Abstract
Background/purpose
Weak opioid combined with acetaminophen (APAP) has been proven to provide better analgesic efficacy and cause fewer complications than either drug alone. However, there are questions about whether different opioids, tramadol and propoxyphene, provide similar efficacy or safety. Thus, we investigated Ultracet (37.5 mg tramadol/325 mg APAP) and Depain-X (65 mg propoxyphene/650 mg APAP). The primary aims of this study were to compare the analgesic efficacy and adverse effects of single-dose oral Ultracet versus Depain-X in acute postoperative pain.
Materials and methods
This was a randomized, open-label, active-controlled parallel study on patients with postsurgical pain. Sixty patients who sustained moderate postsurgical pain (visual analog scale33 cm) after undergoing implantation of venous access were randomized to two groups to receive either Ultracetor Depain-X for postoperative analgesia. Assessment items included pain intensity and pain relief ratings at the first 4 hours, and adverse events.
Results
There were initially 107 patients who were enrolled in this trial, but up to 45 (42.1%) of them were withdrawn during the study. In these 62 patients who complied with treatment (Ultracet: Depain-X = 29: 33), pain relief scale indicated that Ultracet could provide a better analgesic effect than Depain-X provided at1 hour (p < 0.05). At 4 hours, the pain score in the Ultracet group was significantly lower than that in the Depain-X group (p < 0.05). Adverse events, such as drowsiness, dizziness, and skin itching did not differ in both groups.
Conclusion
Among patients with mild to moderate postoperative wound pain, single-dose Ultracet can provide slightly better analgesic efficacy than Depain-X in terms of onset and duration. Depain-X is no longer marketed in Europe, America, Taiwan and other countries, therefore, Ultracet can serve as a good substitute for treating postoperative pain.
Keywords
acetaminophen; pain, postoperative; tramadol;
1. Introduction
Clinical evidence has shown that acetaminophen (APAP) combined with weak opioids (codeine, propoxyphene or tramadol) can serve as a first-line analgesic for postoperative pain.1, 2, 3, 4 Combination of these two sorts of analgesic agents with complementary mechanisms of action may enhance analgesia and at the same time reduce the risk of adverse events.5 These combination drugs can provide a safe and effective analgesic option for ambulatory surgery.
Propoxyphene is another weak opioid that is structurally similar to methadone. The analgesic efficacy of propoxyphene is one-half to two-thirds as potent as codeine, meaning that 90–120 mg propoxyphene provides pain relief equal to that of 60 mg codeine. Propoxyphene (65 mg) plus 650 mg APAP (Depain-X) has a similar analgesic efficacy to that of 100 mg tramadol but with a lower incidence of adverse effects. 6 Thus, Depain-X is a good analgesic for moderate to severe postsurgical pain.
Tramadol has recently been recommended as first-line analgesic for postsurgical pain because it causes less respiratory depression, cardiac depression, dizziness and drowsiness than morphine does.7 Use of a combination of 37.5 mg tramadol and 325 mg APAP (Ultracet) allows reduction of tramadol dose, causes a lower incidence of adverse effects, and provides a better analgesic effect. 7 In recent years, most of the therapeutic trials of Ultracet were conducted with the dental pain model (pain after removal of impacted third molars), which is a useful clinical model for evaluation of oral analgesics for treatment of acute pain. The results had proven that Ultracet could provide greater relief of dental pain with faster onset and longer duration than either of its constituent agents as monotherapy.8, 9, 10 Although this dental pain model is successful, determination of the safety and effectiveness of this new analgesic in other postsurgical pain models warrants investigation.
The objective of these studies was to determine the therapeutic profile (efficacy, onset, duration, and safety) of single-dose Ultracet (tramadol/APAP) and Depain-X (propoxyphene/APAP) for the treatment of postoperative pain after implantation of an intravenous access device (IVAD).
2. Patients and methods
2.1. Patients
This randomized, open-label, active-controlled study had an enrollment of 107 patients aged between 18 and 75 years with an American Society of Anesthesiologists (ASA) physical status I or II. They underwent implantation of and IVAD under total intravenous general anesthesia. The study protocol was approved by the Committee for Human Investigation of National Taiwan University Hospital, and informed consent was obtained from each patient. Patients who had a history of drug abuse, psychiatric disorders, dementia, sleep apnea, or known contraindication to opioids and acetaminophen were excluded. We also excluded pregnant or lactating women, and patients who took tramadol or propoxyphene within 30 days of the proposed operation, or those who used sedatives, antiemetics or antipruritics within 24 hours of the operation.
Patients were allocated randomly into one of the two treatment groups (Ultracet or Depain-X) using a computer-generated randomized number table. Patients were considered to have completed the study if they had received at least one treatment dose and assessments of pain intensity with a 10-cm visual analog scale (VAS), pain relief ratings, and sustained adverse event 4 hours after taking study medication.
2.2. Treatment and assessment
All patients underwent implantation of the same type of port(PORT-A-CATH II Implantable Venous Access Systems; Deltec, Kennett Square, PA, USA), which was made possible with the implantable infusion port introducer kit (Arrow Inc. Mt holly, NY, USA), and through percutaneous infraclavicular landmark, the subclavian vein was accessed. Anesthesia was induced with midazolam and fentanyl, and maintained with propofol infusion. No local anesthesia was performed.
Following the surgical procedure, the subjects with VAS pain score ≥ 3 were administered one tablet of the study drug. The patients were not allowed to take any acetaminophen-containing agent, apart from the study medication for the first 4 hours postoperatively. Four hours after surgery, the patients were allowed to receive supplemental analgesic medication. Those who received supplemental pain medication were considered to withdraw from the study.
Pain intensity was evaluated with a 10-cm VAS at baseline (before the single dose) and at 30 minutes, 1 hour and 4 hours after the single dose of the study medication. Additionally, at 30minutes, 1 hour and 4 hours after the single dose of study drug, the patients were asked to rate the degree of pain relief compared with the pain experienced before taking the single dose of study medication using a six-point scale11 (4 = complete; 3 = a lot; 2 = moderate; 1 = slight; 0 = none; –1 = worse). Adverse events were also assessed at these time points.
2.3. Statistical methods
Patient characteristics were presented as means ± standard deviation for continuous variables and proportions for categorical variables. The comparison between two groups was tested by Wilcoxon rank-sum test for continuous variables and by χ2 test for categorical variables. The primary set of analysis data was an intent-to-treat population, that is, having completed post randomization efficacy assessment and taken the study medication. The efficacy variables were the VAS changes from baseline after administration of the single-dose study medication. The changes in VAS for each time point were presented by each group and analyzed by signed-rank test. The comparison between Ultracet and Depain-X was tested by Wilcoxon rank-sum test. The incidence of adverse events was analyzed by χ2 test and Fisher’s exact test. All statistical tests of the efficacy parameters were conducted at the two-sided, 5% significance level. No interim analysis was conducted.
3. Results
3.1. Demographic and baseline pain characteristics
Among the 107 patients who were enrolled, 45 (42.06%) withdrew from the study at their own desire (Fig. 1). Of the patients who withdrew, 21 (38.89%) belonged to the Depain-X group of 54 and 24 (45.28%) belonged to Ultracet group of 53. The withdrawal rate in the two groups did not differ (p = 0.5029). The number of intent-to-treat (ITT) patients was 62, and the number in the Depain-X and Ultracet treatments groups was 33 and 29, respectively. The ITT population was defined as the randomized patients who received at least one treatment dose and a baseline pain assessment (VAS value). The number of per-protocol (PP) patients was 57, and the number in the Depain-X and Ultracet treatment groups was 32 and 25, respectively. One patient in the Depain-X group and four in the Ultracet group had protocol deviation in randomization. The PP population was defined as the randomized patients who completed the study without any major deviation.
Download full-size image
A summary of patient characteristics in the ITT population is shown in Table 1. These characteristics were comparable between the groups. There were no significant differences between the treatment groups in terms of sex, age, weight, heart rate, and blood pressure. In the PP population, there were also no significant differences between the two groups for all characteristics (Table 1).
Mean baseline VAS scores of the ITT population were 4.52 cm in the Ultracet group and 4.88 cm in the Depain-X group. In the PP population, mean baseline VAS scores were 4.48 cm and 4.81 cm, respectively. Both ITT and PP populations showed no difference in mean baseline VAS scores between the Ultracet and Depain-X groups (p > 0.10) (Table 2).
3.2. Efficacy
Pain intensity (VAS score) changes from baseline at 30 minutes, 1 hour and 4 hours after medication in the ITT population (n = 62) are illustrated in Fig. 2. At 30 minutes assessment, Ultracet helped decrease the mean pain intensity by 2.04 cm from 4.52 cm to 2.48 cm (–44.88% change from baseline). Depain-X decreased the mean pain intensity by 1.64 cm from 4.88 cm to 3.24 cm (–33.14% change from baseline). In comparison, patients who received Ultracet had a lower mean pain intensity score (p < 0.1) and higher percentage change from baseline (p = 0.0525<0.1) than those who received Depain-X. Both figures almost achieved statistical significance. In comparison at 1 hour, Ultracet lowered the baseline VAS score of 3.00 cm to 1.52 cm, whereas Depain-X lowered the baseline score of 4.88 cm by 2.76 cm to 2.12 cm. VAS score was lower (p < 0.1) in the Ultracet group at 1 hour, but there were no significant differences in mean and percentage changes from baseline (p > 0.1). At 4 hours after medication, the Ultracet group still had lower (p < 0.05) mean pain score (0.79 cm) than the Depain-X group had (1.30 cm); the two groups did not differ for percentage change from baseline (p > 0.10).
Download full-size image
For the final pain relief rating scores (4 = complete; 3 = a lot; 2 = moderate; 1 = slight; 0 = none; –1 = worse) in the ITT population (Fig. 3), the mean score at 30 minutes was 2.14 in the Ultracet group and 1.76 in the Depain-X group (p = 0.1402). After 1 hour, the mean score in the Ultracet group was significantly higher than that of the Depain-X group (2.97 vs. 2.55, p < 0.05). After 4 hours, the mean score for pain relief in the Ultracet group was 3.59 compared with 3.21 in the Depain-X group (p = 0.1265) (Table 3).
Download full-size image
With regard to pain intensity between the two groups in the PP population (n = 57), the baseline VAS score of 4.48 cm in the Ultracet group (n = 25) did not differ greatly (p = 0.3715) from that in the Depain-X group (4.81 cm) (n = 32). (Table 2) at 30 minutes after administration. Ultracet decreased the mean pain intensity by 1.96 cm from 4.48 cm to 2.52 cm (–43.86% change from baseline), while Depain-X group decreased the mean pain intensity by 1.53 cm from 4.81 cm to 3.28 cm (–31.94% change from baseline). The data revealed that the patients who received Ultracet had a lower mean pain intensity score (p < 0.1) and higher percentage change from baseline (p < 0.1) than those who received Depain-X. After 1 hour, the Ultracet group did not differ significantly from the Depain-X group for pain intensity (p = 0.1296), mean change from baseline (p = 0.5686), and percentage change from baseline (p = 0.2597). Similar results were also noted after 4 hours (p > 0.1).
For the pain relief rating scores in the PP population, the mean score at 30 minutes and 4 hours did not differ between the two groups (p = 0.1933 and 0.3230). After 1 hour, the mean score in the Ultracet group was higher than that in the Depain-X group (2.92 vs. 2.53, p < 0.1) (Table 3).
3.3. Adverse events
Drowsiness and dizziness were the most common treatment-related adverse events in the Ultracet group (Table 4). Four (13.79%) patients complained of drowsiness after 1 hour and 4 hours drug administration. There were one (3.45%) and two (6.90%) patients who suffered from dizziness at 1 hour and 4 hours, respectively. The Depain-X group had a similar rate of drowsiness to the Ultracet group at 1 hour. However, at 4 hours, there were 10 patients (30.30%) who suffered from drowsiness, but the comparison showed no significant difference between the two groups (p > 0.1). Dizziness was also a common complication after administration of Depain-X. Four patients (12.12%) had dizziness in the first hour, but the number decreased to three (9.09%) at 4 hours. Skin itching was noted in one patient (3.03%) at 4 hours in the Depain-X group. All comparisons of adverse events between Ultracet and Depain-X showed no significant difference (p > 0.1) neither at hour 1, nor at hour 4. In this study, no serious adverse events related to the study medication were observed.
4. Discussion
This randomized, open-label, active-controlled parallel study carried out on 107 patients with postoperative pain demonstrated that Ultracet could provide better pain relief than Depain-X at 1 hour and 4 hours after drug administration. Most of the assessments such as pain intensity comparison, percentage change from baseline and pain relief scale showed that Ultracet could provide better analgesic efficacy than Depain-X, although the difference was not statistically significant. The comparison of medication-related adverse events showed no difference between the Ultracet group and Depain-X group.
The number of the enrolled patients (n = 107) was much greater than what we expected. According to our protocol, we initially planned to recruit 60 patients at random. However, many patients withdrew from the study, mainly because they considered that the operation was not as painful as they expected. This high withdrawal rate (42.06%) revealed that we overestimated the pain severity of IVAD implantation. Their refusal also represented the conservative concept in our culture about the use of analgesics for pain management. Among the enrolled patients, only 57(32 received Depain-X and 25 took Ultracet) completed the study under randomization without any major deviation. Depain-X had already fulfilled the expected case number, therefore, we skipped the rest of the patients who were randomized to take Depain-X and tried to achieve the required number for the Ultracet group. The final four patients who entered the Ultracet group were in such a situation. After the trial had closed, we found an error in randomization. One patient belonging to the Ultracet group wrongly took Depain-X, which added one more case to the Depain-X group in the ITT population. Therefore, our ITT population who had received at least one treatment dose and baseline pain assessment became 62 in number (33 in the Deapin-X group and 29 in the Ultracet group) (Table 2).
In comparison of pain intensity and pain relief scale between the two medications, the results tended to show that Ultracet could provide stronger analgesic efficacy than Depain-X, especially in the ITT population. Comparing the data at 30 minutes after the drugs were taken, we saw that Ultracet successfully decreased pain intensity by 44.88% from baseline. This contrasted markedly with the 33.14% in the Depain-X group, and was close to statistical significance (p = 0.0525). This difference indicates that the onset of Ultracet is faster than that of Depain-X. Although not statistically significant, Ultracet still had a lower pain score than Depain-X at the 4-hour measurement. The statistically significant difference in pain relief scale at 1 hour after medication between the two groups showed that Ultracet offered better amelioration of pain than did Depain-X in the ITT population. Therefore, we are of the opinion that Ultracet can provide slightly better analgesic efficacy than Depain-X in patients with mild to moderate postoperative wound pain, in terms of onset and duration. Besides, the above findings suggest that Ultracet could possibly be a faster and longer acting analgesic than Depain-X for postoperative pain control within 4 hours.
The fast onset and long duration of action of Ultracet were not only demonstrated in our study. Similar results have also been reported in a study with the dental pain model.8 Robert et al have confirmed that the estimated onset of pain relief was 17 minutes for Ultracet compared with 51 minutes for tramadol. The duration of analgesia (time to remedication) for Ultracet was 302 minutes, which was much longer than tramadol and APAP (122 and 183 minutes, respectively).8 In the study of Fricke et al, the median time to onset of pain relief was approximately 34.0 minutes and the median time to remedication with a supplemental analgesic agent was 169.0 minutes.9 Evidence reveals that single-dose Ultracet is undoubtedly a faster and longer-duration analgesic for acute pain.
For comparison of pain relief between Ultracet and Depain-X in our study, Ultracet was surprisingly superior to Depain-X at 1 hour after medication. In accordance with the review of Collins et al,4 65 mg propoxyphene combined with 650 mg APAP (Depain-X) has a similar analgesic efficacy to that of 100 mg tramadol. In another clinical trial, tramadol/APAP (75 mg/650 mg; two tablets of Ultracet) was superior to 100 mg tramadol for treatment of acute pain following oral surgery.9 In this situation, the analgesic efficacy of Depain-X should be lower than that of two tablets of Ultracet. Nevertheless, in our clinical investigation, we showed that one tablet of Ultracet appeared to provide better analgesia than Depain-X for treatment of acute postoperative pain after IVAD implantation.
From another point of view, Depain-X, which combined 100% of the suggested dose of propoxyphene (65 mg) and 130% of the suggested dose of APAP (650 mg), should undoubtedly be stronger than Ultracet, which only combined 75% of the suggested dose of tramadol (37.5 mg) and 65% of the suggested dose of APAP (325 mg). However, in our study, the results overruled the suggestion.
The pain model in our study was different from that for dental pain. Compared with oral surgery, the use of local anesthetics and the severity of pain intensity were different from ours. Local anesthetics that were not applied in our trial were used in the dental pain model. Local anesthetics may change the characteristics of pain, resulting in different outcomes. In the dental pain model, we noticed that the baseline pain intensity was usually higher, most of which may be greater than 6–7 cm.9, 10 However, in our study, the mean baseline VAS scores were 4–5 cm. This observation revealed that the pain caused by implantation of IVAD was moderate pain. Our result that Ultracet seemingly provides a faster, longer and stronger analgesic effect than Depain-X leads us to conclude that Ultracet is only for mild to moderate postoperative pain.
The case number of the study is also a determining factor for the outcomes. In this study, we noticed that there were lots of p values between 0.05 and 0.10, and more p values came closer to 0.05 in the ITT population (n = 62) than in the PP population (n = 57). We consider that the case number influenced the difference between the PP and ITT populations. Therefore, we can absolutely expect that if the case number increases, the results will become significant.
Besides the characteristics of being fast- and long-acting, we were also concerned about the safety of the medication. As we know, Ultracet is a safe medication because its component tramadol, unlike pure opioids, only rarely has clinically relevant respiratory or cardiovascular effects at recommended doses for postoperative pain.12 Ultracet is a safe medication also because postmarketing surveillance has revealed that the dependence and abuse potential with tramadol is negligible.13 In the dental pain study of Fricke et al, the most common adverse events with tramadol were dizziness, drowsiness, headache, nausea and vomiting.9, 11 In that trial, the incidence of adverse effects in the two-tablet (34.0%) and one-tablet (30.0%) Ultracet group was lower than the placebo group (48.0%).10 In our study, the most common adverse effects were drowsiness and dizziness in both groups, and one patient had skin itch in the Depain-X group. The outcome of our trial cannot differentiate safety between the two drugs.
In conclusion, the above findings suggest that single-dose Ultracet (37.5 mg tramadol/325 mg APAP) can provide slightly better analgesic efficacy in terms of onset and duration than Depain-X (65 mg propoxyphene/650 mg APAP) in patients with mild to moderate postoperative wound pain. The clinical evidence tendered by this study also suggests that Ultracet could provide faster analgesic response than Depain-X to some extent. Depain- X has been withdrawn from the market in Europe, America and other countries, therefore, Ultracet can serve as a good substitute in treating mild to moderate postoperative pain.