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Anesth Analg 2004;98:401-407
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000095150.76735.5D

PAIN MEDICINE

The Effects of Remifentanil and Gabapentin on Hyperalgesia in a New Extended Inflammatory Skin Pain Model in Healthy Volunteers

Burkhard Gustorff, MD DEAA, Katharina Hoechtl, Cand med, Thomas Sycha, MD, Evangelos Felouzis, MD DEAA, Stephan Lehr, MSc, and Hans G. Kress, MD PhD

From the Department of Anesthesia and General Intensive Care Medicine (B), University of Vienna, Vienna, Austria

Address correspondence and request for reprints to: Burkhard Gustorff, MD, DEAA, Department of Anesthesia and General Intensive Care Medicine (B), University of Vienna, Währinger-Gürtel 18–20, A-1090 Vienna, Austria. Address email to burkhard.gustorff{at}univie.ac.at


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We tested the responsiveness of measures of hyperalgesia in a model of UVB-induced inflammatory hyperalgesia with remifentanil, gabapentin, and the combination of both drugs in a double-blinded, active placebo-controlled, 4-way-crossover design in 16 volunteers. A circular skin area was irradiated with UVB-light 20 h before the application of gabapentin (600 mg) and 2 h later remifentanil (0.08 µg · kg-1 · min-1, 40 min). In the sunburn spots we observed stable decreases of the heat pain perception thresholds (HPPT, mean difference, 4.45°C; 95% confidence interval [CI], 3.32°–5.59°) and heat pain tolerance thresholds (HPTT; mean difference, 5.43°C; 95% CI, 4.50°–6.35°) compared with normal skin. Further, large areas of mechanical hyperalgesia to pinprick adjacent to the erythema spots developed in all subjects. Overall remifentanil increased the HPPT (mean increase, 2.47°C; 95% CI, 1.86°–3.09°, P < 0.001) and HPTT (mean increase, 3.18°C; 95% CI, 2.65°–3.71°, P < 0.001) and reduced the area of secondary hyperalgesia by 59% (mean decrease, 5326 mm2; 95% CI, 4233–6419 mm2, P < 0.001) compared with placebo. In the sunburn remifentanil markedly increased the HPTT by 86% compared with normal skin (additional increase, 2.57°C; 95% CI, 1.71°–3.43°). This different effect was not seen in the HPPT. With the exception of a small increase of HPTT in the sunburn (P = 0.02) gabapentin had no noticeable effect on either hyperalgesia. In conclusion, opioid analgesia was reliably demonstrated in this new extended pain model.

IMPLICATIONS: Opioid analgesia was reliably demonstrated in a new inflammatory model of primary and secondary hyperalgesia. Gabapentin showed no antihyperalgesic and no opioid-enhancing effect in this model.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Experimental human models of pain and hyperalgesia serve as important methods for defining the analgesic efficacy of drugs in early clinical trials. UVB light-induced inflammatory skin is a valid human model of primary hyperalgesia. The analgesic effect and antiinflammatory potency of nonsteroidal antiinflammatory drugs has recently been studied in this model (1). In a preceding study we extended the model and showed for the first time the development of secondary hyperalgesia in the area surrounding the sunburn (2). Additionally, we demonstrated the prolonged stability of both primary and secondary hyperalgesia over 10 h. Primary hyperalgesia is explained by peripheral sensitization of nociceptors; secondary hyperalgesia is explained by a central excitatory state. Similar patterns of hyperalgesia were observed in postoperative pain suggesting common underlying mechanisms (3). Taken together, the sunburn model of inflammatory skin may be particularly interesting for further studies on antihyperalgesic and analgesic drugs.

Short-acting opioids have successfully been used to characterize previous pain models (4–6). The anticonvulsant, gabapentin, is a potent new drug for the treatment of chronic neuropathic pain (7). Gabapentin produces an antihyperalgesic effect (8,9), and in animal studies it exerted an antihyperalgesic effect in both acute inflammatory and neuropathic pain models (10–13).

We used remifentanil and gabapentin to further validate the sensitivity of the sunburn model and tested the hypothesis that remifentanil reduces primary and secondary hyperalgesia, that gabapentin reduces the area of secondary hyperalgesia, and that it enhances the analgesic effect of remifentanil.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study was approved by the Vienna University IRB. Written informed consent was obtained from 16 paid healthy volunteers (8 females, 8 males) who also had a medical interview. All subjects were aged 19–40 yr and had a body mass index in the normal range (between 15th–85th percentiles). Exclusion criteria were any current acute or chronic pain conditions, use of analgesics within 1 wk, a history of drug abuse, any skin diseases on the relevant areas, pregnancy, and participation in a clinical trial in the 4 wk preceding the study. Subjects agreed to abstain from alcohol, nicotine, and caffeinated drinks during the study period. They were not allowed any oral intake for 6 h before drug administration.

This study was double-blinded, active placebo-controlled, 4-way crossover with respect to oral gabapentin or placebo and IV remifentanil or IV placebo. The volunteers were stratified for gender and subsequently randomly assigned by computer to one of the following 4 groups:

Placebo + placebo.
600 mg gabapentin + placebo.
Placebo + 0.08 µg · kg-1 · min-1 remifentanil.
600 mg gabapentin + 0.08 µg · kg-1 · min-1 remifentanil.

Each subject was studied in 4 sessions at an interval of at least 7 days. In all 16 volunteers all study drug combinations were tested.

Outcome variables for primary hyperalgesia were heat pain perception threshold (HPPT) and heat pain tolerance threshold (HPTT) in the sunburn. The outcome variable for secondary hyperalgesia was the area of secondary hyperalgesia assessed by pinprick.

Study sessions were performed in a quiet, unstressful environment at the same air-conditioned location, always starting at the same time in the morning. One single trained observer performed all tests. After sleeping for 7–8 h, subjects arrived for the study session. A resting period in supine position of at least 10 min was observed before the measurements. Measurements were done at each time point in a uniform sequence: reaction time, pinprick test, then HPPT and HPTT. All measurements started at 20 h after UVB at baseline and were repeated 2 h after intake of gabapentin/placebo, 40 min after start, and 45 min after stop of infusion of remifentanil/placebo.

A single oral dose of gabapentin (Neurontin®, Pfizer Austria) 600 mg or 2 mg of diazepam (Gewacalm®, Nycomed, Austria) serving as active placebo was applied immediately after baseline measurements. Both drugs were packed in identical placebo capsules prepared by a study nurse not involved in the study.

Before each session an impartial nurse prepared an indistinguishable infusion syringe containing remifentanil (Ultiva®, GlaxoWellcome, Vienna, Austria, 20 µg/mL in saline) or diazepam (Gewacalm®, 116.6 µg/mL). The syringes were attached to a continuous syringe pump (Perfusor® fm; Braun, Melsungen, Germany) and piggybacked into a glucose 5% infusion. Remifentanil (0.08 µg · kg-1 · min-1) or IV diazepam ( 0.028 mg · kg-1 · h-1, approximately 2 mg in 30 min for subjects with 70 kg body weight) was infused via an IV catheter (20-gauge) in the left cubital vein for 40 min and then continued until the end of measurements.

From the beginning of the infusion, subjects were continuously monitored for heart rate, respiratory rate, oxygen saturation, and noninvasive arterial blood pressure (right arm, 10-min interval). During the administration of the study drugs, a sedation score (0: awake, 1: tired, 2: asleep but arousable, 3: nonarousable) was assessed every 10 min. All side effects were noted. During each infusion oxygen (2 L/min) was applied via a nasal cannula. Infusion was discontinued in case of a decrease of the respiratory rate <8 breaths/min and/or decrease of peripheral oxygen saturation <85% or sedation score >1.

Sunburn Pain Model
A calibrated UVB-source (Sellasol; Sellas Medizinische Geräte GMBH, Gevelsberg-Vogelsang, Germany; wavelength 290–320 nm) was used to induce an inflammatory skin response to UVB-light. As the degree of inflammation and hyperalgesia depends on the individual skin type, the individual Minimal Erythema Dose (MED) was fixed for all volunteers 24 h after an ascending UVB dose at the lateral side of an upper leg. A circular spot of 5 cm diameter was irradiated with 3 x MED of UVB light at the ventral-medial side of an upper leg. This procedure led to an erythema with a particularly small interindividual variability (14). An area of sunburn per session was induced at the upper leg and repeated subsequently at either contralateral side during the following study sessions. The side of first irradiation was randomized. In no case were blisters observed. The study was performed in late autumn and winter to avoid additional UV exposure during the study period.

Measurements
HPPT and HPTT measurements were performed using a commercially available thermal sensory testing device (TSA-2001; Medoc, Ramat Yishai, Israel). The Peltier thermode, sized 18 x 18 mm, was attached to the skin at the measure sites (erythema, contralateral upper leg) using elastic. To minimize variation of probe application pressure, the elastic was wrapped tightly around the upper leg. Then the elastic was stretched by 2 cm and the ends were adhered. To achieve optimal contact between the probe and the leg surface, care was taken to consider upper leg curvatures in placing the probe. Skin adaptation temperature was 32°C, and rate of temperature change was 0.8°C/s. with a return rate of 4°C/s. Stimulator temperature range was 32°C to 54°C. HPPTs were measured through the method of limits as described previously (15). Subjects were initially trained in a standardized manner to perceive the thresholds. They were instructed to stop the increase of temperature at the first perception of unpleasant heat (HPPT). This test was repeated three times and averaged. There was a 15-s interstimulus rest period between each determination. Afterwards the volunteers were instructed to stop the increase of temperature when the stimulus became intolerable (HPTT). This test was repeated twice and averaged. There was a 60-s interstimulus rest period between each tolerance threshold determination.

Standardized training and measurements of thresholds were conducted before UVB irradiation. This approach avoids sequence effects because bias among sessions other than the first is considered unlikely (16).

Area of Hyperalgesia, Pinprick Test
The area of secondary hyperalgesia was determined at the skin surrounding the erythema by pricking with a hand-held rigid von Frey filament (150 g). Volunteers were asked to keep their eyes closed. Stimulation started approximately 8 cm away from the erythema and was repeated along a pattern of 8 radial spokes. With movement along each spoke at a distance of 5 mm, the subject was asked to report when the sensation of the pricking changed definitely ("different," "burning," or "unpleasant" sensation). This spot was marked with a pen and erased after the measurement of the distance to avoid bias during the following measurements. From these 8 marked edges the area of pinprick hyperalgesia was determined by calculating an octogon.

Reaction Time
The reaction time was assessed by pressing the button of a stopwatch initialized with an acoustic signal. Subjects were asked to stop the watch as fast as possible when the signal appeared. They were blinded as to the start. Measurements were repeated three times and averaged. Signals were presented in intervals of 5 to 15 s in random order.

Statistical Analysis
The main outcome variables were HPPT and HPTT in the sunburn and area of secondary hyperalgesia. Confidence intervals (95% CI) were estimated to quantify the mean baseline differences between normal skin and sunburn (the values of the four sessions were averaged for each volunteer). To examine the variables under the present experimental conditions, analysis of covariance with the fixed factors gabapentin, remifentanil, study day (4 levels), time within study day (2 levels: measurement 2 h after administration of gabapentin and 40 min after infusion of remifentanil), "location" (2 levels: sunburn and normal skin), sex, the covariate baseline measurement, and the random factor volunteer (nested within) sex was performed. The interaction between remifentanil and gabapentin was also included in the model to test whether the analgesic effect is enhanced by the administration of both treatments. A P value < 0.05 was considered to indicate statistical significance, and 95% CI for the least-squares mean differences were estimated. Furthermore, the model was extended by all other potential twofold interactions, which were explored to detect substantial deviations from additivity. To analyze the area of secondary hyperalgesia, the same analysis of covariance model was applied omitting the factor "location." No adjustment for multiple comparisons was performed because the main results were supported by very small P values.

In a previous study with the same sunburn model we observed a standard deviation of the difference between 2 study days of 0.42°C and 2107 mm2 for HPTT and area of secondary hyperalgesia, respectively (2). To detect a 0.5°C reduction of HPTT in the sunburn with 80% power in a 2 x 2 crossover design, a sample size of 2 x 4 (4 patients in each sequence) suffices, assuming a 2-sided significance level of 5%. A 30% reduction of secondary hyperalgesia area (which is equal to a mean decrease of 2090 mm2) can be detected with 2 x 6 patients. Calculations were performed using the SAS software system V8.2 (SAS Institute Inc., 2002, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The sunburn induced a highly significant decrease of the HPPT and HPTT compared with normal skin (mean difference, 5.43°C; 95% CI, 4.50–6.35; and 4.45°C; 95% CI, 3.32–5.59). Figures 1 and 2 show the mean (± SD) HPPT and HPTT at baseline and during treatment. Table 2 summarizes the treatment effect on the main outcome variables for each drug combination in comparison to placebo. Overall, remifentanil increased significantly the HPPT and HPTT in the sunburn and in normal skin (mean increase, 2.47°C; 95% CI, 1.86°–3.09°, P < 0.001; and 3.18°C; 95% CI, 2.65°–3.71°, P < 0.001) compared with placebo. The effect of remifentanil on the HPPT in normal skin was comparable to that in inflamed skin; no significant interaction between remifentanil and the site of measurement (sunburn or normal skin) could be found for HPPT. In contrast, remifentanil exerted an additional increase of the HPTT in the sunburn of 68% compared with normal skin (additional increase, 2.75°C; 95% CI, 1.71°–3.43°, P < 0.001).



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  		Figure 1. Heat pain perception thresholds (HPPT) in normal skin and in the sunburn at baseline (time point 0), 2 h after treatment with gabapentin or diazepam (time point 1), 40 min after remifentanil or diazepam (time point 2), and 45 min after stop of infusion (time point 3). Mean (± SD), n = 16 for each session.

 


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  		Figure 2. Heat pain tolerance thresholds (HPTT) in normal skin and in the sunburn at baseline (time point 0), 2 h after treatment with gabapentin or diazepam (time point 1), 40 min after remifentanil or diazepam (time point 2), and 45 min after stop of infusion (time point 3). Mean (± SD), n = 16 for each session.

 

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  		Table 2. Effect of Gabapentin, Remifentanil, and the Combination in Comparison with Placebo
 
Large areas of secondary hyperalgesia to pinprick developed in all subjects (mean, 9085 mm2, SD, 2449 mm2, Fig. 3). Remifentanil reduced the area of secondary hyperalgesia by 59% (mean reduction, 5326 mm2; 95% CI, 4233–6419 mm2, P < 0.001) compared with placebo. After stopping remifentanil HPPT, HPTT, and the area of secondary hyperalgesia returned to baseline values.



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  		Figure 3. Area of secondary hyperalgesia at baseline (time point 0), 2 h after treatment with gabapentin or diazepam (time point 1), 40 min after remifentanil or diazepam (time point 2), and 45 min after stop of infusion (time point 3). Mean (± SD), n = 16 for each session.

 
Gabapentin had no noticeable effect on HPPT and the area of secondary hyperalgesia compared with placebo (95% CI of the mean gabapentin minus placebo difference, 0.37°C, -0.06°–0.81° and 579 mm2 -194–1353 mm2. HPTT was slightly increased (mean increase, 0.45°C; 95% CI, 0.07°–0.83°, P = 0.02.). Moreover, there was no difference between the effect of remifentanil alone and remifentanil in combination with gabapentin on either outcome variable (P = 0.69, P = 0.35 and P = 0.97 respectively).

Table 1 shows the average reaction time. It increased during the study session by 0.02 s in the active placebo group and by 0.03 s during the combination of gabapentin and remifentanil.


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  		Table 1. Reaction Time During Diazepam Used as Active Placebo, Gabapentin, and Remifentanil, Respectively
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study we used remifentanil and gabapentin to validate the sensitivity of our recently extended model of inflammatory hyperalgesia. Primary hyperalgesia developed in the sunburn, evidenced by significant decreases of HPPT and HPTT as well as large areas of secondary hyperalgesia around the sunburn. It is the major finding of this study that remifentanil significantly reduced both types of hyperalgesia and that gabapentin did not, except for a small increase of HPTT in the sunburn.

Previous human pain models focused particularly on hyperalgesia. The intradermal application of capsaicin induces a well known feature of hyperalgesic response to mechanical stimuli. However, this effect is of short duration. Therefore further human models of continuing hyperalgesia have been under investigation and have been validated using opioids. Petersen et al. (5) repetitively applied heating stimuli to capsaicin-treated skin to prolong the effect. In this model, opioid analgesia and suppression of secondary hyperalgesia was reliably demonstrated with remifentanil. Koppert et al. (4) established a new model of long-lasting electrically-induced hyperalgesia over 2 hours and demonstrated a significant reduction of pinprick hyperalgesia with alfentanil.

Pedersen and Kehlet (17) addressed the central origin of secondary hyperalgesia in a model of burn-induced inflammatory skin pain. Mechanical hyperalgesia was present within the area of secondary hyperalgesia to pinprick around the burn, whereas HPPT was not changed. Recently we extended the sunburn model by demonstrating the UVB-induced development of secondary hyperalgesia around the sunburn (2). As in the burn injury HPPT and HPTT were not changed within the area of secondary hyperalgesia. In the present study we did not assess HPPT in secondary hyperalgesia. However, taken together it is plausible that the opioid induced reduction of the area of hyperalgesia was of central origin.

Secondary hyperalgesia in the burn model seems to be shorter lasting as compared with the UVB burn. This may be an advantage of the new pain model.

We used remifentanil at a small dose, at which significant increases of HPPT have been demonstrated without relevant side effects (5). In this study we could show that even the reaction time is not relevantly impaired at a dose of 0.08 µg · kg-1 · min-1. Even at this small dose, remifentanil increased HPPT and HPTT significantly and reduced the area of secondary hyperalgesia to pinprick by more than 59%. These data characterize experimental sunburn as a highly opioid-sensitive model for primary and secondary hyperalgesia.

Opioids provide analgesia via the block of opioid receptors in the central nervous system (18). They reduce hyperalgesia when applied systemically as in this study or epidurally (19). Interestingly, in sunburn the analgesic effect of remifentanil on HPTT was highly (68%) and significantly larger than in normal skin, whereas this difference was not seen in HPPT. In a human model of heat injury Brennum et al. (19) found a stronger effect of epidural morphine with superior analgesia in the HPPT than in the HPTT. Further studies will have to show whether these differences result from different spinal and supraspinal sites of sensitization and mechanisms of opioid responsiveness.

Gabapentin is an established treatment for neuropathic pain (20). The exact mechanism and site of action of gabapentin is not known. It is not known, particularly in humans, whether gabapentin acts predominantly in the peripheral or central nervous system. However, with the exception of a small increase of HPTT in the sunburn (P = 0.02) we could not find any effect of gabapentin on HPPT nor particularly on secondary hyperalgesia. Our results are consistent with previous findings, where in a human skin injury pain model 1200 mg gabapentin did not reduce the primary hyperalgesia to heat nor the secondary hyperalgesia to pinprick (21). In the heat-capsaicin sensitization model, 1200 mg gabapentin did not affect the primary hyperalgesia response, but reduced secondary hyperalgesia to pinprick (22). In this model, central sensitization is repetitively induced. Gabapentin may therefore act on sensitization and provide preemptive effects, whereas in our study gabapentin was given after established hyperalgesia. In the cold pressure test, 600 mg gabapentin did not influence the tolerance to the acute pain stimulus in volunteers (23).

There is increasing evidence that gabapentin does not provide analgesia in human pain models. The experimental antihyperalgesic effect of gabapentin remains controversial. This may be attributable to differences between hyperalgesia based on sensitization and neuropathic pain. Another reason may be time of application or dosing because, in patients, effective analgesia requires repetitive and larger daily doses (7,24).

Gabapentin enhanced the analgesic effect of morphine in the cold pressure test (23), whereas gabapentin alone had no effect. We failed to demonstrate any opioid-enhancing effect of gabapentin in this study. Dosage does not explain this contradictory fact because in both studies a single dose of 600-mg gabapentin was given. Therefore, it may be explained by the difference of the pain models. Our model is a model of hyperalgesia, whereas the cold pressure test provides acute nociceptive stimuli. However, the same controversy remains for clinical pain where, in a case series, first experiences with gabapentin as an adjuvant to opioid analgesia had been highly promising (25), but further reports were disappointing (26).

As in our sunburn pain model, similar patterns of hyperalgesia and response to remifentanil were observed in postoperative pain patients (3). Therefore our model may share common mechanisms of central neuronal sensitization of postoperative pain. This contribution to some aspects of postoperative pain makes the sunburn model interesting for further studies.

In conclusion opioid analgesia was reliably demonstrated in this new extended model of primary and secondary hyperalgesia. Opioid responsiveness was highly superior in sensitized skin in the HPTT. With the exception of a small increase of HPTT in the sunburn, gabapentin showed no antihyperalgesic and no opioid-enhancing effect in this model.


   Footnotes
 
Presented, in part, at the Annual Meeting of the German Pain Society at Aachen, Germany 2002, and at the Austrian International Anesthesia Congress at Vienna, Austria 2002.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 21, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press