A Review of the Pharmacokinetics and Pharmacodynamics of Remifentanil

Over the past 30 yr, there have been marked improvements in the opioids available to clinicians. The major emphasis in the development of opioids has been increasing potency, increasing safety, and more suitable pharmacokinetics. The development of newer opioids is still directed at achieving these same goals; safety is aimed primarily at differentiating analgesic efficacy from respiratory depressant potency, and pharmacokinetics are aimed toward providing a titratable analgesic with rapid onset and rapid offset. Remifentanil has recently been approved in a number of countries for use as an opioid in the perioperative period, and initial results indicate that through its esterase-based metabolism, it will provide the pharmacokinetic advantages of a truly titratable opioid. Physiochemical Characteristics Remifentanil is a piperidine derivative, a 3-(4-methoxycarbonyl-4-(L-oxopropyl)-phenylamino-L-piperidine) propanoic acid, methyl ester. It is supplied as remifentanil hydrochloride, a white lyophilized powder. The present formulation also contains glycine. It is supplied as 1-, 2-, and 5-mg vials that must be reconstituted and diluted to 25- or 50-μg/mL solutions before administration. Once reconstituted, it has a pH of ±3.0 and a pKa of 7.07 (data on file, Glaxo Wellcome). It undergoes spontaneous degradation, but at a pH 80% is subsequently recovered in urine. Remifentanil acid is approximately 1/300 to 1/2000 the potency of the parent compound. Reprinted with permission from Glass PSA, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra–short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993;77:1031–40.Several studies describing the pharmacokinetics of remifentanil (4–6) have been performed in humans. In the initial assessment, remifentanil demonstrated a rapid onset, small volume of distribution, rapid redistribution, and clearance with a terminal elimination half-life of 8.8–40 min, compared with a terminal elimination half-life for alfentanil of 60–120 min (Table 1) (4–6). The rapid onset of remifentanil is demonstrated by its brief half-time for equilibration between plasma and its effect compartment (t1/2 ke0 of 1.0–1.5 min), which is similar to that of alfentanil (4,5). This short t1/2 ke0, together with its rapid redistribution, results in a time to peak drug effect after a bolus of 1.5 min. Again, this is similar to the rapid onset of effect seen with alfentanil, and it contrasts with the onset of peak effect observed after fentanyl 3–4 min or morphine 20 min. This rapid onset and offset of remifentanil and, thus, minimal latency between dose administration and observed effect should, in clinical practice, translate into an opioid that is very easy to titrate. Table 1: Pharmacokinetics of Remifentanil Compared with Alfentanil and FentanylPublished studies differ in the exact terminal elimination half-life of remifentanil. The reason for this is that a slower elimination phase is only observed when very large doses are administered. When typical clinical doses are given, this slower phase occurs at concentrations below the limit of detection of the assay. However, all published studies agree that remifentanil provides a very rapid decrease in concentration after termination of its administration. This rapid offset in concentration is best demonstrated by its context-sensitive half-time, which is extremely short—3–5 min regardless of the duration of infusion. The context-sensitive half-time is derived from computer simulations that determine the time taken for the plasma drug concentration to decrease by 50% after an infusion scheme designed to obtain and maintain a steady concentration for a given duration. Thus, the context-sensitive half-time includes the contributions of both elimination and redistribution to the rate of decline of drug concentration. The contribution of redistribution to the rate of decline is dependent on the duration of the infusion; thus, the time for a 50% decline is context-sensitive, i.e., it is dependent on the duration of the infusion. Context-sensitive decrement times for any percent decline can be determined through computer simulations using the published pharmacokinetic parameters of remifentanil. Such simulations also predict that the time for its concentration to decrease by 80% is 45 min for alfentanil (Figure 4). In another study, patients administered remifentanil over an 80-fold range of infusion rates were all breathing adequately within 10 min after the infusions (11). In a clinical study in which remifentanil and alfentanil were administered to approximately equipotent doses during a nitrous oxide narcotic technique, the requirement for naloxone 5 min after termination of the infusion was significantly greater in the alfentanil group (50%) compared with the remifentanil group (17%). 2 This very rapid decline in drug effect due to esterase-based metabolism is likely to prevent any delayed respiratory depression after the administration of this drug during anesthesia, even when given at relative concentrations several times greater than those presently used with other opioids. Similarly, its analgesic effect will terminate rapidly; thus, if analgesia is required, the clinician will have to plan to provide pain relief for the patient before discontinuing the drug. Figure 2: Times for an 80% decrease in plasma concentration and the context-sensitive half-time of remifentanil and alfentanil for an infusion maintained at a constant plasma concentration for 1–360 min as modeled from the pharmacokinetics derived from volunteers in this study. Reprinted with permission from Glass PSA, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics and pharmacodynamics of an ultra–short-acting opioid: remifentanil (GI87084B). Anesth Analg 1993;77:1031–40.Figure 3: In the upper graph, the solid line represents the best fit of the percent decline in remifentanil whole blood concentration. In the lower graph, the line represents the percent recovery of minute ventilation for all eight subjects after the termination of a 3-h infusion adjusted to maintain a 40%–70% decrease in minute ventilation when breathing 7.5% CO2. The dots are the measured percent decrease in remifentanil whole blood concentration or minute ventilation for each individual at the set time points.Figure 4: In the upper graph, the solid line represents the best fit of the percent decline in alfentanil whole blood concentration. In the lower graph, the line represents the percent recovery of minute ventilation for all eight subjects after termination of a 3-h infusion adjusted to maintain a 40%–70% decrease in minute ventilation when breathing 7.5% CO2. The dots are the percent decrease in alfentanil whole blood concentration or minute ventilation for each individual at the set time points. Reprinted with permission from Kapila A, Glass PSA, Jacobs JR, et al. Measured context-sensitive half-times of remifentanil and alfentanil. Anesthesiology 1995;83:968–75.The esterase-based metabolism of remifentanil makes its pharmacokinetics independent of end-organ failure. The pharmacokinetics of remifentanil were unaltered in patients with documented hepatic (12) or renal failure (13). Patients with hepatic failure seemed more sensitive to opioids, requiring lower concentrations to produce a 50% suppression of minute ventilation, although variability was high in this study. Thus, patients with liver disease may require smaller doses for a given effect, but recovery from the opioid should remain equally rapid. Patients with renal failure did not demonstrate this increased sensitivity; thus, dosing of remifentanil in these patients will be unaltered, and recovery will remain equally rapid. The lung is not thought to be an important site for metabolism of remifentanil. Delivery of remifentanil to the effect site in the brain after IV administration therefore, should not be subject to first-pass effects occurring in the lung (14). The primary metabolite of remifentanil is dependent on renal excretion and accumulates in patients with renal failure. However, because of the very low potency of the metabolite, simulations indicate that even after a 24-h infusion, the metabolite will not reach clinically significant concentrations (9). In pediatric patients aged 2–12 yr, the pharmacokinetics of remifentanil were very similar to those reported in adults (15). In the elderly, recent data indicate that the onset of drug effect is slower, and the elderly are much more sensitive to remifentanil (as they are to all μ-opioid receptor agonists) as measured by the concentration of remifentanil required to decrease the spectral edge of the EEG by 50%(16). The elderly also tend to have a smaller volume of distribution and a slightly lower clearance. The net result of these differences is that dosing should be decreased with increasing age. It is recommended that in patients >65 yr of age, the initial loading dose should be decreased by 50% and then titrated as required for the individual patient. Like other opioids of the piperidine class, remifentanil readily crosses the placenta (17). However, unlike other opioids, it continues to be rapidly metabolized in the fetus. Preliminary data demonstrated no difference in Apgar score when remifentanil 0.1 μg · kg−1 · min−1 IV was compared with fentanyl 100 μg administered epidurally. However, 2 of the 39 parturients experienced mild respiratory depression after delivery and after the addition of epidural morphine. Further studies are needed to assess the suitability of remifentanil in this population (17). The current formulation of remifentanil contains glycine and therefore cannot be administered epidurally. Work in humans has been with IV administration only. Pharmacodynamics Assessment of Potency All μ-opioid receptor agonists have essentially similar effects; thus, describing their pharmacodynamics is essentially a matter of determining their relative potencies. The potency of an opioid is often quoted in terms of morphine equivalents, which usually refers to its potency after a single bolus administration. However, opioids are given as a single dose or an infusion and, with the advent of target-controlled drug delivery systems, to a target plasma or effect-site concentration (18). Because of the differences in drug disposition, potency varies considerably between these modes of drug administration. Ideally the potency of an opioid is determined by its ability to provide pain relief. Because pain relief is very subjective, numerous other measures of opioid effect have been used to determine relative potencies. These include the ability to suppress the spectral edge of the EEG, induce loss of consciousness, prevent movement on skin incision (when combined with nitrous oxide), reduce the minimum alveolar anesthetic concentration (MAC) of a volatile anesthetics that is necessary to prevent movement on skin incision, or provide a set degree of respiratory depression. The dose/concentration required for any one of these measures of effect seems to vary for any given μ-opioid receptor agonist, but the relative potency of the different opioids seems consistent regardless of which measure is used. Remifentanil produces dose-dependent increases in analgesic effect. Based on its ability to provide analgesia in volunteers after a single bolus-dose administration, remifentanil is 20–30 times more potent than alfentanil (on a milligram for milligram basis) (5). Like alfentanil, increasing analgesic potency is paralleled by increasing respiratory depression. The ability of remifentanil to induce loss of consciousness for the induction of anesthesia has also been compared in a double-blind study with alfentanil. The 50% effective dose (ED50) for loss of consciousness with remifentanil was 12 μg/kg, and with alfentanil was 176 μg/kg, confirming the 10–20 times greater potency of remifentanil compared with alfentanil after a single dose (19). During a 4-h continuous infusion, remifentanil 0.05 μg · kg−1 · min−1 produced an equal degree of respiratory depression to alfentanil 0.5 μg · kg−1 · min−1(11) (Figure 5). Thus, in terms of an infusion, based on its ability to produce respiratory depression in volunteers, remifentanil is 10 times more potent than alfentanil. Recently, Randel et al. 3 established the minimal infusion rate of remifentanil and alfentanil in the presence of 66% nitrous oxide to prevent movement at skin incision. The ED50 for remifentanil was 0.1 μg · kg−1 · min−1 and its ED80 was 0.5 μg · kg−1 · min−1. The response rate after an alfentanil infusion of 0.75 μg · kg−1 · min−1 was the same as the response rate during a remifentanil infusion of 0.04 μg · kg−1 · min−1; thus, both of these studies indicate that remifentanil is 10–20 times more potent than alfentanil in terms of infusion rate. Figure 5: Minute ventilation (percent change) versus time in volunteers receiving a 4-h infusion of remifentanil or alfentanil. Reprinted with permission from Glass PSA, Hardman HD, Kamiyama Y, et al. Pharmacodynamic comparison of GI87084B (GI) a novel ultra-short acting opioid and alfentanil (alf) abstract. Anesth Analg 1992;74:S113.In this same study by Randel et al., 3 whole blood remifentanil concentrations were also measured. The blood/plasma concentration that will prevent a hemodynamic, sympathetic, or somatic response to skin incision in 50% of patients (Cp50skin incision) for remifentanil in the presence of 66% nitrous oxide was 2 ng/mL and for alfentanil was ng/mL blood This with the established incision of alfentanil of ng/mL and for fentanyl of ng/mL The study with remifentanil used as an induction those the of fentanyl and alfentanil had no given with Thus, the for remifentanil of 2 ng/mL may the It is important to that remifentanil is measured as the whole blood other opioids are measured as the plasma concentration. other studies have compared the potency of remifentanil with that of fentanyl or alfentanil in terms of drug concentration. The concentration of remifentanil required to reduce the spectral edge of the EEG by 50% was compared with that of alfentanil The relative potency in this that remifentanil was times more potent than alfentanil. Remifentanil was also compared with alfentanil in a double-blind study, in which both were administered with a target-controlled infusion to produce an equal degree of respiratory depression. In this study, remifentanil was times more potent than alfentanil, based on whole blood or approximately times more potent compared with the alfentanil plasma concentration. The ability of remifentanil to reduce the of has been The same have also the ability of fentanyl and alfentanil to reduce the of The concentration of the opioid to provide a 50% can be to be Based on the potency of remifentanil is approximately equal to that of fentanyl times greater than alfentanil and the potency of (Table Table 2: of the Opioid Based on to the of by In doses to 2 μg/kg, remifentanil produces minimal of blood and rate (5). When remifentanil was compared with alfentanil as an induction drug in the of any other doses of remifentanil and alfentanil produced a similar in blood with a mild decrease in rate (19). Remifentanil doses of in the presence of in a decrease in blood and similar in rate In all of these the in seemed to be greater in blood have occurred in the presence of other and were due to marked which be by patients with Remifentanil does not result in in doses rates of remifentanil 1 μg · kg−1 · min−1 have been to the response (as measured by the concentrations in and after the administration of remifentanil, other results in dose-dependent respiratory depression. In the of any a remifentanil infusion rate of μg · kg−1 · min−1 results in 50% depression of minute ventilation in the presence of in 1 the degree of respiratory depression that results from any dose of remifentanil is dependent not only on the dose but also on such as age, presence of and other The primary of remifentanil over other is that it can be administered during anesthesia, when ventilation is at doses that result in marked respiratory depression and for spontaneous ventilation within 10 min of the infusion. Similarly, if respiratory depression is in a patient is breathing during remifentanil administration, or the infusion will rapidly within 3 required, remifentanil’s respiratory depressant effect can be by naloxone (3). Remifentanil a dose-dependent suppression of the have not been reported during the administration of remifentanil to humans. effects on blood and metabolic rate similar to those of other It has been used in patients with increased for Like other opioids, remifentanil a dose-dependent in the and of Because the onset of effect is very rapid with remifentanil, is more likely to be observed compared with fentanyl or When compared at equipotent the and of was similar between remifentanil and alfentanil. given over 1 min have not been reported to a the initial dose of remifentanil should not 1 given over 1 min. used before the induction of anesthesia, have not observed if a drug is given within of remifentanil. remifentanil is for the of during anesthesia it be more to remifentanil as an infusion. a infusion, the time to reach a concentration is very rapid 5 min to of the concentration or 10 min to of the steady thus, there is to a bolus dose to provide is a brief for a bolus of 1 will provide analgesia at 1 min, for min. a brief of may will prevent any Pharmacodynamic Because remifentanil has an extremely rapid onset and it may be used for the induction of The ED50 for loss of consciousness was 12 However, even at 20 μg/kg, not all patients had In a high of patients and, in the of loss of consciousness was to Thus, the induction of anesthesia with only an opioid is because of the large differences in to opioids and their doses of remifentanil reduce the dose of required to provide loss of dose of remifentanil the induction dose of by approximately to (19). This single dose of remifentanil, may not to the response to and After a loading dose of remifentanil of 1 and a dose of an infusion of μg · kg−1 · min−1 of remifentanil in only of patients to and 3 In the same study, when anesthesia was with and 66% nitrous a remifentanil infusion of 0.5 μg · kg−1 · min−1 a response in 80% of patients at skin incision. 3 The best at induction may be to an infusion of remifentanil at 0.5 μg · kg−1 · min−1 within 30 of the drug to induce loss of The remifentanil infusion is then maintained at this rate has been remifentanil concentration of approximately ng/mL will reduce by The is at a remifentanil concentration of ng/mL (Figure Thus, after the infusion can be adjusted to μg · kg−1 · min−1 to a in Because the pharmacokinetics of remifentanil are and to a its whole blood concentration can be as 20–30 times the infusion rate after it has been maintained for 10 min, an infusion of μg · kg−1 · min−1 is approximately equal to a a ng/mL concentration is required and can be with an infusion of μg · kg−1 · min−1. Figure The in concentration to prevent movement at skin incision in 50% of patients by increasing measured remifentanil whole blood a patient patient did not The solid line is the for a patient aged The patients not receiving any are illustrated in the but are not used in determining the Reprinted with permission from Kapila A, D, et al. of minimal alveolar concentration by remifentanil. Anesthesiology should be by either nitrous nitrous or simulations have the plasma concentrations of by an · kg−1 · min−1 and ng/mL remifentanil by a · kg−1 · min−1 for the rapid when used in a 3-h infusion. this patients are to consciousness in min. This is much than dosing of with alfentanil min), fentanyl min), and These simulations also indicate that increasing the than remifentanil will result in recovery However, because remifentanil cannot loss of consciousness and of a minimal infusion μg · kg−1 · or volatile anesthetic concentration must be administered in with remifentanil. the of it is only to maintain analgesia with remifentanil if the infusion is It is to reduce the infusion rate to μg · kg−1 · min−1 and then alter the infusion rate in · kg−1 · min−1 to obtain a between analgesia and doses of remifentanil should not be used for analgesia due to the for respiratory depression or Because remifentanil has a very rapid elimination half-life and t1/2 ke0, small in the infusion rate will provide rapid in effect for clinical the for bolus When an infusion of remifentanil is used a loading although of its effect is observed 5 min after the of the infusion, its concentration will to over the 30 min. Thus, it is that and of dose to effect is maintained remifentanil is administered to a breathing patient. Remifentanil has properties similar to other potent μ-opioid receptor It have with a rapid onset and rapid offset of effect, regardless of the duration of its administration. remifentanil seems to be a very titratable opioid providing analgesia for either very brief in which analgesia is required or over the for These also provide opioid concentrations that reduce the of volatile which rapid recovery and to