A Comparative Study for Post Operative Analgesia in the Emergency Laparotomies: Thoracic Epidural Ropivacaine with Nalbuphine and Ropivacaine with Butorphanol.

BACKGROUND: Adequate postoperative pain therapy for emergency abdominal surgeries is important far beyond the perioperative period because sensitization to painful stimuli can cause postoperative morbidity. A prospective, double-blind, randomized study was carried out to compare the quality of postoperative analgesia and side-effect profile between epidurally administered butorphanol and nalbuphine as an adjuvant to 0.2% ropivacaine.
MATERIALS AND METHODS: A total of eighty patients, 43 men and 37 women between the age of 18 and 65 years of American Society of Anesthesiologists (ASA) Class I E and II E, who underwent intestinal perforation repair surgery were randomly allocated into two groups ropivacaine with butorphanol (RB) and ropivacaine with nalbuphine (RN), comprising of 40 patients each. Group RB received 0.2% ropivacaine containing 2 mg butorphanol while Group RN received 0.2% ropivacaine containing 10 mg nalbuphine through thoracic epidural catheter. Quality of analgesia, cardiorespiratory parameters, side-effects, and the need of rescue intravenous analgesia were observed.
RESULTS: The demographic profile and ASA Class were comparable between the groups. RN group had good quality of analgesia and stable cardiorespiratory parameters for the initial 6 h of postoperative period, after which they were comparable in both groups. Furthermore, the need of rescue analgesia was higher (20%) in the RB group during the first 6 h. The side-effect profile was comparable with a little higher incidence of nausea in both groups.
CONCLUSION: Thoracic epidurally administered ropivacaine with nalbuphine is more effective than ropivacaine with butorphanol for immediate postoperative pain relief in patients undergoing emergency exploratory laparotomy.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Thoracic epidural analgesia is frequently used for major thoracic and abdominal procedures.[123] The insufficient treatment of postoperative pain, especially in upper abdominal surgeries, results in reduced pulmonary compliance, inability to breathe deeply or cough forcefully, leading to retention of secretions, atelectasis, and pneumonia.[4] Epidural analgesia has been shown to promote early mobilization, reduce the time for tracheal extubation, reduce the pulmonary morbidity, reduce the rehabilitation time, and reduce the length of hospital stay.[56]

The new era in the field of postoperative analgesia started with the discovery of opioid receptors in the central nervous system. Opioids, in combination with local anesthetics as an adjuvant, are synergistic and can improve the analgesia and reduce the adverse effects of both classes of drug.[7] The epidural administration of parent opioids like morphine has been associated with lower efficacy and undesirable side-effects as nausea, vomiting, pruritus, respiratory depression, and urinary retention.[8] Both nalbuphine and butorphanol are partial opioid agonist-antagonist with strong k-receptor agonism and weak μ-receptor agonist and antagonist activity.[910] They have strong analgesic potency and sedative properties with a ceiling effect on μ-receptor activity of respiratory depression.[1112] Nalbuphine has the potential to maintain or even enhance µ-opioid based analgesia while simultaneously mitigating the µ-opioid side-effects.

There is no literature available on the head to head comparison between nalbuphine and butarphanol as an epidural adjuvant for postlaparotomy pain. Hence, we designed a double-blind prospective randomized study to compare the efficacy of nalbuphine and butarphanol with ropivacaine in thoracic epidural analgesia for postlaparotomy pain in patients undergoing emergency abdominal surgeries.

We aimed to compare the quality of analgesia, postoperative hemodynamic variations, side-effect profile, and the need for rescue analgesia between the two groups in the early postoperative period of first 24 h after surgery.

MATERIALS AND METHODS

After obtaining Institutional Ethics Committee approval and written informed consent from the patients, this prospective, randomized, double-blind study was conducted. Eighty patients of American Society of Anaesthesiologists (ASA) Class I E and II E, between 18 and 45 years of age undergoing emergency laparotomy for intestinal perforation repair were enrolled. Exclusion criteria were contraindication to epidural anesthesia, allergy to local anesthetic, cardiac disease, psychiatric disease, respiratory distress, hemodynamic instability, acid-base disorders, and history of drug abuse. In the operation theater, two intravenous (i.v) access using wide bore cannulas were secured in all patients. Premedication done with i.v injection ranitidine 0.5 mg/kg and injection glycopyrrolate 0.01 mg/kg. All noninvasive monitoring devices (noninvasive blood pressure, electrocardiograph [ECG] leads, pulse oximetry [SpO2], and temperature probe) were attached, and the baseline cardiorespiratory parameters were recorded. Patient dehydration status was corrected preoperatively using ringer lactate solution. All cases of exploratory laparotomy were conducted under general anesthesia with standard protocol. Intraoperatively, patient heart rate, mean arterial pressure (MAP), SpO2, ECG, end-tidal CO2, and urine output were monitored. Intraoperative fluid and blood loss were replaced using ringer lactate solution and packed red cells. After completion of skin closure and dressing, under maintenance of general anesthesia, the patient was positioned laterally, and epidural catheterization was done at T9–T10 interspinous space using loss of resistance technique. The patient made supine from lateral position and extubated after adequate reversal. Patients were shifted to postoperative recovery room, and monitoring was continued. Once the patient in postoperative room complain of pain (visual analog scale [VAS] of >3), the study started. Test dose of 3 ml lignocaine with adrenaline (1:200,000) was injected through the epidural catheter and the patients were randomly allocated to one of the following two groups in a double-blinded fashion based on a computer-generated code: Group RN (n = 40): Received 0.2% ropivacaine with nalbuphine 10 mg and Group RB (n = 40): Received 0.2% ropivacaine with butorphanol 2 mg. In both groups, 14 ml of test drug was administered epidurally by the investigator who was blinded to the trial. Epidural top up was repeated 6 hourly for 24 h. During the study period, patient's heart rate, MAP, respiratory rate, and VAS score was noted at 15 min after the drug administration and 2 hourly for the first 6 h, and then 6 hourly for the next 18 h. Side-effects such as nausea, vomiting, respiratory depression, motor blockade (Bromage scale >1), deep sedation (Ramsay sedation score >3), shivering, and pruritus were noted. All patients were given rescue analgesic (injection diclofenac 75 mg i.v) whenever they complained of pain or VAS score >3 before the next epidural top up. Hypotension (fall in systolic blood pressure >20% of baseline) was treated with fluid boluses and injection mephentermine 6 mg i.v bolus. Bradycardia (heart rate <50/min) was treated with 0.02 mg/kg of injection atropine. Nausea and vomiting were treated with 0.1 mg/kg of i.v ondansetron. Postoperative maintenance i.v fluids were given as per body weight.

Statistical analysis

Sample size was selected on the basis of crossover pilot study of 15 patients in both groups to detect a projected difference of 35% between the two groups for quality of analgesia for type I error (α) of 0.05 and power of study 0.8. At the end of the study, all the data were compiled systematically and analyzed using unpaired Student's t-test and Chi-square test. Statistical Package for Social Science (IBM Software Group, Chicago, IL 60606, USA) version, 20.0 for windows, was used to compare the continuous variables between the two groups. Data were expressed as mean ± standard deviation. P < 0.05 was considered significant and P < 0.0001 as highly significant.

RESULTS

The two groups of patients were comparable with respect to age, weight, height, ASA Class, and duration of surgery [Table 1]. Baseline heart rate, MAP, and respiratory rate were also comparable in both groups, and they did not vary significantly.

Table 1

The demographic profile of patients and duration of surgery in both groups

During the first 6 h postoperatively, VAS score was significantly lower in RN group than RB group (P < 0.05). After 6 h, VAS score was stable and comparable in both groups [Figure 1]. Eight patients in RB group received rescue analgesia (injection i.v diclofenac 75 mg) whereas in RN group only one patient received rescue analgesia during the first 6 h. No patients in both groups needed rescue analgesia after 6 h for the next 18 h of the study period.

Figure 1

Visual analog score observation between ropivacaine with nalbuphine and ropivacaine with butorphanol groups.

Comparative incidence of various side effects in both groups was observed in the postoperative period. The incidence of nausea was little higher in both groups, but none of them had vomiting. The incidence of dry mouth, pruritus, and shivering was lower in both groups and found to be nonsignificant. Level of sedation was adequate, and there was no incidence of deep sedation (Ramsay sedation score >3) in both groups. None of the patients in both groups reported other side-effects such as motor blockade and respiratory depression [Table 2].

Table 2

Comparison of side effect profile observed in ropivacaine with nalbuphine and ropivacaine with butorphanol groups

The heart rate and MAP were maintained ± 20% around the baseline during the study period in both groups. The heart rate and MAP were significantly lower for the first 6 h in RN group when compared with the RB group (P < 0.05). However, this significant difference was not observed in the next 20 h of the study period. None of the patients showed bradycardia or hypotension at any time [Figures 2 and 3].

Figure 2

Comparison of heart rate between ropivacaine with nalbuphine and ropivacaine with butorphanol groups at different time intervals.

Figure 3

Comparison of mean arterial pressure between ropivacaine with nalbuphine and ropivacaine with butorphanol groups at different time intervals.

The mean respiratory rate was also significantly lower in RN group for the first 6 h. But thereafter, the difference in mean respiratory rate was statistically not significant (P > 0.05) at different time intervals. None of the patients showed respiratory depression (<10/min) at any time.

DISCUSSION

Pain is often inadequately treated in many emergency laparotomies. Acute postoperative pain can cause detrimental effects on multiple organ systems such as cardiovascular stress, autonomic hyperactivity, tissue breakdown, increased metabolic rate, pulmonary dysfunction, fluid retention, dysfunction of the immune system, delayed return of bowel function, and development of chronic pain syndromes.[145] Opioids as epidural adjuvants to local anesthetics improve the quality of analgesia and provide a dose-sparing effect. Since both nalbuphine and butarphanol have k-agonist and μ antagonistic properties, we chose to investigate the analgesic efficacy of nalbuphine and butorphanol, as an epidural adjuvant to 0.2% ropivacaine for postoperative analgesia.

Thoracic epidural for postlaparotomy pain

The postlaparotomy pain is the major cause for respiratory morbidity and delays the early ambulant resulting in increase in length of hospital stay. The surgical incision for laparotomies extends from sub-xiphoid level to supra-pubic level covering almost seven spinal dermatomes (T7-L1). Hence, we did epidural catheterization at T9–T10 interspinous space and took constant drug volume of 14 ml (2 ml per spinous segment) in both groups for the study. It is based on the previous studies by Kato et al.,[13] and Saravana Babu et al.[14]

Quality of postoperative analgesia

In our study, postoperative pain was assessed using VAS. The test drugs were given when the VAS score is >3, because, in the immediate postoperative period, the residual effects of intraoperative anesthetic drugs make the patients to tolerate minimal pain due to residual analgesia and hypnosis.[15] Although VAS score started decreasing after 15 min of drug administration in both groups, it was significantly lower in RN group than RB group till first 6 h, thereafter VAS score became comparable in both groups [Figure 1]. Furthermore, the need of rescue analgesia (injection i.v diclofenac 75 mg) was higher in the RB group (20%) than RN group (2%) during the first 6 h only. This shows that ropivacaine with nalbuphine having an earlier onset of action than ropivacaine with butarphanol, breaks the pain cycle early and effectively, leading to decreased need of rescue analgesia in the immediate postoperative period. Our study results on quality of analgesia are similar to the previous studies by Chatrath et al.,[16] and Kaur and Bajwa,[17] where addition of nalbuphine to local anesthetics provided effective postoperative epidural analgesia when compared to other opioids.

Postoperative hemodynamic

Although there are chances of hemodynamic instability with epidural local anesthetics, the heart rate, and MAP remained ± 20% around the baseline. This is due to the lower concentration of ropivacaine (0.2%) blocking the pain impulses effectively, sparing the autonomic and motor blockade. These findings were similar to the study results of Doss et al.,[18] and Bhattacharyya and Dutta.[19] In RN group, heart rate, MAP, and respiratory rate was significantly lower than RB group during the first 6 h. This may be due to decreased VAS score and increased patient satisfaction in the RN group during the first 6 h. These results were in accordance with the previous studies conducted by Weber et al.[3] and Li et al.[20]

Postoperative side-effects

The side-effect profile in both groups was quite favorable as none of the patients had motor blockade or respiratory depression. Although the incidence of nausea was little higher in both groups, none of them had vomiting. The incidence of dry mouth, pruritus and shivering was very low in both the groups and found to be nonsignificant. Both nalbuphine and butorphanol provided adequate, arousable level of sedation with no incidences of deep comatose state. This may be due to their antagonistic properties against μ opioid receptors. These findings were similar to the previous studies conducted by Gupta et al.[15] and Chatrath et al.[16]

Epidural catheterization under general anesthesia

Placing epidural catheter under general anesthesia has lot of controversies, but there was no evidence to suggest it as unsafe.[2122] Literature by Fischer,[23] has discussed the incidence of nerve damage following regional blockade in both awake and anesthetized patients. Since our study participants are cases of abdominal emergency, it was not possible to place the epidural catheter in awake state. Hence, we did it at the end of surgery by an experienced trainee in epidural blockade. Furthermore, before the administration of test drug, we checked for any neurological deficit and confirmed the position of epidural catheter by giving a test dose.

Limitation of the study

The limitation of the study is that it was conducted for the first 24 h after surgery because we aimed to compare the effectiveness of analgesia in the immediate postoperative period. We were not able to follow-up the patients for 48 h of postoperative period to study the complete analgesic efficacy of both groups.

Strength of the study to literature

The results of our study add strength and evidence to the studies by Chatrath et al.,[16] and Zeng et al.,[24] which showed epidural ropivacaine with nalbuphine has higher analgesic efficacy in the immediate postoperative period and decreased the incidence of side-effects and the need of rescue analgesics.

Future directions

Further research studies comparing the analgesic efficacy between nalbuphine and other opioids as adjuvant to ropivacaine should be carried out so that epidural analgesia technique with high efficacy and less side-effect profile can be safely provided to emergency laparotomy patients.

CONCLUSION

It can concluded from the study, that thoracic epidural ropivacaine with nalbuphine is more effective than ropivacaine with butorphanol for postoperative analgesia during the immediate postoperative period of first 6 h.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.