Postoperative analgesia with intraperitoneal ropivacaine with and without fentanyl after laparoscopic cholecystectomy: a randomized double-blind controlled trial

Abstract


Introduction
Laparoscopic operative procedures have revolutionized surgery with many advantages: a smaller and more cosmetic incision, reduced blood loss, reduced postoperative stay and pain, which cut down hospital costs.However, patients undergoing laparoscopic procedures do experience postoperative pain, especially in upper and lower abdomen and back and shoulder regions.Pain intensity usually peaks during the irst postoperative hours and usually declines over the following 2 to 3 days.Pain after laparoscopy results from the stretching of intra-abdominal cavity, peritoneal in lammation and phrenic nerve irritation caused by residual CO 2 in peritoneal cavity [1][2][3] .Intraperitoneal injections of local anaesthetic have been proposed to minimize postoperative pain after laparoscopic surgery.Several reports are available on the ef icacy of intraperitoneal administration of local anaesthetic for analgesia after laparoscopic surgery 4 .Combinations of intraperitoneal local anaesthetic with many opioids have been tested in the past 5,6 .Till date, there has been no study on the intraperitoneal use of ropivacaine and fentanyl to reduce postoperative analgesia.Therefore, this study will show the ef icacy of ropivacaine and ropivacaine with fentanyl in reducing postoperative pain after laparoscopic cholecystectomy (LC) and also sideeffects, if any.

Materials and methods
This work conforms to the values laid down in the Declaration of Helsinki (1964).The protocol of this study has been approved by the relevant ethical committee at our institution where it was performed.All subjects gave full informed consent to participate in this study.
A randomized, double-blind, placebo-controlled trial was carried out on 150 patients, who were divided into 3 groups (n = 50).Patients (both male and female) included in this study were aged between 20 and 70 years, belonged to American Society of Anesthesiologists (ASA) Physical Status 1 to 3, had ±20% ideal body weight and scheduled for LC.Patients excluded were those with emergency operation, history of malignancy, on non-steroidal anti-in lammatory Licensee OA Publishing London 2013.Creative Commons Attribution Licence (CC-BY) F : Singh A, Mathur SK, Shukla VK.Postoperative analgesia with intraperitoneal ropivacaine with and without fentanyl after laparoscopic cholecystectomy: a randomized double-blind controlled trial.OA Anaesthetics 2013 May 01;1(1):9.drugs (NSAIDS) or any other analgesic, had a history of alcohol or drug abuse, con irmed local anaesthetic toxicity, and chronic pain syndrome, where pain evaluation was judged unreliable due to neurological disease or treatment with steroids prior to surgery.
All patients undergoing laparoscopic cholecystectomy received pre-medication in the form of glycopyrrolate (0.005 mg/kg) and ondansetron (01 mg/kg) intravenously 30 minutes prior to administration of anaesthesia and fentanyl (3μg/ kg) intravenously just before induction.Surgery was carried out under general anaesthesia with propofol (2-2.5 mg/kg) for induction and vecuronium (0.12 mg/kg) to facilitate tracheal intubation.Anaesthesia was maintained at 60% N 2 O in oxygen with 0.5% to 1% iso lurane.Adequate muscle relaxation was achieved with vecuronium bromide (0.01 m/kg).Ventilation (tidal volume 8-10 ml/kg) was adjusted to maintain end tidal CO 2 between 35 and 40 mmHg.Patients were placed in 15° to 20° reverse trendelenberg position.During laparoscopy, intraabdominal pressure was maintained at 12 mmHg.The CO 2 was carefully evacuated at the end of surgery by manual compression of abdomen with open trocars.All patients were administered oxygen therapy and monitored for the next 6 hours in post-anaesthesia-care unit.
Patients were randomized into one of the three groups using a computergenerated table of random numbers.Drug solution was prepared by a doctor who had not participated in the study.The drug was illed in precoded 50-ml syringes.The surgeon and the anaesthetist in the postanaesthesia-care unit were unaware of the groups to which each patient was randomized in the postoperative period.
Group 1: Patients received 50 ml of 0.9% normal saline as placebo.
Group 2: Patients received 0.75% ropivacaine in a dose of 2 mg/kg diluted in normal saline to make a solution of 50 ml.Group 3: Patients received 0.75% ropivacaine in a dose of 2 mg/ kg with fentanyl 100 mcg (2 ml) diluted in normal saline to make a solution of 50 ml.
In the operating room, baseline heart rate, non-invasive arterial blood pressure, pulse oximetry and respiration rate values were recorded.Furthermore, 18G peripheral venous cannula was inserted on the dorsal side of patient's left hand, and 5 ml/ kg ringer lactate was preloaded intravenously to all patients before they were pre-medicated.
Before induction of anaesthesia, patients were instructed on how to use a 100-cm visual analogue scale (VAS), with anchors ranging from 'no pain' to 'worst possible pain', and verbal rating scale (VRS) for pain, with the following scores: 0 = no pain and patient sedated, 1 = patient awake and no pain on coughing, 2 = pain on coughing but not on deep breathing, 3 = pain on deep breathing but not at rest, 4 = slight pain at rest and 5 = severe pain at rest.The degree of postoperative pain was assessed using VAS in case of spontaneous pain and VRS upon patient's arrival in the recovery room, immediately postoperatively and thereafter every hour for a period of 12 hours postoperatively.Those patients with VAS scores >40 after surgery were administered a bolus of diclofenac aqueous (75 mg IV as rescue analgesia.A second dose of diclofenac can be repeated only after 1 hour after the administration of irst dose.Ondansetron (0.1 mg/ Kg IV) was administered if patient complained of nausea.Time to irst analgesic requirement, total analgesic consumption in the irst 12 hours postoperatively and occurrence of adverse events were also recorded.Patients were regularly asked about pruritis and shoulder pain, blood pressure was regularly monitored for episodes of hypotension (MAP <60 mmHg), heart rate was regularly monitored for episodes of bradycardia (heart rate <60).Total duration of surgery was recorded for all cases.All perioperative complications such as biliary spillage, haemorrhage, intraoperative bradycardia, hypotension and hypertension were recorded.
Statistical analysis was performed with three-way analysis of variance (ANOVA) and p values <0.05 were considered signi icant.Data are presented as M ± SD, proportion or n (%).Analysis of variance and chi-square tests were used to check whether the study groups were matched in terms of demographic data.For VAS and VRS, one-way ANOVA test followed by Bonferroni post hoc tests were used.

Results
All three groups were similar in age, sex, physical parameters and duration of surgery (Table 1).VAS and VRS scores were higher in Group 1 than in Group 2 and minimum in Group 3 at all time intervals.The difference between Group 1 and 2 was statistically signi icant immediately postoperatively and at 2 hours postoperatively, whereas the difference between Groups 1 and 3 and Group 2 and 3 was statistically signi icant at all time intervals (Table 2; Figures 1, 2).Time for requirement of irst-dose rescue analgesia was longer in Group 3 than in Group 2 and was minimum in Group 1, indicating better and longer pain relief in Group 3 as compared to Groups 1 and 2. The difference was also statistically signi icant among all the three groups.Total analgesic consumption was maximum in Group 1 and minimum in Group 3 (Table 3  and 4).
Pruritus was maximum in Group 3 than in Group 1 and 2, but the difference is statistically non-signi icant.Pruritus was observed in 18% patients; it appeared within 20 to 30 minutes but was self-limiting.Emetic symptoms were maximum in Group 1 than in Groups 1 and 2, but the difference was statistically non-signi icant.The incidence of hypotension was similar in all three groups.The incidence of bradycardia was maximum in Group 3 as compared to Groups 1 and 2, and the difference was statistically signi icant.Shoulder pain was maximum in Group 1, no pain was observed in Groups 1 and 2 and the difference was statistically signi icant (Table 5).

Discussion
LC is one of the most frequently performed elective general surgical   operations.It is ideally performed as a day-case or short-stay procedure, and therefore, provision of adequate postoperative pain relief is considerably important.Instillation of intraperitoneal LA to reduce postoperative pain has been studied through randomized trials for more than 10 years.Patients usually experience postoperative pain, especially in upper and lower abdomen and back and shoulder regions.Pain intensity usually peaks during the irst postoperative hours and is maximum in the irst 12 to 24 hours and declines over the next 2 to 3 days.Postoperative pain is unpredictable, which explains the need for systematic prevention of pain before the patient wakes up from anaesthesia 3 .
LC results in less postoperative pain and/or reduced analgesic consumption as compared with open cholecystectomy.Nonetheless, pain after laparoscopy may be moderate or even severe for some patients and may require opioid treatment.
Interestingly, the type of pain after laparoscopy differs considerably from that seen after laparotomy.Indeed, whereas laparotomy results mainly in parietal pain (abdominal wall), patients complain more of visceral pain after operative laparoscopy 7 .Visceral pain peaks during the irst hour and is exacerbated by coughing, respiratory movements and mobilization.It requires opioid administration when patient is recovering from anaesthesia.Scapular pain, especially when exaggerated trendelenberg position is used, tends to appear during the night after surgery and hinders sleep.In iltration of local anaesthetics decreases scapular pain.
Ropivacaine has been in iltrated in doses of 300 and 375 mg for hernia repair without reaching toxic concentrations 8 .The range of the mean plasma concentration (0.08-0.3 mg/ ml) after wound in iltration and drain lavage with 225-mg ropivacaine after major shoulder surgery was also below toxic concentrations of 0.6 mg/ml 9,10 .All three groups were almost similar for age, sex, physical parameters and duration of surgery.
On comparing Groups 1 and 2 we found there was a signi icant difference in heart rates immediately after surgery and postoperatively up to the 6th postoperative hour; thereafter difference in heart rate was statistically insigni icant till the 12th hour.However, comparing Groups 1 and 3 we saw a signi icant difference in heart rates till the 10th hour.Comparing Groups 2 and 3 we found a statistically signi icant difference between these two groups till the 8th postoperative hour, and thereafter it became statistically insigni icant up to the 12th postoperative hour, showing that better analgesia in Groups 2 and 3 lead to lower heart rates as compared to Group 1. Heart rates were lower in Group 3 than in Group 2, and for a longer time, probably due to more dense and prolonged analgesia and systemic absorption of fentanyl from peritoneal cavity.Incidence of bradycardia was signi icantly higher in Group 3 than in Group 2 and 1 (Table 1), which was statistically signi icant.Also, higher incidence of bradycardia may probably be due to systemic absorption of fentanyl.
Blood pressures (systolic, diastolic, mean) were all comparable and statistically insigni icant in all the three study groups.One reason for this is the rescue analgesia given on demand whenever VAS scores reached 40 mm.Hence, the rise in blood pressure due to pain was not    6,11,12 .
Our study showed that VAS scores are signi icantly higher in Group 1 than in Group 2 and 3 (p < 0.05).VAS scores immediately postoperatively were 44.00 ± 19.16 in Group 1, 22.20 ± 5.06 in Group 2 and 23.20 ± 8.67 in Group 3 (p < 0.001), and at the 6th hour, 35.40 ± 9.52 in Group 1, 29.40 ± 4.24 in Group 2 and 27.80 ± 5.0 in Group 3 (p < 0.001).There was a signi icant difference between VAS scores of Group 1 and 2 and between Groups 1 and 3.However, the difference was not signi icant between Groups 2 and 3.The ropivacaine effect was prolonged by fentanyl as shown by the lowest VAS score at 12th hour in Group 3 patients (23.80 ± 4.90 in Group 1, 21.40 ± 4.50 in Group 2 and 16.20 ± 4.93 in Group 3).No differences were found between VAS scores of Group 1 and 2 after the 11the hour when the pain was, in general, mild in intensity in both groups.
Similarly, VRS scores (2.60 ± 0.88 in Group 1, 0.96 ± 0.74 in Group 2 and 1.62 ± 0.56 in Group 3) were signi icantly reduced immediately postoperatively in Group 3. At the 6th hour, VRS scores were 2.32 ± 0.79 in Group 1, 1.94 ± 0.42 in Group 2 and 1.80 ± 0.49 in Group 3, which indicates signi icantly less pain in patients receiving ropivacaine with fentanyl.VRS scores at the end of 11th hour showed the signi icant effect of fentanyl with ropivacaine: 1.3 ± 0.46 in Group 1, 1.26 ± 0.44 in Group 2 and 1.00 ± 0.00 in Group 3 (p < 0.001).Therefore, VAS and VRS scores were higher in Group 1 than in Group 2 and minimum in Group 3 at all time intervals.The difference between Group 2 and 3 was statistically signi icant immediately postoperatively and at 2 hours postoperatively, whereas the difference between Group 1 and 2 and Group 1 and 3 was statistically signi icant at all time intervals.
Our results showed that there was a signi icant difference between VAS scores of Group 1 and 2 immediately postoperatively and at 1st, 2nd, 3rd, 4th, 6th, 7th, 9th, 10th postoperative hours.Also, the difference was statistically signi icant up to the 12th hour, postoperatively, when Group 1 was compared with Group 3. VAS scores were similar in Group 2 and 3 up to the 4th postoperative hour.Beyond the 5th postoperative hour, VAS score was found to be signi icantly lower in Group 3 as compared to Group 2; similar results were obtained using VRS scores (Table 6).
A study done by Gupta et al. also showed that intraperitoneal instillation of fentanyl (100 μg) along with bupivacaine (0.5% 20 ml) signi icantly reduces immediate postoperative pain.It also reduces intensity of pain even after 24 hours 3 .Our study also revealed that ropivacaine alone, and with fentanyl, also reduces intensity of pain up to 12 hours.Ropivacaine plus fentanyl was more effective than normal saline and ropivacaine alone in the irst 12 hours.Refaie et al. also concluded that intensity of pain is reduced with bupivacaine than is observed with the normal saline group 13 .Trikoupi A et al. also revealed the capacity of ropivacaine to reduce pain was signi icantly higher than that of normal saline 14 .Kim TH et al. also concluded that intraperitoneal instillation of ropivacaine at the beginning of LC combined with normal saline infusion is effective for reducing pain after LC 12 .Newcomb et al. conducted a study to compare the ef icacy of local anaesthetic in iltration with or without preoperative nonsteroidal anti-in lammatory drugs 15 .They concluded that the use of preoperative rofecoxib, 0.5% bupivacaine in iltration or both for postoperative analgesia did not decrease postoperative pain or decrease length of stay after LC compared with placebo.However, in our study, intraperitoneal instillation of ropivacaine with or without fentanyl reduced pain scores signi icantly.

Table 6 Mean verbal ra ng scale (VRS) scores in various groups at diff erent intervals
Table 3 shows that in Group 1 half of the patients required a irst dose of rescue analgesia immediately postoperatively and the remaining half within the 1st hour, whereas in patients receiving ropivacaine alone and with fentanyl required the irst dose in the 2nd and 3rd hours, indicating effective analgesia for a longer duration due to blocking of nociceptive afferent ibres causing analgesia itself and also prolongation of the effect of opioid analgesic.After the administration of irst-dose rescue analgesic, further requirement of rescue analgesia was lowest in patients receiving fentanyl with ropivacaine as compared to ropivacaine alone or normal saline.Patients receiving normal saline required more frequent dosing, which lasted up to later periods of monitoring in postoperative hours, requirement of second dose of analgesia got decreased and interval between two doses were increased considerably in patients receiving ropivacaine.In patients receiving ropivacaine with fentanyl only, only a few patients required a second dose of rescue analgesia and even fewer required analgesia after 4 hours.Total doses of rescue analgesia were lowest in fentanyl, with ropivacaine and highest in normal saline.
Table 3 showed that out of 50 patients receiving ropivacaine with fentanyl, 16 patients did not require any rescue analgesic dose and 3 out of these 16 received ropivacaine.There were no patients in normal saline group who did not require any analgesic dose, which suggests patients receiving ropivacaine with fentanyl had more intense analgesia and for a longer duration of postoperative time.This inding further supports our hypothesis.A study by Rafaei et al. revealed that the number of patients who needed postoperative analgesia in Group 1 (bupivacaine) was signi icantly lower than that of Group 2 (control; 7 out of 32 vs 19 out of 31; p < 0.05) 13 .
Table 4 shows that time to irst analgesic requirement was shortest in Group 1 and longest in Group 3. The total analgesic dose consumption was highest in Group 1 and lowest in Group 3; the differences in time to irst analgesic requirement and total analgesic consumption were statistically signi icant (p < 0.05).
Our study (Table 1) revealed that total analgesic consumption was also signi icantly lower in Group 3 patients (p < 0.001).In Group 1 patients receiving normal saline intraperitoneally, the total analgesic (diclofenac) consumption was 149 ± 42 mg.In Group 2 patients receiving ropivacaine intraperitoneal, total analgesic consumption was 97 ± 47 mg and was 84 ± 25 mg in Group 3 patients receiving ropivacaine intraperitoneally along with fentanyl, which clearly showed total analgesic consumption was maximum in Group 1 and minimum in Group 3. Therefore, ropivacaine along with fentanyl reduces not only the intensity of pain but also the total dose of analgesic consumption.Total dose of analgesic consumption was higher in our study groups as compared to Gupta et al., which is probably due to tramadol given in pre-medication, and longer duration of surgery in their study could have led to multiple doses of fentanyl and, hence, to denser analgesia and sedation that in turn could have further led to lesser dosing.Time to requirement of irstdose rescue analgesia was longer in patients receiving ropivacaine with fentanyl than in patients receiving ropivacaine only and was minimum in patients receiving normal saline, indicating better and longer pain relief in patients receiving ropivacaine with fentanyl as compared to patients receiving ropivacaine alone and those receiving normal saline.Time to irst-dose analgesic requirement in patients receiving normal saline was 13.00 ± 7.55 minutes, in patients receiving ropivacaine it was only 117.55 ± 46.85 min and in those receiving ropivacaine with fentanyl it was 138.97 ± 34.10 min.The difference was also statistically signi icant between all the three groups (p < 0.001).
A study conducted by Gupta et al. using a sample of 180 patients showed that total analgesic (diclofenac) consumption was less in fentanyl plus bupivacaine group as compared to bupivacaine only (65 ± 15 mg vs 128 ± 25 mg) 3 .Also, time to requirement of irst-dose rescue analgesia was also less in fentanyl plus bupivacaine group (106 ± 28.6 vs 14.0 ± 8.9 min) as similarly recorded in our study.
Trikoupi et al. also recorded the time of irst-dose analgesic demand and the total amount of morphine received through patient-controlled analgesia (PCA) in the irst 24 hours; their results are similar to our study results 14 .
Goldstein et al. recorded morphine consumption at wake-up stage, and over the irst 24 hours, it was found to be signi icantly lower with bupivacaine and with ropivacaine than with normal saline.A study by Rafaei et al. revealed that the number of patients who needed postoperative analgesia in Group 1 (bupivacaine) was signi icantly lower than that observed in Group 2 (control) 16 .

Complications
Our study ( hypotension, bradycardia and shoulder pain in all the three groups. The incidence of pruritis was highest in Group 3 patients (12%) than in Group 2 (4%) and Group 1 (2%), which was probably due to absorption of fentanyl.Fentanyl can cause increased incidence of pruritis, but the difference found was statistically non-signi icant (p = 0.084).Gupta R et al. conducted a similar study on bupivacaine instillation and observed pruritus was highest in patients who received bupivacaine plus fentany 13 .Also, pruritis was self-limiting.
Incidence of emesis (as shown in Table 5) was highest in patients receiving normal saline intraperitoneally (18%) and was the same in patients receiving ropivicaine alone and with fentanyl (6% each).This shows ropivacaine instillation reduces the incidence of nausea and vomiting.The cause could be higher incidence of pain, and thus greater autonomic response in the placebo group, as well as repeated doses of analgesic given as rescue analgesia for these patients.The difference was statistically insigni icant (p = 0.069).Goldstein et al. carried out a study on ropivacaine and bupivacaine in preventing pain and post-op nausea and vomiting (PONV) and found that ropivacaine with bupivacaine decreases the incidence of PONV 11 .Similar results were obtained by Tricoupi et al., Kucuk et al. and Gupta et al 5,6,14 .
Incidence of hypotension was highest in patients receiving ropivacaine with fentanyl (6%) than in those who received ropivacaine alone or normal saline.Also, the results were statistically insigni icant (p = 0.166).Similar results were obtained by Gupta et al., Goldstein et al. and Tae han kim 3,11,12 .
Incidence of bradycardia was signi icant in patients receiving fentanyl along with ropivacaine (18%) than with patients receiving ropivacaine alone and normal saline (2%) each, and bradycardia was self-limiting.Increased incidence of bradycardia may be due to fentanyl absorption, which is known to cause bradycardia as a side-effect.Gupta et al. did the same study with bupivacaine, but there was no increased incidence of bradycardia; the reason for difference could not be ascertained 3 .Their results were also statistically signi icant (p < 0.05).
Shoulder pain is a common outcome after LC and can delay return to normal activities.Incidence of shoulder pain after LC is 35% to 63% and maximum incidence occurs the night after surgery 11 .The proposed mechanism of shoulder pain seems to be a diaphragmatic stretching with phrenic nerve neuropraxia, which is possibly due to increased concavity of diaphragm induced by pneumoperitoneum and reference of pain from the traumatized area.Shoulder pain was not observed in any of the three groups in the irst 8 hours postoperatively; however, after 8 hours, shoulder pain incidence was statistically signi icant in Group 1 patients (12%).No shoulder pain was observed in patients receiving ropivacaine alone or with fentanyl even after 8 hours postoperatively.The reason could be the blocking of nociceptive inputs generated by in lamed diaphragm peritoneum caused by instillation of ropivacaine.Joris et al. obtained similar results using ropivacaine and showed that use of ropivacaine decreased incidence of shoulder pain even after 24 hours postoperatively 10 .Studies by Gupta et al. using bupivacaine and Kim et al. using ropivacaine showed similar results, which further supports our results 6,12,17 .However, this difference was not statistically signi icant.The incidence of shoulder pain was less in our study since the time taken by us to observe the patient in the postoperative period was less.Mild complications such as spillage and haemorrhage observed in various groups, but those are statistically non-signi icant (p > 0.05).No complication was observed preoperatively in any of the 3 study groups 11 .
The limitations of this study were that the control group was a sham study group of simple, normal-saline, peritoneal instillation, which itself had positive in luences on peritoneal irritation, and a separate comparison made for original uncontrolled pneumoperitoneum, omitting all other comparisons among the groups, might have demonstrated differences in intensity and periods.In this study, intensity of pain was only described only in terms of integration of dichotomy and not of description of quality, and quantity was also a concern.As a result, without multifactorial individualized assessment on characters of pain, visceral and somatic pain was indistinguishable in the process.Moreover, the 12-hour duration of observation might have led to overestimation of rescue analgesic dose with reference to time and underestimation of shoulder pain incidences, since after 12 hours pain was found to decrease, requiring fewer analgesic doses.Duration of analgesia provided could have been ascertained more precisely if the study were conducted for longer periods.

Conclusion
Intraperitoneal instillation of local anaesthetic is an easy, cheap and noninvasive method that provides good analgesia in the immediate postoperative period after laparoscopic surgery.Intraperitoneal ropivacaine produces postoperative analgesia better than what was obtained with intraperitoneal placebo.The combination of intraperitoneal ropivacaine and fentanyl is superior to plain ropivacaine for reducing postoperative pain in patients who underwent laparoscopic surgery, without any signi icant increase in adverse events.Ropivacaine with or without fentanyl reduces not only the intensity of pain but also the total dose of rescue analgesic consumption.Better and longer pain relief is attained by using fentanyl with ropivacaine

Figure 1 :
Figure 1: Mean visual analogue scale (VAS) scores in various groups at different intervals.

Figure 2 :
Figure 2: Mean visual rating scale (VAS) scores in various groups at different intervals.

Table 4
Mean me to fi rst analgesic requirement (±SD) and mean analgesic dose consump on (in mg) in the threeTime to fi rst analgesic requirement (in minutes) prominent in any of the three groups.Studies done by Gupta et al., Tae han kim et al., Goldstein et al. also revealed the same indings; moreover none of the agents used intraperitoneally was found causing a rise in blood pressure

Table 5 Incidence of pruritus, emesis, hypotension, bradycardia and shoulder pain in three groups
Licensee OA Publishing London 2013.Creative Commons Attribution Licence (CC-BY) F : Singh A, Mathur SK, Shukla VK.Postoperative analgesia with intraperitoneal ropivacaine with and without fentanyl after laparoscopic cholecystectomy: a randomized double-blind controlled trial.OA Anaesthetics 2013 May 01;1(1):9.