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 Table of Contents  
Year : 2020  |  Volume : 7  |  Issue : 1  |  Page : 57-64

Comparative study between intraperitoneal bupivacaine and bupivacaine-nalbuphine for postoperative pain relief after laparoscopic cholecystectomy

Department of Anesthesia and Intensive Care, Faculty of Medicine, Minia University, Minia, Egypt

Date of Submission30-Nov-2018
Date of Acceptance10-Sep-2019
Date of Web Publication16-Apr-2020

Correspondence Address:
Wegdan A Ali
Department of Anesthesia and Intensive Care, Faculty of Medicine, Minia University, Minia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/roaic.roaic_101_18

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Background Postoperative pain relief following laparoscopic cholecystectomy (LC) has been achieved using intraperitoneal (i.p.) local anesthetics. Addition of opioids can prolong postoperative analgesia. Nalbuphine is an agonist–antagonist opioid that provides analgesia without the undesirable effects of pure agonists. This study was performed to compare between postoperative analgesia of i.p. bupivacaine and bupivacaine combined with nalbuphine in patients undergoing LC.
Patients and methods This study included 90 patients undergoing LC. They were randomly divided into three groups, with 30 patients each. Postoperatively, group C received 50-ml normal saline (NS), group B0 received bupivacaine 100 mg diluted with NS to 50 ml, and group BN received bupivacaine 100 mg with nalbuphine 10 mg diluted with NS to 50 ml. Pain was assessed using the visual analog scale (VAS) for 24 h, and the first analgesic request was recorded. Total analgesic consumption in 24 h, hemodynamic parameters, and adverse effects were also noted.
Results Postoperative VAS values were significantly lower in group BN up to 24 h. Moreover, i.p. bupivacaine showed lower VAS values than in control group. The duration of analgesia was 11.5±0.9, 7.5±0.9, and 1.5±0.6 h in groups BN, B0, and C, respectively (P<0.001). The total analgesic consumption in 24 h. was significantly less in BN group than other groups. The hemodynamic parameters were steadier in BN group than other groups, with no significant adverse effects.
Conclusion Addition of i.p. nalbuphine to bupivacaine provides superior analgesia than bupivacaine only after LC without an increase in adverse events.

Keywords: bupivacaine, intraperitoneal, laparoscopic cholecystectomy, nalbuphine, pain relief

How to cite this article:
Ali WA, Ali NS, Sewefy AM, Ahmed AH. Comparative study between intraperitoneal bupivacaine and bupivacaine-nalbuphine for postoperative pain relief after laparoscopic cholecystectomy. Res Opin Anesth Intensive Care 2020;7:57-64

How to cite this URL:
Ali WA, Ali NS, Sewefy AM, Ahmed AH. Comparative study between intraperitoneal bupivacaine and bupivacaine-nalbuphine for postoperative pain relief after laparoscopic cholecystectomy. Res Opin Anesth Intensive Care [serial online] 2020 [cited 2020 Jul 11];7:57-64. Available from: http://www.roaic.eg.net/text.asp?2020/7/1/57/282582

  Introduction Top

Laparoscopic cholecystectomy (LC) has become the treatment of choice for symptomatic gallstone disease. Being a minimally invasive procedure, it came into routine practice with many benefits compared with open cholecystectomy, including reduced surgical trauma, less postoperative pain, cosmetically smaller incision, fewer postoperative pulmonary complications, and shorter recovery time and hospital stay. However, pain after LC may be moderate or severe in some patients, which can lengthen hospital stay and increase morbidity and costs. Adequate pain control after LC is therefore increasingly important as many centers are performing this surgery as a day-case procedure.

The origin of pain after LC is multifactorial and complex in nature. Pain arising from incision sites is parietal pain, whereas pain from the gall bladder bed is mainly visceral in nature, and shoulder pain is mainly referred owing to the residual CO2 irritating the diaphragm. Therefore, effective pain management will depend on multimodal approach [1]. This involves the use of paracetamol [2], NSAIDs [3], opioids [4], and local anesthetics [5].

Many authors suggest that i.p. instillation of local anesthetics is effective for postoperative analgesia if administered at the end of LC [6],[7]. This route of administration is noninvasive, simple to perform, does not involve additional neuraxial block, and is particularly suited for the practice of ambulatory anesthesia. However, duration of analgesia may be limited for few hours. So, addition of adjuvants such as narcotics [8],[9],[10],[11], α2 agonists [12], or NSAIDs [13] has been proposed to prolong the postoperative analgesia. This prospective randomized, double-blinded, placebo-controlled study was conducted to compare postoperative analgesia produced by intraperitoneal (i.p.) bupivacaine with that of i.p. bupivacaine combined with nalbuphine in patients undergoing LC.

  Aim Top

This study was performed to compare postoperative analgesic effect of i.p. bupivacaine with that of bupivacaine combined with nalbuphine in patients undergoing LC.

  Patients and methods Top

This prospective, randomized, double-blinded, placebo-controlled study was conducted in Minia University Hospital during the period from May 2017 to November 2017, after approval of the university ethical committee and obtaining informed consent from all patients. A total of 90 adult patients aged between 18 and 60 years old, of both sexes, belonging to American Society of Anesthesiologists grade I or II, and scheduled to undergo LC surgery under general anesthesia were included in the study.

Patients with history of allergy to the study drugs, or with acute cholecystitis, with severe cardiac, pulmonary, or neurological diseases, previous abdominal surgery, drug abuse or on analgesics for any reason, or patients in whom surgery had to be converted to open cholecystectomy or with complications which could increase postoperative pain such as biliary spillage owing to puncture of the gall bladder or extensive dissection owing to adhesions were excluded from the study.

The patients were randomly allocated into three groups, according to computer-generated numbers, having 30 patients each.
  • Group C received i.p. 50-ml normal saline (NS).
  • Group B0 received i.p. bupivacaine 100 mg (20 ml, bupivacaine 0.5%), diluted with NS to total volume of 50 ml.
  • Group BN received i.p. bupivacaine 100 mg (20 ml, bupivacaine 0.5%) with 10-mg nalbuphine, diluted with NS to total volume of 50 ml.

The study solutions were drawn into precoded sterile syringes by an anesthetist not involved in the study and given to the surgeon after completion of surgery for i.p. instillation in a double-blinded manner. The protocol was opened after the study had been completed.

Preoperative assessment was done for the patients by taking medical history, and performing general and physical examination, including blood pressure, heart rate (HR), respiratory rate, chest, heart, and abdomen. Then, routine and relevant investigations were carried out such as complete blood picture, renal and liver function tests, and random blood sugar. A detailed explanation of the visual analog scale (VAS) was done for the patients before surgery. VAS consists of a straight vertical 10 cm line; the bottom point (0 cm) represents no pain and the top (10 cm) represents the worst imaginable pain. Patients were fasted for 6 h for solid food and 2 h for water and clear liquids.

On arrival to the operating theater, standard monitoring was applied including noninvasive blood pressure, electrocardiogram, and pulse oximetry. Then, an intravenous 18 G cannula was inserted, and preloaded Ringer’s solution 10–15 ml/kg was given. Conventional balanced anesthesia was administered for all patients after preoxygenation with 100% O2 for 3 min and premedication with midazolam 0.05 mg/kg. Induction of anesthesia was achieved with fentanyl 2 µg/kg and propofol 1% 2.5–3.5 mg/kg until loss of verbal response, followed by atracurium 0.5 mg/kg to facilitate tracheal intubation with an appropriate size cuffed endotracheal tube. Anesthesia was maintained with inhalational isoflurane 1–1.5% in 100% oxygen to keep mean arterial pressure (MAP) and HR ±20% of baseline values. Ventilation was controlled with tidal volume of 6–8 ml/kg and respiratory rate of 12–14 breaths/min. The ventilation parameters were adjusted to keep end-tidal CO2 at 35–40 mmHg. Intravenous fluid therapy was given according to the calculated formula (4/2/1 rule) per fasting hours, for maintenance of fluid requirements, 4 ml/kg/h for third space loss, and replacement of surgical bleeding if present. Nasogastric tube was inserted for all patients after intubation and removed at the end of surgery.

Pneumoperitoneum was created by insufflation of CO2 to maintain intra-abdominal pressure between 12 and 15 mmHg throughout the surgery. After removal of the gall bladder, hemostasis, washing of the peritoneal cavity, and suctioning of the fluid used for irrigation were performed. Then, the study solutions were instilled by the surgeon i.p., under direct vision into the right hepatodiaphragmatic space, on the gall bladder bed, near and above hepatoduodenal ligament, with the patient in Trendelenberg’s position which was maintained for 5 min. The instillation was done using metallic suction cannula keeping its knob at irrigation point and syringe nozzle attached to the inlet, while keeping suction outlet closed and secured ensuring no spillage or loss of study medications. All the operations were performed by a team of surgeons that has at least 3 years of experience in laparoscopic surgery.

Recovery was performed by discontinuation of inhalational anesthesia and reversal of neuromuscular blockade with neostigmine 0.05 mg/kg and atropine 0.01 mg/kg. Then, patients were extubated and shifted to the recovery room. No analgesics were given to the patients before recovery.

In the recovery room, HR, MAP, and SpO2 were monitored. Measurements of HR and MAP were taken every 10 min for the first half an hour after recovery. Severity of pain was assessed using VAS ranging from 0 to 10. Pain assessment was done by the patients at the following time points: immediately after recovery (regarded as 0 h) and at 1, 2, 4, 6, 8, 10, 12, and 24 h postoperatively. For patients with VAS score more than or equal to 4, rescue analgesia was given, using NSAIDs such as i.v. tenoxicam 20 mg and opioid like fentanyl 1–2 µg/kg. The time to first analgesic request and the total analgesic consumption in the postoperative 24 h were recorded. The total analgesic requirements in 24 h were evaluated by the number of patients requiring rescue analgesia (tenoxicam and/or fentanyl) and the frequency and doses of these analgesia. Adverse effects such as hypotension (>20% decrease of MAP from baseline), bradycardia (HR <60 bpm), nausea and vomiting, pruritis, respiratory depression (SpO2<90% on room air or respiratory rate <10 breaths/min), shoulder pain, or drowsiness were reported.

The primary outcomes were the VAS score and time to first analgesic request, whereas the total analgesic consumption in 24 h, hemodynamics, and adverse effects were the secondary outcomes.

Statistical analysis

Sample size calculation was performed after conducting a pilot study with 10 patients in each group. In that study, the mean postoperative VAS scale was 3.75, 3, and 2.75 in control, B0, and BN groups, respectively. A sample size of minimum 25 patients in each group was necessary to provide α=0.05 and power of study 80%. We enrolled 30 patients in each group to compensate for patients excluded during the study.

Data were statistically analyzed using SPSS program software, SPSS version 23 (IBM Corporation, Armonk, NY, USA). Analyses were done for parametric quantitative data among the three groups using one-way analysis of variance test followed by post hoc Tukey correction between each two groups, and for nonparametric quantitative data among the three groups using Kruskal–Wallis test followed by Mann–Whitney test between each two groups. The significance was accepted as P value less than 0.05.

  Results Top

A total of 90 patients undergoing LC under general anesthesia were enrolled in this study. They were randomized into three groups (n=30 in each group) with no patient dropouts. The study groups were found to be comparable with respect to patient characteristics and operative data such as age, sex, weight, American Society of Anesthesiologist grade, duration of surgery, and anesthesia time ([Table 1]).
Table 1 Patient characteristics and operative data

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Regarding the intensity of postoperative pain, the VAS values were significantly lower in bupivacaine-nalbuphine group as compared with other two groups (bupivacaine alone and control) throughout the whole study period up to 24 h. postoperatively except at the 12th hour after surgery, where VAS score was significantly higher in BN group than in B0 group only. Comparison between B0 and C groups revealed significant decrease in VAS scores in group B0 at all times of measurement, except at the 8th postoperative hour, where VAS values were significantly higher in B0 group than their corresponding values in C group ([Figure 1]).
Figure 1 Postoperative VAS in the study groups. VAS, visual analog scale.

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The time to the first analgesic request was significantly longer in BN group (11.5±0.9 h) than that in B0 (7.5±0.9 h) and in C (1.5±0.6 h) groups, indicating better and longer duration of postoperative analgesia in BN group. Group B0 showed longer duration of analgesia when compared with control group (P<0.001) ([Table 2]).
Table 2 Time to first analgesic request and total analgesic consumption in 24 h

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According to the analgesic consumption in 24 h, number of patients requiring rescue analgesics was significantly less in group BN than those in bupivacaine only and saline groups (17, 25, and 30 patients in BN, B0, and C groups, respectively). The frequency of rescue analgesia administration and the doses used (tenoxicam and fentanyl) were significantly lower in group BN than in other groups (B0 and C). Compared with the control group, patients in B0 group requested for rescue analgesics (tenoxicam and fentanyl) less frequently and consumed lower doses of them, and this difference attained statistical significance ([Table 2]).

Regarding hemodynamic changes upon recovery, there was a significant decrease in HR values in group BN compared with their corresponding values in B0 and C groups immediately after recovery and at 10, 20, and 30 min after recovery. In addition, HR values were significantly lower in group B0 than in group C at the same time intervals after recovery ([Table 3]). Moreover, mean MAP values were significantly lower in group BN than in other groups (B0 and C) at all time points of measurement. On comparison between B0 and C groups, MAP readings were significantly higher in control group than their corresponding values in B0 group at 10, 20, and 30 min after recovery ([Table 4]).
Table 3 Changes in heart rate (bpm) in the study groups

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Table 4 Changes in mean arterial pressure (mmHg) in the study groups

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The baseline values of oxygen saturation were similar in the three groups. There were no significant differences concerning arterial oxygen saturation, either between the groups or within each group throughout the whole study period, as demonstrated in [Figure 2].
Figure 2 Arterial oxygen saturation in the study groups.

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None of the patients in our study had hypotension, bradycardia, itching, respiratory depression, or fits in the postoperative period. Only four patients in BN group experienced drowsiness. No significant difference was found regarding occurrence of shoulder pain in the three groups postoperatively. However, higher incidence of emesis was reported in the control group (23 patients, 76.7%) compared with other groups. No significant difference was demonstrated regarding incidence of emesis in B0 and BN groups (26.7 and 16.7% in B0 and BN groups, respectively) ([Table 5]).
Table 5 Adverse events in the study groups

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  Discussion Top

Although LC is a minimally invasive procedure, it may be associated with significant postoperative pain [6]. Pain after LC is multifactorial and should be managed in multimodal fashion. Local anesthetics techniques are part of this multimodal approach for postoperative pain management after LC.

I.p. administration of local anesthetics is used by many surgeons as a method to provide effective pain relief while minimizing the adverse effects of systemic analgesics, including NSAIDs and opioids. The rationale for this route of administration is that the local anesthetics will block the visceral nociceptive conduction from peritoneum. In addition, systemic absorption from the large peritoneal surface may occur, providing additional mechanism of analgesia [7]. This technique was first evaluated in patients undergoing gynecological laparoscopy and showed reduction in postoperative shoulder pain [14]. With the possibility that a similar analgesic effect might be achieved in LC, several trials assessing the efficacy of i.p. local anesthetics in LC were carried out with conflicting results, regarding severity of postoperative pain, duration of analgesia, and total analgesic consumption in 24 h. The difference in outcome of studies on i.p. instillation of local anesthetics may result from dose, volume, or concentration of the drug; timing of instillation (before or after surgery); site of administration (subdiaphragmatic, over gall bladder bed, and/or port infiltration); and instillation in Trendelenberg’s versus supine position [15].

Bupivacaine was considered to be an optimal choice for i.p. administration owing to its potency and long duration of action. It has been reported to produce analgesia for an average of 6 h. In our study, we used bupivacaine in a dose of 100 mg safely without any evidence of systemic toxicity. It was found that the mean plasma concentration (0.92–1.14 µg/ml) after i.p. instillation of plain bupivacaine 100–150 mg [16] is below the toxic concentration of 3 µg/ml [17]. I.p. administration of opioids added to local anesthetics, in an attempt to enhance and prolong postoperative analgesia, has shown good results. Peripheral antinociceptive effect of opioids occurs owing to interaction of opioids with opioid receptors, which are located on peripheral intact perineurium on sensory nerves. Lipophilic opioids, such as tramadol, fentanyl, buprenorphine, and nalbuphine, can diffuse easily across the intact perineural barrier, resulting in better analgesia on i.p. administration [18].

Our study showed that i.p. bupivacaine combined with nalbuphine provided better postoperative analgesia than that obtained with i.p. bupivacaine alone. This effective pain relief observed in group BN was reflected by lower VAS values in BN than those in B0 group, longer time to first analgesic request, and lower total consumption of rescue analgesics. VAS values were lower in BN group than their corresponding values in B0 group at all time points of measurements except at the 12th postoperative hour. This was explained by effect of rescue analgesics administered earlier in B0 group owing to shorter time for first analgesic demand. In addition, i.p. instillation of bupivacaine resulted in more effective analgesia, when compared with i.p. saline. This was demonstrated by lower VAS scores in B0 group than in control group, longer postoperative analgesia, and less consumption of supplemental analgesics, in terms of frequency of administration and total doses used. Similar to our findings, several studies demonstrated reduced pain scores and lower analgesic requirements with i.p. bupivacaine, when compared with i.p. saline in patients undergoing LC [19],[20],[21],[22]. Moreover, a meta-analysis was done recently and showed effective postoperative analgesia with i.p. instillation of bupivacaine in patients undergoing LC specifically in the first 12 h after surgery [23]. However, other studies showed lower pain scores with i.p. bupivacaine compared with i.p. saline, with no significant difference regarding the total analgesic consumption [24],[25]. Both research studies used small volume of local anesthetic (i.e. 20 ml of 0.25% or 0.5%); one of them [24] injected bupivacaine 0.25% into the region of gall bladder bed only and found the analgesic effect of i.p. bupivacaine in early postoperative period, whereas the other study [25] reported lower pain scores in bupivacaine group at all time intervals up to 24 h postoperatively.

Contrary to our results, other studies did not find effective postoperative pain relief with i.p. application of bupivacaine at the end of LC surgery [26],[27],[28],[29]. Two trials used large volume of low concentration of bupivacaine [26],[27], whereas another study instilled only 20 ml of bupivacaine 0.5%, which might not be sufficient to irrigate most of the peritoneal surface, and pain assessment in their study was performed at less frequent intervals (at 1, 6, 24, and 48 h after surgery) [29]. Although the study by Zmora et al. [28] used similar volume and concentration of bupivacaine to that used in ours, they did not report any advantage of i.p. instillation of bupivacaine for postoperative analgesia after LC. This may be explained by the smaller number of patients in their study, where nine patients were excluded owing to conversion to open cholecystectomy and having a drain left in the peritoneal cavity. Additionally, their pain assessment was done at different time intervals (at 1, 2, 4, and 14 h after surgery).

In accordance with our results, opioids applied i.p., like morphine [30],[31], fentanyl [9], tramadol [12], pethidine [8], or buprenorphine [10],[32] produced favorable effects for postoperative analgesia, including lower pain scores, lower analgesic consumption over 24 h, or longer duration of analgesia when compared with local anesthetics alone. On the contrary, addition of tramadol to bupivacaine i.p. after LC in the study by Golubovic et al. [21] did not offer better pain relief than i.p. bupivacaine alone regarding postoperative VAS scores and analgesic requirements. They used different opioid from ours. In addition, Schulte-Steinberg et al. [33] did not find effective analgesia with i.p. 0.25% bupivacaine or 0.005% morphine after LC. This may be attributed to an insufficient dose and rapid dilution of both drugs within the peritoneal cavity. Interpleural bupivacaine but not morphine produced analgesia, as the intact perineural barrier in the noninflammed pleural cavity prevents the transperineal passage of opioid to its receptors on intercostal nerves.

Nalbuphine is highly lipid-soluble synthetic opioid with agonist–antagonist activity. It acts as antagonist at µ-receptors and agonist at k-receptors. Its affinity to k-opioid receptors produces analgesia, sedation, and cardiovascular stability with minimal respiratory depression [34]. It was widely used as an adjuvant to local anesthetics in central neuraxial blocks to improve the quality of perioperative analgesia as it provides potent analgesia for visceral nociception [35],[36].

In the present study, hemodynamic variables (i.e. HR and MAP) measured postoperatively were significantly lower in group BN than in other groups, indicating more dense analgesia owing to analgesic effect of nalbuphine added to bupivacaine. In addition, the analgesia evidenced in group B0 produced more hemodynamic stability when compared with control group.

Our findings were in agreement with those of Morsy and Abdalla [37] who studied the analgesic effect of i.p. nalbuphine (10 mg) administered at end of surgery in patients undergoing LC. They found better postoperative pain relief up to 8 h and more stable hemodynamic profile than control group. Similarly, Singh et al. [11] added i.p. nalbuphine (2 mg) to ropivacaine for pain relief after LC. Consistent with our results, they reported lower VAS scores in patients who received i.p. ropivacaine with nalbuphine as compared with those having i.p. ropivacaine alone or saline at all time points. Moreover, duration of postoperative analgesia was longer and total analgesics consumed were lower in ropivacaine-nalbuphine group in comparison with other groups.Regarding adverse effects, shoulder pain occurred similarly in the three groups, with no significant difference. Many studies that used i.p. opioids found no significant difference between patients given i.p. opioids and the controls in terms of shoulder pain [30],[38] or did not encounter shoulder pain in their patients [31]. Several factors could result in reduced incidence and severity of shoulder pain such as careful emptying of the residual i.p. CO2 by the surgeon, instillation of the prepared solution in head-down position, slow rate of insufflation, and maintenance of low inflation pressures [39],[40]. On the contrary, both studies that used i.p. nalbuphine either alone [37] or combined with ropivacaine [11] found less or no patients having shoulder pain in the study groups compared with the control ones correspondingly. One of them used i.p. nalbuphine alone [37] and the nalbuphine dose in the other study was smaller than our dose and the local anesthetic was ropivacaine instead of bupivacaine [11].

Postoperative nausea and vomiting (PONV) was significantly higher in control group than in other groups, with no significant difference between BO and BN groups. Administration of i.p. local anesthetics after LC was effective in reducing PONV [41],[42]. However, incidence of PONV was greater in nalbuphine and control groups as compared with lidocaine group in the study by Morsy and Abdalla [37]. This may be attributed to the different methodology of their paper.

  Conclusion Top

The findings of the current study proved the better analgesic effect of i.p. administration of bupivacaine combined with nalbuphine at the end of LC, compared with bupivacaine alone, as reflected by the lower VAS values, longer duration of analgesia, and less rescue analgesic requirements in 24 h. In addition, it produces better hemodynamic stability without significant increase in the adverse effects.

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Conflicts of interest

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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