Development of Acute Opioid Tolerance During Infusion of Remifentanil for Pediatric Scoliosis Surgery

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1 PEDIATRIC ANESTHESIA SECTION EDITOR PETER J. DAVIS SOCIETY FOR PEDIATRIC ANESTHESIA Development of Acute Opioid Tolerance During Infusion of Remifentanil for Pediatric Scoliosis Surgery Mark W. Crawford, MBBS, FRCPC, Chantal Hickey, MD, FRCPC, Christian Zaarour, MD, Andrew Howard, MD, FRCSC, and Basem Naser, MBBS, FRCPC Department of Anesthesia, Division of Orthopedic Surgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada We tested the hypothesis that continuous intraoperative infusion of remifentanil is associated with the development of clinically relevant acute opioid tolerance in adolescents undergoing scoliosis surgery. Thirty adolescents were randomly assigned to receive an intraoperative analgesic regimen consisting of continuous remifentanil infusion or intermittent morphine alone. Postoperative analgesic consumption was assessed with a patient-controlled analgesia device that was used to self-administer morphine. Cumulative postoperative morphine consumption, pain scores, and sedation scores were recorded by a blinded investigator every hour for the first 4 h postoperatively and then every 4 h for a total of 24 h. Cumulative morphine consumption in the remifentanil group was significantly more than that in the morphine group at each time point in the initial 24 h after surgery (P ). At 24 h after surgery, cumulative morphine consumption was 30% greater in the remifentanil group ( mg/kg) than in the morphine group ( mg/ kg) (95% confidence interval for the difference, 0.11 to 0.65 mg/kg). Differences in pain and sedation scores were not statistically significant. These data suggest that intraoperative infusion of remifentanil is associated with the development of clinically relevant acute opioid tolerance in adolescents undergoing scoliosis surgery. (Anesth Analg 2006;102:1662 7) Anesthetic challenges presented by scoliosis surgery include the need to provide profound intraoperative analgesia and facilitate intraoperative neurophysiologic monitoring of the spinal cord and wake-up testing (1). Intraoperative infusion of the synthetic opioid remifentanil hydrochloride is an established technique that is commonly used to meet these needs. The ultra-short duration of action of remifentanil is independent of dose, allowing infusion of large doses throughout surgery with little risk for postoperative delayed awakening or respiratory depression (2). However, an important concern with intraoperative infusion of remifentanil is the possible development of acute opioid tolerance or hyperalgesia, manifesting as increased postoperative analgesic requirement (3 6). In laboratory studies, acute tolerance to opioids developed more rapidly with potent Accepted for publication January 26, Supported, in part, from Abbott Laboratories Limited, Canada. Address correspondence and reprint requests to Mark W. Crawford, MBBS, FRCPC, Department of Anesthesia, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Address to mark.crawford@sickkids.ca. DOI: /01.ane c2 opioids such as remifentanil and alfentanil than with morphine and with continuous infusions more so than with intermittent boluses (7,8). Although acute tolerance to opioids has been demonstrated consistently in animal studies, the results of clinical trials in humans are controversial (9,10). It is possible that in some clinical studies the dose and duration of remifentanil infusion were insufficient or that the surgical procedures did not cause enough postoperative pain to demonstrate a difference in morphine requirement. No study has investigated the development of acute opioid tolerance in the pediatric population. Scoliosis surgery is associated with considerable postoperative pain. Indeed, analgesic requirements after pediatric scoliosis surgery generally exceed those for other major orthopedic and abdominal procedures (11). We hypothesized that the relatively large dose and long duration remifentanil infusion that is required for pediatric scoliosis surgery is associated with the development of acute opioid tolerance, manifesting clinically as an even larger postoperative analgesic requirement. To test this hypothesis, we evaluated postoperative morphine consumption and pain scores in adolescents who received an intraoperative analgesic regimen consisting of either continuous 2006 by the International Anesthesia Research Society 1662 Anesth Analg 2006;102: /06

2 ANESTH ANALG PEDIATRIC ANESTHESIA CRAWFORD ET AL ;102: REMIFENTANIL AND ACUTE OPIOID TOLERANCE infusion of remifentanil or intermittent morphine boluses alone for surgical correction of idiopathic scoliosis. Methods With approval by the Research Ethics Board, 30 unpremedicated ASA physical status I-II children, aged yr, scheduled to undergo posterior instrumentation for correction of idiopathic scoliosis were enrolled in this prospective, randomized, double-blind study. Written consent was obtained from parents or guardians and verbal assent was obtained from children. Exclusion criteria included opioid use within 3 mo before surgery, inability to self-administer morphine using a patient-controlled analgesia (PCA) device, elective postoperative ventilation, and obesity ( 130% of ideal body weight). Patients were randomly assigned to a remifentanil (n 15) or morphine (control) (n 15) group using a random number table. Group assignments were kept in sealed, opaque, sequentially numbered envelopes that were opened after obtaining consent and assent. In the preoperative period, a medical history and physical examination were obtained and patients were instructed in the use of a PCA device and a numeric rating scale (NRS) for assessment of postoperative pain intensity (0 no pain; 10 worst possible pain). On arrival to the operating room, standard intraoperative monitors were applied and baseline values were recorded. Seventy percent nitrous oxide in oxygen was administered via a facemask and a peripheral IV catheter was inserted. After administration of oxygen, anesthesia was induced using propofol 4 mg/kg, glycopyrrolate 10 g/kg, and morphine 100 g/kg. Tracheal intubation was facilitated with the use of rocuronium 0.6 mg/kg, and ventilation was controlled to maintain normocapnia. A radial artery catheter and a second IV catheter were inserted. To facilitate intraoperative monitoring of motor evoked potentials, neuromuscular blocking drugs, nitrous oxide, and inhaled anesthetics were not used during surgery. For children in the remifentanil group, anesthesia was maintained using a mixture of 30% oxygen in air, continuous infusion of propofol at a rate of g kg 1 min 1, and continuous infusion of remifentanil starting at 0.25 g kg 1 min 1 and titrating in increments of 0.05 g kg 1 min 1 according to hemodynamic response. For children in the morphine group, anesthesia was maintained using a mixture of 30% oxygen in air, continuous infusion of propofol at a rate of g kg 1 min 1, and intermittent morphine boluses of 50 g/kg according to hemodynamic response. In keeping with our standard practice, induced hypotension was not used to avoid exacerbation of any spinal cord ischemia resulting from surgical distraction: the target mean arterial blood pressure was mm Hg in each group (12). Other methods of blood conservation including infiltration with epinephrine of the skin and subperiosteal space along spinal laminae, use of predonated autologous blood, and cell salvage were used as indicated. The operating room anesthesiologist was not blinded as to group assignment. Remifentanil infusion was discontinued at skin closure. In the remifentanil group, a bolus dose of 100 g/kg morphine was administered IV approximately 30 min before the anticipated end of surgery. After tracheal extubation, patients were transferred to the postanesthetic care unit, where an anesthesiologist or nurse who was blinded as to treatment group assessed pain control and administered 50 g/kg morphine at 5-min intervals until the patient appeared to be comfortable, defined as the absence of any verbal or behavioral expression of pain. Thereafter, PCA was initiated using an IV syringe pump (3300; Graseby, Herts, UK) containing 1 mg/ml morphine that was set to deliver a bolus dose of 20 g/kg with a 6-min lockout interval and a background infusion of 10 g kg 1 h 1. All postoperative outcome data were collected by an anesthesiologist or nurse who was blinded as to the intraoperative anesthetic regimen. Cumulative morphine consumption, pain scores at rest and on coughing, and sedation scores were recorded every hour for 4 h and then every 4 h for a total of 24 h. Sedation was rated on a numeric scale of 1 to 5, defined as follows: 1, completely awake; 2, awake but drowsy; 3, asleep but responsive to verbal commands; 4, asleep but responsive to tactile stimuli; 5, asleep but not responsive to any stimulus. The initial 24-h morphine consumption was calculated as the sum of the morphine administered in the postanesthesia care unit and the PCA morphine self-administered in the first 24 h after surgery divided by the body weight (kg). Propofol and remifentanil requirements were computed by dividing the total dose administered by the duration of anesthesia (min) and body weight. Postoperative nausea, vomiting, pruritus, and pyrexia were recorded. Ondansetron 0.1 mg/kg was given IV for nausea or vomiting, diphenhydramine 0.5 mg/kg IV for pruritus, and acetaminophen 20 mg/kg orally for postoperative pyrexia, all 6 hourly as needed. The primary outcome variable was the consumption of morphine in the initial 24 h after surgery. The sample size estimation was based on a study from this institution in which the sd of the initial 24-h morphine consumption after scoliosis surgery was 0.31 mg/kg. 1 To demonstrate a 25% difference in morphine consumption (0.40 mg/kg), we estimated that 15 patients per group would be required for a two-tailed of O Hare BP, Sims C, Shorten GD, et al. Efficacy of intrathecal morphine in pediatric scoliosis surgery. Anesthesiology 1995;83: A1146.

3 1664 PEDIATRIC ANESTHESIA CRAWFORD ET AL. ANESTH ANALG REMIFENTANIL AND ACUTE OPIOID TOLERANCE 2006;102: Table 1. Patient Characteristics and Intraoperative Outcomes Morphine (n 15) Remifentanil (n 15) Age (yr) Weight (kg) Male:female 1:14 5:10 Thoracic Cobb angle (degrees) 57 (42 88) 60 (40 84) Length of instrumentation (vertebral levels) 10 (7 14) 10 (6 12) Anesthesia duration (min) Total intraoperative morphine ( g/kg) Propofol infusion rate ( g kg 1 min 1 ) Remifentanil infusion rate ( g kg 1 min 1 ) Values are mean sd, ratio, or median (range). Patient demographics and extent of surgery were comparable in the two groups. and a of 0.1 (power 90%). Two-way repeated measures analysis of variance was used for comparison of the initial 24-h morphine consumption. The Friedman statistic was used for between-group comparison of NRS scores. The Mann-Whitney rank-sum test was used for comparison of ordinal data where appropriate, and Fisher s exact test was used for categorical data. Data are presented as mean sd or median and range. All comparison tests were twotailed and a significance level of 0.05 was used. Results Treatment groups were similar with respect to age, weight, gender, thoracic Cobb angle, number of vertebral levels instrumented, and duration of anesthesia (Table 1 ). The male/female ratio did not differ significantly between groups (P 0.17). All patients completed the study. Figure 1 summarizes the cumulative morphine consumption in the initial 24 h after surgery. Cumulative consumption of morphine in the remifentanil group was significantly more than in the morphine group at each time point in the initial 24 h after surgery (P ). At 4 h after surgery, cumulative morphine consumption in the remifentanil group was double that in the morphine group (Fig. 1). At 24 h after surgery, cumulative morphine consumption in the remifentanil group ( mg/kg) was 30% more than that in the morphine group ( mg/kg), with a difference in sample means of 0.38 mg/kg (95% confidence interval [CI], 0.11 mg/kg to 0.65 mg/kg) (Fig. 1). Regarding NRS scores, no significant difference was found between groups, either at rest (Fig. 2) or on coughing (Fig. 3), during the initial 24 h after surgery. Differences in sedation scores (Fig. 4) and in the incidence of nausea or vomiting (13% versus 20% in the remifentanil and morphine groups, respectively) and pruritus (33% versus 40% in the remifentanil and morphine groups, respectively) were not statistically significant. Three patients in the remifentanil group and four in the morphine group received acetaminophen for postoperative pyrexia. There were no respiratory, cardiovascular, or neurological complications. Figure 1. Cumulative postoperative morphine consumption in the initial 24 h after scoliosis surgery in adolescents who received intraoperative continuous infusion of remifentanil or intermittent boluses of morphine. Postoperative morphine consumption was significantly more in the remifentanil group than in the morphine group at each time point in the initial 24 h after surgery (P ). The cumulative consumption of morphine at 24 h was 30% more in the remifentanil group ( mg/kg) than in the morphine group ( mg/kg) (95% confidence interval for the difference in sample means, 0.11 to 0.65 mg/kg). Discussion The results of the present study show that a continuous intraoperative infusion of remifentanil, when compared with intermittent morphine boluses, significantly increased postoperative morphine consumption in adolescents undergoing scoliosis surgery. Postoperative morphine consumption was significantly larger in the remifentanil group than in the morphine group at each time point in the initial 24 hours after surgery. These findings support the hypothesis that intraoperative remifentanil infusion is associated with the development of clinically relevant acute opioid tolerance or hyperalgesia and are in agreement with previous studies in the adult population (3,4). Guignard et al. (3) reported that adults receiving large-dose remifentanil infusion for colorectal surgery needed

4 ANESTH ANALG PEDIATRIC ANESTHESIA CRAWFORD ET AL ;102: REMIFENTANIL AND ACUTE OPIOID TOLERANCE Figure 2. Box and whisker plot showing numeric rating scale (NRS) pain scores at rest in the initial 24 h after surgery. Differences between groups were not statistically significant. Values are median, interquartile range, and range. Figure 4. Box and whisker plot showing sedation scores in the initial 24 h postoperatively. Differences between groups were not statistically significant. Values are median, interquartile range, and range. Figure 3. Box and whisker plot showing numeric rating scale (NRS) pain scores during cough in the initial 24 h after surgery. Differences between groups were not statistically significant. Values are median, interquartile range, and range. nearly double the amount of morphine and had higher pain scores in the first 24 hours after surgery as compared with patients administered small-dose remifentanil infusion. The mean infusion rate in their largedose group (0.30 g kg 1 min 1 ) was comparable to that in the present study. In another study, adults receiving a continuous remifentanil infusion demonstrated a threefold increase in pain threshold minutes after the start of infusion, at which time the analgesic effect began to decline, reaching one fourth the peak value at 3 hours (4). However, the results of clinical studies are controversial (9,10). Schraag et al. (9) studied adult patients who self-administered their own postoperative analgesia by using target-controlled infusions of alfentanil or remifentanil. Neither group demonstrated a significant increase in postoperative opioid requirement, leading the authors to conclude that acute tolerance to alfentanil or remifentanil did not develop. Cortinez et al. (10) found no difference in morphine consumption or pain scores in patients randomized to receive remifentanil (mean infusion rate, 0.23 g kg 1 min 1 ) or sevoflurane anesthesia for gynecological surgery. These investigators postulated that the lack of development of acute tolerance might be attributed to the relatively short duration of remifentanil infusion (averaging 116 minutes) in their study. Given the fourfold longer duration of remifentanil infusion in the present study, our results support that hypothesis. The most likely explanation for the increased morphine consumption in the present study is the development of acute opioid tolerance or hyperalgesia (3 6). The exact mechanism underlying the development of acute opioid tolerance and hyperalgesia is unknown and may involve activation of dorsal horn N-methyl-d-aspartate (NMDA) systems (13,14), inactivation of -opioid receptors (15), spinal dynorphin release (16), and upregulation of the cyclic adenosine monophosphate pathway (17). The possible involvement of NMDA systems suggests that the NMDA receptor antagonists ketamine and magnesium may be useful adjuncts to morphine for the treatment of postoperative pain after remifentanil infusion (18,19). The present study was designed to detect a clinically relevant difference of 25% in the primary outcome, the initial 24-hour morphine consumption. Thus, our finding that the initial 24-hour morphine consumption was 30% more in the remifentanil group allowed us to reject the null hypothesis. However, Guignard et al. (3) reported a much greater effect of remifentanil infusion in adults. These investigators found that intraoperative infusion of large-dose remifentanil almost doubled the 24-hour postoperative morphine consumption when compared with a control group receiving small-dose remifentanil for colorectal surgery. When comparing our results with those of Guignard et al., the possibility of age-related

5 1666 PEDIATRIC ANESTHESIA CRAWFORD ET AL. ANESTH ANALG REMIFENTANIL AND ACUTE OPIOID TOLERANCE 2006;102: differences must be considered. However, another factor that could explain the different degrees of tolerance is the intensity of postoperative pain. In an animal model, surgical pain was associated with significant attenuation of acute tolerance to morphine antinociception when compared with a control group (20). The authors hypothesized that surgical pain could slow or inhibit the development of tolerance by counteracting the mobilization of the antianalgesic systems participating in the development of acute tolerance (20). Postoperative morphine consumption in the current study, although typical for children undergoing scoliosis surgery (1,11), was more than double that in the study by Guignard et al. (averaging 1.27 mg/kg and 0.46 mg/kg in the respective control groups). Taken together, these findings suggest that a greater intensity of postoperative pain in our study could have attenuated the development of opioid tolerance. A third possibility is that morphine administered at induction of anesthesia might have had a preemptive analgesic effect in our study and thereby attenuated the development of acute opioid tolerance; however, controversy remains over the efficacy of preemptive analgesia (21). As secondary outcomes, we assessed pain scores and the incidence of postoperative morphine-related side effects. Pain scores were measured at rest and during cough, as the latter requires a vital capacity breath akin to that needed for effective postoperative incentive spirometry. Between-group differences in pain scores were not significant, suggesting that patients self-administered morphine to achieve a comparable level of analgesia in each group, albeit at a larger dose of morphine in the remifentanil group. Despite the larger dose of morphine in the remifentanil group, the incidence of postoperative side effects, including nausea, vomiting, and pruritus, was relatively infrequent in the present study, and did not differ significantly between groups. Given this infrequent incidence, the study was under-powered to reveal a difference in side effects. Omission of nitrous oxide and neostigmine may account in part for the relatively infrequent incidence of nausea and vomiting in the immediate postoperative period. Consideration should be given to the limitations of the current study. First, randomization of subjects yielded five male subjects in the remifentanil group and one in the morphine group. Whether gender affects susceptibility to morphine analgesia is debatable (22). In a recent study in adults, women had higher initial postoperative pain scores and morphine requirement ( 11%) than men, although this genderrelated difference disappeared in the elderly (23). This difference, if it were to hold true for the pediatric population, would tend to bias our results in favor of greater postoperative morphine consumption in the morphine group; however, our data show the reverse. Moreover, that the pooled 24-hour morphine consumption for female subjects ( mg/kg) did not differ significantly from that for males ( mg/kg) (P 0.2) suggests that gender-related differences did not contribute significantly to our results. A second limitation of the study is that the mean dose of propofol in the morphine group was larger than in the remifentanil group. Propofol, by acting noncompetitively at NMDA receptors (24), could attenuate the development of tolerance or hyperalgesia to intraoperative morphine and thereby reduce postoperative analgesic requirement. However, postoperative morphine consumption in the morphine group, notwithstanding the dose of propofol administered, was identical to that reported for children who received non-propofol anesthesia for scoliosis surgery in a previous study (53.1 g kg 1 h 1 ) (11), suggesting that propofol had little effect on postoperative morphine requirement in the present study. Further studies are needed to elucidate whether propofol exerts a clinically significant effect on opioid-induced tolerance and hyperalgesia. In summary, to achieve comparable postoperative pain scores after scoliosis surgery, adolescents who received intraoperative remifentanil infusion needed significantly more postoperative morphine than those who received intermittent morphine boluses, suggesting that remifentanil infusion is associated with the development of clinically relevant acute opioid tolerance or hyperalgesia. The benefits of continuous remifentanil infusion as the analgesic component of balanced general anesthesia for scoliosis surgery must be weighed against the potential for development of acute opioid tolerance. We recommend that care should be taken to account for intraoperative exposure to remifentanil when prescribing PCA after scoliosis surgery. References 1. Gibson PRJ. Anaesthesia for correction of scoliosis in children. Anaesth Intensive Care 2004;32: Thompson JP, Rowbotham DJ. An opioid for the 21st century. Br J Anaesth 1996;76: Guignard B, Bossard AE, Coste C, et al. Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000;93: Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998;86: Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103: Angst MS, Koppert W, Pahl I, et al. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003;106: Kissin I, Lee SS, Arthur GR, Bradley EL Jr. Time course characteristics of acute tolerance development to continuously infused alfentanil in rats. Anesth Analg 1996;83:600 5.

6 ANESTH ANALG PEDIATRIC ANESTHESIA CRAWFORD ET AL ;102: REMIFENTANIL AND ACUTE OPIOID TOLERANCE 8. Kissin I, Brown PT, Robinson CA, et al. Acute tolerance in morphine analgesia: continuous infusion and single injection in rats. Anesthesiology 1991;74: Schraag S, Checketts MR, Kenny GNC. Lack of rapid development of opioid tolerance during alfentanil and remifentanil infusions for postoperative pain. Anesth Analg 1999;89: Cortinez LI, Brandes V, Munoz HR, et al. No clinical evidence of acute opioid tolerance after remifentanil-based anesthesia. Br J Anaesth 2001;87: Gaukroger PB, Tomkins DP, Van Der Walt JH. Patientcontrolled analgesia in children. Anaesth Intensive Care 1989; 17: Mooney J, Bernstein R, Hennrikus W, MacEwen GD. Neurological risk management in scoliosis surgery. J Pediatr Orthoped 2002;22: Jordan B, Devi LA. Molecular mechanisms of opioid receptor signal transduction. Br J Anaesth 1998;81: Kissin I, Bright C, Bradley L. Acute tolerance to continuously infused alfentanil: the role of cholecystokinin and N-methyl-daspartate-nitric oxide systems. Anesth Analg 2000;91: Trafton JA, Abbadie C, Marek K, Basbaum AI. Postsynaptic signaling via the -opioid receptor: responses of dorsal horn neurons to exogenous opioids and noxious stimulation. J Neurosci 2000;20: Gardell LR, Wang R, Burgess SE, et al. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 2002;22: Borgland SL. Acute opioid receptor desensitization and tolerance: is there a link? Clin Exp Pharmacol Physiol 2001;28: Shimoyama N, Shimoyama M, Inturrisi CE, Elliot KJ. Ketamine attenuates and reverses morphine tolerance in rodents. Anesthesiology 1996;85: McCarthy RJ, Kroin JS, Tuman KJ, et al. Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats. Anesth Analg 1998; 86: Ho St, Wang JJ, Liaw WJ, et al. Surgical pain attenuates acute morphine tolerance in rats. Br J Anaesth 1999;82: Kissin I. Preemptive analgesia. Anesthesiology 2000;93: Fillingim RB, Ness TJ, Glover TL, et al. Experimental pain models reveal no sex differences in pentazocine analgesia in humans. Anesthesiology 2004;100: Aubrun F, Salvi N, Coriat P, Riou B. Sex- and age-related differences in morphine requirements for postoperative pain relief. Anesthesiology 2005;103: Grasshoff C, Gillessen T. Effect of propofol on N-methyl-daspartate receptor-mediated calcium increase in cultured rat cerebrocortical neurons. Eur J Anaesth 2005;22: