extradural bupivacaine and morphine on post- operative stump sensation in 31 patients under- going amputation of the lower limb in a prospective, randomized ...
British Journal of Anaesthesia 1998; 81: 348–354
Effect of preoperative extradural bupivacaine and morphine on stump sensation in lower limb amputees L. NIKOLAJSEN, S. ILKJÆR AND T. S. JENSEN
Summary We have examined the effect of preoperative extradural bupivacaine and morphine on postoperative stump sensation in 31 patients undergoing amputation of the lower limb in a prospective, randomized, double-blind study. Patients were allocated randomly to one of two groups: group 1 received extradural 0.25% bupivacaine 4–7 ml h91 and morphine 0.16–0.28 ml h91 before and during operation; group 2 received extradural saline before and during amputation and conventional analgesics for pain treatment. All patients received general anaesthesia for the amputation and extradural bupivacaine and morphine after operation. Sensory examination of the limb/stump was carried out before amputation, and after 1 week and 6 months. The following were measured: pressure pain thresholds (pressure algometry), touch and pain detection thresholds (von Frey hairs), thermal sensibility (thermal rolls), and allodynia and wind-up-like pain. There were no differences between the two groups at any of the postoperative assessments for mechanical and thermal sensibility or rate of allodynia and wind-up-like pain. Our study suggests that preoperative and intraoperative extradural block had no long-term prophylactic effect on hyperalgesia, allodynia or wind-up-like pain. (Br. J. Anaesth. 1998; 81: 348–354). Keywords: analgesic techniques, extradural; anaesthetics local, bupivacaine; analgesics opioid, morphine; surgery, amputation; pain, phantom limb
Pain after amputation is a significant problem among amputees. Approximately 60–70% of amputees suffer from phantom pain in the first year after amputation.1 2 The mechanisms underlying pain in amputees are not clear but experimental and clinical evidence suggests that sensitization of central neurones before and during amputation may play a role.3–6 Previous studies have shown that phantom pain is more likely to be present in amputees who had severe pain in the limb before amputation compared with those with less severe pain.1 7 8 In a recent prospective study of 56 patients undergoing amputation, intense pain before amputation was associated with phantom pain in the first 6 months after amputation, and stump and phantom pain were significantly related 1 week after amputation.2 Some studies have reported that phantom pains are similar to previously experienced pains
in a high proportion of amputees5 9 suggesting that pain experienced before amputation creates an imprint in pain memorizing structures in the central nervous system (CNS).10 Taken together these findings suggest that long-term and intense noxious input from the periphery may induce changes in the CNS resulting in sensitization and chronic pain. The manifestations of sensitization include, apart from pain, reduction in pain threshold (hyperalger sia), evocation of pain, by non-noxious stimuli (allodynia) (for review see Willis11) and pain elicited by repeated pricking stimuli (wind-up-like pain).12 Consistent with this are reports of abnormal stump sensibility in 50% of amputees1 and descriptions of wind-up-like pain in amputees.13 Central sensitization after persistent noxious input raises the question of whether or not such neuronal hyperexcitability can be prevented. Several studies support the notion that signs of hyperexcitability after experimental nerve injury can be reduced by various treatments before or during injury.14–16 A clinical correlate to such pre-emptive effects was the observation that preoperative extradural block prevented phantom pain.17 However, not all studies support this finding. In a recent study, extradural bupivacaine and morphine administered for 18 h before, during and after amputation failed to reduce the rate and intensity of phantom pain in the first year after amputation.18 Previous clinical studies have suggested that it is possible to prevent signs of hyperexcitability other than pain by preoperative or intraoperative treatment.9–21 For example, Richmond, Bromley and Woolf19 found lower pain sensitivity around the wound in 15 patients who received morphine before hysterectomy compared with 12 patients who received morphine after operation. While these studies suggest that intense treatment may reduce hyperexcitability in the early postoperative period, there is limited evidence for a reduction in long-term hyperexcitability. This is important because some surgical procedures, such as amputation, mastectomy and thoracotomy, are often associLONE NIKOLAJSEN*, MD, TROELS STAEHELIN JENSEN, MD, PHD, Department of Neurology, University Hospital of Aarhus, DK8000 Aarhus, and the Danish Pain Research Centre, University of Aarhus, DK-8000 Aarhus, Denmark. SUSANNE ILKJÆR, MD, Department of Anaesthesiology, Skejby Hospital, University Hospital of Aarhus, DK-8200 Aarhus, Denmark. Accepted for publication: February 20, 1998. *Address for correspondence: Danish Pain Research Centre, Bygning 1 C, Aarhus Kommunehospital, 8000 Aarhus C, Denmark.
Stump sensation in amputees ated with long-term pain, allodynia, hyperalgesia and wind-up-like pain.22–25 Therefore, we have examined, in a prospective, randomized, double-blind study, if extradural pain treatment started before amputation and continued into the postoperative period would reduce mechanical and thermal hyperalgesia, allodynia and wind-up-like pain 1 week and 6 months after amputation.
Patients and methods Patients were recruited from 60 patients who took part in a major study of the effect of extradural bupivacaine and morphine in the prevention of stump and phantom pain after amputation.18 All were invited to participate in sensory testing of the stump, in addition to answering questionnaires on pain. Inclusion criteria were age more than 18 yr and undergoing amputation of the lower limb. Exclusion criteria were acute amputation, ipsilateral re-amputation, amputation of the foot or toes only, extradural pain treatment started before inclusion, dementia and contraindications to placement of an extradural catheter or combined extradural and general anaesthesia. Informed written consent was obtained from patients and approval was obtained from the regional Ethics Committee and the Danish National Board of Health. Patients were allocated randomly to one of two groups of equal size. Group 1 (active treatment group) received extradural bupivacaine and morphine before and during amputation and group 2 (control group) received extradural saline and oral–i.m. morphine. Details of randomization have been described previously18 but briefly patients were stratified on the basis of the intensity of pain before amputation: the first patient entering the study with a pain intensity before amputation of :30 on a visual analogue scale (VAS) (0–100 mm) was assigned to group 1 or 2 by tossing a coin. The next patient with a VAS score :30 was assigned to the opposite treatment. The same procedure was followed for patients with a pain intensity ⱖ30 on a VAS. Blindness during the study was ensured by two investigators (L. N. and S. I). L. N. was responsible for the following: recruitment of patients, postoperative pain treatment, and pain assessment and examination of the limb/stump before amputation and after 1 week and 6 months. S. I. was responsible for randomization, placement of extradural catheters, pain treatment from placement of the extradural catheter until the end of anaesthesia, and pain assessment and examination of the limb in the operating theatre. L. N. knew that patients were stratified according to pain intensity before amputation but did not know treatment assignment. For safety reasons the attending nurse anaesthetist was informed of treatment assignment. Otherwise staff and patients were blinded.
349 sory block was below or at T12, as assessed by an alcohol wipe, additional 1-ml increments of bupivacaine were given. This was followed by continuous infusion of 0.25% extradural bupivacaine 4–7 ml h91 and morphine 0.16–0.28 mg h91. Infusion rates were adjusted to individual patient responses (i.e. block level and haemodynamic stability). If the patient reported pain or discomfort in the limb before amputation, infusion rates were increased or additional increments of bupivacaine were given. In the operating theatre and before induction of anaesthesia, a bolus dose of 0.5% bupivacaine 5–15 ml was administered. Further increments were given if sensory block was below or at T12. The degree of motor block after the bolus dose of bupivacaine was assessed on a scale from 0–100.26 Extradural infusion of bupivacaine and morphine was maintained until the end of anaesthesia. If duration of surgery exceeded 90 min an extra bolus of 0.5% bupivacaine (volume:half the initial bolus dose) was given. All bolus doses of bupivacaine were adjusted to the condition of the patient. Patients in group 2 received oral or i.m. morphine 5–20 mg, 4–6 times a day, and 5–10 mg on demand and paracetamol 1 g four times daily was given for pain treatment before amputation. The dose of morphine was adjusted to individual needs (i.e. age, weight, present pain and previous consumption of morphine). After placement of the extradural catheter a bolus dose of saline 5 ml was given. This was followed by extradural infusion of saline 4–7 ml h91, maintained until the end of anaesthesia. Before induction of anaesthesia another bolus of saline 5 ml was given and before the end of anaesthesia a bolus dose of 0.5% bupivacaine 5–10 ml was administered. In both groups, amputation was performed under general anaesthesia. Premedication comprised diazepam 2.5–20 mg orally, 1–2 h before operation. Anaesthesia was induced with thiopental and maintained with enflurane and nitrous oxide in oxygen. Fentanyl was administered as intermittent bolus doses of 25–100 g. Atracurium was used to facilitate tracheal intubation and to maintain neuromuscular block. Neuromuscular block was antagonized by neostigmine and atropine. All doses were adjusted according to age, weight and administration of extradural pain. Postoperative pain treatment Postoperative pain treatment was similar in the two groups. Bupivacaine 0.25% (3–7 ml h91) and bolus doses of morphine 2–8 mg, 2–4 times daily were administered extradurally. Infusion rates and doses of morphine were adjusted to individual needs. Infusion of bupivacaine was stopped 2–3 days after amputation, but treatment with extradural morphine was continued for as long as considered necessary. The extradural treatment was supplemented by paracetamol 1 g four times daily.
PAIN MANAGEMENT AND ANAESTHESIA
Preoperative and intraoperative pain management
Pain assessment
In all patients extradural catheters were placed in the L2–3 or L3–4 interspace on the day before amputation and tested using 2% lidocaine with epinephrine 3 ml. Patients in group 1 received a bolus dose of extradural morphine 2 mg and 0.5% bupivacaine 5–10 ml. If the patient was not free of pain or if sen-
Pain was assessed using a VAS (0–100 mm) on the day before amputation (before randomization and before placement of the extradural catheters), in the operating theatre (before administration of the bolus dose of bupivacaine), and after 1 week and 6 months. On the day before amputation, intensity of pain in the
350 limb was recorded. In the operating theatre, pain was assessed by recording mean pain intensity experienced from the time of placement of the extradural catheter until amputation, and at the postoperative interviews, intensities of stump and phantom pain were recorded. Sensory testing On the day before amputation (before randomization and before placement of the extradural catheters) pressure pain thresholds, touch and pain detection thresholds, and thermal sensibility were measured. In the operating theatre and after administration of the bolus dose of bupivacaine, pressure pain thresholds were measured. After 1 week and 6 months, pressure pain thresholds, touch and pain detection thresholds, and thermal sensibility were recorded. Also, after 6 months, rates of allodynia and wind-up-like pain were examined. Measurements were performed at the lateral aspect of the limb/stump. If amputation was performed at the thigh or knee, the L2–3 dermatome was examined (above m. vastus lateralis) and if amputation of the calf was performed, the L4 dermatome was examined (above m. tibialis anterior). Pressure sensibility Pressure pain threshold (PPT) was determined using a hand-held electronic pressure algometer (Somedic AB, Sweden). The procedure has been described previously.27 Briefly, a circular probe with an area of 1 cm2 was used. The pressure application rate was 20 kPa s91. The patient was told to say “stop” when a sensation of pressure changed to a sensation of pain. This was recorded as PPT and the value on the digital display was read by the examiner. Each value was determined three times with an interval of at least 30 s. Tactile sensibility Tactile sensibility was determined using von Frey hairs, consisting of 20 monofilaments of increasing diameter calibrated to deliver a specific force on the skin (Semmes-Weinstein monofilaments, Stoelting, IL, USA). The filaments were applied in an ascending and descending order of magnitude. The force required to bend the filament at the touch detection threshold (TDT) and at the pain detection threshold (PDT) was recorded. Thermal sensibility Thermal sensibility was examined using thermal rollers. The rollers were made of steel with steel handles. Sensibility to cold was examined with a thermal roll cooled in a box filled with ice. Sensibility to warmth and heat was examined with thermal rolls heated to 30 and 45 ⬚C in a water bath. All sensations were described on a scale from 1 to 9, as reported previously,28 (1:painful heat, 2:very warm, 3:warm, 4:slightly warm, 5:neutral, 6:slightly cold, 7:cold, 8:very cold, 9:painfully cold). Wind-up-like pain Wind-up-like pain was carried out using a procedure described previously by Eide and colleagues.12 The
British Journal of Anaesthesia skin was pricked repeatedly with a von Frey filament (6.65 units:447 g) at a rate of 3 s91. The stimulation was not painful initially but after a few seconds the patients reported a marked increase in pain. Stimulation was continued for 30 s but discontinued before if the pain became unbearable. Five sites on the stump were stimulated: one site at the end of the stump, and anterior and posterior sites on the lateral and medial aspect of the stump. Wind-up-like pain was considered present if pain could be elicited at at least one site of the stump. Allodynia Allodynia was determined by a von Frey hair at the touch detection threshold. The monofilament was moved along the stump and allodynia was considered present if sensation changed from a feeling of touch to a clear sensation of pain. STATISTICAL ANALYSIS
Results are presented as mean (SD) or median (range). The Mann–Whitney rank sum test was used to analyse differences between medians. Differences between the two groups in postoperative values of PPT, TDT and PDT were analysed as follows: for each patient a standardized value, postoperative/preoperative, was calculated. The standardized values in the two groups were compared on a logarithmic scale (i.e. the values were log-transformed and the mean values in the two groups were compared using a t test and 95% confidence intervals for the difference between means). The estimated mean difference and confidence interval were then transformed back to the original scale, yielding an estimate and 95% confidence interval of the median ratio between the standardized values in the two groups. Fisher’s exact test was used to compare rates of allodynia and wind-up-like pain in the two groups. P:0.05 was considered significant.
Results Forty-five patients agreed to participate in sensory examination of the stump: 23 patients in group 1 and 22 in group 2. There were no differences between patients who agreed to take part in sensory testing and those who refused, in age, sex distribution or intensity of pain before amputation (data not shown). There were 31 patients at the 6-month interview: two patients (one from each group) were withdrawn from the study before amputation (in one patient the extradural catheter was displaced accidentally and the other patient only underwent toe amputation); three patients underwent re-amputation (all belonged to group 1) and nine patients died (four in group 1 and five in group 2). Patient characteristics and surgical details are shown in table 1. PERIOPERATIVE PAIN, AND STUMP AND PHANTOM PAIN AFTER AMPUTATION
Perioperative pain Median duration of preoperative extradural block (group 1) was 16.5 (range 12–45) h and median duration of postoperative extradural pain treatment (both groups) was 214 (14–756) h.
Stump sensation in amputees
351
Table 1 Patient characteristics and surgical details (mean (SD)) (% or number)
No. of patients Sex (M/F) Age (yr) Diabetes Medical treatment because of cardiovascular disease Previous contralateral amputation Pain at inclusion (VAS 0–100) Daily opioid consumption at admission (mg) Level of amputation Below knee Through knee joint Above knee
Group 1
Group 2
14 6/8 61.7 (30.5) 5
17 13/4 69.2 (10.2) 10
8 0
12 2
61.7 (30.5)
46.1 (29.4)
61.4 (45.7)
54.1 (57)
8 3 0
12 0 5
There was a highly significant difference in pain experienced at the time from placement of the extradural catheter until amputation, between the extradural block and extradural saline groups (P:0.001). Eleven of 14 patients in group 1 were pain-free after the extradural pain treatment and scored 0 on a VAS. Two patients continued to have slight and intermittent pain (VAS scores 2 and 4). One patient continued to feel pain despite the extradural treatment. Median intensity of pain in group 1 was 0 (range 0–31). All patients in group 2, except one, had pain during the time from placement of the extradural catheter until amputation. Median pain intensity was 29 (0–80). Postoperative stump and phantom pain Details on stump and phantom pain have been presented previously.2 18 Briefly, there was no difference between the groups at the postoperative interviews when comparing rates of phantom pain. After 1 week the percentage of patients with phantom pain was 57.1% in group 1 and 58.8% in group 2. After 6 months the corresponding values were 78.6% and 58.8% in groups 1 and 2, respectively. Intensities of stump and phantom pain were also similar in the two groups (data not shown). SENSORY TESTING
It was not possible to perform all types of sensory testing in all patients at all postoperative assessments, mainly because of lack of consent. Obvious contraindications to examination such as delayed healing and infection of the stump occurred in a few cases. Block before amputation PPT was examined in 22 patients (nine in group 1 and 13 in group 2) after the bolus dose of bupivacaine in the operating theatre. PPT was not reached by any patient in group 1. To avoid damage to the skin, a cutoff point for PPT was set at twice the value obtained on the day before amputation. Median PPT was 400 (range 300–650) kPa in group 1 and 238 (75–600) kPa in group 2 (P:0.0001). The degree of motor block after the bolus dose of bupivacaine before amputation,
Figure 1 Pressure pain thresholds (PPT) after 1 week and 6 months for groups 1 (n:7) and 2 (n:1l). The standardized value, postoperative/preoperative PPT, is shown for each patient.
assessed using the Bromage scale (group 1), was complete (100%) in one patient (unable to move legs or feet), almost complete (66%) in 11 patients (unable to flex knees, but with free movement of feet) and partially complete (33%) in two patients (just able to flex knees, free movement of feet). Pressure and tactile sensibility PPT was examined in 18 patients (seven in group 1 and 11 in group 2) on the day before amputation and after 1 week and 6 months. Before amputation, median PPT was 227 kPa in group 1 and 195 kPa in group 2. Figure 1 shows the postoperative PPT values in the two groups. The standardized value, postoperative/preoperative PPT, is presented for each patient. After 1 week the standardized PPT values in group 1 were, on average, 0.59 times the standardized PPT values in group 2 (95% CI 0.21 to 1.66; P:0.3). After 6 months the standardized PPT values in group 1 were, on average, 0.51 times the standardized PPT values in group 2 (95% CI 0.24 to 1.1; P:0.08) TDT and PDT were measured in 16 patients (seven in group 1 and nine in group 2). Median TDT and PDT were 0.41 g and 8.51 g, respectively, in group 1 before amputation; corresponding values were 8.51 g and 75.8 g in group 2. Postoperative TDT and PDT values are shown in figure 2. The standardized values, postoperative/preoperative TDT and PDT, are presented for each patient. After 1 week the standardized TDT values in group 1 were, on average, 1.0 times the standardized TDT values in group 2 (95% CI 0.78 to 1.3; P:0.9) and the standardized PDT values in group 1 were, on average, 1.3 times the standardized values in group 2 (95% CI 1.0 to 1.6; P:0.04). After 6 months the standardized TDT values in group 1 were, on average, 1.2 times the standardized TDT values in group 2 (95% CI 0.89 to 1.59; P:0.2) and the standardized PDT values in group 1 were, on average, 1.2 times the standardized values in group 2 (95% CI 0.97 to 1.38; P:0.09). Thermal sensibility In 15 patients (six in group 1 and nine in group 2), thermal sensibility was measured before amputation, and after 1 week and 6 months. Thermal sensibility
352
British Journal of Anaesthesia Table 2 Incidence of wind-up-like pain and allodynia 6 months after amputation (number (%))
Group 1 No. (%) Group 2 No. (%)
Figure 2 Touch and pain detection thresholds (TDT and PDT) after 1 week and 6 months for groups 1 (n:7) and 2 (n:9). The standardized values, postoperative/preoperative TDT and PDT, are shown for each patient.
was similar in the two groups both before and after amputation. Also, postoperative thermal sensibility was not different from thermal sensibility before amputation (fig. 3). Wind-up-like pain and allodynia At the 6-month interview, 19 patients (10 in group 1 and nine in group 2) were examined for wind-up-like pain. Wind-up-like pain was elicited in 11 patients, eight in group 1 and three in group 2 (P:0.07). The incidence of allodynia was examined in 28 patients after 6 months (12 in group 1 and 16 in group 2). Allodynia was present in nine patients: four in group 1 and five in group 2 (ns). There was no difference between rates of allodynia and wind-up-like pain in the two groups (table 2).
Discussion In this prospective, randomized study, we found no effect of intense preoperative and intraoperative extradural block on postoperative stump sensibility to mechanical and thermal noxious and non-noxious stimuli. Therefore, our findings suggest that extradural analgesia does not prevent late signs of hyperexcitability at the level of the stump. However, before accepting this notion, some points need consideration.
Wind-up-like pain
Allodynia
8 of 10 (80%)
4 of 12 (33.3%)
3 of 9 (33.3%)
5 of 16 (31.3%)
First, it may be argued that selection bias and a limited number of patients were responsible for our negative findings. Although selection bias cannot be excluded, patient characteristics were similar in those who agreed to participate in sensory testing and those who refused. The fact that there was no consistent trend towards an effect of extradural block on stump sensibility after amputation suggests that our failure to find an effect cannot be explained by the small number of patients. Second, it is possible that central sensitization was not present and therefore could not be blocked. However, pressure pain thresholds were reduced after amputation, and allodynia and wind-up-like pain were present in a relatively large proportion of patients in the block and non-block groups, thus indicating that sensitization to mechanical stimuli was present and amenable to block. Third, it is also unlikely that our failure to see an effect was a result of selection of stimuli or stimulation of receptors unresponsive to sensitization. We assessed both thermal and mechanical modalities, in addition to different types of mechanical stimuli. Therefore, it is likely that afferent input via Cmechano-heat receptors and low threshold mechano-receptors conveyed by C, A⭸ and Aß fibres, respectively, were examined in this study. The discrepancy between our findings and those reported in experimental and clinical studies may have several explanations. In experimental studies on the effect of treatment before injury, conditioning stimuli are usually of short duration and may consist of brief C-fibre stimulation,29 and localized mechanical,30 thermal6 or chemical31 injury. In studies in human volunteers, different methods of producing hyperalgesia (e.g. localized burn injury or intradermal or topical application of capsaicin) have been used, characterized by producing an afferent C-fibre volley of intense but short duration.32–34
Figure 3 Thermal sensibility in the range 0–45 ⬚C before (A), and 1 week (B) and 6 months (C) after amputation for groups 1 (n:6) and 2 (n:9). All sensations were described on a scale from 1 to 9 (1:painful heat, 2:very warm, 3:warm, 4:slightly warm, 5:neutral, 6:slightly cold, 7:cold, 8:very cold, 9:painfully cold). Values are medians.
Stump sensation in amputees In contrast, the nociceptive barrage of the CNS in patients undergoing amputation is intense and longlasting. We propose that the extradural block in our study was insufficient to block afferent C-fibre input and hence reduce central sensitization. This notion is supported by previous studies. It has been shown that a lumbar extradural block with bupivacaine did not completely prevent impulses, as assessed by somatosensory evoked potentials, in reaching the CNS.35 Furthermore, Dahl and colleagues32 found that a short-lasting block of the skin with lidocaine before experimental burn injury postponed but did not prevent secondary hyperalgesia. It may be impossible to prevent afferent input from reaching the CNS during surgery but we cannot exclude the fact that other forms of regional analgesia would be able to influence central sensitization. Clinical studies have not provided consistent results. In the study of Richmond, Bromley and Woolf,19 patients undergoing hysterectomy were allocated randomly to one of three groups: morphine 10 mg i.m., 1 h before operation (i.m. pre) (n:8), morphine i.v. at induction of anaesthesia (i.v. pre) (n:7) or morphine i.v. at closure of the peritoneum (i.v. post) (n:12). Pain sensitivity around the wound, as assessed by von Frey hair, was reduced after 24 and 48 h in both preoperative treatment groups compared with the i.v. post group. Tverskoy and colleagues20 found that pre- and intraoperative administration of morphine (n:9) or ketamine (n:9) reduced the intensity of pain to suprathreshold pressure on the, wound 48 h after hysterectomy. The effect of ketamine on postoperative hyperalgesia was studied21 and the area of hyperalgesia was reduced in 10 patients who received ketamine during and for 72 h after nephrectomy compared with 10 patients who received placebo. Johansson and colleagues36 examined 66 patients undergoing cholecystectomy. The abdominal wall was infiltrated with ropivacaine or saline before surgical incision. The pressure exerted to reach maximum pain tolerance was assessed at intervals for 7 days after operation. The only difference between the two groups was after 6 h, which could be explained by a residual effect of ropivacaine. The difference between our results and those of others19 20 may have several explanations. Other workers have studied only early postoperative hyperalgesia, and differences in the extent of surgical trauma, patient categories and methods of assessment may also play a role. The positive findings in the study by Stubhaug and colleagues21 may be explained by the use of an N-methyl D-aspartate (NMDA) receptor antagonist as the NMDA receptor is known to be involved in central hyperexcitability.37–39 After amputation, neuromas of the nerve endings are formed. Such neuromas display a series of abnormalities, including spontaneous activity40 and increased sensitivity to chemical, mechanical and metabolic factors.41 Axotomized cell bodies in dorsal root ganglia may also show abnormal spontaneous activity42 so that dorsal horn neurones receive abnormal input from axotomized nerve endings and from sensitized dorsal root ganglion cells. In our study, it is likely that the afferent barrage from the periphery outlasted postoperative extradural block and thus induced or maintained central sensitization beyond the early postoperative period.
353 In summary, while there is circumstantial evidence from experimental and clinical studies that analgesic treatment before injury prevents pain and hyperalgesia, our study suggested that preoperative and intraoperative extradural block had no long-term prophylactic effect on hyperalgesia, allodynia and wind-up-like pain.
Acknowledgements This study was supported by grants from the Danish Medical Research Council (No. 120828–1), Danish Cancer Society (No. 78400) and Danish Pain Research Centre. We thank M. Frydenberg (Department of Biostatistics, University of Århus) for statistical advice and Dr J. H Christensen, Dr K. Krøner, and the staff at the Orthopaedic Surgical Department and the staff at the Department of Anaesthesia.
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