Balanced analgesia with propacetamol associated with non-steroidal anti-inflammatory drugs (NSAIDs) is commonly used in the postoperative period . Ketoprofen has a central and peripheral action, by blockade of prostaglandin synthesis. Propacetamol is an intravenous (i.v.) pro-drug of paracetamol and has been recommended for postoperative analgesia, either as monotherapy or in combination with other analgesics . A synergistic effect of propacetamol and NSAIDs with opioids has often been described as an opioid sparing effect [3,4]. However, combinations of non-opioid analgesics, although widely used, has poorly been studied [5,6] and there is a lack of consensus on whether such combinations are useful. Each of these non-opioid analgesics may have its own synergistic effect with the opioid. Thus, the benefit of a combination of an NSAID and propacetamol will be difficult to assess when a residual effect of the opioid which that was used during surgery is still present in the postoperative period. In addition, any potential benefit may be attenuated by the remaining postoperative analgesic effect of the opioid, especially if the surgery is not very painful. To avoid a residual effect of the opioid, we have performed surgery with a remifentanil regimen. Thus, the aim of our study was to evaluate the analgesic efficacy of propacetamol alone, ketoprofen alone and their combination after thyroid surgery performed under general anaesthesia with remifentanil.
Materials and methods
After institutional Ethics Committee approval, and written informed consent from all participating subjects, 97 adults undergoing subtotal or total thyroidectomy were included in this prospective randomized, double-blinded study. Exclusion criteria were age beyond 80 yr and contraindication to NSAIDs or propacetamol.
Patients were premedicated the previous evening and again 2 h before surgery with an oral combination of hydroxyzine (1 mg kg−1) and alprazolam (0.5 mg). General anaesthesia was induced with propofol (2.5 mg kg−1) and an infusion of remifentanil (0.5 μg kg−1 min−1) started. Orotracheal intubation was performed without muscle relaxant. Anaesthesia was maintained with remifentanil (0.2 μg kg−1min−1) and with a mixture of oxygen (O2)/nitrous oxide (N2O) (50%/50%) with isoflurane (one minimum alveolar concentration (MAC) end-tidal), and stopped when as the neck dressings had been applied at the end of surgery. Extubation was performed in the operating theatre. All patients were kept 2 h in the recovery room and were then transferred to the ward.
After induction, patients were randomly allocated to one of the three groups: propacetamol 2 g, ketoprofen 100 mg, or propacetamol 2 g + ketoprofen 100 mg. Analgesics were infused i.v. in a 5% 100 mL glucose solution within 15 min by an anaesthetist 30 min before the end of surgery. A second and a third identical infusion was given at 6 and 12 h after the first infusion.
Postoperative pain was evaluated using a visual analogical scale (VAS) ranging from 0 (no pain) to 100 (worst possible pain). In addition, the number of patients who required a dose of rescue analgesic drug (tramadol 100 mg) was recorded. The two variables were recorded 1 and 2 h after arrival in the recovery room, and then 2 h after each infusion on the ward (i.e. 8 and 14 h after the end of the surgery).
Tramadol (100 mg) was administered i.v. to the patients when the VAS was >40 mm. The VAS was evaluated every 10 min in the recovery room, and 2 h after each analgesic infusion on the ward.
To maintain the double-blind status, the three analgesic regimens were infused in 5% 100 mL glucose without any identification, and patients and observers were not aware of the preparation. Randomization was performed and the first infusion given by an anaesthetist in the operating room. Pain was evaluated by a nurse in the recovery room and by a second anaesthetist on the ward; observers were not aware of group assignment.
All adverse effects were noted (e.g. nausea, vomiting and headache). Patients' satisfaction was evaluated the day after surgery using a 5-point verbal score (0: poor; 1: moderate; 2: good; 3: very good; 4: perfect).
Data were compared using analysis of variance (ANOVA) and were expressed as means ± standard deviation (SD). The difference between groups was assessed using the Scheffé's post hoc test. The difference in tramadol requirement was analysed with a Kaplan-Meier graph and a Logrank test with a Bonferoni's correction. Significant P values are <0.05.
Ninety-seven patients were included, 32 had propacetamol alone, 33 ketoprofen alone, and 32 received propacetamol plus ketoprofen. Groups were similar with respect to age (46 ± 11, 47 ± 12, 46 ± 12 yr, respectively), and gender ratio (M : F 5 : 27, 4 : 29, 4 : 28, respectively).
One hour after surgery, pain scores were high (>30 mm) in all three groups and without differences between groups (Table 1). Two hours after surgery, pain scores were significantly higher with propacetamol compared with ketoprofen (P < 0.01). However, no significant difference was found between ketoprofen alone and ketoprofen plus propacetamol. The average pain score was <30 mm with no difference between groups on the 8 and 14 h after surgery. The number of patients at each time point who had less than moderate pain (VAS < 30 mm) is reported in Table 1.
One hour after surgery, 20 patients had received tramadol. The number of patients requiring tramadol was significantly higher (P < 0.01) with propacetamol compared with the two other groups (14/32, 4/33, 2/32, respectively). Two hours after surgery, 38 patients had received tramadol (24/32, 6/33, 8/32, respectively; P < 0.01). Ten patients needed additional tramadol, and no differences were found between groups on 8 and 14 h.
The number of patients who did not require tramadol over time was significantly lower with ketoprofen and ketoprofen plus propacetamol compared with propacetamol alone (P < 0.01) (Fig. 1).
Satisfaction was similar between groups for the 76 patients who responded (Table 2). Adverse effects were rare. Nausea or vomiting occurred in eight patients with propacetamol (seven of those had received tramadol) and in one with ketoprofen. Headache was observed in two patients with propacetamol (both had received tramadol), in one patient with ketoprofen, and in one with ketoprofen plus propacetamol. No significant differences were found between the groups.
Our results show that during the first 2 h after thyroid surgery performed under general anaesthesia with remifentanil, an NSAID alone (ketoprofen 100 mg) is more effective for pain relief than a single infusion of propacetamol (2 g). The combination of propacetamol with ketoprofen does not improve analgesia compared with ketoprofen alone. Differences in pain scores were significant 2 h after surgery and the number of patients who required tramadol was significantly higher when propacetamol was used alone.
Only 22% of the patients who received ketoprofen with or without propacetamol required tramadol. This result is in accordance with our knowledge on the analgesic properties of NSAIDs . For the same type of surgery, ketoprofen, when compared with paracetamol, has shown efficacy by decreasing pain intensity and morphine consumption . NSAIDs have been shown to be as potent as opioids in adults and in children for dental or major surgery [1,7,8]. In our study, tramadol consumption was higher with propacetamol compared with ketoprofen. The difference in pain score values was probably minimized by tramadol administration as the scale reflects analgesia due to the propacetamol infusion associated with tramadol. Thus, despite an increased consumption of tramadol in those who were randomized to propacetamol (78% of those who received propacetamol required tramadol vs. 22% with ketoprofen), the differences in pain score remained significant between the propacetamol group and the two other groups. This result emphasizes the high analgesic potency of ketoprofen and confirms that it provides better analgesia than propacetamol for post-thyroidectomy analgesia.
Despite complementary tramadol in 75% of the patients, pain remained high 2 h after surgery when propacetamol was used alone. This result is in agreement with other authors who have shown less analgesic potency of propacetamol compared with NSAIDs [5,9-11] and insufficient pain relief [6,11,12]. However, the effect of paracetamol when compared with placebo has been demonstrated . Paracetamol has been described as a highly effective drug for postoperative analgesia  and as potent as NSAIDs after trauma surgery . The different nociceptive mechanisms involved in pain could account for such differences. Also, the poor efficacy of propacetamol during the first 2 h after surgery could be explained by other conditions of our study. For instance, plasma levels of paracetamol may not have been sufficient since the end of the infusion was only 15 min before the end of surgery and a single infusion of 2 g only was given.
Finally, it is interesting to note that eight of nine patients who presented with nausea and vomiting received propacetamol without ketoprofen, and seven of those had received tramadol. As 78% of the patients in the propacetamol group received tramadol, the increased number of patients with adverse effects may be related to the use of tramadol.
The combination of propacetamol and ketoprofen did not show any clinically relevant additional analgesic effect compared with ketoprofen alone. No difference was found in pain scores or the number of patients who received tramadol. The difference in sites of action of each drug suggests a potential benefit of a combination [2,5,15]. However, although the superiority of a paracetamol-NSAID combination compared with paracetamol alone has been shown, the superiority of the combination when compared with NSAID alone needs more investigation [16-19]. As noted in a recent review article , few studies have focused on paracetamol-NSAID vs. NSAID alone, and any beneficial effect of adding paracetamol to NSAID needs to be confirmed. Across studies, different NSAIDs have been tested and their analgesic properties are not equivalent [9,20,21]. Also, route and time of administration are variable (oral, rectal, i.v.; pre-, peri-, postoperative) [9,13]. Pain relief may be dependent on surgery and the absence of a clinical benefit of the association of propacetamol and ketoprofen, observed after thyroidectomy, needs to be tested for other operations.
Different studies have compared morphine consumption in patients receiving paracetamol, NSAID alone or a combination [17-19,22]. An opioid-sparing effect has been demonstrated with paracetamol [10,11,13,23]. In our study, the postoperative effect of the ketoprofen-propacetamol combination has been evaluated without addition of morphine and without a residual effect of the intraoperative analgesic since we used remifentanil. An additional analgesic effect has been observed in other operations when morphine was used for postoperative pain relief; the benefit of propacetamol may be more important in these cases. Analgesia after thyroidectomy does not require morphine systematically as shown by the pain scores and the tramadol consumption when patients received ketoprofen alone. The combination with propacetamol did not modify this result. A sparing effect of propacetamol and ketoprofen with tramadol could not be excluded but the pain relief was not different between the two groups of patients who received ketoprofen with or without propacetamol. We did not observe acute postoperative pain due to potential opioid tolerance which was after general anaesthesia with remifentanil ; this is probably due to the short length of surgery, though the phenomenon has been described after longer procedures .
In summary, our study shows that after thyroid surgery performed with remifentanil and without morphine for postoperative analgesia, the use of ketoprofen 100 mg is efficient for pain relief. Additional propacetamol does not provide any analgesic improvement.
1. Souter AJ, Fredman B, White PF. Controversies in the perioperative use of nonsteroidal antiinflammatory drugs. Anesth Analg
2. Fletcher D. Analgésie Balancée. In: Conférences d'actualisation, 38ème Congrès de la Société Française d'Anesthésie et de Réanimation
. Paris: Elsevier, 1996: 171-178.
3. Reuben SS, Connelly NR, Steinberg R. Ketorolac as an adjunct to patient-controlled morphine in postoperative
spine surgery patients. Reg Anesth
4. Delbos A, Boccard E. The morphine-sparing effect of propacetamol in orthopedic postoperative pain
. J Pain Symptom Manage
5. Dahl V, Raeder JC. Non-opioid postoperative analgesia
. Acta Anaesthesiol Scand
6. Basto ER, Waintrop C, Mourey FD, Landru JP, Eurin BG, Jacob LP. Intravenous ketoprofen
in thyroid and parathyroid surgery. Anesth Analg
7. Littlejohn IH, Tarling MM, Flynn PJ, Ordman AJ, Aiken A. Post-operative pain
relief in children following extraction of carious deciduous teeth under general anaesthesia: a comparison of nalbuphine and diclofenac. Eur J Anaesthesiol
8. Lieh-Lai MW, Kauffman RE, Uy HG, Danjin M, Simpson PM. A randomized comparison of ketorolac tromethamine and morphine for postoperative analgesia
in critically ill children. Crit Care Med
9. Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol
, NSAIDs or their combination in postoperative pain
management: a qualitative review. Br J Anaesth
10. Rømsing J, Hertel S, Harder A, Rasmussen M. Examination of acetaminophen for outpatient management of postoperative pain
in children. Paediatr Anaesth
11. Verchere E, Grenier B, Mesli A, Siao D, Sesay M, Maurette P. Postoperative pain
management after supratentorial craniotomy. J Neurosurg Anesthesiol
12. Dejonckheere M, Desjeux L, Deneu S, Ewalenko P. Intravenous tramadol
compared to propacetamol for postoperative analgesia
following thyroidectomy. Acta Anaesthesiol Belg
13. Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol
, and paracetamol
in combination with NSAIDs, for postoperative analgesia
. Br J Anaesth
14. Hoogewijs J, Diltoer MW, Hubloue I, et al
. A prospective, open, single blind, randomized study comparing four analgesics in the treatment of peripheral injury in the emergency department. Eur J Emerg Med
15. Fletcher D, Benoist JM, Gautron M, Guilbaud G. Isobolographic analysis of interactions between intravenous morphine, propacetamol, and diclofenac in carrageenin-injected rats. Anesthesiology
16. Sunshine A, Olson NZ, Zighelboim I, De Castro A. Ketoprofen
, acetaminophen plus oxycodone, and acetaminophen in the relief of postoperative pain
. Clin Pharmacol Ther
17. Siddik SM, Aouad MT, Jalbout MI, Rizk LB, Kamar GH, Baraka AS. Diclofenac and/or propacetamol for postoperative pain
management after cesarean delivery in patients receiving patient controlled analgesia
morphine. Reg Anesth Pain Med
18. Morton NS, O'Brien K. Analgesic efficacy of paracetamol
and diclofenac in children receiving PCA morphine. Br J Anaesth
19. Montgomery JE, Sutherland CJ, Kestin IG, Sneyd JR. Morphine consumption in patients receiving rectal paracetamol
and diclofenac alone and in combination. Br J Anaesth
20. Silvanto M, Lappi M, Rosenberg PH. Comparison of the opioid-sparing efficacy of diclofenac and ketoprofen
for 3 days after knee arthroplasty. Acta Anaesthesiol Scand
21. Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain
1992; 44 (Suppl 5)
22. Fletcher D, Negre I, Barbin C, et al
. Postoperative analgesia
with i.v. propacetamol and ketoprofen
combination after disc surgery. Can J Anaesth
23. Chauvin M. Utilisation du rémifentanil. In: Conférences d'actualisation, 40ème congrès de la Société Française d'Anesthésie et de Réanimation
. Paris: Elsevier, 1998: 20-34.
24. Guignard B, Bossard AE, Coste C, et al
. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain
and morphine requirement. Anesthesiology
25. Cortinez LI, Brandes V, Munoz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth