Postoperative pain management remains unsatisfactory despite many studies and guidelines [1]. The reasons are multiple and include: complexity of pain, which makes it difficult to study, lack of knowledge regarding methods of pain management, underestimation of pain reported by patients and fear of side effects of analgesics. There is no one universal and safe method of pain relief and therapeutic protocols require audit and adjustment to a particular situation. Therefore, novel, simple yet effective and safe methods for pain management are being searched for.

At present, multimodal analgesia and pre-emptive analgesia are considered the most appropriate methods of pain management.

In multimodal analgesia drugs of various mechanisms of action are combined to obtain the desirable analgesic effect and to reduce side effects [2]. In the postoperative period, the combined use of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids reduces the opioid consumption by 40-50%, which makes the treatment safer [3]. High hopes are pinned on paracetamol, which was found to be effective and convenient in use, particularly administered intravenously [4].

Pre-emptive analgesia is defined in various ways. The management involving analgesic administration before the exposure to a nociceptive stimulus is the simplest, not necessarily the most appropriate, definition used [5]. In many cases, the studies based on this definition do not confirm the efficacy of this concept [6]. Pre-emptive analgesia is better explained as all activities aiming at prevention of sensitization underlain by neuronal functional changes caused by repeated stimulation. The source of stimuli in patients undergoing surgical procedures is nociceptive impulsation developing during and after surgery and an inflammatory reaction at the site of a surgical wound.

Despite a number of studies carried out, there is no consensus on the efficacy of pre-emptive analgesia provided with NSAIDs. The difference between the convincing theoretical basis and findings of animal studies versus results of clinical studies is striking [7]. The efficacy of perioperative ketoprofen is not explicit [8, 9]. Moreover, the findings of meta-analyses concerning preoperative NSAIDs are ambiguous [10, 11]. In spite of such controversies, the Polish guidelines for postoperative pain management published in 2008 recommend the use of ketoprofen before surgery [12].

The aim of the present study was to determine the extent the use of pre-emptive ketoprofen reduced pain sensations in patients after urologic surgeries. 

METHODS

The study design was approved by the Bioethics Committee of the Medical University of Lublin. The prospective, randomized, double blind trial was carried out. The trial included ASA I, II or III patients qualified for laparotomy by a retroperitoneal approach. The exclusion criteria were: sensitivity to NSAIDs and opioids, alcohol or other psychoactive drug abuse, advanced neoplastic diseases, NSAIDs used within 24 h and/or steroids over 7 days before surgery, creatinine concentration >130 mmol L-1, clotting disturbances or surgery duration >3 h.

After the informed consent was obtained, patients were randomly allocated to the control or study group using the computer-generated randomization list. One hour before surgery, the study group received 100 mg of ketoprofen in a short intravenous infusion (250 mL 0.9% NaCl) and the control group was administered placebo. All patients were premedicated with oral diazepam 0.15 mg kg-1 and intravenous atropine 0.01 mg kg-1 – immediately before anaesthesia. Anaesthesia was induced with thiopentone 5 mg kg-1 and suxamethonium 1 mg kg-1 and maintained using the mixture of N2O and O2 (FIO2=33%), sevoflurane 0.5-2% as well as fractionated doses of fentanyl 1.5 mg kg-1. Vecuronium 0.1 mg kg-1 was used for muscle relaxation. All patients were artificially ventilated maintaining ETCO2 within 35-45 mm Hg (4.6-6.0 kPa). After surgery, neuromuscular block was reversed with neostigmine 2.5 mg following the administration of atropine 0.5 mg. Anaesthesia was administered by the anaesthesiologist not involved in the study. 

After surgery, both groups of patients were administered identical analgesic management. At 8, 16, 24, 36 and 48 h since pre-emptive ketoprofen (or placebo), all patients received ketoprofen 100 mg (in 250 mL 0.9% NaCl) in a short intravenous infusion. After 48 h (postoperative day 2) ketoprofen was administered on demand and the daily dose did not exceed 200 mg. Once pain relief was unsatisfactory (VAS> 4), pethidine 1 mg kg-1was used.

In the postoperative period, the following parameters were recorded: SAP/DAP, HR, body temperature, severity of pain according to VAS, and consumption of additional analgesics. The patients were assessed at 1, 3, 6, 10 and 12 h after surgery, at 24 and 30 h (postoperative day 1), at 43 and 48 h (day 2). Since day 3 until discharge, the patients were assessed once a day in the morning. During the first two postoperative days, pain was evaluated at rest, on day 3 and successive days – also during motor activity. Moreover, concentrations of serum creatinine and ALAT were determined before surgery as well as on postoperative day 1 and 4. Furthermore, all adverse side effects of drugs were recorded.

Results were statistically analysed using the ANOVA test. P <0.05 was considered significant.

RESULTS

The study encompassed 68 patients; 16 were excluded at individual stages due to various reasons (intraoperative haemorrhaging, re-surgery, additional NSAIDs, discontinuation of examinations by patients, inconsistency with the study protocol). Fifty-two patients completed the study: 23 controls and 29 in the study group. The groups were comparable in age, gender, BMI, ASA assessment and surgery duration (Table 1). 

Thirty patients underwent total nephrectomy, 18 – partial nephrectomy, 2 – ureterolithotomy, and 2 – pyeloplasty. All procedures were performed by the retroperitoneal access.

During anaesthesia the study group of patients received in total 0.45±0.12 mg of fentanyl whereas controls – 0.43±0.1 mg (differences not significant).

During the first 2 postoperative days pain sensations were severe in all patients. Throughout the observation period (7 days), the severity of rest pain in the study group did not differ from that in controls (Fig. 1). Moreover, there were no significant intergroup differences in pain during motor activity (days 3-6) (Fig. 2).

The consumption of additional analgesics in both groups was comparable (Fig.3). The highest number of pethidine injections was noted during the first 12 postoperative hours. On day 3 and 4, every other patient required ketoprofen.

The laboratory tests did not demonstrate elevated serum creatinine and ALAT levels. Moreover, no significant intergroup differences in SAP/DAP, HR and body temperature were observed. In all patients, the postoperative course was uneventful. No adverse side effects of analgesics were noted.

DISCUSSION

Our results do not confirm the reports demonstrating beneficial effects of pre-emptive NSAIDs on postoperative analgesia [8, 11, 13, 14, 15]. It is believed that to assess the efficacy of pre-emptive analgesia, an analgesic should be administered before surgery and continued after surgery. The essence of this concept consists in continuation of antinociceptive management during the postoperative period when afferent nociceptive impulsation is mainly caused by the inflammatory reaction, with its highest intensity observed between 12-48 h after surgery [6]. For these reasons, in our study we assumed that it was necessary to administer ketoprofen in the study group before surgery and to continue it in both groups on all postoperative days when pain sensations were reported by patients (until day 3 or 5). The available literature does not provide any reports in which NSAIDs were administered for so long and systematically during the postoperative period. In the majority of cases, “on demand” pain management is provided rather than according to the hour schedule and over a short time, mostly on day 0 or 1 after surgery.

Since the main cause of sensitization is afferent nociceptive impulsation induced mainly by the inflammatory process, the administration of NSAIDs should be extremely beneficial. These agents, by inhibiting the synthesis of prostaglandins, reduce the inflammation, thus the extent of nociceptive impulsation, which limits the development of sensitization, both peripheral and central. Although prostaglandins alone do not stimulate the nociceptors, they decrease the excitability threshold of neurons [16]. Unfortunately, in our study, despite the use of ketoprofen before the development of inflammatory reaction and its maximum doses administered during the postoperative period, the management was not found effective. During the inflammatory process, the amount of cyclooxygenase increases markedly, hence increased synthesis of prostaglandins. It is likely that ketoprofen administered before the development of inflammatory reaction, although available at the site of tissue injury, exerts no clinical effect as at this moment the synthesis of cyclooxygenase is not increased due to ketoprofen-related inactivation. This would explain its inefficacy in pre-emptive analgesia in anaesthetized patients.

The majority of studies evaluating the efficacy of pre-emptive analgesia concern orthopaedic, gynaecological and laparoscopic abdominal procedures [10, 13]. A few studies assessed the usefulness of NSAIDs after thoracotomy [11]. In our study, urologic surgeries were performed by the retroperitoneal approach, therefore the surgical stress was higher and more extensive and nociceptive impulsation conveyed via the somatic and autonomic system reached the CNS at many levels. For these reasons, among others, the severity of pain during the first 48 postoperative hours might have been higher than after procedures involving other body regions.

The use of NSAIDs for postoperative pain relief is well grounded; nevertheless, the administration of an agent inhibiting the activation and aggregation of platelets before surgery seems controversial [3]. By affecting the synthesis of eicosanoids, NSAIDs may modulate the surgical wound healing, which, however, requires further studies [17].

CONCLUSION

Pre-emptive analgesia with ketoprofen in patients undergoing urologic surgical procedures does not affect pain sensations after surgery.

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REFERENCES

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10.    Møiniche S, Kehlet H, Dahl JB: A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002; 96: 725-741.

11.    Ong CK, Lirk P, Seymour RA, Jenkins BJ: The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 2005; 100: 757-773.

12.    Dobrogowski J, Mayzner-Zawadzka E, Drobnik L, Kusza K, Woroń J, Wordliczek J: Uśmierzanie bólu pooperacyjnego – zalecenia 2008. Ból 2008; 9: 2.

13.    Boccara1 G, Chaumeron A, Pouzeratte Y, Mann C: The preoperative administration of ketoprofen improves analgesia after laparoscopic cholecystectomy in comparison with propacetamol or postoperative ketoprofen. Br J Anaesth 2005; 94: 347-355.

14.    Wnęk W, Zajączkowska R, Wordliczek J, Dobrogowski J, Korbut R: Influence of pre-operative ketoprofen administration (preemptive analgesia) on analgesic requirement and the level of prostaglandins in the early postoperative period. Pol J Pharmacol 2004; 56: 547-552.

15.    Kaczmarzyk T, Wichlinski J, Stypulkowska J, Zaleska M, Woron J: Preemptive effect of ketoprofen on postoperative pain following third molar surgery. A prospective, randomized, double-blinded clinical trial. Int J Oral Maxillofac Surg 2010; 39: 647-652.

16.    Fanelli G, Berti M, Baciarello M: Updating postoperative pain management: from multimodal to context-sensitive treatment. Minerva Anestesiol 2008; 74: 489-500.

17.    Boursinos LA, Karachalios T, Poultsides L, Malizos KN: Do steroids, conventional non-steroidal anti-inflammatory drugs and selective Cox-2 inhibitors adversely affect fracture healing? J Musculoskelet Neuronal Interact 2009; 9: 44-52.

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address:

*Rafał Rutyna
I Klinika Anestezjologii i Intensywnej Terapii
Uniwersytet Medyczny w Lublinie
ul. Jaczewskiego 8, 20-950 Lublin
tel.: 81 724 43 32
e-mail: anest@umlub.pl

received: 13.08.2010
accepted: 20.11.2010