Therapeutics

Naproxen

Overview

Name: Naproxen
Synonyms: Aleve™, Anaprox™, Naprosyn™
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Procter & Gamble
Approved for: Over-the-counter drug for reduction of pain, fever, inflammation, and stiffness.

Background

Naproxen is an over-the-counter nonsteroidal anti-inflammatory drug (NSAID). It inhibits COX-1 and COX-2, both isoforms of the cyclooxygenase enzyme, and reduces inflammation through reduced prostaglandin synthesis.

In the Alzheimer's field, interest in NSAIDs arose when epidemiological studies started reporting lower rates of Alzheimer's or cognitive decline among people who had been taking these drugs for chronic treatment of inflammatory conditions (e.g., Mar 1997 newsin't Veld et al., 1998Nov 2001 news; Vlad et al., 2008Obermann et al., 2013). Experimental studies supported the argument that inflammation plays a role in Alzheimer's disease, prompting a wave of clinical trials of various NSAIDs, e.g., ibuprofen, rofecoxib, celecoxib, and R-flurbiprofen.

Findings

Three clinical trials of naproxen in Alzheimer's disease have been conducted.

In 2000 and 2001, the Alzheimer's Disease Study Group conducted a 40-center trial that compared one year of treatment with 220 mg twice daily of naproxen or 25 mg once daily of rofecoxib to placebo in 351 people with mild to moderate Alzheimer's disease. The trial assessed whether these drugs would slow cognitive decline, but found that neither showed any consistent benefit over placebo (Jul 2002 conference news; Aisen et al., 2003).

The second trial was the Alzheimer's Disease Anti-Inflammatory Prevention Trial, aka ADAPT. Funded by the NIA, this primary prevention study started in 2001 to enroll 2,625 people 70 or older who had a parent or sibling with Alzheimer's or another dementing illness of aging. Conducted at six U.S. sites, this study aimed to determine whether naproxen or celecoxib can delay the onset of AD or age-related cognitive decline. ADAPT was to conduct annual cognitive assessments for five to seven years; however, the trial soon became embroiled in a public controversy (see Sep 2002 news). In September 2004, Merck withdrew the related NSAID celebrex. In December 2004, the NIA halted dosing in ADAPT, citing an increase in cardiovascular side effects in its naproxen arm (Sep 2004 news; Dec 2004 news). A separate report raising concerns about a slightly elevated risk of heart attack with long-term naproxen and other NSAID treatment soon followed (Graham et al., 2005). ADAPT safety data were subsequently published but failed to end ongoing controversy over the decision to halt the trial (Nov 2006 news).

Efficacy data from ADAPT showed that neither naproxen nor celecoxib delayed incident dementia or cognitive decline; naproxen was reported to have hastened cognitive decline slightly (ADAPT Research Group 2007; ADAPT Research Group 2008). ADAPT came to exemplify conflicting findings between observational epidemiology, which continued to report protective effects of NSAIDs on cognition, and RTCs, which were negative (May 2008 news story).

Analysis of ADAPT data continued for some years. Results from a further two years of follow-up until 2007 indicated a dichotomy whereby people who were symptomatic at baseline worsened on naproxen compared to placebo, but people who were cognitively normal at baseline were less likely to decline and had a healthier CSF biomarker signature at that point (Jul 2009 conference news; Breitner et al., 2011). A subsequent follow-up evaluation of some 1,500 participants in 2010 and 2011 reported that one to three years of preventive treatment with naproxen in people with a family history of AD conferred no protection against cognitive decline (Alzheimer's Disease Anti-inflammatory Prevention Trial Research Group 2013ADAPT-FS Research Group 2014 ).

Additional analyses attempted to distinguish between slow and fast decliners and to identify a time window during the prodromal phase of AD in which naproxen might be beneficial. A possible benefit of naproxen only during the presymptomatic phase was seen as being consistent with both ADAPT and epidemiological data (e.g., Leoutsakos et al., 2011).

A third trial, started in 2012 in Montreal, enrolled 195 cognitively normal people 55 and older who have a parent or multiple siblings with AD; biomarker evidence of preclinical AD was not required for inclusion. Participants were randomized to 220 mg twice daily of naproxen or placebo for two years. Primary outcomes were the global score on the Repeatable Battery for Assessment of Neuropsychological Status, as well as a composite Alzheimer progression score (APS) derived from multiple cognitive and biomarker measures of preclinical Alzheimer's disease. Safety parameters, naproxen kinetics, CSF biomarkers of AD pathology, and plasma/CSF markers of inflammation were secondary outcome measures. Efficacy data indicated no benefit of naproxen over placebo on the trajectory of the APS, or on any of the underlying measures. The naproxen group had more adverse events, including hypertension, gastrointestinal, and vascular or cardiac problems. While the trial was underpowered to have detected a potential small naproxen effect, the authors conclude such an effect would be difficult to demonstrate in a randomized prevention trial, and that the drug’s proven adverse effects would raise ethical concerns (see Meyer et al., 2019, Apr 2019 news).

Last Updated: 12 Apr 2019

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References

News Citations

  1. Stockholm: Bad News Official: The Rofecoxib and Naproxen Clinical Trial Has Failed
  2. Trials and Tribulations: Does ADAPT Have to Adapt?
  3. Merck Withdraws Vioxx®
  4. Safety Concerns Halt ADAPT Trial
  5. ADAPT Safety Data Released—Controversy Persists
  6. NSAIDs in AD: Epi and Trial Data at Odds—Again
  7. Vienna: New Genes, Anyone? ICAD Saves Best for Last
  8. Closing the Book on NSAIDs for Alzheimer’s Prevention
  9. Ibuprofen Linked to Reduced Alzheimer's Risk
  10. Large Prospective Study Finds NSAIDs Reduce Risk of Developing AD

Therapeutics Citations

  1. Ibuprofen
  2. Rofecoxib

Paper Citations

  1. . Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2819-26. PubMed.
  2. . Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005 Feb 5-11;365(9458):475-81. PubMed.
  3. . Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. Epub 2007 Apr 25 PubMed.
  4. . 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 Jul;65(7):896-905. Epub 2008 May 12 PubMed.
  5. . Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement. 2011 Jul;7(4):402-11. PubMed.
  6. . Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT). Alzheimers Dement. 2013 Nov;9(6):714-23. Epub 2013 Apr 3 PubMed.
  7. . Follow-up evaluation of cognitive function in the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial and its Follow-up Study. Alzheimers Dement. 2014 Jul 8; PubMed.
  8. . Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.
  9. . INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology. 2019 Apr 5; PubMed.
  10. . NSAIDs and incident Alzheimer's disease. The Rotterdam Study. Neurobiol Aging. 1998 Nov-Dec;19(6):607-11. PubMed.
  11. . Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008 May 6;70(19):1672-7. PubMed.
  12. . Exploration of 100 commonly used drugs and supplements on cognition in older adults. Alzheimers Dement. 2013 Aug 14; PubMed.

Other Citations

  1. R-flurbiprofen

Further Reading

Papers

  1. . Elevated ratio of urinary metabolites of thromboxane and prostacyclin is associated with adverse cardiovascular events in ADAPT. PLoS One. 2010;5(2):e9340. PubMed.
  2. . Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. CNS Neurol Disord Drug Targets. 2010 Apr;9(2):140-8. PubMed.
  3. . Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment?. Front Aging Neurosci. 2010;2 PubMed.
  4. . Role of APOE and Age at Enrollment in the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). Dement Geriatr Cogn Dis Extra. 2012 Jan;2(1):304-11. PubMed.
  5. . Celecoxib or Naproxen Treatment Does Not Benefit Depressive Symptoms in Persons Age 70 and Older: Findings From a Randomized Controlled Trial. Am J Geriatr Psychiatry. 2011 Jul 19; PubMed.
  6. . Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.
  7. . Naproxen for presymptomatic Alzheimer disease: Is this the end, or shall we try again?. Neurology. 2019 Apr 5; PubMed.
  8. . A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. J Alzheimers Dis. 2018;66(1):97-104. PubMed.
  9. . Determining the Molecular Pathways Underlying the Protective Effect of Non-Steroidal Anti-Inflammatory Drugs for Alzheimer's Disease: A Bioinformatics Approach. Comput Struct Biotechnol J. 2017;15:1-7. Epub 2016 Oct 29 PubMed.
  10. . Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: a systematic review and meta-analysis of treatment effect. Drugs Aging. 2015 Feb;32(2):139-47. PubMed.