Educational Considerations for the Clinical Introduction and Use of Remifentanil

The educational goals for the release and use of any new drug require a thorough understanding of the pharmacology involved. This is particularly true for drugs that have unique pharmacologic characteristics. Remifentanil has the pharmacodynamic profile of other μ-opioid receptor agonists but has very unique pharmacokinetic characteristics. Any educational program should review the common, as well as the unique, pharmacology of a new compound. The purpose of this brief article is to organize the educational approach to the release and continuing use of remifentanil. There is no attempt to repeat the scientific material that is available in this supplement and that has been adequately reviewed previously (1,2). General Properties of All μ-Opioid Receptor Agonists The primary clinical benefit of μ-opioid receptor agonists is dose-related analgesia. The relative potency of these drugs differs, as do their pharmacokinetic profiles, but they are all potent analgesics that are used widely in clinical practice throughout anesthesia and pain management. Unfortunately, μ-opioid receptor agonists also share adverse effects which are generally undesirable in the nonintubated patient. These include respiratory depression, muscle rigidity (which is infusion rate-dependent, i.e., the more rapidly administered, the higher the incidence of muscle rigidity), bradycardia, and nausea and vomiting. These side effects are dose-related and can be reversed, as can the primary analgesic effects, with selective opioid receptor antagonists, such as naloxone. Although these effects are well known to anesthesiologists, any educational program must include an overview of the general risks and benefits of μ-opioid receptor agonists. These opiate agonists provide analgesia but also cause respiratory depression, muscular rigidity, and nausea, and these side effects must be emphasized. Unique Pharmacokinetics of Remifentanil Remifentanil has a unique pharmacologic profile among μ-opioid receptor agonists, which makes its educational program vitally important. Most importantly, remifentanil is rapidly metabolized by nonspecific esterases throughout the blood and tissues (3); the resulting hydrolysis of remifentanil renders the compound inactive. Consequently, remifentanil has a very rapid plasma clearance and, therefore, a very rapid offset of action. The clearance of remifentanil is much more rapid than that of other opioids. The obvious clinical corollary of this unique property is that, to maintain a therapeutic analgesic level of the drug, a continuous infusion of the drug must be used, which also enables titration to the required drug effect for each individual patient. A second and equally important consequence of this rapid clearance is that analgesia also disappears rapidly on termination of remifentanil. Both of these facts require a major educational effort to inform clinicians and to help them to develop the most effective ways for using remifentanil in clinical practice. Another distinctive pharmacokinetic characteristic of remifentanil is its rapid blood-brain equilibration time. The rapid clearance and blood-brain equilibration time enable remifentanil to act like a single-compartment drug with predictable plasma concentrations; these two factors are analogous to the inhaled anesthesia gas nitrous oxide, which has a rapid onset and offset of effect with which most clinicians are familiar. Likewise, the rapid clearance of remifentanil means that the drug has a very rapid offset. In addition, the time taken for the effect site concentration of remifentanil to decrease by 50% (i.e., the context-sensitive half-time of remifentanil) (4) is short and constant over time, whereas other opioids have an increase in the disappearance half-time with increasing duration of infusion (Figure 1). Thus, remifentanil can be administered without fear of accumulation over time; therefore, patients are not at risk of delayed awakening postoperatively. Figure 1: A simulation of the time necessary to achieve a 50% decrease in drug concentration in the blood (or plasma) after variable-length IV infusions of remifentanil, fentanyl, sufentanil, and alfentanil. The simulations for remifentanil, fentanyl, alfentanil, and sufentanil were performed using pharmacokinetic parameters compiled with permission from Egan et al. (5). Although the curve shown for fentanyl does not appear to approach a plateau value as for the other drugs, this does, in fact, happen: this portion of the curve is simply off the scale of this graph.A final consideration for the clinical application of remifentanil is the effect of pathology and age on its pharmacokinetics. Liver disease, renal disease, and age do not seem to significantly alter the clearance of remifentanil, which implies that the drug may be used safely for prolonged infusion in these patients. These facts can be a focus of education. Pharmacodynamics of Remifentanil Unlike the pharmacokinetics, the pharmacodynamics of remifentanil are not particularly different from those of other opioids, except that there is a very quick offset of the drug’s effects because of its rapid clearance. The major pharmacodynamic effects, both desirable (analgesia) and undesirable (respiratory depression, muscle rigidity, bradycardia, nausea, and vomiting) have been previously discussed. The primary educational issue is the rapid offset, which must be emphasized in all educational presentations. The offset of remifentanil is quick and dramatic, with the loss of effective analgesia occurring within minutes of infusion cessation. Remifentanil also has a rapid onset, which is approximately equivalent to that of alfentanil. This dynamic effect is desirable and helpful in rapidly establishing therapeutic concentrations. The onset of effect is slower in elderly patients who may be opioid-sensitive and therefore require lower plasma levels. Thus, care must be taken to avoid the overdosing of elderly patients, and educational programs concerning titration in the elderly should stress a slower onset of effect with lower infusion doses. It is recommended that the initial dose of remifentanil administered to patients aged >65 yr be half that given to younger adults. Like μ-opioid receptor agonists, remifentanil interacts with other anesthetic drugs. The interaction with the benzodiazepine midazolam is one of synergism. Thus, if benzodiazepines and other hypnotics are used with remifentanil, the dose of each drug should be reduced. This is true for all opioids; therefore, although educational materials must address these interactions, there is nothing unusual about the interaction of remifentanil per se with the other drugs often used together in anesthesia. Nevertheless, dosing must take into consideration which other drugs are being used, the relative dosing of remifentanil, and the reduced dose requirements compared with those required when each drug is used alone. A final comment about pharmacodynamic interaction relates to the therapeutic ceiling that occurs with all opioids. There seems to be a plasma level above which very little additional analgesia is achieved. This blood level is approximately 5–8 ng/mL with remifentanil and is approximately 2–3 ng/mL with fentanyl. The key point is that if remifentanil is administered with an inhaled anesthetic, there is little point in exceeding the infusion rate that produces a blood level of 5–8 ng/mL. This dose in most adults is 0.2–1.0 μg · kg−1 · min−1. Specific Educational Objectives There are several key educational objectives that must be emphasized in the clinical use of remifentanil and that physicians must understand to ensure that they use remifentanil appropriately. These are detailed below. • Remifentanil is supplied as a lyophilized powder and must be reconstituted and diluted before use. The careful mixing of the drug with one of the recommended diluents (sterile water for injection USP, 5% dextrose injection USP, 5% dextrose and 0.9% sodium chloride injection USP, 0.9% sodium chloride injection USP, 0.45% sodium chloride USP) lactated Ringer’s solution, and 5% dextrose injection, USP is essential. Errors in dilution of the drug can easily result in over- or underdosage. • Remifentanil is most effectively given by continuous infusion but does not require any one specific infusion device. It can be administered with a relatively simple syringe driver or a more complex infusion pump. Bolus doses can be used, but particular care is needed in the nonintubated patient, and doses should be given over 30–60 s to avoid the risk of apnea or muscle rigidity. • The infusion rates and blood levels that produce ceiling effects of remifentanil must be clearly recognized. However, unlike all other opioids, remifentanil can be dosed at relatively high levels (95% effective dose) to provide profound intra-operative analgesia without delaying recovery. • Remifentanil infusion must be continued until the surgical procedure is complete. It should not be treated like the traditional opioids, which are typically down-titrated or stopped altogether 10–15 min before the end of surgery. • Postprocedural analgesia can be most satisfactorily obtained by using other analgesics administered in a variety of ways. Clinicians must be thoroughly educated about the many adjuvant methods to achieve analgesia after rapid clearance of remifentanil to avoid pain in patients. Suggestions for different postoperative pain man-agement strategies after remifentanil-based anesthesia are detailed by Albrecht et al. (6) in this supplement. The initiation of postoperative analgesia should begin before cessation of the administration of remifentanil. • Remifentanil is not to be administered in the epidural or intrathecal spaces as it is formulated with glycine. • Interruption of an infusion of ULTIVA will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects on discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia. • Use of ULTIVA is associated with apnea and respiratory depression. ULTIVA should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiratory and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation.