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From the Departments of *Anaesthesiology, and Gynecology and Obstetric, Cukurova University Faculty of Medicine, Adana, Turkey.
Address correspondence and reprint requests to Dr. Hakki Unlugenc, Department of Anaesthesiology, Cukurova University Faculty of Medicine, 01330 Adana, Turkey. Address e-mail to unlugenc{at}cu.edu.tr.
Abstract
We designed this prospective, randomized, double-blind study to compare the analgesic effectiveness and side effects of IV patient-controlled morphine, pethidine, and tramadol for postoperative pain management. One-hundred-twenty-six ASA physical status I or II patients undergoing abdominal hysterectomy were randomly allocated to receive IV-patient controlled morphine (M), pethidine (P), or tramadol (T) for postoperative analgesia. The cumulative analgesic consumption over 24 h was 25.7 ± 9.5 mg for morphine, 266 ± 90 mg for pethidine, and 320 ± 10 mg for tramadol. The average supplementary fentanyl dose used was significantly higher in group T than in groups M and P (P < 0.05). In conclusion, morphine, pethidine, and tramadol resulted in equivalent pain scores and side effects, but tramadol group T required more rescue analgesic doses of fentanyl.
Morphine, pethidine, and tramadol are the most frequently used drugs for postoperative pain management.1–4 Among morphine, pethidine, and tramadol, there is a lack of consensus regarding the most appropriate drug for IV patient-controlled analgesia (IV PCA) for postoperative pain management after abdominal hysterectomy, as few objective comparative data are available.2,3
Several studies have compared the analgesic effect of patient-controlled tramadol with morphine3,4 for the treatment of postoperative pain; no such comparison has been made with patient-controlled pethidine. In addition, at equianalgesic doses, the efficacy and side effects of these drugs when used for IV PCA for postoperative pain management have not been compared.
This prospective, randomized, double-blind study was designed to compare the analgesic efficacy and side effects of morphine, pethidine, and tramadol, at equianalgesic doses, administered by PCA for postoperative pain after abdominal hysterectomy.
METHODS
After ethics committee approval and informed patient consent, 126 ASA physical status I or II patients, between 34 and 63 years, scheduled for elective abdominal hysterectomy with general anesthesia, were recruited. Exclusion criteria included allergy to the study drugs, inability to use the PCA device, long-term use of opioid medications, history of hepatic, cardiopulmonary, or renal disease, and a history of chronic pain.
All patients were premedicated with IV midazolam 0.15 mg/kg 45 min before surgery. Anesthesia was induced with thiopental sodium (5 mg/kg) and maintained with 4%–6% desflurane in a mixture of 66% nitrous oxide and 34% oxygen. Neuromuscular relaxation was induced and maintained by IV boluses of vecuronium bromide.
Twenty minutes before the end of surgery, patients were randomly allocated to receive one of three study drugs (using computer-generated random numbers). First, three syringes and three packages were prepared by an anesthesiologist, who was not one of the observers. They were marked only with a coded label to maintain double blinding. The syringes were identical and contained morphine HCl (Galen Corporation, Istanbul, Turkey) 10 mg, or pethidine HCl (Liba Laboratories, Istanbul, Turkey) 100 mg, or tramadol HCl (Grünenthal GmbH, Stolberg, Germany) 100 mg, 10 mL each. The packages were also identical and contained morphine 50 mg (0.5 mg/mL), or pethidine 500 mg (5 mg/mL), or tramadol 500 mg (5 mg/mL), each in 100 mL normal saline solution. Twenty minutes before the end of surgery, as a standardized initial loading dose of study drug, patients in the morphine group (group M) (n = 42) received IV 0.1 mg/kg morphine HCl, the pethidine group (group P) (n = 42) received 1 mg/kg pethidine HCl, and the tramadol group (group T) (n = 42) received 1 mg/kg tramadol for postoperative analgesia. Ondansetron 4 mg was routinely administered 15 min before the end of surgery for the prophylaxis of opioid-induced emesis.
After total recovery from anesthesia (as judged by the ability to open the eyes, grip a finger, and breathe deeply on request), when patients complained of pain, they were allowed to use a PCA pump (Abbott Pain Management Provider, Class II, Type CF, North Chicago, IL) with the equianalgesic concentration of each drug in each volume according to the study protocol. The settings were IV bolus dose of study drugs (morphine [0.5 mg/mL], pethidine [5 mg/mL], or tramadol [5 mg/mL]), with a lockout time of 10 min and no background infusion or maximal dose. Whenever patients requested analgesia, they received a standardized bolus dose volume of study drugs (morphine [0.02 mg/kg], pethidine [0.2 mg/kg] or tramadol [0.2 mg/kg]). The PCA settings were determined by an anesthesiologist, blinded to group assignments. The cumulative dose of study drugs was recorded at 1, 2, 6, 12, and 24 h after PCA administration. In each group, rescue analgesia with IV 1 µg/kg fentanyl was allowed if the patient could not obtain pain relief verbal rating scale (VRS score <4) from the PCA regimen.
Scores for pain, sedation, and the hemodynamic variables (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and peripheral oxygen saturation) were recorded by an anesthesiologist, who was blinded to the patient’s group, at 1 min after recovery and at 1, 2, 6, 12, and 24 h after the start of PCA administration. The level of pain was assessed by a VRS score from 0 to 10 (0 = no pain, 10 = the worst pain imagined), and sedation was assessed using a 5-point scale with 0 = alert and 4 = deep sleep. Duration of anesthesia, time to tracheal extubation, time to recovery, number of patients requiring supplementary fentanyl, average supplementary fentanyl dose, and any side effects were also recorded.
In this study, as a primary outcome, we sought to detect a difference of 0.8 U among the groups M, P, and T on the 10-point VRS. This was calculated to provide an 80% power to detect, at a type 1 error rate of 0.05, a difference of 0.8 U among groups M, P, and T on a 10-point VRS. Based on these calculations, the required study size was 36 patients per group. However, 42 patients in each group were enrolled to compensate for losses and increase the power. Demographic data were analyzed using one way ANOVA. The Kruskal–Wallis test was used for comparison of group differences. Time-dependent intragroup data were analyzed by Wilcoxon test. The incidence of postoperative adverse events was analyzed using 
2 tests. Values of P < 0.05 were considered statistically significant.
RESULTS
Patient demographic variables are shown in Table 1. There were no differences among groups in patient characteristics (age and weight), duration of anesthesia, mean time to tracheal extubation at the end of anesthesia, and time to recovery (Table 1). There were no large variations or statistically significant differences in the respiratory or hemodynamic variables among groups. Values remained within the normal range throughout the study period (data not presented). Postoperative pain after abdominal hysterectomy was treated successfully in all three groups; there were eight withdrawals; six were because of inadequate data collection in groups M and T, and 2 in group P because of a protocol violation. These patients were dropped from the study.
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Comparisons within groups indicated that VRS and sedation scores decreased significantly with time in each group (P < 0.05). Pain scores after the start of PCA administration are shown in Figure 1. There were no significant differences among groups in mean pain and sedation scores at any time point.
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The average initial loading doses were 6.6 ± 0.7 mg for morphine, 69.8 ± 8 mg for pethidine, and 69.6 ± 9.5 mg for tramadol. The cumulative analgesic consumption was 25.7 ± 9.5 mg for morphine, 266 ± 90 mg for pethidine, and 320 ± 10 mg for tramadol in 24 h (Table 2). The ratio of morphine/pethidine/ tramadol dose sizes used for postoperative pain management was 1/10/13, respectively.
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The number of patients requiring supplementary fentanyl and average supplementary fentanyl dose for rescue analgesic was significantly higher in group T than in groups M and P (P < 0.05). However, there was no difference between groups M and P (Table 1).
There were no overall significant differences in the incidence of side effects among groups (Table 3).
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DISCUSSION
In this study, we demonstrated that, at equianalgesic doses, morphine and pethidine, administered PCA for postoperative pain after abdominal hysterectomy, provided effective analgesia with an acceptable side effect profile. Although acceptable postoperative analgesia was achieved in group T, more patients required supplemental fentanyl to achieve lower pain scores during the first 24 h postoperatively. Studies of IV PCA morphine have shown conflicting results. In the literature, superior pain relief with morphine compared with pethidine has been demonstrated in two studies,1,5 whereas other studies have failed to show any superiority of morphine.6,7 In this study, PCA morphine and pethidine were equally effective for controlling postoperative pain and had similar side effects. A number of studies have compared morphine and tramadol for postoperative pain control, but results have not been consistent. Several studies have reported morphine to be more effective than tramadol for pain control,4,8 whereas others have found no difference.3,9 In this study, morphine provided better postoperative pain relief than did tramadol. The reason for the discrepant results might have been related to the variables studied to demonstrate the efficacy of these drugs. At least five potential problems in previous studies have been suggested10; these include small numbers of patients, the lack of a sufficient power to detect differences among drugs, inadequate loading, and bolus dose sizes, and nonequianalgesic bolus dose size used for each drug. To achieve effective pain relief with PCA, the size of the initial loading dose of analgesic used for pain management is a crucial factor.11 Thus, we chose 0.1 mg/kg loading doses of morphine, 1 mg/kg bolus doses of pethidine or tramadol for equipotency. The optimal bolus dosage is controversial. Owen et al.12 studied the effect of a range of doses of morphine (0.5, 1, and 2 mg) and found that 1 mg was the optimal bolus PCA dose. Therefore, we chose 0.02 mg/kg (average 1–2 mg) for our study, as have others.13 Given IV, pethidine and tramadol have an analgesic potency one-tenth that of morphine.8,14 We therefore chose 0.2 mg/kg (average 10–20 mg) bolus doses of pethidine or tramadol for equipotency.
Discrepant results have also been reported regarding the incidence of adverse effects related to opioid and non-opioid drugs. Ozalevli et al.8 reported a lower incidence of nausea and vomiting after tonsillectomy under general anesthesia with postoperative PCA tramadol compared with PCA morphine. In contrast, two clinical trials have reported that the use of tramadol for IV PCA after lower abdominal surgery15 and breast reconstruction3 is associated with more frequent nausea and vomiting compared with morphine. In the present study, the incidence of nausea in the tramadol group was 12.5%, which was similar to that of morphine and pethidine.
In conclusion, in patients who underwent abdominal hysterectomy, morphine, pethidine, and tramadol administration resulted in equivalent pain scores and side effects, but group T required more rescue analgesic doses of fentanyl. However, tramadol might be indicated in patients for whom morphine and pethidine are contraindicated.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the assistance of nursing staff and thank G. Seydaog lu, PhD, for expert statistical advice. The study was not supported by external funds.
Footnotes
Accepted for publication August 21, 2007.
REFERENCES
sley AH, Inglis S. Morphine Patient-Controlled Analgesia Is Superior to Meperidine Patient-Controlled Analgesia for Postoperative Pain. Anesth Analg 1997;84:794–9[Abstract]
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P < 0.05 compared to 1st min within groups by Wilcoxon test. There were no significant differences among groups in mean pain scores at any time point. Group M = morphine; P = pethidine; T = tramadol.
