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Anesth Analg 2003;97:1347-1352
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Detection of Acute Tolerance to the Analgesic and Nonanalgesic Effects of Remifentanil Infusion in a Rabbit Model

Masakazu Hayashida, MD PhD*, Atsuo Fukunaga, MD PhD{dagger}, and Kazuo Hanaoka, MD PhD*

*Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; and the {dagger}Department of Anesthesiology, Harbor UCLA Medical Center, Torrance, California

Address correspondence and reprint requests to Masakazu Hayashida, MD, Research Hospital Surgical Center, Institute of Medical Science, The University of Tokyo, 4–6-1 Shiroganedai, Minato-ku, Tokyo, 108–8639, Japan. Address email to hayashida-todai{at}umin.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Although acute tolerance to analgesia develops rapidly with remifentanil, it is unknown whether acute tolerance also develops to its nonanalgesic effects. We investigated the analgesic and cardiorespiratory effects of remifentanil during a continuous infusion in a rabbit model. Ten tracheotomized New Zealand White rabbits with arterial and venous accesses were placed on a sling that allowed for reasonably free movement. In spontaneously breathing conscious animals, remifentanil was infused IV at a constant-rate of 0.3 µg · kg-1 · min-1 for 360 min. Sedative/analgesic and cardiorespiratory variables were assessed repeatedly during remifentanil infusion, including the number of animals behaviorally unresponsive to clamping the forepaw (nonresponders) and subcutaneous electrical stimulation thresholds required to elicit head lift (HLT: pain detection/arousal threshold) and escape movement responses (EMT: pain tolerance threshold). Within 60–120 min of starting the infusion, the number of nonresponders, HLT, EMT, and PaCO2 increased significantly, whereas blood pressure, heart rate, and respiratory rate decreased. Thereafter, all variables returned towards preinfusion levels despite continuing infusion. These results indicate that during a remifentanil infusion acute tolerance develops for both its analgesic and cardiorespiratory effects.

IMPLICATIONS: Using a new rabbit model, we found that during continuous, constant-rate remifentanil infusion acute tolerance developed within the first few hours, not only to its analgesic but also to its cardiovascular and respiratory effects, albeit in slightly different time courses.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Several studies have demonstrated that acute tolerance to their analgesic effects develops rapidly during continuous infusions of various opioids, including morphine (1–4), alfentanil (5,6), sufentanil (7), and remifentanil (8). This may require an increase in the infusion rate to maintain an analgesic effect (5). The increase in the infusion rate, however, may compromise safety because acute tolerance to adverse effects may develop at different rates than analgesic tolerance (5,8). During morphine infusion, for example, tolerance to respiratory depression did not develop although tolerance to analgesia developed rapidly (9). Therefore, it seems crucial to evaluate rates of tolerance development to various analgesic and nonanalgesic effects of a clinically important opioid.

Remifentanil is a novel, potent, and titratable opioid with ultra-short action (8,10,11). Continuous infusions of remifentanil have been used as the analgesic component of balanced general anesthesia, as an analgesic adjunct in local and regional anesthesia (10,12), and as an analgesic in the immediate postoperative period before transitioning patients to longer-acting analgesics (10,13). The rapid development of tolerance to analgesia has been observed during remifentanil infusion in humans (8). It is not known, however, whether or not acute tolerance develops also to its nonanalgesic effects.

We have developed a rabbit pain model that allows for repeated, quantitative assessment of the level of analgesia and simultaneous evaluations of a variety of physiological variables including cardiovascular and respiratory variables (14). The aim of this study, conducted in the rabbit model, was to determine whether development of acute tolerance to remifentanil analgesia could be detected, and whether acute tolerance would develop to its nonanalgesic, cardiovascular, and respiratory effects.


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
The study protocol was reviewed and approved by the Institutional Animal Research Committee. Ten male New Zealand White rabbits weighing approximately 3 kg were studied. Preparation of experimental animals has been described in detail elsewhere (14). In brief, animals were tracheotomized under 3% isoflurane anesthesia. A marginal ear vein was cannulated with a 24-gauge catheter for drug and fluid administration. Lactated Ringer’s solution was infused at a rate of 8 mL · kg-1 · h-1. A central ear artery was cannulated with a 22-gauge catheter for continuous blood pressure monitoring and blood sampling. All surgical incisions were made with additional local infiltration of 1% lidocaine. Arterial blood pressure, heart rate (HR), and percutaneous (lead II) electrocardiogram (ECG) were continuously monitored and recorded on a polygraph. A heating lamp was used to maintain rectal temperature between 38°C and 39°C. A urinary balloon catheter was inserted to monitor urine output.

The rabbits were then placed on a rubber sling that allowed animals to move the head and all extremities freely. A pair of subcutaneous platinum needle electrodes (Grass Type 2, Grass Medical Instruments, Quincy, MA) was placed in the plantar aspect of a forepaw 10 mm apart and 5 mm deep into the skin. These electrodes were connected to Grass S48 stimulator (Grass Medical Instruments) for electrical stimulation.

After completion of all preparations, isoflurane was discontinued, and the animals were fully awoken. Continuous remifentanil infusion at a constant rate of 0.3 µg · kg-1 · min-1 was initiated in the spontaneously breathing conscious rabbit 30 min after awakening from isoflurane anesthesia. The remifentanil infusion was continued for 360 min. Before, during, and after the remifentanil infusion, cardiovascular, respiratory, and analgesic variables were measured at the following time points: immediately before the remifentanil infusion (baseline: 0 min), 15 min after starting the infusion and then every 30 min during the infusion, and after the end of infusion (390 and 420 min).

To estimate the analgesic effect of remifentanil, movement reactions in response to two different types of noxious stimuli (mechanical clamping and electrical stimulation) were evaluated as follows. A neoprene-covered 16-cm hemostat was applied across a forepaw and moved back and forth until the animal moved (15) or 10 s had passed (16). A gross purposeful movement such as running and jumping, not confined to the clamped-side forepaw was considered as a positive movement (15). At each measurement time point, the number of animals that did not respond behaviorally to clamping the forepaw (nonresponders) was determined, as an alternative to the percentage probability of no response to noxious stimuli, to quantify the depth or level of anesthesia or analgesia (16–19).

An electric current (square wave, 1 ms duration, 5 Hz frequency) was applied subcutaneously to the other forepaw. The intensity of the stimulus was increased gradually until two consecutive movement responses (the head lift response (HLT): sudden head lifting with wide opening of eyes, and the subsequent escape movement response (EMT): running or jumping) were evoked or 150 volts (the maximum cutoff voltage to avoid tissue damage) was reached. Thus threshold intensities required to evoke the HLT (pain detection/arousal threshold, sedative/hypnotic index) and the EMT (pain tolerance threshold, analgesic index) were determined (14).

As cardiovascular and respiratory variables, continuous ECG, HR, systolic, diastolic, and mean arterial blood pressures (SAP, DAP, MAP), and respiratory rate (RR) were monitored. Arterial blood gas analysis was performed repeatedly with a blood gas analyzer (Statprofile 5, Nova Biomedical, Waltham, MA).

Data are presented as mean ± SD. Changes in SAP, DAP, MAP, HR, RR, and the HLT as well as EMT were analyzed with repeated-measures analysis of variance followed by multiple comparisons with Fisher’s protected least significant difference test. The number of nonresponders at each measurement time point was compared with that at 0 min (baseline) as well as with its maximal value using the {chi}2 test. A value of P < 0.05 was considered as statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
After the start of the remifentanil infusion, the number of nonresponders increased rapidly and significantly (Fig. 1A). After reaching a maximum at 90 min, the number began to decrease toward the baseline level. When compared with the maximal value, the decrease reached statistical significance at 360 min (i.e., at the end of remifentanil infusion). The number returned to 0 after the end of remifentanil infusion (Fig. 1A).



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  		Figure 1. Changes in analgesic variables: the number of nonresponders (A) and HLT as well as EMT (B) before, during, and after remifentanil infusion. *P < 0.05 vs the baseline value at 0 min; #P < 0.05 vs the maximal value at 60 or 90 min. The number of nonresponders = the number of animals behaviorally unresponsive to clamping the forepaw determined at each measurement time point, HLT = electrical stimulation threshold of the head lift response (pain detection/arousal threshold: sedative/hypnotic index), EMT = electrical stimulation threshold of the escape movement response (pain tolerance threshold: analgesic index).

 
During the remifentanil infusion, the HLT (pain detection/arousal threshold: sedative/hypnotic index) and the EMT (pain tolerance threshold: analgesic index) increased rapidly and significantly (Fig. 1B). They reached their peak values at 60 min and 90 min, respectively, and then began to decrease. The decreases, compared with their maximums, reached statistical significance by 180 min, although they did not return to baseline levels during remifentanil infusion. After the end of the infusion, the HLT and EMT returned to baseline levels (Fig. 1B).

After the start of the remifentanil infusion, DAP and MAP decreased significantly and reached their minimums at 90 min, whereas SAP did not decrease significantly. Then DAP and MAP began to increase and returned to baseline levels by 210 min, i.e., during the infusion (Fig. 2A).



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  		Figure 2. Changes in cardiovascular variables: arterial blood pressure (A) and heart rate (B) before, during and after remifentanil infusion. *P < 0.05 vs the baseline value at 0 min; # P < 0.05 vs the minimal value at 60 or 90 min. SAP, DAP, and MAP = systolic, diastolic, and mean arterial blood pressures, respectively.

 
HR decreased rapidly and significantly after starting the remifentanil infusion. After reaching its minimum at 60 min, HR began to increase and returned to the baseline level by 120 min during the infusion (Fig. 2B).

With remifentanil, RR decreased rapidly and significantly. After reaching its minimum at 90 min, RR began to increase (Fig. 3A). The increase compared with the minimum reached statistical significance by 270 min though it did not return to the baseline level during the infusion. After the end of infusion, RR returned to the baseline level (Fig. 3A).



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  		Figure 3. Change in respiratory variables: respiratory rate (A) and PaCO2 (B) before, during, and after remifentanil infusion. *P < 0.05 vs the baseline value at 0 mi;, #P < 0.05 vs the minimal respiratory rate at 90 min or the maximal PaCO2 at 120 min.

 
Carbon dioxide tension of arterial blood (PaCO2) increased significantly during the remifentanil infusion (Fig. 3B). After reaching its maximum at 120 min, PaCO2 began to decrease. The decrease compared with the maximum reached statistical significance by 330 min, although it did not return to the baseline level during the infusion. After the end of infusion, PaCO2 returned to the baseline level (Fig. 3B).

Base excess of arterial blood decreased significantly during the first 30 min of remifentanil infusion. After reaching its minimum at 30 min, it began to increase and returned to the baseline level by 60 min of infusion (Fig. 4A). Similarly, pH of arterial blood decreased significantly with remifentanil. After reaching its minimum at 30 min, it began to increase, reaching statistical significance by 60 min, though it did not return to the baseline level (Fig. 4B).



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  		Figure 4. Changes in base excess and pH of arterial blood before, during, and after remifentanil infusion. *P < 0.05 vs the baseline value at 0 min; #P < 0.05 vs the minimal values at 30 min.

 
The rectal temperature was kept within a narrow range (37.7°C–38.9°C) in each animal and remained statistically unchanged throughout the experiment.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Remifentanil is a µ-opioid receptor agonist that is metabolized rapidly by plasma nonspecific esterases. It has a very short context-sensitive half-time (approximately 3 minutes) (20). During a continuous remifentanil infusion at a constant rate, its plasma concentration rapidly increases to reach a steady-state level (10,11,20). Thus, as long as its pharmacodynamic property remains unchanged, a steady-state level of analgesia should be maintained at its steady-state plasma concentration during constant-rate infusion.

Changes in behavioral responses to both mechanical clamping (the number of nonresponders) and electrical stimulation (the EMT; analgesic index) observed in this study indicated that analgesic efficacy of remifentanil began to decline after reaching its peak at 90 minutes despite the continuing infusion. The results of our study in conscious rabbits, and results of the study by others in conscious humans (8), indicate that acute tolerance to analgesia began to develop within a few hours during continuous infusion of remifentanil. It is not known, however, whether acute tolerance also develops to its nonanalgesic (e.g., cardiovascular and respiratory) effects. Changes in the HLT (sedative/hypnotic index) indicated that acute tolerance to the sedative effect of remifentanil also developed.

In the present study, MAP and HR, which initially decreased with remifentanil infusion, returned to baseline levels despite continuing infusion, indicating that acute tolerance to cardiovascular effects of remifentanil developed and was completed within a few hours. Similarly, RR decreased and PaCO2 increased initially but then returned toward baseline levels during the continuing infusion. Body temperature, which would affect the basal metabolic rate and thus RR, remained unchanged throughout the experiment. These results indicated that tolerance also developed to the respiratory depressant effects of remifentanil. In the very early stage of the remifentanil infusion, a brief period of metabolic acidosis developed. Presumably, transient stress imposed on animals before the onset of remifentanil analgesia might have caused a stress response, leading to subsequent lactic acidosis coupled with hyperglycemia (21,22). This transient metabolic acidosis could have stimulated respiration, partly counteracting the remifentanil-induced respiratory depression in the early stage and somewhat obscuring development of respiratory tolerance. Therefore, if metabolic acidosis had been absent, development of acute tolerance to the respiratory depressant effect of remifentanil might have been more obvious. Metabolic acidosis might exert some influence also on the analgesic effect of remifentanil, as it increases anesthetic potency of inhaled anesthetics, albeit only slightly (23).

After the start of the continuous remifentanil infusion at a constant rate, the cardiovascular effects (BP and HR) and the sedative (HLT) as well as analgesic (EMT) effects peaked at 60–90 minutes, whereas the respiratory effects (RR and PaCO2) peaked at 90–120 minutes of infusion. The significant cardiovascular effect became undetectable by 120–210 minutes during the infusion, indicating completion of cardiovascular tolerance. However, significant sedative/analgesic and respiratory effects persisted throughout the infusion period and significant declines in the sedative/analgesic and respiratory effects compared with their peaks were observed by 180 minutes and 270–330 minutes, respectively. Taken together, it is likely that cardiovascular tolerance evolved and was completed more rapidly than sedative/analgesic tolerance, and conversely, respiratory tolerance evolved more slowly than sedative/analgesic tolerance.

Few studies have been conducted on the development of acute tolerance to cardiorespiratory effects of opioids. One study in rats, however, suggested that acute tolerance to respiratory depression did not develop during long-lasting morphine infusion despite rapid development of acute tolerance to its analgesic effect (9). Similarly, another study in dogs demonstrated that the pulse rate, which decreased acutely after the start of morphine infusion, remained at the decreased level throughout the infusion period, suggesting that acute tolerance to cardiovascular effects of morphine might not develop, although tolerance to analgesia developed rapidly (2). These findings with morphine appear to be contradictory to our findings with remifentanil. However, other authors reported that in anesthetized rats, acute tolerance to cardiovascular depressant effects of morphine developed slowly with repeated injections of small bolus doses of morphine but very rapidly with those of large doses (25). These findings seem to be compatible to our results.

It has been suggested that multiple mechanisms are involved in the development of opioid tolerance (5,6,24). Variable contributions of the different mechanisms involved in opioid tolerance can result in significant differences in the character of opioid tolerance development, for example, because of different conditions studied (5,9), different doses of an opioid administrated (5,25), and different choices of opioids (7). Kissin et al. (7) noted, for example, that the tolerance tended to develop at a more rapid rate with alfentanil than with morphine. Likewise, acute tolerance to respiratory and cardiovascular depression might develop more rapidly with remifentanil than with morphine. The possibility could not be excluded, however, that discrepancies between our results with remifentanil in rabbits and those with morphine in dogs (2) and rats (9) might result from the different animal species used in experiments. Therefore, differential time courses of cardiovascular, respiratory, sedative, and analgesic effects of remifentanil infusion should be carefully evaluated also in humans in further studies.

Using a clamp test (the number of nonresponders) alone, a statistically significant decrease in efficacy of analgesia could be detected only at 360 minutes after the start of remifentanil infusion. Using the electrical stimulation threshold (the EMT), a significant decline in analgesic efficacy could be detected much earlier (by 180 minutes of infusion). Therefore, electrical stimulation in combination with a clamp test allowed us more sensitive quantification of the continuously changing efficacy of remifentanil analgesia than a traditional clamp test alone. Furthermore, our results clearly demonstrated the characteristic pharmacological profiles, not only sedative/analgesic but also cardiovascular as well as respiratory effects of remifentanil infusion. Our novel animal model with multi-modal tests and various monitors that closely mimic the clinical anesthetic practice seemed very useful in researching surgical anesthesia/analgesia.

In conclusion, acute tolerance develops within a few hours during continuous remifentanil infusion in the rabbit model not only to its sedative/analgesic but also to its nonanalgesic, cardiorespiratory effects, although cardiovascular tolerance and respiratory tolerance may evolve more rapidly and more slowly, respectively, than sedative/analgesic tolerance.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 10, 2003.




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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