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Preventing Postoperative Pain by Local Anesthetic Instillation After Laparoscopic Gynecologic Surgery: A Placebo-Controlled Comparison of Bupivacaine and Ropivacaine

Goldstein, Andrei, MD*; Grimault, Patrick, MD*; Henique, Aude, MD*; Keller, Michèle, MD*; Fortin, Anne, MD; Darai, Emile, MD, PhD

doi: 10.1213/00000539-200008000-00032
REGIONAL ANESTHESIA AND PAIN MEDICINE
Free

We tested the hypothesis that local anesthetics instilled at the end of laparoscopic gynecologic procedures are able to prevent postoperative pain at wake-up and during the first 24 h. A total of 180 patients were randomly assigned into three groups to receive an intraperitoneal instillation of 20 mL of either bupivacaine 0.5% (Group B), ropivacaine 0.75% (Group R) or saline (Group S) at the end of surgery. All patients received analgesia with acetaminophen and ketoprofen IV infusions. Pain was assessed by using a 0–10 graded numerical scale (NS) every 5 min in the postanesthesia care unit and IV morphine was administered if NS was >4. Assessment of pain was continued every 4 h on the ward, and subcutaneous morphine was injected if needed to keep the NS score < 4. Postoperative nausea and vomiting (PONV) was rated on a 4-point scale. The morphine consumption at wake-up and over the first 24 h was significantly lower (P < 0.05) in Group B (mean, 0.92 mg at wake-up; 3.08 mg over 24 h) and in Group R (mean, 0.25 mg at wake-up; 0.69 mg over 24 h), than in Group S (mean, 4.18 mg at wake-up; 12.93 mg over 24 h). The morphine-sparing effect of ropivacaine was significantly greater than that of bupivacaine. Both local anesthetics were effective in the prevention of PONV. We concluded that local anesthetics should be instilled in all gynecologic patients at the end of all laparoscopic procedures.

Implications Local anesthetic instillation (ropivacaine rather than bupivacaine) at the end of laparoscopy prevents postoperative pain and dramatically decreases the need for morphine. This technique, compared with placebo, is safe, improves patient comfort, shortens the stay in the postoperative care unit and decreases nursing care in the ward.

Departments of *Anesthesiology and †Gynecology, Hotel-Dieu Hospital Paris, France

April 12, 2000.

Address correspondence and reprint requests to Andrei Goldstein, MD, Department of Anesthesiology, Hotel-Dieu Hospital, 1 Place du Parvis Notre-Dame, 75181 Paris Cédex 04, France. Address e-mail to goldsteinandrei@yahoo.fr.

After laparoscopic gynecologic surgery, rapid recuperation of patient autonomy, the shortening of hospital stay, decreased morbidity, and costs are related to improved postoperative pain management. Postoperative pain is unpredictable, which explains the need for a systematic prevention of the pain before wake-up from anesthesia.

There are four components of pain after laparoscopic gynecologic surgery. Scapular pain secondary to peritoneal insufflation, especially when shoulder holders and exaggerated Trendelenbourg position are used, tends to increase after the eighth postoperative hour, appears during the night after surgery, and hinders sleep. Infiltration of local anesthetics decreases scapular pain (1,2). Visceral pain has its maximal intensity during the first hours and is exacerbated by coughing, respiratory movements, and mobilization. It requires morphine administration when patients awaken from anesthesia. Morphine, however, is only partially effective, and cannot completely eliminate pain caused by pelvic inflammation and traction on the uterine tubes. The fact that the pain comprises several components accounts for the necessity of multimodal analgesic techniques to provide effective postoperative analgesia.

Local anesthetic infiltration attenuates postoperative pain after laparoscopic cholecystotomy (1–6). Only a few reports are available, however, on the efficacy of intraperitoneal local anesthetic administration for analgesia after laparoscopic gynecologic surgery (7–9). Bupivacaine had been used by all of these authors except one, who used ropivacaine. No comparative data on bupivacaine and ropivacaine have been reported. Ropivacaine is less cardiotoxic than bupivacaine (10) and can hence, be administered in larger doses. Intraperitoneal instillation of 100 mg of bupivacaine provides effective analgesia with plasma concentrations below toxic levels (11). A dose of 150 mg of ropivacaine was selected to test whether this dose would increase the analgesic efficacy over that of bupivacaine. We undertook a prospective, double-blinded, randomized, placebo-controlled study of 180 patients. Our objectives were to prove that intraperitoneal instillation of local anesthetics decreases postoperative pain and delays its appearance after laparoscopic gynecologic surgery and to compare the efficacy of bupivacaine and ropivacaine.

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Methods

The study was approved by our ethics committee. All patients gave written, informed consent. Patients aged 18–70 yr, scheduled for laparoscopic gynecologic surgery, and classified as ASA physical status I or II were eligible. Patients with diagnostic laparoscopy without surgical procedure, those presenting contraindications to acetaminophen (allergy, liver disease) or to nonsteroidal antiinflammatory drugs (NSAIDs) (esophagogastroduodenal disease, renal insufficiency, abnormal coagulation), or with confirmed local anesthetic allergy, were excluded, as were those whose pain evaluation was judged unreliable because of neurological disease, or treatment by steroids, NSAIDs or opioids before surgery.

Patients received oral premedication, either 100 mg hydroxyzine 60 min before surgery or 5 mg midazolam 30 min before surgery. General anesthesia was induced with 20–30 μg sufentanil and propofol. Muscle relaxation was induced with vecuronium or cisatracurium and monitored for the full duration of surgery (train-of-four). The neuromuscular block was not antagonized systematically in order not to increase the postoperative nausea and vomiting (PONV) induced by laparoscopy and gynecologic surgery. Controlled ventilation was maintained with a mixture of 50% oxygen and 50% nitrous oxide with 1–1.2 minimum alveolar anesthetic concentration desflurane or 0.8–1 minimum alveolar concentration sevoflurane. The mechanical ventilator was set to maintain Paco2 between 32 and 40 mm Hg depending on the different stages of laparoscopy. Sufentanil reinjections were only administered if perioperative analgesia was insufficient (10–20 μg/h). Naloxone was never administered at the end of surgery.

Patients were randomly allocated to one of three groups: bupivacaine (Group B), ropivacaine (Group R), and saline (Group S). A 20-mL syringe, containing 20 mL of the solution was prepared by a nurse, who had no further involvement in the study. The surgeons and nurses in the postanesthetic care unit (PACU) and on the ward were unaware of the treatment to which each patient had been randomized. All patients had an instillation of 20 mL of blinded solution in a standardized manner by the operating surgeon, under visual control, at the end of the surgical procedure: 7 mL under each sub-diaphragmatic area and 6 mL at the surgical site (in case of a bilateral procedure: 5 + 5 + 5 + 5 mL). Group B received 20 mL of bupivacaine 5 mg/mL (100 mg) with epinephrine 1:200 000. Group R received 20 mL of ropivacaine 7.5 mg/mL (150 mg). Group S received 20 mL of physiological saline solution (0.9% sodium chloride).

The standard analgesia regimen used at our hospital, includes the administration of acetaminophen, NSAIDs, and morphine. An infusion containing 2 g propacetamol and 100 mg ketoprofen was started 30 to 60 min before completion of surgery and was repeated every 6 h for 24 h (propacetamol 2 g × 4 and ketoprofen 50 mg × 4). In the PACU, pain was evaluated every 5 min by assistant anesthesia nurses by using a numeric scale (NS) (0 = no pain and 10 = unendurable pain), which was explained to the patients during the preanesthetic visit. In case of a pain rating >4 on the NS, 2 mg boluses of IV morphine were injected and repeated every 5 min until a pain score of <4 was obtained.

The dose of IV morphine required at wake-up from anesthesia allowed calculation of the dosage of subcutaneous morphine to be administered on the ward for analgesia (Appendix). To prevent PONV 1 mg IV droperidol was administered. The injection was to be repeated and associated with the administration of 4 mg ondansetron in case of nausea. Pain assessment using the NS scale was done every 4 h by the nursing staff on the ward. The dose and frequency of subcutaneous morphine injections were to be adapted to the patient’s condition including pain, sedation, and respiratory rate (Appendix).

The efficacy of the local anesthetic instillation was determined by the dose of morphine required at wake-up from anesthesia and by the dose of morphine required to provide analgesia (NS <4) during the first 24 postoperative hours. Parenteral analgesia was administered for 24 h on the ward, after which the patients received oral nonopioid analgesics on request.

PONV was rated by the nurses on a four-point scale (0 = no PONV, 1 = only nausea, 2 = mild vomiting successfully treated by droperidol, 3 = heavy vomiting requiring other treatments in addition to droperidol), every 4 h during the 24-h period.

Two efficacy variables, the morphine consumption at wake-up and during the first 24 h in the ward, were selected to decide whether Groups B, R, and S had a significantly different behavior with regard to the postoperative analgesia. A two-sided Student’s t-test was used for pair-wise comparison of the morphine dose among the groups. The number of degrees of freedom for each comparison of a pair of distribution was therefore, 118. At the 5% level of significance, the hypothesis of equal mean should be rejected, if the value of the test statistic is greater than 1.98:MATH ΔM denotes the difference between the means of the two distributions; S2 is the average of the estimated variances of the two distributions; and n1 = n2 = 60 are the number of measurements in each distribution.

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Results

One hundred eighty patients were enrolled in the study, 60 randomized to each group. The mean ages were 37 yr in both Groups B and R and 42 yr in Group S. The groups were comparable with respect to the distribution of types of surgical procedure (Table 1).

Table 1

Table 1

The morphine dose required to obtain a NS score <4 at wake-up (Table 2) was significantly smaller in Groups B and R than in Group S. The morphine consumption in Group R was also significantly less than in Group B (T = 2.24). The consumption of subcutaneous morphine during the first 24 h in the ward (Table 3) was significantly less in Groups B and R than in Group S. The morphine consumption in Group R was also significantly less than in Group B (T = 3.34).

Table 2

Table 2

Table 3

Table 3

Both local anesthetics were effective in the prevention of PONV with statistically significant differences for all levels of PONV compared with saline (Table 4). There was no significant difference between Groups B and R. Symptomatic antiemetic treatment was required for only 10% of the patients in Group B and 15% in Group R, whereas 43% of the patients in Group S needed treatment. No hemodynamic adverse effects, change in heart rate or convulsion, were observed in any of the three groups.

Table 4

Table 4

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Discussion

We have shown that intraperitoneal instillation of 100 mg of bupivacaine or 150 mg of ropivacaine at the end of laparoscopic gynecologic surgery significantly reduced the need for morphine administration, both at wake-up from anesthesia and during the first 24 hours, and significantly reduced the incidence of PONV when patients received supplemental analgesia with acetaminophen and NSAIDs at the end of the surgery. In preventing postoperative pain, 150 mg of ropivacaine was significantly more effective than 100 mg of bupivacaine.

The use of local anesthetic infiltration, as in our study, for efficacious postoperative analgesia should allow widespread use of laparoscopic day-case surgery. Fleischer et al. (12) clearly showed that the limits for ambulatory laparoscopic surgery are not of a medical nature, but there is patient preference for staying overnight at the hospital. The problem of postoperative pain was not explicitly brought up by the patients in the study, but it is likely that the fear of experiencing pain and of it not being effectively relieved makes the patient reticent of leaving the hospital the evening of surgery. The medical factor limiting hospital discharge was PONV, although infrequently (12%). Although we studied gynecologic patients with a frequent incidence of PONV related to the procedures, we found that 10% to 15% of the patients in Groups B and R required antiemetic treatment, compared with 43% in Group S.

The efficacy of local anesthetic infiltration has been demonstrated in numerous studies in laparoscopic cholecystectomy. Chundrigar et al. (3) reported, in a randomized, placebo-controlled study on 60 patients, that bupivacaine 0.25% reduced postoperative pain in 1–2 h, but with similar analgesic consumption over the first 24 hours. The dose was 50 mg bupivacaine, one-half the dose we advocate. With 100 mg of bupivacaine 0.125%, Narchi et al. (11), in a study of 80 patients, showed statistically significant efficacy, whereas Joris et al. (4) did not find statistical significance in a study of 40 patients. Pasqualucci et al. (2) demonstrated a statistically significant effect on surgical metabolic endocrine response (glucose and cortisol) and on postoperative pain scores by instillation of 100 mg of bupivacaine after creation of pneumoperitoneum and 200 mg at the end of surgery. Szem et al. (6) showed only reduced pain scores for the first 6 h in a randomized study of 55 patients. Mraovic et al. (1) confirmed the efficacy of a 150 mg dose of bupivacaine on 80 patients in a randomized study. All of these studies have shown that local anesthetic administration was effective in pain prevention but there is a lack of consensus regarding the dose, concentration, site, and manner of the administration. Only the study by Scheinin et al. (5) failed to show efficacy; however, the entire dose of 150 mg of bupivacaine was instilled under the right hemidiaphragm.

In gynecology, decreased postoperative pain scores after local anesthetic administration have been reported (7,8,13,14). Here as well, however, the mode of the administration lacks standardization, e.g., infiltration on the trajectory of the trocars, infiltration of the uterine tubes, and peritoneal instillation before and after insufflation. Alexander et al. (15) showed that infiltration of the mesosalpinx by bupivacaine reduced pain after tubal sterilization, which was confirmed by Benhamou et al. (16). Callesen et al. (9) combined peritoneal instillation and incisional infiltration by using 285 mg of ropivacainein a double-blinded, randomized, placebo-controlled study on 80 patients. Significant improvement of pain scores over the first 8 h on coughing and during mobilization was demonstrated; however, scapular pain and PONV were not improved. Our large study clearly proved the efficacy of bupivacaine and ropivacaine both on pain and PONV in a number of gynecologic procedure of various complexity, although the doses used were much smaller. The effectiveness in PONV prevention is not a direct effect but stems from opioid-sparing.

Narchi et al. (11) showed that intraperitoneal instillation of 100 mg of bupivacaine did not result in toxic plasma concentrations. The absence of toxicity was confirmed by Deans et al. (17) who determined plasma concentrations after instillation of 1.5 mg/kg bupivacaine in the preperitoneal space during hernia repair. Ropivacaine has been infiltrated in doses of 300 and 375 mg for hernia repair without reaching toxic concentrations (18). Expression of neurological toxicity is a function of the cerebral concentration of local anesthetic and its rate of increase; it is thus, caused by a direct intravascular injection or a rapid absorption. The maximal tolerated dose before manifestation of central nervous system toxicity is 12% (19) to 25% (20) higher with ropivacaine than with bupivacaine.

We compared 100 mg of bupivacaine and 150 mg of ropivacaine (21). The higher security margin of ropivacaine makes it possible to use larger doses. It would be interesting to investigate whether the analgesic efficacy can be further increased by larger doses of ropivacaine. However, absorption after intraperitoneal instillation may be rapid, leading to plasma concentrations above the central nervous system toxicity threshold. During general anesthesia, signs of neurological toxicity are masked, which calls for caution in dosing. Callesen (9) reported an absence of local anesthetic toxicity in his study using 285 mg, but no plasma concentrations were determined, and signs of toxicity may have been masked by general anesthesia. The analgesic efficacy compared with placebo does not appear to argue for the use of almost twice the dose we used.

In summary, both bupivacaine and ropivacaine were effective at preventing pain and PONV at wake-up and over the first 24 h after laparoscopic gynecologic surgery when intraperitoneally instilled at the end of laparoscopy. Our study showed 150 mg ropivacaine significantly reduced the need for morphine compared with 100 mg of bupivacaine. This technique is simple, safe, and without adverse effects. Because postoperative pain is unpredictable, local anesthetics should be instilled in all patients at the end of all laparoscopic procedures. Ropivacaine is the best choice because of its higher efficacy and larger safety margin. A systematic instillation is likely to be cost-effective, because it decreases time in the PACU for morphine titration and resource utilization on the ward for treatment of postoperative pain and emesis.

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References

1. Mraovic B, Jurisic T, Kogler-Majeric V, Sustic A. Intraperitoneal bupivacaine for analgesia after laparoscopic cholecystectomy. Acta Anesth Scand 1997; 41:193–96.
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3. Chundrigar T, Hedges AR, Morris R, Samatakis JD. Intraperitoneal bupivacaine for effective pain relief after laparoscopic cholecystectomy. Ann Roy Coll Surg Engl 1993; 75:437–39.
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6. Szem JW, Hydo L, Barie PS. A double-blinded evaluation of intraperitoneal bupivacaine vs saline for the reduction of postoperative pain and nausea after laparoscopic cholecystectomy. Surg Endosc 1996; 10:44–8.
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9. Callessen T, Hjort D, Mogensen T, et al. Combined field block and IP instillation of ropivacaine for pain management after laparoscopic sterilization. Br J Anaesth 1999; 82:586–90.
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11. Narchi P, Benhamou D, Bouaziz H, et al. Serum concentrations of local anaesthetics following intraperitoneal administration during laparoscopy. Eur J Clin Pharmacol 1992; 42:223–5.
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14. Loughney AD, Ryall EA. Intraperitoneal bupivacaine for relief of pain following day case laparoscopy. Br J Obst Gyn 1994; 101:449–51.
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17. Deans GT, Richardson T, Wilson MS, Brough WA. Absorption of bupivacaine from the pre-peritoneal space in laparoscopic hernia repair. Minim Invasive Ther 1995; 4:175–7.
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Appendix 1.

Protocol for Administration of Subcutaneous Morphine for Postoperative Analgesia on the Ward

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1. Monitor Every 4 h

Pain by graded numerical scale (NS) Sedation Respiration Pulse and arterial blood pressure

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2. Determination of the Dose of Subcutaneous Morphine Based on the Titration Dose (T)

T < 3 mg: propacetamol ± ketoprofen (protocol), ± morphine subcutaneous on request; maximum 5 mg per 6 h (except if morphine is contraindicated) 4 mg<T<6 mg: subcutaneous morphine 5 mg per 6 h 7 mg<T<15 mg: subcutaneous morphine corresponding to two-thirds of T per 4 h i.e., T = 7 or 8 mg: subcutaneous morphine 5 mg per 4 h T = 9 or 10 mg: subcutaneous morphine 6 mg per 4 h T = 11 or 12 mg: subcutaneous morphine 7 mg per 4 h T = 13 or 14 mg: subcutaneous morphine 8 mg per 4 h In case of severe renal insufficiency, schedule the injections every 6 h.

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3. Administration of Subcutaneous Morphine

First injection, 4 or 6 h after the beginning of the titration, if no somnolence. Assess the pain 1 h after the first injection of subcutaneous morphine and/or if change of the morphine subcutaneous dose, if pain 4<NS<6.5, and no somnolence, reinject 2 mg morphine subcutaneously 1 h after the first injection, but continue the doses determined initially. If somnolence and/or respiration rate is between 8 and 10, see procedure for respiratory depression. If pain >6.5 on the NS, call anesthetist and reassess the pain. If no particular problem, increase the dose 2 mg compared to the predetermined dose for all subsequent administrations. Do not inject if heart rate is >120 or <50 bpm or if arterial blood pressure is <100 mm Hg. Stimulate, nasal O2 3–6 L/min. Call anesthetist. Do not inject at night if the patient is asleep. Do not systematically inject morphine in the morning if there has been no injection over the last 8 h with pain level <4. Do not use any sedative drugs (sleeping medication, benzodiazepines) together with morphine.

© 2000 International Anesthesia Research Society