A new extended-release formulation of hydrocodone that has antiabuse properties has been shown to provide safe and long-lasting pain relief in a variety of patients with chronic pain, including those who have used opioids before and those who are opioid-naive.
It may also be much less appealing to would-be hydrocodone abusers, according to new research.
Manufacturer Purdue Pharma in Stamford, Connecticut, has filed a new drug application with the US Food and Drug Administration (FDA) to market the once-daily, single-entity hydrocodone bitartrate tablet (HYD).
The company announced its intention to file here at the American Pain Society (APS) 33rd Annual Scientific Meeting.
“Our primary objective was to evaluate the safety of long-term treatment with once-a-day hydrocodone, and we also collected effectiveness measures,” Warren Wen, PhD, from Purdue Pharma, Stamford, Connecticut said.
“Approximately 50% of our patients had chronic low back pain; the rest had osteoarthritis of the knee and hip, some leg pain, and some neck pain as well. The safety profile was what you would expect to see with this formulation,” Dr. Wen said.
A total of 922 subjects received open-label HYD. Those who were opioid-naive were started on 20 mg per day, and opioid-experienced subjects were converted to an HYD dose of 20, 40, 60, or 80 mg once daily.
Of these subjects, 728 achieved a stable dose of HYD at the end of the titration period, which lasted up to 45 days. They then entered a 12-month maintenance period, and 410 (56%) completed the study. Most subjects who dropped out of the study did so because of adverse events.
“Adverse events tended to occur more during the titration period, early in treatment. Once patients reached a stable dose and entered the 12-month maintenance period of the study, the safety profile was more benign,” Dr. Wen said.
Adverse events were typical of mu opioid agonists and included nausea, constipation, vomiting, fatigue, dizziness, somnolence, and headache.
Suspected or confirmed abuse of HYD occurred in less than 0.5% of the participants, and 2% of the subjects were withdrawn from the study because of suspected or confirmed drug diversion.
“There were no unanticipated safety concerns, and no ototoxicity associated with HYD was shown on comprehensive audiologic testing,” Dr. Wen said.
Treatment with HYD resulted in significant improvement compared with baseline in pain relief, sleep, overall function, and quality-of-life outcomes throughout the 12 months.
In addition, the average daily dose of HYD was stable during this time, with just 3% of patients requiring an increase in their dose.
Drug Liking Decreased
In a related study, Purdue Pharma colleague Stephen C. Harris, MD, presented an evaluation of the intranasal abuse potential of the new formulation in 35 healthy, nondependent recreational opioid users.
In the study, which was done according to FDA guidelines outlined in its January 2013 draft guidance, participants received HYD intact, HYD chewed, HYD milled, hydrocodone solution, and placebo in a randomized, double-blind, crossover fashion.
The HYD milled treatment was produced using an industrial mill and was included to test the limits of the abuse-deterrent technology, Dr. Harris explained.
Drug liking was measured up to 36 hours after dosing, using a visual analog scale.
The results showed that HYD intact and HYD chewed had significantly lower drug liking scores than hydrocodone solution.
In comparison with hydrocodone solution, 83% of participants had a reduction of at least 30% in maximum drug liking score after intact HYD injection, and 74% of participants had a reduction of at least 50%.
When chewed, HYD was compared with hydrocodone solution, and 69% of subjects had a reduction of at least 30% in maximum drug liking score; 60% of subjects had a reduction of at least 50%. When milled, HYD also was compared with hydrocodone solution, and 17% of subjects had a reduction of at least 30% in maximum drug liking score; 9% of subjects had a reduction of at least 50%.
“The dosage has 60 mg of hydrocodone, which is something that abusers will abuse if they can get their hands on it, but in this case, the product is formulated with excipients that make the dosage form, which is a hardened tablet, more difficult to crush or chop. This makes intranasal administration, which is what was tested in this study, more difficult to prepare for and less effective,” Dr. Harris said. “If you try to prepare it for intravenous injection, you get a viscous solution that’s difficult if not impossible to inject, so our conclusion is that we believe it will deter abuse.”
Abuse Deterrent Formulation
Commenting on this study for Medscape Medical News, Edward Michna, MD, from Brigham and Women’s Hospital, Boston, Massachusetts, said: “This agent contains the same active opioid as does Zohydro, but in an abuse-deterrent formulation. This would allow the prescribing of a hydrocodone extended-release medication with the limited additional protections that abuse deterrence affords.”
Zohydro ER (Zogenix) is a single-entity extended-release hydrocodone that has been met with opposition, including both a state ban in Massachusetts, which was later overturned, and bills introduced into the House and Senate to reverse its approval.
It’s clear with the reaction to the approval of Zohydro, with the uproar by the families who have lost children to overdose and state authorities, like the governor of Massachusetts calling for its ban, that extended release opioids that are new to the market will probably be required to incorporate some type of abuse deterrent technology in the future.Dr. Michna
Dr. Michna emphasized that this abuse-deterrent technology “only addresses a small portion of abuse, as most abuse is purely taking more of a drug, not adulterating the control release mechanism.”
The fact that HYD is a once-a-day, 24-hour medication may benefit some patients because of its ease of use, and it may possibly provide a more consistent level of pain relief.
“One other interesting fact was that there appeared to be very little dose increase over the 12 months, yet patients continued to have adequate pain control,” he noted.
“It is clear with the reaction to the approval of Zohydro, with the uproar by the families who have lost children to overdose, and state authorities like the governor of Massachusetts calling for its ban, that extended-release opioids that are new to the market will probably be required to incorporate some type of abuse-deterrent technology in the future,” Dr. Michna added.
American Pain Society (APS) 33rd Annual Scientific Meeting: Abstract 461, 441. Presented May 1, 2014.