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  • CLASSES

    Opiate Anesthetics

    BOXED WARNING

    Alcoholism, depression, substance abuse

    Remifentanil is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Addiction may occur in patients who obtain remifentanil illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence.

    Accidental exposure, potential for overdose or poisoning

    Like all opioid analgesics, remifentanil is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Remifentanil should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure may cause respiratory failure and a fatal overdose.

    DEA CLASS

    Rx, schedule II

    DESCRIPTION

    Opiate agonist for use during anesthesia with inhaled anesthetics and/or hypnotics; attenuates hemodynamic response to intubation and helps maintain cardiovascular stability during anesthesia; rapid onset, peak effect and ultra-short duration of action; metabolized by blood esterases; administration only by one trained in the use of intravenous and general anesthetics.

    COMMON BRAND NAMES

    Ultiva

    HOW SUPPLIED

    Remifentanil/Remifentanil Hydrochloride/Ultiva Intravenous Inj Pwd F/Sol: 1mg, 2mg, 5mg

    DOSAGE & INDICATIONS

    For general anesthesia induction (through intubation).
    NOTE: Remifentanil should not be used as the sole agent for general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.
    In coronary artery bypass surgery.
    Intravenous dosage
    Adults

    1 mcg/kg/minute by continuous IV infusion.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    Intravenous dosage
    Adults

    0.5 to 1 mcg/kg/minute by continuous IV infusion. If intubation is to occur less than 8 minutes after the start of the infusion, then an initial dose of 1 mcg/kg IV may be administered over 30 to 60 seconds.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    For general anesthesia maintenance .
    NOTE: Remifentanil should not be used as the sole agent for general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.
    With nitrous oxide.
    Intravenous dosage
    Adults

    With nitrous oxide (66%), 0.4 mcg/kg/minute (range: 0.1 to 2 mcg/kg/minute) by continuous IV infusion. Carefully titrate in up to 25% to 100% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Supplemental IV doses of 1 mcg/kg IV may be given every 2 to 5 minutes in response to light anesthesia or transient episodes of intense surgical stress. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    Infants 3 to 11 months

    0.25 mcg/kg/minute by continuous IV infusion with inhalational anesthesia (e.g., sevoflurane, isoflurane, nitrous oxide). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Mean dose: 0.36 to 0.45 mcg/kg/minute. Dosage range: 0.05 to 1 mcg/kg/minute. Clearance in young infants is higher than in older children and adults. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. Increased clearance in younger infants may also influence recovery time. Median time to extubation was 6 minutes in patients (n = 15; age range: 7 days to 3 months) anesthetized with remifentanil and isoflurane for major abdominal surgery. In contrast, median time to extubation was 12.5 minutes in patients (n = 20; age range 3 to 12 months) anesthetized with remifentanil, isoflurane, and nitrous oxide (50%) for cleft palate surgery.

    Neonates and Infants 1 to 2 months weighing 2.5 kg or more

    0.4 mcg/kg/minute by continuous IV infusion administered adjunctively with nitrous oxide (70%). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Dosage range: 0.4 to 1 mcg/kg/minute. Supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes; smaller bolus doses may be required with potent inhalation agents, neuraxial anesthesia, significant comorbidities, significant fluid shifts, or in those not pretreated with atropine. Clearance in neonates is highly variable and generally higher than in older children and adults. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. In clinical trials, median time from anesthesia discontinuation to spontaneous purposeful movement was 6.5 minutes (range: 1 to 13 minutes). Median time to extubation was 8.5 minutes (range: 1 to 14 minutes).

    With isoflurane (0.4 to 1.5 MAC).
    Intravenous dosage
    Adults

    0.25 mcg/kg/minute (range: 0.05 to 2 mcg/kg/minute) by continuous IV infusion. Carefully titrate in up to 25% to 100% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Supplemental IV doses of 1 mcg/kg IV may be given every 2 to 5 minutes in response to light anesthesia or transient episodes of intense surgical stress. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    Adolescents

    There are no specific dosing recommendations for the use of remifentanil in adolescents. The dose of remifentanil should be based upon the individual's response. Younger adolescents (16 years and younger) have slightly decreased clearance and reach healthy adult values by 17 years; increased clearance may necessitate an increased infusion rate and/or additional bolus to maintain adequate anesthesia. An initial infusion rate of 0.25 mcg/kg/minute IV is recommended for children (in adjunct with halothane, sevoflurane, or isoflurane) and adults (in adjunct with isoflurane or propofol); an initial infusion rate of 0.4 mcg/kg/minutes IV is recommended for adults when administered adjunctively with nitrous oxide (66%). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Recommended infusion rates range from 0.05 to 1.3 mcg/kg/minute in children and up to 2 mcg/kg/minute in adults. Supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents.

    Children

    0.25 mcg/kg/minute by continuous IV infusion. Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Dosage range: 0.05 to 1.3 mcg/kg/minute. An initial bolus of 1 mcg/kg may be administered over 30 to 60 seconds; supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. In clinical trials, median time from anesthesia discontinuation to spontaneous purposeful movement was 8 to 15 minutes (range: 1 to 75 minutes). Median time to extubation was 9 to 13 minutes (range: 1 to 31 minutes).

    Infants 3 to 11 months

    0.25 mcg/kg/minute by continuous IV infusion with inhalational anesthesia (e.g., sevoflurane, isoflurane, nitrous oxide). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Mean dose: 0.36 to 0.45 mcg/kg/minute. Dosage range: 0.05 to 1 mcg/kg/minute. Clearance in young infants is higher than in older children and adults. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. Increased clearance in younger infants may also influence recovery time. Median time to extubation was 6 minutes in patients (n = 15; age range: 7 days to 3 months) anesthetized with remifentanil and isoflurane for major abdominal surgery. In contrast, median time to extubation was 12.5 minutes in patients (n = 20; age range 3 to 12 months) anesthetized with remifentanil, isoflurane, and nitrous oxide (50%) for cleft palate surgery.

    With propofol (100 to 200 mcg/kg/minute).
    Intravenous dosage
    Adults

    0.25 mcg/kg/minute (range: 0.05 to 2 mcg/kg/minute) by continuous IV infusion. Carefully titrate in up to 25% to 100% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Supplemental IV doses of 1 mcg/kg IV may be given every 2 to 5 minutes in response to light anesthesia or transient episodes of intense surgical stress. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. Intraoperative awareness has been reported when remifentanil has been administered with propofol infusion rates of less than 75 mcg/kg/minute.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    With halothane (0.3 to 1.5 MAC).
    Intravenous dosage
    Adolescents

    There are no specific dosing recommendations for the use of remifentanil in adolescents. The dose of remifentanil should be based upon the individual's response. Younger adolescents (16 years and younger) have slightly decreased clearance and reach healthy adult values by 17 years; increased clearance may necessitate an increased infusion rate and/or additional bolus to maintain adequate anesthesia. An initial infusion rate of 0.25 mcg/kg/minute IV is recommended for children (in adjunct with halothane, sevoflurane, or isoflurane) and adults (in adjunct with isoflurane or propofol); an initial infusion rate of 0.4 mcg/kg/minutes IV is recommended for adults when administered adjunctively with nitrous oxide (66%). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Recommended infusion rates range from 0.05 to 1.3 mcg/kg/minute in children and up to 2 mcg/kg/minute in adults. Supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents.

    Children

    0.25 mcg/kg/minute by continuous IV infusion. Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Dosage range: 0.05 to 1.3 mcg/kg/minute. An initial bolus of 1 mcg/kg may be administered over 30 to 60 seconds; supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. In clinical trials, median time from anesthesia discontinuation to spontaneous purposeful movement was 8 to 15 minutes (range: 1 to 75 minutes). Median time to extubation was 9 to 13 minutes (range: 1 to 31 minutes).

    With sevoflurane (0.3 to 1.5 MAC).
    Intravenous dosage
    Adolescents

    There are no specific dosing recommendations for the use of remifentanil in adolescents. The dose of remifentanil should be based upon the individual's response. Younger adolescents (16 years and younger) have slightly decreased clearance and reach healthy adult values by 17 years; increased clearance may necessitate an increased infusion rate and/or additional bolus to maintain adequate anesthesia. An initial infusion rate of 0.25 mcg/kg/minute IV is recommended for children (in adjunct with halothane, sevoflurane, or isoflurane) and adults (in adjunct with isoflurane or propofol); an initial infusion rate of 0.4 mcg/kg/minutes IV is recommended for adults when administered adjunctively with nitrous oxide (66%). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Recommended infusion rates range from 0.05 to 1.3 mcg/kg/minute in children and up to 2 mcg/kg/minute in adults. Supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents.

    Children

    0.25 mcg/kg/minute by continuous IV infusion. Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Dosage range: 0.05 to 1.3 mcg/kg/minute. An initial bolus of 1 mcg/kg may be administered over 30 to 60 seconds; supplemental IV doses of 1 mcg/kg may be administered every 2 to 5 minutes. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. In clinical trials, median time from anesthesia discontinuation to spontaneous purposeful movement was 8 to 15 minutes (range: 1 to 75 minutes). Median time to extubation was 9 to 13 minutes (range: 1 to 31 minutes).

    Infants 3 to 11 months

    0.25 mcg/kg/minute by continuous IV infusion with inhalational anesthesia (e.g., sevoflurane, isoflurane, nitrous oxide). Carefully titrate in up to 50% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Mean dose: 0.36 to 0.45 mcg/kg/minute. Dosage range: 0.05 to 1 mcg/kg/minute. Clearance in young infants is higher than in older children and adults. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents. Increased clearance in younger infants may also influence recovery time. Median time to extubation was 6 minutes in patients (n = 15; age range: 7 weeks to 3 months) anesthetized with remifentanil and isoflurane for major abdominal surgery. In contrast, median time to extubation was 12.5 minutes in patients (n = 20; age range 3 to 12 months) anesthetized with remifentanil, isoflurane, and nitrous oxide (50%) for cleft palate surgery.

    In coronary artery bypass surgery.
    Intravenous dosage
    Adults

    1 mcg/kg/minute (range: 0.125 to 4 mcg/kg/minute) by continuous IV infusion. Carefully titrate in up to 25% to 100% increments or 25% to 50% decrements every 2 to 5 minutes as needed to achieve desired clinical response. Supplemental IV doses of 0.5 to 1 mcg/kg may be given every 2 to 5 minutes in response to light anesthesia or transient episodes of intense surgical stress. If anesthesia is not adequate at a rate of 1 mcg/kg/minute, consider increasing the concomitant anesthetic agents.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    For total intravenous anesthesia (TIVA).
    Intravenous dosage
    Infants, Children, and Adolescents

    0.1 to 0.2 mcg/kg/minute IV in combination with propofol; titrate in 0.05 mcg/kg/minute increments every 3 to 5 minutes to effect. Remifentanil given as a 0.5 to 1.5 mcg/kg IV load over 1 to 3 minutes (0.5 mcg/kg/minute) followed by a maintenance infusion ranging from 0.1 to 0.5 mcg/kg/minute IV has been utilized.

    Neonates

    0.1 to 0.2 mcg/kg/minute IV in combination with propofol; titrate in 0.05 mcg/kg/minute increments every 3 to 5 minutes to effect. Remifentanil given as a 0.5 to 1.5 mcg/kg IV load over 1 to 3 minutes (0.5 mcg/kg/minute) followed by a maintenance infusion ranging from 0.1 to 0.5 mcg/kg/minute IV has been utilized.

    For the management of moderate pain and severe pain.
    In the immediate postoperative period following general anesthesia.
    Continuous Intravenous Infusion dosage
    Adults

    0.1 mcg/kg/minute (range: 0.025 to 0.2 mcg/kg/minute) by continuous IV infusion. Titrate dose every 5 minutes in 0.025 mcg/kg/minute increments to balance the patient's level of analgesia and respiratory rate. Infusion rates greater than 0.2 mcg/kg/minute are associated with respiratory depression (less than 8 breaths per minute). Bolus doses administered simultaneously with a continuous infusion of remifentanil to spontaneously breathing patients are not recommended.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    In the ICU after coronary artery bypass surgery.
    Continuous Intravenous Infusion dosage
    Adults

    1 mcg/kg/minute (range: 0.05 to 1 mcg/kg/minute) by continuous IV infusion. Titrate dose every 5 minutes in 0.025 mcg/kg/minute increments to balance the patient's level of analgesia and respiratory rate. Infusion rates greater than 0.2 mcg/kg/minute are associated with respiratory depression (less than 8 breaths per minute). Bolus doses administered simultaneously with a continuous infusion of remifentanil to spontaneously breathing patients are not recommended.

    Geriatric

    Starting doses should be decreased by 50% (see adult dosage). Titrate dose to effect.

    In mechanically-ventilated pediatric patients†, in the post-operative or intensive care setting.
    Continuous Intravenous Infusion dosage
    Children and Adolescents 3 to 17 years

    Limited data available; cardiac surgery patients may have larger opioid requirements than the general intensive care population. Remifentanil 0.1 mcg/kg/minute IV, titrated by 0.025 mcg/kg/minute increments to obtain adequate pain intensity scores, provided comparable analgesia to a fentanyl infusion in 22 mechanically-ventilated pediatric patients (median age: 13 years [range: 3 to 16 years]) after orthopedic spinal surgery in a randomized, double-blind study. Maximum infusion rate was not specified, however, patients in the remifentanil group proceeded through a mean of 3 dose titrations (range: 0 to 7 titrations). Remifentanil 0.8 mcg/kg/minute IV for 1 hour, decreased by 0.1 mcg/kg/minute every 20 minutes until awakening, provided satisfactory sedation when used in combination with a midazolam infusion in a small study of pediatric patients receiving mechanical ventilation after cardiac surgery (n = 26; median age: 1.77 years [range: 1 month to 9.25 years]). Infusion duration ranged from 19 minutes to 20.6 hours (median: 3.2 hours).

    Children 1 to 2 years

    Limited data available; cardiac surgery patients may have larger opioid requirements than the general intensive care population. Remifentanil 0.8 mcg/kg/minute IV for 1 hour, decreased by 0.1 mcg/kg/minute every 20 minutes until awakening, provided satisfactory sedation when used in combination with a midazolam infusion in a small study of pediatric patients receiving mechanical ventilation after cardiac surgery (n = 26; median age: 1.77 years [range: 1 month to 9.25 years]). Infusion duration ranged from 19 minutes to 20.6 hours (median: 3.2 hours).

    Infants

    Limited data available; cardiac surgery patients may have larger opioid requirements than the general intensive care population. A continuous infusion of remifentanil at a rate of 0.25 mcg/kg/minute IV, begun 1 hour after intensive care admission and continued for 12 hours, provided effective postoperative analgesia in infants (n = 20; mean age: 7.3 months [range: 4 to 11 months]) after craniosynostosis repair. Remifentanil was the sole analgesic and sedative agent used. Remifentanil 0.8 mcg/kg/minute IV for 1 hour, decreased by 0.1 mcg/kg/minute every 20 minutes until awakening, provided satisfactory sedation when used in combination with a midazolam infusion in a small study of pediatric patients receiving mechanical ventilation after cardiac surgery (n = 26; median age: 1.77 years [range: 1 month to 9.25 years]). Infusion duration ranged from 19 minutes to 20.6 hours (median: 3.2 hours); 1 patient (1-month-old) required overnight sedation at an infusion rate of 0.8 mcg/kg/minute before criteria for step-down were met.

    Neonates

    0.15 mcg/kg/minute IV; titrate in 0.05 mcg/kg/minute increments to achieve adequate clinical response. Max: 0.5 mcg/kg/minute IV. A double-blind, controlled, pilot study demonstrated median extubation times after discontinuation of opioid infusion of 80 minutes and 782.5 minutes (p = 0.004) in mechanically-ventilated neonates (n = 23) randomized to a sedation and analgesia regimen of remifentanil/midazolam or fentanyl/midazolam, respectively. Patients in the remifentanil arm (n = 11; mean age: 1.6 days [range: 1 to 8 days]; mean weight: 3.4 kg) received a mean opioid dose of 0.23 mcg/kg/minute IV for a mean duration of 64.5 hours (range: 12.3 to 103.8 hours). Both regimens provided adequate analgesia and midazolam doses were similar in each group. When the neonate was ready for extubation, sedation and analgesia were discontinued at the same time without dose reduction. There was a tendency for a longer need of mechanical ventilation and, therefore, sedation and analgesia in the remifentanil group (mean difference: 25 hours, 95% CI: -2.3 to 52.3 hours); the authors contributed this difference to a more pronounced initial respiratory distress in the remifentanil group.

    Premature Neonates 25 weeks gestation and older

    0.075 to 0.5 mcg/kg/minute IV; titrate to achieve adequate clinical response. Max reported dose: 0.94 mcg/kg/minute. Maintain infusion until extubation, then reduce by half for 30 minutes prior to drug discontinuation. Remifentanil, at a dose of 0.075 mcg/kg/minute IV and 0.09 mcg/kg/minute IV, provided adequate analgesia in 27% and 97% of patients, respectively, when used as a sole agent in mechanically-ventilated premature neonates (n = 48; mean gestational age: 28.5 weeks; mean birth weight: 1.1 kg). In the study, mean dose administered was 0.11 mcg/kg/minute IV and mean duration of therapy was 5.9 days (range: 1 to 20 days). Upon drug discontinuation, mean time to extubation was 36 minutes, with no correlation to the duration of infusion. Early extubation is a major advantage of remifentanil use. Times to awakening and extubation were 18.9 and 12.2 times longer, respectively, in the morphine/midazolam arm (n = 10; mean infusion duration: 8 hours) compared to the remifentanil/midazolam arm (n = 10; mean infusion duration: 8.6 hours) in a randomized controlled trial of mechanically-ventilated premature neonates with respiratory distress syndrome (mean gestational age: 31 weeks; mean birth weight [remifentanil]: 1.5 kg). Adequate analgesia and sedation were demonstrated in each group.

    For sedation and analgesia prior to non-emergent endotracheal intubation† or rapid-sequence intubation (RSI)†.
    Intravenous dosage
    Adolescents

    Limited data available. Remifentanil 1.25 mcg/kg/dose IV over 30 seconds, administered after propofol, produced good or excellent intubating conditions in 67% of patients (n = 30; age range: 2 to 16 years) presenting for elective surgery; 1 patient could not be intubated and another required a second attempt. Of note, a comparator arm receiving propofol with succinylcholine had significantly better intubating conditions (i.e., more excellent scores for jaw relaxation, ease of laryngoscopy, vocal cord position, coughing, and limb movement) (p less than 0.05) with 87% of patients (n = 30) achieving good or excellent intubating conditions.

    Infants and Children

    1 to 4 mcg/kg/dose IV over 30 to 60 seconds. Give dose 60 to 90 seconds prior to intubation. In a dose-response study including infants 2 months and older (n = 32) and children 1 to 6 years (n = 32), patients were randomized to receive remifentanil 1.25, 1.5, 1.75, or 2 mcg/kg/dose IV immediately after propofol to facilitate tracheal intubation. At these doses, the incidence of excellent or good intubating conditions was 13%, 38%, 50%, and 75%, respectively, in infants and 13%, 38%, 75%, and 89%, respectively, in children. Dose-response data indicated remifentanil 3 mcg/kg/dose IV should provide excellent or good intubating conditions in more than 98% of patients. However, the incidence of successful intubation after the administration of remifentanil has been variable. In children (n = 112; age range: 3 to 12 years), remifentanil 1 mcg/kg/dose, 2 mcg/kg/dose, or 3 mcg/kg/dose IV coadministered with propofol resulted in good or excellent intubating conditions in 50%, 69%, and 82% of patients, respectively. In another study (n = 40; age range: 2 to 12 years), remifentanil 1 mcg/kg/dose IV followed by propofol led to near ideal intubating conditions in 80% of children. Remifentanil has also been used for non-emergent intubation in conjunction with inhalational gases. In one study (n = 20; age range: 1 to 9 years), remifentanil 1 mcg/kg/dose IV coadministered with sevoflurane yielded excellent intubating conditions in 85% of patients. In another study, (n = 64; age range: 1 to 7 years) remifentanil 1 or 2 mcg/kg/dose IV added to sevoflurane and nitrous oxide (50%) provided acceptable intubating conditions in 96.9% and 100% of patients, respectively.

    Neonates

    1 to 3 mcg/kg/dose IV over 60 to 120 seconds; may repeat in 2 to 3 minutes if needed. Give dose 60 to 90 seconds prior to intubation.

    Premature Neonates 28 weeks gestation and older

    1 to 2 mcg/kg/dose IV over 60 seconds; may repeat dose. Give dose 60 to 90 seconds prior to intubation. In a small study of premature neonates (gestational age: 28 to 34 weeks) with respiratory distress syndrome, all patients receiving remifentanil 1 mcg/kg/dose IV and midazolam (n = 10) achieved satisfactory intubating conditions, defined as excellent (60%) or good (40%) on the first attempt. Overall, intubation conditions were significantly better (p = 0.0034) in patients receiving remifentanil compared to those receiving morphine (n = 10; good conditions: 60%; poor conditions 40%). In another study, premature neonates (n = 21; gestational age: 29 to 32 weeks) receiving remifentanil 2 mcg/kg/dose IV as a sole induction agent for the INSURE (Intubation Surfactant Extubation) procedure achieved satisfactory intubating conditions, defined as excellent (67%) or good (33%). Two patients awoke after intubation but during surfactant administration and were administered a second dose. Mean time to extubation after surfactant administration was 16.9 minutes (range: 1 to 45 minutes).

    Intranasal dosage
    Children 1 to 7 years

    Limited data available; optimal dose is not established. Remifentanil 1 and 4 mcg/kg/dose administered intranasally has resulted in satisfactory intubating conditions. Remifentanil 4 mcg/kg/dose (prepared as a 100 mcg/mL solution and divided equally and dripped in each nare) was more effective than placebo and achieved good or excellent intubating conditions at 2 minutes postdose in 68% and at 3 minutes postdose in 92% of children after sevoflurane induction in a randomized, controlled trial (n = 188; age range: 1 to 7 years). However, 0.998 mcg/kg/dose at 2 minutes postdose was the estimated 95% effective dose (ED95) of intranasal remifentanil (administered via a mucosal atomization device) for successful laryngeal mask airway insertion in children (n = 75; age range: 2 to 5 years) after sevoflurane induction during a randomized, controlled trial comparing 0, 0.25, 0.5, 0.75 and 1 mcg/kg/dose.

    For procedural sedation†.
    Intermittent Intravenous dosage
    Children and Adolescents 2 to 17 years

    0.5 to 1 mcg/kg IV as a single dose given alone or in combination with propofol or midazolam. In one study, additional doses of 0.5 mcg/kg/dose IV were given upon movement or signs of awakening; the mean remifentanil dose given was 1.2 mcg/kg/dose.

    Continuous Intravenous Infusion dosage
    Children and Adolescents 2 to 17 years

    0.05 to 0.2 mcg/kg/minute IV as a continuous infusion has produced adequate sedation levels with varying incidence of adverse respiratory and hemodynamic effects; some studies have utilized an initial bolus up to 2 mcg/kg/dose IV prior to infusion initiation. In a case study of 26 pediatric patients (age range: 3 to 14 years) undergoing diagnostic flexible bronchoscopy, remifentanil 0.05 mcg/kg/minute IV as a continuous infusion in conjunction with intermittent IV propofol boluses produced good sedation levels in all patients. All patients were awake within 5 minutes after procedure termination and transferred out of the recovery room 60 minutes after the end of the investigation. There was no need for assisted ventilation, intubation, or opioid antagonists. Remifentanil plus midazolam produced adequate sedation in 85% of patients but resulted in a high incidence of respiratory depression in another case series including 17 children (age range: 2 to 12 years) undergoing 20 brief, painful procedures. After midazolam premedication, a bolus of remifentanil 1 mcg/kg/dose IV was infused over 60 seconds, followed by an infusion of 0.1 mcg/kg/minute IV (optimal dose: 0.4 mcg/kg/minute). In the successful cases, discharge criteria were met approximately 10 minutes after procedure termination. However, a prospective study of pediatric patients undergoing bone marrow biopsy (n = 77; mean age: 9 +/- 5 years), utilized lower bolus doses of remifentanil (0.15 mcg IV) followed by a continuous infusion of 0.1 mcg/kg/minute IV in addition to a standard propofol sedation regimen and observed a lower rate of respiratory depression than described in the previous study. The addition of remifentanil improved procedure conditions, reduced the total amount of propofol, and reduced the time to discharge. In a dose-finding trail, remifentanil 0.2 mcg/kg/minute was more effective than 0.1 mcg/kg/minute in children (n = 60; age range: 2 to 12 years) undergoing diagnostic cardiac catheterization.

    Infants and Children 1 month to 1 year

    Limited data available. Most experience with remifentanil for short-term diagnostic or therapeutic procedures is with older age groups (i.e., older toddler to adolescent). Infusion rates of 0.06 mcg/kg/minute IV and 0.1 mcg/kg/minute IV have been reported in case series of pediatric patients undergoing magnetic resonance imaging (MRI) and cardiac catheterization, respectively. A continuous infusion of 0.1 mcg/kg/minute IV produced satisfactory analgesia and sedation as a sole agent in 23 patients (42%) undergoing cardiac catheterization (n = 55; mean age: 4.17 years [range: 2 months to 12 years]). The other 32 patients required additional drugs (18 midazolam IV and 14 midazolam plus ketamine IV). Upon remifentanil discontinuation, mean time to recovery was 2 minutes; recovery times were significantly longer in patients also receiving midazolam (4.25 minutes) or midazolam plus ketamine (4 minutes) (p < 0.05). Remifentanil 0.06 mcg/kg/minute IV and propofol infusion were used in a observational case series of pediatric patients receiving light anesthesia for MRI (n = 56; age range: 29 days to 11 years). Mean times to recovery and discharge were 8.9 and 28.2 minutes, respectively, with no significant differences between the age groups.

    Neonates

    Limited data available; most experience with remifentanil for short-term diagnostic or therapeutic procedures is with older age groups (i.e., older toddler to adolescent). More rapid drug clearance rates in neonates (and infants younger than 3 months) would suggest higher infusion rates may be necessary; however, particularly in spontaneously breathing patients, doses should be carefully titrated to achieve adequate clinical response. Remifentanil at a mean rate of 0.06 mcg/kg/minute IV has been described in patients as young as 29 days old. In the observational case series, remifentanil, along with propofol, was used in patients receiving light anesthesia for magnetic resonance imaging (MRI) (n = 56; age range: 29 days to 11 years). Mean times to recovery and discharge were 8.9 and 28.2 minutes, respectively, with no significant differences between the age groups. In pediatric patients as young as 2 months undergoing cardiac catheterization (n = 55; mean age: 4.17 years [range: 2 months to 12 years]), a continuous infusion of remifentanil 0.1 mcg/kg/minute IV produced satisfactory analgesia and sedation as a sole agent in 23 patients (42%) after premedication with oral midazolam and hydroxyzine. In contrast, much larger infusion rates (0.75 to 1 mcg/kg/minute IV, titrated rapidly up to 3 to 5 mcg/kg/minute IV [mean: 4 mcg/kg/minute]) have been described in a small study of mechanically-ventilated premature neonates (n = 6) undergoing laser therapy for retinopathy of prematurity.

    Premature Neonates

    Limited data available. Reported infusion rates range from 0.2 to 10 mcg/kg/minute IV during laser treatment for retinopathy of prematurity (ROP) and 0.03 to 0.25 mcg/kg/minute IV during PICC line placement. An initial infusion rate of 0.75 to 1 mcg/kg/minute IV, titrated up to 3 to 5 mcg/kg/minute, was described in mechanically-ventilated premature neonates (n = 6; gestational age: 24 to 28 weeks; weight at treatment: 1.2 to 1.7 kg) undergoing laser therapy for ROP. In the case series, the remifentanil infusion was progressively titrated, based on hemodynamic and respiratory changes as well as spontaneous movement, to a mean value of 4 mcg/kg/minute within a few minutes. Maximum mean dose was 10.3 mcg/kg/minute; a single case attained a maximum dose of 20 mcg/kg/minute, which was maintained for 10 minutes or less. Remifentanil was discontinued at the end of laser therapy. Another study (n = 64; mean gestational age: 27.3 weeks; mean weight at treatment: 1.9 kg) utilized an initial infusion rate of 0.2 mcg/kg/minute IV, titrated up to 0.6 mcg/kg/minute (mean infusion rate: 0.4 mcg/kg/minute). Remifentanil 0.03 mcg/kg/minute, in addition to sucrose and non-nutritive sucking, had a synergistic analgesic effect, but did not make PICC placement quicker or easier compared to placebo in a trial of 54 premature neonates (mean gestational age: 28 weeks; mean birth weight: 1.1 kg). In a small comparison study, remifentanil 0.1 mcg/kg/minute (n = 5) failed to show noninferiority to 0.25 mcg/kg/minute IV (n = 7) during PICC placement in mechanically-ventilated premature neonates (median gestational age: 26 weeks; median birth weight: 825 grams). Changes in the Premature Infant Pain Profile were 1.43 in the high dose group and -0.6 in the low dose group.

    †Indicates off-label use

    MAXIMUM DOSAGE

    IV opioid dosage should be individualized based on clinical response and cardiorespiratory parameters.

    Adults

    For anesthesia, 1 mcg/kg/dose IV; continuous infusion rates greater than 2 mcg/kg/minute IV should be administered only after careful consideration.

    Geriatric

    For anesthesia, 1 mcg/kg/dose IV; continuous infusion rates greater than 2 mcg/kg/minute IV should be administered only after careful consideration. Starting doses should be decreased by 50%.

    Adolescents

    For general anesthesia maintenance, 1 mcg/kg/dose IV; continuous infusion rates greater than 1.3 mcg/kg/minute IV should be administered only after careful consideration. Safety and efficacy have not been established for other indications; however, doses up to 1.25 mcg/kg/dose IV have been used off-label for intubation.

    Children

    For general anesthesia maintenance, 1 mcg/kg/dose IV; continuous infusion rates greater than 1.3 mcg/kg/minute IV should be administered only after careful consideration. Safety and efficacy have not been established for other indications; however, doses up to 4 mcg/kg/dose IV have been used off-label for intubation.

    Infants

    For general anesthesia maintenance, 1 mcg/kg/dose IV; continuous infusion rates greater than 1 mcg/kg/minute IV should be administered only after careful consideration. Safety and efficacy have not been established for other indications; however, doses up to 4 mcg/kg/dose IV have been used off-label for intubation.

    Neonates

    Neonates: For general anesthesia maintenance, 1 mcg/kg/dose IV; continuous infusion rates greater than 1 mcg/kg/minute IV should be administered only after careful consideration. Safety and efficacy have not been established for other indications; however, doses up to 3 mcg/kg/dose IV have been used off-label for intubation.
    Premature Neonates 28 weeks gestation and older: Safety and efficacy have not been established; however, doses up to 2 mcg/kg/dose IV have been used off-label for intubation.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Remifentanil is administered intravenously (IV) and should only be given by individuals trained in the administration of general anesthetics and the management of the respiratory effects of potent opioids. The ability to establish and maintain a patent airway is imperative.
    Do not use IV without the availability of an appropriate opiate antagonist, oxygen, and resuscitative and intubation equipment. Continuous vital sign and oxygen saturation monitoring are recommended. Administration of supplemental oxygen is recommended.
    Do not use remifentanil in diagnostic or therapeutic procedures outside the monitored anesthesia care setting.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer if there are particles in the solution or if the solution is not colorless.

    Intravenous Administration

    Reconstitution of vials:
    Use strict aseptic technique when handling remifentanil. The product does not contain preservatives.
    Reconstitute by adding 1 ml of diluent per mg of remifentanil. Shake the vial well to dissolve. The product will contain 1 mg/ml of remifentanil.
    The solution should be further diluted prior to administration. Dilute in SWI, 0.9% Sodium Chloride (NS), D5W, 0.45% Sodium Chloride, D5NS, LR, or D5LR to a final concentration of 20, 25, 50, or 250 mcg/ml. After further dilution, the solution is stable for 24 hours at room temperature (4 hours at room temperature if LR is the diluent).
    A final concentration of 25 mcg/ml is recommended when remifentanil is used as an analgesic component of monitored analgesia care. A final concentration of 20—25 mcg/ml is recommended when remifentanil is used for children at least 1 year of age.
     
    Intravenous (IV) injection administration:
    IV bolus administration should be used only during the maintenance of general anesthesia.
    Inject remifentanil into IV tubing at or close to the venous cannula. Any remifentanil remaining in the tubing could be inadvertently administered at a later time. Replace or clear the tubing to avoid accidental delivery of remifentanil, which can cause life-threatening effects (e.g., apnea).
    In nonintubated patients, administer IV push over 30—60 seconds.
    Remifentanil is compatible with SWI, NS, D5W, 0.45% Sodium Chloride, D5NS, LR, D5LR, and propofol when coadministered into a running IV set. Do not administer remifentanil into the same IV tubing as blood. Hydrolysis of remifentanil by nonspecific esterases in blood products could occur. The compatibility of remifentanil with other drugs or solutions has not been evaluated.
     
    Intravenous (IV) infusion administration:
    Continuous infusions should be administered only by an infusion device.
    Continuous infusions longer than 16 hours have not been studied.
    Remifentanil is compatible with SWI, NS, D5W, 0.45% Sodium Chloride, D5NS, LR, D5LR, and propofol when coadministered into a running IV set. Do not administer remifentanil into the same IV tubing as blood. Hydrolysis of remifentanil by nonspecific esterases in blood products could occur. The compatibility of remifentanil with other drugs or solutions has not been evaluated.

    STORAGE

    Ultiva:
    - Discard unused portion. Do not store for later use.
    - Store between 36 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Remifentanil should not be used as the sole agent for general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.
     
    Intraoperative awareness has been reported in patients younger than 55 years when remifentanil has been administered with propofol infusion rates of 75 mcg/kg/minute or less.

    Opiate agonist hypersensitivity

    Although true opiate agonist hypersensitivity is rare, remifentanil use is contraindicated in patients with known remifentanil hypersensitivity or fentanyl-analog hypersensitivity; further such patients who have demonstrated a prior hypersensitivity reaction to remifentanil should not receive other opiate agonists of the phenylpiperidine subclass (meperidine, sufentanil, alfentanil, fentanyl). It may be possible to treat these patients with an opioid agonist from the phenanthrene subclass (including oxycodone, codeine and hydromorphone) or the diphenylheptane subclass (methadone).

    Abrupt discontinuation

    Abrupt discontinuation of a remifentanil infusion will cause a rapid offset of effect regardless of infusion length. If needed, establish adequate postoperative analgesia before stopping a remifentanil infusion.

    Acute abdomen, constipation, diarrhea, GI disease, GI obstruction, ileus, inflammatory bowel disease, ulcerative colitis

    Due to the effects of opiate agonists on the gastrointestinal tract, remifentanil should be used cautiously in patients with GI disease, including GI obstruction or ileus, ulcerative colitis, or pre-existing constipation. Opiate agonists may obscure the diagnosis or clinical course in patients with an acute abdomen. Patients with acute ulcerative colitis or other inflammatory bowel disease may be more sensitive to the constipating effects of opiate agonists. Although opiate agonists are contraindicated for use in patients with diarrhea secondary to poisoning or infectious diarrhea, antimotility agents have been used successfully in these patients. If possible, opiate agonists should not be given until the toxic substance has been eliminated.

    Obesity

    The presence of obesity can alter cardiovascular and respiratory physiology. Cautious use of the opioid agonist, remifentanil is recommended, especially in morbidly obese patients. Also, obese patients (> 30% over their ideal body weight) should receive starting doses based on ideal body weight.

    Chronic obstructive pulmonary disease (COPD), coadministration with other CNS depressants, cor pulmonale, ethanol ingestion, ethanol intoxication, pulmonary disease, requires a specialized care setting, requires an experienced clinician, respiratory depression, respiratory insufficiency

    Serious, fatal, or life-threatening respiratory depression has been reported with the use of opioids, even at recommended dosages. Remifentanil use requires an experienced clinician trained in the use of anesthetic drugs, airway management, and assisted ventilation. Remifentanil use also requires a specialized care setting; adequate facilities should be available for postoperative monitoring and ventilation of patients who were given anesthetic doses of remifentanil. Monitor oxygen saturation continuously. Usual therapeutic doses of remifentanil may decrease respiratory drive and cause apnea in patients with chronic obstructive pulmonary disease (COPD), cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, respiratory insufficiency, upper airway obstruction, or preexisting respiratory depression. Patients with advanced age, debilitation, or sleep apnea are also at an increased risk for the development of respiratory depression associated with remifentanil. Monitor such patients closely including vital signs, particularly when initiating and titrating remifentanil and during coadministration with other CNS depressants. Hypotension, profound sedation, respiratory depression, and death may result from remifentanil coadministration with other CNS depressants. Respiratory depression in spontaneously breathing patients is generally managed by decreasing the remifentanil infusion rate or temporarily discontinuing the infusion. Advise patients to avoid ethanol ingestion or ethanol intoxication for 24 hours after surgery.

    Angina, bradycardia, cardiac disease, heart failure, hypotension, hypovolemia

    Opiate agonists, including remifentanil, can stimulate a vasovagal response that will produce sinus bradycardia, which could be troublesome in patients with cardiac disease (e.g., angina, heart failure), hypotension, cardiac arrhythmias or hypovolemia. In addition, opiate agonists can exacerbate orthostatic hypotension by inducing histamine release; however, elevations in plasma histamine concentrations were not apparent in patients and normal volunteers after remifentanil administration during clinical trials. To avoid hypotension during the induction phase, consideration of the concomitant medications is advisable.

    Bladder obstruction, oliguria, prostatic hypertrophy, renal disease, urethral stricture, urinary retention

    Remifentanil and other opiate agonists can cause urinary retention and oliguria. Patients more prone to these effects include those with bladder obstruction, pelvic tumors, prostatic hypertrophy, urethral stricture, or renal disease.

    Epidural administration, intrathecal administration

    Remifentanil injection is contraindicated in epidural administration or intrathecal administration due to the presence of glycine in the formulation. Intrathecal administration of glycine formulations without remifentanil to dogs resulted in agitation, pain, hind limb dysfunction, and incoordination. These adverse events are believed to be attributed to glycine. However, glycine is a common excipient in IV medications and this finding has no relevance on the IV administration of remifentanil.

    Head trauma, increased intracranial pressure, seizure disorder, seizures

    Remifentanil should be used with extreme caution in patients with head trauma, increased intracranial pressure (ICP), or a preexisting seizure disorder. Opiate agonists can compromise the evaluation of neurologic parameters. Rapid administration of high-dose opiate agonists may transiently elevate intracranial pressure and reduce cerebral perfusion pressures. These events are associated with opiate-induced lowering of mean arterial pressure, which stimulates a regulatory response to increase cerebral blood flow leading to increased ICP. Opiate agonist-induced respiratory depression can produce cerebral hypoxia and raise CSF pressure, which is unrelated to but may exaggerate the injury. Opiate analgesics, especially in high doses, can precipitate seizures.

    Geriatric

    Geriatric patients are more sensitive to the analgesic effects of opiate agonists and more susceptible to adverse reactions from opiate agonists; especially sedation and respiratory depression. The clearance of remifentanil in patients over 65 years of age may be reduced by approximately 25%. Elderly patients have been shown to be twice as sensitive to the pharmacodynamic effects of remifentanil. Therefore, initial doses of remifentanil should be reduced by 50% and then cautiously titrated to effect taking into account analgesic effects and adverse reactions.[28897] According to the Beers Criteria, opiate agonists are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except in the setting of severe acute pain, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. In patients receiving palliative care or hospice, the balance of benefits and harms of medication management may differ from those of the general population of older adults.[63923]

    Biliary tract disease

    Morphine and related opiates can produce spasm of the sphincter of Oddi. Remifentanil, a member of a different chemical group, is less likely to produce this effect. Nevertheless, remifentanil should be used cautiously in patients with biliary tract disease, or in those who are undergoing surgery of the biliary tract.

    Alcoholism, depression, substance abuse

    Remifentanil is an opioid agonist and therefore has abuse potential and risk of fatal overdose from respiratory failure. Addiction may occur in patients who obtain remifentanil illicitly or in those appropriately prescribed the drug. The risk of addiction in any individual is unknown. However, patients with mental illness (e.g., major depression) or a family history of substance abuse (including alcoholism) have an increased risk of opioid abuse. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive opioids routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate pain management in any patient, but requires more intensive counseling and monitoring. Abuse and addiction are separate and distinct from physical dependence and tolerance; patients with addiction may not exhibit tolerance and symptoms of physical dependence.

    Driving or operating machinery

    Any patient receiving remifentanil should be warned about the possibility of sedation and to use caution when driving or operating machinery.

    Females

    Females may be less sensitive to anesthesia than men and may require increased doses of anesthetic agents during surgery. Women tend to report awareness during surgery more frequently than men. In a study of patients receiving propofol, alfentanil, and nitrous oxide, women woke significantly faster than men after anesthesia ended. The time to eye opening after anesthesia and response to verbal commands was also shorter in women. However, in clinical trials with remifentanil, no differences in pharmacodynamic activity or pharmacokinetic parameters were observed between males and females.

    Neonates

    Remifentanil has only been studied in full term neonates that weighed at least 2500 grams. Due to variable clearance in neonates and the absence of data in premature or low-weight babies, remifentanil may not be a desirable agent to use in neonates that are not full term or of a weight at least 2500 grams. In clinical trials, all neonates were pretreated with atropine, which can blunt the potential for bradycardia. Neonates that do not receive atropine pretreatment, those that receive supplementation with potent inhalation agents or neuraxial anesthesia, those with significant comorbidities, or those undergoing large fluid shifts may need smaller bolus doses of remifentanil to avoid hypotension or bradycardia.

    Labor, neonatal opioid withdrawal syndrome, obstetric delivery, pregnancy

    Available data with remifentanil use in human pregnancy are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In a human clinical trial, the average maternal remifentanil concentrations were approximately twice those of the fetus. However, in some cases fetal concentrations were similar to those in the mother. The umbilical arteriovenous ratio of remifentanil concentrations was approximately 30%, which suggests metabolism by the neonate. In pregnant rats administered remifentanil during gestation through lactation, no malformations and decreased body weight of offspring were observed at doses approximately 2-times a human induction dose of 1 mcg/kg IV with a maintenance dose of 2 mcg/kg/minute IV based on body surface area for a surgical procedure lasting 3 hours based on body surface area, respectively. Increased maternal mortality was observed. Remifentanil is not recommended for use during or immediately prior to labor or obstetric delivery. Opioids cross the placenta and may cause respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist and resuscitative equipment should be readily available. Opioids can prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation. Further, the prolonged maternal use of opioids during pregnancy may result in neonatal opioid withdrawal syndrome (NOWS). The syndrome can be life-threatening. Severe symptoms may require pharmacologic therapy managed by clinicians familiar with neonatal opioid withdrawal. Monitor the neonate for withdrawal symptoms including rapid breathing, irritability, hyperactivity, abnormal sleep pattern, high-pitched crying, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity of opioid withdrawal may vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination by the newborn.

    Breast-feeding

    It is not known if remifentanil is excreted into breast milk. Because other fentanyl analogs are excreted into breast milk, use caution when administering remifentanil to a breast-feeding woman. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for remifentanil and any potential adverse effects on the breast-fed infant from remifentanil or the underlying maternal condition. Monitor infants exposed to remifentanil through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. In general, the healthy term infant can safely nurse as soon as the mother is awake and alert from receiving a fentanyl analog for anesthesia during a surgery.

    Accidental exposure, potential for overdose or poisoning

    Like all opioid analgesics, remifentanil is associated with a significant potential for overdose or poisoning; proper patient selection and counseling is recommended. Remifentanil should be kept out of the reach of pediatric patients, others for whom the drug was not prescribed, and pets as accidental exposure may cause respiratory failure and a fatal overdose.

    Adrenal insufficiency, hypothyroidism, myxedema

    Use remifentanil with caution in patients with adrenal insufficiency (i.e., Addison's disease), hypothyroidism, or myxedema. Such patients may be at increased risk of adverse events. Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH); however, the thyroid stimulating hormone may be either stimulated or inhibited by opioids. Rarely, adrenal insufficiency has been reported in association with opioid use. Patients should seek immediate medical attention if they experience symptoms such as nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or hypotension. If adrenocortical insufficiency is suspected, confirm with diagnostic testing as soon as possible. If diagnosed, the patient should be treated with physiologic replacement doses of corticosteroids, and if appropriate, weaned off of opioid therapy. If the opioid can be discontinued, a follow-up assessment of adrenal function should be performed to determine if corticosteroid treatment can be discontinued. Other opioids may be tried; some cases reported use of a different opioid with no recurrence of adrenocortical insufficiency. It is unclear which, if any, opioids are more likely to cause adrenocortical insufficiency. In addition, chronic opioid use may lead to symptoms of hypogonadism, resulting from changes in the hypothalamic-pituitary-gonadal axis. Monitor patients for symptoms of opioid-induced endocrinopathy, particularly those receiving a daily dose equivalent to 100 mg or more of morphine. Patients presenting with signs or symptoms of androgen deficiency should undergo laboratory evaluation.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 3.0-12.0
    bradycardia / Rapid / 0-7.0
    chest wall rigidity / Rapid / 0-5.0
    pleural effusion / Delayed / 0-5.0
    visual impairment / Early / 3.0-3.0
    ventricular fibrillation / Early / 1.0-1.0
    arrhythmia exacerbation / Early / 1.0-1.0
    asystole / Rapid / 0-1.0
    atrial flutter / Early / 1.0-1.0
    AV block / Early / 0-1.0
    ileus / Delayed / 0-1.0
    laryngospasm / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    oliguria / Early / 0-1.0
    seizures / Delayed / 0-1.0
    stroke / Early / 0-1.0
    hyperkalemia / Delayed / 0-1.0
    neonatal opioid withdrawal syndrome / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    pulmonary edema / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    apnea / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    SIADH / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / 4.0-29.0
    constipation / Delayed / 0-9.0
    hypertension / Early / 1.0-6.0
    sinus tachycardia / Rapid / 0-4.0
    edema / Delayed / 2.0-2.0
    hypoxia / Early / 0-2.0
    anemia / Delayed / 0-2.0
    bleeding / Early / 0-2.0
    premature ventricular contractions (PVCs) / Early / 0-1.0
    dysphagia / Delayed / 0-1.0
    dyspnea / Early / 1.0-1.0
    lymphopenia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    erythema / Early / 0-1.0
    dysuria / Early / 0-1.0
    urinary retention / Early / 0-1.0
    urinary incontinence / Early / 0-1.0
    amnesia / Delayed / 0-1.0
    dysphoria / Early / 0-1.0
    involuntary movements / Delayed / 0-1.0
    hallucinations / Early / 0-1.0
    nystagmus / Delayed / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    chest pain (unspecified) / Early / Incidence not known
    psychological dependence / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    tolerance / Delayed / Incidence not known
    hypoventilation / Rapid / Incidence not known
    respiratory depression / Rapid / Incidence not known
    confusion / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known

    Mild

    nausea / Early / 0-45.0
    vomiting / Early / 0-22.0
    pruritus / Rapid / 0-18.0
    headache / Early / 3.0-18.0
    fever / Early / 5.0-13.0
    diaphoresis / Early / 6.0-6.0
    dizziness / Early / 0-5.0
    shivering / Rapid / 0-5.0
    anxiety / Delayed / 0-3.0
    diarrhea / Early / 0-2.0
    agitation / Early / 0-2.0
    infection / Delayed / 2.0-2.0
    syncope / Early / 0-1.0
    abdominal pain / Early / 0-1.0
    pyrosis (heartburn) / Early / 0-1.0
    xerostomia / Early / 0-1.0
    gastroesophageal reflux / Delayed / 0-1.0
    cough / Delayed / 0-1.0
    nasal congestion / Early / 0-1.0
    hiccups / Early / 0-1.0
    pharyngitis / Delayed / 0-1.0
    rhinorrhea / Early / 0-1.0
    leukocytosis / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    rash / Early / 0-1.0
    nightmares / Early / 0-1.0
    paresthesias / Delayed / 0-1.0
    tremor / Early / 0-1.0
    flushing / Rapid / 1.0-1.0
    injection site reaction / Rapid / Incidence not known
    amenorrhea / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    chills / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Acetaminophen; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Diphenhydramine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Pentazocine: (Major) Concurrent use of pentazocine may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms. If coadministration is necessary, carefully observe the patient, especially during remifentanil initiation and dosage adjustment. Consider discontinuing remifentanil and instituting alternative analgesia if the patient is not responding appropriately. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Acrivastine; Pseudoephedrine: (Major) Avoid coadministration of opioid agonists with acrivastine due to the risk of additive CNS depression.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity such as opiate agonists. In addition, aldesleukin, IL-2, is a CYP3A4 inhibitor and may increase oxycodone plasma concentrations and related toxicities including potentially fatal respiratory depression. If therapy with both agents is necessary, monitor patients for an extended period and adjust oxycodone dosage as necessary.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Almotriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Alosetron: (Major) Patients taking medications that decrease GI motility may be at greater risk for serious complications from alosetron, like constipation, via a pharmacodynamic interaction. Constipation is the most frequently reported adverse effect with alosetron. Alosetron, if used with drugs such as opiate agonists, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Alvimopan: (Moderate) Patients should not take alvimopan if they have received therapeutic doses of opiate agonists for more than seven consecutive days immediately before initiation of alvimopan therapy. Patients recently exposed to opioids are expected to be more sensitive to the effects of mu-opioid receptor antagonists and may experience adverse effects localized to the gastrointestinal tract such as abdominal pain, nausea, vomiting, and diarrhea.
    Amide local anesthetics: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amitriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amobarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Amoxapine: (Major) Consider alternative therapy or reduce the dose of one or both drugs if remifentanil is used with another CNS depressant, such as amoxapine. The magnitude and duration of CNS and cardiovascular effects may be enhanced. Monitor patients for hypotension or prolonged respiratory depression and sedation. Consider the total dose of all opioid agonists before ordering opioid analgesics during recovery from anesthesia.
    Amphetamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Amphetamine; Dextroamphetamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Amphetamines: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Anticholinergics: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Apomorphine: (Major) Apomorphine may cause additive sedation or hypotension with remifentanil. Monitor patients receiving remifentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
    Apraclonidine: (Minor) Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as opiate agonists. Although no specific drug interactions were identified with systemic agents and apraclonidine during clinical trials, apraclonidine can cause dizziness and somnolence.
    Aripiprazole: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Articaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Asenapine: (Moderate) Concomitant use of opioid agonists with asenapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with asenapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Concomitant use of remifentanil with orphenadrine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with orphenadrine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of remifentanil with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of remifentanil with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Atenolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Atenolol; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Atropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of remifentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Atropine; Edrophonium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Azelastine: (Minor) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Azelastine; Fluticasone: (Minor) Concomitant use of opioid agonists with azelastine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with azelastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Azilsartan; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Baclofen: (Major) Concomitant use of remifentanil with baclofen may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with baclofen to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Barbiturates: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Belladonna; Opium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Bendroflumethiazide; Nadolol: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with remifentanil may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of benzhydrocodone with remifentanil to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking remifentanil, reduce initial dosage and titrate to clinical response. If remifentanil is prescribed in a patient taking benzhydrocodone, use a lower initial dose of remifentanil and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and remifentanil because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of remifentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Benzonatate: (Moderate) The vagal effects and respiratory depression induced by opiate agonists may be increased by the use of benzonatate.
    Benzphetamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Benztropine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Beta-blockers: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Betaxolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Bethanechol: (Moderate) Bethanechol facilitates intestinal and bladder function via parasympathomimetic actions. Opiate agonists impair the peristaltic activity of the intestine. Thus, these drugs can antagonize the beneficial actions of bethanechol on GI motility.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bisoprolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Brexpiprazole: (Major) Concomitant use of opioid agonists with brexpiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with brexpiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists.
    Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of opiate agonists. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Brompheniramine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with brompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with brompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Bupivacaine Liposomal: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Bupivacaine; Meloxicam: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Buprenorphine: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as remifentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Buprenorphine; Naloxone: (Major) Buprenorphine is a mixed opiate agonist/antagonist with strong affinity for the mu-receptor that may partially block the effects of full mu-receptor opiate agonists and reduce analgesic effects. In some cases of acute pain, trauma, or during surgical management, opiate-dependent patients receiving buprenorphine maintenance therapy may require concurrent treatment with opiate agonists, such as remifentanil. In these cases, health care professionals must exercise caution in opiate agonist dose selection, as higher doses of an opiate agonist may be required to compete with buprenorphine at the mu-receptor. Management strategies may include adding a short-acting opiate agonist to achieve analgesia in the presence of buprenorphine, discontinuation of buprenorphine and use of an opiate agonist to avoid withdrawal and achieve analgesia, or conversion of buprenorphine to methadone while using additional opiate agonists if needed. Closely monitor patients for CNS or respiratory depression. When buprenorphine is used for analgesia, avoid co-use with opiate agonists. Buprenorphine may cause withdrawal symptoms in patients receiving chronic opiate agonists as well as possibly potentiate CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Bupropion; Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7-10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. The usual doses of remifentanil will be ineffective in patients receiving naltrexone. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. However, respiratory depression from remifentanil is not expected to last longer than the effect of a single naloxone dose. Other non-opioid medications should be used prior to, during, and after surgery as increased doses of opiate agonists are required to override the antagonistic effects of naltrexone and may induce prolonged and more severe adverse effects. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Buspirone: (Moderate) Concomitant use of CNS depressants, such as buspirone, can potentiate the effects of remifentnil, which may potentially lead to respiratory depression, CNS depression, sedation, or hypotensive responses. If concurrent use is imperative, reduce the dose of one or both drugs if clinically indicated.
    Butabarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Butalbital; Acetaminophen: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Butalbital; Acetaminophen; Caffeine: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Butorphanol: (Major) Concurrent use of butorphanol may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms. If coadministration is necessary, carefully observe the patient, especially during remifentanil initiation and dosage adjustment. Consider discontinuing remifentanil and instituting alternative analgesia if the patient is not responding appropriately. Butorphanol is a mixed opiate agonist/antagonist that may block the effects of opiate agonists. Concurrent use of butorphanol with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Calcium-channel blockers: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving calcium-channel blockers due to additive hypotensive effects.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Cannabidiol: (Moderate) Concomitant use of opioid agonists with cannabidiol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cannabidiol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Capsaicin; Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. If concomitant use of remifentanil and metaxalone is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Carbetapentane; Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbetapentane; Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including morphine.
    Carbinoxamine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with carbinoxamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with carbinoxamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Cariprazine: (Moderate) Concomitant use of opioid agonists like remifentanil with cariprazine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cariprazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carisoprodol: (Major) Concomitant use of remifentanil with carisoprodol may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with carisoprodol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Carteolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Carvedilol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Cenobamate: (Moderate) Concomitant use of remifentanil with cenobamate may cause excessive sedation and somnolence. Limit the use of remifentanil with cenobamate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cetirizine: (Moderate) Concomitant use of opioid agonists with cetirizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cetirizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Cetirizine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with cetirizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cetirizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlophedianol; Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chloral Hydrate: (Major) Concomitant use of opioid agonists with chloral hydrate may cause excessive sedation and somnolence. Limit the use of opioid pain medications with chloral hydrate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The dose of chloral hydrate may need to be reduced up to 75% with the coadministration of remifentanil. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorcyclizine: (Moderate) Concomitant use of opioid agonists with chlorcyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorcyclizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlordiazepoxide: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Chlordiazepoxide; Amitriptyline: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation. (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Chlordiazepoxide; Clidinium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Chloroprocaine: (Minor) Due to the CNS depression potential of all local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Chlorothiazide: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorpheniramine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with chlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with chlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpromazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorthalidone; Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorzoxazone: (Major) Concomitant use of remifentanil with chlorzoxazone may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with chlorzoxazone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Citalopram: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Clemastine: (Moderate) Concomitant use of opioid agonists with clemastine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clemastine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Clobazam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clomipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Clonazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clonidine: (Major) Concomitant use of opioid agonists with clonidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with clonidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Clopidogrel: (Moderate) Coadministration of opioid agonists, such as remifentanil, delay and reduce the absorption of clopidogrel resulting in reduced exposure to active metabolites and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Coadministration of intravenous morphine decreased the Cmax and AUC of clopidogrel's active metabolites by 34%. Time required for maximal inhibition of platelet aggregation (median 3 hours vs. 1.25 hours) was significantly delayed; times up to 5 hours were reported. Inhibition of platelet plug formation was delayed and residual platelet aggregation was significantly greater 1 to 4 hours after morphine administration.
    Clorazepate: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Clozapine: (Moderate) Remifentanil should be combined cautiously with clozapine due to the potential for additive depressant effects and possible respiratory depression or hypotension. Combining clozapine with opiate agonists may also lead to reduced intestinal motility or bladder function.
    Codeine; Phenylephrine; Promethazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Codeine; Promethazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    COMT inhibitors: (Major) COMT inhibitors may cause additive sedation or hypotension with remifentanil. Monitor patients receiving remifentanil with other CNS depressants for hypotension and prolonged respiratory depression and sedation. In such cases of combined treatment, a dose reduction of one or both agents may be necessary.
    Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and opiate agonists are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as opiate agonists, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
    Cyclizine: (Moderate) Concomitant use of opioid agonists with cyclizine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with cyclizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cyclobenzaprine: (Major) Concomitant use of remifentanil with cyclobenzaprine may cause respiratory depression, hypotension, profound sedation, and death. Additionally, concomitant use may result in serotonin syndrome. Limit the use of opioid pain medications with cyclobenzaprine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. Monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Cyproheptadine: (Moderate) Concomitant use of opioid agonists with cyproheptadine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cyproheptadine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dantrolene: (Major) Concomitant use of remifentanil with dantrolene may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with dantrolene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Darifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when darifenacin, an anticholinergic drug for overactive bladder, is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of remifentanil if the two drugs are coadministered.
    Delavirdine: (Major) Delavirdine is a potent inhibitor of CYP3A4 and an inhibitor (in vitro) of CYP2D6, CYP2C9, and CYP2C19. Therefore, delavirdine may alter the response to various opiate agonists. Increased concentrations of the CYP substrates alfentanil, fentanyl, hydrocodone, morphine, sufentanil, and oxycodone may be noted. Due the potential for increased formation of neurotoxic metabolites, concurrent use of delavirdine and meperidine or propoxyphene is not recommended. Delavirdine may decrease the efficacy of codeine-containing analgesics by inhibiting the conversion of codeine to morphine via CYP2D6. Delavirdine may also inhibit the metabolism of methadone, requiring a decrease in methadone doses.
    Desflurane: (Moderate) Concurrent use with opiate agonists can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
    Desipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including opiate agonists. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Deutetrabenazine: (Major) Concomitant use of opiate agonists with deutetrabenazine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with deutetrabenazine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking deutetrabenazine, use a lower initial dose of the opiate and titrate to clinical response. If deutetrabenazine is prescribed for a patient taking an opiate agonist, use a lower initial dose of deutetrabenazine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dexbrompheniramine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexbrompheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexbrompheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dexchlorpheniramine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with dexchlorpheniramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dexchlorpheniramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dexmedetomidine: (Moderate) Concomitant use of opioid agonists with dexmedetomidine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with dexmedetomidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dexpanthenol: (Moderate) Use caution when using dexpanthenol with drugs that decrease gastrointestinal motility, such as opiate agonists, as it may decrease the effectiveness of dexpanthenol.
    Dextroamphetamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Dicyclomine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Dimenhydrinate: (Moderate) Concomitant use of opioid agonists with dimenhydrinate may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dimenhydrinate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenhydramine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenhydramine; Ibuprofen: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenhydramine; Naproxen: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with other opiate agonists can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration. In addition, diphenoxylate/difenoxin use may cause constipation; cases of severe GI reactions including toxic megacolon and adynamic ileus have been reported. Reduced GI motility when combined with opiate agonists may increase the risk of serious GI related adverse events. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Dolasetron: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor antagonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dorzolamide; Timolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Doxepin: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Doxylamine: (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Doxylamine; Pyridoxine: (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dronabinol: (Moderate) Concomitant use of opioid agonists with dronabinol may cause excessive sedation and somnolence. Limit the use of opioid pain medication with dronabinol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Droperidol: (Major) Concomitant use of opioid agonists with droperidol may cause excessive sedation and somnolence. Limit the use of opioid pain medications with droperidol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Duloxetine: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Eletriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as remifentanil. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle within the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Closely monitor for increased side effects if these drugs are administered together.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Enflurane: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as general anesthetics, can potentiate the effects of remifentanil on respiration, sedation, and hypotension.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Escitalopram: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Esketamine: (Major) Concomitant use of opioid agonists with esketamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with esketamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Patients who have received a dose of esketamine should be instructed not to drive or engage in other activities requiring complete mental alertness until the next day after a restful sleep. Educate patients about the risks and symptoms of excessive CNS depression.
    Esmolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Estazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Eszopiclone: (Major) Concomitant use of opioid agonists with eszopiclone may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with eszopiclone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking opioids. Alcohol consumption may result in additive CNS depression and may increase the risk for opioid overdose. Consider the patient's use of alcohol when prescribing opioid medications. If the patient is unlikely to be compliant with avoiding alcohol, consider prescribing naloxone especially if additional risk factors for opioid overdose are present.
    Ethotoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
    Etomidate: (Major) Concomitant use of remifentanil with other CNS depressants, such as etomidate, can potentiate the effects of remifentanil on respiration, CNS depression, sedation, and hypotension. Both the magnitude and duration of CNS and cardiovascular effects may be enhanced. Less etomidate is generally required under these circumstances.
    Fenfluramine: (Moderate) Concomitant use of opioid agonists with fenfluramine may cause excessive sedation and somnolence. Limit the use of opioid agonists with fenfluramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fesoterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when fesoterodine, an anticholinergic drug for overactive bladder is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Flavoxate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Flibanserin: (Moderate) Concomitant use of opioid agonists with flibanserin may cause excessive sedation and somnolence. Limit the use of opioid pain medication with flibanserin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Fluoxetine: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fluphenazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Flurazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Fluvoxamine: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Fosphenytoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
    Frovatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Gabapentin: (Major) Concomitant use of opioid agonists with gabapentin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of remifentanil with gabapentin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Glycopyrrolate; Formoterol: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Granisetron: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor antagonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Guanabenz: (Moderate) Guanabenz is associated with sedative effects. Guanabenz can potentiate the effects of CNS depressants such as opiate agonists, when administered concomitantly.
    Guanfacine: (Moderate) Concomitant use of opioid agonists with guanfacine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with guanfacine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Haloperidol: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as haloperidol, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Halothane: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as general anesthetics, can potentiate the effects of remifentanil on respiration, sedation, and hypotension.
    Homatropine; Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hydantoins: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrocodone: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Hydromorphone: (Major) Concomitant use of hydromorphone with other central nervous system (CNS) depressants, such as other opiate agonists, can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hydroxyzine: (Major) Concomitant use of opioid agonists with hydroxyzine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with hydroxyzine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hyoscyamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Avoid concomitant use of remifentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Ibuprofen; Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Iloperidone: (Moderate) Concomitant use of iloperidone with other centrally-acting medications such as opiate agonists, may increase both the frequency and the intensity of adverse effects including drowsiness, sedation, and dizziness.
    Imipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Isocarboxazid: (Major) The use of remifentanil is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
    Isoflurane: (Moderate) Concomitant use of remifentanil with other CNS depressants, including general anesthetics, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Ketamine: (Major) Both the magnitude and duration of central nervous system and cardiorespiratory effects may be potentiated when remifentanil is given concurrently with ketamine. Monitor for CNS depression, hypotension, and respiratory depression during use together. Prolonged recovery time may occur. Postoperative confusional states may occur during the recovery period during use of ketamine. The patient should be cautioned that driving an automobile, operating hazardous machinery or engaging in hazardous activities should not be undertaken for 24 hours or more (depending upon the dosage of ketamine and consideration of other drugs employed) after anesthesia.
    Labetalol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Lasmiditan: (Moderate) Concomitant use of remifentanil with lasmiditan may cause excessive sedation, somnolence, and serotonin syndrome. Limit the use of remifentanil with lasmiditan to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Lemborexant: (Moderate) Concomitant use of remifentanil with lemborexant may cause excessive sedation and somnolence. Limit the use of remifentanil with lemborexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Levobetaxolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Levobunolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Levobupivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Levocetirizine: (Moderate) Concomitant use of opioid agonists with cetirizine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with cetirizine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Levomilnacipran: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Lidocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lidocaine; Prilocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Linezolid: (Major) Avoid concomitant use of remifentanil in patients receiving linezolid or within 14 days of stopping treatment with linezolid due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
    Lisdexamfetamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Lithium: (Moderate) If concomitant use of remifentanil and lithium is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and remifentanil. Lofexidine can potentiate the effects of CNS depressants.
    Loperamide: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Loperamide; Simethicone: (Moderate) Additive constipation may be seen with concurrent use of opiate agonists and antidiarrheals. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Concurrent use of selected antidiarrheals (e.g., loperamide, diphenoxylate) and opiate agonists can lead to additive CNS depression.
    Lopinavir; Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of remifentanil if the two drugs are coadministered.
    Lorazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Lorcaserin: (Moderate) If concomitant use of remifentanil and lorcaserin is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Loxapine: (Moderate) Concomitant use of opioid agonists, such as remifentanil, with loxapine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with loxapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Lumateperone: (Moderate) Concomitant use of opioid agonists like remifentanil with lumateperone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lumateperone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Lurasidone: (Moderate) Concomitant use of opioid agonists like remifentanil with lurasidone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with lurasidone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Major) Consider alternative therapy or reduce the dose of one or both drugs if remifentanil is used with another CNS depressant, such as maprotiline. Limit the use of opioid pain medications with maprotiline to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Melatonin: (Moderate) Concomitant use of opioid agonists with melatonin may cause excessive sedation and somnolence. Limit the use of opioid pain medications with melatonin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Mepenzolate: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Meperidine; Promethazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Mephobarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mepivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Mepivacaine; Levonordefrin: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Meprobamate: (Moderate) Concomitant use of remifentanil with meprobamate can potentiate the effects of remifentanil on respiration, CNS depression, sedation, and hypotension. Both the magnitude and duration of CNS and cardiovascular effects may be enhanced. Postoperative respiratory depression associated with remifentanil may also be augmented. If used together, a reduction in the dose of one or both drugs may be needed.
    Mesoridazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Metaxalone: (Major) Concomitant use of opioid agonists with metaxalone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with metaxalone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. If concomitant use of remifentanil and metaxalone is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Methadone: (Major) Concomitant use of methadone with another CNS depressant can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Methamphetamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid concomitant use of remifentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methocarbamol: (Major) Concomitant use of remifentanil with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methohexital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methscopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Methyclothiazide: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Methyldopa: (Moderate) Concomitant use of opioid agonists with methyldopa may cause excessive sedation and somnolence. Limit the use of opioid pain medication with methyldopa to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Methylene Blue: (Major) Avoid concomitant use of remifentanil in patients receiving methylene blue or within 14 days of stopping treatment with methylene blue due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression. If cannot avoid use, choose the lowest possible methylene blue dose and observe the patient closely for up to 4 hours after administration.
    Methylphenidate Derivatives: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with methylphenidate derivatives. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Metoclopramide: (Moderate) The effects of metoclopramide on gastrointestinal motility are antagonized by narcotic analgesics. Concomitant use of opioid agonists with metoclopramide may also cause excessive sedation and somnolence. Limit the use of opioid pain medications with metoclopramide to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Metolazone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Metoprolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with opiate agonists can result in additive sedative effects.
    Midazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Milnacipran: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Mirtazapine: (Major) Concomitant use of opioid agonists with mirtazapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with mirtazapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Molindone: (Moderate) Concomitant use of opioid agonists like remifentanil with molindone may cause excessive sedation and somnolence. Limit the use of opioid pain medication with molindone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Monoamine oxidase inhibitors: (Major) The use of remifentanil is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
    Nabilone: (Major) Avoid coadministration of opioid agonists with nabilone due to the risk of additive CNS depression.
    Nadolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Nalbuphine: (Major) Concurrent use of nalbuphine may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms. If coadministration is necessary, carefully observe the patient, especially during remifentanil initiation and dosage adjustment. Consider discontinuing remifentanil and instituting alternative analgesia if the patient is not responding appropriately. Nalbuphine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists. Concurrent use of nalbuphine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Naltrexone: (Major) When naltrexone is used as adjuvant treatment of opiate or alcohol dependence, use is contraindicated in patients currently receiving opiate agonists. Naltrexone will antagonize the therapeutic benefits of opiate agonists and will induce a withdrawal reaction in patients with physical dependence to opioids. Also, patients should be opiate-free for at least 7-10 days prior to initiating naltrexone therapy. If there is any question of opioid use in the past 7-10 days and the patient is not experiencing opioid withdrawal symptoms and/or the urine is negative for opioids, a naloxone challenge test needs to be performed. If a patient receives naltrexone, and an opiate agonist is needed for an emergency situation, large doses of opiate agonists may ultimately overwhelm naltrexone antagonism of opiate receptors. The usual doses of remifentanil will be ineffective in patients receiving naltrexone. Immediately following administration of exogenous opiate agonists, the opiate plasma concentration may be sufficient to overcome naltrexone competitive blockade, but the patient may experience deeper and more prolonged respiratory depression and thus, may be in danger of respiratory arrest and circulatory collapse. However, respiratory depression from remifentanil is not expected to last longer than the effect of a single naloxone dose. Other non-opioid medications should be used prior to, during, and after surgery as increased doses of opiate agonists are required to override the antagonistic effects of naltrexone and may induce prolonged and more severe adverse effects. Non-receptor mediated actions like facial swelling, itching, generalized erythema, or bronchoconstriction may occur presumably due to histamine release. A rapidly acting opiate agonist is preferred as the duration of respiratory depression will be shorter. Patients receiving naltrexone may also experience opiate side effects with low doses of opiate agonists. If the opiate agonist is taken in such a way that high concentrations remain in the body beyond the time naltrexone exerts its therapeutic effects, serious side effects may occur.
    Naratriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Nebivolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Nebivolol; Valsartan: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Nefazodone: (Major) Concomitant use of opioid agonists with nefazodone may cause excessive sedation and somnolence. Limit the use of opioid pain medications with nefazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as opiate agonists. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with opiate agonists.
    Nortriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Octreotide: (Moderate) Octreotide can cause additive constipation with opiate agonists such as remifentanil. Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Monitor patients during concomitant use.
    Olanzapine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olanzapine; Fluoxetine: (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olanzapine; Samidorphan: (Contraindicated) Salmidorphan is contraindicated in patients who are using opiate agonists or undergoing acute opioid withdrawal. Salmidorphan increases the risk of precipitating acute opioid withdrawal in patients dependent on opioids. Before initiating salmidorphan, there should be at least a 7-day opioid-free interval from the last use of short-acting opioids, and at least a 14-day opioid-free interval from the last use of long-acting opioids. In emergency situations, if a salmidorphan-treated patient requires opiates for anesthesia or analgesia, discontinue salmidorphan. The opiate agonist should be administered by properly trained individual(s), and the patient properly monitored in a setting equipped and staffed for cardiopulmonary resuscitation. In non-emergency situations, if a salmidorphan-treated patient requires opiate agonist treatment (e.g., for analgesia) discontinue salmidorphan at least 5 days before opioid treatment. Salmidorphan, as an opioid antagonist, may cause opioid treatment to be less effective or ineffective shortly after salmidorphan discontinuation. (Major) Concomitant use of opioid agonists with olanzapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with olanzapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Oliceridine: (Major) Concomitant use of oliceridine with remifentanil may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of oliceridine with remifentanil to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of remifentanil if the two drugs are coadministered.
    Ondansetron: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor antagonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Orphenadrine: (Major) Concomitant use of remifentanil with orphenadrine may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with orphenadrine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Oxybutynin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Oxycodone: (Major) Concomitant use of oxycodone with other opiate agonists may lead to additive respiratory and/or CNS depression. Hypotension, profound sedation, coma, respiratory depression, or death may occur. Prior to concurrent use of oxycodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxycodone, a reduced dosage of oxycodone and/or the CNS depressant is recommended; use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. Monitor for sedation and respiratory depression.
    Oxymorphone: (Major) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Respiratory depression, hypotension, profound sedation, or coma may result from combination therapy. Prior to concurrent use of oxymorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxymorphone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxymorphone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Slowly titrate the dose as necessary for adequate pain relief and monitor for sedation or respiratory depression.
    Ozanimod: (Major) When remifentanil is administered to patients who have received ozanimod within 14 days, monitor patients for hypertension and ensure ready availability of vasodilators and beta-blockers for the treatment of hypertension as needed. Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported rarely with remifentanil. An active metabolite of ozanimod inhibits MAO-B. The MAOI interactions with opioids may also manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
    Paliperidone: (Moderate) Drugs that can cause CNS depression such as opiate agonists, if used concomitantly with paliperidone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Advise patients to avoid driving or engaging in other activities requiring mental alertness as directed by their healthcare provider after administration of remifentanil.
    Palonosetron: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor antagonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Paroxetine: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Pegvisomant: (Moderate) In clinical trials, patients taking opiate agonists often required higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opiate agonists. The mechanism of this interaction is unknown.
    Penbutolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Pentazocine: (Major) Concurrent use of pentazocine may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms. If coadministration is necessary, carefully observe the patient, especially during remifentanil initiation and dosage adjustment. Consider discontinuing remifentanil and instituting alternative analgesia if the patient is not responding appropriately. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Pentazocine; Naloxone: (Major) Concurrent use of pentazocine may reduce the analgesic effect of remifentanil and/or precipitate withdrawal symptoms. If coadministration is necessary, carefully observe the patient, especially during remifentanil initiation and dosage adjustment. Consider discontinuing remifentanil and instituting alternative analgesia if the patient is not responding appropriately. Pentazocine is a mixed opiate agonist/antagonist that may block the effects of opiate agonists. Concurrent use of pentazocine with other opiate agonists can cause additive CNS, respiratory, and hypotensive effects. The additive or antagonistic effects are dependent upon the dose of the opiate agonist used; antagonistic effects are more common at low to moderate doses of the opiate agonist.
    Pentobarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Perampanel: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Perphenazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Perphenazine; Amitriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility. (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Phenelzine: (Major) The use of remifentanil is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
    Phenobarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Phenothiazines: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Phenytoin: (Moderate) Additive CNS depression could be seen with the combined use of the hydantoin and opiate agonists. Methadone is a primary substrate for the CYP3A4 isoenzyme. Serum concentrations of methadone may decrease due to CYP3A4 induction by phenytoin; withdrawal symptoms may occur.
    Pimozide: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as pimozide, can potentiate the effects of remifentanil on respiration, sedation, and hypotension.
    Pindolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Pramipexole: (Major) Concomitant use of opioid agonists with pramipexole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with pramipexole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like pramipexole have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
    Pramlintide: (Major) Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications with the potential to slow GI motility, such as opiate agonists, should be used with caution, if at all, with pramlintide until more data are available from the manufacturer. Monitor blood glucose.
    Prasugrel: (Moderate) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant opioid agonists. Coadministration of opioid agonists with prasugrel delays and reduces the absorption of prasugrel's active metabolite due to slowed gastric emptying.
    Pregabalin: (Major) Concomitant use of opioid agonists with pregabalin may cause excessive sedation, somnolence, and respiratory depression. Limit the use of remifentanil with pregabalin to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
    Prilocaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Prilocaine; Epinephrine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Primidone: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Procaine: (Minor) Due to the CNS depression potential of all local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists.
    Procarbazine: (Moderate) Opiate agonists may cause additive sedation or other CNS effects when given in combination with procarbazine.
    Prochlorperazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Promethazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Promethazine; Dextromethorphan: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Promethazine; Phenylephrine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Propantheline: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Propranolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics. (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Protriptyline: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Pseudoephedrine; Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Pyrilamine: (Moderate) Concomitant use of opioid agonists with pyrilamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with pyrilamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Quazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Quetiapine: (Major) Concomitant use of opioid agonists with quetiapine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with quetiapine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Ramelteon: (Moderate) Concomitant use of opioid agonists with ramelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with ramelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Rasagiline: (Major) Avoid concomitant use of remifentanil in patients receiving rasagiline or within 14 days of stopping treatment with rasagiline due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
    Remimazolam: (Major) Concomitant use of opioid agonists with remimazolam may cause respiratory depression, hypotension, profound sedation, and death. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
    Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally acting medications including remifentanil.
    Ritonavir: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of remifentanil if the two drugs are coadministered.
    Rizatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Ropinirole: (Major) Concomitant use of opioid agonists with ropinirole may cause excessive sedation and somnolence. Limit the use of opioid pain medication with ropinirole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Dopaminergic agents have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Reassess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
    Ropivacaine: (Moderate) The use of these drugs together must be approached with caution. Although commonly used together for additive analgesic effects, the patient must be monitored for respiratory depression, hypotension, and excessive sedation due to additive effects on the CNS and blood pressure. In rare instances, serious morbidity and mortality has occurred. Limit the use of opiate pain medications with local anesthetics to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. The use of the local anesthetic will allow for the use a lower initial dose of the opiate and then the doses can be titrated to proper clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Rotigotine: (Major) Concomitant use of opioid agonists with rotigotine may cause excessive sedation and somnolence. Limit the use of opioid pain medications with rotigotine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. Dopaminergic agents like rotigotine have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment.
    Safinamide: (Contraindicated) Concomitant use of safinamide with opioids is contraindicated due to the risk of serotonin syndrome. Allow at least 14 days between discontinuation of safinamide and initiation of treatment with opioids.
    Scopolamine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Secobarbital: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Selective serotonin reuptake inhibitors: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Selegiline: (Major) Avoid concomitant use of remifentanil in patients receiving selegiline or within 14 days of stopping treatment with selegiline due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Serotonin-Receptor Agonists: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Serotonin-Receptor Antagonists: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor antagonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Sertraline: (Moderate) If concomitant use of remifentanil and selective serotonin reuptake inhibitors (SSRIs) is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Sevoflurane: (Moderate) Concurrent use of sevoflurane with opiate agonists such as remifentanil can reduce the minimal alveolar concentration (MAC) and increase the CNS depression, hypotension, and respiratory depression associated with sevoflurane administration. However, concurrent use of sevoflurane is compatible with opioids is common in surgical practice.
    Sibutramine: (Moderate) If concomitant use of remifentanil and sibutramine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Sodium Oxybate: (Major) Concomitant use of opioid agonists with sodium oxybate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with sodium oxybate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as opiate agonists. Caution should be exercised when using these agents concurrently.
    Solifenacin: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug, such as solifenacin. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Sotalol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Spironolactone: (Moderate) Opiate agonists like remifentanil may potentiate orthostatic hypotension when given concomitantly with spironolactone.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists like remifentanil may potentiate orthostatic hypotension when given concomitantly with spironolactone. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    St. John's Wort, Hypericum perforatum: (Moderate) If concomitant use of remifentanil and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Sumatriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Sumatriptan; Naproxen: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Suvorexant: (Moderate) Concomitant use of opioid agonists with suvorexant may cause excessive sedation and somnolence. Limit the use of opioid pain medications with suvorexant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tapentadol: (Major) Concomitant use of tapentadol with remifentanil may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of tapentadol with remifentanil to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Tasimelteon: (Moderate) Concomitant use of opioid agonists with tasimelteon may cause excessive sedation and somnolence. Limit the use of opioid pain medications with tasimelteon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tedizolid: (Major) Avoid concomitant use of remifentanil in patients receiving tedizolid or within 14 days of stopping treatment with tedizolid due to the risk of serotonin syndrome or opioid toxicity, including respiratory depression.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Temazepam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tetrabenazine: (Moderate) Additive effects are possible when tetrabenazine is combined with other drugs that cause CNS depression. Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as opiate agonists, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Tetracaine: (Major) Due to the central nervous system depression potential of local anesthetics, they should be used with caution with other agents that can cause respiratory depression, such as opiate agonists. Excitation or depression of the CNS may be the first manifestation of CNS toxicity. Restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression, or drowsiness may be early warning signs of CNS toxicity. After each local anesthetic injection, careful and constant monitoring of ventilation adequacy, cardiovascular vital signs, and the patient's state of consciousness is advised.
    Thalidomide: (Major) Avoid coadministration of opioid agonists with thalidomide due to the risk of additive CNS depression.
    Thiazide diuretics: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Thiethylperazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Thiopental: (Major) Concomitant use of remifentanil with a barbiturate may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a barbiturate to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Thioridazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Thiothixene: (Moderate) Concomitant use of opioid agonists like remifentanil with thiothixene may cause excessive sedation and somnolence. Limit the use of opioid pain medication with thiothixene to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Ticagrelor: (Moderate) Coadministration of opioid agonists, such as remifentanil, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Timolol: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving beta-blockers or calcium-channel blockers due to additive hypotensive effects.
    Tizanidine: (Major) Concomitant use of remifentanil with a skeletal muscle relaxant may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with a skeletal muscle relaxant to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response; use the lowest effective doses and minimum treatment durations. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tolterodine: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug, such as tolterodine. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Tramadol: (Major) Concomitant use of tramadol and remifentanil increases the risk of adverse effects including seizures, serotonin syndrome, and additive opioid toxicity. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected or significant adverse events occur.
    Tramadol; Acetaminophen: (Major) Concomitant use of tramadol and remifentanil increases the risk of adverse effects including seizures, serotonin syndrome, and additive opioid toxicity. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected or significant adverse events occur.
    Tranylcypromine: (Major) The use of remifentanil is not recommended in patients who have received a monoamine oxidase inhibitor (MAOI) within 14 days due to a risk for serotonin syndrome or opioid toxicity, including respiratory depression. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
    Trazodone: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering remifentanil with trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Triazolam: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tricyclic antidepressants: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Trifluoperazine: (Moderate) Phenothiazines can potentiate the CNS depressant action of other drugs such as opiate agonists. A dose reduction of one or both drugs may be warranted.
    Trihexyphenidyl: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
    Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like opiate agonists, may potentiate the effects of either trimethobenzamide or the opiate agonist.
    Trimipramine: (Major) Concomitant use of opioid agonists with tricyclic antidepressants may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. The anticholinergic properties of tricyclic antidepressants may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Limit the use of opioid pain medications with tricyclic antidepressants to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. Monitor for signs of urinary retention and reduced gastric motility.
    Triprolidine: (Moderate) Concomitant use of opioid agonists with triprolidine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with triprolidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when trospium, an anticholinergic drug for overactive bladder. is used with opiate agonists. The concomitant use of these drugs together may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Both agents may also cause drowsiness or blurred vision, and patients should use care in driving or performing other hazardous tasks until the effects of the drugs are known.
    Valerian, Valeriana officinalis: (Moderate) Concomitant use of opioid agonists with valerian may cause excessive sedation and somnolence. Limit the use of opioid pain medication with valerian to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Valproic Acid, Divalproex Sodium: (Moderate) Concomitant use of opioid agonists with valproic acid may cause excessive sedation and somnolence. Limit the use of opioid pain medications with valproic acid to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions.
    Venlafaxine: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with opiate agonists.
    Vilazodone: (Moderate) Because of the potential risk and severity of excessive sedation, somnolence, and serotonin syndrome, caution should be observed when administering remifentanil with vilazodone. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Inform patients taking this combination of the possible increased risks and monitor for the emergence of excessive CNS depression and serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Vortioxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with vortioxetine. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Zaleplon: (Major) Concomitant use of opioid agonists with zaleplon may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zaleplon to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression.
    Ziconotide: (Moderate) Concurrent use of ziconotide and opiate agonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
    Ziprasidone: (Moderate) Because of the potential for additive sedation and CNS depression, caution should be observed when administering remifentanil with ziprasidone. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. There are case reports of serotonin syndrome with use of ziprasidone postmarketing but causality is not established. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Zolmitriptan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with serotonin-receptor agonists. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Zolpidem: (Major) Concomitant use of opioid agonists with zolpidem may cause excessive sedation, somnolence, and complex sleep-related behaviors (e.g., driving, talking, eating, or performing other activities while not fully awake). Limit the use of opioid pain medications with zolpidem to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Instruct patients to contact their provider immediately if sleep-related symptoms or behaviors occur. Educate patients about the risks and symptoms of excessive CNS depression. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known if remifentanil is excreted into breast milk. Because other fentanyl analogs are excreted into breast milk, use caution when administering remifentanil to a breast-feeding woman. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for remifentanil and any potential adverse effects on the breast-fed infant from remifentanil or the underlying maternal condition. Monitor infants exposed to remifentanil through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. In general, the healthy term infant can safely nurse as soon as the mother is awake and alert from receiving a fentanyl analog for anesthesia during a surgery.

    MECHANISM OF ACTION

    Mechanism of Action: Remifentanil is a potent agonist at the µ- opiate receptor. Opiate receptors are coupled with G-protein (guanine-nucleotide-binding protein) receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Opioid-G-protein systems include adenylyl cyclase-cyclic adenosine monophosphate (cAMP) and phospholipase3 C inositol1,4,5 triphosphate (Ins(1,4,5)P3)-Ca2). Opiates do not alter the pain threshold of afferent nerve endings to noxious stimuli, nor do they affect the conductance of impulses along peripheral nerves. Analgesia is mediated through changes in the perception of pain at the spinal cord (µ2-, delta-, kappa-receptors) and higher levels in the CNS (µ1- and kappa3 receptors). There is no ceiling effect of analgesia for opiates. The emotional response to pain is also altered. Opioids close N-type voltage-operated calcium channels (kappa-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (µ and delta receptor agonist) resulting in hyperpolarization and reduced neuronal excitability. Binding of the opiate stimulates the exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the G-protein complex. Binding of GTP leads to a release of the G-protein subunit, which acts on the effector system. In this case of opioid-induced analgesia, the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane. Thus, opioids decrease intracellular cAMP by inhibiting adenylate cyclase that modulates the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and norepinephrine. Opioids also modulate the endocrine and immune systems. Opioids inhibit the release of vasopressin, somatostatin, insulin and glucagon.The analgesic effects of remifentanil are rapid in onset and offset. The effects and side effects to remifentanil are dose-dependent and similar to other µ-opioids. The pharmacodynamic effects of remifentanil correlate directly between dose, blood levels, and response. Clinically, stimulation of µ-receptors produces analgesia, euphoria, respiratory depression, miosis, decreased gastrointestinal motility, and physical dependence. Kappa-receptor stimulation also produces analgesia, miosis, respiratory depression, dysphoria and some psychomimetic effects (i.e., disorientation and/or depersonalization). Miosis is produced by an excitatory action on the autonomic segment of the nucleus of the oculomotor nerve. Opiate-induced respiratory depression is caused by direct action on respiratory centers in the brain stem. Recovery from respiratory depression following surgery is more rapid with remifentanil than morphine or fentanyl. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine, and the sphincters. Opiate agonists also decrease secretions from the stomach, pancreas, and biliary tract. The combination of effects of opiate agonists on the GI tract results in constipation and delayed digestion. Urinary smooth muscle tone is also increased by opiate agonists. The tone of the bladder detrusor muscle, ureters, and vesical sphincter is increased, which sometimes causes urinary retention. Muscle rigidity of the chest and abdominal muscles is often seen with opiate agonist anesthesia. This effect may be due to opiate stimulation of spinal reflexes or interference with basal ganglia integration. Remifentanil does not appear to stimulate the release of histamine. Bradycardia is due to medullary vasomotor center depression and vagal nucleus stimulation and may lead to decreased cardiac output; however, bradycardia is rare with remifentanil alone. Myocardial contractility does not appear to be affected by remifentanil. When used as part of anesthesia, opiate agonists provide analgesic protection against hemodynamic responses to surgical stress by attenuating the catecholamine response. The incidence of postoperative hypertension, need for vasoactive agents and requirements for postoperative analgesics are generally reduced in patients administered moderate or high doses of remifentanil as compared to patients given inhalation anesthetics

    PHARMACOKINETICS

    Remifentanil is administered intravenously only. It is approximately 70% bound to plasma proteins of which two-thirds is bound to alpha1-acid glycoprotein. Remifentanil is an esterase-metabolized opioid. A labile ester linkage renders it susceptible to hydrolysis by non-specific blood and tissue esterases, which produces a carboxylic acid metabolite that is essentially inactive. Remifentanil is not metabolized by plasma cholinesterases and is not appreciably metabolized by the liver or lung. Clearance correlates with total body weight except in patients who are severely obese.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Intravenous Route

    Following intravenous administration of remifentanil, the onset of action is immediate. Following IV bolus doses administered over 60 seconds, the pharmacokinetics of remifentanil fit a three-compartment model with a rapid distribution half-life of 1 minute, a slower distribution half-life of 6 minutes and an elimination half-life of 10—20 minutes. The elimination phase contributes less than 10% of the overall area under the curve (AUC) making the effective biological half-life 3—10 minutes. This is consistent with the 3—10 minute half-life measured after termination of prolonged infusions up to 4 hours and correlates with recovery times after continuous infusions up to 12 hours. Direct correlation between the dose, blood concentration and response exists for remifentanil. In general, every 0.1 mcg/kg/minute change in the infusion rate will cause a 2.5 ng/ml change in the remifentanil concentration in the blood. A new steady-state will be achieved within 5—10 minutes. Achievement of a new steady-state can be obtained within 3—5 minutes if a 1 mcg bolus dose is given with an infusion rate increase. Unlike other fentanyl analogs, the duration of action of remifentanil does not increase with prolonged administration.