BJA Advance Access originally published online on February 6, 2004
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British Journal of Anaesthesia, 2004, Vol. 92, No. 4 532-535
© 2004 The Board of Management and Trustees of the British Journal of Anaesthesia
Review Article |
Testing of a new pneumatic device to cause pain in humans
1 Department of Trauma Surgery and Sports Medicine, 2 Department of Anaesthesia and Intensive Care Medicine, 3 Department of Magnetic Resonance Imaging, 4 Department of Vascular Surgery and 5 Department of Pathology, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
*Corresponding author. E-mail: heinrich.schubert@uibk.ac.at
Accepted for publication: June 29, 2003
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Abstract |
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Background. Surgical pain typically combines superficial and deep pain. We wished to generate pain that resembled surgical pain, reliably and reproducibly, in volunteers.
Methods. We constructed a computer-controlled pneumatic device to apply pressure to the anterior tibia. The reproducibility of the pain was tested by rating the pressure that caused pain rated 4–5 on a visual analogue scale (VAS) on days 0, 7, and 24 in 10 volunteers. The effect of remifentanil (0.025, 0.05, 0.075, and 0.1 µg kg–1 min–1) on pain tolerance in another set of volunteers (n=11) was used as an indirect measure of the reliability of pain production.
Results. The pressure needed (0.7 (0.3) to 0.9 (0.4) atm (mean (SD)) to induce pain rated 4–5 (VAS) did not vary, showing long-term reproducibility of the method. When pressure was applied to cause increasing pain in volunteers (n=11) 0.05 µg kg–1 min–1 remifentanil increased pain tolerance by 50%. An approximate doubling of the dose (0.1 µg kg–1 min–1) increased pain tolerance significantly more. The linear logarithmic dose-effect relationship shows that the device causes pain reliably, and this can be reduced with opioid treatment.
Conclusion. This pneumatic device can apply pain reliably and reproducibly.
Br J Anaesth 2004; 92: 532–5
Keywords: analgesics opioid, remifentanil; pain, experimental; pain, stimulus; pain, tolerance; volunteers
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Introduction |
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Although experimental non-cutaneous pain in humans1–4 has been studied, most studies are of skin nociception.5 6 Combining cutaneous pain with muscle and bone pain is clinically more relevant because this most resembles pain after surgery.7 Experimental pain should be similar to surgical pain, but it is important that major tissue damage should not result.8 We wished to conduct qualitative and quantitative studies of central pain processing with functional magnetic resonance imaging (fMRI)5 9 so we needed a device to apply painful stimuli that would be suitable for MRI, that is the device must not be magnetizable or disturb the magnetic field.
We constructed a pneumatic device to reliably and reproducibly apply a painful stimulus, with computer control of intensity and duration. We measured reproducibility from the pressure needed to induce pain of a set subjective intensity (4 or 5 on a visual analogue scale (VAS)) on three occasions 7 and 24 days apart. We assessed reliability using a remifentanil infusion where the dose–effect relationship is known.
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Methods |
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TopAbstractIntroductionMethodsResults and commentReferences |
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Pneumatic pressure pain device (all the mechanical parts were designed and constructed by F.Z.)
The device consists of a pneumatic thumper (a pneumatically movable piston with a contact area of 1.2 cm2) set in a cuff, driven by a computer-controlled compressed air source and a switch. The cuff containing the soft PVC thumper is made of plexiglass. Inside the cuff a rubber membrane transmits changes in air pressure to the thumper, which transmits this pressure to a site on the anterior margin of the tibia we choose a position that is sensitive to pressure pain, 10 cm above the ankle. Non-elastic Velcro® tapes fix the cuff with the thumper to the volunteer’s leg (Fig. 1). Pressure-resistant PVC tubes connect the device to the computerized pressure controller, which is supplied from the hospital compressed air supply. The computerized controller uses Labview software (Labview-programmed; Labview 6.0i, National Instruments Corp., Austin, TX, USA) run on a Compaq® Deskpro EP, Series 6350/6.4, PC equipped with an NI DAQ Pad-6020 E card (National Instruments Corp.). It controls the waveform pressure supplied to the pneumatic piston (which can be rectangular but also incremental, decremental, or combinations) and the duration of pressure application, which can be fixed, or applied for increasing or decreasing times. Different patterns of pressure application can be created and run automatically. A pneumatic feedback from the pressure tube supplying the thumper shows any differences between set and applied pressure on the control screen. This control system can be used with other types of stimulation (e.g. heat stimulation) without changing the software.
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The volunteers are given a switch to allow them to turn off the device in pain tolerance experiments, where increasing pressure is applied to generate increasing pain.
Non-magnetizable materials were used to construct the device. To test the suitability of the device for fMRI measurements we made MRI phantom measurements, separate from the volunteer studies.
Experimental protocol
After approval by the local University Ethics Committee and with written informed consent, we enrolled 21 right-handed, non-smoking, healthy, male volunteers (ASA physical status I) with no history of chronic medication or drug or alcohol abuse.
Reproducibility of pain stimulus (10 subjects)
To test the reproducibility of the pain stimulus, the device was fixed to the anterior margin of the left tibia 10 cm above the ankle. We applied enough pressure to cause pain that was rated 4–5 on a VAS of 0–11. The pressure exerted was recorded on the first occasion and repeated after 7 and 24 days.
Reliability of pain stimulus (11 subjects)
The reliability of pain stimulus was tested by studying the effect of remifentanil (0.025, 0.05, 0.075, and 0.1 µg kg–1 min–1) on pain tolerance (per cent of maximum possible effect (%MPE); for details see ‘Statistical analysis’). The device was fixed as before. We set it to deliver a pressure, which increased by 0.2 atm every 5 s. The volunteers were instructed to switch off the device when the pain became intolerable. The time before the device was turned off was taken as the measure of pain tolerance. To prevent possible tissue damage the cut-off time for pressure application was set at 90 s and the cut-off pressure at 3 atm.
Following control measurement of pain tolerance, a continuous infusion of remifentanil was started. Each continuous infusion rate was preceded by a loading dose, where the infusion rate was increased by 25% for a period of 5 min. After an additional 15 min infusion of remifentanil, pain tolerance was measured. The doses were tested in ascending order, at 0.025, 0.05, 0.075, and 0.1 µg kg–1 min–1. The remifentanil infusion was then discontinued and a final control measurement was made 20 min later.
Statistical analysis
The time before the device was turned off is expressed as %MPE. The effect of the drug on the time for which pain is tolerated is expressed as a percentage of the maximum acceptable increase in toleration.
%MPE was calculated as follows:
where predrug time=time pain was tolerated before drug administration; postdrug time=time pain was tolerated during drug administration.
Data are given as mean (SD) or, for age, mean (range) and descriptive data analysis was used. As the Kolmogorov–Smirnov test showed normal distribution of data, analysis of variance (ANOVA) for repeated measurements with Least-Square Difference (LSD) correction for multiple testing was done to compare %MPE at the various doses of remifentanil. A P
0.05 was considered statistically significant. The 50% MPE dose was interpolated from the dose–effect curves measured for remifentanil.
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Results and comment |
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All volunteers (n=21; age: 32 (5) yr; weight: 81 (12) kg; height: 181 (6) cm) completed the study without complications. The mechanical pressure necessary to induce pain rated 4–5 (VAS) did not vary on days 0, 7, and 24 (Table 1), showing that the device gave a reproducible pain stimulus. To avoid habituation to the pain stimulus, we tested the influence of remifentanil on pain tolerance (an indirect measure of the reliability of the pain effect) in another group of volunteers (n=11). Incremental pressure was applied to induce increasing pain during control and remifentanil administration. The correspondence between set and delivered pressure was excellent, as shown on the steering screen. An important difference between earlier studies10 11 and our study was the quality of pain presented. The pain we used was similar to surgical pain, combining superficial and deep qualities, which is relevant for research into perioperative pain. As remifentanil is effective for this type of pain,12 we tested the effect of remifentanil on pain tolerance using this device, using the concept of percentage of the %MPE.
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No difference in pain tolerance was seen in measurements made before or after administration of remifentanil, which makes habituation to repeated stimulation, which has been a problem in other studies13 unlikely in this study. At the lowest dose (0.025 µg kg–1 min–1) remifentanil did not increase pain tolerance (%MPE). Pain tolerance was found to be comparable at 0.05 and 0.075 µg kg–1 min–1and at 0.075 and at 0.1 µg kg–1 min–1. The interpolated 50% MPE dose of remifentanil was 0.05 µg kg–1 min–1 (Fig. 2), which agrees with previous findings in a human heat pain model.14
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If the logarithmic dose–effect relationship was not linear, this would imply that either acute tolerance develops to remifentanil in humans or the application of pressure by our pressure pain device is not reliable. Gustorff and colleagues have shown that continuous low-dose remifentanil does not cause acute opioid tolerance in humans.15 Therefore, if the logarithmic dose–effect relationship was not linear, this could be from unreliable pressure application. However, we found, like others,14 that the logarithmic dose–effect relationship for remifentanil was linear (Fig. 3), suggesting our device allows reliable pressure application.
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For safety reasons we chose a progressive escalation, rather than random application of the tested doses for our young and healthy volunteers. A carry-over effect (application of a lower dose before a higher dose might affect the response to the higher dose) can largely be excluded as the dose–effect relationship we found accords with that reported by others.14
Nausea, vomiting, or even respiratory depression are known side effects in patients given remifentanil for postoperative analgesia (0.025–0.15 µg kg–1 min–1).16 These did not occur in our volunteers (n=11; age 27(4) yr; weight 79 (11) kg; height 182 (6) cm).
The materials used for construction of the cuff with the thumper and tubing were MRI-suitable, shown by an additional (non-volunteer) MRI phantom measurement (results not published). The pneumatic pressure pain device is suitable for fMRI studies on cerebral pain processing, which was a requirement for the device.
In conclusion, we constructed a computer-controlled pneumatic device to apply a painful stimulus, which is reliable and reproducible.
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Acknowledgement |
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The authors are indebted to their volunteers at Innsbruck University Hospital whose participation made this study possible.
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References |
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