Remifentanil (Monograph)
Brand name: Ultiva
Drug class: Opiate Agonists
VA class: CN101
Chemical name: 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1-piperidine]propanoic acid methyl ester, hydrochloride salt
Molecular formula: C20H28N2O5 HCl
CAS number: CAS-132539-07-2; CAS-132875-61-7
Warning
A standardized concentration for this drug has been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. The drug is included in a standard concentration list which may apply to an IV or oral compounded liquid formulation. For additional information, see the ASHP website [Web].
Introduction
Selective μ-receptor opiate agonist; fentanyl analog.1 2 3 4 10 11 12
Uses for Remifentanil
General Anesthesia
As the analgesic component in the induction and maintenance of general anesthesia for inpatient and outpatient procedures.1 2 3 9 10 12 Although remifentanil has been used as the primary agent for induction of anesthesia, its use as the sole agent in general anesthesia is not recommended 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 intensive care unit (ICU).1 25 36 37 38 39 40 41 Long-term (i.e., >16 hours) use of remifentanil in ICU patients has not been established to date.1
May be particularly useful in surgical procedures requiring a rapid onset of analgesia and rapid recovery.2 3 8
Monitored Anesthesia Care
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
Related/similar drugs
lidocaine, fentanyl, ketamine, hyoscyamine, propofol, glycopyrrolate
Remifentanil Dosage and Administration
General
Premedication
-
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
Concomitant Anesthetics
-
Selection of concomitant anesthetic agent(s) must be based on the individual needs of the patient.1
-
Synergistic activity with other anesthetics; dosage adjustment for concomitantly administered anesthetic(s) may be needed.1 3 (See Specific Drugs under Interactions.)
Discontinuance of Therapy
-
Clear remifentanil from the IV tubing upon discontinuance of the drug to prevent subsequent inadvertent administration of residual drug.1 (See Discontinuance of Therapy under Cautions.)
-
Residual analgesic activity absent within 5–10 minutes of drug discontinuance.1 Consider administering alternative analgesics prior to remifentanil discontinuance in surgical patients who may experience postoperative pain.1 3 9 10 Choose analgesic based on surgical procedure and level of follow-up care.1
Administration
IV Administration
For solution and drug compatibility information, see Compatibility under Stability.
Use a controlled-infusion device to ensure precise control of flow rate during continuous IV infusion of the drug.1
Inject remifentanil 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
Clear remifentanil from the IV tubing upon discontinuance of the drug to prevent subsequent inadvertent administration of residual drug.1 (See Discontinuance of Therapy under Cautions.)
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 [see Compatibility under Stability]) 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 (See Storage and also see Compatibility, under Stability.)
Final Volume (mL) After Reconstitution and Dilution |
|||
---|---|---|---|
Final Concentration (mcg/mL) |
1-mg Vial |
2-mg Vial |
5-mg Vial |
20 |
50 |
100 |
250 |
25 |
40 |
80 |
200 |
50 |
20 |
40 |
100 |
250 |
... |
... |
20 |
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 under Dosage and Administration.
Administer rapid IV (bolus) doses of remifentanil only during the maintenance phase of general anesthesia.1
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 are not recommended because of risk for respiratory depression and muscle rigidity.1
Not recommended.1
Infusion Rate (mL/kg per hour) |
||||
---|---|---|---|---|
Dosage (mcg/kg per minute) |
20 mcg/mL |
25 mcg/mL |
50 mcg/mL |
250 mcg/mL |
0.0125 |
0.038 |
0.03 |
0.015 |
— |
0.025 |
0.075 |
0.06 |
0.03 |
— |
0.05 |
0.15 |
0.12 |
0.06 |
0.012 |
0.075 |
0.23 |
0.18 |
0.09 |
0.018 |
0.1 |
0.3 |
0.24 |
0.12 |
0.024 |
0.15 |
0.45 |
0.36 |
0.18 |
0.036 |
0.2 |
0.6 |
0.48 |
0.24 |
0.048 |
0.25 |
0.75 |
0.6 |
0.3 |
0.06 |
0.5 |
1.5 |
1.2 |
0.6 |
0.12 |
0.75 |
2.25 |
1.8 |
0.9 |
0.18 |
1 |
3 |
2.4 |
1.2 |
0.24 |
1.25 |
3.75 |
3 |
1.5 |
0.3 |
1.5 |
4.5 |
3.6 |
1.8 |
0.36 |
1.75 |
5.25 |
4.2 |
2.1 |
0.42 |
2 |
6 |
4.8 |
2.4 |
0.48 |
Risk of muscle rigidity is related to the 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 (See Musculoskeletal Effects under Cautions.)
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 (See Respiratory Depression under Cautions.)
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 (See Specific Drugs under Interactions.)
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 InfusionIn 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 clinical trials 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 Individualize dosage.1 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 InfusionIn 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 InfusionRemifentanil 0.5–1 mcg/kg per minute given in conjunction with a volatile anesthetic or hypnotic agent in patients with ASA physical status of 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 InfusionIn conjunction with 66% nitrous oxide: Remifentanil 0.4 mcg/kg per minute in patients with ASA physical status of 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 of 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 InfusionInitial postoperative infusion rate of 0.1 mcg/kg per minute in patients with ASA physical status of 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 not recommended 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 InfusionRemifentanil 1 mcg/kg per minute in patients with ASA physical status of 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 InfusionAs 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 of 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 InfusionRemifentanil 1 mcg/kg per minute in patients with ASA physical status of 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 of 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 InfusionWhen used alone in patients with ASA physical status of 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 not recommended.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 (See Geriatric Use under Cautions.)
Consider extending anticipated time to clinical effect by 50–100% in geriatric patients.9 (See Absorption: Special Populations under Pharmacokinetics.)
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.1
Warnings/Precautions
Warnings
Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.1 2 3
Supervised Administration
Remifentanil should only be administered by persons trained in the use of anesthetic drugs and the management of respiratory effects of opiates, including respiratory and cardiac resuscitation.1 Such training must include the establishment and maintenance of a patent airway and assisted ventilation.1
Do not use for diagnostic or therapeutic procedures outside a monitored anesthesia care setting.1 Patients receiving the drug for monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure.1
Monitor oxygen saturation continuously and have resuscitative and intubation equipment, oxygen, and an opiate antagonist readily available.1
Discontinuance of Therapy
Clear remifentanil from the IV tubing upon drug discontinuance; failure to remove residual remifentanil associated with respiratory depression, apnea, and muscle rigidity upon administration of fluids or drugs through the same tubing.1
Respiratory Depression
Apnea and dose-dependent respiratory depression reported with remifentanil.1 2 3 9 11 Remifentanil infusion rates of 0.05–0.1 mcg/kg per minute are associated with minimal decreases in respiratory rate; doses of 0.5–1 mcg/kg administered in conjunction with a continuous IV infusion of the drug, incremental increases in infusion rate of >0.05 mcg/kg per minute, and plasma concentrations >5 ng/mL are associated with transient and reversible respiratory depression and apnea.1 Peak respiratory depression after rapid IV (bolus) doses generally occurs within 2.5–5 minutes.2 8 11
Respiratory depression may occur up to 30 minutes after discontinuance of remifentanil infusion secondary to residual effects of concomitant anesthetics.1 Monitor patients in postoperative period to ensure adequate recovery without stimulation.1 To date, no reported cases of remifentanil-induced delayed respiratory depression occurring >30 minutes after drug discontinuance.1
Recovery of respiratory drive after a 3-hour infusion was faster and less variable with remifentanil than with alfentanil (when dosed to produce equal levels of respiratory depression). 1
Manage respiratory depression in spontaneously breathing patients by reducing infusion rate of remifentanil by 50% or by temporarily discontinuing the infusion.1 Spontaneous respiration occurs at plasma remifentanil concentrations of 4–5 ng/mL in the absence of other anesthetic agents.1 In patients undergoing general anesthesia, rate of respiratory recovery is dependent upon concomitant anesthetics.1 (See Duration under Pharmacokinetics.)
Supplemental oxygen strongly recommended for patients receiving remifentanil for monitored anesthesia care.1
Use for Postoperative Analgesia in Conjunction with Benzodiazepines or Other CNS Depressants
Concomitant use of remifentanil and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in hypotension, profound sedation, respiratory depression, coma, and death.416 417 418 437 700 701 702 (See Specific Drugs under Interactions.)
Musculoskeletal Effects
Dose-dependent muscle rigidity, particularly involving respiratory muscles.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 Peripheral rigidity may occur at lower doses.1 Supplemental doses of 0.5–1 mcg/kg, incremental increases in infusion rate of >0.05 mcg/kg per minute, and plasma concentrations >5 ng/mL are associated with transient and reversible muscle rigidity.1
To manage rigidity occurring during anesthesia induction, administer a neuromuscular blocking agent prior to or simultaneously with the induction regimen.1 Administration of an induction dose of propofol or thiopental or a paralyzing dose of a muscle relaxant prior to or simultaneously with remifentanil during anesthesia induction decreased incidence of muscle rigidity from 20% to <1% in clinical studies.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
Adrenal Insufficiency
Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400
If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400
General Precautions
Monitor vital signs and oxygenation continuously during remifentanil administration.1
Cardiovascular Effects
Dose-dependent bradycardia and hypotension reported in premedicated patients who received remifentanil doses of <2 mcg/kg over 1 minute.1 Additional doses of >2 mcg/kg (up to 30 mcg/kg) did not produce further decreases in heart rate or BP.1 Duration of hemodynamic change directly proportional to plasma concentrations of the drug, with peak hemodynamic effects occurring within 3–5 minutes after a single remifentanil dose or infusion rate increase.1
Bradycardia responsive to ephedrine or antimuscarinic agents (e.g., atropine, glycopyrrolate).1 Hypotension responsive to decreases in rate of administration of remifentanil or concomitant anesthetics, administration of IV fluids, or catecholamines (e.g., ephedrine, epinephrine, norepinephrine).1 (See Elimination: Special Populations, under Pharmacokinetics.)
Intraoperative Awareness
Intraoperative awareness reported in patients <55 years of age when remifentanil administered with propofol (≤75 mcg/kg per minute).1
Postoperative Analgesia
Because of rapid offset of action (within 5–10 minutes) after drug discontinuance, patients undergoing surgical procedures should receive other analgesics prior to remifentanil discontinuance.1 3
Induction of Anesthesia
Do not use remifentanil as the sole agent for induction of anesthesia since loss of consciousness cannot be ensured and a high incidence of apnea, muscle rigidity, or tachycardia is possible.1 3
Obesity
Use remifentanil with caution in morbidly obese individuals since alterations in cardiovascular and respiratory physiology may be present.1
Hypogonadism
Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;400 401 402 403 404 causality not established.400 Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.400 Perform appropriate laboratory testing in patients with manifestations of hypogonadism.400
Specific Populations
Pregnancy
Category C.1
Safety of remifentanil during labor or delivery not established to date.1 Respiratory depression and other opiate effects may occur in neonates whose mothers are given remifentanil shortly prior to delivery.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
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 (See Geriatric Patients under Dosage and Administration.)
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 (See Elimination: Special Populations, under Pharmacokinetics.)
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 (See Elimination: Special Populations, under Pharmacokinetics.)
Common Adverse Effects
Respiratory depression,1 9 10 11 bradycardia,1 2 9 10 11 12 hypotension,1 2 9 10 11 12 skeletal muscle rigidity,1 2 9 10 11 12 nausea,1 2 9 11 12 vomiting,1 2 9 11 12 pruritus,1 9 headache,1 shivering,1 2 11 12 dizziness.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 (See Advice to Patients.)
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
Drug |
Interaction |
Comments |
---|---|---|
Anesthetics, general (e.g., isoflurane, propofol, thiopental) |
Synergistic effect when administered concomitantly with remifentanil;1 2 3 12 increased risk of hypotension, profound sedation, respiratory depression, coma, or death437 700 703 Clearance of remifentanil unaltered by thiopental, isoflurane, or propofol1 Propofol or thiopental may attenuate development of remifentanil-associated muscle rigidity1 |
Use lowest effective dosages and shortest possible duration of concomitant therapy437 700 May need to reduce dosage of anesthetic by up to 75%1 3 Monitor closely for respiratory depression and sedation437 700 |
Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), SNRIs (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), tricyclic antidepressants (TCAs), mirtazapine, nefazodone, trazodone, vilazodone |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, the antidepressant, and/or any concurrently administered opiates or serotonergic agents400 |
Antiemetics, 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, the 5-HT3 receptor antagonist, and/or any concurrently administered opiates or serotonergic agents400 |
Antimuscarinics (atropine, glycopyrrolate) |
May blunt the potential for remifentanil-associated bradycardia1 3 |
|
Antipsychotics (e.g., aripiprazole, asenapine, cariprazine, chlorpromazine, clozapine, fluphenazine, haloperidol, iloperidone, loxapine, lurasidone, molindone, olanzapine, paliperidone, perphenazine, pimavanserin, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, ziprasidone) |
Risk of hypotension, profound sedation, respiratory depression, coma, or death437 700 703 |
Use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation437 700 |
Benzodiazepines (e.g., alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, triazolam) |
Risk of hypotension, profound sedation, respiratory depression, coma, or death416 417 418 437 700 701 703 Midazolam: Synergistic effect; remifentanil hydrolysis was not inhibited in vitro1 Temazepam: Clearance of remifentanil unaltered1 |
Use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation437 700 Midazolam: May need to reduce midazolam dosage by up to 75%1 |
Buspirone |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, buspirone, and/or any concurrently administered opiates or serotonergic agents400 |
Cholinesterase inhibitors |
Remifentanil hydrolysis was not inhibited by neostigmine or physostigmine in vitro1 9 |
|
CNS depressants (e.g., alcohol, anxiolytics, other opiate agonists, tranquilizers) |
Risk of hypotension, profound sedation, respiratory depression, coma, or death437 700 703 |
Use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation437 700 Advise patient to avoid alcohol use for 24 hours after surgery437 |
Dextromethorphan |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, dextromethorphan, and/or any concurrently administered opiates or serotonergic agents400 |
Esmolol |
Remifentanil hydrolysis was not inhibited by esmolol in vitro1 Esmolol metabolism was not altered by remifentanil9 |
|
5-HT1 receptor agonists (triptans; e.g., almotriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, the triptan, and/or any concurrently administered opiates or serotonergic agents400 |
Lithium |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, lithium, and/or any concurrently administered opiates or serotonergic agents400 |
MAO inhibitors (e.g., isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, tranylcypromine) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, the MAO inhibitor, and/or any concurrently administered opiates or serotonergic agents400 |
Neuromuscular blocking agents |
May attenuate development of remifentanil-associated muscle rigidity1 Remifentanil hydrolysis was not inhibited by atracurium or mivacurium in vitro1 Succinylcholine metabolism was not altered by remifentanil 9 |
|
Sedative/hypnotic agents (e.g., butabarbital, eszopiclone, pentobarbital, ramelteon, secobarbital, suvorexant, zaleplon, zolpidem) |
Risk of hypotension, profound sedation, respiratory depression, coma, or death437 700 703 |
Use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation437 700 |
Skeletal muscle relaxants (e.g., baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, tizanidine) |
Risk of hypotension, profound sedation, respiratory depression, coma, or death437 700 703 Cyclobenzaprine: Risk of serotonin syndrome400 |
Use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation437 700 Cyclobenzaprine: If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, cyclobenzaprine, and/or any concurrently administered opiates or serotonergic agents400 |
St. John’s wort (Hypericum perforatum) |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, St. John’s wort, and/or any concurrently administered opiates or serotonergic agents400 |
Tryptophan |
Risk of serotonin syndrome400 |
If concomitant use warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases400 If serotonin syndrome suspected, discontinue remifentanil, tryptophan, and/or any concurrently administered opiates or serotonergic agents400 |
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 Remifentanil has a 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 Remifentanil does not accumulate during prolonged administration; therefore, its duration of action (unlike that of other fentanyl analogs) 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 of 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 evident within 5–10 minutes after change in 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
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 children 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 children 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 remifentanil1 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
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
Compatibility
Parenteral
May be incompatible with blood products.1 (See IV Administration under Dosage and Administration.)
Solution Compatibility
Compatible |
---|
Dextrose 5% in water1 |
Dextrose 5% in sodium chloride 0.9%1 |
Sodium chloride 0.45 or 0.9%1 |
Dextrose 5% in Ringer's injection, lactated1 |
Ringer's injection, lactated1 |
Drug Compatibility
Compatible |
---|
Acyclovir sodium |
Alfentanil HCl |
Amikacin sulfate |
Aminophylline |
Ampicillin sodium |
Ampicillin sodium–sulbactam sodium |
Aztreonam |
Bretylium tosylate |
Bumetanide |
Buprenorphine HCl |
Butorphanol tartrate |
Calcium gluconate |
Cefazolin sodium |
Cefepime HCl |
Cefotaxime sodium |
Cefotetan disodium |
Cefoxitin sodium |
Ceftazidime |
Ceftizoxime sodium |
Ceftriaxone sodium |
Cefuroxime sodium |
Cimetidine HCl |
Ciprofloxacin |
Cisatracurium besylate |
Clindamycin phosphate |
Co-trimoxazole |
Dexamethasone sodium phosphate |
Dexmedetomidine HCl |
Digoxin |
Diphenhydramine HCl |
Dobutamine HCl |
Dopamine HCl |
Doxycycline hyclate |
Droperidol |
Enalaprilat |
Epinephrine HCl |
Esmolol HCl |
Famotidine |
Fenoldopam mesylate |
Fentanyl citrate |
Fluconazole |
Furosemide |
Ganciclovir sodium |
Gatifloxacin |
Gentamicin sulfate |
Haloperidol lactate |
Heparin sodium |
Hydrocortisone sodium succinate |
Hydromorphone HCl |
Hydroxyzine HCl |
Imipenem-cilastatin sodium |
Inamrinone lactate |
Isoproterenol HCl |
Ketorolac tromethamine |
Lidocaine HCl |
Linezolid |
Lorazepam |
Magnesium sulfate |
Mannitol |
Meperidine HCl |
Methylprednisolone sodium succinate |
Metoclopramide HCl |
Metronidazole |
Midazolam HCl |
Morphine sulfate |
Nalbuphine HCl |
Nitroglycerin |
Norepinephrine bitartrate |
Ondansetron HCl |
Phenylephrine HCl |
Piperacillin sodium–tazobactam sodium |
Potassium chloride |
Procainamide HCl |
Prochlorperazine edisylate |
Promethazine HCl |
Ranitidine HCl |
Sodium bicarbonate |
Sufentanil citrate |
Theophylline |
Thiopental sodium |
Ticarcillin disodium–clavulanate potassium |
Tobramycin sulfate |
Vancomycin HCl |
Zidovudine |
Incompatible |
Amphotericin B cholesteryl sulfate complex |
Variable |
Amphotericin B |
Chlorpromazine HCl |
Diazepam |
Compatible with propofol (Diprivan) when both drugs are administered into a running IV infusion solution.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
Advice to Patients
-
Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with benzodiazepines or other CNS depressants, including alcohol and other opiates, either therapeutically or illicitly.700 703 Importance of advising patients to avoid alcohol for 24 hours after surgery.437
-
Potential risk of serotonin syndrome with concurrent use of remifentanil and other serotonergic agents.400 Importance of immediately contacting clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.400
-
Potential risk of adrenal insufficiency.400 Importance of contacting clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.400
-
Possible risk (although causality not established) of hypogonadism or androgen deficiency with long-term opiate agonist or partial agonist use.400 Importance of informing clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs following therapy.400
-
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
-
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).1
-
Importance of informing patients of other important precautionary information.1 (See Cautions.)
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
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Parenteral |
For injection, for IV use only |
1 mg (of remifentanil) |
Ultiva (C-II;) |
Abbott |
2 mg (of remifentanil) |
Ultiva (C-II;) |
Abbott |
||
5 mg (of remifentanil) |
Ultiva (C-II;) |
Abbott |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions March 3, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
References
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2. Scott LJ, Perry CM. Remifentanil: a review of its use during the induction and maintenance of general anesthesia. Drugs. 2005; 65:1793-1823. http://www.ncbi.nlm.nih.gov/pubmed/16114980?dopt=AbstractPlus
3. Bürkle H, Dunbar S, Van Aken H. Remifentanil: a novel, short-acting, μ-opioid. Anesth Analg. 1996; 83:646-51.
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.
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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. http://www.ncbi.nlm.nih.gov/pubmed/10735790?dopt=AbstractPlus
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18. Gelb AW, Salevsky F, Chung F et al. Remifentanil with morphine transitional analgesia shortens neurological recovery compared to fentanyl for supratentorial craniotomy. Can J Anesth. 2003; 50:946-52. http://www.ncbi.nlm.nih.gov/pubmed/14617595?dopt=AbstractPlus
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22. Hogue CW Jr, Bowdle TA, O'Leary C et al. A multicenter evaluation of total intravenous anesthesia with remifentanil and propofol for elective inpatient surgery. Anesth Analg. 1996; 83:279-85. http://www.ncbi.nlm.nih.gov/pubmed/8694306?dopt=AbstractPlus
23. Rowbotham DJ, Peacock JE, Jones RM et al. Comparison of remifentanil in combination with isoflurane or propofol for short-stay surgical procedures. Br J Anaesth. 1998; 80:752-5. http://www.ncbi.nlm.nih.gov/pubmed/9771302?dopt=AbstractPlus
24. Wilhelm W, Grundmann U, Van Aken H et al. A multicenter comparison of isoflurane and propofol as adjuncts to remifentanil-based anesthesia. J Clin Anesth. 2000; 12:129-35. http://www.ncbi.nlm.nih.gov/pubmed/10818327?dopt=AbstractPlus
25. Schuttler J, Albrecht S, Breivik H et al. A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery. Anaesthesia. 1997; 52:307-17. http://www.ncbi.nlm.nih.gov/pubmed/9135180?dopt=AbstractPlus
26. Sneyd JR, Camu R, Doenicke A et al. Remifentanil and fentanyl during anaesthesia for major abdominal and gynaecological surgery. An open, comparative study of safety and efficacy. Eur J Anaesthesiol. 2001; 18:605-14. http://www.ncbi.nlm.nih.gov/pubmed/11553256?dopt=AbstractPlus
27. Twersky RS, Jamerson B, Warner DS et al. Hemodynamics and emergence profile of remifentanil versus fentanyl prospectively compared in a large population of surgical patients. J Clin Anesth. 2001; 13:407-16. http://www.ncbi.nlm.nih.gov/pubmed/11578883?dopt=AbstractPlus
28. Cartwright DP, Kvalsvik O, Cassuto J et al. A randomized, blind comparison of remifentanil and alfentanil during anesthesia for outpatient surgery. Anesth Analg. 1997; 85:1014-9. http://www.ncbi.nlm.nih.gov/pubmed/9356093?dopt=AbstractPlus
29. Philip BK, Scuderi PE, Chung F et al. Remifentanil compared with alfentanil for ambulatory surgery using total intravenous anesthesia. Anesth Analg. 1997; 84:515-21. http://www.ncbi.nlm.nih.gov/pubmed/9052293?dopt=AbstractPlus
30. Davis P. Galinkin J, McGowan FX et al. A randomized multicenter study of remifentanil compared with halothane in neonates and infants undergoing pyloromyotomy. I. Emergence and recovery profiles. Anesth Analg. 2001; 93:1380-6 http://www.ncbi.nlm.nih.gov/pubmed/11726411?dopt=AbstractPlus
31. Gold MI, Watkins WD, Sung YF et al. Remifentanil versus remifentanil/midazolam for ambulatory surgery during monitored anesthesia care. Anesthesiology. 1997; 87:51-7. http://www.ncbi.nlm.nih.gov/pubmed/9232133?dopt=AbstractPlus
32. Ahmad S, Leavell ME, Fragen RJ et al. Remifentanil versus alfentanil as analgesic adjuncts during placement of ophthalmologic nerve blocks. Reg Anesth Pain Med. 1999; 24:331-6. http://www.ncbi.nlm.nih.gov/pubmed/10445772?dopt=AbstractPlus
33. Leidinger W, Schwinn P, Hofmann HM et al. Remifentanil for analgesia during retrobulbar nerve block placement. Eur J Anaesthesiol. 2005; 22:40-3. http://www.ncbi.nlm.nih.gov/pubmed/15816572?dopt=AbstractPlus
34. Dilger JA, Sprung J, Maurer W et al. Remifentanil provides better analgesia than alfentanil during breast biopsy surgery under monitored anesthesia care. Can J Anaesth. 2004; 51:20-4. http://www.ncbi.nlm.nih.gov/pubmed/14709455?dopt=AbstractPlus
35. Avramov MN, Smith I, White PF. Interactions between midazolam and remifentanil during monitored anesthesia care. Anesthesiology. 1996; 85:1283-9. http://www.ncbi.nlm.nih.gov/pubmed/8968175?dopt=AbstractPlus
36. Yarmush J, D'Angelo R, O'Leary C et al. Remifentanil versus morphine for acute postoperative analgesia (abstract). Anesth Analg. 1996; 82:S504.
37. Yarmush J, D'Angelo R, Kirkhart B et al. A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofil. Anesthesiol. 1997; 87:235-45.
38. Camu F, Sneyd JR, Holgersen D et al. Efficacy and safety of remifentanil to control immediate postoperative pain prior to transfer to ward analgesia (abstract). Presented at the 11th World Congress of Anaesthesiologists, 14-20 April 1996, Sydney, D311.
39. Bowdle TA, Camporesi EM, Maysick L et al. A multicenter evaluation of remifentanil for early postoperative analgesia. Anesth Analg. 1996; 83:1292-97. http://www.ncbi.nlm.nih.gov/pubmed/8942602?dopt=AbstractPlus
40. Bowdle TA, Ready LB, Kharasch ED et al. Transition to post-operative epidural or patient-controlled intravenous analgesia following total intravenous anaesthesia with remifentanil and propofol for abdominal surgery. Eur J Anesth. 1997; 14:374-79.
41. Abbott, Abbott Park, IL: Personal communication.
400. US Food and Drug Administration. Drug safety communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. Silver Spring, MD; 2016 Mar 22. From FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm489676.htm
401. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009; 25:170-5. http://www.ncbi.nlm.nih.gov/pubmed/19333165?dopt=AbstractPlus
402. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004; 100:851-8. http://www.ncbi.nlm.nih.gov/pubmed/14770444?dopt=AbstractPlus
403. Abs R, Verhelst J, Maeyaert J et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000; 85:2215-22. http://www.ncbi.nlm.nih.gov/pubmed/10852454?dopt=AbstractPlus
404. Fraser LA, Morrison D, Morley-Forster P et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009; 117:38-43. http://www.ncbi.nlm.nih.gov/pubmed/18523930?dopt=AbstractPlus
416. Park TW, Saitz R, Ganoczy D et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015; 350:h2698. http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4462713&blobtype=pdf http://www.ncbi.nlm.nih.gov/pubmed/26063215?dopt=AbstractPlus
417. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med. 2015; 49:493-501. http://www.ncbi.nlm.nih.gov/pubmed/26143953?dopt=AbstractPlus
418. Dasgupta N, Funk MJ, Proescholdbell S et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med. 2016; 17:85-98. http://www.ncbi.nlm.nih.gov/pubmed/26333030?dopt=AbstractPlus
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