Hospital Clínico Universidad Católica de Chile, Departamento de Anestesiología, Marcoleta 367, PO Box 114-D, Santiago, Chile*Corresponding author
Accepted for publication: July 17, 2001
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Abstract |
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Br J Anaesth 2001; 87: 8669
Keywords: analgesics opioid, remifentanil; analgesics opioid, tolerance; pain, postoperative
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Introduction |
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It has been demonstrated that development of acute opioid tolerance to the analgesic effect of opioids occurs in animals.47 However, the occurrence of this phenomena in humans is controversial,8 9 and even more its clinical relevance.10 11 The objective of this study was to determine whether remifentanil-based anaesthesia is associated with clinically relevant acute opioid tolerance, expressed as greater postoperative pain scores or morphine consumption, when compared with sevoflurane-based anaesthesia.
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Methods |
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In the operating room before induction of anaesthesia, patients were instructed on how to use the patient-controlled analgesia (PCA) device and the visual analogue scale (VAS) (0=no pain; 100=worst possible pain). The average of three consecutive (5-min interval) non-invasive arterial pressure (NIBP) measurements was considered as the basal value. After standard monitoring (ECG, pulse oximeter, NIBP), anaesthesia was induced with fentanyl 3 µg kg1, propofol 2 mg kg1, rocuronium 0.6 mg kg1, and 2% sevoflurane. The trachea was then intubated. Then, patients were assigned to one of two groups by a table of random numbers generated with the StatView statistical software package. Patients in group R (remifentanil-based anaesthesia) were initially maintained with 0.5% sevoflurane inspired fraction, 50% nitrous oxide in oxygen (4 litres min1) and remifentanil 0.25 µg kg1 min1. Patients in group S (sevoflurane-based anaesthesia) were initially maintained with 2% sevoflurane inspired fraction and 50% nitrous oxide in oxygen (4 litres min1). Arterial pressure was measured every 2.5 min. Increments or decrements of 0.050.1 µg kg1 min1 of remifentanil (group R, n=30) and 0.51.0% sevoflurane (group S, n=30) were administered in order to maintain mean arterial pressure within 20% of basal values. All patients were mechanically ventilated to maintain end tidal carbon dioxide 3035 mm Hg. Rocuronium 5 mg bolus was given to maintain one or two responses of the adductor pollicis to train-of-four stimulation. Administration of atropine, ephedrine and i.v. fluid administration was left to the anaesthetists discretion. Neostigmine 13 mg and atropine 0.51.5 mg were administered at the end of surgery to antagonize residual neuromuscular block, if required. The anaesthetist was not blinded to group assignment.
All patients were extubated in the operating room and transferred to the recovery unit, breathing room air. Postoperative pain was assessed and managed by the staff of the pain service of our hospital (blinded to group assignment). Dynamic pain VAS pain scores were assessed by asking patients to cough in the supine position at 0, 15, 30, 45, 60, 90, 120 min and 24 h after arrival in the recovery unit. Initially, morphine 3 mg bolus doses were given intravenously until VAS pain scores were <50 mm and then the PCA system was connected (bolus dose morphine 1 mg and droperidol 0.2 mg; 8 min lockout). The following postoperative complications were recorded: nausea and vomiting, sedation (evaluated with a four point rating scale: 0=fully awake; 1=somnolent, responsive to verbal commands; 2=somnolent, responsive to tactile stimulation; and 3=asleep, responsive to painful stimulation), hypoxaemia (pulse oximeter saturation <90%, breathing room air), and respiratory depression (ventilatory frequency <10 min1). Nausea and vomiting were treated with ondansetron 4 mg i.v. Hypoxaemia was treated with 35% oxygen administered by mask.
Patient satisfaction with anaesthesia and pain management was assessed 24 h after surgery with a four point rating scale (1=very satisfied; 2=satisfied; 3=unsatisfied; 4=very unsatisfied).
Mean sevoflurane requirements for each patient were estimated from the vaporizer setting, which was recorded every 15 min. Mean remifentanil requirements were calculated by dividing the total amount of remifentanil infused (mg) by duration of anaesthesia (min) and weight (kg) for each patient.
The sample size was estimated to demonstrate a difference of at least 30% in morphine consumption (based on data of morphine consumption in this type of surgery obtained by the pain service of our hospital) with ß=0.90 and =0.05. The chi-squared and the unpaired Students t-tests were used to study the homogeneity of general data. Two-way ANOVA was used to compare morphine consumption and VAS scores, and MannWhitney U-test to compare sedation and satisfaction. The level of statistical significance was set at P<0.05. All analyses were performed using the StatView statistical software package.
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Results |
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Discussion |
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Some recent studies have suggested that acute opioid exposure to large doses of fentanyl13 or remifentanil10 during surgery can be associated with a clinically important tolerance effect to opioid analgesia, manifested by greater pain scores or opioid consumption during the postoperative period. Moreover, delayed hyperalgesia from opioid exposure has been proposed as another possible explanation for the apparently worse pain and greater opioid consumption.10 14 15 Both acute opioid tolerance and delayed hyperalgesia seem to share some similar molecular mechanisms which involve the activation of excitatory glutamate receptors of the N-methyl-D-aspartate (NMDA) system in the central nervous system.15 16 However, many other mechanisms and systems are probably involved in the development of opioid tolerance.17
Evidence is controversial in humans. Gustorff,8 using electrical pain stimulation in a placebo-controlled volunteers study, did not find early tolerance during 3 h of 0.08 µg kg1 min1 remifentanil infusion. Nonetheless, Vinik and Kissin9 showed in volunteers that the analgesic effect of remifentanil 0.1 µg kg1 min1 was maximum at 6090 min and then progressively declined, reaching 25% of the peak value after 3 h of constant-rate infusion. The main weakness of this study was the lack of a control group to rule out a learning or customing effect to painful stimulation. However, even though the study by Vinik and Kissin did not adequately reflect the complex perioperative clinical condition, anaesthesia duration might be a key factor influencing the development of acute opioid tolerance.4 As a result, it could be that, in spite of the higher doses of remifentanil used in our study, longer anaesthesia might have led to the development of clinically significant acute opioid tolerance effect. This idea is reinforced by Guignards study,10 which showed, in patients who had received remifentanil-based anaesthesia for surgery averaging 4 h, their demand for morphine in the first 24 h was nearly twice that of those who received desflurane-based anaesthesia.
Intensity of pain might be another factor that can influence the appearance of acute opioid tolerance. Using two animal models (upper and lower abdominal surgery), Ho and colleagues18 explored the effect of postoperative pain on the prevention of acute tolerance to morphine antinociception in rats. They found that both types of surgery were associated with significant attenuation of acute opioid tolerance after i.v. infusion of morphine when compared with a control group. Similar results have been found in other animal models.19 In our study, patients of both groups had high pain scores during the first 2 postoperative hours and this could have precluded the appearance of a clinically detectable opioid tolerance effect.
In animals, higher doses of morphine are more likely to produce acute opioid tolerance than lower doses.4 Thus, the slightly higher remifentanil infusion rate in Guignards study compared with ours cannot be ruled out as an additional explanation for the different results between both studies. With respect to postoperative complications and patient satisfaction, both anaesthesia regimens seem to be equally good. The higher rates of nausea observed in group R need to be confirmed because we do not have a record of fluid and neostigmine administration to be sure that both groups are comparable in this regard.
There is still a lot to learn with respect to the occurrence of acute tolerance, delayed hyperalgesia and pre-emptive opioid effect, their molecular mechanisms, their interactions and their clinical relevance in the perioperative period. However, based on our results we can conclude that remifentanil-based anaesthesia in this type of surgery is not associated with greater postoperative pain scores or morphine requirements when compared with sevoflurane-based anaesthesia. Clinical evidence of acute opioid tolerance is not supported by our results.
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References |
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