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PAIN MEDICINE

Perioperative Small-Dose S(+)-Ketamine Has No Incremental Beneficial Effects on Postoperative Pain When Standard-Practice Opioid Infusions Are Used

Wolfgang Jaksch, MD, DEAA^*, Stefan Lang, MD, DEAA^*, Robert Reichhalter, MD^*, Gerald Raab, MD, DEAA^*, Klaus Dann, MD, and Sylvia Fitzal, MD^*

*Department of Anesthesiology and Intensive Care Medicine, Ludwig Boltzmann Institute of Experimental Anesthesiology and Research in Intensive Care Medicine; and Department of Traumatology, Wilhelminenspital, Vienna, Austria

Address correspondence and reprint requests to Wolfgang Jaksch, MD, DEAA, Department of Anesthesiology and Intensive Care Medicine, Wilhelminenspital, Montleartstrasse 37, 1171 Vienna, Austria. Address e-mail to wolfgang.jaksch{at}chello.at

	Abstract

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Several studies report that when small-dose racemic ketamine, an N-methyl-D-aspartate receptor antagonist, is administered perioperatively, opioid consumption is reduced postoperatively. S(+)-ketamine has a higher affinity for the N-methyl-D-aspartate receptor and less-serious side effects than racemic ketamine. Thirty patients scheduled for elective arthroscopic anterior cruciate ligament repair were enrolled in this randomized, double-blinded clinical trial designed to determine the preemptive effect of S(+)-ketamine on postoperative analgesia requirements in a setting of clinically relevant perioperative analgesia. Total IV anesthesia was induced and maintained with remifentanil (0.125–1.0 µg · kg^-1 · min^-1) and a propofol target-controlled infusion (target 2–4 µg/mL). The Ketamine group received a bolus of 0.5 mg/kg S(+)-ketamine before incision, followed by a continuing infusion of 2 µg · kg^-1 · min^-1 until 2 h after emergence from anesthesia. The Control group received NaCl in the same sequence. After IV morphine provided pain relief down to 3 on a visual analog scale scored from 0 to 10, patients were connected to a patient-controlled analgesia device. There were no significant differences between the two groups in terms of total morphine consumption or VAS scores, either at rest or with movement. In our study, S(+)-ketamine did not contribute to postoperative pain reduction, possibly because of the clinically routine perioperative opioid analgesia.

IMPLICATIONS: Small-dose S(+)-ketamine had no positive effect on postoperative analgesia when administered perioperatively for elective arthroscopic anterior cruciate ligament repair. Unlike investigations of the racemic mixture of ketamine, our study methods included timely standard-practice perioperative opioid analgesia, which seems to make supplemental analgesia unnecessary.

	Introduction

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The severity of posttraumatic pain, such as that after surgery, is largely determined by pathologically elicited hypersensitivity. In response to repeated painful stimuli generated by repetitive stimulation of the primary afferent C fibers, the dorsal horn neurons of the spinal cord engage in progressively increased activity both intra- and postoperatively (wind-up) (1). This wind-up phenomenon and the temporal summation of repeated painful stimuli as the psychophysical correlate of wind-up lead to central sensitization and to hyperalgesia.

Both wind-up and the temporal summation of pain seem to depend on the activation of the N-methyl-D-aspartate (NMDA) receptor (2). Thus, in experimental trials, the wind-up phenomenon was only delayed and diminished by the administration of morphine but was actually prevented by the blockade of the NMDA receptor (3). Similar investigations have been performed on the influence of various anesthetics on molecular changes in the area of the dorsal horn neurons. These experimental pain models in rats have shown that the expression of pain-specific "immediate early genes," such as c-fos, can be inhibited by opioids only in part, but by NMDA receptor antagonists they can be inhibited entirely. These genes effect long-lasting changes in the pain-processing system, resulting in hyperexcitation. Munglani (4) thus has suggested, in an editorial evaluating a number of such investigations, that the use of an NMDA receptor antagonist such as ketamine, in addition to an opioid, should be considered in an anesthetic regimen.

Perioperative ketamine is successful in reducing postoperative analgesic requirements (5–9). Ketamine inhibits the NMDA receptor via a noncompetitive antagonism, and an antihyperalgesic effect can be achieved by far smaller doses of ketamine than are required in anesthesia. Small-dose ketamine has been defined as not more than 1 mg/kg when delivered as an IV bolus and not more than 20 µg · kg^-1 · min^-1 when delivered as a continuous infusion (10). Isolated out of the racemic mixture of ketamine, the right-handed enantiomer S(+)-ketamine has recently become available in several European countries. Its affinity for the phencyclidine receptor, the principal binding site at the NMDA receptor, is three to four times higher than that of the R(-)-enantiomer (11). In an experimental trial with healthy subjects, S(+)-ketamine was approximately twice as potent as the racemic mixture of ketamine in preventing central summation of pain (12). Furthermore, although the psychotomimetic side effects (principally vivid, disturbing dreams and hallucinations) reported after the administration of ketamine occur approximately as often with S(+)-ketamine, they are far milder (13).

In all the studies on the administration of IV perioperative small-dose ketamine (5–9), the racemic mixture was used. Our study investigated for the first time the effect of perioperatively administered S(+)-ketamine on postoperative analgesia. By design, the investigation took place in a setting of clinically relevant anesthesia. Thus, the aim of our study was to determine to what extent small-dose S(+)-ketamine, when used in conjunction with total IV anesthesia (TIVA) and remifentanil, has an opioid-sparing effect in the postoperative period.

	Methods

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After receiving approval from the institutional ethics committee, we enrolled 30 patients scheduled for elective arthroscopic anterior cruciate ligament repair with or without meniscus repair in this randomized, double-blinded clinical trial. All patients gave written, informed consent. Inclusion criteria were age 19 yr or older and ASA physical status I or II. Excluded from the study were pregnant and breast-feeding women, as well as patients with a history of substance abuse or chronic analgesic use or those for whom opioids, ketamine, or nonsteroidal antiinflammatory drugs were contraindicated. All patients were instructed preoperatively in the use of the patient-controlled analgesia (PCA) device (Abbott Lifecare 4200; Abbott Critical Care Systems, Morgan Hill, CA) and a 10-step visual analog scale (VAS; 0 = no pain, 10 = greatest imaginable pain).

After being premedicated with oral midazolam 7.5 mg 1 h before skin incision, all patients received a standardized anesthetic regimen. TIVA was induced and maintained with remifentanil 0.5 µg · kg^-1 · min^-1 (range, 0.125–1.0 µg · kg^-1 · min^-1) and a propofol target-controlled infusion (MASTER TCI; Fresenius Vial S.A., Brezins, France) at a target concentration of 3 µg/mL (range, 2–4 µg/mL). We maintained blood pressure and heart rate at levels within 30% of preoperative values. After we administered rocuronium 0.6 mg/kg, an endotracheal tube was inserted and ventilation was performed with oxygen in air (fraction of inspired oxygen 30%).

Patients randomized to the Treatment group received an IV bolus of S(+)-ketamine (Ketanest S^®; Parke-Davis, Berlin, Germany) after the induction of anesthesia. Thereafter a continuous infusion of the drug was started. The Control group received an isotonic sodium chloride solution in both the bolus and the infusion. Envelopes containing identification of the preparation administered were available for emergencies.

Before the induction of anesthesia in each patient, intensive care unit nurses not involved in the study prepared two syringes per a randomization list. The first syringe contained the bolus dose. For the Ketamine group, the 10-mL syringe contained 5 mg/mL of S(+)-ketamine. For the Control group, the syringe contained isotonic sodium chloride solution. For the continuous infusion, the second syringe, with a capacity of 50 mL, contained either 2 mg/mL of S(+)-ketamine or isotonic sodium chloride solution for patients randomized, respectively, to the Ketamine or Control group. After the induction of anesthesia, but at least 5 min before skin incision, 0.1 mL/kg of the bolus was administered IV. In the Treatment group, this corresponded to a dose of 0.5 mg/kg of S(+)-ketamine. After the bolus, a continuous infusion of 0.06 mL · kg^-1 · h^-1, delivered by an infusion pump and continuing until 2 h after each patient emerged from anesthesia, was begun in all the patients. In the Ketamine group, this corresponded to an S(+)-ketamine dose of 2 µg · kg^-1 · h^-1. Fifteen minutes before wound closure, all patients received 8 mg of lornoxicam in 100 mL of isotonic sodium chloride solution and 5 mg of morphine IV. At this point, the propofol target-controlled infusion was discontinued, but remifentanil was continued until the end of surgery.

After extubation, patients were moved to the postanesthesia care unit with the infusion pump in place and running. Patients remained there at least until the study medication was discontinued. If typical side effects of S(+)-ketamine arose, the dose delivered by the infusion pump was reduced by half to 1 µg · kg^-1 · min^-1 and was discontinued if the side effects persisted.

During the first postoperative hour, patients with VAS scores >3 received fractionated morphine IV (no more than 2 mg per 5 min). One hour postoperatively, each patient was connected to a PCA pump, which remained in place until the fifth postoperative day at the latest. Morphine 1.5 mg was administered as a bolus every 8 min maximally with no background infusion and no hourly limit. Patients were instructed to so manage their pain with the PCA that VAS scores at rest did not exceed 3. From the evening of the day of surgery until the morning of the fifth postoperative day, all patients also received 2 x 8 mg of oral lornoxicam as basic analgesia. Pain scores at rest were determined with a VAS every 5 min during the first hour and then at 2, 24, 48, 72, and 120 h postoperatively. Pain with movement was standardized by flexion of the knee to 40° by using continuous passive motion. Pain scores were recorded at 48, 72, and 120 h. Side effects that appeared within the first five postoperative days, including nausea, postoperative shivering, sedation, visual disturbances, itching, urinary retention, and respiratory depression, were recorded.

Sample size estimation was based on a mean morphine consumption level of 36.8 mg (SD, 18.6 mg) in the first 24 h, as derived from our own pilot data. Assuming a target of 40% morphine consumption reduction with an error of 5%, a ß error of 10%, and a two-tailed alternative hypothesis, a sample size of 35 patients per group was estimated. After a total of 30 patients had been entered into the study (intent-to-treat analysis), an adaptive interim analysis according to Bauer and Köhne was done as planned.

Demographic data were analyzed with the two-sample Student’s t-test. After having first been tested for normal distribution with the Kolmogorov-Smirnov test, morphine consumption and VAS scores were analyzed with the Mann-Whitney U-test. Secondary outcome variables were analyzed with Student’s t-test, the Mann-Whitney U-test, or Wilcoxon’s signed rank test. The level of significance was set at P < 0.05.

	Results

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All 30 patients entered into the study were evaluable. Because the planned adaptive interim analysis according to Bauer and Köhne yielded an error >50%, we assumed the null hypothesis and stopped recruitment at 30 patients. Each group contained 15 patients. There were no significant differences between the two groups in demographics—age, weight, or sex—or in blood pressure or heart rate (Table 1). There was no difference in length of anesthesia or surgery, and the levels of intraoperative consumption of remifentanil and propofol were also comparable in the two groups.

View larger version (28K): [in this window] [in a new window]   Figure 1. Cumulative morphine consumption in the first five postoperative days. Values are median (25th–75th percentile).

View larger version (33K): [in this window] [in a new window]   Figure 2. Pain scores at rest (visual analog scale 1–10), mean ± SD.

View larger version (34K): [in this window] [in a new window]   Figure 3. Pain scores with movement (visual analog scale 0–10), mean ± SD.

	Discussion

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Our results demonstrated that the right-handed enantiomer of ketamine did not have a positive effect on postoperative analgesia. The first postoperative request for analgesia was not delayed, nor was there a morphine-sparing effect at any point in time. Pain scores at rest and with movement were equally low in both groups and were within the upper limits of 3 at rest and 5 with movement; these scores are generally accepted as tolerable.

As discussed in two review articles by Katz (14) and Dahl (15), studies on substances with a preemptive or antihyperalgesic effect should aim to show that these substances have this effect postoperatively when clinically relevant anesthesia, including perioperative opioids, has also been delivered. Among the studies cited in the introduction on the successful use of perioperative IV small-dose racemic ketamine (5–9), only in that of Stubhaug et al. (8) did patients receive continuous opioid analgesia with repeated doses of fentanyl, although the regimen is not clearly defined in the article. In the study of Roytblat et al. (6), the patients also received fentanyl intraoperatively but at precisely fixed time points and at a total maximal dose of 5 µg/kg. In view of the considerable differences among individuals in their sensitivity to opioids, as well as individual differences in pharmacokinetics, we conclude that in this study the opioid analgesia was not really continuous. Fu et al. (7) administered no opioids, either pre- or intraoperatively. The patients in the study of Barbieri et al. (9) received a small fentanyl dose of 1 µg/kg before the induction of anesthesia and received no additional intraoperative opioids. In the study of Menigaux et al. (5), the most recent study on this topic, continuous opioid analgesia was provided with sufentanil. However, the administration of sufentanil was not started until 10 minutes after incision to exclude the possibility that it might have a preemptive effect. But even this short time period without opioid analgesia could suffice to elicit central sensitization (16).

Like Menigaux et al. (5), we chose anterior cruciate ligament repair as the clinical model, because the moderate to severe pain arising after this operation requires postoperative opioid analgesia (17). The results from the Menigaux study, which showed that the time point at which ketamine is administered has no influence on its antihyperalgesic effectiveness, prompted us to forego comparing pre- with postoperative administration, as had been advocated by McQuay (18). Thus, we applied S(+)-ketamine in accordance with the recommendations of Stubhaug et al. (8), administering both a bolus and an infusion. Because severe pain can occur in the recovery phase after anesthesia with remifentanil (19), we continued to administer S(+)-ketamine until two hours postoperatively to prevent possible wind-up also during this period. In line with the thinking of Katz (14) and Dahl (15), we delivered anesthesia as TIVA, including a continuous remifentanil infusion.

The ultrashort-acting remifentanil that we used continuously intraoperatively acts selectively at the µ-opioid receptor. Because it can be titrated so precisely, it is possible to achieve profound analgesia intraoperatively (20). This proved to be the case in both study groups. There was practically no activation of the sympathetic nervous system caused by pain, as shown by the absence of increases in blood pressure or heart rate. Because of the extremely short context-sensitive half-time of remifentanil, the early postoperative phase is particularly critical with regard to acute pain onset. To prevent extreme pain as well as sensitization at this point, we administered, as often recommended (19), 5 mg of morphine and 8 mg of lornoxicam IV 15 minutes before the end of surgery. Still, one would expect that if the S(+)-ketamine had an antihyperalgesic effect, it would be demonstrated particularly clearly in the immediate postoperative phase, with significantly less consumption of morphine in the Ketamine group. However, even here there were no differences between the two groups. In the first hour postoperatively, neither the consumption of morphine nor the length of time during which patients scored their pain higher than the targeted score of 3 (Ketamine group, 38 minutes, versus Control group, 35 minutes) showed more favorable results in the Ketamine group.

In our investigation we aimed to effect a reduction in the patients’ VAS score to 3 as quickly as possible through the repetitive administration of morphine in the early postoperative period. In comparison with the investigation of Menigaux et al. (5), cumulative morphine use in our patients at 24 and 48 hours was somewhat increased, but the VAS scores were considerably lower. We considered whether the larger postoperative morphine consumption in our study might have been caused by an acute opioid tolerance resulting from the intraoperative administration of remifentanil, as postulated in recent publications (21,22). However, another study on this issue found no indication that rapid opioid tolerance develops consequent to remifentanil infusions (23). At the same time, the recently published study of Kissin et al. (24) seemed to be of particular interest in this connection. In the animal model, a subanalgesic dose of ketamine prevented the development of acute opioid tolerance after an infusion of alfentanil. Because the mechanisms of hyperalgesia and opioid tolerance have common features on the neuronal level (25), Kissin et al. (24) concluded that the positive results from some of the ketamine studies were at least in part caused by suppression of the development of tolerance to intraoperatively administered opioids. However, our results are not in conformity with these conclusions, either. Although the remifentanil dose was considerably larger than in the one clinical study on acute opioid tolerance (22), it was absolutely comparable in our two study groups.

We examined a number of other possible explanations for the lack of antihyperanalgesic effect attributable to S(+)-ketamine on postoperative analgesia and the consumption of analgesics. The first possibility was that the S(+)-ketamine dose we used was too small. We rejected this explanation. Considering that in an experimental pain model, S(+)-ketamine proved twice as potent as ketamine in impeding central summation of pain (12), our dose was surely larger than that of Stubhaug et al. (8) or that of the other studies on IV perioperative small-dose ketamine (5–9), all of which had a positive outcome.

We next considered the binding behavior of S(+)-ketamine at the NMDA receptor. We quickly rejected this as a possible factor contributing to an explanation of our results. As stated earlier, the right-handed enantiomer S(+)-ketamine has an affinity for the phencyclidine binding site of the NMDA receptor that is almost four times as strong as that of the left-handed enantiomer (11). S(+)-ketamine has been shown in an experimental human model to be very well capable of preventing central summation of pain (12).

We believe the only plausible explanation of our results to be the consistently administered continuous perioperative opioid analgesia. Because even short phases of C-fiber input from surgical tissue trauma can lead to sensitization of the central nervous system (16), it seems that the continuous, properly timed intraoperative administration of remifentanil is superior to repeated boluses of, for example, fentanyl, which usually are geared to clinical signs of diminishing analgesia. This could also explain the absent effect of S(+)-ketamine in our study in contrast with that of Menigaux et al. (5): the patients in that study were without opioid analgesia for 10 minutes at the beginning of the operation. However, in the study of Stubhaug et al. (8), the only one with repeated—even if discontinuous—intraoperative opioid analgesia throughout surgery, the morphine-sparing effect of (racemic) ketamine was also small and was limited to the first five hours postoperatively.

In our clinical model, the consistent intra- and postoperative administration of opioids seems to have inhibited, at the presynaptic opioid receptors at the terminals of the C fibers, the release of primary afferent transmitters. Because C-fiber input to the nociceptor neurons of the dorsal horns was then suppressed, the additional administration of an NMDA receptor antagonist was superfluous.

We conclude that our study has demonstrated the importance of continuous intraoperative opioid analgesia in addition to adequate control of postoperative pain.

	Acknowledgments

 
We thank Jane Neuda for editorial assistance.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (27) Citing Articles via Google Scholar Google Scholar Articles by Jaksch, W. Articles by Fitzal, S. Search for Related Content PubMed PubMed Citation Articles by Jaksch, W. Articles by Fitzal, S. Related Collections Pain Pharmacology

Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999