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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.
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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