Suzuki, Manzo MD*; Kinoshita, Takao MD*; Kikutani, Takehiko MD*; Yokoyama, Kenji MD*; Inagi, Toshiichiro MD*; Sugimoto, Kikuzo MD, PhD*; Haraguchi, Shuji MD†; Hisayoshi, Takao MD†; Shimada, Yoichi MD, PhD*
Evidence suggests that administration of an opioid after tissue injury activates N-methyl-d-aspartate (NMDA) receptors, which are ligand-gated ion channels in the spinal dorsal horn. On opening of these ion channels, the intracellular calcium level increases, leading to an increase in the protein kinase C level and subsequent reduction in the sensitivity of μ-opioid receptors (1). In an animal study, coadministration of an NMDA receptor antagonist (i.e., ketamine, dextromethorphan, or MK-801) and an opioid provided superior analgesia than administration of opioid alone (2).
Coadministration of subanalgesic doses of morphine and ketamine in normal volunteers produced a substantial analgesic effect to electrical stimulation, suggesting that ketamine enhances opioid-induced analgesia (3). However, another study showed that coadministration of an opioid analgesic and ketamine had an additive effect (4). Conflicting results have been reported concerning the enhancement of opioid-mediated antinociception by NMDA receptor antagonists. In acute pain management, IV coadministration of ketamine and morphine reduced postoperative morphine consumption and prevented morphine-related side effects (5). Javery et al. (5) reported that ketamine in combination with morphine provided superior postsurgical pain relief than morphine alone. However, Edwards et al. (6) reported that adding ketamine to morphine did not improve postoperative analgesia. Because the side effects of ketamine alone or in combination with an opioid include somnolence, dreaminess, and a perceptual feeling, if ketamine is administered by continuous infusion, it is important to know the optimal plasma concentration of ketamine that enhances opioid-induced analgesia.
Epidural coadministration of an opioid and a local anesthetic is a mainstay of postoperative pain management after thoracic surgery; it has a synergistic effect and provides sufficient analgesia with fewer side effects than systemic opioid administration (7). On epidural administration of morphine, its concentration in the cerebrospinal fluid immediately increases. Frequent co-localization of mu-opioid and NMDA receptors at postsynaptic sites in the spinal dorsal horn indicates that an opioid administered epidurally may enhance NMDA receptor activation (8,9). The effect of IV ketamine on analgesia induced by epidural morphine and bupivacaine is not known. The purpose of this study was to estimate the minimal ketamine plasma concentration that enhances epidural bupivacaine-and-morphine-induced analgesia without side effects.
Twenty-four ASA physical status I-II adults of either gender who were scheduled to undergo video-assisted thoracic surgery with a small incision (length approximately 5 cm) were enrolled in this double-blind, placebo-controlled, 3-group parallel study. The diagnoses of the patients were lung carcinoma (n = 18) and metastatic lung tumor (n = 6). This study was approved by our institutional ethics committee. Written informed consent was obtained from each patient. Exclusion criteria were morbid obesity, patients with drug abuse, patients with diabetes, and patients requiring blood transfusion during or after the surgery. The day before surgery, one of the investigators visited the patient to explain the study and how to use the visual analog scale (VAS).
Premedication consisted of atropine sulfate, 0.5 mg, and hydroxyzine, 25 mg, which were injected IM 30 min before induction of anesthesia. In the operating room, the left or right antecubital vein was secured and an epidural catheter was placed through the thoracic 5-6 interspace, followed by epidural injection of 6–8 mL of 1.5% mepivacaine. General anesthesia was induced by 4 mg/kg thiopental, and 0.2 mg/kg vecuronium bromide facilitated tracheal intubation and was maintained by 0.5%–1.0% isoflurane and 50%–70% oxygen with a nitrous oxide mixture as well as incremental epidural administration of 1.5% mepivacaine.
All patients received epidural infusion of 0.125% bupivacaine at 5 mL/h by an epidural infusion pump (Infuser LV 5™ Baxter™, Deerfield, IL) as basal postoperative pain management. To examine the interactions between morphine and ketamine, placebo and ketamine, or morphine and placebo, the patients were assigned to 1 of 3 groups by a computer-generated randomization schedule: the morphine + ketamine group (n = 8) received 1% preservative-free morphine sulfate (0.25 mL), mixed with a bolus of 0.25% bupivacaine (5-mL) epidurally; the placebo + ketamine group (n = 8) received saline (0.25-mL), mixed with a bolus of 0.25% bupivacaine (5-mL) epidurally; and the morphine + placebo group (n = 8) received 1% preservative-free morphine sulfate (0.25-mL), mixed with a bolus of 0.25% bupivacaine (5-mL) epidurally, at the end of skin closure. A rescue analgesic, flurbiprofen, 50 mg IV, was prepared in case the patients requested additional analgesics before the examination, which was started at 4 h after the end of surgery.
Three hours after the surgery, a blinded investigator (MS) visited the surgical ward and weighed the patient. All patients were asked to assess their pain at rest using the 100-mm VAS. In patients who rated their pain at rest below 10 mm, epidural infusion of bupivacaine was discontinued for 1 h; however, the rescue analgesic was available at any time for all patients. Four hours after surgery, all patients were asked to assess their levels of pain at rest, pain on coughing, somnolence (drowsiness), and nausea. Patients who rated their pain at rest below 10 mm were excluded from the study. Epidural infusion was restarted in patients in whom epidural infusion had been discontinued at 3 h. The patients in the morphine + ketamine and placebo + ketamine groups were asked to assess their levels of pain at rest, pain on coughing, somnolence, and nausea during infusion of increasing concentrations of ketamine, and the patients in the morphine + placebo group were asked to do so during infusion of placebo (saline). The mixture for epidural injection and ketamine or placebo was prepared by one of the investigators who did not participate in the assessment. For the subjects in the morphine + ketamine and placebo + ketamine groups, a 20-mL syringe containing 1 mg/mL ketamine was prepared. To maintain a stable plasma concentration, ketamine was infused at 1 mg/mL using an infusion pump (Graseby 3500™, Graseby Medical Limited™, Hertfordshire, UK) that was controlled by the STANPUMP program (Steven L. Shafer, MD, Department of Anesthesiology, Stanford University) based on pharmacokinetic data presented by Domino et al. (10). Six target plasma concentrations of ketamine (0, 10, 20, 30, 40, and 50 ng/mL) were successively maintained for 20 min each. For the subjects in the morphine + placebo group, a 20-mL syringe containing normal saline was prepared. Saline was infused using the same apparatus as in the other two groups. In the morphine + placebo group, the plasma concentration of ketamine was zero throughout the study. The time course of the study protocol is shown in Figure 1. Four hours after surgery, the patient was asked to assess levels of pain at rest, pain on coughing, somnolence, and nausea at the plasma concentration of ketamine of 0 ng/mL. Five minutes later, infusion of ketamine or placebo was started. After 15 min, the patient was asked about his/her perceptual feelings such as, “Do you feel like you are floating?” Then, the patient was asked to rate his/her pain at rest, pain on coughing, somnolence, and nausea using the 100-mm VAS, which was anchored by “not at all” at 0 mm and by “worst possible” at 100 mm. Blood pressure, heart rate, and arterial hemoglobin-oxygen saturation (Spo2) were measured at the end of the 20-min interval for each concentration of ketamine or placebo. The level of sedation was assessed by the Observer’s Assessment of Alertness/Sedation (OAA/S) scale: 5 = responds readily to name spoken in normal tone; 4 = lethargic response to name spoken in normal tone; 3 = responds only after name is called loudly and/or repeatedly; 2 = responds only after mild prodding or shaking; and 1 = does not respond to mild prodding or shaking (11).
Repeated-measures analysis of variance was used to examine the significance of differences among the three groups in the VAS scores for pain at rest, pain on coughing, somnolence, and nausea at the respective concentrations. If applicable, multiple comparisons with Games/Howell analysis were performed. In the morphine + ketamine group, to evaluate the effect of ketamine on the VAS scores for pain at rest and pain on coughing, the VAS scores were expressed as a percentage of the respective baseline value as shown in the following equation: percentage value = VAS score at each concentration of ketamine/VAS score at baseline. Effective concentration 50% (EC50) was defined as the concentration of ketamine that resulted in a percentage value of 50%. The significance of the difference in the OAA/S score among the three groups was assessed using the Kruskal-Wallis test. The significance of the difference in OAA/S scores over the different blood concentrations of ketamine or placebo within each group was examined using Wilcoxon’s single rank sum test. Differences were considered to be significant at P < 0.05.
The demographic characteristics of the patients are summarized in Table 1. At 3 h after surgery, one patient in the morphine + ketamine group and one patient in the morphine + placebo group stated a pain score at rest of below 10 mm. In these 2 patients, epidural infusion was discontinued until 4 h after surgery. At 4 h after surgery, all patients had pain scores at rest of 10 mm or above, and no patient was excluded from the study. No patient requested rescue analgesia before or during the study. All patients completed the study without remarkable complications. The cumulative dose of ketamine administered to a representative patient (age, 65 yr; height, 165 cm; weight, 65 kg) at the end of the 20-min interval for each plasma concentration of ketamine is shown in Figure 1. In this patient, the total dose of ketamine administered throughout the study was 8.5 mg.
In the placebo + ketamine group who initially received saline and bupivacaine, infusion of ketamine at any plasma concentration did not result in significant changes in the VAS score for pain at rest (Fig. 2). In the morphine + placebo group who initially received morphine and bupivacaine at the end of skin closure, the VAS score for pain at rest did not significantly change on infusion of placebo. However, in the morphine + ketamine group who initially received morphine and bupivacaine, on administration of ketamine at a plasma concentration of 10 ng/mL, the mean VAS score for pain at rest was nearly 50% of the mean baseline score, and the mean VAS score for pain at rest on administration of ketamine at a concentration of 20 ng/mL or above was <30% of the baseline score (Fig. 2). There were significant reductions in the VAS score for pain at rest compared with the baseline score at ketamine concentrations of 20 ng/mL and larger (P < 0.05 each). The VAS score for pain at rest at a ketamine concentration of 20 ng/mL or larger in the morphine + ketamine group was significantly lower than that at the respective concentration in the placebo + ketamine group as well as in the morphine + placebo group (Fig. 2). Figure 3 shows the percentage value of the VAS score for pain at rest at each plasma concentration of ketamine or placebo compared with the respective baseline score, in the morphine + ketamine group and the other two groups. According to the graph, the EC50 value of ketamine after morphine-and-bupivacaine-induced analgesia for pain at rest was between 10 and 20 ng/mL.
In the placebo + ketamine group, at any plasma concentration of ketamine, the VAS score for pain on coughing did not significantly change. In the morphine + placebo group, the VAS score for pain on coughing did not significantly change on administration of placebo. However, in the morphine + ketamine group, on administration of ketamine at a plasma concentration of 20 ng/mL or larger, there was a 50% reduction in the mean VAS score for pain on coughing (Fig. 4). The VAS scores for pain on coughing at a plasma concentration of ketamine of 30 ng/mL or larger in the morphine + ketamine group were significantly lower than those at the respective plasma concentrations of ketamine in the placebo + ketamine group and placebo in the morphine + placebo group (Fig. 4). Figure 5 shows the percentage values of the VAS scores for pain on coughing at various concentrations of ketamine or placebo in the morphine + ketamine group and the other two groups. The EC50 value of ketamine after morphine-and-bupivacaine-induced analgesia for pain on coughing was approximately 20 ng/mL.
Two patients in the morphine + ketamine group and one patient in the placebo + ketamine group stated drowsiness when the plasma ketamine concentration was maintained at 50 ng/mL. One patient in the morphine + ketamine group reported nausea at baseline, with a VAS score for nausea of 40 mm. In this patient, the VAS score for nausea did not change during the study. No patient vomited before or during the study. All patients were alert and comfortable during the study and no patient complained of any unpleasant feeling. The vital signs (systolic blood pressure, heart rate, and Spo2) of all patients during the study were stable, and there were no significant differences in vital signs among the different concentrations of ketamine or placebo within the three groups. In each group, the VAS score for drowsiness did not significantly change on administration of any dose of ketamine or placebo from the respective baseline score, and the VAS scores for drowsiness were comparable among the three groups (Fig. 6). There were neither significant differences in the OAA/S scores among the three groups nor among the different plasma concentrations of ketamine or placebo in each group (P > 0.05).
We found that ketamine at a plasma concentration of 20 ng/mL or larger reduced the VAS score for pain at rest by a mean rate of approximately 60% compared with the baseline value in the morphine-administered group. The same concentrations also significantly reduced the VAS score for pain on coughing in the morphine-administered group. In the placebo + ketamine group who initially received bupivacaine and placebo, ketamine did not reduce the VAS scores for pain at rest nor pain on coughing, indicating that, at the plasma concentrations maintained in this study, ketamine does not possess an analgesic effect and does not enhance epidural bupivacaine-induced analgesia. Examination of the effect of ketamine or placebo was performed 4 hours after surgery, when the effect of epidural anesthesia subsided. The amount of mepivacaine administered during the surgery did not significantly differ among the three groups (Table 1). After epidural administration of morphine, its concentration in the cerebrospinal fluid gradually increases and the analgesia induced continues over 8 hours (12). In the morphine + ketamine group, ketamine was administered 4 hours after the bolus infusion of bupivacaine and morphine, and bupivacaine-and-morphine-induced antinociception most likely remained at the time ketamine was administered. In the morphine + placebo group who received morphine and bupivacaine and then a placebo 4 hours later, there were no changes in the VAS scores for pain at rest and pain on coughing on administration of the placebo, indicating that the reductions in the VAS scores for pain in the morphine + ketamine group were not a placebo effect. Therefore, this reduction of pain was not related to a change in the effect of epidural bupivacaine infusion; it was most likely attributable to interaction between ketamine and epidural morphine. The largest plasma concentration of ketamine maintained in this study was approximately 10% of that producing antinociception when ketamine is administered alone (13). The reduction of pain in the morphine + ketamine group may have been a result of enhancement of epidural morphine-induced analgesia by very small-dose ketamine.
In the present study, much smaller plasma concentrations of ketamine enhanced morphine-induced analgesia than in previous studies. In an electrophysiological study of normal volunteers, the plasma concentration of ketamine was maintained at more than 50 ng/mL (3). Koppert et al. (14) demonstrated that s-ketamine at a plasma concentration of 100 ng/mL reduced the pain and hyperalgesia associated with withdrawal of remifentanil, a mu-receptor agonist. In a clinical study after renal surgery, a much larger dose of ketamine (more than 100 ng/mL) did not enhance epidural morphine-induced analgesia (15). A study on capsaicin-induced hyperalgesia, an experimental pain model for allodynia or hyperalgesia, in normal volunteers demonstrated that there was an additive effect between ketamine and morphine rather than enhancement by ketamine, even though a much larger dose of ketamine than in our study was administered (4). Different results obtained in these studies may have been due to the pain models reflecting different pathophysiological states (i.e., acute pain, allodynia, or hyperalgesia) and differences in the dose ratio of ketamine to opioid. In our study, the precise reason why a much smaller concentration of ketamine compared with previous studies enhanced opioid-induced analgesia is not known. One reason may be that the pain relief induced by epidural morphine and bupivacaine before and during the study was adequate because of their coadministration, although relatively small doses of each drug were administered. If our patients had higher pain scores at baseline, the effect of ketamine in enhancing morphine might be different. Because the dose of epidural morphine was relatively small in our study, the impact of morphine on activation of NMDA receptors may also have been small. The relationship between the dose of opioid that is initially administered and the dose of ketamine that is required to prevent hyperalgesia has not been studied.
In the morphine + ketamine group, the effect of ketamine on the VAS score for pain at rest or pain on coughing was dose-independent at plasma concentrations between 20 and 50 ng/mL; the pain scores on a ketamine dose more than 20 ng/mL were nearly zero. In the present study, if the pain score at rest at baseline had been higher or if a higher dose of morphine had been administered, the results might have been different. It is not known whether the effect of ketamine on enhancement of morphine-induced analgesia is dose-dependent.
The interaction between ketamine and morphine may result in psychedelic side effects (4). In the present study, two patients stated drowsiness at a ketamine concentration of 50 ng/mL. However, at smaller concentrations of ketamine, no patient reported any central nervous system side effects. The VAS score for drowsiness and the OAA/S score did not significantly differ among the three groups. Because of the relatively short interval between emergence from general anesthesia and the times at which the levels of pain, somnolence, and nausea were assessed in the present study, the effect of general anesthesia may have remained. However, all patients had an OAA/S score of 4 or 5 and a mean VAS score for somnolence of approximately 50 mm, indicating that there may be no interaction between ketamine at the plasma concentrations used in this study and the epidural morphine 2.5 mg that had been injected 4 hours earlier, on somnolence. The lack of interaction between ketamine and morphine with regard to side effects in the central nervous system may be in agreement with an animal study that found interaction of ketamine and morphine occurring at the spinal level but not at the supraspinal level (16). In conclusion, our results suggest that the plasma concentration of ketamine that enhances epidural morphine-and-bupivacaine-induced analgesia is 20 ng/mL or larger considering the safety of small doses. Accordingly, a clinical study on continuous infusion of ketamine for postoperative pain management with epidural morphine-and-bupivacaine-induced analgesia should be started.
We thank Dr. Mohamad Ghazizadeh, Instute of Gerontology, Nippon Medical School, for preparing this manuscript.
1. Mao J, Price DD, Mayer DJ. Mechanism of hyperalgesia and morphine tolerance: a current view of their interactions. Pain 1995;62:259–75.
2. Wiesenfeld-Hallin Z. Combined opioid -NMDA antagonist therapies: What advantages do they offer for the control of pain syndromes? Drugs 1998;55:1–4.
3. Bossard AE, Gurimand F, Flecher D, et al. Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers. Pain 2002;98:447–57.
4. Sethna NF, Liu M, Gracely R, et al. Analgesic and cognitive effects of intravenous ketamine-alfentanyl combinations versus either drug alone after intradermal capsaicin in normal subjects. Anesth Analg 1998;86:1250–6.
5. Javery KB, Ussery TW, Steger HG, et al. Comparison of morphine and morphine with ketamine for postoperative analgesia. Can J Anaesth 1996;43:212–5.
6. Edwards ND, Fletcher A, Cole JR, Peacock JE. Combined infusion of morphine and ketamine for postoperative pain in elderly patients. Anaesthesia 1993;48:124–7.
7. Kavanagh BP, Katz J, Sandler AN. Pain control after thoracic surgery: a review of current techniques. Anesthesiology 1994;81:737–59.
8. Commons KG, Van Bockstaele EJ, Pfaff DW. Frequent colocalization of mu opioid and NMDA-type glutamate receptors at postsynaptic sites in periaqueductal gray neurons. J Comp Neurol 1999;408:549–59.
9. Koyuncuglu H, Nurten A, Yamantrk P, et al. The importance of the number of NMDA receptors in the development of supersensitivity or tolerance to and dependence on morphine. Pharmacol Res 1999;39:311–9.
10. Domino EF, Zsigmond EK, Domino LE, et al. Plasma concentration of ketamine and two of its metabolites in surgical patients using a gas chromatographic mass fragmentographic assay. Anesth Analg 1982;61:87–92.
11. Chernik DA, Gilling D, Laine H, et al. Validity and reliability of the observer’s assessment of alertness/sedation scale: study with intravenous midazolam. J Clin Psycopharmacol 1990;10:244–51.
12. Sjostrom S, Hartvig P, Person MP, Tamsen A. Pharmacokinetics of epidural morphine and meperidine in humans. Anesthesiology 1987;67:877–88.
13. Clements JA, Nimmo WS, Grant IS. Bioavailability, Pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci 1982;71:539–42.
14. Koppert W, Sittl R, Scheuber K, et al. Differential modulation of remifentail-induced analgesia and postinfusion hyperalgesia by s-ketamine and clonidine in humans. Anesthesiology 2003;99:152–9.
15. Ilkjaer S, Nikolajsen L, Hansen TM, et al. 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.
16. Suh HW, Song DK, Kim YH, et al. Differential antagonism by MK-801 against antinociception induced by opioid receptor agonists administered supraspinally in mice. Eur J Pharmacol 1994;263:217–21.