Sublingual Opioid Sufentanil Gets FDA Committee Vote, Faces Public Scrutiny

Major news outlets quick to lambast the US Food and Drug Administration (FDA) panel support for sufentanil sublingual tablet (Dsuvia) as a pain management therapy seemed to have lost crucial details when writing their headlines.

This week, the FDA Anesthetic and Analgesic Drug Products Advisory Committee voted 10-3 in favor of recommendation for the marketing approval for AcelRx Pharmaceuticals 30 mcg sufentanil tablet. The vote of support will follow the opioid’s new drug application (NDA) to the FDA, who will decide whether or not to approve it for the management of moderate-to-severe acute pain in medically supervised settings for adult patients.

A significant amount of coverage to come from the committee vote has focused on the drug’s potency—“FDA Could Approve Opioid 10 Times Stronger Than Fentanyl,” read a Rolling Stone headline, while others have emphasized its effects as “500 times more powerful than morphine.”

News of the decision—as well as even more differing measures of the drug’s strength—has reached political forum. On Thursday, Sen. Edward J. Markey (D-Mass) released a statement on his site urging the FDA to reject the NDA for sufentanil, citing the opioid is “up to 10 times more powerful than fentanyl and 1000 times more powerful than morphine.”

“An opioid that is a thousand times more powerful than morphine is a thousand times more likely to be abused, and a thousand times more likely to kill,” Markey stated. “Even in the midst of the worst drug crisis our nation has ever seen, the FDA once again is going out of its way to approve a new super-charged painkiller that would only worsen the opioid epidemic.”

Some of the headlines have reached the attention of Jeff Gudin, MD, director of Pain Management and Palliative Care at the Englewood Hospital & Medical Center, NJ. In an interview with MD Magazine®, Gudin noted coverage of sufentanil’s strength comparative to morphine and fentanyl has omitted a key difference: sufentanil tablets would not be available in prescription or over-the-counter settings.

The Data

“I agree with the advisory board’s recommendation for approval,” Gudin said. “Although we are in the midst of an opioid crisis, from my understanding, this will only be administered by professional healthcare providers in a hospital or similar setting.”Indeed, data submitted to the FDA in support of AcelRx’s NDA submission compared sufentanil tablet’s analgesic efficacy versus placebo in patients with acute moderate-to-severe pain following outpatient abdominal surgery—a setting which it would strictly be indicated for.

The US multicenter trial, which randomized patients 2:1 to receive either 30 mcg therapy as needed or placebo, limited treatment to up to 48 hours following procedure. Patients were offered standard-of-care postoperative pain management and required a pain intensity of ≥4 on an 11-point numeric rating scale (NRS) within 8 hours to be randomized for treatment. Patients could only receive sufentanil beyond 24 hours if they continued to report a pain intensity of ≥4.

Investigators required patients wait a minimum of 1 hour between doses, and provided a rescue medication of morphine 1 mg intravenous (IV), no sooner than 10 minutes after therapy administration.

In the 161 patients randomized to receive the investigative drug, a majority were under 65 years old and female. The most common surgery in patients was abdominoplasty, followed by laparoscopic abdominal surgery and hernioplasty. A majority of patients administered sufentanil completed both 12- and 24-hour treatment regiments, while fewer patients administered placebo reached either mark.

Patients on sufentanil reported a median time of 54 minutes to meaningful pain relief, while placebo patients reported a median time of 84 minutes. In the first 12- and 24-hour study periods, the mean duration between administered doses of sufentanil were 3 to 3.5 hours.

In gauging for safety, investigators noted that more patients administered sufentanil 30 mcg suffered instances of nausea (n= 35 [32.7%]) and vomiting (8 [7.5%]), than patients on placebo (16, 1 [29.6%, 1.9%], respectively).

The next most common adverse events in patients administered the therapy were headache (22 [20.6%]), dizziness (6 [5.6%]), and hypotension (6 [5.6%]).

Supplemental data presented at the American Society of Anesthesiologists (ASA) in San Francisco, CA, this week showed sufentanil’s efficacy and safety versus placebo in post-operative patients following bunionectomy or abdominal surgery. In the 2 open-label, single-arm trials, the therapies were administered in emergency department settings to older patients, many with comorbidities.

The Correction

Investigators reported statistically significant improvements in pain intensity difference over 12 hours for patients on sufentanil versus those on placebo. Nausea was again the most commonly reported adverse event across patient populations.Its safety for patients was a particular emphasis of the AcelRx NDA, as the company received a Complete Response Letter (CRL) in lieu of supplemental safety data from the FDA last year. The CRL primarily recommended that supplemental data on at least 50 patients dosed at the maximum rate of proposed labeling shows its safety. It also recommended and that certain changes to its Directions for Use address use-related errors to be validated through another study.

Despite the CRL hindering its US market consideration, Dsuvia was approved 1 month later by the European Medicines Agency, in June 2018.

In a statement regarding the ASA data, Jacob Hutchins, MD, associate professor at the University of Minnesota Medical Center, emphasized the need for pain management options in surgery settings.

“Pain is the most common reason for delayed discharge from outpatient surgery centers and the main reason for unanticipated hospital admissions," Hutchins said. "Inadequate management of pain in the perioperative period causes unnecessary suffering and discomfort, and these results show that Dsuvia could offer potential analgesic advantages in patients requiring non-invasive, acute pain management."

Gudin echoed its potential to “play a role” in outpatient care—one similar to that of IV painkiller options such as morphine, only in supervised, provider-managed circumstances.

“I certainly agree in the midst of potential opioid shortages, where appropriate, this medication could fill an unmet need,” Gudin said.

Now with updated safety data, a committee backing, and a November 3 PDUFA date, the FDA will have 2 weeks to decide on the benefits versus implied risks of sublingual sufentanil for pain management. What can’t be lost in that decision is the critical detail of its circumstantial use.