Anesth Pain Med 2011; 6: 138～142 ￭Research Article￭
Effects of intraoperative continuous infusion of low dose remifentanil and intravenous bolus dose of fentanyl on postoperative pain
Department of Anesthesiology and Pain Medicine, School of Medicine, Catholic University of Daegu, Daegu, Korea
Jin Yong Jung, Jong Hae Kim, and Sang Hyuk Son
Background: The aim of this study was to evaluate whether continuous infusion of remifentanil during propofol anesthesia could produce opioid-induced hyperalgesia (OIH) and whether an intra- INTRODUCTION venous bolus of fentanyl could control OIH in the management of postoperative pain. Opioids are useful for controlling moderate or severe pain. It Methods: One hundred fifty-nine women undergoing gynecologic has become increasingly clear that opioids can produce allody- surgery were randomly divided into four groups. Group C: nitrous nia and hyperalgesia [1,2]. Although the underlying patho- oxide and propofol infusion (3−4 μg/ml, n = 40), Group F: propofol infusion and intravenous bolus administration of fentanyl (1μg/kg) physiology of opioid induced hyperalgesia (OIH) is still after suturing the peritoneum (n = 40), Group R: propofol and unclear, Xu et al. [3] explained OIH in terms of an opioid- remifentanil infusion (2−4 ng/ml, n = 40) and Group RF: propofol, induced imbalance between the internal antinociceptive and remifentanil infusion and intravenous bolus administration of fentanyl pronociceptive systems. They speculated that the increased (n = 39). Patient controlled analgesia was started after the opera- tion. The postoperative visual analog scale (VAS) was measured release of excitatory peptides, such as substance P, produces in the recovery room, then at 2 h, 6 h, 12 h, and 24 h after the transient hyperalgesia immediately after morphine administration operation. and that morphine itself somehow paradoxically activates the Results: The VAS scores for Groups R and F in the recovery room pronociceptive system. were lower than for group C (P ＜ 0.05), but there were no differences 2 h after the operation. The VAS scores for Group RF Remifentanil is a popular opioid used for intravenous 6 h and 12 h after the operation were higher than those for group anesthesia due to its fast onset and rapid breakdown by un- ＜ C (P 0.05). specialized esterases in the blood or tissue. Therefore, remifen- Conclusions: Our results suggest that low dose (2−4 ng/ml) tanil has a wide margin of safety, and it can be administered continuous infusion of remifentanil during propofol anesthesia does not produce marked hyperalgesia. However, an intravenous bolus to patients who have renal or hepatic disease. However, of fentanyl can aggravate OIH induced by remifentanil. (Anesth remifentanil can produce OIH and be a problem in regards to ∼ Pain Med 2011; 6: 138 142) postoperative pain control [4-6]. It has also been demonstrated Key Words: Fentanyl, Hyperalgesia, Postoperative pain, Remi- that remifentanil has the potential to decrease the threshold for fentanil. pain recognition, as noted by increased pain ratings in volunteers [7]. Joly et al. [4] reported that a relatively large dose of intraoperative remifentanil (0.4μg/kg/min) can increase postoperative pain sensitivity. Received: December 13, 2010. Revised: 1st, December 29, 2010; 2nd, January 21, 2011. This study was designed to address the questions: (1) Does Accepted: February 7, 2011. the continuous infusion of low-dose remifentanil (2−4 ng/mg) Corresponding author: Jin Yong Jung, M.D., Department of Anesthesiology during propofol anesthesia produce OIH? and (2) Could an and Pain Medicine, School of Medicine, Catholic University of Daegu, 3056-6, Daemyeong 4-dong, Nam-gu, Daegu 705-718, Korea. Tel: intravenous bolus of fentanyl be a treatment for OIH in the 82-53-650-4505, Fax: 82-53-650-4517, E-mail: [email protected] management of postoperative pain? This study included 159 This paper had been performed a poster presentation at American Society patients who underwent gynecologic surgery. of Anesthesiologists Annual Meeting, October 16-20, 2010, San Diego, USA.
138 Jin Yong Jung, et al：Effects of remifentanil on postoperative pain 139
(0.2 mg/kg). Extubation was performed when the patient MATERIALS AND METHODS responded to a verbal command and the BIS was greater than 80. After the patient was awake, a PCA was started. The PCA With approval of the Ethics Committee at our hospital, 159 consisted of 100 ml of a mixed solution made with fentanyl adult patients with ASA physical status I or II undergoing 200−300μg and ketorolac 210−240 mg at a 1 ml/hr infusion elective gynecologic surgery were enrolled in this double-blind rate with a 15 minute lock-out interval and a 1 ml demand study. All patients accepted the use of patient-controlled anal- dose. gesia (PCA) for postoperative pain control. The VAS score was measured in the recovery room and at On the day before surgery, patients were instructed on the 2 h, 6 h, 12 h, and 24 h after the operation by an anes- visual analogue scale (VAS; 0 = no pain, 10+ = worst pain thesiologist who did not know about the patients' group. He imaginable). All patients received midazolam 1.0 mg and also asked the satisfaction score for pain control at 48 h after glycopyrrolate 0.2 mg, intramuscularly, 30 min before surgery. the operation. The satisfaction score was graded as dissatisfac- In the operating room, patients were monitored with an electro- tion: 1, indifferent: 2, satisfied: 3 or greatly satisfied: 4. The cardiogram, pulse oximeter, noninvasive arterial pressure awake time, that is the time between stopping the propofol monitoring and bispectral index (BIS). Patients were randomly and remifentanil to endotracheal tube extubation was measured assigned to one of the four groups. as well. In the control group (group C), anesthesia was induced with All data were reported as mean ± SEM. Statistical Package a continuous infusion of propofol by target-controlled infusion for the Social Sciences (SPSS) version 11.0 was used for the (TCI) to reach 4μg/ml. In the fentanyl group (group F), the statistical analysis. Age, body weight, height, duration of the anesthesia technique was the same as in group C but, fentanyl operation, satisfaction scores and awake time were analyzed by 1μg/kg was injected intravenously after the surgeon sutured one-way analysis of variance (ANOVA). The VAS score was the patient's peritoneum. In the remifentanil group (group R), analyzed by repeated measures of ANOVA for inter-group anesthesia was induced with a continuous infusion of propofol comparisons. A P value of less than 0.05 was considered to and remifentanil by TCI to reach 4μg/ml and 4 ng/ml, be statistically significant. respectively. In the remifentanil-fentanyl group (group RF), the anesthesia technique was same as in group R except that the RESULTS intravenous injection of fentanyl 1μg/kg was started after the surgeon sutured the patient's peritoneum. The pharmacokinetic Demographic data are presented in Table 1. There was no sets used to calculate target effect-site concentrations of propo- significant difference among the four groups in regards to fol and remifentanil were those published by Schnider et al. patients’ age, body weight, height, duration of operation and [8] and Minto et al. [9], respectively. satisfaction score with pain control. After the induction of anesthesia, rocuronium 1 mg/kg was The awake time was shorter in groups R (7.4 ± 0.5 min) used to facilitate tracheal intubation. Anesthesia was maintained and RF (8.0 ± 0.9 min) than groups C (12.2 ± 0.6 min) and with intravenous anesthetics and 50% nitrous oxide. The target F (12.6 ± 0.8 min; P ＜ 0.05) (Table 1). concentrations of propofol and remifentanil were 3−4μg/ml VAS scores were different among groups in the recovery and 2−4 ng/ml, respectively, according to vital signs and BIS. room. The VAS scores in the recovery room for groups R The vital signs were kept within 20% of their values at a (5.1 ± 0.3) and F (5.0 ± 0.4) were significantly lower than basal state. BIS was maintained at 40−60 during the opera- for group C (6.4 ± 0.3) (P ＜ 0.05). In the RF group, the tion. Mechanical ventilation was adjusted to maintain an end-ti- VAS scores (5.4 ± 0.2) in the recovery room were lower than dal carbon dioxide concentration of 30−35 mmHg throughout those for group C, but there was no statistically significant surgery using an anesthetic/respiratory gas analyzer. difference between groups. Two hours after the operation, these After the surgeon sutured the patient's peritoneum, fentanyl differences in VAS scores disappeared. Six and 12 h after the 1μg/kg was injected intravenously in patients assigned to operation, there was a significant difference in VAS scores groups F and RF. At the end of the surgery, propofol and between groups C (3.5 ± 0.4 at 6 h, 2.6 ± 0.4 at 12 h) and remifentanil were discontinued. The neuromuscular block was RF (5.4 ± 0.4 at 6 h, 3.9 ± 0.3 at 12 h). Twenty-four hours reversed by glycopyrrolate (0.008 mg/kg) and pyridostigmine after the operation, there was no significant difference in the 140 Anesth Pain Med Vol. 6, No. 2, 2011
Table 1. Demographic Data
Group C (n = 40) Group F (n = 40) Group R (n = 40) Group RF (n = 39)
Age (yr) 45.7 ± 1.7 44.4 ± 1.7 45.4 ± 1.6 44.8 ± 1.5 Weight (kg) 57.7 ± 1.2 59.7 ± 1.5 58.7 ± 1.6 61.0 ± 1.6 Height (cm) 158.7 ± 0.7 158.2 ± 0.8 159.4 ± 0.7 160.3 ± 0.9 Duration of operation (min) 108.8 ± 4.5 100.7 ± 8.9 112.9 ± 4.2 111.0 ± 4.7 Satisfaction score 3.0 ± 0.1 2.9 ± 0.1 2.8 ± 0.1 2.7 ± 0.1 Awake time (min) 12.2 ± 0.6 12.6 ± 0.8 7.4 ± 0.5* 8.0 ± 0.9*
There was no significant difference among the groups with the exception of awake time. Awake time was significantly shorter in groups R and RF compared to groups C and F. Values are expressed as mean ± SEM. *: P ＜ 0.05 compared to group C. Group C: propofol infusion (3 −4μg/ml) only, Group F: propofol infusion + intravenous bolus administration of fentanyl (1μg/kg), Group R: propofol + remifentanil infusion (2−4 ng/ml), Group RF: propofol + remifentanil infusion + bolus of fentanyl, Satisfaction score: satisfaction with pain control graded as dissatisfaction; 1, indifferent; 2, satisfied; 3 or greatly satisfied; 4. Awake Time: duration from the end of the continuous infusion of drugs to extubation.
DISCUSSION
The purpose of this study was to determine if low dose remifentanil infusion during propofol anesthesia could induce OIH after an operation. The present results demonstrate that the continuous infusion of remifentanil does not produce marked hyperalgesia, whereas intravenous bolus with fentanyl might aggravate the hyperalgesic effect induced by remifentanil. It has become increasingly clear that opioids can produce paradoxical pain and hyperalgesia in many clinical circumst- ances [1,2]. After an online and manual search, Mitra [10] Fig. 1. This figure shows the visual analog scale (VAS) scores for each group. The VAS scores in the recovery room for groups R and F are reported that the underlying pathophysiology of OIH is still significantly lower than those for group C. At 6 h and 12 h after the unclear and that OIH is included in the clinical differentiation operation, there were significant differences between groups C and RF. Values are expressed as mean ± SEM. *: P ＜ 0.05 group R vs. group of an opioid tolerance state. C. †: P ＜ 0.05 group F vs. group C. ‡: P ＜ 0.05 group RF vs. group Recently, several reports have demonstrated that the conti- − μ C.Group C:propofol infusion (3 4 g/ml) only, Group F: propofol infusion nuous infusion of remifentanil also induces hyperalgesia, which + intravenous bolus administration of fentanyl (1μg/kg), Group R: propofol + remifentanil infusion (2−4 ng/ml), Group RF: propofol + is similar to findings with other opioids. Angst et al. [11] remifentanil infusion + bolus of fentanyl. reported that hyperalgesia developed within 30 min after stopping a 90 min remifentanil infusion in healthy human volunteers. In that study, the infusion rate for remifentanil was VAS scores among groups (Fig. 1). In group C, changes in set at 0.1 mg/kg/min, to achieve a stable plasma concentration the VAS scores as a function of time nearly linearly declined. ranging between 2.7 and 2.9 ng/ml during the infusion, However, those changes were different in groups F and RF. In without any other anesthetic drug. Vinik et al. [12] reported groups F and RF, the VAS scores increased 2 h after the that a profound tolerance to analgesia developed within 60 to operation compared to those in the recovery room, and the 90 min during a 4-h-long constant rate remifentanil infusion in time point with the highest VAS scores was 2 h after the volunteers. The remifentanil infusion rate was 0.1 mg/kg/min operation. After that time point, the VAS scores decreased but and they also did not use any other anesthetics. Cho et al. [6] were still higher than those for group C. reported that the intraoperative use of remifentanil with sevo- flurane in gynecologic operations may be related to increased postoperative pain during the early postanesthetic period. They Jin Yong Jung, et al：Effects of remifentanil on postoperative pain 141 used a TCI device for the remifentanil infusion and compared There are several reports discussing the treatment of OIH, remifentanil target concentrations of 1 ng/ml or 3 ng/ml with such as NMDA receptor antagonists [4,17], parecoxib [18,19], normal saline. With the remifentanil target concentrations of 1 and opioid rotation [20]. Joly et al. [4] reported that a small ng/ml and 3 ng/ml, the VAS scores were significantly higher dose of a ketamine infusion prevented opioid induced hyper- than those for the saline group up to 60 min after arrival to algesia in their 75 patients undergoing major abdominal the postanesthetic care unit. However, the VAS scores were surgery. With an electrophysiologic record of rat dorsal horn not significantly different among the groups 6 h after the neurons treated with remifentanil, Zhao and Joo [21] reported operation. that remifentanil induced rapid, persistent increases in NMDA In contrast, our results revealed that there was no marked responses that were dependent on the activation of both mu- hyperalgesia in the R, F or RF groups in the recovery room. and delta-opioid receptors. They concluded that selective Although the remifentanil infusion rate was similar to that delta-opioid inhibition may attenuate acute paradoxical increases used by Cho et al. [6], there was no hyperalgesic effect in the in pain and tolerance to opioids. Troster et al. [18] enrolled R group. Moreover, postoperative VAS scores in the recovery 15 volunteers in their study and reported that hyperalgesia room in the R and F groups was significantly lower than that could be controlled with parecoxib administration 30 min for the C group, suggesting that a residual effect of remi- before a remifentanil infusion. They emphasized adequate fentanil or intravenous fentanyl may produce an analgesic timing for the antihyperalgesic effects of cyclooxygenase-2 effect in the recovery room. It appears that there are several inhibitors. differences in postoperative effects between propofol and Fentanyl has been reported to have a different effect on inhaled anesthetics [13,14]. In a study examining the effect of OIH. Lenz et al. [22] compared a fentanyl pre-treatment group propofol on remifentanil-induced hyperalgesia, clinically relevant with a placebo group in their double-blind study in 100 interactions of propofol and remifentanil existed, and propofol patients who underwent anterior cruciate ligament repair. They could delay and weaken remifentanil-induced hyperalgesia [15]. concluded that pre-treatment with fentanyl 1.5μg/kg did not Recently, Shin et al. [16] reported that remifentanil hyperal- reduce postoperative pain or analgesic consumption after 90 gesia was induced by high doses of remifentanil-based min of remifentanil-based anesthesia. In the current study, we anesthesia during sevoflurane anesthesia, whereas that was not could not find any preventive effect of intravenous bolus with apparent during propofol anesthesia. Also, remifentanil hyper- fentanyl in regards to OIH induced by remifentanil. Further- algesia did not occur during low dose administration of remi- more, our results strongly indicate that fentanyl could aggravate fentanil-based anesthesia. They used remifentanil concentrations OIH induced by remifentanil. From the concept proposed by of 1 ng/ml or 4 ng/ml for the low dose or high dose group, Xu et al. [3], we believe that both remifentanil and fentanyl respectively, during propofol or sevoflurane anesthesia. These have their own effects on the pronociceptive system as well as results are consistent with our results, suggesting that propofol an additional effect. This theory awaits experimental verifica- was the main reason for no hyperalgesia in the R group in tion. spite of the relatively similar remifentanil infusion rate as In addition, the R and RF groups had a shorter recovery compared to Cho et al [6]. time compared to the other groups. Taking these findings into However, VAS scores were increased at 2 h, 4 h, 6 h and consideration, we speculate that the reason is due to a larger 24 h in the R and F groups, but there was no significant volume of propofol infused in the C and F groups compared difference compared to the C group. These findings suggest to the R and RF groups. that a continuous infusion of remifentanil or an intravenous There are several limitations of this study. The first limita- bolus of fentanyl has minimal signs and characteristics of OIH, tion is that the PCA used in this study contained a small however, it is suggested that our clinical setup, such as the amount of fentanyl. Because the fentanyl in the PCA might be use of a low dose remifentanil infusion, might not produce another factor related to the development of OIH or OIH marked OIH. Although there were different results in the R treatment, we think that OIH in this clinical setting can be group as compared with those from Joly et al. 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