Formulary Drug Review: Sufentanil Sublingual

Abstract

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Generic Name: SUFENTANIL CITRATE SUBLINGUAL TABLETS

Proprietary Name: Dsuvia (AcelRx Pharmaceuticals)

Approval Rating: 3S

Therapeutic Class: Opioid Analgesics

Similar Drugs: Sufentanil Injection

Sound-/Look-Alike Names: Alfentanil, Fentanyl, Sufenta

Indications

Sufentanil sublingual tablets are approved for use in adults in a certified medically supervised health care setting (eg, hospitals, surgical centers, emergency departments) for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.^1,2

The Food and Drug Administration (FDA) approval includes the following limitations of use¹:

• Not for home use or for use in children. Discontinue treatment with sufentanil sublingual tablets before patients leave the certified medically supervised health care setting.

• Not for use for more than 72 hours.

• Only to be administered by a health care provider.

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

Sufentanil sublingual tablet has been used or is being evaluated for the treatment of postoperative pain associated with various surgical procedures (eg, bunionectomy; knee or hip arthroplasty; abdominal, back, urogenital, or vertebral surgery), moderate to severe acute pain in the emergency department, and cancer-related pain. The restrictions placed on the distribution and use of sufentanil sublingual tablets may limit some of these uses.^3-8

Because of its advantage in patients unable to swallow oral medication or in cases in which access to intravenous (IV) pain relief is not possible (eg, on the battlefield), the Department of Defense worked closely with the sponsor on development of sufentanil sublingual. The Pentagon considers this type of agent a priority medical product because it helps fulfill an unmet need in treating wounded soldiers on the battlefield.⁹

Clinical Pharmacology

Sufentanil is an opioid agonist that is relatively selective for the mu-opioid receptor but can bind to various opioid receptors at higher doses.^1,10

Stimulation of opioid-specific receptors is thought to be the mechanism of action for sufentanil’s analgesic and sedative properties. As with all full opioid agonists, there is no “ceiling effect” for analgesia.¹

Sufentanil’s other pharmacodynamic effects include dose-dependent respiratory depression through direct action on brain stem respiratory centers; miosis, even in total darkness; reduced gastrointestinal tract (GI) motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum; decreased propulsive peristaltic waves in the colon; possibility for spasms in the colon leading to constipation; reduction in biliary and pancreatic secretions; spasm of sphincter of Oddi; transient elevations in serum amylase; peripheral vasodilation that may result in orthostatic hypotension or syncope; histamine release; inhibition of adrenocorticotropic hormone, cortisol, and luteinizing hormone secretion; stimulation of prolactin, growth hormone secretion, and pancreatic secretion of insulin and glucagon; and possible immunosuppression.¹

Pharmacokinetics

Systemic bioavailability after a single dose of sublingual sufentanil is 53% of a 1-minute IV sufentanil 30 µg infusion; time to peak plasma concentration is 1 hour. Peak plasma concentrations with sublingual administration are 17-fold lower than with IV administration.^1,11,12 If any of the sublingual tablet form is swallowed, oral bioavailability of that portion is 9%. After hourly administration over 11 hours, geometric mean area under the curve is increased by 3.7-fold and peak plasma concentration is increased by 2.3-fold compared with single-dose administration. Steady-state plasma concentrations are achieved after 7 doses.¹

Plasma protein binding in adults is greater than 90%. Following a single sublingual dose, mean terminal half-life is 13.4 hours and apparent plasma clearance is 108 L/h. The majority of sufentanil is metabolized in the liver and small intestine by the CYP3A4 enzyme system to inactive metabolites; approximately 80% of the IV administered drug is excreted within 24 hours and 2% of the dose is eliminated as unchanged drug.^1,10,12

Sufentanil is metabolized in the liver and its clearance may be decreased in patients with hepatic impairment. Sufentanil and its metabolites are excreted by the kidney and elimination may be altered in patients with severe renal impairment. Clearance is not affected by race, gender, or mild or moderate renal impairment.¹

Comparative Efficacy

Indication: Moderate to Severe Acute Pain

Studies

• Drug: Sufentanil Sublingual vs Placebo

• Reference: Minkowitz HS, et al, 2017 (SAP301 trial)^1,13

• Study Design: Randomized, double-blind, placebo-controlled, multicenter, phase 3 study

• Study Funding: AcelRx Pharmaceuticals

• Patients: 161 patients (18-69 years of age) classified as American Society of Anesthesiologists physical class 1 to 3 who were scheduled to undergo abdominoplasty, open tension-free inguinal hernioplasty (Lichtenstein repair with mesh), or laparoscopic abdominal surgery (under general or spinal anesthesia that did not include intrathecal opioids during the operation). Patients were required to have acute postoperative pain (pain intensity score of 4 or higher on an 11-point numeric rating scale [NRS] where 0 = no pain and 10 = worst possible pain) following abdominal surgery (studied up to 48 hours). Patients were excluded if they had taken an opioid at a daily dose of greater than 15 mg of oral morphine (or equivalent) for more than 30 consecutive days within the 3 months prior to surgery. Mean age was 40.9 years; 1.2% were 65 years or older; 67.7% were women; 70.2% were white, 19.3% were black or African American, and 37.9% were Hispanic or Latino; and 49.7% underwent abdominoplasty, 20.5% underwent hernioplasty, and 29.8% underwent abdominal laparoscopy.

• Intervention: Patients were randomized 2:1 to pain control with sufentanil 30 µg sublingual tablets (n = 107) or identical placebo (n = 54). Additional doses of the study medication could be given, with a minimum 60-minute redosing interval. If requested, rescue analgesia for postoperative pain (morphine 1 mg IV) was allowed hourly. Acetaminophen could be used to treat a headache.

• Results:

• Primary End Point(s):

  • Time-weighted summed pain intensity difference (SPID) over 12 hours was higher (greater reduction in pain intensity from baseline) in the sufentanil sublingual group compared with the placebo group (25.84 vs 13.14; treatment difference, 12.7; 95% confidence interval [CI], 7.16-18.23; P < .001).
• Secondary End Point(s):

  • Mean SPID over 1 hour was 1.09 with sufentanil sublingual compared to −0.37 with placebo (treatment difference, 1.46; 95% CI, 0.97-1.95; P < .001); mean SPID over 24 hours was 57.96 and 37.28, respectively (treatment difference, 20.68; 95% CI, 9.51-31.85; P < .001).
  • Time-weighted total pain relief (TOTPAR) over 12 hours was 21.18 with sufentanil sublingual compared to 15.36 with placebo (treatment difference, 5.83; 95% CI, 3.03-8.63; P < .001); mean TOTPAR over 24 hours was 45.8 and 35.45, respectively (treatment difference, 10.36; 95% CI, 4.5-16.22; P = .001).
  • Summed pain relief intensity difference (SPRID) score over 12 hours was 47.03 with sufentanil compared to 28.62 with placebo (treatment difference, 18.41; 95% CI, 10.79-26.02; P < .001); SPRID over 24 hours was 103.88 and 73.05, respectively (treatment difference, 30.83; 95% CI, 15.24-46.42; P < .001).
  • Proportion of patients and health care providers who responded “good” or “excellent” on the global assessments was greater with sufentanil sublingual compared with placebo.
  • Decrease in pain intensity from baseline was greater with sufentanil sublingual compared with placebo at the first evaluation time point (15 minutes; P = .002) and was numerically better at all other time points, but was not statistically different at 3 time points (4, 20, and 22 hours).
  • Number of patients who required use of rescue morphine due to inadequate analgesia was higher in the placebo group than the sufentanil sublingual group (64.8% vs 27.1%; P < .001). Mean cumulative number of rescue morphine doses during the 24-hour study period was also higher in the placebo group compared with the sufentanil sublingual group (2.1 vs 0.5; P < .001).

• Comments: Efficacy was assessed using patient reports of pain intensity and pain relief; pain intensity was rated on the 11-point NRS and pain relief was rated on a 5-point scale (0 = no relief; 1 = a little relief; 2 = moderate relief; 3 = a lot of relief; 4 = complete relief). This study was conducted in 4 hospitals in the United States. There was no restriction on type of surgical anesthesia or analgesia allowed, except for long-acting regional anesthesia. Treatment groups were stratified by gender. Subgroup analyses of SPID over 12 hours showed scores were higher with sufentanil sublingual than placebo in all subgroups (ie, age, gender, race, body mass index [BMI], type of surgery); however, the number of patients in each subgroup was relatively small. This study is the only pivotal trial described in the prescribing information. In 2 randomized, placebo-controlled studies, a 15 µg dose of sufentanil sublingual tablets was also effective for management of postoperative pain.^14,15

• Limitations: The number of patients was limited and there was no active-comparator group.

Contraindications, Warnings, and Precautions

Contraindications

Sufentanil is contraindicated in patients with significant respiratory depression; patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; patients with known or suspected GI obstruction, including paralytic ileus; and patients with hypersensitivity to sufentanil or any component of the formulation (ie, mannitol, dicalcium phosphate anhydrous, hypromellose, croscarmellose sodium, FD&C blue No. 2, stearic acid, magnesium stearate).¹

Warnings and Precautions

The product labeling includes a boxed warning regarding the Dsuvia Risk Evaluation and Mitigation Strategy (REMS) program as well as risk of accidental exposure; life-threatening respiratory depression; addiction, abuse, and misuse; concomitant use with CYP3A4 inhibitors or discontinuation of CYP3A4 inducers; and concomitant use with benzodiazepines or other central nervous system (CNS) depressants.¹

Sufentanil sublingual is only for use in adults in a certified medically supervised health care setting. Use outside this type of setting can increase the risk of accidental exposure in others for whom it is not prescribed. The product must be discontinued prior to discharge or transfer from the certified medically supervised health care setting. The product labeling states it is not for home or pediatric use.¹

Accidental ingestion or exposure to even 1 dose of sufentanil sublingual can result in respiratory depression and death due to an overdose. Patients should be monitored closely for opioid-related respiratory depression. Serious, life-threatening, or fatal respiratory depression can occur at any time during the use of sufentanil sublingual, but risk is greatest during initiation of therapy. Monitor patients closely for respiratory depression during treatment with sufentanil sublingual.¹

Addiction, abuse, and misuse are possible with sufentanil; it is classified as a Schedule II controlled substance. Risk of opioid addiction, abuse, or misuse should be assessed prior to prescribing sufentanil sublingual or any other opioid.¹

Concomitant use with a CYP3A4 inhibitor may increase plasma concentrations of sufentanil and prolong opioid adverse reactions, especially if the inhibitor is added after a stable dose of sufentanil is achieved. Discontinuation of a CYP3A4 inducer may also increase sufentanil plasma concentrations and prolong opioid adverse reactions. Similarly, concomitant use with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease sufentanil plasma concentrations, decrease opioid efficacy, or possibly lead to a withdrawal syndrome in a patient who had developed physical dependence to sufentanil.¹

Concomitant use of sufentanil with benzodiazepines or other CNS depressants (eg, nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) can cause profound sedation, respiratory depression, coma, and death. Concomitant use should be avoided when possible.¹

Patients with chronic pulmonary disease and elderly, cachectic, or debilitated patients may experience life-threatening respiratory depression during treatment with sufentanil sublingual. Use of sufentanil sublingual in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients with substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at the recommended dosage of sufentanil sublingual.¹

Serotonin syndrome has been reported during concomitant use of sufentanil with serotonergic drugs. Sufentanil should be used with caution with serotonergic drugs (eg, selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants [TCAs], triptans, 5-HT₃ receptor antagonists, drugs that affect the serotonergic neurotransmitter system [eg, mirtazapine, trazodone, tramadol], drugs that impair metabolism of serotonin [eg, including monoamine oxidase inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and IV methylene blue]).¹

Cases of adrenal insufficiency have been reported with opioid use, more often after a month or more of use.¹

Severe hypotension, including orthostatic hypotension and syncope in ambulatory patients, may occur with sufentanil therapy. Risk of hypotension is increased in patients with reduced blood volume or with coadministration of certain CNS depressants (eg, phenothiazines, general anesthetics). Sufentanil also may cause vasodilation that can further reduce cardiac output and blood pressure; therefore, use should be avoided in patients with circulatory shock.¹

In patients who may be susceptible to the intracranial effects of CO₂ retention (eg, those with evidence of increased intracranial pressure or brain tumors), use of sufentanil may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure.¹

Use of opioids in a patient with a head injury may obscure the clinical course; therefore, sufentanil should be avoided in patients with impaired consciousness or coma. Sufentanil is not suitable for use in patients who are not alert and able to follow directions.¹

Sufentanil can cause spasm of the sphincter of Oddi; opioids may cause increases in serum amylase. Patients with biliary tract disease, including acute pancreatitis, may experience worsening of symptoms. Sufentanil is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.¹

Sufentanil may increase frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.¹

Bradycardia may occur with the use of sufentanil.¹

Prolonged use of opioids, including sufentanil, during pregnancy can cause neonatal withdrawal syndrome in the newborn that may be life-threatening if not recognized and treated according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure appropriate treatment will be available.¹

According to the manufacturer, the decision to continue or discontinue breastfeeding should consider the risk of infant exposure, benefits of breastfeeding to the infant, and benefits of treatment to the mother. Infants exposed to sufentanil through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms may occur in breastfed infants when maternal opioid therapy is stopped or when breastfeeding is stopped.¹

Safety and efficacy of sufentanil sublingual have not been established in pediatric patients. Use of sufentanil sublingual is not recommended in children because they may not be able to comply with the sublingual dosing instructions and could swallow the tablet or spit it out, which could impact efficacy and safety.¹

Adverse Reactions

Safety of sufentanil sublingual tablets was evaluated in 646 patients with moderate to severe acute postoperative pain or pain due to trauma that required opioid analgesia. In the pivotal, placebo-controlled trial, the most commonly reported (2% or greater) adverse reactions probably or possibly related to sufentanil sublingual were nausea, headache, vomiting, dizziness, and hypotension (see Table 1).¹

Table 1.

Adverse Reactions Occurring in ≥2% of Patients Treated With Sufentanil Sublingual and More Frequently Than in Patients Treated With Placebo in SAP301 Trial.¹

Adverse reactions	Sufentanil sublingual (n = 107)	Placeboa (n = 54)
Nausea	29%	22.2%
Headache	12.1%	11.1%
Vomiting	5.6%	1.9%
Dizziness	5.6%	3.7%
Hypotension	4.7%	3.7%

^aMorphine 1 mg intravenous was permitted as a rescue medication.

Other adverse reactions associated with the use of sufentanil sublingual and occurring in at least 0.1% of patients included sinus tachycardia, bradycardia, constipation, dyspepsia, flatulence, diarrhea, dry mouth, eructation, retching, abdominal discomfort, abdominal distension, upper abdominal pain, gastritis, postoperative ileus, oral hypoesthesia, decreased oxygen saturation, decreased respiratory rate, decreased urine output, increased aspartate aminotransferase (AST), abnormal electrocardiogram, increased hepatic enzyme, muscle spasms, somnolence, sedation, presyncope, lethargy, memory impairment, insomnia, confusional state, anxiety, agitation, disorientation, euphoric mood, hallucination, mental status changes, urinary retention, urinary hesitation, oliguria, renal failure, hypoxia, bradypnea, hiccups, apnea, atelectasis, hypoventilation, respiratory distress, respiratory failure, pruritus, hyperhidrosis, rash, hypotension, hypertension, orthostatic hypotension, and flushing.¹

Discontinuation due to adverse events occurred in 0.9% (1 of 107) of sufentanil sublingual–treated patients and 3.7% (2 of 54) of placebo-treated patients in the pivotal trial. The most common reasons for discontinuation were decreased oxygen saturation in the sufentanil group (0.9%) and dizziness, hemiparesis, somnolence, and syncope in the placebo group (1.9% each).¹

Drug Interactions

Potential drug interactions associated with sufentanil as well as clinical impact and recommended interventions are summarized in Table 2.¹

Table 2.

Clinically Significant Drug Interactions With Sufentanil.¹

	Clinical impact	Intervention
CYP3A4 inhibitors (eg, macrolide antibiotics [eg, erythromycin], azole antifungal agents [eg, ketoconazole], protease inhibitors [eg, ritonavir])	Concomitant use can increase sufentanil plasma concentration, resulting in increased or prolonged opioid effects. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.	If concomitant use is necessary, consider an alternative medication that permits dose titration. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the sufentanil sublingual dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin)	Concomitant use can decrease sufentanil plasma concentration, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.	If concomitant use is necessary, consider an alternative medication that permits dose titration. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider sufentanil sublingual dosage reduction and monitor for signs of respiratory depression.
Benzodiazepines and other CNS depressants (eg, alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids)	Due to additive pharmacologic effect, concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.	Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.
Serotonergic drugs (eg, SSRIs, SNRIs, TCAs, triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system [eg, mirtazapine, trazodone, tramadol], MAOIs [those intended to treat psychiatric disorders and others, such as linezolid and IV methylene blue])	Concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue sufentanil sublingual if serotonin syndrome is suspected.
MAOIs (eg, phenelzine, tranylcypromine, linezolid)	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (eg, respiratory depression, coma).	Use of sufentanil sublingual is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed agonist/antagonist and partial agonist opioid analgesics (eg, butorphanol, nalbuphine, pentazocine, buprenorphine)	May reduce the analgesic effect of sufentanil sublingual and/or precipitate withdrawal symptoms.	Avoid concomitant use.
Muscle relaxants	Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the muscle relaxant dosage as necessary, or consider discontinuing use of sufentanil sublingual.
Diuretics	Opioids can reduce the efficacy of diuretics by inducing release of antidiuretic hormone.	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the diuretic dosage as needed.
Anticholinergic drugs	Concomitant use may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.	Monitor patients for signs of urinary retention or reduced gastric motility when sufentanil sublingual is used concomitantly with anticholinergic drugs.

Note. CNS = central nervous system; SSRIs = selective serotonin reuptake inhibitors; SNRIs = serotonin-norepinephrine reuptake inhibitors; TCAs = tricyclic antidepressants; MAOI = monoamine oxidase inhibitor; IV = intravenous.

Recommended Monitoring

Monitor respiratory function closely and at frequent intervals; monitor heart rate and blood pressure, and for adequate analgesia, potential opioid-related adverse reactions, and symptoms of opioid withdrawal.¹

Dosing

The recommended dosage is sufentanil 30 µg sublingually as needed, with a minimum of 1 hour between doses. The maximum cumulative daily dose is 360 µg (12 tablets); do not use for more than 72 hours.¹

Sufentanil sublingual is only for administration by a health care provider; it is only to be used in a certified medically supervised health care setting (eg, hospitals, surgical centers, emergency departments) and must be discontinued prior to the patient leaving the certified medically supervised setting.¹

Gloves should be worn when administering the sublingual formulation. If the patient experiences excessive dry mouth, ice chips should be provided prior to administration of the sublingual tablet. After placement of the sublingual tablet under the tongue, the patient should not eat or drink and should minimize talking for 10 minutes. The used single-dose applicator should be discarded in a biohazard waste container.¹

The prescribing information does not provide dosing recommendations for hepatic or renal impairment.¹

Each dose is supplied in a single-dose applicator and should not be reused. If the single-dose applicator is damaged, the product should not be used. Sufentanil sublingual tablets should not be chewed or swallowed.¹

Product Availability

Sufentanil sublingual was approved on November 2, 2018.^1,2

Sufentanil sublingual is supplied as tablets containing sufentanil citrate 30 µg. Each tablet is housed in a disposable single-dose applicator packaged within a tamper-evident laminate foil pouch. The tablet is an immediate-release formulation for sublingual administration only.¹

Unopened pouches should be stored at room temperature (20ºC-25ºC [68ºF-77ºF]), with excursions permitted to 15ºC to 30ºC (59ºF-86ºF), in a secure, limited-access location in accordance with institutional procedures for Schedule II controlled products. Once opened, the product should be used immediately.¹

Drug Safety/REMS

The Dsuvia REMS Program requires that sufentanil sublingual be dispensed only to patients in a certified medically supervised health care setting in order to mitigate the risk of respiratory depression resulting from accidental exposure. Health care settings that dispense sufentanil sublingual tablets must be able to manage an acute opioid overdose, including respiratory depression; train all relevant staff that sufentanil sublingual tablets must not be dispensed for use outside the certified health care setting; train all relevant staff involved in administration of sufentanil sublingual tablets to refer to the Directions of Use prior to administration; and establish processes and procedures to verify that sufentanil sublingual tablets are not dispensed for use outside the certified health care setting. Wholesalers that distribute sufentanil sublingual tablets must establish processes and procedures to ensure that sufentanil sublingual tablets are distributed only to certified medically supervised health care settings and distribute only to certified medically supervised health care settings.^1,2

Conclusion

Sufentanil sublingual tablets are approved for use in adults in a certified medically supervised health care setting (eg, hospitals, surgical centers, emergency departments) for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Sufentanil sublingual tablets offer a short-term alternative delivery system for a potent analgesic in restricted health care settings. The sublingual formulation is an option in patients unable to swallow oral medication or in cases in which access to IV pain relief is not possible. Compared with placebo, sufentanil sublingual produced a more rapid onset of analgesia and higher rates of pain control. It is associated with numerous limitations for use, and a REMS program is required to decrease risks of respiratory depression, abuse, or unapproved use. Sufentanil sublingual’s role in approved health care settings needs to be established.