Remifentanil is the latest piperidine-derived opioid that acts as a μ-receptor agonist. The pharmacokinetic properties of remifentanil are unique among the opioids, with the drug having a very rapid plasma clearance and onset time and a very short context-sensitive half-life (2–10 min.). Consequently, it can be administered in prolonged infusion without the risk of accumulation (1,2). The absence of residual analgesia after remifentanil-based anesthesia requires the provision of adequate postoperative analgesia before suspending infusion of the drug, or the maintenance of remifentanil infusion at analgesic doses during the postoperative period (3). In a study by Bowdle et al. (4) adequate postoperative analgesia with IV remifentanil infusions between 0.05–0.15 μg · kg−1 · min−1 was reported. In this study, variations in the infusion rate and supplementary boluses were allowed; a frequent incidence of respiratory adverse events (29%) was noted.
The most effective analgesic approach and dose regimen for remifentanil in the postoperative period when the drug is used as a single analgesic during surgery remains to be determined.
We hypothesized that a constant-dose continuous infusion of remifentanil 0.1 μg · kg−1 · min−1 IV maintained for 4 h is effective and safe for the treatment of moderate-severe postoperative pain. Thus, the aim of this clinical trial was to compare two different continuous constant-small-dose infusions of remifentanil, without infusion rate increments or the addition of boluses after surgery, in patients with severe postoperative pain after propofol-remifentanil general anesthesia.
After local ethics committee approval and written informed consent, 30 patients ASA physical status I-II, 18 yr of age or older, scheduled to undergo elective abdominal or thoracic surgery, were enrolled in this randomized, double-blinded study. The efficacy of two different infusion rates of IV remifentanil for the treatment of severe postoperative pain after propofol-remifentanil general anesthesia.
The patients were randomly assigned to two groups of 15 subjects each according to the remifentanil dose administered postoperatively in constant infusion: 0.1 μg · kg−1 · min−1 IV (Group A) or 0.05 μg · kg−1 · min−1 IV (Group B). Exclusion criteria were cardiovascular or central nervous pathology; allergies to opioids, chronic opioid or psychoactive drug use, or a history of drug addiction or alcohol abuse.
All patients were subjected to general anesthesia involving a standard technique. Anesthesia was induced with remifentanil 1 μg · kg−1 · min−1, propofol 1.5–2.0 mg/kg and vecuronium 0.1 mg/kg−1 IV to facilitate tracheal intubation, and maintained with a continuous infusion of propofol 75 μg · kg−1 · min−1 and remifentanil between 0.5–1.0 μg · kg−1 · min−1 IV and intermittent boluses of vecuronium to maintain adequate surgical neuromuscular block. Fifteen minutes before the end of surgery, the propofol infusion was reduced to 50% and the neuromuscular block was reversed when required. At the end of surgery, propofol infusion was discontinued and remifentanil infusion was reduced according to the study group involved, i.e., to 0.1 μg · kg−1 · min−1 IV (Group A) or 0.05 μg · kg−1 · min−1 IV (Group B). The trachea was extubated with the assigned remifentanil infusion running when adequate spontaneous ventilation and response to verbal stimulation were obtained. No patient received naloxone.
All patients were transferred to the postanesthetic care unit (PACU) with the assigned remifentanil infusion maintained for the first 4 h postoperatively without increments or reductions in infusion rate or the administration of supplementary IV boluses. An Anne® infusion pump (Abbott Laboratories, North Chicago, IL) was used with a remifentanil concentration of 50 μg/mL. At admission to the PACU, heart rate and blood pressure were monitored, along with respiratory frequency and oxygen saturation (Spo2).
From admission to the PACU and every 20 min thereafter, assessments were made of the hemodynamic (heart rate and systolic, diastolic and mean blood pressure) and respiratory (respiratory rate and oxygen saturation) variables, and of the degree of sedation. A postanesthetic recovery score was recorded using the six-point scale described by Ramsey et al. (5) (Appendix) and the 1–10 point Aldrete score (6), respectively. The time to potential discharge from the recovery unit was also recorded. The intensity of postoperative pain was assessed by the simple verbal scale (SVS) involving 4 degrees (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain), and the visual analog scale (VAS) (0 = no pain, 10 = worst imaginable pain) at rest. The SVS was evaluated continuously for the first 4 h postoperatively, and the patients had been informed that when they experienced moderate-severe pain (SVS ≥ 2), a rescue analgesic would be administered (meperidine 0.5 mg/kg IV). The number of patients meeting the criteria for adequate analgesia (SVS 0–1, respiratory rate >8 breaths/min with oxygen saturation >90%) was recorded, along with the adverse events and the need for rescue analgesia.
A prestudy power analysis revealed that a sample size of 15 patients per group would provide 80% power and α = 0.05 to detect a difference of at least 40% in the percentage of patients with SVS <2 between the groups. Data are expressed as mean values ± sd or percentages. The statistical analysis was performed with the Mann-Whitney U-test for nonpaired data, the Wilcoxon test for paired data, and the χ2 test for the categorical data. Statistical significance was considered for P < 0.05.
The two treatment groups were similar with respect to demographic data and surgical procedures (Table 1). The hemodynamic variables (Table 2) and respiratory rates remained stable throughout the study; there were no differences between the two groups or with respect to the basal values. Oxygen saturation values by pulse oximetry (Spo2) were stable during the infusion of remifentanil (96%–98%).
The analgesia achieved during the 4 h of the study resulted in a significant decrease in pain intensity in both groups (Group A P < 0.01; Group B P < 0.05) on both the SVS and the VAS, with respect to the ratings recorded at admission to the PACU. The percentage of patients with SVS 0–1 on PACU admission were: 51% (Group A) vs 11% (Group B) (P < 0.05) and 78% (Group A) vs 75% (Group B) at the end of the study. VAS scores on PACU admission were 4.0 ± 3.0 (Group A) vs 5.3 ± 1.9 (Group B) and VAS score at the end of the study were 1.7 ± 2.0 (Group A) vs 2.5 ± 1.5 (Group B). By the end of the analgesic infusion period the percentage of patients with adequate analgesia were 78% and 75% in Groups A and B respectively (P = ns). However, on arrival in the PACU there appeared to be statistically significant differences in the criteria for adequate analgesia between groups (P < 0.05) (Fig. 1). Meperidine rescue was significantly more in Group B (26%) than in Group A (6%) (P < 0.05). The Ramsey score was 2–3 in 100% of patients in both groups during the entire study. No statistically significant differences were recorded between the two dosing groups in terms of the time required to score 8 on the Aldrete scale and to allow potential for discharge from the PACU, though both times were first reached in Group A: Aldrete >8 (20 ± 10 min in Group A and 38 ± 23 min in Group B); eligible discharge (99 ± 36 min in Group A and 127 ± 41 min in Group B). There were no episodes of hypoxemia (oxygen saturation < 90%) or apnea. Nausea and emesis occurred in one patient in each group (6.5%).
In the present study, the continuous infusion of remifentanil at the constant dose of 0.1 μg · kg−1 · min−1 IV, without modifications in the infusion rate or the addition of boluses, provided adequate analgesia (SVS 0–1) in 78% of the patients by the end of this four-hour study.
The pharmacodynamics of remifentanil are not particularly different from those of other opioids but the pharmacokinetic characteristics of remifentanil are unique. The absence of residual analgesia during the immediate postoperative period makes it necessary to commence postoperative pain therapy before the antinociceptive effects of remifentanil have dissipated (7,8). In surgical interventions associated with severe postoperative pain, remifentanil has been used to control pain in the immediate postoperative period as a transition measure toward the administration of longer-acting analgesics (9). In our study, the patients were scheduled for major surgery (open thoracotomies and laparotomies), which can be associated with moderate or severe postoperative pain (9). Respiratory depression clearly appears to be the most important limiting factor in the use of IV opioids in conscious patients. In this context, adequate postoperative monitoring is required, as are correct functioning of the infusion pumps and constant vigilance of the patient when using remifentanil as a postoperative analgesic (10,11).
In a multicenter study, Bowdle et al. (4) reported adequate analgesia (SVS 0–1) in 78% of patients after administering remifentanil at doses of between 0.05–0.15 μg · kg−1 · min−1 IV in the first 30 min postoperatively, allowing infusion rate increments of 0.025–0.1 μg · kg−1 · min−1 IV and/or associated 0.25–0.5 μg/kg IV boluses for the control of postoperative pain. However, the observed incidence of adverse respiratory events was frequent (29%), with a 7% incidence of apnea. This is because remifentanil bolus dosing and infusion rate increments induce rapid changes in drug plasma concentration which, in turn, lead to respiratory depression, apnea, and muscle rigidity (12).
Yarmush et al. (13) found that infusions of between 0.05–0.23 μg · kg−1 · min−1 IV (0.125 μg · kg−1 · min−1 IV on average), and adding only infusion increments of 0.025 μg · kg−1 · min−1 IV, offered safe and effective treatment of postoperative pain in 58% of patients in the first 35 min after extubation. The observed incidence of apnea and respiratory depression was 14%, i.e., less than the results reported by Bowdle et al. (4) with similar remifentanil doses. At the doses used, remifentanil provided more postoperative analgesic efficacy than 0.15 mg/kg of morphine sulfate followed by five 2-mg boluses of morphine (13).
Applying the criteria of adequate analgesia at the end of the study, our results are similar or superior to those reported by Bowdle et al. (4) and Yarmush et al. (13) in the treatment of postoperative pain with remifentanil, and were achieved without bolus dosing or infusion rate increments. Exclusively assessing the first 60 min after surgery, constant dosing of 0.05 μg · kg−1 · min−1 IV was found to be insufficient. However, constant dosing of 0.1 μg · kg−1 · min−1 IV provided results similar to those of Yarmush et al. (13). In our opinion, variable dose adjustment in the first postoperative hour, followed by constant dosing of 0.1 μg · kg−1 · min−1 could optimize patient analgesia and comfort after surgery associated with intense postoperative pain. Manually controlled remifentanil infusion for a prolonged period after surgery (4 h, which corresponds to the most painful interval) has not been described in the literature (4,12,13); only periods of under 1 h after extubation have been evaluated. We consider between 2–4 h of remifentanil infusion in the immediate postoperative period to be adequate for ensuring patient adaptation to other analgesic techniques that prove difficult to initiate in under 1 h.
Patient controlled analgesia with target controlled infusion (PCA-TCI) is the only administration method using remifentanil as a postoperative analgesic to exhibit satisfactory analgesia (VAS<3) in 100% of patients without episodes of respiratory depression or apnea in the first 6 h postoperatively. This technique maintained a mean drug plasma concentration of 2.02 (1.87–2.16) ng/min, using increments of 0.2 ng/min every 2 min as a supplement to the remifentanil plasma concentration while maintaining spontaneous breathing, and followed by automatic reduction by 0.2 ng/min in the absence of demand for 30 min (14).
The needs for rescue analgesia in our study were 6% and 26% with remifentanil infusions of 0.1 and 0.05 μg · kg−1 · min−1 IV, respectively, versus 8% in other studies (4). This suggests that 0.05 μg · kg−1 · min−1 IV may be more effective for the treatment of slight to moderate postoperative pain, reserving 0.1 μg · kg−1 · min−1 IV for cases of severe postoperative pain.
The incidence of nausea and vomiting in our study (6.5%) is less than the 17–47% reported in previous studies (4,12,13). Respiratory depression is one of the most frequently observed adverse effects (14–29%) when remifentanil boluses are administered and/or the infusion rate is increased rapidly (4,12,13). Such a dosing regimen is thus inadvisable for postoperative analgesia. In agreement with Schraag et al. (14), who performed dosing with the PCA-TCI system, we observed no case of respiratory depression. In our study hemodynamic stability was maintained during the titration period. Similar findings have been published (4,13).
The time required among our patients to score >8 on the Aldrete scale, and thus become eligible for discharge, was similar to that reported in other studies (4,13), as was the degree of sedation observed (slight) (14). We do not know the causes for a longer recovery score in the smaller dose group, though they are possibly related to the administration of rescue analgesia in this group.
One of the limitations of our study is the small number of patients evaluated, though the results obtained are nevertheless quite consistent and coincide with those of other authors (4,13,14). Our study showed that a continuous constant rate infusion of remifentanil for a prolonged period of time for postoperative analgesia provides adequate analgesia without the adverse respiratory side effects often associated with infusion techniques using boluses and rate changes. This method of administering remifentanil is different from that reported in the literature. It is easier to provide than other methods of IV analgesia, is associated with fewer adverse effects and has an analgesic effectiveness comparable to previous methods.
In conclusion, in the presence of adequate patient vigilance, remifentanil was an effective and safe opioid for the treatment of postoperative pain, providing adequate analgesia in 78% of patients at a constant dose of 0.1 μg · kg−1 · min−1 IV without signs of respiratory depression. Although the two infusion rates produced similar results at the end of the study, a remifentanil constant dose of 0.1 μg · kg−1 · min−1 provided a difference in the pain intensity on admission to the PACU, receiving 4 times less rescue analgesia than 0.05 μg · kg−1 · min−1 infusion rate. This approach represents an alternative to other analgesic techniques for the treatment of immediate postoperative pain after surgery associated with severe pain. Variable dose adjustment during the first hour after surgery, followed by constant dosing, could optimize patient analgesia and comfort. Additional studies are needed to investigate the role of remifentanil infusion for postoperative pain.
We thank Antonio Escolar MD, Ann Galbraith, and Aurora Alba, for their help and cooperation on this paper.
Modified Ramsey Sedation Scale (5) is a six-point scale widely used clinically as a guide to level of sedation in postanesthetic care unit (PACU). TABLE
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