Sufentanil sublingual tablets (Dsuvia) were found to be well tolerated for treating acute pain in a manufacturer-sponsored safety analysis, which follows the agent’s controversial November approval that saw healthcare leaders warning against the drug’s potential for abuse and diversion.
Among 804 patients across 10 studies, the adverse event rates were similar for individuals on the ultra-potent opioid and those on placebo (60.5% vs 61.4%, respectively), though more patients administered sufentanil tablets experienced treatment-related adverse events (43.8% vs 33.5%), reported James Miner, MD, of the Hennepin County Medical Center in Minneapolis, and colleagues.
Nausea was the most common adverse event (28.5%) for patients receiving any sufentanil dose, followed by vomiting (6.5%) and headache (5.0%), they wrote in Pain Management.
In total, 12 of the sufentanil-treated patients experienced a severe adverse event (nausea, headache, oxygen saturation decrease, procedural vomiting, and others) compared with 3 of the placebo patients.
Steven Meisel, PharmD, director of medication safety at Fairview Health Services in Minneapolis, said the results from this pooled analysis were similar to those discussed at the October 12 FDA advisory committee meeting, where AcelRx Pharmaceuticals presented data from the randomized phase III SAP-301 trial (he with two others voted against recommending approval of the drug at that meeting). In that trial, oxygen saturation was the most common reason for discontinuing sufentanil.
However, Meisel noted that this new study is not a formal meta-analysis and compiles varying doses and patient populations. For example, most patients received two 15 mcg doses (n=427) within 20 to 25 minutes, but in the U.S. the agent is approved at a single 30 mcg dose, he said. Additionally, only one open-label emergency department study was included, despite the fact that the drug was designed for use in emergency and military settings.
In the FDA’s approval, Commissioner Scott Gottlieb, MD, said this formulation would be particularly useful in battlefield situations when intravenous administration is not possible, stating that it was a “high priority” to ensure soldiers had access to treatment.
Meisel told MedPage Today that a fixed dose of medication for analgesia, particularly in trauma or postoperative settings “goes against any modern thinking of pain management” and is “problematic.” And the agent’s 45-minute latency period could increase the risk of dose-stacking, which is one of the most common factors in oversedation, he said.
“The fact that the authors reported relatively few oversedation events at the dose selected says nothing about what will be experienced when clinicians inevitably give higher, more effective doses,” Meisel wrote in an email. “At those doses, we should expect to see a higher rate of adverse events.”
In this analysis, 3.8% of patients on placebo discontinued treatment due to adverse events, as did 2.9% of patients receiving the active treatment — 1.5% due to respiratory-related events, including 6 patients with oxygen desaturation.
Across the 10 studies, three patients administered the 30 mcg sufentanil dose required the opioid-reversal agent naloxone (Narcan), including one patient who experienced an oxygen saturation decrease. There were two deaths (renal failure, sepsis) involving patients administered the 15 mcg tablets, but both were considered unrelated to the treatment.
Meisel said the rationale that one of the advantages of the sufentanil sublingual tablets is that clinicians can avoid putting it in an IV line is “solving a problem that doesn’t exist” in postoperative settings, since any patient who goes into the operating room will already have an IV. He added that if there is a problem and a patient needs reversal medication, inserting an IV will complicate matters and delay the administration of drugs like naloxone.
Leading up to the agent’s approval, Raeford Brown, Jr., MD, chair of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee, expressed concern that the tiny tablets (0.5 mm thick and 3 mm in diameter), which are 10 times more potent than fentanyl, could be diverted and abused by healthcare professionals.
Shortly after the drug’s approval, watchdog group Public Citizen issued a statement claiming the FDA made the “wrong call,” and that this “super-strong opioid medication will be abused and kill people.”
Miner, who also works as a consultant to AcelRx, said concerns over the new agent being diverted were misplaced, explaining that it would be more difficult than with standard IV drugs, since they are small, solid tablets that cannot be broken up or taken partially without their absence being detected.
“From my perspective as a manager of an emergency department, I’m much less worried about this drug getting misused or abused by healthcare professionals than I am about standard IV drugs,” he told MedPage Today. “It’s at least as safe from my perspective, but probably better.”
This pooled analysis collected data from patients with moderate-to-severe pain (pain intensity ≥4 on an 11-point numeric rating scale). Participants were a median age of 56 years and were mostly women (60.9%), white (79.4%), and with a body mass index <30 (58%).
The majority of patients had undergone abdominal (43.7%) or orthopedic (42.8%) surgery. Patients on 30-mcg sufentanil received a median 7.0 doses in the first 24 hours of treatment while those on the 15 mcg dose received a median 25.0 doses (these patients had more extensive surgeries).
Miner and his team noted that the main study limitation was the lack of an active comparator in most of the trials. Additionally, the 24-hour range of dosing in the group that received 15-mcg was 1.8-times higher than it was for those who received the 30-mcg dose, which could explain the higher number of adverse events experienced by the 15-mcg group. Lastly, consequences of opioid use, like tolerance and addiction, were not measured in this study.
The current study was funded by AcelRx Pharmaceuticals, while those included in the analysis were funded by AcelRx and in part by the Clinical and Rehabilitative Medicine Research Program of the U.S. Army Medical Research and Materiel Command.
Several of the authors are consultants, employees, or have stock ownership of AcelRx, and many received research funding from the company.
One co-author also received research funding from Avenue, Recro, and Trevena.