Effects of preincisional ketamine treatment on natural killer cell activity and postoperative pain management after oral maxillofacial surgery CPT Michael W. Bentley, CRNA, MSN, AN, USA Fort Carson, Colorado CPT John M. Stas, CRNA, MSN, AN, USA Fort Jackson, South Carolina CPT Jimmie M. Johnson, CRNA, MSN, AN, USA Fort Hood, Texas Bruce C. Viet, PhD El Paso, Texas COL Normalynn Garrett, CRNA, PhD, AN, USA Fort Sam Houston, Texas Poorly controlled pain may lead to increased risk of cancer metastasis by suppressing natural killer (NK) cell activity. Ketamine may be beneficial by potentiating opioid-induced analgesia. We enrolled 59 participants in a randomized double-blind, placebo-controlled clinical trial and assigned them to receive propofol plus (1) saline, 2 mL; (2) ketamine, 0.5 mg/kg; or (3) ketamine, 1.2 mg/kg, followed by a standardized anesthesia protocol. The visual analogue scale (VAS) and 24-hour opioid consumption measured postoperative pain perception. NK cell activity was measured before and 24 hours after ketamine administration using the chromium 51 release assay. Nonparametric analysis of VAS data revealed that women

H

undreds of thousands of people die of cancer in the United States yearly, and most of the deaths are due to metastatic spread of the disease. Natural killer (NK) cells are one of the body’s first defenses against the metastatic spread of cancer1; however, the activity of these cells is suppressed by a major treatment modality for cancer—surgery.2 Currently, the mechanism or mechanisms by which surgery suppresses NK cell activity have not been fully elucidated. One hypothesis is that pain related to surgery can suppress NK cell activity and thereby increase the risk of tumor metastasis.3 Therefore, the adequate treatment of postoperative pain, which continues to be inadequately managed,4 is more than just a humane or ethical matter, but one that may prolong life. Classically, postoperative pain has been treated with opioid analgesics, but these drugs have important limitations. Opioid-related side effects, such as

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receiving 0.5 mg/kg of ketamine reported less pain (P < .05) compared with the saline 1.2 mg/kg–ketamine groups. This finding was not evident in men. Comparing opioid consumption among the 3 groups (using analysis of variance) revealed a drug-gender interaction (P < .05): 0.5 mg/kg of ketamine decreased postoperative opioid consumption for women more than for men. Although not statistically significant, women receiving 0.5 mg/kg of ketamine had the least NK cell suppression compared with preoperative values (repeated analysis of variance). These findings suggest that for women, low-dose ketamine may be beneficial. Key words: Ketamine, natural killer cell, postoperative pain.

respiratory depression, have been cited as reasons that healthcare professionals are reluctant to treat pain.5 Second, tolerance limits the usefulness of opioids. Tolerance is characterized by resistance to the analgesic effects of an opioid. Morphine tolerance has been shown extensively in animals.6 Furthermore, acute tolerance may develop with a single bolus dose of an opioid,7,8 such as occurs in high-dose opioid anesthetic techniques. Although human studies regarding opioid tolerance have shown conflicting results, acute and chronic opioid tolerance clearly can develop in surgical and cancer patients.9,10 If the pain of undergoing and recovering from surgery indeed increases the risk of metastatic sequelae through suppression of NK cell activity, and opioids have limitations, then other pharmacological agents must be explored as potential supplements to opioids.8,11,12 This study was designed to investigate the effects of ketamine, a noncompetitive N-methyl-D-

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aspartate (NMDA) receptor antagonist, administered preincisionally to patients having oral maxillofacial surgery. Two research questions directed this study: (1) Does the preincisional administration of ketamine improve postoperative pain perception? (2) What are the effects of a preincisional dose of ketamine on NK cell activity? By using an experimental metastasis model in adult male and female rats, Page and colleagues13 suggested that the metastatic-enhancing effects of surgery were ameliorated by the preoperative administration of opioid and/or the local anesthetic, bupivacaine. Whereas untreated rodents showed a 3- to 4-fold increase in retention of cancerous cells, rodents treated with subcutaneous fentanyl preoperatively and postoperatively and those treated with intrathecal bupivacaine and morphine had 65% and 45% reductions in tumor retention, respectively. However, neither opioids nor local anesthetic completely reversed this life-threatening consequence of surgery, suggesting that other pharmacological agents should be explored as potential adjuncts to opioids. One class of agents that may mitigate the undesirable effects of opioids and provide benefit with regard to NK cell activity is the NMDA receptor antagonists. The NMDA antagonist compounds have 2 particularly desirable qualities: (1) inhibition of central sensitization, a hyperexcitable state within the central nervous system that can be initiated by surgery and has profound effects on pain transmission such that the intensity and duration of painful stimuli are enhanced8,11,12 and (2) prevention of the development of opioid tolerance, the phenomenon whereby a patient is less susceptible to the effect of an opioid as a consequence of its prior administration.11 Findings from studies suggest that NMDA receptor antagonists are effective as preemptive analgesics14 and potentiate the effect of analgesics such as morphine, local anesthetics, and nonsteroidal anti-inflammatory drugs.15-17 Combining an NMDA antagonist with an opioid provides a synergistic effect that offers greater pain control while minimizing the amount of each agent used. Only a few NMDA antagonists are clinically available. These include ketamine and dextromethorphan. These drugs are being used increasingly for chronic pain, including cancer pain, and acute perioperative pain.18,19 Yet NMDA receptor antagonists may have one serious side effect that has not been studied in humans. This class of drug may suppress NK cell activity.20 Findings from early studies suggest that ketamine suppresses NK cell activity in mice.21,22 In addition, outcomes from a more recent study suggest that the competitive and noncompetitive NMDA antagonists

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LY235959 and MK-801, respectively, increase tumor metastasis via suppression of NK cell activity in adult male and female Fischer 344 rats.20 To our knowledge, no study has investigated the effects of ketamine on human NK cell activity or subsequent metastasis, nor have there been studies exploring additive or synergistic effects of ketamine plus opioid administration on NK cell activity. This study examined whether a preincisional dose of ketamine provides preemptive analgesia that decreases postoperative pain perception as measured by a visual analog scale (VAS) and 24hour postoperative opioid consumption and assayed the effect of ketamine on NK cell activity.

Materials and methods A randomized, double-blind, placebo-controlled clinical trial was used for this study. The inclusion of male and female subjects was intentional; therefore, the design was factorial so that men and women were compared regarding each outcome variable. The study was approved through the Medical Center Institutional Review Board at William Beaumont Army Medical Center, Fort Bliss, Tex, and the University of Texas Health Science Center, Houston, Tex. The a priori sample size calculation suggested that 90 subjects would be required to demonstrate a significant difference; however, exigencies of military deployments forced the investigators to end the study without the intended 90 participants. The study used a convenience sample of 59 patients scheduled for elective oral maxillofacial surgery at a Texas medical center. The data from 9 participants were excluded due to protocol violations; therefore, the data from 50 participants, 26 men and 24 women, were evaluated. All participants were 18 to 65 years old, able to communicate in spoken or written English, and ASA physical status I or II. After obtaining written informed consent, we randomly assigned participants to 1 of 3 groups: (1) those who received an induction dose of propofol, 200 mg, mixed with 2 mL of saline; (2) those who received an induction dose of propofol, 200 mg, mixed with 0.5 mg/kg of ketamine; or (3) those who received an induction dose of propofol, 200 mg, mixed with 1.2 mg/kg of ketamine. A standard anesthesia protocol was followed such that all patients received intravenous midazolam, 1 to 3 mg, in the preoperative holding area and fentanyl, 100 to 250 µg, with rocuronium, 0.5 to 0.7 mg/kg; lidocaine, 50 mg; and 200 mg of the propofol–additive solution intravenously at induction. General anesthesia was maintained with fentanyl, 3 to 6 µg/kg per hour (not to exceed a total perioperative dose of 6 µg/kg per hour, including the induction

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dose), isoflurane, nitrous oxide, and rocuronium titrated to effect. The VAS (anchored at one end by the label “No Pain” and at the other end by “Worst Possible Pain”) measured participants’ perception of pain at 1 hour postoperatively. Prolonged pain perception was derived from participants’ 24-hour opioid (or its equivalent) consumption (Table 1). The NK cell activity was measured before and 24 hours after ketamine administration using the chromium 51 (51Cr) release assay and flow cytometric analysis. • Measurement of NK cell cytotoxic activity and NK cell numbers. Peripheral blood mononuclear cells (effector cells) obtained from study subjects were prepared by Ficoll-Hypaque density gradient separation and cocultured with 51Cr-labeled K562 cells (target cells), an established human NK-sensitive chronic myelogenous leukemia cell line. Cell mixtures were incubated in effector/target cell ratios of 100:1, 50:1, 20:1, 10:1, 5:1, and 2.5:1 for 4 hours followed by quantitation of 51Cr released from target cells as a function of NK-mediated target cell cytotoxicity. The percentage of specific cytolysis of K562 cells was calculated as follows: 51

51

Experimental Cr cpm – Spontaneous Cr cpm % specific K562 cytolysis = ———––––––––––––––––––––— × 100 51 51 Maximum Cr cpm – Spontaneous Cr cpm

Flow cytometric analysis was used to quantitate the numbers of NK (CD56+) cells in the effector cell populations. Peripheral blood mononuclear cells were incubated with phycoerythrin (PE)-labeled anti-CD56 (Becton Dickinson, San Jose, Calif) or PE-labeled mouse IgG1 as an isotype control. Labeled cells were then analyzed in a FACS Vantage flow cytometer (Becton Dickinson, San Jose, Calif). Lymphocytes were gated with forward angle vs 90° light scatter and numbers of fluorescent- (PE-) positive lymphocytes determined within the gated region. Ten thousand gated events were collected, and the percentage of specific CD56+ cells was calculated as follows: % Specific CD56+ cells = [number of PE-anti-CD56+ cells] – [number of PE-mouse IgG1+ cells]

Results All parametric data met the assumptions for the statistical analysis used; however, not all of these assumptions are equally important. Whereas violation of the assumption that samples are randomly and independently assigned may not be violated, the analysis of variance (ANOVA) is a robust statistic and a moderate deviation of normality in each sample is

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Table 1. Drugs calculated to 10 mg of parental morphine sulfate

Dose

Morphine equivalent (mg)

Acetaminophen with codeine

1 tablet

1.5

Acetaminophen with oxycodone

1 tablet

1.67

Fentanyl

100 µg

10

Hydromorphone

1 mg

6.66

Ketorolac

30 mg

9

Tramodol

100 mg

10

Drug

tolerated without significantly affecting the integrity of the test. The assumption of equal variance is more sensitive; however, if groups are of equal or almost equal size, the concern about this assumption is minimal for factorial ANOVA. Groups in this study were near equal in size and met the assumption of homogeneity of variance as measured by the Levene test. The χ2 statistic was used for analysis of the demographic data regarding gender and physical status category. A multivariate ANOVA was used to examine the remaining demographics for the sample (eg, age, height, and weight). Table 2 shows the descriptive statistics for these covariates. There were no statistically significant differences by group or gender except height and weight by gender, which was expected. This was controlled for in the study design by administering all drugs on a kilogram basis. The Kruskal-Wallis nonparametric statistic was used to analyze VAS scores (ordinal data) among groups by gender at 1 hour into their postanesthesia recovery. The decision was made a priori to compare the pain scores of men and women separately. Post hoc comparisons were performed with a MannWhitney U test when the Kruskal-Wallis demonstrated a significant difference among groups. Women in the 0.5-mg/kg ketamine group showed a statistical difference ( χ2, 6.128; P < .05) in their VAS scores compared with the control (saline) and 1.2 mg/kg of ketamine groups. However, this finding was not evident in men (P > .05). Thus, women receiving a 0.5-mg/kg bolus of ketamine before incision reported significantly less pain (VAS mean score, 1.96) during the immediate postoperative recovery period compared with women in the control group (VAS mean score, 4.1) and women in the 1.2 mg/kg of ketamine group (VAS mean score, 6.01). This is rep-

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Table 2. Demographic data by group and gender* Group Age (y)

Placebo 0.5 mg/kg ketamine 1.2 mg/kg ketamine

Height (in)

Placebo 0.5 mg/kg ketamine 1.2 mg/kg ketamine

Weight (kg)

Placebo 0.5 mg/kg ketamine 1.2 mg/kg ketamine

Intraoperative local anesthetic (mg)

Placebo 0.5 mg/kg ketamine 1.2 mg/kg ketamine

Intraoperative fentanyl (µg/kg/min)

Placebo 0.5 mg/kg ketamine 1.2 mg/kg ketamine

Surgery (h)

Placebo 0.5 mg/kg ketamine 1.2 mg/kg ketamine

Sex

Mean

SD

M F M F M F

33.20 35.27 30.22 30.20 31.90 31.63

10.56 8.12 6.51 15.33 9.72 9.88

M F M F M F

70.00 66.31 69.77 68.00 70.90 65.75

2.82 2.96 3.86 4.52 2.96 2.05

M F M F M F

91.40 67.93 86.51 70.74 86.02 69.60

14.39 12.98 17.80 16.24 11.34 12.44

M F M F M F

223.80 249.45 230.22 266.40 250.10 228.75

133.36 88.81 33.30 120.94 86.14 103.88

M F M F M F

3.75 4.08 3.72 3.37 3.87 3.58

.92 1.30 1.27 1.01 .59 .57

M F M F M F

2.90 3.10 2.70 3.93 3.60 3.34

1.18 1.11 .73 1.34 1.76 1.56

* There were no significant differences found among the groups except for height and weight by gender.

resented graphically in Figure 1. The SD and SEM were not calculated because this was a nonparametric statistic. The VAS scores for men are not shown. A 2 × 3 ANOVA comparing 24-hour opioid consumption among the 3 groups by gender revealed a drug-gender interaction (P < .05), such that a 0.5mg/kg ketamine bolus decreased postoperative opioid

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consumption for women more than for men. Whereas women receiving the 0.5-mg/kg bolus of ketamine on induction had a mean 24-hour morphine equivalent consumption of 4.04 mg, the mean opioid consumption for men receiving 0.5 mg/kg of ketamine was 17.54 mg. This interaction is illustrated in Figure 2. Finally, postoperative NK cell activity was sup-

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Figure 1. Visual analog scale (VAS) ranked scores among women. Kruskal-Wallis one-way analysis of variance by ranks

Figure 2. 24-hour morphine (or its equivalent) consumption (in mg) among groups, 2 × 3 factorial analysis of variance

7

Sex

30

Male

6.01

Female 24-hour opioid (or equivalent) use

Mean rank VAS, women

6 5 4.10

4

*

3

1.96

2

24

20 20 17

11 10 7

*

1

4

0 Placebo

0.5 mg/kg ketamine

1.2 mg/kg ketamine

Women in the 0.5 mg/kg of ketamine group reported significantly (P < .05) less pain compared with women in other groups. * Significant value.

pressed in men and women and in all groups compared with preoperative values (2 × 3 RANOVA, P < .05); however, there was no significant main effect or interaction when comparing attenuation of NK cell suppression among groups or by gender. To present the data in more clinically relevant terms, we reanalyzed and graphed the data using the change scores (delta) method. Whereas male and female subjects who did not receive ketamine demonstrated 65% and 44% suppression of NK cell activity, respectively, compared with preoperative values, and men and women who received 1.2 mg/kg of ketamine demonstrated 51% and 60% suppression, and men who received 0.5 mg/kg of ketamine demonstrated a 49% suppression of NK cell activity, women who received 0.5 mg/kg of ketamine demonstrated 35% suppression of NK cell activity compared with preoperative values. Although there was not a statistically significant attenuation of NK cell suppression identified among the groups or by gender, there are 2 factors that are important to discuss with regard to these data. First, we performed a sample size calculation a priori based on our previous animal research regarding NMDA antagonists administered before surgery. These previous studies suggested a medium effect size (0.25) for the ANOVA statistic. The post hoc observed effect size for the present study sample size was 0.1, which suggests a small effect size for the ANOVA statistic. Sec-

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0 Placebo

0.5 mg/kg ketamine

1.2 mg/kg ketamine

There is no main effect, but there is a significant (P < .05) interaction by gender such that women given 0.5 mg/kg of ketamine consumed less morphine than women in the other 2 groups, whereas men given 0.5 mg/kg of ketamine consumed more morphine than did the men in either group. Bars represent the mean and error bars the SEM.

ond, unlike our prior animal research, which suggested that NMDA antagonists suppress NK cell activity in a dose-dependent manner after surgery,20 in the present study, ketamine did not suppress NK cell activity in this manner (Figure 3). There were no statistically significant differences (RANOVA; P > .05) in preoperative and postoperative percentages of CD56+ peripheral blood lymphocytes among groups or by gender, which suggests that changes in NK cell activity are due to lytic activity and not to changes in the number of NK cells.

Discussion The overall purpose of this study was to explore the effects of preincisional ketamine on postoperative pain perception and attenuating surgery-induced suppression of NK cell activity. It has been suggested that pain is a stimulator of surgery-induced NK cell suppression and that adequate pain management ameliorates this phenomenon3; however, to our knowledge, no anesthetic regimen has been shown to completely reverse surgical suppression of NK cell activity. This study was designed to examine the effects of preincisional ketamine on postoperative pain perceptions and NK cell activity when used with an opioid–inhalation agent anesthetic protocol.

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Figure 3. Effects of placebo or ketamine on postoperative natural killer (NK) cell activity calculated as percent change from preoperative baseline values, 2 × 3 factorial analysis of variance (change score)

% mean suppression of NK cell activity from baseline

Placebo

0.5 mg/kg ketamine

1.2 mg/kg ketamine

0

–25

35

–50

44 49

51 60

65 –75

Sex Female Male

Bars represent mean values and error bars the SEM. There were no significant differences.

Most clinical trials of ketamine have centered on its analgesic efficacy during the perioperative period. Low dose (10-20 µg/kg per minute) infusions of ketamine intraoperatively have been suggested to decrease surgical wound hyperalgesia as measured by algometer23 and to decrease postoperative pain measured by VAS and morphine consumption.24 Administered as a single small intravenous dose (75-100 µg/kg) postoperatively, ketamine was shown to decrease morphine consumption in patients undergoing outpatient surgery.19 Studies showing the effectiveness of preincisional ketamine have yielded mixed results. Compared with control and postincisional administration, a moderate (100 mg) single bolus of intravenous ketamine produced significantly lower VAS scores in patients undergoing abdominal hysterectomies with no increase in the incidence of side effects.25 Similarly, low-dose preincisional ketamine was shown to be an effective analgesic as measured by morphine consumption in patients undergoing anterior cruciate ligament repair26 and in children undergoing tonsillectomy.27 On the other hand, 2 studies examining the preincisional analgesic effects of small-dose intravenous ketamine (0.15-0.4 mg/kg) in patients undergoing abdominal hysterectomy or total mastectomy showed no significant effect on postoperative analgesia.28,29 In the present study, women given a 0.5-mg/kg

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bolus of ketamine before surgical incision had significantly lower VAS scores 1 hour postoperatively compared with women in other groups and men in all groups. They also had significantly lower 24-hour morphine (or equivalent) use postoperatively compared with men in the same group, suggesting a benefit of low-dose ketamine in women. The U shape of the VAS graph and the morphine equivalent graph for women suggest a ceiling effect associated with ketamine, indicating that the higher dose of ketamine (1.2 mg/kg) has no greater efficacy with regard to analgesia and may, in fact, promote the well-known psychotomimetic effects. Similarly, a ceiling effect for ketamine and other NMDA receptor antagonists has been described for the neuroprotective effect of NMDA antagonists.30 Furthermore, the U shape of the NK cell suppression graph for women mirrored the female VAS and 24-hour morphine equivalent graphs. Women given a 0.5-mg/kg bolus of ketamine exhibited the least suppression of NK cell activity compared with the other female groups, suggesting that the preservation of NK cell activity may be related to the analgesic effect of ketamine. Women given a 0.5-mg/kg bolus of ketamine had only a 35% suppression of NK cell activity compared with preoperative values, whereas women given no ketamine and those given a 1.2-mg/kg bolus of ketamine had 44% and 60% suppression of NK cell activity, respectively. It is interesting that all of the outcome measures suggest that the 0.5-mg/kg dose of ketamine was the most efficacious for women. These findings may be explained by the unique pharmacological properties of ketamine. Ketamine is a nonselective noncompetitive NMDA receptor antagonist that is metabolized by the cytochrome P-450 system of the liver with minimal unchanged urinary excretion. Of the known primary NMDA receptor antagonists, ketamine alone has analgesic properties. These analgesic properties may be explained by evidence showing ketamine activity at all 3 opioid receptors (µ, κ, and δ).31 Because ketamine is an NMDA receptor antagonist and an agonist at the opioid receptors, we speculate that activity at one, some, or all of these receptors may contribute to the findings of this research. The κ agonists have been suggested to be more efficacious in women than in men. For example, Gear and associates32 explored the efficacy of pentazocine, a κ-opioid agonist, as a postoperative analgesic, in male and female participants undergoing dental surgery. Their findings suggested that women receiving pentazocine experienced greater postoperative analgesia than did men.32 Further studies comparing the

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efficacy of nalbuphine and butorphanol (κ opioids) as postoperative analgesics for dental surgery supported the previous study such that nalbuphine and butorphanol provided women greater postoperative analgesia compared with men. Finally, low-dose (5 mg) nalbuphine produced antianalgesia in men but not women, further supporting gender differences in the efficacy of κ opioids.33 Our findings suggest a similar gender-sex–related difference in the response to ketamine such that women but not men were provided analgesic benefit with a 0.5-mg bolus of ketamine administered preoperatively. Furthermore, the interaction effect in this study was such that men who received 0.5 mg/kg of ketamine consumed more morphine equivalent (17.5 mg) postoperatively than men who received placebo (7.5 mg) or 1.2 mg/kg (10.5 mg) of ketamine, whereas women who received 0.5 mg/kg of ketamine consumed less morphine equivalent (4.04 mg) than did women who received placebo (17.54 mg) or 1.2 mg/kg (24.53 mg) of ketamine. There is also evidence supporting sex-related differences in responses to pure NMDA antagonists.34,35 Non–opioid mediated swim stress-induced analgesia has been shown to be blocked by the preadministration of MK-801, an NMDA antagonist, in male mice only.35 Furthermore, NMDA receptor antagonism also may influence κ opioid analgesia in a sex-dependent way. Whereas, male mice exhibit a reduced analgesic response to κ opioids when pretreated with the competitive NMDA antagonist, NPC 12626, no such effects were observed in females.34 Moreover, high serum levels of progesterone have been examined as a mechanism by which NMDA-mediated hyperalgesia may be ameliorated in the rodent suggesting a sexdependent characteristic to NMDA-mediated hyperalgesia. When hyperalgesia is produced in female Sprague-Dawley rats through intrathecal injection of NMDA, nociceptive activity is attenuated significantly in lactating females with high plasma levels of progesterone compared with normal cycling female rats.36 Finally, NMDA receptor antagonists have been shown to enhance µ receptor–induced antinociception in rodents in a sex-related manner. For example, NMDA competitive and noncompetitive receptor antagonists, including ketamine, enhance the peak effect of morphine (µ agonist) in female but not male rats and have been shown to increase the magnitude and duration of opioid analgesia in female rats more than in male rats.21,37 Together, this evidence suggests that a drug such as ketamine, with both opioid agonist and NMDA antagonist properties, may demonstrate sex-related differ-

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ences that favor a more beneficial effect in females. Thus, as our findings suggest, ketamine may be a more efficacious analgesic for women than for men. In addition to the effects of ketamine on opioid and NMDA receptors, ketamine also has been shown to increase monoamine levels within the brain.38 All NMDA antagonists increase monoamine and other neurotransmitter levels in the prefrontal cortex, amygdala, nucleus accumbens, and other areas of the brain.39,40 Increases in monoamines such as dopamine, serotonin, and norepinephrine are associated with the psychotomimetic effects of ketamine. Dopamine, glutamate, and serotonin exquisitely regulate cortical function. Changes within these neurotransmitter systems due to the administration of ketamine may contribute to a patient’s altered sensory perception. For example, increased dopamine and serotonin levels in the frontal cortex appear to contribute to the symptoms of schizophrenia, such as anhedonia (an inability to feel well) and restriction of range and intensity of emotion.41 In our study, neither women nor men received an analgesic benefit from the 1.2-mg/kg bolus of preincisional ketamine compared with placebo. Although monoamine levels in the brain were not measured, extensive research suggests that ketamine potentiates monoaminergic neurotransmission. Therefore, we speculate that the higher dose of ketamine may have been associated with changes in monoamine systems, resulting in the promotion of psychotomimetic side effects, thus blunting the analgesic benefit of high-dose ketamine. Women in the 0.5-mg/kg ketamine bolus group had significantly lower VAS scores and less 24-hour morphine equivalent use than men in the same group, whereas men and women in the 1.2-mg/kg ketamine bolus group experienced no such effect. This finding suggests that there may be dose-related and genderrelated differences in the response to ketamine. In a rodent model, Sershen et al42 suggested that the resulting neuronal dopamine increase secondary to NMDA receptor antagonist activity is significantly less in female rodents than in male rodents. If this phenomenon is true in humans as well, this may account, in part, for the beneficial effects of the 0.5-mg/kg ketamine bolus demonstrated in women compared with men but no beneficial effects for either group at the higher dose. A relatively reduced dopamine milieu after NMDA antagonist administration in women compared with men also may account for the findings regarding NK cell activity in women in the 0.5-mg/kg ketamine bolus group. NMDA antagonists have been shown to

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increase dopamine levels (noncompetitive > competitive) in the nucleus accumbens and prefrontal cortex of the brain in mice and rats.39,40 Stress also has been shown to increase dopamine levels in these same areas of the brain43,44 and suppress NK cell activity in rodents.45,46 Furthermore, dopamine levels in the prefrontal cortex and nucleus accumbens have been shown to be increased in female rats exposed to waterimmersion stress with concomitant suppression of NK cell activity, suggesting an association between increased dopamine levels in these brain areas and NK cell suppression.47 Stress-induced activation of the prefrontal cortex also is associated with NK cell suppression in humans.48 Stress-induced decreases in NK cell activity due to dopamine release in the prefrontal cortex and nucleus accumbens have not been fully established; however, several reports indicate that brain dopamine levels influence NK cell activity in rodents and humans.49,50 One explanation of our findings may be that at the 0.5-mg/kg ketamine dose, women experienced lower dopamine levels secondary to ketamine administration compared with men in either group and, therefore, were able to benefit from the analgesic effects of ketamine. Thus, pain perception and 24-hour postoperative opioid consumption were decreased significantly in women receiving 0.5 mg/kg of ketamine compared with men and other groups. Furthermore, women who received a 0.5-mg/kg bolus of ketamine had only a 35% suppression of NK cell activity. Further research is warranted to investigate the effects of preemptive ketamine and its modulation of analgesia and NK cell activity. The interaction of NMDA antagonists, dopamine, serotonin, and NK cell activity is not fully elucidated. The addition of a dopamine antagonist within the structure of this protocol may further clarify the contribution of neuronal dopamine release to NK cell activity. The addition of a dopamine antagonist may be beneficial such that NK cell activity is conserved and the psychotomimetic side effects of ketamine are mitigated. In addition, the interaction of sex hormones on NMDA antagonists and pain perception has not been explained fully. Therefore, to explore this interaction, we are conducting a follow-up study using the same protocol in which female participants are assigned to menstrual phase through assay of serum progesterone levels. Women who were given a 0.5-mg/kg bolus of ketamine on induction of anesthesia perceived less pain postoperatively as measured by the VAS and consumed less opioid or its equivalent within the 24-hour postoperative period. Moreover, although statistical significance was not reached, women who were given a 0.5-

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mg/kg bolus of ketamine demonstrated the least suppression of NK cell activity compared with baseline. These findings, if corroborated with further studies, may have significant impact on the anesthetic care of surgical patients undergoing solid tumor excision. For the millions of individuals who undergo surgery each year, any intervention that may reduce a risk such as immune suppression potentially would impact a large portion of the general population. If NK cell activity has a role in inhibiting spontaneous metastasis in humans and surgery suppresses NK cell activity, then any intervention shown to ameliorate surgery-induced decreases in host resistance to metastasis, even if that effect is small, potentially may decrease the risk of spontaneous metastasis and increase long-term survival. Finally, the findings of this research have the potential to support and extend findings implicating pain in the negative immune and metastatic consequences of undergoing and recovering from surgery. REFERENCES 1. Lotzová E. Natural killer cells: Immunobiology and clinical perspectives. Cancer Invest. 1991;9:173-184. 2. Pollock RE, Lotzová E, Stanford S. Surgical stress impairs natural killer cell programming of tumor for lysis in patients with sarcoma and other solid tumors. Cancer. 1992;70:2192-2202. 3. Page GG, Ben-Eliyahu S, Yirmiya R, Liebskind JC. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain. 1993;54:21-28. 4. D’Arcy YC, Ebner MK. A two site comparison of surveys for patient satisfaction, nursing knowledge, and physician knowledge about pain management. Abstract presented at the 17th Annual Scientific Meeting of the American Pain Society; November 5-8, 1998; San Diego, Calif. 5. Bonica JJ. History of pain concepts and therapies. In: Bonica JJ, ed. The Management of Pain. Philadelphia, Pa: Lea and Febiger; 1990:2-17. 6. Bot G, Blake AD, Li S, Reisine T. Fentanyl and its analogs desensitize the cloned mu opioid receptor. J Pharmacol Exp Ther. 1998; 285:1207-1218. 7. Ness TJ, Follett KA. The development of tolerance to intrathecal morphine in rat models of visceral and cutaneous pain. Neurosci Lett. 1998;248:33-36. 8. Fairbanks CA, Wilcox GL. Acute tolerance to spinally administered morphine compares mechanistically with chronically induced morphine tolerance. J Pharmacol Exp Ther. 1997;282: 1408-1417. 9. Cooper DW, Lindsay SL, Ryall DM, Kokri MS, Eldabe SS, Lear GA. Does intrathecal fentanyl produce acute cross-tolerance to i.v. morphine? Br J Anaesth. 1997;78:311-313. 10. Mercadante S, Dardanoni G, Salvaggio L, Armata MG, Agnello A. Monitoring of opioid therapy in advanced cancer pain patients. J Pain Symptom Manage. 1997;13:204-212. 11. Bilsky EJ, Inturrisi CE, Sadee W, Hruby VJ, Porreca F. Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists. Pain. 1996;68:229-237. 12. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: implications for post-injury pain and hypersensitivity states. Pain. 1991;44:293-299. 13. Page GG, Blakeley W, Ben-Eliyahu S. Evidence that postoperative

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pain is a mediator of the tumor-promoting effects of surgery in rats. Pain. 2001;90:191-199. 14. Gilron I, Quirion R, Coderre TJ. Pre- versus postformalin effects of ketamine or large-dose alfentanil in the rat: discordance between pain behavior and spinal Fos-like immunoreactivity. Anesth Analg. 1999;89:128-135. 15. Advokat C, Rhein FQ. Potentiation of morphine-induced antinociception in acute spinal rats by the NMDA antagonist dextrorphan. Brain Res. 1995;699:157-160. 16. Lin TC, Wong CS, Chen FC, Lin SY, Ho ST. Long-term epidural ketamine, morphine and bupivacaine attenuate reflex sympathetic dystrophy neuralgia. Can J Anaesth. 1998;45:175-177. 17. Price DD, Mao J, Lu J, Caruso FS, Frenk H, Mayer DJ. Effects of the combined oral administration of NSAIDs and dextromethorphan on behavioral symptoms indicative of arthritic pain in rats. Pain. 1996;68:119-127. 18. Pellier I, Monrigal JP, Le Moine P, Rod B, Rialland X, Granry JC. Use of intravenous ketamine-midazolam association for pain procedures in children with cancer; a prospective study. Paediatr Anaesth. 1999;9:61-68. 19. Suzuki M, Tsueda K, Lansing PS, et al. Small dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg. 1999;89:98-103. 20. Garrett N. Effects of LY235959 on Surgery-Induced Immunosuppression and Tumor Metastasis in Rats [dissertation]. Baltimore, Maryland: Johns Hopkins University. 2000. 21. Markovic SN, Murasko DM. Anesthesia inhibits interferoninduced natural killer cell cytotoxicity via induction of CD8+ suppressor cells. Cell Immunol. 1993;151:474-480. 22. Markovic SN, Mursako DM. Anesthesia inhibits poly I:C induced stimulation of natural killer cell cytotoxicity in mice. Clin Immunol Immunopathol. 1990;56:202-209. 23. Tverskoy M, Oz Y, Isakson A, Finger J, Bradley ELJ, Kissin I. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg. 1994;78:205-209. 24. Fu ES, Miguel R, Scharf JE. Preemptive ketamine decreases postoperative narcotic requirements in patients undergoing abdominal surgery. Anesth Analg. 1997;84:1086-1090. 25. Hazama K, Nakao M, Kawaguchi R, Nakatani K, Nakagawa M, Unetani H. Pre-incisional administration of ketamine reduced the postoperative pain. Masui. 1999;48:1302-1307. 26. 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;90:129-135. 27. Elhakim M, Khalafallah HA, El-Fattah S, Khattab A. Ketamine reduces swallowing-evoked pain after paediatric tonsillectomy. Acta Anaesthesiol Scand. 2003;47:604-609.

34. Kavaliers M, Choleris E. Sex differences in N-methyl-δ-aspartate involvement in kappa opioid and non-opioid predator-induced analgesia in mice. Brain Res. 1997;768:30-36. 35. Mogil JS, Sternberg WF, Kest B, Marek P, Liebskind JC. Sex differences in the antagonism of swim stressed–induced analgesia: effects of gonadectomy and estrogen replacement. Pain. 1993;53: 17-25. 36. Ren K, Wei F, Dubner R, Murphy A, Hoffman GE. Progesterone attenuates persistent inflammatory hyperalgesia in female rats: involvement of spinal NMDA receptor mechanisms. Brain Res. 2000;865:272-277. 37. Holtman JR, Jing X, Wala EP. Sex-related differences in the enhancement of morphine antinociception by NMDA receptor antagonists in rats. Pharmacol Biochem Behav. 2003;76:285-293. 38. Nishimura M, Sato K, Okada T, et al. Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology. 1998;88:768-774. 39. Svensson A, Carlsson ML, Carlsson A. Crucial role of the accumbens nucleus in the neurotransmitter interactions regulating motor control in mice. J Neural Transm. 1995;101:127-148. 40. Feenstra MGP, van der Weij W, Botterblom MHA. Concentrationdependent dual action of locally applied N-methyl-D-aspartate on extracellular dopamine in the rat prefrontal cortex. Neurosci Lett. 1995;201:175-178. 41. Stamford JA, Muscat R, O’Connor JJ, et al. Voltammetric evidence that subsensitivity to reward following chronic stress is associated with release of mesolimbic dopamine. Psychopharmacology (Berl). 1991;105:275-282. 42. Sershen H, Hashim A, Lajtha A. Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release. Brain Res. 1998;801:67-71. 43. Goldstein LE, Rasmusson A, Bunney BS, Roth RH. The NMDA glycine site antagonist (+)-HA-966 selectively regulates conditioned stress-induced metabolic activation of the mesoprefrontal cortical dopamine but not serotonin systems: a behavioral, neuroendocrine, and neurochemical study in the rat. J Neurosci. 1994;14:4937-4950. 44. Imperato A, Puglisi-Allegra S, Casolini P, Angelucci L. Changes in brain dopamine and acetylcholine release during and following stress are independent of the pituitary-adrenocortical axis. Brain Res. 1991;538:111-117. 45. Ben-Eliyahu S, Page GG, Yirmiya R, Shakhar G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer. 1999;80:880-888. 46. Lu ZW, Song C, Ravindran AV, Merali Z, Anisman H. Influence of a psychogenic and neurogenic stressor on several indices of immune functioning in different strains of mice. Brain Behav Immun. 1998;12:7-22.

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AUTHORS CPT Michael W. Bentley, CRNA, MSN, AN, USA, is a staff nurse anesthetist at Evans Army Community Hospital, Fort Carson, Colo. He was a graduate student in the US Army Graduate Program in Anesthesia

AANA Journal/December 2005/Vol. 73, No. 6

435

Nursing at William Beaumont Army Medical Center, El Paso, Tex, at the time of this study. CPT John M. Stas, CRNA, MSN, AN, USA, is a staff nurse anesthetist at Moncrief Army Community Hospital, Fort Jackson, SC. He was a graduate student in the US Army Graduate Program in Anesthesia Nursing at William Beaumont Army Medical Center, El Paso, Tex, at the time of this study. CPT Jimmie M. Johnson, CRNA, MSN, AN, USA, is a staff nurse anesthetist at Darnall Army Community Hospital, Fort Hood, Tex. He was a graduate student in the US Army Graduate Program in Anesthesia Nursing at William Beaumont Army Medical Center, El Paso, Tex, at the time of this study.

436

AANA Journal/December 2005/Vol. 73, No. 6

Bruce C. Viet, PhD, is chief, Immunology Section, Department of Clinical Investigation, William Beaumont Army Medical Center, El Paso, Tex. COL Normalynn Garrett, CRNA, PhD, AN, USA, is the director of the US Army Graduate Program in Anesthesia Nursing, Fort Sam Houston, Tex. At the time of the study she was chief, Anesthesia Nursing Section, William Beaumont Army Medical Center, El Paso, Tex. Email: [email protected]

DISCLAIMER The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.

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