Low doses of naproxen in a fine powder provide pain relief, but not statistically better relief than standard formulations of the drug, a new study shows.
The submicron particles are designed to be more bioavailable, allowing lower doses and theoretically fewer adverse reactions.
"We can give a lower dose by mechanically manipulating the drug," co-author Bill H. McCarberg, MD, adjunct assistant clinical professor at the University of California, San Diego, told Medscape Medical News.
The results were reported here at PAINWeek by Clarence L. Young, MD, chief medical officer of Iroko Pharmaceuticals, which licensed from iCeutica a technique called SoluMatrix to mill more finely nonsteroidal anti-inflammatory drugs (NSAIDs).
He paired the results on naproxen with results from a similar trial on submicron diclofenac, findings of which the company presented in May at the American Pain Society 31st Annual Scientific Meeting.
The company previously referred to the particle size as "nano" but changed the characterization to "submicron" because it did not fit the technical definition of nano, said Dr. McCarberg.
Lowest Dose, Shortest Duration
NSAIDs can cause cardiovascular, gastrointestinal, and renal adverse reactions, and these effects are more likely with higher doses, Dr. McCarberg said.
The US Food and Drug Administration (FDA) has issued a Public Health Advisory stating that NSAIDs should be administered at the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
Smaller particles have greater surface area per dose and therefore are more bioavailable, so in theory, a smaller dose might achieve the same effect, said Dr. McCarberg.
To test this approach, researchers recruited more than 450 patients experiencing moderate to severe pain within six hours of wisdom tooth extractions. They randomly assigned patients to receive one of the following: diclofenac 18 mg or 35 mg, naproxen 200 mg or 400 mg, celecoxib 400 mg (as an active control), standard formulation naproxen 250 mg or 450 mg, or placebo.
Compared with the placebo group, a higher proportion of all other groups rated their pain relief as "some," "a lot," or "complete" during the 12 hours after random assignment (P < .001).
The proportions of patients rating their pain relief in this range for each group in the submicron particle naproxen trial were as follows:
- Submicron particle naproxen 200 mg, 84.0% (42/50)
- Submicron particle naproxen 400 mg, 94.1% (48/51)
- Naproxen 250 mg, 82.0% (41/50)
- Naproxen 500 mg, 90.2% (46/51)
- Placebo, 41.2% (21/51)
Results in the submicron particle diclofenac phase 2 trial were reported as follows:
All groups took a single dose of the assigned medication.
- Submicron particle diclofenac 18 mg, 83.7% (41/49)
- Submicron particle diclofenac 35 mg, 84.3% (43/51)
- Celecoxib 400 mg, 58.8% (30/51)
- Placebo, 25.5% (13/51)
Differences between submicron formulations and reference active medications were not statistically significant.
Dr. Young acknowledged that the study does not show that submicron formulations achieve equivalent pain relief at a lower dose compared with standard formulations. However, he said that the drugs make take effect more quickly.
The mean time to pain relief for nano-formulated naproxen 400 mg was just over an hour vs more than three hours for placebo (P < .002) and an hour and a half for standard naproxen 500 mg, Iroko said in a press release. The company did not report whether the difference between the standard formulation and the submicron formulation was statistically significant.
Adverse reactions were similar in the various groups.
Commenting on the study, Srinivas Nalamachu, MD, co-director of the Pain Management Institute in Overland Park, Kansas, pointed out that if reducing adverse reactions is the main point of milling the drug as a finer powder, then its success remains to be shown, because the most common serious adverse reactions occur with chronic use, and this drug was given only in a single dose.
In response, Dr. McCarberg said, "If bioavailability predicts side effects, we would have the same side effects — ulcers and so on."
However, the submicron drugs produce a lower overall serum concentration, he said. "If blood level predicts side effects, then you would get fewer side effects with this formulation."
Also, the drug in submicron formulation may have less contact with the stomach, which might further reduce adverse reactions, said Dr. McCarberg.
Longer-term trials have not been conducted.
Dr. McCarberg has disclosed that he is an advisor to Iroko Pharmaceuticals, and Dr. Young has disclosed that he is an employee of that company. Dr. Nalamachu has disclosed no relevant financial relationships.
PAINWeek: Abstract 55. Presented September 6, 2012.
Laird Harrison • Medscape Medical News © 2012 WebMD, LLC