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Anesth Analg 2007;104:1397-1403
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000261305.22324.f3

ANESTHETIC PHARMACOLOGY

Section Editor:
Marcel E. Durieux Section Editor Tony Gin

Modulation of Remifentanil-Induced Postinfusion Hyperalgesia by Propofol

Boris Singler, MD*, Andreas Tröster, MD*, Neil Manering{dagger}, Jürgen Schüttler, MD, Prof.*, and Wolfgang Koppert, MD*

From the *Department of Anesthesiology, University Hospital Erlangen, Erlangen, Germany; and {dagger}Department of Anesthesia, Stanford University School of Medicine, Stanford, California.

Address correspondence and reprint requests to Prof. Dr. med. Wolfgang Koppert, Department of Anesthesiology, University Hospital Erlangen, Krankenhausstr. 12, D-91054 Erlangen, Germany. Address e-mail to koppert{at}kfa.imed.uni-erlangen.de.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. During anesthesia, however, opioids are commonly administered in combination with either IV or inhaled hypnotic drugs. In this investigation we sought to determine the analgesic and antihyperalgesic properties of propofol in subhypnotic concentrations on remifentanil-induced postinfusion hypersensitivity in an experimental human pain model.

METHODS: Fifteen healthy volunteers were included in this randomized, double-blind, and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (41.7 ± 14.3 mA) induced spontaneous acute pain (numerical rating scale = 6 of 10) and stable areas of hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during and after a 30 min target-controlled infusion of propofol (1.5 µg/mL) and remifentanil (0.05 µg · kg–1 · min–1), either alone or in combination (propofol 1.5 µg/mL with remifentanil 0.025 or 0.05 µg · kg–1 · min–1).

RESULTS: During infusion, propofol significantly reduced the electrically evoked pain to 72% ± 21% of control. Subhypnotic concentrations of propofol did not lead to any hyperalgesic effects. Coadministration of remifentanil led to synergistic analgesic effects (to 62% ± 26% and 58% ± 25% of control, for 0.025 or 0.05 µg · kg–1 · min–1, respectively), but upon withdrawal, pain and hyperalgesia increased above control level.

CONCLUSIONS: The results suggest clinically relevant interactions of propofol and remifentanil in humans, since propofol led to a delay and a weakening of remifentanil-induced postinfusion anti-analgesia in humans. Nevertheless, pronociceptive effects were not completely antagonized by propofol, which may account for the increased demand for analgesics after remifentanil-based anesthesia in clinical practice.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Brief exposures to µ receptor agonists can induce hyperalgesic effects for days (1,2), which is clinically significant because large doses of intraoperative µ opioid receptor agonists can increase postoperative pain and morphine consumption (3–5). Based on the observation that administration of opioids can induce pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms, such as activation of the N-methyl-d-aspartate (NMDA)-receptor system (6–9).

However, the clinical relevance of these observations is still unclear. During general anesthesia, opioids are commonly administered with either IV or inhaled hypnotic drugs, and several studies have been designed to evaluate if hypnotics per se are analgesic or hyperalgesic (10–15). The results of these studies are conflicting, especially regarding the IV hypnotic drug propofol: while some authors found analgesic effects when administering propofol in subhypnotic concentrations (11,12), others observed an enhanced pain sensitivity from propofol administration (10,14,15). Furthermore, propofol was shown to interact with NMDA-receptors (16–18). Thus, it is suggested that propofol might modulate analgesia and postinfusion hyperalgesia elicited by opioids. The effects of propofol, especially in the latter context, have not been examined in humans.

The objective of this study was to investigate the effects of subhypnotic concentrations of propofol on remifentanil-induced postinfusion hyperalgesia in a human model of electrically evoked pain and secondary hyperalgesia (19). Continuous electrical stimulation induces central sensitization by an activation of primarily mechano-insensitive ("silent") C-nociceptors (20), a class of nociceptors activated during tissue damage and inflammation. Thus, it is suggested that this experimental model mimics some aspects of continuous pain and enhanced pain sensitivity under clinical conditions, e.g., in postoperative pain states.

Remifentanil, a short-acting µ opioid receptor agonist, was chosen because it has been reported to rapidly induce tolerance (9,21,22) and because of its rapid pharmacokinetics, which make it extremely suitable for volunteer studies.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Fifteen healthy male volunteers were enrolled in this randomized, double-blind, and placebo-controlled study in a cross-over design. The average age was 26.5 ± 3.5 yr (range 22–35 yr) (Table 1). All volunteers were familiarized with the stimulation procedures before participation. No volunteer had a known drug allergy or was taking medication that may have interfered with pain sensations (i.e., analgesics, antihistamines, calcium, or sodium channel blockers). Each volunteer gave informed consent to take part in the study. The experiments were performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty of the University of Erlangen-Nuremberg.


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  		Table 1. Demographic Data

 

Transdermal electrical stimulation was used to induce continuous pain and secondary mechanical hyperalgesia as described previously (9,19,23). Briefly, two microdialysis fibers equipped with internal stainless steel wires were inserted intradermally at a distance of 4 mm in the central volar forearm of the volunteers. Monophasic, rectangular electrical pulses of 0.5 ms duration were applied with alternating polarity via a constant current stimulator (Digitimer S7, Digitimer, Hertfordshire, UK) at 2 Hz. The current was gradually increased during the first 15 min of stimulus administration, targeting a pain rating of 6 on a 11-point numeric rating scale (NRS; 0 = no pain and 10 = maximum tolerable pain), and was then kept constant for the remaining 135 min of the experiment.

Five separate treatment trials were performed, at least 2 wk apart. The volunteers received remifentanil (Ultiva, Glaxo SmithKline, Germany) as a constant IV infusion of 0.05 µg · kg–1 · min–1, or propofol (Disoprivan, AstraZeneca, Germany) as a target-controlled infusion, targeting a propofol effect site concentration of 1.5 µg/mL. The target-controlled infusion pump was set to reach this concentration in 5 min. Propofol was administered either alone or in combination with a constant IV infusion of remifentanil at two doses (0.025 or 0.05 µg · kg–1 · min–1). Saline served as control (Fig. 1). All drugs were delivered for 30 min, starting 30 min after onset of stimulation. The continuous constant-dose infusions of remifentanil were chosen according to previous studies in which a infusion rate up to 0.05 µg · kg–1 · min–1 was found to be effective and safe when administered with propofol in subhypnotic concentrations (24).


Figure 114
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  		Figure 1. Schematic illustration of the experimental protocol. The volunteers received propofol (1.5 µg/ mL) and remifentanil (0.05 µg · kg–1 · min–1), either alone or in combination (propofol 1.5 µg/mL with remifentanil 0.025 or 0.05 µg · kg–1 · min–1). Saline served as control. Continuous pain and areas of punctate-hyperalgesia and allodynia were repeatedly determined.

 

An examiner asked the volunteers to report side effects such as sedation, dizziness, pruritus, and nausea. The observer's assessment of alertness/sedation scale (25) was obtained to measure the level of alertness in sedated volunteers (5 = awake/alert, 4 = awake but drowsy, 3 = asleep but easily rousable, 2 = asleep but difficult to rouse, 1 = asleep/unrousable). Pulse oximetry (Spo2), electrocardiogram, and noninvasive arterial blood pressure were monitored continuously during the study.

The volunteers were told to rate the intensity of continuous pain induced by the electrical stimulation on the NRS every 5 min (Fig. 1). The area of pinprick hyperalgesia was determined with a 450 mN von Frey filament (Stoelting, Chicago, IL) every 10–15 min (Fig. 1). The borders of the hyperalgesic areas were delineated by moving along four linear paths parallel and vertically to the axis of the forearm from distant starting points towards the stimulation site (step size 0.5 cm), until the volunteer reported increased pain sensations evoked by the von Frey filament (pinprick hyperalgesia). For further analysis, both diameters were used to estimate the areas of secondary hyperalgesia (D/2 x d/2 x {pi}). Areas of pinprick-hyperalgesia were repeatedly tested in 15 min intervals during the first 90 min and in 30 min intervals during the next 60 min of the experiment.

Treatment effects over time were evaluated using two-way repeated measures analysis of variance (ANOVA) including the effects "treatment" and "time course." If significant treatment effects were detected, pain ratings as well as data of secondary hyperalgesia were transformed in areas under the curve (AUC) of subsequent 30 min intervals and post hoc testing was performed using two-sided Student's t-tests corrected with the Bonferroni procedure. For statistical evaluation, pain ratings and hyperalgesic areas of volunteers who did not respond to the questions of the examiner (observer's assessment of alertness/sedation scale <2) were arbitrarily set to "0." However, they were displayed in two different ways: with values arbitrarily set to "0" at the time points volunteers did not respond, or with missing values at those time points. Significance levels throughout this study were P ≤ 0.05. The STATISTICA software package (Statsoft, Tulsa, OK) was used for statistical analysis.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
To provoke a pain rating of NRS 6 (NRS from 0 to 10), the average current was increased to 38 ± 14 mA (range 11–72 mA) during the first 15 min of electrical stimulation. No significant session differences were observed. After keeping the current constant, the pain ratings decreased significantly, reaching NRS 5.5 ± 0.7 at 30 min (P < 0.001, by ANOVA) (Fig. 3A). No significant differences between the treatment groups were observed until this time point. During the first 30 min of electrical stimulation, areas of pinprick-hyperalgesia remained stable at about 32 ± 15 cm2 (100%, Fig. 3B).


Figure 314
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  		Figure 3. Pain ratings (A) and hyperalgesic areas to pinprick (B) were significantly reduced during propofol administration, either alone or in combination with remifentanil. Upon withdrawal, administration of remifentanil either alone or in combination with propofol, led to increased pain ratings and areas of secondary hyperalgesia. Data are expressed as mean ± sem (lower panels), and as mean area under the curve ± sem of 30 min time-intervals (upper panels, *P < 0.05, by ANOVA and planned comparisons corrected with the Bonferroni procedure, active treatment versus placebo). Pain ratings and hyperalgesic areas were displayed in two different ways: with missing values at the time points volunteers did not respond, or with values arbitrarily set to "0" at those time points (gray shaded).

 

Almost all subjects developed subjective side effects during the drug infusion (Table 2). Sedation was more pronounced during coadministration of remifentanil, and was paralleled by a significant decrease in oxygen saturation and mean arterial blood pressure (P < 0.05, respectively, by ANOVA and planned comparisons) (Fig. 2). During infusions of propofol with remifentanil four volunteers were unrousable for different time intervals (Table 2). No more than 15 min after termination of the infusions, all subjects were awake and promptly answered the investigators' questions, their pain ratings and estimations of hyperalgesic areas were accurate and reproducible. At no time did subjects complain of negative side effects or anxiety; neither respiratory depression nor muscular rigidity was observed. Heart rates remained unchanged during the infusion (n.s., by ANOVA) (Fig. 2).


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  		Table 2. Sedative Effects of Drug Infusions

 

Figure 214
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  		Figure 2. Time course of oxygen saturation (Spo2), median arterial blood pressure (MAP) and heart rate (HR) in the four treatment groups. Infusion of propofol with remifentanil resulted in a significant decrease in (Spo2) and MAP (P < 0.05; respectively, by ANOVA), while HR remained unchanged (n.s.; by ANOVA). Data are expressed as mean and sem (note that error bars are depicted in one direction only to increase clarity).

 

Remifentanil significantly decreased pain ratings during the infusion as compared to placebo (Fig. 3A) (P < 0.01, by ANOVA). However, 15 min after cessation of the infusion, pain ratings had increased and exceeded the levels observed after the placebo infusion. Analgesic effects during infusion of propofol were less intense than those observed after remifentanil (P < 0.05, by ANOVA, as compared to placebo). After cessation of the infusion the pain ratings did not exceed the levels observed after the placebo infusion. Coadministration of remifentanil 0.025 and 0.05 µg · kg–1 · min–1 decreased pain ratings during the infusion similar to those observed after remifentanil (P < 0.01, by ANOVA, for propofol and remifentanil 0.025 or 0.05 µg · kg–1 · min–1, respectively, as compared to placebo) (Fig. 3A). However, although pain ratings after propofol infusion remained below the control values, those after coadministration of propofol and remifentanil increased and exceeded control values (P < 0.001, by ANOVA). The anti-analgesic effect after the combination of propofol and remifentanil was most prominent at 60–90 min after cessation of infusion.

Infusion of propofol significantly reduced the areas of punctate-hyperalgesia to 23 ± 13 cm2 (P < 0.05, by ANOVA, as compared to placebo) (Fig. 3B). These antihyperalgesic effects were only prominent during infusion; after cessation of the infusion, hyperalgesic area values were not different from control values (by ANOVA, Fig. 3B). Administration of remifentanil, either alone or in combination with propofol, led to diminished hyperalgesic areas during infusion similar to those observed during the infusion of propofol alone. However, shortly after cessation of the infusions, hyperalgesic areas tended to exceed the values observed after placebo infusion (P < 0.1, by ANOVA, as compared to placebo). The coadministration of propofol and remifentanil 0.05 µg · kg–1 · min–1 led to significantly increased hyperalgesic areas as compared to propofol alone (P < 0.05, by ANOVA and planned comparisons) (Fig. 3B).


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study we investigated the effects of subhypnotic concentrations of propofol on remifentanil-induced analgesia and postinfusion hyperalgesia in a human model of electrically evoked pain and secondary hyperalgesia. Our results provide experimental evidence for a delay and a weakening of remifentanil-induced anti-analgesia by subhypnotic doses of propofol. Nevertheless, hyperalgesic effects of the opioid have been observed even after they have been combined with propofol, which may have contributed to increased postoperative demand for analgesics after remifentanil-based anesthesia in clinical practice (4,5).

Remifentanil is a pure and short-acting µ opioid receptor agonist with rapid pharmacokinetics. It has been reported to rapidly induce tolerance in healthy volunteers (9,21,22), which makes it suitable for investigating opioid-induced tolerance and hyperalgesia. Single, continuous, constant-dose infusions of remifentanil up to 0.1 µg · kg–1 · min–1 were found to be effective and safe in healthy volunteers (26) and in patients (27,28). However, when coadministered with propofol, remifentanil produced pronounced sedative effects and respiratory depression. Viviand et al. (24) found constant-dose infusions of remifentanil not higher than 0.05–0.06 µg · kg–1 · min–1 suitable for sedation-analgesia in labor when combining it with propofol. On the basis of these data, we decided to administer remifentanil at two continuous constant doses, 0.05 and 0.025 µg · kg–1 · min–1. Both continuous constant doses were combined with propofol at a target concentration of 1.5 µg/mL. This propofol concentration is commonly used during regional anesthesia or interventional procedures, such as radiology. Furthermore, propofol, at target concentrations between 1.0 and 1.2 µg/mL, was shown to decrease anxiety without over-sedation (29) and reduce pruritus, nausea, and vomiting (30).

Almost all subjects developed drowsiness during infusion of the active drug; sedation was significantly more pronounced during coadministration of remifentanil. Six volunteers were unrousable for part of the infusion of propofol with remifentanil. Thus, sedation can be expected to influence psychophysical responses, especially during coadministration of remifentanil. The importance of sedation for the evaluation of psychophysical responses to experimental pain was shown by Petersen-Felix et al. (14) who tested subhypnotic concentrations of propofol and analgesic concentrations of alfentanil on painful electrical and heat stimulation and on mechanical pressure pain. In the present study, 15 min after termination of the infusions all subjects were awake and alert, and promptly answered the investigators' questions. Thus, sedative effects of propofol on remifentanil-induced postinfusion anti-analgesia and hyperalgesia can be surely ruled out in this period which developed only 15 min after end of the infusions. The pronociceptive effects of the µ opioid receptor agonist, remifentanil, were studied using electrically evoked pain and secondary hyperalgesia. This validated pain model provides a stable experimental approach which is suitable to test the analgesic and antihyperalgesic effects of different classes of drugs with high temporal resolution and minimum tissue damage (8,9,19,31). Strong electrical stimuli were used to activate, besides conventional C- and A{delta}-nociceptors, a subpopulation of mechano-insensitive C-nociceptors (silent nociceptors) that are characterized by an unusually high electrical threshold (>20 mA). This class of nociceptors is critically involved in the induction of central sensitization leading to secondary mechanical hyperalgesia. It is suggested that continuous electrical stimulation mimics continuous activity of chemonociceptors, such as in postoperative pain states, or in some neuropathic pain conditions.

In previous studies, remifentanil resulted in a dose-dependent alleviation of electrically induced pain during a short-term infusion, but pain ratings exceeded placebo levels in the early postinfusion period (9,23). Interestingly, acute heat pain and electrical pain thresholds were not decreased during this period (22). The underlying mechanism of postinfusion anti-analgesia is still unclear. Opioid-induced facilitation of NMDA-receptor activation has been linked to postinfusion hyperalgesia in rodents (1); however, NMDA antagonists did not block postinfusion anti-analgesia or the decrease of pressure pain tolerance in humans (9,22). Alternative explanations for opioid-induced postinfusion anti-analgesia include internalization, and thereby inactivation, of µ opioid receptors by remifentanil, a remifentanil-induced up-regulation of the cAMP-pathway, or spinal dynorphin release leading to enhanced exocytosis of excitatory amino acids (32). In our study, propofol led to a delay and a weakening of remifentanil-induced anti-analgesia: Significant anti-analgesic effects of single, continuous constant dose infusions of remifentanil were already observed 15–30 min after its cessation, while the anti-analgesic effects after coadministration of remifentanil with propofol were not prominent until 60 min after cessation of infusion. Thus, propofol might counteract in a clinically relevant manner pronociceptive systems, possibly by direct action on spinal {gamma}-amino-butyric acid A and glycine receptors (33,34). Alternative explanations for the antinociceptive actions of propofol include a propofol-induced release of β-endorphins (35), or activation of cannabinoid receptors (36).

As mentioned earlier, secondary mechanical hyperalgesia observed in our pain model is based on central sensitization processes. NMDA-receptors were shown to play a crucial role in the induction and maintenance of central sensitization (37), and NMDA-receptor antagonists were able to reduce areas of secondary hyperalgesia in our model (19). Interestingly, direct activation of different subunit combinations of the NMDA-receptor system by remifentanil has been identified as accounting for remifentanil-induced secondary hyperalgesia (38), even though it has been suggested that remifentanil activates NMDA-receptors only in the presence of glycine (39). In line with these experimental findings, combining remifentanil with the NMDA-receptor antagonist ketamine has been shown to reduce postoperative opioid requirements in clinical practice (5). Since propofol was shown to inhibit the NMDA-receptor, presumably via inhibitory effects of propofol on NMDA-receptor NR1 subunit phosphorylation in neurons (18), it could be assumed that propofol might attenuate postinfusion hyperalgesia elicited by remifentanil. However, our results did not support this assumption: Areas of secondary hyperalgesia after a single administration of remifentanil, as well as after coadministration of remifentanil with propofol, were enlarged as compared to placebo, which may have been because the threshold concentration for significant effects of propofol on the NMDA- receptor-induced increase of intraneuronal calcium were in the upper limit of propofol concentrations that are considered to be clinically relevant (17).

Moreover, coadministration of propofol with remifentanil 0.05 µg · kg–1 · min–1 led to the most pronounced hyperalgesic effects. Thus, our results are in line with previous reports concerning the hyperalgesic effects of subhypnotic concentrations of propofol on mechanical pressure pain and thermal thresholds in humans (14,15). The proposed mechanisms for this effect comprise a modulation of the {gamma}-amino-butyric acid A ionophore and of the descending inhibition at supraspinal levels (34).

In conclusion, we have shown that propofol interacts differentially with remifentanil-induced pro- and antinociceptive mechanisms: Propofol, while attenuating opioid-induced postinfusion anti-analgesia, led to enlarged areas of secondary hyperalgesia. However, under clinical conditions, it is more problematic to clearly distinguish between anti-analgesia and hyperalgesia. In addition, pronounced postinfusion hyperalgesia is observed clinically at higher remifentanil doses, which can hardly be tested in our setup due to marked sedation and respiratory depression. Thus, further studies are warranted to determine the effects of propofol on remifentanil in higher dose ranges.


   Footnotes
 
Accepted for publication February 6, 2007.

Presented in part at the Anniversary Meeting of the German Society for the Study of Pain (DGSS), October 6–10, 2004, Leipzig, Germany; and the Euroanaesthesia 2005 (ESA), May 28–31, 2005, Vienna, Austria.

The work should be attributed to the Department of Anesthesiology, University Hospital Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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