The preoperative administration of ketoprofen improves analgesia after laparoscopic cholecystectomy in comparison with propacetamol or postoperative ketoprofen

G. Boccara1,*, A. Chaumeron2, Y. Pouzeratte2 and C. Mann2

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, 75674 Paris Cedex 14, France. E-mail: gboccara{at}hopital-saint-joseph.org

Accepted for publication November 8, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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 N2O 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 K1) or propacetamol (group P1) before induction of anaesthesia and saline after surgery, or saline before surgery and ketoprofen (group K2) or propacetamol (group P2) after surgery. Postoperative visual analogue pain scores (VAS 0–100 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 K1 (33.5%) than the others (K2 0%, P1 0%, P2 7.5%). VAS scores were significantly lower in K1 (P=0.001), with less nalbuphine consumption compared with P1. VAS and opioid request were similar in K2 and P2.

Conclusion. Preoperative administration of ketoprofen improves postoperative analgesia after laparoscopic cholecystectomy compared with its postoperative administration and pre- and postoperative propacetamol.

Keywords: anaesthesia, general ; analgesia, postoperative ; analgesia, pre-emptive ; analgesics non-opioid, ketoprofen ; analgesics non-opioid, propacetamol ; surgery, laparoscopic cholecystectomy


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Laparoscopic cholecystectomy can cause intense postoperative pain;1 2 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 surgery4 5 and laparoscopic cholecystectomy.6 7 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.10 11

Propacetamol, an injectable prodrug of paracetamol, is an effective non-opioid analgesic. After i.v. administration, propacetamol is rapidly hydrolysed by non-specific plasma esterases to paracetamol and therefore inhibits the cyclooxygenase pathway at the central level.12 13 The use of propacetamol has made it possible to reduce morphine consumption in both orthopaedic14 and gynaecological15 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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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 18–70 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 µg 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 28–34 mmHg range. Anaesthesia was maintained with isoflurane 0.8–1.2 MAC and fentanyl 1 µg kg–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 K1, ketoprofen was administered before induction and saline after surgery. In group K2, saline was administered before induction and ketoprofen after surgery. In group P1, propacetamol was administered before induction and saline after surgery. In group P2, 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 K1, K2, P1 and P2 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 {alpha} risk of 0.05 and a ß risk of 0.20. 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 {chi}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 (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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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 K1, one in K2 and two in P1) and two for incomplete data (one in K1 and one in K2). The four groups of patients were similar with respect to weight, age, sex, surgical time and fentanyl consumption (Table 1).


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Table 1 Patient and surgical characteristics. No significant differences. Data are mean (range) or mean (SD)

 
For postoperative pain intensity (VAS), ketoprofen infused before anaesthesia (K1) provided significantly better pain relief (P=0.001; Fig. 1) than ketoprofen after surgery (K2) and propacetamol (P1 and P2), especially during the 3 postoperative hours. Patients in group P2 had lower VAS than patients from P1 during the H2–H5 period, but there was no difference between the postoperative analgesic infusion groups (K2 and P2).



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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 K1 and other groups.

 
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 K1 (33.5%) than in the three other groups (K2 0%, P1 0%, P2 7.5%) (Table 2). Among the patients requiring postoperative analgesia, time to first demand was longer in patients from the group K1 (Table 2).


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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).

 
Ketoprofen perfused before induction of anaesthesia (K1) significantly decreased the rate of patients having high pain intensity and nalbuphine requirement in the postoperative 4 and 8 h compared with group P1 (Fig. 2). The total dose of nalbuphine was comparable between the four groups, but the time to first analgesic demand was greater in group K1 than in K2 (Table 2).



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Fig 2 Percentage of patients receiving nalbuphine in the postoperative period, when the VAS was ≥50 (VAS scale 0–100 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).

 
Sedation scores were similar in all groups (Table 3). The number of satisfied patients (4 or 5) concerning postoperative analgesia was higher in group K1 than in the other groups (Table 3). Twice as many patients experienced postoperative emesis in group P2 than in group K1.


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Table 3 Side-effects in the postoperative period. P<0.05 corresponds to a significant difference compared with P2* and P1**

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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.

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.1618 Beneficial effects have been reported with ketorolac in orthopaedic surgery9 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.20 21 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.22 23 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 7 mg 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.24

In contrast to chronic use, ketoprofen25 26 or other NSAIDs in recommended doses do not seem to lead to gastrointestinal or haemorrhagic complications.15 27 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 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.


    Acknowledgments
 
The authors greatly appreciate the contribution of statistician Christine Vergnes of the University Hospital of Montpellier.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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15 Varrassi G, Mainangeli F, Agro F, et al. A double-blinded evaluation of propacetamol versus ketorolac in combination with patient-controlled analgesia morphine: analgesic efficacy and tolerability after gynecologic surgery. Anesth Analg 1999; 88: 611–6[Abstract/Free Full Text]

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20 Buggy DJ, Wall C, Carton EG. Preoperative or postoperative diclofenac for laparoscopic tubal ligation. Br J Anaesth 1994; 73: 767–70[Abstract]

21 Vanlersberghe C, Lauwers MH, Camus F. Preoperative ketorolac administration has no preemptive analgesic effect for minor orthopaedic surgery. Acta Anaesthesiol Scand 1996; 40: 948–52[ISI][Medline]

22 Kissin I. Preemptive analgesia, why its effect is not always obvious. Anesthesiology 1996; 84: 1015–9[CrossRef][ISI][Medline]

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28 Rogers JE, Fleming BG, Macintosh KC, et al. Effect of timing of ketorolac administration on patient-controlled opioid use. Br J Anaesth 1995; 75: 15–8[Abstract/Free Full Text]





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