NSAIDS Don't Keep the Brain Nimble

By Crystal Phend
BALTIMORE, 13 may 2008 -- Patients at risk for Alzheimer's disease may see no cognitive benefits from the nonsteroidal anti-inflammatory drugs naproxen (Aleve) and celecoxib (Celebrex), researchers found.Global cognitive scores and cognitive impairment scores worsened over time with both naproxen and celecoxib compared with placebo (P=0.02 and P=0.04), reported Barbara K. Martin, Ph.D., of Johns Hopkins, and colleagues online in the Archives of Neurology. These secondary findings from the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) reinforce the lack of benefit for the primary endpoint of Alzheimer's disease prevention reported last year in Neurology.
However, the weak negative effect -- seen particularly with naproxen -- shouldn't be overly concerning to patients, Dr. Martin said. "I don't think it's applicable to decisions for pain use."
Inflammatory processes have been implicated in Alzheimer's disease as well as in cognitive impairment in the elderly, but the support for use of NSAIDs in prevention has come entirely from epidemiological evidence, the researchers said . So, the researchers analyzed cognitive function outcomes for 2,117 participants in the randomized, multicenter, chemoprevention ADAPT study. It included men and women 70 and older with a family history of Alzheimer's disease but no cognitive impairment at baseline.
Participants were randomized to receive double-blind celecoxib at a dose of 200 mg twice a day, naproxen at a dose of 220 mg twice a day, or placebo.
Dosing was halted in December 2004 when another study linked celecoxib to increased cardiovascular risk.
Cognitive testing scores through six months after treatment ended showed that mean scores typically declined during follow-up, but most of the declines were small and not statistically significant at individual points.
"Only for the 3MS-E [Modified Mini-Mental State Examination] do the differences approach a 10th of a standard deviation, or about one-third of a point on this 100-point scale, over a median follow-up of close to two years," the researchers wrote.
Scores on the exam were 0.32 points lower with celecoxib than with placebo (P=0.04) and 0.36 points lower with naproxen than placebo (P=0.03).
These declines for both NSAID groups were apparent at all time points and overall the difference compared with placebo was "equivalent to the average yearly decline in 3MS-E score in the placebo group."
Global summary scores combining results of seven individual cognitive assessment tests declined over time by 0.05 standard deviations with naproxen (P=0.02). Both placebo and celecoxib showed a 0.01 standard deviation decline (P=0.47).
Although longer follow-up is warranted because dementia and Alzheimer's disease are slow to develop, the researchers said "for now we suggest that naproxen and celecoxib should not be used for the prevention of Alzheimer's disease."
Reasons that previous studies have found strong epidemiologic evidence benefit whereas ADAPT showed the opposite could include confounding and duration of use or follow-up, Dr. Martin said.
Also, she said, ibuprofen (Advil, Motrin) accounted for most of the NSAID use in the observational trials. "So there's a question as to whether there is a difference within the class of NSAIDs as to how these medications might work in the possible prevention of Alzheimer's disease."
The study was supported by a grant from the National Institute on Aging. Pfizer provided celecoxib and matching placebo and Bayer Healthcare provided naproxen and matching placebo for the trial.
Dr. Martin declared no conflicts of interest. Other researchers reported conflicts of interest with Pfizer, GlaxoSmithKline, Forest Laboratories, Myriad Pharmaceuticals, SmartGenetics, AstraZeneca, Eisai, Janssen, Lilly, Novartis, Abbott Laboratories, Bristol-Meyers Squibb, sanofi-aventis, Schwabe, Elan, Merck, Neurochem, Ono, Ortho-McNeil, Takeda, patents for the use of NSAIDs for the prevention of Alzheimer's disease, and the Bryan Alzheimer's Disease Research Center.

Primary source: Archives of NeurologySource reference:ADAPT Research Group "Cognitive function over time in the Alzheimer's disease anti-inflammatory prevention trial (ADAPT): Results of a randomized, controlled trial of naproxen and celecoxib" Arch Neurol 2008; 65.