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ANALGESIA

Postoperative Pain and Analgesic Requirements After Anesthesia with Sevoflurane, Desflurane or Propofol

Argyro Fassoulaki, MD, PhD, DEAA^*, Aikaterini Melemeni, MD, DESA^*, Anteia Paraskeva, MD, DESA^*, Ioanna Siafaka, MD^*, and Constantine Sarantopoulos, MD, PhD, DEAA

From the *Department of Anesthesiology, Aretaieio Hospital, Medical School, University of Athens; and Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Address correspondence and reprint requests to Argyro Fassoulaki, MD, PhD, DEAA, Department of Anesthesiology, Aretaieio Hospital, 76 Vassilissis Sofias Ave., 11527, Athens, Greece. Address e-mail to fassoula{at}aretaieio.uoa.gr or afassou1{at}otenet.gr.

Abstract

BACKGROUND: General anesthetics may have nociceptive actions that affect postoperative pain. In studies evaluating postoperative pain, the effect of general anesthetics on analgesic requirements has not been considered except for one recent study suggesting that propofol anesthesia provides better analgesia after surgery than isoflurane.

METHODS: In this prospective, blind, randomized trial we recorded postoperative analgesic requirements (mg of morphine) and pain scores (visual analog scale in mm) 2, 4, 8, and 24 h postoperatively in patients undergoing abdominal hysterectomy or myomectomy under sevoflurane, desflurane or propofol anesthesia, titrated to maintain Bispectral Index values between 35 and 45. Pain scores were also recorded immediately after transfer to the postanesthesia care unit.

RESULTS: Cumulative morphine consumption did not differ among the three groups 2, 4, 8, or 24 h postoperatively (P = 0.50). The morphine consumed within 24 h postoperatively was 28 ± 13.8 mg in the sevoflurane group, 25 ± 11.7 mg in the desflurane group and 27 ± 16.1 mg in the propofol group. The visual analog scale values at rest or after cough immediately after patient transport to the postanesthesia care unit and 2, 4, 8, and 24 h after surgery did not differ among the three groups (P = 0.40, 0.39, 0.50, 0.47, 0.06 at rest and P = 0.67, 0.45, 0.22, 0.26, 0.29 after cough respectively).

CONCLUSION: Morphine consumption and pain 24 h postoperatively did not differ among the sevoflurane, desflurane, and propofol groups.

General anesthetics may alter nociceptive processes in various ways. Thiopental decreases the pain threshold to a pressure stimulus but increases the pain threshold to heat.1 Anker-Moller et al. applied laser stimulation to volunteers and demonstrated that both thiopental and propofol decrease the amplitude of the pain-evoked potential and increased the pain threshold.2

Inhaled anesthetics have been used for pain relief in labor. Methoxyflurane, trichloroethylene and, later, isoflurane have been used as obstetric analgesics.3,4 Most recently, sevoflurane has been used for analgesia during uterine contractions in labor and was found to be more beneficial than Entonox administration.5,6

The differential effects of general anesthetics on nociceptive pathways may influence postoperative pain development. Our hypothesis was that general anesthetics administered to maintain anesthesia will not affect analgesic requirements and pain after surgery when factors such as analgesics given pre and intraoperatively are constant. The aim of the study was to investigate analgesic consumption and pain intensity during the first 24 h postoperatively in patients undergoing abdominal hysterectomy or myomectomy under sevoflurane, desflurane or propofol anesthesia.

METHODS

Patient Recruitment
After obtaining written informed patient consent and approval from the IRB, 105 patients aged between 21 and 59 yr, ASA physical status I-II, undergoing elective abdominal hysterectomy or myomectomy were recruited for the study. Study recruitment was between November 11, 2005 and May 17, 2007. The evening before surgery patients were informed about the use of the patient-controlled analgesia pump and postoperative analgesia assessment using the visual analog scale (VAS). Exclusion criteria were body weight >20% of the ideal, calcium channel blockers, β-blockers, antidepressants, anxiolytics, and analgesics intake within the last month, and cardiovascular or respiratory, or nervous system disease.

Randomization and Blindness
Patients were randomly assigned to sevoflurane, desflurane or propofol for maintenance of general anesthesia. Randomization was done by two independent anesthesiologists using 105 opaque sealed envelopes, 35 for each group, indicating patient group assignment and describing the anesthetic protocol for this particular group. The patients and anesthesiologists involved in assessing postoperative pain, analgesic consumption, data collection and analysis of results, were not aware of group assignment (AF and CS).

Anesthetic Technique
In the operating room a peripheral venous catheter was inserted, a Ringer's lactated solution infusion was started and 10 mg of metoclopramide and 0.750 mg of droperidol were administered IV. Standard monitoring was used, and the inspired oxygen concentration, concentrations of nitrous oxide and the volatile anesthetic were monitored (Datex-Ohmeda S/5^TM Anesthesia Monitor, Helsinki, Finland). A Zipprep^TM electrode (Aspect Medical Systems Inc., Newton MA) was applied to the patient's forehead and the Bispectral Index (BIS) was monitored.

In the three groups anesthesia was induced with IV morphine 0.15 mg/kg and propofol 2.5 mg/kg. Cisatracurium 0.15 mg/kg was administered IV to facilitate tracheal intubation and to provide muscle relaxation intraoperatively. Muscle relaxant administration was repeated as required to maintain satisfactory muscle relaxation. The inspired concentration of nitrous oxide in all groups was 70%. After removal of the uterus or after myomectomy, all patients received 1200 mg of paracetamol IV.

In the sevoflurane group anesthesia was maintained with sevoflurane, in the desflurane group with desflurane and in the propofol group with continuous propofol infusion. All anesthetics were titrated to maintain intraoperative BIS values between 35 and 45. At the end of the procedure 4 mg of ondansetron was given IV. Neuromuscular block was antagonized with 2.5 mg of IV neostigmine and 1.2 mg of atropine and the patient was transferred to the postanesthesia care unit (PACU).

Postoperative Analgesia and Assessment of Postoperative pain
In the PACU patients had access to a patient-controlled analgesia pump containing morphine solution 1 mg/mL (Freedom5®, VYGON, B.P. 7–95440 ECOUEN-France). This pump when activated releases 1 mL solution with a lockout interval of 7 min and is not interrogated regarding the number of demands. All patients received 10 mg of metoclopramide 8 hourly for the first 24 h after surgery.

The VAS scale was a straight line on white paper with 100 mm and the patient was asked to draw a vertical line indicating the intensity of pain, considering 0 = no pain and 100 the worst imaginable pain. VAS at rest and VAS after cough were recorded 5 times: 0 (in PACU), 2, 4, 8, and 24 h postoperatively. Cumulative morphine consumption was recorded 2, 4, 8, and 24 h after surgery.

The primary end-point of the study was postoperative analgesic requirements (cumulative morphine consumption during the first 24 h after surgery). Secondary end-points were the VAS pain scores at rest and after cough. We provided antiemetic prophylaxis to all our patients but did not monitor the incidence of nausea and vomiting, since such observation and recording could have biased the anesthesiologist collecting data, as propofol has an antiemetic effect.

Statistics
The primary outcome was cumulative analgesic consumption within the first 24 h postoperatively. Based on initial pilot measurements we estimated the standard deviation within each group to be approximately 11 and an effect size equal to approximately 0.32. The error was assumed to be 0.05. Post hoc computation of the achieved power was 0.833. For an a priori sample size estimation, and post hoc achieved power computation, we used G*Power software, version 3.0.8 for Mac OS X and guidelines by Lenth RV (2006): Java Applets for Power and Sample Size, available at http://www.stat.uiowa.edu/~rlenth/Power.

Patient characteristics (age, weight, height), duration of surgery, and VAS pain scores at each time point were compared among the three groups by one-way analysis of variance. The number of patients who had myomectomy in each group was compared with those having abdominal hysterectomy with Pearson ² test. Postoperative morphine consumption at 2, 4, 8, and 24 h, and BIS values were compared by SPSS Univariate General Linear Model, regarding the main effects of time and group. For post hoc comparisons we used Scheffe test, as needed. For data analysis we used SPSS Software, Version 11.0.4 for Mac Os X.

RESULTS

The three groups did not differ in age, height, and body weight (Table 1). Duration of surgery differed among the groups (F = 3.232; df = 2.97; P = 0.04) and was longer in the propofol when compared to the sevoflurane group (P = 0.04 by Scheffe test) but did not differ from the desflurane group. The length of surgery also did not differ between the sevoflurane and desflurane groups.

The number of patients who had myomectomy (17, 14, and 19 in the sevoflurane, desflurane, and propofol groups) did not differ from the number of patients who had hysterectomy (17, 18, and 16 for the sevoflurane, desflurane, and propofol groups). BIS values did not differ with regard to the main effect of group (F = 2.631, df = 2.1170; P = 0.07) (Fig. 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Intraoperative Bispectral Index values in the sevoflurane, desflurane, and propofol group. Values are mean ± sd.

Cumulative morphine consumption did not differ among the 3 groups 2, 4, 8, or 24 h postoperatively regarding to the main effect of group (F = 0.687; df = 2.385; P = 0.50) (Fig. 2). The overall morphine consumed postoperatively was 28 ± 13.8 mg in the sevoflurane group, 25 ± 11.7 mg in the desflurane group and 27 ± 16.1 mg in the propofol group.

View larger version (9K): [in this window] [in a new window]   Figure 2. Cumulative morphine consumption (mg) in the sevoflurane, desflurane and propofol group during the 24 h postoperatively. Values are mean ± sd.

Similarly, we found no differences among the three groups in VAS values at rest or after cough, immediately after patient transport to the PACU as well as 2, 4, 8, and 24 h after surgery (P = 0.40, 0.39, 0.50, 0.47, 0.06 at rest and P = 0.67, 0.45, 0.22, 0.26, 0.29 after cough respectively) (Fig. 3).

View larger version (15K): [in this window] [in a new window]   Figure 3. Visual analog scale (mm) values at rest (A) and after cough (B) in the sevoflurane, desflurane and propofol group immediately after the end of anesthesia as well as 2, 4, 8, and 24 h postoperatively.

DISCUSSION

Our results showed that the choice of the anesthetic, inhaled (sevoflurane or desflurane) or IV (propofol), to maintain anesthesia has no effect on analgesic requirements or postoperative pain during the first 24 h. These results may suggest that either the subanesthetic doses of the three anesthetics during the elimination phase do not exert any analgesic properties or that the effects exerted by these drugs such as hyperalgesia or analgesia are similar.

The effect of propofol on noxious stimuli is controversial. In rats, propofol suppressed nociception induced by spinal sensitization,7 and in goats it decreased the dorsal horn responses to mechanical noxious stimuli applied to the hindlimb.8 In the rat formalin model, subcutaneous injection of propofol in the dorsal surface of the hindpaw produced antinociception in a dose-dependent manner.9 Other studies failed to demonstrate analgesic properties of propofol. In mice that received intraplantar formalin injection, a bolus administration of propofol had no effect on the fos-like immunoreactivity or the nociceptive behaviors elicited by formalin injection.10 Thus the authors of the study concluded that propofol has no analgesic properties.

Therefore, experimental data give various results regarding the analgesic properties of propofol, whereas two human studies suggest an analgesic effect. Anker-Moller et al.2 found that, in healthy subjects, propofol increases the pain threshold and decreases the amplitude of the evoked potential when the noxious stimulus is produced by argon laser stimulation. Recently, propofol was shown to be associated with less morphine consumption and less postoperative pain when compared to isoflurane anesthesia.11

Volatile anesthetics may have analgesic properties. In rats desflurane attenuates the response to tibial nerve stimulation and the pressor response to electrical stimulation.12 These actions indicate antinociceptive properties of this anesthetic. Sevoflurane decreased the number of fos-like immunoreactive neurons in the dorsal horn of the spinal cord in rats that were subjected to the formalin test.13 This effect was antagonized by administration of naloxone and naltrexone. The literature assessing postoperative pain does not address the possible impact of general anesthetics on postoperative pain, except for a recent study by Cheng et al.11 showing that propofol anesthesia was associated with less postoperative pain than isoflurane anesthesia. Possible explanations for the different results between our study and the study by Cheng et al. are the different volatile anesthetics studied, the different intraoperative analgesic regimes (as we administered morphine and paracetamol while Cheng et al. administered fentanyl) and the use of nitrous oxide in our study. We also titrated the anesthetics to obtain BIS values 35 to 45 whereas Cheng et al. titrated the anesthetics to a higher BIS value.

As pain assessment and analgesic requirements were recorded during the first 24 h postoperatively, our results apply rather to the impact of the subanesthetic concentrations of the three anesthetics on postoperative pain than to the concentrations we administered to maintain general anesthesia. Experimental data suggest that subanesthetic concentrations of inhaled anesthetics, like isoflurane, produce hyperalgesia with a maximal effect at 0.1 minimum alveolar anesthetic concentration.14 The physical characteristics of the inhaled anesthetics we studied, sevoflurane and desflurane, predict faster elimination from the body than isoflurane, which will remain in the body longer during the recovery period. If these experimental data apply to humans, then the longer period of hyperalgesia produced by isoflurane might affect the different results of our study and those of Cheng et al.11 On the other hand, Freye et al.15 demonstrated that 1 and 2 minimum alveolar concentration of desflurane or sevoflurane anesthesia produced the same depression of the propagation of sensory afferent stimuli to the central nervous system pain centers.

We found longer duration of surgery in the propofol group when compared to the sevoflurane group only, despite use of the same types of procedures in all groups. This may be a limitation of our study. However, this difference does not affect postoperative pain and analgesics used between the propofol versus desflurane groups and the sevoflurane versus desflurane groups. Nevertheless, we also found no difference between the sevoflurane and propofol groups.

In conclusion, under the present study design, maintenance of general anesthesia by sevoflurane, desflurane or propofol did not influence early postoperative analgesic requirements or pain development in patients undergoing myomectomy or elective abdominal hysterectomy.

Footnotes

Accepted for publication April 16, 2008.

Supported by Departmental Sources.

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