Submicron Diclofenac Reduces Postsurgical Pain

Nancy A. Melville

September 16, 2013

LAS VEGAS — An investigational submicron particle formula of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac (Iroko Pharmaceuticals LLC) was effective in reducing the need for opioid rescue medication in patients with acute postoperative pain, a new study shows.

The submicron technology reduces NSAID drug particles so that they become at least 10 times smaller than those with standard formulations, promoting absorption, explained coauthor Srinivas R. Nalamachu, MD, who is president and medical director of the International Clinical Research Institute Inc and co-director of the Pain Management Institute in Overland Park, Kansas.

"In using the submicron particle technology, you're increasing the surface area of exposure and you get the same kind of efficacy as standard diclofenac by using the lower dose," he told Medscape Medical News.

The results were presented here at PAINWeek 2013.

Submicron Technology

The phase 3, double-blind study involved 428 adults, aged 18 to 65 years, recovering from bunionectomy surgery with regional anesthesia. Acute pain from a bunionectomy is a model the US Food and Drug Administration (FDA) uses for evaluating NSAID efficacy in postoperative pain, Dr. Nalamachu explained.

For the study, patients with moderate to severe pain, with a pain intensity rating of 40 or more mm on a 100-mm visual analog scale, were randomly assigned to the diclofenac submicron particle capsules (35 or 18 mg 3 times daily [TID]; n = 216), celecoxib (400 mg loading dose, then 200 mg twice daily [BID]; n = 106), or placebo (n = 106).

Patients were permitted to receive rescue opioid medication of hydrocodone/acetaminophen, 10 mg/325 mg, every 4 to 6 hours or oxycodone/acetaminophen, 7.5 mg/325 mg, every 6 hours after the first hour of the study drug administration.

After the first hour, 82% of patients treated with the diclofenac submicron particle capsules 35 mg TID (P = .002) and 85.3% of those receiving 18 mg TID (P = .005) required the opioid rescue medication compared with 84.9% of those in the celecoxib 200 mg BID group (P = .006) and 97.2% of the placebo group.

Patients in the diclofenac capsules 35 mg group required the rescue medication an average of 5.9 hours after study entry (P< .001), whereas the average period in the 18 mg group was 9.1 hours (P = .003); the celecoxib 200 mg group received the rescue medication after an average of 4.9 hours (P = .013) compared with placebo (2.7 ± 0.5 hours).

In a previous study, the mean overall pain intensity difference compared with placebo (77.1) for patients receiving diclofenac capsules 35 mg TID was 524.0 (P < .001), 393.2 for the 18 mg group (P = .010), and 390.2 for the celecoxib 200 mg group (P = .011), compared with placebo (77.1).

Adverse events did not significantly differ across the treatment groups . The most common non–procedure-related adverse events were nausea (29.7%), headache (12.9%), dizziness (11.7%), and vomiting (11.2%).

The findings were included in Iroko Pharmaceuticals' New Drug Application (NDA) for submicron diclofenac, which was accepted by the FDA in February 2013.

The submicron formulation is being developed in response to concerns about NSAID adverse effects that recommendations from the FDA that physicians prescribe the drugs "at the lowest effective dose for the shortest duration consistent with individual patient treatment goals."

"By using a lower dose of submicron we are achieving the same clinical efficacy as celecoxib 200 mg BID with the loading dose of 400 mg, which essentially means we can get efficacy with 30% less of submicron diclofenac, which translates to a better safety profile," Dr. Nalamachu said.

The standard formulation of diclofenac has been associated with a significant increase in cardiovascular risk, and a recent review, reported at that time by Medscape Medical News, concluded that the increased risk with diclofenac was similar to that with the cyclooxygenase-2 inhibitor rofecoxib (Vioxx, Merck), which was removed from the market because of that risk.

Cardiovascular Risk?

Pharmacologist James B. Ray, PharmD, who also spoke at the PAINWeek meeting, said that the troubling cardiovascular risk concerns associated with standard diclofenac would cause him to give pause before prescribing the submicron formulation.

"I have significant biases against diclofenac because of its greater cardiovascular risk profile compared to other NSAIDs," said Dr. Ray, pharmacy clinical coordinator for pain and palliative care at the University of Virginia Health System in Charlottesville.

"I doubt that I would recommend consideration of this formulation for use without a lot more data."

The study was supported by Iroko Pharmaceuticals LLC. Dr. Nalamachu is a consultant for Iroko Pharmaceuticals. Dr. Ray is a consultant and on the speaker's bureau for Millennium Laboratories and consultant to Cadence Pharmaceuticals.

PAINWeek 2013. Abstract 139. Presented September 5, 2013.


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