REMIFENTANIL (hydrochloride salt of 3-[4-methoxy-carbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid, methyl ester), formerly known as GI87084B, is a synthetic opioid that exhibits classic micro-agonist pharmacologic effects. 
Although chemically related to the fentanyl family of short-acting 4-anilidopiperidine derivatives commonly used as supplements to general anesthesia, remifentanil is structurally unique among currently available opioids because of its ester linkages. As an ester, remifentanil is susceptible to hydrolysis by blood and tissue nonspecific esterases, resulting in rapid metabolism to essentially inactive compounds. Preliminary evidence from volunteer and patient studies suggests that remifentanil may constitute the first true ultrashort-acting opioid for use as a supplement to general anesthesia. [2-4]
The aim of this study was to contrast the clinical pharmacology of remifentanil and alfentanil in healthy, adult male volunteers by constructing a detailed pharmacokinetic/pharmacodynamic model for each drug using an open-label, randomized, crossover study design.
Materials and Methods
Recruitment, Instrumentation, and Safety Monitoring
After obtaining Institutional Review Board approval and informed consent, ten American Society of Anesthesiology (ASA) physical status 1 volunteers were enrolled in the study. Only English-speaking men between the ages of 18-40 yr without history of significant medical illness or medication requirements who were within 15% of their ideal body weight were eligible for participation. Prospective volunteers were ineligible if they had a history of alcohol abuse or illegal drug use, a habit of tobacco use greater than 10 cigarettes per day, a history of hypersensitivity to opioids, or a record of significant psychiatric disease. To confirm eligibility, each subject underwent a physical examination and a comprehensive battery of laboratory tests, including serum chemistries, liver and renal function tests, a complete blood count, a urinalysis, a urine drug screen, and an electrocardiogram.
Each subject was brought to the study site without premedication. An 18-G catheter was placed in a forearm vein for drug and fluid administration. A 20-G radial artery catheter was placed for blood sampling and continuous blood pressure monitoring. A solution of normal saline was infused intravenously at an approximate rate of 60 ml/h. Safety monitors included a continuous five-lead electrocardiogram, continuous pulse oximetry, and a precordial stethoscope.
Instrumentation for electroencephalographic (EEG) monitoring was performed in accordance with the International 10-20 system. 
Four channels (F3
) of the EEG were amplified and recorded using a Nihon Kohden EEG machine (model 5210, Nihon Kohden, Irvine, CA).
After the instrumentation was completed, the volunteers received 0.2 mg glycopyrrolate intravenously to prevent opioid-induced bradycardia and 0.5 mg pancuronium intravenously to mitigate opioid-induced muscle rigidity. Volunteers breathed 100% Oxygen2 by face mask delivered via a nonrebreathing circuit in preparation for drug administration.
Volunteers were randomized to receive either remifentanil or alfentanil during their initial visit and the other drug on their subsequent visit. Study sessions were separated by at least 2 weeks but no longer than 4 weeks. Both remifentanil and alfentanil were administered intravenously as a constant rate infusion by a laboratory syringe pump (Harvard Apparatus XG2000, South Natick, MA) for at least 10 min or until maximal changes were evident on the raw EEG. Remifentanil was administered at 3 micro gram *symbol* kg sup -1 *symbol* min1 (except the first subject, who received 2 micro gram *symbol* kg sup -1 *symbol* min sup -1), and alfentanil was administered at 1,500 micro gram *symbol* min sup -1.
During both visits, 3-ml arterial blood samples were obtained at preset intervals, with more rapid sampling during the infusion and immediately after termination of the infusion. After the infusion commenced, samples were collected every 30 s from 1 to 5 min, every minute from 6 to 10 min, and every 2 min from 12 to 20 min until the infusion was terminated. After the infusion was stopped, samples were collected every 30 s from 1 to 5 min, every minute from 6 to 10 min, and every 2 min from 12 to 20 min. Thereafter, samples were obtained at 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 150, 180, 210, and 240 min after the infusion was stopped. Additional samples at 360, 480, and 600 min after infusion were obtained during the alfentanil sessions.
During drug infusion, ventilation was assisted by bag and mask with 100% Oxygen2 as needed. A continuous infusion of succinylcholine was used as necessary to mitigate the effects of opioid-induced rigidity and to facilitate ventilation. Frequent arterial blood gas analysis confirmed the adequacy of ventilation and oxygenation.
Vital signs and subjective well-being were monitored after the end of the infusion for at least 3 h. Adverse events associated with drug administration were recorded as they occurred. Nausea and/or vomiting were treated as necessary by an intravenous injection of 10 mg metoclopramide.
Blood Sample Processing and Concentration Assay
Because of remifentanil's metabolic pathway, special processing was necessary to prevent continued metabolism of remifentanil after sample collection. The details of our sample-processing technique have been described previously. 
Both the remifentanil and alfentanil samples were processed in this manner.
Remifentanil blood concentrations were measured by a high-resolution, gas chromatographic, mass spectrometry assay with a quantitation limit of 0.1 ng *symbol* ml sup -1 and an interassay coefficient of variation of less than 15% for concentrations greater than 0.1 ng *symbol* ml sup -1. Tetradeuterated remifentanil was included in the collection tubes as an internal standard to correct for variations in recovery among samples. 
Alfentanil blood concentrations were determined by a gas chromatographic, mass spectrometry technique with an interassay coefficient of variation of less than 10% and a quantitation limit of 1 ng *symbol* ml1
Fentanyl was included as an internal standard.
EEG Signal Processing
The digitized raw EEG data were processed by computer to obtain the spectral edge parameter, a univariate summary descriptor identifying the frequency below which 95% of the EEG power is located. 
After filtering with a 50-Hz low-pass filter, the raw signal was analyzed in epochs of 2 s by Fourier transformation to separate it into frequency bins between 0.5 and 30 Hz. The power spectrum was calculated by squaring the amplitudes of the individual frequency components. Finally, the spectral edge was determined by calculating the area under the power versus frequency histogram and identifying the frequency below which 95% of the total area is found.
The pharmacokinetics were analyzed using three techniques. A classic moment analysis (area under the curve analysis) was done to facilitate comparison of each drug's model independent parameters in the same individual. A mixed-effect population approach based on the computer program NONMEM* was completed to estimate the population compartmental pharmacokinetic parameters. Finally, to address the clinical aspects of the mathematically based pharmacokinetic analysis, computer simulations of the context-sensitive half-times based on the NONMEM population pharmacokinetic parameters were performed.
Moment Analysis. Applying the theory of statistical moments to pharmacokinetics, 
a model independent moment analysis was performed to calculate the clearance (CL), mean residence time (MRT), and apparent volume of distribution at steady-state (VDss
) for both drugs in each subject. The area under the concentration versus time curve (AUC) was calculated for each blood concentration (Cb
) versus time (t) plot using the trapezoidal method with linear interpolation when concentrations were increasing and log-linear interpolation when concentrations were decreasing. 
The terminal slope for each data set was estimated by log-linear regression after visually identifying the terminal portion of each curve.
CL, MRT, and VDss were calculated using standard equations. Individual moment analysis parameters for both drugs in each subject were contrasted in graph form.
Nonlinear Mixed Effects Model Compartmental Analysis. The population compartmental pharmacokinetic parameters for both drugs were estimated using the NONMEM approach. Because it had been previously demonstrated for the remifentanil dose range studied, linear pharmacokinetics was assumed for the purposes of this analysis. [2,3]
In contrast with the two-stage approach, wherein the population pharmacokinetic model is obtained by averaging the parameters estimated from individuals, NONMEM simultaneously analyzes an entire population's data and provides estimates of typical values for the pharmacokinetic parameters with an estimate of the parameter's interindividual variability within the population studied.
A three-compartment mamillary model was fit to the remifentanil and alfentanil concentration versus time data. Interindividual error on each parameter was modeled using a log-normal error model: Equation 1
is the true value in the individual, Thetatypical
is the population mean estimate, and etaindividual
is a random variable whose distribution is estimated by NONMEM with a mean of zero and a variance of omega2
. Residual error was modeled assuming a log-normal distribution.
After obtaining estimates for the population volumes and clearances from NONMEM, the other three-compartment mamillary model parameters (micro and macro rate constants) were calculated using standard equations. 
The performance of the population models constructed by NONMEM for both drugs was assessed in terms of the ability to predict the measured blood concentrations. The models were quantitatively assessed in terms of weighted residuals (WRs), the difference between a measured blood concentration (Cm
) and the model-predicted concentration (Cp
) in terms of Cp
. Thus, WR can be defined as: Equation 2
Using this definition, the WRs for the NONMEM population models were computed at every measured data point. Using the WR data, the overall inaccuracy of the model was determined by computing the median absolute weighted residual (MDAWR), defined as: Equation 3
where n is the total number of samples in the study population. Using this formula, the MDAWRs for the population models constructed by NONMEM were computed for each drug.
The performance of the models was visually assessed by plotting the Cm/Cp versus time and examining the plots for accuracy and bias.
Computer Simulations. Computer simulations using the pharmacokinetic parameters obtained from the NONMEM compartmental analysis were performed to provide an illustration of the predicted decline in blood concentrations when remifentanil and alfentanil are administered by infusion. These simulations predict the time necessary to achieve a 50% or 80% decrease in drug concentration in the blood after termination of a variable-length infusion targeted to a constant drug concentration. The simulations are based on Euler's solution to the three-compartment model with a step size of 1 s.
The pharmacodynamics were described using an effect compartment model in which ke0
, a first-order elimination rate constant characterizing effect-site equivalent, is used to estimate the apparent effect-site concentrations. 
The pharmacodynamic analysis proceeded in three steps for each data set. First, ke0
was estimated using a hysteresis loop minimization technique. Second, the apparent concentration-effect relationship resulting from the hysteresis loop minimization technique was parametrically modeled assuming a sigmoidal shape for the relationship. Finally, making use of the ke0
and other pharmacokinetic and pharmacodynamic parameters estimated from the study, computer simulations were performed to contrast the onset, magnitude, and duration of effect resulting from equipotent doses of remifentanil and alfentanil.
Estimation Procedure. Ke0
was estimated using a hysteresis loop minimization technique. 
The theoretical foundation of this technique is that, in the effect site, there should be no delay or hysteresis between changes in drug concentration and changes in pharmacologic effect. In summary, this ke0
-estimating technique performs a numeric convolution of the measured drug concentrations with a candidate ke0
value to calculate the apparent effect-site concentrations. The optimal ke0
value minimizes the area of the hysteresis loop formed by plotting the apparent effect-site concentration versus effect. Potential ke0
values are sequentially tested until the optimal estimate of ke0
is obtained. The algorithm is thus an iterative process in which the hysteresis loops determined by numeric convolution of the measured drug concentrations with a potential ke0
are successively "collapsed" until a ke0
that results in minimal hysteresis is found. The optimal ke0
is used to calculate the apparent effect-site concentrations and thus identify the "pseudosteady-state" concentration-effect relationship.
Parametric Modeling of the Concentration-Effect Relationship. Because plots of the concentration-effect relationship determined by the estimation of ke0
were sigmoid in shape, an inhibitory "sigmoid Emax
" equation (i.e., Hill equation) was used to model the relationship parametrically. 
Using extended least-squares nonlinear regression implemented on an Excel spreadsheet (Microsoft, Redmond, WA), the equation: Equation 1
where E is the predicted effect, E0
is the baseline effect level, Emax
is maximal effect, Ce
is effect-site concentration, gamma is a measure of curve steepness, and EC50
is the effect-site concentration that produces 50% of maximal effect, was fit to the effect versus effect-site concentration data. Having estimated the pharmacodynamic parameters, the model was used to calculate a predicted effect at each measured concentration of remifentanil and alfentanil.
Computer Simulations. Computer simulations were performed using the full pharmacokinetic/pharmacodynamic model from the study to illustrate the clinical application of the estimated parameters. The first simulation, intended to illustrate time to peak concentration, was a simulation of effect-site levels of remifentanil and alfentanil after bolus administration of equipotent doses (185 micro gram remifentanil, 3,500 micro gram alfentanil). The second simulation, intended to illustrate magnitude and duration of effect, was a simulation of effect-site concentrations that result from a 2-h computer-controlled infusion using Stanpump (Stanford University, Palo Alto, CA) targeted to an EC50 level for both remifentanil and alfentanil.
Recruitment, Instrumentation, and Safety Monitoring
All ten volunteers originally enrolled completed the study. The volunteers were comparable in terms of age, lean body mass, and ASA physical status. Demographic means included an age of 28.5+/-4.8 yr, weight of 83.5+/-11.2 kg, and height of 183.7+/-5.8 cm (+/-SD).
All subjects received at least a 10-min infusion of remifentanil and alfentanil. One remifentanil subject required 14 min to exhibit maximal EEG changes, whereas two alfentanil subjects required infusions of 16 and 14 min, respectively, to reach maximal EEG changes. No infusion was terminated early because of an adverse event.
With the exception of adverse events such as muscular rigidity and nausea/vomiting that were anticipated as part of this protocol, no significant or unexpected complications were associated with remifentanil or alfentanil administration. In particular, there were no untoward hemodynamic events such as severe bradycardia, tachycardia, or hypotension requiring therapy or termination of the infusion. One subject experienced a brief (31 s) period of asymptomatic supraventricular tachycardia during remifentanil administration that spontaneously resolved.
The infusion schemes applied in this protocol resulted in concentration versus time curves characteristic of brief intravenous infusions. The raw data plots for each drug are contrasted in Figure 1
Moment Analysis. The moment analysis reveals substantial differences in the pharmacokinetics of remifentanil and alfentanil. Remifentanil CL is approximately 8 times greater than alfentanil's. Similarly, remifentanil's MRT is roughly 13-fold shorter than alfentanil's. With respect to distribution, the drugs are more alike. Alfentanil's VDss is approximately 1.6 times greater than remifentanil's.
The individual and mean CL, MRT, and VDss
values are shown in Table 1
. Figure 2
contrasts the model independent parameters for each drug in the same individual.
Nonlinear Mixed Effects Model Compartmental Analysis. As with the moment analysis, the NONMEM compartmental analysis reveals significant contrast between the pharmacokinetic parameters of remifentanil and alfentanil. Remifentanil's steady-state distribution volume is moderately smaller than alfentanil's. Remifentanil's clearance, however, is significantly greater than alfentanil's, a difference that is nearly an order of magnitude. The three-compartment model parameters for each drug estimated using the NONMEM approach are shown in Table 2
The performance of the NONMEM models for both drugs are representative of what is generally expected for compartmental population models, with an MDAWR of approximately 15%. The MDAWRs for both models, along with the 10th and 90th percentiles, are shown in Table 3
. Figure 3
is a plot of the Cm
versus time of these NONMEM models. Although there is no gross systematic bias, the models are obviously less accurate during the first few minutes of the infusion, during the first few minutes after stopping the infusion, and near the end of sampling.
Computer Simulations. The context-sensitive half-time simulations indicate that the decrease in blood concentration after drug administration is stopped is substantially more rapid for remifentanil than for alfentanil. Only 3 min is necessary to achieve a 50% decrease in remifentanil blood drug concentration after termination of an infusion despite lengthy infusions. Similarly, an 80% decrease in remifentanil blood concentration (i.e., 80% decrement time) can be achieved in 11 min. This is in contrast to the simulations for alfentanil; the time to achieve a decrease in blood concentration by 50% or 80% eventually plateaus at 46 and 161 min, respectively, exhibiting a marked dependence on the infusion duration. The results of these computer simulations are depicted in Figure 4
EEG Pharmacodynamic Analysis
Both remifentanil and alfentanil produce EEG changes characteristic of potent micro-receptor agonists. These changes consist of decreasing frequency and increasing amplitude in the raw EEG waveform, culminating eventually in pronounced delta-wave activity at maximal drug effect. An example of raw EEG signal from a remifentanil subject that is representative of the EEG changes observed in all subjects for both drugs is shown in Figure 5
When processed by computer, the profound delta-wave activity produced by both drugs translates into a significant downward shift in the spectral edge parameter of the EEG. Figure 6
shows a typical set of spectral edge parameter versus time data from a remifentanil subject.
Estimation. Remifentanil and alfentanil are similar with respect to the time required for equilibration of peak blood concentration and peak effect, as evidenced by their roughly equivalent k sub e0 values. Remifentanil's T1
is 1.6 min; alfentanil's is 0.96 min. The ke0
values for each subject are shown in Table 4
. The upper panel of Figure 7
contrasts the T1
values for each drug in the same subject. Raw and collapsed remifentanil hysteresis loops representative of the entire data set for both drugs are shown in the upper and middle panels of Figure 8
. Figure 8
illustrates how the ke0
-optimizing procedure results in "collapsing" the raw hysteresis loop, thus identifying the pseudosteady-state concentration-effect relationship that then can be subjected to parametric modeling.
Parametric Modeling of the Concentration-Effect Relationship. Except for potency, the parametric modeling fails to reveal any significant differences in the EEG pharmacodynamics of remifentanil and alfentanil. The lower panel of Figure 8
depicts a typical fit of the parametric model to the raw concentration-effect relationship. Remifentanil is 18.9 times more potent than alfentanil, as determined by comparison of the EC50
values. Remifentanil's mean EC50
is 19.9 ng *symbol* ml sup -1 compared with 375.9 ng *symbol* ml sup -1 for alfentanil. EC50
values for each subject, along with the other pharmacodynamic parameters, are displayed in Table 4
. The lower panel of Figure 7
contrasts the EC50
values for each drug in the same subject. Figure 9
depicts the concentration-effect relationships for both drugs in each individual, as determined by the pharmacodynamic parameters estimated.
Computer Simulations. The computer simulations using the full pharmacokinetic/pharmacodynamic model reveal important similarities and differences in the clinical pharmacology of remifentanil and alfentanil. The simulation of equipotent bolus doses (Figure 10
, upper panel) illustrates a nearly identical time to peak effect-site concentration for the two drugs. The simulation of a 2-h infusion targeted to equivalent effect-site concentrations (Figure 10
, lower panel) illustrates the expected rapid decrease in remifentanil concentration after termination of the infusion compared to the more prolonged decline in alfentanil concentration.
This study has contrasted the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in a population of healthy adult male volunteers using a randomized, open-label, crossover design. In summary, although differing in potency, remifentanil exhibits alfentanil-like pharmacodynamics with a shorter-acting pharmacokinetic profile.
Each of the three data analysis techniques confirmed the pharmacokinetic differences between remifentanil and alfentanil. Inspection of the raw data (Figure 1
) provides perhaps the most compelling and assumption-free evidence of how remifentanil's pharmacokinetics differ from alfentanil's. The slope of remifentanil's concentration decline after termination of the infusion is markedly steeper than alfentanil's.
) illustrates that remifentanil CL is nearly an order of magnitude greater than alfentanil's. This is reflected in the short MRT. With regard to tissue distribution, the differences are not as marked, with alfentanil's VDss
being slightly greater than remifentanil's.
The NONMEM analysis, although encumbered with the assumptions of compartmental analysis, illustrates the pharmacokinetic differences between remifentanil and alfentanil. The most striking difference is remifentanil's rapid clearance, a difference that, as in the moment analysis, approaches an order of magnitude. As with the moment analysis, the differences in tissue distribution were not nearly as marked.
The context-sensitive half-time simulations based on the NONMEM population parameters are perhaps the most clinically interpretable way of illustrating the pharmacokinetic differences between remifentanil and alfentanil. Using concepts developed by Shafer and Varvel, 
these simulations are an attempt to provide context-sensitive half-times, as proposed by Hughes et al. 
In this case, the "context" is the duration of a continuous infusion. Defined as the time required to achieve a 50% decrease in concentration after termination of a continuous infusion targeting a constant concentration, context-sensitive half-times are a method of providing some clinically interpretable meaning to what can be a confusing table of pharmacokinetic parameters. 
The simulations depicted in Figure 4
contrast the short, time-independent context-sensitive half-time of remifentanil with the longer, time-dependent context-sensitive half-time of alfentanil (80% decrement times are also included in Figure 5
The pharmacokinetic parameters and the related conclusions published herein for both remifentanil and alfentanil are consistent with the existing literature. [2-4,18,19]
Compared to prior reports, however, a unique feature of this study is the crossover design, enabling prospective comparison of each drug's pharmacokinetics in a single group of subjects. Prior comparisons of remifentanil and alfentanil pharmacokinetics have relied on literature values for alfentanil. [2,3]
The only other prospective comparison study involved smaller doses given to conscious volunteers and employed a parallel group design in which neither group received both drugs. 
This study is thus the first prospective, crossover confirmation of the previously reported pharmacokinetic differences between remifentanil and alfentanil.
The pharmacokinetic parameters estimated for remifentanil in prior studies and confirmed in this study closely approximate those theoretically required when a rapid decline in blood concentration is desired after termination of drug administration. Recent pharmacokinetic simulations by Youngs and Shafer indicate that, when a rapid decrease in blood concentration is the goal, it is beneficial to have a small central volume and a large central clearance. 
From a clinical viewpoint, remifentanil possesses these desirable pharmacokinetic parameters to ensure a rapid decline in concentration after termination of an infusion. 
An important limitation of our pharmacokinetic analysis is that our estimates of VDss assume that all clearance occurs in the central compartment. This assumption may not be fully applicable to remifentanil. Thus, our estimates of remifentanil's VDss may be low.
The EEG pharmacodynamic data for each drug were analyzed using a hysteresis minimization technique followed by parametric modeling of the apparent concentration-effect relationship. With the exception of a 19-times greater potency, this analysis confirms remifentanil's pharmacodynamic similarity with alfentanil and, by extrapolation, the other fentanyl congeners.
Inspection of the raw pharmacodynamic data (Figure 6
) reveals the nearly identical pharmacodynamic profile for the two drugs. Both exhibit identical changes in the raw EEG waveform and spectral edge parameter in terms of onset speed and magnitude of effect. Recovery to a baseline EEG pattern, however, is more rapid with remifentanil, as judged by the raw data plots. The nature and magnitude of these EEG changes are classic for the potent micro agonists and can be viewed as the EEG fingerprint of this drug class. 
With regard to the latency to peak effect, the hysteresis loop minimization technique results suggest that both drugs will exhibit rapid onset when administered in sufficient doses. The t1
parameter, a factor known to be important in determining onset of peak drug effect, 
is similar for the two drugs. This is in contrast to fentanyl and sufentanil, both of which exhibit slower equilibration between plasma and effect-site concentrations and thus are known to be drugs of relatively longer latency to peak effect unless administered in high doses. [24,25]
The parametric modeling of the concentration-effect relationship estimated an 18.9-times greater potency of remifentanil compared to alfentanil. This finding confirms that remifentanil is moderately less potent than fentanyl. 
However, in comparing the potencies of remifentanil and the other fentanyl congeners, it is important to note that the EC50
values for the other congeners have traditionally been reported in terms of plasma concentration. [18,24,25]
Thus, correction for the partitioning of alfentanil between whole blood and plasma using a ratio of 0.63 is necessary when making extrapolations from previously published alfentanil literature. 
When comparing a remifentanil whole blood EC50
value from this study with a corrected plasma alfentanil EC50
value (596.7 ng *symbol* ml sup -1), remifentanil is 30 times more potent than alfentanil.
The pharmacodynamic simulations are perhaps the most important means of contrasting the clinical pharmacology of the two drugs. Because they make use of the full pharmacokinetic/pharmacodynamic model, these simulations illustrate the complex interaction of all the kinetic-dynamic parameters in a clinically comprehensible way. 
The simulation depicted in the upper panel of Figure 10
confirms that, when administered in equipotent bolus doses, remifentanil will exhibit a short latency to peak effect that is comparable to alfentanil. The second simulation (Figure 10
, lower panel) suggests that, after a 2-h equipotent infusion is terminated, remifentanil will exhibit an obviously more rapid decline in effect-site concentration. Based on these simulations, remifentanil can be expected to be a rapid-onset, rapid-offset opioid.
The implication of the first simulation may not appear to be consistent with the fact that alfentanil's T1
is shorter than remifentanil's. Because T1
/2k e0 is only one of many factors that contribute to drug onset time, the finding is not surprising. Drugs that manifest an extremely rapid decline in plasma concentration after termination of drug administration inevitably exhibit a short time to peak effect, because effect-site concentrations are driven by the central compartment concentration gradient. If central compartment concentrations decline rapidly, peak effect-site concentration will be reached quickly, albeit at a lower peak. Thus, remifentanil's pharmacokinetic profile, in addition to its T1
, contributes to its rapid latency to peak effect. For practical purposes, the results of this study would suggest that remifentanil and alfentanil are essentially equivalent in terms of latency to peak effect; that is, both drugs should be regarded as rapid-onset agents. It should be emphasized that simulation of effect-site concentrations that result from bolus dosing are potentially limited by the fact that compartmental models do not consider the effect of recirculatory peaks. 
For infusions of short duration (e.g., 10 min in this case) the pharmacokinetic differences between remifentanil and alfentanil are not readily apparent. Only after infusions of longer duration (Figure 4
) do the pharmacokinetic differences become more obviously evident. The context-sensitive half-times for the currently marketed fentanyl congeners are not grossly divergent until infusions of longer than 20-30 min. 
The results of the pharmacodynamic modeling for both remifentanil and alfentanil reported here are consistent with the existing literature. A previous report of remifentanil pharmacodynamics employing an experimental pain model revealed a t1
of 1.3 min and a 20-30-times greater potency of remifentanil compared to alfentanil. 
Similarly, previous reports of alfentanil pharmacodynamic parameters included t1
values of 0.9 and 1.1 min and EC0
values of 479 and 520 ng *symbol* ml sup -1. [18,24]
Anesthesiologists have long recognized the need for a short-acting opioid with predictable pharmacokinetics. Because the lengths of surgical procedures often are unpredictable, and because the level of surgical stimulation against which the depth of anesthesia must be balanced is highly variable and dynamic, the advantages of predictably short-acting agents are obvious. Recent advances in drug development for anesthesia have trended toward shorter-acting agents of all types, including muscle relaxants, sedative hypnotics, and inhalation gases. Remifentanil represents an example of this direction toward shorter-acting agents. Future clinical use will determine whether the theoretical advantages associated with a short-acting opioid are realized.
*Beal SL, Sheiner LB: NONMEM User's Guide. San Francisco, University of California, San Francisco, 1979.
1. James MK, Feldman PL, Schuster SV, Bilotta JM, Brackeen MF, Leighton HJ: Opioid receptor activity of GI87084B, a novel ultra-short acting analgesic, in isolated tissues. J Pharmacol Exp Ther 1991; 259:712-8.
2. Egan TD, Lemmens HJM, Fiset P, Hermann DJ, Muir KT, Stanski DR, Shafer SL: The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. ANESTHESIOLOGY 1993; 79:881-92.
3. Westmoreland CL, Hoke JF, Sebel PS, Hug CC, Muir KT: Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. ANESTHESIOLOGY 1993; 79:893-903.
4. Glass PSA, Hardman D, Kamiyama Y, Quill TJ, Marton G, Donn KH, Grosse CM, Hermann D: Preliminary pharmacokinetics and pharmacodynamics of an ultra-short acting opioid: Remifentanil (GI87084B). Anesth Analg 1993; 77:1031-40.
5. Jasper HH: The ten twenty electrode system of the international federation. Electroencephalogr Clin Neurophysiol 1958; 10:371-5.
6. Grosse CM, Davis IM, Arrendal RF, Jersey J, Amin J: Determination of remifentanil in human blood by liquid-liquid extraction and capillary GC-HRMS-SIM using a deuterated internal standard. J Pharm Biomed Anal 1994; 12:195-203.
7. Jersey JA, Guyan S, Abbey L, Grosse CM, Davis IM: Determination of alfentanil in whole blood by GC/MS using liquid-liquid and solid phase extractions. Pharm Res 1993; 10(suppl):1180.
8. Levy WJ, Shapiro HM, Maruchak G, Meathe E: Automated EEG processing for intraoperative monitoring: A comparison of techniques. ANESTHESIOLOGY 1980; 53:223-36.
9. Yamaoka K, Nakagawa T, Uno T: Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm 1978; 6:547-58.
10. Gibaldi M, Perrier D: Absorption kinetics and bioavailability, Pharmacokinetics. 2nd edition. Edited by Swarbrick J. New York, Marcel Dekker, 1982, pp 145-98.
11. Wagner JG: Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. J Pharmacokinet Biopharm 1976; 4:443-67.
12. Hull CJ, van Beem HBH, Mcleod K, Sibbald A, Watson MJ: A pharmacodynamic model for pancuronium. Br J Anaesth 1978; 50:1113-23.
13. Verotta D, Sheiner LB: Simultaneous modeling of pharmacokinetics and pharmacodynamics: An improved algorithm. Comput Appl Biosci 1987; 3:345-9.
14. Holford NHG, Sheiner LB: Understanding the dose-effect relationship: Clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981; 6:429-53.
15. Shafer SL, Varvel JR: Pharmacokinetics, pharmacodynamics and rational opioid selection. ANESTHESIOLOGY 1991; 74:53-63.
16. Hughes MA, Glass PSA, Jacobs JR: Context-sensitive half-times in multicompartment pharmacokinetics models for intravenous anesthetic drugs. ANESTHESIOLOGY 1991; 76:334-41.
17. Shafer SL, Stanski DR: Improving the clinical utility of anesthetic drug pharmacokinetics. ANESTHESIOLOGY 1992; 76:327-30.
18. Scott JC, Stanski DR: Decreased fentanyl and alfentanil dose requirements with age: A simultaneous pharmacokinetic and pharmacodynamic evaluation. J Pharmacol Exp Ther 1987; 240:159-66.
19. Bovill JG, Sebel PS, Blackburn CL, Heykants J: The pharmacokinetics of alfentanil (R39209): A new opioid analgesic. ANESTHESIOLOGY 1982; 57:439-43.
20. Youngs EJ, Shafer SL: Pharmacokinetic parameters relevant to recovery from opioids. ANESTHESIOLOGY 1994; 81:833-42.
21. Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ: Design, synthesis, and pharmacological evaluation of ultrashort to long acting opioid analgetics. J Med Chem 1991; 34:2202-8.
22. Stanski DR: Pharmacodynamic modeling of anesthetic EEG drug effects. Annu Rev Pharmacol Toxicol 1992; 32:423-47.
23. Jacobs JR, Reyes JG: Effect site equilibration time is a determinant of induction dose requirement. Anesth Analg 1993; 76:1-6.
24. Scott JC, Ponganis KV, Stanski DR: EEG quantitation of narcotic effect: The comparative pharmacodynamics of fentanyl and alfentanil. ANESTHESIOLOGY 1985; 62:234-41.
25. Scott JC, Cooke JE, Stanski DR: Electroencephalographic quantitation of opioid effect: Comparative pharmacodynamics of fentanyl and sufentanil. ANESTHESIOLOGY 1991; 74:34-42.
26. Meuldermans WEG, Hurkmans RMA, Heykants JJP: Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Arch Int Phramacodyn 1982; 257:4-19.
27. Ebling WF, Lee EN, Stanski DR: Understanding pharmacokinetics and pharmacodynamics through computer simulation: I. The comparative clinical profiles of fentanyl and alfentanil. ANESTHESIOLOGY 1990; 72:650-8.
28. Henthorn TK, Avram MJ, Krejcie TC, Shanks CA, Asada A, Kaczynski DA: Minimal compartmental model of circulatory mixing of indocyanine green. Am J Physiol 1992; 262:903-10.
© 1996 American Society of Anesthesiologists, Inc.