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Anesth Analg 2008; 106:1856-1861
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e3181732776
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ANALGESIA

Section Editor:
Spencer S. Liu

Postoperative Ketamine Administration Decreases Morphine Consumption in Major Abdominal Surgery: A Prospective, Randomized, Double-Blind, Controlled Study

Jérome Zakine, MD*, David Samarcq, MD*, Emmanuel Lorne, MD*, Mona Moubarak, MD*, Philippe Montravers, MD, PhD{dagger}, Sadek Beloucif, MD, PhD{ddagger}, and Hervé Dupont, MD, PhD*

From the *Department of Anesthesiology and Critical Care, University Hospital of Amiens, France; {dagger}Department of Anesthesiology and Surgical Critical Care, APHP, Bichat-Claude Bernard University Hospital, Paris, France; and {ddagger}Department of Anesthesiology and Critical Care, APHP, Avicenne University Hospital, Bobigny, France.

Abstract

BACKGROUND: Ketamine decreases postoperative morphine consumption, but its optimal dosing and duration of administration remain unclear. In this study, we compared the effects of ketamine administration on morphine consumption limited to the intraoperative period, or continued for 48 h postoperatively.

METHODS: Eighty-one patients scheduled for abdominal surgery were prospectively randomized under double-blind conditions to three groups: (1) PERI group receiving intraoperative and postoperative ketamine for the first 48 h after surgery (2 µg · kg–1 · min–1 after a 0.5 mg/kg bolus); (2) INTRA group receiving intraoperative ketamine administration only (2 µg · kg–1 · min–1 after a 0.5 mg/kg bolus); and (3) CTRL group receiving placebo. Morphine consumption, visual analog scale scores and side effects (sedation score, nausea-vomiting score, nightmares, psychiatric disorders, or delusions) were recorded for the first 48 h.

RESULTS: Cumulative morphine consumption 24 h after surgery was significantly lower in the PERI group (median = 27 mg, interquartile range = [19]) than in the INTRA group (48 mg [41.5]) and CTRL group (50 mg [21]) (P < 0.005). Postoperative visual analog scale scores were significantly lower in the PERI group and INTRA group than in the CTRL group (P < 0.001). A higher rate of nausea was observed in the CTRL group compared with the PERI group (27% vs 4%, P = 0.005). No difference in sedation scores or psychiatric disorders was observed among groups.

CONCLUSIONS: Low-dose ketamine improved postoperative analgesia with a significant decrease of morphine consumption when its administration was continued for 48 h postoperatively, with a lower incidence of nausea and with no side effects of ketamine.

Morphine administration is the cornerstone of pain therapy, but acute tolerance after opioid exposure has been described as early as the immediate postoperative period.1,2 Tolerance and delayed hyperalgesia from opioid exposure are associated with activation of central nervous system N-methyl-d-aspartate (NMDA) receptors.3–5 Ketamine, a competitive NMDA receptor antagonist, prevents experimentally opioid-induced hyperalgesia, and ketamine in combination with morphine decreases both pain and morphine consumption during the postoperative period.6–9

However, the optimal dosing and duration of ketamine administration remains to be determined. Low-dose ketamine induces a morphine-sparing effect when this administration is limited to the intraoperative period10 or extended to the postoperative period,11,12 but no study has compared the effects of intraoperative IV ketamine administration alone versus intraoperative and postoperative administration.

In the present study, we evaluated the postoperative morphine-sparing effect, pain reduction, and side effects when ketamine administration in abdominal surgery was restricted to the intraoperative period alone or continued for 48 h during the postoperative period.

METHODS

After obtaining independent ethics committee approval (No. 99H43, CCPPRB of Amiens University, France) and signed informed consent from each patient, 81 patients undergoing major abdominal surgery were prospectively randomized according to a double-blind design to three groups: (1) INTRA group receiving an IV bolus of 0.5 mg/kg of ketamine 10 min before the incision, followed by an IV infusion of 2 µg · kg–1 · min–1 of ketamine during surgery, and IV infusion of 50 mL of normal saline for 48 h postoperatively; (2) PERI group receiving the same ketamine bolus before the incision as the previous group, but followed by IV infusion of 2 µg · kg–1 · min–1 of ketamine starting after this bolus and continued for 48 h postoperatively and (3) CTRL group (placebo) receiving a 10 mL IV bolus of normal saline 10 min before the incision and IV infusion of 50 mL of normal saline during surgery and for 48 h postoperatively.

The inclusion criteria were patients over the age of 18 yr scheduled to undergo major abdominal, urologic, or vascular surgery. Exclusion criteria were history of chronic pain, opioid self-administration, and psychiatric disorders. Patients were randomized by means of computer-generated opaque envelopes containing the patient number and group assignment. On the day before surgery, patients were instructed on how to use the patient-controlled analgesia device (PCA Alaris IVAC®, USA) for postoperative analgesia. They were also introduced to the visual analog scale (VAS). All patients were premedicated with 1 mg/kg of oral hydroxyzine 1 h before surgery. Anesthesia was induced with sufentanil 0.5 µg/kg, propofol 1.5 mg/kg, and cisatracurium 0.15 mg/kg and was maintained by continuous infusion of sufentanil 0.5 µg · kg–1 · h–1, inhaled desflurane with a mixture of 50% N2O/O2 and cisatracurium. All patients received 1 g of IV paracetamol 30 min before the end of the surgical procedure. Paracetamol was administered for at least 48 h (1 g/6 h). In the postanesthesia care unit, when the patient indicated a VAS score ≥ 40, a loading dose of 3 mg of IV morphine was administered, followed by another 3 mg dose, 5 min later if necessary, until a VAS ≤ 40 was achieved. A PCA pump device was then started in all three groups. The PCA contained 1 mg/mL of morphine base and 2.5 mg/50 mL of droperidol. The lockout time was 7 min with no limit dose or background infusion. This PCA regimen was continued for 48 h.

The primary end-point was cumulative morphine consumption 48 h after surgery. Secondary end-points were the following: VAS evolution, sedation and nausea-vomiting scores, and psychiatric disorders.

Demographic characteristics such as gender, age, ASA grade, type of surgical procedure, and duration of surgery were recorded for all patients. The dose of sufentanil administered intraoperatively was recorded. Morphine use in the postanesthesia care unit and PCA morphine requirements at 4, 24, and 48 h were recorded. VAS scores (ranging from 0 to 100) were recorded at the same time. A sedation score and a nausea and vomiting score were recorded 24 and 48 h postoperatively. Nightmares, psychiatric disorders, such as hallucinations, dysphoria, or other psychomimetic adverse effects, were recorded when present. The following sedation score was used: no sedation, awake; light sedation, awake with verbal stimulation; moderate sedation, awake with multiple verbal stimulations; deep sedation, awake only with painful stimulation. The following nausea and vomiting score was used: none, mild nausea; severe nausea; vomiting.

Calculation of the sample size indicated that a minimum of 66 patients (22 per group) would be required to detect a 40% difference in morphine consumption between the PERI group and the CTRL group for an {alpha} risk of 0.05 and a power of 0.90, assuming a mean morphine consumption of 50 mg ± 20 in the CTRL group based on our previous data. It was therefore decided to include 81 patients (27 per group). Data are expressed as median and interquartile range (range between the 25th and 75th percentiles) or as number and percentage. A repeated measure analysis of variance was performed to compare morphine consumption and VAS scores, using Bonferroni correction for post hoc analysis. Kruskal–Wallis test and Mann–Whitney U-test were used to compare quantitative parameters. Pearson {chi}2 with Yates’ correction, if necessary or Fisher tests were used to compare qualitative parameters. P < 0.05 was considered significant.

RESULTS

Eighty-one patients were randomized in this study. Four patients were excluded because of protocol violation (two received an additional analgesic treatment in the surgical ward and double-blinding was not observed for two other patients). All four patients had been randomized to the PERI group. Seventy-seven patients were therefore eligible for evaluation: 27 in the CTRL group, 27 in the INTRA group and 23 in the PERI group. Demographic characteristics, duration of surgery, type of surgical procedure, and dose of sufentanil were comparable in the three groups (Table 1). Concerning the primary end-point of the study, significantly less cumulative morphine consumption in the PERI group was observed (P = 0.008) compared with the other two groups: 27 mg[19] in the PERI group versus 48 mg [41.5] in the INTRA group and 50 mg[21] in the CTRL group. No difference in morphine consumption was observed between the INTRA group and the CTRL group. A significant difference was observed for the timing of postoperative morphine consumption among the three groups (P = 0.003), as shown in Figure 1. The time-course of the pain VAS (Fig. 2) was significantly different among the three groups (P < 0.001). VAS scores were significantly lower in the INTRA and PERI groups than in the CTRL group at H4 (P = 0.004), H24 (P = 0.0001) and H48 (P = 0.001).


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  		Table 1. Main Demographic Characteristics in the Three Study Groups

 

Figure 140
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  		Figure 1. Postoperative timing of morphine consumption in the three groups (P = 0.003 by repeated measure analysis of variance). Results are expressed in boxplots where, e.g., bar is the median value, upper and lower limits of the box ere the 75th and the 25th percentile and upper and lower tails are the 90th and the 10th percentile. INTRA group: ketamine at induction of anesthesia and intraoperatively; PERI group: ketamine at induction of anesthesia, intraoperatively and for 48 h postoperatively; CTRL group: placebo at induction, intraoperatively and postoperatively. (a) Less morphine consumption at H4 in the PERI group than in the CTRL group (P = 0.05). (b) Less morphine consumption between H4 and H24 in the PERI group than in the CTRL group (P = 0.01) and the INTRA group (P = 0.02). (c) Less morphine consumption between H24 and H48 in the PERI group than in the CTRL group (P = 0.02).

 

Figure 240
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  		Figure 2. Time-course of mean visual analog scale (VAS) score during the study (P < 0.001 by repeated measure analysis of variance). Results are expressed in boxplots where, e.g., bar is the median value, upper and lower limits of the box ere the 75th and the 25th percentile and upper and lower tails are the 90th and the 10th percentile. INTRA group: ketamine at induction of anesthesia and intraoperatively; PERI group: ketamine at induction of anesthesia, intraoperatively and for 48 h postoperatively; CTRL group: placebo at induction, intraoperatively and postoperatively. (a) VAS at H4 significantly higher in the CTRL group than in the INTRA and PERI groups (P = 0.004). (b) VAS at H24 significantly higher in the CTRL group than in the INTRA and PERI groups (P = 0.0001). (c) VAS at H48 significantly higher in the CTRL group than in the INTRA and PERI groups (P = 0.001).

 

The main side effects of postoperative analgesia are indicated in Table 2. No difference in nausea and vomiting scores at H24 and H48 was observed. However, a significant difference was observed in the percentage of patients experiencing nausea or vomiting among the three groups (P = 0.01). Patients in the PERI group experienced significantly less nausea or vomiting than those in the CTRL group (P = 0.005). No differences in sedation scores were observed among groups at either H24 or H48. No psychiatric disorders, delusions, nightmares, or other sleep disorders were observed in the three groups.


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  		Table 2. Comparison of Main Side Effects of Analgesia Among the Three Study Groups

 

DISCUSSION

This study shows that a 48-h low-dose continuous IV infusion of ketamine combined with morphine PCA limited to the intraoperative period reduced morphine consumption compared with ketamine administration, with a lower incidence of nausea due to morphine consumption and without any increase of side effects such as sedation or psychiatric disorders due to ketamine.

Ketamine has a chiral center at the carbon-2 atom of the cyclohexanone ring and therefore exists as optical stereoisomers S(+) and R(–) ketamine. S(+) ketamine has a four-fold higher affinity for NMDA receptors than R(–) ketamine. However, R(–) ketamine was used in this study because it is the only form commercially available in France. The value of ketamine is generally considered to be limited by its adverse effects, but this is not supported by the results in the treatment of acute postoperative pain, which is associated with no or only minor adverse effects.8,13 In a meta-analysis, Bell et al. observed that ketamine reduced postoperative nausea and vomiting.6 This could have been due to a morphine-sparing effect or other undetermined factors. In the present study, a statistically significant difference was observed between the groups (PERI vs. CTRL) for morphine side effects such as nausea and vomiting despite systematic prophylactic administration of droperidol in all patients directly via the morphine PCA device. Droperidol is a useful antiemetic drug that probably minimized postoperative nausea and vomiting.14 However, the study was not powered to answer to this question.

One of the surprising results of this study was the similar level of pain reduction observed in the two groups receiving ketamine despite significantly less morphine consumption in the PERI group. Many studies have suggested that perioperative ketamine administration could be useful to control postoperative pain, but their results are difficult to compare due to the various ketamine dose regimens used.6,8 The optimal ketamine dosage remains controversial. In our study, we used a 0.5 mg/kg IV bolus followed by a 2 µg · kg–1 · min–1 ketamine infusion to obtain a theoretical plasma ketamine concentration in the range of 100 µg/mL as described by Clements and Nimmo15 and also used by Adriaenssens et al.16 This dosage induces very low plasma ketamine concentrations with no significant signs of accumulation.17 This low dose of ketamine (compared with the study by Edwards et al. using a dose of 7.8 µg · kg–1 · min–118) would also avoid psychomimetic effects.8 No psychomimetic effects were observed with this low-dose ketamine infusion, even when ketamine administration was continued for 48 h in the PERI group. However, the discrepancy between the decrease of morphine consumption and the lack of effect on VAS changes may have been due to another cause. Ketamine in subanesthetic doses profoundly affects the emotional and behavioral state of healthy subjects.19,20 The decrease in opioid consumption could be, at least to some extent, a result of its effect on patient’s performance that does not reflect pain intensity. However, its use at low doses < 2.5 µg · kg–1 · min–1 in postoperative patients has been reported to be safe, without hallucination or impairment of cognitive functioning.9,21

Another controversial issue is the timing of ketamine administration. Some studies have reported a morphine-sparing effect and pain reduction when ketamine was administered only intraoperatively,10,22–25 whereas other studies have reported similar results with postoperative ketamine administration.7,11,12,16 In the present study, a similar degree of pain reduction was observed in both ketamine groups (INTRA and PERI) compared with the CTRL group. This pain reduction was not associated with a morphine-sparing effect in the INTRA group compared with the CTRL group. Less morphine consumption was observed only when ketamine was administered intraoperatively and postoperatively, suggesting the hypothesis that the process of central sensitization may be induced, not only during surgery, but also postoperatively by other mechanisms of pain: inflammatory injuries, incision, acute neuropathic pain due to nerve injury, etc.22,26,27 This could explain why a morphine-sparing effect was only observed with 48-h postoperative ketamine administration, due to the short half-life of ketamine. Ketamine administration limited to the intraoperative period may be insufficient to control pain during the prolonged inflammatory process, as suggested by the morphine requirements in the INTRA group for similar degrees of postoperative pain. Nitrous oxide used in our anesthetic regimen could have been a confounding factor. It may have enhanced NMDA receptor inhibition by ketamine, as it has been reported to exert NMDA antagonist properties.28 In addition to inhibition of sensitization in nociceptive pathways, prevention of opiate-related activation of pronociceptive systems and opiate tolerance may be another mechanism of pain prevention by ketamine.21 However, the exploration of this effect was not the aim of this study.

This study was not designed to evaluate a possible preemptive analgesic effect of ketamine, which is why the ketamine bolus was administered at the same time, before the incision, in the two groups. Previous studies have compared pre- and postincisional ketamine administration to investigate the concept of preemptive analgesia, but most failed to demonstrate any significant difference in the morphine-sparing effect.23,29–31 McCartney et al. suggested that the term "preventive analgesia" provides a broader, more clinically relevant concept in which the administration of a drug at any point in the perioperative period and the presumed associated reduction in central sensitization may reduce pain, analgesic consumption, or both beyond the clinical activity of the target drug.32 Acetaminophen was also systematically used in all three groups, but recent meta-analyses reported a morphine-sparing effect of acetaminophen in major surgery, corresponding to about 8–9 mg for the first 48 h.33,34

In conclusion, this study demonstrated the value of ketamine administration during the first 48 h postoperatively in combination with morphine to control postoperative pain after major abdominal surgery. The decreased morphine consumption was associated with a reduction of the side effects of morphine such as nausea and the use of low doses of ketamine was not associated with any psychomimetic effects. The effect on long-term postoperative pain remains to be evaluated.

ACKNOWLEDGMENTS

The authors are indebted to Georges Mion, MD, for insightful comments and help in the preparation of this manuscript.

Footnotes

Accepted for publication February 7, 2008.

Supported by a grant from the French Ministry of Health (PHRC n°9522, 1998).

Address correspondence and reprints to Hervé Dupont, Pôle d’Anesthésie-Réanimation, CHU Amiens, Place Victor Pauchet, 80054 Amiens cedex, France. Address e-mail to dupont.herve{at}chu-amiens.fr.

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2008 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press