Anesth Analg 2004;98:1574-1580
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000113237.89875.5D
PAIN MEDICINE
The Synergistic Effect of Combined Treatment with Systemic Ketamine and Morphine on Experimentally Induced Windup-Like Pain in Humans
Helène Schulte, MD,
Alf Sollevi, MD, PhD, and
Märta Segerdahl, MD, PhD
Center for Surgical Sciences, Unit for Anaesthesia, Karolinska Institutet at Huddinge University Hospital, Huddinge, Sweden
Address correspondence and reprint requests to Helène Schulte, MD, Center for Surgical Sciences, Unit for Anesthesia, Karolinska Institutet at Huddinge University Hospital, S-141 86 Stockholm, Sweden. Address e-mail to helene.schulte{at}cfss.ki.se
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Abstract
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In this study, we evaluated whether combined treatment with ketamine (KET), an N-methyl-D-aspartate receptor antagonist, and morphine (MO) results in positive analgesic effects. Eleven volunteers were exposed to a skin burn injury on the leg. The effects of IV KET (9 µg · kg–1 · min–1; 45 min) and MO (10 µg · kg–1 · min–1; 10 min) alone and in combination, as well as placebo (saline; 10 min), were studied in a randomized, crossover, double-blinded design. The area of secondary hyperalgesia (SH) for mechanical stimulation was diminished by KET as compared with placebo. Mechanical pain thresholds were increased severalfold with KET and with KET plus MO, both in the primary hyperalgesic (PH; burn injury) and SH area. MO infusion showed no effect on the SH area or pain threshold. Windup-like pain was evaluated by continuous assessment on a visual analog scale during 30 s of repetitive stimulation (40-g load at 3 Hz) and analyzed as a sum of pain scores. The combined treatment (KET plus MO) almost abolished windup-like pain both in the PH and the SH areas, an effect that was not present with monotherapy with KET or MO. This study provides experimental support for a positive analgesic interaction between an N-methyl-D-aspartate receptor antagonist and an opioid on central summation of pain.
IMPLICATIONS: This is the first experimental study in humans to find synergistic analgesic effects with coadministration of the N-methyl-D-aspartate receptor antagonist ketamine and morphine on pain involving central sensitization phenomena.
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Introduction
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There is a substantial amount of evidence that N-methyl-D-aspartate (NMDA) receptors play an important role in the generation and maintenance of pain (1). On repeated afferent fiber stimulation, NMDA receptors are activated, resulting in depolarization of the dorsal horn neurons and facilitated transmission in pain pathways and central sensitization (2). Clinically, this is observed as cutaneous hypersensitivity in areas surrounding noxious stimuli, such as surgical trauma, secondary hyperalgesia (SH) (3), or windup-like pain, which describes a progressive increase in pain intensity on repeated stimulation (4).
NMDA receptors play a critical role in central nervous system plasticity, making them potential targets for pharmacological modulation. Ketamine (KET) is the most powerful NMDA receptor antagonist available for clinical use. Numerous studies have demonstrated that KET effectively reduces the magnitude of hyperalgesia and windup-like pain in human experimental models (5,6). Moreover, clinical studies have confirmed that KET suppresses postoperative pain (7) and postherpetic neuralgia (8). However, treatment with KET requires relatively large doses. This limits the clinical usefulness of the drug because of an unfavorable adverse effect profile (9).
Preclinical reports have shown not only that NMDA receptor antagonists inhibit central sensitization, but also that they prevent acute tolerance to opioids and opioid-induced hyperalgesia (10). Therefore, new strategies for pain treatment involve a combination of NMDA receptor antagonists and opioids to enhance the analgesic efficacy, extend the analgesic duration, and prevent tolerance (11). The efficacy of such treatment has been confirmed in several clinical studies on postoperative pain that have demonstrated positive analgesic interactions, often referred to as an opioid-sparing effect, between the two drug categories (12–14). Additionally, a reduced requirement for morphine (MO) in patients with terminal cancer pain has been shown when KET was coadministered (15). In contrast, other studies have not succeeded in proving increased pain relief with a MO and KET combination (16). Thus, combined treatment with NMDA receptor antagonists and opioids for clinical pain relief is controversial: the timing of the drug administration, the dose used, and the pain modality seem to be of great importance (17).
This study was undertaken because clinical studies investigating the role of the combination therapy have shown inconsistent findings, and there are few data regarding synergistic interactions with NMDA receptor antagonists and opioids on specific pain mechanisms in humans. Human experimental pain models are valuable tools for studying pharmacological modulation of nociception in greater detail, because the confounding factors often found in clinical studies are negligible. To more clearly define the effects of combining MO and KET, we examined whether such a combined therapy would give rise to positive analgesic effects on pain phenomena involving central sensitization when evaluated in a human experimental model of acute pain.
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Methods
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Eleven healthy volunteers (six men and five women; mean age, 36 yr; range, 22–50 yr) were included in the study after written, informed consent was obtained. The study was approved by the Huddinge University Hospital Ethics Committee and was performed in accordance with the Declaration of Helsinki. None of the subjects had a history of systemic disease or chronic pain or was taking any concomitant medication. After a run-in test in which the volunteers were familiarized with the experimental procedures, each subject participated in four test sessions separated by at least 1 wk. Procedures were double-blinded, and the same investigator performed all tests in a single individual.
Hyperalgesia was induced by a superficial skin burn injury to the medial side of the right calf, as previously described (18). For this purpose, a computerized system was used (Thermotest®; Somedic Sales AB, Sweden) to which a Peltier thermode (2.5 x 5 cm) was connected and firmly applied to the skin by a weight of 250 g. The temperature of the thermode started at 30°C and then increased quickly (15 s) to 46°C, where the temperature was maintained for 7 min and thereafter reset to 30°C (Fig. 1).
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Figure 1. Schematic presentation of the experimental setup: time course of the skin burn injury, drug infusions, and pain variables, including the area of secondary hyperalgesia (SH), pain threshold (PT), and sum of pain score (SPS) during repetitive stimulation. These were measured as indicated in the primary hyperalgesic area (PH) and in the SH area. The start of drug infusion is represented by time 0 (0 min). MO = morphine; KET = ketamine.
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The primary hyperalgesic (PH) area was defined as the application area of the Peltier thermode (skin burn). Around the skin burn, an area of SH developed. The size of this area was measured as previously described (18) by tapping the skin once every 2 s with a calibrated von Frey filament (45 g; SENSELab, Somedic Sales AB), a stimulus that did not evoke pain on uninjured skin. Tactile tests started well outside the burned area and approached it radially in steps of 
0.5 cm from eight encircling directions. The volunteers, who were not allowed to view the test area, reported when the stimulus became painful. These points were indicated on the skin with a felt-tipped pen. The borders were marked onto a transparent acetate film, and the resulting areas were measured planimetrically.
Tactile perception and pain thresholds (PT) were determined by using the method of limits with a series of calibrated von Frey filaments (0.03–152.2 g). The thresholds represent the average of the first stimulus of an ascending series of strength to touch/pain ("yes" values) and the first stimulus of a descending series not to be perceived/painful ("no" values), repeated three times in each direction. The mean ratings of "yes" and "no" values were calculated and considered thresholds for perception and pain, respectively. Thresholds were assessed bilaterally on the medial sides of the calves before the burn injury to exclude sensory disturbances (control, –45 min). In addition, PT was assessed before (baseline, –15 min) and 15, 45, and 75 min after the drugs were started (Fig. 1). This was done both in the PH and 1–2 cm outside the burned area.
Repetitive stimulation was performed with a novel computer-controlled testing device. A 0.5-mm-diameter von Frey filament connected to a handheld transducer was applied to the skin with a force corresponding to a 40-g load at 3 Hz for 30 s. The subjects were instructed to indicate continuing pain by using a computerized visual analog scale, graded 0–100, where 0 represents no pain and 100 represents maximum pain. Thus, the maximum sum of pain scores (SPS; visual analog scale x time) with this experimental setup was 3000 mm x s. Pain to repetitive stimulation was tested before (control, –45 min) and repeatedly after (–15, 15, 45, and 75 min) the skin burn injury (Fig. 1). Tests were performed in the PH area and 1–2 cm outside.
Drugs were administered IV via an antecubital vein. The double-blinded and randomized infusions started after the burn injury (0 min) and consisted of MO 10 µg · kg–1 · min–1 (Morfin®; Pharmacia Upjohn) or placebo (PLAC) (NaCl; normal saline) for 10 min and KET 9 µg · kg–1 · min–1 (Ketalar®; Parke-Davis) or PLAC for 45 min (Fig. 1). Doses of MO and KET were chosen from previous studies, in which these doses were effective without affecting cognitive functioning as assessed by reaction time (19). Blood samples for drug plasma concentrations were collected from the contralateral arm 15, 45, and 75 min after the start of infusions, centrifuged at 3500 rpm for 15 min, and frozen at –18°C for later analysis. The drug plasma concentrations were determined by high-performance liquid chromatography in an external laboratory. Subjects were repeatedly asked to report any adverse effects. When the test was completed, 0.1 mg of IV naloxone (Narcanti®; du Pont Pharma) was given to all subjects to reverse or prevent adverse effects (e.g., nausea) before they were discharged from the hospital.
The sample size was based on earlier power calculations in the burn injury model, in which a 30% SH area reduction could be detected with 80% power and 95% probability with 10 subjects (unpublished data, 2000). The normality of data of drug effects was evaluated by using the Shapiro-Wilks W test. SH areas and log-transformed PT values followed a Gaussian distribution, whereas SPS did not. Therefore, PT and SH areas are presented as mean ± SD, whereas SPS is given as median ± 25th and 75th percentiles. Before entering statistical analyses for between-drug effects, data from each subject were normalized in relation to baseline (data obtained before drug administration). Differences between each assessment and baseline were used. Changes in SH areas and PT over time, as well as differences between drug effects, were analyzed with a parametric analysis of variance and a planned comparison of least-square means as a post hoc test. A nonparametric Friedman’s analysis of variance and the associated multiple comparison tests for two-tailed values were chosen for statistical analyses of SPS. A 
2 test was used to compare the incidence of adverse effects between the different drug groups. A P value of <0.05 was considered to be statistically significant.
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Results
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Blood sample analysis showed that the plasma concentration of MO peaked shortly after the infusion was stopped (at 10 min). Plasma levels of KET were stable and above the previously reported threshold for experimental antinociceptive effects in humans (360 nM) (20). Drug infusions frequently induced minor subjective adverse effects (Table 1) but in no case caused termination of the experiment. Adverse effects were not considerably aggravated when KET and MO were combined, except for nausea/vomiting, which tended to be more frequent (P = 0.09).
Thermal injury resulted in a localized first-degree burn without any visible blisters or edema. No spontaneous pain was reported from the injured area after removal of the thermode. An area of SH surrounding the skin burn injury developed in all subjects. The SH area after the burn injury remained stable over time (P = 0.23; PLAC session) (Table 2). KET, but not MO or KET plus MO, treatment significantly reduced the SH area at 45 min as compared with PLAC (Fig. 2). At 75 min, the SH areas were not reduced by any of the drugs as compared with PLAC.
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Figure 2. Changes in the secondary hyperalgesic (SH) area during IV infusion of placebo (PLAC), morphine (MO), ketamine (KET), or the combination of KET and MO (KET+MO). Data are normalized to baseline values and given as mean ± SE (box) and mean ± SD (whisker). *Difference from PLAC (P < 0.05).
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Control values (before the burn injury, –45 min) for perception thresholds (data not shown) and PT (Table 2) were in the normal range (6,21). After the thermode was removed (baseline value, –15 min), the PT was significantly reduced in the PH and the SH area (P < 0.001). The PT in the PH area was further transiently reduced, whereas the PT in the SH area was stable over time (Table 2). KET increased PT severalfold in both the PH and SH areas as compared with PLAC, most prominently at 45 min (Fig. 3). A comparable response on PT at 45 min could be seen when KET was combined with MO. MO treatment did not change PT in either the PH or the SH area as compared with PLAC.
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Figure 3. Pain thresholds (PT) measured with graded von Frey filaments in (A) the primary hyperalgesic area (PH) and (B) the secondary hyperalgesic area (SH). Drug infusions consisted of placebo (PLAC), morphine (MO), ketamine (KET), and their combination (KET+MO). Graphs illustrate the difference of log-transformed PT versus baseline values, given as mean ± SE (box) and mean ± SD (whisker). Differences between PLAC and the various drug treatments are as follows: *P < 0.05; **P < 0.01; and ***P < 0.001.
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Repetitive stimulation (3 Hz; 40 g for 30 s) induced windup-like pain measured as SPS in the PH and the SH area (Table 2). There was no significant variability in SPS over time when PLAC was administered. Neither of the two single drug regimens (MO or KET) significantly affected windup-like pain, whereas the drug combination demonstrated clear synergistic effects. During repetitive stimulation in the PH area, reduced pain was seen 15 min after initiation of the combined treatment (KET plus MO) as compared with PLAC (Fig. 4A). In the SH area, only the combined treatment reduced pain ratings, but in contrast to the response in the PH area, this effect persisted during the entire experiment (75 min) (Fig. 4B).
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Figure 4. Pain ratings were assessed as the sum of pain score (SPS) on repetitive stimulation (40 g; 3 Hz; 30 s) in (A) the primary hyperalgesic area (PH) and (B) the secondary hyperalgesic (SH) area. Data are normalized to baseline values and given as median values ± 25th and 75th percentiles (box) ± minimum and maximum nonoutliers (whisker). Drug infusions consisted of placebo (PLAC), morphine (MO), ketamine (KET), and their combination (KET+MO): there was a difference (P < 0.05) between a)*KET+MO and MO and between b)*KET+MO and KET.
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Discussion
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The primary finding in this study was the clear synergistic analgesic effects of KET plus MO on central sensitization assessed as windup-like pain in the human experimental burn injury model. Other findings were a transient reduction in the SH area and PT with KET alone as a treatment.
Noxious heat is an extensively used model for studying cutaneous hyperalgesia. In this study, a skin burn injury, which represents a validated pain model for the investigation of drug effects in humans, was used for this purpose (5,6,21). The PT and the SH areas before drug treatment (control and baseline) were in the range of previously published data (6,21).
Earlier studies on the pharmacodynamic effects of analgesic drugs on tactile hyperphenomena in experimentally induced cutaneous pain have mainly focused on measuring the size of the SH areas. Hence, the more methodologically challenging assessments concerning the temporal aspects of central sensitization have been less investigated. In this study, both the spatial and temporal aspects of pain were assessed. The findings presented in this study are important because different mechanisms of pain may respond differently to various pharmacological treatments. Temporal summation was studied by repetitive stimulation of the skin at 3 Hz to induce windup-like pain mediated through the NMDA receptor system (2). This analysis was made possible by the development of a novel computer-controlled device, thereby increasing the sensitivity of the method. This equipment also provides precise and simultaneous pain rating analyses during a defined period of time. Therefore, we consider the current experimental setup reliable for the evaluation of tactile static and dynamic aspects of pain in the skin burn model.
Drug doses were chosen on the basis of previous studies describing the pain-reducing effects with both experimental and clinical pain in humans (16,22) and were further adjusted according to pilot experiments. Even though adverse effects were frequently observed during MO and KET infusions (but not during the PLAC sessions), this did not jeopardize the cooperation of the subjects, and there were no dropouts because of adverse effects in any of the experimental runs. The lack of adverse effect in the PLAC session may have resulted in incomplete blinding, but because KET, MO, and KET plus MO showed differential effects on the pain variables, this did not seem to bias the results systematically.
This study clearly demonstrates that systemically administered KET reduces the SH area after a local thermal skin injury. KET treatment also increased the PT as measured in the PH and SH area. The pain-reducing effects of KET as a sole analgesic are in agreement with earlier published reports that applied similar techniques (5,6). In contrast, treatment with IV MO had no effect on the SH area or on PT. These data are also in accordance with earlier published data with slightly larger doses of MO (0.15 mg/kg) on experimental burn-induced hyperalgesia in humans (6). With respect to the SH area and to PT, there was no indication of an enhanced analgesic effect when MO was administered together with KET. In contrast, pain on repetitive stimulation (windup-like pain) was almost abolished during the combined drug treatment, whereas KET and MO in monotherapy had no analgesic effects at the present doses. In the PH area, this effect was significant only 15 minutes after the infusions were initiated, whereas in the SH area, the effect persisted throughout the experimental session (75 minutes), i.e., even after the cessation of the effect duration of KET. However, similar drug response patterns were seen in both the PH and SH areas, as illustrated in Figure 4. Analysis of the variability of the current data indicates that a few more subjects would probably have also generated significant effects during the entire experimental session in the PH area.
It is evident from these results that the advantage of combining NMDA receptor antagonists and opioids is pain modality specific. Thus, the reason why the synergistic effects of KET plus MO were detected only on windup-like pain may be that PT and SH do not evoke central summation of pain in the dorsal horn neurons to the same degree as with pain from repetitive stimulation.
This is the first study to show synergistic effects with KET plus MO in a human experimental pain model reflecting central sensitization. One earlier human experimental study by Sethna et al. (23) showed additive effects on pinprick hyperalgesia when KET was combined with the µ-opioid agonist alfentanil. Another recent report has demonstrated that KET increases the analgesic effect of the ultra-short-acting opioid remifentanil on intramuscular but not on cutaneous experimental pain (24).
Our study does not permit assumptions regarding the underlying mechanisms of the demonstrated drug synergy, because different doses of MO and KET were not administered in a crossover manner. However, one possible explanation for the reduction of windup-like pain is KET-induced prevention of acute tolerance to MO (10). The intracellular mechanisms that mediate the interaction between KET and MO are probably diverse, but activation of protein kinase C via opioid receptors has been shown to be of great importance in facilitating NMDA receptor function (25). It has also been suggested that KET can function partly as an opioid agonist (26). However, additional work is necessary to determine the exact underlying mechanisms for this drug interaction.
In conclusion, because different mechanisms account for various pain symptoms in the clinic, it is important to evaluate the analgesic potential of drugs in a multimodal experimental pain setup. This study provides experimental support for positive analgesic interactions between NMDA receptor antagonists and opioids in clinically moderate doses for reducing windup-like pain. Clinical trials often focus more on opioid consumption or the surface area of punctate mechanical hyperalgesia as an outcome variable. We suggest that a quantitative suprathreshold assessment, e.g., a standardized measure such as repetitive stimulation, to evaluate the modulation of central sensitization could be used as a more specific outcome variable.
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Acknowledgments
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This study was supported by Karolinska Institutet, the Swedish Medical Research Council (Project 7485), and AstraZeneca.
The authors thank Ylva Jansson, CRNCC, Huddinge University Hospital, for her excellent technical assistance throughout the study.
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Accepted for publication December 1, 2003.
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Abstract
Introduction
