Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.55 no.4 Campinas July/Aug. 2005
Low S(+) ketamine doses: a review*
S(+) cetamina en bajas dosis: actualización
Ana Luft, M.D.I; Florentino Fernandes Mendes, TSA, M.D.II
IIMestre em Farmacologia pela FFFCMPA, Doutor em Medicina pela FMSCSP
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
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.
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.
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.
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.
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.
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.
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.
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-1 36. 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.
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.
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Dra. Ana Luft
Address: Rua Osmar Amaro de Freitas, 200
ZIP: 91210-130 City: Porto Alegre, Brazil
Submitted for publication October 4, 2004
Accepted for públication March 22, 2005
* Received from Serviço de Anestesiologia na Santa Casa de Porto Alegre; Núcleo de Pesquisa em Anestesiologia; Núcleo de Tratamento da Dor