PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Opiate Anesthetics

    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

    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 mg/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 < 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 mg/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 mg/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 mg/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 mg/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 mg/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:
    - 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.

    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.

    Asthma, chronic obstructive pulmonary disease (COPD), pulmonary disease, respiratory depression, respiratory insufficiency

    Remifentanil should be used with extreme caution in patients with a history of pulmonary disease, such as acute bronchial asthma, upper airway obstruction, patients with respiratory insufficiency due to decreased respiratory reserve or chronic obstructive pulmonary disease (COPD). Because remifentanil can cause respiratory depression, an opiate antagonist, oxygen, and controlled respiration facilities should be available during and immediately following IV administration. However, unlike other fentanyl analogs, the duration of action of remifentanil at a given dose does not increase with increasing duration of administration due to lack of drug accumulation. During general anesthesia, the rate of respiratory recovery depends upon the concurrent anesthetic (N2O < propofol < isoflurane) used.

    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 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. 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, with the exception of pain management due to recent fractures or joint replacement, since opiates can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an opiate must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. Individuals receiving palliative care or those in hospice settings are excluded from the Beers Criteria; the balance of benefits and harms of medication management for these patients may differ from those of the general population of older adults.

    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, substance abuse

    Because remifentanil is a strong opiate agonist, it is subject to substance abuse and psychologic dependence (i.e., drug addiction) or criminal diversion. Drug addiction is characterized by compulsive use, use for non-medical purposes, and continued use despite harm or risk for harm. Patients with a previous history of substance abuse may be at increased risk of relapse if treated with remifentanil. Abuse and addiction are separate and distinct from physiologic dependence and tolerance. Physicians should be aware that psychologic dependence may not be accompanied by concurrent tolerance and symptoms of physiologic dependence. In addition, abuse of opiate agonists can occur in the absence of true psychologic dependence and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Health care professionals should not let concerns over psychologic dependence deter them from using adequate amounts of opiate agonists in the management of severe pain. Patients should also be counseled regarding misconceptions regarding the use of opiate agonists for pain management. Remifentanil is not approved for the management of substance abuse (alcoholism or drug dependence). The use of remifentanil in patients with alcohol or drug dependence, either active or in remission, is for the treatment of pain requiring opiate agonist analgesia. Patients receiving opiate substitution therapy for opiate substance abuse will have increased tolerance to the analgesic effects of opiate agonists used for acute pain, and will require higher and more frequent dosing to control their pain.

    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, obstetric delivery, pregnancy

    Remifentanil is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. The safety of remifentanil during labor or obstetric delivery has not been demonstrated. Respiratory depression and other opiate effects may occur in newborns whose mothers received remifentanil shortly before delivery. In human clinical trials, maternal remifentanil concentrations were approximately twice those of the fetus. However, in some cases fetal concentrations were similar to those in the mother. Remifentanil should be used during pregnancy only if potential benefits to the mother justify potential risks to the fetus.

    Breast-feeding

    It is not known if remifentanil is excreted into breast milk. Because other fentanyl analogs are excreted into breast milk, caution should be exercised when remifentanil is given to women who are breast-feeding. The infant may experience sedation and/or respiratory depression. The drug has a short half-life. 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. Observe the infant for somnolence, excessive irritability, or poor feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Accidental exposure, ocular exposure

    Avoid ocular exposure to remifentanil. Thoroughly rinse hands and eyes after any accidental exposure to remifentanil to avoid systemic absorption and the possibility of side effects.

    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 abstinence syndrome / Early / 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
    withdrawal / Early / Incidence not known
    physiological dependence / Delayed / 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 (unspecified) / 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; Butalbital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Acetaminophen; Butalbital; Caffeine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Diphenhydramine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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; 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.
    Acetaminophen; 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.
    Acrivastine; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    Amitriptyline; 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. (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Amobarbital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Amoxapine: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as amoxapine, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Amyl Nitrite: (Moderate) Administration of nitrates such as amyl nitrite to patients receiving other hypotension-producing agents, such as opiate agonists, can cause additive hypotensive or orthostatic effects.
    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: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and CNS depressants could result in additive depressant effects.
    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.
    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) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including opiate agonists.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Aspirin, ASA; Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. 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.
    Atracurium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    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) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a potent MAOI. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or methylene blue. (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: (Major) 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; Diphenoxylate: (Major) 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.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental (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: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including opiate agonists. A dose reduction of one or both drugs may be warranted.
    Azilsartan; Chlorthalidone: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Baclofen: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Barbiturates: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental (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.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a potent MAOI. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or methylene blue. (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.
    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: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including opiate agonists.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Brompheniramine; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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.
    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. (Major) Naloxone is the pharmacologic opposite of remifentanil. Naloxone can block the analgesic, respiratory depressant and CNS depressant actions of remifentanil. Naloxone also reverses the skeletal muscle rigidity induced by remifentanil. Naloxone should be carefully used to reverse undesired effects without affecting with pain management. Administration of an naloxone can also lead to sympathetic hyperactivity. Respiratory depression from remifentanil is not expected to last longer than the effect of a single naloxone dose.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    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-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.
    Capsaicin; Metaxalone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Carbamazepine: (Moderate) Inducers of CYP3A4 such as carbamazepine may induce the hepatic metabolism of opiate agonists, which may lead to opiate withdrawal or inadequate pain control. This interaction is most significant if the enzyme-inducing agent is added after opiate therapy has begun in patients who are opiate tolerant. Clinicians should be alert to changes in the effect of the opioid agonist. Opiate doses may need to be increased if carbamazepine is added. Conversely, doses may need to be decreased if carbamazepine is discontinued.
    Carbetapentane; Chlorpheniramine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (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.
    Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    Carbinoxamine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Carbinoxamine; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including opiate agonists.
    Carisoprodol: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. 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.
    Cetirizine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Cetirizine; Pseudoephedrine: (Moderate) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorcyclizine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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; 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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Chlorzoxazone: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cisatracurium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Citalopram: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Clemastine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    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: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    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.
    COMT inhibitors: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Cyclobenzaprine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Cyproheptadine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Dantrolene: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. 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 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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    Desloratadine; Pseudoephedrine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, rare CNS effects such as dizziness and sedation have been reported. For this reason, it would be prudent to monitor for drowsiness or dizziness when used concurrently with other CNS depressants such as opiate agonists.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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.
    Dexchlorpheniramine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with opiate agonists likely to lead to an enhancement of CNS depression.
    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.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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 remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Ibuprofen: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Naproxen: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Phenylephrine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Dolasetron: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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.
    Doxacurium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Doxepin: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    Doxylamine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Doxylamine; Pyridoxine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Dronabinol, THC: (Moderate) Concomitant use of opiate agonists and other CNS depressants such as dronabinol, THC may result in respiratory depression, CNS depression, and/or hypotension. Prior to concurrent use of opiate agonists 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. When concomitant treatment is necessary, reduce the dose of 1 or both drugs. When levorphanol is used with dronabinol, reduce the initial levorphanol dose by approximately 50% or more.
    Droperidol: (Major) Central nervous system (CNS) depressants have additive or potentiating effects with droperidol. Following administration of droperidol, the dose of the other CNS depressant should be reduced. Furthermore, according to the manufacturer, ethanol abuse and the use of benzodiazepines and intravenous opiates are risk factors for the development of prolonged QT syndrome in patients receiving droperidol.
    Duloxetine: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Eletriptan: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Opiate agonists are a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of the opiate agonist is possible. Monitor patients for adverse reactions if eltrombopage is administered with an opiate agonist.
    Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as opiate agonists. 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. In addition, the CYP3A4 metabolism of some opiate agonists may be inhibited by eluxadoline. Although the CYP3A4 inhibitory effects of eluxadoline have not been definitively established, the manufacturer recommends caution when administering eluxadoline concurrently with CYP3A4 substrates that have a narrow therapeutic index, such as fentanyl and alfentanil. Closely monitor for increased side effects if these drugs are administered together. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
    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.
    Entacapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Escitalopram: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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: (Moderate) Concomitant use of remifentanil with eszopiclone 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. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. If used together, a reduction in the dose of one or both drugs may be needed.
    Ethanol: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    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.
    Fesoterodine: (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.
    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) The concomitant use of flibanserin with CNS depressants, such as opiate agonists, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluoxetine: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Fluoxetine; Olanzapine: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as olanzapine, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted. (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Gabapentin: (Moderate) Pain medications that contain opiate agonists may intensify CNS depressive adverse effects seen with gabapentin use, such as drowsiness or dizziness. Patients should limit activity until they are aware of how coadministration affects them.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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) Central-acting adrenergic agonists like guanfacine have CNS depressive effects and can potentiate the actions of other CNS depressants including opiate agonists.
    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; Irbesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly. (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Metoprolol: (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.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Propranolol: (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.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Spironolactone: (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.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Opiate agonists may potentiate orthostatic hypotension when used concurrently with thiazide diuretics.
    Hydrochlorothiazide, HCTZ; Valsartan: (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: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a potent MAOI. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or methylene blue. (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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    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.
    Isocarboxazid: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or the MAOI.
    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.
    Lactobacillus: (Moderate) Concurrent use of antidiarrheals and opiate agonists, can lead to severe constipation and possibly additive CNS depression. 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.
    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) Additive drowsiness may occur if cetirizine or levocetirizine is administered with other drugs that depress the CNS, including opiate agonists.
    Levomilnacipran: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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.
    Lincosamides: (Moderate) Lincosamides, which have been shown to exhibit neuromuscular blocking action, can enhance the effects of opiate agonists if used concomitantly, enhancing respiratory depressant effects. They should be used together with caution and the patient carefully monitored.
    Linezolid: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Linezolid is a nonselective MAOI. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or linezolid.
    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.
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    Loratadine; Pseudoephedrine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as opiate agonists.
    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.
    Loxapine: (Moderate) Loxapine can potentiate the actions of other CNS depressants such as opiate agonists. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as opiate agonists.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as maprotiline, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Meclizine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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.
    Mephobarbital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    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 opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    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.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a potent MAOI. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or methylene blue. (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 opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Methohexital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    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) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants, such as opiate agonists, when administered concomitantly.
    Methylene Blue: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Methylene blue is a potent MAOI. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or methylene blue.
    Metoclopramide: (Moderate) Opiate agonists antagonize GI motility and can decrease the gastroprokinetic effects of metoclopramide.
    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.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as opiate agonists, should be used with caution. Additive drowsiness and/or dizziness is possible. Also, hydrocodone is metabolized by CYP3A4. Metyrapone, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with metyrapone.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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: (Moderate) Concomitant use of mirtazapine and remifentanil increases the risk serotonin syndrome and can potentiate the effects of remifentanil on respiration, sedation, and hypotension. 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.
    Mivacurium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Molindone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as molindone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or molindone is recommended. 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.
    Monoamine oxidase inhibitors: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or the MAOI.
    Nabilone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants, such as nabilone, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    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.
    Naloxone: (Major) Naloxone is the pharmacologic opposite of remifentanil. Naloxone can block the analgesic, respiratory depressant and CNS depressant actions of remifentanil. Naloxone also reverses the skeletal muscle rigidity induced by remifentanil. Naloxone should be carefully used to reverse undesired effects without affecting with pain management. Administration of an naloxone can also lead to sympathetic hyperactivity. Respiratory depression from remifentanil is not expected to last longer than the effect of a single naloxone dose.
    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.
    Naproxen; Sumatriptan: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Naratriptan: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as nefazodone, can potentiate the effects of remifentanil on respiration, sedation, and hypotension.
    Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with opiate agonists.
    Neuromuscular blockers: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as olanzapine, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Orphenadrine: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. 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.
    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.
    Palonosetron: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Pancuronium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Papaverine: (Moderate) Papaverine is a benzylisoquinoline alkaloid of opium and may have synergistic effects with opiate agonists. Concurrent use of papaverine with potent CNS depressants could lead to enhanced sedation.
    Paroxetine: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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. (Major) Naloxone is the pharmacologic opposite of remifentanil. Naloxone can block the analgesic, respiratory depressant and CNS depressant actions of remifentanil. Naloxone also reverses the skeletal muscle rigidity induced by remifentanil. Naloxone should be carefully used to reverse undesired effects without affecting with pain management. Administration of an naloxone can also lead to sympathetic hyperactivity. Respiratory depression from remifentanil is not expected to last longer than the effect of a single naloxone dose.
    Pentobarbital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as opiate agonists.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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. (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) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or the MAOI.
    Phenobarbital: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as pramipexole, can potentiate the effects of remifentanil on respiration, sedation, and hypotension.
    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.
    Pregabalin: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include pregabalin. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    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.
    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.
    Protriptyline: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including atypical antipsychotics, can potentiate the effects of remifentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Rapacuronium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Rasagiline: (Moderate) Opiate agonists (e.g., alfentanil, codeine, hydrocodone, morphine, sufentanil, etc.) may cause additive CNS depression, drowsiness, dizziness or hypotension, so use with MAOIs should be cautious; lower initial dosages of the opiate are recommended followed by careful titration.
    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) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Rocuronium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Ropinirole: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as ropinirole can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    Sedating H1-blockers: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Selective serotonin reuptake inhibitors: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Selegiline: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or the MAOI.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Serotonin-Receptor Agonists: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Serotonin-Receptor Antagonists: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Sertraline: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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.
    Sildenafil: (Moderate) Prolonged erections have been reported in two patients taking sildenafil with dihydrocodeine. Although more data are needed, use caution when prescribing opiate agonists and sildenafil concomitantly.
    Skeletal Muscle Relaxants: (Major) Concomitant use of opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Sodium Oxybate: (Major) Additive CNS depressant effects may be possible when sodium oxybate is used concurrently with opiate agonists.
    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.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort (Hypericum perforatum) may increase the risk for serotonin syndrome when combined with remifentanil, and may also intensify or prolong the effects of general anesthetics. The onset of serotonergic symptoms generally occurs within several hours to a few days of concomitant use, but may occur later. Monitor the patient closely if use of St. John's Wort is reported pre-operatively. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that, if possible, patients should stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions. If use together is necessary and serotonin syndrome is suspected, discontinue remifentanil.
    Succinylcholine: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Sumatriptan: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tapentadol: (Major) Additive CNS depressive effects are expected if tapentadol is used in conjunction with other CNS depressants, including other opiate agonists. Severe hypotension, profound sedation, coma, or respiratory depression may occur. Prior to concurrent use of tapentadol 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 an opiate agonist is used concurrently with tapentadol, a reduced dosage of tapentadol and/or the opiate agonist is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    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 the concomitant use of thalidomide with opiate agonists; antihistamines; antipsychotics; anxiolytics, sedatives, and hypnotics; and other central nervous system depressants due to the potential for additive sedative effects.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. Drugs that should be used cautiously with remifentanil include the barbiturates. A dose reduction of remifentanil or the other drugs may be warranted. Remifentanil acts synergistically with the activity of selected sedatives, inhaled anesthetics, and other anesthetics (e.g. thiopental); the dose of these medications may need to be reduced up to 75% with the coadministration of remifentanil. Remifentanil clearance is not altered by concomitant administration of thiopental
    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) Thiothixene can potentiate the CNS-depressant action of other drugs such as opiate agonists. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    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 opiate agonists with skeletal muscle relaxants may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with skeletal muscle relaxants 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 skeletal muscle relaxant, use a lower initial dose of the opiate and titrate to clinical response. If a skeletal muscle relaxant is prescribed for a patient taking an opiate agonist, use a lower initial dose of the skeletal muscle relaxant and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
    Tolcapone: (Moderate) Concomitant use of opiate agonists with other central nervous system (CNS) depressants such as COMT inhibitors can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of an opiate 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 these agents are used together, a reduced dosage of the opiate and/or the CNS depressant is recommended. 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.
    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.
    Tranylcypromine: (Major) Remifentanil use is not recommended in patients who are receiving or who have received monoamine oxidase inhibitors (MAOIs) within the previous 14 days. Concomitant use of remifentanil with other serotonergic drugs such as MAOIs may result in serious adverse effects including serotonin syndrome. MAOIs may cause additive CNS depression, respiratory depression, drowsiness, dizziness, or hypotension when used with opiate agonists such as remifentanil. If urgent use is necessary, use test doses of remifentanil with frequent titration of small doses and close monitoring. If serotonin syndrome is suspected, discontinue remifentanil and/or the MAOI.
    Trazodone: (Moderate) Concomitant use of trazadone and remifentanil increases the risk serotonin syndrome and can potentiate the effects of remifentanil on respiration, sedation, and hypotension. 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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    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: (Moderate) Concomitant use of remifentanil with other CNS depressants, including tricyclic antidepressants (TCAs), can potentiate opioid-induced CNS and cardiorespiratory effects and the duration of these effects. Additionally, cases of serotonin syndrome have been reported with concomitant use of opioids and serotonergic agents. 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.
    Triprolidine: (Moderate) Concomitant use of remifentanil with other CNS depressants can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Trospium: (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opiate agonists are used concomitantly with an anticholinergic drug, such as trospium. The concomitant use of opiate agonists 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.
    Tubocurarine: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Valerian, Valeriana officinalis: (Moderate) Any substances that act on the CNS may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. The sedative effect may be additive to other drugs with sedative actions, such as the opiate agonists. Consider the patient's use of alcohol or illicit drugs. If valerian is used concurrently with a CNS depressant, a reduced dosage of the CNS depressant may be required, or, the valerian supplement may be discontinued. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression.
    Vancomycin: (Moderate) The concurrent administration of vancomycin and anesthetics has been associated with erythema, histamine-like flushing, and anaphylactoid reactions.
    Vecuronium: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as neuromuscular blockers, can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Venlafaxine: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    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) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as opiate agonists.
    Zaleplon: (Moderate) Concomitant use of remifentanil with zaleplon 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.
    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) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant, including remifentanil.
    Zolmitriptan: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Zolpidem: (Moderate) Concomitant use of remifentanil with zolpidem 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. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night.

    PREGNANCY AND LACTATION

    Pregnancy

    Remifentanil is classified as FDA pregnancy risk category C. There are no adequate and well-controlled studies in pregnant women. The safety of remifentanil during labor or obstetric delivery has not been demonstrated. Respiratory depression and other opiate effects may occur in newborns whose mothers received remifentanil shortly before delivery. In human clinical trials, maternal remifentanil concentrations were approximately twice those of the fetus. However, in some cases fetal concentrations were similar to those in the mother. Remifentanil should be used during pregnancy only if potential benefits to the mother justify potential risks to the fetus.

    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.