Nancy A. Melville

October 01, 2012

October 1, 2012 (Phoenix, Arizona) — A submicron particle formulation of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac shows efficacy in providing rapid-onset control of acute pain, as well as the potential safety benefits of a lower dosage, a new study suggests.

The proprietary formulation, made by Iroko Pharmaceuticals, Philadelphia, Pennsylvania, demonstrates pharmacokinetic characteristics, such as faster Tmax and similar Cmax, that allow for administration of diclofenac in lower doses than those commonly used for acute pain.

"Given the legitimate concern regarding the use of NSAIDs, this study highlights the potential of a new preparation in development that would allow for successful treatment of postoperative pain at a lower NSAID dose," lead author Charles Argoff, MD, from the Albany Medical College Neurology Group, New York, told Medscape Medical News.

The findings were presented here at the American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting. 

Compared With Celecoxib

To evaluate the investigational drug's analgesic efficacy and compare it with that of the NSAID celecoxib, as well as placebo, researchers randomly assigned 428 adult patients in the multicenter, double-blind study.

After surgery with regional anesthesia, patients who experienced pain intensity of 40 mm/100 mm or greater on the Visual Analogue Scale (VAS) when their nerve block was discontinued were randomly assigned to receive diclofenac submicron particle capsules (18 mg or 35 mg three times daily), celecoxib (400-mg loading dose, then 200 mg twice daily), or placebo.

The primary endpoint for the study was the summed pain intensity differences by VAS over 48 hours; secondary endpoints included the VAS pain intensity difference at various time points compared with that in the placebo group.

The results showed significant pain control with diclofenac submicron particle 35 mg (P < .001) and 18 mg (P = .01) and celecoxib (P = .011) compared with placebo.

Patients in the diclofenac submicron particle 35-mg treatment group reported greater pain relief at 30 minutes (4.52) compared with the celecoxib (0.80), diclofenac submicron particle 18-mg (0.31), and placebo (0.12) groups.

Pain control increased over time in all active treatment groups, with 35 mg diclofenac submicron particle (10.15) significantly improved over placebo (4.28; P =.025).

The higher pain control remained 5 hours after study entry for the 35-mg diclofenac submicron particle group (higher mean VAS pain intensity difference score, 9.43; P = .002), 18 mg (8.35; P = .009), and celecoxib (6.62; P = .032) treatment groups compared with placebo (2.30).

The most frequent treatment-emergent adverse events were postprocedural edema (32.7%), nausea (29.7%), headache (12.9%), and dizziness (11.7%).

Unique Approach

The drug's proprietary formulation offers a unique approach that could give it an advantage over opioids for acute pain, said pain specialist Lynn R. Webster, MD, who is medical director of Lifetree Clinical Research in Salt Lake City, Utah.

"I think the potential with this drug is in the speed of onset, but not because pain disorders need a speed of onset over what exists with Celebrex (celecoxib)," he explained.

"The wind up of the spinal cord begins with the beginning of any nociceptive information that reaches the spinal cord by the brain, so if you can prevent that a nociceptive bombardment at the spinal cord level, you can mitigate the intensity and overall amount of pain that is going to be received," he explained.

"Unlike opioids, which essentially do nothing to prevent the activation process of pain to be slowed, NSAIDs can actually decrease the quantity of neurotransmitter activation at the spinal cord, and that's a good thing, so the earlier onset with an NSAID, the better chance you have to decrease the peak intensity of pain as well as the overall experience of pain."

"The fact that there was pain intensity difference at 24 or 48 hours was less compared to the other NSAID in this study to me supports the idea that the earlier onset works," Dr. Webster said.

The benefits of a lower dose, however, remain to be seen, he said. "I think there may be some potential benefit of the lower dose, but it would likely only be evident in evaluating adverse events after long-term use involving lots of patients."

"So if there is some potential to be a safer drug, we'll only know if it gets FDA [Food and Drug Administration]-approved and we can see over the long haul."

The study was supported by Iroko Pharmaceuticals LLC. Dr. Argoff has received an honorarium or grant for serving as an advisor, on the speaker's bureau, and as an investigator and/or speaker for Endo Pharmaceuticals, Pfizer Inc., Eli Lilly and Company, Forest Laboratories, NeurogesX Inc., King Pharmaceuticals Inc., sanofi-aventis, Boehringer Ingelheim, Jannsen Pharmaceuticals, Nuvo Research Inc., Jazz Pharmaceuticals, Depomed Inc., Shinogi Pharmaceuticals, Insys Pharmaceuticals, and Gruenthal Pharmaceuticals. Dr. Webster reports that he receives consulting fees from Boston Scientific Corporation, Covidien, Iroko Pharmaceuticals LLC, Medtronic, Nektar Therapeutics, Pfizer Inc., and Salix Pharmaceuticals.

American Academy of Pain Management (AAPM) 23rd Annual Clinical Meeting.  Poster abstract 25. Presented September 21, 2012.