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Ketamine and Remifentanil Interactions on the Sevoflurane Minimum Alveolar Concentration and Acute Opioid Tolerance in the Rat

Aguado, Delia, DVM*; Abreu, Mariana, DVM*; Benito, Javier, DVM; García-Fernández, Javier, MD, PhD; Gómez de Segura, Ignacio A., DVM, PhD, DECLAM, DECVA*

doi: 10.1213/ANE.0b013e318227517a
Anesthetic Pharmacology: Research Reports
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BACKGROUND: Ketamine is used at low doses for its analgesic and antihyperalgesic properties when combined with opioids but also when opioid-induced hyperalgesia and tolerance appear. In this study we determined the interaction of ketamine and remifentanil on the minimum alveolar concentration (MAC) of sevoflurane in rats and to determine whether ketamine may block acute opioid tolerance (AOT).

METHODS: Male Wistar rats were anesthetized with sevoflurane, and the MAC was determined before and after ketamine administration (10, 20, 40, and 80 mg kg−1 or saline) alone or combined with remifentanil (120 and 240 μg kg−1 h−1, low and high doses, respectively). One additional group received the lowest ketamine dose after starting a remifentanil infusion. Finally, naloxone was administered to determine the potential action of ketamine on opioid receptors. MAC was determined from intratracheal gas samples, and tail clamping was used as a supramaximal stimulus. End-tidal anesthetic concentrations were assayed using a side stream gas analyzer. Statistical analysis was performed with an analysis of variance.

RESULTS: Ketamine and remifentanil dose-dependently reduced the MAC. Adding the low dose of remifentanil to ketamine did not improve the MAC reduction, whereas the high dose of remifentanil enhanced ketamine reduction in a subadditive fashion. Nevertheless, ketamine was unable to block the development of AOT to remifentanil at either dose. Finally, naloxone blocked the MAC reduction produced by ketamine.

CONCLUSIONS: A subadditive effect between ketamine and remifentanil was found on the sevoflurane MAC reduction rats. In addition, ketamine was unable to block AOT. The clinical relevance of these findings should be elucidated in future studies to reduce anesthetic requirements.

Published ahead of print July 21, 2011

From the *Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Madrid, Spain; Comparative Pain Research Laboratory, Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh; Department of Pediatric Anesthesiology, La Paz University Hospital, Madrid, Spain.

Funding: This work was supported by a grant from the Fondo de Investigaciones Sanitarias, Spanish Health Ministry, grant number FIS 08/0422.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Ignacio Álvarez Gómez de Segura, DVM, PhD, DECLAM, DECVA, Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Avda, Puerta de Hierro s/n, 28040 Madrid, Spain. Address e-mail to iagsegura@vet.ucm.es.

Accepted May 12, 2011

Published ahead of print July 21, 2011

Ketamine is an N-methyl-d-aspartate (NMDA) antagonist1 with anesthetic properties, but it is also associated with clinically relevant adverse effects that have limited its use.2 Therefore, ketamine is used at lower doses for its analgesic3 and for its antihyperalgesic properties.4,5 Intraoperative use of low doses of ketamine improve postoperative pain relief and decrease morphine requirements during the first 24 hours. These results are obtained whether ketamine is administered via an epidural catheter or systemically, but it is preferably given at a constant rate of infusion.3,69 Despite the strong evidence-based improvement in pain therapy and reduction in opioid requirements produced by ketamine,1014 a lack of improved postoperative analgesia has also been reported.15 Besides the antiopioid-induced hyperalgesia action of ketamine, this drug has been used for its antitolerance action.5,8,1618 Therefore, because acute opioid tolerance may develop during anesthesia,1921 ketamine might be useful to limit or prevent it.22,23

A method to determine the relative analgesic potency of analgesic drugs used in the intraoperative period is the determination of the reduction in the minimum alveolar concentration (MAC) of inhalation anesthetics.24 We hypothesized that the MAC reduction by ketamine and remifentanil would be additive or synergistic but also that ketamine, in combination with opioids, would block AOT. Therefore, the purpose of this study was to determine the effect of ketamine, administered alone or in combination with remifentanil, on the sevoflurane MAC (MACSEV) in rats and to determine whether ketamine may blunt or prevent AOT.

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METHODS

After obtaining the approval of the Institutional Animal Care Committee (La Paz University Hospital, Madrid, Spain), the reduction of MACSEV in response to ketamine and remifentanil was evaluated in rats. Sevoflurane was obtained from Abbott (Sevorane; Abbott Laboratories, Madrid, Spain), ketamine from Parke-Davis (Ketolar 500; Parke-Davis-Pfizer, Madrid, Spain), remifentanil from Glaxo-Wellcome (Ultiva; Glaxo-Wellcome Laboratories, Madrid, Spain), and naloxone from Sigma-Aldrich (naloxone hydrochloride dehydrate; Sigma-Aldrich, St. Quentin Fallavier, France).

One hundred two adult male Wistar rats (Charles River Laboratories, Barcelona, Spain), weighing 321 ± 34 g, were housed in groups of 4 to 6 animals per cage (macrolon type IV) with a 12-hour light, 12-hour dark cycle, relative humidity of 40%–70%, and 20° ± 2°C ambient temperature. Food (B&K Universal; Grimston, UK) and water were provided ad libitum. Animals were allowed to acclimatize for at least 1 week. All of the studies were performed during the morning (starting at 8:30 am).

Rats were placed in an induction chamber, into which 8% sevoflurane in a continuous oxygen flow of 3 L min−1 was directed (Sevoflurane Vaporizer; Sevorane Dragër Vapor 2000, Lubeck, Germany). Endotracheal intubation was performed using a 14-gauge polyethylene catheter (Terumo Surflo IV Catheter; Terumo Europe NV, Leuven, Belgium) with the animal positioned in sternal recumbency. A flexible, blunt-tipped wire guide was inserted into the trachea with an otoscope and used to direct the endotracheal catheter. After the catheter was properly positioned, it was connected to a small T piece breathing system with minimum dead space. Fresh gas flow to the T piece was adjusted to 1 L min−1 of oxygen (100%), and the sevoflurane concentration was adjusted to 1.5 × MAC (3.5%–4%). Rats were kept under spontaneous ventilation during the whole experiment, because these remifentanil doses did not produce hypercapnia (Paco2 below 45 mm Hg),25 which might have modified the MAC.26,27 However, when signs of hypoventilation occurred, spontaneous ventilation was stimulated by touching the rat's thorax softly. Remifentanil was administered with an infusion pump (syringe pump, model Sep11S; Ascor S.A., Medical Equipment, Warsaw, Poland) by a 22-gauge polyethylene catheter inserted in a tail vein.

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Monitoring

The carotid artery was catheterized (Venocath-18, Venisystems; Hospira, Sligo, Ireland) via the surgical cut-down approach. This access point allowed for arterial blood sampling and blood pressure measurement via a calibrated pressure transducer (Transpac IV; Abbott Laboratories, Abbott Park, IL). Systolic, diastolic, and mean arterial blood pressures, arterial oxygen hemoglobin saturation (via pulseoximetry), and heart and respiratory rates were recorded continuously (RGB; Medical Devices, Madrid, Spain). Arterial blood (1 mL) was collected for blood gas analysis (Rapidlab 1265; Bayer AG, Leverkusen, Germany) at the end of the study to ensure that values at that time were within normal limits of pH (7.35 to 7.47), oxygen (Pao2; >120 mm Hg), and carbon dioxide arterial partial pressures (Paco2; 35 to 55 mm Hg). Rectal temperature was also monitored and maintained between 37.0°C and 38.5°C by means of a water-circulating warming blanket (Heat Therapy Pump, Model TP-220; Gaymar, Orchand Park, NY) and a heating lamp.

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Determination of the Minimum Alveolar Concentration

Intratracheal gas sampling was used to measure anesthetic gas concentration and to determine the MAC. This method has been described in detail.28 In brief, a fine catheter with a 0.9-mm external diameter was inserted through the endotracheal catheter with the fine catheter tip located at the level of the carina. The proximal end of the catheter was connected to a 10-mL gas-tight glass syringe (Hamilton Syringe, 1000 series Gastight, model 26,211-U; Sigma-Aldrich, St. Quentin Fallavier, France). Samples were obtained by withdrawing 10 mL of gas over a 5-minute period using an infusion pump (model KDS-210; Harvard Apparatus, Millis, MA). The fine catheter was withdrawn between samples. After every step change in anesthetic concentration delivered by the anesthetic circuit, at least 10 minutes were allowed for equilibration before the noxious stimulus was applied. The samples were assayed using a side-stream infrared analyzer (Capnomac Ultima; Datex-Ohmeda, Hertfordshire, UK).

MACSEV was established according to a method described elsewhere.29 A supramaximal noxious stimulus was applied with a long hemostat (8-inch Rochester Dean Hemostatic Forceps) clamped to the first ratchet lock on the tail for 60 seconds, immediately before the gas sample was obtained from the trachea. The tail was always stimulated proximally to a previous test site when the previous response was negative, or it was stimulated distally if it was positive, starting 6 cm from the tail base. A positive response was considered to be a gross purposeful movement of the head, extremities, or body. A negative response was considered to be the lack of movement or grimacing, swallowing, chewing, or tail flicking. When a negative response was seen, the sevoflurane concentration was reduced in decrements of 0.2% until the negative response became positive. Similarly, when a positive response was seen, the sevoflurane concentration was increased until the positive response became negative. The MAC was considered to be the concentration midway between the highest concentration that permitted movement in response to the stimulus and the lowest concentration that prevented such movement. Determination of the MAC was performed in a laboratory at 650 m above sea level.

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Experimental Design and Drug Groups

The MACSEV was determined 4 times in every animal. Once the animals were anesthetized and instrumented, a baseline MAC (MACSEV) was determined, and each animal acted as its own control. In the first experiment, ketamine was then administered intraperitoneally, and remifentanil (high and low doses or saline) was continuously infused into the tail vein 30 minutes later with no initial loading dose. The MAC was redetermined (MAC-2), and again approximately 90 minutes later (MAC-3). Finally, the remifentanil infusion was stopped, and the MAC was determined once more (MAC-4). Periods of 30 minutes were allotted between MAC determinations, and periods of 40 to 60 minutes were usually necessary to determine the MAC value. Overall, every experiment lasted >6 hours. Fifteen groups (drug × dose; n = 6 per group) were established in the first experiment according to the drug administered: ketamine (4 doses and saline), remifentanil (2 doses), or a combination of the 2. Therefore, 5 groups were administered ketamine at doses of 10, 20, 40, and 80 mg kg−1 or saline intraperitoneally once the MACSEV was determined. Ten additional groups were given the same doses of ketamine or saline and were also administered remifentanil at either 120 or 240 μg kg−1 h−1 (low and high doses, respectively) during the MAC-2 and MAC-3 determinations.

In a second experiment, to evaluate the potential blocking action of ketamine in AOT, another group of animals (n = 6) was administered the lowest dose of ketamine (10 mg kg−1) after the MAC-2 was determined with remifentanil at 120 μg kg−1 h−1.

In a third experiment, we aimed to assess whether the observed effects of ketamine on the MAC would have been mediated, at least in part, through opioid receptors. To test this, we administered naloxone 10 mg kg−1, without remifentanil, to a group of rats treated with ketamine 40 mg kg−1 (n = 6), 15 minutes after the determination of the MAC-2.

Animals were euthanized with an overdose of potassium chloride given IV while they were still deeply anesthetized (Fig. 1).

Figure 1

Figure 1

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Statistical Analysis

Sample size calculations indicated an n value of 6 necessary to determine differences with a power of 80% and a P value of 0.05. Mean and SD was obtained from a previous study,21 and the statistical package used was N Query Advisor (version 2.0; Statistical Solutions. Saugus, MA).

Results are presented as mean ± sd. Rats in every experiment were randomly allocated using a random number generator (Excel 2007, Microsoft Office). Data were tested for normality with the Kolmogorov–Smirnov test. To assess the interaction between remifentanil and ketamine in the MAC, a 2-way analysis of variance (ANOVA) was used. A 1-way ANOVA was used to determine the effect of ketamine on the prevention of AOT (experiments 1 and 2) as well as the effect of naloxone and ketamine in the MAC (Experiment 3). The Bonferroni test was used to compare groups. A P value of <0.05 was set to indicate statistical significance. All analyses were performed using the SPSS statistical package (version 15 for Windows, 2006; SPSS Inc., Chicago, IL).

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RESULTS

The baseline MACSEV determined in all rats was 2.3% ± 0.3% volume (n = 102) and was similar among groups (P = 1.00).

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Effects of Ketamine and Remifentanil on the MAC (Experiment 1; Fig. 2)

Figure 2

Figure 2

Ketamine dose-dependently reduced the MAC with a maximum reduction (MAC-2) of 4% ± 8%, 12% ± 8%, 25% ± 2%, and 41% ± 10% with 10, 20, 40, and 80 mg kg−1, respectively. The MAC reduction observed in a further MAC determination (MAC-3) was similar to that determined in MAC-2 in all groups (MAC reduction of 6% ± 10%, 13% ± 9%, and 16% ± 11% with 10, 20, and 40 mg kg−1, respectively; P > 0.05), with the exception of the group that was administered ketamine 80 mg kg−1 (MAC reduction of 29% ± 12%; P = 0.008). In the last MAC determination (MAC-4), values were not different from baseline (as percentage of variation from baseline; P > 0.05) in all groups, with the exception of the ketamine 80 mg kg−1 group in which MAC-4 was lower than baseline values (P < 0.001).

Remifentanil, given alone, dose-dependently reduced the MAC (MAC-2) by 20% ± 9% and 30% ± 6% with the low and high doses, respectively. However, an AOT effect to remifentanil was observed approximately 1.5 hours later (MAC-3) as determined by a lower MAC reduction, 14% ± 4% and 18% ± 2% with the low and high doses, respectively (P = 0.001 and P = 0.004, respectively), even though the same remifentanil constant rate of infusion had been maintained (Table 1).

Table 1

Table 1

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Effects of Combined Action of Ketamine and Remifentanil on the MAC and AOT (Experiment 1; Fig. 2)

There was no significant interaction between remifentanil and ketamine, and individual doses of ketamine were not compared (P = 0.32). The high dose of remifentanil (P < 0.001), but not the low dose (P = 0.12), significantly increased the MAC reduction produced by ketamine (all doses) combined with saline. Individual MAC-2 reductions were 5% ± 10%, 17% ± 5%, 28% ± 6% ,and 38% ± 9% with remifentanil at 120 μg kg−1 h−1, and 23% ± 5%, 38% ± 12%, 47% ± 16%, and 62% ± 10% with remifentanil at 240 μg kg−1 h−1, combined with ketamine at 10, 20, 40, and 80 mg kg−1, respectively.

Remifentanil administration produced an AOT effect in all groups determined by a significantly lower MAC reduction (MAC-2 vs. MAC-3; P < 0.05), with the exception of the remifentanil low-dose (120 μg kg−1 h−1) and the ketamine lowest-dose group (10 mg kg−1) (Table 1).

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A Delayed Administration of A Low Dose of Ketamine did not Prevent Remifentanil-induced AOT in the MAC (Experiment 2, Table 2)

Table 2

Table 2

A remifentanil-induced AOT was observed when remifentanil was administered alone at 120 μg kg−1 h−1 (1.7% ± 0.2% volume and 1.9% ± 0.3% volume MAC-2 and MAC-3, respectively; P = 0.01). When the lowest dose of ketamine, 10 mg kg−1, was administered after the remifentanil infusion was started and the MAC-2 determined, an AOT to remifentanil was observed because MAC-3 (2.0% ± 0.2% volume) was different from MAC-2 (1.8% ± 0.2% volume) (P = 0.007).

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Naloxone Blunted the MAC Reduction Produced by Ketamine (Experiment 3; Fig. 3)

Figure 3

Figure 3

Naloxone (10 mg kg−1) significantly blocked (MAC reduction of 4% ± 1%) the MAC reduction produced by ketamine (40 mg kg−1) (MAC reduction of 20% ± 1%) (P = 0.001).

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DISCUSSION

Given alone, ketamine and remifentanil both dose-dependently reduced the MACSEV in the rats. However, the combination of both drugs during sevoflurane anesthesia enhanced the MAC reduction produced by either drug alone in a subadditive fashion. In fact, the dose-dependent anesthetic-sparing effect of ketamine was not improved by the low dose of remifentanil, and a 20% further reduction in the MAC was observed after the high dose of this opioid with every ketamine dose given to the rats.

There is evidence suggesting that ketamine in subanesthetic doses (a dose below that required to produce anesthesia) administered in the perioperative period is effective in reducing opioid requirements postoperatively in humans3,4,69,15,3032 and animals.3335 However, controversial results have been reported regarding the efficacy of ketamine in improving pain relief when combined with opioids. A recent qualitative review of randomized trials concluded that the benefit of adding ketamine to morphine in IV patient-controlled analgesia for orthopedic or abdominal surgery remains unclear with 5 clinical trials of 11 failing to demonstrate improved postoperative analgesia.15 Besides, although most studies have assessed postoperative pain, no study has screened the effects of these drugs in the intraoperative period during inhaled anesthesia. Results from our study suggest a subadditive interaction between remifentanil and ketamine in terms of MAC reduction because the effects of the combination are less than the sum of the expected effects of the 2 drugs alone. Furthermore, the low dose of remifentanil, which reduced the MAC by 20%, did not improve the anesthetic-sparing action of ketamine.

The use of opioids is associated with a gradual decrease in their analgesic efficacy due to opioid tolerance, and eventually a dose escalation is necessary to maintain the same net analgesic effect in the long term.21,36 A link between opioid tolerance and NMDA activity has been proposed by which opioids might enhance NMDA receptor function37,38 in cancer16 or surgical patients.4,5 Remifentanil not only acts on opioid receptors but also on NMDA receptors, potentially triggering opioid tolerance.37,39 Morphine induces up-regulation of the spinal NMDA receptor NR2B subunit expression, and activation of JNK in the spinal cord, leading to morphine antinociceptive tolerance,40 which can be prevented or reversed by NMDA antagonists.1,22,23,41 Therefore, remifentanil-induced hyperalgesia and acute tolerance19,20 might be thwarted by the administration of ketamine. However, although an AOT effect has been observed that leads to blunting of the MAC reduction produced by remifentanil in rats,21 a preventive action of ketamine could not be determined from the results of the present study.

A potential explanation for the limited additive action of ketamine and remifentanil, in comparison with morphine, is a potential variable degree of interaction of ketamine with opioids at the μ receptor. Ketamine binds to μ opioid receptors,4244 and their activation can reduce the MACSEV45 while their blockade by the opioid antagonist naloxone46 determined the suppression of the ketamine-induced MAC reduction. Additional evidence for a differential interaction of opioids with ketamine has been found at the spinal cord. Epidural ketamine selectively enhances epidural morphine but may antagonize the antinociceptive activity of fentanyl in rats.35 Also, a lack of analgesic interaction has been determined with epidural meperidine in dogs.47 The combination of 2 lipophilic and fast-acting drugs, such as ketamine42,48 and remifentanil, might cause competition for the μ receptor, with less μ receptor occupancy by remifentanil and thus potential antagonism of the remifentanil-induced antinociception by ketamine. Other potential explanations35 may involve a variable binding affinity for the opioid receptor by morphine and fentanyl, a competitive impairment in the passive diffusion of both drugs, a competition for binding to the same transporter through the blood-brain barrier, or reduced metabolism through the inhibition of morphine glucuronidation by ketamine.49

Another relevant issue when determining the enhancement between ketamine and opioids is the measurement method. Previous studies have reported an improvement in analgesic efficacy in the postoperative period, whereas our study determined the MAC. The MAC is a standard measure of the potency of inhalation anesthetics,29 and comparison among different analgesic substances can be made by determining the degree of MAC reduction they produce. Furthermore, this method is of clinical value because it better mimics the intraoperative period. However, the MAC reduction is not only the result of the antinociceptive effects of the drugs but also the result of complex interactions between the analgesic drugs and volatile anesthetics.24 The MAC actually measures immobility to a noxious stimulus,50 immobility that is considered to be the result of anesthetic effects at the spinal cord.51

The noxious stimulus used for the determination of MAC may also influence the observed interaction between remifentanil and ketamine. Remifentanil increases all thresholds for pain detection and tolerance to pressure as well as to electrical nociceptive stimuli.5 Ketamine failed to prevent tolerance to remifentanil and opioid-induced hyperalgesia in healthy volunteers when a nociceptive pressure stimulus, similar to that used in the MAC method, was applied. However, a preventive action of ketamine was observed with repeated electrical stimulation,52 inducing central temporal summation and involving NMDA receptors.53

Differences in the doses of drugs between people and rats may account for the observed effects. Extrapolation of doses from rats to humans should be based on allometric escalation, and refer to body surface rather than body weight. Doses of ketamine below 80 mg kg−1 should be considered subanesthetic,41,54 and actually higher doses necessary to produce anesthesia should be combined with sedatives such as α-2 adrenoceptor agonists. The doses of remifentanil that we used25 were based on their ability to produce a significant MAC reduction.55 Nevertheless, the observed results should not be directly extrapolated between species because the same opioids and doses may actually account for large variations in the MAC.50,56

In conclusion, a subadditive effect between ketamine and remifentanil was found on the MACSEV reduction in rats, and in addition, ketamine was unable to block the acute tolerance to remifentanil, leading to a blunting effect on the MAC reduction produced by the opioid. Further studies should determine whether the interaction observed in rats is of clinical relevance.

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DISCLOSURES

Name: Delia Aguado, DVM.

Contribution: Study design, conduct of study, data analysis, and manuscript preparation.

Name: Mariana Abreu, DVM.

Contribution: Conduct of study.

Name: Javier Benito, DVM.

Contribution: Study design and manuscript preparation.

Name: Javier García-Fernández, MD, PhD.

Contribution: Study design and manuscript preparation.

Name: Ignacio A. Gómez de Segura, DVM, PhD, DECLAM, DECVA.

Contribution: Study design, data analysis, and manuscript preparation.

This manuscript was handled by Marcel E. Durieux, MD, PhD.

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ACKNOWLEDGMENTS

The authors thank Drs. E. de Miguel and C. Largo, Department of Experimental Surgery, La Paz University Hospital, Madrid, Spain.

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REFERENCES

1. Yamamura T, Harada K, Okamura A, Kemmotsu O. Is the site of action of ketamine anesthesia the N-methyl-D-aspartate receptor? Anesthesiology 1990;72:704–10
2. Eger EI 2nd. Characteristics of anesthetic agents used for induction and maintenance of general anesthesia. Am J Health Syst Pharm 2004;61(Suppl 4):S3–10
3. 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
4. Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147–55
5. Luginbuhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M. Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg 2003;96:726–32
6. Elia N, Tramer MR. Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain 2005;113:61–70
7. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005;49:1405–28
8. Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother 2006;60:341–8
9. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg 2004;99:482–95
10. Batra YK, Shamsah M, Al-Khasti MJ, Rawdhan HJ, Al-Qattan AR, Belani KG. Intraoperative small-dose ketamine does not reduce pain or analgesic consumption during perioperative opioid analgesia in children after tonsillectomy. Int J Clin Pharmacol Ther 2007;45:155–60
11. Subramaniam B, Subramaniam K, Pawar DK, Sennaraj B. Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect. Anesth Analg 2001;93:1321–6
12. Englelhardt T, Zaarour C, Naser B, Pehora C, de Ruiter J, Howard A, Crawford MW. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg 2008;107:1170–5
13. Van Elstraete AC, Lebrun T, Sandefo I, Polin B. Ketamine does not decrease postoperative pain after remifentanil-based anaesthesia for tonsillectomy in adults. Acta Anaesthesiol Scand 2004;48:756–60
14. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology 2005;102:211–20
15. Carstensen M, Moller AM. Adding ketamine to morphine for intravenous patient-controlled analgesia for acute postoperative pain: a qualitative review of randomized trials. Br J Anaesth 2010;104:401–6
16. Chazan S, Ekstein MP, Marouani N, Weinbroum AA. Ketamine for acute and subacute pain in opioid-tolerant patients. J Opioid Manag 2008;4:173–80
17. Cohen SP, Wang S, Chen L, Kurihara C, McKnight G, Marcuson M, Mao J. An intravenous ketamine test as a predictive response tool in opioid-exposed patients with persistent pain. J Pain Symptom Manag 2009;37:698–708
18. Weinbroum AA. A single small dose of postoperative ketamine provides rapid and sustained improvement in morphine analgesia in the presence of morphine-resistant pain. Anesth Analg 2003;96:789–95
19. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998;86:1307–11
20. 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
21. Gomez de Segura IA, de la Vibora JB, Aguado D. Opioid tolerance blunts the reduction in the sevoflurane minimum alveolar concentration produced by remifentanil in the rat. Anesthesiology 2009;110:1133–8
22. Kissin I, Bright CA, Bradley EL Jr. 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
23. 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
24. Docquier MA, Lavand'homme P, Ledermann C, Collet V, De KM. Can determining the minimum alveolar anesthetic concentration of volatile anesthetic be used as an objective tool to assess antinociception in animals? Anesth Analg 2003;97:1033–9
25. Criado AB, Gomez e Segura IA. Reduction of isoflurane MAC by fentanyl or remifentanil in rats. Vet Anaesth Analg 2003;30:250–6
26. Quasha AL, Eger EI 2nd, Tinker JH. Determination and applications of MAC. Anesthesiology 1980;53:315–34
27. Brosnan RJ, Eger EI 2nd, Laster MJ, Sonner JM. Anesthetic properties of carbon dioxide in the rat. Anesth Analg 2007;105:103–6
28. Pajewski TN, DiFazio CA, Moscicki JC, Johns RA. Nitric oxide synthase inhibitors, 7-nitro indazole and nitroG-L-arginine methyl ester, dose dependently reduce the threshold for isoflurane anesthesia. Anesthesiology 1996;85:1111–9
29. Eger EI 2nd, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965;26:756–63
30. 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
31. Menigaux C, Fletcher D, Dupont X, Guignard B, Guirimand F, Chauvin M. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000;90:129–35
32. Remerand F, Le TC, Baud A, Couvret C, Pourrat X, Favard L, Laffon M, Fusciardi J. The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Anesth Analg 2009;109:1963–71
33. Holtman JR Jr, Crooks PA, Johnson-Hardy J, Wala EP. Interaction between morphine and norketamine enantiomers in rodent models of nociception. Pharmacol Biochem Behav 2008;90:769–77
34. Kosson D, Klinowiecka A, Kosson P, Bonney I, Carr DB, Mayzner-Zawadzka E, Lipkowski AW. Intrathecal antinociceptive interaction between the NMDA antagonist ketamine and the opioids, morphine and biphalin. Eur J Pain 2008;12:611–6
35. Hoffmann VL, Baker AK, Vercauteren MP, Adriaensen HF, Meert TF. Epidural ketamine potentiates epidural morphine but not fentanyl in acute nociception in rats. Eur J Pain 2003;7:121–30
36. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–87
37. Zhao M, Joo DT. Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance. Anesthesiology 2008;109:308–17
38. Hahnenkamp K, Nollet J, Van Aken HK, Buerkle H, Halene T, Schauerte S, Hahnenkamp A, Hollmann MW, Strumper D, Durieux ME, Hoenemann CW. Remifentanil directly activates human N-methyl-D-aspartate receptors expressed in Xenopus laevis oocytes. Anesthesiology 2004;100:1531–7
39. Ghelardini C, Galeotti N, Vivoli E, Norcini M, Zhu W, Stefano GB, Guarna M, Bianchi E. Molecular interaction in the mouse PAG between NMDA and opioid receptors in morphine-induced acute thermal nociception. J Neurochem 2008;105:91–100
40. Guo RX, Zhang M, Liu W, Zhao CM, Cui Y, Wang CH, Feng JQ, Chen PX. NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinociceptive tolerance. Neurosci Lett 2009;467:95–9
41. 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. Anesthesiology 2000;92:465–72
42. Smith DJ, Bouchal RL, deSanctis CA, Monroe PJ, Amedro JB, Perrotti JM, Crisp T. Properties of the interaction between ketamine and opiate binding sites in vivo and in vitro. Neuropharmacology 1987;26:1253–60
43. Finck AD, Ngai SH. Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982;56:291–7
44. Hirota K, Okawa H, Appadu BL, Grandy DK, Devi LA, Lambert DG. Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology 1999;90:174–82
45. Koyama T, Mayahara T, Wakamatsu T, Sora I, Fukuda K. Deletion of mu-opioid receptor in mice does not affect the minimum alveolar concentration of volatile anaesthetics and nitrous oxide-induced analgesia. Br J Anaesth 2009;103:744–9
46. Crisp T, Perrotti JM, Smith DL, Stafinsky JL, Smith DJ. The local monoaminergic dependency of spinal ketamine. Eur J Pharmacol 1991;194:167–72
47. Amarpal, Aithal HP, Kinjavdekar P, Singh GR. Interaction between epidurally administered ketamine and pethidine in dogs. J Vet Med A Physiol Pathol Clin Med 2003;50:254–8
48. Sarton E, Teppema LJ, Olievier C, Nieuwenhuijs D, Matthes HW, Kieffer BL, Dahan A. The involvement of the mu-opioid receptor in ketamine-induced respiratory depression and antinociception. Anesth Analg 2001;93:1495–500
49. Qi X, Evans AM, Wang J, Miners JO, Upton RN, Milne RW. Inhibition of morphine metabolism by ketamine. Drug Metab Dispos 2010;38:728–31
50. Brosnan RJ, Pypendop BH, Siao KT, Stanley SD. Effects of remifentanil on measures of anesthetic immobility and analgesia in cats. Am J Vet Res 2009;70:1065–71
51. Antognini JF, Carstens E. Macroscopic sites of anesthetic action: brain versus spinal cord. Toxicol Lett 1998;100–101:51–8
52. Arendt-Nielsen L, Brennum J, Sindrup S, Bak P. Electrophysiological and psychophysical quantification of temporal summation in the human nociceptive system. Eur J Appl Physiol Occup Physiol 1994;68:266–73
53. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 1987;26:1235–8
54. Smith DJ, Pekoe GM, Martin LL, Coalgate B. The interaction of ketamine with the opiate receptor. Life Sci 1980;26:789–95
55. Lang E, Kapila A, Shlugman D, Hoke JF, Sebel PS, Glass PS. Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 1996;85:721–8
56. Steffey EP, Baggot JD, Eisele JH, Willits N, Woliner MJ, Jarvis KA, Elliott AR, Tagawa M. Morphine–isoflurane interaction in dogs, swine and rhesus monkeys. J Vet Pharmacol Ther 1994;17:202–10
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