Skip Navigation LinksHome > July 2003 - Volume 99 - Issue 1 > Differential Modulation of Remifentanil-induced Analgesia an...
Anesthesiology:
Pain and Regional Anesthesia

Differential Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by S-Ketamine and Clonidine in Humans

Koppert, Wolfgang M.D.*; Sittl, Reinhard M.D.†; Scheuber, Karin M.D.‡; Alsheimer, Monika M.D.†; Schmelz, Martin M.D.§; Schüttler, Jürgen M.D.∥

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: Experimental studies and clinical observations suggest a possible role for opioids to induce pain and hyperalgesia on withdrawal. The authors used a new experimental pain model in human skin to determine the time course of analgesic and hyperalgesic effects of the μ-receptor agonist remifentanil alone or in combination with the N-methyl-D-aspartate-receptor antagonist S-ketamine or the α2-receptor agonist clonidine.
Methods: Thirteen volunteers were enrolled in this randomized, double-blind, placebo-controlled study. Transcutaneous electrical stimulation at a high current density (2 Hz, 67.3 ± 16.8 mA, mean ± SD) induced acute pain (numerical 11-point rating scale: 5–6 out of 10) and stable areas of mechanical hyperalgesia to punctate stimuli and touch (allodynia). The magnitude of pain and area of hyperalgesia were assessed before, during, and after drug infusion (remifentanil at 0.1 μg · kg−1 · min−1 and S-ketamine at 5 μg · kg−1 · min−1 over a period of 30 min, respectively; clonidine infusion at 2 μg/kg for 5 min).
Results: Remifentanil reduced pain and areas of punctate hyperalgesia during infusion. In contrast, postinfusion pain and hyperalgesia were significantly higher than control. During infusion of S-ketamine, pain and hyperalgesia decreased and gradually normalized after infusion. When given in combination, S-ketamine abolished postinfusion increase of punctate hyperalgesia but did not reduce increased pain ratings. Clonidine alone did not significantly attenuate pain or areas of hyperalgesia. However, when given in combination with remifentanil, clonidine attenuated postinfusion increase of pain ratings.
Conclusions: Opioid-induced postinfusion hyperalgesia could be abolished by S-ketamine, suggesting an N-methyl-d-aspartate-receptor mechanism. In contrast, elevated pain ratings after infusion were not reduced by ketamine but were alleviated by the α2-receptor agonist clonidine. The results of this study suggest different mechanisms of opioid-induced postinfusion antianalgesia and secondary hyperalgesia.
OPIOIDS have been hypothesized to prevent postoperative pain when administered during surgery. However, instead of improved postoperative analgesia, recent clinical studies suggest that on their withdrawal, opioids can even enhance pain sensitivity. 1,2 Activation of N-methyl-d-aspartate (NMDA)-receptors by μ-receptor agonists has been assumed to be an underlying mechanism, 3,4 but experimental evidence from humans could not yet be provided because a suitable model was lacking. Recently, a new human model of electrically evoked pain and secondary hyperalgesia was introduced that is suitable to test the analgesic and antihyperalgesic effects of anesthetics. 5
The present work was designed to determine mechanisms of opioid-induced antianalgesia and hyperalgesia in humans. Therefore, we first studied the effects of the short-acting μ-receptor agonist remifentanil, the NMDA-receptor antagonist S-ketamine, or clonidine during and after infusion in the model of electrically evoked pain and secondary hyperalgesia described above. Because it has been suggested that opioids might interfere with NMDA- and α2-receptors, the effects of the remifentanil infusion were compared with a combination of the μ-receptor agonist with either S-ketamine or clonidine.
Back to Top | Article Outline

Materials and Methods

Thirteen healthy men were enrolled in this randomized, crossover, double-blind, and placebo-controlled study. The average age was 31.2 ± 5.3 yr (range, 20–40 yr). All subjects were familiarized with study procedures before participation. No subject had a known drug allergy or was taking medication that might interfere with itch or pain sensations and flare response (i.e., analgesics, antihistamines, or calcium or sodium channel blockers). Each subject gave informed consent to take part in the study; the experiments were performed in accordance with the Declaration of Helsinki and were approved by the Ethics Committee of the Medical Faculty of the University of Erlangen-Nuremberg.
Back to Top | Article Outline
Experimental Pain Models
Transdermal electrical stimulation was used to induce ongoing pain and secondary mechanical hyperalgesia as described previously. 5 Briefly, a stainless steel needle (Nicolet-EME, Kleinostheim, Germany) was inserted intradermally to a length of 1 cm at the central volar forearm of the subjects. A skin surface electrode (1.0 × 0.5 cm) was attached directly above the needle serving as anode. Monophasic, rectangular electrical pulses of 0.5-ms duration were applied via a constant-current stimulator (Digitimer DS7A, Digitimer Ltd., Hertfordshire, England) at 2 Hz. The current was gradually increased during the first 15 min of stimulation, targeting a pain rating of 5 to 6 (out of 10) and then was kept constant for the remaining time of the experiment.
Back to Top | Article Outline
Medication and Side Effects
Fig. 1
Fig. 1
Image Tools
In six separate treatment trials at least 1 week apart, subjects received hidden intravenous infusions of remifentanil at 0.1 μg · kg−1 · min−1 for 30 min, S-ketamine at 5 μg · kg−1 · min−1 for 30 min, clonidine at 2 μg/kg over a period of 5 min, or saline. In addition, combinations of remifentanil with either ketamine or clonidine at the above-described infusion rates were applied (fig. 1). All subjects received the single infusions first; they were randomized by Latin square. For the combined infusions, the sequence was alternated between the subjects. Neither the subjects nor the experimenter who was responsible for the psychophysics handled the infusions, and both had no direct view of them.
During the infusion, an examiner asked the subjects about such side effects as sedation, dizziness, pruritus, or nausea. Oxygen saturation measured by pulse oximetry (Spo2), ECG, and noninvasive arterial pressure were monitored continuously during the time of the study.
Back to Top | Article Outline
Sensory Testing
During an experiment, a second examiner asked the subject to rate the intensity of ongoing pain induced by the electrical stimulation every 5 min on a numerical 11-point rating scale). The end points of the scale were defined as “no pain” (0) and “maximum pain” (10). The area of punctate hyperalgesia was determined with a 450-mN von Frey filament (Stoelting, Chicago, IL), and the area of touch-evoked allodynia was determined with a cotton-wool tip gently stroked on the skin. The borders of the hyperalgesic areas were determined by moving along four linear paths parallel and vertical to the axis of the forearm from distant starting points toward the stimulation site until the volunteer reported increased pain sensations evoked by the von Frey filament (punctate hyperalgesia) or unpleasant sensations evoked by stroking the skin with the cotton wool (allodynia). These sites were marked on the skin and traced on an acetate sheet at the end of the experiment. For further analysis, both diameters were used to estimate the areas of secondary hyperalgesia (D/2 × d/2 × π).
Back to Top | Article Outline
Statistical Analysis
All results were expressed as mean ± SD. Treatment effects over time were evaluated by two-way repeated-measures ANOVA; Scheffé tests were performed as post hoc tests. Because of possible biphasic effects over time (analgesia vs. hyperalgesia), comparisons between treatments were analyzed separately during and after infusion. Differences between treatments at individual time points were compared by use of planned comparisons, corrected with the Bonferroni procedure. Significance levels throughout this study were P ≥ 0.05.
Back to Top | Article Outline

Results

Transdermal Stimulation
To achieve a pain rating of 5–6, the average current was increased to 67.3 ± 16.8 mA (range, 30–90 mA) during the first 15 min of intradermal electrical stimulation. Thereafter, pain ratings decreased significantly from 5.5 ± 0.5 to 3.6 ± 1.1 (F24,288 = 20.73, P < 0.001; Scheffé test, P < 0.001 at 80 min and remaining time), whereas areas of punctate hyperalgesia increased from 37.1 ± 14.1 to 46.2 ± 20.9 cm2 (F8,96 = 2.31, P < 0.05; Scheffé test, P = not significant [NS]). The allodynic areas remained stable during the intradermal electrical stimulation (F8,96 = 0.13, P = NS).
Back to Top | Article Outline
Remifentanil Infusion
Fig. 2
Fig. 2
Image Tools
Infusion of remifentanil 0.1 μg · kg−1 · min−1 led to a fast onset of analgesia. After 30 min of infusion, calculated plasma levels reached a steady state (fig. 2, A). During this time, almost all subjects developed subjective side effects, primarily a moderate sedation, which generally appeared after 10 min of infusion time and was paralleled by a slight decrease in oxygen saturation (F12,144 = 4.87, P < 0.001) (fig. 2, B). However, all subjects felt comfortable and answered promptly to the questions of the investigators, and assessments of hyperalgesic areas were accurate and reproducible. At no time did subjects complain of bothersome side effects; heart rate and blood pressure remained unchanged.
Remifentanil significantly decreased pain ratings during the infusion compared with control (F5,60 = 24.40, P < 0.001) (fig. 2, C). However, shortly after cessation of the infusion, pain ratings increased and exceeded control values (F11,132 = 28.71, P < 0.001). This antianalgesic effect was most prominent at 30 min after cessation of infusion. Thereafter, ratings gradually declined but remained elevated compared with control (F24,288 = 40.08, P < 0.001; Scheffé test, P = NS).
Infusion of remifentanil reduced the areas of punctate hyperalgesia compared with control (F2,24 = 4.74, P < 0.05) (fig. 2, D). However, antihyperalgesic effects were prominent only during infusion: Shortly after cessation of the infusion, areas of punctate hyperalgesia exceeded control values (F3,36 = 5.58, P < 0.01) (fig. 2, D). In addition, hyperalgesic areas remained significantly enlarged compared with baseline values (F8,96 = 15.53, P < 0.001; Scheffé test, P < 0.05 at 75, 95, and 105 min).
Remifentanil also significantly reduced allodynic areas during the infusion compared with control (F2,24 = 5.03, P < 0.05) (fig. 2, E). Maximal antiallodynic effects were observed 5 min before termination of the infusion. Thereafter, no differences from control values were found (F3,36 = 2.86, P = NS) (fig. 2, E).
Back to Top | Article Outline
S-Ketamine Infusion
Fig. 3
Fig. 3
Image Tools
Infusion of ketamine 5 μg · kg−1 · min−1 for 30 min led to calculated S-ketamine peak plasma levels of approximately 100 ng/ml, followed by a rapid decline (fig. 3, A). During S-ketamine infusion, eight subjects reported side effects, primarily hyperacusis and a moderate sedation, which started after approximately 10 min of infusion and were accompanied by a slight increase in blood pressure (F12,144 = 4.10, P < 0.001) (fig. 3, B). However, all subjects felt comfortable and answered promptly to the questions of the investigators. No dissociative effects were observed.
Infusion of S-ketamine significantly decreased pain ratings during the infusion compared with control (F5,60 = 10.27, P < 0.001) (fig. 3, C). Thereafter, pain ratings increased and reached control values. No significant differences were observed for the remainder of the experiment.
In addition, areas of punctate hyperalgesia were significantly reduced during infusion of S-ketamine (F2,24 = 5.76, P < 0.01) (fig. 3D). However, this antihyperalgesic effect was only short-lasting; 15 min after cessation of the infusion, hyperalgesic areas increased and reached control values (F3,36 = 3.36, P < 0.05) (fig. 3, D).
Allodynic areas were not affected by S-ketamine. Although allodynic areas were slightly decreased, this failed to be significant (F2,24 = 0.82, P = NS and F3,36 = 1.63, P = NS, during and after infusion, respectively) (fig. 3, E).
Back to Top | Article Outline
Clonidine Infusion
Fig. 4
Fig. 4
Image Tools
Because of its long terminal half-time, clonidine plasma levels after a 5-min intravenous infusion of 2 μg/ml have to be assumed to be still elevated at the end of the observation period (fig. 4, A). During this time, oxygen saturation (F12,144 = 4.91, P < 0.001) and blood pressure (F12,144 = 12.56, P < 0.001) were significantly decreased compared with control (fig. 4, B). Almost all subjects developed moderate sedation after clonidine infusion. However, all subjects felt comfortable and answered promptly to the questions of the investigators.
No effect of clonidine on pain ratings and areas of secondary hyperalgesia was observed in our model of intradermal electrical stimulation (fig. 4, C, D, and E, respectively).
Back to Top | Article Outline
Coadministration of Remifentanil and S-Ketamine
Fig. 5
Fig. 5
Image Tools
Coadministration of remifentanil and S-ketamine resulted in a significant decrease in oxygen saturation compared with remifentanil alone (F12,144 = 2.20, P < 0.05) (fig. 5, A). Blood pressure and heart rate remained unchanged. As shown for S-ketamine alone, hyperacusis and a moderate sedation were the most frequent side effects.
Furthermore, coadministration of S-ketamine enhanced remifentanil-induced analgesia (F10,120 = 18.19, P < 0.001; Scheffé test, P < 0.05) (fig. 5, B) but did not affect the increased pain ratings observed after cessation of the infusion (F22,264 = 13.60, P < 0.001; Scheffé tests, P < 0.05 compared with control;P = NS compared with remifentanil alone).
Areas of punctate hyperalgesia were significantly reduced by coadministration of S-ketamine (F4,48 = 7.64, P < 0.001; Scheffé test, P < 0.01) (fig. 5, C); this antihyperalgesic effect was observed for the remainder of the experiment (F6,72 = 2.72, P < 0.05; Scheffé tests, P < 0.05 compared with control and with remifentanil alone).
In addition, coadministration of S-ketamine decreased allodynic areas during infusion (F4,48 = 2.69, P < 0.05; Scheffé test, P < 0.05) (fig. 5, D) and after infusion (F6,72 = 3.04, P < 0.05; Scheffé tests, P < 0.05 compared with control and with remifentanil alone).
Back to Top | Article Outline
Coadministration of Remifentanil and Clonidine
Fig. 6
Fig. 6
Image Tools
Coadministration of remifentanil and clonidine led to significantly decreased oxygen saturations, especially during the time of remifentanil infusion (minimum, 88 ± 11%) (F12,144 = 3.76, P < 0.001) (fig. 6, A). As observed for clonidine alone, blood pressure was significantly decreased (F12,144 = 8.23, P < 0.001), whereas heart rate remained unchanged (fig. 6, A). Moderate sedation was observed in all subjects; however, they all felt comfortable and answered promptly and reproducibly to the questions of the investigators.
Although clonidine alone failed to produce analgesic effects, coadministration of clonidine and remifentanil decreased pain ratings (F10,120 = 9.17, P < 0.001; Scheffé test, P < 0.05) (fig. 6, B). Furthermore, clonidine significantly diminished enhanced pain ratings after cessation of remifentanil infusion (F22,264 = 12.34, P < 0.001; Scheffé test, P = NS compared with control;P < 0.05 compared with remifentanil alone).
Coadministration of clonidine reduced areas of postinfusion hyperalgesia compared with remifentanil alone (F6,72 = 3.18, P < 0.01; Scheffé test, P < 0.05) (fig. 6, C), and hyperalgesic areas were no longer significantly different from control (Scheffé test, P = NS).
Allodynic areas were not affected by coadministration of clonidine either during remifentanil infusion (F4,48 = 1.34, P = NS) or after the infusion (F6,72 = 1.76, P = NS) (fig. 6, D).
Back to Top | Article Outline

Discussion

Our results provide clear experimental evidence for the existence of opioid-induced antianalgesia and hyperalgesia after short-term application in humans and their differential modification by NMDA-receptor antagonists and α2-receptor agonists.
Back to Top | Article Outline
Medication
The doses for the continuous constant-dose infusions of remifentanil were chosen according to previous studies in which an infusion rate of 0.1 μg · kg−1 · min−1 was found to be effective and safe in healthy volunteers 6 and in postoperative pain control. 7 In accordance with these findings, no respiratory depression was observed; however, a slight decrease in oxygen saturation was noted in almost every subject. S-Ketamine was administered in a “low-dose” regimen, which was defined as an infusion rate less than 20 μg · kg−1 · min−1 (of the racemate) and which was shown to improve postoperative pain management and to reduce opioid-related adverse effects. 8 The same was true for clonidine: an intravenous bolus injection of 2 μg/kg was shown to enhance opioid-mediated analgesia in postoperative pain states with minimal side effects. 9 However, coadministration of remifentanil and clonidine significantly increased the number of episodes with oxygen desaturation. Although all subjects felt comfortable and answered promptly to the questions of the investigators, this fact may limit the use of this combination for postoperative pain control.
Back to Top | Article Outline
Punctate Hyperalgesia
Remifentanil significantly reduced the area of secondary mechanical hyperalgesia during its infusion. This effect is in accordance with recent publications reporting antihyperalgesic effects of opioids with intradermal capsaicin injection, thus showing similarities between the two different pain models. 10,11 However, the antihyperalgesic effect of remifentanil turned into a hyperalgesic effect in the postinfusion period. Opioid-induced hyperalgesia has been observed in animal models. 3,4,12 A trend toward larger areas of mechanical hyperalgesia after alfentanil and remifentanil was reported in a modified capsaicin model in humans as well. 5,11
Several mechanisms have been hypothesized to account for opioid-induced pronociceptive effects. They include opioid-induced up-regulation of the cyclic adenosine monophosphate pathway 13 and spinal dynorphin release, which enhances exocytosis of excitatory amino acids 14,15 and down-regulates spinal glutamate transporters. 16 However, because these processes require longer application periods, their role in our experimental protocol is unclear. Activation of the NMDA-receptor system by opioids 17,18 has been identified to account for opioid-induced hyperalgesia. 3,19,20 In fact, combining remifentanil with the NMDA-receptor antagonist ketamine has been shown to reduce postoperative opioid requirement. 21 In our study, S-ketamine abolished remifentanil-induced postinfusion hyperalgesia, supporting a major role of NMDA-receptors in its generation.
There is evidence for synergistic effects of NMDA antagonists and opioids from animal work. 22,23 However, in clinical studies, unequivocal results were obtained. 24–31 The results of our study reflect the ambiguity observed in the clinical studies:S-ketamine clearly reduced postinfusion hyperalgesia, suggesting that the NMDA-receptor is crucially involved in the generation of opioid-induced hyperalgesia. However, it would be of major clinical relevance to evaluate the long-term hyperalgesic effects of remifentanil infusions with or without coadministration of S-ketamine or clonidine, because a delayed hyperalgesia was reported in animal models. 3,4
Back to Top | Article Outline
Acute Pain
Remifentanil reduced electrically induced pain during a short-term infusion, but this analgesic effect turned into a pronociceptive analgesic effect in the postinfusion period. This result is in line with reports on opioid-induced pronociceptive effects in rat. 3,4,12 Moreover, it confirms clinical observations of increased postoperative pain and morphine requirement after remifentanil. 2 However, a pronociceptive effect was not observed in a recent study using alfentanil in this pain model. 5 Therefore, the increasing pain ratings shortly after termination of the remifentanil infusion might well reflect a withdrawal reaction caused by the rapid offset of action of remifentanil. Furthermore, differences in opioid-receptor interactions have to be considered as well. In line with this hypothesis, systemic remifentanil but not morphine induced μ-opioid–receptor internalization in rat spinal cord. 32 Internalization and concomitant inactivation of μ-opioid receptors, in turn, will render these cells less susceptible to endogenous or exogenous opioids until the receptors recycle. Clinically, these differences would clearly indicate the importance of an adequate pain therapy after discontinuation of remifentanil infusion, especially for surgical procedures in which moderate or severe postoperative pain is expected.
During combined application of S-ketamine and remifentanil, electrically induced pain was significantly reduced compared with remifentanil alone. However, this effect was observed only during the application. In the postinfusion period, pain ratings increased above control levels and reached the same level as seen after remifentanil alone. Thus, S-ketamine abolished opioid-induced postinfusion hyperalgesia but did not alleviate postinfusion antianalgesia. Differential effects of NMDA blockers on opioid-induced tolerance has been reported for analgesia versus hyperthermia 33 or for opioid sensitization versus tolerance, 34 but as yet, the mechanisms by which the differential effects of S-ketamine on hyperalgesia and antianalgesia might be explained are unclear.
The α2-receptor agonist clonidine given intravenously had no analgesic or antihyperalgesic effects in our study. This result is accordance with the lack of antihyperalgesic effects of intravenous clonidine in the capsaicin model, 35 whereas intrathecal and epidural application reduced pain and hyperalgesia. 36 These results confirm synergistic analgesic effects of α2-receptor agonists and opioids that have been reported previously. 37–41 N-type Ca channels and pertussis-sensitive G proteins 42 have been reported to be involved, but the underlying mechanism of the synergistic effect is largely unknown. It is of potential clinical relevance that the synergism between opioids and α2-receptor agonists has also been found in neuropathic pain 43 and in inflammatory pain models. 44 In accordance with these findings, the route of administration and plasma concentrations of the α2-receptor agonists seemed to be of major relevance also for postoperative pain control. Epidural administration of clonidine has been documented to produce adequate analgesia, but only high doses of intravenous clonidine were analgesic when given alone, whereas lower doses of clonidine were effective only when administered together with opioids. 9,45–49
In addition to the synergistic effect during their application, remifentanil-induced postinfusion hyperalgesia and antianalgesia were alleviated by clonidine. Clonidine reduced the intensity of postinfusion antianalgesia and hyperalgesia, but they did not decrease below control levels. This effect has certain similarities with the reduction of opioid withdrawal reaction by clonidine, 50,51 in which adrenergic descending inhibitory systems seem to be of potential relevance. 52 Activating the α2-adrenoceptor triggers an inwardly rectifying potassium conductance in dorsal horn neurons that causes hyperpolarization and reduced excitability, thus partially mimicking opioid-receptor activation.
Back to Top | Article Outline
Allodynia
As shown for the punctate hyperalgesia, remifentanil significantly reduced the area of allodynia during its infusion. However, areas hyperalgesic to touch showed a greater variance than areas hyperalgesic to punctate stimuli. Again, this is consistent with previously published literature on intradermal capsaicin. 53,54 Thus, hyperallodynic effects after cessation of remifentanil infusion did not reach a statistically significant level. Coadministration of S-ketamine further decreased allodynic areas during and after the infusion, which is in line with previous reports in humans. 5,55,56
Back to Top | Article Outline

Summary

Our results provide clear experimental evidence for the existence of opioid-induced antianalgesia and hyperalgesia in humans. Cessation of a short-lasting infusion of remifentanil caused a significant antianalgesic effect, possibly reflecting opioid withdrawal. The results suggest a modulating effect of the α2-receptor agonist in opioid-induced postinfusion antianalgesia. Different mechanisms were suggested for opioid-induced antianalgesia and secondary hyperalgesia, because only the latter was prevented by the NMDA-receptor antagonist. Although our experimental setting resembles many aspects of the perioperative situation, it does not allow us to deduce specific therapeutic procedures from the results. Instead, they may help to clarify underlying mechanisms of pain and hyperalgesia and thereby further develop therapeutic concepts for clinical application.
The authors thank Harald Ihmsen, Ph.D. (Resident, Department of Anesthesiology, University Clinic of Erlangen, Erlangen, Germany), for valuable discussions.
Back to Top | Article Outline

References

1. Chia YY, Liu K, Wang JJ, Kuo MC, Ho ST: Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999; 46: 872–7

2. Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M: Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. A nesthesiology 2000; 93: 409–17

3. Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G: Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. A nesthesiology 2000; 92: 465–72

4. Rivat C, Laulin JP, Corcuff JB, Celerier E, Pain L, Simonnet G: Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: Prevention by the N-methyl- d -aspartate receptor antagonist ketamine. A nesthesiology 2002; 96: 381–91

5. Koppert W, Dern SK, Sittl R, Albrecht S, Schuttler J, Schmelz M: A new model of electrically evoked pain and hyperalgesia in human skin: The effects of intravenous alfentanil, S (+)-ketamine, and lidocaine. A nesthesiology 2001; 95: 395–402

6. Gustorff B, Felleiter P, Nahlik G, Brannath W, Hoerauf KH, Spacek A, Kress HG: The effect of remifentanil on the heat pain threshold in volunteers. Anesth Analg 2001; 92: 369–74

7. Calderon E, Pernia A, De Antonio P, Calderon-Pla E, Torres LM: A comparison of two constant-dose continuous infusions of remifentanil for severe postoperative pain. Anesth Analg 2001; 92: 715–9

8. Schmid RL, Sandler AN, Katz J: Use and efficacy of low-dose ketamine in the management of acute postoperative pain: A review of current techniques and outcomes. Pain 1999; 82: 111–25

9. Marinangeli F, Ciccozzi A, Donatelli F, Di Pietro A, Iovinelli G, Rawal N, Paladini A, Varrassi G: Clonidine for treatment of postoperative pain: A dose-finding study. Eur J Pain 2002; 6: 35–42

10. Wallace MS, Ridgeway B III, Leung A, Schulteis G, Yaksh TL: Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human volunteers: Effects on acute thresholds and capsaicin-evoked hyperpathia. J Clin Pharmacol 2002; 42: 70–80

11. Petersen KL, Jones B, Segredo V, Dahl JB, Rowbotham MC: Effect of remifentanil on pain and secondary hyperalgesia associated with the heat-capsaicin sensitization model in healthy volunteers. A nesthesiology 2001; 94: 15–20

12. Li X, Angst MS, Clark JD: A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res 2001; 86: 56–62

13. Borgland SL: Acute opioid receptor desensitization and tolerance: Is there a link? Clin Exp Pharmacol Physiol 2001; 28: 147–54

14. Vanderah TW, Ossipov MH, Lai J, Malan TP, Porreca F: Mechanisms of opioid-induced pain and antinociceptive tolerance: Descending facilitation and spinal dynorphin. Pain 2001; 92: 5–9

15. Gardell LR, Wang R, Burgess SE, Ossipov MH, Vanderah TW, Malan TP Jr, Lai J, Porreca F: Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 2002; 22: 6747–55

16. Mao J, Sung B, Ji RR, Lim G: Chronic morphine induces downregulation of spinal glutamate transporters: Implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22: 8312–23

17. Kow LM, Commons KG, Ogawa S, Pfaff DW: Potentiation of the excitatory action of NMDA in ventrolateral periaqueductal gray by the mu-opioid receptor agonist, DAMGO. Brain Res 2002; 935: 87–102

18. Sakurada T, Watanabe C, Okuda K, Sugiyama A, Moriyama T, Sakurada C, Tan-No K, Sakurada S: Intrathecal high-dose morphine induces spinally-mediated behavioral responses through NMDA receptors. Brain Res Mol Brain Res 2002; 98: 111–8

19. Celerier E, Laulin J, Larcher A, Le Moal M, Simonnet G: Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Res 1999; 847: 18–25

20. Laulin JP, Maurette P, Corcuff JB, Rivat C, Chauvin M, Simonnet G: The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance. Anesth Analg 2002; 94: 1263–9

21. Guignard B, Coste C, Costes H, Sessler DI, Lebrault C, Morris W, Simonnet G, Chauvin M: Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Anesth Analg 2002; 95: 103–8

22. Allen RM, Dykstra LA:N-Methyl- d -aspartate receptor antagonists potentiate the antinociceptive effects of morphine in squirrel monkeys. J Pharmacol Exp Ther 2001; 298: 288–97

23. Lutfy K, Doan P, Weber E: ACEA-1328, a NMDA receptor/glycine site antagonist, acutely potentiates antinociception and chronically attenuates tolerance induced by morphine. Pharmacol Res 1999; 40: 435–42

24. Jaksch W, Lang S, Reichhalter R, Raab G, Dann K, Fitzal S: Perioperative small-dose S (+)-ketamine has no incremental beneficial effects on postoperative pain when standard-practice opioid infusions are used. Anesth Analg 2002; 94: 981–6

25. Reeves M, Lindholm DE, Myles PS, Fletcher H, Hunt JO: Adding ketamine to morphine for patient-controlled analgesia after major abdominal surgery: A double-blinded, randomized controlled trial. Anesth Analg 2001; 93: 116–20

26. Subramaniam K, Subramaniam B, Pawar DK, Kumar L: Evaluation of the safety and efficacy of epidural ketamine combined with morphine for postoperative analgesia after major upper abdominal surgery. J Clin Anesth 2001; 13: 339–44

27. Aida S, Yamakura T, Baba H, Taga K, Fukuda S, Shimoji K: Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: A randomized double-blind study. A nesthesiology 2000; 92: 1624–30

28. Adam F, Libier M, Oszustowicz T, Lefebvre D, Beal J, Meynadier J: Preoperative small-dose ketamine has no preemptive analgesic effect in patients undergoing total mastectomy. Anesth Analg 1999; 89: 444–7

29. Adriaenssens G, Vermeyen KM, Hoffmann VL, Mertens E, Adriaensen HF: Postoperative analgesia with i.v. patient-controlled morphine: Effect of adding ketamine. Br J Anaesth 1999; 83: 393–6

30. Suzuki M, Tsueda K, Lansing PS, Tolan MM, Fuhrman TM, Ignacio CI, Sheppard RA: Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999; 89: 98–103

31. Weinbroum AA, Gorodetzky A, Nirkin A, Kollender Y, Bickels J, Marouani N, Rudick V, Meller I: Dextromethorphan for the reduction of immediate and late postoperative pain and morphine consumption in orthopedic oncology patients: A randomized, placebo-controlled, double-blind study. Cancer 2002; 95: 1164–70

32. Trafton JA, Abbadie C, Marek K, Basbaum AI: Postsynaptic signaling via the μ-opioid receptor: Responses of dorsal horn neurons to exogenous opioids and noxious stimulation. J Neurosci 2000; 20: 8578–84

33. Bhargava HN, Matwyshyn GA: Dizocilpine (MK-801) blocks tolerance to the analgesic but not to the hyperthermic effect of morphine in the rat. Pharmacology 1993; 47: 344–50

34. Scheggi S, Mangiavacchi S, Masi F, Gambarana C, Tagliamonte A, De Montis MG: Dizocilpine infusion has a different effect in the development of morphine and cocaine sensitization: Behavioral and neurochemical aspects. Neurosci 2002; 109: 267–74

35. Eisenach JC, Hood DD, Curry R: Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg 1998; 87: 591–6

36. Eisenach JC, Hood DD, Curry R: Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicin-induced allodynia. Pain 2000; 84: 57–64

37. Wilcox GL, Carlsson KH, Jochim A, Jurna I: Mutual potentiation of antinociceptive effects of morphine and clonidine on motor and sensory responses in rat spinal cord. Brain Res 1987; 405: 84–93

38. Spaulding TC, Fielding S, Venafro JJ, Lal H: Antinociceptive activity of clonidine and its potentiation of morphine analgesia. Eur J Pharmacol 1979; 58: 19–25

39. Fairbanks CA, Nguyen HO, Grocholski BM, Wilcox GL: Moxonidine, a selective imidazoline-α2 -adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injured mice. A nesthesiology 2000; 93: 765–73

40. Fairbanks CA, Wilcox GL: Spinal antinociceptive synergism between morphine and clonidine persists in mice made acutely or chronically tolerant to morphine. J Pharmacol Exp Ther 1999; 288: 1107–16

41. Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL: The α2a adrenergic receptor subtype mediates spinal analgesia evoked by α2 agonists and is necessary for spinal adrenergic-opioid synergy. J Neurosci 1997; 17: 7157–65

42. Wei ZY, Karim F, Roerig SC: Spinal morphine/clonidine antinociceptive synergism: Involvement of G proteins and N-type voltage-dependent calcium channels. J Pharmacol Exp Ther 1996; 278: 1392–407

43. Ossipov MH, Lopez Y, Bian D, Nichols ML, Porreca F: Synergistic antinociceptive interactions of morphine and clonidine in rats with nerve-ligation injury. A nesthesiology 1997; 86: 196–204

44. Mansikka H, Zhou L, Donovan DM, Pertovaara A, Raja SN: The role of μ-opioid receptors in inflammatory hyperalgesia and alpha2-adrenoceptor-mediated antihyperalgesia. Neuroscience 2002; 113: 339–49

45. Eisenach JC, Lysak SZ, Viscomi CM: Epidural clonidine analgesia following surgery: Phase I. A nesthesiology 1989; 71: 640–6

46. Bernard JM, Hommeril JL, Passuti N, Pinaud M: Postoperative analgesia by intravenous clonidine. A nesthesiology 1991; 75: 577–82

47. Bernard JM, Kick O, Bonnet F: Comparison of intravenous and epidural clonidine for postoperative patient-controlled analgesia. Anesth Analg 1995; 81: 706–12

48. De Kock MF, Pichon G, Scholtes JL: Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth 1992; 39: 537–44

49. De Kock MF, Crochet B, Morimont C, Scholtes JL: Intravenous or epidural clonidine for intra- and postoperative analgesia. A nesthesiology 1993; 79: 525–31

50. Gowing LR, Farrell M, Ali RL, White JM: Alpha2-Adrenergic agonists in opioid withdrawal. Addiction 2002; 97: 49–58

51. Ahmadi-Abhari SA, Akhondzadeh S, Assadi SM, Shabestari OL, Farzanehgan ZM, Kamlipour A: Baclofen versus clonidine in the treatment of opiates withdrawal, side-effects aspect: A double-blind randomized controlled trial. J Clin Pharm Ther 2001; 26: 67–71

52. Millan MJ: Descending control of pain. Prog Neurobiol 2002; 66: 355–474

53. LaMotte RH, Lundberg LER, Torebjörk HE: Pain, hyperalgesia and activity in nociceptive-C units in humans after intradermal injection of capsaicin. J Physiol (Lond) 1992; 448: 749–64

54. Wallace MS, Laitin S, Licht D, Yaksh TL: Concentration-effect relations for intravenous lidocaine infusions in human volunteers: Effects on acute sensory thresholds and capsaicin-evoked hyperpathia. A nesthesiology 1997; 86: 1262–72

55. Park KM, Max MB, Robinovitz E, Gracely RH, Bennett GJ: Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects. Pain 1995; 63: 163–72

56. Warncke T, Stubhaug A, Jorum E: Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: A double-blind, cross-over comparison with morphine and placebo. Pain 1997; 72: 99–106

57. Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL: Remifentanil versus alfentanil: Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. A nesthesiology 1996; 84: 821–33

58. Ihmsen H, Geisslinger G, Schuettler J: Stereoselective pharmacokinetics of ketamine: R(−)-ketamine inhibits the elimination of S (+)-ketamine. Clin Pharmacol Ther 2001; 70: 431–8

59. Frisk-Holmberg M, Edlund PO, Paalzow L: Pharmacokinetics of clonidine and its relation to hypotensive effects in patients. Br J Clin Pharmacol 1978; 6: 227–32

Cited By:

This article has been cited 77 time(s).

European Journal of Pain
The impact of intra-operative sufentanil dosing on post-operative pain, hyperalgesia and morphine consumption after cardiac surgery
Fechner, J; Ihmsen, H; Schuttler, J; Jeleazcov, C
European Journal of Pain, 17(4): 562-570.
10.1002/j.1532-2149.2012.00211.x
CrossRef
Journal of Palliative Medicine
The Use of Very-Low-Dose Methadone for Palliative Pain Control and the Prevention of Opioid Hyperalgesia
Salpeter, SR; Buckley, JS; Bruera, E
Journal of Palliative Medicine, 16(6): 616-622.
10.1089/jpm.2012.0612
CrossRef
European Journal of Pain
Evaluation of the effects of a metabotropic glutamate receptor 5-antagonist on electrically induced pain and central sensitization in healthy human volunteers
Kalliomaki, J; Huizar, K; Kagedal, M; Hagglof, B; Schmelz, M
European Journal of Pain, 17(): 1465-1471.
10.1002/j.1532-2149.2013.00327.x
CrossRef
Pain Physician
American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part I - Evidence Assessment
Manchikanti, L; Abdi, S; Atluri, S; Balog, CC; Benyamin, RM; Boswell, MV; Brown, KR; Bruel, BM; Bryce, DA; Burks, PA; Burton, AW; Calodney, AK; Caraway, DL; Cash, KA; Christo, PJ; Damron, KS; Datta, S; Deer, TR; Diwan, S; Eriator, I; Falco, FJE; Fellows, B; Geffert, S; Gharibo, CG; Glaser, SE; Grider, JS; Hameed, H; Hameed, M; Hansen, H; Harned, ME; Hayek, SM; Helm, S; Hirsch, JA; Janata, JW; Kaye, AM; Kaye, AD; Kloth, DS; Koyyalagunta, D; Lee, M; Malla, Y; Manchikanti, KN; McManus, CD; Pampati, V; Parr, AT; Pasupuleti, R; Patel, VB; Sehgal, N; Silverman, SM; Singh, V; Smith, HS; Snook, LT; Solanki, DR; Tracy, DH; Vallejo, R; Wargo, BW
Pain Physician, 15(3): S1-S65.

Pain Physician
American Society of Interventional Pain Physicians (ASIPP) Guidelines for Responsible Opioid Prescribing in Chronic Non-Cancer Pain: Part 2-Guidance
Manchikanti, L; Abdi, S; Atluri, S; Balog, CC; Benyamin, RM; Boswell, MV; Brown, KR; Bruel, BM; Bryce, DA; Burks, PA; Burton, AW; Calodney, AK; Caraway, DL; Cash, KA; Christo, PJ; Damron, KS; Datta, S; Deer, TR; Diwan, S; Eriator, I; Falco, FJE; Fellows, B; Geffert, S; Gharibo, CG; Glaser, SE; Grider, JS; Hameed, H; Hameed, M; Hansen, H; Harned, ME; Hayek, SM; Helm, S; Hirsch, JA; Janata, JW; Kaye, AM; Kaye, AD; Kloth, DS; Koyyalagunta, D; Lee, M; Malla, Y; Manchikanti, KN; McManus, CD; Pampati, V; Parr, AT; Pasupuleti, R; Patel, VB; Sehgal, N; Silverman, SM; Singh, V; Smith, HS; Snook, LT; Solanki, DR; Tracy, DH; Vallejo, R; Wargo, BW
Pain Physician, 15(3): S67-S116.

Pediatric Anesthesia
Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease
Neri, CM; Pestieau, SR; Darbari, DS
Pediatric Anesthesia, 23(8): 684-689.
10.1111/pan.12172
CrossRef
Pain Physician
Tramadol Induced Paradoxical Hyperalgesia
Lee, SH; Cho, SY; Lee, HG; Choi, JI; Yoon, MH; Kim, WM
Pain Physician, 16(1): 41-44.

3Rd World Congress of Total Intravenous Anaesthesia & Target Controlled Infusion
S-Ketamine: Implications for the Military and Austere Medicine Community
Christopher, VM; Micah, B; Jacob, JH; Leandro, C
3Rd World Congress of Total Intravenous Anaesthesia & Target Controlled Infusion, (): 57-62.

Naunyn-Schmiedebergs Archives of Pharmacology
Non-invasive combined surrogates of remifentanil blood concentrations with relevance to analgesia
Lotsch, J; Skarke, C; Darimont, J; Zimmermann, M; Brautigam, L; Geisslinger, G; Ultsch, A; Oertel, BG
Naunyn-Schmiedebergs Archives of Pharmacology, 386(): 865-873.
10.1007/s00210-013-0889-5
CrossRef
Pain Physician
High-Dose Daily Opioid Administration and Poor Functional Status Intensify Local Anesthetic Injection Pain in Cancer Patients
Kim, SH; Yoon, DM; Choi, KW; Yoon, KB
Pain Physician, 16(3): E247-E256.

International Journal of Oral and Maxillofacial Surgery
Effect of remifentanil on the hemodynamic responses and recovery profile of patients undergoing single jaw orthognathic surgery
Nooh, N; Abdelhalim, AA; Abdullah, WA; Sheta, SA
International Journal of Oral and Maxillofacial Surgery, 42(8): 988-993.
10.1016/j.ijom.2013.02.001
CrossRef
Drug and Alcohol Dependence
Opioids and abnormal pain perception: New evidence from a study of chronic oploid addicts and healthy subjects
Pud, D; Cohen, D; Lawental, E; Eisenberg, E
Drug and Alcohol Dependence, 82(3): 218-223.
10.1016/j.drugalcdep.2005.09.007
CrossRef
Anaesthesia and Intensive Care
Anaesthesia for robot-assisted anatomic prostatectomy. Experience at a single institution
Costello, TG; Webb, P
Anaesthesia and Intensive Care, 34(6): 787-792.

Anesthesia and Analgesia
Modulation of remifentanil-induced postinfusion hyperalgesia by propofol
Singler, B; Troster, A; Manering, N; Schuttler, J; Koppert, W
Anesthesia and Analgesia, 104(6): 1397-1403.
10.1213/01.ane.0000261305.22324.f3
CrossRef
Acta Anaesthesiologica Scandinavica
Administration of fentanyl before remifentanil-based anaesthesia has no influence on post-operative pain or analgesic consumption
Lenz, H; Raeder, J; Hoymork, SC
Acta Anaesthesiologica Scandinavica, 52(1): 149-154.
10.1111/j.1399-6576.2007.01471.x
CrossRef
Anesthesia and Analgesia
The effect of nefopam on morphine overconsumption induced by large-dose remifentanil during propofol anesthesia for major abdominal surgery
Tirault, M; Derrode, N; Clevenot, D; Rolland, D; Fletcher, D; Debaene, B
Anesthesia and Analgesia, 102(1): 110-117.
10.1213/01.ANE.0000181103.07170.15
CrossRef
Pain
Multiple dose gabapentin attenuates cutaneous pain and central sensitisation but not muscle pain in healthy volunteers
Segerdahl, M
Pain, 125(): 158-164.
10.1016/j.pain.2006.05.008
CrossRef
Anaesthesist
Drugs for postoperative analgesia: Routine and new aspects - Part 2: Opioids, ketamine and gabapentinoids
Jage, J; Laufenberg-Feldmann, R; Heid, F
Anaesthesist, 57(5): 491-+.
10.1007/s00101-008-1327-9
CrossRef
Addiction Biology
Lack of effect of chronic dextromethorphan on experimental pain tolerance in methadone-maintained patients
Compton, PA; Ling, W; Torrington, MA
Addiction Biology, 13(): 393-402.
10.1111/j.1369-1600.2008.00112.x
CrossRef
British Journal of Anaesthesia
Interaction of physostigmine and alfentanil in a human pain model(dagger)
Wehrfritz, AP; Ihmsen, H; Schmidt, S; Muller, C; Filitz, J; Schuttler, J; Koppert, W
British Journal of Anaesthesia, 104(3): 359-368.
10.1093/bja/aep372
CrossRef
Pediatric Anesthesia
Intraoperative low-close S-ketamine has no preventive effects on postoperative pain and morphine consumption after major urological surgery in children
Becke, K; Albrecht, S; Schmitz, B; Rech, D; Koppert, W; Schuttler, J; Hering, W
Pediatric Anesthesia, 15(6): 484-490.
10.1111/j.1460-9592.2005.01476.x
CrossRef
Anesthesia and Analgesia
Determining the plasma concentration of ketamine that enhances epidural bupivacaine-and-morphine-induced analgesia
Suzuki, M; Kinoshita, T; Kikutani, T; Yokoyama, K; Inagi, T; Sugimoto, K; Haraguchi, S; Hisayoshi, T; Shimada, Y
Anesthesia and Analgesia, 101(3): 777-784.
10.1213/01.ane.0000166952.12290.45
CrossRef
Experimental Brain Research
Somatosensory function following painful repetitive electrical stimulation of the human temporomandibular joint and skin
Ayesh, EE; Jensen, TS; Svensson, P
Experimental Brain Research, 179(3): 415-425.
10.1007/s00221-006-0801-3
CrossRef
Neuropharmacology
Nitrous oxide (N2O) prevents latent pain sensitization and long-term anxiety-like behavior in pain and opioid-experienced rats
Bessiere, B; Richebe, P; LaboureyraS, E; Laulin, JP; Contarino, A; Simonnet, G
Neuropharmacology, 53(6): 733-740.
10.1016/j.neuropharm.2007.08.003
CrossRef
Current Drug Targets
Clinical Uses of Low-Dose Ketamine in Patients Undergoing Surgery
Berti, M; Baciarello, M; Troglio, R; Fanelli, G
Current Drug Targets, 10(8): 707-715.

European Journal of Pain
Antihyperalgesic and analgesic properties of the N-methyl-D-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia
Klein, T; Magerl, W; Hanschmann, A; Althaus, M; Treede, RD
European Journal of Pain, 12(1): 17-29.
10.1016/j.ejpain.2007.02.002
CrossRef
Schmerz
Opioid-induced analgesia and hyperalgesia
Koppert, W
Schmerz, 19(5): 386-+.
10.1007/s00482-005-0424-9
CrossRef
Journal of Pain
Psychophysics, flare, and neurosecretory function in human pain models: Capsaicin versus electrically evoked pain
Geber, C; Fondel, R; Kramer, HH; Rolke, R; Treede, RD; Sommer, C; Birkleln, F
Journal of Pain, 8(6): 503-514.
10.1016/j.jpain.2007.01.008
CrossRef
Current Drug Targets
Clonidine in Perioperative Medicine and Intensive Care Unit: More Than An Anti-Hypertensive Drug
Gregoretti, C; Moglia, B; Pelosi, P; Navalesi, P
Current Drug Targets, 10(8): 799-814.

Regional Anesthesia and Pain Medicine
Management of perioperative pain in patients chronically consuming opioids
Carroll, IR; Angst, MS; Clark, JD
Regional Anesthesia and Pain Medicine, 29(6): 576-591.
10.1016/j.rapm.2004.06.009
CrossRef
Trends in Pharmacological Sciences
Opioid hyperalgesia and tolerance versus 5-HT1A receptor-mediated inverse tolerance
Xu, XJ; Colpaert, F; Wiesenfeld-Hallin, Z
Trends in Pharmacological Sciences, 24(): 634-639.
10.1016/j.tips.2003.10.005
CrossRef
Anaesthesist
Opioid-induced hyperalgesia. Pathophysiology and clinical relevance
Koppert, W
Anaesthesist, 53(5): 455-466.

Pain
A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model
Staahl, C; Christrup, LL; Andersen, SD; Arendt-Nielsen, L; Drewes, AM
Pain, 123(): 28-36.
10.1016/j.pain.2006.02.006
CrossRef
British Journal of Anaesthesia
Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers
Chizh, BA; Gohring, M; Troster, A; Quartey, GK; Schmelz, M; Koppert, W
British Journal of Anaesthesia, 98(2): 246-254.
10.1093/bja/ael344
CrossRef
Journal of Pain
Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model
Koppert, W; Filitz, J; Troster, A; Ihmsen, H; Angst, M; Flor, H; Schuttler, J; Schmelz, M
Journal of Pain, 6(): 757-764.
10.1016/j.jpain.2005.07.002
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Intraoperative infusion of dexmedetomidine reduces perioperative analgesic requirements
Gurbet, A; Basagan-Mogol, E; Turker, G; Ugun, F; Kaya, EN; Ozcan, B
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 53(7): 646-652.

Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
New possibilities of systemic analgesia
Pogatzki-Zahn, EM; Zahn, PK
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 42(1): 22-31.

British Journal of Anaesthesia
Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers
Absalom, AR; Lee, M; Menon, DK; Sharar, SR; De Smet, T; Halliday, J; Ogden, M; Corlett, P; Honey, GD; Fletcher, PC
British Journal of Anaesthesia, 98(5): 615-623.
10.1093/bja/aem063
CrossRef
Pain
Supra-additive effects of tramadol and acetaminophen in a human pain model
Filitz, J; Ihmsen, H; Gunther, W; Troster, A; Schwilden, H; Schuttler, J; Koppert, W
Pain, 136(3): 262-270.
10.1016/j.pain.2007.06.036
CrossRef
Anaesthesia Pain Intensive Care and Emergency Medicine - A.P.I.C.E, Vol 1 and 2
Pain relief by ketamine
Himmelseher, S; Kochs, E
Anaesthesia Pain Intensive Care and Emergency Medicine - A.P.I.C.E, Vol 1 and 2, (): 903-913.

British Journal of Clinical Pharmacology
Oral opioid administration and hyperalgesia in patients with cancer or chronic nonmalignant pain
Reznikov, I; Pud, D; Eisenberg, E
British Journal of Clinical Pharmacology, 60(3): 311-318.
10.1111/j.1365-2125.2005.02418.x
CrossRef
European Journal of Neuroscience
Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain
Rivat, C; Vera-Portocarrero, LP; Ibrahim, MM; Mata, HP; Stagg, NJ; Felice, M; Porreca, F; Malan, TP
European Journal of Neuroscience, 29(4): 727-737.
10.1111/j.1460-9568.2009.06616.x
CrossRef
Journal of Clinical Anesthesia
Opioid consumption in total intravenous anesthesia is reduced with dexmedetomidine: a comparative study with remifentanit in gynecologic videolaparoscopic surgery
Bulow, NMH; Rocha, JBT; Barbosa, NV
Journal of Clinical Anesthesia, 19(4): 280-285.
10.1016/j.jclinane.2007.01.004
CrossRef
Anaesthesia
M-Entropy guidance vs standard practice during propofol-remifentanil anaesthesia: a randomised controlled trial
Gruenewald, M; Zhou, J; Schloemerkemper, N; Meybohm, P; Weiler, N; Tonner, PH; Scholz, J; Bein, B
Anaesthesia, 62(): 1224-1229.
10.1111/j.1365-2044.2007.05252.x
CrossRef
British Journal of Clinical Pharmacology
Assessing analgesic actions of opioids by experimental pain models in healthy volunteers - an updated review
Staahl, C; Olesen, AE; Andresen, T; Arendt-Nielsen, L; Drewes, AM
British Journal of Clinical Pharmacology, 68(2): 149-168.

Pain
Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans
Koppert, W; Angst, M; Alsheimer, M; Sittl, R; Albrecht, S; Schuttler, J; Martin, S
Pain, 106(): 91-99.
10.1016/S0304-3959(03)00294-X
CrossRef
Pharmacogenetics and Genomics
Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence
Liang, DY; Liao, G; Lighthall, GK; Peltz, G; Clark, DJ
Pharmacogenetics and Genomics, 16(): 825-835.

Pain
Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model
Koppert, W; Ihmsen, H; Korber, N; Wehrfritz, A; Sittl, R; Schmelz, M; Schuttler, J
Pain, 118(): 15-22.
10.1016/j.pain.2005.06.030
CrossRef
Iranian Journal of Pharmaceutical Research
Abdominal Pain after Cataract Surgery with Remifentanil Based Anesthesia
Bameshki, A; Jahanbakhsh, S
Iranian Journal of Pharmaceutical Research, 8(1): 47-51.

Anaesthesist
Remifentanil-based intraoperative anaesthesia and postoperative pain therapy. Is there an optimal treatment strategy?
Zollner, C; Schafer, M
Anaesthesist, 56(): 1038-1046.
10.1007/s00101-007-1246-1
CrossRef
Pain
No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans
Angst, MS; Chu, LF; Tingle, MS; Shafer, SL; Clark, JD; Drover, DR
Pain, 142(): 17-26.
10.1016/j.pain.2008.11.001
CrossRef
Pain Medicine
Do Opioids Induce Hyperalgesia in Humans? An Evidence-Based Structured Review
Fishbain, DA; Cole, B; Lewis, JE; Gao, JR; Rosomoff, RS
Pain Medicine, 10(5): 829-839.
10.1111/j.1526-4637.2009.00653.x
CrossRef
Pain
Dose-dependent effects of morphine on experimentally induced cutaneous pain in healthy volunteers
Schulte, H; Sollevi, A; Segerdahl, M
Pain, 116(3): 366-374.
10.1016/j.pain.2005.05.005
CrossRef
Anaesthesia and Intensive Care
Remifentanil-induced abdominal pain: a randomised clinical trial
Jahanbakhsh, S; Bameshki, A; Khashayar, P
Anaesthesia and Intensive Care, 37(3): 447-449.

Journal of Pain
Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: A preliminary prospective study
Chu, LF; Clark, DJ; Angst, MS
Journal of Pain, 7(1): 43-48.
10.1016/j.jpain.2005.08.001
CrossRef
Basic & Clinical Pharmacology & Toxicology
Experimental human pain models: A review of standardised methods for preclinical testing of analgesics
Staahl, C; Drewes, AM
Basic & Clinical Pharmacology & Toxicology, 95(3): 97-111.

Prehospital Emergency Care
Pain Management in Current Combat Operations
Black, IH; McManus, J
Prehospital Emergency Care, 13(2): 223-227.
10.1080/10903120802290778
CrossRef
Drug and Alcohol Dependence
Gabapentin improves cold-pressor pain responses in methadone-maintained patients
Compton, P; Kehoe, P; Sinha, K; Torrington, MA; Ling, W
Drug and Alcohol Dependence, 109(): 213-219.
10.1016/j.drugalcdep.2010.01.006
CrossRef
Anesthesiology
Ketamine Improves the Management of Exaggerated Postoperative Pain Observed in Perioperative Fentanyl-treated Rats
Richebé, P; Rivat, C; Laulin, J; Maurette, P; Simonnet, G
Anesthesiology, 102(2): 421-428.

PDF (360)
Anesthesiology
Opioid-induced Hyperalgesia in a Murine Model of Postoperative Pain: Role of Nitric Oxide Generated from the Inducible Nitric Oxide Synthase
Célérier, E; González, JR; Maldonado, R; Cabañero, D; Puig, MM
Anesthesiology, 104(3): 546-555.

PDF (642)
Anesthesiology
Opioid-induced Hyperalgesia: A Qualitative Systematic Review
Angst, MS; Clark, JD
Anesthesiology, 104(3): 570-587.

PDF (635)
Anesthesiology
Postoperative Hyperalgesia: Its Clinical Importance and Relevance
Wilder-Smith, OH; Arendt-Nielsen, L
Anesthesiology, 104(3): 601-607.

PDF (1305)
Anesthesiology
A Genetic Analysis of Opioid-induced Hyperalgesia in Mice
Liang, D; Liao, G; Wang, J; Usuka, J; Guo, Y; Peltz, G; Clark, JD
Anesthesiology, 104(5): 1054-1062.

PDF (1079)
Anesthesiology
Production of Paradoxical Sensory Hypersensitivity by α2-Adrenoreceptor Agonists
Quartilho, A; Mata, HP; Ibrahim, MM; Vanderah, TW; Ossipov, MH; Lai, J; Porreca, F; Malan, TP
Anesthesiology, 100(6): 1538-1544.

PDF (330)
Anesthesiology
Effects of Remifentanil on N-methyl-d-aspartate Receptor: An Electrophysiologic Study in Rat Spinal Cord
Guntz, E; Dumont, H; Roussel, C; Gall, D; Dufrasne, F; Cuvelier, L; Blum, D; Schiffmann, SN; Sosnowski, M
Anesthesiology, 102(6): 1235-1241.

PDF (573)
Anesthesiology
Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine
Joly, V; Richebe, P; Guignard, B; Fletcher, D; Maurette, P; Sessler, DI; Chauvin, M
Anesthesiology, 103(1): 147-155.

PDF (430)
Anesthesiology
Enhancement of Spinal N-Methyl-d-aspartate Receptor Function by Remifentanil Action at δ-Opioid Receptors as a Mechanism for Acute Opioid-induced Hyperalgesia or Tolerance
Zhao, M; Joo, DT
Anesthesiology, 109(2): 308-317.
10.1097/ALN.0b013e31817f4c5d
PDF (894) | CrossRef
Anesthesiology
Comparative Analgesic and Mental Effects of Increasing Plasma Concentrations of Dexmedetomidine and Alfentanil in Humans
Angst, MS; Ramaswamy, B; Davies, MF; Maze, M
Anesthesiology, 101(3): 744-752.

PDF (350)
Anesthesiology
Nitrous Oxide Revisited: Evidence for Potent Antihyperalgesic Properties
Simonnet, G; Richebé, P; Rivat, C; Creton, C; Laulin, J; Maurette, P; Lemaire, M
Anesthesiology, 103(4): 845-854.

PDF (681)
Anesthesiology
S(+)-ketamine Effect on Experimental Pain and Cardiac Output: A Population Pharmacokinetic-Pharmacodynamic Modeling Study in Healthy Volunteers
Sigtermans, M; Dahan, A; Mooren, R; Bauer, M; Kest, B; Sarton, E; Olofsen, E
Anesthesiology, 111(4): 892-903.
10.1097/ALN.0b013e3181b437b1
PDF (1337) | CrossRef
Anesthesiology
Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by Parecoxib in Humans
Tröster, A; Sittl, R; Singler, B; Schmelz, M; Schüttler, J; Koppert, W
Anesthesiology, 105(5): 1016-1023.

PDF (739)
Critical Care Medicine
Prehospital advances in the management of severe penetrating trauma
Mabry, R; McManus, JG
Critical Care Medicine, 36(7): S258-S266.
10.1097/CCM.0b013e31817da674
PDF (502) | CrossRef
Critical Care Medicine
The evolution of pain management in the critically ill trauma patient: Emerging concepts from the global war on terrorism
Malchow, RJ; Black, IH
Critical Care Medicine, 36(7): S346-S357.
10.1097/CCM.0b013e31817e2fc9
PDF (423) | CrossRef
The Clinical Journal of Pain
Opioid-induced Hyperalgesia in Humans: Molecular Mechanisms and Clinical Considerations
Chu, LF; Angst, MS; Clark, D
The Clinical Journal of Pain, 24(6): 479-496.
10.1097/AJP.0b013e31816b2f43
PDF (229) | CrossRef
The Clinical Journal of Pain
Enhanced Postoperative Sensitivity to Painful Pressure Stimulation After Intraoperative High Dose Remifentanil in Patients Without Significant Surgical Site Pain
Schmidt, S; Bethge, C; Förster, MH; Schäfer, M
The Clinical Journal of Pain, 23(7): 605-611.
10.1097/AJP.0b013e318122d1e4
PDF (180) | CrossRef
European Journal of Anaesthesiology (EJA)
Low‐dose ketamine failed to spare morphine after a remifentanil‐based anaesthesia for ear, nose and throat surgery
Ganne, O; Abisseror, M; Menault, P; Malhière, S; Chambost, V; Charpiat, B; Ganne, C; Viale, JP
European Journal of Anaesthesiology (EJA), 22(6): 426-430.
10.1017/S0265021505000724
PDF (96) | CrossRef
European Journal of Anaesthesiology (EJA)
Opioid‐induced hyperalgesia or opioid‐withdrawal hyperalgesia?
Tzabazis, AZ; Koppert, W
European Journal of Anaesthesiology (EJA), 24(9): 811-812.
10.1017/S0265021507000506
PDF (47) | CrossRef
Back to Top | Article Outline

© 2003 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share