A review of several late-phase studies of sufentanil sublingual tablets (Dsuvia, AcelRx) concluded that the investigational product is effective and well tolerated for the short-term management of people suffering from moderate to severe acute pain.
“Our goal with this review was to articulate any differences between IV sufentanil and the sublingual sufentanil tablet, identify the patient populations in which the sublingual formulation works best, and note any side effects associated with the tablet,” said Jacob L. Hutchins, MD, an assistant professor of anesthesiology at the University of Minnesota, in Minneapolis.
The drug’s proposed indication is for management of moderate to severe acute pain in medically supervised settings, such as short-stay surgery and emergency medicine. “That’s a key point here,” he said. “This drug is going to be used under the supervision of clinicians. It’s not something that we’re going to be prescribing to patients to take at home.”
Sublingual sufentanil, he added, appears well-suited for short-duration acute pain management because it acts rapidly (with a plasma–central nervous system [CNS] equilibration time of six minutes), does not require an invasive route of delivery, and boasts a predictable offset, partly due to a lack of active metabolites.
“So why sufentanil as a sublingual medication?” Dr. Hutchins asked. “Hydrophilic opioids tend to have a delay between their application and uptake in the central nervous system. Morphine equilibrates in about 2.8 hours; hydromorphone in about 46 minutes. What’s nice about sufentanil is that it works really quickly without requiring an IV, which is beneficial in acute pain settings.”
Nevertheless, the sublingual version of the drug will still not boast the rapid bioavailability of its IV counterpart. “Although it’s not bioavailable as quickly as IV sufentanil, it’s on board for much longer,” Dr. Hutchins said. “So while you have to give IV sufentanil over and over again, the time for sublingual sufentanil plasma concentrations to drop 50% from peak levels is much longer than following IV administration, resulting in a more prolonged effect.”
Four late-phase trials were conducted of 30-mcg sublingual sufentanil tablets. Two randomized controlled trials examined patients after either bunionectomy or abdominal surgery; two open-label studies evaluated the drug in ER settings as well as in older postoperative patients, many of whom suffered comorbidities.
A total of 437 patients were included in the four trials: 399 patients aged younger than 65 years; 30 aged 65 to 74 years; and eight aged at least 75 years (range, 18-84 years). The drug’s efficacy was assessed by patient-reported pain numeric rating scale scores; the primary variable was time-weighted summed pain intensity difference (SPID) relative to baseline over 12 hours for the postoperative studies and over one hour for the emergency medicine study.
As Dr. Hutchins reported at the 2017 annual meeting of the American Society of Anesthesiologists (abstract JS02), the placebo-controlled trials found that sublingual sufentanil patients younger than 65 had significantly greater decreases in 12-hour SPID scores than those receiving placebo (P<0.001 and P=0.002 for abdominal surgery and bunionectomy, respectively). The investigators did not analyze patients older than 65 due to limited sample size.
By comparison, the open-label trials revealed that mean reductions in pain intensity scores with sublingual sufentanil were equivalent for patients younger than 65 and at least 65 years of age. Adverse events were experienced by 44%, 54% and 13% of patients younger than 65, 65 to 75 and at least 75 years of age, respectively, although no statistical difference was found in terms of adverse event occurrence rates between patients receiving the study drug or placebo.
“What’s nice about the sublingual tablet is that it’s small and dissolves in just a few minutes when placed underneath the tongue using the applicator,” Dr. Hutchins said. “It maintains effective drug levels for up to three hours and minimizes saliva production, so there’s less likelihood of a patient accidentally swallowing it. Also, you don’t have to worry about setting up a [patient-controlled analgesia pump] or drawing up the medication in a syringe.”
Drug Offers Some Important Benefits
In the most recently published study of the drug (Pain Med 2017 Nov 3. doi: 10.1093/pm/pnx248, [Epub ahead of print]), 140 adult patients at least 40 years of age were enrolled; each had a postoperative pain intensity scoreof at least 4 on an 11-point numeric rating scale and received the agent as requested for pain (minimum 60-minute re-dosing interval) over a 12-hour study period. The mean time-weighted SPID to baseline over 12hours was 36.0. It was also found that mean pain intensity decreased significantly starting 30minutes after the study drug dose, while mean pain relief increased significantly beginning 15minutes post-dose and remained relatively stable through 12hours. Four patients discontinued the study because of inadequate analgesia, and 45 patients had one or more adverse events that were considered possibly or probably related to the study drug.
Harold Minkowitz, MD, the director of clinical investigations at HD Research Corp., in Houston, and an author of the study, said he believes the novel agent represents a therapeutic breakthrough. “This drug is interesting because it provides a different profile and experience for the patient compared to the intravenous formulation,” Dr. Minkowitz said. “Given intravenously, sufentanil blood levels increase and decrease rapidly, which results in a short-acting agent with a relatively high peak plasma level. Given sublingually, however, the drug offers a much lower peak and a much longer duration.”
Another important advantage of the sublingual formulation, Dr. Minkowitz continued, is its rapid uptake into the CNS. “This affords very little lag between drug administration and analgesia onset. So the highly lipophilic drug works rapidly via the sublingual route, avoiding needlesticks. Its single-dosage strength makes it easy and consistent to administer, with the potential for fewer dosing errors than current agents.”
In fact, one of the only challenges Dr. Minkowitz foresaw with sublingual sufentanil was for fellow clinicians to recognize its utility in clinical practice. “As with anything new, people tend to be skeptical. So the challenge is going to be in getting people to understand the advantages of this novel therapy.”
The manufacturer received a complete response letter from the FDA in October 2017 regarding its New Drug Application, and is currently working to provide the FDA with additional safety data.