The idea of combining an N-methyl-d-aspartate (NMDA) receptor antagonist, inhibiting pain-induced central hypersensitivity, with an opioid (1) has stirred considerable interest in analgesia research. Ketamine as a clinically available NMDA receptor antagonist has been especially attractive in this regard. The authors of a recent review summarizing studies on combined ketamine-opioid administration in postoperative pain concluded that results on the ability of ketamine to improve opioid analgesia are rather contradictory (2). Sethna et al. (3) demonstrated only simple additivity in the effects of ketamine and alfentanil on experimental pain in volunteers. The analgesic effect of ketamine in postoperative pain was observed when the drug was used in a dose range from 0.3 to 0.5 mg/kg, and the effect lasted only for 40 to 60 min (4–6).
Some of the clinical studies (7–9) revealed that ketamine administered during surgery reduced postoperative opioid consumption. These authors used small doses of ketamine (75–150 μg/kg) that could not provide analgesic concentrations in the biophase during the postoperative period. The reduction of opioid consumption was explained by the effect of ketamine on pain-induced central sensitization (7–9). An alternative explanation could be based on the ability of NMDA receptor antagonists to inhibit acute tolerance to the analgesic effect of opioids. We have reported previously (10) that the NMDA receptor antagonist dizocilpine attenuates the development of acute tolerance to analgesia induced in rats by IV infusion of alfentanil. This outcome is similar, although not identical, to the results reported in studies on chronic tolerance in which NMDA receptor antagonists (11–13) or NMDA receptor defect (14) blocked tolerance to the analgesic effect of morphine. Suppression of acute tolerance to alfentanil by dizocilpine, which does not have an analgesic effect by itself, indicates that the direct analgesic effect of ketamine and its effect on opioid-induced analgesia are not necessarily related: the opioid-induced analgesia could be enhanced by the effect of ketamine on opioid acute tolerance that reveals itself in relatively small subanalgesic doses.
Our principal purpose was to test the hypothesis that acute tolerance induced by alfentanil infusion can be attenuated by ketamine in a dose that is not large enough to provide a direct antinociceptive effect. With this aim, it will be possible to substantiate an approach to the treatment of postoperative pain that was actually used in a few clinical studies with ketamine, but the mechanism of ketamine-induced potentiation of opioid analgesia was not identified correctly. The potential of NMDA receptor antagonists to reduce acute tolerance to opioids may be a basis for a novel and important contribution to the relief of postoperative pain. An additional purpose of our study was to examine the effect of ketamine on another opioid-induced adaptive response-delayed hyperalgesia that follows the alfentanil infusion.
Experiments were performed on male Sprague-Dawley rats weighing 320–370 g. The animals were housed with a 12-h light-dark cycle, and food and water were available ad libitum. The protocol for this study was approved by the Institutional Panel on Laboratory Animal Care.
A catheter for the drug infusion was chronically implanted into the jugular vein, and its free end was exteriorized through the skin at the back of the neck. The surgical procedure for implantation was performed under pentobarbital (55 mg/kg intraperitoneally [IP]) anesthesia several days before the experiment. Alfentanil was infused with a Harvard Apparatus pump (model 55–2222; Harvard Apparatus Co., Natick, MA). Alfentanil infusion algorithm was based on the constants of one compartment model for rats derived from our previous study (15).
The responses to mechanical noxious stimulation were determined by measuring the threshold of motor response to increasing pressure applied to the tail—tail compression test (16) with the use of an Analgesy-Meter® (Ugo Basile, Milan, Italy). The rat’s tail was positioned on a Teflon platform, and the pressure plate (0.7-mm edge) attached to this device was applied to the tail while the rat was held in the experimenter’s hand. Pressure was increased at a constant rate (cutoff pressure of 2.375 kg) until coordinated struggle occurred. Three consecutive measurements were recorded, and the mean of the last two measurements was taken as the pressure threshold. For each consecutive determination of the pain threshold, the pressure plate was moved 2-mm cephalad. Measurements were made by an experimenter who was unaware of expected changes in the reaction thresholds among the treatment groups.
Animals were randomly divided into four groups: Alfentanil-Ketamine, Alfentanil-Dizocilpine, Alfentanil-Saline (bolus), and Saline (infusion)-Ketamine, each consisting of eight rats. In all groups, alfentanil was administered as described previously (15,17): a bolus dose of 50 μg/kg followed by an infusion rate of 155 μg · kg−1· h−1 for 4 h. This pattern was chosen to rapidly achieve and maintain a stable alfentanil plasma concentration. The degree of acute tolerance was determined on the basis of decline in the level of pressure threshold during the infusion period. After the alfentanil administration, the pressure threshold was measured twice: 1.5 h and 23 h after the infusion. The last measurement was made to determine the rebound hyperalgesia after the alfentanil infusion. According to preliminary experiments, the measurements made the next day revealed the maximal rebound hyperalgesia that disappeared in a few days after the infusion.
The interacting drugs were administered IV with the first injection given 60 min before the beginning of alfentanil infusion. The following doses were used: ketamine 10 mg/kg (Alfentanil Infusion-Ketamine Bolus Group); dizocilpine 0.1 mg/kg (Alfentanil Infusion-Dizocilpine Bolus Group); isotonic saline (Alfentanil Infusion-Saline Bolus Group); and ketamine 10 mg/kg (Saline Infusion-Ketamine Bolus Group).
The selection of the dose of ketamine was based on the preliminary experiments in which it was verified that 10 mg/kg was not providing an analgesic effect immediately after the drug injection. To further reduce the probability of some direct analgesic influence by ketamine, the interval between the injection of ketamine and the start of alfentanil administration was extended to 1 h. In the rat, ketamine 60 mg/kg IM provides incomplete analgesia, and only at doses of 100 to 120 mg/kg IP can it provide a complete anesthetic effect (18). A more specific NMDA receptor antagonist, dizocilpine, was used in a dose of 0.1 mg/kg.
In the above doses, neither ketamine nor dizocilpine produced behavioral effects interfering with the pressure threshold measurements. The interacting drugs were also administered 5 min after the last measurement of the pressure threshold on the day of alfentanil infusion (second administration) and on the next day, 19 h after the end of alfentanil infusion (third administration), both in the same dose as the first injection (see schedule for drug administration in Table 1).
The pressure threshold in each of the groups was determined before, and 5 min after, the administration of an interacting drug, at 30, 60, 120, 180, and 240 min after the beginning of alfentanil infusion, and at 1.5 and 23 h after the end of alfentanil infusion. Racemic ketamine hydrochloride was from Parke-Davis (Morris Plains, NJ), dizocilpine maleate (MK-801) was from Sigma Chemical Co. (St. Louis, MO), and alfentanil hydrochloride was from Taylor Pharmaceuticals (Decatur, IL).
The pressure threshold was treated as a continuous variable and was analyzed using a two-way (groups and time) analysis of variance with time treated as a repeated measures factor. Comparisons among groups at each time were performed with the use of an one-way analysis of variance. Multiple comparisons among pairs of means were made by using the Fisher’s protected least significant difference method (19). Differences were declared statistically significant if P < 0.05.
Table 1 shows a summary of the data obtained in all four groups of experiments. The comparison of the pressure threshold before, and 5 min after, ketamine administration (10 mg/kg) indicates that ketamine had no significant analgesic effect. Because alfentanil administration was started 60 min after the ketamine injection, the presence of any direct analgesic effect of ketamine at that time would be even less likely. Dizocilpine also did not produce any changes in the pressure threshold measured 5 min after its injection.
The effect of ketamine on acute tolerance to alfentanil is illustrated by Figure 1, which shows a comparison of the alfentanil-induced changes in the pressure threshold. It demonstrates (A segment) that, in the Alfentanil-Saline Group, the pressure threshold before the end of alfentanil infusion was only insignificantly more than that before the start of infusion (808 ± 78 g vs 733 ± 66 g, not significant). At the same time, in the Alfentanil-Ketamine Group, the pressure threshold at the end of alfentanil infusion was much higher than that before the start of infusion (1078 ± 191 g vs 763 ± 64 g, P < 0.001); and it was higher than in the Alfentanil-Saline Group at the same time interval (1078 ± 191 g vs 808 ± 78 g, P < 0.05). The changes in the Alfentanil-Dizocilpine Group were similar to those in the Alfentanil-Ketamine Group. The Saline-Ketamine Group demonstrated a constant pressure threshold level for the whole study period.
The effects of ketamine and dizocilpine for reduction of the initial analgesic response at various time intervals during alfentanil infusion are presented in Figure 1B. Both drugs significantly (P <0.05) attenuated tolerance development at all time intervals as presented by cumulative reduction of the initial analgesic effect (explanation in the legend to Figure 1B). The effect of dizocilpine had a tendency to be more pronounced than that of ketamine, although this tendency did not reach statistical significance.
In addition to the attenuation of acute tolerance to alfentanil, ketamine inhibited the alfentanil-induced rebound hyperalgesia. After the 4-h alfentanil infusion, there was a decrease in the pressure threshold that reached its maximum the day after infusion and then gradually returned to the baseline level, usually 1–2 days later. Table 1 indicates that in the Alfentanil-Saline Group, 23 h after the end of alfentanil infusion, the pressure threshold was decreased 27% from baseline level (532 ± 65 g vs 733 ± 66 g, P < 0.001). In the Alfentanil-Ketamine Group, animals received three injections of ketamine 10 mg/kg (60 min before the start of alfentanil infusion, and 5 min and 19 h after its end). This treatment resulted in a decrease of the pressure threshold decline 23 h after the end of alfentanil infusion (539 ± 65 g in Alfentanil-Saline Group vs 692 ± 54 g in the Alfentanil-Ketamine Group, P < 0.001). Figure 2 shows a comparison of the degree of the rebound hyperalgesia with and without the NMDA receptor antagonist’s administration. Both ketamine and dizocilpine suppressed it, with dizocilpine completely suppressing it; however, statistical significance (P = 0.058) of the difference between the Dizocilpine and Ketamine Groups did not reach the accepted level of P value.
Both alfentanil-induced adaptive changes assessed in the present study—acute tolerance and rebound hyperalgesia—were attenuated by ketamine. The development of acute tolerance to the antinociceptive effect of alfentanil was decreased by ketamine at all time-intervals of the four-hour alfentanil infusion. The ability of ketamine to attenuate chronic tolerance to morphine was reported with systematic and intrathecal drug administration in rodents (20–22).
In our experiments, ketamine 10 mg/kg was administered IV one hour before the beginning of alfentanil infusion. The baseline pressure threshold measured five minutes after ketamine was not changed (Table 1), and the peak of the alfentanil-induced antinociceptive effect with ketamine pretreatment was the same as that with the saline pretreatment (Table 1 and Figure 1A). These results indicate that the dose of ketamine we used was not large enough to provide a direct antinociceptive effect, even in combination with alfentanil. Similar results with systemic ketamine 10 mg/kg were reported in mice: ketamine did not change the response to mechanical or thermal nociceptive stimuli (23). Also, when ketamine 10 mg/kg was administered with morphine in rats, the morphine dose-response curve was not changed to any significant degree (21). With phasic pain, ketamine provides analgesia only in very large doses (24). That agrees well with the fact that, in rats, only at doses 100 to 120 mg/kg IP does it block motor nociceptive responses in minor surgical procedures (18).
The pattern of ketamine biodisposition is characterized by a very rapid redistribution from the brain to other tissue (25). In the rat, 60 minutes after an IV ketamine injection, its brain level declined 20-fold compared with the level measured immediately after the injection (26). This indicates that when attenuation of acute tolerance to alfentanil occurred (two to five hours after ketamine bolus injection), in our experiments, the ketamine biophase concentration was at least 20-fold smaller than that immediately after the injection. Thus, despite the fact that the ketamine concentration was too small to produce a direct antinociceptive effect, it effectively attenuated the development of acute tolerance to alfentanil.
Bilsky et al. (12) reported that NMDA receptor antagonists blocked chronic antinociceptive tolerance to morphine, but not however, to selective μ or δ agonists, including fentanyl. They concluded that the effect of NMDA receptor antagonists on opioid tolerance is not a general phenomenon related at all opioids. Alfentanil, used in our study, belongs to the same group of opioids as fentanyl. The difference in the results is probably related to the difference in the model of tolerance (chronic versus acute).
Rebound hyperalgesia that was present the day after the alfentanil infusion was also attenuated by ketamine. This confirms similar observations with delayed hyperalgesia induced by multiple bolus injections of fentanyl (27). The rebound hyperalgesia observed during opioid abstinence could result from reduction of a tonic inhibitory modulation that was present before opioid administration; however, the activation of modulatory neurons that facilitate nociceptive transmission could also be involved (28).
Ketamine is a nonspecific noncompetitive NMDA receptor antagonist; however, its effects on acute tolerance to alfentanil and on delayed hyperalgesia were almost the same as those of dizocilpine, a specific noncompetitive NMDA receptor antagonist. The effects of dizocilpine were only insignificantly more pronounced than those of ketamine.
The activation of NMDA receptors in the central nervous system is seen as a mechanism involved in the adaptive changes underlying both tolerance to opioids and delayed hyperalgesia. It was suggested that activation of opioid receptors leads to protein kinase C-mediated activation of NMDA receptors (29,30). The attenuation of acute tolerance and rebound hyperalgesia by the NMDA receptor antagonists is in agreement with this suggestion.
Could our results be relevant to the clinical experience with acute opioid exposure in surgery? The tolerance to analgesia during remifentanil infusion in humans is profound and develops very rapidly (31). Chia et al. (32) reported that the preoperative and intraoperative use of fentanyl in large doses (15 μg/kg plus 100 μg/h for 2–3 h) resulted in an increased postoperative fentanyl consumption via patient-controlled analgesia (up to 50%) and increased pain severity compared with preoperative administration of a small dose of fentanyl (1 μg/kg). It was also found that patients who received more morphine during the initial postoperative period had increased opioid requirements for pain relief after the initial period (33). In a recent editorial, Eisenach (34) concluded that we may be contributing to postoperative pain by the use of large doses of opioids intraoperatively. Thus, attenuation of the development of acute tolerance to opioids could be a clinically important approach for the treatment of postoperative pain, and the possible role of ketamine in this regard deserves specific attention.
The value of ketamine in the treatment of postoperative pain is a very controversial issue (2,25). To provide a direct analgesic effect, ketamine should be used in relatively large doses, which is associated with significant adverse effects. However, several authors (7–9) reported that ketamine administered during surgery in small doses (75–150 μg/kg) reduced postoperative opioid consumption. We hypothesize that this effect is the result of attenuation of acute tolerance to opioids. Figure 3 illustrates this suggestion by presenting three antinociceptive effects of ketamine that require different concentrations of the drug. Attenuation of tolerance to the analgesic effect of opioids occurs at the smallest concentration. Therefore, ketamine in subanesthetic (effect on phasic pain) or subanalgesic (effect on tonic pain) doses can still reduce opioid consumption.
There is a separate pharmacologic property of ketamine that is related to the treatment of postoperative pain. NMDA receptor antagonists, including ketamine, can prevent the induction of injury-induced central sensitization and abolish hypersensitivity to pain once it is established (35). This property is a basis for the use of ketamine for preemptive analgesia (2). In a study on surgical patients, we could not demonstrate the preemptive effect of ketamine (used in a large dose of 2 mg/kg bolus + 20 μg · kg−1 · min−1 infusion during surgery) on spontaneous or movement-induced pain; however, its effect on hyperalgesia to pressure on the wound was observed even 48 hours after the surgery (36). The effect of ketamine on pain-induced central sensitization could be a factor in the decrease of postoperative pain, and consequently, in the reduction of opioid requirements (7–9). This study suggests that the ketamine-induced attenuation of acute tolerance to opioids might also be a potentially beneficial mechanism in the treatment of postoperative pain resulting in reduction of opioid requirements. It is interesting that mechanisms underlying injury-induced central sensitization and opioid-induced tolerance have close relationships. Mao et al. (30) suggested that these two seemingly unrelated phenomena may have common neural substrates that interact at the level of excitatory amino acid receptor activation and related intracellular events.
In conclusion, ketamine attenuated the development of acute tolerance to analgesia during alfentanil infusion and suppressed rebound hyperalgesia observed the day after the infusion.
1. Chapman V, Dickenson AH. The combination of NMDA antagonism and morphine produces profound antinociception in the rat dorsal horn. Brain Res 1992; 573: 321–3.
2. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain 1999; 82: 111–25.
3. Sethna NF, Liu M, Gracely R, et al. Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects. Anesth Analg 1998; 86: 1250–6.
4. Sadove MS, Shulman M, Hatano S, Fevold N. Analgesic effects of ketamine administered in subdissociative doses. Anesth Analg 1971; 50: 452–7.
5. Austin TR. Ketamine hydrochloride: a potent analgesic. Br Med J 1976; 2: 943.
6. Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain 1989; 36: 37–41.
7. Roytblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effect of low-dose ketamine in addition to general anesthesia. Anesth Analg 1993; 77: 1161–5.
8. Suzuki M, Tsueda K, Lansing P, et al. Small-dose ketamine enhances morphine-induced analgesia after outpatient surgery. Anesth Analg 1999; 89: 98–103.
9. Menigaux C, Fletcher D, Dupont X, et al. The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair. Anesth Analg 2000; 90: 129–35.
10. Kissin I, Bright CA, Bradley EL Jr. Acute tolerance to the analgesic effect of alfentanil: role of CCK and NMDA-NO systems. Anesth Analg 2000; 91: 110–6.
11. Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251: 85–7.
12. Bilsky EJ, Inturrisi CE, Sadée W, et al. Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective μ or δ opioid agonists in mice. Pain 1995; 68: 229–37.
13. Dunbar S, Yaksh TL. Concurrent spinal infusion of MK801 blocks spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Anesthesiology 1996; 84: 1177–88.
14. Kolesnikov Y, Jain S, Wilson R, Pasternak GW. Lack of morphine and enkephalin tolerance in 129/SvEv mice: evidence for a NMDA receptor defect. J Pharmacol Exp Ther 1998; 284: 455–9.
15. Kissin I, Lee SS, Arthur GR, Bradley EL Jr. Time course characteristics of acute tolerance development to continuously infused alfentanil in rats. Anesth Analg 1996; 83: 600–5.
16. Green AF, Young PA. A comparison of heat and pressure analgesimetric methods in rats. Br J Pharmacol 1951; 6: 572–85.
17. Kissin I, Lee SS, Arthur GR, Bradley EL. Effect of midazolam on development of acute tolerance to alfentanil: the role of pharmacokinetic interactions. Anesth Analg 1997; 85: 182–7.
18. Green CJ. Animal anaesthesia. London: Laboratory Animals Ltd, 1982.
19. Carmer SG, Swanson MR. An evaluation of ten pairwise multiple comparison procedure by Monte Carlo methods. J Am Stat Assoc 1973; 68: 66–74.
20. Trujillo KA, Akil H. Inhibition of opiate tolerance by non-competitive N
-methyl- d -aspartate receptor antagonists. Br Res 1994; 633: 178–88.
21. Shimoyama N, Shimoyama M, Inturrisi C, et al. Ketamine attenuates and reverses morphine tolerance in rodents. Anesthesiology 1996; 85: 1357–66.
22. Miyamoto H, Saito Y, Kirihara Y, et al. Spinal coadministration of ketamine reduces the development of tolerance to visceral as well as somatic antinociception during spinal morphine infusion. Anesth Analg 2000; 90: 136–41.
23. McLeod AL, Ritchie J, Cuello AC. Transgenic mice over-expressing substance P
exhibit allodynia and hyperalgesia which are reversed by substance P
-methyl- d -aspartate receptor antagonists. Neuroscience 1999; 89: 891–9.
24. Lakin ML, Winters WD. Behavioral correlates of naloxone inhibition of analgesia induced by various CNS excitatory drugs in the rat. Proc West Pharmacol Soc 1978; 21: 27–30.
25. White PF, Way WL, Trevor AJ. Ketamine: its pharmacology and therapeutic uses. Anesthesiology 1982; 56: 119–36.
26. White PF, Marietta MP, Pudwill CR, et al. Effects of halothane anesthesia on the biodisposition of ketamine in rats. J Pharmacol Exp Ther 1976; 196: 545–55.
27. Célèrier E, Rivat C, Jun Y, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology 2000; 92: 465–72.
28. Kaplan H, Fields HL. Hyperalgesia during acute opioid abstinence: evidence for a nociceptive facilitating function of the rostral ventromedial medulla. J Neurosci 1991; 11: 1433–9.
29. Chen L, Huang LYM. Protein kinase C reduces Mg2+
block of NMDA-receptor channels as a mechanism of modulation. Nature 1992; 356: 521–3.
30. Mao JR, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 1995; 62: 259–74.
31. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11.
32. Chia YY, Liu K, Wang JJ, et al. Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999; 46: 872–7.
33. Marshall H, Porteus C, McMillan I, et al. Relief of pain by infusion of morphine after operation: does tolerance develop? Br Med J 1985; 291: 19–21.
34. Eisenach JC. Preemptive hyperalgesia, not analgesia? Anesthesiology 2000; 92: 308–9.
35. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N
-methyl- d -aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293–9.
36. Tverskoy M, Oz Y, Isakson A, et al. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994; 78: 205–9.