British Journal of Anaesthesia 94 (3): (2005) doi: /bja/aei056 Advance Access publication December 24, 2004

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1 British Journal of Anaesthesia 94 (3): (2005) doi: /bja/aei056 Advance Access publication December 24, 2004 PAIN The preoperative administration of ketoprofen improves analgesia after laparoscopic cholecystectomy in comparison with propacetamol or postoperative ketoprofen G. Boccara 1 *, A. Chaumeron 2, Y. Pouzeratte 2 and C. Mann 2 1 Department of Anaesthesiology and Critical Care, Hospital Saint-Joseph, Paris, France. 2 Department of Anaesthesiology and Critical Care, Hospital Saint-Eloi, Montpellier, France *Corresponding author: Département d Anesthésie-Réanimation, Hôpital Saint-Joseph, 185 Rue Raymond Losserand, Paris Cedex 14, France. gboccara@hopital-saint-joseph.org Background. Non-opioid analgesics, paracetamol and non-steroid anti-inflammatory drugs (NSAIDs) are proposed for pain relief after laparoscopy. We compared perioperative propacetamol (P) and ketoprofen (K) to provide analgesia after laparoscopic cholecystectomy. Methods. After ethical committee approval, we included 104 ASA I II patients, without preoperative analgesic drugs, who were scheduled to undergo laparoscopic cholecystectomy. Anaesthesia was standardized using propofol, fentanyl, atracurium, isoflurane and N 2 O 50%. Ketoprofen 100 mg or propacetamol 2 g or a saline drip (a 100-ml unit of saline in 10 min) was infused blindly and randomly. Patients received either ketoprofen (group ) or propacetamol (group ) before induction of anaesthesia and saline after surgery, or saline before surgery and ketoprofen (group ) or propacetamol (group ) after surgery. Postoperative visual analogue pain scores (VAS mm) were recorded during 24 h. If VAS was >30, a second dose (placebo, ketoprofen or propacetamol) was infused. Nalbuphine 0.2 mg kg 1 i.v. was given as rescue analgesic if VAS was >50. Results. Ninety-eight patients were studied The number of patients not requiring the second analgesic was greater in (33.5%) than the others ( 0%, 0%, 7.5%). VAS scores were significantly lower in (P=0.001), with less nalbuphine consumption compared with. VAS and opioid request were similar in and. Conclusion. Preoperative administration of ketoprofen improves postoperative analgesia after laparoscopic cholecystectomy compared with its postoperative administration and preand postoperative propacetamol. Br J Anaesth 2005; 94: Keywords: anaesthesia, general; analgesia, postoperative; analgesia, pre-emptive; analgesics non-opioid, ketoprofen; analgesics non-opioid, propacetamol; surgery, laparoscopic cholecystectomy Accepted for publication: November 8, 2004 Laparoscopic cholecystectomy can cause intense postoperative pain; 12 it may be worse than that after subcostal laparotomy. 3 Such pain justifies the use of opioids, making outpatient surgery difficult. A solution could be found with a more rational use of non-opioid analgesics; for example, paracetamol or non-steroid anti-inflammatory drugs (NSAIDs). Administration of NSAIDs has been reported to be associated with a reduced opioid requirement and improved pain relief after laparoscopic surgery 45 and laparoscopic cholecystectomy. 67 Ketoprofen, a phenylpropionic acid derivative NSAID, inhibits nociceptive transmission through blockage of the cyclooxygenase pathway in both damaged tissue and spinal neurons. 8 In patients undergoing minor or medium surgery, preoperative administration of NSAIDs would appear to be more effective than postoperative administration. 9 However, the possible pre-emptive analgesic effect of NSAIDs is currently being debated. Propacetamol, an injectable prodrug of paracetamol, is an effective non-opioid analgesic. After i.v. administration, # The Board of Management and Trustees of the British Journal of Anaesthesia All rights reserved. For Permissions, please journal.permissions@oupjournals.org

2 Boccara et al. propacetamol is rapidly hydrolysed by non-specific plasma esterases to paracetamol and therefore inhibits the cyclooxygenase pathway at the central level The use of propacetamol has made it possible to reduce morphine consumption in both orthopaedic 14 and gynaecological 15 surgery. To our knowledge, no previous controlled study has assessed the effects of paracetamol in patients after laparoscopic surgery. We therefore performed a prospective, double-blinded, randomized and controlled study in patients undergoing laparoscopic cholecystectomy. Our objectives were: (i) to compare the efficacy of propacetamol and ketoprofen on pain and their opioid-sparing effect; (ii) to determine the optimal preoperative or postoperative administration time for each analgesic; and (iii) to evaluate the tolerance for each of these agents. Materials and methods The study was conducted in accordance with the ethical principles of the current amended version of the Declaration of Helsinki, and approved by the Montpellier Hospital Ethical Committee. Patients aged yr, scheduled for laparoscopic cholecystectomy and with ASA physical status I or II, were eligible. Patients were excluded if they had any history of allergy to paracetamol, NSAIDs or opioids, if they had a history of severe hepatic, renal, gastric or coagulative diseases, or if they had received analgesic drugs within 2 weeks before surgery. All patients gave written informed consent the day before surgery. After oral premedication with hydroxyzine 100 mg and alprazolam 0.5 mg, general anaesthesia was induced with propofol 2 3 mg kg 1 and fentanyl 3 mg kg 1. Tracheal intubation was facilitated by atracurium 0.5 mg kg 1. All patients were mechanically ventilated with an equal mixture of oxygen and nitrous oxide. Mechanical ventilation parameters were adjusted to obtain end-tidal carbon dioxide pressure in the mmhg range. Anaesthesia was maintained with isoflurane MAC and fentanyl 1 mgkg 1 according to 20% variations in blood pressure and/or heart rate compared with basal values, or if there was lacrimation. Laparoscopy was performed after intraperitoneal insufflation of carbon dioxide with an intra-abdominal pressure that was automatically maintained constant at 14 mmhg. Patients were warmed to approximately 36 C. Perioperative analgesic management was performed with an i.v. infusion of ketoprofen 100 mg or propacetamol 2 g (yields 1 g of paracetamol) or a saline drip (a 100-ml unit of saline in 10 min). The first unit was administered on induction of anaesthesia and the second after surgery using a pain visual analogue scale (VAS). Patients were randomly assigned to one of four treatment groups. In group, ketoprofen was administered before induction and saline after surgery. In group, saline was administered before induction and ketoprofen after surgery. In group, propacetamol was administered before induction and saline after surgery. In group, saline was administered before induction and propacetamol after surgery. All medicines were prepared by a nurse who had no other involvement in the study. None of the patients, managing anaesthetists or nurses were aware of the randomization code. In the postanaesthesia care unit (PACU) and surgical ward, pain was evaluated every hour and each time that the patient complained of pain over a period of 12 h and at 24 h, using a VAS score that ranged from 0 (no pain) to 100 mm (maximum pain). The scale was explained to the patient during the pre-anaesthesia consultation. In case of a VAS score >30 mm, a second dose was administered. If the VAS score was >50 mm after 30 min, nalbuphine was administered at a dose of 0.2 mg kg 1 and was repeated every hour as long as the VAS score remained >50 mm. The definitions of postoperative moderate pain and severe pain were a VAS score of >30 and >50 mm respectively. At the same time, patient sedation was assessed using a sedation scale (wide awake=0; mildly sleepy and responsive to verbal command=1; moderately sleepy and responsive to nociceptive stimulation=2, extremely sleepy and unrousable to nociceptive stimulation=3). The patients were asked about nausea and vomiting (yes or no). During the first 24 h, parenteral analgesia was continued with propacetamol 2 g and ketoprofen 100 mg per 8 h. Nalbuphine 0.2 mg kg 1 was administered if the VAS score was >50 mm. A five-item overall satisfaction questionnaire according to postoperative analgesia (1=very dissatisfied; 2=somewhat dissatisfied; 3=somewhat satisfied; 4=satisfied; 5=very satisfied) was administered to all patients at discharge. Two efficacy variables, pain intensity during the first 12-h postoperative period and nalbuphine consumption required during the first 24-h period, were selected to decide whether groups,, and had significantly different behaviour with respect to postoperative analgesia. Safety and tolerability were evaluated by reporting adverse events (nausea, vomiting, gastralgia, bleeding and anaphylactic reactions). However, the main end-point was the time to the first analgesia demand, defined as the period between the end of surgery to the first VAS score >30 mm during the postoperative 24 h. We calculated that 25 patients in each group would be necessary for the assessment of a 30% increase in the time to the first analgesia demand with an a risk of 0.05 and a b risk of Allocation to treatment groups was performed using a computer-generated random list. Continuous data are presented as mean (SD) or median (25 75th percentiles) when data were not normally distributed. Categorical variables are presented as frequencies (percentages of patients). Preoperative patient characteristics, perioperative and postoperative data in the four groups were compared using the x 2 test for categorical variables and Wilcoxon s rank sum test for continuous variables. Postoperative assessment for all variables measured over time were evaluated using repeated measures analysis 348

3 Ketoprofen propacetamol laparoscopy (Friedman s two-way non-parametric analysis of variance) using SAS (version 6.12, SAS Institute, Cary, NC, USA). A value of P<0.05 was considered statistically significant. Results A total of 104 patients who underwent scheduled laparoscopic cholecystectomy in our institution over a period of 18 months were included. Six patients were excluded from postoperative data analysis because four needed intraoperative laparotomy (one in, one in and two in ) and two for incomplete data (one in and one in ). The four groups of patients were similar with respect to weight, age, sex, surgical time and fentanyl consumption (Table 1). For postoperative pain intensity (VAS), ketoprofen infused before anaesthesia () provided significantly better pain relief (P=0.001; Fig. 1) than ketoprofen after surgery () and propacetamol ( and ), especially during the 3 postoperative hours. Patients in group had lower VAS Table 1 Patient and surgical characteristics. No significant differences. Data are mean (range) or mean (SD) Age (yr) 45.9 (20 70) 44.1 (19 70) 48.4 (19 70) 52.1 (25 70) Weight (kg) 71.0 (10.9) 67.3 (15.9) 65.9 (15.7) 67.0 (10.4) Sex ratio (F/M) 13/11 19/5 17/7 17/9 ASA I/II 19/5 19/5 18/6 20/6 Surgical time (min) 100 (28) 91 (24) 91 (25) 104 (28) Fentanyl dose (mg) 536 (142) 503 (140) 511 (111) 533 (97) than patients from during the H2 H5 period, but there was no difference between the postoperative analgesic infusion groups ( and ). In Table 2, patients were assigned to three levels of pain intensity according to no or slight pain (VAS <30, pain-free patients), moderate pain (VAS >30) successfully treated by the second infusion, and significant pain (VAS >50 mm) requiring nalbuphine. The percentage of pain-free patients during the postoperative 24 h was significantly greater in group (33.5%) than in the three other groups ( 0%, 0%, 7.5%) (Table 2). Among the patients requiring postoperative analgesia, time to first demand was longer in Table 2 Postoperative pain relief. Percentage of patients requiring postoperative analgesic (second dose) and nalbuphine for rescue, time to first analgesic demand (second dose) and for nalbuphine, and cumulative dose of nalbuphine in 8 h and 24 h after operation. Values are numbers (percentages) of patients, mean (SD)or mean (95% confidence interval). *P<0.05 corresponds to a significant difference. **Corresponds to a significant difference with and. Corresponds to a significant difference with only No. of pain-free patients 8* (33.5) 0 (0) 0 (0) 2 (7.5) during 24 h: n (%) Moderate pain (30<VAS<50) No. of patients: n (%) 7 (29) 12 (50) 6 (25) 13 (50) Time to complaint (min) 115 (40)* 48 (21) 65 (21) 69 (37) Severe pain (VAS>50) No. of patients: n (%) 9** (37.5) 12 (50) 18 (75) 11 (42.5) Time to complaint (min) 240 (47)* 82 (29) 140 (50) 130 (35) (95% confidence interval) 8 h nalbuphine dose (mg) 7 (8) 7 (8) 14 (12)* 8 (9) 24 h nalbuphine dose (mg) 17 (7) 17 (10) 15 (14) 24 (18) 70 VAS (0-100 mm) Postoperative time (h) 24 Fig 1 VAS scores (0 100 mm) during the postoperative period in each group (mean and SD). *P<0.05 corresponded to a significant difference between and other groups. 349

4 Boccara et al. Patients requiring nalbuphine (%) Postoperative times (h) Fig 2 Percentage of patients receiving nalbuphine in the postoperative period, when the VAS was >50 (VAS scale mm). Ketoprofen administered before induction of anaesthesia decreased the number of patients with high pain intensity and nalbuphine requirement in the postoperative 4 and 8 h compared with the preoperative propacetamol group (*P<0.05). Table 3 Side-effects in the postoperative period. P<0.05 corresponds to a significant difference compared with * and ** No. of patients with nausea or vomiting episode: n (%) No. of patients with sedation score 2: n (%) Satisfied patients (scores 4 and 5): n (%) patients from the group (Table 2). Ketoprofen perfused before induction of anaesthesia () significantly decreased the rate of patients having high pain intensity and nalbuphine requirement in the postoperative 4 and 8 h compared with group (Fig. 2). The total dose of nalbuphine was comparable between the four groups, but the time to first analgesic demand was greater in group than in (Table 2). Sedation scores were similar in all groups (Table 3). The number of satisfied patients (4 or 5) concerning postoperative analgesia was higher in group than in the other groups (Table 3). Twice as many patients experienced postoperative emesis in group than in group. Discussion We have shown that pain following laparoscopic cholecystectomy was better relieved by preoperative administration of ketoprofen than by postoperative administration of ketoprofen or by the use of propacetamol both pre- and postoperatively. 5* (21) 8 (33) 7 (29) 13 (50) 3 (12) 3 (12) 4 (16) 4 (15) 23** (96) 20 (83) 15 (65) 19 (73) The authors of studies on the pre-emptive analgesic effects of NSAIDs have reported contradictory results, although its clinical and experimental existence has been established Beneficial effects have been reported with ketorolac in orthopaedic surgery 9 and with ketoprofen during laparoscopic tubal ligation. 19 In contrast, other authors have reported no benefit for preoperative administration of NSAIDs on postoperative analgesia with ketorolac or diclofenac after orthopaedic or laparoscopic gynaecological surgery In the present study, preoperative administration of ketoprofen relieved pain after laparoscopic cholecystectomy more effectively than postoperative administration. This positive result recorded during the first 12 postoperative hours explains the greater proportion of patients who were very satisfied. However, this beneficial effect would appear to wear off after this period since the accumulated consumption of nalbuphine was similar for both means of administration at the 8th and the 24th hour. According to McQuay and Kissin, any discussion of preventive analgesia requires that (i) the agent under study be compared with a placebo and with the same agent at similar postoperative doses; (ii) postoperative administration of analgesic be strictly systematized or controlled by the patient; and (iii) postoperative analgesic efficacy be greatly prolonged after the expected pharmacodynamic effect According to the McQuay and Kissin criteria, it is therefore impossible to report a real pre-emptive effect in the present study as it could be due to the synergy of the NSAIDs and the perioperative opioids. The analgesic efficacy of propacetamol was comparable to that of ketoprofen. This result confirmed those of Varrassi et al. in gynaecological surgery, where there was a 30% reduction in the postoperative use of both propacetamol and ketorolac. 15 On the other hand, our study showed that, contrary to ketoprofen, there was no advantage in using propacetamol preoperatively. In fact, in this case, although the postoperative pain scores were not different, we noted that nalbuphine consumption doubled (14 vs 7mg at the 8th hour). Propacetamol therefore presented no pre-emptive analgesic effect and its effect had worn off 6 h after injection. Gustafsson and colleagues made the same observations after maxillofacial surgery In contrast to chronic use, ketoprofen or other NSAIDs in recommended doses do not seem to lead to gastrointestinal or haemorrhagic complications However, Rogers and colleagues found that intraoperative median blood loss in patients receiving ketorolac before laparoscopic gynaecological surgery exceeded that of patients who received it after surgery. 28 The potential side-effects of anaphylactic or toxic reactions (e.g. bronchospasm, renal function impairment) must not be ignored. 25 For propacetamol, its absence of effects on the peripheral cyclooxygenase pathways explains why it is better tolerated than NSAIDs, with the exception of anaphylactic reactions. None of these side-effects was observed in the present study. However, it is difficult to draw conclusions, given the 350

5 Ketoprofen propacetamol laparoscopy small population. It should also be noted the preoperative administration of ketoprofen was accompanied by a lower incidence of nausea and vomiting, which was probably linked to the lower consumption of nalbuphine and better pain control. Acknowledgement The authors greatly appreciate the contribution of statistician Christine Vergnes of the University Hospital of Montpellier. References 1 Joris J, Thiry E, Paris P, et al. Pain after laparoscopic cholecystectomy: characteristics and effect of intraperitoneal bupivacaine. Anesth Analg 1995; 81: Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth Analg 1996; 82: Narchi P, Benhamou D, Fernandez H. Intraperitoneal local anesthetics and scapular pain following daycase laparoscopy. Lancet 1991; 338: Gillberg LE, Harsten AS, Stahl LB. Preoperative diclofenac sodium reduces post-laparoscopy pain. Can J Anaesth 1993; 40: Hovorka J, Kallela H, Korttila K. Effect of intravenous diclofenac on pain and recovery profile after day-case laparoscopy. Eur J Anaesth 1993; 10: Fredman B, Olsfanger D, Jedeikin R. A comparative study of ketorolac and diclofenac on post-laparoscopic cholecystectomy pain. Eur J Anaesth 1995; 12: Fredman B, Jedeikin R, Olsfanger D, Flor P, Gruzman A. Residual pneumoperitoneum: a cause of postoperative pain after laparoscopic cholecystectomy. Anesth Analg 1994; 79: Bjorkman R. Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat. Acta Anaesthesiol Scand Suppl 1995; 103: Fletcher D. Pre-emptive analgesia. Ann Fr Anesth Réanim 1998; 17: Dahl JB, Kehlet H. The value of pre-emptive analgesia in the treatment of postoperative pain. Br J Anaesth 1993; 70: Katz J, Kavanagh B, Sandler A, et al. Preemptive analgesia. Clinical evidence of neuroplasticity contributing to postoperative pain. Anesthesiology 1992; 77: Bannwarth B, Netter P, Lapicque F, et al. Plasma and cerebrospinal fluid concentrations of paracetamol after single intravenous dose of propacetamol. Br J Clin Pharmacol 1992; 34: Piletta P, Porchet HC, Dayer P. Central analgesic effect of acetaminophen but not aspirin. Clin Pharmacol Ther 1991; 49: Peduto VA and the Italian Collaborative group on Propacetamol, Ballabio M, Stefanini S. Efficacy of propacetamol in the treatment of postoperative pain. Morphine-sparing effect in orthopedic surgery. Acta Anaesthesiol Scand 1998; 42: Varrassi G, Mainangeli F, Agro F, et al. A double-blinded evaluation of propacetamol versus ketorolac in combination with patientcontrolled analgesia morphine: analgesic efficacy and tolerability after gynecologic surgery. Anesth Analg 1999; 88: Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52: Wall PD. The prevention of postoperative pain. Pain 1988; 33: Woolf CJ, Chong M. Pre-emptive analgesia treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993; 77: Eriksson H. Effect of intravenous ketoprofen on pain after outpatient laparoscopic sterilisation. Acta Anaesthesiol Scand 1995; 39: Buggy DJ, Wall C, Carton EG. Preoperative or postoperative diclofenac for laparoscopic tubal ligation. Br J Anaesth 1994; 73: Vanlersberghe C, Lauwers MH, Camus F. Preoperative ketorolac administration has no preemptive analgesic effect for minor orthopaedic surgery. Acta Anaesthesiol Scand 1996; 40: Kissin I. Preemptive analgesia, why its effect is not always obvious. Anesthesiology 1996; 84: McQuay HJ. Pre-emptive analgesia [editorial]. Br J Anaesth 1992; 69: Gustafsson I, Nystrom E, Quiding H. Effect of preoperative paracetamol on pain after oral surgery. Eur J Clin Pharmacol 1983; 24: Benhamou D, Bouaziz H, Zerrouk N, Préaux N. Audit of ketoprofen prescribing after orthopedic and general surgery. Can J Anaesth 1999; 46: Dahl JB, Kehlet H. Non steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth 1991; 66: Rorarius MG, Baer GA. Non-steroidal anti-inflammatory drugs for postoperative pain relief. Curr Opin Anaesth 1994; 7: Rogers JE, Fleming BG, Macintosh KC, et al. Effect of timing of ketorolac administration on patient-controlled opioid use. Br J Anaesth 1995; 75: