Skip Navigation LinksHome > July 2005 - Volume 103 - Issue 1 > Remifentanil-induced Postoperative Hyperalgesia and Its Prev...
Anesthesiology:
Pain and Regional Anesthesia

Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine

Joly, Vincent M.D.*; Richebe, Philippe M.D.†; Guignard, Bruno M.D.*; Fletcher, Dominique M.D.‡; Maurette, Pierre M.D.§; Sessler, Daniel I. M.D.∥; Chauvin, Marcel M.D.#

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

Background: Remifentanil-induced secondary hyperalgesia has been documented experimentally in both animals and healthy human volunteers, but never clinically. This study tested the hypotheses that increased pain sensitivity assessed by periincisional allodynia and hyperalgesia can occur after relatively large-dose intraoperative remifentanil and that small-dose ketamine prevents this hyperalgesia.
Methods: Seventy-five patients undergoing major abdominal surgery were randomly assigned to receive (1) intraoperative remifentanil at 0.05 μg ·kg−1 ·min−1 (small-dose remifentanil); (2) intraoperative remifentanil at 0.40 μg ·kg−1 ·min−1 (large-dose remifentanil); or (3) intraoperative remifentanil at 0.40 μg ·kg−1 ·min−1 and 0.5 mg/kg ketamine just after the induction, followed by an intraoperative infusion of 5 μg · kg−1 · min−1 until skin closure and then 2 μg ·kg−1 ·min−1 for 48 h (large-dose remifentanil–ketamine). Pain scores and morphine consumption were recorded for 48 postoperative hours. Quantitative sensory tests, peak expiratory flow measures, and cognitive tests were performed at 24 and 48 h.
Results: Hyperalgesia to von Frey hair stimulation adjacent to the surgical wound and morphine requirements were larger (P < 0.05) and allodynia to von Frey hair stimulation was greater (P < 0.01) in the large-dose remifentanil group compared with the other two groups, which were comparable. There were no significant differences in pain, pressure pain detection threshold with an algometer, peak flow, cognitive tests, or side effects.
Conclusion: A relatively large dose of intraoperative remifentanil triggers postoperative secondary hyperalgesia. Remifentanil-induced hyperalgesia was prevented by small-dose ketamine, implicating an N-methyl-d-aspartate pain-facilitator process.
OPIOIDS are potent analgesics and are often necessary for treating moderate to severe pain. However, experimental studies report that opioids may also elicit hyperalgesia (increased sensitivity to noxious stimuli) and allodynia (nociceptive responses to innocuous stimulation). Animal studies have demonstrated the development of opioid-induced hyperalgesia.1–5 In some, opioid-induced hyperalgesia was observed to follow analgesia and lasted long after opioid exposure ended.1,2,4 In others, though, there was evidence of opioid-induced hyperalgesia during continuous opioid exposure.3,5 Opioid-induced processes that underlie hyperalgesia decrease antinociception and contribute to opioid tolerance.3,5,6
Similar phenomena are probably present when acute opioid tolerance occurs in patients. For example, tolerance to analgesia during 4-h-long constant-rate remifentanil infusions is profound in volunteers and develops within 60–90 min.7 Moreover, delayed hyperalgesia develops from short-acting opioid exposure,8–10 and relatively large intraoperative opioid doses are associated with greater postoperative opioid consumption and higher pain scores.11,12 However, unlike the experimental conditions in which changes in baseline nociceptive thresholds are measured in a controlled setting, it is often difficult to determine whether pain sensitivity changes in response to opioid administration in clinical situations.
Mechanical hyperalgesia surrounding the wound in postoperative patients shares the same central neuronal mechanism as heat-induced secondary hyperalgesia and confirms a degree of central sensitization.13 Also, it is possible to use periincisional mechanical allodynia and hyperalgesia as objective measures of opioid-induced hyperalgesia in clinical settings.
Among the potential mechanisms leading to opioid-induced hyperalgesia and antinociceptive tolerance, N-methyl-d-aspartate (NMDA) pain-facilitator processes seem to play a key role.14,15 Experimental studies performed in animals and volunteers have shown that NMDA receptor antagonists such as ketamine inhibit central sensitization and prevent opioid-induced hyperalgesia.1,2,8,16 Previously, we observed that small-dose ketamine was a useful adjuvant to remifentanil-based anesthesia by decreasing intraoperative remifentanil use and postoperative morphine consumption.17 However, we did not study the action of ketamine and specially the effects of ketamine on remifentanil-induced hyperalgesia in the postoperative setting, which have yet to be evaluated. Therefore, we tested the hypothesis that relatively large intraoperative doses of remifentanil provoke postoperative hyperalgesia as indicated by periincisional allodynia and hyperalgesia and that small-dose ketamine prevents hyperalgesia.
Back to Top | Article Outline

Materials and Methods

With approval of the Ethics Committee of the Hôpital Ambroise Paré, adult patients who were scheduled to undergo open colorectal surgery lasting at least 2 h were studied in two centers (Hôpital Ambroise Paré, Boulogne, France, and Hôpital Saint André, Bordeaux, France). All had American Society of Anesthesiologists physical status I–III.
Patients were excluded from the study when (1) immediate extubation was not planned after surgery; (2) they had chronic inflammatory disease including inflammatory bowel disease; (3) they regularly took analgesics or had used opioids within 12 h of surgery; (4) they had a history of drug or alcohol abuse, psychiatric disorder, or obesity (> 130% of ideal body weight); (5) they had contraindications to the self-administration of opioids (i.e., unable to understand the patient-controlled analgesia [PCA] device); or (6) they had a condition, such as a psychiatric disorder, acute cardiovascular disorder, or unstable hypertension, for which the use ketamine was contraindicated.
Back to Top | Article Outline
Protocol
During the preoperative anesthetic evaluation, the evening before surgery, patients were instructed in the use of quantitative sensory tests, the PCA pump (Master PCA; Vial Fresenius, Brezins, France), the peak flow monitor (Mini-Wright; Mediflux, Bry sur Marne, France), a four-point verbal rating scale for pain (0 = no pain, 1 = slight pain, 2 = moderate pain, 3 = intense or severe pain), the 100-mm visual analog scale (VAS) for pain (0 = no pain to 100 = worst pain), and an anxiety VAS (0 = no anxiety to 100 = worst imaginable anxiety). Control measures of cognitive function, peak flow, and quantitative sensory tests on skin area of surgery were also performed during this visit. Patients were premedicated with 1 mg lorazepam orally the night before surgery.
Anesthesia was induced with 6 mg/kg thiopental followed by 0.5 mg/kg atracurium to facilitate orotracheal intubation. Two minutes after the thiopental injection, a 1-μg/kg initial dose of remifentanil was given over 60 s. After tracheal intubation, the patients were ventilated to normocapnia with 50% oxygen and without nitrous oxide. An atracurium infusion was titrated to maintain one twitch in response to a supramaximal train-of-four stimulus at the orbicularis oculi; atracurium was discontinued 15 min before the end of surgery. Anesthesia was maintained with remifentanil per randomized dosing described below and desflurane at an initial end-tidal concentration of 0.5 minimum alveolar concentration (MAC), adjusted to age.18
Patients were randomly assigned, in a double-blinded fashion, to one of three groups (25 patients/group). Before the study began, a random-number table was generated, specifying the group to which each patient would be assigned upon entry into the trial. For each patient, an envelope containing the group assignment was prepared, sealed, and sequentially numbered. On the morning of surgery and before induction of anesthesia, a nurse not involved in the evaluation of the patient opened the patient’s envelope and prepared remifentanil and ketamine or saline solution syringes. None of the other investigators involved in patient management or data collection were aware of the group assignment. In case of emergency, the attending anesthesiologist was able to break the code. The three treatment groups were as follows:
1. Small-dose remifentanil: Patients were given an intraoperative infusion of remifentanil at a rate of 0.05 μg ·kg−1 ·min−1, which has been demonstrated not inducing hyperalgesia in volunteers,9 and a saline placebo infusion.
2. Large-dose remifentanil: Patients were given an intraoperative infusion of remifentanil at a rate of 0.4 μg ·kg−1 ·min−1, an amount that has been shown to maximally reduce anesthetic requirement during abdominal surgery,19 and a saline placebo infusion.
3. Large-dose remifentanil–ketamine: Patients were given an intraoperative infusion of remifentanil at a rate of 0.4 μg ·kg−1 ·min−1 and ketamine. The dosing scheme for the ketamine infusion was calculated using published pharmacokinetic variables20 to achieve target plasma concentrations of 250 ng/ml intraoperatively and 100 ng/ml postoperatively. These ketamine concentrations, especially 100 ng/ml, are in the range known to counteract hyperalgesia while producing minimal side effects.21 The initial loading dose of ketamine, given just after induction, was 0.5 mg/kg; this was followed by a maintenance infusion of 5 μg ·kg−1 ·min−1 intraoperatively until skin closure and subsequently by an infusion of 2 μg ·kg−1 ·min−1 during the initial 48 postoperative hours.
Insufficient anesthesia was defined as a heart rate that exceeded preinduction values by 15%, systolic arterial blood pressure exceeding baseline values by 20% for at least 1 min, and/or a Bispectral Index of 70 or greater. Patient movement, coughing, tearing, and sweating were also considered signs of inadequate anesthesia. Inspired desflurane concentration was increased stepwise by 1% when insufficient anesthesia was suspected. Hypotension, defined by a systolic arterial pressure less than 80 mmHg or a mean arterial pressure less than 60 mmHg, prompted stepwise 1% reductions in desflurane concentration for Bispectral Index values that remained less than 70. Additional intravenous fluids were also given as deemed appropriate by the responsible anesthesiologist. Similarly, atropine or intermittent boluses of ephedrine were given as required to treat bradycardia or persistent hypotension.
Thirty minutes before the anticipated end of surgery, a 0.15-mg/kg bolus dose of morphine was given intravenously. After skin closure, desflurane and remifentanil were discontinued, and residual neuromuscular blockade was antagonized with 40–60 μg/kg intravenous neostigmine and 15–20 μg/kg intravenous atropine. The trachea was extubated when patients responded to the verbal commands, spontaneous respiratory rate exceeded 12 breaths/min, and end-tidal carbon dioxide partial pressure was less than 45 mmHg.
Patients were transferred to the postanesthesia care unit (PACU) within 5 min of tracheal extubation. They remained in the unit for at least 4 h and were given oxygen via a facemask at a rate of 5 l/min throughout this period. Postoperative pain was initially treated with morphine chlorohydrate, which was titrated as required by nurses who were unaware of patients’ group assignments. Boluses of morphine (3 mg) were given at 5-min intervals until the behavioral pain score (defined in the Measurements section) was less than 1 or the verbal rating scale score for pain was less than 2. However, morphine administration was discontinued in patients when the sedation score (defined in the Measurements section) was greater than 2 or the respiratory rate was less than 12 breaths/min. Subsequently, within 4 h after tracheal extubation, patients were connected to a PCA device set to deliver 1 mg morphine as an intravenous bolus with a 5-min lockout interval; continuous infusion was not allowed. This PCA regimen was continued for 48 h after tracheal extubation.
Back to Top | Article Outline
Measurements
Baseline heart rate and systolic arterial pressure were defined as the mean of the two lowest measurements recorded during a 3- to 5-min interval immediately before induction of anesthesia. Values from all routine anesthetic monitors, including Bispectral Index monitoring (Aspect A-2000® EEG monitor; Aspect Medical Systems, Natick, MA), were recorded at 5-min intervals during surgery.
The total dose of remifentanil given in the operating room was recorded, as was the age-adjusted desflurane dose in MAC/h.18 Complications including laryngospasm, bronchospasm, respiratory depression, muscular rigidity, agitation, and shivering were recorded. Pain was evaluated for the first 15 min after extubation with a behavioral score (0 = calm patient with no verbal or behavioral manifestation of pain, 1 = behavioral or verbal expression of pain, 2 = intense behavioral or verbal manifestation [crying or extreme agitation]). This behavioral pain scale was performed 5, 10, and 15 min after tracheal extubation.
Patients assessed pain intensity by giving both VAS and verbal rating scale scores at 15-min intervals during the first hour and then hourly for 3 h. Subsequently, pain was evaluated only with the VAS at 4-h intervals for an additional 44 h.
The pain threshold for mechanical static (punctuate) stimuli was assessed using calibrated von Frey hairs (0.057–178 g/mm2). The patients were instructed to close their eyes during the procedure. Care was taken to avoid stroking the skin with the hair and to apply only a pressure stimulus. Filaments were applied to the designated point on the skin for approximately 1 s. Von Frey hair applications were separated by at least 30 s to reduce the likelihood of anticipatory responses. The von Frey filaments were applied in ascending order of stiffness. Tactile pain threshold was defined as the smallest force (g/mm2) necessary to bend a von Frey hair, which was just perceived as painful. Three determinations with an interval of 30 s were made at each assessment, and a mean was calculated. If tactile pain threshold exceeded hair number 19 (178 g/mm2), the sensitivity was censored at number 20.
A handheld electronic pressure algometer (Somedic AB, Stockholm, Sweden) with a 0.28-cm2 probe area was used to determine pressure pain threshold. The patients were instructed to immediately activate a push button, which freezes the digital display, when pain was perceived. The average of three measurements with an interstimulus interval of 60 s was defined as pressure pain threshold value. Values were expressed in kPa.
Tactile and pressure pain thresholds were measured in an area 2–3 cm from the incision at three levels (top, middle, and bottom) and on the inner forearm. A mean value for the three periincisional regions was calculated and used for statistical comparisons.
The extent of mechanical static (punctuate) hyperalgesia to von Frey hair stimulation proximal to the surgical wound was assessed with von Frey hair No. 16 (pressure = 122 g/mm2) according to the methods described by Ilkjaer et al.22 Hyperalgesia was determined by stimulating along three linear paths at right angles to the top, middle, and bottom sides of the surgical incision in steps of 5 mm at 1-s intervals, starting well outside the hyperalgesic area. During the first test, the regions were marked. Stimulations continued toward the incision until patients reported a clear change in sensation (e.g., burning, tenderness, or more intense pricking). The distance (in cm) from the incision to where sensations changed was measured, and a sum of the three assessments (top, middle, and button) was calculated and used for statistical comparisons.
Dynamic allodynia was investigated using a soft brush 2–3 cm from the incision. Allodynia was considered to be present if stroking the skin evoked a clear sensation of pain. We repeated this test three times at 24 and 48 h after surgery. Peak flow (l/min) was determined the evening before surgery. Postoperative pain scores on a VAS scale during peak flow measurement were also assessed.
Anesthetic-related complications were recorded, including nausea, vomiting, pruritus, dysphoria, hallucinations, and diplopia. Nausea and vomiting were treated by intravenous bolus of 0.5 mg droperidol. Sedation was monitored using the following four-point rating scale: 0 = patient fully awake, 1 = patient somnolent and responsive to verbal commands, 2 = patient somnolent and responsive to tactile stimulation, 3 = patient asleep and responsive to painful stimulation. Postoperative respiratory depression was defined by the combination of a sedation score greater than 1 and a respiratory rate less than 10 breaths/min.
We assessed short-term memory and working memory using the Digit Span Backward Test (DSBT).23 For this test, subjects were asked to repeat a string of digits in the original order (digit span forward, maximal score = 7) and in the reverse order (digit span backward, maximal score = 7). To measure cognitive and perceptual speed, patients were asked to take a Digit Symbol Substitution Test (DSST).23 DSBT, DSST, and anxiety VAS were performed preoperatively the evening before surgery, and postoperatively at 24 and 48 h.
Patients were asked to complete a written questionnaire on the first and second postoperative days to evaluate psychopharmacologic effects that have been reported after ketamine; these included altered color perception, reduced visual acuity, changes in hearing, hallucinations, altered body image, feelings of unreality, anxiety, aggression, altered physical strength, dizziness, discomfort, illness, and nausea.24
Quantitative sensory tests were performed in each center by the same experienced investigator (V. J. or P. R.) preoperatively the evening before surgery and postoperatively at 24 and 48 h. The study ended after 48 h.
Back to Top | Article Outline
Statistical Analysis
The extent of hyperalgesia to von Frey hair stimulation proximal to the surgical wound was considered our primary endpoint. The secondary endpoints were other results of quantitative sensory tests, VAS pain scores, and morphine consumption. Our sample-size estimate was based on the expected differences in the extent of hyperalgesia to von Frey hair stimulation proximal to the surgical wound at 48 h between the large- and small-dose remifentanil groups. In a preliminary study of 20 patients, we observed that the extent of hyperalgesia for punctuate mechanical stimuli around a xiphopubic incision was 7 cm with a SD of 4 cm. A sample size estimate indicated that 21 patients/group would give a power of 80% at an α level of 0.05 for detecting a difference in 50% in the extent of hyperalgesia to von Frey hair stimulation proximal to the surgical wound. The study size was thus prospectively set to 75 patients (25 patients/group).
Age, weight, height, duration of procedures, temperature at end of the study, and cumulative postoperative morphine consumption at 48 h were compared with an unpaired Student t test. The relative frequencies of sex, American Society of Anesthesiologists physical status, ephedrine use, psychopharmacologic effects, nausea, and vomiting were compared with the Fisher exact test. Hemodynamic variables, Bispectral Index, pain thresholds, peak flow, and VAS scores for 48 h were analyzed with two-way analysis of variance for repeated measures. DSBT and DSST scores were analyzed with the nonparametric Kruskal-Wallis test. Statistical analysis was performed with Statview for Windows (version 5.0; SAS Institute Inc, Cary, NC). Results are presented as mean ± SD or median (interquartile range); P < 0.05 was considered statistically significant.
Back to Top | Article Outline

Results

Seventy-five patients were enrolled in the study. One patient was excluded from the large-dose remifentanil–ketamine group because of respiratory depression that occurred postoperatively in the PACU and was treated with a 0.4-mg injection of naloxone. This patient arrived in the PACU with a VAS pain score of 100 mm. He received a morphine dose of 21 mg by intravenous titration, which corresponded to a total dose of 33 mg, including the intraoperative bolus of 0.15 mg/kg. Respiratory depression occurred 1 h after the last morphine injection. It was attributed to excessive perioperative morphine administration.
Table 1
Table 1
Image Tools
Table 2
Table 2
Image Tools
Morphometric and demographic characteristics, duration of surgery and anesthesia, and types of surgical procedures were comparable in the three treatment groups (table 1). Desflurane requirement was significantly greater in the small-dose remifentanil group than in the other two groups (P < 0.05; table 2). The times from the remifentanil discontinuation until awakening and tracheal extubation were comparable in the three groups (table 2).
Table 3
Table 3
Image Tools
Bispectral Index values were comparable in the large- and small-dose remifentanil groups but greater in the large-dose remifentanil–ketamine group (P < 0.05; table 3). Intraoperatively, systolic and diastolic pressures were similar in the three groups; however, heart rate was generally higher (P < 0.05; table 3) in the small-dose remifentanil group. More ephedrine was required in the large-dose remifentanil–ketamine group than in the two other groups to maintain hemodynamic stability (P < 0.05; table 2).
Fig. 1
Fig. 1
Image Tools
Table 4
Table 4
Image Tools
Tactile pain thresholds adjacent to the incision were significantly less at 24 and 48 postoperative hours in the large-dose remifentanil group than in the other groups (P < 0.01; fig. 1). However, there were no significant differences among the groups for pressure pain threshold determined with the algometer at 2–3 cm from the incision (table 4). Moreover, no clear sensation of pain could be evoked in any patient by stroking the skin with a brush adjacent to the incision.
Fig. 2
Fig. 2
Image Tools
Extent of hyperalgesia to von Frey hair stimulation proximal to the surgical incision was easily detected in all patients and was significantly larger at 24 and 48 h in the large-dose remifentanil group than in the other two groups (P < 0.03; fig. 2).
Tactile and pressure pain thresholds measured on the forearm did not differ preoperatively versus postoperatively in any group (data not shown).
Fig. 3
Fig. 3
Image Tools
Visual analog scale (fig. 3) and verbal rating scale (data not shown) pain scores at rest and after peak flow (table 3) did not differ among the three groups. Peak flow values were also comparable (table 4).
Although the mean time to first morphine administration and the cumulative amount of intravenous morphine given by nurses in the PACU did not differ among the three groups (table 2), postoperative morphine consumption, including morphine titrated in the PACU, was significantly greater throughout the 48-h postoperative period in the large-dose remifentanil group than in the other groups (P < 0.05; table 2).
The incidences of nausea and vomiting and of droperidol consumption (table 2), the distribution of sedation and anxiety scores (data not shown), and the responses to the written questionnaire evaluating postoperative ketamine psychopharmacologic effects were similar in all groups. However, one patient in the large-dose remifentanil–ketamine group reported hallucinations at 24 and 48 h after surgery and altered body image at 24 h, and another patient in the same group reported altered color perception, dizziness, and reduced visual activity at 24 h. Eight patients in the small-dose remifentanil group, five in the large-dose remifentanil group, and six in the large-dose remifentanil–ketamine group declined to take the DSST postoperatively. All patients performed the DSBT at 24 and 48 h, however. No intergroup differences were found in the results of the DSBT or DSST. The DSBT score (mean scores between 12 and 17) was not impaired postoperatively in any group; however, the mean DSST scores, which were between 41 and 47 preoperatively, were significantly decreased by 22–34% at 24 h after surgery and returned to baseline at 48 h in all three groups.
Back to Top | Article Outline

Discussion

We confirmed our hypothesis that a relatively large dose of intraoperative remifentanil increases pain sensitivity as evidenced by a reduction of the postoperative tactile pain threshold proximal to the surgical wound and an extension of periincisional hyperalgesia in our large-dose remifentanil group. This phenomenon lasted throughout both postoperative days and was associated with an increase in morphine administered by PCA. We also found that giving a small dose of ketamine during and after surgery completely prevented the increase in postoperative pain sensitivity and punctuate hyperalgesia that otherwise resulted from large-dose remifentanil administration. Moreover, patients who received a large dose of remifentanil with ketamine had significantly less postoperative morphine requirements than those receiving the large dose of remifentanil only; in fact, the dose was comparable to that of the small-dose remifentanil patients.
The differences in postoperative morphine requirements between the small- and large-dose remifentanil groups were less marked than we observed in a previous study.12 The reasons are likely related to differences in the design of these two studies. In the current study, we gave remifentanil a constant rate throughout the intraoperative period, whereas in the previous study, remifentanil was titrated to patient responses. Consequently, in the previous study,12 the remifentanil infusion rate frequently exceeded our current limit of 0.4 μg ·kg−1 ·min−1. This difference in the rate of infusion may account for the differences observed in postoperative morphine requirements in the large-dose remifentanil groups in the two studies because acute opiate tolerance seems to be dose dependent.1,9,11,25
Previous studies clearly demonstrated that there is an area of mechanical hyperalgesia around a surgical incision.22,26–28 However, the current study is the first to evaluate to what extent intraoperative opioid use contributes to this hyperalgesia. Koppert et al.9 reported that, in volunteers, the area of hyperalgesia surrounding a transcutaneous electrical stimulation at a high current density increased after discontinuation of remifentanil when administered at a rate of 0.10 μg ·kg−1 ·min−1 but not at a rate of 0.05 μg ·kg−1 ·min−1. It would also be reasonable to assume that periincisional hyperalgesia observed in the small-dose remifentanil group was mainly induced by surgery, whereas 0.40 μg ·kg−1 ·min−1 remifentanil used in the large-dose remifentanil group triggered approximately half of the observed mechanical hyperalgesia.
As in animal experiments,25 it is possible to imagine that postoperative morphine potency was reduced in the large-dose remifentanil patients in whom allodynia proximal to the wound was most profound and extended, which accounts to greatest total postoperative PCA morphine consumption in these patients—possibly resulting from an acute tolerance to the analgesic effects of morphine.
In contrast to static mechanical allodynia triggered with von Frey filaments, we were unable to detect dynamic mechanical allodynia triggered by brushing as in experimental models of secondary mechanical hyperalgesia.9 One reason may be that these two types of allodynia have dissimilar origins. Punctuate allodynia is elicited by input from high-threshold A-δ fibers,29 whereas mechanical dynamic allodynia is elicited from low-threshold A-β fibers.30
Despite the differences between the large-dose remifentanil group and the other groups in tactile pain threshold proximal to the surgical wound and in extent of hyperalgesia tested by von Frey hair filament, pressure pain thresholds tested by algometer and VAS pain scores at rest and during peak flow were comparable in the three groups. These results are difficult to explain; however, they support those of other studies using the same measurements.26,28,31 One explanation would be that the potential increase in pain scores was counteracted by increased PCA morphine use. Moreover, the lack of differences in postoperative peak flow values between the groups in the current study may be due to the dependence of this measurement on pain after abdominal surgery.32
Although the clinical implication of the area of periincisional hyperalgesia remains poorly understood, hyperalgesia proximal to the wound was found to be present 3 months after surgery in patients recovering from abdominal hysterectomy,22 and long-term incisional pain at 1 month, 6 months, and 1 yr after open colorectal surgery was more frequent in patients who experienced the most extended hyperalgesia surrounding the surgical wound during the initial 72 postoperative hours.28 Therefore, our results suggest that relatively large doses of intraoperative remifentanil without concomitant small-dose ketamine might be deleterious in patients at risk for chronic postoperative pain such as those undergoing thoracotomy and amputation.33 Further studies are necessary though to confirm whether the extension of periincisional hyperalgesia may be considered a prognostic factor of chronic postsurgical pain.
Many mechanisms may explain remifentanil-induced hyperalgesia observed in the current study;15 these include extensive internalization and thereby inactivation of μ-opioid receptors by remifentanil,34 opioid-induced up-regulation of the cyclic adenosine monophosphate pathway,35 spinal dynorphin release,3,36 and activation of central NMDA nociceptive systems.15,25 That the NMDA receptor antagonist ketamine was able to prevent the increase in postoperative hyperalgesia triggered by a large dose of remifentanil is consistent with the hypothesis that pronociceptive processes involving NMDA receptor activation account for opioid-induced hyperalgesia and acute opioid tolerance. In accord with this hypothesis, it was recently reported that remifentanil stimulates different NMDA receptor subunit combinations (NR1A/2A, NR1A/2B).37 The ability of ketamine to reduce both hyperalgesia and postoperative morphine consumption supports the possibility that the effect of ketamine on opioid-induced hyperalgesia results in the reduction of opioid consumption.2,25,33
Few side effects were noted in the large-dose remifentanil–ketamine group. The case of severe respiratory depression requiring naloxone was likely caused by the large dose of morphine that was administered perioperatively (33 mg), as we have previously observed.38 Effectively, according to studies evaluating respiratory interactions between opioids and ketamine,39,40 it seems unlikely that this case of respiratory depression was related to ketamine. Two patients in the large-dose remifentanil–ketamine group had ketamine-induced central nervous system side effects at the specific written questionnaire, albeit without significant differences in patient responses among the three groups. However, we did not detect any effect of small dose ketamine on DSBT or DSST. The results of the current study seem consistent with a quantitative systematic reviews in which small-dose ketamine (< 2.5 μg ·kg−1 ·min−1) given postoperatively did not specifically increase the incidence of hallucinations or impair cognitive functioning.33,41–43
Because the patients in the small-dose remifentanil group received larger doses of desflurane, an alternative explanation for our findings would be that the larger doses of desflurane prevented surgery-induced hyperalgesia, compared with the smaller doses received by the patients in the large-dose remifentanil group. Indeed, halogenated anesthetics have been shown to decrease hyperexcitability of spinal dorsal horn neurons after tissue injury.44 Volatile anesthetics, including desflurane, seem to block NMDA receptors.45 However, volatile anesthetics do not prevent subsequent hyperexcitability of spinal dorsal horn neurons even though they suppress evoked responses to incision.44 Furthermore, response of NMDA receptors expressed in oocytes to glutamate are suppressed only 20% at 0.5 MAC and 40% at 1.0 MAC desflurane. This suggests that the small 0.3% difference in desflurane concentration does not account for the exaggerated hyperalgesia in the large-dose remifentanil group.
In summary, intraoperative administration of a relatively large dose of remifentanil increased postoperative pain sensitivity, specifically periincisional hyperalgesia. A small dose of ketamine prevented hyperalgesia, implicating NMDA receptors in remifentanil-induced hyperalgesia and confirmed the benefits of administering small-dose ketamine when relatively large intraoperative remifentanil doses are required.
Back to Top | Article Outline

References

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

2. Kissin I, Bright CA, Bradley Jr: EL The effect of ketamine on opioid-induced acute tolerance: Can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg 2000; 91:1483–8

3. Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM, Zhang ET, Malan TP, Ossipov MH, Lai J, Porreca F: Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 2000; 20:7074–9

4. Li X, Angst MS, Clark JD: Opioid-induced hyperalgesia and incisional pain. Anesth Analg 2001; 93:204–9

5. Laulin JP, Celerier E, Larcher A, Le Moal M, Simonnet G: Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 1999; 89:631–6

6. Mao J: Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002; 100:213–7

7. Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86:1307–11

8. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M: Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003; 106:49–57

9. Koppert W, Angst M, Alsheimer M, Sittl R, Albrecht S, Schüttler J, Schmelz M: Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans. Pain. 2003; 106:91–9

10. Hood DD, Curry R, Eisenach JC: Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 2003; 97:810–5

11. 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

12. 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. Anesthesiology 2000; 93:409–17

13. Dirks J, Moiniche S, Hilsted KL, Dahl JB: Mechanisms of postoperative pain: clinical indications for a contribution of central neuronal sensitization. Anesthesiology 2002; 97:1591–6

14. Feng J, Kendig JJ: N-methyl-D-aspartate receptors are implicated in hyperresponsiveness following naloxone reversal of alfentanil in isolated rat spinal cord. Neurosci Lett 1995; 189:128–30

15. Mao J, Price DD, Mayer DJ: Mechanisms of hyperalgesia and morphine tolerance: A current view of their possible interactions. Pain 1995; 62:259–74

16. Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J: Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003; 99:152–9

17. 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

18. Gold MI, Abello D, Herrington C: Minimum alveolar concentration of desflurane in patients older than 65 yr. Anesthesiology 1993; 79:710–4

19. Vuyk J, Mertens MJ, Olofsen E, Burm AGL, Bovill JG: Propofol anesthesia and rational opioid selection. Anesthesiology 1997; 87:1549–62

20. Domino EF, Domino SE, Smith RE, Domino LE, Goulet JR, Domino KE, Zsigmond EK: Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther 1984; 36:645–53

21. Leung A, Wallace MS, Ridgeway B, Yaksh T: Concentration-effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain. Pain 2001; 91:177–87

22. Ilkjaer S, Bach LF, Nielsen PA, Wernberg M, Dahl JB: Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain 2000; 86:19–24

23. Ghoneim MM, Hinrichs JV, O’Hara MW, Mehta MP, Pathak D, Kumer V, Clark CR: Comparison of psychologic and cognitive functions after general or regional anesthesia. Anesthesiology 1988; 69:507–15

24. Oye I, Paulsen O, Maurset A: Effects of ketamine on sensory perception: Evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 1992; 260:1209–13

25. 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

26. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A: Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997; 41:1124–32

27. Ilkjaer S, Nikolajsen L, Hansen TM, Wernberg M, Brennum J, Dahl JB: Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth 1998; 81:707–12

28. De Kock M, Lavand’homme P, Waterloos H. “Balanced analgesia” in the perioperative period: Is there a place for ketamine? Pain 2001; 92:373–80

29. Magerl W, Fuchs PN, Meyer RA, Treede RD: Roles of capsaicin-insensitive nociceptors in cutaneous pain and secondary hyperalgesia. Brain 2001; 124:1754–64

30. Torebjork HE, Lundberg LE, LaMotte RH: Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 1992; 448:765–80

31. Burstal R, Danjoux G, Hayes C, Lantry G: PCA ketamine and morphine after abdominal hysterectomy. Anaesth Intensive Care 2001; 29:246–51

32. Gilron I, Tod D, Goldstein DH, Parlow JL, Orr E: The relationship between movement-evoked versus spontaneous pain and peak expiratory flow after abdominal hysterectomy. Anesth Analg 2002; 95:1702–7

33. Subramaniam K, Subramaniam B, Steinbrook RA: Ketamine as adjuvant analgesic to opioids: A quantitative and qualitative systematic review. Anesth Analg 2004; 99:482–95

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

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

36. Gardell LR, Wang R, Burgess SE, Ossipov MH, Vanderah TW, Malan Jr, TP 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

37. Hahnenkamp K, Nollet J, Van Aken HK, Buerkle H, Halene T, Schauerte S, Hahnenkamp A, Hollmann MW, Strümper D, Durieux ME, Hoenemann CW: Remifentanil directly activates human N-methyl-d-aspartate receptors expressed in Xenopus laevis oocytes. Anesthesiology 2004; 100:1531–7

38. Fletcher D, Pinaud M, Scherpereel P, Clytis N, Chauvin M: The efficacy of intravenous 0.15 versus 0.25 mg/kg intraoperative morphine for immediate postoperative analgesia after remifentanil-based anesthesia for major surgery. Anesth Analg 2000; 90:666–71

39. Bourke DL, Malit LA, Smith TC: Respiratory interactions of ketamine and morphine. Anesthesiology 1987; 66:153–6.

40. Persson J, Scheinin H, Hellstrom G, Björkman S, Götharson E, Gustafsson LL: Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers. Acta Anaesthesiol Scand 1999; 43:744–52

41. McCartney CJL, Sinha A, Katz J: A qualitative systemic review of the role of N-methyl-d-aspartate receptor antagonists in preventive analgesia. Anesth Analg 2004; 98:1385–400

42. Elia N, Tramèr MR: Ketamine and postoperative pain: A quantitative systematic review of randomised trials. Pain 2005; 113:61–70

43. Himmelseher S, Durieux ME: Ketamine for perioperative pain management. Anesthesiology 2005; 102:211–20

44. Kawamata M, Narimatsu E, Kozuka Y, Takahashi T, Sugino S, Niiya T, Namiki A: Effects of halothane and isoflurane on hyperexcitability of spinal dorsal horn neurons after incision in the rat. Anesthesiology 2005; 102:165–74

45. Hollmann MW, Liu HT, Hoenemann CW, Liu WH, Durieux ME: Modulation of NMDA receptor function by ketamine and magnesium: II. Interactions with volatile anesthetics. Anesth Analg 2001; 92:1182–91

Cited By:

This article has been cited 80 time(s).

Progress in Neurobiology
Prevention of chronic postoperative pain: Cellular, molecular, and clinical insights for mechanism-based treatment approaches
Deumens, R; Steyaert, A; Forget, P; Schubert, M; Lavand'homme, P; Hermans, E; De Kock, M
Progress in Neurobiology, 104(): 1-37.
10.1016/j.pneurobio.2013.01.002
CrossRef
Neuropharmacology
Remifentanil produces cross-desensitization and tolerance with morphine on the mu-opioid receptor
Nowoczyn, M; Marie, N; Coulbault, L; Hervault, M; Davis, A; Hanouz, JL; Allouche, S
Neuropharmacology, 73(): 368-379.
10.1016/j.neuropharm.2013.06.010
CrossRef
Annales Francaises D Anesthesie Et De Reanimation
Postoperative pain trajectories to identify risk of chronic postsurgical pain in living donors for liver transplantation
Bonnet, A; Lavand'homme, P; France, MN; Reding, R; De Kock, M
Annales Francaises D Anesthesie Et De Reanimation, 31(): 945-949.
10.1016/j.annfar.2012.09.011
CrossRef
Journal of Pain
mu-Opioid Receptor Gene A118G Polymorphism Predicts Pain Recovery After Sexual Assault
Ballina, LE; Ulirsch, JC; Soward, AC; Rossi, C; Rotolo, S; Linnstaedt, SD; Heafner, T; Foley, KA; Batts, J; Collette, R; Holbrook, D; Zelman, S; McLean, SA
Journal of Pain, 14(2): 165-171.
10.1016/j.jpain.2012.10.013
CrossRef
Therapie
Prevention of psychedelic side effects associated with low dose continuous intravenous ketarnine infusion
Remerand, F; Couvret, C; Pourrat, X; Le Tendre, C; Baud, A; Fusciardi, J
Therapie, 62(6): 499-505.
10.2515/therapie:200802
CrossRef
Molecular Pain
Tyrosine phosphorylation of the N-Methyl-D-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine
Gu, XP; Wu, XL; Liu, Y; Cui, SQ; Ma, ZL
Molecular Pain, 5(): -.
ARTN 76
CrossRef
Acta Anaesthesiologica Scandinavica
Does chronic opioid management change pain processing?
Werner, MU
Acta Anaesthesiologica Scandinavica, 51(): 70-71.

Annales Francaises D Anesthesie Et De Reanimation
Anaesthetic agents in children: risk or benefit?
Constant, I
Annales Francaises D Anesthesie Et De Reanimation, 26(6): 516-523.

Annales Francaises D Anesthesie Et De Reanimation
Ketamine for paediatric anaesthesia: useful, fool or... ?
De Kock, M
Annales Francaises D Anesthesie Et De Reanimation, 26(6): 524-528.
10.1016/j.annfar.2007.04.009
CrossRef
Minerva Anestesiologica
Updating postoperative pain management: from multimodal to context-sensitive treatment
Fanelli, G; Berti, M; Baciarello, M
Minerva Anestesiologica, 74(9): 489-500.

Anesthesia and Analgesia
Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery
Engelhardt, T; Zaarour, C; Naser, B; Pehora, C; de Ruiter, J; Howard, A; Crawford, MW
Anesthesia and Analgesia, 107(4): 1170-1175.
10.1213/ane.0b013e318183919e
CrossRef
Anesthesia and Analgesia
The evolution of primary hyperalgesia in orthopedic surgery: Quantitative sensory testing and clinical evaluation before and after total knee arthroplasty
Martinez, V; Fletcher, D; Bouhassira, D; Sessler, DI; Chauvin, M
Anesthesia and Analgesia, 105(3): 815-821.
10.1213/01.ane.0000278091.29062.63
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.

Biomedicine & Pharmacotherapy
The role of ketamine in pain management
Visser, E; Schug, SA
Biomedicine & Pharmacotherapy, 60(7): 341-348.
10.1016/j.biopha.2006.06.021
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
Acta Anaesthesiologica Scandinavica
Remifentanil and the brain
Fodale, V; Schifilliti, D; Pratico, C; Santamaria, LB
Acta Anaesthesiologica Scandinavica, 52(3): 319-326.
10.1111/j.1399-6576.2007.01566.x
CrossRef
Anesthesia and Analgesia
An evaluation of the postoperative antihyperalgesic and analgesic effects of intrathecal clonidine administered during elective cesarean delivery
Lavand'homme, PM; Roelants, F; Waterloos, H; COllet, V; De Kock, MF
Anesthesia and Analgesia, 107(3): 948-955.
10.1213/ane.0b013e31817f1595
CrossRef
Annales Francaises D Anesthesie Et De Reanimation
Pupillary dilatation monitoring to evaluate acute remifentanil tolerance in cardiac surgery
Coquin, J; Tafer, N; Mazerolles, M; Pouquet, O; Pfeiff, R; Richebe, P; Janvier, G
Annales Francaises D Anesthesie Et De Reanimation, 28(): 930-935.
10.1016/j.annfar.2009.07.073
CrossRef
Molecular Pharmacology
Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice
Campillo, A; Gonzalez-Cuello, A; Cabanero, D; Garcia-Nogales, P; Romero, A; Milanes, MV; Laorden, ML; Puig, MM
Molecular Pharmacology, 77(2): 185-194.
10.1124/mol.109.059790
CrossRef
Journal of Neuroscience
Control of chronic pain by the ubiquitin-proteasome system in the spinal cord
Ossipov, MH; Bazov, I; Gardell, LR; Kowal, J; Yakovleva, T; Usynin, I; Ekstrom, TJ; Porreca, F; Bakalkin, G
Journal of Neuroscience, 27(): 8226-8237.
10.1523/JNEUROSCI.5126-06.2007
CrossRef
Anesthesia and Analgesia
The analgesic effects of oploids and immersive virtual reality distraction: Evidence from subjective and functional brain imaging assessments
Hoffman, HG; Richards, TL; Van Oostrom, T; Coda, BA; Jensen, MP; Blough, DK; Sharar, SR
Anesthesia and Analgesia, 105(6): 1776-1783.
10.1213/01.ane.0000270205.45146.db
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
Development of acute opioid tolerance during infusion of remifentanil for pediatric scoliosis surgery
Crawford, MW; Hickey, C; Zaarour, C; Howard, A; Naser, B
Anesthesia and Analgesia, 102(6): 1662-1667.
10.1213/01.ane.0000216036.95705.c2
CrossRef
Pediatric Anesthesia
Hemodynamic differences between propofol-remifentanil and sevoflurane anesthesia for repair of cleft lip and palate in infants
Steinmetz, J; Holm-Knudsen, R; Sorensen, MK; Eriksen, K; Rasmussen, LS
Pediatric Anesthesia, 17(1): 32-37.
10.1111/j.1460-9592.2006.01999.x
CrossRef
Anesthesia and Analgesia
The addition of a small-dose ketamine infusion to tramadol for postoperative analgesia: A double-blinded, placebo-controlled, randomized trial after abdominal surgery
Webb, AR; Skinner, BS; Leong, S; Kolawole, H; Crofts, T; Taverner, M; Burn, SJ
Anesthesia and Analgesia, 104(4): 912-917.
10.1213/01.ane.0000256961.01813.da
CrossRef
Pain
Oral opioid use alters DNIC but not cold pain perception in patients with chronic pain - New perspective of opioid-induced hyperalgesia
Ram, KC; Eisenberg, E; Haddad, M; Pud, D
Pain, 139(2): 431-438.
10.1016/j.pain.2008.05.015
CrossRef
Pain
The pro-nociceptive effects of remifentanil or surgical injury in mice are associated with a decrease in delta-opioid receptor mRNA levels: Prevention of the nociceptive response by on-site delivery of enkephalins
Cabanero, D; Celerier, E; Garcia-Nogales, P; Mata, M; Roques, BP; Maldonado, R; Puig, MM
Pain, 141(): 88-96.
10.1016/j.pain.2008.10.011
CrossRef
Current Drug Targets
Anesthetic and Adjunctive Drugs for Fast-Track Surgery
Baldini, G; Carli, F
Current Drug Targets, 10(8): 667-686.

Pain Medicine
Reduced Cold Pain Tolerance in Chronic Pain Patients Following Opioid Detoxification
Younger, J; Barelka, P; Carroll, I; Kaplan, K; Chu, L; Prasad, R; Gaeta, R; Mackey, S
Pain Medicine, 9(8): 1158-1163.
10.1111/j.1526-4637.2008.00475.x
CrossRef
Drugs
Analgo-Sedation of Patients with Burns Outside the Operating Room
Gregoretti, C; Decaroli, D; Piacevoli, Q; Mistretta, A; Barzaghi, N; Luxardo, N; Tosetti, I; Tedeschi, L; Burbi, L; Navalesi, P; Azzeri, F
Drugs, 68(): 2427-2443.

European Journal of Pain
Postoperative analgesia and early rehabilitation after total knee replacement: A comparison of continuous low-dose intravenous ketamine versus nefopam
Aveline, C; Gautier, JF; Vautier, P; Cognet, F; Le Hetet, H; Attali, JY; Leconte, V; Leborgne, P; Bonnet, F
European Journal of Pain, 13(6): 613-619.
10.1016/j.ejpain.2008.08.003
CrossRef
Critical Care Clinics
Pharmacology of Sedative-Analgesic Agents: Dexmedetomidine, Remifentanil, Ketamine,Volatile Anesthetics, and the Role of Peripheral Mu Antagonists
Panzer, O; Moitra, V; Sladen, RN
Critical Care Clinics, 25(3): 451-+.
10.1016/j.ccc.2009.04.004
CrossRef
Burns
The management of pain in the burns unit
Richardson, P; Mustard, L
Burns, 35(7): 921-936.
10.1016/j.burns.2009.03.003
CrossRef
Medical Science Monitor
Magnesium sulfate reduces postoperative morphine requirement after remifentanil-based anesthesia
Kaya, S; Kararmaz, A; Gedik, R; Turhanoglu, S
Medical Science Monitor, 15(2): PI5-PI9.

Pain
Altered quantitative sensory testing outcome in subjects with opioid therapy
Chen, L; Malarick, C; Seefeld, L; Wang, SX; Houghton, M; Mao, JR
Pain, 143(): 65-70.
10.1016/j.pain.2009.01.022
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.

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.

Journal of Pain
Ketamine as an adjuvant for treatment of cancer pain in children and adolescents
Finkel, JC; Pestieau, SR; Quezado, ZMN
Journal of Pain, 8(6): 515-521.
10.1016/j.jpain.2007.02.429
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 Palliative Medicine
Myoclonus associated with high-dose parenteral methadone
Ito, S; Liao, S
Journal of Palliative Medicine, 11(6): 838-841.
10.1089/jpm.2008.0040
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Pre-treatment with morphine does not prevent the development of remifentanil-induced hyperalgesia
McDonnell, C; Zaarour, C; Hull, R; Thalayasingam, P; Pehora, C; Ahier, J; Crawford, MW
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 55(): 813-818.

Current Opinion in Investigational Drugs
Multimodal analgesia: Its role in preventing postoperative pain
White, PF
Current Opinion in Investigational Drugs, 9(1): 76-82.

Annales Francaises D Anesthesie Et De Reanimation
Administration of ketamine during induction and maintenance of anaesthesia in postoperative pain prevention Clinical trial in oncology
Colombani, S; Kabbani, Y; Mathoulin-Pelissier, S; Gekiere, JP; Dixmerias, F; Monnin, D; Lakdja, F
Annales Francaises D Anesthesie Et De Reanimation, 27(3): 202-207.
10.1016/j.annfar.2007.11.025
CrossRef
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
Molecular Pain
Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision
Liang, DY; Shi, XY; Qiao, YL; Angst, MS; Yeomans, DC; Clark, JD
Molecular Pain, 4(): -.
ARTN 7
CrossRef
Expert Opinion on Drug Safety
Remifentanil, a different opioid: potential clinical applications and safety aspects
Stroumpos, C; Manolaraki, M; Paspatis, GA
Expert Opinion on Drug Safety, 9(2): 355-364.
10.1517/14740331003672579
CrossRef
Anesthesia and Analgesia
Propofol Alters Ketamine Effect on Opiate-Induced Hyperalgesia
Ben-David, B; Chelly, JE
Anesthesia and Analgesia, 108(4): 1353.
10.1213/ane.0b013e318197c7e1
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Perioperative pain management in the patient treated with opioids: Continuing Professional Development
Richebe, P; Beaulieu, P
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 56(): 969-981.
10.1007/s12630-009-9202-y
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
European Journal of Pain
Perioperative ketamine does not prevent chronic pain after thoracotomy
Duale, C; Sibaud, F; Guastella, V; Vallet, L; Gimbert, YA; Taheri, H; Filaire, M; Schoeffler, P; Dubray, C
European Journal of Pain, 13(5): 497-505.
10.1016/j.ejpain.2008.06.013
CrossRef
Pediatric Anesthesia
Early awakening and extubation with remifentanil in ventilated premature neonates
Silva, YPE; Gomez, RS; Marcatto, JDO; Maximo, TA; Barbosa, RF; Silva, CSE
Pediatric Anesthesia, 18(2): 176-183.
10.1111/j.1460-9592.2007.02378.x
CrossRef
Journal of Clinical Anesthesia
Severe remifentanil-induced acute opioid tolerance following awake craniotomy in an adolescent
Stricker, PA; Kraemer, FW; Ganesh, A
Journal of Clinical Anesthesia, 21(2): 124-126.
10.1016/j.jclinane.2008.06.032
CrossRef
European Journal of Pain
Peroperative ketamine and morphine for postoperative pain control after lumbar disk surgery
Aveline, C; Le Hetet, H; Vautier, P; Gautier, JF; Bonnet, F
European Journal of Pain, 10(7): 653-658.
10.1016/j.ejpain.2005.10.005
CrossRef
British Journal of Anaesthesia
Effects of a loading dose of morphine before i.v. morphine titration for postoperative pain relief: a randomized, double-blind, placebo-control study
Aubrun, F; Amour, J; Rosenthal, D; Coriat, P; Riou, B
British Journal of Anaesthesia, 98(1): 124-130.
10.1093/bja/ael284
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats
Richebe, P; Rivalan, B; Rivat, C; Laulin, JP; Janvier, G; Maurette, P; Simonnet, G
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 56(2): 126-135.
10.1007/s12630-008-9023-4
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.

Journal of Cardiothoracic and Vascular Anesthesia
Remifentanil infusion does not induce opioid tolerance after cardiac surgery
Lahtinen, P; Kokki, H; Hynynen, M
Journal of Cardiothoracic and Vascular Anesthesia, 22(2): 225-229.
10.1053/j.jvca.2007.07.004
CrossRef
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
International Journal of Oral and Maxillofacial Surgery
Quantitative sensory testing of intraoral open wounds
Ettlin, DA; Hitz, T; Ramel, C; Meier, ML; Roos, M; Gallo, LM; Svensson, P; Hammerle, CH
International Journal of Oral and Maxillofacial Surgery, 42(3): 401-405.
10.1016/j.ijom.2012.11.010
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Effects of Nefopam on Early Postoperative Hyperalgesia After Cardiac Surgery
Richebe, P; Picard, W; Rivat, C; Jelacic, S; Branchard, O; Leproust, S; Cahana, A; Janvier, G
Journal of Cardiothoracic and Vascular Anesthesia, 27(3): 427-435.
10.1053/j.jvca.2012.08.015
CrossRef
European Journal of Pain
Preoperative scar hyperalgesia is associated with post-operative pain in women undergoing a repeat Caesarean delivery
Ortner, CM; Granot, M; Richebe, P; Cardoso, M; Bollag, L; Landau, R
European Journal of Pain, 17(1): 111-123.
10.1002/j.1532-2149.2012.00171.x
CrossRef
Medicina-Lithuania
Comparison of Different Anesthetic Regimens in Patients Undergoing Laparoscopic Adjustable Gastric Banding Operations: A Prospective Randomized Trial
Kontrimaviciute, E; Sipylaite, J; Aksionova, D; Cincileviciute, G; Brimas, G
Medicina-Lithuania, 48(): 613-618.

Pain Physician
A Negative Correlation Between Hyperalgesia and Analgesia in Patients with Chronic Radicular Pain: Is Hydromorphone Therapy a Double-Edged Sword?
Suzan, E; Eisenberg, E; Treister, R; Haddad, M; Pud, D
Pain Physician, 16(1): 65-76.

Minerva Anestesiologica
A year in review in Minerva Anestesiologica 2012
Chiumello, D; Allegri, M; Cavaliere, F; De Cosmos, G; Iohom, G; Langeron, O; Pietrini, D; Rossi, M
Minerva Anestesiologica, 79(4): 454-469.

Annales Francaises D Anesthesie Et De Reanimation
Chronic postsurgical pain
Martinez, V; Baudic, S; Fletcher, D
Annales Francaises D Anesthesie Et De Reanimation, 32(6): 422-435.
10.1016/j.annfar.2013.04.012
CrossRef
Neonatology
Remifentanil-Induced Tolerance, Withdrawal or Hyperalgesia in Infants: A Randomized Controlled Trial. RAPIP Trial: Remifentanil-Based Analgesia and Sedation of Paediatric Intensive Care Patients
Welzing, L; Link, F; Junghaenel, S; Oberthuer, A; Harnischmacher, U; Stuetzer, H; Roth, B
Neonatology, 104(1): 34-41.
10.1159/000348790
CrossRef
CNS Neuroscience & Therapeutics
Ketamine: Use in Anesthesia
Marland, S; Ellerton, J; Andolfatto, G; Strapazzon, G; Thomassen, O; Brandner, B; Weatherall, A; Paal, P
CNS Neuroscience & Therapeutics, 19(6): 381-389.
10.1111/cns.12072
CrossRef
Seminars in Respiratory and Critical Care Medicine
Evaluation and Treatment of Pain in Critically Ill Adults
Joffe, AM; Hallman, M; Gelinas, C; Herr, DL; Puntillo, K
Seminars in Respiratory and Critical Care Medicine, 34(2): 189-200.
10.1055/s-0033-1342973
CrossRef
European Journal of Anaesthesiology (EJA)
Postoperative recovery profile after elective abdominal hysterectomy: a prospective, observational study of a multimodal anaesthetic regime
Jensen, K; Kehlet, H; Lund, CM
European Journal of Anaesthesiology (EJA), 26(5): 382-388.
10.1097/EJA.0b013e32831f3429
PDF (117) | CrossRef
Anesthesiology
Postoperative Hyperalgesia: Its Clinical Importance and Relevance
Wilder-Smith, OH; Arendt-Nielsen, L
Anesthesiology, 104(3): 601-607.

PDF (1305)
Anesthesiology
Lack of Impact of Intravenous Lidocaine on Analgesia, Functional Recovery, and Nociceptive Pain Threshold after Total Hip Arthroplasty
Martin, F; Cherif, K; Gentili, ME; Enel, D; Abe, E; Alvarez, JC; Mazoit, JX; Chauvin, M; Bouhassira, D; Fletcher, D
Anesthesiology, 109(1): 118-123.
10.1097/ALN.0b013e31817b5a9b
PDF (247) | CrossRef
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
Preventive Analgesia to Reduce Wound Hyperalgesia and Persistent Postsurgical Pain: Not an Easy Path
Brennan, TJ; Kehlet, H
Anesthesiology, 103(4): 681-683.

PDF (229)
Anesthesiology
Pronociceptive Effects of Remifentanil in a Mouse Model of Postsurgical Pain: Effect of a Second Surgery
Cabañero, D; Campillo, A; Célérier, E; Romero, A; Puig, MM
Anesthesiology, 111(6): 1334-1345.
10.1097/ALN.0b013e3181bfab61
PDF (1189) | 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
Current Opinion in Anesthesiology
Something new about ketamine for pediatric anesthesia?
Lois, F; De Kock, M
Current Opinion in Anesthesiology, 21(3): 340-344.
10.1097/ACO.0b013e3282f82bde
PDF (97) | CrossRef
European Journal of Anaesthesiology (EJA)
Systemic administration of lidocaine reduces morphine requirements and postoperative pain of patients undergoing thoracic surgery after propofol–remifentanil-based anaesthesia
Cui, W; Li, Y; Li, S; Wang, R; Li, J
European Journal of Anaesthesiology (EJA), 27(1): 41-46.
10.1097/EJA.0b013e32832d5426
PDF (338) | CrossRef
European Journal of Anaesthesiology (EJA)
Effect of a low‐dose ketamine regimen on pain, mood, cognitive function and memory after major gynaecological surgery: a randomized, double‐blind, placebo‐controlled trial
Riou, B; Aubrun, F; Gaillat, C; Rosenthal, D; Dupuis, M; Mottet, P; Marchetti, F; Coriat, P
European Journal of Anaesthesiology (EJA), 25(2): 97-105.
10.1017/S0265021507002566
PDF (133) | CrossRef
European Journal of Anaesthesiology (EJA)
Anaesthetic management and perioperative monitoring of a patient with narcolepsy
Staikou, C; Tsaroucha, A; Fassoulaki, A
European Journal of Anaesthesiology (EJA), 24(10): 898-899.
10.1017/S0265021507000841
PDF (52) | CrossRef
Journal of Neurosurgical Anesthesiology
Systemic Lidocaine Inhibits Remifentanil-induced Hyperalgesia via the Inhibition of cPKCgamma Membrane Translocation in Spinal Dorsal Horn of Rats
Cui, W; Li, Y; Li, S; Yang, W; Jiang, J; Han, S; Li, J
Journal of Neurosurgical Anesthesiology, 21(4): 318-325.
10.1097/ANA.0b013e3181abbde5
PDF (455) | CrossRef
Back to Top | Article Outline

© 2005 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