Laparoscopic cholecystectomy in healthy patients is routinely performed at our hospital on a day case basis. Despite being minimally invasive, this operation may cause patients to experience severe pain and lead to the administration of strong opioids, e.g. morphine. However, morphine is not an ideal analgesic for day case anaesthesia because of adverse effects such as sedation, nausea, vomiting and gastrointestinal ileus. Other methods that provide morphine-sparing analgesia, e.g. non-selective non-steroidal anti-inflammatory drugs (NSAIDs) , selective cyclo-oxygenase 2 inhibitors  and local anaesthetic infiltration , are often used to supplement analgesia.
Intraperitoneal instillation of local anaesthetic 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 in the postoperative period [4-6]. However, in previous studies of intraperitoneal local anaesthetics following laparoscopic cholecystectomy it has not been possible consistently to demonstrate reliable analgesic effects [7-12]; this may be related to nociceptive conduction from incisional sites that is not blocked by local anaesthetics given into the intraperitoneal cavity. Thus, the object of this study in patients undergoing laparoscopic cholecystectomy was to evaluate the value of levobupivacaine, with epinephrine, instilled intraperitoneally in the provision of analgesia to combat visceral and shoulder pain; all these patients also received local anaesthetic at the site of the surgical incision.
Local Research Ethics Committee approval and informed patient consent were obtained. We studied 48 ASA I-II patients scheduled for laparoscopic cholecystectomy in a prospective double-blind randomized controlled trial. Patients who had a chronic pain syndrome or who used analgesics regularly were excluded.
All patients were given a standardized anaesthetic comprising propofol 2-4 mg kg−1, fentanyl 2 μg kg−1, ondansetron 4mg intravenous (i.v.); atracurium 0.5 mg kg−1 was used for muscular relaxation. Patients' lungs were ventilated with nitrous oxide and isoflurane 1-1.5% in oxygen. Suppositories of diclofenac 100 mg and acetaminophen (paracetamol) 1 g were administered at the induction of anaesthesia. Surgery was performed in a standard fashion using 2 × 5 and 2 × 10 mm ports, the first port being introduced using a blunt open technique. The cystic artery and duct were divided between Liga clips® (Ethicon, Edinburgh, UK) and the gallbladder from the liver bed using a diathermy hook. The gallbladder was removed at the umbilicus and a suction drain was inserted at the surgeon's discretion.
Prior to wound closure, either 2.5 mg mL−1 levobupivacaine 30 mL, with epinephrine 5 μg mL−1, or normal saline 30 mL, with epinephrine 2.5 μg mL−1, was injected into the gallbladder bed and the peritoneal cavity. This allocation was done randomly by computer in blocks of six and from instructions in envelopes that were sealed and opaque so that they could not be viewed, e.g. by shining a light. The treatment solution was prepared by the anaesthetist who was not involved further in the study.
During closure of the wound the incisional sites were infiltrated with levobupivacaine 20 mL 2.5 mg mL−1, with epinephrine 5 μg mL−1, in all patients. The linea alba at the umbilicus was closed with a 2.0 Vicryl® (Ethicon, Edinburgh, UK) suture. A subcuticular 3.0 Vicryl® Rapide suture was used for skin closure. Residual neuromuscular blockade was antagonized with a mixture of neostigmine 2.5 mg and glycopyrrolate 500 μg.
In the postoperative period, patients were assessed on awakening and then at 1, 2, 3 and 4h by a trained observer who was blinded to the drug given. Intra-abdominal pain at rest and during deep inspiration, and any pain in the right shoulder were assessed on a visual analogue scale (VAS) comprising a horizontal line of 100 mm representing 'no pain' at 0 mm and 'worst imaginable pain' at 100 mm. Patients were advised that intra-abdominal pain was deep pain that they could not touch. 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. In the postanaesthetic care unit (PACU), i.v. morphine 2 mg was administered, at 5 min intervals, to ensure that intra-abdominal pain at rest was <35 mm.
For this method of analgesia to be useful in day-surgery, the dose of rescue morphine should be as close to zero as possible. We estimated that, at the 5% significance level, 20 patients per treatment group were required to allow an 80% chance of detecting a 75% reduction in the dose rescue of morphine in the PACU. This assumption was based on pilot data in which we found that the rescue mean morphine consumption was 8 mg in patients receiving placebo and the SD was 6.6 mg.
Data were processed in Microsoft Excel 2000® and SPSS® v. 11.0 (SPSS Inc., Chicago, IL, USA). Pain, sedation and nausea scores for the first 4 h after operation (five values) were summed. All data were tested for normality using the Kolmogorov-Smirnov test. Normally distributed data, i.e. age, height and weight, were analysed by t-test. Data that were not normally distributed, i.e. duration of surgery, morphine dose, dihydrocodeine consumption as well as pain, sedation and nausea scores were analysed using the U-test. The χ2-test was used to test for numerical data. P < 0.05 was considered to be significant.
Of 48 patients recruited, five were excluded (Fig. 1). In the placebo group, intraperitoneal solution was not administered in one patient, and another patient declined to participate further in the study. In the levobupivacaine group, there were two protocol violations and in one patient haemorrhage precluded a standard laparoscopic surgical technique.
Of 43 patients studied, there were no significant differences between the two treatment groups in age, height, weight, ASA grade, duration of surgery or number of patients with abdominal drains inserted (Table 1).
The median (interquartile range) total abdominal pain during inspiration in the levobupivacaine group was significantly (P < 0.041) lower (71 (21-129) mm) than in the placebo group (123 (71-179) mm), (Table 2). However, the median (interquartile range) total abdominal pain at rest in the levobupivacaine group was not shown to be significantly (P = 0.078) lower (72 (35-128) mm) than that in the placebo group (101 (76-134) mm). In addition, the median (interquartile range) total right shoulder pain of 0 (0-20) mm in the levobupivacaine group did not differ significantly (P = 0.067) from the higher value of 16 (0-49) mm in the placebo group.
The number of patients needing rescue morphine, or morphine and dihydrocodeine, in the levobupivacaine group was lower - but not significantly so - compared with those in the placebo group. The median (interquartile range) total rescue morphine consumption in the levobupivacaine group was not significantly lower (0 (0-7) mg) than in the placebo group (2 (0-10) mg). The need for dihydrocodeine and cyclizine was also not significantly different between the two groups. In addition, there was no significant difference in total sedation score, total nausea score or in the number of episodes of vomiting between the groups.
We have shown that intraperitoneal instillation of 30 mL of levobupivacaine 2.5 mg mL−1 with epinephrine 5 μg mL−1 significantly reduced (P = 0.041) total abdominal pain during inspiration compared with placebo. Total abdominal pain at rest, and right shoulder pain, was lower - but not significantly so - in the levobupivacaine group compared with the placebo group. In addition, there was no significant difference between the two groups in sedation, nausea, episodes of vomiting, or the need for rescue morphine or dihydrocodeine.
Our results are consistent with other studies in which intraperitoneal administration of local anaesthetic has been shown to have a modest analgesic effect. Of 13 clinical trials considered in a systematic review it was found that the intraperitoneal administration of bupivacaine 50-200 mg, in volumes of 10-100 mL, produced significant analgesia in seven studies but not in the remainder. In only five of the studies were supplemental analgesic consumption significantly reduced .
Intraperitoneal local anaesthetics would be expected to be useful for treating visceral pain. In our study it is likely that intraperitoneal levobupivacaine in the right hypochondrial area had an analgesic effect. It significantly reduced total abdominal pain during inspiration and there was a trend towards lower scores for total abdominal pain at rest and for total right shoulder pain. However, the analgesic effect observed in our study was modest, possibly because of the inadequate dose used and rapid dilution of local anaesthetic in the peritoneal cavity. We used a total dose of 125 mg levobupivacaine of which only 75 mg in 30 mL were instilled into the peritoneal cavity. However, it is not recommended that the dose of levobupivacaine be increased because of the risk of systemic toxicity.
Local anaesthetic toxicity is a serious problem, which limits dosage and efficacy. 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 death and cardiac arrest . Chiral manipulation has resulted in the development of levobupivacaine, the S(−) enantiomer of racemic bupivacaine, used in this study . In sheep, levobupivacaine has been found to produce less central nervous system (CNS) toxicity and was less likely to cause fatal dysrhythmias than bupivacaine [16-18]. In human being volunteers, i.v. levobupivacaine was associated with significantly less reduction in mean stroke index, acceleration index and ejection fraction than i.v. racemic bupivacaine . There have been case reports of CNS toxicity after administration of levobupivacaine for epidural , axillary [21-22] and lumbar plexus blockade . However, no cardiovascular complications occurred in these patients.
Laparoscopic cholecystectomy is currently considered to be a relatively minor operation. It has been classified as a basket procedure (analogous to shopping with a supermarket basket) in the UK government's publication on day-surgery , and thus the expectation is that patients will be ambulant soon after surgery. But an important factor that limits recovery is postoperative pain. Intraperitoneal instillation of local anaesthetics is a simple method of analgesia and should be considered in addition to other morphine-sparing analgesics such as NSAIDs, acetaminophen and incisional local anaesthetics. In high doses, the risk of systemic toxicity may be minimized by use of levobupivacaine rather than racemic bupivacaine and also by the addition of epinephrine that reduces absorption and hence reduces peak plasma concentrations of local anaesthetic. Other methods of pain relief such as epidural analgesia  and insertion of a suprahepatic suction drain  have been shown to be useful following laparoscopic cholecystectomy; but these methods are invasive and unsuitable for the practice of ambulatory surgery and anaesthesia.
In conclusion, we have found that, compared with placebo, intraperitoneal instillation of levobupivacaine with epinephrine reduced total abdominal pain during inspiration in the immediate postoperative period after laparoscopic cholecystectomy. Although the analgesic effect was modest, this method of analgesia may be recommended for ambulatory surgery, when used in combination with other morphine-sparing techniques. Both surgeons involved in the study continue to use this method of analgesia as part of their routine practice.
The work was presented, in part, to the Anaesthetic Research Society on 3 April 2003; Br J Anaesth 2003; 90: 820P-821P.
1. Ng A, Parker J, Toogood L, Cotton BR, Smith G. Does the opioid-sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient? Br J Anaesth
2. Ng A, Smith G, Davidson AC. Analgesic effects of parecoxib following total abdominal hysterectomy. Br J Anaesth
3. Ng A, Swami A, Smith G, Davidson AC, Emembolu J. The analgesic effects of intraperitoneal and incisional bupivacaine with epinephrine after total abdominal hysterectomy. Anesth Analg
4. Pasqualucci A, de Angelis V, Contardo R, et al.
Preemptive analgesia: intraperitoneal local anesthetic in laparoscopic cholecystectomy. A randomized, double-blind, placebo-controlled study. Anesthesiology
5. Elhakim M, Elkott M, Ali NM, Tahoun HM. Intraperitoneal lidocaine for postoperative pain after laparoscopy. Acta Anaesthesiol Scand
6. Gharaibeh KI, Al-Jaberi TM. Bupivacaine instillation into gallbladder bed after laparoscopic cholecystectomy: does it decrease shoulder pain? J Laparo Endosc Adv Surg Tech A
7. Ng A, Smith G. Intraperitoneal analgesia. Is it of any utility? Br J Anaesth
8. Raetzell M, Maier C, Schroder D, Wulf H. Intraperitoneal application of bupivacaine during laparoscopic cholecystectomy - risk or benefit? Anesth Analg
9. Scheinin B, Kellokumpu I, Lindgren L, Haglund C, Rosenberg PH. Effect of intraperitoneal bupivacaine on pain after laparoscopic cholecystectomy. Acta Anaesthesiol Scand
10. Joris J, Thiry E, Paris P, Weerts J, Lamy M. Pain after laparoscopic cholecystectomy: characteristics and effect of intraperitoneal bupivacaine. Anesth Analg
11. Elfberg BA, Sjovall-Mjoberg S. Intraperitoneal bupivacaine does not effectively reduce pain after laparoscopic cholecystectomy: a randomized, placebo-controlled and double-blind study. Surg Laparosc Endosc Percutan Tech
12. Zmora O, Stolik-Dollberg O, Bar-Zakai B, et al.
Intraperitoneal bupivacaine does not attenuate pain following laparoscopic cholecystectomy. J Soc Laparoendoscopic Surg
13. Moiniche S, Jorgensen H, Wetterslev J, Dahl JB. Local anesthetic infiltration for postoperative pain after laparoscopy: a qualitative and quantitative systematic review of intraperitoneal, port-site infiltration and mesosalpinx block. Anesth Analg
14. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology
15. Tucker GT. Chiral switches. Lancet
16. Chang DH, Ladd LA, Wilson KA, Gelgor L, Mather LE. Tolerability of large-dose intravenous levobupivacaine in sheep. Anesth Analg
17. Nancarrow C, Rutten AJ, Runciman WB, et al.
Myocardial and cerebral drug concentrations and the mechanisms of death after intravenous doses of lidocaine, bupivacaine, and ropivacaine in the sheep. Anesth Analg
18. Huang YF, Pryor ME, Mather LE, Veering BT. Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesth Analg
19. Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol
20. Kopacz DJ, Allen HW. Accidental intravenous levobupivacaine. Anesth Analg
21. Crews JC, Rothman TE. Seizure after levobupivacaine for interscalene brachial plexus block. Anesth Analg
22. Pirotta D, Sprigge J. Convulsions following axillary brachial plexus blockade with levobupivacaine. Anaesthesia
23. Breslin DS, Martin G, Macleod DB, D'ercole F, Grant SA. Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: a report of two cases. Reg Anesth Pain Med
24. Department of Health. In: Day Surgery: Operational Guide.
London, UK: Department of Health Publications, 2002: 23.
25. Fujii Y, Toyooka H, Tanaka H. Efficacy of thoracic epidural analgesia following laparoscopic cholecystectomy. Eur J Anaesthesiol
26. Jorgensen JO, Gillies RB, Hunt DR, Caplehorn JR, Lumley T. A simple and effective way to reduce postoperative pain after laparoscopic cholecystectomy. Aust NZ J Surg