Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.51 no.6 Campinas Dec. 2001
The effect of preemptive intravenous morphine on postoperative analgesia and surgical stress response*
Efecto preemptivo de la morfina por vía venosa en la analgesia pós-operatoria y en la respuesta al trauma quirúrgico
Levent Kiliçkan, M.D.
Professor de Anaesthesiology and Reanimation, Kocaeli University, Kocaeli, Türkiye
BACKGROUNDS AND OBJECTIVES:
Although initial studies of preemptive analgesia showed that preoperative blockade
with local anaesthetics or pre-operative administration of systemic opioids
was more effective in reducing postoperative pain than control conditions involving
no treatment, the result of subsequent investigations comparing the effects
of pre-operative treatment with the same treatment initiated after surgery have
produced inconsistent results.The reasons for the lack of consistency are not
clear. Studies about the relationship of preemptive analgesia and both analgesic
consumption and surgical stress response are limited. The purpose of this study
was to evaluate the effect of preemptive intravenous morphine on both postoperative
analgesic consumption and surgical stress response.
METHODS: Sixty patients, ASA lor II, aged 20-60, undergoing total abdominal hysterectomy plus bilateral salphingo-opherectomy were randomly assigned to three groups of 20 patients. Group I (n = 20) received 0.15 mg.kg-1 of morphine following induction and placebo saline during peritoneal closure. Group II (n = 20) received placebo saline following induction and 0.15 mg.kg-1 of morphine during peritoneal closure. Group III (n = 20) received placebo salin, both during induction and peritoneal closure. Blood cortisol, glucose levels and leukocyte count were measured in the pre and postoperative period.
RESULTS: Postoperative total morphine consumption was significantly lower in group I compared with group III (p < 0.001). In all groups, plasma cortisol levels increased significantly within 4 h of surgery as compared to pre-op values (p < 0.001). Plasma glucose levels also increased significantly in all groups of the postoperative at 30 minutes and 8 hours period (p < 0.001). Postoperative leukocytosis was observed in all groups and the leukocyte count was significantly greater during the postoperative period than preoperative values (p < 0.001).
CONCLUSIONS: Preemptive intravenous morphine 0.15 mg.kg-1 has decreased total morphine consumption but has failed to supress the surgical stress response.
Key Words: ANALGESIA, Preemptive, Postoperative: patient controlled analgesia; ANALGESICS, Opoids: morphine
JUSTIFICATIVA Y OBJETIVOS:
No obstante los primeros estudios sobre analgesia preemptiva hayan demostrado
que el bloqueo pré-operatorio con anestésicos locales o la medicación
pré-anestésica con opioides sistemicos eran mas eficaces en el alivio
del dolor pós-operatorio de que cualquier otro tratamiento, el resultado
de otros estudios comparando los efectos del tratamiento pré-operatorio
al mismo tratamiento iniciado después de la cirugía, produjeron efectos
inconsistentes. Las razones para esa falta de consistencia no son claras. Son
pocos los estudios sobre la relación entre analgesia preemptiva y el consumo
de analgésicos y la respuesta al trauma quirúrgico. El objetivo de
este estudio fue evaluar el efecto preemptivo de la morfina por vía venosa
preemptiva en el consumen pós-operatorio de analgésicos y en la respuesta
al trauma quirúrgico.
MÉTODO: Participaron de este estudio 60 pacientes, estado físico ASA I ó II, con edades entre 20 y 60 años, escaladas para histerectomía abdominal total y salpingo-ooferectomia bilateral, que fueron aleatoriamente distribuidos en tres grupos de 20 pacientes. Grupo I (n=20) - 0,15 mg.kg-1 de morfina después de la inducción anestésica y suero fisiológico durante el cerramiento del peritoneo Grupo II (n=20) - suero fisiológico después de la inducción y 0,15 mg.kg-1 de morfina durante el cerramiento del peritoneo. Grupo III (n=20) suero fisiológico durante la inducción y el cerramiento del peritoneo. Fueron medidos los niveles sanguíneos de cortisol y de glucosa y hecho el contage de leucocitos en los períodos pré y pós-operatorios.
RESULTADOS: El consumen total de morfina pós-operatoria fue significativamente mas bajo en el grupo I comparado al grupo III (p < 0,001). Los niveles de cortisol aumentaron significativamente en todos los grupos 4 horas después de la cirugía, cuando comparados a los valores pré-operatorios (p < 0,001). Los niveles de glucosa plasmática también aumentaron significativamente en todos los grupos 30 minutos y 8 horas después de la cirugía (p < 0,01). Todos los grupos presentaron leucocitosis pós-operatoria y el contage de leucócitos fue significativamente mas alto en el período pós-operatorio de que en el pré-operatorio (p < 0,01).
CONCLUSIONES: Morfina preemptiva por vía venosa, en la dosis de 0,15 mg.kg-1 disminuyó el consumen total de morfina mas no consiguió suprimir la respuesta al trauma quirúrgico.
It has been shown that preemptive analgesia with intravenous morphine reduced postoperative pain and analgesic consumption1-3. But there are some problems associated with outcome measures used in studies on preemptive analgesia. Pain intensity and opioid consumption are routine measures of outcome. However, opioid consumption probably is not a reliable index for assessing preemptive analgesia and the use of patient controlled analgesia (PCA) because no convincing evidence exists for proportionality between postoperative pain intensity and analgesic requirements. Opioid plasma concentration analgesic response curves are surprisingly steep4. As a result, the within-patient difference between opioid concentration that is still ineffective, and the concentration that provides complete analgesia is difficult to detect. Currently patient-controlled analgesia is commonly used in studies on preemptive analgesia. However, the use of patient-controlled analgesia for pain evaluation has several problems that undermine its usefulness. Analgesic requirement is significantly influenced by such factors as mood, anxiety, expectations of recovery and perception of support5. As a result, analgesic consumption reflects not only pain intensity but also other postoperative distress factors. PCA for pain evaluation has several problems that undermine its usefulness. Opioid consumption with PCA is profoundly influenced by various psychological factors not necessarily related to pain. Co-administration of the fixed rate opioid infusion with PCA does not proportionally reduce the number of demands made by patients. Opioid consumption with PCA depends on the size of the demand dose. Preemptive analgesia has been tried in a variety of surgical procedures but with conflicting results. Why its effect is not always obvious?
This is not clear6. Studies about the relationship of preemptive analgesia and both analgesic consumption and surgical stress response are limited7. The purpose of this study was to evaluate the effect of preemptive intravenous morphine on both postoperative analgesic consumption and surgical stress response.
After obtaining the Ethics Committee approval and informed patient consent, we studied in a double-blind, randomized study, sixty female patients, physical status ASA lor II, aged 20-60 yr, undergoing total abdominal hysterectomy, with or without salpingoopherectomy. Those with chronic pain syndromes, frequent analgesic consumers and uncooperative patients were excluded from participating in the study. Before starting the study our hospital pharmacy prepared 120 pairs of ampoules, each ampoule containing 10 ml of colourless solution. Each pair of ampoules was boxed and numbered consecutively, 1 to 120, and comprised one ampoule labelled "induction" and one labelled "closure". Each pair of ampoules contained one of three possible combination. Group I: morphine 1.5 mg.mI-1 in the induction ampoule, placebo in the closure ampoule. Group II: placebo in the induction ampoule, morphine 1.5 mg.ml-1 in the closure ampoule. Group III: placebo in the induction and closure ampoule. Investigators were blinded as to the contents of the pairs of ampoules; codes of randomization were held only in the pharmacy. Each patient was randomly allocated to the next pair of consecutively numbered ampoules. Group I (n = 20) received 0.15 mg.kg-1 of morphine following induction and placebo saline during peritoneal closure. Group II received (n = 20) placebo saline following induction and 0.15 mg.kg-1 of morphine during peritoneal closure. Group III (n = 20) received placebo saline both during induction and peritoneal closure. Saline was used as placebo. In all patients, standardized general anaesthesia was performed. Tracheal intubation was facilitated with vecuronium 0.1 mg.kg-1 following anaesthesia induction with thiopental 5 mg.kg-1 and anaesthesia was maintained with isoflurane and 66% nitrous oxide in oxygen. Invasive blood pressure, ECG, SpO2, esophageal temperature and PETCO2 were monitored during the operation. Arterial blood samples for cortisol were taken on the afternoon and on the morning before surgery because of their known diurnal variation and also 4 h after arrival in the intensive care unit and on the postoperative morning. Arterial blood for plasma cortisol was collected into 10 ml EDT A tubes and centrifuged immediately, and the plasma was stored at - 200º C until assayed. Plasma glucose concentration was measured by a Hitachi analyser (glucose oxydase method) and plasma cortisol concentration by radioimmunassay. Leukocyte and blood glucose levels were measured in the preoperative period and at 30 min, 4, 8, 24 hours after the operation. Patients were assessed immediately upon arrival in the PACU (post-anaesthetic care unit) and were connected to a PCA pump system (Abbott Life Care Infuser). Every 10 min, patients were asked whether they were in need of pain relief. An affirmative response was followed by a 2 mg i. v. bolus of morphine administered by a nurse observer who was unaware of the group to which the patients had been assigned. This procedure was repeated until the patients were alert enough to begin using the PCA pump. The PCA pump was set to deliver a 1 mg i. v. bolus dose of morphine with a lockout time of 5 min, a maximum dose of 20 mg in any 4 h period, and no continuous background infusion. After 24 hours, the PCA machine was removed and the cumulative dose of morphine administered by the pump was recorded. Pain scores were recorded using a visual analogue score (VAS) (0 mm = no pain, 100 mm = worst imaginable pain) at rest and on movement at 3, 6,12, 24 and 48 after operation. Pain induced by movement was assessed by asking patients to sit up from lying position and perform two maximal inspirations using an incentive spirometer before rating their pain. Sedation and nausea were rated by the patients using a V AS for sedation (0 mm = wide awake, 100 mm = extremely sleepy) and nausea (0 = no nausea, 100 = terrible vomiting). Data are presented as the mean and standard error of the mean (SEM). Significance was tested by unpaired two-tailed Student´s t test or Mann-Whitney U test and parametric one way analysis of variance (ANOVA) when appropriate. Results were considered significant when p < 0.05.
Demografic data, type and duration of surgery were similar within the three groups (Table I). The apparent difference in total postoperative morphine consumption between group I and group II was not statistically significant. Postoperative total morphine consumption was significantly lower in group I compared with group III (p < 0.001). Total morphine consumption was 32% lower in group I compared with group III (Table I). Sedation and nausea scores were similar in the three groups and were not significantly different among the three groups (Table II). In all groups, plasma cortisol levels increased significantly within 4 h of surgery as compared to pre-operative values (p < 0.001) but there was no significant difference among groups (Figure 1). Plasma glucose levels also increased significantly in all groups at 30 minutes and 8 h of the postoperative period (p < 0.001) but there was no significantly different among groups (Figure 2). Postoperative leukocytosis was observed in all groups and the leukocyte count was significantly greater during the postoperative period than preoperative values (p < 0.001) but there was no significantly different among groups (Figure 3). VAS pain scores at rest and on movement at 3, 6, 12, 24 and 48 h were not significantly different among the groups (Figure 4).
Management of pain after surgery is often adequate but optimal pain relief is important as it may reduce postoperative complications, speed recovery and discharge of patients from hospital. The objective of preemptive analgesia is to prevent reflex central neural hyperexcitability which occurs in the spinal cord in the response to the afferent barrage from peripheral nociceptors after a noxious stimulus. But this central sensitization is difficult to supress. In our study, postoperative low morphine consumption was similar to that described in the literature for pre-emptive intravenous morphine1-3. In relation to morphine consumption with PCA, we found a significantly lower value of cumulative doses at 24 h after surgery in group I as compared to group II and III. In all groups, plasma cortisol glucose levels and leukocyte count increased significantly as compared to preoperative values but there was no significant difference within three groups. Preemptive analgesia is a misleading term. Because high intensity noxious stimulation is generated not only by incisions (primary phase of injury) but also by the release of chemicals and enzymes from damaged tissues (secondary phase of injury extended well into the postoperative period). The absence of difference in outcome measures between groups with preincisional and postincisional antinociceptive interventions can not be a reliable arguement against the existence of a preemptive effect because noxious stimuli can initiate altered central processing after surgery, during the secondary inflammatory phase. A correct definition of preemptive analgesia should emphasize the importance of treatment that prevents the development of central hyperexcitability, even if it occurs after surgery. The most important study on this subject was conducted by Shir et al who compared three groups of patients undergoing radical prostatectomy with general, epidural and combined epidural and general anaesthesia8. Preemptive analgesia was observed only with epidural anaesthesia because this type of anaesthesia allows for even minor discomfort to be noticed and treated during surgery. The authors concluded that complete intraoperative blockade was not controlled. Studies by Kehlet's group have clearly demonstrated difficulties in providing complete blockade of noxious stimuli during surgery indicated by an increase in plasma cortisol concentration and other metabolic response9-11. So in this study we aimed to determine the relationship of preemptive analgesia to both analgesic consumption and surgical stress response.
The prevention of postoperative pain is based on two phenomena:
1. The effective blockade of noxious stimuli generated during surgery and during the initial postoperative period (inflammatory phase-phenomenon of preemptive analgesia in the broad sense).
2. An antinociceptive treatment started before surgery is more effective in the reduction of postoperative pain than the treatment given on recovery from general anesthesia (phenomenon of preemptive analgesia in a narrow sense).
Both phenomena can be induced by neural blockades with local anaesthetics and by sistemic or epidural opioids. Clinically impressive effects are observed when the blockade of noxious stimuli is complete.
In conclusion, preemptive intravenous morphine 0.15 mg.kg-1 has decreased total morphine consumption but has failed to suppress the surgical stress response.
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Submitted for publication September 13, 2000 * Received
from Department of Anaesthesiology and Reanimation, Kocaeli University, Kocaeli,
Accepted for publication July 4, 2001
Submitted for publication September 13, 2000
* Received from Department of Anaesthesiology and Reanimation, Kocaeli University, Kocaeli, Türkiye