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* From the Departments of Anesthesiology,
Gynecology, and
Pharmacy, Hospital Bichat; and
the Department of Biostatistics, Hospital Saint-Louis, Paris, France.
Address correspondence to: Dr. Hawa Keita, Department of Anesthesiology and Intensive Care, Hospital Bichat, 46 rue Henri Huchard, 75018 Paris, France. Phone: 33-1-40-25-81-16; Fax: 33-1-42-28-99-96; E-mail: hawakeita{at}club-internet.fr
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Abstract |
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Methods: We conducted a randomized, double-blinded, study to compare the efficacy of prophylactic ip administration of 0.9% saline (n = 16), 0.5% bupivacaine (100 mg, n = 15), morphine (3 mg, n = 16) and a mixture with 0.5% bupivacaine (100 mg) and morphine (3 mg, n = 18) to reduce both postoperative pain scores and analgesic requirements after gynecologic laparoscopic surgery. A multimodal analgesia regimen (acetaminophen, nonsteroidal anti-inflammatory drugs and morphine) was used for postoperative analgesia.
Results: No difference was observed in postoperative pain scores (visual analogue scale at rest and on coughing), or analgesic requirements during the first 24 postoperative hours between the four groups. There was also no significant intergroup difference in sedation scores and incidence of nausea and vomiting.
Conclusion: When multimodal postoperative analgesia is used, prophylactic ip administration of 100 mg bupivacaine and/or 3 mg morphine does not significantly improve postoperative analgesia in patients undergoing laparoscopic gynecologic surgery.
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Introduction |
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Intraperitoneal injection of opioids for postoperative analgesia has been evaluated as an alternative approach. It has been suggested that peripheral antinociceptive effects of opioid agonists could be elicited by activation of opioid receptors localized on peripheral sensory nerves.10 However, Schulte-Steinberg et al. failed to demonstrate any analgesic effect of ip morphine (0.25 mg) after laparoscopic cholecystectomy.11 This result was explained, in part, by a very small amount of drug delivered to the surgical site. On the basis of these data, we conducted a study where we hypothesized that prophylactic ip administration of higher doses of morphine (3 mg) and/or 100 mg bupivacaine before the beginning of laparoscopic gynecologic surgery provides more effective postoperative analgesia compared to placebo when associated to multimodal analgesia.
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Methods |
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The same surgical team carried out all operations.
Patients received oral premedication with 1 mg•kg-1 hydroxyzine one hour before surgery. General anesthesia was induced and maintained with propofol in target-controlled infusion mode using a Graseby 3400 syringe pump (Graseby Medical, Watford, UK) and alfentanil infusion at a plasma target concentration of 60 ng•mL-1 (Stanpump, pharmacokinetic model reported by Maitre et al.).12 Propofol target concentration was adjusted to maintain mean arterial pressure and/or heart rate within -30% and -10% of the baseline values respectively. Tracheal intubation was facilitated with vecuronium bromide (0.1 mg•kg-1). Additional doses of vecuronium were administrated for abdominal muscle relaxation and to facilitate the surgical procedure. Ventilation (tidal volume, 8–10 mL•kg-1) was adjusted to maintain end-tidal carbon dioxide between 35 and 40 mmHg with 50% nitrous oxide in oxygen. During surgery, all patients received an iv infusion of lactated Ringer’s solution at a rate of 5–7 mL•kg-1•hr-1 intraoperatively and 1–2 mL•kg-1•hr-1 during the subsequent 24-hr period.
The test solutions were drawn into four coded syringes by the pharmacist: a 20-mL syringe containing 20 mL of 0.5% bupivacaine with epinephrine 1:200 000 or 20 mL 0.9% saline and a 5-mL syringe containing 3 mL of either morphine in 0.9% saline or 0.9% saline. The anesthesiologist, the surgeon and postanesthesia care unit (PACU) and ward nurses were unaware of patient allocation. Patients were assigned to four different groups by use of a random number table (18 patients per group). Group B: 20 mL of 0.5% bupivacaine with epinephrine 1:200 000 and 3 mL 0.9% saline; Group M: 3 mg morphine and 20 mL 0.9% saline; Group B + M: 20 mL of 0.5% bupivacaine with epinephrine 1:200 000 and 3 mg morphine; Group S: 23 mL 0.9% saline. Treatment solutions (23 mL for each patient) were administered immediately after creation of a pneumoperitoneum, before the beginning of surgery. The surgeon sprayed 12 mL in the right subdiaphragmatic area and 11 mL into the pelvic cavity under visual control.
Postoperative management
After surgery, patients were transferred to the PACU and asked every five minutes to evaluate their pain on the VAS. If a patient reported pain (VAS 
40), the nursing staff administered boluses of iv morphine 3 mg every five minutes until the pain score was < 40 mm on the VAS. For the first 24 hr, the analgesia regimen, based on pain intensity, included the iv administration of propacetamol, ketoprofen, and the sc administration of morphine. When the VAS was 
40 mm, propacetamol (2 g•6 hr-1) was administered. When the VAS was > 40 and 60 mm, ketoprofen was given (50 mg•6 hr-1). When the VAS was > 60 mm, additional sc morphine was given (0.1 mg•kg-1). The degree of postoperative pain was assessed with the VAS at rest (VAS-R; supine, 20°–30° head up) on arrival at the PACU (time zero hour), 15, 30, 45 min and one-, two-, four-, six-, 12-, 24-hr intervals after surgery, and on coughing (VAS-C) at four-, six-, 12-, 24-hr intervals after surgery. Moreover, the incidence of shoulder pain, time to first analgesic request, analgesic requirements and existence of nausea or vomiting were assessed at the same time interval. Nausea and vomiting were treated as needed with 20 mg iv metoclopramide. Sedation was also assessed using a four-point scale: 0 = awake, 1 = sleepy but awakened by oral command, 2 = sleepy but awakened by tactile stimulation, 3 = not awakened.
Statistical analysis
We calculated that a power of 0.9 could be obtained, using a significance level of 0.05 and four groups of 13 patients, if a 25-mm reduction in VAS (SD = 35 mm) in the treatment group was to be regarded as a clinically significant result, based on the study by Narchi et al.9 To account for possible patient dropout we decided to include 18 patients per group.
As most analyzed quantitative variables could not meet the assumption of normality, with clearly skewed distributions, non parametric statistical methods were used for analysis. Such variables are presented as the median (25th–75th percentiles), while categorical variables are presented as frequencies (percentage of patients).
Quantitative variables were compared between groups at time zero and after two, six and 24 hr by Kruskal-Wallis tests. Chi-square tests or Fisher’s exact test when more appropriate were used to compare categorical variables across groups. In case of a significant difference when comparing the four groups, post-hoc two-by-two between-groups comparisons were performed with Bonferroni correction, using either Wilcoxon rank-sum tests for quantitative variables or Chi-square or Fisher’s exact tests for categorical variables. Comparison of VAS-R and VAS-C was performed separately for each group, using Wilcoxon signed rank sum tests.
Statistical significance was inferred for P 0.05, and all tests were two-sided. Data were analyzed using SAS v8.1 software (SAS Institute, Cary, NC, USA).
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Results |
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Demographic, surgical and anesthetic variables
Demographic data (age, weight, height), ASA physical status, duration of surgery, total amount of propofol and alfentanil were similar in the four groups (Table I
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, Figures 1 and 2). Time to first analgesic request or postoperative analgesic consumption were not different between groups (Table II). The rate of shoulder pain was similar in the four groups (Table II). Also, there were no significant differences in the incidence of side effects between patients. The four groups were comparable for sedation scores and for the number of patients experiencing nausea and vomiting (Table III).
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Discussion |
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This study failed to demonstrate a superior analgesic efficacy of ip injection of local anesthetic compared to placebo. In their recent review, Moiniche et al., observed that studies of ip local anesthetics after laparoscopic surgery were poorly supportive of an effect on postoperative pain, especially after laparoscopic cholecystectomy. They concluded that the clinical benefit of this procedure, at least regarding pain scores, was questionable. In their review, a statistically significant weighted mean difference of -13 mm VAS in favour of the treatment groups was observed after cholecystectomy. The difference was somewhat more pronounced in other procedures, including gynecological laparoscopy, with significant VAS reductions of up to 26 mm.5 In our study, patients reported low postoperative pain scores in all groups, especially at rest. They also needed small doses of supplemental analgesics. This situation might be related to the short duration of surgery13 and/or to the fact that we used multimodal analgesia.14 We think that such low pain scores might have contributed to our inability to detect any analgesic effects of bupivacaine and/or morphine. It can also be argued that the failure to detect analgesic effects of ip bupivacaine is related to an insufficient amount of drug delivered to the surgical site. In fact, in 1991, Narchi and coworkers described the use of large volumes of dilute local anesthetic (80 mL lidocaine 0.5% or 80 mL bupivacaine 0.125%, both with epinephrine) administered before surgery into the peritoneal cavity for the treatment of pain after laparoscopy.9 They demonstrated significant reductions in mean pain scores in the local anesthetic groups from eight to 24 hr after surgery compared to the control group. Thus, a possible explanation could be that, despite the administration of the same dose of bupivacaine (100 mg with epinephrine), the volume of solution was too small to reach the surgical site.
Despite the use of larger doses (3 mg morphine at the surgical site instead of 0.25 mg in a previous study),11 we observed a similar negative result and the inefficacy of ip morphine. Schulte-Steinberg et al. have attributed the lack of efficacy of ip morphine in reducing postoperative pain after laparoscopic cholecystectomy to an insufficient dosage.11 Using a twelve-fold higher dose of morphine, we observed the same result. To date, only the intra-articular injection of morphine showed a relatively constant efficacy.15 We speculate that, contrary to the knee joint which is a closed space and where doses of morphine between 0.5 and 5 mg produce very high local concentrations, similar doses of morphine injected into the peritoneal cavity may be rapidly diluted and produce much lower local concentrations. An additional issue is that the knee joint model better reflects the inflammatory process that is thought to be of importance in sensitizing peripheral opioid receptors.16
A basic point of our study is that we investigated the value of prophylactic and not preemptive analgesia. In fact, contrary to preemptive analgesia which is defined as a treatment started before incision and covers both the period of surgery and initial postoperative period,17 we only evaluated the administration of treatment solutions at the beginning of the surgery.
A potential limitation of the current study is that we did not use patient-controlled analgesia morphine to quantify analgesic requirements. Nevertheless, we applied a standardized analgesic protocol adapted to regular and systematic evaluation of postoperative pain scores. Such a procedure has been reported to be comparable to patient-controlled analgesia for postoperative pain management.18
We conclude that in patients undergoing minor laparoscopic gynecologic surgery who receive a multimodal analgesic regimen, the prophylactic ip administration of 100 mg bupivacaine with epinephrine and/or 3 mg morphine does not provide significant analgesic benefit. However, since recent studies have reported an improvement of postoperative analgesia after laparoscopic cholecystectomy with the fractionated injection of local anesthetic (before and at the end of surgery),19,20 this practice should be evaluated in gynecologic surgery.
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Footnotes |
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Revision received January 16, 2003. Accepted for publication October 22, 2002.
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2 Soper NJ, Barteau JA, Clayman RV, Ashley SW, Dunnegan DL. Comparison of early postoperative results for laparoscopic versus standard open cholecystectomy. Surg Gynecol Obstet 1992; 174: 114–8.[Medline]
3 Wiesel S, Grillas R. Patient-controlled analgesia after laparoscopic and open cholecystectomy. Can J Anaesth 1995; 42: 37–40.
4 Joris J, Cigarini I, Legrand M, et al. Metabolic and respiratory changes after cholecystectomy performed via laparotomy or laparoscopy. Br J Anaesth 1992; 69: 341–5.
5 Moiniche S, Jorgensen H, Wetterslev J, Dahl JB. Local anesthetic infiltration for postoperative pain relief after laparoscopy: a qualitative and quantitative systematic review of intraperitoneal, port-site infiltration and mesosalpinx block. Anesth Analg 2000; 90: 899–912.
6 Callesen T, Hjort D, Mogensen T, et al. Combined field block and i.p. instillation of ropivacaine for pain management after laparoscopic sterilization. Br J Anaesth 1999; 82: 586–90.
7 Goldstein A, Grimault P, Henique A, Keller M, Fortin A, Darai E. Preventing postoperative pain by local anesthetic instillation after laparoscopic gynecologic surgery: a placebo-controlled comparison of bupivacaine and ropivacaine. Anesth Analg 2000; 91: 403–7.
8 Helvacioglu A, Weis R. Operative laparoscopy and postoperative pain relief. Fertil Steril 1992; 57: 548–52.[Medline]
9 Narchi P, Benhamou D, Fernandez H. Intraperitoneal local anaesthetic for shoulder pain after day-case laparoscopy. Lancet 1991; 338: 1569–70.[Medline]
10 Picard PR, Tramer MR, McQuay HJ, Moore RA. Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 1997; 72: 309–18.[Medline]
11 Schulte-Steinberg H, Weninger E, Jokisch D, et al. Intraperitoneal versus interpleural morphine or bupivacaine for pain after laparoscopic cholecystectomy. Anesthesiology 1995; 82: 634–40.[Medline]
12 Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR. Population pharmacokinetics of alfentanil: the average dose–plasma concentration relationship and interindividual variability in patients. Anesthesiology 1987; 66: 3–12.[Medline]
13 Dahmani S, Dupont H, Mantz J, Desmonts JM, Keita H. Predictive factors of early morphine requirements in the post-anaesthesia care unit (PACU). Br J Anaesth 2001; 87: 385–9.
14 Kehlet H. Synergism between analgesics. Ann Med 1995; 27: 259–62.[Medline]
15 Gupta A, Bodin L, Holmstrom B, Berggren L. A systematic review of the peripheral analgesic effects of intraarticular morphine. Anesth Analg 2001; 93: 761–70.
16 Nagasaka H, Awad H, Yaksh T. Peripheral and spinal actions of opioids in the blockade of the autonomic response evoked by compression of the inflamed knee joint. Anesthesiology 1996; 85: 808–16.[Medline]
17 Kissin I. Preemptive analgesia. Anesthesiology 2000; 93: 1138–43.[Medline]
18 Choinière M, Rittenhouse BE, Perreault S, et al. Efficacy and costs of patient-controlled analgesia versus regularly administered intramuscular opioid therapy. Anesthesiology 1998; 89: 1377–88.[Medline]
19 Pasqualucci A, De Angelis V, Contardo R, et al. Preemptive analgesia: intraperitoneal local anesthetic in laparoscopic cholecystectomy. Anesthesiology 1996; 85: 11–20.[Medline]
20 Labaille T, Mazoit JX, Paqueron X, Franco D, Benhamou D. The clinical efficacy and pharmacokinetics of intraperitoneal ropivacaine for laparoscopic cholecystectomy. Anesth Analg 2002; 94: 100–5.
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