Novel Extended-Release Opioid Formulation Deters Abuse
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LAS VEGAS — MNK-795, an oral extended-release formulation of oxycodone and acetaminophen, shows efficacy in a phase 3 study, as well as abuse-deterrent properties that result in reduced "likability" for potential abusers when the drug is crushed, first clinical data released on the investigational drug show.
Opioid abuse is a substantial public health problem and the new formulation, which would be the first extended-release form of oxycodone-acetaminophen on the market, is designed with tamper-resistant technology to lessen or eliminate the reward or "liking" for someone attempting to abuse the drug.
"The greatest problem we have with prescription drugs is they have rewarding properties and become even more lethal when an extended-release formulation can be crushed and converted into an immediate-release formulation," said coauthor Lynn Webster, MD, medical director of Lifetree Clinical Research and Pain Clinic.
"MNK-795 will be very difficult to be converted, and even if it is manipulated, it is much less liked than an immediate-release formulation."
In a key human abuse liability study that was among several studies on MNK-795 presented here at the annual PAINWeek 2013, the drug's abuse likability was compared with that of instant-release oxycodone-acetaminophen (Percocet), with 55 recreational opioid users receiving various doses over seven periods, with 72-hour washout periods between the treatments.
The treatment groups included placebo vs intact low-dose MNK-795 or low-dose immediate-release Percocet (15 mg/650 mg); placebo, intact high-dose MNK-795, or high-dose Percocet (30 mg/1300 mg); or crushed versions of the drugs in the same low-dose and high-dose comparisons.
After completion of the treatments, patients reported significantly lower levels of drug liking, drug high, and good drug effects with low-dose intact MNK-795 compared with low-dose Percocet (P < .001).
The time to the peak drug effect was longer for high-dose, intact MNK-795 than for high-dose Percocet, and all of the comparisons were similar for the crushed formulations of the drugs.
The crushed MNK-795 also showed a significantly longer time until the peak drug effect than Percocet with the crushed formulation.
Dr. Webster noted that although the drug liking is reduced after the drug is crushed, the tamper-resistant technology even makes crushing the drug much more difficult in the first place.
"The bottom line is this resists manipulation, so if you tried to crush it you would have a tough time, but even if it is crushed, rather than have an additional release to produce more of a liking effect or euphoria, it actually is less liked, or has less of a high than if taken as it is intended, so that is very unique," he said.
MNK-795 is being developed for the indication of moderate to severe pain, and in a separate phase 3 study of the drug involving 329 patients with moderate to severe pain following a bunionectomy, the drug was shown to be effective and well tolerated.
During a double-blind phase of the trial, the patients were randomly assigned to receive 2 tablets of MNK-795 or placebo every 12 hours, for a total of 4 doses. Those with a pain intensity score of 3 or higher at the completion of the double-blind study continued in a 14-day open-label phase of the trial.
Among them, 129 patients (88.4%) finished the open-label extension, with more than 80% reporting being satisfied or very satisfied with the treatment.
The adverse events were consistent with those experienced with other opioids; the most common adverse events were nausea (17.8%), vomiting (7.5%), and constipation (6.2%).
True Duration of Relief?
While agreeing that an extended-release oxycodone-acetaminophen formulation would be a welcome addition to the marketplace, neurologist Egilius L.H. Spierings, MD, PhD, emphasized that he would be most concerned about the true duration of pain relief.
"I would be looking at the factual duration of action of the controlled-release formulation, because it's anything like the controlled-release Oxycontin, it could be a problem," said Dr. Spierings, an associate clinical professor of neurology at Brigham and Women's Hospital in Boston, Massachusetts.
"The controlled-release Oxycontin is supposed to work for 12 hours, but in my experience it never works that long — it usually only works for 8 hours," he told Medscape Medical News.
"And it's a tremendous disadvantage to have to take an extended-release formulation 3 or 4 times a day — it almost defeats the purpose," he said. "If this new drug does work for 12 hours that would be great."
The abuse deterrent capabilities would also be an important benefit, he said. "I think it's interesting that this is a tamper-resistant formulation that performs worse regarding drug liking when it is crushed versus intact. I'm wondering how this works."
The study was sponsored by Mallinckrodt Inc., and Dr. Webster is on the advisory board for Mallinckrodt. Dr. Spierings has disclosed no relevant financial relationships.
PAINWeek 2013. Abstracts 69, 104. Presented September 5, 2013.