1 Department of Anaesthesia and General Intensive Care Medicine (B), University of Vienna, Währinger-Gürtel 1820, A-1090 Vienna, Austria. 2 Department of Anaesthesia and Intensive Care, Marienkrankenhaus, Soest, Germany
Corresponding author. E-mail: burkhard.gustorff@univie.ac.at This study was presented in part at the Annual Meeting of the German Pain Society, Hamburg, Germany, September 2000 and at the Annual Meeting of the European Society of Anaesthesiologists, Vienna, April 2000.
Accepted for publication: April 19, 2003
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Abstract |
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Methods. Eighteen healthy volunteers were randomized in a placebo-controlled, double-blind crossover study to receive an infusion of remifentanil 0.08 µg kg1 min1 or saline for 40 min. Test procedures included determination of pain perception thresholds (PPT) and pain tolerance thresholds (PTT) to heat, cold, and current at 5, 250 and 2000 Hz, at baseline and at the end of the infusion.
Results. Both current at 5 Hz (PPT 3.69 (SD 2.48) mA vs 2.01 (1.52) mA; PTT 6.42 (2.79) mA vs 3.63 (2.31) mA; P<0.001) and 250 Hz (PPT 4.31 (2.42) mA vs 2.89 (1.57) mA; PTT 7.08 (2.68) mA vs 4.81 (2.42) mA; P<0.001) and heat (PPT 47.4 (2.7)°C vs 45.2 (3)°C; PTT 51.1 (1.8)°C vs 49.7 (1.8)°C; P<0.05) detected a significant analgesic effect of remifentanil compared with placebo. No analgesic effect was shown on cold or current at 2000 Hz. The magnitude of responsiveness of current stimuli at 5 Hz and 250 Hz was superior to heat stimuli.
Conclusion. Both current (5 and 250 Hz) and heat sensory testing detected a significant analgesic effect of a remifentanil infusion compared with saline. There was more response to current testing.
Br J Anaesth 2003; 91: 2038
Keywords: analgesics opioid; pain, experimental
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Introduction |
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An alternative for determining the effect of analgesics is quantitative sensory testing (QST). QST has the particular advantage of being a functional test that provides a quantitative pain stimulus and assesses the subjects individual response to the stimulus.2 3 The repeatability of the visual analogue scale has been shown to be poor in a setting of human experimental heat pain compared with thermal QST.4 QST also provides a reliable assessment of changes in pain thresholds.
Both thermal and current sensory testing are currently used. Thermal QST (heat and cold) allows a distinction between predominantly C-fibre activity and A-fibre activity. Current sensory testing by the means of the Neurometer® stimulator device offers the possibility of predominant stimulation of C, A
and Aß fibres.5
The assessment of pain and pain tolerance thresholds is established in QST. However, there are conflicting data indicating which parameter is the more sensitive for the detection of analgesic effects.2 Also, the data on opioid sensitivity of thermal and current QST are conflicting. Recently we showed a dose-dependent increase in heat pain thresholds during a stepped remifentanil infusion in normal skin of volunteers.6 In contrast, heat pain tolerance thresholds (PTT) during a stepped alfentanil infusion were not significantly different from saline, whereas electrical PTT showed a significant doseresponse relationship.7 For QST, neither heat nor cold stimuli, or different electrical stimuli have been compared in relation to a defined opioid dose, nor has this been done for pain thresholds and pain tolerance thresholds in either model.
The aim of this study was to investigate the responsiveness of thermal and current QST to a constant dose of the µ-opioid receptor agonist remifentanil. We set out to compare heat and cold pain stimuli and to compare current sine-wave electrical stimuli at three different frequencies (5, 250 and 2000 Hz). We further compared pain perception thresholds (PPT) and PTT during each type of stimulation.
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Methods |
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Measurements
PPT and PTT were assessed by both thermal and current quantitative sensory testing. Thermal sensory testing was done using a commercially available thermal sensory testing device (TSA-2001, Medoc, Ramat Yishai, Israel). The Peltier thermode, size 18x18 mm, was attached to the left volar forearm. Skin adaptation temperature was 32°C, and the rate of temperature change was 0.8°C s1, with a return rate of 4°C s1. Stimulator temperature range was 3253°C and 1°C. Thresholds were measured by the method of limits as described previously.8 Subjects were initially trained in the use of the device in a standardized manner. They were instructed to stop the decrease or increase in temperature at the first perception of unpleasant cold (cold pain perception threshold, CPPT) and heat (heat pain perception threshold, HPPT) by means of a switch. Pain thresholds were measured in triplicate and averaged. Interstimulus intervals were 30 s. Afterwards the volunteers were instructed to stop the decrease and increase of temperature at the perception of unbearable cold (cold pain tolerance threshold, CPTT) and heat (heat pain tolerance threshold, HPTT). This was performed twice and averaged. Interstimulus intervals were 60 s.
Current sensory testing was performed by means of the neuroselective stimulator device Neurometer® (CPT, Neurotron, Baltimore, USA) through the method of limits at three frequencies: 2000, 250 and 5 Hz. Current PTT (EPPT) and PTT (EPTT) were assessed in a similar manner to the thermal sensory testing. They were performed at the tip of the left index finger in triplicate and twice, respectively, for each frequency, and averaged. Interstimulus intervals were 15 s and 60 s, respectively.
Measurements were made at baseline (before drug infusion) and then repeated at 25 min (TSA) and 35 min (Neurometer) after the start of the drug infusion.
Study sessions were performed in a quiet, unstressful environment in the same air-conditioned location, always at the same time in the afternoon, and with the volunteer in a sitting position. The same trained observer supervised all tests.
From the beginning of the study, subjects were continuously monitored for heart rate, ventilatory frequency, oxygen saturation and non-invasive arterial pressure (right arm). During the application of the study drugs, a sedation score (0=awake, 1=tired, 2=asleep but arousable, 3=non-arousable) was assessed every 10 min. All side effects were noted.
Subjects were randomly assigned by computer to two groups receiving consecutively either remifentanil (group 1) (Ultiva®, GlaxoWellcome, Austria) or saline (group 2) in a crossover fashion. The order of applications was randomized between the groups. Each subject was studied in two sessions at least 5 days apart.
Before each session, a study nurse not otherwise participating in the study prepared an indistinguishable infusion syringe containing remifentanil or saline. The syringes were attached to a continuous syringe pump and administered as though each contained active drug.
After insertion of an i.v. catheter (20G) at the left cubital vein, a continuous infusion of remifentanil 0.08 µg kg1 min1 or saline was applied for 40 min. Based on our previous study, this dose significantly increased HPPT without inducing side-effects.6
During each session glucose 5% 150 ml was infused continuously and oxygen 2 litre min1 was administered nasally. The infusion was stopped in the event of a drop in ventilatory frequency to less than 7 bpm, peripheral oxygen saturation less than 85%, heart rate less than 40 beats min1, mean blood pressure less than 60 mm Hg, sedation preventing adequate handling of the switch (sedation score 2), or at the volunteers request.
Statistical analysis
The intention was to detect a 50% difference between pain threshold values, an effect level of 0.75, with an error of 5%. Using a two-tailed Students t-test, the study population was calculated to be 18 participants to reach a minimum power of 85% (nQuery software for Windows, Statistical Solutions, Boston, MA, USA).
Raw data were corrected to baseline values. Assessment of the non-linear association between CPPT, CPTT, HPPT, HPTT, EPPT and EPTT values and probability of pain reception was accomplished by the means of the binary logistic regression procedure of the SPSS software, version 10.0 for Macintosh (SPSS inc., Chicago, IL, USA).
Significance of the coefficient estimate was calculated using the Wald test,9 and a model fit to the observed data was performed by the Hosmer and Lemeshow goodness-of-fit-test.10 The prediction probability was also calculated for each variable. To identify possible best combinations of testing procedures, procedures showing a significant association with pain perception were then entered into a stepwise logistic regression model and non-significant variables were eliminated.
The area under the receiver operating characteristic (ROC) curve was used to summarize the accuracy of threshold values. The ROC curve for each index plots sensitivity (fraction of responsive volunteers who are correctly predicted to be responsive) against 1specificity (fraction of unresponsive volunteers who are correctly identified) and reflects the discriminating power of the index.11 The area under the ROC curve was determined non-parametrically together with SE and 95% confidence interval (CI).12 The prediction probability was calculated.13 Values can be between 0 and 1. A value of 0.5 indicates that the screening measure is not better than chance, whereas a value of 1 implies perfect performance.14
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Results |
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Discussion |
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QST is well established in the assessment of nociception in man. Both thermal and current threshold testing provide standardized and quantitative results.3 However, the interindividual variability of pain perception is high. We therefore performed a crossover trial, allowing intra-individual comparisons with placebo. Sensitivity to opioid analgesia has separately been shown for both methods. 2 15 16 The direct quantitative comparison of two different measurement methods like heat and current is not possible. We therefore chose an approach of calculating the ROC curves.
Our study is the first to find significant opioid sensitivity of both heat and current sensory testing methods at a given dose of opioid. In contrast Luginbühl and colleagues7 using a similar methodology failed to demonstrate a significant analgesic effect of alfentanil on electrical and heat PTT compared with placebo. With the same 5-Hz current stimulus used in our study, Liu and colleagues16 demonstrated a 50% increase in pain perception at fentanyl 1 µg kg1 i.v.
Moreover, we found a clear tendency towards a more pronounced opioid responsiveness of current compared with heat. These findings add pharmacological evidence to neurophysiological findings that electrical nociception is different from heat nociception and should be considered separately.
The observation that remifentanil increased pain thresholds at 5 and 250 Hz, but not at 2000 Hz is consistent with the hypothesis that pain evoked by 5 and 250 Hz is mediated predominantly by nociception of C and A fibres and that opioids inhibit dorsal horn activity evoked by small unmyelinated C fibres.1719
We did not show an analgesic effect of remifentanil on cold pain stimuli. The negative result could be because of the small size of our probe. However, for heat, we demonstrated highly significant effects with the same thermode. To our knowledge, this is the first study that shows, for thermal sensory testing, a lack of opioid-induced analgesia for cold pain at a significant analgesic dose for heat pain. The absence of cold analgesia is in agreement with findings that cold stimulation of normal skin induces activity in small myelinated fibres, whereas opioid activity is predominately on C fibres. Thus, the exclusive opioid responsiveness to heat pain stimuli is consistent with the fibre selectivity of thermal QST as described by Yarnitsky and colleagues20 in untreated volunteers. Taken together these findings support further pharmacological approaches to characterize pain mechanisms and may lead to better understanding of controversial opioid responsiveness in hyperalgesia.21
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Acknowledgement |
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References |
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