REMIFENTANIL
CLINICAL USE OF AN EVANESCENT OPIOID

JOHN BRAMHALL PhD MD
Anesthesiology Division [Box 359724]
Harborview Medical Center
325 Ninth Avenue
Seattle, WA 98104

TEL 206-731-2847
FAX 206-731-8624
bramhall@u.washington.edu

OPIOIDS IN CLINICAL USE
Morphine and fentanyl are the two most widely used intra-operative analgesics in current anesthetic practice. Morphine is the prototypic opioid, against which all others are compared; fentanyl, a potent synthetic structural analog of morphine, was introduced by Paul Janssen in 1964. This was followed in the mid 1970s by sufentanil, and in the late 1970s by alfentanil. These synthetic opioids, although structurally closely related phenylpiperidines, differ markedly in their potency, speed of onset and in their relative rates of redistribution and clearance. The duration of analgesic effect after intravenous bolus administration of a single, small dose of opioid is: morphine>fentanyl>sufentanil>alfentanil; however, this simplistic sequence is complicated by the phenomenon of context sensitivity, a term used to describe the variation in duration of effect for a given drug caused by variations in the size of the dose (or duration of its administration). For example, the analgesic and sedative effects of fentanyl are generally quite short-lived when it is given as a single, small bolus. This is because the drug is rapidly redistributed from the blood to other tissues. If, however, a large dose is given, particularly over time as an infusion, then redistribution routes are overwhelmed and fentanyl then behaves as a relatively persistent drug, longer-acting, in fact, than morphine. Sufentanil and alfentanil both display similar context-sensitivity but to markedly lower extents because of variations in their apparent volume of distribution and the differing rates at which they are cleared, completely, from the body.

Potent inhaled volatile anesthetics can be administered in such a way as to maintain a relatively constant blood concentration of agent. This is facilitated by real-time assay of anesthetic levels in the patient's blood by continuous sampling and analysis of exhaled vapors and subsequent fine calibration of inhaled dose. Intravenous agents are much more difficult to assay in real time so that dosing is problematic if the goal is to attain defined, stable plasma concentrations of any given opioid analgesic or hypnotic. Much effort has been expended in designing dosing algorithms that will predictably establish these defined plasma concentrations of agent in a variety of clinical settings. The phenomenon of context-sensitivity, and existence of multiple sites within the body tissues where drugs may be sequestered after initial administration, complicates the calculations necessary to achieve this goal. Everything is so much simpler if a given drug is redistributed and eliminated, rapidly and predictably from the body, rather than being shunted from compartment to compartment. Anesthesiologists have long recognized the need for a short-acting opioid with a predictable pharmacokinetic profile. This was the logical force leading to the commercial development of remifentanil.
GENERAL PROPERTIES OF REMIFENTANIL
Remifentanil is in the same structural family as fentanyl and the other phenylpiperidines (FIGURE 1). It was brought to clinical trials in 1991, released to the North American market in 1996 and is currently in the late stages of world-wide distribution. It is a novel, short-acting m-receptor opioid agonist; a member of the 4-anilidopiperidine class; unique among the currently marketed agents in being highly vulnerable to inactivation by virtue of its ester structure. Remifentanil undergoes widespread extrahepatic metabolism by blood and tissue nonspecific esterases, resulting in an extremely rapid clearance of approximately 40-60 mL/min. 4,5 Pseudocholinesterase plays no role in remifentanil clearance, hence patients with pseudocholinesterase deficiencies display the same inactivation kinetics as normal subjects.6,7

Like the other members of this class of drugs, remifentanil is lipophilic and is widely distributed in body tissues with a steady-state volume of distribution of approximately 0.3-0.4 L/kg (TABLE 1).4,5 Because of its unique structure, termination of the therapeutic effect of remifentanil mostly depends on metabolic clearance rather than on redistribution. The major metabolite, GR90291, is 2 x 10-4 as potent as remifentanil and exhibits this extremely low in vivo potency because of its low affinity to the m-opioid receptor in combination with a poor brain penetration.8,9

As noted above, the context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modeling using known pharmacokinetic parameters and is defined as the time necessary to achieve a 50% decrease in blood/plasma concentration after termination of a variable-length, continuous infusion targeted to maintain a steady-state concentration; the 'context' is the duration of the infusion. The lack of context-sensitivity for remifentanil is perhaps the most compelling evidence of the pharmacokinetic singularity of the drug.

It is not intuitively obvious whether the modeled context-sensitive half-time simply reflects the time for a 50% decrease in drug concentration or of actual drug effect. In a recent study by Kapila et al. 10 thirty volunteers received a 3-h infusion of remifentanil or alfentanil at equi-effective concentrations. Depression of minute ventilation in response to 7.5% exhaled CO2 was used as a measure of drug effect. Minute ventilation response was measured, and blood samples for drug concentration were taken during and after drug infusion. The recovery of minute ventilation (drug effect) and decrease in blood drug concentration were plotted, and the time for a 50% change in each parameter was determined. Half-time for abolition of clinical effects of remifentanil was approximately 3 minutes (compared to 50 minutes for alfentanil) and was essentially independent of dosage or infusion duration whereas the terminal elimination half-life was 12-30 min for remifentanil (110 min for alfentanil).

Pharmacodynamically, remifentanil is similar to the other fentanyl congeners. The drug produces physiological changes consistent with potent m-receptor agonist activity, including analgesia and sedation. Its adverse effect profile (like that of the other drugs of this class) includes ventilatory depression and apnea, nausea, vomiting, muscular rigidity, bradycardia and pruritus.11 Because it does not release histamine upon injection, remifentanil has fewer adverse hemodynamic effects than morphine.

Dosing of remifentanil can be confusing; there are significant differences between ED50, the dose required to attain half maximal effect of a given clinical parameter, and EC50, the blood concentration required. For opioids the parameter monitored is generally either a defined measure of analgesic effect (reduction of physiologic or behavioral response to a standardized noxious stimulus) or an "anesthetic sparing" effect (the extent to which the amount of anesthetic agent required to inhibit response to noxious stimulus is reduced by the presence of a given dose of opioid). Remifentanil is commonly used as an intravenous infusion with typical rates of 0.1-0.5 mg/kg/min. Comparison of this rate with typical fentanyl infusion rates of 1-2 mg/kg/h would suggest a clinical potency for remifentanil approximately 1/10 of that for fentanyl. However, when actual blood levels of opioid are compared the therapeutic potency of remifentanil turns out to be only slightly less than that of fentanyl, with an EC50 (measured by electroencephalography) of approximately 10 to 20 mg/L.5,12

Remifentanil shows onset kinetics more similar to alfentanil than fentanyl. When these two fast-onset opioids were compared using EEG criteria (the estimated concentration of opioid eliciting 50% of the maximum response (EC50) for delta EEG activity and spectral edge95%), remifentanil was found to be approximately 8 times more potent than alfentanil.9 However, other studies have shown remifentanil to be 20 times more potent than alfentanil, based on the EC50 to achieve loss of response to a verbal command (15 times more potent than alfentanil when assessed by the ED50)13 and very recent studies have suggested that remifentanil is approximately 40 times more potent than alfentanil both when assessed by analgesia tested at several different dose levels using a cold-pressor test14 and when based on comparison of remifentanil and alfentanil whole-blood concentrations necessary to depress the minute ventilatory response to CO2.15

Onset of effect of remifentanil is very rapid and is similar to that of alfentanil, which is reflected in a t1/2 ke0 (min) (a parameter used to characterize the delay between peak blood drug concentration and peak pharmacodynamic effect) of approximately 1 minute.4,5 Studies in dogs yielded similar comparative results, the blood-brain equilibration half-life being 2-5 min for remifentanil and 3.5 min for alfentanil9. This rapid equilibration between blood and brain, coupled with the relative evanescence of remifentanil's effects, allows changes in infusion rate to be very closely couples to changes in clinical response and permits very precise titration to effect. This mitigates some of the uncertainty about precise potency correlations between remifentanil and other opioids. The rapid onset also results in dramatic responses to bolus administration and it is reasonable to point out that extreme caution must be exercised when giving remifentanil by bolus dosing. Note, however, that studies in human volunteers have demonstrated a rapidly developing acute tolerance to the analgesic effect of remifentanil administered by continuous i.v. infusion, leading to the conclusion that the development of tolerance must also be included in the calculations for target-controlled infusions.16

CLINICAL APPLICATIONS
INTUBATION
In a study of 80 healthy, premedicated patients with favorable airway,17 good or excellent intubation conditions (jaw relaxed, vocal cords open, and fewer than two coughs in response to intubation) were reliably attained 90 s after the administration of relatively large doses of remifentanil, with propofol but without use of neuromuscular relaxants. Remifentanil 3 mg/kg was infused intravenously over 90 s. Sixty seconds after beginning the remifentanil infusion, propofol 2 mg/kg was infused over 5 s. Ninety seconds after the administration of propofol, laryngoscopy and tracheal intubation were attempted and graded; excellent intubating conditions were said to be obtained in 80% of the patients. The mean time to resumption of spontaneous ventilation after induction was 5 min and no patient manifested clinically significant muscle rigidity. The report states that the mean arterial pressure decreased 28% immediately before tracheal intubation, but that no patient required treatment for hypotension or bradycardia. Note, however, that a variety of other studies have shown that the use of remifentanil by i.v. bolus administration (in contrast to controlled infusion) seems much more likely to induce clinically significant bradycardia and/or muscle rigidity. 18,19

In a parallel study using smaller doses, the effect of bolus administration of remifentanil on the pressor response to laryngoscopy and tracheal intubation during rapid sequence induction of anesthesia was assessed.20 After preoxygenation, anesthesia was induced with thiopental 5-7 mg kg-1 followed immediately by saline (placebo) or remifentanil 0.5, 1.0 or 1.25 mg/kg given as a bolus over 30 s. Cricoid pressure was applied just after loss of consciousness; succinylcholine 1 mg/kg was given for neuromuscular blockade; laryngoscopy and tracheal intubation were performed 1 min later. Remifentanil 0.5 mg/kg was relatively ineffective in controlling the increase in heart rate and arterial pressure after intubation; the 1.0 and 1.25 mg/kg doses were more effective but the 1.25 mg/kg dose was associated with significant decreases in systolic arterial pressure.

MAINTENANCE
Multiple drugs are used to maintain anesthesia, and potent inhaled volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the potent inhaled anesthetic that will prevent purposeful movement in 50% of patients at skin incision. However, further increases in opioid dose provide only a small additional decrease in MAC. The effect is exponential and a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MACaware (the concentration of volatile agent necessary to ensure oblivion in 50% of patients in the absence of surgical stimulation). Thus, although opioids can be used empirically to reduce the requirements for potent inhaled volatile agent, the precise interaction between opioids and volatile anesthetics is complex. Nevertheless, quantitating the interaction provides a basis for more rational dosing schemes when such combinations are used for anesthesia and allows the anesthetic potency of remifentanil relative to other opioids to be determined.

Recently, two centers enrolled patients into a study in which MAC reduction of isoflurane by remifentanil was determined.21 In this study, the MAC of isoflurane alone was 1.3%. Remifentanil caused the expected exponential reduction in the MAC of isoflurane (a blood concentration of 32 ng/ml remifentanil caused a 90% reduction of isoflurane MAC). This MAC reduction of isoflurane by remifentanil is similar to that produced by other opioids; a 50% isoflurane MAC reduction was produced by 1.37 ng/ml remifentanil whole blood concentration compared to previously published plasma concentrations of fentanyl of 1.67 ng/ml or sufentanil of 0.14 ng/ml); but note that although remifentanil was given at extremely high concentrations, in the absence of isoflurane it did not provide adequate anesthesia. This is an important point, opioids are not anesthetics and the possibility of intraoperative awareness (and of later recall) is very real when appropriate amnestics or hypnotics are missing from the anesthetic regimen.

A similar study by Drover and Lemmens 22 avoiding the use of potent volatile agents demonstrated that the remifentanil blood concentration for which there is a 50% probability of adequate anesthesia during abdominal surgery in the presence of 66% nitrous oxide was 4.1 ng/ml in men and 7.5 ng/ml in women. Comparable values for prostatectomy, nephrectomy, and other abdominal procedures were 3.8, 5.6, and 7.5 ng/ml, respectively.

To put this type of data in a more clinically useful form, a remifentanil infusion of 0.5 mg/kg/min has been shown to be as effective as an alfentanil infusion of 2 mg/kg/min in suppressing intraoperative responses during abdominal surgery.23

EMERGENCE
Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are permissive of adequate spontaneous ventilation and awakening. Combining low dose volatile agent (>MACaware) with analgesic doses of remifentanil makes it likely that, at the termination of a case, both volatile agent and opioid levels will rapidly fall below the critical thresholds for hypnosis and ventilatory depression - the patient will wake up quickly - but the opioid level will also rapidly fall below the critical threshold for acceptable analgesia - the patient will wake up quickly and in pain! Clearly, remifentanil facilitates faster awakening times than any other opioid, but pre-emptive administration of postoperative analgesia (either in the form of peripheral nerve blockade or alternative systemic analgesics) is essential to facilitate comfortable discharge from the OR.

REMIFENTANIL AND CO-MORBIDITY

OBESITY
Egan and co-workers investigated the effects of body mass on remifentanil dosing.24 The essential finding of the study was that the absolute volumes and clearances (i.e., parameters that are not reported per kilogram body weight) are similar in obese versus lean patients. A related finding is that simulated total body weight (TBW)-based dosing in obese patients results in excessively high remifentanil concentrations. The clinical implications of this investigation are clear. Because remifentanil pharmacokinetic parameters appear to be more closely related to lean body mass (LBM) than to TBW, remifentanil dosing should be based on LBM rather than TBW. For practical purposes, because the estimation of LBM requires a somewhat cumbersome calculation that is not well suited to the clinical environment, the report suggested that ideal body weight (IBW), a parameter closely related to LBM and one that is perhaps more easily "guesstimated" by the clinician is probably an acceptable alternative.

To the clinician in everyday practice, this simply means that all patients should be treated as though they are close to IBW when calculating remifentanil dosing schemes. Even substantially overweight and morbidly obese patients should receive remifentanil doses based on IBW. This translates into infusion rates of 0.125 - 1 mg/kg/min and bolus doses of 0.25 - 0.5 mg/kg of IBW for most common "balanced anesthetic" applications.
Surprisingly, the effect of weight on the pharmacokinetics of the previously marketed fentanyl congeners has not been conclusively investigated; much of the existing
literature did not appear beyond abstract form. There are no formal manuscripts, for example, specifically designed to contrast the pharmacokinetics of fentanyl in
obese versus lean subjects. With regard to sufentanil, a report by Schwartz et al.25 suggests that sufentanil exhibits more extensive distribution in obese patients; as for alfentanil, a sophisticated analysis by Maitre et al.26 of a large group of patients who received alfentanil suggests that the volume of the central compartment does correlate with TBW. It is conceivable that the findings of the Egan remifentanil study would not be fully applicable to the other fentanyl congeners because of remifentanil's unusual metabolic pathway.

RENAL DISEASE
An ester linkage renders remifentanil susceptible to rapid metabolism by blood and tissue esterases. This hydrolysis produces metabolites with very weak opioid activity that do not contribute much to the opioid agonist effects of the parent drug. (As previously noted, the major metabolite, GR90291, has extremely low in vivo potency - over 4000 times less potent than remifentanil itself9 - because of a low affinity for the m-opioid receptor in combination with a poor brain penetration8). Thus it was hypothesized that analgesic effectiveness would be unchanged in cases of renal failure because remifentanil elimination itself would be independent of renal function, and GR90291, although eliminated renally, should cause little dependence on renal function of opioid agonism; studies have shown that this is, indeed, the case.3 Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure.27 Thus the steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. However, there were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure; the pharmacokinetics and pharmacodynamics of remifentanil were not altered in patients with renal disease, even though the elimination of its principal metabolite was markedly reduced. Based on simulations, the concentration of GR90291 at the end of a 12-h remifentanil infusion of 2 mg/kg/min is not likely to produce significant opioid effects.27

HEPATIC DISEASE
By similar logic (above) clearance of remifentanil should also be relatively unaffected by changes in hepatic function. In an early study28 10 volunteers with chronic, stable, severe hepatic disease (awaiting liver transplantation) and 10 matched controls were studied. There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups. However, the subjects with liver disease were noted to be more sensitive to the ventilatory depressant effects of remifentanil, a finding of uncertain clinical significance, considering the extremely short duration of action of the drug.

In a later case report, Dumont and co-workers29 described the case of a 73-yr-old woman anesthetized for a laminectomy. The subject suffered from hepatic failure with mild encephalopathy complicated by several exacerbations associated with previous sedative and opioid therapy. The challenge for anesthesia management was to provide adequate analgesia yet avoid causing perioperative hepatic encephalopathy. Remifentanil was used to provide intraoperative and postoperative analgesia and close monitoring of the respiratory and neurological status throughout the administration led to the conclusion that remifentanil can provide excellent perioperative analgesia for otherwise fragile patients at risk of developing hepatic encephalopathy.

CARDIAC DISEASE
A major benefit of opioid anesthesia (particularly fentanyl) is the cardiovascular stability that obtains during induction and throughout operation, even in patients with severely impaired cardiac function. Opioids decrease the sympathetic and somatic responses to noxious stimulation and can be administered in high doses without negative inotropic effects, even in patients with impaired cardiac function. High doses of opioids can reduce or prevent many of the hormonal and metabolic responses to the stress of surgery. However, it should be appreciated that even very large doses of fentanyl or its analogs do not prevent marked increases in plasma catecholamine concentrations in response to cardiopulmonary bypass; and also that the reductions in hormonal and metabolic stress response does not appear to continue post-operatively, after discontinuation of the high-dose opioid therapy.30

With previously available opioids, precise titration of dose to effect was often quite difficult, and high doses often resulted in drug accumulation and prolonged respiratory depression. Remifentanil with its rapid onset, short latency to peak effect, and a very short duration of action when withheld could be presumed to be ideal for many cardiac cases.3 For cardiac surgery that does not involve cardiopulmonary bypass (CPB), such as pacemaker implantation or mini-CAB procedures, remifentanil certainly does seem to be useful. Remifentanil use in patients with severely reduced left ventricular function has been shown to be safe, well-controllable, and permissive of early extubation, e.g. after implantation of defibrillator devices.31 A corollary of this study is that, because patients without complications did not need a postoperative intensive care unit stay, costs may be considerably reduced.

Is remifentanil equally useful in cases involving CPB? To assess the effects of bypass on remifentanil pharmacokinetics, 16 patients undergoing coronary revascularization requiring CPB received high dose remifentanil (2 or 5 mg/kg/min) by infusion over 1 min at three different time points: after sternotomy but before commencing CPB, during hypothermic CPB and during CPB after rewarming.32 Only hypothermic CPB reduced the rate of clearance of remifentanil, by an average of 20%; this reduction being attributed to the effect of temperature on blood and tissue esterase activity. The results from a number of similar studies suggest that, although the pharmacokinetics relating to clearance become more complex when CPB is involved, remifentanil certainly seems still to be useful for patients presenting with poor ventricular function, permitting high-dose opioid therapy without sacrificing early wake-up.33 It really has to be emphasized again, however, that after balanced anesthesia with remifentanil there is significant risk of pronounced sympatho- adrenergic stimulation occurring. This is because of the more rapid clearance of the analgesic effect in the recovery period compared to fentanyl or alfentanil - necessitating skillful and timely administration of more analgesics and medications for the control of the hemodynamic parameters in the immediate postoperative period.34

EXTREMES OF AGE
The unique features of remifentanil are its rapid clearance and binding kinetics, resulting in a rapid onset and offset of drug effect. These characteristics make remifentanil an easy drug to titrate to effect but patient covariates such as early or advanced age must be acknowledged when choosing a dosing regimen.35 The rapid onset of drug effect may be accompanied by rapid onset of adverse events such as apnea and muscle rigidity. The rapid offset of drug effect can result in patients who are in severe pain at a time when the anesthesiologist is ill equipped to deal the problem, for example when the patient is in transit to the recovery room. It is thus important that when treating geriatric or pediatric patients anesthesiologists understand the proper dose adjustment required for the extremes of age.

In the case of elderly patients, dosing of remifentanil should be cautiously reduced in comparison with normal adult values. It is difficult to give specific dose recommendations, but when the pharmacokinetics and pharmacodynamics of remifentanil were studied in complex simulation exercises, and also in 65 healthy volunteers, using the electroencephalogram (EEG) to measure the opioid effect, the infusion rate required to maintain 50% EEG effect in a typical 80-yr old was found to be approximately one third that required in a typical 20-yr old.36,37 Failure to adjust the infusion rate for age resulted in a more rapid onset of EEG effect and more profound steady-state EEG effect in the simulated elderly population. Also, when bolus dosing was analyzed, an 80-yr old person required approximately one half the bolus dose of a 20-yr old of similar size and weight to reach the same peak EEG effect. Simulations suggested that the time required for a decrease in effect site concentrations will be more variable in the elderly, and, as a result, elderly patients may occasionally have a slower emergence from anesthesia than expected.37

Remifentanil is safe for use in children, although no data are available on the use of remifentanil in pediatric patients under 2 years of age. Dosing should be determined by lean body weight and, to re-emphasize, appropriate analgesia should be supplied during and after emergence from anesthesia in order to minimize the risks of complications such as emesis , agitation and laryngospasm. Postoperative agitation and nausea do not, in general, appear to be problems associated with remifentanil use in children. Several studies have been conducted; in one 38 propofol-remifentanil anesthesia was compared with a desflurane-nitrous anesthesia with particular regard to the recovery of characteristics in 50 children (4-11 years old) scheduled for ENT surgery. In one group anesthesia was maintained with infusion of propofol and remifentanil, ventilation was with oxygen in air. In the second group anesthesia was maintained with desflurane in 50% N20. The conclusion of the study was that anesthesia remifentanil and propofol is a well-tolerated anesthesia method, with a lower perioperative heart rate and less postoperative agitation compared with a desflurane-nitrous based anesthesia.38

A randomized, controlled clinical trial of 115 patients undergoing dental restoration indicated that an anesthetic technique using remifentanil provided quality of emergence comparable to, and no greater incidence of vomiting than, a non-opioid technique.39 The study sample consisted of 115 pediatric patients undergoing dental restoration and extraction who were randomly assigned to the non-opioid or remifentanil groups based on their hospital admission numbers. The non-opioid patients received sufficient desflurane to prevent movement, typically 7%-9%. The remifentanil group received remifentanil 0.2 mg/kg/min and enough desflurane to prevent movement, typically 3.2%-3.6% end-tidal at equilibrium. A trained post-anesthesia care unit nurse, blinded to the anesthetic technique, assessed the quality of emergence and incidence of vomiting.

SPECIFIC APPLICATIONS
NEUROANESTHESIA
Remifentanil appears to behave in a similar fashion to other agents such as fentanyl and alfentanil and may offer significant advantages for neurosurgical procedures in which prolonged anesthetic effects can delay assessment of the patient.40 Remifentanil allows for early neurologic evaluation without sacrificing the hemodynamic stability of high-dose opioid techniques. Induction hemodynamics can be controlled (remifentanil is 31 times more potent than alfentanil for effects on MAP - mean arterial pressure41), intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are relatively stable for any given MAP42 and cerebrovascular CO2 reactivity is maintained.43

When transcranial Doppler sonography was used to monitor remifentanil-induced changes in cerebral perfusion it was found that large doses of remifentanil (3 mg/kg/min) reduced cerebral blood flow velocity despite constant perfusion pressure,44 perhaps implicating a central mechanism for cerebral hemodynamic effects of remifentanil.

Remifentanil and propofol in combination may be a useful technique for awake craniotomy.45 Infusions of these agents were used to provide analgesia and sedation during an awake craniotomy to resect a left frontoparietal glioblastoma near the motor speech center. This type of operation presents anesthetic requirements ranging from adequate analgesia during bone flap removal to an appropriate level of consciousness during cortical speech mapping. Changes in infusion rates of both propofol and remifentanil are quickly followed by changes in the effect site concentrations which correspond well with the desired changes in patient sedation and analgesia.

In neurosurgical cases involving monitoring somatosensory evoked potentials, such as occurs with posterior fossa manipulations or complex spinal surgery, variation of remifentanil infusion dosage provides an excellent method for responding to variable physiologic stressors (intermittent surgical stimulation) without compromising the electrophysiologic monitoring. Comparable variation of potent inhaled volatile agent concentration (e.g. isoflurane) invariably leads to changes in SSEP signal intensity that can be confusing when they occur at the same time as significant surgical manipulation of the brain-stem or cord structures. It is interesting (although of unclear clinical significance) that, in cats, morphine and fentanyl both disrupt cholinergic neurotransmission in the pontine network known to modulate REM sleep and cortical electroencephalographic activation whereas remifentanil apparently does not.46

AMBULATORY SURGERY
It might be thought that an evanescent analgesic capable of precise titration during surgical procedures or manipulations would be an ideal agent for day-surgery cases where the emphasis seems frequently to be on rapid and predictable discharge from the surgical facility. The tendency is to avoid the use of volatile anesthetics - because of their association with nausea and postoperative malaise - and to use hypnotics such as propofol and midazolam in conjunction with small doses of analgesic opioids or regional nerve blocks (See TIVA below). Even when regional anesthesia is the principal technique, patients often require (or request) concomitant medication for comfort and, occasionally, it is necessary to provide modest analgesia during certain types of nerve block placement (e.g., ankle block or retrobulbar block). Because remifentanil is a powerful analgesic and seems to exhibit, at low doses, distinct sedative properties it ought to be useful for short-term analgesia or supplementation of regional anesthesia in day-surgery settings.47

Not surprisingly, then, several recent studies have attempted to compare remifentanil with a propofol-based sedation technique for monitored anesthesia care. In one,48 44 patients were enrolled in a recent study and received intravenous midazolam 2 mg, followed by a continuous infusion of either propofol 75 mg/kg/min, or remifentanil 0.1 mg/kg/min (which was subsequently titrated to maintain optimal patient comfort without respiratory depression). Remifentanil provided comparable intraoperative conditions and patient comfort at a lower sedation level compared with propofol. However, use of remifentanil resulted in greater respiratory depression compared with propofol, with decreases in the remifentanil infusion rate required by a high proportion of patients because of a slow respiratory rate (<8 breaths/min) and/or oxygen desaturation measured by pulse oximetry (SpO2 <90%). Median times to ambulation and to being judged "fit for discharge" were found to be slightly, but significantly, shorter following propofol (40 and 47 minutes, respectively) compared with remifentanil (52 and 58 minutes, respectively). The conclusion was that remifentanil provided comparable intraoperative conditions and patient comfort at a lower sedation level compared with propofol, but that remifentanil was associated with greater respiratory depression and a longer time to home readiness.

In similar study of adult patients who underwent orthopedic or urogenital surgery with axillary, ankle, or spinal block,49 patients were randomized to receive either an infusion of remifentanil 0.2 mg/kg/min or propofol 100 mg/kg/min 5 minutes before nerve block placement; the infusions were decreased by 50% on block completion, increased by 50% for patient discomfort, and decreased by 50% for hypoventilation (<8 breaths/min) or hemodynamic instability. At the doses studied, remifentanil was more effective than propofol in minimizing pain without producing excessive sedation, but again it was associated with more transient respiratory depression and, in this study, troublesome short-term nausea.

In another open, prospective trial,50 patients were randomly allocated to receive continuous infusions of remifentanil (0.1 mg/kg/min) or propofol (180 mg/kg/min) for sedation during spinal or axillary regional anesthesia. Infusion rates were titrated to maintain an acceptable sedation level. Return to normal alertness after discontinuation of the infusion occurred after 10 (± 6 min) in the remifentanil group and after 16 (± 15 min) in the propofol group. The incidence of hypotension, bradycardia, and nausea and vomiting were similar in both groups, but intraoperative respiratory depression and nausea were more prominent in the remifentanil group. The conclusion of the authors was that, when titrated to the same sedation level, remifentanil provided a smoother hemodynamic profile than propofol during regional anesthesia, but that the frequent occurrence of remifentanil-induced respiratory depression requires very cautious administration of this agent.51,50

The singular clinical advantage of remifentanil in the out-patient setting is its rapid and predictable clearance from the body. It is therefore quite surprising that studies (above) suggest that it takes close to 1 hour for patients to recover from the effects of remifentanil infusion.48 It is possible that co-administration of 2 mg midazolam affected the discharge times. However, it is worth noting that in a recent study,14 a psychomotor test administered a full 60 min after a remifentanil infusion had been discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. In this study 10 healthy volunteers were enrolled in a randomized, double-blind, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test. A psychomotor test administered 60 min after the remifentanil infusion had been discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. The authors of this study caution that the notion that all the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be treated with some degree of caution.14

OBSTETRICS
Remifentanil certainly crosses the placenta but appears to be rapidly metabolized and redistributed and, with well-controlled infusions, maternal sedation and respiratory changes occur, but without apparent adverse neonatal or maternal effects. Kan et al. evaluated the placental transfer of remifentanil and the neonatal effects when it is administered as an intravenous infusion.52 Nineteen parturients undergoing nonemergent cesarean section with epidural anesthesia received 0.1 mg/kg/min remifentanil intravenously, which was continued until skin closure. Maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood samples were obtained at delivery for analysis of drug concentrations of remifentanil, its metabolite, and blood gases. The means and standard deviations from the mean of UV:MA and UA:UV ratios for remifentanil were 0.88 ± 0.78 and 0.29 ± 0.07, respectively. Mean clearance was 93 ml/min/kg. The mean MA (GR90291):MA (remifentanil) ratio was 2.92 ± 3.65. There were no adverse effects on the neonates even in the presence of a sedative and respiratory depressant effect on the mothers.

A recent case report describes how remifentanil was effective in producing stable hemodynamic conditions, without severe neonatal respiratory depression, during induction and maintenance of general anesthesia for a Cesarean delivery in a parturient with a large intracranial tumor.53

POST-ANESTHESIA CARE UNIT (PACU)
Remifentanil can be administered (in the United States) as a postoperative analgesic agent, however, it should only be used in the presence of adequate supervision and monitoring of the patient; administration of bolus doses is not recommended in this setting.11,54 A recent report describing a case of postoperative apnea in the recovery room, 25 minutes after tracheal extubation, in a fully awake patient.55 This event occurred after flushing of an obstructed IV line into which remifentanil had been injected through a 3-way stopcock during anesthesia.

TOTAL INTRAVENOUS ANESTHESIA (TIVA)
"Smart" infusion pumps for the administration of propofol by target controlled infusion are now commercially available and are becoming more widely used. Among currently available analgesic drugs, alfentanil and remifentanil are considered to be the most suitable for administration by target controlled infusion,56 but commercial systems for administration of these agents are not yet available. The goal is to deliver controlled infusion of drug to attain constant steady-state plasma concentration without necessitating regular assay of blood samples. As mentioned earlier, the whole approach is quite complex when the drug in question undergoes multiple transformations and/or redistribution so an agent such as remifentanil is well-suited to TIVA techniques. Even with such agents, however, the calculations are far from simple; constant plasma levels may not equate to constant clinical effectiveness. For example, tolerance to opioid agonists can be profound and may develop very rapidly. Studies in experimental animals and also in human volunteers have demonstrated a rapidly developing acute tolerance to the analgesic effect of opioids administered by continuous i.v. infusion.

In one such study,16 the analgesic effect of remifentanil, infused at a constant rate of 0.1 mg/kg/min for 4 h, was evaluated by measuring pain tolerance with thermal (2o C water) and mechanical (pressure) noxious stimulations in 13 paid volunteers. The constant-rate infusion of remifentanil resulted in a threefold increase in pain tolerance with both tests. After reaching its maximum in 60-90 min, the analgesic effect of remifentanil began to decline despite the constant-rate infusion, and after 3 h of infusion, it was only one fourth of the peak value. Leading to the conclusion that the development of tolerance must also be included in the calculations for target-controlled infusions.

To make things slightly more complicated, a very recent study57 found that venous concentrations were lower than arterial concentrations during the infusion of remifentanil and that, as a consequence, pharmacokinetic parameters estimated from venous and arterial data differed significantly. When arterial concentrations were plotted against electroencephalographic effect, a classic counterclockwise hysteresis loop was observed, indicating a time-lag between changes in concentration and changes in effect. However, concentrations from venous blood produced a clockwise hysteresis loop that would classically suggest the development of acute tolerance. If this study had been conducted with venous samples alone, inappropriate conclusions such as acute tolerance might have been inferred. When designing studies to measure the acute time course (i.e., non-steady state) of concentration and effect, the potential effects of sampling site on pharmacokinetic and pharmacodynamic characteristics must be carefully considered, particularly when the arteriovenous drug concentration difference is large.57

COST
In today's climate of cost- consciousness, careful economic evaluation of new anesthetic regimens is considered necessary and new (expensive) agents have a hard time gaining admission to institutional formularies. Remifentanil cost a lot to bring to clinical practice (probably in the region of $0.5 billion) and North American sales have so far been quite modest . Clearly, an overall cost-effectiveness analysis of new anesthetic regimens must balance the direct cost of anesthetics and beneficial effects leading to improved patients' comfort and safety. Current outpatient acquisition costs of synthetic opioids as determined by the University of Washington pharmacies are listed below for general, approximate, comparative purposes (TABLE 2).

Again, purely for comparative purposes, a typical opioid infusion during a 2-4 hour general surgical case might be 2 mg/kg/h for fentanyl, 0.5 mg/kg/h for sufentanil, 100 mg/kg/h for alfentanil, and 15 mg/kg/h for remifentanil. To put this information in its appropriate context, OR time is priced at $20-25 per minute in a typical large medical center in the United States; a 5 minute delay in transfer from OR to PACU "costs" about $100; so, if a new agent such as remifentanil, can be demonstrated to facilitate rapid transfer from OR to PACU at the conclusion of surgery (and rapid discharge from the PACU) then its use may readily be justified even if the primary considerations driving agent selection are economic. A further, slightly contentious, editorial point to make is that the expenditure on anesthetic agents normally represents a trivial proportion of the overall cost of almost any surgical procedure; "saving" money by using the cheapest muscle relaxants, hypnotics and analgesics can often result in a much greater overall cost in other resources.

In a 1999 study, Suttner and co-workers58 found that the cost of discarded anesthetic drugs accounted for almost 18% of total intraoperative costs. A TIVA regimen using propofol and remifentanil was compared with a standard propofol anesthesia regimen and an inhaled anesthetic technique using isoflurane. Target-controlled infusion/total IV anesthesia was associated with the largest intraoperative costs but allowed the most rapid recovery from anesthesia, was associated with fewest postoperative side effects, and permitted earlier discharge from the postanesthesia care unit.

CONCLUSION
New agents become available infrequently in anesthesia; they are usually brought to market because they fit a "niche" or because they offer cost or safety or efficiency advantages over currently available agents, or perhaps because they allow techniques to be used that were previously impractical. For example, the introduction of sevoflurane facilitated pleasant, efficient mask induction of adult patients; the introduction of EMLA made i.v. sticks a little more palatable for children; the introduction of ondansetron offered non-sedating nausea prophylaxis; cis-atracurium significantly reduced the cost of short-term muscle relaxation; the LMA provided an alternative to direct laryngoscopy for many patients undergoing general anesthesia - the list is quite long. These novel agents are always certified to be safe but it is very difficult to demonstrate that they are 'safer'. The question of whether or not they are 'cheaper' or can be made to appear cost-effective often involves gymnastics on the part of corporate representatives and is, in most cases, highly dependent on styles of clinical practice and case mix. However, the general trend is for anesthetic agents to become more easy to use: easier to administer, easier to titrate to effective dose, easier to reverse, faster to act when their action is required, quicker to be eliminated when they are no longer needed, and these are all properties that can be assessed quite accurately, if subjectively, by individual anesthetists in their daily practice.

The unique pharmacokinetic profile of remifentanil facilitates 'real time' management of intraoperative stress, as well as provision of optimal intraoperative analgesia without compromising recovery for a variety of surgical procedures. It is a safe drug when used appropriately (monitors, constant observation) and it is relatively easy to titrate; clinicians should have less need to consider patient covariates such as extremes of age or size or co-morbidity when choosing a dosing regimen. However, the rapid onset of drug effect may be accompanied by rapid onset of adverse events such as apnea and muscle rigidity; and the rapid offset of drug effect can result in patients who are in severe pain upon discharge from the Operating Room at a time when the anesthesiologist is ill equipped to deal the problem.59 In most regards remifentanil is an elegant drug; potent, precise, facilitating tight control of the analgesic regimen to match the intensity of stimulation. this author suspects that the principal reason that it has not become much more widely has to do with its apparent pharmacy cost. It would be unfortunate for this drug to fall into disuse largely because of our failure to appreciate the subtle relationship between price, cost and cost effectiveness.

REFERENCES
1. Patel SS, Spencer CM: Remifentanil. Drugs 52: 417-27, 1996
2. Hughes MA, Glass P.S., Jacobs J.R.: Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 76: 334-343, 1992
3. Michelsen LG, Hug CC, Jr.: The pharmacokinetics of remifentanil. J Clin Anesth 8: 679-82, 1996
4. Glass PSA, Gan TJ, Howell S: A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesth Analg 89: S7-14, 1999
5. Egan TD: Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet 29: 80-94, 1995
6. Selinger K, Nation RL, Smith GA: Enzymatic and chemical hydrolysis of remifentanil. Anesthesiology 83: A385, 1995
7. Stiller RL, Davis PJ, McGowan FX: In vitro metabolism of remifentanil: the effects of pseudocholinesterase deficiency. Anesthesiology 83: A381, 1995
8. Cox EH, Langemeijer MW, Gubbens-Stibbe JM, Muir KT, Danhof M: The comparative pharmacodynamics of remifentanil and its metabolite, GR90291, in a rat electroencephalographic model. Anesthesiology 90: 535-44, 1999
9. Hoke JF, Cunningham F, James MK, Muir KT, Hoffman WE: Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs. J Pharmacol Exp Ther 281: 226-32, 1997
10. Kapila A, Glass PS, Jacobs JR, Muir KT, Hermann DJ, Shiraishi M, Howell S, Smith RL: Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 83: 968-75, 1995
11. Schuttler J, Albrecht S, Breivik H, Osnes S, Prys-Roberts C, Holder K, Chauvin M, Viby-Mogensen J, Mogensen T, Gustafson I, Lof L, Noronha D, Kirkham AJ: A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery. Anaesthesia 52: 307-17, 1997
12. Michelsen LG, Salmenpera M, Hug CC, Jr., Szlam F, VanderMeer D: Anesthetic potency of remifentanil in dogs. Anesthesiology 84: 865-72, 1996
13. Jhaveri R, Joshi P, Batenhorst R, Baughman V, Glass PS: Dose comparison of remifentanil and alfentanil for loss of consciousness. Anesthesiology 87: 253-9, 1997
14. Black ML, Hill JL, Zacny JP: Behavioral and physiological effects of remifentanil and alfentanil in healthy volunteers. Anesthesiology 90: 718-26, 1999
15. Glass PS, Iselin-Chaves IA, Goodman D, Delong E, Hermann DJ: Determination of the potency of remifentanil compared with alfentanil using ventilatory depression as the measure of opioid effect. Anesthesiology 90: 1556-63, 1999
16. Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 86: 1307-11, 1998
17. Stevens JB, Wheatley L: Tracheal intubation in ambulatory surgery patients: using remifentanil and propofol without muscle relaxants. Anesth Analg 86: 45-9, 1998
18. Thompson JP, Hall AP, Russell J, Cagney B, Rowbotham DJ: Effect of remifentanil on the haemodynamic response to orotracheal intubation. Br J Anaesth 80: 467-9, 1998
19. Hogue CW, Jr., Bowdle TA, O'Leary C, Duncalf D, Miguel R, Pitts M, Streisand J, Kirvassilis G, Jamerson B, McNeal S, Batenhorst R: A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. Anesth Analg 83: 279-85, 1996
20. O'Hare R, McAtamney D, Mirakhur RK, Hughes D, Carabine U: Bolus dose remifentanil for control of haemodynamic response to tracheal intubation during rapid sequence induction of anaesthesia. Br J Anaesth 82: 283-5, 1999
21. Lang E, Kapila A, Shlugman D, Hoke JF, Sebel PS, Glass PS: Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 85: 721-8, 1996
22. Drover DR, Lemmens HJ: Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery [In Process Citation]. Anesthesiology 89: 869-77, 1998
23. Kovac AL, Azad SS, Steer P, Witkowski T, Batenhorst R, McNeal S: Remifentanil versus alfentanil in a balanced anesthetic technique for total abdominal hysterectomy. J Clin Anesth 9: 532-41, 1997
24. Egan TD, Huizinga B, Gupta SK, Jaarsma RL, Sperry RJ, Yee JB, Muir KT: Remifentanil pharmacokinetics in obese versus lean patients [see comments]. Anesthesiology 89: 562-73, 1998
25. Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacokinetics of sufentanil in obese patients. Anesth Analg 73: 790-3, 1991
26. Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR: Population pharmacokinetics of alfentanil: The average dose-plasma concentration relationship and interindividual variability in patients. Anesthesiology 66: 3-12, 1987

27. Hoke JF, Shlugman D, Dershwitz M, Michalowski P, Malthouse-Dufore S, Connors PM, Martel D, Rosow CE, Muir KT, Rubin N, Glass PS: Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers. Anesthesiology 87: 533-41, 1997
28. Dershwitz M, Hoke JF, Rosow CE, Michalowski P, Connors PM, Muir KT, Dienstag JL: Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology 84: 812-20, 1996
29. Dumont L, Picard V, Marti RA, Tassonyi E: Use of remifentanil in a patient with chronic hepatic failure. Br J Anaesth 81: 265-7, 1998
30. Stanley TH: Opiate anaesthesia. Anaesth Intensive Care 15: 38-59, 1987
31. Lehmann A, Boldt J, Zeitler C, Thaler E, Werling C: Total intravenous anesthesia with remifentanil and propofol for implantation of cardioverter-defibrillators in patients with severely reduced left ventricular function. J Cardiothorac Vasc Anesth 13: 15-9, 1999
32. Russell D, Royston D, Rees PH, Gupta SK, Kenny GN: Effect of temperature and cardiopulmonary bypass on the pharmacokinetics of remifentanil. Br J Anaesth 79: 456-9, 1997
33. Camu F, Royston D: Inpatient experience with remifentanil. Anesth Analg 89: S15-21, 1999
34. Apitzsch H, Olthoff D, Thieme V, Wiegel M, Bohne V, Vetter B: [Remifentanil and alfentanil: Sympathetic-adrenergic effect in the first postoperative phase in patients at cardiovascular risk]. Anaesthesist 48: 301-9, 1999
35. Shafer SL: The role of newer opioids in geriatric anesthesia. Acta Anaesthesiol Belg 49: 91-103, 1998
36. Minto CF, Schnider TW, Shafer SL: Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology 86: 24-33, 1997
37. Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL: Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 86: 10-23, 1997
38. Grundmann U, Uth M, Eichner A, Wilhelm W, Larsen R: Total intravenous anaesthesia with propofol and remifentanil in paediatric patients: a comparison with a desflurane-nitrous oxide inhalation anaesthesia. Acta Anaesthesiol Scand 42: 845-50, 1998

39. Pinsker MC, Carroll NV: Quality of emergence from anesthesia and incidence of vomiting with remifentanil in a pediatric population. Anesth Analg 89: 71-4, 1999
40. Warner DS: Experience with remifentanil in neurosurgical patients. Anesth Analg 89: S33-39, 1999
41. Warner DS, Hindman BJ, Todd MM, Sawin PD, Kirchner J, Roland CL, Jamerson BD: Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in patients undergoing supratentorial craniotomy. Anesth Analg 83: 348-53, 1996
42. Guy J, Hindman BJ, Baker KZ, Borel CO, Maktabi M, Ostapkovich N, Kirchner J, Todd MM, Fogarty-Mack P, Yancy V, Sokoll MD, McAllister A, Roland C, Young WL, Warner DS: Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions. Anesthesiology 86: 514-24, 1997
43. Ostapkovich ND, Baker KZ, Fogarty-Mack P, Sisti MB, Young WL: Cerebral blood flow and CO2 reactivity is similar during remifentanil/N2O and fentanyl/N2O anesthesia. Anesthesiology 89: 358-63, 1998
44. Paris A, Scholz J, von Knobelsdorff G, Tonner PH, Schulte am Esch J: The effect of remifentanil on cerebral blood flow velocity. Anesth Analg 87: 569-73, 1998
45. Johnson KB, Egan TD: Remifentanil and propofol combination for awake craniotomy: case report with pharmacokinetic simulations. J Neurosurg Anesthesiol 10: 25-9, 1998
46. Mortazavi S, Thompson J, Baghdoyan HA, Lydic R: Fentanyl and morphine, but not remifentanil, inhibit acetylcholine release in pontine regions modulating arousal. Anesthesiology 90: 1070-7, 1999
47. Servin F, Desmonts JM, Watkins WD: Remifentanil as an analgesic adjunct in local/reional anesthesia and in monitored anesthesia care. Anesth Analg 89: S28-32, 1999
48. Smith I, Avramov MN, White PF: A comparison of propofol and remifentanil during monitored anesthesia care. J Clin Anesth 9: 148-54, 1997
49. Mingus ML, Monk TG, Gold MI, Jenkins W, Roland C: Remifentanil versus propofol as adjuncts to regional anesthesia. Remifentanil 3010 Study Group. J Clin Anesth 10: 46-53, 1998
50. Lauwers MH, Vanlersberghe C, Camu F: Comparison of remifentanil and propofol infusions for sedation during regional anesthesia. Reg Anesth Pain Med 23: 64-70, 1998
51. Lauwers M, Camu F, Breivik H, Hagelberg A, Rosen M, Sneyd R, Horn A, Noronha D, Shaikh S: The safety and effectiveness of remifentanil as an adjunct sedative for regional anesthesia. Anesth Analg 88: 134-40, 1999

52. Kan RE, Hughes SC, Rosen MA, Kessin C, Preston PG, Lobo EP: Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology 88: 1467-74, 1998
53. Bedard JM, Richardson MG, Wissler RN: General anesthesia with remifentanil for Cesarean section in a parturient with an acoustic neuroma. Can J Anaesth 46: 576-80, 1999
54. Yarmush J, D'Angelo R, Kirkhart B, O'Leary C, Pitts MC, 2nd, Graf G, Sebel P, Watkins WD, Miguel R, Streisand J, Maysick LK, Vujic D: A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofol. Anesthesiology 87: 235-43, 1997
55. Fourel D, Almanza L, Aubouin JP, Guiavarch M: [Remifentanil: postoperative respiratory depression after purging of the infusion line]. Ann Fr Anesth Reanim 18: 358-9, 1999
56. Milne SE, Kenny GN: Future applications for TCI systems. Anaesthesia 53 Suppl 1: 56-60, 1998
57. Hermann DJ, Egan TD, Muir KT: Influence of arteriovenous sampling on remifentanil pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 65: 511-8, 1999
58. Suttner S, Boldt J, Schmidt C, Piper S, Kumle B: Cost analysis of target-controlled infusion-based anesthesia compared with standard anesthesia regimens. Anesth Analg 88: 77-82, 1999
59. Glass PS, Gan TJ, Howell S, Ginsberg B: Drug interactions: volatile anesthetics and opioids. J Clin Anesth 9: 18S-22S, 1997
60. Bovil JG: Pharmacokinetics and pharmacodynamics of opioid agonists. Anaesthetic Pharmacology Review 1: 122-132, 1993

TABLE 1

Morphine Fentanyl Sufentanil Alfentanil Remifentanil
pKa 7.9 8.4 8.0 6.5 7.1
Protein binding (%) 35 84 93 92 92
Clearance (L/min) 1 1.5 1 0.25 3-4
Vdss (L) 224 335 123 27 30
Elimination t1/2 (h) 2-3 3-6 2-5 1-2 0.15-0.3
t1/2 ke0 (min) 4-5 0.6-1.2 1.0-1.5

TABLE 1
Physicochemical characteristics and pharmacokinetics of remifentanil compared with other opioids (data for 70 kg adults).

pKa = equilibrium dissociation constant; Vdss = steady-state volume of distribution; t1/2 ke0 (min)= half-time for equilibration between plasma and effect compartment.
Modified from 60 and Glass et al..4

TABLE 2

Morphine Fentanyl Sufentanil Alfentanil Remifentanil
Amount (mg) 10 0.25 0.25 2.5 5
Cost (US$) 0.46 2.34 29.52 11.88 35.62

Current outpatient acquisition costs, University of Washington pharmacies (source: University of Washington Drug Formulary, 17th edition).

FIGURE LEGEND

FIGURE 1

Comparative structures of opioids in common clinical use, showing their structural relationships to the phenylpiperidine ring system.