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© 1999 International Anesthesia Research Society
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Abstract |
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Studies in animals and volunteers have suggested the development of acute tolerance to opioid analgesics. In this article, we present data from patients who regulated their own target-controlled infusions of alfentanil and remifentanil to provide analgesia in the immediate postoperative period. Fifty-one patients received alfentanil for 24 h after cardiac surgery, and 30 patients received remifentanil for 6 h after orthopedic surgery. Satisfactory analgesia, defined as a rating of
3 on an 11-point visual analog scale, was obtained by patients after each type of surgery. The target concentrations of the opioids required to produce postoperative analgesia and the cumulative opioid doses administered over the course of the clinical observation suggest there was no tolerance to the analgesic effects of the opioids. The requirements for both analgesic drugs in individual patients had a large variation (>200%). We conclude that our results may indicate an absence of tolerance to opioids in postoperative analgesia. Nonetheless, our data show that the postoperative requirement for these rapidly acting drugs is qualitatively similar to that for other opioids in that dosage escalation does not occur. Implications: The development of acute tolerance to opioid analgesics has been suggested based on experimental studies in animals and volunteers. Our report from patients who self-controlled their analgesic requirements by using target-controlled infusions of alfentanil and remifentanil for postoperative analgesia provides no evidence of tolerance to opioids.
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Introduction |
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Animal studies have demonstrated the development of an acute tolerance to analgesia with opioids, especially a tolerance to morphine analgesia in experimental pain in rodents (1,2). This seems to represent an alteration in the pharmacodynamics of the drugs over time.
Alfentanil was introduced as an analgesic with rapid onset (keO 1.2 min) and offset of action. The duration of analgesia after a single dose is approximately 8 min (3). However, its context-sensitive half-time increases with the duration of infusion and reaches a plateau after approximately 1 h (4).
Remifentanil, the latest of the µ-agonist fentanyl congeners, has been introduced as a supplement to general anesthesia. It undergoes rapid metabolism by tissue and blood esterases and has an extremely short duration of action, with a context-sensitive half-time of approximately 3–4 min, which is unaffected by the duration of infusion (5).
In a recent article (6), the authors suggest that the analgesic effect of remifentanil decreases to one quarter of its peak effect after a 3-h infusion in volunteers exposed to experimental pain. However, no studies have examined the development of tolerance to the analgesia provided by alfentanil and remifentanil used to provide analgesia after surgery. Thus, the conclusions drawn during animal or volunteer studies have been extrapolated to the clinical situation (7). The problem is that both alfentanil and remifentanil are difficult to use to provide adequate postoperative analgesia without the development of respiratory depression or nausea.
We examined unpublished data collected during an evaluation of the clinical efficacy of alfentanil (8) and remifentanil (9) for evidence of the development of acute tolerance to these analgesics in terms of possible changes in drug requirements during clinical use to provide postoperative analgesia.
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Methods |
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Both studies used specially designed patient-maintained target-controlled infusion (TCI) systems in which the TCI software was incorporated into an external microcomputer connected via a serial port to a syringe pump. These patient-maintained analgesia (PMA) systems are further developments of the prototype system for propofol used in previous studies (10) and can rapidly achieve and maintain predefined target concentrations of alfentanil and remifentanil. The infusion rates for each target concentration are adjusted frequently over time based on mathematical solutions of a multicompartment pharmacokinetic model algorithm of either drug.
Alfentanil
Fifty-one patients scheduled for elective cardiac bypass surgery were studied. The study was approved by the hospital ethics committee, and all patients gave written, informed consent. Patients with poor ventricular function, as defined by an ejection fraction <40% measured during coronary angiography, were excluded from the study, as were those with hepatic or renal impairment.
All patients were shown how to use the PMA the day before surgery. A standardized anaesthetic technique, in which anesthesia was induced and maintained with TCI propofol and alfentanil using the pharmacokinetic data sets of Marsh et al. (11) and Maitre et al. (12), respectively, was used for all patients. Patients continued to receive the TCI alfentanil infusion and returned to the cardiac intensive care unit (CICU) after surgery. Patients were given a PMA handset that was plugged into the alfentanil TCI system when they could open their eyes and obey simple commands. When pain relief was requested by the patient by pushing the PMA button, the target concentration of alfentanil delivered was increased by 5 ng/mL with a lockout time of 2 min. If analgesia was not requested during a 30-min period, the target concentration was automatically reduced by 5 ng/mL. If the button was subsequently not pressed, the target concentration was further reduced in steps of 5 ng/mL every 30 min for the first 4 h of use, every 45 min for the next 4 h and every 60 min thereafter. The system was programmed to deliver a minimal plasma alfentanil concentration of 15 ng/mL and a maximal concentration of 150 ng/mL.
The study period lasted for the first 24 postoperative hours. Patients were traditionally extubated when they could obey simple commands, had stable cardiovascular and respiratory indices, and were rewarmed with a core temperature >36.5°C. Pain scores were recorded on an 11-point visual analog scale (VAS) by the CICU nursing staff, with the patients at rest, (0 = no pain and 10 = the maximal imaginable pain level).
Remifentanil
Thirty male patients, ASA physical status I and II, scheduled to undergo elective orthopedic surgery, were studied. The study was approved by the hospital ethics committee, and all patients gave written, informed consent. Patients >65 yr of age or with a known history of chronic drug or alcohol abuse were excluded, as were those with obesity, expressed as a body mass index >30 kg/m2. During the preanesthetic visit, patients were instructed in the principles of PMA, and the use of a PMA handset was demonstrated after arrival at the preoperative area.
Anesthesia was induced and maintained with propofol and remifentanil using TCI systems programmed with pharmacokinetic data for propofol (11) and remifentanil (13). The remifentanil concentration used was 1 mg/50 mL (20 µg/mL).
Approximately 10 min before the anticipated end of the surgical procedure, the propofol infusion was stopped, and the remifentanil target concentration was progressively reduced until the patients were breathing spontaneously. After the patient regained consciousness and was tracheally extubated, every patient continued to receive a remifentanil infusion with this individual target concentration until he was transferred to the postanesthesia care unit (PACU).
A handset was connected to the TCI controller in a manner similar to that described for alfentanil, and the patient was given control of this. Patients indicated their demand for increased analgesia by pushing the demand button twice within 1 s. The target concentration of remifentanil was increased by 0.2 ng/mL after every successful demand. There was a lockout time of 2 min after each increase in target concentration. In the absence of a demand within 30 min, the target concentration was automatically reduced by 0.2 ng/mL during the first 4 h and every 45 min with the same incremental reductions for the following 4 h.
Patients were observed for the following 6 h, and respiration rate, oxygen saturation, VAS pain scores, and the level of sedation were monitored.
All patients were introduced to an 11-point VAS beforehand and were instructed to titrate analgesia to a level at which they feel comfortable (VAS score 3). The particular infusion regimen of both alfentanil and remifentanil for incremental increases to every demand, the lockout interval, and the stepwise adjustment by which the TCI system decreased the target concentration during patient inactivity were programmed based on initial feasibility studies (14) and have since been refined.
Data concerning the target concentrations required and the cumulative dose demanded by patients were stored automatically within the TCI system in both studies and were downloaded for further off-line analysis. Target alfentanil and remifentanil concentrations are presented as mean values (interquartile range [IQR]) for the first 24 and 6 h, respectively. Pain scores are reported as means (95% CI), and patient ratings 3 were considered adequate. Statistical analysis was performed by using analysis of variance with Fisher's protected least square difference test for multiple comparisons among means. Sample sizes for alfentanil and remifentanil were calculated based on the assumption that a minimal difference of 15%, which we defined as a clinical relevant variation of target concentrations, could be assessed with a power of 0.9. Probability values <0.05 were considered significant.
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Results |
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Alfentanil
The time profile of patient demand and the cumulative total dose for alfentanil is shown in Figure 1. After admission to ICU, the target concentration of alfentanil declined during the first 4–8 h. Thereafter, the target concentration demanded by the patients remained stable. The system was designed to decrease the target concentration automatically if no demand was made by the patient within varying time periods. The cumulative total dose increased at an almost constant rate over the 24-h period of study. The mean overall VAS score of 2.3 (2.3–2.8) for the 24-h period indicated that patients received satisfactory analgesia during the study period (Figure 2). Of patients who used the alfentanil TCI system, 91% rated their postoperative analgesia as either excellent or good, whereas the remaining 9% felt that it was only satisfactory or poor.
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= cumulative alfentanil requirements. Mean values and interquartile range (n = 51).
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Remifentanil
The profile of patient demand for remifentanil and the consumption of remifentanil in the 6 h after surgery also had a remarkable stability and gave no evidence of development of acute tolerance (Figure 3). The mean time to adequate analgesia (VAS score
3) was 18.9 min (15.89–21.91). With two exceptions, every patient reached a level of adequate analgesia within half an hour of beginning patient-controlled analgesia. Pain levels remained stable, with a mean overall VAS score of 2.9 (1.4–4.2), as shown in Figure 4. Although the absolute level of VAS ratings and its variation tended to be slightly higher compared with the alfentanil group, this nonsignificant difference seems neglectable in the light of the difference in observation period length. There were no episodes of hypoxemia (oxygen saturation <95%) or apnea, and the lowest respiration rate was 9 breaths/min. Nausea occurred in 26.6% of patients, and 10% vomited. The mean sedation score was 2 of 6.
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Neither alfentanil (analysis of variance P = 0.63) nor remifentanil (analysis of variance P = 0.75) target concentrations showed a statistically significant trend toward an increase in opioid requirements. Thus, the constant relationship between VAS score and target concentrations assumes a correlation of infusion pattern with alfentanil and remifentanil effect site receptor occupancy.
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Discussion |
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A previous study by Vinik and Kissin (6) examined the development of tolerance to analgesia during remifentanil infusion in 13 paid human volunteers. Two of the volunteers responded to an infusion of placebo, whereas one other volunteer did not demonstrate a reliable analgesic response to a remifentanil infusion. Another patient was withdrawn following persistent nausea and vomiting. The exclusion of almost one quarter of the patients for inappropriate analgesic responses suggest that the results obtained from this study may not be reliable and should not be applied to the clinical situation.
In the present analyses, we provide data after infusions of alfentanil and remifentanil, which show that, when used clinically to provide postoperative analgesia, there is no evidence of the development of acute tolerance to the analgesic effects of these drugs. The target concentrations required by the patients to provide satisfactory analgesia and the cumulative doses administered during the study periods show no effects with time in either group. Furthermore, examination of individual data during the observation periods also discloses no statistically significant or clinically relevant increases in remifentanil and alfentanil requirements.
These findings are consistent even after a much longer period of time (6 hours for remifentanil and 24 hours for alfentanil) compared with the observations of Vinik and Kissin (6) who studied their patients only for a 240-minute interval.
A theoretical drawback influencing our results of stable target concentrations over time in the context of tolerance may be the course of pain intensity itself. Assuming a declining pain intensity across the observation period, the absence of changes in the opioid target concentrations could suggest the development of tolerance. However, our data on pain intensity levels, expressed as comparable and stable VAS scores, do not support the development of tolerance after only three hours of infusion as suggested by Vinik and Kissin (6). In this early postoperative phase, a significant reduction in pain intensity is unlikely to occur in the patients studied.
Another important issue in postoperative analgesia is the variation in analgesic requirements due to a different individual perception of pain produced by a similar type of noxious stimulation. In our population, we observed a 200% variation in remifentanil target concentrations in 30 patients. A comparable extent of variability has been reported for alfentanil (15), and it would be expected that the eight volunteers studied by Vinik and Kissin (6) also demonstrated a similar variability. Unfortunately, their article provides no information about individual values.
The observation of inconsistencies between experimental and clinical pain is a very old one (16), and the discussion still continues. Even if studies reported acute tolerance to the analgesic effect of opioids in postoperative pain (17), most studies show that no opioid tested to date in a postoperative patient-controlled analgesia algorithm produces acute tolerance (18).
Experimental pain with a defined and constant stimulation may well be a model of opioid effects at the cellular level and may reveal the underlying mechanisms of neuroplastic changes, such as tolerance, sensitization, and modulation of pain memories. However, postoperative pain is characterized by a complex interaction and modulation of signal transduction mechanisms and intracellular processes that lead to alterations in protein phosphorylation and gene expression by both opioid drugs and endogenously released opioid peptides (19), although an animal model for postoperative pain has been described (20). This may fill the gap in explaining the mechanisms underlying the phenomenon of postoperative pain by future studies.
The main problem with using alfentanil and remifentanil to provide postoperative analgesia is the difficulty in obtaining stable blood concentrations. The use of alfentanil to provide postoperative analgesia has been investigated using patient-controlled analgesia with bolus doses delivered in response to a patient demand, but this technique did not provided satisfactory analgesia (21). Davies et al. (14) first demonstrated the use of TCI alfentanil to produce good postoperative analgesia with the target concentrations controlled by nurses. Several studies have also examined the feasibility of using a manually controlled remifentanil infusion to provide satisfactory postoperative analgesia. Without exception, these studies have reported excessive episodes of respiratory depression (22) due to problems of individual adaptation of drug levels.
This may be overcome by TCI technology. Because both alfentanil and remifentanil blood concentrations are closely related to their effect site concentrations, every new target concentration results in rapid onset of a stable level of drug effect. Van den Nieuwenhuyzen et al. (23) reported that, when used as TCI, alfentanil has a significantly faster onset of analgesia compared with standard morphine PCA. We did not measure either alfentanil or remifentanil blood concentrations, as the pharmacokinetic data used to program the TCI controller have been shown to be sufficiently reliable in previous studies (12,13). Even if we knew the actual blood levels, the measured pharmacodynamic variance of the required target concentrations always would exceed the expected pharmacokinetic error (23).
One may argue that the usage pattern of PCA may not accurately reflect the need for analgesia, especially in the early hours after surgery, and therefore may not be an objective means by which to quantify the analgesic requirements. However, compared with traditional methods of on-demand analgesic delivery, patient-controlled analgesia has been shown to provide immediate and superior analgesia with less total drug use, less sedation, fewer nocturnal sleep disturbances, and a more rapid return to physical activity (24). In particular, because patients determine a low level of pain at which they feel comfortable by individual titration, the patient-controlled analgesia technique has become standard for studies comparing postoperative analgesic requirements (18).
Even if there are theoretical and experimental data supporting the possibility of development of tolerance to opioids, this by no means suggests that pharmacokinetic calculations for TCIs should include corrections for this pharmacodynamic phenomenon. By definition, TCIs are specifically designed to rapidly achieve and maintain a certain blood concentration. The changing requirements of a patient, due to either alterations in the intensity of the noxious stimulation or a possible tolerance, would not alter the pharmacokinetics of a drug.
In conclusion, we were unable to show any evidence of rapid development of tolerance to analgesia during alfentanil and remifentanil infusions for postoperative pain. The role that these drugs will play in providing analgesia will depend on the systems used to deliver them. TCI systems provide a level of control that enables these rapid-onset analgesics to provide high-quality postoperative analgesia over a considerable period of time.
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- Cox BM, Ginsburg M, Osman OH. Acute tolerance to narcotic drugs in rats. Br J Pharmacol 1968;33:245–56.[Web of Science][Medline]
- Kissin I, Brown PT, Robinson CA, et al. Acute tolerance in morphine analgesia continuous infusion and single injection in rats. Anesthesiology 1991;74:166–71.[Web of Science][Medline]
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- 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.[Abstract]
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Checketts MR, Gilhooly CJ, Kenny GNC. Patient maintained analgesia with target controlled alfentanil infusion after cardiac surgery a comparison with morphine PCA. Br J Anaesth 1998;80:748–51.
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- Bowdle TA, Camporesi EM, Maysick L, et al. A multicenter evaluation of remifentanil for early postoperative analgesia. Anesth Analg 1996;83:1292–7.[Abstract]
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