A comparative study on postoperative pain relief in laparoscopic cholecystectomy: Intraperitoneal bupivacaine versus combination of bupivacaine and buprenorphine.

CONTEXT: To assess the analgesic efficacy of the combination of bupivacaine and buprenorphine in alleviating postoperative pain following laparoscopic cholecystectomy. AIMS: Laparoscopic cholecystectomy is comparatively advantageous as it offers less pain in the postoperative period and requires a shorter hospital stay. There are only a few studies performed to evaluate the analgesic efficacy of intraperitoneal instillation of buprenorphine and bupivacaine during laparoscopic cholecystectomy. SETTINGS AND
DESIGN: The present research is a randomized, double-blind controlled study conducted in the Department of Anaesthesiology, Dayanand Medical College and Hospital Ludhiana, Punjab after formal ethical approval from Hospital's Ethics Committee. SUBJECTS AND METHODS: This study analyzed 90 adults admitted for elective laparoscopic cholecystectomy. After the procedure, subjects were divided into three equal groups to conduct the study. Three Groups A, B, and C had intraperitoneal instillation of the 25 ml of physiological saline (0.9% normal saline), 0.25% of bupivacaine, 0.25% bupivacaine, and 0.3 mg buprenorphine, respectively. Necessary vitals were monitored and recorded. Visual analog scale (VAS) and verbal rating scale (VRS) scores were recorded and analyzed systematically. STATISTICAL ANALYSIS USED: All observations were analyzed using analysis of variance and Student's t-test.
RESULTS: The mean pain scores were highest in Group A compared to Group B and Group C. Mean VAS and VRS scores were highest in Group C comparatively and lowest in Group A.
CONCLUSION: Combination of buprenorphine and bupivacaine intraperitoneally is comparatively more effective in relieving postoperative pain in comparison to intraperitoneal instillation of bupivacaine alone for postoperative pain management after laparoscopic cholecystectomy.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Laparoscopic cholecystectomy is comparatively advantageous over open cholecystectomy in pain management with shorter duration of hospital stays.[1] Pain management is medically pertinent for optimal care in surgical patients. Although development and advancement in understanding of the pathophysiology of pain, analgesic's pharmacology and the development of better effective techniques for postoperative pain control, patients still continue to experience considerable discomfort. Laparotomy results in parietal pain, whereas laparoscopy has a visceral component, a somatic component and shoulder pain secondary to diaphragmatic irritation as a result of CO2 pneumoperitoneum.[2] The degree of the pain after laparoscopic procedures has multifactorial influence including the volume of residual gas,[3] type of gas used for pneumoperitoneum,[4] pressure created by the pneumoperitoneum[5] and insufflated gas temperature.[6]

Earlier scientists have also reported several beneficial effects of the intraperitoneal application of bupivacaine with morphine on postoperative pain management after laparoscopic cholecystectomy.[7] Buprenorphine is a semisynthetic, highly lipophilic opioid and showed slow receptor association, but high affinity to multiple sites from which dissociation was very slow and incomplete (T-half = 166 min, 50% binding after 1 h), in contrast fentanyl achieved equilibrium rapidly and also dissociated rapidly and completely (T-half = 6.8 min and 100% by 1 h). Thus, buprenorphine has a longer duration of analgesia action compared to fentanyl. Studies have also shown that when buprenorphine is given in combination with a local anesthetic in inflamed tissues, it improves the quality of analgesia.[8] When this drug is given intrathecally, it improves quality and duration of postoperative analgesia as it is a µ receptor agonist with low intrinsic activity.[9] However, buprenorphine has side effects similar to those of opioids, that is, sedation, nausea, vomiting, dizziness, sweating, and headache. It is 25–50 times more potent comparatively. Thus, we have used buprenorphine and not fentanyl for our study. Studies have also reported that buprenorphine added to the local anesthetic, for brachial plexus block, for upper extremity surgery results in longer postoperative analgesia than traditional opioids.[10] A review of the literature, especially from our country, shows that studies to assess the analgesic efficacy of intraperitoneal instillation of buprenorphine and bupivacaine during laparoscopic cholecystectomy are rarely undertaken.

Objective

To assess the analgesic efficacy of the combination of bupivacaine and buprenorphine in alleviating postoperative pain following laparoscopic cholecystectomy.

SUBJECTS AND METHODS

The present research is a randomized, double-blind prospective controlled study conducted in the Department of Anaesthesiology, Dayanand Medical College and Hospital Ludhiana, Punjab after formal ethical approval from Hospital's Ethics Committee. The study sample consisted of 90 adults patients, age group 22–65 years, of either sex belonging to American Society of Anesthesiologists (ASA) classification I and II and scheduled for elective laparoscopic cholecystectomy under a standardized general anesthesia technique. A prior written informed consent was obtained from all the subjects. Prior to the procedure, detailed history, general physical examination and relevant systemic examination of all the patients were done following all standard protocols and precautions. Routine investigations such as hemogram, urine routine, renal function test, liver function tests, serum electrolytes, random blood sugar, and electrocardiogram were performed and analyzed in detail prior to procedure following all standard precautions and protocols required. Exclusion criteria consisted those who were uncooperative, unwilling, having history of anaphylaxis to local anesthetics and/or opioids and the drugs to be used, history of drug abuse, morbidly obese patients, ASA classification III, IV, V and patients having any other significant co-morbidities or any other with psychiatric disease.

The subjects were shifted to surgical theater followed by carefully measuring the required vital parameters such as heart rate, blood pressure (BP), respiratory rate and pulse oximeter oxygen saturation level (SpO2) and recording them accordingly. Intravenous (i.v.) access achieved. After preoxygenation with 100% oxygen (O2) for 3 min, induction of anesthesia was achieved with thiopentone sodium (2.5%) 4–6 mg/kg i.v. slowly (until the abolition of eyelash reflex) along with the injection of fentanyl 1.5 mcg/kg i.v. Intubation with an appropriate cuffed endotracheal tube was facilitated using neuromuscular blocker suxamethonium 1.5 mg/kg i.v. Anesthesia was maintained using controlled ventilation with halothane (0.5–1.5%) and nitrous oxide 66% + O2 (33%) using Bain's circuit. Vital parameters including heart rate, BP, electrocardiogram, temperature, end-tidal CO2 and SpO2 were carefully monitored throughout the procedure. Neuromuscular blockade was achieved with pancuronium bromide or atracurium besylate. All patients were given an injection of metoclopramide 10 mg i.v. intraoperatively. We have used commercially available bupivacaine and buprenorphine (i.v. injection) from NEON Company, Mumbai, India, under the brand name ANAWIN (0.5%) and BUPRIGESIC. At the end of the procedure, all the subjects were randomly allocated to groups using computer-generated random numbers. Each group of 30 subjects, that is, Group A: Physiological saline (0.9% normal saline) 25 ml after the surgery completion; Group B: Bupivacaine 25 ml (0.25%) after surgery completion; Group C: Bupivacaine 25 ml (0.25%) + buprenorphine (0.3 mg) after surgery completion. The surgeon, unaware of the nature of the study drug, was requested to instill the drug on the upper surface of liver and on the right subdiaphragmatic space to allow it to diffuse into the space near and above the hepatoduodenal ligament and above the gall bladder. Residual neuromuscular blockade was reversed with an injection of neostigmine 2.5 mg i.v. plus glycopyrrolate 0.5 mg i.v. The trachea was extubated, and subjects shifted to the recovery room, where the observations were made and recorded by an anesthesiologist; unaware of the group to which subject belongs. All subjects were made familiar with the visual analogue scale (VAS) score preoperatively and instructed in detail on its use as a tool for measuring postoperative pain. All subjects were asked to describe the pain relief at 0 (on arrival at recovery), 1, 2, 3, 4, 8, 12 and 24 h postoperatively on a four-point scale. Patients were informed before surgery that they could request an analgesic as if required. A total number of subjects in each group requiring supplemental analgesic was recorded. Subjects showing a VAS ≥3 and/or verbal response scale (VRS) <2 scores were administered a supplemental analgesic during the postoperative period. Analgesia was supplemented either with intramuscular nonsteroidal anti-inflammatory medications (NSAIDs) such as diclofenac sodium or another opioid like tramadol.

Statistical analysis

All observations recorded were carefully collected, segregated, categorized, tabulated, and meticulously analyzed working with a critical difference through analysis of variance and Student's t-test. The level of significance of inter-group as well as in intra-group variation was seen by comparing the actual mean difference on the two values with a critical difference. Variation between two groups or two values within a group was considered to be statistically significant only when mean difference found equal or more than the critical difference. Also, P < 0.05 was considered significant for analysis.

RESULTS

The demographic profile of the subjects is shown in Table 1. Major observations recorded on four major parameters considered are given in brief:

Table 1

Sample demographic profile observations

Rescue analgesic

Rescue analgesic was given when VAS ≥ 3 or VRS < 2 scores. In Group A, 30 patients were given rescue analgesic and mean time to first drug was 0.43 ± 0.86 h [Table 2]. In Group B, 15 patients received rescue analgesic and mean time to first dose of analgesic was 3.07 ± 0.46 h which when compared to Group A was significant statistically [Table 3]. In Group C [Table 4], only five patients received rescue analgesic and mean time to first dose of analgesic was 9.60 ± 2.19 h which were significantly later than Group A and Group B (P < 0.01) [Figure 1].

Table 2

Comparison of “VAS” in Group A

Table 3

Comparison of “VAS” in Group B

Table 4

Comparison of “VAS” in Group C

Figure 1

Trends in visual analogue scale score at rest on different groups

Mean pain scores

The mean pain scores (mean VAS) at a cough were highest in Group A and the maximum values were 5.50 ± 2.29 cm at 0 h. At all-time intervals, mean pain scores were higher in Group A than Group B and Group C. Mean VAS was lowest in Group C and highest in group A at all-time intervals. Mean VAS was lower in Group B than Group A at all-time intervals.

Verbal response scale score

Mean VRS was higher in Group C as compared to Group A and Group B. This difference was statistically significant (P < 0.001). Mean VRS score was low in Group A as compared to Group B and Group C at an all-time interval, which was statistically significant (<0.001) [Figure 2].

Figure 2

Trends in verbal rating scale score in different groups

Pulse rate and blood pressure

Mean pulse rate was lowest in Group C. It was significantly low statistically as compared to Group A and Group B at all-time intervals. Mean systolic BP was lower in Group C and was significantly low statistically as compared to all inter-groups at all-time intervals. Mean systolic BPs was highest in Group A as compared to Group B and Group C at all-time intervals that were statistically significant.

DISCUSSION

Laparoscopic surgeries produced medical revolution by bringing out many advantages and short incision, reduced blood loss, reduced stay in hospital and pain, that has brought down the cost of care process overall. However, patients undergoing laparoscopic procedures experience postoperative pain especially in back, abdomen and shoulder region that is one of the critical medical areas to be explored. However, it is associated with less pain and disability without increasing mortality or overall morbidity.[11] Pain after laparoscopic cholecystectomy involves several components (parietal, visceral and shoulder pain) with different intensities and their own time courses.[12] Clinicians have used various modalities and measures to ameliorate this pain associated with laparoscopy with significant success rate. Some of the measures were; evacuation of the insufflating gas,[13] application of local anesthetic to the site of surgery,[14] infiltration of local anestheic to the skin and muscle wounds[15] and usage of appropriate NSAIDS.[16] The doses of bupivacaine used in our study were lower than those thought to cause systemic toxicity. All the groups were statistically comparable with respect to age, sex distribution, body weight.

Our results significantly correlate with the previous observation of various authors who studied the efficacy of 15 ml of 0.5% bupivacaine (Group A) administered intraperitoneally immediately after pneumoperitoneum and the same amount at the end of operation and compared it to the control group (15 ml of 0.9% saline) in laparoscopic cholecystectomies.[17] VAS pain scores were significantly lower up to 8 h in Group A as compared to Group B. The prolonged analgesia observed in this study can be attributed to the use of higher volumes and concentration of bupivacaine. In Group C mean pain scores (VAS) at rest over the 24 h period was lower than Group A and Group B. VAS score remained low in 83.33% of patients up to 24 h. The results are consistent with the observation of scientists who demonstrated that intraperitoneal administration of bupivacaine 0.25% 30 ml plus morphine 2 mg significantly reduced postoperative analgesic requirement during the first 6 h after laparoscopic cholecystectomy. In our study also the requirement of postoperative analgesic in 10% of patients was delayed up to 8 h in Group C.[7] This longer duration may be attributed to the lipophilic nature of the buprenorphine compared to hydrophilic morphine, due to which it is longer acting analgesic. In our study, mean VRS scores were higher in Group C as compared to Group A and Group B at all-time intervals during the 24 h postoperative period. Scores of 2 (good relief) or 3 (complete relief) on the VRS were reported more often by patients in Group C than in Group A and Group B which resulted in higher total pain relief scores.

Finally, a detailed comparison of VAS and VRS scores among the various groups shows that the intraperitoneal instillation of bupivacaine with lipophilic opioids, that is, buprenorphine local anesthetic results in a significant reduction in pain and lesser need of analgesic postoperatively [Figure 3]. In our study, it was found that only five patients (16.67%) needed analgesic in Group C. Rest 25 patients did not need rescue analgesic up to 24 h postoperatively. In Group B, 15 patients (50%) required analgesic. In Group A, all 30 patients (100%) required analgesia, 21 patients at 0 h, seven patients at 1st h, one patient each at 2nd and 4th h, respectively. Thus, the number of patients requiring analgesic was higher in Group A (100%) as compared to Group B (50%) and Group C (16.67%) in 24 h postoperative period and the difference in the number of patients requiring rescue analgesic between all groups was statistically significant (P < 0.01). This further supports the fact that analgesic effect of intraperitoneal bupivacaine plus buprenorphine is better comparatively.

Figure 3

Trends in systolic blood pressures in different groups

In our study, the control group showed a significant increase in heart rate up to 24 h postoperatively when compared to Group C at all-time intervals and to Group B as well. The systolic BP and diastolic pressures were significantly low in Group C as compared to Group A and Group B at all-time intervals postoperatively [Figure 4]. There was no statistical significant difference in diastolic BP between the Group A and Group B except at 8th, 12th and 24th h postoperatively. The respiratory rate was significantly low in Group C as compared to Group A and Group B at all-time intervals throughout 24 h period postoperatively. These results were similar to the study by other authors,[18] who studied the effect of intra-peritoneal bupivacaine as an analgesic in laparoscopic cholecystectomy postoperative pain management. Thus, hemodynamic parameters also showed significant improvement in Group C indicating better postoperative analgesia in Group C patients receiving a combination of bupivacaine and buprenorphine.

Figure 4

Trends in diastolic blood pressure in different groups

To conclude our observations and groups behavior clearly shows that instillation of combination of buprenorphine along with 0.25% bupivacaine intra-peritoneally effectively relieves postoperative pain for a longer duration after laparoscopic cholecystectomy as compared to the instillation of only bupivacaine or 0.9% normal saline.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest