Professional Drug Information > Fentanyl Derivatives

Fentanyl Derivatives (Systemic)

This monograph includes information on the following:

1) Alfentanil
2) Fentanyl
3) Sufentanil

VA CLASSIFICATION
Primary: CN101
Secondary: CN206


Note: Controlled substance classification

Note: Controlled substance classification—

U.S.—Schedule II

Canada— N
Commonly used brand name(s): Alfenta¹; Sublimaze²; Sufenta³.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anesthesia adjunct (opioid analgesic)—Alfentanil; Fentanyl; Sufentanil;

Analgesic—Fentanyl; Sufentanil;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Anesthesia, general or local adjunct—Fentanyl and its derivatives are indicated as opioid analgesic supplements to general anesthesia^{{01}{03}{08}{09}{11}{12}{14}{15}{16}{18}{19}{20}{21}{22}{23}{24}{26}{27}{32}{33}{34}{36}{37}{39}{41}{42}{45}}. During surgery, they are often used in conjunction with other agents, such as a combination of an ultrashort-acting barbiturate, a neuromuscular blocking agent, and an inhalation anesthetic (usually nitrous oxide), for the maintenance of “balanced” anesthesia.
—Fentanyl and its derivatives are also indicated as primary agents for the induction of anesthesia in patients undergoing general surgery^{01}{52}{53}.
—[Fentanyl]¹ is indicated as an anesthetic agent during surgery in neonates^{65}.
—Fentanyl and sufentanil are also indicated as primary agents for the maintenance of anesthesia in selected patients undergoing major surgery^{52}{53}{54}. In these cases, they are administered in high doses with 100% oxygen or nitrous oxide plus oxygen and a neuromuscular blocking agent^{52}{53}.
—Fentanyl [and sufentanil]¹ are indicated to provide neuroleptanalgesia (in conjunction with a neuroleptic agent such as droperidol) or neuroleptanesthesia (in conjunction with a neuroleptic agent and nitrous oxide ^{52}).
—Alfentanil¹, fentanyl, [ and sufentanil]¹ are indicated as the analgesic supplements to regional or local anesthesia in a monitored anesthesia setting.
—Fentanyl is approved by U.S. and Canadian regulatory agencies for use as presurgical medication^{52}. However, because of its short duration of action (following administration of single analgesic doses), fentanyl may be less desirable than longer-acting opioid analgesics for this purpose.

Pain, postoperative (treatment)—Fentanyl and [ sufentanil] are indicated for prevention or relief of pain in the immediate postoperative period^{52}.

Pain, obstetrical (treatment)—Sufentanil is indicated for epidural administration, in combination with low-dose bupivacaine, for prevention or relief of the pain of labor and vaginal delivery ^{{53} {54}}.

[Sedation and analgesia]¹—Fentanyl is indicated to provide analgesia and/or sedation during mechanical ventilation in neonates^{66}.

Acceptance not established
Fentanyl has been studied for the facilitation of Broviac catheter placement and endotracheal intubation in neonates. However, there are insufficient data to establish its efficacy for these indications; therefore, further studies are warranted^{66}.

Unaccepted
Alfentanil has also been investigated for use as the primary agent, administered in conjunction with 100% oxygen and a neuromuscular blocking agent, for the maintenance of anesthesia in selected patients undergoing cardiovascular surgery^{24}{36}. However, the patient must be heavily premedicated and continuous intravenous infusion of extremely high doses is required.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Alfentanil hydrochloride: 471 ^{07}
    Fentanyl citrate: 528.61 ^{10}
    Sufentanil citrate: 578.69 ^{06}

pKa—
    Alfentanil: 6.5 ^{08}
    Fentanyl: 8.43
    Sufentanil: 8.01

Partition coefficient (octanol:water; pH 7.4)
    Alfentanil hydrochloride: 130 ^{{08} {09}}.
    Fentanyl citrate: 816.
    Sufentanil citrate: 1727.

Mechanism of action/Effect:

Low to moderate doses of fentanyl and its derivatives produce analgesia. During surgery, analgesic actions provide dose-related protection against hemodynamic responses to surgical stress; however, patient responsiveness to the pharmacodynamic actions of these medications is highly variable ^{{08} {12} {14} {15} {19} {22} {23} {24}}. Although high doses of these medications produce loss of consciousness, the ability of opioid analgesics (when used alone) to induce a true anesthetic state has been questioned ^{47}.

Opioid analgesics bind with stereospecific receptors at many sites within the central nervous system (CNS) to alter processes affecting both the perception of and emotional response to pain. Although the precise sites and mechanisms of action have not been fully determined, alterations in the release of various neurotransmitters from afferent nerves sensitive to painful stimuli may be partially responsible for the analgesic effects ^{63}.

It has been proposed that there are multiple subtypes of opioid receptors, each mediating various therapeutic and/or side effects of opioid drugs. The actions of an opioid analgesic may therefore depend upon whether it acts as a full agonist or a partial agonist or is inactive at each type of receptor. Fentanyl and its derivatives probably produce their effects via agonist actions at the mu receptor ^{64}.


Other actions/effects:

Fentanyl and its derivatives may produce signs and symptoms common to opioid analgesics including respiratory depression (characterized by decreases in respiratory rate, tidal volume, minute ventilation, and ventilatory response to carbon dioxide) ^{{03} {38}}, ureteral spasm, biliary spasm, decreased gastrointestinal motility, euphoria, miosis, hypotension, and bradycardia. However, unlike many other opioid analgesics, fentanyl and its derivatives have not been shown to cause histamine release (in doses used clinically) ^{{01} {52} {53}}.

Fentanyl and its derivatives, especially in moderate or high doses, may induce skeletal muscle rigidity ^{{01} {52} {53} {54} {55}}.

Fentanyl and its derivatives may produce a dose-related decrease in certain hormonal responses during surgery ^{{01} {03}}, such as increased blood concentrations of circulating growth hormone, catecholamines, cortisol, antidiuretic hormone, and prolactin ^{{01} {03}}. However, alfentanil's effects on endocrine responses to surgical stimulation have not been fully evaluated. Also, in patients undergoing coronary bypass surgery, these agents may not suppress such endocrine responses, especially increased catecholamine concentrations, during the period of cardiopulmonary bypass.

Volume of distribution

Alfentanil—Usually 0.4 to 1 liter ^{01} per kg of body weight but subject to interpatient variability; ^{14} values ranging from 0.23 to 2.47 liters per kg of body weight have been reported ^{{03} {12} {14}}. The volume of distribution may be increased during aortocoronary bypass ^{03} or decreased in children ^{03}, but is not altered by obesity ^{08} or hepatic function impairment ^{18}. However, the distribution volume of total alfentanil (but not of the unbound [free] fraction) may be increased in patients with renal failure ^{16}.

Fentanyl—Usually 4 liters per kg of body weight ^{52}, although values ranging from 3.1 to 7.8 liters per kg of body weight have been reported ^{03}.

Sufentanil—1.08 to 2.78 liters per kg of body weight ^{03}.

Note: Fentanyl and its derivatives readily cross the blood-brain barrier; however, because of alfentanil's lower degree of lipophilicity (and therefore lower degree of tissue binding) and its lower pKa, alfentanil reaches receptors in the brain significantly more rapidly than fentanyl ^{12}.
Fentanyl and sufentanil are rapidly distributed to body tissues. The relatively poor blood flow to fatty tissues limits the rate of the medications' accumulation in these tissues. However, accumulation in body fat, as well as in other tissues, may occur with large or multiple doses or prolonged administration ^{52}. Clearance of either of these agents from tissues may result in therapeutic blood concentrations being maintained following discontinuation of administration, leading to a prolonged duration of action.
Alfentanil is also rapidly distributed to body tissues. Although accumulation of alfentanil may occur with prolonged continuous infusion or with repeated administration of single doses and may lead to a prolonged duration of action, alfentanil's accumulation in body tissues is significantly less than that of fentanyl or sufentanil ^{01}. Therefore, alfentanil's duration of action is less likely than that of fentanyl or sufentanil to be substantially prolonged by clearance from body tissues.


Protein binding:

Alfentanil—About 92% ^{{01} {08}}; primarily to glycoproteins (especially alpha-1-acid glycoprotein [AAG]) ^{{03} {08} {15} {18}}. Although independent of alfentanil plasma concentration ^{03} or plasma pH ^{{03} {08}}, alfentanil protein binding is subject to interpatient variability ^{15} and may be decreased in patients with alcoholic hepatic cirrhosis ^{{03} {18}} or renal failure ^{16} and during cardiopulmonary bypass ^{03}.

Fentanyl—80 to 89%, primarily to albumin and lipoproteins ^{{03} {08}}; dependent on plasma pH.

Sufentanil—92.5%, primarily to AAG ^{53}; independent of sufentanil plasma concentration but highly dependent on plasma pH.

Biotransformation:

Hepatic; sufentanil may also undergo some metabolism in the small intestine. Alfentanil, fentanyl, and sufentanil are oxidized by the cytochrome P450 3A4 isoenzyme ^{{17} {62}}. The rate of metabolism is dependent on total dosage, hepatic function ^{57}, and factors affecting hepatic blood flow ^{{15} {18} {19}} (possibly including certain surgical manipulations ^{{03} {15} {18}} or, to a much lesser extent, concurrent use of a potent inhalation anesthetic) ^{18}. The rate of fentanyl or sufentanil metabolism is also dependent on the rate of its release from various body tissues. The rate of alfentanil metabolism is decreased in geriatric patients ^{20}, obese patients ^{{03} {08}}, and patients with hepatic function impairment ^{{03} {12} {18}}. In addition, genetic polymorphism has been suspected as a cause of unusually slow alfentanil metabolism in a few patients ^{{03} {12} {17}}.

Half-life:


Alfentanil:


Triphasic (with a dose of 50 or 125 mcg per kg of body weight)—

Distribution—0.4 to 3.1 minutes ^{{01} {14}}.

Redistribution—4.6 to 21.6 minutes ^{{01} {14} {32}}.

Elimination—Generally 1 to 2.1 hours ^{{01} {12} {14} {20}}, although values well outside this range have been reported ^{03}. The elimination half-life is not altered in patients with renal failure ^{16} but may be decreased in children ^{02}. Also, the elimination half-life is highly dependent on factors affecting the rate of metabolism. Increased values have been reported in patients with reduced hepatic function ^{{01} {02} {12} {18}} (up to 4.9 hours in asymptomatic patients with abnormal liver function test values ^{12} and up to 5.8 hours in patients with active hepatic [alcoholic] cirrhosis) ^{18}, geriatric patients (about 2.3 hours) ^{{01} {02} {20}}, and obese patients (about 3 hours) ^{08}.




Fentanyl:


Triphasic (with a dose of 6.4 mcg per kg of body weight)—

Distribution—1.7 minutes ^{52}.

Redistribution—13 minutes ^{52}.

Elimination—3.6 hours; may be greatly prolonged during and following cardiopulmonary bypass and in geriatric patients. One study showed an average elimination half-life of 15.75 hours following administration of 10 mcg per kg of body weight to patients 60 years of age or older ^{52}.




Sufentanil:


Triphasic (with a dose of 5 mcg per kg of body weight)—

Distribution—1.4 minutes ^{53}.

Redistribution—18 minutes ^{53}.

Elimination—2.7 hours; may be greatly prolonged during and following cardiopulmonary bypass ^{53}.



Onset of action:


Alfentanil:


Analgesic effects (anesthesia adjunct doses)—

Within 1 minute ^{01}.



Time to loss of consciousness (induction doses)—

Dependent on rate of administration; generally within 1 to 2 minutes ^{{03} {26}}.




Fentanyl:


Analgesic effects (anesthesia adjunct doses)—

Intramuscular—7 to 15 minutes ^{52}.

Intravenous—1 to 2 minutes ^{52}.



Time to loss of consciousness (induction doses)—

Dependent on rate of administration; 4 to 5 minutes when administered intravenously at a rate of 400 mcg per minute.




Sufentanil:


Analgesic effects—

Anesthesia adjunct doses—Within 1 minute ^{54}.

Epidural use in obstetrics—Within 10 minutes ^{53}.



Time to loss of consciousness (induction doses)—

Dependent on rate of administration; 1 to 1.6 minutes when administered intravenously at a rate of 300 mcg per minute.



Note: The time to loss of consciousness with induction doses of these medications may be substantially decreased by premedication with a benzodiazepine ^{{03} {21} {24} {32}}.


Therapeutic plasma concentration

Requirements are highly subject to interpatient variability and dependent on the intensity of the surgical stimulus ^{{01} {12} {22} {23} {24} {26}}. With alfentanil, it has been shown that the highest plasma concentrations are required near the beginning of surgery (with intubation requiring higher concentrations than incision) and the lowest toward the end of surgery (i.e., during skin closure) ^{{01} {22} {23}}. Studies of therapeutic plasma concentrations of fentanyl or sufentanil required for different types of surgery, or at different times during a surgical procedure, have not been done.


For use of alfentanil as a supplement to inhalation (nitrous oxide/oxygen) anesthesia:

For superficial surgery: 100 to > 300 nanograms per mL ^{{01} {12}}.

For intra-abdominal surgery: 310 to > 400 nanograms per mL ^{{01} {12}}.


Time to peak effect:


Alfentanil:


Single analgesic dose of up to 500 mcg—

Within 1.5 to 2 minutes (for both analgesia and respiratory depression) ^{{02} {42}}.




Fentanyl:


Analgesic effects—

Intramuscular—20 to 30 minutes ^{52}.

Intravenous—3 to 5 minutes ^{52}.



Respiratory depressant effects—

5 to 15 minutes following administration of a single intravenous dose ^{52}.



Duration of action:


Alfentanil:


Analgesic effects (single dose of up to 500 mcg)—

5 to 10 minutes ^{{02} {03} {21}}.



Time to awakening (when used as a supplement to nitrous oxide/oxygen anesthesia)—

Usually within 10 minutes following the end of surgery when administered either as single injections or as a variable-rate infusion that is discontinued approximately 15 minutes before the end of surgery ^{{23} {26} {34}}.

Note: Alfentanil's duration of action may be decreased in children ^{02}.





Fentanyl:


Analgesic effects (anesthesia adjunct doses)—

Intramuscular—1 to 2 hours ^{52}.

Intravenous—0.5 to 1 hour (single dose of up to 100 mcg) ^{52}.



Time to awakening (high doses)—

0.7 to 3.5 hours following an average total dose of 122 mcg per kg of body weight.




Sufentanil:


Analgesic effects—

Anesthesia adjunct doses—5 minutes.

Epidural use in obstetrics—95 minutes (initial dose); 70 minutes (subsequent doses) ^{53}.



Time to awakening (high doses)—

0.7 to 2.9 hours following an average total dose of 12.9 mcg per kg of body weight.



Note: The duration of action of fentanyl and its derivatives is dose-dependent ^{59}. The effects of a low to moderate single dose of any of these medications are terminated rapidly because of redistribution ^{60}.
With high or multiple doses or prolonged administration of fentanyl or sufentanil, the duration of action is prolonged because substantial plasma concentrations of these agents may be maintained during their clearance from tissue storage sites (although accumulation of sufentanil is less than that of fentanyl). Accumulation of alfentanil resulting in a prolonged duration of action may occur with prolonged continuous infusion ^{{01} {03} {15}} or, to a lesser extent, with repeated administration of single injections ^{01} during lengthy surgical procedures ^{15}. However, because accumulation of alfentanil in body tissues is significantly less extensive than that of fentanyl or sufentanil, alfentanil's duration of action after multiple doses or prolonged continuous infusion is more highly dependent on total body clearance than on redistribution ^{{03} {19}} and subsequent removal from tissue storage sites. Therefore, alfentanil's duration of action may be affected to a greater extent than that of fentanyl or sufentanil by factors that tend to decrease the rate of metabolism (see Biotransformation ).
When fentanyl or sufentanil is administered in high doses as the primary agent for maintenance of anesthesia, respiratory depression requiring continued mechanical ventilation may persist for many hours after the patient awakens ^{52}.


Elimination:
    Alfentanil—Hepatic; only 0.2% of a dose is excreted in the urine as unchanged alfentanil. Inactive metabolites are also excreted in the urine. Approximately 81% of a dose is excreted within 24 hours ^{01}.
    Fentanyl—Primarily hepatic; 10 to 25% of a dose may be excreted in the urine as unchanged fentanyl ^{52}. About 70% of a dose is excreted within 4 days.
    Sufentanil—Via metabolism; about 2% of a dose is excreted in the urine as unchanged sufentanil ^{54}. About 80% of a dose is excreted within 24 hours ^{54}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to fentanyl may be hypersensitive to the chemically related alfentanil or sufentanil also, and vice versa.

Carcinogenicity

Long-term animal studies of the carcinogenic potential of alfentanil have not been done ^{01}.

Mutagenicity

Alfentanil—No evidence of mutagenicity was demonstrated in the Ames Salmonella metabolic activating test. Also, no mutagenicity was demonstrated in the micronucleus test in female rats or the dominant lethal assay in female and male mice with single intravenous doses of up to 20 mg per kg of body weight (mg/kg) (approximately 40 times the maximum recommended human dose) ^{01}.

Sufentanil—Sufentanil has not been shown to have mutagenic potential in the micronucleus test in female rats (with single intravenous doses of up to 80 mcg per kg) or in the Ames test ^{53}.

Pregnancy/Reproduction

Pregnancy—

First trimester


Alfentanil—

Although adequate and well-controlled studies in humans have not been done, one study demonstrated that alfentanil readily crosses the placenta ^{{01} {27}}. Studies in rats and rabbits have not shown that alfentanil is teratogenic. However, embryocidal effects (possibly related to maternal toxicity) occurred following administration of 2.5 times the maximum recommended human dose for 10 to more than 30 days ^{01}.

FDA Pregnancy Category C ^{01}.



Fentanyl—

Although studies on the teratogenic potential of fentanyl have not been done in either animals or humans, one study showed that fentanyl crosses the placenta when it is administered to the mother prior to cesarean section.

FDA Pregnancy Category C ^{52}.



Sufentanil—

Although adequate and well-controlled studies in humans have not been done, studies in rats and rabbits have not shown that sufentanil is teratogenic. However, embryocidal effects (possibly related to maternal toxicity, decreased food consumption, and anoxia) occurred in rats and rabbits following administration of up to 2.5 times the maximum human dose for 10 to more than 30 days ^{53}.

FDA Pregnancy Category C ^{53}.




Labor and delivery—

Drowsiness (but no other adverse effect) was observed in 4-hour-old neonates after administration of fentanyl to the mother prior to cesarean section. This effect was associated with a concentration of 0.8 nanogram (or more) of fentanyl per mL of cord blood. Drowsiness was not present 24 hours after birth.

Breast-feeding

Problems in humans have not been documented.


Alfentanil:

In one study, 0.88 nanogram of alfentanil per mL was measured in colostrum 4 hours following maternal administration of 60 mcg per kg of body weight. Measurable concentrations were not present 28 hours following administration ^{01}.



Fentanyl and sufentanil:

It is not known whether fentanyl and sufentanil are distributed into breast milk ^{{52} {53}}.


Pediatrics

Neonates may be more susceptible to the effects, especially the respiratory depressant effects, of opioid analgesics. Caution is recommended if fentanyl is used as presurgical or postsurgical medication in these patients.

Neonates have been found to have low concentrations of alpha-1-acid glycoprotein, leading to a reduced protein-binding capacity for alfentanil and an increase in the quantity of the medication available to receptor sites ^{27}. However, one study has demonstrated an increased alfentanil dosage requirement in neonates ^{51}.

The elimination half-life and duration of action of alfentanil may be decreased in pediatric patients. More frequent administration of supplemental doses than is usually needed by adults may be required ^{02}.

Muscle rigidity was observed in 20% of mechanically ventilated neonates who received alfentanil at the dose of 9 to 15 mcg per kg of body weight prior to treatment procedures. In some neonates, the rigidity caused difficulty with ventilation ^{25}.


Geriatrics


Geriatric patients may be more susceptible to the effects, especially the respiratory depressant effects, of opioid analgesics. Also, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving alfentanil (because of decreased protein-binding, which increases the effects of alfentanil by increasing its concentration at receptor sites) or fentanyl (because excretion of fentanyl may be slowed). Lower initial and supplemental doses, a slower infusion rate, and/or a longer interval between doses than are usually recommended for younger adults may be required for these patients ^{{01} {03} {20}}. However, geriatric patients may also be more sensitive to the therapeutic effects of opioid analgesics so that lower doses may be sufficient. In one study, possible increased brain sensitivity to alfentanil was demonstrated in geriatric patients ^{03} (compared with healthy young adults) as shown by a 40% reduction in the dose required to produce delta waves in the electroencephalogram (EEG) ^{{01} {03}}.

Many studies have indicated that clearance of opioid analgesics is significantly reduced in geriatric patients. Specifically, studies have shown that alfentanil clearance is reduced ^{{01} {03} {20}} by approximately 30% ^{{03} {20}} (leading to a prolonged elimination half-life) ^{20} in patients older than 65 years of age, and that the elimination half-life of fentanyl may be greatly prolonged (in one study, to 15.75 hours) because of reduced clearance in patients 60 years of age and older. Reduced clearance may lead to a risk of delayed postoperative recovery ^{01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, peridural conduction or
Anesthetics, spinal    (alterations in respiration caused by high levels of spinal or peridural blockade may be additive to fentanyl derivative–induced alterations in respiratory rate and alveolar ventilation; also, the vagal effects of fentanyl derivatives may be more pronounced in patients with high levels of spinal or epidural anesthesia, possibly leading to bradycardia and/or hypotension)


Antihypertensives or
Diuretics or
Hypotension-producing medications, other (see Appendix II)    (hypotensive effects of these medications may be potentiated when they are used concurrently with a fentanyl derivative; patients should be monitored for excessive fall in blood pressure during and following concurrent use ^{{40} {43} {44} {61}})


» Benzodiazepines    (premedication with a benzodiazepine such as diazepam, lorazepam, or midazolam may decrease the dose of a fentanyl derivative required for induction of anesthesia ^{{03} {11} {21} {24}} and decrease the time to loss of consciousness with induction doses ^{{11} {21}}; also, administration of a benzodiazepine prior to or during surgery may decrease the risk of patient recall of surgical events postoperatively; however, these potential benefits must be weighed against the potential risks of concurrent use, such as an increased risk of severe hypotension ^{{01} {03} {32}} associated with decreases in systemic vascular resistance, increased risk of respiratory depression ^{32}, and delayed recovery time ^{{01} {11} {21}}, especially when the benzodiazepine is administered intravenously ^{01})


Beta-adrenergic blocking agents    (preoperative chronic use of systemic beta-adrenergic blocking agents may decrease the frequency and/or severity of hypertensive responses to surgery, especially during sternotomy and sternal spread in cardiac or coronary artery surgery ^{{03} {24}}; however, chronic preoperative use of systemic beta-adrenergic blocking agents ^{{03} {24}} or ophthalmic beta-adrenergic blocking agents [especially levobunolol or timolol] may also increase the risk of initial bradycardia following induction doses of a fentanyl derivative)


» Buprenorphine and other partial mu-receptor agonists    (use of buprenorphine as presurgical medication prior to opioid analgesic–assisted anesthesia should be undertaken with caution because this partial mu-receptor agonist has high affinity for, and dissociates slowly from, the mu receptor and may therefore decrease the therapeutic effects of a subsequently administered mu-receptor agonist)

    (buprenorphine and other partial mu-receptor agonists have the potential to reverse respiratory depressant effects induced by high doses of other opioid analgesics [while providing adequate postoperative analgesia] or to cause additive respiratory depression, hypotension, and/or CNS depression if administered in conjunction with low doses of other opioids; although the effects of buprenorphine administered following alfentanil- or sufentanil-assisted anesthesia have not been determined, in one study, administration of 0.3 or 0.45 mg of buprenorphine intramuscularly every 6 hours following opioid-assisted anesthesia with total doses of 0.2 or 0.3 mg of fentanyl caused a higher incidence of hypotension, respiratory depression, and CNS depression than equianalgesic doses [10 or 15 mg] of morphine intramuscularly every 6 hours)

^{59}
» Cimetidine or
» Erythromycin    (concurrent use of cimetidine or erythromycin with alfentanil can cause reduced clearance of alfentanil, can prolong recovery from alfentanil, and may increase the risk of respiratory depression ^{{01} {13}}; other inhibitors of cytochrome P450 3A4 enzymes have not been tested; however chronic preoperative administration or perioperative use of hepatic enzyme inhibitors may decrease plasma clearance and prolong the duration of action of alfentanil ^{01})


» CNS depression–producing medications, other, including those commonly used as preanesthetic medication or for induction, supplementation, or maintenance of anesthesia (see Appendix II )    (concurrent use with a fentanyl derivative may result in increased CNS depressant, respiratory depressant, and hypotensive effects; caution is recommended and the dosage of each agent should be carefully titrated)

    (it is recommended that initial dosage of other opioid agonist analgesics used during recovery from fentanyl- or sufentanil-assisted anesthesia be decreased to as low as one fourth to one third of the usual recommended dose)

    (dosage requirements of volatile inhalation anesthetics may be decreased by 30 to 50% for the first hour of maintenance following administration of anesthetic induction doses of alfentanil ^{01})


Monoamine oxidase (MAO) inhibitors    (caution is recommended when using a fentanyl derivative in patients who have received an MAO inhibitor within 14 days because concurrent use of MAO inhibitors with meperidine has resulted in unpredictable, severe, and sometimes fatal reactions, including immediate excitation, sweating, rigidity, and severe hypertension, or, in some patients, hypotension, severe respiratory depression, coma, seizures, hyperpyrexia, and vascular collapse; the risk of a significant reaction with fentanyl-derivative opioid analgesics has been questioned ^{59} because a few reports indicate that fentanyl caused no adverse reactions when administered to patients receiving MAO inhibitor therapy; however, there are reports in the medical literature of adverse reactions that might have resulted from an interaction between fentanyl and MAO inhibitors ^{28})


Nalbuphine or
Pentazocine    (these opioid agonist/antagonist analgesics may partially antagonize the analgesic, respiratory depressant, and CNS depressant effects of fentanyl derivatives; however, because of their agonist activity, concurrent use of these agents also has the potential to produce additive CNS, respiratory, and hypotensive effects; the extent to which antagonistic or additive effects will predominate may depend upon dosage of the fentanyl derivative, with antagonism being more likely with low to moderate doses)


Naloxone    (naloxone antagonizes the analgesic, hypotensive, CNS, and respiratory depressant effects of fentanyl derivatives; dosage of the antagonist should be carefully titrated when used to reverse the effects of opioid analgesics used during surgery in order to achieve the desired effect without interfering with control of postoperative pain or inducing other adverse effects)

    (naloxone also reverses skeletal muscle rigidity induced by fentanyl derivatives)


» Naltrexone    (usual doses of opioid analgesics will be ineffective if administered to a patient receiving naltrexone, which blocks the therapeutic effects of opioid analgesics; if possible, alternative [nonopioid] medications should be used prior to, during, and following surgery, because administration of increased doses of opioids to override naltrexone blockade of opioid receptors may result in increased and more prolonged respiratory depression and/or circulatory collapse; naltrexone should be discontinued several days prior to elective surgery if administration of an opioid is unavoidable)


Neuromuscular blocking agents    (concurrent use with high doses of sufentanil may reduce the initial dosage requirements for a nondepolarizing neuromuscular blocking agent; it is recommended that a peripheral nerve stimulator be used to determine dosage ^{53})

    (concurrent use of a neuromuscular blocking agent prevents or reverses muscle rigidity induced by fentanyl derivatives ^{53})

    (a neuromuscular blocking agent having vagolytic activity such as pancuronium or gallamine may decrease the risk of fentanyl derivative–induced bradycardia or hypotension ^{{03} {19} {36}}, especially in patients receiving chronic therapy with beta-adrenergic blocking agents and/or vasodilators for treatment of coronary artery disease; however, concurrent use may also increase the risk of tachycardia or hypertension in some patients ^{21})

    (a nonvagolytic neuromuscular blocking agent such as succinylcholine will not decrease the risk of bradycardia or hypotension induced by a fentanyl derivative; however, in some patients, especially those with compromised cardiac function and/or those receiving a beta-adrenergic blocking agent preoperatively, concurrent use may increase the incidence and/or severity of these effects)

    (respiratory depressant effects of neuromuscular blocking agents may be additive to respiratory depressant effects of fentanyl derivatives; although increased or prolonged respiratory depression or paralysis [apnea] may occur, clinical significance is minimal while the patient is being mechanically ventilated; however, patients should be carefully monitored during and following concurrent use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively ^{53})


Nitrous oxide    (in addition to the increased CNS depressant, respiratory depressant, and hypotensive effects that may occur when a fentanyl derivative is used concurrently with any CNS depressant, concurrent use of nitrous oxide with high doses of these agents may decrease mean arterial pressure, heart rate, and cardiac output; these effects may be more pronounced in patients with poor left ventricular function ^{03})


Phenothiazines    (in addition to the increased CNS depressant, respiratory depressant, and hypotensive effects that may occur when a phenothiazine is used concurrently with an opioid analgesic, some phenothiazines increase, while others decrease, the effects of opioid analgesic supplements to anesthesia; however, the effect of various phenothiazines on fentanyl derivative–assisted anesthesia has not been determined)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Gastric emptying studies    (opioid analgesics may delay gastric emptying, thereby invalidating test results)


Hepatobiliary imaging using technetium Tc 99m disofenin    (delivery of technetium Tc 99m disofenin to the small bowel may be prevented because of opioid analgesic–induced constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization and thus resemble obstruction of the common bile duct; contraction of the sphincter of Oddi has been demonstrated with alfentanil and fentanyl and, although not yet documented, should be considered a possibility with sufentanil also)


Plasma amylase determinations and
Plasma lipase determinations    (activity of these enzymes may be increased because alfentanil and fentanyl can cause contractions of the sphincter of Oddi and increased biliary tract pressure; the possibility should be considered that the diagnostic utility of determinations of these enzymes may be compromised for up to 24 hours after fentanyl administration or for several hours after alfentanil administration; although documentation is not yet available, the possibility exists that similar effects may occur with sufentanil)

With physiology/laboratory test values
Cerebrospinal fluid pressure    (opioid analgesics may increase cerebrospinal fluid pressure; effect is secondary to respiratory depression–induced carbon dioxide retention)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist

For all indications:
Allergic reaction to fentanyl or its derivatives, history of
Cardiac bradyarrhythmias    (may be induced or exacerbated)


Cardiac conditions leading to compromised cardiac reserve    (increased risk of severe bradycardia and/or undesirably large decreases in mean blood pressure, especially following rapid administration of induction doses of a fentanyl derivative ^{42})


Head injury or
Increased intracranial pressure, pre-existing or
Intracranial lesions    (risk of respiratory depression and further elevation of cerebrospinal fluid pressure is increased; also, opioid analgesic–induced sedation and pupillary changes may obscure clinical course of head injury)


» Hepatic function impairment or cirrhosis    (studies have demonstrated that alfentanil clearance rate is reduced, leading to increased elimination half-life and prolonged duration of action ^{{01} {02} {18}}; although clearance of fentanyl or sufentanil may not be altered as greatly as that of alfentanil, caution is advised)

    (alfentanil's effects may also be increased because of decreased protein-binding leading to increased concentration of medication at receptor sites; a reduction of alfentanil dosage may be required ^{18})


Hypothyroidism    (risk of respiratory depression and prolonged CNS depression is greatly increased; a reduction in dosage of the fentanyl derivative may be required ^{02})


Renal function impairment    (elimination of fentanyl [up to 25% of a dose is excreted unchanged in the urine] may be slowed)

    (alfentanil's effects may be increased because of decreased protein-binding leading to increased concentration of medication at receptor sites; however, alfentanil's clearance rate and duration of action are not affected ^{16})


Respiratory impairment or pulmonary disease, pre-existing    (opioid analgesics may further decrease respiratory drive and increase airway resistance; although clinical significance is minimal if the patient is being mechanically ventilated during surgery, respiratory support may be required with doses that usually permit spontaneous breathing)


Caution is also advised in elderly, very ill, or debilitated patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of opioid analgesics.
For use of a fentanyl derivative for indications other than as a component of anesthesia:
Abdominal conditions, acute    (diagnosis or clinical course may be obscured)


Gallbladder disease or gallstones    (opioid analgesics may cause biliary tract spasm)


Gastrointestinal tract surgery    (opioid analgesics may decrease gastrointestinal motility)


Prostatic hypertrophy or obstruction or
Urethral stricture or
Urinary tract surgery    (opioid analgesics may cause urinary retention)


» Respiratory impairment or pulmonary disease, pre-existing    (opioid analgesics may further decrease respiratory drive and increase airway resistance)


» Caution is also advised in elderly, very ill, or very young patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of opioid analgesics.

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Monitoring of vital signs, especially blood pressure and respiratory status    (required during and following administration; prolonged postoperative surveillance may be necessary following high or multiple doses or prolonged administration because of the risk of prolonged respiratory depression, especially after use of fentanyl or sufentanil; also, following high or multiple doses or prolonged administration of alfentanil or fentanyl, respiratory depression, respiratory arrest, bradycardia, asystole, arrhythmias, and hypotension have occurred or recurred following initial recovery ^{{01} {15}})




Side/Adverse Effects

Note: Fentanyl derivatives may cause rigidity in muscles of respiration in the chest and pharynx, which may lead to difficulty in establishing pulmonary ventilation ^{{01} {03} {11} {21} {22} {26} {41}}. Rigidity may occur more rapidly with alfentanil than with fentanyl or sufentanil ^{01}. In addition, alfentanil may cause rigidity of abdominal muscles ^{41}; flexion of the fingers, wrists, and elbows ^{{03} {11} {41}}; extension of the toes, ankles, knees, and hips ^{41}; contraction of neck muscles; immobility of the head; and/or clenching of the jaw ^{{03} {41}}. These effects are dose-dependent and must be anticipated with anesthetic induction doses. Abnormal eye movements (i.e., disconjugate gaze) have also been reported during induction with alfentanil ^{60}. Chest wall rigidity has also been reported during emergence from fentanyl- or sufentanil-assisted anesthesia.
Delayed respiratory depression, respiratory arrest, bradycardia, asystole, arrhythmias, and hypotension have been reported to occur or recur following initial recovery from alfentanil- or fentanyl-assisted anesthesia ^{{01} {15}} and should be considered a possibility following sufentanil-assisted anesthesia also.
Like other opioid analgesics, fentanyl derivatives may cause physical dependence following prolonged use ^{{01} {52} {53}}. It has been proposed that adverse effects (such as tachycardia, hypertension, hyperpnea, hyperalgesia, nausea, and vomiting) occurring (rarely) after naloxone is administered for reversal of opioid effects following lengthy surgical procedures may be manifestations of an induced abstinence syndrome in acutely dependent individuals ^{30}. Alternatively, adverse effects occurring after administration of naloxone may be due to the abrupt reversal of analgesia in patients with significant acute postoperative pain ^{31}.
In addition to the side effects listed below, hypertension, tachycardia, and skeletal muscle movements (not related to onset of rigidity) may occur during surgery. These effects may be indicative of a failure to suppress autonomic responses to surgical stimulation rather than a direct effect of the medication. The incidence and severity of these effects are lower with sufentanil than with alfentanil or fentanyl.
Although not all of the side/adverse effects listed below have been reported with all of the fentanyl derivatives, they have been reported with at least one of these medications and/or encountered during administration of other opioid analgesics. Therefore, they should be considered potential side effects of any of the fentanyl derivatives.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bradycardia^{01}{52}{53} (dizziness, lightheadedness, or feeling faint)
    
hypotension^{01}{52}{53} (dizziness, lightheadedness, or feeling faint)—most likely to occur shortly after administration; blood pressure may return to preadministration values with surgical stimulation
    
respiratory depression, intraoperative or postoperative^{{01}{38}{52}{53}} —may progress to apnea

Incidence less frequent
    
Cardiac arrhythmia^{01}{52}{53} (dizziness, lightheadedness, or feeling faint)—incidence 2% with alfentanil or fentanyl; < 1% with sufentanil
    
confusion, postoperative^{01}{52}{53} —rare with alfentanil

Incidence rare
    
Bronchospasm, allergic (shortness of breath, trouble in breathing, tightness in chest, or wheezing)—not caused by histamine release
    
circulatory depression^{01}{52}{53} (dizziness)—may lead to cardiac arrest
    
dermatitis, allergic (skin rash, hives, and/or itching)
    
laryngospasm^{01} (shortness of breath, trouble in breathing, tightness in chest, or wheezing)—may be a form of rigidity
    
mental depression, postoperative^{01}{52}{53}
    
paradoxical CNS excitation or delirium^{01}{52}{53} (unusual excitement)
    
seizures (convulsions)—reported with fentanyl and sufentanil only



Those common to opioid analgesics (but not necessarily reported specifically with fentanyl derivatives) and indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Drowsiness, postoperative^{01}{52}{53} —less frequent with alfentanil
    
nausea or vomiting^{01}{52}{53} —lower incidence reported with sufentanil than with alfentanil or fentanyl but highly variable; may depend on the specific surgical procedure performed, e.g., especially likely following gynecologic surgery^{34}

Incidence less frequent or rare
    
Biliary spasm (abdominal pain)
    
blurred or double vision or other changes in vision
    
chills^{01}{52}{53}
    
constipation
    
ureteral spasm (decreased or difficult urination)
    
urinary retention (difficult urination)





Overdose
For specific information on the agents used in the management of an overdose, see:
   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Naloxone (Systemic) monograph;
   • Neuromuscular Blocking Agents (Systemic) monograph; and/or
   • Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Bradycardia
    
circulatory depression
    
cold, clammy skin
    
dizziness, severe
    
drowsiness, severe
    
hypotension
    
nervousness or restlessness, severe
    
pinpoint pupils of eyes
    
respiratory depression
    
weakness, severe


Treatment of overdose


Specific treatment:
For bradycardia—Administering atropine. Alternatively, if a neuromuscular blocking agent is being used, administration of a neuromuscular blocking agent with vagolytic activity, such as pancuronium or gallamine, may antagonize fentanyl derivative–induced bradycardia.

For respiratory depression—During surgery, respiratory depression may be managed via endotracheal intubation and assisted or controlled respiration. If respiratory depression persists following surgery, prolonged mechanical ventilation may be required. Also, intravenous administration of the opioid antagonist naloxone may be required. Dosage of naloxone should be titrated to achieve the desired effect without interfering with control of postoperative pain or causing other adverse effects; hypertension and tachycardia, sometimes resulting in left ventricular failure and pulmonary edema, have occurred following naloxone administration in these circumstances (especially in cardiac patients). Initial doses as small as 0.5 mcg (0.0005 mg) of naloxone per kg of body weight have been recommended. Because the duration of respiratory depression may exceed the duration of action of a single intravenous dose of the antagonist, continued monitoring of the patient is mandatory so that additional antagonist may be administered as necessary. Continuous intravenous infusion of naloxone may provide continuing control of undesirable opioid effects.

For hypotension—Administration of appropriate parenteral fluid therapy is recommended. Repositioning of the patient to improve venous return to the heart should be considered when surgical conditions permit. If necessary, a vasopressor (during or following surgery) and/or naloxone (postoperatively only) may be administered.

For muscle rigidity—Administering a neuromuscular blocking agent and assisting respiration via controlled ventilation with oxygen. Alternatively, if muscle rigidity should occur upon emergence, naloxone may be administered. ^{53}



Supportive care:
Other supportive measures should also be employed as needed. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Narcotic Analgesics—For Surgery and Obstetrics (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Allergic reaction to fentanyl or its derivatives

Pregnancy—Alfentanil and fentanyl cross the placenta





Use in children—Increased sensitivity to the effects of opioid analgesics in neonates






Use in the elderly—Increased sensitivity to the effects of opioid analgesics
Other medications, epecially benzodiazepines, buprenorphine and other partial mu-receptor agonists, cimetidine, CNS depressants, erythromycin, naltrexone, and “street” drugs
Other medical problems, especially hepatic function impairment or cirrhosis and pulmonary disease

Precautions after receiving this medication

To be followed for about 24 hours after receiving this medication as part of an outpatient regimen
» Caution if dizziness, drowsiness, lightheadedness, or blurred vision occurs

» Avoiding use of alcohol or other CNS depressants unless specifically prescribed or otherwise approved by physician or dentist


Side/adverse effects
Signs and symptoms of potential side effects, especially bradycardia, hypotension, cardiac arrhythmias, confusion, bronchospasm, circulatory depression, allergic dermatitis, laryngospasm, mental depression, paradoxical excitement, seizures


General Dosing Information
Fentanyl derivatives should be administered only by personnel experienced in the use of intravenous anesthetics and in the management of the respiratory effects of opioid analgesics.

An opioid antagonist, resuscitative medications, intubation equipment, and oxygen should be readily available during and following administration of a fentanyl derivative. Careful monitoring of the patient's respiratory status is necessary during and following surgery. These medications suppress respiration, especially in elderly, very ill, or debilitated patients and those with respiratory problems. Postoperative respiratory depression may be prolonged or may recur following initial recovery, especially following use of moderate or high doses. Following administration of fentanyl or sufentanil, respiratory depression requiring mechanical ventilation may be greatly prolonged. Alfentanil-induced respiratory depression is of shorter duration than that induced by fentanyl or sufentanil ^{{03} {34}}. The peak respiratory depressant effect of fentanyl occurs 5 to 15 minutes after administration of a single intravenous dose and may persist longer than the analgesic effect ^{52}.

Sufentanil is approximately 5 to 7 times more potent than fentanyl on a mcg-to-mcg (and mL-to-mL) basis. Administration of 100 mcg of fentanyl or 13 to 20 mcg of sufentanil produces analgesic effects equivalent to 10 mg of morphine ^{52}. Alfentanil has been reported to be 3 to 10 times less potent than fentanyl on a mcg-to-mcg basis (as determined by dosage requirements) ^{{03} {09} {14} {21} {34}}. However, because of alfentanil's considerably smaller volume of distribution, much higher plasma concentrations are achieved with alfentanil than with equal doses of fentanyl ^{{09} {34}}; studies comparing plasma concentrations of fentanyl or alfentanil required to produce similar effects have indicated that fentanyl may be up to 75 times more potent than alfentanil ^{{03} {09} {34}}. Also, interpatient variability in responsiveness to these medications and/or differences in analytic methodology may have contributed to the difficulty in determining relative potency.

The usual adult and pediatric doses stated below are intended as a guideline only. Dosage must be individualized on the basis of the age, weight, body size, and physical status of the patient; underlying pathology; other medications used concurrently, especially the type of anesthesia to be used; type and anticipated duration of the surgical procedure involved; and patient response. Also, for obese patients (more than 20% above ideal body weight), the dosage of alfentanil ^{01} or sufentanil ^{53} should be determined on the basis of lean body weight.

It is recommended that initial dosage be reduced in elderly or debilitated patients. The effects of the initial dose should be considered in determining supplemental doses ^{{01} {52} {53}}. Lower doses may also be required in patients with chronic hepatic disease (especially for alfentanil) or hypothyroidism ^{02}.

Fentanyl derivatives may cause rigidity of chest and abdominal muscles, which may interfere with pulmonary ventilation ^{52}. Alfentanil may also cause rigidity in other muscles ^{01}. The risk of muscle rigidity may be reduced if intravenous injections are administered slowly ^{01}. A neuromuscular blocking agent compatible with the patient's condition may be administered prophylactically to prevent muscle rigidity or to induce muscle relaxation after rigidity occurs ^{01}. Rigidity has also been reported upon emergence from fentanyl- or sufentanil-assisted anesthesia and should be considered a possibility upon emergence from alfentanil-assisted anesthesia.

It is recommended that intravenous injections of fentanyl or sufentanil be given slowly over a period of at least 1 to 2 minutes, especially if high doses are being administered. It is recommended that induction doses of alfentanil also be given slowly. Although the manufacturer's prescribing information recommends that induction doses of alfentanil be administered over a period of approximately 3 minutes ^{01}, many investigators have administered induction doses within 90 seconds ^{60}. Slow intravenous administration of these medications may reduce the incidence and/or severity of rigidity, bradycardia, and hypotension ^{{01} {03} {21}}. Also, rapid intravenous administration of other opioid analgesics has caused anaphylactoid reactions, severe respiratory depression, hypotension, peripheral circulatory collapse, and cardiac arrest.

Premedication with a benzodiazepine may reduce induction dose requirements and decrease the time to loss of consciousness. In addition, administration of a benzodiazepine or other amnestic agent may help to prevent patient recall of intrasurgical events postoperatively. Patient recall of intrasurgical events despite the absence of autonomic or hormonal responses indicative of light or inadequate anesthesia has been reported following use of high-dose fentanyl with 100% oxygen and, although not reported to date, should be considered a possibility following use of high-dose sufentanil with 100% oxygen or following administration of alfentanil also ^{48}. However, the fact that concurrent use of a benzodiazepine with a fentanyl derivative may increase the risk of hypotension, respiratory depression, or delayed recovery must be kept in mind ^{01}. Alternatively, detection of signs of inadequate anesthesia may be facilitated if the neuromuscular blocking agent being used is administered in doses titrated to avoid complete paralysis.

Fentanyl derivatives, even in very high doses, may fail to suppress autonomic responses to surgical stimulation. Tachycardia and hypertension may occur and are more likely to respond rapidly to additional doses of alfentanil or sufentanil than to additional fentanyl ^{49}. However, administration of a suitable antihypertensive agent may be required in some patients. In patients undergoing cardiac surgery, administration of a beta-adrenergic blocking agent with the presurgical medication (or continuation of previously instituted therapy with a beta-adrenergic blocking agent up to the time of surgery) may reduce or prevent these responses.

Like other opioid analgesics, fentanyl derivatives may cause physical dependence following prolonged use ^{01}. Rarely, symptoms possibly indicating a type of withdrawal syndrome (e.g., tachycardia, hypertension, hyperpnea, hyperalgesia, nausea, and vomiting) may occur following administration of naloxone (especially in high doses) for reversal of opioid effects postoperatively. It has been proposed that adverse effects occurring after administration of naloxone for reversal of opioid effects following lengthy surgical procedures may be manifestations of an induced withdrawal syndrome in acutely dependent individuals ^{46}. Alternatively, adverse effects occurring after administration of naloxone may be due to the abrupt reversal of analgesia in patients with significant acute postoperative pain ^{50}.

For treatment of adverse effects
Recommended treatment may include

   • For hypotension—Administration of appropriate parenteral fluid therapy is recommended. Repositioning of the patient to improve venous return to the heart should be considered when surgical conditions permit. If necessary, a vasopressor (during or following surgery) and/or naloxone (postoperatively only) may be administered.
   • For muscle rigidity—Administering a neuromuscular blocking agent and assisting respiration via controlled ventilation with oxygen. Alternatively, if muscle rigidity should occur upon emergence, naloxone may be administered.
Other supportive measures should also be employed as needed.

ALFENTANIL
Summary of Differences
Indications: See Indications .

Pharmacology/pharmacokinetics: See Pharmacology/Pharmacokinetics .

Pediatrics: Duration of action may be reduced in children. Muscle rigidity occurs more commonly in neonates receiving alfentanil than in older children or adults ^{25}.

Drug interactions and/or related problems: Hepatic enzyme inhibitors may prolong duration of action.

Side/adverse effects: See Side/Adverse Effects .


Additional Dosing Information
See also General Dosing Information.

The anesthetic ED ₉₀ in unpremedicated patients (induction dose required to attenuate or abolish the response to placement of a nasopharyngeal airway in 90% of the patients) is approximately 169 ^{11} to 182 ^{01} mcg per kg of body weight (using a rapid induction) ^{60}; however, values ranging from 137 to 383 mcg per kg of body weight have been reported ^{11}.

An initial loading dose of alfentanil is required to achieve therapeutic plasma concentrations rapidly ^{12}. Administration of the induction or loading dose may be followed by continuous intravenous infusion of the medication and/or administration of supplemental single injections as required ^{01}. Continuous intravenous infusion, with the rate of infusion adjusted according to the observed clinical effect, may reduce the total maintenance dosage requirement ^{{26} {34}}, decrease the risk of postoperative respiratory depression ^{{12} {22} {26} {34}}, and speed recovery time ^{34}, and may be the preferred method of administration ^{{03} {12} {16} {34}}. If necessary, small single doses may be administered, in addition to or instead of increasing the infusion rate, as required to prevent ^{39} or abolish ^{{12} {26} {34}} responses to surgical stimuli or other signs of light or inadequate anesthesia.

Because alfentanil requirements are the lowest near the end of surgery, it is recommended that the maintenance infusion be discontinued 10 to 20 minutes before the end of surgery ^{01}. If further administration of alfentanil is required after the infusion is discontinued, single injections of 7 to 15 mcg per kg of body weight may be given ^{01}.

Because of alfentanil's short duration of action, postoperative pain requiring treatment may occur relatively early in the recovery period ^{{03} {34}}.


Parenteral Dosage Forms

ALFENTANIL HYDROCHLORIDE INJECTION

Note: Alfentanil injection contains alfentanil hydrochloride, but the dosing and strengths are expressed in terms of alfentanil base.


Usual adult dose
Anesthesia adjunct (opioid analgesic) ^{01}


Induction of anesthesia (for procedures lasting 45 minutes or longer) :
Intravenous, 130 to 245 mcg (0.13 to 0.245 mg) (base) per kg of body weight ^{01}. Induction with alfentanil may be followed by administration of an inhalation anesthetic (with the required concentration of inhalation anesthetic generally being reduced by 30 to 50% during the first hour of maintenance) or by further administration of alfentanil in maintenance doses ^{01}.



Maintenance of anesthesia (in conjunction with nitrous oxide and oxygen) :
Procedures lasting up to 30 minutes—Intravenous, 8 to 20 mcg (0.008 to 0.02 mg) (base) per kg of body weight as an initial loading dose, followed by administration of single doses of 3 to 5 mcg (0.003 to 0.005 mg) per kg of body weight as required or by continuous infusion at a rate of 0.5 to 1 mcg (0.0005 to 0.001 mg) per kg of body weight per minute ^{01}.

Procedures lasting longer than 30 minutes—Intravenous, 20 to 75 mcg (0.02 to 0.075 mg) (base) per kg of body weight as an initial loading dose (if an agent other than alfentanil has been used for induction), followed by continuous infusion at a rate of 0.5 to 3 mcg (0.0005 to 0.003 mg) per kg of body weight per minute and/or by single injections of 5 to 15 mcg (0.005 to 0.015 mg) per kg of body weight as required. Following induction with alfentanil, infusion rate requirements may be reduced by 30 to 50% during the first hour of maintenance ^{01}.

Note: For maintenance of anesthesia, continuous infusions of alfentanil are generally administered at an average rate of 0.5 to 1.5 mcg (0.0005 to 0.0015 mg) (base) per kg of body weight per minute ^{01}. However, a variable rate of infusion is recommended, with the rate being increased in response to signs of light or inadequate anesthesia or decreased when signs of light or inadequate anesthesia have been absent for a suitable period of time ^{01}.



Sedation, conscious
Intravenous, 3 to 8 mcg (0.003 to 0.008 mg) (base) per kg of body weight as an initial loading dose, followed by administration of single doses of 3 to 5 mcg (0.003 to 0.005 mg) per kg of body weight as required ^{01}.


Usual pediatric dose
[Anesthesia adjunct (opioid analgesic) for maintenance of anesthesia]¹—Intravenous, 30 to 50 mcg (0.03 to 0.05 mg) (base) per kg of body weight as an initial loading dose ^{02}, followed by supplemental single doses of 10 to 15 mcg (0.01 to 0.015 mg) per kg of body weight as required, or by continuous infusion at a rate of 0.5 to 1.5 mcg (0.0005 to 0.0015 mg) per kg of body weight per minute ^{02}.

Note: Alfentanil's half-life and duration of action are decreased in children as compared with adults; therefore, more frequent supplemental dosing may be required ^{02}.


Strength(s) usually available
U.S.—


Without preservative: 500 mcg (0.5 mg) (base) per mL (Rx) [Alfenta]

Canada—


Without preservative: 500 mcg (0.5 mg) (base) per mL (Rx) [Alfenta]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), protected from light, unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
Alfentanil hydrochloride injection may be diluted with 0.9% sodium chloride injection, 5% dextrose and sodium chloride injection (0.9% sodium chloride), 5% dextrose injection, or lactated Ringer's injection to a convenient concentration. As an example, 20 mL of alfentanil hydrochloride injection may be added to 230 mL of diluent to provide a solution containing 40 mcg (0.04 mg) of alfentanil per mL ^{01}.

Stability:
Alfentanil hydrochloride injection is stable when diluted to a concentration of 25 to 80 mcg of alfentanil base per mL using any of the solutions listed in Preparation of dosage form above ^{01}.

Note: Controlled substance in the U.S., Canada, and the U.K.



FENTANYL
Summary of Differences
Indications: See Indications .

Pharmacology/pharmacokinetics: See Pharmacology/Pharmacokinetics .

Pediatrics: Neonates may be more susceptible to respiratory depressant effects, especially if used as presurgical or postsurgical medication.

Side/adverse effects: See Side/Adverse Effects .


Additional Dosing Information
See also General Dosing Information .

A reduction in dosage may be required in very young patients receiving fentanyl as presurgical or postsurgical medication.


Parenteral Dosage Forms

FENTANYL CITRATE INJECTION USP

Note: Fentanyl injection contains fentanyl citrate, but the dosing and strengths are expressed in terms of fentanyl base.


Usual adult dose
Anesthesia, general, adjunct


For minor surgery:
Intravenous, 2 mcg (0.002 mg) (base) per kg of body weight ^{52}.



For major surgery:
Moderate dose—Intravenous, 2 to 20 mcg (0.002 to 0.02 mg) (base) per kg of body weight ^{52}.

High dose (for open-heart surgery or complicated neurological or orthopedic procedures requiring prolonged anesthesia and abolition of stress response)—Intravenous, 20 to 50 mcg (0.02 to 0.05 mg) (base) per kg of body weight ^{52}.

Note: The total moderate or high dosage recommended during major surgery may be given as a single dose or in divided doses. The quantity of fentanyl given as an initial loading dose and as subsequent maintenance doses must be individualized, depending upon the anesthetic regimen being used, the type and anticipated duration of the surgical procedure involved, and the occurrence of signs of surgical stress or lightening of anesthesia during surgery ^{52}. Although fentanyl may be administered intramuscularly during surgery, it is usually administered intravenously.



Anesthesia, local, adjunct
Intravenous or intramuscular, 50 to 100 mcg (0.05 to 0.1 mg) (base) ^{52}.

Anesthesia, as primary agent in major surgery
Intravenous, 50 to 100 mcg (0.05 to 0.1 mg) (base) per kg of body weight, to be administered with 100% oxygen or oxygen plus nitrous oxide and a neuromuscular blocking agent ^{52}.

Note: Up to 150 mcg (0.l5 mg) (base) per kg of body weight may be required in some patients ^{52}.
In order to provide both immediate and sustained effects throughout a prolonged surgical procedure, administration of an initial loading dose of fentanyl simultaneously with or followed by continuous intravenous infusion is recommended.


Presurgical medication
Intramuscular, 50 to 100 mcg (0.05 to 0.1 mg) (base) thirty to sixty minutes prior to surgery ^{52}.

Postoperative (in recovery room period)
Intramuscular, 50 to 100 mcg (0.05 to 0.1 mg) (base); may be repeated in one or two hours as needed ^{52}.


Usual pediatric dose
Anesthesia, as primary agent in major surgery
[Neonates ]¹: Intravenous, 10 to 30 mcg (base) per kg of body weight (mcg/kg)^{65}.

Children 2 to 12 years of age: Intravenous, 2 to 3 mcg (0.002 to 0.003 mg) (base) per kg of body weight^{52}.

[Analgesia, during mechanical ventilation]¹
Neonates: Intravenous, 1 to 3 mcg/kg (base) as a loading dose followed by 0.5 to 2 mcg/kg per hour and titrated to the requirements and response of the individual patient^{66}{67}.


Strength(s) usually available
U.S.—


Without preservative: 50 mcg (0.05 mg) (base) per mL (Rx) [Sublimaze][Generic]

Canada—


Without preservative: 50 mcg (0.05 mg) (base) per mL (Rx)[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Note: Controlled substance in the U.S., Canada, and the U.K.



SUFENTANIL
Summary of Differences
Indications: See Indications .

Pharmacology/pharmacokinetics: See Pharmacology/Pharmacokinetics .

Drug interactions and/or related problems: See information on interaction with neuromuscular blocking agents in Drug interactions and/or related problems section for information that may not apply to alfentanil or fentanyl.

Side/adverse effects: See Side/Adverse Effects .


Parenteral Dosage Forms

SUFENTANIL CITRATE INJECTION USP

Note: Sufentanil injection contains sufentanil citrate, but the dosing and strengths are expressed in terms of sufentanil base.


Usual adult dose
Anesthesia, general, adjunct
Low dose: Intravenous, 0.5 to 2 mcg (0.0005 to 0.002 mg) (base) per kg of body weight initially ^{54}. Supplemental doses of 10 to 25 mcg (0.01 to 0.025 mg) may be administered as needed ^{53}.

Moderate dose (for major surgical procedures requiring some attenuation of sympathetic response to surgical stimuli): Intravenous, 2 to 8 mcg (0.002 to 0.008 mg) (base) per kg of body weight initially ^{53}. Supplemental doses of 10 to 50 mcg (0.01 to 0.05 mg) may be administered as needed ^{53}.

Note: When administered with nitrous oxide and oxygen for procedures lasting up to eight hours, total doses of 1 mcg (0.001 mg) per kg of body weight per hour, or less, are recommended ^{53}.


Anesthesia, as primary agent in major surgery
Intravenous, 8 to 30 mcg (0.008 to 0.03 mg) (base) per kg of body weight initially, administered with 100% oxygen ^{{53} {54}}. Supplemental doses of 25 to 50 mcg (0.025 to 0.05 mg) may be administered as needed ^{{53} {54}}.

Note: In order to provide both immediate and sustained effects throughout a prolonged surgical procedure, administration of an initial loading dose of sufentanil simultaneously with or followed by continuous intravenous infusion is recommended.


[Pain, postoperative (treatment) ]
Epidural, 30 to 60 mcg (0.03 to 0.06 mg) (base) in 10 mL of 0.9% sodium chloride injection. Additional 25-mcg doses may be administered at intervals of not less than one hour ^{54}.

Pain, obstetrical (treatment)
Epidural, 10 to 15 mcg (0.01 to 0.015 mg) (base) in combination with 10 mL bupivacaine 0.0125%. Two additional doses may be administered at one hour intervals, if needed, to control pain ^{53}.


Usual pediatric dose
Anesthesia, as primary agent in cardiovascular surgery
Initial: Intravenous, 10 to 25 mcg (0.01 to 0.025 mg) (base) per kg of body weight, administered with 100% oxygen ^{54}.

Maintenance: Intravenous, up to 25 to 50 mcg (0.025 to 0.05 mg) (base) ^{54}.


Strength(s) usually available
U.S.—


Without preservative: 50 mcg (0.05 mg) (base) per mL (Rx) [Sufenta][Generic]

Canada—


Without preservative: 50 mcg (0.05 mg) (base) per mL (Rx) [Sufenta]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), protected from light, unless otherwise specified by manufacturer. Protect from freezing.

Note: Controlled substance in both the U.S. and Canada.

Revised: 02/14/2001

References

1. Alfentanil package insert (Alfenta, Janssen—US), Rev 5/95, Rec 7/98.
   

2. Rapifen Data Sheet, Janssen, in ABPI-DSC 85-86: 648-9.
   

3. Reitz JA. Alfentanil in anesthesia and analgesia. Drug Intell Clin Pharm 1986; 20: 335-41.
   

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6. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 689.
   

7. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 31.
   

8. Hull CJ. The pharmacokinetics of alfentanil in man. Br J Anaesth 1983; 55 Suppl 2: 157S-164S.
   

9. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 234-41.
   

10. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 306.
    

11. McDonnell TE, Bartkowski RR, Williams JJ. ED50 of alfentanil for induction of anesthesia in unpremedicated young adults. Anesthesiology 1984; 60: 136-40.
    

12. Shafer A, Sung ML, White PF. Pharmacokinetics and pharmacodynamics of alfentanil infusions during general anesthesia. Anesth Analg 1986; 65: 1021-8.
    

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14. Bovill JG, Sebel PS, Blackburn CL, et al. The pharmacokinetics of alfentanil (R39209): a new opioid analgesic. Anesthesiology 1982; 57: 439-43.
    

15. Reitz JA, Howie MB, Hoffer L, et al. The pharmacokinetics of alfentanil in gynecologic surgical patients. J Clin Pharmacol 1986; 26: 60-4.
    

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17. Yun C, Wood M, Wood A, et al. Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P450 3A4. Anesthesiology 1992; 77: 467-74.
    

18. Ferrier C, Marty J, Bouffard Y, et al. Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology 1985 Apr; 62: 480-4.
    

19. Chauvin M, Bonnet F, Montembault C, et al. The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient. Anesth Analg 1986; 65: 999-1003.
    

20. Helmers H, Van Peer A, Woestenborghs R, et al. Alfentanil kinetics in the elderly. Clin Pharmacol Ther 1984; 36: 239-43.
    

21. Nauta J, de Lange S, Koopman D, et al. Anesthetic induction with alfentanil: a new short-acting narcotic analgesic. Anesth Analg 1982; 61: 267-72.
    

22. Ausems ME, Hug CC Jr, Stanski DR, et al. Plasma concentrations of alfentanil required to supplement nitrous oxide anesthesia for general surgery. Anesthesiology 1986; 65: 362-73.
    

23. Ausems ME, Hug CC. Plasma concentrations of alfentanil required to supplement nitrous oxide anaesthesia for lower abdominal surgery. Br J Anaesth 1983; 55 Suppl 2: 191S-197S.
    

24. de Lange S, de Bruijn NP. Alfentanil-oxygen anaesthesia: plasma concentrations and clinical effects during variable-rate continuous infusion for coronary artery surgery. Br J Anaesth 1983; 55 Suppl 2: 183S-189S.
    

25. Pokela M, Ryhänen P, Koivisto M, et al. Alfentanil-induced rigidity in newborn infants. Anesth Analg 1992; 75: 252-7.
    

26. Ausems M, Hug C, de Lange S. Variable rate infusion of alfentanil as a supplement to nitrous oxide anesthesia for general surgery. Anesth Analg 1983; 62: 982-6.
    

27. Gepts E, Heytens L, Camu F. Pharmacokinetics and placental transfer of intravenous and epidural alfentanil in parturient women. Anesth Analg 1986; 65: 1155-60.
    

28. Insler S, Kraenzler E, Licina M, et al. Cardiac surgery in a patient taking monoamine oxidase inhibitors: an adverse fentanyl reaction. Anesth Analg 1994; 78: 593-7.
    

29. Noble W, Baker A. MAO inhibitors and coronary surgery: a patient death. Can J Anaesth 1992; 39: 1061-6.
    

30. Martin W. Naloxone. Ann Intern Med 1976; 85: 765-8.
    

31. Panel comment, 5/97.
    

32. Silbert BS, Rosow CE, Keegan CR. The effect of diazepam on induction of anesthesia with alfentanil. Anesth Analg 1986; 65: 71-7.
    

33. Hynynen MJ, Turunen MT, Korttila KT. Effects of alfentanil and fentanyl on common bile duct pressure. Anesth Analg 1986; 65: 370-2.
    

34. White PF, Coe V, Shafer A, et al. Comparison of alfentanil with fentanyl for outpatient anesthesia. Anesthesiology 1986; 64: 99-106.
    

35. Coda B, Brown M, Schaffer R, et al. Pharmacology of epidural fentanyl, alfentanil, and sufentanil in volunteers. Anesthesiology 1994; 81: 1149-61.
    

36. Sebel PS, Bovill JG, van der Haven A. Cardiovascular effects of alfentanil anaesthesia. Br J Anaesth 1982; 54: 1185-90.
    

37. Spiss CK, Coraim F, Haider W, et al. Haemodynamic effects of fentanyl or alfentanil as adjuvants to etomidate for induction of anaesthesia in cardiac patients. Acta Anaesthesiol Scand 1984; 28: 554-6.
    

38. Goldberg M, Torjman M, Bartkowski R, et al. Time-course of respiratory depression after an alfentanil infusion-based anesthetic.
    

39. Jellicoe JA. A comparison of alfentanil, halothane and enflurane for day-case gynaecological surgery. Anaesthesia 1985; 40: 810-2.
    

40. Pavlin D, Coda B, Shen D, et al. Effects of combining propofol and alfentanil on ventilation, analgesia, sedation, and emesis in human volunteers. Anesthesiology 1996; 84: 23-37.
    

41. Benthuysen JL, Smith NT, Sanford TJ, et al. Physiology of alfentanil-induced rigidity. Anesthesiology 1986; 64: 440-6.
    

42. Bartkowski R, McDonnell T. Alfentanil as an anesthetic induction agent—a comparison with thiopental-lidocaine. Anesth Analg 1984; 63: 330-4.
    

43. Vuyk J, Engbers F, Burm A, et al. Pharmacodynamic interaction between propofol and alfentanil when given for induction of anesthesia. Anesthesiology 1996; 84: 288-99.
    

44. Vuyk J, Lim T, Engbers F, et al. The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women. Anesthesiology 1995; 83: 8-22.
    

45. Bovill JG, Sebel PS, Wauquier A, et al. Influence of high-dose alfentanil anaesthesia on the electroencephalogram: correlation with plasma concentrations. Br J Anaesth 1983; 55 Suppl 2: 199S-209S.
    

46. Martin W. Naloxone. Ann Intern Med 1976; 85: 765-8.
    

47. Bovill JG, Sebel PS, Stanley TH. Opioid analgesics in anesthesia: with special reference to their use in cardiovascular anesthesia. Anesthesiology 1984; 61: 731-55.
    

48. Mummaneni N, Rao TL, Montoya A. Awareness and recall with high-dose fentanyl-oxygen anesthesia. Anesth Analg 1980; 59: 948-9.
    

49. Stanski D, Hug J. Alfentanil—a kinetically predictable narcotic analgesic. Anesthesiology 1982; 57: 435-8.
    

50. Panel comment, 5/97.
    

51. Singleton MA, Rosen JI, Fisher DM. Plasma concentrations of fentanyl in infants, children and adults. Can J Anaesth 1987; 34: 152-5.
    

52. Fentanyl package insert (Abbott—US), Rev 5/92, Rec 7/98.
    

53. Sufentanil package insert (Elkins-Sinn—US), Rev 1/96, Rec 7/98.
    

54. Sufentanil package insert (Sufenta, Janssen-Ortho—Canada), Rev 3/98, Rec 6/98.
    

55. Alfentanil package insert (Alfenta, Janssen-Ortho—Canada), Rev 3/98, Rec 6/98.
    

56. Panel comment.
    

57. Panel comment.
    

58. Panel comment.
    

59. Panel comment.
    

60. Panel comment.
    

61. Bernard JM, Lagerde D, Souron R. Balanced postoperative analgesia: effect of intravenous clonidine on blood gases and pharmacokinetics of intravenous fentanyl. Anesth Analg 1994; 79: 1126-32.
    

62. Tateishi T, Krivoruk Y, Ueng Y, et al. Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth Analg 1996; 82: 167-72.
    

63. Murkin JM. Central analgesic mechanisms: a review of opioid receptor physiopharmacology and related antinociceptive systems. J Cardiothorac Vasc Anesth 1991; 5: 268-77.
    

64. Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding. Br J Anaesth 1985; 57: 192-6.
    

65. Consensus on review of evidence table, 12/2000.
    

66. Consensus on review of evidence table, 09/2000.
    

67. Panel comment, 02/2001.
    

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