AHFS Class:

• Opioid Agonists 28:08.08

Generic Name(s):

• SUFentanil Citrate

Sufentanil citrate is a synthetic phenylpiperidine-derivative opiate agonist. 4,5,90,91

Analgesic Adjunct to General Anesthesia

Sufentanil injection is used as an IV analgesic adjunct in the maintenance of balanced general anesthesia in adult and pediatric patients who are intubated and ventilated.90 91

Sufentanil injection has produced adequate analgesia and/or general anesthesia in patients undergoing various types of surgery, including cardiovascular (e.g., arteriography, coronary artery bypass, valve replacement, vascular),10,12,13,16,18,35,40,43,44,45,47,48 neurologic (e.g., craniotomy),19,46 gynecologic,17 abdominal,48 orthopedic (e.g., total hip replacement),17,34,36,48 urologic,48 general surgery,34,48 and thoracotomy.48 Sufentanil has also produced adequate analgesia and/or general anesthesia in children as young as 1 day of age undergoing cardiovascular surgery.8,89

Clinical Perspective

General anesthesia is defined as a drug-induced depression of the CNS that results in loss of response to and perception of all external stimuli; patients enter a state of unconsciousness where they are not arousable, even to painful stimuli.824,1002 During general anesthesia, hypnosis, amnesia, analgesia, and muscle relaxation are provided using a combination of drugs.824,1002 Opioids contribute to the primary clinical outcomes of general anesthesia (autonomic nervous system control, unconsciousness, amnesia, and immobility), and are therefore used in balanced anesthesia and multimodal general anesthesia approaches.1002

Perioperative Anesthesia

Sufentanil injection is used as a primary IV anesthetic agent for induction and maintenance of anesthesia in patients undergoing major surgical procedures who are intubated and ventilated, to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated.90 When used for this indication, sufentanil is administered in conjunction with 100% oxygen.10,11,12,13,15,16,18,35,37,38,39,43,44,45 90

Epidural Analgesia

Sufentanil injection is used epidurally as an analgesic combined with low dose (usually 12.5 mg per administration) bupivacaine during labor and vaginal delivery.90 Sufentanil and bupivacaine should be mixed together before administration.90

Efficacy of sufentanil injection for epidural analgesia is supported by the results of 2 double-blind, randomized clinical trials in 340 patients.90 Doses ranged from 10-15 mcg sufentanil and were delivered in a 10 mL volume of 0.125% bupivacaine with and without epinephrine 1:200,000.90 Sufentanil was administered following a dose of local anesthetic to test proper catheter placement.90

Individual doses of 10-15 mcg sufentanil plus bupivacaine 0.125% with epinephrine provided analgesia during the first stage of labor with a duration of 1-2 hours, with an onset of action within 10 minutes.90 Profound analgesia resulting in complete pain relief occurred in 80-100% of patients.90 The duration of action of sufentanil plus bupivacaine with epinephrine was approximately 95 minutes with initial doses and 70 minutes with subsequent doses.90

Clinical Perspective

Guidelines from the American Society of Anesthesiologists for obstetric anesthesia recommend that neuraxial analgesia be provided to patients in early labor (i.e., <5 cm dilation) when this service is available, and should be offered on an individualized basis regardless of cervical dilation.1003 These experts state that continuous epidural infusion can offer effective analgesia during labor and delivery.1003 When a continuous epidural infusion is used during labor and delivery, an opioid may be added to reduce the concentration of local anesthetic, improve analgesia, and minimize motor block.1003 A practice bulletin by the American College of Obstetricians and Gynecologists (ACOG) states that commonly used local anesthetics for epidural analgesia and anesthesia include bupivacaine and ropivacaine, and commonly used opioids include fentanyl and sufentanil.1008

Acute Severe Pain

Sufentanil sublingual tablets (Dsuvia^®) are used in adults in a certified medically supervised healthcare setting, such as a hospital, surgical center, or emergency department, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.91 Sufentanil sublingual tablets are not for home use or for use in children.91 Discontinue treatment before patients leave the certified medically supervised healthcare setting in which the drug is administered.91

Do not use sufentanil sublingual tablets for more than 72 hours; use beyond this period has not been studied.91

Only healthcare providers should administer sufentanil sublingual tablets.91

Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve sufentanil sublingual tablets for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products) have not been or are not expected to be tolerated or have not provided or are not expected to provide adequate analgesia.91

Clinical Experience

Efficacy of sufentanil sublingual tablets is supported by a randomized, double-blind, placebo-controlled trial in 161 adults with acute postoperative pain, defined as pain intensity of 4 or greater on a 0-10 Numeric Rating Scale (NRS) after ambulatory abdominal surgery.91,92 Patients received sufentanil 30 mcg sublingually or placebo once every 60 minutes as needed.91 The primary endpoint was the time-weighted summed pain intensity difference over 12 hours (SPID12).91,92

Patients treated with sublingual sufentanil experienced substantially higher SPID12 (greater pain intensity reduction from baseline) than patients treated with placebo (25.8 versus 13.1).91,92,1004 The median time to onset of meaningful pain relief was shorter with sublingual sufentanil compared with placebo (54 versus 84 minutes).91 Rescue medication was required within the first 12 hours of the treatment phase in approximately 22% of patients treated with sublingual sufentanil compared with 65% of patients treated with placebo.91

Clinical Perspective

A guideline on management of postoperative pain published by the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia recommends oral instead of IV opioids for postoperative analgesia in patients who can tolerate oral intake.1005 When the parenteral route is needed, IV patient-controlled analgesia is recommended.1005 These experts recommend multimodal analgesia regimens, and consideration of surgical site-specific local anesthetic infiltration, peripheral regional anesthesia, and neuraxial anesthesia depending on the specific surgical procedure and patient characteristics.1005 The Society of Hospital Medicine recommends that once the decision is made to initiate opioid therapy for treatment of acute noncancer pain during hospitalization, immediate-release formulations are preferred over long-acting or extended-release formulations.1006 Similarly, the Centers for Disease Control and Prevention (CDC) recommend that when opioids are used for treatment of acute pain, the lowest effective dose of immediate-release opioids should be prescribed in a quantity no greater than that needed for the expected duration of severe pain; 3 days or fewer of opioid analgesia is often sufficient, and use for over 7 days is rarely needed.1007

General

Pretreatment Screening

• Evaluate and screen for behaviors and conditions indicating risk of addiction, abuse, and misuse prior to therapy.90,91

Patient Monitoring

• Monitor for behaviors and conditions indicating risk of addiction, abuse, and misuse during therapy.90,91
• Monitor vital signs routinely during administration of sufentanil injection; ensure facilities for postoperative monitoring and assisted or controlled respiration are available following administration of anesthetic doses of the drug (i.e., 8 mcg/kg or greater).90
• Monitor for severe cardiovascular depression (e.g., severe bradycardia, hypotension) during initiation and titration.90,91
• Monitor patients who may be susceptible to the effects of increased intracranial pressure.90,91
• Monitor patients with biliary tract disease for worsening symptoms.90,91
• Monitor patients with a history of seizure disorders for worsened seizure control during therapy.90,91

Dispensing and Administration Precautions

• Handling and Disposal: Wear gloves when administering sufentanil sublingual tablets.91
• Sufentanil injection should be used only by individuals experienced in the use of parenteral anesthetics and in the maintenance of adequate airway and respiratory support.90 Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be immediately available whenever sufentanil is used.90 An opiate antagonist (e.g., naloxone) should be readily available.90
• Because of the risk of life-threatening respiratory depression, sufentanil sublingual tablets should only be administered by a healthcare provider in a certified medically supervised healthcare setting, such as a hospital, surgical center, or emergency department.91 Treatment must be continued prior to the patient leaving the certified medically supervised setting.91
• Based on the Institute for Safe Medication Practices (ISMP), opioids are high-alert medications that have a heightened risk of causing significant patient harm when used in error.401

REMS

• Sufentanil sublingual tablets are only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Dsuvia^® REMS Program because of the potential for life-threatening respiratory depression due to accidental exposure.91
• Healthcare settings must be able to manage an acute opioid overdose, train all relevant staff regarding dispensation and administration, and establish processes to verify that dispensation outside of the certified healthcare setting does not occur.91
• Wholesalers must establish processes to ensure distribution of sufentanil sublingual tablets only to certified healthcare settings.91

Administration

Sufentanil is administered IV or epidurally, or as sublingual tablets (Dsuvia^®).90,91

Parenteral Administration

Sufentanil citrate may be administered by IV injection, intermittent or continuous IV infusion, or epidural injection.90 The drug has also been administered byIM injection†.21 To administer small volumes of sufentanil injection accurately, the use of a tuberculin syringe or equivalent is recommended.90

Store sufentanil citrate injection at 20-25ºC and protect from light.90

Sublingual Administration

Sufentanil sublingual tablets should be administered by a healthcare provider in a certified medically supervised healthcare setting, such as a hospital, surgical center, or emergency department.91 Treatment must be discontinued prior to the patient leaving the certified medically supervised setting.91

Instruct patients to not chew or swallow sufentanil sublingual tablets.91

Instruct patients to not eat or drink and to minimize talking for 10 minutes after receiving sufentanil sublingual tablets.91

Store sufentanil sublingual tablets at 20-25 ºC (excursions permitted to 15-30 ºC) in a secure, limited access location, in accordance with institutional procedures for Schedule II controlled substances.91

Do not use sufentanil sublingual tablets if the product pouch seal is broken or if the Single-Dose Applicator (SDA) is damaged.91 Wear gloves when administering sufentanil sublingual tablets.91

If a patient experiences excessive dry mouth with sufentanil sublingual tablets, provide ice chips prior to administration.91

Dosage

Dosage of sufentanil citrate is expressed in terms of sufentanil.90 91 Dosage must be carefully adjusted according to body weight, individual requirements and response, physical status and underlying pathologic condition, premedication or concomitant medication(s), the anesthetic(s) being used, and the nature and duration of the surgery.90 91

Analgesic Adjunct to General Anesthesia

In adults, in minor but painful general surgical procedures (anticipated duration of anesthesia of 1-2 hours) requiring endotracheal intubation and assisted or controlled respiration, a total sufentanil dosage of 1-2 mcg/kg is administered IV in conjunction with nitrous oxide and oxygen; approximately 75% or more of the total dosage (titrated to patient response) may be administered by slow IV injection or infusion prior to intubation.90 Supplemental IV doses of 10-25 mcg or, alternatively, intermittent or continuous maintenance IV infusions may be given as necessary when movement and/or changes in vital signs indicate surgical stress or lightening of anesthesia.90 Maintenance infusion rates should be adjusted based on the induction dose so that the total sufentanil dosage does not exceed 1 mcg/kg per hour of anticipated surgical time.90 In the absence of evidence of lightening of anesthesia, maintenance infusion rates should be adjusted downward until there is some response to surgical stimulation.90

In more complicated, major surgical procedures (anticipated duration of anesthesia of 2-8 hours) in adults, a total sufentanil dosage of 2-8 mcg/kg is administered IV in conjunction with nitrous oxide and oxygen; approximately 75% or less of the total dosage (titrated to patient response) may be administered by slow IV injection or infusion prior to intubation.90 Supplemental IV doses of 10-50 mcg or, alternatively, intermittent or continuous maintenance IV infusions may be given as necessary when movement and/or changes in vital signs indicate surgical stress or lightening of anesthesia.90 Maintenance infusion rates should be adjusted based on the induction dose so that the total sufentanil dosage does not exceed 1 mcg/kg per hour of anticipated surgical time.90 In the absence of evidence of lightening of anesthesia, infusion rates should be adjusted downward until there is some response to surgical stimulation.90

Perioperative Anesthesia

When used as the primary anesthetic agent to provide general anesthesia in adults, a total sufentanil dosage of 8-30 mcg/kg, administered IV by slow injection, infusion, or injection followed by infusion, may be used in conjunction with oxygen and a skeletal muscle relaxant.90 Depending on the initial dose, maintenance IV doses of 0.5-10 mcg/kg may be given by slow IV injection in anticipation of surgical stress (e.g., incision, sternotomy, cardiopulmonary bypass); alternatively, intermittent or continuous maintenance IV infusions may be given as necessary as determined by changes in vital signs that indicate surgical stress and lightening of anesthesia.90 Maintenance infusion rates should be adjusted based on the induction dose so that the total sufentanil dosage for the procedure does not exceed 30 mcg/kg.90 In the absence of evidence of lightening of anesthesia, infusion rates should be adjusted downward until there is some response to surgical stimulation.90 IV doses of 8-25 mcg/kg generally attenuate catecholamine release and those of 25-30 mcg/kg generally block sympathetic responses including catecholamine release during surgery90 but not during cardiopulmonary bypass.11,12,55 High dosages are used in adults undergoing major surgical procedures such as cardiovascular surgery or neurosurgery performed with the patient in the sitting position to provide favorable myocardial and cerebral oxygen balance or when extended postoperative ventilation is anticipated.90

The manufacturers state that when sufentanil is used to provide induction and maintenance of anesthesia without additional anesthetic agents in children younger than 12 years of age undergoing cardiovascular surgery, an initial anesthetic dose of 10-25 mcg/kg is administered IV in conjunction with 100% oxygen and a skeletal muscle relaxant;8,90 additional IV doses of up to 25-50 mcg each are recommended as necessary based on response to the initial dose and as determined by changes in vital signs that indicate surgical stress or lightening of anesthesia.90

Epidural Analgesia

The epidural dose for labor and delivery is 10-15 mcg of sufentanil and 10 mL of bupivacaine 0.125% with or without epinephrine.90 Doses may be repeated twice (for a total of 3 doses) at not less than 1-hour intervals until delivery.90

Acute Severe Pain

The recommended dosage of sufentanil sublingual tablets is 30 mcg sublingually as needed with a minimum of 1 hour between doses.91 The maximum cumulative daily dose of sufentanil is 360 mcg or 12 tablets (12 tablets x 30 mcg/dose) within 24 hours.91

Special Populations

Hepatic Impairment

Administer sufentanil with caution to patients with hepatic impairment because of the drug's extensive hepatic metabolism.90 Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.90,91

Renal Impairment

Administer sufentanil with caution to patients with renal impairment because of the renal excretion of sufentanil and its metabolites.90 Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.90,91

Geriatric Use

In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.90 Titrate the dosage of sufentanil injection slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression.90 Because the dose of sufentanil sublingual tablets cannot be titrated, monitor geriatric patients closely for signs of CNS and respiratory depression or consider an alternate medication that can be titrated.91

Contraindications

• Hypersensitivity to sufentanil.90,91
• Significant respiratory depression (sufentanil sublingual tablets).91
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment (sufentanil sublingual tablets).91
• Known or suspected GI obstruction, including paralytic ileus (sufentanil sublingual tablets).91

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

The prescribing information for all sufentanil preparations contains a boxed warning regarding the risks of addiction, abuse, and misuse, which can lead to overdose and death.90,91 Assess patient's risk before prescribing and monitor regularly for these behaviors and conditions.90,91 Sufentanil is a Schedule II controlled substance, which exposes users to the risks of addiction, abuse, and misuse.90,91 Consider these risks when handling sufentanil.90,91 Although risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression), these risks should not prevent the proper management of pain in any given patient.91

Accidental Exposure

The prescribing information for sufentanil sublingual tablets contains a boxed warning regarding accidental exposure.91 Accidental ingestion or exposure to even one dose, especially in children, can result in respiratory depression and death due to an overdose of sufentanil.91 Sufentanil sublingual tablets should be used only in a certified medically supervised healthcare setting, consistent with the REMS program.91 Following accidental ingestion of sufentanil sublingual tablets, monitor patients for opioid-related adverse events, such as respiratory depression.91

Life-threatening Respiratory Depression

Sufentanil can severely compromise respiratory function.91 The prescribing information for all sufentanil preparations contains a boxed warning regarding the risk of life-threatening respiratory depression, especially during initiation or following dosage increases.90,91

Sufentanil injection should be used only by individuals who are experienced in the use of parenteral anesthetics and the management of the respiratory effects of potent opioids, including airway management and cardiac resuscitation.90 Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be immediately available whenever anesthetic doses of the drug (i.e., 8 mcg/kg or greater) are used.90 An opiate antagonist (e.g., naloxone) should be readily available.90

Because of the risk of life-threatening respiratory depression, sufentanil sublingual tablets should only be administered by a healthcare provider in a certified medically supervised healthcare setting.91

Monitor patients closely for respiratory depression throughout treatment with sufentanil, particularly when initiating and titrating therapy.90,91 Risk of decreased respiratory drive is increased in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression.90,91 Risk is also increased in elderly, cachectic, or debilitated patients, who may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.90,91 Monitor such patients closely when initiating and titrating sufentanil and when sufentanil is given concomitantly with other drugs that depress respiration; consider the use of non-opioid analgesics in these patients.90,91 Opioids increase the risk of central sleep apnea.90,91 In patients who present with central sleep apnea, consider decreasing the opioid dosage using best practices for opioid taper.90,91 .91

Concomitant Use with Cytochrome P-450 (CYP) 3A4 Inhibitors and Inducers

The prescribing information for sufentanil contains a boxed warning regarding concomitant use of sufentanil CYP3A4 inhibitors and inducers.90,91 Concomitant use of sufentanil with a CYP3A4 inhibitor may increase plasma concentrations of sufentanil; this may prolong opioid adverse reactions and may cause potentially fatal respiratory depression.90,91 Inhibitors of CYP3A4 include macrolide antibiotics (e.g., erythromycin), azole antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir).90,91

Similarly, discontinuation of a CYP3A4 inducer in sufentanil-treated patients may increase sufentanil plasma concentrations and prolong opioid adverse reactions.90,91 Inducers of CYP3A4 include rifampin, carbamazepine, and phenytoin.90,91

When using sufentanil with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in sufentanil-treated patients, monitor patients closely and consider dosage reduction of sufentanil.90,91 Conversely, concomitant use of sufentanil with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could result in lower than expected sufentanil plasma concentrations, and decrease efficacy or result in withdrawal syndrome in patients with physical dependence.90,91 When using sufentanil with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely and consider increasing the dosage of sufentanil.90,91

Concomitant Use with Benzodiazepines or Other CNS Depressants

The prescribing information for sufentanil contains a boxed warning regarding concomitant use with benzodiazepines and other CNS depressants.90,91 Concomitant use of sufentanil and benzodiazepines or other CNS depressants may result in hypotension or decreased pulmonary arterial pressure; even relatively small dosages of diazepam may cause cardiovascular depression when used with high or anesthetic dosages of sufentanil.90,91

Consider the potential for such concomitant therapy to decrease pulmonary arterial pressure when performing diagnostic or surgical procedures where interpretation of pulmonary arterial pressure measurements might determine patient management.90 If hypotension occurs with sufentanil injection, the possibility of hypovolemia should be considered and managed with appropriate fluid therapy.90 When operative conditions permit, consider repositioning of the patient to improve venous return to the heart.90

Because of the potential for orthostatic hypotension, care should be exercised when moving and repositioning the patient.90 If volume expansion and other countermeasures do not correct hypotension, consider administration of a pressor agent (other than epinephrine, which may cause a reduction in blood pressure in patients receiving a neuroleptic with α-adrenergic blocking activity).90

Concomitant use of sufentanil with benzodiazepines or other CNS depressants may result in profound sedation, respiratory depression, coma, and death.90,91 Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.91 If the decision is made to manage postoperative pain with sufentanil and a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage, titrate based on clinical response, and monitor closely for signs and symptoms of respiratory depression, sedation, and hypotension.90,91 Ensure fluids or other measures to counter hypotension are available.90

Muscle Rigidity and Skeletal Muscle Movement

Muscle rigidity, particularly involving the muscles of respiration, may occur with IV administration or unintentional intravascular injection during epidural administration of sufentanil.90 The incidence and severity of muscle rigidity is related to the dose and speed of injection.90 Skeletal muscle rigidity may also occur or recur in the extended postoperative period, usually following high doses of sufentanil.90 Skeletal muscle movements may also occur during induction of anesthesia with sufentanil.90 On rare occasions, these movements have been strong enough to pose patient management problems.90

The selection of preanesthetic medication(s) should be based on the individual needs of the patient.90 The neuromuscular blocking agent used should be compatible with the patient's condition, taking into account the hemodynamic effects of the drug, the cardiovascular status of the patient, existing drug therapy (e.g., preoperative use of β-adrenergic blocking agents), and the degree of skeletal muscle relaxation required.90 For sufentanil doses up to 8 mcg/kg, up to 25% of the full paralyzing dose of a nondepolarizing neuromuscular blocking agent should be administered just prior to sufentanil; for anesthetic doses of sufentanil greater than 8 mcg/kg that are titrated by slow IV infusion, a full paralyzing dose of a neuromuscular blocking agent should be administered following loss of consciousness.90 For rapidly administered anesthetic doses of sufentanil greater than 8 mcg/kg, a full paralyzing dose of a neuromuscular blocking agent should be administered simultaneously with sufentanil.90

Severe Cardiovascular Depression

Sufentanil may cause severe bradycardia, severe hypotension including orthostatic hypotension, and syncope.90,91 Risk of severe cardiovascular depression is increased in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics).90,91 In patients with circulatory shock, sufentanil may cause vasodilation that can further reduce cardiac output and blood pressure.90,91 Monitor these patients for hypotension after initiating or titrating sufentanil citrate injection dosages; avoid use of sufentanil sublingual tablets in patients with circulatory shock.90,91 Monitor patients with bradyarrhythmias for changes in heart rate, particularly when initiating therapy with sufentanil sublingual tablets.91

Serotonin Syndrome With Concomitant Use of Serotonergic Drugs

Serotonin syndrome has been reported during concomitant use of sufentanil with serotonergic drugs, including at recommended sufentanil dosages.90,91 Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT₃ receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and IV methylene blue).91

Signs and symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).90,91 The typical onset of symptoms is within several hours to a few days of concomitant use, but may occur later.90,91 Discontinue sufentanil if serotonin syndrome is suspected.90,91

Improper Epidural Injection

Verify proper placement of the needle or catheter in the epidural space before sufentanil is injected to assure that unintentional intravascular or intrathecal administration does not occur.90 Unintentional intravascular injection could result in serious overdose.90 Unintentional intrathecal injection of the full sufentanil/bupivacaine epidural doses and volume could produce effects of high spinal anesthesia including prolonged paralysis and delayed recovery.90 If analgesia is inadequate, verify the placement and integrity of the catheter prior to administration of any additional epidural medications.90 Administer sufentanil epidurally by slow injection.90

Use in Patients With Increased Intracranial Pressure, Brain Tumors, or Head Injury

Sufentanil may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure in patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors).90,91 Monitor such patients for signs of increasing intracranial pressure with use of sufentanil citrate injection, and for signs and symptoms of sedation and respiratory depression, particularly when initiating therapy, with sufentanil sublingual tablets.90

Use in Patients With GI Conditions

Sufentanil may cause spasm of the sphincter of Oddi.90,91 Opioids may cause increases in serum amylase.90,91 Monitor for worsening symptoms in patients with biliary tract disease, including those with acute pancreatitis.90,91

Increased Risk of Seizures in Patients With Seizure Disorders

In patients with seizure disorders, sufentanil may increase the frequency of seizures and the risk of seizures occurring in other clinical settings associated with seizures.90,91 Monitor patients with a history of seizure disorders for worsened seizure control during sufentanil therapy.90,91

Risks of Driving and Operating Machinery

Sufentanil may impair the ability to perform potentially hazardous activities such as driving a car or operating machinery.90 Warn patients not to engage in such behaviors after sufentanil administration.90

Adrenal Insufficiency

Adrenal insufficiency has been reported with opioid use, generally following greater than one month of use.91 Signs and symptoms of adrenal insufficiency may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.91 If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.91 If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.91 Wean the patient off the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.91 Consider trials of other opioids; some cases reported use of a different opioid without recurrence of adrenal insufficiency, although no particular opioid has been identified to have a greater association with adrenal insufficiency.91

Neonatal Opioid Withdrawal Syndrome

Prolonged use of sufentanil sublingual tablets during pregnancy can result in withdrawal in the neonate.91 Unlike adults, withdrawal syndrome in neonates may be life-threatening if not recognized and treated according to protocols developed by neonatology experts.91 Observe newborns for signs of neonatal opioid withdrawal syndrome and institute appropriate therapy.91 Advise pregnant females using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.91

Abuse Potential and Dependence

Sufentanil has high potential for abuse, similar to other opioids including hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol.90,91 Sufentanil products can be abused and are subject to misuse, addiction, and criminal diversion.90,91 Carefully monitor all patients treated with opioids for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.90,91 Abuse of opioid drugs can be limited with proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage.90,91 Both tolerance and physical dependence can develop during chronic opioid therapy.90,91 Physical dependence can result in withdrawal symptoms following abrupt discontinuation or a significant dose reduction.90,91

Specific Populations

Pregnancy

Prolonged use of opioids during pregnancy may cause neonatal opioid withdrawal syndrome.90 Data on sufentanil in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage.90,91

In animal studies, embryolethality and maternal toxicity occurred in rabbits with IV sufentanil administration at 0.9 times the human procedural dose of 30 mcg/kg during organogenesis.90 Decreased live fetuses and pup survival were noted in rats treated with sufentanil late in gestation and throughout lactation at doses below the human procedural dose.90,91 No malformations were observed in either rats or rabbits at doses below the human procedural dose.90,91 Sufentanil should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Sufentanil injection is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.90 Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.90

Epidural administration of sufentanil in combination with bupivacaine 0.125% with or without epinephrine is indicated for labor and delivery.90 Sufentanil is not recommended for IV use or for use of larger epidural doses during labor and delivery because of potential risks to the newborn infant after delivery.90

Lactation

Consider the developmental and health benefits of breastfeeding along with the mother's need for sufentanil and any potential adverse effects on the breastfed infant or from the underlying maternal condition.90,91 Monitor infants exposed to sufentanil through breast milk for excess sedation and respiratory depression.90

Females and Males of Reproductive Potential

Females and males of reproductive potential may experience infertility with chronic use of opioids.90,91 It is not known whether these effects are reversible.90,91

Pediatric Use

Safety and efficacy of sufentanil citrate injection in children as young as 1 day of age have been documented in a limited number of patients undergoing cardiovascular surgery.8,89 Safety and efficacy of sufentanil sublingual tablets in pediatric patients have not been established; use is not recommended in these patients because of the risk of noncompliance with sublingual dosing instructions.91

The clearance of sufentanil in healthy neonates is approximately one-half that in adults and children.90 The clearance rate of sufentanil can be further reduced by up to a third in neonates with cardiovascular disease, resulting in an increase in the elimination half-life.90

Geriatric Use

Elderly patients may have increased sensitivity to sufentanil.90 No special population studies in geriatric patients have been performed for sufentanil sublingual tablets.91 In patients who received sublingual sufentanil, the overall rate of adverse events and most common adverse events tended to increase with age, although vomiting was less common in patients aged ≥75 years than in younger patients.91

In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.90 Titrate the dosage of sufentanil citrate injection slowly in geriatric patients and monitor closely for signs of CNS and respiratory depression.90 Because the dose of sufentanil sublingual tablets cannot be titrated, monitor geriatric patients closely for signs of CNS and respiratory depression or consider an alternate medication that can be titrated.91

Hepatic Impairment

Sufentanil should be administered with caution to patients with hepatic impairment because of its extensive hepatic metabolism.90,91 Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.90,91

Renal Impairment

Sufentanil should be administered with caution to patients with renal impairment because of the renal excretion of sufentanil and its metabolites.90 No significant changes have been observed in patients with mild or moderate renal impairment.91 Reduce the dosage as needed and monitor closely for signs of respiratory depression, sedation, and hypotension.90

Common Adverse Effects

The most common adverse reactions associated with sufentanil citrate injection were respiratory depression, apnea, rigidity, and bradycardia.90

The most common adverse reactions (≥2%) associated with sufentanil sublingual tablets were nausea, headache, vomiting, dizziness and hypotension.91

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4

Concomitant use of sufentanil and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after achieving a stable dose of sufentanil.90,91 After stopping a CYP3A4 inhibitor, the sufentanil plasma concentration will decrease as the effects of the inhibitor decline; this may result in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.90,91 If sufentanil is administered with a concomitant CYP3A4 inhibitor, consider dosage reduction of sufentanil until stable drug effects are achieved, and monitor for respiratory depression and sedation.90 If concomitant use is necessary, consider an alternate medication to sufentanil sublingual tablets that allows dose titration.91 If a concomitant CYP3A4 inhibitor is discontinued, consider increasing the sufentanil dosage until stable drug effects are achieved, and monitor for signs of opioid withdrawal.90

Inducers of CYP3A4

Concomitant use of sufentanil and CYP3A4 inducers can decrease the plasma concentration of sufentanil, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil.90,91 After stopping a CYP3A4 inducer, the sufentanil plasma concentration will increase as the effects of the inducer decline, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.90,91 If concomitant use is necessary, consider an alternate medication to sufentanil sublingual tablets that allows dose titration.91 If a CYP3A4 inducer is discontinued, consider sufentanil dosage reduction and monitor for signs of respiratory depression.90,91

Benzodiazepines and Other CNS Depressants

Concomitant use of sufentanil and benzodiazepines or other CNS depressants, including alcohol, may result in hypotension or decreased pulmonary arterial pressure; even relatively small dosages of diazepam may cause cardiovascular depression when used with high or anesthetic dosages of sufentanil.90,91 Clinicians should consider the potential for such concomitant therapy to decrease pulmonary arterial pressure when performing diagnostic or surgical procedures where interpretation of pulmonary arterial pressure measurements might determine patient management.90 If hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate fluid therapy.90 When operative conditions permit, repositioning of the patient to improve venous return to the heart should be considered.90 Because of the potential for orthostatic hypotension, care should be exercised when moving and repositioning the patient.90 If volume expansion and other countermeasures do not correct hypotension, administration of a pressor agent (other than epinephrine, which may cause a reduction in blood pressure in patients receiving a neuroleptic with α-adrenergic blocking activity) should be considered.90

Concomitant use of opiate agonists, including sufentanil, and benzodiazepines or other CNS depressants, including other opiate agonists, anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and alcohol, also may result in profound sedation, respiratory depression, coma, and death.90,416,417,418,700,701,702,703 If used in the immediate postoperative period for analgesia in conjunction with a benzodiazepine or other CNS depressant, sufentanil should be initiated at a reduced dosage and titrated based on clinical response, and the patient should be monitored closely for respiratory depression, sedation, and hypotension.90,700 Fluids or other measures to counteract hypotension should be available.90

Serotonergic Drugs

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.90,91 If concomitant use is warranted, monitor the patient, particularly during treatment initiation and dose adjustment.90,91 Discontinue sufentanil if serotonin syndrome is suspected.90,91

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors may interact with opioids and may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).90,91 Sufentanil is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.90,91

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Mixed agonist/antagonist and partial agonist opioid analgesics may reduce the analgesic effect of sufentanil and/or precipitate withdrawal symptoms; avoid concomitant use.90,91

Muscle Relaxants

Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants, producing an increased degree of respiratory depression.90,91 Monitor for respiratory depression that may be greater than otherwise expected and reduce the dosage of sufentanil or the muscle relaxant as necessary.90,91

Diuretics

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.90,91 Monitor for signs of diminished diuresis and/or effects on blood pressure; increase the dosage of diuretics as needed.90,91

Anticholinergic Drugs

Concomitant use of sufentanil with anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.90,91 Monitor for signs of urinary retention and reduced gastric motility.90,91

Nitrous Oxide

Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of sufentanil citrate injection.90 Monitor for signs of cardiovascular depression that are greater than otherwise expected.90

BetaBeta-Adrenergic Blocking Agents

Bradycardia and hypotension have been reported with other muscle relaxants during sufentanil-oxygen anesthesia; this effect may be more pronounced in the presence of beta-adrenergic blocking agents.90

Calcium Channel Blocking Agents

Bradycardia and hypotension have been reported with other muscle relaxants during sufentanil-oxygen anesthesia; this effect may be more pronounced in the presence of calcium channel blockers.90

Description

Sufentanil citrate is an opioid agonist with high affinity and selectivity for the µ-opiate receptor in the CNS; the drug reportedly is more selective and binds more tightly to this receptor than fentanyl. 4,29 Partial occupancy of the µ-receptor by naloxone (an opiate antagonist) has been shown to substantially decrease the analgesic effect of sufentanil.49

Sufentanil produces dose-related analgesia;4 at doses up to 8 mcg/kg, the drug has a potent analgesic effect. Higher doses usually produce substantial CNS depression resulting in hypnosis and anesthesia;4,9,10,11,12,13,19 however, hypnosis may occur at doses of 1.5 mcg/kg.4 The analgesic potency of sufentanil appears to be 5-12 times that of fentanyl on a weight basis.12,23,39,40,47,48,50 Sufentanil doses of 8 mcg/kg or greater result in EEG patterns indicative of a deep level of anesthesia; 44 the drug induces a shift to the left in EEG amplitude and frequency that is consistent with central anesthetic activity.43

Following IV administration, sufentanil has a more rapid onset of action than does morphine or fentanyl. 4,15,16,27 The onset of action of sufentanil as determined by time to unconsciousness (i.e., loss of response to voice command) reportedly ranges from 1.2-3 minutes following total mean doses of 4.9-30 mcg/kg.4,10,13,15,16,18 The mean duration of anesthesia is reportedly 40 minutes following initial doses of 0.4 mcg/kg of sufentanil; the mean duration of anesthesia of additional doses of 0.1 mcg/kg of sufentanil is reportedly 41-44 minutes.20

Following a single sublingual administration, sufentanil has a bioavailability of approximately 53% relative to a 1-minute IV sufentanil infusion of 30 mcg.91 Compared to IV administration, sublingual maximum concentration values were 17-fold lower.91 The sublingual route of administration of sufentanil avoids intestinal and hepatic first-pass effects.91 Following a single dose of sufentanil sublingual tablets, maximum concentrations occur at a median time of 1 hour.91 After 12 multiple hourly doses over 11 hours, the geometric mean for the AUC within a dosing interval (AUC_0-60min) and maximum concentration values were increased by 3.7-fold and 2.3-fold greater compared to single-dose administration, respectively.91 Steady-state plasma concentrations were achieved after 7 doses.91

Distribution of sufentanil injection into human body tissues and fluids has not been fully characterized;14 however, the drug is highly lipophilic and is rapidly and extensively distributed in animals.4 The drug is approximately 93% bound in plasma in healthy males, 4,6,14 mainly to albumin; α-, α₁-, β-, and γ-globulins; and α₁-acid glycoprotein.6,14 Plasma concentrations of sufentanil decline rapidly secondary to redistribution and appear to decline in a triphasic manner. 4,5,14,22 In adults with normal renal and hepatic function, the plasma half-life of sufentanil citrate injection in the initial (distribution) phase averages 0.72-1.2 minutes, the plasma half-life in the second (redistribution) phase averages 13.7-17 minutes, and the plasma half-life in the terminal (elimination) phase averages 140-158 minutes. 4,5,14,22,23 The elimination half-life is longer (434 minutes) in neonates but shorter in infants and children (97 minutes), compared with adults (164 minutes).89 90 Following a single dose of sufentanil sublingual tablets, the mean terminal half-lfe is 13.4 hours.91 The clearance of sufentanil in healthy neonates is approximately one-half that reported in adults and children, and the clearance may be further reduced by up to one-third in neonates with cardiovascular disease.89

The major sites of biotransformation of sufentanil are the liver and small intestine via N -dealkylation at the piperidine nitrogen and O -demethylation.4 The O -demethylated metabolite appears to have about 10% of the analgesic activity of the unchanged drug.4 Sufentanil and its metabolites are excreted principally in urine and also in feces via biliary elimination; approximately 80% of the administered dose is excreted in urine and feces within 24 hours after administration. 90 Only 2% of the dose is excreted unchanged in urine and feces.90

Advice to Patients

• Inform patients that accidental exposure to sufentanil sublingual tablets, especially by children, may result in respiratory depression or death.91
• Inform patients of the risk of life-threatening respiratory depression, including that the risk is greatest when starting sufentanil sublingual tablets.91
• Inform patients that the use of sufentanil sublingual tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death.91 Instruct patients not to share sufentanil sublingual tablets with others and to take steps to guard against theft or misuse.91
• Inform patients of the risk for and symptoms of serotonin syndrome.91 Advise patients to seek immediate medical attention if symptoms develop, and to inform their physicians if they are taking, or plan to take serotonergic medications.91
• Inform patients that opioids could cause adrenal insufficiency.91 Advise patients to seek medical attention if they experience signs or symptoms of adrenal insufficiency, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.91
• Advise patients to allow sufentanil sublingual tablets to dissolve under the tongue and not to chew or swallow the tablet.91 Advise patients not to eat or drink and to minimize talking for 10 minutes after each sublingual dose.91
• Inform patients that sufentanil sublingual tablets may cause orthostatic hypotension and syncope.91 Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).91
• Inform patients that anaphylaxis has been reported with ingredients contained in sufentanil sublingual tablets.91 Advise patients how to recognize such a reaction and when to seek medical attention.91
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.91 Inform female patients of reproductive potential that sufentanil sublingual tablets can (or may) cause fetal harm and to inform the prescriber of a known or suspected pregnancy.91
• Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.91
• Advise nursing mothers to monitor infants for increased sleepiness (more than usual), breathing difficulties, or limpness.91 Instruct nursing mothers to seek immediate medical care if they notice these signs.91
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
• Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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