A Single Small Dose of Postoperative Ketamine Provides Rapid and Sustained Improvement in Morphine Analgesia in the Presence of Morphine-Resistant Pain Avi A. Weinbroum,
MD
Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
It is a common clinical observation that postoperative pain may be resistant to morphine. The analgesic potentials of ketamine have also been well documented. In this study, we evaluated the effects of postoperative coadministration of small doses of ketamine and morphine on pain intensity, Spo2, and subjectively rated variables in surgical patients who underwent standardized general anesthesia and complained of pain (ⱖ6 of 10 on a visual analog scale [VAS]) despite ⬎0.1 mg/kg of IV morphine administration within 30 min. Patients randomly received up to three boluses of 30 g/kg of morphine plus saline (MS; n ⫽ 114) or 15 g/kg of morphine plus 250 g/kg of ketamine (MK; n ⫽ 131) within 10 min in a double-blinded manner. The MS group’s
T
he common occurrence of surgical patients perceiving pain intensively, despite the postoperative administration of ample amounts of IV morphine, suggests a failure of sustained effectiveness. Large opioid dosages were shown to be hazardous to the awakening patient because of potential respiratory and hemodynamic depression. Supplementation with rescue analgesics can compensate for the unsatisfactory effect of the primary antinociceptive drug, but they too might evoke adverse effects. There is evidence to suggest that the lack of effectiveness of postoperatively administered morphine is due to the activation of the N-methyl-d-aspartate (NMDA) receptors (1). If not effectively inhibited in time, the process may evolve into a complex change in neural plasticity, resulting in central sensitization and severe pain (1). Insofar as surgery and opioids share NMDA receptor activation, adequate blockade of these receptors before Accepted for publication November 6, 2002. Address correspondence and reprint requests to Avi A. Weinbroum, MD, Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center, Weizman St., Tel-Aviv 64239, Israel. Address e-mail to
[email protected]. DOI: 10.1213/01.ANE.0000048088.17761.B4 ©2003 by the International Anesthesia Research Society 0003-2999/03
pain VAS scores were 5.5 ⫾ 1.18 and 3.8 ⫾ 0.9 after 10 and 120 min, respectively, after 2.52 ⫾ 0.56 injections, versus the MK group’s VAS scores of 2.94 ⫾ 1.28 and 1.47 ⫾ 0.65, respectively (P ⬍ 0.001), after 1.35 ⫾ 0.56 injections (P ⬍ 0.001). The 10-min level of wakefulness (1–10 VAS) in the MS group was significantly (P ⬍ 0.001) less (6.1 ⫾ 1.5) than the MK group’s (8.37 ⫾ 1.19). Spo2 decreased by 0.26% in the MS group but increased by 1.71% in the MK patients at the 10-min time point (P ⬍ 0.001). Thirty MS versus nine MK patients (P ⬍ 0.001) experienced nausea/vomiting; nine MK patients sustained a 2-min light-headed sensation, and one patient had a weird dream after the second drug injection. (Anesth Analg 2003;96:789 –95)
incision (as shown by dextromethorphan) (2) might benefit the patient by evoking attenuation of pain and secondary hyperalgesia, morphine consumption-sparing effect, and amelioration of several subjective variables. Ketamine, a noncompetitive NMDA receptor antagonist like dextromethorphan, was recently shown to enhance opioid-induced antinociception (1). Furthermore, animal studies have indicated that ketamine reduces hyperalgesia and prevents the induction of opioid tolerance (3,4). Similarly to dextromethorphan (3), a marked decrease in opioid consumption and in pain intensity accompanied continuous IV infusion (5,6) or epidural (7,8) coadministration of ketamine and opioids. Because analgesic doses of ketamine alone (⬍500 g/ kg) have been reported to produce dose-dependent antinociception (4,9), associated, however, with cognitive and mood disturbances (10 –12), it was hypothesized that the combined administration of small-dose ketamine and morphine (MK) would promptly reduce pain perception even in patients who already had severe pain that was nonresponsive to morphine, reduce morphine requirements, ameliorate wakefulness and feelings of well-being, and, at the same time, minimize ketamineand morphine-related side effects. Anesth Analg 2003;96:789–95
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Methods Patients with ASA physical status I to III, scheduled for elective surgery from January to March 2002, were recruited for this randomized, double-blinded study. They gave written, informed consent approved by our human studies committee before undergoing abdominal general surgery, orthopedic surgery (knee replacement and disk surgery were excluded), or transthoracic lung biopsy or wedge resection under general anesthesia during the morning prime shift. Exclusion criteria included morbid obesity; disturbances of the central nervous system; chemical substance abuse; chronic pain; cardiovascular, hepatic, renal, or psychiatric diseases; age younger than 18 yr; and noncoherence. General anesthesia was administered by the same team and consisted of IV sodium thiopental 2–3 mg/kg for induction, rocuronium infusion to facilitate tracheal intubation and obtain muscle relaxation, fentanyl 2–3 g/kg for intraoperative analgesia, and nitrous oxide/oxygen (2:1 L) enriched with isoflurane as deemed necessary by the attending anesthesiologist. All patients had volume-controlled ventilation. Neuromuscular relaxation was not reversed pharmacologically at the end of surgery: complete and normal recovery of neuromuscular activity was based on normal train-of-four and clinical criteria (ability to lift the head for 10 s, satisfactory hand-grasp strength, adequacy of respiratory rate, and normal ETco2) (2). No regional anesthesia was used in any of the patients. While recovering in the postanesthesia care unit (PACU), all patients routinely received morphine IV (per patient request) consisting of 2-mg increments every 4 –5 min until pain was relieved. Patients who were given at least 100 g/kg of morphine within a 25- to 30-min period but still complained of pain (ⱖ6 of 10 on a visual analog scale [VAS; see below]), whom the attending physician found in an acceptable cognitive state (ⱖ15 in the Mini-Mental State Examination [MMSE]; see below), or who rated themselves not sedated (ⱖ5 of 10 on a VAS) were randomly enrolled into one of the two treatment protocols on alternate days. A cutoff score of ⱖ6 of 10 on a pain VAS was chosen on the basis of previous experience in acute pain control, where a 4 of 10 VAS expressed sustained but not severe pain (2,13). Drug injections consisted of 30 g/kg of morphine plus saline (group MS) or 15 g/kg of morphine plus 250 g/kg of ketamine (group MK). Patients were given up to three such IV boluses either until the pain VAS was ⱕ4 of 10 or 10 min had passed. An anesthesiologist who did not participate in the study prepared the separate syringes. If pain was not attenuated with either regimen, a rescue dose of IM diclofenac 75 mg was given. The effect of a subanesthetic dose of ketamine plus saline
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was not tested for ethical reasons (ineffectiveness per se) (14). Before starting treatment, the attending physician evaluated the patient’s cognitive state by using the MMSE (from 0 to 30) (15,16) or a sedation scale. The attending nurse, who was blinded to the drug assignment, assessed the variables listed below for each patient during his or her entire stay in the PACU. VAS scores were assessed by using the 10-cm chiroscience pain gauge every 5 min for the first hour and every 15 min afterward. 1. Subjective pain intensity was graded on a selfrating VAS, graded as “no pain” ⫽ 0 and by “worst possible pain” ⫽ 10. 2. The patient’s subjective level of wakefulness was assessed by a self-rated VAS from 1 ⫽ heavily sedated to 10 ⫽ fully awake. 3. Subjective feelings of well-being were recorded by a VAS of 1 ⫽ sad and gloomy to 10 ⫽ happy and content. If patients were asleep, they were awakened to obtain their rating; the data of a patient unable to cooperate were excluded from the study from that time onward. Vital signs included noninvasive blood pressure, a five-lead electrocardiogram, respiratory rate, and fingertip pulse-derived oxygen saturation (Spo2) (Cardiocap™; Datex®, Helsinki, Finland) on air. An Spo2derived value of 92% under 40% oxygen by face mask was the lower limit for inclusion in the study. Untoward effects (e.g., nausea, vomiting, or any distress) were recorded by the nurse and treated if deemed necessary by the attending physician, who was also blinded to group assignment (e.g., metoclopramide 10 mg IV for nausea or vomiting). The patients were kept for observation for an additional hour after the end of the 1-h study period; on-ward diclofenac use and side effects were later recorded. The analyses were performed at the Statistical Laboratory of the School of Mathematics, Tel-Aviv University, by using the SPSS Release for Windows, Version 9 (SPSS Inc., Chicago, IL). The demographic data (age and weight) and background characteristics (amounts of morphine used before test drug administration, MMSE, VAS scores, and vital signs) of the two study groups were compared by using Student’s t-test. Sex and group distribution of the type of procedure and the incidence of the side effects were analyzed with the Pearson 2 test. The numbers of injections of the test drugs between the groups and among the surgical subgroups were evaluated with the 2 test; the mean number of injections per group was assessed with Student’s t-test. All physiological variables during the observation period in the PACU were analyzed with one-way analysis of variance with repeated measures. Analyses of PACU and on-ward use
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of diclofenac and the use of metoclopramide were performed with Fisher’s exact test. All values are expressed as mean ⫾ sd, with significance defined as P ⱕ 0.05.
Results During the study period, two-hundred-forty-five (22%) (114 MS and 131 MK recipients) of 1088 eligible surgical patients fulfilled study entry criteria. The demographic and surgical data were similar between the two study groups (Table 1). All baseline vital signs, patients’ self-rated pain-intensity scores, and levels of wakefulness and feeling before the study were similar, as were the MMSE scores (Figs. 1–3, Table 2) and the amounts of morphine used (data not shown). The amounts of analgesics that were requested by the patients to alleviate pain were found to be associated with the drug regimen. They were significantly (P ⬍ 0.001) less for the MK compared with the MS subjects, with the former sufficing with 35% of the total amount of morphine used by the latter (Table 2). In addition, the MS patients received almost twofold the number of injections (P ⬍ 0.001) and threefold the diclofenac (P ⫽ 0.002) administered to the MK patients for pain control. Furthermore, whereas 63 of the 114 MS patients received 3 injections, 89 of the 131 MK patients requested only 1 injection (Table 2). The numbers of injections within the surgical subgroups showed the same trend as for the entire cohort (data not shown). Finally, a similar number of patients in each group used the rescue drug in the ward during the following 24 h (Table 2). The subjectively evaluated pain intensity during the 2-h PACU stay was significantly lower for the MK patients compared with their MS counterparts (P ⬍ 0.001) despite the larger amounts of morphine administered to the latter group. There was an immediate (⬍10 min) significant decline in pain intensity in the MK patients, compared with only a slight attenuation in the VAS of the MS groups (P ⫽ 0.01). Additionally, there was evidence of a drug ⫻ time interaction (P ⬍ 0.001), indicating that the initial antinociceptive effect of MK continued over time (Fig. 1). The patients subjectively rated wakefulness and feelings of well-being (Fig. 2, top and bottom) and indicated that the administration of MK was associated with better scores (P ⬍ 0.001) than those with MS. Although the levels of the two variables in the MK group improved significantly within the first 10 min of treatment (P ⫽ 0.01), the MS patients’ scores deteriorated somewhat. Improvement in these two self-rated variables in the MK patients continued over time, indicating an overall (drug ⫻ time effect; P ⬍ 0.001) better and sustained effect of MK on each variable throughout the observation period compared with
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MS. MMSE scores at 30 min after the injections were much better in the MK than in the MS patients (Table 2), as they were at the end of the observation period (data not shown). Respiratory rates and Spo2 levels also appeared to be affected differently by the two drug protocols. Respiratory rates in the MK patients increased more than the MS patients’ during the initial 10-min period of drug administration (P ⬍ 0.05; drug effect); they then stabilized, indicating more efficient respiration in the MK group (P ⬍ 0.001, drug ⫻ time effect; Fig. 3). Fingertip oximetry on air was also maintained better in the MK than in the MS individuals (P ⬍ 0.001): it increased in the former within the first 15 min after drug administration and reached a maximal gain of 2.47%, whereas Spo2 levels in the MS patients decreased by 0.26% (P ⬍ 0.01; drug effect). Spo2 started to increase in the MS patients only 25 min after study onset but lagged behind the MK group’s oximetry values (P ⬍ 0.001; drug ⫻ time effect). Thirty minutes after the drug injections, the heart rate, blood pressure, and ETco2 in the MK patients were similar to the preoperative values; the MS patients required almost 60 min to reach such levels (data not shown). The MS group had significantly more side effects (P ⬍ 0.001) than the MK group (Table 2); all were short lived. Forty-two incidences (a rate of 38%) of postoperative nausea and/or vomiting (PONV) were recorded among the MS patients both in the PACU and on the ward, compared with 16 (12%) among the MK patients (P ⬍ 0.001). The rate of metoclopramide use was 5:1.1 (P ⬍ 0.01) in the MS and the MK patients, respectively. Nine MK patients versus no MS patients (P ⬍ 0.001) described a sensation of light-headedness, which lasted 1–2 min after a second injection of MK; it disappeared spontaneously. At no time did patients report hallucinations; one patient described an unpleasant dream immediately after the second dose of MK. None of these ketamine-attributable symptoms recurred in the 24-h follow-up period. None of the patients in either group was kept in the PACU for more than the protocol period, and all were discharged to the ward in accordance with PACU regulations. All of the study patients were discharged home uneventfully in accordance with departmental discharge policies.
Discussion This study demonstrated that IV administration of a combined small dose of MK promptly and satisfactorily resolved pain that had been unresponsive to IV morphine, whereas a threefold dose of MS only partially attenuated it. Pain intensity was still less in the
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Table 1. Patient Demographic and Surgical Data (mean ⫾ sd) Variable
MS (n ⫽ 114)
MK (n ⫽ 131)
P value
Age (yr) Weight (kg) Male/female Surgery type (GS/ORT/THX) Duration of surgery (min)
53 ⫾ 19 69 ⫾ 15 60/54 43/49/22 101 ⫾ 37
53 ⫾ 20 67 ⫾ 12 72/59 55/57/19 95 ⫾ 22
0.9 0.1 0.51 0.35 0.3
MS ⫽ morphine plus saline; MK ⫽ morphine plus ketamine; GS ⫽ general surgery; ORT ⫽ orthopedic procedures; THX ⫽ transthoracic lung biopsy or wedge resection.
Figure 1. Self-rated (by a 0 –10 visual analog scale [VAS]) pain intensity (mean ⫾ sd). *P ⬍ 0.001 between the groups (by analysis of variance).
Figure 2. Self-rated levels (by a 0 –10 visual analog scale [VAS]) of awakening (top) and feelings of well-being (bottom) (mean ⫾ sd). *P ⬍ 0.001 between the groups (by analysis of variance).
former group after two hours. A single dose of 250 g/kg of ketamine plus 15 g/kg of morphine provided antinociception in 89 of the 131 MK patients, compared with only 4 of the 114 MS patients who received morphine 30 g/kg with saline. Sixty-three MS patients needed the maximal three injections compared with only five in the former group; diclofenac was used threefold more by MS patients than MK patients during their stay in the PACU. Additionally,
Figure 3. Nurse-assessed respiratory rate (top) and fingertipderived arterial blood saturation on air (Spo2) (bottom) (mean ⫾ sd). *P ⬍ 0.001 between the groups (by analysis of variance).
whereas hemodynamic and respiratory variables remained depressed in the MS group for ⬎30 minutes, ketamine coadministration was associated with an immediate increase in Spo2, which remained higher than in the MS group throughout the observation period. These objective effects were associated with an increased self-rated level of wakefulness, better feelings of well-being and a better cognitive state, minimal incidence of PONV, and negligible ketamine-related side effects. If given alone, ketamine at small doses (ⱕ250 g/kg IV) might produce subanalgesia that would last a few minutes during the large plasma concentrations, immediately after injection. Whereas the plasma half-life of ketamine is ⬃15 minutes, the analgesic effect of our MK was clearly evident throughout the 120-minute observation period, i.e., more than seven plasma halflives and twice that which was reported earlier (5,17). The dose and drug combination used in this study allowed for an immediate and short-lasting reduction in pain and in morphine consumption. In a recent study by Guignard et al. (18), the desfluraneremifentanil anesthesia that was supplemented with small-dose ketamine led to a morphine-sparing effect persisting up to 24 hours, much longer than the pharmacological actions of ketamine alone. On the basis of
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Table 2. Immediate and Late Postoperative Analgesic Consumption and Incidence of Side Effects (Mean ⫾ sd or Absolute Numbers) Variable
MS (n ⫽ 114)
MK (n ⫽ 131)
P value
Pretreatment morphine use (mg) Totala morphine use (mg/kg) Number of injections Distribution of injections (1/2/3)b Pretreatment MMSE 30-min MMSE Diclofenac use in PACU Diclofenac use in ward Side effects in PACU PONV Light-headed sensation Bad dreams Hallucinations Side effects in ward PONV Light-headed sensation Bad dreams Hallucinations
7.8 ⫾ 2.1 1.21 2.52 ⫾ 0.56 4/47/63 16.6 ⫾ 1.2 19.3 ⫾ 2.4 17 70
7.52 ⫾ 2.7 0.42 1.35 ⫾ 0.56 89/37/5 16.3 ⫾ 1.9 27.1 ⫾ 1.7 5 76
0.07 ⬍0.001 ⬍0.001 ⬍0.001 0.1 ⬍0.001 0.002 0.2
30 0 0 0
9 9 1 0
⬍0.001 ⬍0.001 0.24
12 0 0 0
7 0 0 0
0.15
MS ⫽ morphine plus saline; MK ⫽ morphine plus ketamine; MMSE ⫽ Mini-Mental State Examination; PACU ⫽ postanesthesia care unit; PONV ⫽ postoperative nausea and vomiting. a The total amount of morphine administered before and during the study period. b The number of patients who received one, two, or three injections in each study group.
these and other data, it cannot be concluded that the extent to which adding small-dose ketamine to a general anesthetic or opioid regimen attenuates postoperative pain is based only on the duration of action of the selected analgesics, but rather on some yet-to-beevaluated long-lasting effects of ketamine. Ketamine may produce antinociception through various mechanisms of action: interaction with spinal receptors, NMDA receptor antagonism, and activation of the descending pain inhibitory monoaminergic pathways (19), which is expressed by ␣2-adrenoceptors at the spinal level (20). The affinity of ketamine for NMDA receptors is more than an order of magnitude higher than that for receptors (21) and is several-fold higher than that for the monoamine transporter sites or other non-NMDA receptors (i.e., the receptor) (22). This would suggest that small doses of the drug, as used herein or elsewhere (17), could interact more selectively with NMDA receptors rather than with the receptor and explains its effective antinociception. Indeed, antinociception generated by IV ketamine 300 g/kg in humans was not reversed by naloxone (21), which suggests that the -receptor agonistic activity was not involved in pain control. Nevertheless, although morphine and other opioids produce antinociception through -receptor agonist activity and the activation of monoaminergic descending pathways at the spinal level (20), they also activate NMDA receptors, resulting in hyperalgesia and the development of tolerance to opioids (1). Thus, if this was the type of tolerance or resistance involved in the sustained and severe postoperative pain in our patients, then it could theoretically be overcome by
small doses of MK either via central desensitization or via antagonization of NMDA activity. A MEDLINE search revealed that these findings of prompt abolition of pain resistance to morphine by one bolus injection of MK in ⬃65% of the treated patients had not been reported. The remarkable rapid and sustained effect of ketamine is more than additive when the total doses of morphine in both groups are compared (1:1⁄3), supporting the contention of an interaction of ketamine with NMDA receptors that could have been activated by either or both of the perioperative nociceptive inputs and by the administration of morphine. Previous studies of my group (2,13) showed that the concomitant use of morphine with dextromethorphan, a noncompetitive NMDA antagonist, generated an ⬃50% reduction of the consumption of postoperative morphine, further supporting such a mechanism of action. Ketamine infusion (100 –500 g/kg) (23) or a bolus injection of (S)-ketamine (50 –200 g/kg) (9,22) produced drowsiness. In this study, wakefulness was increased in the MK group. The former findings can be attributed to ketamine’s being administered by infusion, and its rapid decay of the plasma concentration after the bolus injection(s) did not evoke sedation (17). Finally, sedation had also been less in the dextromethorphan-treated morphine-administered patients compared with those who were given placebo plus morphine in my group’s previous studies (2,17). Heart rate and blood pressure are negatively affected by large morphine doses given within a short lapse of time, but, most importantly, respiratory rate,
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patency of the upper airway, oxygenation, and adequate ventilation may drastically worsen because of the increased sedation and the patient’s loss of lucidity. Such precarious situations were observed in several MS patients, in whom no vital signs were ameliorated even when pain was partly controlled, presumably because of the large morphine consumption. The concomitant administration of small-dose MK improved the Spo2 level, the clinically most reliable and rapid indicator (5–10 seconds) of adequate respiration. This could be because less pain would enable the patient to breathe more deeply, cough better, and maintain adequate minute ventilation with only negligible upper-airway obstruction compared with heavily sedated postoperative patients. Because MS did not control pain as did MK, saturation in the former remained lower as well. In addition, ketamine characteristically increases respiratory muscle tone (24), which could have also contributed to airway patency and better Spo2, even though a subanesthetic dose of ketamine was applied. All the abovementioned reasons could also have contributed to the maintenance of a normal respiratory rate in the MK group (25). The negligible incidence of PONV in the MK group appears to be related to the smaller dose of morphine consumed by the MK group. Although it is true that PONV is a multifactorial phenomenon, the threefold amount of morphine consumed in the MS group was probably a causative factor. Short-lived hallucinations are the most common side effects of ketamine: the one case of an unpleasant dream in the current cohort is much less than previously reported (16), possibly because of the smaller total dose of ketamine. White (26) had reported that more than one third of the patients may experience unpleasant dreams or acute psychosis-like symptoms that may or may not be associated with hallucinations on emergence when anesthetic doses (1–3 mg/kg) of ketamine are administered IV. Subanesthetic doses of ketamine impaired some cognitive function, such as attention, free recall, and recognition memory, in healthy human volunteers (9,11,23), and larger doses could alter mood states and produce dose-related impairment of sensory perception or the process of sensory integration (11,23). There were no changes in cognition, perception, or mood swings in any of our patients even 24 hours after ketamine administration. This may be because the dose used in this study was in between the ones used in the above-mentioned studies and because the plasma ketamine concentration could be expected to decline rapidly because of its short plasma half-life. In conclusion, the postoperative administration of concomitant small doses of MK provided rapid and sustained improvement in pain control; better than that obtained by morphine alone in patients who had
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received morphine earlier. There was minimal risk for ketamine-associated side effects, a better level of blood oxygen saturation, greater wakefulness, and negligible PONV incidence. Large-scale studies are still warranted to confirm these promising results. Esther Eshkol is thanked for editorial assistance and Dr. Nissim Marouani for intellectual input. The author also wishes to express his gratitude to the nursing staff of the PACU for their conscientious contribution, without which this work would not have been possible.
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