1 Department of Algology and 2 Department of Anaesthesiology, Istanbul Medical Faculty and 3 Department of Cancer Epidemiology and Biostatistics, Institute of Oncology, Capa Klinikleri, Istanbul, 34390 Capa, Istanbul, Turkey. 4 Laboratory for Experimental Pain Research, Center for Sensory-Motor Interaction, Aalborg University, Denmark
* Corresponding author. E-mail: yucel{at}istanbul.edu.tr
Accepted for publication March 20, 2004.
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Abstract |
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Methods. The study was randomized, double blinded and placebo controlled. With the approval of the Faculty Ethics Committee, 60 patients undergoing elective thoracotomy were randomized into three equal groups. Group IM had i.m. ketamine 1 mg kg1 in 2 ml plus epidural normal saline; Group EPI had epidural ketamine 1 mg kg1 in 10 ml plus i.m. normal saline; Group C had epidural normal saline 10 ml plus i.m. normal saline 10 ml. Anaesthesia was standardized. Postoperative analgesia was maintained with epidural patient-controlled analgesia using bupivacaine and morphine. Visual analogue scale values and analgesic consumption were evaluated at 2, 4, 6, 8, 10, 12, 24 and 48 h after surgery. The areas of allodynia, pin-prick hyperalgesia and pressure hyperalgesia were measured at 48 h, and days 15 and 30 in all groups.
Results. Intraoperative fentanyl requirement was significantly lower in Group EPI than Group C. The morphine and bupivacaine requirements were significantly lower in Group EPI than the other two groups in the postoperative period. There was reduced pin-prick hyperalgesia and touch allodynia in the EPI group. There were no side-effects attributable to ketamine.
Conclusion. The results of the present study demonstrate that pre-emptive epidural ketamine is effective in reducing intra- and postoperative analgesic requirements, hyperalgesia and touch allodynia.
Keywords: analgesics, postoperative ; analgesic techniques, extradural ; analgesic techniques, i.m. ; measurement techniques, quantitative sensory testing ; pain, acute ; pain, mechanism ; pain, postoperative ; pain, threshold ; pharmacology, ketamine ; surgery, postoperative period ; surgery, thoracic ; theory of analgesic action
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Introduction |
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Several experimental studies have shown that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists inhibits the spinal processing of nociceptive input.57 Ketamine has been used for postoperative pain relief. It not only abolishes peripheral afferent noxious stimulation, but it may also prevent central sensitization of nociceptors.79
There are several contradictory results in the literature regarding the analgesic properties of pre-emptively administered ketamine. Studies using i.v. ketamine have heterogenous designs such as single bolus,10 continuous infusion or continuous infusion combined with other drugs.7 11 Authors have suggested that subanesthetic doses of i.v. ketamine significantly improved postoperative analgesia in these studies. Some investigators have suggested that i.v. ketamine might have some advantages over epidural ketamine when administered with epidural morphine in blocking nociceptive sensitization.12 Moreover, this beneficial effect may only be obtained after systemic administration.8
Chronic post-thoracotomy pain syndrome occurs in 50% of patients after thoracotomy and is generally considered to be neuropathic in origin.13 14 It is thought that providing pre-emptive analgesia to minimize postoperative neuropathic pain may be important in these patients. The prevention of chronic pain after thoracotomy is an area in need of further research.
The aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of pre-emptive ketamine via i.m. and epidural routes for the control of postoperative and chronic post-thoracotomy pain.
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Methods |
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During the preoperative anaesthetic evaluation, patients were instructed in the use of quantitative sensory tests, visual analogue scale (VAS) and the patient-controlled analgesia (PCA) pump.
Patients were not premedicated. In all patients, using the loss-of-resistance technique and under fluoroscopic control, an 18G epidural catheter (Perifix®, Braun Melsungen, Germany) was placed before the operation at T67, T78 or T89 interspace as appropriate to the surgical incision. The catheters were advanced approximately 5 cm into the epidural space. In the i.m. injection group (Group IM), ketamine (Ketalar®, Parke-Davis) 1 mg kg1 in 2 ml normal saline was injected i.m. and normal saline 10 ml was injected epidurally. In the epidural injection group (Group EPI), normal saline 2 ml was injected i.m. and preservative-free ketamine (Ketalar®, Parke-Davis) 1 mg kg1 in 10 ml of normal saline was injected epidurally. The control group (Group C) received normal saline 2 ml i.m. and 10 ml epidurally. All injections were performed 15 min before the induction of general anesthesia.
General anesthesia and surgical techniques
In all three groups, anesthesia was induced with propofol 23 mg kg1, fentanyl 2 µg kg1 and vecuronium 0.1 mg kg1. Following oral intubation using a double-lumen technique, anaesthesia was maintained with isoflorane 11.5% in oxygen/air mixture ( 50%), fentanyl 0.5 g kg1 and vecuronium 0.03 mg kg1. Intraoperative analgesia was controlled with i.v. fentanyl boluses 0.5 µg kg1 titrated to clinical variables such as heart rate and arterial pressure. The isoflurane concentration and fentanyl doses were adjusted with the intention of keeping heart rate and arterial pressure within 20% of pre-incisional baseline values. Continuous monitoring of ECG, arterial pressure, central venous pressure,
and
were performed. The final fentanyl dose was given approximately 20 min before the end of surgery. The total intraoperative fentanyl requirement was recorded.
All incisions were conventional 6th rib posterolateral thoracotomies, and conventional 28 French apical and basal drains were placed before closure in all patients.
Postoperative analgesia
All patients received a standardized epidural PCA (PCEA) regimen (APM®, Abbott Laboratories); the solution contained bupivacaine 1.25 mg ml1 and morphine 0.0750.1 mg ml1, and the PCEA device was programmed to administer a 5 ml loading dose with a bolus dose of 5 ml, and with a 4 h limit of 20 ml. The lockout interval was 30 min. The total bupivacaine and morphine consumption was noted at 48 h.
Measurements
The intensity of pain was rated using a 10 cm VAS (0=no pain; 10=most intense pain imaginable) at 0, 2, 4, 6, 12, 24 and 48 h after the operation. The PCEA regimen was adjusted according to the pain intensity and VAS 3 at rest was considered as satisfactory pain relief.
Areas of pin-prick hyperalgesia, allodynia and pressure hyperalgesia were measured. Pin-prick hyperalgesia was tested using a von Frey hair (745 mN) on the skin starting from outside the hyperalgesic area where no pain sensation was experienced and advancing toward the centre of the incision until the patient reported a distinct change in perception. The measurement was repeated in eight vectors separated by 45°, the distance to the centre was noted, and the surface area calculated using a vector algorithm.15 16 Allodynia was tested by a brush, which was applied in the same manner as the von Frey hair. Pressure hyperalgesia was tested by a manual algometer (Pain Diagnostic & Thermography®, Italy). The threshold was measured before and after surgery in each patient; pressure hyperalgesia was tested in eight vectors separated by 45°, starting from outside the hyperalgesic area and advancing toward the centre of the incision. At the point where the threshold was different from the preoperative measure, its distance to the centre was noted, and surface area calculated using a vector algorithm.
Sensory measurements were performed at 48 h, day 15 and one month after the operation. An anaesthetist blinded to the drug given recorded all parameters.
Side-effects such as sedation, nausea, vomiting, pruritus, urinary retention, hypotension and respiratory depression were noted.
Statistical analysis
Age, weight, duration of surgery, total requirement of intraoperative fentanyl, and postoperative bupivacaine and morphine requirements were analysed using Student's t-test. Areas of allodynia, pin-prick hyperalgesia and pressure hyperalgesia were compared using the MannWhitney U-test. P<0.05 was considered to be statistically significant. Data were analysed using the Statistical Package for Social Scientist (SPSS, Version 7.5) for WindowsTM.
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Results |
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Discussion |
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The analgesic properties of ketamine have been known for a long time; the mechanism or mechanisms are still unclear. Ketamine can act on several receptor systems such as opioid,17 cholinergic17 18 and monoaminergic systems.19 It also shows local anaesthetic effects by the blockade of sodium channels.20 Most clinicians have observed that a low dose of epidural ketamine (410 mg) does not produce significant postoperative analgesic effects in adults.4 21 The different results of various studies using epidurally administered ketamine may be due to malposition of the epidural cathetereither placement outside the epidural space or inappropriate dermatomal placement. In our study, the epidural catheters were inserted under radiographic guidance; thus, the catheter location was confirmed. Another debatable point is the effect of multireceptor applications in postoperative pain. Pre-emptive multireceptor analgesia with ketamine, morphine and local anaesthetics improves postoperative analgesia.4 22 23 Wu and colleagues22 have shown that multimodal pre-incisional analgesia with morphine, bupivacaine and ketamine is better than post-incisional administration.
There are several contradictory results in the literature regarding the analgesic properties of pre-emptive ketamine.4 Burton and colleagues24 have reported that mechanical allodynia is reduced after administration of intrathecal ketamine in a rat model, probably by preventing sensitization in the spinal cord. They further suggested that this effect was sustained for at least 2 weeks, but diminished after 1 month. Lee and colleagues25 have reported that only i.v. ketamine produced pre-emptive analgesia in a rat model. However, the observation period was shorter than that in the Burton study. It seems that blocking the NMDA receptors to inhibit central sensitization may be necessary for only a relatively short time. Contrary to these results, in the present study, the areas of pin-prick hyperalgesia and touch allodynia were significantly smaller in the group receiving epidural ketamine and i.m. ketamine than in controls, even 1 month after surgery. It could be argued that the results of the experimental studies have limited clinical relevance. However, many clinicians believe that in surgical procedures such as thoracotomy and mastectomy, pre-emptive approaches may help to prevent post-surgical neuropathic pain.13 14 In most of the clinical studies using ketamine, authors have not assessed wound hyperalgesia.7 8 26 Tverskoy and colleagues27 have shown that ketamine is effective for wound hyperalgesia but not for postoperative pain. They believe the pre-emptive inhibitory effect on wound hyperalgesia by fentanyl and ketamine is due to prevention of central sensitization. Ilkjaer and colleagues26 have studied pre-emptive i.v. ketamine infusion and found no effect on the pressure pain threshold or pin-prick sensation using a von Frey hair on the second postoperative day. In the present study, the areas of pin-prick hyperalgesia and touch allodynia were significantly smaller in Group EPI than in Groups IM and C 15 days and 1 month after surgery. The areas of pressure hyperalgesia were significantly smaller in Groups EPI and IM than in Group C, and the areas of Group EPI were significantly smaller than in Group C patients 1 and 15 days after surgery. The differences between our findings and Ilkjaeker's results could be explained by differences in methodology, as their evaluation of mechanical hyperalgesia was 10 cm from the surgical incision, not in the area of hyperalgesia around the wound. In addition, their observation period was only 2 days, which was shorter than our study. Stubhaug and colleagues7 reported a reduction of the area of mechanical hyperalgesia around the surgical wound on postoperative days 1, 3 and 7. However, they did not find reduced pain intensity or morphine consumption.
The results of De Kock and colleagues' study8 support our results, which suppose that a subanesthetic dose of ketamine reduces wound hyperalgesia. However, they only evaluated mechanical hyperalgesia using a von Frey hair and only found an effect after systemic administration. The results of the present study support their results as we have also found significant differences between Groups IM and C 1 month after surgery. However, there is an important difference between the two studies; the results of the group receiving epidural ketamine are better than that of the group receiving i.m. ketamine in our study with respect to pin-prick hyperalgesia and allodynia. This difference could be explained by different protocols. De Kock and colleagues used local anaesthetics, opioids and 2 agonists before and during surgery.8 It may be that these agents blocked the effect of ketamine on spinal NMDA receptors. Another important difference is that they only evaluated mechanical hyperalgesia for 72 h. Despite the differences between our results and De Kock's study, both evaluated the long-term effects of ketamine and found reduced wound hyperalgesia and residual pain, which supports the proposal that central sensitization can be blocked by pre-emptive ketamine.
Different stimulation modalities are widely used to study the mechanisms of pain in humans.15 16 28 Despite experience with experimental pain models using sensory testing such as thermal, mechanical and electrical stimuli, the appropriate measurements in clinical trials of acute and chronic pain are still unclear.
We still do not know if unrelieved acute postoperative pain is a risk factor for developing chronic postoperative pain, and whether we can inhibit such a mechanism. The use of different types of stimuli and stimulusresponse functions such as the degree of hyperalgesia may give more information about the mechanisms of chronic neuropathic pain after surgery, as well as the effect of different drugs and modalities to control it.
In conclusion, pre-emptive epidural ketamine is effective in reducing pin-prick hyperalgesia, and touch allodynia. Unfortunately, there are several issues for future investigation such as the most effective dose, timing of administration and necessity for continuous infusion.
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References |
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