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Anesth Analg 2001;92:1296-1300
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA AND PAIN MEDICINE

Can Inflammatory Pain Prevent the Development of Acute Tolerance to Alfentanil?

Igor Kissin, MD, PhD*, Cheryl A. Bright, BS*, and Edwin L. Bradley, Jr., PhD{dagger}

*Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and {dagger}Department of Biostatistics, University of Alabama, Birmingham, Alabama

Address correspondence to Dr. Igor Kissin, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Address e-mail to kissin{at}zeus.bwh.harvard.edu


   Abstract
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Constant pain could, in principle, counteract mobilization of antianalgesia systems and prevent the development of acute tolerance to the analgesic effects of opioids. We sought to determine whether a tonic nociceptive input caused by inflammation inhibits the development of acute tolerance to alfentanil. The inflammation was induced by injection of carrageenan into the rat hind paw. A threshold of motor response to increasing pressure on the paw was used to determine analgesia. Alfentanil was administered IV with an infusion algorithm designed to maintain a constant plasma level of opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia. The continuous decline of the analgesic effect from its peak at 30 min to the end of the 4-h infusion period was profound, despite the constant-rate infusion of alfentanil. The degrees of decline were very similar in rats with and without carrageenan-induced inflammation (from 242 ± 31 to 154 ± 20 g, P < 0.0001; and from 242 ± 33 to 148 ± 14 g, P < 0.0001, respectively). The results suggest that inflammatory nociceptive input does not prevent the development of acute tolerance to opioid-induced analgesia measured as an increased reaction threshold to painful pressure. We conclude that acute tolerance to the analgesic effect of opioids is profound and develops very rapidly, even in the presence of constant nociceptive input.

Implications: We examined whether inflammatory pain can prevent the rapid decline in analgesic effectiveness (acute tolerance) of alfentanil during its IV infusion. We found that acute tolerance to the analgesic effect of alfentanil, in the presence of constant pain caused by inflammation, develops as rapidly as without it.


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Rapid development of tolerance to the analgesic effect of opioids observed in experimental animals with noxious stimulation lasting up to 20 s (1,2) carries over into humans: tolerance to analgesia during remifentanil infusion measured in volunteers with mechanical (painful pressure) and thermal (iced water) stimulation is profound and develops within several hours (3). However, the development of acute tolerance to opioids in long-lasting tonic pain may be different. Constant pain could, in principle, counteract mobilization of antianalgesia systems participating in the development of acute tolerance. The authors of several studies on the effect of pain on chronic opioid tolerance in rats have reported that nociceptive stimulation prevents the development of tolerance to analgesia (4–6). However, this conclusion on the role of pain in the development of chronic opioid tolerance could not be confirmed by others (7,8). A multiplicity of mechanisms participating, to various degrees, in different types of opioid tolerance (9) suggest that acute tolerance to opioids could be mechanistically different from chronic tolerance. There are no studies on the role of sustained pain in the development of acute opioid tolerance.

The literature on the analgesic effects of opioids in pain is also very contradictory. Several studies have demonstrated that pain-induced hyperalgesia, including inflammatory hyperalgesia, once established, leads to a decrease in the analgesic effect of morphine (10). Morphine analgesia in rats with inflammation induced by Freund’s adjuvant was found to be decreased (8). On the contrary, in several studies with inflammation induced by Freund’s adjuvant or carrageenan, the analgesic effect of morphine was reported as increased (7,11).

The aim of this study was to determine whether a tonic nociceptive input caused by inflammation inhibits the development of acute tolerance to alfentanil. A secondary purpose of the study was to determine whether tonic nociceptive input changes the analgesic effectiveness of alfentanil (initial analgesic effect that takes place before tolerance development).


   Methods
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Experiments were performed on male Sprague-Dawley rats weighing 275 to 325 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.

The responses to mechanical noxious stimulation were determined by measuring the threshold of motor response (coordinated struggle) to increasing pressure with the use of an Analgesy-Meter (Ugo Basile, Milan, Italy). The threshold was measured by positioning the hind paws on a Teflon platform and directing the device’s 2-mm pressure cone on its dorsal surface. The cutoff pressure was 50% above baseline.

Inflammation was induced by injection of 0.1 mL of 2% carrageenan (Sigma Chemical, St. Louis, MO) subcutaneously (30-gauge needle) in the plantar surface of the hind paw under halothane (2%) anesthesia. This is a commonly accepted method for the assay of antiinflammatory drugs (12). Hyperalgesia was determined by measuring changes in the threshold of motor response. We used a model of inflammation induced by two carrageenan injections administered in the same paw 7 days apart (13). The second injection of carrageenan was exactly the same as the first one. This model of reinjection of carrageenan provided a more prolonged period of nociceptive input before the administration of alfentanil.

Alfentanil was administered via a catheter chronically implanted into the jugular vein. The surgical procedure for implantation was performed under 60 mg/kg intraperitoneal ketamine and 12 mg/kg intraperitoneal xylazine anesthesia several days before alfentanil administration. Alfentanil was administered with the following pattern: 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. It is based on the constants of one compartment model for rats derived from our previous study (14). Alfentanil was infused with a Harvard Apparatus pump (Model 55-2222; Harvard Apparatus Co., Natick, MA).

To determine the development of acute tolerance to alfentanil, the pressure threshold for motor response was measured before and 30, 60, 120, 180, and 240 min after the beginning of alfentanil infusion. The degree of acute tolerance was determined on the basis of decline in the level of analgesia during the infusion period. We demonstrated previously (2) that, in this experimental model of tolerance, the extent of the threshold decline is independent of the number of repeatedly made measurements.

The study consisted of four groups of eight rats each. In the first group, carrageenan was injected twice into the same hind paw 7 days apart; the alfentanil administration was started 2 h after the second injection of carrageenan and continued for 4 h. In the second group, 2 h after the second carrageenan injection, a 4-h 0.9% saline infusion was provided instead of alfentanil. In the third group, alfentanil was administered as in the first and second group but without carrageenan pretreatment. The fourth group received only a 4-h 0.9% saline infusion. Immediately after the last threshold measurement, the animals were killed by the inhalation of 5% halothane.

Pressure threshold for motor response was treated as a continuous variable and was analyzed by using a two-way (groups and time) analysis of variance, with time treated as a repeated-measures factor. Comparisons between groups at each time were performed with the use of a one-way analysis of variance. Multiple comparisons among pairs of means were made with the Fisher’s protected least significant difference method. Differences were declared statistically significant if P < 0.05.


   Results
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Figure 1 summarizes the results obtained in all four groups of experiments. In the Carrageenan-Only group, the pressure threshold for motor response was gradually declining during 6 h of observation presented in the figure: 2 h later it went from 177 ± 16 to 142 ± 23 g, and 6 h later it went to 106 ± 18 g (P < 0.0001 for both). This indicates that carrageenan produced a profound inflammatory hyperalgesia.



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  		Figure 1. Effect of carrageenan-induced nociceptive input on alfentanil analgesia. Carrageenan (2% 0.1 mL) was injected in the plantar surface of the hind paw. Alfentanil was administered IV as a bolus of 50 µg/kg followed by a constant-rate infusion at 155 µg · kg-1 · h-1 for 4 h. Four groups of eight rats each are represented with the following abbreviations: CA = carrageenan-alfentanil with carrageenan injection at -120 min; CS = carrageenan-saline with carrageenan injection at -120 min; A = alfentanil only; S = saline only. Each dot reflects a mean ± SD for a group at various time intervals. Within-group differences: +P < 0.0001 vs value at -130 min in the group; # P < 0.05, {dagger}P < 0.0001, both versus the value at -10 min in the group; *P < 0.0001 vs value at 30 min in each of the groups. Between-group differences are in the text. Figure Insert: Columns along the horizontal axis reflect pressure thresholds 10 min before (-10) and 30 min after (30) the beginning of alfentanil administration in the A and CA groups. Numbers above arrows indicate the degree (%) of pressure threshold increases. *P < 0.02 vs percentage in the Alfentanil-Only group.

 
In the Carrageenan-Alfentanil group, pressure threshold measured 10 min before alfentanil administration was 141 ± 18 vs 164 ± 20 g in the Alfentanil-Only group (P < 0.05 for the difference). Pressure threshold 30 min after the beginning of alfentanil administration increased to the same level in both groups—242 ± 31 and 243 ± 33 g, respectively. Before the end of the 4-h alfentanil infusion, pressure threshold declined to 154 ± 20 and 148 ± 14 g, respectively. The comparison of the initial effects of alfentanil on pressure threshold in the Carrageenan-Alfentanil and Alfentanil-Only groups are presented in the figure insert. The figure demonstrates that although pressure threshold in both groups increased to the same level, the degree of the threshold increase relative to its level immediately before alfentanil administration was more in the Carrageenan-Alfentanil group (75% ± 27% vs 47% ± 11%, P < 0.02) because the lower baseline for pressure threshold resulted from carrageenan-induced hyperalgesia.

Development of acute tolerance to alfentanil is demonstrated by the continuous decline of the analgesic effect from its peak at 30 min despite the constant-rate infusion of the opioid. Figure 1 illustrates that, in the Alfentanil-Only group, pressure thresholds before the start and the end of alfentanil infusion were quite close. The decline of the analgesic effect in the Carrageenan-Alfentanil group was no different from that in the Alfentanil-Only group; before the end of the 4-h alfentanil infusion, pressure thresholds in both groups were indistinguishable (154 ± 20 and 148 ± 14 g, respectively). However, the pressure threshold in the Carrageenan-Alfentanil group at the end of the alfentanil infusion did not decrease below the level of pressure threshold in the Saline-Only group and was more than that in the Carrageenan-Only group (154 ± 20 vs 106 ± 18 g, P < 0.0001). This indicates that the developing decrease of pressure threshold did not cross the border with the zone of carrageenan-induced hyperalgesia, i.e., the border between the hypoalgesic and antihyperalgesic effects of alfentanil.


   Discussion
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Our results show that a persistent nociceptive input does not prevent the development of acute tolerance to the analgesic effect of alfentanil. This finding is consistent with the results of several clinical studies indicating that acute tolerance can develop when opioids are used intraoperatively for general anesthesia or postoperatively for the treatment of pain. Chia et al. (15) reported that the preoperative and intraoperative use of fentanyl in large doses (15 µg/kg plus 100 µg/h for two to three hours) resulted in an increased postoperative fentanyl consumption via patient-controlled analgesia (PCA) (up to 50%) and increased pain severity compared with the preoperative administration of a small dose of fentanyl (1 µg/kg). Guignard et al. (16) compared two groups of patients with fast (0.3 µg · kg-1 · min-1) and slow (0.1 µg · kg-1 · min-1) infusion rates of remifentanil during surgery. They found that in the Fast-Remifentanil group, postoperative pain scores were significantly more and that morphine consumption during the first 24 postoperative hours (postoperative titration followed by PCA) was nearly twice that of those in the Slow-Remifentanil group. McQuay et al. (17) also suggested that intraoperative use of opioids may result in the development of acute tolerance. This suggestion was based on their finding of no difference in the PCA fentanyl requirements among three groups of patients who received intraoperatively large, medium, and small doses of fentanyl. However, this outcome could also be explained by an ineffective demand dose of fentanyl of 2 µg(compare with 10–20 µg). In another study, patients who received more morphine during the initial postoperative period had larger opioid requirements for pain relief after the initial period (18).

Acute and chronic opioid tolerance may have different combinations of underlying compensatory mechanisms. Therefore, our findings demonstrating that acute tolerance to alfentanil develops in the presence of inflammatory nociceptive input does not directly contradict studies in rats indicating that nociceptive stimulation prevents the development of chronic tolerance to analgesia (4–6). At the same time, our results are compatible with studies (also in rats) reporting that pain does not prevent the development of chronic opioid tolerance (7,8).

We have found previously (19) that dizocilpine, an N-methyl-D-aspartate receptor antagonist, attenuates acute tolerance to alfentanil-induced analgesia, suggesting that increased glutamate release may contribute to the development of acute tolerance to analgesia. Therefore, a pain state that is associated with an increase in spinal glutamate (20) is an unlikely factor in reducing acute tolerance.

Although acute tolerance in our experiments with carrageenan-induced inflammation was almost as profound as that without inflammation, some difference was noticeable between the decline of pressure threshold for motor response during the four-hour alfentanil in-fusion in the Alfentanil-Only group and in the Carrageenan-Alfentanil group. In the Alfentanil-Only group, pressure threshold returned to a level that was close to the level immediately before alfentanil administration. In the Carrageenan-Alfentanil group, the decline of pressure threshold did not cross the border with the zone of hyperalgesia caused by inflammation: before the end of the four-hour alfentanil infusion, the pressure threshold in the Carrageenan-Alfentanil group was higher than that before the end of the four-hour saline infusion in the Carrageenan-Only group (154 ± 20 vs 106 ± 18 grams, P < 0.0001). To explain this, two components of the analgesic effect of alfentanil observed in our experiments—hypoalgesic and antihyperalgesic—should be regarded separately.

We suggest that acute tolerance to the analgesic effect of alfentanil is related only to the hypoalgesic component of analgesia and not to the antihyperalgesic component. The method of pressure threshold measurement used in our experiments is associated with phasic pain. Inhibition of the response to phasic pain is one example of opioid-induced hypoalgesia. The development of tolerance to the hypoalgesic and antihyperalgesic effects of opioids could have quite different mechanisms, including a peripheral component (21,22). An alternative explanation for the absence of the decline of pressure threshold into the zone of hyperalgesia (at the end of the four-hour infusion of alfentanil, the Carrageenan-Alfentanil group) may be as follows. The decline could develop further, into the zone of hyperalgesia, but it requires time beyond the four-hour period provided in our studies.

In our experiments, the initial analgesic effect of alfentanil reached the same level of pressure threshold (242 grams) with and without carrageenan-induced hyperalgesia (Fig. 1). However, because of the lower level of prealfentanil pressure threshold in the Carrageenan group, the degree of the threshold increase relative to its level immediately before alfentanil administration was more with hyperalgesia. An approximately equal or greater analgesic effect of opioids in rats with experimental inflammation in comparison with normal animals was also reported in several studies (8,13). These results could be interpreted as an indication that the hypoalgesic component of alfentanil analgesia is actually the same with or without inflammation. However, if inflammation-induced hyperalgesia is present, alfentanil also provides an additional antihyperalgesic effect.

Mao et al. (23) suggested that hyperalgesia and morphine tolerance may be interrelated by common neural substrates that interact at the level of excitatory amino acid receptor activation and related intracellular events. On the basis of this hypothesis, they suggested that hyperalgesia (including inflammatory hyperalgesia) may lead to decreased analgesic effect of opioids. Our results do not provide support for this suggestion. However, the decreased effect could be related exclusively to the hyperalgesic, not the hypoalgesic, component of opioid analgesia. At the same time, in our experiments, the hyperalgesic component could be disguised because of the profound alfentanil-induced hypoalgesia.

A growing body of evidence suggests that acute opioid tolerance may lead to deleterious consequences (24). It was recently demonstrated that a number of drugs, including ketamine (25), can reduce acute opioid tolerance. This can point the way toward combined opioid therapy that prevents tolerance development.

In conclusion, inflammatory nociceptive input did not prevent development of acute tolerance to alfentanil-induced analgesia measured as increased reaction threshold to painful pressure; it also did not change the analgesic effectiveness of alfentanil. However, this type of response to opioids may be typical only for inflammatory pain. If acute tolerance to the analgesic effect of opioids is profound and develops very rapidly, even in the presence of nociceptive input, the perioperative use of large doses of opioids should be regarded with concern. Tolerance to the antinociceptive effect leads to an increase in opioid use to maintain an effective level of antinociception, resulting in an excessive effect of opioids on the functions with slower tolerance development. The other clinical implication is that calculations for target-controlled infusions of opioids during anesthesia should probably include corrections for the development of tolerance.


   Acknowledgments
 
Supported by National Institutes of Health Grant GM35135.


   References
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 

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Accepted for publication December 20, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press