New Oxycodone-Acetaminophen Combination Treatment Produces Positive Results in Acute Pain Patients

Just a little over a month after the US Food and Drug Administration granted priority review to a New Drug Application from specialty pharmaceutical manufacturer Mallinckrodt for MNK-795, a novel controlled-release combination oxycodone-acetaminophen analgesic (CR OC/APAP), the company presented a slew of positive clinical data on the drug’s tamper-resistant properties, pharmacokinetics, dose proportionality, bioavailability, tolerability, and efficacy and safety in the form of 15 posters at PAINWeek 2013.

For their “Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of the Safety and Analgesic Efficacy of MNK-795 CR OC/APAP Tablets in an Acute Pain Model” poster, Mallinckrodt researchers teamed up with investigators from Lotus Clinical Research LLC in Pasadena, CA, to study the effectiveness, safety, and tolerability of MNK-795 in 329 patients “undergoing unilateral, first metatarsal bunionectomy who reported moderate or severe pain intensity and numeric rating scale score of at least 4 out of 10 between the hours of 4:00 a.m. and 12:00 p.m. on the first postoperative day.”

After enrollment in the study, patients were randomized to receive either two tablets of 7.5 mg oxycodone hydrochloride/325 mg acetaminophen or placebo every 12 hours over a period of two days following their bunionectomies.

According to the poster authors, results of the efficacy analysis of both patient groups found that the change in pain intensity difference over the first 48 hours from baseline was “significantly greater in the CR OC/APAP group compared with placebo, indicating a greater reduction in pain over 48 hours for those patients receiving CR OC/APAP.” Additionally, the mean pain intensity difference for CR OC/APAP patients was “numerically superior beginning at the earliest time point measured (15 minutes) and each time point thereafter” compared to placebo patients, with statistical significance reached at 30 minutes after the first dose, the researchers wrote. Total pain relief sustained over the first 48 hours for CR OC/APAP patients also indicated significant improvement compared to placebo, and while the median time to confirmed perceptible pain relief was 48 minutes for CR OC/APAP, that time point could not be determined for placebo.

Examining the results of the double-blind safety and tolerability analysis, the researchers found that 37.7 percent of CR OC/APAP patients experienced a treatment-emergent adverse event that was consistent with other opioids, including “nausea (30.7 percent), dizziness (13.3 percent), headache (9.6 percent), vomiting (9 percent), constipation (4.2 percent), and sleepiness (3.6 percent).”

Based on the findings from those three analyses, the poster authors concluded that MNK-795 was “efficacious and well-tolerated for the treatment of moderate to severe acute pain in an acute postoperative pain model, (and) CR OC/APAP administered twice daily (two tablets) for four doses demonstrated a fast onset of pain relief with sustained analgesia over 48 hour following a surgical procedure; (therefore), CR OC/APAP may be appropriate for patients with moderate to severe acute pain.”

Additional MNK-795 study results indicated that:

• “The similarity of the relevant pharmacokinetics (PK) parameters to those of the immediate-release (IR) marketed compounds supports the proposed 12 hour dosing interval of CR OC/APAP for patients with moderate to severe acute pain,” according to the authors of Mallinckrodt’s “Comparison of the Pharmacokinetic Profile of a Single Dose of MNK-795 and Marketed Immediate-Release Opioids and Opioid/Acetaminophen Combination Tablets” poster.
• “CR OC/APAP has physicochemical properties that could deter extraction of a sufficient bolus dose, injection or snorting of the manipulated drug product, and resist dose dumping in the presence of alcohol,” according to the authors of the “Evaluation of the Tamper-Resistant Properties of MNK-795 CR OC/APAP Tablets” poster.
• “Oral administration of CR OC/APAP resulted in less drug liking, drug high, and good drug effects compared with IR OC/APAP, suggesting potentially lower abuse liability,” according to the authors of the “Comparison of Subjective Drug Effects of Orally Administered MNK-795 CR OC/APAP vs Immediate-Release Oxycodone/Acetaminophen Tablets in Recreational Users of Prescription Opioids” poster.