- Email: [email protected]
Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: A randomized, double-blind, multicenter study
Efficacy and Safety of Dipyrone Versus Tramadol in the Management of Pain After Hysterectomy: A Randomized, Double-Blind, Multicenter Study Luis M. Torres, Manuel J. Rodrı´guez, Antonio Montero, Jeronimo Herrera, Enrique Caldero´n, Jesus Cabrera, Rocio Porres, M. Rosalia de la Torre, Tomas Martı´nez, Jose L. Go´mez, Jorge Ruiz, Inmaculada Garcı´a-Magaz, Javier Ca´mara, and Pablo Ortiz Background and Objectives: We assessed the efficacy and safety of dipyrone in comparison with tramadol in the relief of early postoperative pain following abdominal hysterectomy. Methods: A total of 151 women between 18 and 60 years of age undergoing abdominal hysterectomy during general anesthesia participated in a randomized, double-blind, controlled, multicenter study. Seventy-three patients received dipyrone and 78 received tramadol. Patients received an intravenous loading dose of the study drug immediately after operation followed by intravenous (IV) maintenance infusion and IV on-demand boluses up to a maximum number of predetermined doses/day of 8 g dipyrone and 500 mg tramadol. The duration of the study was 24 hours. Results: The mean (SD) number of boluses in the dipyrone group was 3.8 (2.4) and 3.5 (2.5) in the tramadol group (95% confidence interval, ⫺0.455 to 1.175), and the percentage of patients requiring rescue IV morphine (dipyrone 26.9%, tramadol 26.8%) was not statistically significant. Other analgesic efficacy parameters, such as pain intensity differences, sum of pain intensity differences, pain relief assessed by the patient, or patients who required the maximum number of demand doses, were not different between treatment groups. A significantly higher percentage of adverse gastrointestinal effects was found in patients given tramadol (42.1%) than in patients given dipyrone (20.2%) (P ⬍ .05). Also, a significantly higher number of tramadol-treated patients required ondansetron to control nausea and vomiting at 1 hour (19% v 7%), 2 hours (26% v 11%), and 24 hours (46% v 29%) (P ⬍ .05) after surgery. Patients and the investigators reported similar tolerability for both study arms. Conclusions: Dipyrone and tramadol showed similar efficacy for early pain relief after abdominal hysterectomy. Nausea and vomiting, possibly caused by the tramadol, occurred more frequently in those patients. In this group, the need of the antiemetic drug ondansetron was also higher. Reg Anesth Pain Med 2001;26:118-124. Key Words:
Dipyrone, Tramadol, Hysterectomy, Patient controlled analgesia.
I
nadequately treated postoperative pain is associated with prolonged hospital stay, increases in morbidity and mortality rates and health care costs,
From the Department of Anesthesiology, Critical Care and Pain Clinic, Hospital Universitario Puerta del Mar (L.M.T., E.C., J. Cabrera, R.P.), Ca´diz, Spain; Hospital Universitario Carlos Haya (M.J.R., M.R.D.T.), Ma´laga, Spain; Hospital Universitario Arnau de Vilanova (A.M., T.M., J.L.G.), Lleida, Spain; Hospital Universitario de Valme (J.H.), Sevilla, Spain; and Department of Statistics and Medical Department, Boehringer Ingelheim Espan˜a (J.R., I.G.-M., J. Ca´mara, P.O.), S.A. Madrid, Spain. Accepted for publication November 2, 2000. Reprint requests: Luis M. Torres, M.D., Unidad del Dolor, Servicio de Anestesia, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, E-11009 Ca´diz, Spain. E-mail: [email protected] © 2001 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/01/2602-0005$35.00/0 doi:10.1053/rapm.2001.21437
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and unnecessary suffering for patients.1 Although in most cases nonsteroidal anti-inflammatory drugs (NSAIDs) can control postoperative pain after ambulatory surgery, antipyretic analgesics or NSAIDs alone are usually insufficient during the early postoperative period in hospitalized patients undergoing major surgical procedures. Opioid analgesics are often under-prescribed due to a fear of respiratory depression. Dipyrone (metamizol) is a nonopioid analgesic with minor adverse effects and powerful painrelieving, antipyretic, and spasmolytic properties.2 Its metabolites inhibit prostaglandin synthesis, thus many classify it as a peripherally acting drug; dipyrone also produces central nervous system effects.3-5 Dipyrone has an antinociceptive effect directly on periaqueductal gray matter, probably
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involving the off and on cells of the rostral ventromedial medulla.6 The central analgesic effect of dipyrone is weaker than that of morphine.4 On the other hand, it is well known that the endorphin system is involved in human stress response and in human endogenous analgesic mechanisms.7,8 A decrease in -endorphin plasma concentrations has been shown during analgesia with dipyrone.9 A variety of clinical studies have shown that dipyrone is effective in the treatment of acute painful conditions, including surgical pain.10-18 Tramadol is an analgesic drug whose mechanism of action is unusual in that one optical isomer exerts typical opioid-type effects and the other isomer interacts with the reuptake and/or release of norepinephrine and serotonin in nerve terminals.19 Tramadol infusion, in addition to on-demand intravenous (IV) tramadol boluses, has been used and recommended for intravenous analgesia in patients recovering from major gynecological operations.20-24 This study was designed to compare the analgesic efficacy and safety of dipyrone and tramadol during the early postoperative period in patients undergoing abdominal hysterectomy. Both drugs were administered using continuous infusion plus limited on-demand boluses over a 24-hour period.
Methods Between January 1995 and January 1996, women scheduled for elective abdominal hysterectomy under general anesthesia were eligible to participate in a short-term (24-hour), randomized, double-blind, controlled multicenter clinical study of the treatment of postoperative pain with either dipyrone or tramadol. The protocol was approved by the ethics committee of the participating centers and by the Spanish health authorities, and written informed consent was obtained from all participants. Eligibility requirements were age 18 to 60 years, American Society of Anesthesiologists (ASA) physical status I-II, duration of surgical operation between 45 and 180 minutes, and mental status sufficient to be able to understand the demand dosing system of patient controlled analgesia (PCA) and to complete efficacy and tolerance tests. Patients with known hypersensitivity to the study medications or with any other disorder contraindicating the administration of dipyrone or NSAIDs, i.e., history of granulocytopenia, thrombocytopenia, aplastic anemia, NSAID-induced bronchial asthma, or NSAIDinduced gastrointestinal bleedings, were excluded. Pregnant women and patients with severe underlying disease or history of drug or alcohol abuse were also excluded.
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Treatment Patients were randomly allocated to either dipyrone treatment or tramadol treatment. The randomization scheme was drawn up using a table of random numbers. The randomization within the centers was performed in blocks of 4 patients to ensure balanced distribution of the treatment groups. Patients in the dipyrone group received a loading dose of 2 g (Nolotil; Boehringer Ingelheim Espan˜a, S.A., Madrid, Spain) administered IV over 15 minutes, followed by continuous infusion of 166 mg dipyrone per hour and demand doses of 333 mg up to a maximum of 6 bolus injections in 24 hours. Patients in the tramadol group were administered a loading dose of 100 mg IV over 15 minutes, followed by continuous infusion of 12.5 mg tramadol per hour and demand doses of 16.5 mg up to a maximum of 6 bolus injections in 24 hours. In all cases, the minimum interval allowed between bolus injections was 30 minutes. Loading doses were administered immediately after surgery. Total duration of treatment was 24 hours. When the patient had received the maximum number of bolus permitted but pain was higher than 4 on a 10-point visual analog scale (VAS) (from point 0 “no pain” to point 10 “unbearable pain”), 1 mg of morphine (rescue medication) was administered IV every 5 minutes until pain intensity decreased to a VAS score lower than 4, and the patient was withdrawn from the study. The night before surgery patients were administered bromazepam 3 mg orally. Immediate anesthetic premedication consisted of IV midazolam 0.1 mg/kg, fentanyl 0.1 to 0.5 g/kg, and atropine 0.01 mg/kg. Anesthesia was induced with IV propofol 2 to 2.5 mg/kg and maintained with 0.5% to 2% isoflurane, N2O in 50% oxygen, and fentanyl 2 to 5 g/kg/h (the final dose had to be administered approximately 30 minutes before the end of surgery). For muscle relaxation, atracurium besylate 0.5 mg/kg was administered IV. When necessary, neuromuscular block was reversed with atropine 0.01 mg/kg and neostigmine 0.03 mg/kg. Naloxone was not allowed to reverse fentanyl-induced respiratory depression. Measurements Assessments were performed at the end of surgery, which was the same time of drug administration (baseline), and at 30 and 60 minutes and at 2, 4, 6, 10, and 24 hours after administration of the loading dose. Pain intensity was evaluated by the patient according to a 10-point VAS (from point 0 “no pain” to point 10 “unbearable pain”). Pain relief was assessed by the patient in a 0-3 verbal rating
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scale (VRS) (0, none; 1, mild; 2, moderate; 3, complete). Pain intensity was graded by the observer at each observation time according to a 0-3 VRS (0, no pain; 1, mild pain described as unpleasant; 2, moderate pain described as intense but bearable; 3, intense pain described as unbearable with psychological restlessness). Both investigator and patient assessed the final global efficacy and the overall tolerability of treatment in a 1-4 VRS (1, excellent; 2, good; 3, moderate; 4, bad). Analgesic efficacy endpoints included the following: number of bolus injections required by the patient during the 24-hour study period (recorded on the “case report form” at 30 and 60 minutes and at 2, 4, 6, 10, and 24 hours after surgery); number of patients requiring rescue medication; pain intensity difference from baseline to post-drug evaluations assessed by the patient on the VAS; pain relief assessed by the patient throughout the observation period; sum of pain intensity differences (estimations of the area under the time-effect curve by summing the pain intensity differences in absolute values); global therapeutic efficacy assessed by the patient and the observer on the VRS; time until first dose of rescue medication (morphine) requested; assessment of pain intensity by the observer on the VRS; number of patients who took the maximum number of demand doses allowed; relief of postoperative shivering; and need of antiemetic agents (ondansetron). To determine presence of any adverse effects, patients were asked the standardized question “Did the drug administered cause any complaint?” at each assessment. The severity of adverse effects judged by the observer as unrelated, possibly related, or definitely related to the study drug was classified as mild (signs or symptoms easily tolerated by the patient), moderate (discomfort enough to cause interference with the patient’s activities), and severe (discomfort incapacitating the ability to undertake any activity or causing the patient to leave the study). Blood pressure and heart rate were measured at each observation time. Laboratory tests (blood cell count, prothrombin time, alanine and aspartate aminotransferases, total bilirubin, total protein, serum glucose, creatinine and blood urea nitrogen, and electrolytes) were performed at baseline and 24 hours after treatment. Statistical Analysis The efficacy of dipyrone and tramadol was considered at least equivalent when there was a mean difference of less than 2.8 bolus injections (standard deviation, SD ⫽ 4 boluses) between both treatment
arms. Analgesic equivalence was based on results of a study by Rodriguez et al.24 in which using a similar design in 160 women undergoing abdominal hysterectomy, the mean number of boluses on demand was 1.6 (SD ⫽ 2) for the tramadol group and 4.4 (SD ⫽ 4) for the dipyrone group. A total of 128 patients (64 patients per group) were needed to have a potency of 0.8 in the most conservative cases (absolute difference of 1 bolus between treatments) and assuming a loss to follow-up of 10%. Differences in the mean number of bolus injections required by patients in the dipyrone group and patients in the tramadol group were analyzed with the 2 1-sided test procedures.25 Confidence intervals (95% CI) on the difference in the effects of the 2 drugs were calculated. The Student’s t-test, the chisquared (2) test, the Fisher’s exact test, the Wilcoxon’s test, and the analysis of variance (ANOVA) for repeated measures were used for the analysis of baseline demographic variables, pain intensity differences, sum of pain intensity differences, number of patients requiring rescue medication, need of antiemetic agents, time until rescue medication, and number of adverse events. The level of significance was set at P ⬍ .05. The Statistical Analysis Systems (SAS; SAS Institute, Cary, NC) was the software package used for the analysis of data. The intention-to-treat analysis, in which the outcomes of all patients were analyzed with the group to which they were originally assigned, whether or not they completed the protocol, was used to examine the effect of the study drugs as a method of adjusting for bias caused by participants leaving the study. The per-protocol analysis was based on patients who completed the protocol. Both type of analyses were performed in this study.
Results The intention-to-treat analysis was performed on the total number of eligible patients (n ⫽ 151), 73 of which were assigned to the dipyrone group and 78 to the tramadol group. However, 19 patients were excluded because of incorrect programming of the pump for the infusion of demand doses and 2 patients were excluded because of the administration of protocol forbidden medications. Therefore, per-protocol analysis is based on 130 patients who completed the study, 63 assigned to receive dipyrone and 67 to receive tramadol. There were no statistically significant differences in baseline data between patients included in the intention-to-treat analysis and patients included in the per-protocol analysis. Duration of hysterectomy was 105 (SD ⫾ 29) minutes in the dipyrone group and 106 (SD ⫾ 29) minutes in the tramadol group.
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Table 1. Number of Patients Remaining at Each Observation Time After Withdrawal of Those Who Took Rescue Medication Study Drug Dipyrone Tramadol
Basal
30 min
60 min
2h
4h
6h
10 h
24 h
63 67
63 67
63 67
63 64
62 63
55 60
50 56
46 49
NOTE. P ⫽ not significant.
All patients received the loading dose of 2 g dipyrone or 100 mg tramadol. Dipyrone-treated patients required a mean of 3.8 demand doses (SD ⫽ 2.4) and tramadol-treated patients a mean of 3.5 (SD ⫽ 2.5). Confidence intervals (95% CI) on the difference between both groups were ⫺0.455 to 1.175 for the per-protocol analysis and ⫺0.340 to 1.160 for the intention-to-treat analysis. The number of patients requiring rescue medication during the 24hour study period was similar, i.e., 16 (25%) patients in the dipyrone group and 13 (19%) in the tramadol group. The mean time elapsed until the administration of rescue medication was 5.9 (SD ⫽ 2.7) hours in the dipyrone group and 8.6 (SD ⫽ 7.4) hours in the tramadol group. As shown in Table 1, the number of patients remaining at each observation period was similar in both study groups. Also, there were no statistically significant differences in the number of patients requiring the maximum number of demand doses permitted (26% or 41.2% in the dipyrone group v 26% or 38.8% in the tramadol group). With regard to the course of pain according to the patient’s evaluation on the VAS at each point in time, no statistically significant differences between patients administered dipyrone and tramadol were observed (Fig 1). The VAS was lower than 30 mm from 4 hours post-drug and remained lower than 1.5 VAS between 10 and 24 hours in both treatment groups. Pain intensity differences according to VAS score showed similar decreases in both treat-
ment groups (Fig 2). Mean sum of pain intensity differences at 24 hours was also similar in both groups, dipyrone ⫺646 (SD ⫾ 489) versus tramadol ⫺760 (SD ⫾ 545). At 24 hours, 100% of patients in the dipyrone group and 94% in the tramadol group had mild or no pain according to the observer, and in 100% of cases in the dipyrone group and 90% in the tramadol group, pain relief was rated as moderate or complete by the patient. The final global efficacy was rated as either excellent or good in 47 (74.6%) cases by either the patient or the observer in the dipyrone group and in 45 (67.1%) cases by the patient and in 46 (68.6%) cases by the observer in the tramadol group. Postoperative shivering was rapidly mitigated by both study medications. After 60 minutes of treatment, the number of patients with postoperative shivering decreased from 19 (30.2%) to 1 (1.6%) in the dipyrone group and from 20 (29.8%) to 1 (1.5%) in the tramadol group. As shown in Table 2, more patients in the tramadol group than in the dipyrone group experienced at least one adverse effect during the study period, with a total number of adverse events of 151 and 110 for the tramadol and dipyrone groups, respectively. Gastrointestinal adverse events, mostly nausea and vomiting, were the most common events in both treatment arms. A significantly higher percentage of these events definitely or possibly related to the study medication was found in patients administered tramadol (42.1%) than in patients ad-
Fig 1. Time-course of the analgesic effect of dipyrone (⽧) and tramadol (■) according to scores on the 0-100 mm VAS.
Fig 2. Pain intensity difference (PID) in the 2 treatment arms throughout the 24-hour study period. (⽧), dipyrone; (■), tramadol.
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Table 2. Intention-to-Treat Analysis. Occurrence of Adverse Effects
Data Patients with at least 1 adverse effect Adverse effects Total no. Nausea/vomiting Definitely/possibly related to the study drug Intensity Mild Moderate Severe Withdrawal due to adverse effect Overall tolerability* Patients Investigators
Dipyrone n ⫽ 73 (%)
Tramadol n ⫽ 78 (%)
43 (58.9)
56 (71.8)
110 79 (71.8)
151 95 (62.9)
16 (20.2)
40 (42.1)
89 (80.9) 15 (13.6) 6 (5.4) 2 (2.7)
111 (73.5) 36 (23.8) 4 (2.6) 5 (6.4)
53 (74.6) 54 (76.1)
51 (69.8) 59 (75.6)
* Excellent or good in a 1-4 VRS.
ministered dipyrone (20.2%) (P ⬍ .05); also, a significantly higher number of patients in the tramadol group than in the dipyrone group required ondansetron for the treatment of nausea and vomiting at the assessments performed at 1 hour (19% v 7%), at 2 hours (26% v 11%), and at 24 hours (46% v 29%) (P ⬍ .05). Five patients in the tramadol group and 2 patients in the dipyrone group discontinued the study because of severe adverse events. Overall tolerability rated as excellent or good either by the patients or by the investigators was similar for both study arms. Significant changes in heart rate and systolic and diastolic blood pressure during the administration of the study drugs and in the results of laboratory tests at the end of the 24-hour study period were not observed.
Discussion The impact of postoperative pain on patient recovery, length of hospital stay, nurse staff costs, and other indirect health care costs can be substantially reduced with the use of appropriate postoperative analgesia. This implies not only the use of an adequate type of analgesic drug, but also an adequate route of administration. However, it seems that the solution to postoperative pain management lies not in the development of new techniques, but in developing acute pain teams to exploit existing expertise.1 The present results show that using the appropriate doses, dipyrone (up to a maximum daily dose of 8 g) and tramadol (up to a maximum daily dose of 500 mg) were equivalent in analgesic efficacy. These findings are consistent with those reported by Torres et al.10 in a study of postoperative pain after
abdominal surgery in which dipyrone administered via PCA pumps had the same analgesic efficacy than buprenorphine and morphine with less adverse effects. In contrast, Rodriguez et al.24 reported higher analgesic effects for tramadol in a comparative study of tramadol versus NSAIDs for managing postoperative pain. A total of 160 patients undergoing abdominal hysterectomy were randomized to receive tramadol, dipyrone, ketorolac, and lysine clonixinate, with 40 patients in each group. Analgesics were administered using continuous infusions plus PCA. Tramadol was significantly better than the other three agents with regard to the number of boluses required per patient and the number of patients requiring supplementary analgesia. However, Rodriguez et al.24 used an initial bolus of 660 mg dipyrone compared with 2 g in our study. These observations confirm the importance of dose selection in obtaining optimum efficacy in the treatment of postoperative pain. In relation to other pain-related parameters, there were no statistically significant differences between dipyrone and tramadol. The number of patients withdrawn for the study due to the need for morphine as rescue medication and the time of application of rescue medication were also similar in both groups. On-demand doses of the study drugs cannot be increased because the purpose of the study was to compare the effect of 8 g/d dipyrone and 500 mg/d tramadol in maximal doses. Although both drugs suppressed postanesthetic shivering, the effect could also be attributed to rewarming of the patients. In the study of Monso et al.,26 dipyrone (25 mg/kg) produced a significantly better postanesthetic shivering response than placebo, but the efficacy of pethidine (0.4 mg/kg) was the highest and the response to it appeared more quickly. The overall therapeutic efficacy of the study medications was also confirmed by a high percentage of patients and physicians considering the use of dipyrone and tramadol infusions in addition to on-demand boluses “excellent” or “good.” With regard to safety data, no serious adverse effects developed and there was no significant difference regarding rate of withdrawals due to adverse events between dipyrone-treated patients and tramadol-treated patients. The most frequent adverse events in both treatment groups were nausea and vomiting, with a significantly higher need of ondansetron in the tramadol group after 60 minutes and at 2 and 24 hours of treatment. The economic cost of antiemetic treatment was 2.15 times higher for the tramadol group. In the observational study of Ure et al.,27 PCA was stopped in 16% of 50 patients administered tramadol combined with dipyrone due to the occurrence of nausea and vom-
Pain Relief After Hysterectomy
iting. Nausea and vomiting are well-known side effects of tramadol,28 and antiemetic prophylaxis before treatment with this drug has been recommended.21 In summary, dipyrone and tramadol administered at maximal predetermined daily doses of 8 g and 500 mg, respectively, showed a similar efficacy for early pain relief after abdominal hysterectomy. Both treatments administered by IV maintenance infusion in addition to on-demand boluses were well tolerated, but nausea and vomiting occurred more frequently in patients administered tramadol.
12.
13.
Acknowledgment We are indebted to Marta Pulido, M.D., for editing the manuscript and for editorial assistance.
14.
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and minimum effective concentrations. Clin J Pain 1990;6:212-220. 24. Rodriguez MJ, De la Torre MR, Perez-Iraola P, Fernandez-Cuervo C, Benitez P, Navarro A, Vidal J. Comparative study of tramadol versus NSAIDS as intravenous infusion for managing postoperative pain. Curr Ther Res 1993;54:375-383. 25. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987;15:657-680. 26. Monso A, Riudebas J, Barbal F, Laporte JR, Arnau
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Dipyrone, Tramadol, Hysterectomy, Patient controlled analgesia.
I
nadequately treated postoperative pain is associated with prolonged hospital stay, increases in morbidity and mortality rates and health care costs,
From the Department of Anesthesiology, Critical Care and Pain Clinic, Hospital Universitario Puerta del Mar (L.M.T., E.C., J. Cabrera, R.P.), Ca´diz, Spain; Hospital Universitario Carlos Haya (M.J.R., M.R.D.T.), Ma´laga, Spain; Hospital Universitario Arnau de Vilanova (A.M., T.M., J.L.G.), Lleida, Spain; Hospital Universitario de Valme (J.H.), Sevilla, Spain; and Department of Statistics and Medical Department, Boehringer Ingelheim Espan˜a (J.R., I.G.-M., J. Ca´mara, P.O.), S.A. Madrid, Spain. Accepted for publication November 2, 2000. Reprint requests: Luis M. Torres, M.D., Unidad del Dolor, Servicio de Anestesia, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, E-11009 Ca´diz, Spain. E-mail: [email protected] © 2001 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/01/2602-0005$35.00/0 doi:10.1053/rapm.2001.21437
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and unnecessary suffering for patients.1 Although in most cases nonsteroidal anti-inflammatory drugs (NSAIDs) can control postoperative pain after ambulatory surgery, antipyretic analgesics or NSAIDs alone are usually insufficient during the early postoperative period in hospitalized patients undergoing major surgical procedures. Opioid analgesics are often under-prescribed due to a fear of respiratory depression. Dipyrone (metamizol) is a nonopioid analgesic with minor adverse effects and powerful painrelieving, antipyretic, and spasmolytic properties.2 Its metabolites inhibit prostaglandin synthesis, thus many classify it as a peripherally acting drug; dipyrone also produces central nervous system effects.3-5 Dipyrone has an antinociceptive effect directly on periaqueductal gray matter, probably
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involving the off and on cells of the rostral ventromedial medulla.6 The central analgesic effect of dipyrone is weaker than that of morphine.4 On the other hand, it is well known that the endorphin system is involved in human stress response and in human endogenous analgesic mechanisms.7,8 A decrease in -endorphin plasma concentrations has been shown during analgesia with dipyrone.9 A variety of clinical studies have shown that dipyrone is effective in the treatment of acute painful conditions, including surgical pain.10-18 Tramadol is an analgesic drug whose mechanism of action is unusual in that one optical isomer exerts typical opioid-type effects and the other isomer interacts with the reuptake and/or release of norepinephrine and serotonin in nerve terminals.19 Tramadol infusion, in addition to on-demand intravenous (IV) tramadol boluses, has been used and recommended for intravenous analgesia in patients recovering from major gynecological operations.20-24 This study was designed to compare the analgesic efficacy and safety of dipyrone and tramadol during the early postoperative period in patients undergoing abdominal hysterectomy. Both drugs were administered using continuous infusion plus limited on-demand boluses over a 24-hour period.
Methods Between January 1995 and January 1996, women scheduled for elective abdominal hysterectomy under general anesthesia were eligible to participate in a short-term (24-hour), randomized, double-blind, controlled multicenter clinical study of the treatment of postoperative pain with either dipyrone or tramadol. The protocol was approved by the ethics committee of the participating centers and by the Spanish health authorities, and written informed consent was obtained from all participants. Eligibility requirements were age 18 to 60 years, American Society of Anesthesiologists (ASA) physical status I-II, duration of surgical operation between 45 and 180 minutes, and mental status sufficient to be able to understand the demand dosing system of patient controlled analgesia (PCA) and to complete efficacy and tolerance tests. Patients with known hypersensitivity to the study medications or with any other disorder contraindicating the administration of dipyrone or NSAIDs, i.e., history of granulocytopenia, thrombocytopenia, aplastic anemia, NSAID-induced bronchial asthma, or NSAIDinduced gastrointestinal bleedings, were excluded. Pregnant women and patients with severe underlying disease or history of drug or alcohol abuse were also excluded.
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Treatment Patients were randomly allocated to either dipyrone treatment or tramadol treatment. The randomization scheme was drawn up using a table of random numbers. The randomization within the centers was performed in blocks of 4 patients to ensure balanced distribution of the treatment groups. Patients in the dipyrone group received a loading dose of 2 g (Nolotil; Boehringer Ingelheim Espan˜a, S.A., Madrid, Spain) administered IV over 15 minutes, followed by continuous infusion of 166 mg dipyrone per hour and demand doses of 333 mg up to a maximum of 6 bolus injections in 24 hours. Patients in the tramadol group were administered a loading dose of 100 mg IV over 15 minutes, followed by continuous infusion of 12.5 mg tramadol per hour and demand doses of 16.5 mg up to a maximum of 6 bolus injections in 24 hours. In all cases, the minimum interval allowed between bolus injections was 30 minutes. Loading doses were administered immediately after surgery. Total duration of treatment was 24 hours. When the patient had received the maximum number of bolus permitted but pain was higher than 4 on a 10-point visual analog scale (VAS) (from point 0 “no pain” to point 10 “unbearable pain”), 1 mg of morphine (rescue medication) was administered IV every 5 minutes until pain intensity decreased to a VAS score lower than 4, and the patient was withdrawn from the study. The night before surgery patients were administered bromazepam 3 mg orally. Immediate anesthetic premedication consisted of IV midazolam 0.1 mg/kg, fentanyl 0.1 to 0.5 g/kg, and atropine 0.01 mg/kg. Anesthesia was induced with IV propofol 2 to 2.5 mg/kg and maintained with 0.5% to 2% isoflurane, N2O in 50% oxygen, and fentanyl 2 to 5 g/kg/h (the final dose had to be administered approximately 30 minutes before the end of surgery). For muscle relaxation, atracurium besylate 0.5 mg/kg was administered IV. When necessary, neuromuscular block was reversed with atropine 0.01 mg/kg and neostigmine 0.03 mg/kg. Naloxone was not allowed to reverse fentanyl-induced respiratory depression. Measurements Assessments were performed at the end of surgery, which was the same time of drug administration (baseline), and at 30 and 60 minutes and at 2, 4, 6, 10, and 24 hours after administration of the loading dose. Pain intensity was evaluated by the patient according to a 10-point VAS (from point 0 “no pain” to point 10 “unbearable pain”). Pain relief was assessed by the patient in a 0-3 verbal rating
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scale (VRS) (0, none; 1, mild; 2, moderate; 3, complete). Pain intensity was graded by the observer at each observation time according to a 0-3 VRS (0, no pain; 1, mild pain described as unpleasant; 2, moderate pain described as intense but bearable; 3, intense pain described as unbearable with psychological restlessness). Both investigator and patient assessed the final global efficacy and the overall tolerability of treatment in a 1-4 VRS (1, excellent; 2, good; 3, moderate; 4, bad). Analgesic efficacy endpoints included the following: number of bolus injections required by the patient during the 24-hour study period (recorded on the “case report form” at 30 and 60 minutes and at 2, 4, 6, 10, and 24 hours after surgery); number of patients requiring rescue medication; pain intensity difference from baseline to post-drug evaluations assessed by the patient on the VAS; pain relief assessed by the patient throughout the observation period; sum of pain intensity differences (estimations of the area under the time-effect curve by summing the pain intensity differences in absolute values); global therapeutic efficacy assessed by the patient and the observer on the VRS; time until first dose of rescue medication (morphine) requested; assessment of pain intensity by the observer on the VRS; number of patients who took the maximum number of demand doses allowed; relief of postoperative shivering; and need of antiemetic agents (ondansetron). To determine presence of any adverse effects, patients were asked the standardized question “Did the drug administered cause any complaint?” at each assessment. The severity of adverse effects judged by the observer as unrelated, possibly related, or definitely related to the study drug was classified as mild (signs or symptoms easily tolerated by the patient), moderate (discomfort enough to cause interference with the patient’s activities), and severe (discomfort incapacitating the ability to undertake any activity or causing the patient to leave the study). Blood pressure and heart rate were measured at each observation time. Laboratory tests (blood cell count, prothrombin time, alanine and aspartate aminotransferases, total bilirubin, total protein, serum glucose, creatinine and blood urea nitrogen, and electrolytes) were performed at baseline and 24 hours after treatment. Statistical Analysis The efficacy of dipyrone and tramadol was considered at least equivalent when there was a mean difference of less than 2.8 bolus injections (standard deviation, SD ⫽ 4 boluses) between both treatment
arms. Analgesic equivalence was based on results of a study by Rodriguez et al.24 in which using a similar design in 160 women undergoing abdominal hysterectomy, the mean number of boluses on demand was 1.6 (SD ⫽ 2) for the tramadol group and 4.4 (SD ⫽ 4) for the dipyrone group. A total of 128 patients (64 patients per group) were needed to have a potency of 0.8 in the most conservative cases (absolute difference of 1 bolus between treatments) and assuming a loss to follow-up of 10%. Differences in the mean number of bolus injections required by patients in the dipyrone group and patients in the tramadol group were analyzed with the 2 1-sided test procedures.25 Confidence intervals (95% CI) on the difference in the effects of the 2 drugs were calculated. The Student’s t-test, the chisquared (2) test, the Fisher’s exact test, the Wilcoxon’s test, and the analysis of variance (ANOVA) for repeated measures were used for the analysis of baseline demographic variables, pain intensity differences, sum of pain intensity differences, number of patients requiring rescue medication, need of antiemetic agents, time until rescue medication, and number of adverse events. The level of significance was set at P ⬍ .05. The Statistical Analysis Systems (SAS; SAS Institute, Cary, NC) was the software package used for the analysis of data. The intention-to-treat analysis, in which the outcomes of all patients were analyzed with the group to which they were originally assigned, whether or not they completed the protocol, was used to examine the effect of the study drugs as a method of adjusting for bias caused by participants leaving the study. The per-protocol analysis was based on patients who completed the protocol. Both type of analyses were performed in this study.
Results The intention-to-treat analysis was performed on the total number of eligible patients (n ⫽ 151), 73 of which were assigned to the dipyrone group and 78 to the tramadol group. However, 19 patients were excluded because of incorrect programming of the pump for the infusion of demand doses and 2 patients were excluded because of the administration of protocol forbidden medications. Therefore, per-protocol analysis is based on 130 patients who completed the study, 63 assigned to receive dipyrone and 67 to receive tramadol. There were no statistically significant differences in baseline data between patients included in the intention-to-treat analysis and patients included in the per-protocol analysis. Duration of hysterectomy was 105 (SD ⫾ 29) minutes in the dipyrone group and 106 (SD ⫾ 29) minutes in the tramadol group.
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Table 1. Number of Patients Remaining at Each Observation Time After Withdrawal of Those Who Took Rescue Medication Study Drug Dipyrone Tramadol
Basal
30 min
60 min
2h
4h
6h
10 h
24 h
63 67
63 67
63 67
63 64
62 63
55 60
50 56
46 49
NOTE. P ⫽ not significant.
All patients received the loading dose of 2 g dipyrone or 100 mg tramadol. Dipyrone-treated patients required a mean of 3.8 demand doses (SD ⫽ 2.4) and tramadol-treated patients a mean of 3.5 (SD ⫽ 2.5). Confidence intervals (95% CI) on the difference between both groups were ⫺0.455 to 1.175 for the per-protocol analysis and ⫺0.340 to 1.160 for the intention-to-treat analysis. The number of patients requiring rescue medication during the 24hour study period was similar, i.e., 16 (25%) patients in the dipyrone group and 13 (19%) in the tramadol group. The mean time elapsed until the administration of rescue medication was 5.9 (SD ⫽ 2.7) hours in the dipyrone group and 8.6 (SD ⫽ 7.4) hours in the tramadol group. As shown in Table 1, the number of patients remaining at each observation period was similar in both study groups. Also, there were no statistically significant differences in the number of patients requiring the maximum number of demand doses permitted (26% or 41.2% in the dipyrone group v 26% or 38.8% in the tramadol group). With regard to the course of pain according to the patient’s evaluation on the VAS at each point in time, no statistically significant differences between patients administered dipyrone and tramadol were observed (Fig 1). The VAS was lower than 30 mm from 4 hours post-drug and remained lower than 1.5 VAS between 10 and 24 hours in both treatment groups. Pain intensity differences according to VAS score showed similar decreases in both treat-
ment groups (Fig 2). Mean sum of pain intensity differences at 24 hours was also similar in both groups, dipyrone ⫺646 (SD ⫾ 489) versus tramadol ⫺760 (SD ⫾ 545). At 24 hours, 100% of patients in the dipyrone group and 94% in the tramadol group had mild or no pain according to the observer, and in 100% of cases in the dipyrone group and 90% in the tramadol group, pain relief was rated as moderate or complete by the patient. The final global efficacy was rated as either excellent or good in 47 (74.6%) cases by either the patient or the observer in the dipyrone group and in 45 (67.1%) cases by the patient and in 46 (68.6%) cases by the observer in the tramadol group. Postoperative shivering was rapidly mitigated by both study medications. After 60 minutes of treatment, the number of patients with postoperative shivering decreased from 19 (30.2%) to 1 (1.6%) in the dipyrone group and from 20 (29.8%) to 1 (1.5%) in the tramadol group. As shown in Table 2, more patients in the tramadol group than in the dipyrone group experienced at least one adverse effect during the study period, with a total number of adverse events of 151 and 110 for the tramadol and dipyrone groups, respectively. Gastrointestinal adverse events, mostly nausea and vomiting, were the most common events in both treatment arms. A significantly higher percentage of these events definitely or possibly related to the study medication was found in patients administered tramadol (42.1%) than in patients ad-
Fig 1. Time-course of the analgesic effect of dipyrone (⽧) and tramadol (■) according to scores on the 0-100 mm VAS.
Fig 2. Pain intensity difference (PID) in the 2 treatment arms throughout the 24-hour study period. (⽧), dipyrone; (■), tramadol.
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Table 2. Intention-to-Treat Analysis. Occurrence of Adverse Effects
Data Patients with at least 1 adverse effect Adverse effects Total no. Nausea/vomiting Definitely/possibly related to the study drug Intensity Mild Moderate Severe Withdrawal due to adverse effect Overall tolerability* Patients Investigators
Dipyrone n ⫽ 73 (%)
Tramadol n ⫽ 78 (%)
43 (58.9)
56 (71.8)
110 79 (71.8)
151 95 (62.9)
16 (20.2)
40 (42.1)
89 (80.9) 15 (13.6) 6 (5.4) 2 (2.7)
111 (73.5) 36 (23.8) 4 (2.6) 5 (6.4)
53 (74.6) 54 (76.1)
51 (69.8) 59 (75.6)
* Excellent or good in a 1-4 VRS.
ministered dipyrone (20.2%) (P ⬍ .05); also, a significantly higher number of patients in the tramadol group than in the dipyrone group required ondansetron for the treatment of nausea and vomiting at the assessments performed at 1 hour (19% v 7%), at 2 hours (26% v 11%), and at 24 hours (46% v 29%) (P ⬍ .05). Five patients in the tramadol group and 2 patients in the dipyrone group discontinued the study because of severe adverse events. Overall tolerability rated as excellent or good either by the patients or by the investigators was similar for both study arms. Significant changes in heart rate and systolic and diastolic blood pressure during the administration of the study drugs and in the results of laboratory tests at the end of the 24-hour study period were not observed.
Discussion The impact of postoperative pain on patient recovery, length of hospital stay, nurse staff costs, and other indirect health care costs can be substantially reduced with the use of appropriate postoperative analgesia. This implies not only the use of an adequate type of analgesic drug, but also an adequate route of administration. However, it seems that the solution to postoperative pain management lies not in the development of new techniques, but in developing acute pain teams to exploit existing expertise.1 The present results show that using the appropriate doses, dipyrone (up to a maximum daily dose of 8 g) and tramadol (up to a maximum daily dose of 500 mg) were equivalent in analgesic efficacy. These findings are consistent with those reported by Torres et al.10 in a study of postoperative pain after
abdominal surgery in which dipyrone administered via PCA pumps had the same analgesic efficacy than buprenorphine and morphine with less adverse effects. In contrast, Rodriguez et al.24 reported higher analgesic effects for tramadol in a comparative study of tramadol versus NSAIDs for managing postoperative pain. A total of 160 patients undergoing abdominal hysterectomy were randomized to receive tramadol, dipyrone, ketorolac, and lysine clonixinate, with 40 patients in each group. Analgesics were administered using continuous infusions plus PCA. Tramadol was significantly better than the other three agents with regard to the number of boluses required per patient and the number of patients requiring supplementary analgesia. However, Rodriguez et al.24 used an initial bolus of 660 mg dipyrone compared with 2 g in our study. These observations confirm the importance of dose selection in obtaining optimum efficacy in the treatment of postoperative pain. In relation to other pain-related parameters, there were no statistically significant differences between dipyrone and tramadol. The number of patients withdrawn for the study due to the need for morphine as rescue medication and the time of application of rescue medication were also similar in both groups. On-demand doses of the study drugs cannot be increased because the purpose of the study was to compare the effect of 8 g/d dipyrone and 500 mg/d tramadol in maximal doses. Although both drugs suppressed postanesthetic shivering, the effect could also be attributed to rewarming of the patients. In the study of Monso et al.,26 dipyrone (25 mg/kg) produced a significantly better postanesthetic shivering response than placebo, but the efficacy of pethidine (0.4 mg/kg) was the highest and the response to it appeared more quickly. The overall therapeutic efficacy of the study medications was also confirmed by a high percentage of patients and physicians considering the use of dipyrone and tramadol infusions in addition to on-demand boluses “excellent” or “good.” With regard to safety data, no serious adverse effects developed and there was no significant difference regarding rate of withdrawals due to adverse events between dipyrone-treated patients and tramadol-treated patients. The most frequent adverse events in both treatment groups were nausea and vomiting, with a significantly higher need of ondansetron in the tramadol group after 60 minutes and at 2 and 24 hours of treatment. The economic cost of antiemetic treatment was 2.15 times higher for the tramadol group. In the observational study of Ure et al.,27 PCA was stopped in 16% of 50 patients administered tramadol combined with dipyrone due to the occurrence of nausea and vom-
Pain Relief After Hysterectomy
iting. Nausea and vomiting are well-known side effects of tramadol,28 and antiemetic prophylaxis before treatment with this drug has been recommended.21 In summary, dipyrone and tramadol administered at maximal predetermined daily doses of 8 g and 500 mg, respectively, showed a similar efficacy for early pain relief after abdominal hysterectomy. Both treatments administered by IV maintenance infusion in addition to on-demand boluses were well tolerated, but nausea and vomiting occurred more frequently in patients administered tramadol.
12.
13.
Acknowledgment We are indebted to Marta Pulido, M.D., for editing the manuscript and for editorial assistance.
14.
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