Sufentanil Sublingual Tablet (Dsuvia)

Number: 0944

Policy

Aetna considers sufentanil (Dsuvia) sublingual tablet as 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.

Aetna considers sufentanil (Dsuvia) sublingual tablet experimental and investigational for all other indications because the safety and effectiveness have not been established in the peer-reviewed published medical literature.

Dosing Recommendations

The recommended dosage of Dsuvia (sufentanil) is 30 mcg sublingually.  It 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 individuals not eat or drink and minimize talking for 10 minutes after receiving the tablet.

Source: Prescribing Information. Dsuvia (sufentanil) sublingual tablet, CII. AcelRx Pharmaceuticals, Inc., 2018.

Background

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 1000 times more potent than morphine (Brooks, 2018). In efforts to offer acute pain management for persons unable to take anything by mouth and 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).

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 into any other work program (NICE, 2016).

The NICE website includes an evidence summary which 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 patient-controlled analgesia [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 RCT showed 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 relative good health who underwent 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). Healthcare 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 November 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 healthcare 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 healthcare 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 shown to be an effective opioid analgesic in postoperative pain management following abdominal surgery. A total of 161 patients (age 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 healthcare 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). 

Scardino and co-workers (2018) noted that currently many total knee arthroplasty (TKA) protocols rely on multi-modal analgesic protocols with PCA systems that administer opioids through a patient controlled IV infusion pump, in addition to concomitant peripheral nerve blocks (PNBs) and local anesthetics.  Although effective, PCA IV opioids do not provide optimal results with fast track rehabilitation protocols.  In a retrospective, pilot study, these researchers compared the novel sublingual sufentanil PCA system (SSTS) to their standard of care foreseeing continuous femoral nerve block (cFNB) within a multi-modal analgesic in a TKA fast-track protocol.  The study evaluated 95 patients on SSTS (SSTS group) and 87 on cFNB (cFNB/control group) and collected data on numeric rating scores (NRS) for pain from day 1 to 3 after surgery (T1, T2, T3), both at rest (NRS) and during movement (mNRS), patient's ability to walk, need for supplementary analgesia (rescue dose), occurrence of adverse effects, length of hospital stay (LOS), and usability rating for SSTS by both patients and hospital staff.  NRS at rest was lower in the cFNB than in the SSTS group for all 3 days after surgery, whereas mNRS scores were lower in the SSTS group at all time-points measured.  Adverse effects were significantly fewer among patients of the SSTS group (6 % patients) than those of the cFNB (74 % patients) (p <  0.001).  Rescue doses were needed by 5 % of SSTS patients versus 60 % of cFNB.  The fewer adverse events (AEs) and lower pain scores for the SSTS group were associated to a notably better ability to ambulate, with all patients (100 %) of the SSTS group being able to stand and walk for 10 m from T1 on; patients in the cFNB group showed a slower recovery with only 40 % being able to stand and walk on T1, 70 % on T2 and 85 % on T3.  All patients of the SSTS group had a LOS of 4 days (day of surgery plus 3 after) as foreseen by the fast track protocol, in comparison only 36 % of cFNB.  Lastly, patient and nursing staff judged SSTS easy to use.  The authors concluded that their experience suggested that SSTS was a valuable strategy for routine post-operative analgesia following TKA in the context of a multi-modal analgesic approach within the fast-track setting.  Moreover, these researchers stated that these results must be considered as evidence of real-life clinical practice, and could not have the strength of a RCT.  They stated that future targeted randomized studies could further evaluate SSTS by addressing parameters such as “minimally important difference” and “threshold of improvement”, as suggested recently by several working groups on patient reported outcomes on pain.

Turi and colleagues (2019) stated that the SSTS is a new, pre-programmed, non-invasive, hand-held system for PCA that may allow a faster post-operative recovery compared with standard PCA.  To the authors’ knowledge, SSTS has never been examined in patients undergoing major surgery within an Enhanced Recovery After Surgery (ERAS) protocol.  This observational, retrospective analysis included consecutive patients who underwent elective major abdominal and gynecological surgery.  All patients received the SSTS device once they were fully awake and had a good control of pain at the end of the surgery.  These researchers analyzed changes in pain intensity according to the NRS throughout the treatment as well as its duration, the number of administrations, and possible related AEs.  Patients were also interviewed to assess their quality of sleep and overall satisfaction with the SSTS device.  The study included 308 patients.  Compared to the first SSTS administration, pain intensity decreased from a median NRS of 6 to 0 at day 3, for an overall reduction of 79 %.  Results were already statistically significant at post-operative day 1 (p < 0.01).  Adverse reactions were observed in 62 patients, with nausea being the most frequent (12 %), and in 93 % of patients SSTS was discontinued because it was considered no longer necessary.  Patient satisfaction was high, with 89 % of them judging the device as "easy" or "very easy" to use.  The authors concluded that although the retrospective and observational nature of the study as well as the absence of a comparative group limited the strength of evidence, these findings showed that SSTS was a safe and effective tool for the management of post-operative pain following major abdominal and gynecological surgery within an ERAS protocol.  Moreover, a small proportion of missing data was not available for the final evaluation.  These researchers stated that further large RCTs are needed to confirm these positive preliminary results and to examine the involvement of different healthcare providers in the management of SSTS therapy.

Fabio and associates (2019) noted that SSTS (Zalviso) is a sublingual system for PCA.  These researchers presented a prospective observational study on the use of SSTS for the management of post-operative pain after thoracic surgery.  They examined the efficacy of Zalviso in reducing pain scores and increasing respiratory ability during post-operative period.  A total of 40 patients who underwent video assisted thoracoscopy were included in the study.  All the enrolled patients signed the informed consent were educated to the use of the device.  Pain NRS were recorded at awakening from anesthesia (T0) and during the next hours, both at rest and with cough.  These investigators evaluated the time to obtain a mean NRS value of less than or equal to 3 and difference in pain scores between first and subsequent measurements as the primary outcomes.  The ability to use incentive spirometer and eventual drug adverse effect were evaluated as secondary outcomes.  All patients in recovery room experienced moderate-to-severe pain.  Pain score at rest and coughing decreased to a mean NRS value of less than or equal to 3 (mild pain) respectively after 2 and 6 hours and the pain score difference continued to increase significantly after repeated measurements; 67.5 % of patients resumed the original spirometric ability in pod 1; 9.5 % in pod 2; 12 % in pod 3.  Only 3 patients out of 40 (7.5 %) experienced nausea; 1 patient (2.5 %) had a vomiting episode.  The authors concluded that the findings of this study showed SSTS as an effective option for post-operative pain management in thoracic surgery, improving pain scores and respiratory ability.  Moreover, these researchers stated that this study lacked a control group; and they assumed pain relief and the increase in spirometry performance as the proof of efficacy for SSTS -- this represented a limitation.  They noted that their data were derived from a small sample (n = 40) analysis; RCTs are needed to confirm these findings.

Leykin and co-workers (2019) stated that gynecological procedures are among the most frequent surgical interventions, and effective post-operative analgesia is associated with improved patient comfort.  Despite the efficacy of neuraxial analgesia, limitations and potential complications have led investigators to seek new strategies for pain relief.  A novel, pre-programmed, non-invasive, hand-held system (SSTS) is approved for use in PCA; however, it has never been used in gynecological procedures.  In a retrospective, observational, case-series study, these researchers examined SSTS for post-operative analgesia.  Data from 42 consecutive patients undergoing open gynecological surgery with Pfannenstiel incision were retrieved from medical charts in 2 Italian hospitals.  The mean age was 49 ± 11 years, and mean body mass index (BMI) was 24.4 ± 4.6 kg/m2.  These investigators reported effective relief on both static and dynamic pain all along the peri-operative period, with good effect on patient's rehabilitation.  Post-operative nausea and vomiting was the most common adverse effect, but the incidence was strongly decreased with medical prophylaxis; SSTS was easy to prepare, use and manage by both patients and care providers.  The authors concluded that SSTS may be an interesting option for post-operative analgesia in gynecologic procedures.  The efficacy in the management of dynamic pain is an interesting outcome that needs to be compared with the other standards of pain management, such as neuraxial techniques.  These researchers stated that rigorous studies are needed to give conclusive evidence, but this was the first report, to the authors’ knowledge, of SSTS use in open gynecologic procedures.  They stated that these preliminary experience encouraged the routine application of SSTS in gynecologic surgery and would help designing future RCTs on the topic

Appendix

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 healthcare 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 healthcare provider.
• Because of the risks of addiction, abuse, and misuse with 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).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
HCPCS codes not covered for indications listed in the CPB:
Sufentanil (Dsuvia) - no specific code :
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
G89.11 - G89.18	Acute pain

The above policy is based on the following references: