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Remifentanil

A Review of its Use During the Induction and Maintenance of General Anaesthesia

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Summary

Abstract

Remifentanil (Ultiva™), a fentanyl derivative, is an ultra-short acting, nonspecific esterase-metabolised, selective μ-opioid receptor agonist, with a pharmacodynamic profile typical of opioid analgesic agents. Notably, the esterase linkage in remifentanil results in a unique and favourable pharmacokinetic profile for this class of agent.

Adjunctive intravenous remifentanil during general anaesthesia is an effective and generally well tolerated opioid analgesic in a broad spectrum of patients, including adults and paediatric patients, undergoing several types of surgical procedures in both the inpatient and outpatient setting. Remifentanil is efficacious in combination with intravenous or volatile hypnotic agents, with these regimens generally being at least as effective as fentanyl- or alfentanil-containing regimens in terms of attenuation of haemodynamic, autonomic and somatic intraoperative responses, and postoperative recovery parameters. The rapid offset of action and short context-sensitive half-time of remifentanil, irrespective of the duration of the infusion, makes the drug a valuable opioid analgesic option for use during balanced general inhalational or total intravenous anaesthesia (TIVA) where rapid, titratable, intense analgesia of variable duration, and a fast and predictable recovery are required.

Pharmacological Profile

Remifentanil, a selective μ-opioid receptor agonist, demonstrates typical opioid agonist effects, including analgesia, respiratory depression and haemodynamic effects (e.g. decreased heart rate and blood pressure). In terms of analgesic intensity, the lack of response to surgical incision and management of intraoperative stress, remifentanil exhibited similar potency to fentanyl and appeared to be 16- to 70-fold more potent than alfentanil in adult healthy volunteers and surgical patients. Naloxone, but not norbinaltorphimine, antagonised the effects of remifentanil. In remifentanil recipients, haemodynamic effects were not associated with the release of histamine. The drug has a rapid onset of analgesic action (1 minute) and fast offset of action (3–10 minutes vs 5–20, 20–30 and 180–240 minutes, respectively, with alfentanil, fentanyl and morphine). Remifentanil recipients experienced no clinically relevant effects on intraocular or intracranial pressure, cerebral blood flow, cerebrovascular carbon dioxide reactivity or cerebral capacity. In association with volatile or intravenous anaesthetic agents, remifentanil demonstrates typical opioid-induced hypnotic sparing effects. The primary metabolite of remifentanil (GR90291) exhibits ≈300- to 4600-fold less activity than the parent compound.

Intravenous remifentanil exhibits a linear, dose-dependent pharmacokinetic profile in surgical patients and in healthy volunteers. The drug is rapidly absorbed and distributed throughout the body (mean volume of distribution at steady state [Vdss] 260–415 mL/kg) and is ≈70% bound to plasma proteins. Remifentanil rapidly crosses the placental barrier, but is quickly metabolised and/or redistributed in the neonate. The drug readily crosses the blood-brain barrier.

Remifentanil is rapidly (mean terminal elimination half-life [t1/2β] ≈10 minutes) and extensively metabolised by nonspecific blood and tissue esterases to the relatively inactive carboxylic acid metabolite GR90291. This metabolite is eliminated mainly (≥88% of the dose) in the urine, with mean t1/2β values ranging from 88.1 to 137.4 minutes following bolus doses of remifentanil 2–30 μg/kg. The mean clearance (CL) rate of remifentanil exceeded the average hepatic blood flow by ≈3- to 4-fold. The pharmacokinetic profile of remifentanil is unlikely to be affected by inherited or acquired deficiencies in plasma cholinesterases. The context-sensitive half-time of remifentanil was independent of the duration of infusion, unlike that of other μ-opioid receptor agonists. Remifentanil recipients had similar mean Vd of the central compartment (Vdc) and distribution half-life values to those of alfentanil recipients; however, the mean CL value was ≈5-fold greater and the mean t1/2β was ≈6-fold shorter with remifentanil treatment (no statistical data reported).

There were no clinically relevant differences in the pharmacokinetic profile of the drug in those with renal or hepatic impairment, or based on gender. During the hypothermic phase (core body temperature 28–30°C) of cardiopulmonary bypass, the mean clearance of remifentanil was reduced by ≈20%. In surgical patients aged 0 to <18 years, after correction for bodyweight, there were no significant differences in pharmacokinetic parameters of remifentanil in these recipients versus those in adults. Between the age of 20 and 85 years, Vdc and CL values decrease by ≈25% and 33% in healthy adult volunteers, requiring a 50% reduction in the initial and subsequent doses of remifentanil in those >65 years of age. These pharmacokinetic parameters are also reduced by about one-third in obese versus lean patients; reductions in dose in obese recipients should be based on the patient’s ideal bodyweight.

Therapeutic Efficacy

Intravenous remifentanil in combination with volatile or intravenous hypnotic agents provided effective analgesia and attenuated responses to various stimuli during the induction and/or maintenance of general anaesthesia in a broad spectrum of surgical patients in several comparative, randomised clinical trials. As per therapeutic recommendations, bolus doses of remifentanil were typically 0.5–1 μg/kg, with infusion rates of 0.2–0.5 μg/kg/min; higher infusion rates (1–2 μg/kg/min) were used in patients undergoing ‘fast-track’ coronary artery bypass graft surgery (CABG).

During induction of anaesthesia in adult patients undergoing various surgical procedures, remifentanil attenuated the stress response to intubation, and facilitated endotracheal intubation without a muscle relaxant. Remifentanil also facilitated laryngeal mask airway insertion during induction of propofol-based TIVA. In morbidly obese patients, remifentanil was as effective as alfentanil or fentanyl in blunting the haemodynamic response to tracheal intubation using propofol-based TIVA.

In surgical patients, remifentanil-containing regimens were generally at least as effective as fentanyl- and alfentanil-containing regimens during the induction and/or maintenance of balanced general anaesthesia, as assessed by various intraoperative responses and postoperative recovery parameters. For instance, in a large (≈2500 inpatients and outpatients) single-blind trial, relative to fentanyl recipients, remifentanil-treated patients responded to verbal commands faster (after both inpatient and outpatient surgery) and, after day surgery, recovered faster and were discharged from hospital sooner. Notably, haemodynamic profiles in response to intraoperative stimuli were generally better and postoperative functional abilities improved at a faster rate in remifentanil than fentanyl recipients. In a large double-blind trial, significantly fewer remifentanil than alfentanil recipients responded to intraoperative surgical stimuli (primary endpoint), intubation or skin incision. Typically, remifentanil recipients experienced effective analgesia and attenuation of intraoperative responses irrespective of their age (including paediatric and elderly patients), bodyweight, the degree of renal or hepatic impairment, type (e.g. major abdominal surgery, CABG, neurosurgery, ear, nose and throat, or opthalmic surgery) and duration of surgery being undertaken, whether the drug was combined with intravenous or volatile hypnotic agents, or whether the drug was used in the inpatient or outpatient setting. Limited data also suggested that intravenous remifentanil was an effective opioid analgesic during Caesarean section, with generally no significant difference in Apgar or Neurologic and Adaptive Capacity Scores at most timepoints in neonates born to mothers receiving a remifentanil-versus a fentanyl-based anaesthetic regimen in a small single-blind trial.

Tolerability

Bolus doses and/or infusions of intravenous remifentanil were generally well tolerated as a component of induction- and maintenance-regimens for general anaesthesia in adults and children undergoing surgery. Common adverse events associated with remifentanil treatment during the perioperative period, such as muscle rigidity (0–8%), bradycardia (2–12%), hypotension (6–30%), nausea (12–47%), vomiting (3–33%) and shivering (6–26%), are typical of those reported with all μ-opioid receptor agonists and resolved rapidly upon discontinuation of the drug or reduction in the infusion rate and/or with appropriate treatment.

The nature of adverse events occurring in remifentanil recipients was generally similar to that seen in fentanyl recipients, although hypotension occurred significantly more frequently in remifentanil recipients (inpatients [18% vs 7%], outpatients [9% vs 3%]) in a large (n = 2438) single-blind trial. A significantly higher percentage of remifentanil recipients experienced at least one drug-related adverse event in the overall population (21% vs 11% of fentanyl recipients) and in subgroup analyses of inpatients (34% vs 16%) and outpatients (26% vs 9%). There were no between-group differences in the intensity of these adverse events, with 3% of patients in each group experiencing at least one severe adverse event. There was no intergroup difference in the incidence of postoperative nausea in either patient populations, although postoperative vomiting occurred significantly more frequently in remifentanil recipients undergoing outpatient surgery (15.5% vs 12.5%).

There was no between-group difference in the nature of treatment-related adverse events in remifentanil groups compared with alfentanil groups, although some individual events occurred with a higher incidence. Eighty-two percent of remifentanil recipients and 75% of alfentanil recipients experienced at least one adverse event in the largest trial (n = 234), with a significantly higher incidence of hypotension (30% vs 10% of patients) and bradycardia (10% vs 3%) in the remifentanil group during the maintenance phase.

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Notes

  1. The use of trade names is for identification purposes only and does not imply endorsement.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Lesley J. Scott & Caroline M. Perry

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  1. Lesley J. Scott
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Correspondence to Lesley J. Scott.

Additional information

Various sections of the manuscript reviewed by: J. Ard, Department of Anesthesiology, New York University Medical Center, New York, New York, USA; D.C.H. Cheng, Department of Anaesthesia and Perioperative Medicine, London Health Science Centre and St Joseph Health Care, University of Western Ontario, London, Ontario, Canada; L. Fleisher, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; R.H. Friesen, Cardiac Anaesthesia, The Children’s Hospital, University of Colorado School of Medicine, Denver, Colorado, USA; L.H. Garvey, Department of Anesthesiology, Centre of Head and Orthopaedics, Copenhagen University Hospital, Copenhagen, Denmark; E.M. Gruber, Department of Cardiothoracic Anaesthesia, Vienna General Hospital, University of Vienna, Vienna, Austria; A.S. Habib, Duke University Medical Center, Durham, North Carolina, USA; J.E. Mandel, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; D. Royston, Department of Cardiothoracic Anaesthesia, Harefield Hospital, Harefield, Middlesex, England.

Data Selection

Sources: Medical literature published in any language since 1980 on remifentanil, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE search terms were ‘remifentanil’ or ‘remifentanyl’. EMBASE search terms were ‘remifentanil’ or ‘remifentanyl’ or ‘GI-87084’. AdisBase search terms were ‘remifentanil’ or ‘remifentanyl’ or ‘GI 87084’. Searches were last updated 8 August 2005.

Selection: Studies in patients undergoing surgery who received remifentanil. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Remifentanil, anaesthesia, opioid, pharmacodynamics, pharmacokinetics, therapeutic use.

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Scott, L.J., Perry, C.M. Remifentanil. Drugs 65, 1793–1823 (2005). https://doi.org/10.2165/00003495-200565130-00007

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