With the Aug. 7 approval of oliceridine (Olinvyk, Trevena Inc.) by the FDA, anesthesiologists have a new opioid in their analgesic armamentarium. While the drug is said to provide the benefits of traditional opioids with fewer potential side effects, its approval has left some clinicians wondering why the world needs a new opioid, given the current opioid crisis that kills tens of thousands of people every year.
“Oliceridine is not just another opiate; it’s an opiate that can reduce the side effects that cause morbidity and mortality,” said Alan D. Kaye, MD, PhD, who was a member of the advisory committee that reviewed the novel opioid agonist in October 2018.
“If there’s a drug that can kill a whole lot less people, then I say that’s a good thing,” continued Kaye, a professor of anesthesiology and pharmacology, the pain program director, and the provost and vice chancellor at the Louisiana State University School of Medicine, in New Orleans. “And that’s why I voted for its approval.”
Nevertheless, Kaye was in the minority in the group, as the advisory committee voted 8 to 7 against oliceridine’s approval. At that time, some committee members expressed concern that low doses of the drug may prove insufficient to treat moderate to severe pain and that higher doses may lead to adverse events such as QT prolongation.
The FDA agreed, and in November 2018, the agency issued a complete response letter asking for additional clinical data on QT prolongation, noting that the safety database for the drug wasn’t large enough for the proposed dose range. Trevena addressed these issues with subsequent research and resubmitted its New Drug Application earlier this year. Among other things, the resubmission package specified a maximum daily oliceridine dose of 27 mg, as previously acknowledged by the FDA. The agency approved the application, this time without the advisory committee’s input.
Now, oliceridine is approved for the management of moderate to severe acute pain in adults, where the pain is severe enough to require an IV opioid and for whom alternative treatments are inadequate. The drug is indicated for short-term IV use in hospitals or other controlled clinical settings, and is not indicated for at-home use by patients. Unlike other IV opioids, oliceridine has a maximum recommended daily dose limit of 27 mg.
The drug is expected to be commercially available when the Drug Enforcement Administration issues its controlled substance schedule, likely sometime in the fourth quarter of 2020.
Road to FDA Approval
As part of the drug’s phase 3 development program, oliceridine was evaluated in more than 1,500 patients in both controlled and open-label trials. Two randomized, double-blind, placebo- and morphine-controlled phase 3 clinical trials (APOLLO-1 and APOLLO-2) studied the drug in 790 patients with moderate to severe acute pain after orthopedic or plastic surgery. In each, participants were randomized to one of three oliceridine treatment regimens, a placebo-controlled regimen or a morphine-controlled regimen. In the oliceridine groups, the loading dose was 1.5 mg, while demand doses were either 0.1, 0.35 or 0.5 mg. In each case, a 0.75-mg supplemental dose was available.
The studies found that patients taking the 0.35- and 0.5-mg oliceridine doses had statistically significant (P<0.0001) improvement in pain scores over their counterparts who received placebo; oliceridine proved noninferior in this respect to 0.5 mg of morphine.
In terms of adverse events, the most common (≥10%) among oliceridine patients were nausea, vomiting, dizziness, headache, constipation, pruritus and hypoxia. The two phase 3 studies assessed respiratory complications using a predefined composite measure of respiratory safety burden (RSB), which represents the cumulative duration of respiratory safety events. In both studies, RSB showed a dose-dependent increase across oliceridine regimens, although none were statistically different from morphine.
Both APOLLO-1 and APOLLO-2 found that gastrointestinal adverse events also increased in a dose-dependent manner among patients receiving oliceridine. Nevertheless, the odds of rescue antiemetic use were significantly lower for oliceridine than for morphine in APOLLO-1. The APOLLO-2 study also found that the proportion of patients experiencing nausea or vomiting was lower with the 0.35- and 0.5-mg oliceridine doses than with morphine.
Oliceridine also was the subject of an open-label safety study (ATHENA) in 768 patients with moderate to severe acute pain, primarily postoperative pain. In this investigation, the study drug was administered via clinician-administered bolus dosing, patient-controlled analgesia or a combination of the two. The real-world investigation found the drug to be safe and well tolerated in the medically complex patient population, which included the elderly, obese and patients with comorbid conditions, such as diabetes and sleep apnea.
Discontinuation rates in the real-world study were comparable to those found in the randomized controlled trials, affecting 3% of patients who received a daily dose no more than 27 mg and 1% of those who received greater than 27 mg per day.
Oliceridine boasts a novel pharmacokinetic profile that lowers its theoretical risk profile compared with traditional opioids, according to Kaye. The drug selectively activates G protein and beta-arrestin signaling pathways, and exhibits a preference for the G pathway over beta-arrestin that is approximately three times greater than either morphine or fentanyl. As such, it is known as a so-called “biased ligand,” which means it preferentially couples with certain intracellular pathways, but not others.
“A biased ligand,” Kaye noted, “has the potential to act as a full agonist for a certain pathway, while simultaneously being inert or displaying inverse efficacy for another.”
The product of this preferential coupling is fewer side effects with oliceridine than with traditional opioids such as morphine. “And those side effects cause a whole lot of morbidity and mortality,” Kaye told Anesthesiology News. “So it’s a big deal.”
Questions and Concerns Remain
Yet not all clinicians are equally enthusiastic about the drug’s release and impending launch. Count among those Clifford M. Gevirtz, MD, who raised several questions about both the drug and the approval process. “There were some significant issues raised back in 2018 by the advisory committee,” said Gevirtz, the medical director of Somnia Inc., in Harrison, N.Y. “So it's interesting to me that the FDA went ahead and approved oliceridine two years later, without sending it back to the advisory committee.”
Gevirtz said data from the APOLLO-1 and APOLLO-2 studies are unconvincing.
“From what I can tell, there is little difference between oliceridine and morphine with respect to this measure they call respiratory safety burden,” he said. “The same is true for gastrointestinal side effects. So I don’t think this drug is ready for prime-time release yet.
“Frankly, I’m amazed the FDA approved it,” Gevirtz added.
Oliceridine demonstrates abuse potential that is comparable to other opioids. And it does carry a boxed warning regarding addiction, abuse and misuse, as well as life-threatening respiratory depression, neonatal opioid withdrawal syndrome, and risks from concomitant use with benzodiazepines or other central nervous system depressants.
Despite these potential effects, oliceridine’s manufacturer was enthusiastic about the drug’s approval, noting that IV opioids remain a necessary treatment option for the management of acute pain.
“As the FDA noted in the press release announcing their decision to approve Olinvyk, addressing the opioid crisis remains top of mind, and they only aim to approve products upon rigorous evaluation of its benefit–risk profile and determination that the data supports efficacy and safety,” commented Mark Demitrack, MD, the senior vice president and chief medical officer at Trevena.
Demitrack explained that oliceridine’s features distinguish it from currently available IV opioid medications, which make the drug an attractive choice in higher-risk patients, who may pose dosing challenges with conventional IV opioids.
“And remember,” he added, “our goal is not to expand opioid usage, but rather to provide a differentiated option when intravenous opioid use is required.”
Kaye agreed that the drug stands to make an important positive impact in clinical practice. “At the FDA, we reject many new drugs that are just more opiates,” he said. “So we’re really looking for something that will improve the opioid situation, and this drug may just do that.”
—Michael Vlessides
Kaye and Gevirtz are both members of the Anesthesiology News editorial advisory board; they reported no relevant financial disclosures.
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Opioid free anesthesia (OFA) eliminates opioid related adverse druge effects (ORADES).