Description
Sufentanil is a Schedule II controlled synthetic opioid analgesic that has been marketed for intravenous (IV) and epidural anesthesia and analgesia. Sufentanil is 5 to 10 times more potent than its analogue, fentanyl, and 1,000 times more potent than morphine (Brooks, 2018). In efforts to offer acute pain management for persons unable to take anything by mouth and who have difficulty achieving IV access, sufentanil sublingual tablet was developed. The sufentanil pharmacokinetic profile when delivered sublingually avoids the high peak plasma levels and short duration of action observed with IV administration (AcelRx, 2018a). The high lipophilicity of sufentanil allows it to be administered subligually and achieve a rapid onset of analgesic effect (NICE, 2016).

Policy
Sufentanil (Dsuvia) sublingual tablet is considered NOT MEDICALLY NECESSARY for the treatment of acute pain severe enough to require an opioid analgesic because the safety for this indication has not been established.

Sufentanil (Dsuvia) sublingual tablet is considered INVESTIGATIONAL for all other indications because the safety and effectiveness have not been established in the peer-reviewed published medical literature.

Rationale
The National Institute for Health and Care Excellence (NICE) has not published guidance on managing acute post‑operative pain. Sufentanil was not considered appropriate for a NICE technology appraisal and is not currently planned in any other work program (NICE, 2016).

The NICE website includes an evidence summary that reviewed two placebo-controlled, phase III, randomized clinical trials (RCT) on the safety and efficacy of sufentanil and management of post-operative pain (Jove et al. 2015 following knee or hip arthroplasty, and Ringold et al. 2015 following open abdominal surgery) and 1 randomized phase III study with an active control (IV morphine PCA, Melson et al. 2014). The Jove et al. 2015 and Ringold et al. 2015 studies found that sufentanil was statistically significantly better at reducing pain intensity over 48 hours following elective major surgery compared with placebo. Treatment differences for pain intensity scores at 48 hours were 87.6 (p<0.001) following knee and hip replacement (Jove et al. 2015) and 50.0 (p=0.001) after open abdominal surgery (Ringold et al. 2015). However, these outcomes were difficult to interpret and the clinical importance of these findings was unclear. These 2 RCTs show that participant withdrawals due to inadequate analgesia were statistically significantly less frequent in the sufentanil group compared with placebo (14.3% compared with 48.1% of people following hip or knee replacement, p<0.001 and 17.4% compared with 31.6% after open abdominal surgery, p=0.035, for sufentanil and placebo respectively). The studies only included people in relatively good health who were undergoing elective major open abdominal and hip and knee replacement, limiting generalizability to other populations or types of surgery. People on chronic opioid therapy were excluded from both RCTs (NICE, 2016).

Melson et al. (2014) is a randomized, open-label, Phase III, non-inferiority trial that compared sufentanil with IV morphine PCA for the management of acute post‑operative pain. The treatment difference for the proportion of participants reporting successful pain control achieved the pre‑defined criteria for non‑inferiority of the sufentanil sublingual tablet system compared with morphine at 48 hours (p < 0.001, the primary outcome). Sufentanil was also found to be statistically significantly superior to morphine for pain control at 48 hours (p = 0.007). Health care professionals also reported statistically significantly more successful pain control with sufentanil compared with morphine (p ≤ 0.012 at all time points). However, the clinical importance of the difference between the 2 treatments for the primary endpoint was difficult to interpret. The European public assessment report (EPAR) noted that the strength of the endpoint is uncertain because of the subjective nature of the patient assessment, the open‑label setting and limitations around the non‑inferiority design. For secondary endpoints, there was no statistically significant difference between sufentanil and morphine for pain intensity (p = 0.569) or pain relief (p = 0.055) over 48 hours. Participant withdrawals due to inadequate analgesia were less frequent in the sufentanil group compared with the morphine group (no analysis reported). The investigators reported that, although participants in the sufentanil group used more supplemental morphine than those in the IV morphine PCA group (p < 0.001), the difference of 1.6 mg over 48 hours was not clinically meaningful. People on chronic opioid therapy were also excluded from this RCT (NICE, 2016).

“The EPAR reports that, because the primary endpoint was difficult to interpret, the [Committee for Medicinal Products for Human Use] CHMP requested further responder analyses to be performed to determine the clinical relevance of the achieved effect in pain reduction with sufentanil sublingual tablet system from the results of the 3 studies. These post‑hoc analyses for Ringold et al. 2015 and Jove et al. 2015 showed that a clinically important 50% pain reduction was achieved in 37% and 31% of sufentanil participants in these trials compared with 17.5% and 9.6% of placebo participants. The responder analysis for Melson et al. 2014, comparing sufentanil and morphine, determined there was a similar clinically important pain reduction in both treatment groups (30% and 32% of participants, respectively). The CHMP concluded that the 3 phase III studies provide sufficient evidence of the efficacy of sufentanil sublingual tablets in acute post‑operative pain” (NICE, 2016).

On Nov. 2, 2018, AcelRx Pharmaceuticals, Inc., announced the U.S. Food and Drug Administration (FDA) approval of Dsuvia, a single-strength solid dosage form of sufentanil administered sublingually via a single-dose applicator, for the management of acute pain in adults that is severe enough to require an opioid analgesic in a certified medically supervised health care setting, such as hospitals, surgical centers, and emergency departments.

Because of the potential for life-threatening respiratory depression due to accidental exposure, Dsuvia (sufentanil) is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) program and is only to be administered by a health care professional in a certified medically supervised setting. In addition, Dsuvia must be discontinued prior to the patient leaving the certified medically supervised setting. As with all opioid usage, individuals require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use (FDA, 2018).

In July 2018, the European Medicines Agency approved sufentanil under the brand name Dzuveo. According to the FDA, Dzuveo and Dsuvia entail a feature that allows the drug to be delivered in a stable form, making it a viable option suited for certain special circumstances where patients may not be able to swallow oral medication, and where access to IV pain relief is not possible, such as soldiers on the battlefield. For that reason, the Department of Defense collaborated with the sponsor on the development of this non-invasive opioid analgesic option that could provide rapid pain relief for soldiers (FDA, 2018).

FDA approval of Dsuvia was based on results from one phase-3, prospective, randomized, double-blind, placebo-controlled trial (SAP301, NCT 02356588) evaluating the efficacy and safety of sufentanil subligual 30 mcg tablet (SST) for the management of pain after ambulatory abdominal surgery.

Minkowitz and colleagues (2017) state that SST has been shown to be an effective opioid analgesic in postoperative pain management following abdominal surgery. A total of 161 patients (ages 18 to 69 years) scheduled to undergo abdominoplasty, open tension-free inguinal hernioplasty, or laparoscopic abdominal surgery under general or spinal anesthesia that did not include intrathecal opioids during the operation were randomized to SST (n = 107) or placebo (n = 54). Patients were dosed with SST 30 mcg or placebo as needed with a minimum of 60 minutes between doses. The primary endpoint was the time-weighted summed pain intensity difference to baseline (SPID) over 12 hours. Secondary endpoints included SPID over 24 and 48 hours, total pain relief, and patient and health care professional (HCP) global assessments. Pain scores were recorded for up to 48 hours. SPID 12 was higher (greater pain intensity reduction from baseline) in the SST group compared with placebo (p < 0.001). In the SST group, a greater proportion of patients and HCPs responded "good" or "excellent" on the global assessments compared with placebo (p < 0.001 for both). Approximately 22% of patients in the Dsuvia group and 65% of patients in the placebo group took rescue medication (morphine sulfate 1 mg IV) within the first 12 hours of the treatment phase. There was a numerically, but not statistically, higher incidence of nausea and headache in the SST group. The investigators found that Dsuvia (sufentanil) sublingual tablet demonstrated a statistically greater summed pain intensity difference from baseline over the first 12 hours of the study compared to placebo. In addition, the pain intensity difference from baseline was superior to that of the placebo group within 15 minutes and median meaningful pain relief occurred following a single dose. Thus, they concluded that not only was SST an effective opioid analgesic postoperatively, but SST was also well tolerated with mild-to-moderate side effects, similar to those found in placebo-treated patients.

The study had several limitations that required careful interpretation of results. The study was meant to reflect the typical surgical population; however, patient enrollment was not limited by age and the elderly were under-represented (1.2 percent of patients were older than 65 years). The primary endpoint included a 12-hour evaluation period, as ambulatory care surgery typically results in same-day discharge; thus, this study cannot fully interpret the longer-term effects of SST in this population. Nonetheless, the majority of patients were followed for 24 hours. In addition, the sample size was limited, which may also affect the generalizability of the results.  Futhermore, all patients, including those in the SST group, were permitted to receive IV opioids in the operating room as well as IV morphine for rescue analgesia. However, according to Mindowitz and colleagues, SST demonstrated superior pain relief compared with placebo despite this potential confound (Minkowitz et al., 2017). 

The Prescribing Information for Dsuvia includes a recommended dosage of 30 mcg sublingually. Dsuvia (sufentanil) is available in a disposable, single-dose applicator (SDA), as needed, with a minimum of 1 hour between doses, not to exceed 12 tablets in 24 hours, with maximum cummulative daily dose of 360 mcg or 12 tablets (12 tablets x 30 mcg/dose).

It is recommended that the individual not eat or drink and minimize talking for 10 minutes after receiving the tablet.

Limitations of use per Prescribing Information (AcelRx, 2018b):

• Not for home use or for use in children. Discontinue treatment with Dsuvia before individual leaves the certified medically supervised health care setting.

• Not for use for more than 72 hours. The use of Dsuvia beyond 72 hours has not been studied.

• Only to be administered by a health care provider.

• Because of the risks of addiction, abuse, and misuse of opioids, even at recommended doses, Dsuvia is reserved for use in persons for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

  • Have not been tolerated, or are not expected to be tolerated,

  • Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

The most commonly reported adverse reactions (2% or greater) were nausea, headache, vomiting, dizziness and hypotension.

Contraindications include significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, and known hypersensitivity to sufentanil or components of Dsuvia (AcelRx, 2018b).

Warnings and precautions include life-threatening respiratory depression in those with chronic pulmonary disease or in elderly, cachectic, or debilitated persons; serotonin syndrome; adrenal insufficiency; severe hypotension; risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness (AcelRx, 2018b).

Specialists consulted during the development of the evidence summary noted on the NICE website advised that anyone having major surgery sufficient to need strong opioid analgesia will probably have an IV infusion in situ. In addition, the recommendation for the patient not to eat or drink and to minimize talking for 10 minutes post‑sufentanil dose may be inconvenient, particularly after the first 24 hours post‑surgery. Furthermore, the marketing authorization for sufentanil sublingual tablet system is limited to the management of post‑operative pain for up to 72 hours; therefore, analgesia may potentially have to be altered in patients who need treatment for longer than this (NICE, 2016).

References

1. AcelRx Pharmaceuticals, Inc. AcelRx announces FDA approval of Dsuvia. News Release. Redwood City, CA: AcelRx; November 2, 2018a.

2. AcelRx Pharmaceuticals, Inc. Dsuvia (sufentanil) sublingual tablet, CII. Reference ID: 4344831. Redwood City, CA: AcelRx; 2018b. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209128s000lbl.pdf. Accessed November 12, 2018.

3. Brooks M. FDA goes ahead with approval of sufentanil despite controversy. Medscape. New York, NY: Medscape; November 2, 2018. Available at: https://www.medscape.com/viewarticle/904330. Accessed November 15, 2018. 

4. Minkowitz HS, Leiman D, Melson T, et al. Sufentanil sublingual tablet 30 mcg for the management of pain following abdominal surgery: A randomized, placebo-controlled, phase-3 study. Pain Pract. 2017;17(7):848-858.

5. U.S. Food and Drug Administration (FDA). Statement from FDA commissioner Scott Gottlieb, M.D., on agency’s approval of Dsuvia and the FDA’s future consideration of new opioids. FDA Statement. Silver Spring, MD: FDA; November 2, 2018.

6. National Institute for Health and Care Excellence (NICE). Moderate to severe acute post-operative pain: Sufentanil sublingual tablet system. London, England. March 2016. Available at: https://www.nice.org.uk/advice/esnm71/chapter/full-evidence-summary. Accessed December 11, 2018.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2019 Forward