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Medical Journal of the Islamic Republic of Iran , Vol. 20, No. 1, May, 2006, pp. 19-22

INTRAPERITONEAL AND INCISIONAL BUPIVACAINE ANALGESIA FOR MAJOR ABDOMINAL/GYNECOLOGIC SURGERY: A PLACEBO-CONTROLLED TRIAL

From the Depts. of *Anesthesiology and **Obstetrics and Gynecology, Tabriz University of Medical Sciences, Tabriz, I.R. Iran.

*Assistant Professor of Anesthesiology, Tabriz University of Medical Sciences, Tabriz.

Corresponding Author: Dr. Simin Atashkhoii: Iran, Tabriz, South Artesh Ave, aL-Zahra Hospital, Departement of Anesthesia. E-mail: siminatashkhoii@yahoo.com, Tel: 00980914-114-8861 Fax: 0098411-5566449

Background: Postoperative pain is an important surgical problem. Recent studies in pain pathophysiology have led to the hypothesis that with periopera-tive administration of analgesics (pre-emptive analgesia) it may be possible to prevent or reduce postoperative pain. This study was planned to investigate the efficacy of pre-emptive analgesia on postoperative pain after major gyneco-logic abdominal surgeries.
Methods: In this prospective, double-blinded, randomized, and placebo-controlled trial, 60 ASA physical status I and II patients undergoing major abdomi-nal gynecologic surgeries were randomized to receive 45 mL of bupivacaine 0.375% or 45mL of normal saline; 30 mL and 15 mL of the treatment solution was administered into the peritoneal cavity and incision, respectively, before wound clo-sure. The pain score of the patients was evaluated by the visual analogue scale (VAS) on awakening, and at 6, 12, and 24h after surgery. Time to first analgesia re-quest and total analgesic requirements in the first 24h were recorded.
Results: Pain scores were significantly higher in the placebo group than in the bupivacaine group on awakening (5.98±1.01 v.s 1.05±1.05; p<0.001), and at 6h after surgery (5.37±0.85 vs. 2.51±1.02; p<0.001). First request to analgesia was significantly longer in the bupivacaine patients than in the placebo group (5.87±3.04 h vs. 1.35±0.36; p<0.001). Meperidine consumption over 24h was 96.00 ±17.53 mg in the placebo group compared with 23.28 ±14.89 mg in the bupivacaine patients (p<0.001).
Conclusion: A combination of intraperitoneal and incisional bupivacaine in-filtration at the end of abdominal gynecologic surgeries reduces postoperative pain on awakening and for 6 hours after surgery, and provides significant opioid-sparing analgesia for 24 h after gynecologic abdominal surgeries.

Keywords: Gynecologic abdominal surgeries, Pre-emptive analgesia, Intraperitoneal infiltration, Bupivacaine

Postoperative pain management is an important com-ponent of patient care after gynecologic surgery. Analge-sic use strategies in the initial postoperative period com-monly include patient-controlled analgesia, and parenteral nonsteroidal anti-inflammatory agents. These strategies address the problem of pain control only after painful stimuli have been initiated. In contrast, pre-emptive anal-gesia is intervention that is provided before or during op-eration to reduce or prevent subsequent pain.^{1, 2}

Recent studies demonstrated that pre-emptive par-enteral agent use including ketamine,³ ketorolac,⁴ pro-methazine,⁵ esmolol⁶ and meloxicum,⁷ and regional anal-gesia (with local anesthetics^{8, 9} or opioids^{10, 11}) reduces pain scores and medication requirements, in many ab-dominal surgeries. The value of locally applied or incisional anesthetics to improve postoperative pain after sur-gery is less certain. Some studies12-17 failed to show a benefit with the application of local anesthetics, while other studies18-29 indicated that pre-emptive intraperitoneal local anesthetics significantly decreased postoperative pain after gynecological laparoscopy or laparotomy.

The purpose of this study was to evaluate the analgesic effects of incisional and intraperitoneal bupivacaine after major gynecologic abdominal operations.

Sixty ASA physical status I or II, 18-65 year old fe-male patients undergoing gynecologic abdominal surger-ies, were enrolled in this prospective, randomized, double-blind, and placebo-controlled, clinical trial over six months after obtaining written informed consent. Ran-domization process of allocating patients into study groups was performed by forming "randomly permuted blocks" in online software (http://www.Randomization.com). Exclusion criteria were history of severe heart, pulmonary, hepatic, renal or psychological disease, or allergy to local anesthetics.

All patients received 5mg oral diazepam 30 minutes before operation. General anesthesia was induced with thiopentone/fentanyl and tracheal intubation. Patients were randomized to receive either 45mL of bupivacaine 0.375% (bupivacaine group, n=30) or 45mL normal saline (placebo group, n=30). Thirty mL and 15 mL of treatment solution were administered into the peritoneal cavity or incision, respectively, before wound closure.

Postoperatively, pain intensity was evaluated using VAS (0-10 cm) on awakening and at 6, 12, and 24h. A standard postoperative analgesic regimen was utilized in all patients. The patient was prescribed 0.5 mg/kg meperidine IM as required for analgesia or with VAS ≥4.

Sedation level was according to a four-point scale (0=awake and alert; 1=mildly sedated or easily aroused; 2= moderately sedated or can be aroused by shaking; 3= deeply sedated or difficult to arouse, even by shaking). Time to first analgesia request and total analgesic (meperidine and tramadol) requirements at 24h postopera-tively, and side effects such as nausea, vomiting, pruritus, and respiratory depression (yes or no) at 24h postopera-tively were recorded.

Statistical analyses were performed using the software package SPSS v12.0 (SPSS. Inc. Chicago. IL). Compari-sons of continuous variables were made using independent t test or Mann-Whitney U test. Analyses of nominal vari-ables were made using χ² or Fisher^'s exact test as appro-priate. Repeated measures ANOVA was done to evaluate VAS score changes with time in each study group. The test results were considered significant if p≤ 0.05.

There was no significant difference in age, weight, ASA class, duration and type of surgery between the pa-tients (Table I).

On awakening and 6h after operation, pain scores were significantly less in the bupivacaine group than in the pla-cebo group (p<0.001). However, at 12h (2.03±1.1 v.s 3.271.30; p=0.16), and 24h (1.29±0.9 v.s 1.79±1.0; p=0.31), there were no differences in pain scores between the two groups (Fig. 1). As shown in Fig. 1 the repeated measures ANOVA of VAS score of patients in the bupivacaine group [F (3, 87) =30.18; p=0.0001], and pla-cebo group [F (3, 87) = 276.97; p= 0.0001] revealed that changes with time was significant.

Pain onset time and time to first request to analgesia were significantly longer in the bupivacaine patients (5.50 3.07 h, 5.87 3.04 h; respectively) than in the placebo group (0.99 ±0.28 h, 1.35 ±0.36 h; respectively; p< 0.001 for both variables; Table II).

The mean meperidine requirement was signifi-cantly smaller in the bupivacaine patients (23.28±14.89 mg) than in the placebo group (96.00±17.53 mg) at 24h postoperatively (p<0.001; Table II). This significant difference was attributable largely to the reduction in meperidine requirements within the first 6h postoperative period. There were no significant differences between the groups in tramadol administration at 24h (p=0.09; Table II).

There were no significant differences between the groups in sedation level (p=0.42; Table II). However, there were significant differences regarding postoperative complications such as nausea, vomiting, pruritus and res-piratory depression (p<0.001), and patients who asked for antiemetic (p=0.004) between the two groups at the first 24h after surgery (Table II).

The aim of the present study was to investigate whether infiltration of a local anesthetic solution in the surgical field would reduce the incidence, intensity, and duration of postsurgical pain compared with infiltration of saline in patients undergoing gynecologic laparotomy.

A number of previous investigations have examined wound instillation and peritoneal analgesia with local an-esthetics. Some studies were unable to demonstrate a benefit of employing this technique in terms of reduction in the patient's perception of pain.^12-17

A qualitative systemic review of the use of incisional local anesthetics for postoperative analgesia after abdominal operations showed that there was improved pain relief after inguinal herniorrhaphy, gynecologic laparoscopy and appendicectomy.^18-27 For other types of surgery, such as total abdominal hysterectomy (TAH), open cholecystec-tomy, cesarean delivery, and major upper abdominal surgery, the evidences showing the value of instillation of local anesthetic into the incision are equivocal.^{12,
17, 28}

In the present study, peritoneal combined with subcu-taneously delivery of local anesthetic compared with pla-cebo, beneficial effects were observed. In the treatment group, patients had a better pain score on awakening, and 6h postoperatively, and had a longer interval to first anal-gesia and had reduced opioid requirement in the first 24h postoperatively.

The failure of some of the previous trials to show sig-nificant analgesic benefits may be attributed to the site of surgery, timing of the administration, and dose of local anesthetic. In addition it is possible that either incisional or intraperitoneal local anesthetics alone may not be ade-quate to produce measurable postoperative analgesia. Our data suggest that block of both visceral and somatic con-duction is important if an analgesic sparing effect is to be demonstrated after major surgery.^{27, 28}

This method of delivery of local anesthetic is easy, and no expertise or special training is required. It was not as-sociated with any untoward side effects and did not interfere with the operative procedure. It appears to be a valu- able adjunct to opioids and have an opioid sparing role.^25-28

Bupivacaine has been shown to have an analgesic ef-fect beyond the duration of its pharmacological action. It has been postulated that bupivacaine suppresses the for-mation of a hyperexcitable state in the central nervous system which is responsible for the maintenance of post-operative pain.²⁷

No adverse effects are detected from the dose of bupivacaine used in previous studies. This observation is consistent with pharmacokinetic studies in which no ad-verse clinical effects were reported from intraperitoneal bupivacaine. In our study bupivacaine was administered in doses similar to that of these studies and peak plasma con-centrations were much smaller than the generally accepted toxic value of 3 μg/mL.^27-29 The dose of bupivacaine used was 150 mg in 45 mL bupivacaine 0.375%, which is lower than the maximum dose (175 mg) of drug for infil-tration anesthesia.¹

The benefits of reducing meperidine administration are thought to be related to improved recovery from surgery and anesthesia. In the postoperative period, analgesia, sedation, nausea, and return of bowel motility are impor-tant factors that facilitate recovery.^27-29 In this study, the application of intraperitoneal and subcutaneous bupiva-caine was associated with lower pain scores and a reduc-tion in meperidine requirements in the first 24 hours after surgery. Furthermore, there was little nausea and vomiting in the 24 hour period.

We conclude that pre-emptive incisional and intraperi-toneal bupivacaine may be recommended because it re-duced pain on awakening and 6h postoperatively, and provided significant supplemental opioid-sparing analgesia for 24 hours after major gynecologic abdominal surgeries.

REFERENCES

Miller RD: Miller's Anesthesia, 6^th ed, Philadelphia: El-sevier, pp. 586, 2731-2, 2005.
Jorgen B, Moiniche D, Moiniche S: Pre-emptive analgesia. Br Med Bulletin 71(1): 13-27, 2004.
Argiriadou H, Himmelsher S, Papagiannopoulou P, Geor-giou M, Kanakoudis F, Giala M, Kochs E: Improvement of pain treatment after major abdominal surgery by intrave-nous s(+)-ketamine. Anesth Analg 98(5): 1413-8, 2004.
Parke TJ, Lowson SM, Uncles DR, Daughtery MO, Sitz-man BT: Pre-emptive versus post-surgical demonstration of ketorolac for hysterectomy. Eur J Anesthesiol 12(6): 549-53, 1995.
Chia YY, Lo Y, Tan PH, Chung NC, Ko NH: The effect of promethazine on postoperative pain: a comparison of pre-operative, postoperative, and placebo administration in pa-tients following total abdominal hysterectomy. Acta Anes-thesiol Scand 48(5): 625-30, 2004.
Chia YY, Chan MH, Ko NH, Liu K: Role of β-blockade in anesthesia and postoperative pain management after hyster-ectomy. Br J Anesth 93(6): 799-805, 2004.
Akarsu T, Karaman S, Akercan F, Kazandi M, Yucebilgin MS, Firat V: Pre-emptive meloxicam for postoperative pain relief after abdominal hysterectomy. Clin Exp Obstet Gyne-col 31(2): 133-6, 2004.
O'Neal MG, Beste T, Shackelford DP: Utility of pre-emptive local analgesia in vaginal hysterectomy. Am J Ob-stet Gynecol 189(6): 1539-41, 2003.
Obta H, Saito S, Fujita N: Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Can J Anesth 46(12): 1127-32, 1999.
Akural EI, Salomarki TE, Tekay AH, Bloiga AH, Alahata SM: Pre-emptive effect of epidural fentanil in abdominal hysterectomy. Br J Anesth 88(6): 803-8, 2002.
Negre I, Guaeneron JP, Jamali SJ, Monin S, Ecoffey C: Preoperative analgesia with epidural morphine. Anesth An-alg 79(2): 298-302, 1994.
Updike GM, Manolitsas TP, Cohn DE, Eaton LA, Fowler JM, Young DC, Copeland LJ: Pre-emptive analgesia in gy-necologic surgical procedures: preoperative wound infiltra-tion with ropivacaine in patients who undergo laparotomy through a midline vertical incision. Am J Obstet Gynecol 188(4): 901-5, 2003.
Sun X, Yokoyama M, Mizobuchi S, Kayu R, Nakatsuka H, Takahashi T, Movito K: The effects of pretreatment with li-docaine or bupivacaine on the spatial and temporal expres-sion of C-FOS protein in the spinal cord caused by plantar incision in the rat. Anesth Analg 98(4): 1093-8, 2004.
Wrigley LC, Howard FM, Gabel D: Transcervical or in-traperitoneal analgesia for laparoscopic tubal sterilization: a randomized controlled trial. Obstet Gynecol 96(6): 895-8, 2000.
Kuan YM, Smith S, Miles C, Grigg M: Effectiveness of intra-operative wound infiltration with long-acting local an-esthetic. ANZ J Surg 72(1): 18-20, 2002.
KO CY, Thompson JR, Alcantra A, Hiyama D: Pre-emptive analgesia in patients undergoing appendectomy. Archives Surg 132(8):874-7, 1997.
Ali PB, Cotton BR, Williamson KM, Smith G: Intraperito-neal bupivacaine or lidocaine does not provide analgesia af-ter total abdominal hysterectomy. Br J Anesth 80(2): 245-7, 1998.
Colert ST, Moran K, O'Hanalon DM, Chambers F, Mckenna P, Moriarity DC, Blunnie WP: An assessment of the value of intraperitoneal meperidine for analgesia post-laparoscopic tubal ligation. Anesth Analg 91 (3): 667-70, 2000.
Jitsu K, Setsuro O, Joel K, Psych C, Hitoshi N, Miho Ka-shiwazaki, Shigeru S, Hajime S: Effects of presurgical local infiltration of bupivacaine in the surgical field on postsurgi-cal wound pain in laparoscopic gynecologic examinations: A possible pre-emptive analgesic effect. Clin Pain 16(1): 12-7, 2000.
Uzunkoy A, Coskun A, Akinci OF: The value of pre-emptive analgesia in the treatment of postoperative pain af-ter laparoscopic cholecystectomy. Eur Surg Res 33(1): 33-41, 2001.
Gupta A, Torn SE, Axelssom K, Larsson LG, Agren G, Holm Strom B, Rawal N: Postoperative pain relief using in-termittent injection of 0.5% ropivacaine through a catheter after laparoscopic cholecystectomy. Anesth Analg 95(2): 450-6, 2002.
Garwood S, Reeder M, Mackenzie IZ, Gailleboud J: Tubal surface lidocaine mediates pre-emptive analgesia in awake laparoscopic sterilization: A prospective, randomized clini-cal trial. Am J Obstet Gyneol 186(3): 383-8, 2002.
Cervini P, Smith LC, Urbach DR: The effect of intraopera-tive bupivacaine administration on parenteral narcotic use after laparoscopic appendectomy. Surg Endosc 6(11): 1579-82, 2002.
Noma H, Kakiachi H, Nojiri K, Izumi R, Tashiro C: Evaluation of postoperative pain relief by infiltration of bupivacaine or epidural block after laparoscopic cholecys-tectomy. Masai 50(11): 1201-4, 2001.
Tverskoy M, Cozacoy C, Ayache M, Bradly EL, Kissin I: Postoperative pain after inguinal herniorrhaphy with differ-ent types of anesthesia. Anesth Analg 70(1): 29-35, 1990.
Holst P, Erichsen GJ, Dahl JB, Hjortso NC, Grinsteel J, Kehlet H: Effects of lidocaine aerosol on postoperative pain and wound tenderness following minor gynecological lapa-rotomy. Acta Anesthesia Scand 36(2): 112-4, 1992.
Colbert S, O'Hanlon DM, Courtney DF, Quill DS, Elynn N: Analgesia following appendicectomy-the value of perito-neal bupivacaine. Can J Anesth 45(8): 729-34, 1998.
Ng A, Swami A, Davidson AC, Ememolu J: The analgesic effects of intraperitoneal and incisional bupivacaine with epinephrine after total abdominal hysterectomy. Anesth Analg 95(1): 158-62, 2002.
Ong CKS, Lirk P, Seymour RA, Jenkina BJ: The efficacy of pre-emptive analgesia for acute postoperative pain man-agement: A meta-analysis. Anesth Analg 100(3): 757-73, 2005.

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