Comparative study of epidural bupivacaine with butorphanol and bupivacaine with tramadol for postoperative pain relief in abdominal surgeries.

INTRODUCTION: To compare the efficacy of combination of epidural local anesthetic with tramadol and butorphanol in major abdominal surgeries. AIMS: To evaluate duration of analgesia, analgesic efficacy, and safety profile of two groups of drugs-epidural butorphanol with bupivacaine and epidural tramadol with bupivacaine.
MATERIALS AND METHODS: A prospective, randomized controlled, double-blinded study was undertaken in 50 patients scheduled for major abdominal surgeries. Group B received epidural butorphanol 2 mg + bupivacaine 0.125% first dose and subsequent doses, butorphanol 1 mg + bupivacaine 0.125% (total volume 10 ml). Group T received epidural tramadol 2 mg/kg + bupivacaine 0.125% first dose and subsequent doses, tramadol 1 mg/kg + bupivacaine 0.125% (total volume 10 ml). Observed parameters were the quality of analgesia, sedation, and hemodynamic parameters in the intra and post-operative period. Time for request of rescue analgesia was noted in all the patients. Continuous data are analyzed by Student's t-test using IBM SPSS software version 20. P ≤0.05 was considered to be statistically significant. P ≤ 0.001 was considered to be statistically highly significant.
RESULTS: Visual analog scale better with butorphanol group than tramadol (0.12 ± 0.332 and 0.84 ± 0.746 for Group B and Group T) at 30 min after first dose. Onset of action (8.44 ± 1.158 min in Group B and 12.80 ± 1.354 min in Group T) faster with butorphanol but duration of analgesia longer with tramadol (5.92 ± 0.76 h in Group B vs. 7.68 ± 0.76 h in Group T). Sedation was seen in patients with butorphanol group. Nausea and vomiting more frequent with tramadol group.
CONCLUSIONS: Epidural tramadol with antiemetic is better than butorphanol for its longer duration in ambulatory surgery, elderly patients, obese patients, and suitable high-risk patients.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Postoperative analgesia is the most important aspect of anesthesia, especially in major abdominal surgeries. Such surgeries cause severe abdominal pain, which if treated inadequately causes shallow breathing, atelectasis of lungs and hence retention of secretions and more time will be required in ambulation. This increases the incidence of postoperative morbidity and leads to delayed recovery.[1] For this, regional anesthesia and analgesia are considered to be the safest and cost-effective method of relieving the postoperative pain. Of this epidural analgesia using local anesthetics provides good pain relief in the perioperative period.[2] The epidural analgesic technique for major abdominal surgeries provide effective pain relief with lesser side effects and hence higher levels of patient satisfaction. It also obtunds central sensitization and pain-induced organ dysfunction, resulting in an improved outcome.

Local anesthetics in addition with opioids increase the duration of analgesia reducing frequent supplementation of drugs and hence reduction in dosage, less frequency of systemic side effects attributable to each. Morphine and pethidine remain the standard opioids used for postoperative pain. However, they are associated with delayed respiratory depression and abuse potential.[3] Butorphanol, a mixed agonist-antagonist opioid, and tramadol, a moderately potent opioid agonist have been used for this purpose separately in very few studies.[456] Combination of butorphanol and local anesthetics has been studied more often during labor in parturients.[7] No study has compared the efficacy of the combination in major abdominal surgeries which is a cause of morbidity in majority of hospital admissions. Butorphanol has been proven to have minimal side effect profile among opioids.[6] Here, an attempt has been made to assess the efficacy of butorphanol in comparison to well-established drug tramadol in combination with local anesthetic agent (bupivacaine) through epidural route for the management of postoperative pain in major abdominal surgeries in view of safety profile among opioids.

MATERIALS AND METHODS

This randomized controlled, prospective double-blinded study was conducted on 50 patients of age 18–60 years of American Society of Anesthesiologists (ASA) Class I and II undergoing major abdominal surgeries such as abdominal hysterectomy, open cholecystectomy, and exploratory laparotomy, after obtaining approval from hospital Ethics Committee. Patients with ASA class III, IV and V and those with neurological disorders, coagulopathies, local or systemic infection, anatomical deformity of spine, patients suffering from respiratory, cardiac, hepatic, renal, central nervous system (CNS) diseases, and hypersensitivity to local anesthetics or study drugs and those who were on monoamine oxidase inhibitors with concurrent meperidine or propoxyphene, alcohol, other CNS depressants, and pregnant patients were excluded from the study.

These patients were allocated by computer generated randomization (www.random.org) into Group B and Group T receiving epidural butorphanol and bupivacaine or epidural tramadol and bupivacaine, respectively. Informed written consent was taken. Preanesthetic evaluation was done a day before surgery and patient kept nil orally for 8 h. In the operation theater, an intravenous line was secured. Readings of heart rate, blood pressure (BP), and oxygen saturation (SpO2) were taken as a baseline.

Epidural catheter insertion was performed in lateral position through midline approach with the help of 18-gauge Tuohy's epidural needle after taking all aseptic precautions. Epidural space was identified by using loss of resistance technique. Test dose given with injection lignocaine 1% with adrenaline (1:200,000) in the volume of 3 ml given through the epidural catheter to confirm the epidural space and prevent inadvertent dural or intravascular puncture. No accidental dural puncture was noted. Subsequently, patients were either given spinal anesthesia or general anesthesia according to the requirement of the surgery.

After completion of surgery, patient shifted to recovery room, the first dose of epidural dose given when visual analog scale (VAS) score is 4. All patients were randomized into two groups:

Group B - Butorphanol 2 mg + bupivacaine 0.125% (total volume 10 ml) first dose and subsequent doses, butorphanol 1 mg + bupivacaine 0.125% (total volume 10 ml).

Group T - Tramadol 2 mg/kg + bupivacaine 0.125% (total volume 10 ml) first dose and subsequent doses, tramadol 1 mg/kg + bupivacaine 0.125% (total volume 10 ml).

0.5% (5 mg/ml) bupivacaine diluted to a concentration of 0.125%.

Randomization was performed by a study coordinator who also encoded the drugs with matching random numbers involved and administered the drugs. Another investigator blinded to group allocation carried out data collection and data analysis.

The first dose of drugs given when the patient had VAS >4 after negative aspiration test and post dose vitals recorded. Monitoring of pain (10 point VAS on which 0 indicated “no pain,” 1- 3 mild pain, 4 - 7 moderate pain and 8 - 10 severe pain), sedation by Ramsay sedation score (1 - anxious and agitated, 2 - cooperative, oriented, tranquil, 3 - asleep and responding to verbal commands, 4 - asleep but brisk response to light stimulus, 5 - sluggish response to stimulus, 6 - asleep without response to stimulation), hemodynamic parameters, respiratory rate (RR) and SpO2 done every 10 min until 30 min and thereafter at hourly intervals after each epidural dose and subsequent doses given 8 hourly or when VAS score >4 for total 24 h. Injection diclofenac sodium 75 mg intramuscularly was given as rescue analgesia. Onset of analgesia (time from injection of the study medication to first reduction in pain intensity to almost complete relief) and duration of analgesia (time from epidural injection to the time of first request for additional pain medication) was observed in both groups following epidural doses.

Incidence of hypotension (systolic BP <90 mm Hg or >25% below baseline) or bradycardia (<50/min) were looked for and treated with vasopressors and atropine, respectively. Side effects that were specifically looked for were nausea, vomiting, pruritis, respiratory distress (RR <12/min), and lower extremity motor blockade.

Statistical analysis

Sample size was calculated on the basis of pilot study on 10 patients in both groups to detect a difference of 16% in increase in duration of analgesia hypothesizing tramadol with better duration for type I error (α) of 0.05 and power of the study 0.9. Sample size was found to be 14 patients in each group. For better validation, we have selected 25 patients in each.

Descriptive data presented as mean ± standard deviation, number, and percentages. Continuous data were analyzed by Student's t-test using IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. P ≤ 0.05 was considered to be statistically significant. P ≤ 0.001 was considered to be statistically highly significant.

RESULTS

The two groups were found to be comparable in demographic data-age and gender [Table 1]. Onset of analgesia was found to be significant between the two groups [Table 2]. Onset was faster with butorphanol than tramadol. The mean VAS score was highly significant in Group B at 10 min, 30 min and 5 h when compared to Group T. Rescue analgesia doses were lesser in Group T because of increased duration of analgesia when compared to Group B [Figure 1]. Time of duration of analgesia in Group T was significantly more when compared to Group B both following first epidural dose and top up doses [Table 3]. In Group T, the patient was calm whereas up to almost 2 h after butorphanol, the patient remained sedated and he could be easily arousable on verbal commands. A statistically significant (P < 0.05) difference was seen between the two groups more so within 4 h of administration of the drug [Figure 2]. Nausea and vomiting more in Group T which was easily treatable with antiemetic [Table 4].

Table 1

Demographic data of patients

Table 2

Onset of analgesia of Group B and Group T

Figure 1

Visual analog scale of Group B and Group T

Table 3

Duration of analgesia of Group B and Group T after first and top up doses

Figure 2

Ramsay sedation score of Group B and Group T

Table 4

Side effects among Group B and Group T

DISCUSSION

Management of postoperative pain still poses a lot of challenges to anesthetists even after all efforts have been taken to make the intra-operative period pain free. Pain relief is necessary for both humanitarian and therapeutic reasons. Intolerable pain in the postoperative period can have unwanted physiological effects.

In recent times, the role of epidural and subarachnoid opioids for the relief of postoperative pain promotes a new platform in this field. This is because of the direct action of the opioids on specific opioid receptors that are richly distributed in the posterior horn of the spinal cord, and epidural opioids have a wider margin of safety as against systemic opioids.

A MEDLINE search was conducted for all pertinent articles on epidural anesthesia. Epidural has been demonstrated to improve postoperative outcome and lessen the physiologic response to surgery.[8]

In comparison with intermittent parenteral opioid injection, epidural analgesia provides superior pain relief, and lesser adverse effects. In current clinical practice, pain management protocols use multimodal therapy with a variety of drugs. Use of nonsteroidal anti-inflammatory drugs parenterally and opioids by any route often improves analgesia by interrupting nociceptive impulses at both central and peripheral sites of pain transmission pathway and reduces the need for opioids. Furthermore, the epidural technique allows mixing of different classes of drugs for synergistic action.

We have used 2 mg of butorphanol in the initial dose based on a study by Hunt et al.[7] With 2 mg, the duration of analgesia was significantly greater and the time to onset of analgesia significantly shorter and the amount of bupivacaine could be reduced to 50%. Furthermore, somnolescence being higher with higher doses of butorphanol, it has ceiling effect on respiratory depression. Sedation is advantageous in the immediate postoperative period and hence 2 mg is beneficial for initial dose. Subsequently, 1 mg butorphanol has been used in top up dosage schedule.

Very few studies have compared epidural butorphanol in combination with local anesthetics. Abboud et al.[9] showed that the addition of 1 or 2 mg of butorphanol to 0.25% bupivacaine epidurally produces significantly longer duration of labor analgesia (139 ± 11 min and 141 ± 14 min, respectively) than does bupivacaine alone (96 ± 6 min). Duration of analgesia was comparable with 2 mg of epidural morphine + 0.25% bupivacaine (199 ± 29 min), with significantly less pruritis in the butorphanol groups. In a dose-response study of a combination of epidural bupivacaine with 0, 1, 2, or 3 mg of butorphanol, Hunt et al.[7] reported significantly faster onset (6.9 ± 3.6 min) and greater duration of labor analgesia (137 ± 18.4 min) with the addition of 2 mg of butorphanol to 0.25% bupivacaine as compared with bupivacaine alone (onset time = 21.3 ± 5.2 min, duration = 59 ± 12.3 min). The addition of 3 mg of butorphanol did not improve the analgesic effect.

Tramadol 100 mg has been used as a study by Siddik-Sayyid et al.[10] has proven that there was no significant difference between 100 and 200 mg tramadol given epidurally. Using an initial dose of 50 mg tramadol was less efficacious. We have used 100 mg tramadol in the first epidural dose followed by 50 mg tramadol both in combination with 0.125% bupivacaine. As pain intensity at surgical site decreases with time, analgesic requirement becomes lesser. We have reduced the dose of study drug keeping in mind the side effects at higher doses.

Traditionally, epidural bupivacaine was used for postoperative analgesia. Epidural bupivacaine 0.5% causes motor, sensory and sympathetic blockade, 0.25% causes sensory and autonomic blockade, and 0.125% causes sensory blockade only.

Results with 2 mg butorphanol with 0.125% bupivacaine is of lesser duration (5.92±0.72 h) in our study in comparison with Bharti and Chari[11] (8.68±0.82 h) due to the difference in type of surgery. As we have used lower doses of butorphanol, the duration of pain relief in our study falls on the lower side. However, with the epidural catheter in place, a shorter duration of analgesia may not be a clinical disadvantage. Our results are comparable with the study of Gupta et al.[2] We have observed longer duration of analgesia with 100 mg tramadol in our study (7.68 ± 0.76 h) compared to Siddik-Sayyid et al.[10] (4.5 ± 3.1 h) might be because of addition of local anesthetic with tramadol. We have observed a lesser duration with 50 mg and 100 mg tramadol group (6.6 ± 0.57 h, 7.68 ± 0.76 h) than Delilkan and Vijayan[13] study (7.40 h, 9.36 h). Difference maybe because subsequent doses were administered on patients request and difference in pain perception by them whereas we have given at 8 hourly intervals taking into account VAS for analgesia assessment. Furthermore, they have used 0.25% bupivacaine, and we have used 0.125% bupivacaine with tramadol.

Pokharel et al.[14] have used VAS satisfaction scale to assess the quality of analgesia and have inferred that quality of analgesia is better with butorphanol. Delilkan and Vijayan[13] have observed better pain relief with 100 mg tramadol compared to 50 mg tramadol. In the study by Bharti and Chari,[11] VAS within 2 h with 2 mg butorphanol with 0.125% bupivacaine was 0–3 and in our study, it has been found to be <2 which is comparable. In the study by Bhagwat and Sanjay[12] VAS at 1 h with 1 mg butorphanol 0.53 ± 0.5 and of 50 mg tramadol 0.9 ± 0.7. In our study, it was 0.12 ± 0.332 and 0.84 ± 0.746 for Group B and Group T respectively. Difference seen in butorphanol might be due to addition of bupivacaine in our study. Thus, quality of analgesia has been proven to be better with butorphanol group in all studies.

A statistically significant difference was seen between the two groups more so within 2 h of administration of the drug (P < 0.05). We differ from other studies in using Ramsay sedation scale. However, there have been comparable results. Mild sedation may be beneficial to patients in the immediate postoperative period.[14]

In our study, in Group B, variation from preoperative pulse rate and mean arterial pressure (MAP) decreased as pain relief began but does not co-relate with the quality of analgesia with time. In Group T, similar decrease in these parameters were seen after giving the drug but this decrease was seen for a longer time as compared to Group B. Pulse and MAP do not co-relate with VAS score as these hemodynamic parameters depend on various other factors like intravascular volume status, intake of drugs such as β blockers or calcium channel blockers, sensitivity of the patient to pain, difference in response of the patient to the study drug and surrounding environment of the patient. No patient developed significant bradycardia or hypotension. The decrease in pulse rate and MAP after administration of the drug might be due to adequate analgesia resulting in less sympathetic discharge and sedation as described by Gupta et al.[2] in their study.

In our study, no significant change in RR has been noticed in either of the two groups. The limitation of our study like the study by Pokharel et al.[14] is that we have used RR alone to assess respiratory depression which is not the only indicator of respiratory depression. Transient depression of the carbon dioxide response curve was observed by Abboud et al.[9] after 1.5 h in patients receiving 2–4 mg of epidural butorphanol.

The mechanism for prevention of nausea by butorphanol is probably μ-opioid receptor antagonism. High lipid solubility and high affinity for opioid receptors are other factors that contribute reduced side effects with butorphanol. Due to high lipid solubility, there is diffusion of drug in the spinal cord, limiting the amount of drug remaining in the cerebrospinal fluid capable of reaching the brainstem, where side effects occur. Nausea and vomiting due to tramadol is due to its action on 5-HT receptors. It occurs more frequently with intravenously when it is given at a faster rate than other routes of administration, even lesser by epidural route. In our study, Group B patients had side effects like nausea but incidence was less when compared to Group T where 12% of patients had nausea, and 8% of patients had vomiting. The difference was statistically significant (P < 0.05). Pruritis has been observed in few patients receiving epidural butorphanol in previous studies.[1516] None of our patients in both groups had pruritis or hypotension.

CONCLUSIONS

VAS is better with butorphanol group than tramadol. Onset of action is faster with butorphanol but duration of analgesia longer with tramadol. Sedation is seen in patients with butorphanol group. Hemodynamic parameters are well within normal limits with no incidence of bradycardia or hypotension. Nausea and vomiting are seen more frequently with tramadol group.

Epidural analgesia relieves postoperative pain and reduces the physiological changes that are associated with pain. However, selection of individual drug must balance the efficacy of analgesia against the occurrence of side effects indicating the safety profile.

Both butorphanol and tramadol were effective for postoperative analgesia when used epidurally in patients undergoing abdominal surgeries. Butorphanol although has shorter duration of analgesia but better pain relief compared to tramadol and faster onset of action. It also caused less nausea and slight sedation which was rather desirable in the postoperative period. Whereas with tramadol, longer duration of analgesia, more nausea and vomiting was observed compared to butorphanol.

In view of the above facts, though epidural butorphanol has better quality of analgesia (VAS) as compared to tramadol, shorter duration and sedation are major disadvantages. Epidural tramadol with antiemetic is better than butorphanol for its longer duration in ambulatory surgery, elderly patients, and obese patients. Sedation and frequent requirement of rescue analgesic requirement are main disadvantages of butorphanol in such patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.