Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations

But better than coffee? WHOM do we got to to get that simple question answered?

Maybe you want to read these two negative articles on diclofenac:

Major Study Points to Cardiac and Stroke Risks of One of World’s Biggest Drugs

EU regulator advises caution on painkiller diclofenac

 

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

5. Parkinson’s Disease May Have Link to Stroke March 2017 

Coffee May Lower Your Risk of Dementia Feb. 2013 

And this: Coffee's Phenylindanes Fight Alzheimer's Plaque 

 

The latest here:

Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations 

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Olaf Stuve, Rick A. Weideman, Danni M. McMahan, ...

First Published June 25, 2020 Research Article

https://doi.org/10.1177/1756286420935676

Article information

Abstract

Background:

Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer’s disease (AD).

Materials and methods:

Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates.

Results:

Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84–1.20, p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09–0.68, p <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07–1.09, p <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60–5.81) indicating that as comorbidities increase, the risk for AD increases very significantly.

Conclusion:

Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.

Keywords Alzheimer’s disease, diclofenac, naproxen, etodolac

Introduction

Alzheimer’s disease (AD) is a chronic, progressive, and irreversible age-related neurodegenerative disorder characterized by cognitive and memory impairment. It is the most common cause of dementia in older adults. It was estimated in 2015 that 44 million people were living with AD worldwide, and this number is expected to double by 2050.¹ More than 95% of people with AD have sporadic or late-onset AD, a multi-factorial disorder with environmental factors and genetic predisposition contributing to the pathology.¹
The pathophysiology of AD is characterized by abnormal extracellular accumulation of amyloid-β peptide (Aβ) in amyloid plaques, and abnormal intracellular accumulation of tau protein in neurofibrillary tangles (NFTs).¹ Several theories are published regarding the AD pathogenesis. The amyloid cascade theory proposes that the accumulation of Aβ plaques in the brain is the primary pathogenic event.^2–4 The tau hypothesis proposes that tau hyperphosphorylation is the underlying etiology.^5–9 The cholinergic theory suggests AD is associated with a reduction in the choline acetyltransferase activity and acetylcholine levels in specific areas of the brain such as the cerebral cortex.^10,11 These proposed disease mechanisms result in a loss of synaptic function, mitochondrial damage, activation of microglia, and neuronal death.¹² Neuroinflammation is mediated primarily by microglia cells, and neuroinflammation contributes to AD pathogenesis.^13–15 Microglia activation has a dual effect on AD progression: it leads to (a) a reduction of Aβ accumulation by increasing phagocytosis, clearance, and degradation, and (b) the release of pro-inflammatory cytokines, and triggers the inflammatory cascade that contributes to neuronal damage and death.¹²
Interleukin-1β (IL-1β) is an important pro-inflammatory cytokine in the brain.^16,17 It is generated by the cytosolic nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes, where nucleotide-binding oligomerization-domain-like receptors (NLRs) are engaged, resulting in increased IL-1β release.¹⁸ Evidence is growing that IL-1β plays a central role in AD progression.^19,20 The NLRP3-IL-1β is synthesized and released from activated microglia and astrocytes. One study has documented that IL-1β interferes with glutamate reuptake in astrocytes, potentially leading to glutamate toxicity.²¹ Another study showed that soluble oligomeric Aβ increases the formation of mature IL-1β in microglia.¹² Over-expression of IL-1β release from microglia and astrocytes surrounding Aβ plaques occurs in the AD brain.^22,23 Several studies have demonstrated that the over-expression of IL-1β exacerbates tau phosphorylation and NFT development.^24–26 Subsequently, synaptic plasticity leads to disruption of the brain’s learning and memory processes.¹² Finally, the blockade or neutralization of IL-1β in an AD mouse model was protective against cognitive defects, decreased tau pathology and the synthesis of Aβ.¹²
Early studies of AD included the use of non-steroidal anti-inflammatory drugs (NSAIDs).²⁷ In a Cochrane NSAID and Alzheimer’s review, these prior studies in AD patients compared aspirin and NSAID exposures to patients who had not received them and the results from these studies were equivocal.²⁷ Vlad and colleagues, however, concluded that over time, ibuprofen and NSAIDs as a group have a protective effect but that other individual NSAIDs did not consistently exhibit this effect, perhaps due to ‘small numbers of users.’²⁸ In addition, many studies do not specify which NSAIDs were used, although the effects of indomethacin,^29,30 celecoxib,³¹ naproxen^32–35 ibuprofen,³⁶ and naproxen have been studied. Of these, only indomethacin²⁹ and ibuprofen²⁸ were associated with less cognitive decline in AD. A recent meta-analysis of 16 NSAID cohort studies³⁷ reported a decreased likelihood of AD with the pooled data of 236,022 patients; however, individual NSAIDs had no effect when stratified by NSAID type.
It is important to note that there are eight different chemical classes of NSAIDs³⁸ and this may have a significant effect on their ability to interrupt the AD process. In 2006, Joo and colleagues³⁹ found a neuroprotective effect of mefenamic acid administration in in vitro and in vivo models. In 2016, Daniels and colleagues⁴⁰ also detected a protective effect of the fenamate class of NSAIDs against AD and they hypothesized that it was due to inhibition of IL-1β release from the NLRP3 inflammasome in immortalized mouse bone-marrow-derived macrophages. In the initial in vitro phase of their study, the fenamates (flufenamic acid, mefenamic acid and meclofenamic acid) were more effective at inhibiting IL-1β release than celecoxib or ibuprofen, which had no effect on IL-1β release.⁴⁰ In contrast, diclofenac was associated with a modest but significant reduction in IL-1β release. In the second phase of their study, Daniels and colleagues showed that the fenamate drug class also prevented Aβ-induced memory deficits in rats,⁴⁰ and it decreased AD-related neuroinflammation in three AD-transgenic (TG) mice that expressed the presenilin mutation PS1M146V,⁴¹ the mutant amyloid precursor protein APPSwe,⁴² and a transgene of the human mutant P301 tau gene (tauP301L transgene).⁴³ These animals develop a progressive neuropathological phenotype with increasing age that includes Aβ plaques and neurofibrillary tangles.⁴⁴ Fenamate treatment was associated with decreased IL-1β expression and microglial activation in AD mice equivalent to levels in wild-type mice.⁴⁰
Very recently, Rivers-Auty and colleagues, evaluating fenamate NSAIDs, reviewed diclofenac use in a database of patients with Alzheimer’s disease and found that it reduced cognitive deterioration.⁴⁵ At this time, however, this finding has only been presented in abstract form.
The purpose of this retrospective cohort study was to determine whether chronic diclofenac use is associated with a lower frequency of AD in a veteran population compared with chronic use of etodolac or naproxen.

Major Study Points to Cardiac and Stroke Risks of One of World’s Biggest Drugs - painkiller, diclofenac

Be careful out there, maybe you want to have your doctor prescribe marijuana.

And since marijuana can help you recover from stroke, you get a twofer. 

My 13 reasons for marijuana use post-stroke.  

Don't follow me, I'm not medically trained.

Can Marijuana Be The Answer For Pain? - WebMD

 

Major Study Points to Cardiac and Stroke Risks of One of World’s Biggest Drugs

 One of the world’s most-used painkillers, diclofenac, sold under a variety of trade names in the U.S. including Voltaren, Cataflam, Cambia, and Zipsor, has been linked to an increased risk of heart attack and stroke in a major study of more than six million people published Wednesday morning. The Danish study, published in the British Medical Journal, finds that regular use of diclofenac, frequently taken for back pain, incurs an “increased risk of major adverse cardiovascular events” compared with use of paracetamol, other painkillers, or none at all. The study authors, based at Aarhus University Hospital, say the findings show it is time to “acknowledge potential health risks of diclofenac and reduce its use.”

EU regulator advises caution on painkiller diclofenac

Be careful out there.

EU regulator advises caution on painkiller diclofenac

Europe's drugs agency warned on Friday that use of the common painkiller diclofenac, especially in high doses, carries extra heart attack risks which should be taken into consideration by doctors prescribing the drug.
While it said the benefits of diclofenac, which is produced by several companies, still outweighed the risks, the European Medicines Agency recommended that precautions should be taken in certain patients.

"Patients who have serious underlying heart or circulatory conditions, such as heart failure, heart disease, circulatory problems or a previous heart attack or stroke, should not use diclofenac," it said in a statement.
EMA's decision, made by it's Pharmacovigilance Risk Assessment Committee, comes after a large international study last month showed that long-term, high-dose use of painkillers such as diclofenac and ibuprofen increases the risk of a major vascular event - a heart attack, stroke or dying from cardiovascular disease - by around a third.

This puts the heart risks of generic non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac on a par with a newer class of NSAIDs known as COX-2 inhibitors or coxibs, which includes Vioxx - a painkiller that US drugmaker Merck pulled from sale in 2004 because of links to heart risks.
EMA also said patients with certain risk factors such as high blood pressure, raised blood cholesterol, diabetes or smoking should "only use diclofenac after careful consideration".

"Healthcare professionals will also be advised to periodically re-assess the need for patients to continue taking the medicine," it added.

The agency said the safety of NSAIDs has been closely monitored in the European Union in recent years and safety reviews carried out in 2005, 2006 and 2012 found they were linked to a small increased risk of blood clots, which in some cases led to heart attacks or strokes.

High-Dose NSAIDs Hike Risk of Heart Attack and Stroke

Be careful out there.
http://www.medpagetoday.com/PainManagement/PainManagement/39457?
High doses of some commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) increased the risk of major vascular events by about a third, according to a new meta-analysis of clinical trials.
The increase -- mainly driven by a higher risk of myocardial infarction -- is similar to that seen with selective COX-2 inhibitors, or coxibs, according to Colin Baigent, MD, of the University of Oxford, and colleagues.
But the analysis suggests the size of the risk can be predicted, which could assist doctors and patients in making clinical decisions, the researchers reported online in The Lancet.
High-dose NSAIDs, widely used to manage pain in inflammatory disorders, have been linked previously with an increased risk of gastrointestinal complications.
The coxibs -- a newer generation of NSAIDs -- were developed to reduce gastrointestinal side effects, but were found to increase the risk of heart attacks and death.
But the vascular effects of the traditional NSAIDs -- diclofenac, ibuprofen, and naproxen at respective doses of 150, 2,400, and 1,000 mg daily -- has not been clear.
To help fill the gap, Baigent and colleagues in the Coxib and traditional NSAID Trialists' Collaboration undertook a meta-analysis of 639 trials of coxibs and traditional NSAIDs compared with each other or with placebo. The coxibs under study were mainly mainly celecoxib (Celebrex), rofecoxib (Vioxx), etoricoxib (Arcoxia), and lumiracoxib (Prexige).
The main outcomes were major vascular events, including non-fatal MI, non-fatal stroke, or vascular death, as well as major coronary events, stroke, mortality, heart failure, and upper gastrointestinal complications.
All told, the trials included more than 353,000 participants with patient-level data available for many of the studies.
The analysis showed:

• Major vascular events were increased by about a third by a coxib, where the rate ratio was 1.37 (95% CI 1.14-1.66, P=0.0009).
• The same was true for diclofenac: the rate ratio was 1.41 (95% CI 1.12-1.78, P=0.003).
• The increases were chiefly due to more major coronary events. The rate ratio for such events for coxibs was 1.76 (P=0.0001), while the ratio for diclofenac was 1.70 (P=0.003).
• Ibuprofen significantly increased major coronary events -- the rate ratio was 2.22 (95% CI 1.10 to 4.48, P=0.0253) -- but not major vascular events.
• Naproxen did not significantly increase major vascular events or vascular deaths.

Heart failure risk was roughly doubled by all NSAIDs and all NSAID regimens increased upper GI complications, with rate ratios of 1.81 for coxibs, 1.89 for diclofenac, 3.97 for ibuprofen, and 4.22 for naproxen.
Compared with placebo, Baigent and colleagues reported, the effect of coxibs or diclofenac was to slightly increase the risk of vascular events. For every 1,000 patients treated with either, rather than a placebo, there were three extra major vascular events, one of which was fatal.
On the positive side, high-dose naproxen seemed to be associated with less hazard, although it's "unclear" if that's true of the lower doses most commonly used in clinical practice, they reported.
"Whilst NSAIDs increase vascular and gastrointestinal risks to a varying extent," Baigent said in a statement, "our analyses indicate that the effects of different regimens in particular patients can be predicted, which may help physicians choosing between alternative NSAID regimens to weigh up which type of NSAID is safest in different patients."
Indeed, the analysis "offers considerable certainty" about the risks of high doses of commonly used NSAIDS, commented Marie Griffin, MD, of Vanderbilt University Medical Center in Nashville.
But in an accompanying commentary, Griffin argued that the study has some major gaps -- the risks associated with lower doses, longer durations of use, and residual effects after stopping treatment.
Clinical trials are not the whole story, she noted, and information to help fill those gaps might be found in observational studies.
But the bottom line, Griffin wrote, is that "identification of safe and effective strategies for chronic pain is sorely needed."
Until those are worked out, she concluded, "long-term use of high-dose NSAIDs should be reserved for those who receive considerable symptomatic benefit from the treatment and understand the risks."

Arthritis painkillers raise stroke, heart attack risk by more than a third, landmark study suggests

So ask your doctor which of these risk reduction ideas will counteract the use of these painkillers. You do expect your doctor to know this, don't you?
http://life.nationalpost.com/2013/05/30/arthritis-painkillers-raise-stroke-heart-attack-risk-by-more-than-a-third-landmark-study-suggests/
Millions of arthritis sufferers could be increasing their risk of a heart attack or stroke by more than a third by taking large doses of drugs such as ibuprofen, according to one of the largest studies into painkillers.
The study of more than 350,000 patients taking prescription doses of such medications found the chance of a heart attack or stroke rose by almost 40%.
The research found that the greater risk of cardiac side-effects from ibuprofen was similar to those of another arthritis drug, Vioxx, which was withdrawn from the market almost a decade ago when research suggested it might double the risk of heart attacks.

The painkillers were also found to double the risk of heart failure and bleeding ulcers when taken in high quantities

The painkillers, which are known as non-steroidal anti-inflammatory drugs (NSAIDs) and taken by millions of arthritis sufferers each day, were also found to double the risk of heart failure and complications such as bleeding ulcers when taken in high quantities.
The authors of the University of Oxford study said that their findings showed that prolonged use of such medicines was “risky”, but added that patients needed to weigh up the benefits against the potential dangers.
More than seven million people in Britain suffer from rheumatoid arthritis and osteoarthritis, and many rely on high doses of NSAIDs, which are also sold in lower quantities over the counter for common ailments.
The study, published in The Lancet, found that for every 1,000 people with a moderate risk of heart disease, about eight would normally have a heart attack or stroke each year.
When similar patients were given a year of treatment with a high dose of ibuprofen (2,400 milligrams daily) or another NSAID called diclofenac (150mg daily), that risk rose, with 11 patients suffering major cardiac events.
One in three of the extra heart attacks was fatal, the study found.
The same dosage, which is the maximum normally prescribed and twice the amount allowed over the counter, more than doubled the risk of heart failure from three cases in 1,000 to seven, and more than doubled the risks of complications such as bleeding ulcers.
If all seven million people with arthritis took the highest dosage of drugs, it would equate to an estimated 21,000 more heart attacks in sufferers, the study suggested.

‘We are trying to say yes, these drugs are risky, but it may be worth it’

Researchers said the study, funded by the Medical Research Council and the British Heart Foundation and led by the council’s unit at Oxford, had looked at the risks from common painkillers in “unprecedented detail.”
The lead author, Colin Baigent from the University of Oxford, said: “The research shows that, when used in high doses, diclofenac and ibuprofen increase the risk of cardiovascular disease, on average causing about three extra heart attacks a year in every 1,000 patients treated, one of which would be fatal.”
He added: “For many people who take these drugs for severe arthritis they make the difference between being able to go about their daily life or not. We are trying to say yes, they are risky, but it may be worth it.”
The findings, from an analysis of 639 randomized trials, found that a third drug, called naproxen, did not increase the risk of heart attacks or strokes when a high dose of 1,000mg a day was taken.
The study found that it was the most likely of the medications to cause bleeding from the stomach, but researchers said such problems were normally less serious.
Researchers said the cardiac risks from ibuprofen and diclofenac were “mainly relevant” to people with arthritis who were prescribed high doses or long periods. “A short course of lower dose tablets purchased without a prescription, for example, for a muscle sprain, is not likely to be hazardous,” said Prof Baigent.
Last year almost 17 million prescriptions were written by doctors in England for NSAIDs. About a third were for ibuprofen, a third for diclofenac and about a sixth for naproxen.
Alan Silman, the medical director of Arthritis Research UK, urged arthritis sufferers not to be “unduly concerned,” but said family doctors were turning increasingly to naproxen because of the potential cardiac risks of the other medications. He said: “There is an urgent need to find alternatives that are as effective, but safer.”
Dr. Shannon Amoils, research advisor at the BHF, said: “People should take the lowest effective dose of these drugs for the shortest time necessary.”

GPs 'ignore heart attack and stroke risk' of painkiller used by millions

Be careful out there. 

GPs 'ignore heart attack and stroke risk' of painkiller used by millions

Research shows that taking the painkiller diclofenac increases the risk of heart attacks and strokes by 63 per cent

Scientists are calling for the drug to be banned as safer alternatives available

UK's drugs watchdog said European safety review of diclofenac is underway

Patients told not to stop taking pill but do seek advice from GP