An Overview of Remifentanil

Remifentanil has been approved for clinical use in the United States since July 1996. This new opioid is now in regular clinical use in many countries worldwide. This progress is remarkable for a drug that was first tested in humans in 1990. The rapidity with which remifentanil has cleared various regulatory hurdles is undoubtedly due to the strength of its clinical development program: unlike the earlier fentanyl derivatives, the basic human pharmacology of remifentanil was characterized using sophisticated pharmacokinetic-pharmacodynamic modeling techniques that were not widely available until the 1980s (1). The early (phase I and II) trials provided an unusually detailed picture of the analgesic potency of remifentanil, its side effects, and pharmacokinetic properties. Phase III trials confirmed these earlier findings and established the utility of the drug in normal perioperative settings. The data demonstrated two unequivocal points: 1. Remifentanil is a typical μ-opioid receptor agonist with pharmacodynamic properties like those of fentanyl and its derivatives. 2. Metabolism by nonspecific esterases gives remifentanil a pharmacokinetic profile unlike that of any other opioid. The clinical advantage of the drug lies in its extremely rapid clearance, and therefore offset of effect, which is independent of excretory organ function. The rapid Food and Drug Administration approval of remifentanil significantly outpaced the speed at which results from studies concerning the drug were published. Several of the pivotal trials did not appear as full articles until 1997, so many clinicians have not yet had a chance to review them. The following articles review the most important trials and a look at the data from some recently completed European and American studies. Why Do We Need Another Opioid? The opioids continue to play a central role in every facet of modern anesthetic practice. Unfortunately, their excellent analgesic properties come at the expense of dose-related toxicity, which prevents us from administering maximally effective doses. For opioids such as fentanyl and its derivatives, our ability to determine a well tolerated and effective dose is limited by variability in both pharmacokinetics and pharmacodynamics. The clinician should be able to find an easy answer to the question, “How long will it take the effect of this drug to disappear?” The answer is not so simple for opioids such as fentanyl and its congeners, which undergo “multicompartment” disposition: they are rapidly distributed throughout the body and are subsequently inactivated by slower hepatic biotransformation. Both of these processes determine the clearance of these traditional opioids, but their relative contributions may be different depending on the dose used and the route of administration (2). For example, the effect of a small bolus of fentanyl is short-lived because it is terminated by rapid redistribution from the brain. A prolonged infusion, however, depends more on hepatic metabolism and may seem quite long-acting. Simply knowing fentanyl distribution and elimination half-lives (determined from single bolus administration) will not allow a clinician to predict recovery after multiple boluses or infusions. Individual patients may also have markedly different distribution volumes and rates of metabolic clearance. These differences mean that the peak opioid concentration after a bolus or the steady-state concentration during an infusion cannot be predicted with certainty. Only a small portion of this pharmacokinetic variability can be minimized by adjusting for factors such as age, gender, weight, and drug interaction, and these data are not available for most opioids. Even if the plasma concentration were known precisely, it would be difficult to predict opioid sensitivity for any individual patient. This is important because an opioid-sensitive patient will experience not only a greater intensity of effect, but also a longer duration (the concentration must be lower for recovery to occur). We anticipate lower opioid requirements in elderly or debilitated patients and in those who have received other depressant drugs; increased requirements might be expected in opioid-tolerant individuals or those undergoing extremely painful procedures. Unfortunately, there is a large amount of interpatient variability due to factors that cannot easily be identified: ample data show that individual patients have a three- to fivefold range of sensitivity to a given concentration of opioid (3). Administering a 99% effective dose to every patient will produce excessive effects in many patients and is obviously not an option in most circumstances. During an operation, achieving adequate analgesia with an acceptable speed of recovery depends on how well the opioid is titrated. There are no uniformly reliable ways to accomplish this, and clinicians rely on some combination of hemodynamics, respiratory rate, and pupil signs for most patients. Intraoperative overdosage with any opioid may not be apparent while ventilation is controlled. How Is Remifentanil Different? As Glass et al. (4) describe in this supplement, the primary advantage of remifentanil is a reduction in pharmacokinetic variability. The drug is cleared by enzymatic hydrolysis with redistribution relegated to a minor role. Remifentanil is metabolized by nonspecific esterases, an enormously active group of enzymes found in blood and tissues throughout the body. Most of this hydrolysis probably occurs in skeletal muscle, and the total remifentanil clearance is 30%–50% of cardiac output. Moreover, this metabolism is not subject to the same sorts of genetic variability and drug interaction seen with specific esterases like plasma cholinesterase (5,6). The clearance is predictable because it is unaffected by so many other variables (bolus versus infusion, hepatic or renal function, gender, drug interaction). The few factors that have been demonstrated to alter remifentanil clearance (e.g., age) and volume of distribution (weight) do not produce great changes in drug duration. This means that, compared with other opioids, an infusion of remifentanil will produce more consistent steady-state blood concentrations and the rate of disappearance will be more uniform within a patient population. There is still pharmacodynamic variability with remifentanil, and the end point for titration is no different than that with other opioids. Unlike older opioids, however, accurate dosing of remifentanil is not quite so critical because rapid recovery is effectively dose-independent. In our initial dose-finding trial, patients were given infusions of 0.025–2.0 μg · kg−1 · min−1 during balanced anesthesia (7). The time to spontaneous ventilation and tracheal extubation averaged 3–7 min for all dose groups. Where Is This Pharmacology Most Likely to Be Advantageous? In theory, remifentanil could be used in any clinical situation calling for a potent opioid analgesic. It makes most sense to use remifentanil for cases requiring intense analgesia for a sharply circumscribed period of time and for cases where a continuous infusion of opioid is particularly desirable. An example of the former might be a painful diagnostic procedure such as ureteroscopy, which is accompanied by very little postoperative pain. The articles by Camu and Royston (8), Peacock and Philip (9), and Warner (10) show that remifentanil can be used for diverse patient populations as part of a balanced anesthetic technique. During general anesthesia, remifentanil may be administered in doses that would be impractical or hazardous with other fentanyl derivatives. The use of a large opioid dose blunts the hemodynamic responses to painful stimuli and greatly reduces the need for other drugs such as propofol or volatile anesthetics. Remifentanil makes it possible to provide these benefits even during short procedures. However, a large dose of any opioid increases the risk of hypotension, bradycardia, and muscle rigidity. Servin et al. (11) summarize the studies using remifentanil for monitored anesthesia care (MAC) or as an analgesic adjunct to local/regional anesthesia. Infusions of 0.05–0.1 μg · kg−1 · min−1 with a small dose of benzodiazepine are effective and well tolerated in most cases (12). Concerns about possible respiratory depression and/or muscle rigidity have led some to suggest that bolus doses be avoided altogether when remifentanil is used for sedation, but this may be an overly conservative approach. For example, Ahmad et al. (13) used a 1-μg/kg bolus of remifentanil before placement of ophthalmologic blocks. The analgesic effect was accompanied by a brief period of slowed breathing in 4 of 26 patients, but the technique seemed well suited to the clinical situation. Remifentanil must be studied in other clinical situations that require a similar, extremely brief period of analgesia. Remifentanil is generally given by continuous infusion because intermittent bolus doses are inconvenient for all but the shortest procedures. Even bolus doses for loading before infusion are not really necessary in many cases because a continuous infusion approaches steady-state concentrations in only 10 min. Using a positive displacement infusion pump rather than a gravity drip ensures accurate and consistent dosing of remifentanil. Avoiding large variations in the infusion rate is particularly important during MAC because these patients do not have secured airways. The Issue of Postoperative Pain It seems obvious that rapid disappearance of analgesia is not desirable in cases in which substantial postoperative pain is anticipated. The clinical trials show that stopping remifentanil, then waiting for the patient to complain of pain, is a poor choice because the offset of remifentanil is faster than the onset of most postoperative analgesics. Patients may experience severe pain that is then very difficult to control. Albrecht et al. (14) review the possible ways to plan for postoperative analgesia after remifentanil and emphasize the need for the anesthetist to plan and implement pain management before the end of the procedure. Local and regional blocks are excellent choices when feasible, and morphine or meperidine are appropriate if they are given enough time to work. Remifentanil can also be continued into the postoperative period, but this requires close monitoring of the patient, which may not be practical in all recovery room settings. Supervision of the remifentanil infusion and transition to another opioid should be handled by the anesthetist. It is reasonable to ask whether the intraoperative use of a short-acting opioid is really advantageous when additional drugs must be administered for postoperative pain. By choosing remifentanil, we are simply separating our decisions about intraoperative and postoperative analgesia. We face the same issue when we administer anesthesia with sevoflurane or desflurane: other drugs must be administered for pain before these volatile anesthetics are eliminated. The intraoperative use of fentanyl or morphine certainly does not guarantee that sufficient analgesia will extend into the postoperative period, but postoperative dosing must take any residual effect into account. With remifentanil, postoperative pain is planned for as a separate event because the intraoperative opioid will be gone. Final Thoughts As Reves (15) notes in the last contribution to this issue, the Food and Drug Administration and its Anesthesia Advisory Panel felt that a particularly strong effort should be made to educate practitioners about remifentanil. This may seem surprising because there is little to distinguish the pharmacodynamic properties of remifentanil from those of fentanyl, sufentanil, or alfentanil. It is clear that the unique pharmacokinetic profile of remifentanil gives it unparalleled flexibility, but vigilance is required to avoid problems. The rapid onset of analgesia can be accompanied by an equally rapid onset of side effects if the dose given is too large or if it is given too rapidly. Use of this new drug invites some rethinking and researching on our part: Will opioid-based anesthesia now be possible in totally new patient populations? Is it safe in women who are breast-feeding? Should it be used outside of the operating room? Should we administer large-dose opioid anesthesia to outpatients? There is little question that remifentanil is a drug that may significantly alter anesthesia practice. It will take some patience, experience, and imagination to translate its theoretical advantages into better care for our patients.