Acute postoperative pain relief, by intraperitoneal application of local anesthetics, during laparoscopic cholecystectomy

Introduction: Intraperitoneal administration of local anesthetic in combination with an opioid, for the relief of postoperative pain, has already been reported after laparoscopic cholecystectomy. This study aimed to assess the analgesic effect of the intraperitoneal administration of bupivacaine and morphine, in patients undergoing laparoscopic cholecystectomy. Methods: 90 patients (30 patients in each group) were included in a double blind, randomized manner. At the end of laparoscopic cholecystectomy, the patients were intraperitoneally treated with 30 ml of: physiological saline (Group 1) or 0.25% bupivacaine (Group 2) or 0.25% bupivacaine + 2 mg morphine (Group 3). Patient’s postoperative pain was evaluated using a visual analogue scale and a verbal rating score. The postoperative analgesic requirement was assessed by the total dose of Ketorolak, administered by intravenous or intramuscular route. Pain, vital signs, supplemental analgesics consumption and side effects were recorded for all patients for 12h. Results: There were no difference between the three groups, regarding pain scores (et rest and coughing) during the study, except in the fi rst 6 h, when scores were lower for patients receiving intraperitoneal bipuvacaine + morphine (p<0.05). Conclusions: In the patients undergoing laparoscopic cholecystectomy, the intraperitoneal administration of bupivacaine + morphine, reduced the analgesic requirements during the fi rst 6 postoperative hours compared with the control groups. The combination of intraperitoneal bupivacaine 0.25% and morphine was more effective for treatment of pain after laparoscopic cholecystectomy. © 2011 All rights reserved


Introduction
Laparoscopic cholecystectomy (LC) is currently considered to be a relatively minor operation (1,2). It has been classifi ed as a basket procedure (analogous to shopping with a supermarket basket) in the UK government's publications on day-surgery (3). But, an important factor that limits recovery is postoperative pain. Intraperitoneal instillation of local anesthetics is a simple method of analgesia and should be considered in addition to other morphine sparing analgesics such as NSAIDs, acetaminophen and incisional local anesthetics (4,5). Laparoscopic cholecystectomy, in healthy patients is routinely performed at our hospital on a day case basis. Intraperitoneal instillation of local anesthetic around the operative site has been used as an analgesic technique on the premise that conduction from visceral sites is blocked and may reduce the extent of referred pain to the shoulder, which results of nerves C3, C4, C5 dia-phragm innervation, gas distension and diaphragmatic shift ing, in the postoperative period (5,6,7). However, in previous studies of intraperitoneal local anesthetics following laparoscopic cholecystectomy it has not been possible consistently to demonstrate reliable analgesic eff ects (8,9,10). Th is may be related to nociceptive conduction from incisional sites that are not blocked by local anesthetics given into the intraperitoneal cavity. Diff erent regimens have been proposed to relieve pain aft er laparoscopic surgery, such as non-steroidal anti-infl ammatory drugs, local wound anesthetics, intraperitoneal anesthetics and saline, gas drainage, heated gas low-pressure gas and nitrous oxide pneumoperitoneum.. Multimodal analgesia (combined use of two or more analgesic agents) for pain relief aft er operation is believed to the more advantageous than single modality treatment, especially when diff erent sites of action are involved, or when a synergistic eff ect, or both, is achieved (11,12). Th e aim of the present study was to determine the effi cacy of the intraperitoneal application of bupivacain-morphine.

Patients and Procedures
A prospective, randomized, double-blind study was undertaken with written informed consent which was obtained from all patients. Each study group consistent of 30 ASA I-II patients scheduled to undergo elective LC for cholelithiasis under general anesthesia. Th e individuals, of both sexes, were aged 26-63 yr. Criteria for exclusion were: psychiatric disease, allergic reactions to drugs or local anesthetics, morbid obesity and severe chronic disease. Patients were also excluded, if they underwent surgery for acute cholecystitis or if the operation was converted to an open procedure. All patients were given a standard anesthetics comprising propofol 2-4 mg/kg, fentanyl 2 μg/kg, ondasetron 4 mg, i.v., Rocuronium 0.6 mg/kg was used for muscular relaxation. Patients lungs were ventilated without nitrous oxide, but with sevofl urane 1-1.5%, with oxygen. Suppositories of diclofenac 100 mg, were administered at the induction of anesthesia. Standard patient monitoring was used. Lung ventilation was adjusted to maintain an end-tidal carbon di-oxide partial pressure of 4.7-5.3 kPa. Intra-abdominal pressure during laparoscopy was automatically maintained at 12 mmHg by a CO2 insuffl ator. At the end of successful LC, patients were allocated randomly to one of three groups. Group 1 (n=30) received physiological sodium chloride 30 ml, intraperitoneally. Group 2 (n=30) bupivacaine 0.25% 30 ml intraperitoneally. Group 3, (n=30) bupivacaine 0.25% 30 ml, intraperitoneally plus morphine 2mg. Each patient received the test solution in the following way: 15 ml was sprayed to both sides of the diaphragm, and another 15 ml, was directly applied to the gall bladder bed and to the right subhepatic space. All patients received ondasetron i.v., during operation (13). During closure of the wound, the incisional sites were infi ltrated with bupivacaine 20 ml, 0.25%, 2.5 mg/ml, with epinephrine 5 μg/ml, in all patients (14). Residual neuromuscular blockade was antagonized with a mixture of neostigmine and atropine (15). In the postoperative period, patients were assessed on awakening and then at 1, aft er 6 and aft er 12 hours by a trained observer. Intraperitoneal pain at rest and during deep inspiration and any pain in the right shoulder were assessed on a visual analogue scale (VAS). Th e degree of postoperative pain was assessed with a VAS (0-100 mm) (0 -no pain, 100 -severe pain) at rest and on coughing. Patients were asked about the location of pain, whether at the shoulder, incision sites and/or inside the abdomen. Pain relief was rated by the patients on a 4 point verbal rating score (VRS). 0 = no pain relief; 1 = partial pain relief; 2 = good pain relief; 3 = excellent pain relief, complete analgesia. Th e VRS recorded during the study was summed obtaining the total pain relief score for that period. Total pain relief scores were used widely in analgesic clinical trials -higher scores signifying better analgesia. Nausea and sedation were assessed also on a similar VAS, representing "no nausea" and "fully awake" on the left and "worst imaginable nausea" and "very drowsy" on the right, respectively. Pain, sedation and nausea scores for the fi rst 6 h aft er operation were summed (11,24).

Statistical analysis
Nominal data were analyzed with the χ 2 -test. Statistical analyses was performed with the software SPSS. p< 0.05 was considered signifi cant.

Results
Th e groups were similar in regard to gender, age, height, weight and duration of the pneumoperitoneum (Table 1).
Values are mean (_+SD). Th ere were no significant diff erences between groups. Th ere were no signifi cant diff erences between the three groups in relation to pain scores (at rest or on coughing) during the study except in the fi rst 6 h, in regard to incisional and intra-abdominal pain scores, respectively, in which pain was signifi cantly lower (p<0.05) in those patients receiving intraperitoneal bupivacaine plus morphine (Figure 1). Scores of 2 (good relief) or 3 (complete relief) on the VRS were reported more oft en by pa-tients in Group 3, which resulted in higher total pain relief scores, although the diff erences were not signifi cant aft er six hours ( Figure 2). 26 patients of the Group 1, 16 in Group 2 and 2 in Group 3 needed a rescue dose, of postoperative analgesic drugs, in the fi rst 6 h. No diff erences in the incidence of nausea/vomiting were observed between groups (40%, 33%, and 40% in Groups 1, 2 and 3, respectively). None of the other above-mentioned side-eff ects was reported by any of the groups.

Discussion
Th e results of this study demonstrated that intraperitoneal administration of bupivacaine 0.25% 30 ml, plus morphine 2mg, signifi cantly reduced postoperative analgesic requirements during the fi rst 6 h, aft er laparoscopic cholecystectomy, compared with the control group. Furthermore, the analgesic requirements were signifi cantly lower during the entire study in patients belong to Group 3, who received intraperitoneal bupivacaine 0.25% 30 ml, plus morphine at the end of surgery. Accordingly, previously we injected the drugs to the subdiaphragmatic area. However, we found a low incidence of shoulder pain in all treatment groups, because the residual intraperitoneal carbon dioxide was defl ated carefully by the surgeon. Our study shows that the intraperitoneal administration of bupivacaine is eff ective aft er LC, as noted in other reports, although the amount of pain reduction and duration of eff ect    were limited (16)(17)(18)(19). It has been suggested that the poor results in pain reduction, when intraperitoneal local anesthesia is used, aft er LC -compared with those in the available gynecological literature -are due to visceral and parietal pain being more severe than shoulder pain aft er LC (20)(21)(22)(23)(24). On the other hand, in a recent study the intraperitoneal instillation of bupivacaine during LC resulted in lower pain scores and in reduced morphine requirements compared with placebo. We used ketorolak, a non-opioid analgesic with minor adverse eff ects and with powerful pain-relieving activity, including surgical pain, in our study to assess analgesic requirements aft er operation. Our data also showed a signifi cant decrease in supplemental ketorolak in patients given morphine intraperitoneal.
We used bupivacaine and low doses of morphine, intraperitoneally to achieve the additional analgesic benefi t from the combined eff ect of a local anesthetic with an opioid agonist (25)(26)(27)(28)(29). Intraperitoneal local anesthetics would be expected to be useful for treating visceral pain. In our study it is likely that intraperitoneal bupivacaine in the right hypochondrial area had an analgesic eff ect (30). It signifi cantly reduced total abdominal pain during inspiration and there was a trend towards lower scores for total abdominal pain at rest and total both shoulder pain. Local anesthetic toxicity is a serious problem, which limits dosage and effi cacy. Bupivacaine is used traditionally as it has a long duration of action. It can cause central and cardiovascular toxicity and there have been reports of accidental deaths and cardiac arrest (36). We did not observe any side-eff ects attributable to the local anesthetic. We did not measure plasma concentrations of bupivacaine, but several reports have shown that the range of mean plasma concentration (0.92 -1.14 μg/ml) aft er the intraperitoneal administration of plain bupivacaine (100 -150 mg) is well below the toxic concentration of 3 μg/ml. Th e doses of bupivacaine in our study were lower than those thought to cause systemic toxicity.
Our results are consistent with other studies in which intraperitoneal administration of local anesthetic has been shown to have a modest analgesic eff ect (31,32). Of 13 clinical trials considered in a systemic review it was found that the intraperitoneal administration of bupivacaine 50-200 mg, in volumes of 10-100 ml, produced signifi cant analgesia in seven studies where supplemental analgesic consumption was signifi cantly reduced (33)(34)(35).
In summary, we have demonstrated that the intraperitoneal administration of morphine plus bupivacaine 0.25% in patients undergoing laparoscopic cholecystectomy reduces ketorolak requirements during fi rst 6 h aft er the operation compared to a control group. However, the intraperitoneal application of bupivacaine 0.25% combined with morphine, at the end of surgery is effective in achieving reduction in pain (36,37,38).

Conclusion
Th erefore, we concluded that combination of intraperitoneal bupivacaine and morphine was better than, bupivacaine without morphine, or placebo, for pain relief aft er laparoscopic cholecystectomy. Th e surgeons involved in the study continue to use this method of analgesia as part of their routine practice (40,41).