5 to 3 times higher hypnotic potency and 3 times higher analgesic potency as compared to R(-), being twice more potent than the racemic mixture ²².

Due to its higher potency, approximately half S(+) ketamine dose should be enough to induce anesthesia and would positively affect recovery. This has been confirmed by several studies comparing S(+) to the racemic mixture ^23-25.

After anesthetic induction with ketamine, classic adverse effects (amnesia, recent memory changes, decreased concentration, decreased alertness, cognition changes, hallucinations, nightmares, nausea and vomiting) were observed with similar incidence to S(+) ketamine or its racemic mixture ²⁶. The incidence of such effects is clearly related to ketamine plasma concentration and psychedelic effects are less likely, although still possible, with lower drug concentrations ⁵. In fact, in a crossover clinical, randomized and double-blind study with healthy volunteers and low equianalgesic ketamine and its isomers doses, there has been less adverse effects with S(+) ketamine as compared to R(-) and racemic forms ². Convincing evidences of low incidence of adverse events during anesthesia with S(+) ketamine are still to be documented ¹.

NEUROPROTECTION

S(+) ketamine decreases ischemic brain injury severity by different mechanisms. First, S(+) ketamine decreases necrotic cell death by preventing cytotoxic injury ²⁷. Ischemic neurons release glutamate in the intracellular space leading to overactivation of NMDA receptors. The resulting increase in intracellular calcium levels promotes cell death ²⁸. In the ischemic brain, the hypothesis of glutamate-calcium overload is recognized as major cell injury mechanism ²⁹. Second, ketamine may influence apoptosis and, as a consequence, may decrease brain ischemia intensity leading to decreased cell death. Engelhard et al. ³⁰ have studied in rats the association of ketamine and dexmedetomidine and have shown influence in the expression of apoptosis-regulating proteins after ischemia/reperfusion, which could involve an anti-apoptosis mechanism, in addition to decreasing cell death. Third, ketamine suppresses pro-inflammatory cytokines production, which may determine less cell death ³¹. Although a promising field, the role of ketamine in protecting against cell injury still requires further studies ³².

PREEMPTIVE ANALGESIA

It is known that nociceptive afference triggered by surgery and tissue inflammation may develop peripheral sensitization and primary hyperalgesia, increasing medullary response to stimulations, noxious or not, due to the wind-up phenomenon and other mechanisms, with central sensitization induction and long-term potentiation. Blocking these mechanisms before they are developed may prevent central sensitization ^33,34.

There are evidences that NMDA receptors are involved in the development of central sensitization, in the wind-up phenomenon and in long-term potentiation, and that the association of low ketamine and morphine doses almost abolishes hyperalgesia in spinal cord dorsal horn, which is not observed with ketamine or morphine alone ³⁴. Long-term potentiation may develop cell memory for pain and increase the response to noxious stimulations ³³.

The principle of preemptive analgesia is to administer antinociceptive treatment before surgical trauma. Peripheral ketamine administration increases anesthetic and analgesic actions of bupivacaine used in infiltrative anesthesia ¹³ and inhibits the development of primary and secondary hyperalgesia after experimental thermal injury model ³⁵.

Low ketamine doses were defined as intravenous doses below 1 mg.kg^-1 and continuous infusion up to 20 µg.kg^-1.min^-136. Studies have shown preemptive effects of low ketamine doses, measured by decreased postoperative opioid consumption ^16,17. When pre-incision administration was compared to administration at the end of surgery, the former has provided better analgesia as compared to the latter ^16,17. Low ketamine doses (10 mg) have resulted in 40% decrease in morphine consumption during the first 5 post-cholecystec- tomy hours ⁷.

Hyperalgesia is a central sensitization indicator and decreased hyperalgesic area could be a sign that ketamine sensitization was prevented. In a meta analysis with 37 selected clinical trials, 20 of them have shown improved analgesia by adding ketamine to opioids. The others have found no benefit whatsoever. Although there is a decrease in the hyperalgesic area, this is not associated to improved outcomes. No correlation has been found between ketamine administration time and analgesic effects. So, in authors' opinion, there is the need to select the type of surgery, the severity of postoperative pain and ketamine administration method to determine its real value for postoperative analgesia ³⁸.

Low epidural ketamine doses before incision promote more pronounced analgesic effects as compared to intravenous administration and placebo. These findings may be related to pharmacokinetic changes of epidural administration ³³ and to ketamine local anesthetic effect ³⁹. In cirrhosis patients, epidural ketamine increases the analgesic effect of epidural morphine and decreases the need for additional analgesia ⁴⁰. In a randomized double-blind study, systemic administration of low ketamine doses associated to patient-controlled epidural analgesia with the association of morphine and bupivacaine, has decreased pain, analgesic request and the incidence of adverse events associated to epidural morphine, such as nausea and pruritus ⁴¹. In spinal anesthesia, the association of ketamine and bupivacaine had negative results in terms of analgesia and adverse effects ⁴².

PREVENTIVE ANALGESIA

The old belief that surgical incision triggers central sensitization has been expanded to include preoperative and other intra and postoperative noxious stimulation effects, suggesting that previous definition of preemptive analgesia is too restrictive ⁴³. So, the term preventive analgesia was coined to emphasize the fact that central sensitization is induced by pre and postoperative noxious stimulations, and has been used to describe decreased pain, analgesic consumption or both during intervention duration. The aim of preventive analgesia is to decrease central sensitization throughout the perioperative period, thus with higher clinical relevance as compared to preemptive analgesia. In a systematic review considering five half-lives of the drug, there has been positive ketamine preventive effect in 58% of the 24 studies included ⁴³.

In a randomized, double-blind study, low doses (100 µg.kg^-1) in bolus and continuous infusion of 2 µg.kg^-1 during radical prostatectomies have decreased morphine consumption in 43% and pain severity at rest in the first 48 postoperative hours, as compared to the control group who have not received ketamine ⁴⁴. A different randomized double-blind clinical trial has shown that patients receiving repeated S(+) ketamine injections (pre-incision and intraoperatively) presented lower pain scores, lower analgesic consumption and improved mood as compared to patients receiving pre-incision injection only or placebo ⁴⁵. The effect of low ketamine doses on mood has been investigated in a randomized double blind clinical trial in patients with preoperative diagnosis of major depression and under anti-depressant drugs. There has been improved mood and analgesia ⁴⁶.

OPIOID-INDUCED TOLERANCE AND HYPERALGESIA

In rats, tolerance induced by opioid infusion may be minimized by ketamine in doses with no direct anti-nociceptive effects ⁴⁷.

For low ketamine doses associated to opioids to be effective as co-analgesic, two recently development concepts are significant ⁴⁴. First it has been shown that opioids activate a pro-nociceptive system in addition to an anti-nociceptive system and may induce acute tolerance and hyperalgia ^47-49. This phenomenon depends on NMDA receptors. The use of µ-opioid agonists, by activating C proteinokinase, promote sustained increase in receptor activation currents and decrease current-dependent blockade induced by ion magnesium ⁵⁰.

Second, it is known that central sensitization is not only induced by incision, but also by postoperative inflammatory process ⁵¹. This determines that efforts to prevent central sensitization should continue in the postoperative period, not being limited solely to the surgical procedure ⁴⁴. A randomized double blind clinical trial has shown that combined morphine and low ketamine doses have relieved pain which was only attenuated by a three times higher morphine dose.

The incidence of nausea and vomiting and the administration of metoclopramide in the PACU were significantly higher in the group receiving higher morphine doses ⁵². In a drug-dependent patient, ketamine has decreased the need for opioids to relief postoperative pain ⁵³, showing potential for use in patients with chronic tolerance.

An experimental study has shown that both S(+) ketamine and ion magnesium has increased inhalational anesthetic inhibitory action on NMDA receptors. The association of S(+) ketamine and ion magnesium has additive effect ⁵⁴, which may explain lower inhalational anesthetic consumption with S(+) ketamine ³. Conversely, by maintaining constant inhalational anesthetic consumption, low ketamine doses have decreased the need for remifentanil supplementation and postoperative morphine without increasing the incidence of adverse events ⁴⁹.

PATIENTS' SATISFACTION / ADVERSE EFFECTS

Pain is a predictive factor for nausea and vomiting ⁵⁵. In addition to the best possible pain control, the postoperative period must be followed by minimal incidence of nausea and vomiting ⁵⁶. Results of Macario et al. ⁵⁷ and Eberhart et al. ⁵⁸ have confirmed that these are major patients' concerns. An observation study has revealed low incidence of nausea and vomiting with ketamine in cosmetic plastic surgeries ⁵⁶. Evidences have shown that low ketamine doses are associated to lower incidence of adverse effects and to major acceptance by patients ⁵², and that analgesic regimens with less adverse effects as compared to opioids should be considered ⁵⁹. Perioperative multimodal analgesia with analgesic regimens without opioids, helps outpatient procedures recovery and improves patients' satisfaction ⁶⁰.

KETAMINE AND PATIENT-CONTROLLED ANALGESIA

A study designed to determine the best morphine and ketamine combination for PCA analgesia has found 1:1 ratio with lockout interval of eight minutes ⁶¹. In physiological pH, morphine and ketamine solution maintains stability in room temperature for four days ⁶². This is still a controversial subject since studies have shown negative results of the association of morphine and ketamine for PCA in hysterectomies ⁶³, arthroscopies ⁶⁴, appendicectomies ⁶⁵, mastectomies ⁶⁶ and in volunteers ⁶⁷.

Low S(+) ketamine doses have decreased CNS sensitization, opioid-induced tolerance and hyperalgesia, anesthetic and analgesic consumption, and the incidence of postoperative adverse effects, thus contributing to improve patients' satisfaction.

REFERENCES

Submitted for publication October 4, 2004

Accepted for públication March 22, 2005

• 01. Kohrs R, Durieux ME - Ketamine: teaching an old drug new tricks. Anesth Analg, 1998;87:1186-1193.
• 02. Pfenninger EG, Durieux ME, Himmelseher S - Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology, 2002;96:357-366.
• 03. Lauretti GR, Lima ICPR, Buscatti RY et al - Avaliação clínica dos efeitos hemodinâmicos, analgésicos, psicodélicos e de bloqueio neuromuscular da cetamina racêmica e de seu S(+) isômero. Rev Bras Anestesiol, 2000;50:357-362.
• 04. Evers AS, Crowder CM - General Anesthesia, em: Hardman JC, Limbird LE, Gilman AG - The Pharmacological Basis of Therapeutics, 10th Ed, McGraw-Hill, 2001;337-365.
• 05. Duval Neto GF - Anestésicos Venosos, em: Manica J - Anestesiologia Princípios e Técnicas, 3ª Ed, Porto Alegre, Artmed, 2004;560-597.
• 06. Hemelrijck JV, White P - Nonopioid Intravenous Anesthesia, em: Barash PG, Cullen BF, Stoelting RK - Clinical Anesthesia, 3^rd Ed, Lippimcott-Raven, 1997;311-327.
• 07. Raeder JC, Stenseth LB - Ketamine: a new look at an old drug. Curr Opin Anaesthesiol, 2000;13:463-468.
• 08. Reves JG, Glass PSA, Lubarsky DA - Nonbarbiturate Intravenous Anesthetics, em: Miller RD - Anesthesia, 5^th Ed, Philadelphia, Churchill Livingstone, 2000;228-272.
• 09. Haas DA, Harper DG - Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog, 1992;39:61-68.
• 10. Werner C, Reeker W, Engelhard K et al - Ketamine racemate and S-(+)-ketamine. Cerebrovascular effects and neuroprotection following focal ischemia. Anaesthesist, 1997;46:(Suppl1): S55-S60.
• 11. Zielmann S, Kazmaier S, Schnull S et al - S-(+)-Ketamine and circulation. Anaesthesist, 1997;46: (Suppl1):S43-S46.
• 12. Johnstone M - The cardiovascular effects of ketamine in man. Anaesthesia, 1976;31:873-882.
• 13. Petrenko AB, Yamakura T, Baba H et al - The role of N-methil-d-aspartate (NMDA) receptor in pain: a review. Anesth Analg, 2003;97:1108-1116.
• 14. Yamamura T, Harada K, Okamura A et al - Is the site of action of ketamine anesthesia the N-methyl-D-aspartate receptor? Anesthesiology, 1990;72:704-710.
• 15. White PF, Schuttler J, Shafer A et al - Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth, 1985;57:197-203.
• 16. Fu ES, Miguel R, Scharf JE - Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg, 1997;84:1086-1090.
• 17. Kwok RF, Lim J, Chan M et al - Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Anesth Analg, 2004;98:1044-1049.
• 18. Marin P, Quignard JF, Lafon-Cazal M et al - Non-classical glutamate receptors, blocked by both NMDA and non-NMDA antagonists, stimulate nitric oxide production in neurons. Neuropharmacology, 1993;32:29-36.
• 19. 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.
• 20. Aronstam RS, Narayanan L, Wenger DA - Ketamine inhibition of ligand binding to cholinergic receptors and ion channels. Eur J Pharmacol, 1982;78:367-370.
• 21. Kress HG - Actions of ketamine not related to NMDA and opiate receptors. Anaesthesist, 1994;43:(Suppl2):15-24.
• 22. Ryder S, Way WL, Trevor A - Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol, 1978;49: 15-23.
• 23. Doenicke A, Angster R, Mayer M et al - The action of S(+) ketamine on serum catecholamine and cortisol. A comparison with ketamine racemate. Anaesthesist, 1992;41:597-603.
• 24. Adams HA, Thiel A, Jung A et al - Studies using S-(+)-ketamine on probands. Endocrine and circulatory reaction recovery in dream experience. Anaesthesist,1992;41:588-596.
• 25. 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.
• 26. White PF, Ham J, Way WL et al - Pharmacology of ketamine isomers in surgical patients. Anesthesiology, 1980;52:231-239.
• 27. Himmelseher S, Pfenninger E, Georgieff M - The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg, 1996;83:505-512.
• 28. Meldrum B - Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr, 2000;130:(Suppl4): 1007S-1015S.
• 29. Nishizawa Y - Glutamate release and neuronal damage in ischaemia. Life Sci, 2001;69:369-381.
• 30. Engelhard K, Werner C, Eberspacher E et al - The effect of the alpha2-agonist dexmedetomidine and the NMDA antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg, 2003;96:524-531.
• 31. Kawasaki T, Ogata M, Kawasaki C et al - Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg, 1999;89:665-669.
• 32. Nagels W, Demeyere R, Van Hemelrijck J et al - Evaluation of the neuroprotective effects of S(+)-ketamine during open-heart surgery. Anesth Analg, 2004;98:1595-1603.
• 33. Xie H, Wang X, Liu G et al - Analgesic effects and pharmcokinetics of a low doses of ketamine preoperatively administered epidurally or intravenously. Clin J Pain, 2003;19: 317-322.
• 34. Schulte H, Sollevi A, Segerdahl M - The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup-like pain in humans. Anesth Analg, 2004;98:1574-1580.
• 35. Warncke T, Jorum E, Stubhaung A - Local treatment with the N-methyl-d- aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action. Neurosci Lett, 1997;227:1-4
• 36. Schmid RL, Sandler AN, Katz J - Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current technique and outcomes. Pain, 1999;82: 111-125.
• 37. Roytblat L, Korotkoruchko A, Katz J et al - Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg, 1993;77:1161-1165.
• 38. Subramaniam K, Subramaniam B, Steinbrook RA - Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative review. Anesth Analg, 2004;99:482-495.
• 39. Haeseler G, Tetzlaff D, Bufler J et al - Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(-)-ketamine. Anesth Analg, 2003;96:1019-1026.
• 40. 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 epidurallly. Anesth Analg, 2003;96:475-480.
• 41. Kararmaz A, Kaya S, Karaman H et al - Intraoperative intravenous ketamine in combination with epidural analgesia: postoperative surgery after renal surgery. Anesth Analg, 2003;97: 1092-1096.
• 42. Kathirvel S, Sadhasivam S, Saxena A et al - Effects of intrathecal ketamine added to bupivacaine for spinal anaesthesia. Anaesthesia, 2000;55:899-904.
• 43. McCartney CJ, Sinha A, Katz J - A qualitative systematic review of the role of N-Methyl-d-Aspartate receptor antagonists in preventive analgesia. Anesth Analg, 2004;98:1385-1400.
• 44. Snijdelaar DG, Cornelisse HB, Schmid RL et al - A randomised controlled study of peri-operative low dose S(+)-ketamine in combination with postoperative patient-controlled S(+)- ketamine and morphine after radical prostatectomy. Anaesthesia, 2004;59:222-228.
• 45. Argiriadou H, Himmelseher S, Papagiannopoulou P et al - Improvement of pain treatment after major abdominal surgery by intravenous S(+)-ketamine. Anesth Analg, 2004;98:1413-1418.
• 46. Kudoh A, Takahira Y, Katagai H et al - Small-dose ketamine improves the postoperative state of depressed patients. Anesth Analg, 2002;95:114-118.
• 47. Kissin I, Bright CA, Bradley EL - The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg, 2000;91:1483-1488.
• 48. Celerier E, Rivat C, Jun Y et al - Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology, 2000;92:465-472.
• 49. Guignard B, Coste C, Costes H et al - Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Anesth Analg, 2002;95:103-108.
• 50. Chen L, Huang LY - Protein kinase C reduces Mg²⁺ block of NMDA-receptor channels as a mechanism of modulation. Nature, 1992;356:521-523.
• 51. Kissin I - Preemptive analgesia. Anesthesiology, 2000;93: 1138-1143.
• 52. Weinbroum AA - A single small dose of postoperative ketamine provides rapid and sustained improvement in morphine analgesia in the presence of morphine-resistant pain. Anesth Analg, 2003;96:789-795.
• 53. Haller G, Waeber JL, Infante NK et al - Ketamine combined with morphine for the management of pain in an opioid addict. Anesthesiology, 2002;96:1265-1266.
• 54. Hollmann MW, Liu HT, Hoenemann C et al - Modulation of NMDA receptor function by ketamine and magnesium. Part II: Interactions with volatile anesthetics. Anesth Analg, 2001;92:1182-1191.
• 55. Chia YY, Kuo MC, Liu K et al - Does postoperative pain induce emesis? Clin J Pain, 2002;18:317-323.
• 56. Friedberg BL - Propofol ketamine anesthesia for cosmetic surgery in the office suite. Int Anesthesiol Clin, 2003;41:39-50.
• 57. Macario A, Weinger M, Carney S et al - Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg, 1999;89:652-658.
• 58. Eberhart LHJ, Morin AM, Wulf H et al - Patient preferences for immediate postoperative recovery. Br J Anaesth, 2002;89: 760-761.
• 59. Gan TJ, Lubarsky DA, Flood EM et al - Patient preference for acute pain treatment. Br J Anaesth, 2004;92:681-688.
• 60. White PF - The role of non-opioid analgesic techniques in the management of pain after ambulatory surgery. Anesth Analg, 2002;94:577-585.
• 61. 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.
• 62. Schmid R, Koren G, Klein J et al - The stability of a ketamine-morphine solution. Anesth Analg, 2002;94:898-900.
• 63. Murdoch CJ, Crooks BA, Miller CD - Effect of the addiction of ketamine to morphine in patient-controlled analgesia. Anaesthesia, 2002;57:484-488.
• 64. 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 infusion are used. Anesth Analg, 2002;94:981-986.
• 65. 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.
• 66. Adam F, Libier M, Oszustowicz T et al - Preoperative small-dose ketamine has no preemptive analgesic effects in patients undergoing total mastectomy. Anesth Analg, 1999;89:444-447.
• 67. Luginbuhl M, Gerber A, Schnider TW et al - Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg, 2003;96: 726-732.

*

Received from Serviço de Anestesiologia na Santa Casa de Porto Alegre; Núcleo de Pesquisa em Anestesiologia; Núcleo de Tratamento da Dor

Publication Dates

• Publication in this collection
  24 Oct 2005
• Date of issue
  Aug 2005

History

• Received
  04 Oct 2004
• Accepted
  22 Mar 2005