Evidence suggests that both hyperalgesia after tissue injury and the development of opiate tolerance involve activation of the N-methyl-D-aspartate (NMDA) receptor and subsequent biochemical processes resulting in central sensitization [1]. Sharing of NMDA receptor activation by both processes suggests that ketamine, an NMDA receptor antagonist, may substantially enhance opiate-induced antinociception [1]. Animal studies have confirmed an interaction between hyperalgesia and opiate tolerance (e.g., hyperalgesia-induced opiate tolerance or opiate tolerance-associated hyperalgesia) [2-5]. Stubhaug et al. [6] showed in humans that 48-h continuous administration of small-dose ketamine, together with patient-controlled analgesia (PCA) with morphine, prolonged time to the first use of PCA-morphine and reduced cumulative morphine. Other studies have demonstrated a marked decrease in opiate consumption and/or pain intensity by systemic [7] or epidural coadministration [8,9] of ketamine and opiates. Analgesic doses of ketamine 150-500 [micro sign]g/kg have been reported to produce dose- or plasma concentration-dependent antinociception [6,10] and cognitive, perceptual, and mood disturbances, as well as psychotomimetic side effects [11-15]. Coadministration of smaller doses of ketamine and opiates may provide adequate analgesia with fewer ketamine-related side effects.
We studied the effects of a systemic coadministration of small doses of ketamine with morphine on postoperative morphine consumption, pain intensity, sedation, perception, cognition, and mood in patients undergoing outpatient surgery under standardized general anesthesia.
Methods
One hundred forty patients of both genders, ASA physical status I or II, who were scheduled for elective outpatient surgery were recruited for this randomized, double-blinded, placebo-controlled, four-group parallel study. Written, informed consent approved by our human studies committee was obtained from each patient. Exclusion criteria included morbid obesity; a history of psychological problems; the use of drugs that affect the central nervous system; chemical substance abuse; chronic pain; pregnancy; seizure disorders; increased intracranial pressure; and cardiovascular, hepatic, renal, or psychiatric disease. Patients were randomly assigned to one of four groups (n = 35 for each) according to a computer-generated randomization schedule (Mini Table Statisticalsoftware, Release 9; Mini Tab, Inc., State College, PA): 1) those receiving placebo; 2) those receiving ketamine 50 [micro sign]g/kg IV 15 min before the end of operation; 3) those receiving ketamine 75 [micro sign]g/kg IV 15 min before the end of operation; and 4) those receiving ketamine 100 [micro sign]g/kg IV 15 min before the end of operation. All patients received morphine 50 [micro sign]g/kg in a separate syringe. Syringes containing ketamine in 10 mL of isotonic sodium chloride solution were prepared by one of the investigators who did not participate in the assessment.
Preoperative medication was midazolam 1-2 mg IV. Anesthesia was induced with IV propofol 2-2.5 mg/kg and was maintained with desflurane in a nitrous oxide/oxygen mixture. Tracheal intubation was facilitated by succinylcholine. Muscle relaxation was provided by vecuronium. End-tidal desflurane concentration ranged from 3% to 8%. Patients received the study drug and morphine 50 [micro sign]g/kg IV approximately 15 min before the end of operation. Muscle relaxation was antagonized at the end of operation with neostigmine 3 mg and glycopyrrolate 0.6 mg IV. In the postanesthesia care unit, patients received IV morphine in 2-mg increments, every 5 min, for pain as per patient request. Nausea was treated with ondansetron dihydrate 4 mg IV. When both pain and nausea were mild (visual analog scale [VAS] score <30% and patients were not bothered by the pain), patients were able to swallow liquid and to sit up in the stretcher, and two successive Aldrete Post Anesthesia Recovery Scores (APARS; 0-10) [16] were >or=to9, patients were discharged from phase 1 to phase 2 (the ambulatory phase) of recovery. Patients were discharged from the phase 2 facility when they were able to dangle for 5 min and to ambulate without feeling dizzy and pain and nausea were mild or absent.
Pain intensity was assessed using a 100-mm VAS, anchored by "no pain" at one end and by "worst possible pain" at the opposite end. Sedation level was assessed using 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 [17]. Subjective level of drowsiness was assessed by using a VAS in which the worst drowsiness was defined as present when patients could hardly keep their eyes open [18]. Nausea was assessed by a subjective VAS anchored by retching and/or vomiting at one end [18].
Cognitive function was assessed using the MiniMental State (MMS, 0-30) [19]. Mood was evaluated using the short form of the Profile of Mood States (POMS) [20,21]. Each of the six mood or affective states in the short form (i.e., anger-hostility, depression-dejection, confusion-bewilderment, fatigue-inertia, tension-anxiety, and vigor-activity) consists of five adjectives scales, each of which is rated on a 5-point intensity rating scale: 0 = not at all, 1 = a little, 2 = moderately, 3 = quite a bit, and 4 = extremely (range 0-25). The score was transformed to T scaling for normalization. A Total Mood Disturbance Score (TMDS), a global estimate of affective state, was obtained by summing the T scores for each of the six mood states. Dissociative state was assessed using a modified Clinician-Administered Dissociative State Scale (CADSS, 0-104) [12]. In addition, patients were asked whether they felt "strange" or "weird." Overall recovery from anesthesia was assessed by using the APARS.
VAS scores for pain, drowsiness, and nausea; MMS, OAA/S, POMS, CADSS, and APARS; and blood pressure, heart rate, and respiratory rate were assessed before premedication. Assessment of VAS scores, vital signs, APARS, and OAAS/S was repeated on arrival to the postanesthesia care unit and every 15 min thereafter until the time of discharge to phase 2 recovery. Assessment of MMS, POMS, and CADSS was repeated immediately before discharge to phase 2 recovery.
Differences among the groups over time in VAS scores, POMS, CADSS, and MMS were tested using analysis of variance for repeated measures. Differences among the groups in the amount of morphine given and the duration of phase 1 recovery in the postanesthesia care unit were tested by using analysis of covariance. Where applicable, the data were further tested using Student's t-tests with Bonferroni corrections. Scores for OAA/S and APARS were analyzed using the repeated-measures permutation test.
Results
All 140 patients completed the study. Seven patients required hospitalization after the operation: two had persistent severe pain, two had persistent retching and vomiting, and three had infection at the operative site requiring an infusion of antibiotics. The data for these seven patients were included in the analysis. There were no significant differences among the groups in age, body weight, height, gender distribution, or type of operation performed (Table 1).
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Table 1: Demographic Data
There was a significant difference in morphine requirement among Groups 1-4 during phase 1 recovery (145 +/- 93, 111 +/- 82, 91 +/- 85, and 89 +/- 77 [micro sign]g/kg, respectively; P < 0.05). Morphine consumption in Groups 3 and 4 was approximately 40% less than that in the control group. There was a significant group main effect in pain scores (P < 0.0001). Pain scores in Groups 3 and 4 were approximately 35% lower than those in the control group at all time periods (P < 0.0001 for all) (Figure 1). There was no significant difference in the pain score between Groups 1 and 2.
Figure 1: Pain visual analog scale (VAS) scores during phase 1 recovery (mean with 95% confidence interval). Group 1 ([square]) received morphine 50 [micro sign]g/kg (n = 35). Group 2 ([black square]) received morphine 50 [micro sign]g/kg and ketamine 50 [micro sign]g/kg (n = 35). Group 3 ([square]) received morphine 50 [micro sign]g/kg and ketamine 75 [micro sign]g/kg (n = 35). Group 4 ([square]) received morphine 50 [micro sign]g/kg and ketamine 100 [micro sign]g/kg (n = 35).a Arrival in the recovery room.b Discharge from phase 1 recovery. *P < 0.0001 versus the control group.
There were no significant group differences in vital signs. There were no significant group differences in OAA/S scores and drowsiness VAS scores for Groups 1-4 (5 +/- 14, 71 +/- 28, 50 +/- 26, 41 +/- 23, 33 +/- 24, and 33 +/- 25; 8 +/- 15 68 +/- 29, 45 +/- 32, 35 +/- 27, 28 +/- 28, and 28 +/- 28; 3 +/- 7, 63 +/- 33, 43 +/- 24, 25 +/- 20, 23 +/- 20, and 23 +/- 20; and 9 +/- 14, 70 +/- 31, 50 +/- 28, 37 +/- 27, 32 +/- 25, and 32 +/- 25, for baseline; arrival in the postanesthesia care unit; 15, 30, and 45 min and discharge from phase 1 recovery, respectively) at any time period. Some patients reported a weird or strange sensation on questioning 15 min after admission to the recovery room (three patients in Group 1, two patients in Group 2, seven patients in Group 3, and eight patients in Group 4). On further questioning, however, all of these patients stated that they were relaxed and comfortable. There were no significant group differences in incidence of and VAS scores for nausea and vomiting; incidence of ondansetron treatment; time to highest APARS or first intake of fluid; or CADSS, TMDS, and MMS scores at discharge from phase 1 recovery (Table 2). None developed psychiatric and/or active psychotomimetic symptoms.
Table 2: Incidence of Nausea, Ondansetron Treatment, Time to Highest APARS and First Oral Fluid Intake, CADSS, TMDS, MMS, and Duration of Phase 1 and Phase 2 Recovery
Analysis of covariance with pain and drowsiness used separately as covariates showed that pain and somnolence were significant covariates (P < 0.05 and P < 0.01, respectively). Analysis of covariance with both pain and drowsiness together as covariates showed drowsiness was significant (P < 0.01 and P = 0.064, respectively). There was no significant group difference in the duration of phase 1 recovery when adjusted for either covariate. There was no significant group difference in the duration of phase 2 recovery.
Discussion
We found that small-dose ketamine 75 and 100 [micro sign]g/kg IV, given together with morphine 50 [micro sign]g/kg IV, reduced postoperative morphine requirements and pain by approximately 40% and 35%, respectively, during phase 1 recovery. Analgesia produced by ketamine occurs at plasma concentrations of 100-150 ng/mL [22]. The plasma half-life of ketamine is <or=to17 minutes. Analgesia produced by ketamine 125 and 250 [micro sign]g/kg IV lasts approximately five minutes when the plasma ketamine concentration is >100 ng/mL [23]. The doses of ketamine used in this study would be expected to produce analgesia for a few minutes or less during the high plasma concentrations immediately after injection. Thus, ketamine concentrations may have been subanalgesic during the entire period of observation in our study. The analgesic effect of ketamine, however, was clearly evident during and at the end of phase 1 recovery (i.e., approximately 3.5 plasma half-lives of ketamine).
Ketamine may produce antinociception through interaction with spinal [micro sign] receptor, NMDA receptor antagonism, and activation of the descending pain inhibitory monoaminergic pathways [23], which is expressed by alpha2-adrenoceptors at the spinal level [24]. The affinity of ketamine for NMDA receptors has been shown to be more than an order of magnitude higher than that for [micro sign] receptor [25], and several-fold higher than that for monoamine transporter sites or other non-NMDA receptors (i.e., acetylcholinesterase and the sigma receptor) [26], which suggests that the smaller the dose, the more selective the ketamine interaction with NMDA receptors may be. Although antinociception after the intrathecal administration of ketamine is reversed by naloxone in rats [23], analgesia produced in humans by systemic ketamine 300 [micro sign]g/kg is not reversed [25], which suggests that the monoaminergic activation, rather than [micro sign] receptor agonist activity, may be involved in antinociception produced by analgesic doses of ketamine. However, although opiates produce antinociception through [micro sign] receptor agonist activity and the activation of monoaminergic descending pathways at the spinal level [24], they activate NMDA receptors, resulting in hyperalgesia and the development of tolerance to the opiates [1]. Other studies have shown that analgesia produced by the systemic coadministration of an opiate and an alpha2-adrenoceptor agonist (e.g., clonidine or meditonidine) is additive [27]. In our patients, plasma ketamine concentrations during phase 1 recovery may have been more than an order of magnitude lower than an analgesic concentration. The marked reduction in both pain score and morphine requirement found in our patients may be explained by the interaction of ketamine with NMDA receptors that had been activated by perioperative nociceptive inputs, as well as by the administration of morphine.
Ketamine 100-500 [micro sign]g/kg infused over 45 minutes [12] in concentrations of 50-200 ng/mL [14], or a bolus injection of (S)-ketamine 50-200 [micro sign]g/kg [11], has been shown to produce drowsiness resembling that after ethanol ingestion. In our study, drowsiness scores were higher when either ketamine or morphine consumption increased. The mean drowsiness score in patients who received 100 [micro sign]g/kg ketamine and used approximately 40% less morphine was identical to the score in controls, which suggests a substantial contribution of ketamine, despite the rapid decay of the plasma concentration, to the state of drowsiness during phase 1 recovery. The mean drowsiness scores for patients who received smaller doses of ketamine and morphine were lower than those in controls. The score was the lowest for those who received 75 [micro sign]g/kg ketamine and used significantly less morphine than controls. Although the differences in the scores were not statistically significant among the groups, analysis of covariance suggests that drowsiness and/or pain may have had a significant influence over the duration of phase 1 recovery. There were no group differences in cognitive function, perception, mood states, or the incidence of nausea and vomiting at discharge. These findings suggest that levels of drowsiness and the intensity of pain may be important factors in determining the duration of phase 1 recovery after outpatient surgery.
Theoretically, coadministration of an opiate and ketamine reduces the amount of opiate and ketamine required for optimal pain relief below that when used alone and thus may lower the incidence of side effects. However, in this study, the coadministration did not alter the incidence of nausea and vomiting (i.e., approximately 26%-30%). General anesthetics influence the incidence of emesis during recovery. The amount of morphine with or without ketamine required in our study was relatively small (e.g., the mean consumption over the 45-minute period was 11 mg in the control group), which suggests that the morphine and/or ketamine used in this study may have contributed less to the pathogenesis of nausea than did general anesthesia.
At anesthetic doses of ketamine (i.e., 1-3 mg/kg), more than one third of patients may have unpleasant dreams or acute psychosis-like symptoms that may or may not be associated with hallucinations on emergence [28]. Subanesthetic doses of ketamine impair some domains of cognitive function, such as attention, free recall, recognition memory, and thought processes in healthy human volunteers [11-13]. Other studies have shown that analgesic doses of ketamine (i.e., 100-500 [micro sign]g/kg) alter mood states and produce dose-related impairment of sensory perception or the process of sensory integration [12-14]. Perceptual and mood changes at larger doses of ketamine (e.g., 500 [micro sign]g/kg) have been shown to resemble some aspects of schizophrenia and/or psychosis and are associated with dysphoria [12]. The doses used in our study were smaller than those used in previous studies. With its short plasma half-life, the plasma ketamine concentration was expected to decline rapidly in our patients. In addition, our patients received a benzodiazepine (i.e., midazolam) premedication, which has been reported to reduce psychotomimetic manifestations effectively during and after emergence from ketamine anesthesia [28]. Although several patients in the groups who received ketamine 75 or 100 [micro sign]g/kg reported having strange or weird feelings early in the recovery phase, none of these patients were dysphoric, and all reported being relaxed and comfortable. None developed psychotomimetic symptoms. There was no evidence of changes in cognition, perception, or mood in our patients at discharge from phase 1 recovery.
Our findings show that small doses of ketamine may enhance the pain relief produced by morphine. The findings seems to be consistent with the concept that ketamine interacts with NMDA receptors activated by nociceptive stimuli and morphine.
We thank Dr. Robert L. Vogel for statistical analysis, Mrs. Patricia Bensinger for her help in the preparation of the manuscript, and nurses in the postanesthesia care unit of the University of Louisville Hospital, Louisville, KY, for the care of patients.
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