Peripheral tissue injury provokes both peripheral and central sensitization. Peripheral sensitization is a reduction in the threshold of nociceptive afferent terminals at the site of injury, and central sensitization is an increase in the excitability of the spinal neurons. The term ‘pre-emptive analgesia’ implies that analgesic drugs given before the painful stimulus prevent or reduce subsequent pain [1,2]. In experimental studies, extradural administration of local anaesthetics blocks afferent transmission in peripheral nerves, and opioids may suppress excitability of dorsal horn neurons [3,4]. Some clinical work supports the concept of pre-emptive analgesia when using opioid , ketamine [6,7], nonsteroidal anti-inflammatory drugs (NSAIDs) , infiltration of local anaesthetic , but the value of these techniques remains unclear [10–12]. This study determines whether epidural fentanyl given before surgical incision decreases the requirements for postoperative opioid analgesia compared with the same dose of epidural fentanyl administered at the end of surgery.
Forty patients scheduled for elective abdominal surgery were randomly allocated to one of two groups according to the time of administered of fentanyl (Table 1). Written informed consent was obtained from all patients and the study was approved by the local Ethical Committee. Patients were excluded from the study if there was known alcohol or drug abuse, history of chronic pain, current treatment with NSAIDs, previous psychiatric history, history of liver disease or allergy to opioids. The use of a patient-controlled analgesia (PCA) device and the visual analogue score (VAS) system was explained to patients by one of the authors (YC), on the day before the operation. None of the patients in either group received premedication; the same anaesthetic technique was used for all patients. Before induction of general anaesthesia, an epidural catheter was inserted at the L2−3 interspace and flushed with 0.9% NaCl. Patients then received 10 mL of solution composed 100 µg fentanyl in 8 mL of 0.9% saline into the epidural space 15 min before awakening at the end of surgery (group I), or else the same dose was given at an estimated time of 15 min before the surgical incision was made (group II). The epidural fentanyl solution was prepared by one of the authors (AE). ECG, arterial pressure (noninvasive), peripheral oxygen saturation and end-tidal CO2 monitoring were instituted before induction of general anaesthesia. Following preoxygenation, all patients received lidocaine 1.5 mg kg−1 i.v., followed by thiopental 5 mg kg−1 and vecuronium 0.1 mg kg−1. The trachea was intubated after the onset of neuromuscular blockade and anaesthesia maintained with 33% nitrous oxide and 1–1.5% isoflurane in oxygen. No additional intraoperative opioid analgesics were administered to patients in either group. When the surgery had finished, residual neuromuscular blockade was antagonized with neostigmine 2.5 mg and atropine 1 mg; the trachea was extubated and the patient transferred to the recovery room. Postoperative analgesia consisted of patient controlled fentanyl i.v. At the end of the operation a patient-controlled analgesia device (Abbott Pain Management Provider 13960) was connected by an i.v. catheter to the patient; a 10-min locking time was set and 5 µg bolus dose of drug was given. The amount of fentanyl used by the patient was noted at 2, 4, 8, 12 and 24 h after operation. Pain scores were assessed using a visual analogue scale (VAS) in the range 0–10 cm (0 cm, no pain; 10 cm worst possible pain) at 0, 2, 4, 8, 12 and 24 h, postoperatively. Sedation was assessed with Ramsay's Sedation Scale  at 0, 2, 4, 8, 12 and 24 h, postoperatively (Table 2).
Pain scores, sedation scores and total fentanyl consumption were assessed by an investigator without knowledge of the timing of epidural fentanyl administration. Patients were asked about the occurrence of any side-effects (nausea, vomiting, pruritus), which were recorded if present. Demographic data and fentanyl consumption were compared using Student's t-test. VAS for pain and sedation scores in the two groups were compared using the Mann–Whitney U-test. A value of P < 0.05 was considered significant.
The two groups were similar in age, weight and duration of operation (Table 3). The mean VAS pain score was lower in group I (1.8 ± 2.3) than group II (4.5 ± 1.9), immediately after the operation (P < 0.05). There was no statistically significant between the mean VAS pain scores of groups at 2, 4, 8, 12 and 24 h after operation (Table 4).
There was no statistically significant difference between the mean sedation scores of the groups at all times postoperatively (Table 5). Postoperatively, the consumption of fentanyl was similar in both groups [total consumption group I, 343 ± 102 µg; group II, 341 ± 120 µg (Figure 1)].
The incidence of side-effects was comparable in both groups (Table 6). Fifteen patients, in both groups, already had a urinary bladder catheter.
We have shown that the use of epidural fentanyl prior to surgical incision does not reduce pain scores and the postoperative consumption of opioids. Demonstration of pre-emptive analgesia with opioid may be extremely difficult because there appears to be little information concerning the doses required. An additional problem with opioids administered pre-emptively is acute tolerance. This process might act to reduce the impact of any pre-emptive analgesic effect of opioids .
McQuay  pointed out the adequate outcome measure to show a true pre-emptive effect is the total analgesic consumption, rather than the time to first postoperative analgesic. In our study, we used the recommendations for the methodology of clinical investigations of pre-emptive analgesia . Furthermore, Dahl and his colleagues  were unable to demonstrate any postoperative benefit in a group of patients receiving epidural infusion of morphine and bupivacaine administered prior to surgery when compared with a group receiving the same infusion dose, administered after the surgery.
Pryle and his colleagues  demonstrated no difference in postoperative pain when abdominal hysterectomy patients were given epidural anaesthesia with 15 mL bupivacaine 0.5% before induction of general anaesthesia compared with a similar group receiving epidural bupivacaine at the end of surgery prior to emergence from anaesthesia. Wilson and colleagues  have demonstrated that the use of alfentanil 40 µg kg−1 i.v. given prior to surgical incision dose not reduce the consumption of morphine postoperatively or the intensity of the pain experienced. Mansfield and colleagues  observed that postoperative morphine consumption and pain scores did not differ when alfentanil 15 µg kg−1 was given i.v. before or after skin incision for abdominal hysterectomy.
Central sensitization may be generated not only during surgery, but also in the postoperative period, because of persistent inflammation and hyperalgesia at the wound site. Thus, intraoperative nociceptive block may not be adequate to reduce postoperative sensitization of central neurones . Furthermore, conventional analgesic methods (local anaesthetics or opioids) may not provide total C-afferent block during surgery . The negative studies may be explaned by insufficient afferent block.
In contrast to the above mentioned work, several studies have described the pre-emptive analgesic effect of opioids. Nègre and his colleagues  demonstrated that a single epidural injection of morphine 5 mg given before major abdominal surgery enhanced the quality of postoperative analgesia and decreased morphine consumption. However, they did not administer epidural morphine to a control group. Fentanyl, as used in our study, is known to have a shorter duration of action than morphine, which was used by Nègre and his colleagues . The dosage of analgesics we used may be lower than routinely used elsewhere; however, this is the standard protocol in our department.
Katz and his colleagues  found that patients given epidural fentanyl before surgical incision reported less pain and less postoperative morphine requirements when compared with the same dose and route of fentanyl administered 15 min after the incision. But their groups were not homogenous and their dose was higher than ours. Richmond and his colleagues  have shown that preoperative morphine compared with intraoperative morphine, reduced postoperative pain and early analgesic requirements after abdominal hysterectomy. Tverskoy and colleagues  showed that infiltration with local anaesthetic before the surgical incision made a measurable difference to pain felt when pressure was applied to the wound. This difference was found as late as 10 days after operation. Dierking and his colleagues  have found no significant differences in morphine requirements and on pain scores between patients with a local anaesthetic field block performed before compared with those in whom block was performed after inguinal herniorrhaphy.
Several studies have described the pre-emptive analgesic effect of preoperative nonsteroidal anti-inflammatory drugs. Hanlon and his colleagues  described a randomized, double blind, controlled study showing that the timing of administration of piroxicam, 20 mg orally, affected postoperative analgesia after diagnostic laparascopy. Patients receiving piroxicam two hours before induction of anaesthesia had less pain in the recovery room and required less analgesia than patients who had received piroxicam at the time of induction of general anaesthesia or one hour postoperatively.
Colbert and his colleagues  demonstrated that tenoxicam administered preoperatively provides superior analgesia after operation than tenoxicam administered after surgical incision in patients undergoing breast biopsy. This may explain why NSAIDs may be better able to ‘break down’ central sensitization than opioids. However, Murphy and Medley  were not able to show that pre-emptive administration of NSAIDs produced better analgesia than the drug given after operation. Our study showed that the dose of fentanyl administered epidurally prior to surgical incision did not cause a clinically useful pre-emptive analgesic effect.
1 McQuay H. Pre-emptive analgesia
. Br J Anaesth
1992; 69: 1–3.
2 Kissin I. Preemptive analgesia
. Why its effect is not always obvious. Anesthesiology
1996; 84: 1015–1019.
3 Woolf CJ, Wall PD. Morphine-sensitive and morphine-insensitive actions of C-fibre input on the rat spinal cord. Neuroscience Lett
1986; 64: 221–225.
4 Dickenson AH, Sullivan AF. Subcutaneous formalin-induced activity of dorsal horn neurons in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain
1987; 30: 349–360.
5 Richmond CE, Bromley LM, Wolf CJ. Preoperative morphine pre-empts postoperative pain
1993; 342: 73–75.
6 Choe H, Choi Y-S, Kim Y-H et al. Epidural
morphine plus ketamine for upper abdominal surgery: improved analgesia
from preincisional versus postincisional administration. Anesth Analg
1997; 84: 560–563.
7 Tverskoy M, Oz Y, Isakson A et al.
Preemptive effect of fentanyl
and ketamine on postoperative pain
and wound hyperalgesia. Anesth Analg
1994; 78: 205–209.
8 Colbert ST, O'Hanlon DM, McDonnell C, Given F, Keane PW. Analgesia
in day case breast biopsy – the value of pre-emptive tenoxicam. Can J Anaesth
1998; 45: 217–222.
9 Ejlersen E, Andersen HB, Eliasen K, Mogensen T. A comparison between preincisional and postincisional lidocaine infiltration and postoperative pain
. Anesth Analg
1992; 74: 495–498.
10 Wilson RJT, Leith S, Jackson IJB, Hunter D. Pre-emptive analgesia
from intravenous administration of opioids. No effect with alfentanil. Anaesthesia
1994; 49: 591–593.
11 Mansfield M, Meikle R, Miller C. A trial of pre-emptive analgesia
. Influence of timing of preoperative alfentanil on postoperative pain
and analgesic requirements. Anaesthesia
1994; 49: 1091–1093.
12 Murphy DF, Medley C. Preoperative indomethacin for pain
relief after thoracotomy: comparison with postoperative
indomethacin. Br J Anaesth
1993; 70: 298–300.
13 Aitkenhead AR. Analgesia
and sedation in intensive care. Br J Anaesth
1989; 63: 196–206.
14 Dahl JB, Hansen BL, Hjortsø NC, Erichsen CJ, Møiniche S, Kehlet H. Influence of timing on the effect of continuous extradural analgesia
with bupivacaine and morphine after major abdominal surgery. Br J Anaesth
1992; 69: 4–8.
15 Pryle BJ, Vanner RG, Enriquez N, Reynolds F. Can pre-emptive lumbar epidural
blockade reduce postoperative pain
following lower abdominal surgery? Anaesthesia
1993; 48: 120–123.
16 Dahl JB, Kehlet H. The value of pre-emptive analgesia
in the treatment of postoperative pain
. Br J Anaesth
1993; 70: 434–439.
17 Nègre I, Guéneron JP, Jamali SJ, Monin S, Ecoffey C. Preoperative analgesia
morphine. Anesth Analg
1994; 79: 298–302.
18 Celleno D, Capogna G, Sebastiani M et al. Epidural analgesia
during and after cesarean delivery. Comparison of five opioids. Reg Anesth
1991; 16: 79–83.
19 Katz J, Kavanagh BP, Sandler AN et al.
: clinical evidence of neuroplasticity contributing to postoperative pain
1992; 77: 439–446.
20 Tverskoy M, Cozacov C, Ayache M, Bradley El Jr , Kissin I. Postoperative pain
after inguinal herniorrhaphy with different types of anesthesia. Anesth Analg
1990; 70: 29–35.
21 Dierking GW, Dahl JB, Kanstrup J, Dahl A, Kehlet H. Effect of pre- vs postoperative
inguinal field block on postoperative pain
after herniorrhaphy. Br J Anaesth
1992; 68: 344–348.
22 O'Hanlon JJ, Muldoon T, Lowry D, McCleane G. Improved postoperative analgesia
with preoperative Piroxicam Can J Anaesth
1996; 43: 102–105.