The place for short-acting opioids: special emphasis on remifentanil

Abstract

Pain is among the worst possible experiences for the critically ill. Therefore, nearly all intensive care patients receive some kind of pain relief, and opioids are most frequently administered. Morphine has a number of important adverse effects, including histamine release, pruritus, constipation, and, in particular, accumulation of morphine-6-glucuronide in patients with renal impairment. Hence, it is not an ideal analgesic for use in critically ill patients. Although the synthetic opioids fentanyl, alfentanil, and sufentanil have better profiles, they undergo hepatic metabolism and their continuous infusion also leads to accumulation and prolonged drug effects. Various attempts have been made to limit these adverse effects, including daily interruption of infusion of sedatives and analgesics, intermittent bolus injections rather than continuous infusions, and selection of a ventilatory support pattern that allows more spontaneous ventilation. However, these techniques at best only limit the effects of drug accumulation, but they do not solve the problem. Another type of approach is to use remifentanil in critically ill patients. Remifentanil is metabolized by unspecific blood and tissue esterases and undergoes rapid metabolism, independent of the duration of infusion or any organ insufficiency. There are data indicating that remifentanil can be used for analgesia and sedation in all kinds of adult intensive care unit patients, and that its use will result in rapid and predictable offset of effect. This may permit both a significant reduction in weaning and extubation times, and clear differentiation between over-sedation and brain dysfunction. This article provides an overview of the use of short-acting opioids in the intensive care unit, with special emphasis on remifentanil. It summarizes the currently available study data regarding remifentanil and provides recommendations for clinical use of this agent.

Figures

Figure 1

Context-sensitive half-times of remifentanil and the other 4-anilido-piperidine opioids. Remifentanil has a context-sensitive half-time of 3 to 4 minutes, regardless of the duration of infusion, whereas continuous infusion of the other opioids results in accumulation and considerable prolongation of effect, making these opioids intermediate-acting or long-acting agents, depending on the duration of infusion. Figure adapted with permission from Egan TD, Lemmens HJ, Fiset P, Hermann DJ, Muir KT, Stanski DR, Shafer SL: The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993, 79:881–892.

Figure 2

Decline of effect site concentrations of different opioids after 24 hours of infusion. The findings are expressed as percentage of the individual maximum effect site concentration. This figure was calculated using Stanpump simulation software (by Shafer S, University of Stanford, CA, USA) for a female individual (age 80 years, height 170 cm, body weight 80 kg) and the following infusion rates: remifentanil 0.15 μg/kg per minute, sufentanil 1 μg/kg per hour, alfentanil 1.5 mg/hour, and fentanyl 0.2 mg/hour.

Figure 3

Extubation times after remifentanil infusion. Shown are extubation times in 46 intensive care unit patients after sedation with a remifentanil infusion (mean duration 9.8 hours, mean dosage 0.14 ± 0.08 μg/kg per minute). Two-thirds of all patients could be extubated within 15 minutes and 87% within 45 minutes after cessation of remifentanil infusion. Figure adapted with permission from: Wilhelm W, Dorscheid E, Schlaich N, Niederprüm, Deller D: The use of remifentanil in critically ill patients. Clinical findings and early experience. Anaesthesist 1999, 48:625–629. © Springer.

Figure 4

Times to offset of opioid effect after down-titration of remifentanil. Shown are times to offset of opioid effect after scheduled down-titrations (SDT) of remifentanil at 8, 24, 48, and 72 hours of infusion in (a) 10 adult intensive care unit patients with normal or mildly impaired renal function and (b) 30 patients with moderate or severe renal impairment with a mean creatinine clearance of 14.7 ml/minute. Offset times were more variable and statistically significantly longer in the renal impairment group (b). However, the time differences between the groups were only in the order of minutes and without clinical importance (about 17 minutes longer [mean] in the renal impairment group after 72 hours of remifentanil infusion). Adapted with permission from Breen and coworkers [30].