AHFS Class:

• Opioid Agonists 28:08.08

Generic Name(s):

• Remifentanil Hydrochloride

Remifentanil hydrochloride, a fentanyl analog, is a selective µ-receptor opiate agonist.1,2,3,4,10,11,12

General Anesthesia

Remifentanil hydrochloride is used as the analgesic component during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.1,2,3,9,10,12 Remifentanil is not recommended as the sole agent in general anesthesia as loss of consciousness cannot be ensured and there is a possibility of a high incidence of apnea, muscle rigidity, or tachycardia.1,2,3

Remifentanil may be continued in the immediate postoperative period in adults for whom later transition to longer-acting analgesics is desired; the drug must be used under the direct supervision of an anesthesia clinician in a postoperative anesthesia care unit or intensive care unit (ICU).1,25,36,37,38,39,40,41 Long-term (i.e., exceeding 16 hours) use of remifentanil in ICU patients has not been established to date.1

Remifentanil may be particularly useful in surgical procedures requiring a rapid onset of analgesia and recovery.2,3,8 Remifentanil has a short duration of action (shorter than alfentanil or fentanyl).1,2,3,4,10 Recovery is rapid (within 3-15 minutes), predictable, and independent of duration of infusion.1,2,8,10,12 Remifentanil does not accumulate during prolonged administration; therefore, its duration of action does not increase proportionally with duration of administration.1,8

For general anesthesia in pediatric patients, remifentanil has been studied only for the maintenance of general anesthesia in outpatient and inpatient surgery and has not been evaluated for use as a postoperative analgesic.1

Clinical Experience

Induction of Anesthesia

Remifentanil was administered with isoflurane, propofol, or thiopental for the induction of anesthesia in 1562 patients; the majority of patients (80%) received propofol as the concurrent agent.1 Remifentanil reduced the propofol and thiopental requirements for loss of consciousness.1 Compared with alfentanil and fentanyl, a higher relative dose of remifentanil resulted in fewer responses to intubation.1 Hypotension occurred in more patients receiving remifentanil compared with those receiving the other opioids (5 versus 2%).1

Remifentanil has been used as a primary agent for the induction of anesthesia; however, it should not be used as the sole agent as loss of consciousness cannot be assured and the occurrence of a high incidence of apnea, muscle rigidity, and tachycardia is possible.1 Administration of an induction dose of propofol or thiopental or a paralyzing dose of a muscle relaxant prior to or concurrently with remifentanil during the induction of anesthesia resulted in a substantial reduction of muscle rigidity from 20% to <1%.1

Maintenance of Anesthesia

Remifentanil, administered in conjunction with nitrous oxide, isoflurane, or propofol, was evaluated in 929 patients in 7 controlled general surgery studies in both inpatient and outpatient settings.1 In these studies, remifentanil was dosed to high levels of opioid effect and rapidly titrated to optimize analgesia intraoperatively without delaying or prolonging recovery.1 Compared with alfentanil and fentanyl, these higher relative doses of remifentanil resulted in fewer responses to intraoperative stimuli and increased hypotension (16 versus 5%).1

In other randomized controlled general anesthesia studies, remifentanil attenuated the signs of light anesthesia after administration of bolus doses (1 mcg/kg) with or without increasing the infusion rate.1 In an additional double-blind, randomized study, remifentanil decreased signs of light anesthesia with a constant infusion rate of 0.25 mcg/kg/min (in patients undergoing laminectomy) or a doubling of the infusion rate to 0.5 mcg/kg/min (in patients undergoing abdominal hysterectomy or radical prostatectomy) before the start of the surgical procedure.1

Recovery

In 2,169 patients receiving remifentanil for periods up to 16 hours, recovery from anesthesia was rapid, predictable, and independent of the duration of the remifentanil infusion.1 In 7 controlled general surgery studies, extubation occurred in a median of 5 minutes (range: -3 to 17 minutes in 95% of patients) in outpatient anesthesia and 10 minutes (range: 0 to 32 minutes in 95% of patients) in inpatient anesthesia.1 Recovery in studies using nitrous oxide or propofol was faster than in studies using isoflurane as the concurrent anesthetic.1 Recovery was faster when remifentanil was used in conjunction with nitrous oxide or propofol than when used in conjunction with isoflurane.1 There was no case of remifentanil-induced delayed respiratory depression occurring more than 30 minutes after discontinuation.1 In those receiving maintenance anesthesia with remifentanil (0.2-0.5 mcg/kg per minute) in conjunction with isoflurane, enflurane, or propofol, with or without nitrous oxide, median or mean times to spontaneous ventilation were 2-11 or 6-8 minutes, respectively.2,21,22,23,24,25,26,27,28,29 In patients receiving maintenance anesthesia with remifentanil (0.2-0.4 mcg/kg per minute) in conjunction with isoflurane or propofol, with or without nitrous oxide, median time to respond to verbal commands was 5-15 minutes.2,21,22,25,26,27,28,29 In patients undergoing neurosurgery and receiving maintenance anesthesia with remifentanil (0.2-0.25 mcg/kg per minute) in conjunction with IV propofol and/or inhalation anesthetics (isoflurane, nitrous oxide), median time to respond to verbal commands and median time to extubation were 5-13 and 5-11 minutes, respectively.1,2,17,18,19

In a double-blind randomized study of 98 patients undergoing major surgery with remifentanil-propofol total IV anesthesia, administration of IV morphine sulfate (0.15 mg/kg) 20 minutes before the anticipated end of surgery did not delay recovery of respiratory drive.1

Spontaneous Ventilation Anesthesia

Two randomized, dose-ranging studies evaluated the administration of remifentanil in 127 outpatients undergoing general anesthesia with a laryngeal mask.1 Starting infusion rates of ≤0.05 mcg/kg/min provided supplemental analgesia while allowing spontaneous ventilation with propofol or isoflurane.1 Bolus doses of remifentanil during spontaneous ventilation led to transient periods of apnea, respiratory depression, and muscle rigidity.1

Pediatric Anesthesia

For general anesthesia in pediatric patients, remifentanil has been studied only for the maintenance of general anesthesia in outpatient and inpatient surgery and has not been evaluated for use as a postoperative analgesic.1

Remifentanil was evaluated for maintenance of general anesthesia in 4 clinical studies involving 410 pediatric patients ranging from birth to 12 years of age undergoing inpatient and outpatient procedures.1

In an open-label, randomized trial (Study 1) remifentanil was compared to alfentanil, isoflurane, or propofol in 129 pediatric patients (2 to12 years of age) undergoing strabismus surgery.1 After induction of anesthesia, remifentanil was administered as an initial infusion of 1 mcg/kg/min with 70% nitrous oxide.1 The infusion rate required during maintenance of anesthesia was 0.73 to 1.95 mcg/kg/min.1 The median time to extubation and purposeful movement was 10 minutes (range 1-24 minutes).1

Study 2 was a double-blind randomized trial that compared remifentanil with fentanyl in 222 pediatric patients (2-12 years of age) undergoing tonsillectomy with or without adenoidectomy.1 After induction of anesthesia, patients received remifentanil 0.25 mcg/kg/min IV infusion or fentanyl by IV bolus with nitrous oxide/oxygen (2:1) and either halothane or sevoflurane for maintenance.1 The mean infusion rate during maintenance of anesthesia was 0.3 mcg/kg/min (range 0.2-1.3 mcg/kg/min).1 The remifentanil continuous infusion rate was reduced to 0.05 mcg/kg/min approximately 10 minutes prior to end of the surgical procedure.1 The median time to spontaneous purposeful movement was 8 minutes (range 1-19 minutes) and the median time to extubation was 9 minutes (range 2-19 minutes).1

An open-label randomized trial (Study 3) compared remifentanil with a regional anesthetic technique in 271 pediatric patients (1-12 years of age) undergoing major abdominal, urological, or orthopedic surgery.1 Patients received remifentanil (1 mcg/kg bolus followed by 0.25 mcg/kg/min IV infusion) or bupivacaine by epidural infusion, along with isoflurane and nitrous oxide after the induction of anesthesia.1 The mean infusion rate of remifentanil required during maintenance was 0.25 mcg/kg/min (range 0-0.75 mcg/kg/min).1 Both treatments were effective in attenuating responses to skin incision during surgery and the hemodynamic profile of the remifentanil group was consistent with an opioid-based general anesthetic technique.1 The median time to spontaneous purposeful movement was 15 minutes (range, 2-75 minutes) and the median time to extubation was 13 minutes (range, 4-31 minutes) in the remifentanil group.1

Study 4 was an open-label randomized trial that compared remifentanil with halothane in 60 ASA 1 or 2 full term neonates and infants ≤8 weeks of age weighing at least 2500 g who were undergoing pyloromyotomy.1 After induction of anesthesia, which included the administration of atropine, patients received 0.4 mcg/kg/min of remifentanil or 0.4% halothane with 70% nitrous oxide for initial maintenance of anesthesia; both agents were adjusted according to clinical response.1 Bolus doses of 1 mcg/kg administered over 30 to 60 seconds were used to treat brief episodes of hypertension and tachycardia, and infusion rates were increased by 50% to treat sustained hypertension and tachycardia.1 The range of infusion rates of remifentanil required during maintenance of anesthesia was 0.4 to 1 mcg/kg/min.1 Supplementary bolus doses or rate increases were required in 71% of remifentanil patients to treat hypertension, tachycardia, movement or somatic signs of light anesthesia; 24% required an increase from the initial rate of 0.4 mcg/kg/min prior to incision, and 26% required an infusion rate between 0.8 and 1.0 mcg/kg/min, most often during gastric manipulation.1 The continuous infusion rate was reduced to 0.05 mcg/kg/min approximately 10 minutes before the end of surgery.1 In the remifentanil group, median time from discontinuation of anesthesia to spontaneous purposeful movement was 6.5 minutes (range, 1-13 minutes) and median time to extubation was 8.5 minutes (range, 1- 14 minutes).1 The initial maintenance infusion regimen of remifentanil evaluated in pediatric patients from birth to 2 months of age was 0.4 mcg/kg/min.1 The clearance rate in the neonatal population was highly variable and on average was 2 times greater than in the young healthy adult population.1 No patients administered remifentanil required naloxone during the immediate postoperative recovery period.1

Coronary Artery Bypass Surgery

Remifentanil was administered to 225 patients undergoing elective coronary artery bypass grafting (CABG) surgery in 2 dose-ranging studies without active comparators.1 Two subsequent double-blind, double-dummy studies evaluated remifentanil at recommended doses compared with fentanyl in a total of 426 patients.1 In the comparator studies, a high-dose opioid technique was used with remifentanil as a component of a balanced or total IV anesthetic regimen.1 The remifentanil regimen effectively attenuated response to maximal sternal spread generally better than the dose and regimen studied for fentanyl.1 Caution is advised in interpreting these results as evidence of superiority of remifentanil over fentanyl, since these studies did not make any attempt to evaluate and compare the optimal analgesic doses of either drug in this setting.1

Neurosurgery

Remifentanil was administered to patients undergoing craniotomy for removal of a supratentorial mass lesion.1 In 30 patients who received remifentanil and 66% nitrous oxide, the median time to extubation and patient response to verbal commands was 5 minutes (range -1 to 19 minutes).1 Intracranial pressure and cerebrovascular responsiveness to carbon dioxide were normal.1

Another randomized controlled study compared remifentanil (1 mcg/kg/min) to fentanyl (2 mcg/kg/min), administered after induction with thiopental and pancuronium.1 A similar number of patients (6%) in both treatment groups had hypotension during induction.1 Anesthesia was maintained with nitrous oxide and a mean remifentanil rate of 0.23 mcg/kg/min or mean fentanyl infusion rate of 0.04 mcg/kg/min; supplemental isoflurane was administered as needed.1 Patients receiving remifentanil required a lower mean isoflurane dose than those receiving fentanyl.1 Remifentanil was discontinued at the end of anesthesia, whereas fentanyl was discontinued at the time of bone flap replacement (median time of 44 minutes before the end of surgery).1 Median time to extubation was similar with remifentanil and fentanyl (5 and 3.5 minutes, respectively).1 None of the patients receiving remifentanil required naloxone versus 7 who received fentanyl; 81% of patients receiving remifentanil recovered (awake, alert, and oriented) within 30 minutes after surgery compared with 59% of patients receiving fentanyl.1 At 45 minutes after surgery, recovery rates were similar for remifentanil and fentanyl (81% and 69%, respectively).1 Patients receiving remifentanil required an analgesic for headache sooner than fentanyl patients (median of 35 minutes compared with 136 minutes, respectively).1

Continuation of Analgesic Use into the Immediate Postoperative Period

Analgesia with remifentanil in the immediate postoperative period (until approximately 30 minutes after extubation) was studied in 401 patients in 4 dose-finding studies and in 281 patients in 2 efficacy studies.1 In the dose-finding studies, the use of bolus doses of remifentanil and incremental infusion rate increases ≥0.05 mcg/kg/min led to respiratory depression and muscle rigidity.1

In 2 efficacy studies, remifentanil 0.1 mcg/kg/min was started immediately after discontinuing anesthesia.1 Incremental infusion rate increases of 0.025 mcg/kg/min every 5 minutes were given to treat moderate to severe postoperative pain.1

In Study 1, 50% decreases in infusion rate were made if the respiratory rate decreased below 12 breaths/min; in Study 2, the same decreases were made if the respiratory rate was below 8 breaths/min.1 With this difference in criteria for infusion rate decrease, the incidence of respiratory depression was lower in Study 1 than in Study 2 (4 versus 12%).1 In both studies, remifentanil provided effective analgesia in approximately 60% of patients at mean final infusion rates of 0.1-0.125 mcg/kg/min.1

Study 2 was a double-blind, randomized controlled study in patients receiving morphine sulfate (0.15 mg/kg administered 20 minutes before the anticipated end of surgery plus 2 mg bolus doses for supplemental analgesia) or remifentanil.1 Anesthesia emergence was similar between groups; median time to extubation was 5-6 minutes for both.1 Remifentanil provided effective analgesia in 58% of patients compared with 33% of those who received morphine.1 Respiratory depression occurred in 12% of patients receiving remifentanil compared with 4% of those receiving morphine.1 For patients who received remifentanil, morphine sulfate (0.15 mg/kg) was administered in divided doses 5 and 10 minutes before discontinuing remifentanil.1 Within 30 minutes after discontinuation of remifentanil, the percentage of patients with effective analgesia decreased to 34%.1

Monitored Anesthesia Care

Remifentanil is used as the analgesic component of monitored anesthesia care (e.g., in conjunction with local or regional anesthesia for surgical procedures, including ophthalmic surgery,1,32,33 breast biopsy,31,34,35 and other superficial surgical procedures1,31 ) in adults.1,9

Clinical Experience

Remifentanil was evaluated in the monitored anesthesia care setting in 609 patients in 8 clinical studies.1 Nearly all patients received supplemental oxygen.1 Two early dose-finding studies demonstrated that use of sedation as an endpoint for titration of remifentanil led to a high incidence of muscle rigidity (69%) and respiratory depression.1 Subsequent trials titrated remifentanil to specific clinical endpoints of patient comfort, analgesia, and adequate respiration (respiratory rate >8 breaths/min), which corresponded with a lower incidence of muscle rigidity (3%) and respiratory depression.1 With doses of midazolam >2 mg (4 to 8 mg), the dose of remifentanil could be decreased by 50%, but the incidence of respiratory depression increased to 32%.1

The efficacy of a single dose of remifentanil (1 mcg/kg over 30 seconds) was compared with alfentanil (7 mcg/kg over 30 seconds) in patients undergoing ophthalmic surgery.1 More patients receiving remifentanil were pain free at the time of the nerve block (77% compared with 44%) and experienced nausea (12% compared with 4%) than those receiving alfentanil.1

In a randomized controlled study of 118 patients, remifentanil 0.5 mcg/kg over 30-60 seconds followed by a continuous IV infusion of 0.1 mcg/kg/min, was compared with a propofol bolus (500 mcg/kg) followed by a continuous IV infusion (50 mcg/kg/min) in patients who received a local or regional anesthetic nerve block 5 minutes later.1 The incidence of moderate or severe pain during placement of the block was similar between groups (2% with remifentanil and 8% with propofol), and more patients receiving remifentanil experienced nausea (26% compared with 2%).1 The final mean infusion rate of remifentanil was 0.08 mcg/kg/min.1

In a randomized double-blind study, remifentanil with or without IV midazolam was evaluated in 159 patients undergoing superficial surgical procedures under local anesthesia; remifentanil was administered without midazolam as a 1 mcg/kg dose over 30 seconds followed by a continuous IV infusion of 0.1 mcg/kg/min.1 In the group of patients who received midazolam, remifentanil was administered as a 0.5 mcg/kg dose over 30 seconds followed by a continuous IV infusion of 0.05 mcg/kg/min, and midazolam 2 mg was administered 5 minutes later.1 The occurrence of moderate or severe pain during the local anesthetic injection was similar between groups (16% and 20%).1 Titration of remifentanil resulted in prompt resolution of respiratory depression (median 3 minutes, range 0 to 6 minutes).1 The final mean infusion rate of remifentanil was 0.12 mcg/kg/min (range 0.03-0.3) for the group receiving remifentanil alone and 0.07 mcg/kg/min (range 0.02-0.2) for the group receiving remifentanil/midazolam.1

General

Patient Monitoring

• Monitor patients closely for signs of sedation and respiratory depression, particularly when initiating therapy and following dosage increases.1

Premedication and Prophylaxis

• Selection of preanesthetic medication(s) must be based on the individual needs of the patient; in clinical studies, remifentanil recipients frequently received a benzodiazepine.1

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), remifentanil is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.704

Other General Considerations

• Selection of concomitant anesthetic agent(s) must be based on the individual needs of the patient.1 Because of synergistic activity with other anesthetics, dosage adjustment for concomitantly administered anesthetics (e.g., propofol, isoflurane, midazolam) may be needed.1,3
• Administration of alternative analgesics prior to remifentanil discontinuance should be considered in surgical patients who may experience postoperative pain.1,3,9,10 Choice of analgesic should be based on the surgical procedure and level of follow-up care.1

Administration

IV Administration

Remifentanil is administered by IV infusion or injection after reconstitution and dilution.1

A controlled-infusion device should be used to ensure precise control of flow rate during continuous IV infusion of the drug.1

IV bolus administration should be used only during the maintenance of general anesthesia.1 Remifentanil should be injected into IV tubing at or close to the venous cannula.1 Administration of remifentanil into the same IV tubing with blood products is not recommended, since premature metabolism of the drug by nonspecific esterases may occur.1 Remifentanil should be cleared from the IV tubing upon discontinuance of the drug to prevent subsequent inadvertent administration of residual drug.1 Residual analgesic activity is absent within 5-10 minutes of drug discontinuance.1

Store remifentanil hydrochloride injection solutions at 2 to 25ºC.1

Reconstitution

Vials containing 1, 2, or 5 mg of remifentanil should be reconstituted by adding 1 mL of diluent (sterile water for injection or other compatible IV fluid) per mg of drug.1 The resultant solution should be shaken well to facilitate dissolution.1 This solution contains approximately 1 mg of remifentanil per mL.1

Dilution

Reconstituted solutions of remifentanil must be diluted prior to administration.1 The reconstituted solution should be diluted to the desired concentration (20, 25, 50, or 250 mcg/mL; see Table 1) in a compatible IV solution.1

A final concentration of 25 mcg/mL is recommended when the drug is used for monitored analgesia care.1 A final concentration of 20 or 25 mcg/mL is recommended for pediatric patients 1 year of age or older.1 Use of 250-mcg/mL solutions of the drug for infusion of dosages of 0.0125-0.025 mcg/kg per minute is not recommended.1

Rate of Administration

The rate of administration should be individualized based on patient response.1,3

In nonintubated patients, single doses of remifentanil should be administered over 30-60 seconds.1

For induction of anesthesia, remifentanil should be administered as a continuous IV infusion.1 If intubation is to occur within 8 minutes after initiation of the infusion, an initial dose of the drug may be given over 30-60 seconds.1

For maintenance of anesthesia, remifentanil should be administered as a continuous IV infusion.1 Rapid IV (bolus) doses may be administered every 2-5 minutes in response to light anesthesia or transient episodes of intense surgical stress.1

For analgesia in the immediate postoperative period, remifentanil may be administered as a continuous IV infusion.1 Infusion rates exceeding 0.2 mcg/kg per minute are associated with respiratory depression.1 Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of the risk for respiratory depression and muscle rigidity.1

For monitored anesthesia care, remifentanil should be administered prior to local or regional (nerve block) anesthesia as a single IV dose given over 30-60 seconds; alternatively, the drug may be administered as a continuous IV infusion.1 Supplemental rapid IV (bolus) doses of remifentanil administered simultaneously with a continuous remifentanil infusion to spontaneously breathing patients are not recommended.1

Risk of muscle rigidity is related to the dose and rate of IV administration.1,11 Chest wall rigidity has been reported after single doses exceeding 1 mcg/kg administered over 30-60 seconds, with infusion rates exceeding 0.1 mcg/kg per minute, or following single doses of less than 1 mcg/kg administered in conjunction with a continuous infusion of the drug.1 Supplemental doses of 0.5-1 mcg/kg and incremental increases in infusion rate exceeding 0.05 mcg/kg per minute are associated with transient and reversible muscle rigidity.1 Prior or simultaneous administration of propofol or thiopental or a neuromuscular blocking agent may attenuate the development of rigidity.1 In patients exhibiting excessive rigidity, a decrease in the infusion rate, discontinuance of the infusion of remifentanil, or administration of a neuromuscular blocking agent or naloxone should be considered.1

Doses of 0.5-1 mcg/kg administered in conjunction with a continuous infusion of the drug and incremental increases in infusion rate exceeding 0.05 mcg/kg per minute are associated with transient and reversible respiratory depression and apnea.1 In spontaneously breathing patients, respiratory depression should be managed by reducing the infusion rate of remifentanil by 50% or by temporarily discontinuing the infusion.1

Standardize 4 Safety

Standardized concentrations for remifentanil have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249 For additional information on S4S (including updates that may be available), see [Web].249

Dosage

Dosage of remifentanil hydrochloride is expressed in terms of remifentanil.1

Because of synergistic activity with other anesthetics, dosage adjustment of concomitantly administered anesthetic(s) may be needed.1,3

General Anesthesia (General Dosage) in Pediatric Patients

Manufacturer makes no specific recommendations regarding use or dosage of remifentanil in adolescents 13 years of age or older.1,41

Maintenance of General Anesthesia in Neonates and Infants Up to 2 Months of Age

IV Infusion: In conjunction with 70% nitrous oxide: An initial remifentanil infusion rate of 0.4 mcg/kg per minute is recommended.1 Because neonatal clearance of remifentanil is variable and may average twice that observed in young adults, some neonates may require an increased infusion rate to maintain adequate anesthesia; titrate dosage carefully according to individual requirements.1 Recommended infusion rate is 0.4-1 mcg/kg per minute.1

Rapid IV (bolus) doses of 1 mcg/kg could be administered every 2-5 minutes in response to signs of inadequate anesthesia in full-term neonates and infants up to 2 months of age with American Society of Anesthesiologists (ASA) physical status of I or II.1,16,30 Some neonates, including those receiving potent inhalation anesthetics or neuraxial anesthesia, those with substantial comorbidities or fluid shifts, and those who have not received atropine premedication, may require smaller bolus doses of remifentanil to avoid hypotension and/or bradycardia.1

Maintenance of General Anesthesia in Children 1-12 Years of Age

IV Infusion: In conjunction with nitrous oxide plus halothane (0.3-1.5 minimum alveolar concentration [MAC]), sevoflurane (0.3-1.5 MAC), or isoflurane (0.4-1.5 MAC): Remifentanil 0.25 mcg/kg per minute is recommended in patients with ASA physical status of I, II, or III.1 Adjust infusion rate upward by 50% or downward by 25-50% based on patient's response at intervals of 2-5 minutes.1 Recommended infusion rate is 0.05-1.3 mcg/kg per minute.1 Rapid IV (bolus) doses of 1 mcg/kg may be administered every 2-5 minutes in response to light anesthesia or transient episodes of intense surgical stress.1

An initial dose of 1 mcg/kg may be administered over 30-60 seconds.1,13

At remifentanil infusion rates exceeding 1 mcg/kg per minute, consider increases in dosage of concomitant anesthetic agent(s) to increase depth of anesthesia.1

General Anesthesia (General Dosage) in Adults

Induction of General Anesthesia

IV Infusion: Remifentanil 0.5-1 mcg/kg per minute given in conjunction with a volatile anesthetic or hypnotic agent is recommended in patients with ASA physical status I, II, or III.1

If intubation is to occur within 8 minutes after initiation of the remifentanil infusion, an initial dose of 1 mcg/kg may be given over 30-60 seconds.1

Maintenance of General Anesthesia

IV Infusion: In conjunction with 66% nitrous oxide: Remifentanil 0.4 mcg/kg per minute is recommended in patients with ASA physical status I, II, or III.1 Adjust infusion rate upward by 25-100% or downward by 25-50% based on patient's response at intervals of 2-5 minutes.1 Recommended infusion rate is 0.1-2 mcg/kg per minute.1 Rapid IV (bolus) doses of 1 mcg/kg may be administered every 2-5 minutes in response to light anesthesia or transient episodes of intense surgical stress.1

In conjunction with isoflurane (0.4-1.5 MAC) or propofol (100-200 mcg/kg per minute): Remifentanil 0.25 mcg/kg per minute is recommended in patients with ASA physical status I, II, or III.1 Adjust infusion rate upward by 25-100% or downward by 25-50% based on patient's response at intervals of 2-5 minutes.1 Recommended infusion rate is 0.05-2 mcg/kg per minute.1 Rapid IV (bolus) doses of 1 mcg/kg may be administered every 2-5 minutes in response to light anesthesia or transient episodes of intense surgical stress.1

At remifentanil infusion rates exceeding 1 mcg/kg per minute, consider increases in dosage of concomitant anesthetic agent(s) to increase depth of anesthesia.1

Analgesia in the Immediate Postoperative Period

IV Infusion: Initial postoperative infusion rate of 0.1 mcg/kg per minute is recommended in patients with ASA physical status I, II, or III.1 Adjust infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate.1 Recommended infusion rate is 0.025-0.2 mcg/kg per minute.1

Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.1

Infusion rates exceeding 0.2 mcg/kg per minute are associated with respiratory depression.1

General Anesthesia for Coronary Artery Bypass Surgery in Adults

Induction of Anesthesia for Coronary Artery Bypass Surgery

IV Infusion: Remifentanil 1 mcg/kg per minute is recommended in patients with ASA physical status III or IV.1 Excessive hypotension was reported in clinical studies when the dosage of concomitantly administered propofol exceeded 0.5 mg/kg over 1 minute followed by 10 mg every 10 seconds until loss of consciousness.1

Maintenance of Anesthesia for Coronary Artery Bypass Surgery

IV Infusion: As the analgesic component of a high-dose-opiate, balanced or IV anesthetic regimen, remifentanil 1 mcg/kg per minute is recommended in patients with ASA physical status III or IV.1 Recommended infusion rate is 0.125-4 mcg/kg per minute.1 Supplemental rapid IV (bolus) doses of 0.5-1 mcg/kg may be administered.1,41

Analgesia in the Immediate Period After Coronary Artery Bypass Surgery

IV Infusion: Remifentanil 1 mcg/kg per minute is recommended in patients with ASA physical status III or IV.1 Recommended infusion rate is 0.05-1 mcg/kg per minute.1

Monitored Anesthesia Care in Adults

Supplemental oxygen is strongly recommended for patients receiving remifentanil for monitored anesthesia care.1

As Analgesic Component of Local or Regional (Nerve Block) Anesthesia

IV (Single dose): When used alone prior to local or regional anesthesia in patients with ASA physical status I, II, or III, a single remifentanil dose of 1 mcg/kg (over 30-60 seconds) administered 90 seconds before the local anesthetic is recommended.1 When used in this manner in conjunction with midazolam 2 mg, reduce remifentanil dose to 0.5 mcg/kg (over 30-60 seconds).1

IV Infusion: When used alone in patients with ASA physical status I, II, or III, administer remifentanil 0.1 mcg/kg per minute beginning 5 minutes before the local anesthetic.1 Because of the risk of respiratory depression, reduce infusion rate to 0.05 mcg/kg per minute following nerve block placement.1 Adjust subsequent infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate.1 Recommended infusion rate is 0.025-0.2 mcg/kg per minute.1

When used in conjunction with midazolam 2 mg, administer remifentanil 0.05 mcg/kg per minute beginning 5 minutes before the local anesthetic.1 Because of the risk of respiratory depression, reduce infusion rate to 0.025 mcg/kg per minute following nerve block placement.1 Adjust subsequent infusion rate in increments of 0.025 mcg/kg per minute at 5-minute intervals based on level of analgesia and respiratory rate.1 Recommended infusion rate is 0.025-0.2 mcg/kg per minute.1

Infusion rates exceeding 0.2 mcg/kg per minute are associated with respiratory depression.1

Administration of rapid IV (bolus) doses of remifentanil concomitantly with a continuous infusion of the drug in spontaneously breathing patients is not recommended.1,11

Special Populations

Geriatric Patients

Decrease initial and, possibly, subsequent doses of remifentanil by 50% in patients older than 65 years of a titrate cautiously.1,2,9,12

Consider extending anticipated time to clinical effect by 50-100% in geriatric patients.9

Obese Patients

Base initial dosage on an estimate of ideal (lean) body weight if body weight exceeds ideal weight by more than 30%.1 Base subsequent dosage reductions on an estimate of ideal body weight.2,9,12

Contraindications

• Contains glycine; contraindicated for epidural or intrathecal administration.1,2,3,9
• Known hypersensitivity to fentanyl analogs (e.g., remifentanil).1

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

As an opioid, remifentanil exposes users to the risks of addiction, abuse, and misuse.1 A boxed warning about the risk of addiction, abuse, and misuse is included in the prescribing information for remifentanil.1

Opioids are sought for nonmedical use and are subject to diversion from a legitimate prescribed use.1 Consider these risks when handling this drug.1 Strategies to reduce these risks include proper product storage and control practices for a C-II drug.1 Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.1

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.1 Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.1 A boxed warning about the risk of serious, life-threatening, or fatal respiratory depression is included in the prescribing information for remifentanil.1

Remifentanil 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 respiration and cardiac resuscitation of patients in the age group being treated.1 Such training must include the establishment and maintenance of a patent airway and assisted ventilation.1 Resuscitative and intubation equipment, oxygen, and opioid antagonists must be readily available.1

Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of remifentanil hydrochloride by 50% or by temporarily discontinuing the infusion.1 Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.1 While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of remifentanil, the risk is greatest during the initiation of therapy or following a dosage increase.1 Monitor patients closely for respiratory depression, especially when initiating therapy and following dosage increases.1

Remifentanil should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia care setting.1 Patients receiving monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure.1 Oxygen saturation should be monitored on a continuous basis.1

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of remifentanil.1 Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression.1 Monitor such patients closely including vital signs, particularly when initiating and titrating remifentanil and when remifentanil is given concomitantly with other drugs that depress respiration.1 To reduce the risk of respiratory depression, proper dosing and titration of remifentanil are essential.1

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

When benzodiazepines or other CNS depressants are used with remifentanil, pulmonary arterial pressure may be decreased.1 This should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient.1 When high dose or anesthetic dosages of remifentanil are employed, even relatively small dosages of benzodiazepines (e.g., diazepam) may cause cardiovascular depression.1 A boxed warning about the risks of concomitant use of remifentanil and benzodiazepines and other CNS depressants is included in the prescribing information for remifentanil.1

When remifentanil is used with CNS depressants, hypotension can occur.1 If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy.1 When operative conditions permit, consider repositioning the patient to improve venous return to the heart.1 Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension.1 If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine.1 Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity.1

Hypotension, profound sedation, respiratory depression, coma, and death may occur when remifentanil is used concomitantly with benzodiazepines or other CNS depressants including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).700,701,702 Patients should be advised to avoid alcohol for 24 hours after surgery.1

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared with use of opioid analgesics alone.1 Because of similar pharmacological properties, it is reasonable to expect a similar risk with concomitant use of other CNS depressant drugs and opioid analgesics.1

If the decision is made to manage postoperative pain with remifentanil concomitantly with a benzodiazepine or other CNS depressant, start with the lowest effective dosage and titrate based on clinical response.1 Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension.1 Fluids or other measures to counter hypotension should be available.1

General Precautions

Opioid-Induced Hyperalgesia and Allodynia

Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.1 This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.1 Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).1 These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.1

Cases of OIH have been reported, both with short- and longer-term use of opioid analgesics.1 Although the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated and there is evidence suggesting a strong biologic link between opioid analgesics and OIH and allodynia.1 If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety).1

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of remifentanil with serotonergic drugs.1 Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT₃ receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and IV methylene blue).1 This may occur within the recommended dosage range.1

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal.1 The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.1 Discontinue remifentanil if serotonin syndrome is suspected.1

Administration Precautions

Continuous infusions of remifentanil should be administered only with an infusion device.1 IV bolus administration of remifentanil should be used only during the maintenance of general anesthesia.1 In nonintubated patients, single doses of remifentanil should be administered over 30-60 seconds.1

Interruption of an infusion of remifentanil will result in rapid offset of effect.1 Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of remifentanil at recommended doses.1 Discontinuation of an infusion of remifentanil should be preceded by the establishment of adequate postoperative analgesia.1

Injections of remifentanil should be made into IV tubing at or close to the venous cannula.1 Upon discontinuation of remifentanil, the IV tubing should be cleared to prevent the inadvertent administration of remifentanil at a later point in time.1 Failure to adequately clear the IV tubing to remove residual remifentanil has been associated with respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing.1

Remifentanil should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.1

Skeletal Muscle Rigidity

Skeletal muscle rigidity can be caused by remifentanil and is related to the dose and speed of administration; chest wall rigidity (inability to ventilate) may occur after single doses >1 mcg/kg administered over 30 to 60 seconds, or after infusion rates >0.1 mcg/kg/min.1 Single doses <1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.1

Muscle rigidity induced by remifentanil should be managed in the context of the patient's clinical condition.1 Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications and can be treated by decreasing the rate or discontinuing the infusion of remifentanil or by administering a neuromuscular blocking agent.1 The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status.1

Muscle rigidity seen during the use of remifentanil in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration.1 Resolution of muscle rigidity after discontinuing the infusion of remifentanil occurs within minutes.1 In the case of life-threatening muscle rigidity, administer a rapid onset neuromuscular blocker or naloxone.1

Bradycardia

Bradycardia has been reported with remifentanil and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.1

Hypotension

Hypotension has been reported with remifentanil and is responsive to decreases in dosage or administration of IV fluids or catecholamine (e.g., ephedrine, epinephrine, norepinephrine).1

Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), remifentanil may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure in spontaneously breathing patients.1 Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with remifentanil.1

Opioids may also obscure the clinical course in a patient with a head injury.1

Risks of Use in Patients with Biliary Tract Disease

Remifentanil may cause spasm of the sphincter of Oddi.1 Opioids may cause increases in serum amylase.1 Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.1

Increased Risk of Seizures in Patients with Seizure Disorders

Remifentanil may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.1 Monitor patients with a history of seizure disorders for worsened seizure control during remifentanil therapy.1

Rapid Offset of Action

Because of rapid offset of analgesic action (within 5-10 minutes) after drug discontinuation in patients undergoing surgical procedures where postoperative pain is generally anticipated, administer other analgesics prior to stopping remifentanil.1

However, respiratory depression may continue in some patients for up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics.1 Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation.1

Specific Populations

Pregnancy

Available data in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage with remifentanil.1

In animal reproduction studies, reduced fetal rat body weight and pup weights were reported at a dose 2.2 times based on a comparable human IV infusion (induction and maintenance) dose for a surgical procedure lasting 3 hours.1 There were no malformations noted when remifentanil was administered via bolus injection to pregnant rats or rabbits during organogenesis at doses approximately 5 times and approximately equal, respectively, to a human IV infusion of an induction and maintenance dose for a surgical procedure lasting 3 hours.1

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates.1 An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate.1 Remifentanil is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.1

Opioid analgesics, including remifentanil, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.1 However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.1 Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.1

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.1 Observe newborns for signs of this condition and manage accordingly.1

Remifentanil crosses the placenta;2,9,12 average maternal remifentanil concentrations are about twice those observed in the fetus.1

Lactation

It is not known whether remifentanil is distributed into human milk.1 However, other fentanyl analogs distribute into human milk.1 Caution is advised if used in nursing women.1

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for remifentanil and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.1

Infants exposed to remifentanil through breast milk should be monitored for excess sedation and respiratory depression.1 Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped.1

Pediatric Use

Safety and efficacy of remifentanil for use in the maintenance phase of general anesthesia in outpatient and inpatient surgery have been established in pediatric patients from birth to 12 years of age.1

Safety and efficacy of remifentanil as an analgesic in the immediate postoperative period or as an analgesic component of monitored anesthesia care have not been established in pediatric patients.1

In pediatric patients 2-12 years of age receiving maintenance anesthesia with remifentanil (0.2-1.95 mcg/kg per minute) in conjunction with nitrous oxide or with nitrous oxide and either halothane or sevoflurane, times to spontaneous purposeful movement and extubation were 1-24 minutes.1,13,14 In pediatric patients 1-12 years of age receiving maintenance anesthesia with remifentanil (up to 0.75 mcg/kg per minute) in conjunction with nitrous oxide and isoflurane, median times to spontaneous purposeful movement and extubation were 15 (range: 2-75) and 13 (range: 4-31) minutes, respectively.1,15 In full-term neonates and infants younger than 8 weeks of age receiving maintenance anesthesia with remifentanil (0.4-1 mcg/kg per minute) and nitrous oxide, median times to spontaneous purposeful movement and extubation were 6.5 (range: 1-13) and 8.5 (range: 1-14) minutes, respectively.1,16

Distribution volume of remifentanil is increased in younger pediatric patients and declines to young healthy adult values by 17 years of age.1 In pediatric patients, remifentanil clearance generally is higher in younger children and declines to young healthy adult values by 17 years of age.1 Neonatal clearance of the drug is variable and may average twice that observed in young adults.1

Geriatric Use

Patients 65 years of age and older may have increased sensitivity to remifentanil.1 Respiratory depression is the primary risk for geriatric patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respiration.1 Titrate the dosage of remifentanil slowly in these patients and frequently reevaluate the patient for signs of CNS and respiratory depression.1

Geriatric patients may exhibit reduced clearance of remifentanil;1,2,9,12 however, half-life is unchanged, and plasma concentrations decline as rapidly after drug discontinuance as in young adults.1 Remifentanil is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.1 Elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.1

Onset of action of remifentanil may be delayed in geriatric patients compared with younger individuals.9 Faster recovery times have been reported for patients younger than 60 years of age compared with those 60 years of age or older receiving remifentanil in conjunction with propofol; mean time to spontaneous respiration was 0.8 versus 3.2 minutes, respectively, and mean time to extubation was 5 versus 9 minutes, respectively.2

Hepatic Impairment

Pharmacodynamics (ventilatory response to hypercarbia) of remifentanil are unaltered in patients with severe hepatic impairment awaiting liver transplantation.1

Pharmacokinetics of remifentanil and its metabolite are unaltered in the presence of hepatic impairment.1,2,3,12

Renal Impairment

Pharmacodynamics (ventilatory response to hypercarbia) of remifentanil are unaltered in patients with end-stage renal disease.1

Pharmacokinetics of remifentanil are unaltered in the presence of renal impairment, including end-stage renal disease.1,2,12 In patients with end-stage renal disease, recovery times appear to be similar to those in patients with normal renal function.2

Obese Patients

As for all potent opioids, caution is advised in obese patients because of alterations in cardiovascular and respiratory physiology.1

In obese patients undergoing outpatient surgery, mean recovery and extubation times after maintenance anesthesia with remifentanil (0.05-2 mcg/kg per minute) in conjunction with sevoflurane and nitrous oxide were 6 and 7 minutes, respectively.2,20

In obese patients, clearance generally correlates with total body weight; however, in severely obese patients, clearance correlates better with ideal body weight.1,2,12

Common Adverse Effects

The most common adverse reactions (≥1%) with remifentanil include respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity.1

Benzodiazepines and Other CNS Depressants

Concomitant use of remifentanil and benzodiazepines or other CNS depressants, including other opiate agonists, anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and alcohol, may result in hypotension, profound sedation, respiratory depression, coma, and death.1,416,417,418,700,701,702,703 The lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700

Midazolam

A synergistic effect was seen when midazolam was administered concomitantly with remifentanil.1,2,3,9 Remifentanil hydrolysis was not inhibited by midazolam in vitro.1

Dosage of midazolam may need to be reduced by up to 75%.1

Temazepam

Clearance of remifentanil is unaltered by temazepam.1

Drugs Associated with Serotonin Syndrome

Serotonin syndrome may occur in patients receiving opiate agonists concomitantly with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

If concomitant use of other serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.400 If serotonin syndrome is suspected, treatment with remifentanil, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.400

Anesthetics

A synergistic effect has been shown when an anesthetic (e.g., isoflurane, propofol, thiopental) was administered concomitantly with remifentanil.1,2,3,12 Clearance of remifentanil is unaltered by thiopental, isoflurane, or propofol.1 Propofol or thiopental may attenuate development of remifentanil-associated muscle rigidity.1

Dosage of the anesthetic may need to be reduced by up to 75%.1,3

Antimuscarinics

Antimuscarinics (e.g., atropine, glycopyrrolate) may blunt the potential for remifentanil-associated bradycardia.1,3

Cholinesterase Inhibitors

Remifentanil hydrolysis was not inhibited by the addition of neostigmine or physostigmine in vitro.1,9

Esmolol

Remifentanil hydrolysis was not inhibited by the addition of esmolol in vitro.1 Esmolol metabolism was not altered by remifentanil when the drugs were used concomitantly.9

Neuromuscular Blocking Agents

Use of neuromuscular blocking agents concomitantly with remifentanil may attenuate development of remifentanil-associated muscle rigidity.1 Remifentanil hydrolysis was not inhibited by atracurium or mivacurium in vitro.1 Succinylcholine metabolism was not altered by remifentanil.9

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Use of mixed agonist/antagonist and partial agonist opioid analgesics (e.g., butorphanol, nalbuphine, pentazocine, buprenorphine) may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms.1

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.1 Consider discontinuing remifentanil if patient is not responding appropriately to treatment and institute alternative analgesic treatment.1

Description

Remifentanil is a selective µ-receptor agonist with similar potency to fentanyl; the drug shares the actions of the opiate agonists.2,3,4,8,9,10,11,12 The drug's precise mechanism of action has not been fully elucidated; opiate agonists act at several CNS sites, involving several neurotransmitter systems to produce analgesia.5,8 Remifentanil exhibits greater affinity for the µ-receptor than for the δ- or κ-receptors;3,11 the drug does not substantially bind to other nonopiate receptors.3

Agonist activity at the opiate µ-receptor can result in analgesia and respiratory depression.2,8 Respiratory depression may be mediated by µ-receptors, possibly µ₂-receptors (which may be distinct from µ₁-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.5,7

Opiate agonists alter perception of and emotional response to pain.5 Pain perception is altered in the spinal cord and higher CNS levels (e.g., substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus).5,6 Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli, nor peripheral nerve impulse conduction.5,6

Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.5

Remifentanil does not substantially affect intracranial pressure,1,2,3,12 intraocular pressure, cerebral blood flow or cerebral capacity,2,12 or cerebrovascular reactivity to carbon dioxide.1,2,3,11,12 Remifentanil does not substantially affect cerebral cortical cells, thereby exerting minimal effect on cognitive function.9

Remifentanil exhibits hypnotic-sparing effects similar to those of other opiates.1,2,3,12 The drug does not appear to cause histamine release and does not appear to alter intraocular pressure1,3,11,12

Remifentanil has a rapid onset of action (within 1-1.5 minutes) and peak analgesic effect (within 1-3 minutes).1,2,4,8,9,10,12 Remifentanil exhibits a linear, dose-dependent pharmacokinetic profile.2,9,12 Plasma concentration of the drug directly correlates with patient response and decreases 50% in 3-6 minutes after a 1-minute infusion or after prolonged continuous infusion (due to rapid distribution and elimination) and is independent of duration of drug administration.1,2,3,4,9,11,12 New steady-state concentrations are evident within 5-10 minutes after a change in the infusion rate.1 Increasing or decreasing the infusion rate by 0.1 mcg/kg per minute generally produces a 2- to 2.5-ng/mL change in plasma remifentanil concentrations within 5-10 minutes.1 A new, higher steady-state concentration may be achieved more rapidly (within 3-5 minutes) in intubated patients if 1 mcg/kg of remifentanil is given by rapid IV (bolus) injection in conjunction with an infusion rate increase.1 Remifentanil is rapidly distributed throughout blood and highly perfused tissues; the drug is subsequently distributed into peripheral tissues.1,2,3,11,12 Remifentanil rapidly equilibrates across the blood-brain barrier.1,2,9,12 Unlike other opiate agonists, remifentanil does not accumulate at high doses or with prolonged administration.1,2,3,11,12 Plasma protein binding of remifentanil is 70-92% (primarily to α₁-acid glycoprotein).1,2,8,9,12

Remifentanil is rapidly and extensively (exceeding 95%) hydrolyzed at the propanoic acid-methyl ester linkage by nonspecific esterases in blood and tissues, resulting in formation of an inactive carboxylic acid metabolite; the drug undergoes N -dealkylation to a lesser extent.1,2,3,4,8,9,10,12 Remifentanil is not metabolized by plasma cholinesterase and is not appreciably metabolized in the liver or lungs.1,2,3 Remifentanil is rapidly eliminated; at least 88% of a dose is eliminated in urine as the carboxylic acid metabolite.1,2,3,9,11,12 Terminal elimination half-life of remifentanil is 8-40 minutes;1,2,8,9,11,12 effective biologic half-life is 3-10 minutes.1,2,3,9,11 The half-life of the carboxylic acid metabolite is 90-120 minutes.1,9

Advice to Patients

• Inform patients that the use of remifentanil, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death.1
• Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting therapy or when the dosage is increased, and that it can occur even at recommended dosages.1 Advise patients to avoid alcohol for 24 hours after surgery.1
• Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain.1
• Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs.1 Warn patients of the symptoms of serotonin syndrome and to seek medical attention immediately if symptoms (e.g., agitation, hallucinations, tachycardia, labile blood pressure, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop after discharge from the hospital.1 Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications.1
• Advise women to inform their clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Mylan. Ultiva^® (remifentanil hydrochloride) injection prescribing information. Morgantown, WV; 2023 Dec.

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4. Martinelli C, Davoli M, Rutili A et al. Remifentanil for analgesia and sedation of critically ill patients in intensive care units (protocol). Cochrane Database of Syst Rev . 2006; 1:CD005577.

5. Bailey PL. Clinical Pharmacology and Applications of Opioid Agonists. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:96-103.

6. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Goodman L, Gilman A, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 6th ed. New York: Macmillan Publishing Company; 1980:494-534.

7. Reisner L, Koo PJS. Pain and its management. In: Koda-Kimble MA, Young LY et al, eds. Applied Therapeutics: the clinical use of drugs. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005: 9-1-9-40.

8. Gutstein HB, Akil H. Opioid analgesics. In: Brunton LL, Lazo JS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 547-90.

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14. Davis PJ, Finkel JC, Orr RJ et al. A randomized, double-blinded study of remifentanil versus fentanyl for tonsillectomy and adenoidectomy surgery in pediatric ambulatory surgical patients. Anesth Analg . 2000; 90:863-7. [PubMed 10735790]

15. Prys-Roberts C, Lerman J, Murat I et al. Comparison of remifentanil versus regional anaesthesia in children anaesthetised with isoflurane/nitrous oxide. International Remifentanil Paediatric Anaesthesia Study group. Anaesthesia . 2000;55:870-6.

16. Galinkin JL, Davis PJ, McGowan FX et al. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. II. Perioperative breathing patterns in neonates and infants with pyloric stenosis. Anesth Analg . 2001; 93:1387-92. [PubMed 11726412]

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