Remifentanil (Monograph)

Brand name: Ultiva
Drug class: Opioid Agonists

Medically reviewed by Drugs.com on Mar 10, 2025. Written by ASHP.

Introduction

Selective μ-receptor opiate agonist; fentanyl analog.^{1 2 3 4 10 11 12}

Uses for Remifentanil

General Anesthesia

Used as the analgesic component during induction and maintenance of general anesthesia for inpatient and outpatient procedures.^{1 2 3 9 10 12 21 22 23 24 25 26 27 28 29} Not recommended as the sole agent for general anesthesia because loss of consciousness cannot be ensured and a high incidence of apnea, muscle rigidity, or tachycardia is possible.^{1 2 3}

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

May be particularly useful in surgical procedures requiring a rapid onset of analgesia and rapid recovery.^{2 3 8}

Monitored Anesthesia Care

Used as the analgesic component of monitored anesthesia care in adults.^{1 9 31 32 33 34 35}

Remifentanil Dosage and Administration

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

Administer IV after reconstitution and dilution.¹

Use a controlled-infusion device 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

Inject remifentanil into IV tubing at or close to the venous cannula.¹

Administration into the same IV tubing with blood products not recommended.¹

Clear remifentanil 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

Reconstitution

Reconstitute vials containing 1, 2, or 5 mg of remifentanil by adding 1 mL of diluent (sterile water for injection or other compatible IV fluid) per mg of drug.¹ Shake well to dissolve.¹ Resultant solution contains approximately 1 mg of remifentanil per mL.¹

Dilution

Reconstituted solutions must be diluted prior to administration.¹

Dilute reconstituted solution to 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.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

Individualize rate of administration based on patient response.^{1 3} For recommended dosage ranges and continuous infusion rates, see Dosage and under Dosage and Administration.

In nonintubated patients, administer single doses of remifentanil over 30–60 seconds.¹

Induction of anesthesia: Administer remifentanil 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

Maintenance of anesthesia: Administer remifentanil as a continuous IV infusion.¹ May administer rapid IV (bolus) doses every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.¹

Analgesia in the immediate postoperative period: Administer as a continuous IV infusion.¹ Infusion rates >0.2 mcg/kg per minute are associated with respiratory depression.¹ Supplemental rapid IV (bolus) doses of remifentanil are not recommended because of risk for respiratory depression and muscle rigidity.¹

Monitored anesthesia care: Administer prior to local or regional (nerve block) anesthesia as a single IV dose given over 30–60 seconds; alternatively, administer 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 notrecommended.¹

Not recommended.¹

Risk of muscle rigidity is related to dose and rate of IV administration.^{1 11} Chest wall rigidity reported after single doses of >1 mcg/kg administered over 30–60 seconds, with infusion rates >0.1 mcg/kg per minute, or following single doses of <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 of >0.05 mcg/kg per minute 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 For excessive rigidity, consider decreasing the infusion rate or discontinuing the infusion of remifentanil or administering a neuromuscular blocking agent or naloxone.¹

Doses of 0.5–1 mcg/kg administered in conjunction with a continuous infusion of the drug and incremental increases in infusion rate of >0.05 mcg/kg per minute are associated with transient and reversible respiratory depression and apnea.¹ In spontaneously breathing patients, manage respiratory depression by reducing 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.²⁴⁹ Because 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

nonreconstituted vial (straight drug)

Dosage

Available as remifentanil hydrochloride; dosage expressed in terms of remifentanil.¹

Synergistic activity with other anesthetics; dosage adjustment of concomitantly administered anesthetic(s) may be needed.^{1 3}

Pediatric Patients

General Anesthesia (General Dosage)

Manufacturer makes no specific recommendations regarding use or dosage of remifentanil in adolescents ≥13 years of age.^{1 41}

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

IV Infusion

In conjunction with 70% nitrous oxide: Initial remifentanil infusion rate of 0.4 mcg/kg per minute.¹ Because neonatal clearance of remifentanil is variable and may average twice that observed in young adults, some neonates may require increased infusion rate to maintain adequate anesthesia; titrate dosage carefully according to individual requirements.¹ Recommended infusion rate: 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 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: 0.05–1.3 mcg/kg per minute.¹ May administer rapid IV (bolus) doses of 1 mcg/kg 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 >1 mcg/kg per minute, consider increases in dosage of concomitant anesthetic agent(s) to increase depth of anesthesia.¹

Adults

General Anesthesia (General Dosage)

Induction of General Anesthesia

IV Infusion

Remifentanil 0.5–1 mcg/kg per minute given in conjunction with a volatile anesthetic or hypnotic agent 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 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: 0.1–2 mcg/kg per minute.¹ May administer rapid IV (bolus) doses of 1 mcg/kg 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 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: 0.05–2 mcg/kg per minute.¹ May administer rapid IV (bolus) doses of 1 mcg/kg every 2–5 minutes in response to light anesthesia or transient episodes of intense surgical stress.¹

At remifentanil infusion rates >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 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: 0.025–0.2 mcg/kg per minute.¹

Supplemental rapid IV (bolus) doses of remifentanil are notrecommended because of risk for respiratory depression and muscle rigidity.¹

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

General Anesthesia for Coronary Artery Bypass Surgery

Induction of Anesthesia for Coronary Artery Bypass Surgery

IV Infusion

Remifentanil 1 mcg/kg per minute in patients with ASA physical status III or IV.¹ Excessive hypotension reported in clinical studies when 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 in patients with ASA physical status III or IV.¹ Recommended infusion rate: 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 in patients with ASA physical status III or IV.¹ Recommended infusion rate: 0.05–1 mcg/kg per minute.¹

Monitored Anesthesia Care

Supplemental oxygen 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, single remifentanil dose of 1 mcg/kg (over 30–60 seconds) administered 90 seconds before the local anesthetic.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, remifentanil 0.1 mcg/kg per minute, beginning 5 minutes before the local anesthetic.¹ Because of 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: 0.025–0.2 mcg/kg per minute.¹

When used in conjunction with midazolam 2 mg, remifentanil 0.05 mcg/kg per minute, beginning 5 minutes before the local anesthetic.¹ Because of 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: 0.025–0.2 mcg/kg per minute.¹

Infusion rates >0.2 mcg/kg per minute 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 notrecommended.^{1 11}

Special Populations

Geriatric Patients

Decrease initial and, possibly, subsequent doses of remifentanil by 50% in patients >65 years of age; 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 >30%.¹ Base subsequent dosage reductions on an estimate of ideal body weight.^{2 9 12}

Cautions for Remifentanil

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

Risks of addiction, abuse, and misuse (see Boxed Warning).¹

Opioids are sought for nonmedical use and are subject to diversion from 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

Risk of serious, life-threatening, or fatal respiratory depression, even when used as recommended.¹ Can occur at any time, but risk is greatest during initiation of therapy or following a dosage increase (see Boxed Warning).¹

Administer only by persons specifically trained in the use of anesthetic drugs and management of respiratory effects of potent opioids, including maintenance of a patent airway and assisted ventilation.¹ Resuscitative and intubation equipment, oxygen, and opioid antagonists must be readily available.¹

Manage respiratory depression in spontaneously breathing patients by decreasing rate of infusion by 50% or by temporarily discontinuing infusion.¹ Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate sedating effects of opioids.¹

To reduce the risk of respiratory depression, proper dosing and titration are essential.¹ Monitor patients closely for signs of respiratory depression.¹

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 and oxygen saturation should be monitored on a continuous basis.¹

Patients with significant COPD or cor pulmonale, or substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive, even at recommended dosages.¹ Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance resulting in greater risk for respiratory depression.¹ Monitor such patients closely, particularly when initiating and titrating remifentanil and when given concomitantly with other drugs that depress respiration.¹

Concomitant Use of Benzodiazepines or Other CNS Depressants

Hypotension, profound sedation, respiratory depression, coma, and death may result from concomitant use of benzodiazepines and/or other CNS depressants (e.g., alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids).¹ (See Boxed Warning.) Patients should be advised to avoid alcohol for 24 hours after surgery.¹

Pulmonary arterial pressure may be decreased when benzodiazepines or other CNS depressants are used concomitantly with remifentanil.¹

If concomitant use with a benzodiazepine or other CNS depressant is necessary, start with 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) may occur when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.¹ Symptoms of OIH include 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

If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or switch to a different opioid drug.¹

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Serotonin syndrome, a potentially life-threatening condition, reported during concomitant use with serotonergic drugs.¹ Symptoms 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).¹

Onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur at a later time.¹ Discontinue drug if serotonin syndrome is suspected.¹

Administration Precautions

Administer continuous infusions only with an infusion device.¹ Administer IV bolus only during the maintenance of general anesthesia.¹

In nonintubated patients, single doses should be administered over 30 to 60 seconds.¹

Interruption of an infusion will result in rapid offset of effect.¹ Precede discontinuation of an infusion by the establishment of adequate postoperative analgesia.¹

Administer injections into IV tubing at or close to the venous cannula.¹ Upon discontinuation, clear the IV tubing to prevent inadvertent administration of residual drug at a later time.¹ Failure to adequately clear the IV tubing has been associated with respiratory depression, apnea, and muscle rigidity when additional fluids or medications are administered through the same IV tubing.¹

Do not administer into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.¹

Skeletal Muscle Rigidity

Skeletal muscle rigidity, related to dose and speed of remifentanil administration, reported.¹ Chest wall rigidity may occur following single remifentanil doses of >1 mcg/kg given over 30–60 seconds, with infusion rates of >0.1 mcg/kg per minute, or following single doses of <1 mcg/kg administered in conjunction with a continuous infusion of the drug.¹

To manage rigidity occurring during anesthesia induction, administer a neuromuscular blocking agent and the concurrent induction medications; muscle rigidity can be treated by decreasing the rate or discontinuing the infusion of remifentanil or by administering a neuromuscular blocking agent.¹

To treat rigidity in spontaneously breathing patients, decrease remifentanil infusion rate or discontinue the drug; resolution of rigidity evident within minutes after infusion discontinuance.¹ For life-threatening rigidity, administer rapid-onset neuromuscular blocking agent or naloxone.¹

Bradycardia

Bradycardia reported; responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.¹

Hypotension

Hypotension reported; responsive to decreases in dosage or administration of IV fluids or catecholamines (e.g., ephedrine, epinephrine, norepinephrine).¹

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

May reduce respiratory drive 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.¹ 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.¹

Risks of Use in Patients with Biliary Tract Disease

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

May increase frequency of seizures in patients with seizure disorders, and may increase risk of seizures 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

Analgesic activity will subside within 5–10 minutes after infusion discontinuation.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 For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to discontinuation.¹

Specific Populations

Pregnancy

No available data to inform a drug-associated risk for major birth defects and miscarriage.¹ Based on animal studies, potential risk to fetus.¹

Opioids cross 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

Not recommended for use in pregnant women during or immediately prior to labor when other analgesic techniques are more appropriate.¹

Opioid analgesics can prolong labor through actions which temporarily reduce 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 during pregnancy may cause neonatal opioid withdrawal syndrome.¹ Observe newborns for signs of this condition and manage accordingly.¹

Lactation

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

Monitor infants exposed through breast milk for excess sedation and respiratory depression.¹ Withdrawal symptoms can occur 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

Geriatric Use

Geriatric patients may be twice as sensitive to the pharmacodynamic effects of remifentanil compared with young adults; monitor carefully.^{1 3 9} Adjust dosage accordingly.^{1 2 9 12}

Respiratory depression is primary risk for geriatric patients; titrate dosage slowly and frequently reevaluate 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

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}

Obese Patients

Caution advised in obese patients because of alterations in cardiovascular and respiratory physiology.¹

Pharmacogenomic Considerations

Genetic variations in CYP2D6, OPRM1(gene coding the mu opioid receptor mu1), and COMT ( enzyme responsible for methylconjugation of catecholamines) can influence clinical effect or adverse effects of some opioid analgesics.⁷⁷⁴

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines for selected opioid analgesics based on these genotypes.⁷⁷⁴

Remifentanil is not metabolized by CYP isoenzymes.¹ There is insufficient evidence to support any therapeutic recommendations for dosing opioids, such as remifentanil, based on either OPRM1 or COMT.⁷⁷⁴

Common Adverse Effects

Most common adverse reactions (≥1%): respiratory depression, bradycardia, hypotension, skeletal muscle rigidity.¹

Drug Interactions

Drugs Associated with Serotonin Syndrome

Risk of serotonin syndrome when used with other serotonergic drugs.⁴⁰⁰ May occur at usual dosages.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, monitor patients for serotonin syndrome, particularly during initiation of therapy and dosage increases.⁴⁰⁰

If serotonin syndrome is suspected, discontinue remifentanil, other opiate therapy, and/or any concurrently administered serotonergic agents.⁴⁰⁰

Specific Drugs

Remifentanil Pharmacokinetics

Absorption

Onset

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 has a faster onset of action than fentanyl or sufentanil.^{8 9}

Duration

Short duration of action.^{1 2 3 4} Shorter duration of action than alfentanil or fentanyl.¹⁰

Recovery is rapid (within 3–15 minutes), predictable, and independent of duration of infusion.^{1 2 8 10 12} Does not accumulate during prolonged administration; therefore, duration of action does not increase proportionally with duration of administration.^{1 8}

In full-term neonates and infants <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}

In patients undergoing general surgery and receiving remifentanil as a component of anesthesia, extubation occurred in a median time of 5 (range: -3–17) and 10 (range: 0–32) minutes in outpatients and inpatients, respectively.^{1 2} Recovery was faster when used in conjunction with nitrous oxide and propofol than when used in conjunction with isoflurane.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}

Plasma Concentrations

Exhibits a linear, dose-dependent pharmacokinetic profile.^{2 9 12} Plasma concentration 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 evident within 5–10 minutes after change in infusion rate.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

Special Populations

In patients with end-stage renal disease, recovery times appear to be similar to those in patients with normal renal function.²

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 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}

Onset of action may be delayed in geriatric patients compared with younger individuals.⁹

Faster recovery times reported for patients <60 years of age compared with those >60 years of age 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

Distribution

Extent

Rapidly distributed throughout blood and highly perfused tissues; subsequently distributed into peripheral tissues; unlike other opiate agonists, remifentanil does not accumulate at high doses or with prolonged administration.^{1 2 3 11 12}

Rapidly equilibrates across blood-brain barrier.^{1 2 9 12}

Crosses placenta;^{2 9 12} average maternal remifentanil concentrations are about twice those observed in fetus.¹

Plasma Protein Binding

70–92% (primarily α₁-acid glycoprotein).^{1 2 8 9 12}

Special Populations

Distribution volumes generally correlate with total body weight; however, in markedly obese patients, distribution volume correlates better with ideal body weight.^{1 2}

Distribution volume is increased in younger children and declines to young healthy adult values by 17 years of age.¹

Elimination

Metabolism

Rapidly and extensively (>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; 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}

Elimination Route

Rapidly eliminated; ≥88% of dose eliminated in urine as carboxylic acid metabolite.^{1 2 3 9 11 12}

Half-life

Remifentanil: Terminal elimination half-life: 8–40 minutes;^{1 2 8 9 11 12} effective biologic half-life: 3–10 minutes.^{1 2 3 9 11}

Carboxylic acid metabolite: 90–120 minutes.^{1 9}

Special Populations

Hepatic impairment: Pharmacokinetics of remifentanil^{1 2 3 12} and carboxylic acid metabolite unchanged.¹

Renal impairment: Pharmacokinetics of remifentanil unchanged.^{1 2 3 12} Half-life of carboxylic acid metabolite is increased to 30 hours in anephric patients.¹ Carboxylic acid metabolite is removed by hemodialysis (dialysis extraction ratio: 30%).¹

Obesity: Clearance generally correlates with total body weight; however, in severely obese patients, clearance correlates better with ideal body weight.^{1 2 12}

Pediatric patients: Clearance is generally higher in younger children and declines to young healthy adult values by 17 years of age.¹ Neonatal clearance is variable and may average twice that observed in young adults.¹

Geriatric patients: Remifentanil clearance is reduced by about 25% in patients >65 years of age compared with young adults;^{1 9 12} however, plasma concentrations decline as rapidly after drug discontinuance as in young adults.¹

Hypothermic cardiopulmonary bypass: Clearance of remifentanil is reduced by about 20%.^{1 2 12}

Stability

Storage

Parenteral

Powder for Injection

Store vials at 2–25°C.¹

Following reconstitution and dilution to final concentration of 20–250 mcg/mL in sterile water for injection, 5% dextrose, 5% dextrose and 0.9% sodium chloride, 0.45 or 0.9% sodium chloride, or 5% dextrose and lactated Ringer's injection, store at room temperature; use within 24 hours.¹

Following reconstitution and dilution to final concentration of 20–250 mcg/mL in lactated Ringer's injection, store at room temperature; use within 4 hours.¹

Actions

• A selective μ-receptor agonist with similar potency to fentanyl; shares the actions of the opiate agonists.^{2 3 4 8 9 10 11 12}

• 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 μ-receptor than for the δ- or κ-receptors.^{3 11} Does not substantially bind to other nonopioid 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} cerebral blood flow or cerebral capacity,^{2 12} or cerebrovascular reactivity to carbon dioxide.^{1 2 3 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}

• Remifentanil does not appear to cause histamine release.^{1 3 11}

• Does not appear to alter intraocular pressure.^{1 2 3 12}

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.¹

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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