Preemptive analgesia

Abstracts

JUSTIFICATIVA E OBJETIVOS: O controle da dor pós-operatória tem sido muito investigado nas últimas décadas, quando se verificou que a analgesia pós-operatória era inadequada. O termo "preemptiva" implica em uma forma de analgesia que, iniciada antes do estímulo doloroso ser gerado, previne ou diminui a dor subseqüente. Este estudo tem como objetivo uma atualização sobre analgesia preemptiva possibilitando novas alternativas para o tratamento da dor pós-operatória. CONTEÚDO: A analgesia preemptiva foi recomendada para prevenir a dor causada por mudanças no sistema nervoso central durante o ato operatório, devido à não supressão da condução do estímulo doloroso para o encéfalo. Vários estudos tanto laboratoriais como clínicos têm sido realizados com o intuito de demonstrar efeito preemptivo de métodos de analgesia, porém os resultados ainda são discutíveis e conflitantes. CONCLUSÕES: Apesar de existir algumas evidências clínicas do efeito da analgesia preemptiva, há necessidade de mais estudos para elucidar o real valor desse tipo de analgesia no controle da dor pós-operatória.

ANALGESIA, Preemptiva

REVIEW ARTICLE

Preemptive analgesia^*

Analgesia preemptiva

João Batista Santos Garcia, TSA, M.D.^I; Adriana Machado Issy, TSA, M.D.^II; Rioko Kimiko Sakata, TSA, M.D.^II

^IProfessor Adjunto de Anestesiologia da Universidade Federal do Maranhão, São Luiz, MA

^IIProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva da UNIFESP - EPM

Correspondence

SUMMARY

BACKGROUND AND OBJECTIVES: Postoperative pain control started to be more investigated in the last decade, when it has been observed that postoperative analgesia was inadequate. The word preemptive implies a type of analgesia which, induced before pain stimulation, prevents or minimizes subsequent pain. This study is an update on preemptive analgesia and provides new alternatives for postoperative pain relief.

CONTENTS: Preemptive analgesia is recommended to prevent pain caused by central nervous system changes during surgery in consequence of the non-suppression of painful stimuli conduction to the brain. Many experimental studies in animals and humans have been performed to show a preemptive effect, but results are still unclear.

CONCLUSIONS: Although some clinical evidences of the effects of preemptive analgesia, more studies are needed to determine the real value of this type of analgesia in controlling postoperative pain.

Key words: ANALGESIA, Preemptive

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: El control del dolor pós-operatorio ha sido muy investigado en las últimas décadas, cuando se verificó que la analgesia pós-operatoria era inadecuada. El término "preemptiva" implica en una forma de analgesia que, iniciada antes del estímulo doloroso ser generado, previene o diminuye el dolor subsecuente. Este estudio tiene como objetivo una actualización sobre analgesia preemptiva posibilitando nuevas alternativas para el tratamiento del dolor pós-operatorio.

CONTENIDO: La analgesia preemptiva fue recomendada para prevenir el dolor causado por cambios en el sistema nervioso central durante el acto operatorio, debido a la no supresión de la conducción del estímulo doloroso para el encéfalo. Varios estudios tanto laboratoriales como clínicos han sido realizados con el intento de demostrar efecto preemptivo de métodos de analgesia, sin embargo los resultados aun son discutibles y conflictantes.

CONCLUSIONES: A pesar de existir algunas evidencias clínicas del efecto de la analgesia preemptiva, hay necesidad de más estudios para elucidar el real valor de ese tipo de analgesia en el control del dolor pós-operatorio.

INTRODUCTION

The interest in postoperative pain control has increased in recent years, when it was observed that postoperative analgesia was inadequate despite of the advances in understanding pain physiology and action mechanism, and of the development of sophisticated systems for drug administration ^1-3.

For this reason, some treatment modalities, such as preemptive analgesia, are being discussed. The word preemptive implies an analgesia which, induced before the painful stimulus, prevents or minimizes subsequent pain.

The concept of preemptive analgesia was initially described in the first decade of the 20^th century, when the association of regional and general anesthesia was recommended to prevent pain caused by central nervous system changes during surgery due to the non-suppression of painful stimuli conduction to the brain ⁴. This idea was revived by Woolf ⁵ who, after studying animals submitted to severe painful stimuli, observed that sensory changes were generated (continuous pain, pain sensitivity increase and pain in response to non-painful stimuli) and explained not only by changes in peripheral mechanisms, but also by changes (hypersensivity) in spinal cord activity.

Wall ⁶, in an editorial, widens such concept by discussing nociceptive afference blockade caused by surgical manipulation and the analgesic treatment started before the noxious stimulus. He discusses a study in patients submitted to orthopedic procedures under different types of anesthesia (general, general preceded by opioids, local, local preceded by opioids) where it was observed that the time needed for postoperative analgesia was progressively longer with opioids, local anesthesia and the association of both ⁷. With superficial general anesthesia the spinal cord received an intense stimulation, which did not happen with regional anesthesia. This study has shown the advantage of preventing stimuli to the central nervous system during surgery, which could be obtained by neural blockers or their association to general anesthesia. The same author discusses another study in diabetes patients with lower limb ischemia and submitted to amputation ⁸. One group received lumbar epidural bupivacaine associated to morphine three days before amputation and were kept under analgesia until surgery, while the other group remained with preoperative pain. No patient receiving previous epidural block referred phantom pain six month after surgery; conversely, 5 of the 13 patients in the control group have referred the syndrome. Similar differences were observed 12 months after surgery. These data showed the possibility of prolonged preoperative analgesic effect even without medication.

In an experimental study, Woolf et al. ⁹ have described that, once spinal cord neurones hyper-excitation is established, very high morphine doses are needed to block such state, while with low doses administered before the stimuli reaching the central nervous system would suppress excitation. This shows that treating preoperative pain could prevent spinal cord hipersensitivity ¹⁰.

The aim of preemptive analgesia is to prevent or minimize any "memory" of pain in the central nervous system, thus resulting in lower analgesic consumption ¹¹.

Since preemptive analgesia is a preoperative intervention which prevents or minimizes postoperative pain, the difference in results of analgesia induced before and after the beginning of a surgery would evidence a preemptive effect. However, emphasis should not be placed only on the time when the treatment is started, but also on the pathophysiological phenomenon to be prevented: sensory processing changes ¹².

It is clear that results obtained by preoperative or pre-incisional interventions unable to prevent central changes should not be considered preemptive because preemptive doesn't mean simply "previous" ¹³.

PERIPHERAL SENSITIZATION

Pain is a consequence of high threshold peripheral receptors activation (nociceptors) by potentially noxious thermal, chemical or mechanical stimuli. This information is transmitted to the central nervous system by Ad and C fibers which, in their vast majority ^14-17, enter into the spinal cord through the dorsal root.

When the stimulus is very severe or prolonged there is tissue injury which releases substances responsible for the inflammatory response that may last for hours or days. Peripheral injury persistence may cause direct or indirect nervous system changes ¹⁴.

Postsurgical pain changes nervous fibers sensitivity, characterizing the peripheral sensitization phenomenon, manifested by spontaneous neuronal activity increase, nociceptors activation threshold decrease and increase in supraliminal stimuli response. Primary afferent nociceptors sensitization causes hyperalgesia, which is defined as an exaggerated response to painful stimuli. There is the primary hyperalgesia, occurring within tissue injury limits and the secondary hyperalgesia, occurring around the injury. A number of non-myelinized primary afferents are in general insensitive to intense thermal and mechanical stimuli, but become responsive in the presence of sensitization. They are called silent nociceptors and intensively respond even to non-nociceptive stimuli ^14-16,18.

The inflammatory response after tissue injury leading to peripheral sensitization is characterized by the release of substances both by injured tissue cells and inflammatory cells, such as mastocytes, macrophages and lymphocytes. There are changes in vascular permeability and local blood flow, activation and migration of immune system cells and changes in trophic and growth factors release by adjacent tissues. There is the release of kinins (especially bradykinin) and arachidonic acid which, under the action of cycloxygenase and lipoxygenase, give origin to prostacyclins, prostaglandins, thromboxane and leucotriens. Prostaglandins release, especially PGE₂, decreases nociceptors excitation thresholds. There is also the release of mediators, such as potassium, serotonin, P substance, histamine and cytokines (IL-1, IL-6, IL-8 and TNFa). Although some mediators may directly act on membrane ion channels changing cell permeability and excitability, the vast majority has an indirect action by activating membrane receptors which are usually, but not exclusively, coupled to second-messengers, activating specific kinases with membrane ion channels phosphorilation ^16,18.

The inflammatory process is related to peripheral opioid antinociceptive actions, characterizing an inhibition modulation mechanism. Studies have shown that the action of opioids is more intense in the presence of inflammation. Associated to this fact, significant b-endorphins and metencephalins concentrations were detected in immune system cells (T and B lymphocytes and macrophages) infiltrating the inflammation site, as well as pro-dorphin and pro-encephalin peptides in sensory ganglia and peripheral nervous terminals. Moreover, it seems to be an increase in opioid receptors synthesis and stimulation of their axonal transport to the periphery during the inflammatory response ^18,19.

CENTRAL SENSITIZATION

Persistent nociceptors stimulation decreases sensitivity thresholds and normally non-painful stimuli end up resulting in pain (alodinia), in addition to spontaneous pain, primary and secondary hyperalgesia which may persist even after tissue healing. This suggests that peripheral sensitization is not responsible for all those changes and that there must be a significant central nervous system involvement in this process, characterizing central sensitization ^14,17,20. The central nervous system presents structural and functional changes, called plasticity, with positive (adequate to changes in the environment) or negative (function abnormality) adaptations ^{10,14,15,17,20,21}.

Central sensitization is triggered by sensory impulses transmitted by C amyelinic fibers that ending in the spinal cord most superficial layers. This sensitization is characterized by increased spontaneous activity, threshold decrease or responsiveness increase to afferent impulses, prolonged discharges after repeated stimuli and peripheral expansion of spinal cord dorsal horn neurons receptive fields. It is worth stressing that those spinal cord changes result in hypersensitivity of low threshold mechano-receptors (which normally do not cause pain) allowing pain to be conducted through sensory A b fibers. In addition to the spinal cord component, there are evidences that peripheral injuries may also induce plasticity in supra-spinal structures affecting response to pain ^17,20-22.

To produce dorsal horn changes, it is necessary that the activation of small primary afferents result in the release of neuropeptides ( substance P, neurokinin-A, somatostatin and peptides genetically related to calcitonin) and excitatory aminoacids (glutamate and aspartate). Such substances are responsible for the generation of post-synaptic excitatory potentials which may be slow (produced by amyelinic C fibers and lasting up to 20 seconds) or fast (produced by low excitability threshold A fibers and lasting for milliseconds) ²³.

Fast post-synaptic excitatory potentials generate short duration ion currents inside the cells and are mediated by glutamate action via AMPA (alpha-amino-3-hydroxi-5- methyl-4-isoxasolpropionic acid) receptors, bound to a sodium ion channel, and metabotropic receptors, bound to membrane G protein and C phospholypase, known as non-NMDA (N-methyl-D-aspartate) receptors. Slow post-synaptic excitatory potentials may also be caused by AMPA receptors but their most consistent generation mechanism is through the action of glutamate on NMDA receptors and the action of tachykinins such as substance P and neurokinin-A. There are three types of tachykinin receptors: neurokinin-1 (NK₁), neurokinin-2 (NK₂) and neurokinin-3 (NK₃), being all post-synaptic, coupled to G protein and located in dorsal horn layers I, II and X. Substance P acts preferably via NK₁ and neurokinin-A via NK₂^{14,15,17,23,24}.

The prolonged action of slow potentials allow that, during repeated afferent stimuli, such potentials be temporarily added, producing a cumulative increase in post-synaptic depolarization (few seconds of C fiber impulses result in several depolarization minutes). This progressive increase in action potential discharge caused by repeated stimulations is known as the wind up phenomenon. For this phenomenon to occur it is necessary that NMDA receptors be activated. Conditions for activating such receptors are complex and involve their binding to glutamate in addition to magnesium ion removal (which normally blocks the channel) and tachykinin modulation action. Magnesium is displaced when there is prolonged and repeated membrane depolarization (frequency-dependent effect), allowing calcium to enter the cell. If C fibers stimuli are maintained with adequate frequency and intensity, NMDA receptor will remain activated resulting in exacerbation and longer hyperalgesia responses ^20,23,25.

Tachykinins are especially important in exacerbating NMDA receptors-mediated responses. Substance P and neurokinin-A activate their NK₁ and NK₂ receptors and, as a consequence, increase diacylglycerol (DAG) and form inositol 1,4,5-triphosphate (IP₃). In the presence of phosphatidylserine and calcium (in intracellular concentrations close to resting conditions), DAG activates protein-kinase C (PKC) which is translocated from the cytoplasm to the membrane and phosphorilates proteins, including NMDA receptors. NMDA receptors phosphorilation changes magnesium ion binding kinetics displacing it and making easier the entrance of calcium in the cells. The increase in intracellular calcium has an additional effect in activating PKC. IP₃ formation may release calcium from intracellular vesicles and induce more PKC activation creating an NMDA receptor activation cycle (positive feedback). So, large amounts of calcium may be generated in the cytoplasm not only through a voltage-dependent mechanism, but also through a different mechanism related to neurokinin receptors ^20.26.

Increased calcium has other consequences, such as nitric oxide-synthetase (NOS) enzyme activation and protoncogenesis transcription stimulation (DNA transcriptional process regulators). NOS causes nitric oxide (NO) production which, acting as a second messenger via GMPc activates proteinokinases which, as previously described, are responsible for ion channels phosphorilation and activation. In addition, NO is backwards spread to the pre-synaptic terminal where it stimulates more glutamate release ^26,27.

C-fos and l c-jun protoncogenes, also called early genes, are originally described as a class of genes rapidly and transiently expressed in central nervous system cells after several types of stimulations. After a painful stimulus, there is a change in spinal cord dorsal horn genes expression which may last for several hours; however, after non-painful stimuli, there is only a limited effect in genes transcription, suggesting that Ad and C fibers are responsible for central genetic transcription effects mediation. Transcription proteins produtc (Fos) are found in spinal cord layers I, II and V neurons (known receptor areas of pain-conducting nervous fibers) and act on the expression of other genes. There are strong evidences suggesting that pre-prodinorphin and pre-proencephalin genes are Fos targets which generates dinorphin and encephalin synthesis. Encephalin has typically antinociceptive effects which may be related to mechanisms minimizing neuroplasticity and hyperalgesia. On the other hand, dinorphin has a complex effect because it causes direct neuronal excitation (causing hyperalgia) and antinociception (by a negative feedback mechanism of dinorphin-containing neurons). These observations led to the possibility of Fos activation direct interaction with endogenous opioid systems in spinal cord. In addition, such genes activate the transcription of RNA messengers controlling synthesis of proteins fundamental for neuron functioning, such as glutamate receptors (increasing their density on the membrane and making the neuron more sensitive to glutamate), ion channels (increasing their excitability) and enzymes, such as phosphorilases and proteinokinases. Since those changes alter phenotype expression, they are long lasting and sometimes permanent, leaving such neurons hypersensitive for a long period ^20,27.

For what has been described, it is consistent to believe that NMDA, neurokinins and Fos generation receptors antagonists have a protecting role by blocking central sensitization development and maintenance. The administration of such substances before a painful stimulus would then have a preemptive effect. NMDA receptors antagonists, such as aminophosphovaleric acid (AP-5), disocilpine (MK-801), ketamine, dextromethorphan and others have been tested in animals and humans and have shown a decrease in central sensitization and wind up phenomena. Opioids and local anesthetics would have a similar action and a decreased Fos generation was shown with such drugs. a₂-agonists, such as medetomidine, also have a Fos suppressing effect on the spinal cord when preemptively used. With such promising results, strategies for a better pain control are being rethought ^25,27-31.

It is important to stress that, although their similarities, wind up and central sensitization are different phenomena. A major difference is that wind up does not persist after its conditioning stimulus while central sensitization is long lasting. Another aspect to be considered is that central sensitization is often associated to an increase in A fibers evoked responses, which does not seem to occur during wind up, suggesting that such phenomenon by itself is not sufficient to produce all characteristics observed in sensitization, such the increase in C fibers afferent impulse, expansion of receptive fields and recruiting of previously non-effective synapses ³².

Central sensitization may occur in the absence of wind up, when there is an increase in intracellular calcium, even without changes in the action potential. Wind up occurs in a very special and artificial situation, in response to slow and repeated stimuli. Central sensitization is more comprehensive and may be produced by the non-synchronized activation of skin, muscle or organs afferents by chemicals or as a consequence of an inflammatory process, but none of them produces a progressive increase in action potential discharge model. Wind up is a phenomenon implied in pain-producing mechanisms and should not be considered equivalent to central sensitization ³³.

EXPERIMENTAL STUDIES

Several animal studies have been performed to show the preemptive effect of analgesia. Most frequent experimental models (especially in rats) use a painful stimulus triggered by formalin (vast majority), capsaicin or carrageenan injections and thermal or mechanical injuries.

The formalin test is widely used and is characterized by two stages of pain. The initial stage (stage 1) is immediate and lasts for approximately five minutes; the next stage (stage 2) starts approximately 15 minutes after injection and lasts for 60 to 90 minutes. Stage 1 seems to be predominantly caused by C fibers activation while stage 2 would be the result of central sensitization mediated by excitatory aminoacids such as glutamate ^34,35.

Dickenson et al. ³⁶ after spinal administration of a µ receptor agonist - Tyr-D-AlaGlyMetPheGlyol (DAGO) - before or after formalin, observed that the pretreatment suppresses stages 1 and 2 and this effect is reverted with naloxone. Treatment after formalin did not suppress stage 2. Similar results were obtained by Yamamoto et al. ³⁷ in comparing spinal morphine and MK-801 (NMDA antagonist) effects when administered before or after formalin. Other authors, however, investigated the same test model and observed that high spinal morphine doses immediately after formalin would inhibit stage 2 similarly to spinal morphine injected before formalin ³⁸.

Abram et al. ³⁹ have studied the effects of inhalational agents and spinal morphine using the formalin test and confirmed previous studies on the pretreatment with opioids with a decrease in stage 2 which was better with the addition of isoflurane. Its isolated use produced just a mild decrease in sensitization, even in higher concentrations. The addition of nitrous oxide to isoflurane produced a major sensitization decrease. Goto et al. ⁴⁰ have administered 30% to 75% nitrous oxide before formalin injection and have observed a dose-dependent suppression of stage 2 activity, partially reverted by naloxone. In this study it was not possible to show a preemptive action with halothane which has also antagonized nitrous oxide effects.

O'Connor et al. ⁴¹ studied a possible preemptive action of intravenous agents, such as thiopental and propofol. The first had no effect on central sensitization and the latter presented a significant suppression. Conversely, other authors reported preemptive analgesia with pentobarbital but have not observed any analgesic effect with propofol ⁴². Even more conflicting are Gilron et al's data ⁴³, showing a preemptive action with alphaxolone but not with propofol and pentobarbital.

Yashpal et al. ⁴⁴ obtained preemptive effects with spinal lidocaine before 2.5% formalin injection in rats, which was not true for animals receiving higher concentrations. When they added intravenous morphine and pentobarbital, there were no significant differences between administrations pre and post 5% formalin injection.

Brennan et al. ⁴⁵ have examined the effects of spinal bupivacaine associated to morphine before or after surgical incision in rats and have not seen significant differences between groups.

For being a non-competitive antagonist of NMDA receptors, ketamine has been used to check a possible preemptive action. Hartrick et al. ⁴⁷ observed that spinal ketamine in rats in a neuropathic pain model, delayed hyperalgesia but did not prevent it ⁴⁶. However, 10 mg.kg^-1 intravenous ketamine before formalin injection had a significant preemptive effect.

Those experimental studies brought about important information and are a support for clinical trials.

CLINICAL TRIALS

Several clinical trials have been performed on the possibility of preventing sensitization, in an attempt to improve postoperative analgesia through preemptive analgesia. However, method and design of many of them do not follow the model of an intervention which, when performed before the painful stimulus, has a significantly better effect as compared to the same intervention performed by the same route and with the same dose after pain.

Some authors have compared one group receiving preoperative treatment to another group without treatment, while others compared previous analgesic administration to its administration before and after the stimulus, making impossible to conclude whether an analgesic approach before surgery would be more, less or as effective as the same therapy adopted afterwards.

Trials included in this review follow the model described by McQuay and compare groups receiving medication and/or techniques before incision to others receiving the same procedures after trauma induction ¹¹, according to figure 1.

Brazilian Journal of Anesthesiology, 2001; 51: 5: 448-463

Preemptive analgesia

João Batista Santos Garcia; Adriana Machado Issy; Rioko Kimiko Sakata

Trials studied local anesthetics, opioids, NMDA receptor antagonists and their combination (multimodal), in addition to non-steroid anti-inflammatory drugs (NSAIDs).

LOCAL ANESTHETICS

Clinical trials with local anesthetics may be divided according to the administration route: epidural or spinal, peripheral nerve block or local infiltrations.

Epidural

By performing sacral blocks with 0.25% bupivacaine (0.5 ml.kg^-1) before or after surgery in 40 children submitted to outpatient procedures, Rice et al. ⁴⁸ observed no significant differences in pain evaluation scales and in the need for additional analgesia. Gunter et al. ⁴⁹, using a similar model in children submitted to hypospadias correction and Ho et al. ⁵⁰ in 60 children submitted to outpatient procedures (herniorrhaphies, orchidopexia,etc.) have also not observed preemptive effects when comparing pre and post incision sacral epidural injection.

Differently from previous studies, Kundra et al. ⁵¹ attained a preemptive effect in 60 children submitted to herniorrhaphy with sacral epidural 0.25% bupivacaine associated to morphine (0.02 mg.kg^-1) before surgery. Pain scores and analgesic consumption were lower and children remained for a longer period with no need for analgesia.

In patients submitted to abdominal hysterectomy or myomectomy, Pryle et al. ⁵² administered 15 ml of 0.5% epidural bupivacaine with epinephrine before or after surgery and evaluated pain by morphine consumption, visual analog scale and verbal scale and found no significant differences between groups. For the same type of surgery, Dakin et al. ⁵³ administered 15 mg of 0.5% spinal hyperbaric bupivacaine before or after surgery with a sensory block from T₃ to S₅ without preemptive effects. However, when administering 15 ml of epidural 0.5% bupivacaine in patients submitted to abdominal surgeries, Katz et al. ⁵⁴ observed that pain scores using McGill's questionnaire and morphine consumption were lower for the group medicated before surgical incision.

Aguilar et al. ⁵⁵ administered 0.5% thoracic epidural bupivacaine with epinephrine in patients submitted to pulmonary resection without differences between groups receiving medication before or after incision as to analgesic consumption, VAS and verbal scale and the preemptive effect could not be demonstrated.

Peripheral Nerve Block

Dierking et al. ⁵⁶ compared ileo-inguinal nerve block efficacy in 32 patients before and after the beginning of inguinal herniorrhaphy using 50 ml of 0.5% lidocaine with epinephrine. Patients were evaluated for 24 hours and on the 7^th postoperative day and no significant differences were observed between groups with regards to time elapsed for analgesics request, drug consumption and pain score.

Campbell et al. ⁵⁷ have not observed differences in pain intensity (McGill's Questionnaire and VAS) in the immediate or late postoperative period with blockade associated to general anesthesia when local anesthetic injection was performed before or after third molar extraction.

Infiltration

Turner et al. ⁵⁸ evaluated 90 patients submitted to appendicectomy under general anesthesia. Two groups received infiltration at surgical incision site and subjacent muscular layer with 1.5% lidocaine with epinephrine (before or after incision) and a third group did not receive infiltration. There were no significant differences in total meperidine dose for postoperative analgesia and in pain scores (VAS) among groups. Dahl et al. ⁵⁹ have also compared subcutaneous cell tissue infiltration with 0.25% bupivacaine (1 mg.kg^-1) before or after herniorrhaphy in children and have not observed a preemptive effect. Conversely, Ejlersen et al. ⁶⁰ studying patients submitted to inguinal herniorrhaphy concluded that pre-incisional 1% lidocaine infiltration was more effective in relieving postoperative pain than post-incisional infiltration. Ke et al. ⁶¹ also observed preemptive effects in women submitted to diagnostic laparoscopy who received infiltration of 0.5% bupivacaine at incision site before surgical stimulation.

In 120 patients submitted to laparoscopic cholecystectomies, Pasqualucci et al. ⁶² used peritoneal instillation of 0.5% bupivacaine with epinephrine before or after surgery. Analgesic consumption and pain intensity were significantly lower for the group receiving local anesthetics before surgery; plasma glucose and cortisol levels were also significantly lower 3 hours after surgery. However, Bouget et al. ⁶³, using a similar model were unable to obtain any preemptive effect.

OPIOIDS

There are clinical trials involving epidural and systemic opioids.

Epidural

Dahl et al. ⁶⁴ studied 32 patients submitted to colon surgeries receiving an equal bolus scheme followed by bupivacaine infusion associated to morphine before skin incision or at closure. There were no significant differences in total analgesic consumption or pain scores by VAS and verbal scale during postoperative evaluation without evidences of preemptive effects. These same authors used a similar scheme of local anesthetics associated to opioids in patients submitted to total knee replacement and obtained the same results ⁶⁵.

Katz et al. ⁶⁶ studied 30 patients submitted to thoracotomies with lumbar epidural fentanyl (4 µg.kg^-1) before or after incision and observed a significant decrease in postoperative pain and drug consumption, thus evidencing preemptive analgesia. Also in thoracotomies, Gill et al. ⁶⁷ were able to show preemptive analgesia with lumbar epidural morphine.

In patients submitted to lumbar laminectomy, Kundra et al. ⁶⁸ administered 3 mg epidural morphine before or after surgery. Postoperative pain scores by VAS, the need for additional analgesia and total morphine consumption were significantly lower for the group receiving pre-incisional medication. In addition, time elapsed for postoperative analgesia was longer.

Systemic

Richmond et al. ⁶⁹ observed that the administration of 10 mg intravenous morphine before hysterectomy reduces opioid consumption during the first 24 postoperative hours, as well as painful sensitivity around the surgical incision as compared to the same dose administered at the end of the surgery. Kiliçkan et al. ⁷⁰, also in patients submitted to hysterectomy, obtained total morphine consumption reduction with 0.15 mg.kg^-1 intravenous morphine before surgical incision.

Three studies evaluating intravenous alfentanil in patients submitted to hysterectomy had different results. Both in the study by Mansfield et al. ⁷¹, with 15 µg.kg^-1 and in the study by Wilson et al. ⁷² with 40 µg.kg^-1, it was impossible to evidence a preemptive effect. However, with a higher dose (70 µg.kg^-1), Griffin et al. ⁷³ obtained a mild decrease in morphine consumption as from 48 postoperative hours.

Fassoulaki et al. ⁷⁴ using intravenous fentanyl (10 µg.kg^-1) and sufentanil (1 µg.kg^-1) in patients submitted to hysterectomy have not observed a preemptive effect. Sarantopoulos et al. ⁷⁵ confirmed such results by isolatedly studying sufentanil in the same dose and in the same type of surgery.

NMDA RECEPTORS ANTAGONISTS

Epidural or intravenous ketamine has been used alone or associated to opioids.

Choe et al. ⁷⁶ have studied 60 patients submitted to gastrectomy under general anesthesia receiving 60 mg epidural ketamine and 2 mg morphine before surgery or after organ resection. Time elapsed for analgesia was longer and the number of patients requiring analgesic supplementation was lower in the presurgical group. Similar results were observed by Wong et al. ⁷⁷, in patients submitted to total knee replacement receiving epidural 20 mg ketamine and 1.5 mg morphine before or after incision. On the other hand, Kukuk et al. ⁷⁸ have administered 60 mg epidural ketamine alone before anesthesia and after peritoneal closing in patients submitted to upper abdominal surgeries and could not confirm the preemptive effect of the method.

Adam et al. ⁷⁹ evaluated 128 women submitted to mastectomy under general anesthesia in whom low intravenous ketamine doses (0.15 mg.kg^-1) were administered before or after surgery. There were no significant differences in pain scores and morphine consumption was lower during the first 2 postoperative hours for the group receiving ketamine after surgery.

Dextromethorphan is also recognized as an NMDA receptor antagonist and, in a study with patients submitted to laparoscopic cholecystectomy a preemptive effect was observed in patients receiving intramuscular 40 mg before incision and after gall bladder resection ⁸⁰.

MULTIMODAL TECHNIQUES

Rockeman et al. ⁸¹ evaluated thoracic epidural mepivacaine and morphine associated to intramuscular diclofenac and intravenous metamizole in 142 patients submitted to major abdominal surgeries. Postoperative analgesia consisted of patient-controlled intravenous morphine for five days. A significant decrease in morphine consumption was observed in the group receiving pre-surgical medication.

Espinet et al. ⁸² evaluated 40 patients submitted to hysterectomy and receiving 20 ml thoracic epidural 0.5% bupivacaine and 100 mg rectal diclofenac before or after incision. When comparing both groups, the authors could not evidence a preemptive effect with the use of the technique before surgery.

ANTI-INFLAMMATORY DRUGS

There are several trials with anti-inflammatory drugs, such as flurbiprofen, diflunisal, naproxen, diclofenac, ketorolac, piroxicam and tenoxicam, administered by different routes in several types of surgeries and different doses. Although a preemptive effect evidenced by some trials, there was a predominance of negative results ^83-94.

Results obtained with different drugs for preemptive analgesia are still confusing and inconclusive.

In a recent study, some authors have observed that the type of surgery could be a factor responsible for different preemptive analgesia results. Epidural morphine was administered in extremity surgeries, mastectomies, gastrectomies, hysterectomies, herniorrhaphies and appendicectomy. Preemptive analgesia was evidenced only in extremity surgeries and mastectomies. In all cases where preemptive analgesia was ineffective there was organ or peritoneal involvement. Such results suggest that nociceptive impulses from organs and/or peritoneum would be a critical factor for preemptive analgesia effectiveness. Abdominal organs and peritoneum are innervated both by segmental and heterosegmental nerves. Segmental spinal nerves emerge from T_5-11 (splanchnic nerves via celiac ganglia), from T₉-L₂ (lumbar splanchnic nerve via upper and lower mesenteric ganglia) and from S_2-4 (sacral parasympathetic nerves), while heterosegmental spinal nerves emerge from C_3-4 (phrenic nerve) and cranial roots (vagus nerve). Extremities and breasts are innervated only by segmental nerves and stimuli in those areas may be better blocked with epidural morphine, thus explaining preemptive analgesia in such surgeries ⁹⁵.

This study has also contributed for the understanding of differences among experimental and clinical trials. In most animal experiments, pain is stimulated on paws or tail which are areas innervated only by segmental spinal nerves which may be easily blocked. One must also take into consideration that painful stimulation in animal trials are short in duration because they are generally performed with formalin or carrageenan and may be relieved or abolished by a single drug in an easier way.

Another aspect is preventive analgesia which, as opposed to preemptive analgesia, is induced at any time (before, during or after surgery), in an attempt to prevent or relieve pain. As a concept, it is possible that the only way to avoid any central sensitization would be a total block of any surgery-induced pain, from the incision until total wound healing, because the nociceptive stimulus is not produced only at incision (primary stage), but also during continuous release by injured tissues of chemical substances and enzymes (secondary stage extending to the postoperative period). This approach seems to be clinically unfeasible ^12,96.

As a conclusion, although several clinical evidences of preemptive analgesia more studies are needed to clarify the real value of this type of analgesia to control postoperative pain.

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Endereço para correspondência:

Dra. Rioko Kimiko Sakata

R. Três de Maio 61/51 - Vila Clementino

04044-020 São Paulo, SP

*

Recebido da Disciplina de Anestesiologia, Dor e Terapia Intensiva da Universidade Federal de São Paulo da Escola Paulista de Medicina (UNIFESP - EPM), São Paulo, SP

Publication Dates

• Publication in this collection
  14 Mar 2011
• Date of issue
  Oct 2001

History

• Received
  06 Feb 2001
• Accepted
  19 Mar 2001