New research may explain unexpected effects of common painkillers

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin are widely used to treat pain and inflammation. But even at similar doses, different NSAIDs can have unexpected and unexplained effects on many diseases, including heart disease and cancer.

Now, a new Yale-led study has uncovered a previously unknown process by which some NSAIDs affect the body. The finding may explain why similar NSAIDs produce a range of clinical outcomes and could inform how the drugs are used in the future.

The study was published May 23 in the journal Immunity.

Until now, the anti-inflammatory effects of NSAIDs were believed to arise solely through the inhibition of certain enzymes. But this mechanism does not account for many clinical outcomes that vary across the family of drugs. For example, some NSAIDs prevent heart disease while others cause it, some NSAIDs have been linked to decreased incidence of colorectal cancer, and various NSAIDs can have a wide range of effects on asthma.

Now, using cell cultures and mice, Yale researchers have uncovered a distinct mechanism by which a subset of NSAIDs reduce inflammation. And that mechanism may help explain some of these curious effects.

The research showed that only some NSAIDs -- including indomethacin, which is used to treat arthritis and gout, and ibuprofen -- also activate a protein called nuclear factor erythroid 2-related factor 2, or NRF2, which, among its many actions, triggers anti-inflammatory processes in the body.

"It's interesting and exciting that NSAIDs have a different mode of action than what was known previously," said Anna Eisenstein, an instructor at the Yale School of Medicine and lead author of the study. "And because people use NSAIDs so frequently, it's important we know what they're doing in the body."

The research team can't say for sure that NSAIDs' unexpected effects are due to NRF2 -- that will require more research. "But I think these findings are suggestive of that," Eisenstein said.

Eisenstein is now looking into some of the drugs' dermatological effects -- causing rashes, exacerbating hives, and worsening allergies -- and whether they are mediated by NRF2.

This discovery still needs to be confirmed in humans, the researchers note. But if it is, the findings could have impacts on how inflammation is treated and how NSAIDs are used.

For instance, several clinical trials are evaluating whether NRF2-activating drugs are effective in treating inflammatory diseases like Alzheimer's disease, asthma, and various cancers; this research could inform the potential and limitations of those drugs. Additionally, NSAIDs might be more effectively prescribed going forward, with NRF2-activating NSAIDs and non-NRF2-activating NSAIDs applied to the diseases they're most likely to treat.

The findings may also point to entirely new applications for NSAIDs, said Eisenstein.

NRF2 controls a large number of genes involved in a wide range of processes, including metabolism, immune response, and inflammation. And the protein has been implicated in aging, longevity, and cellular stress reduction.

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Aspirin is linked with increased risk of heart failure in some

Aspirin use is associated with a 26% raised risk of heart failure in people with at least one predisposing factor for the condition. That's the finding of a study published today in ESC Heart Failure, a journal of the European Society of Cardiology (ESC).1 Predisposing factors included smoking, obesity, high blood pressure, high cholesterol, diabetes, and cardiovascular disease.

"This is the first study to report that among individuals with a least one risk factor for heart failure, those taking aspirin were more likely to subsequently develop the condition than those not using the medication," said study author Dr. Blerim Mujaj of the University of Freiburg, Germany. "While the findings require confirmation, they do indicate that the potential link between aspirin and heart failure needs to be clarified."

The influence of aspirin on heart failure is controversial. This study aimed to evaluate its relationship with heart failure incidence in people with and without heart disease and assess whether using the drug is related to a new heart failure diagnosis in those at risk.

The analysis included 30,827 individuals at risk for developing heart failure who were enrolled from Western Europe and the US into the HOMAGE study. "At risk" was defined as one or more of the following: smoking, obesity, high blood pressure, high cholesterol, diabetes and cardiovascular disease. Participants were aged 40 years and above and free of heart failure at baseline. Aspirin use was recorded at enrolment and participants were classified as users or non-users. Participants were followed-up for the first incidence of fatal or non-fatal heart failure requiring hospitalisation.

The average age of participants was 67 years and 34% were women. At baseline, a total of 7,698 participants (25%) were taking aspirin. During the 5.3-year follow-up, 1,330 participants developed heart failure.

The investigators assessed the association between aspirin use and incident heart failure after adjusting for sex, age, body mass index, smoking, alcohol use, blood pressure, heart rate, blood cholesterol, creatinine, hypertension, diabetes, cardiovascular disease, and treatment with renin-angiotensin-aldosterone-system inhibitors, calcium channel blockers, diuretics, beta-blockers and lipid-lowering drugs. Taking aspirin was independently associated with a 26% raised risk of a new heart failure diagnosis.

To check the consistency of the results, the researchers repeated the analysis after matching aspirin users and non-users for heart failure risk factors. In this matched analysis, aspirin was associated with a 26% raised risk of a new heart failure diagnosis. To check the results further, the analysis was repeated after excluding patients with a history of cardiovascular disease. In 22,690 participants (74%) free of cardiovascular disease, aspirin use was associated with a 27% increased risk of incident heart failure.

Dr. Mujaj said: "This was the first large study to investigate the relationship between aspirin use and incident heart failure in individuals with and without heart disease and at least one risk factor. Aspirin is commonly used -- in our study one in four participants were taking the medication. In this population, aspirin use was associated with incident heart failure, independent of other risk factors."

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Aspirin's health benefits under scrutiny

Taking a baby aspirin every day to prevent a heart attack or stroke should no longer be recommended to patients who haven't already experienced one of these events.

That's according to a new study published in Family Practice.

Nearly one-quarter of Americans over the age of 40 have reported taking aspirin daily even if they don't have a history of heart disease or stroke.

That's a problem, says study author University of Georgia researcher Mark Ebell.

As a physician and epidemiologist at UGA's College of Public Health, Ebell's work evaluates the evidence underpinning clinical practice and health behaviors. The current recommendation for taking aspirin as the primary form of heart attack or stroke prevention is limited to adults aged 50 to 69 who have an increased cardiovascular risk.

"We shouldn't just assume that everyone will benefit from low-dose aspirin, and in fact the data show that the potential benefits are similar to the potential harms for most people who have not had a cardiovascular event and are taking it to try to prevent a first heart attack or stroke," said Ebell.

Aspirin was first found to reduce the risk of fatal and nonfatal heart attacks 30 years ago, and subsequent studies found evidence that aspirin may also reduce risk of stroke and colon cancer.

But aspirin use has always carried risks, said Ebell, namely bleeding in the stomach and brain.

More recent studies have begun to suggest that potential harms of taking aspirin may outweigh the benefits by today's medical standards.

"If you look back in the 1970s and '80s when a lot of these original studies were done, patients were not taking statin drugs to control cholesterol, their blood pressure was not as well controlled, and they weren't getting screenings for colorectal cancer," said Ebell.

Ebell and his colleague Frank Moriarty of the Royal College of Surgeons in Ireland compared aspirin studies using patient data from 1978 to 2002 to four large-scale aspirin trials occurring after 2005, when statin use and colorectal cancer screenings had become more widespread.

They found that for 1,000 patients treated for five years, there were four fewer cardiovascular events and seven more major hemorrhages. Ebell was particularly alarmed by the number of brain bleeds experienced by aspirin users.

"About 1 in 300 persons who took aspirin for five years experienced a brain bleed. That's pretty serious harm. This type of bleeding can be fatal. It can be disabling, certainly," he said. "One in 300 is not something that the typical doctor is going to be able to pick up on in their practice. That's why we need these big studies to understand small but important increases in risk."

Ebell cautions people who are concerned about their cardiovascular risk, but who haven't had a heart attack or stroke, to talk with their doctors about other ways to prevent a major event.

These days, he says, treatment for blood pressure, cholesterol and diabetes are more aggressive, and the rate of other risk factors like smoking has dropped.

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Migraine headaches? Consider aspirin for treatment and prevention

Migraine headache is the third most common disease in the world affecting about 1 in 7 people. More prevalent than diabetes, epilepsy and asthma combined, migraine headaches are among the most common and potentially debilitating disorders encountered by primary health care providers. Migraines also are associated with an increased risk of stroke.

There are effective prescription medications available to treat acute migraine headaches as well as to prevent recurrent attacks. Nonetheless, in the United States many patients are not adequately treated for reasons that include limited access to health care providers and lack of health insurance or high co-pays, which make expensive medications of proven benefit unaffordable. The rates of uninsured or underinsured individuals have been estimated to be 8.5 percent nationwide and 13 percent in Florida. Furthermore, for all patients, the prescription drugs may be poorly tolerated or contraindicated.

Researchers from Florida Atlantic University's Schmidt College of Medicine have proposed aspirin as a possible option for consideration by primary care providers who treat the majority of patients with migraine. Their review includes evidence from 13 randomized trials of the treatment of migraine in 4,222 patients and tens of thousands of patients in prevention of recurrent attacks.

Their findings, published in the American Journal of Medicine, suggest that high-dose aspirin, in doses from 900 to 1,300 milligrams given at the onset of symptoms, is an effective and safe treatment option for acute migraine headaches. In addition, some but not all randomized trials suggest the possibility that daily aspirin in doses from 81 to 325 milligrams may be an effective and safe treatment option for the prevention of recurrent migraine headaches.

"Our review supports the use of high dose aspirin to treat acute migraine as well as low dose daily aspirin to prevent recurrent attacks," said Charles H. Hennekens, M.D., Dr.PH, corresponding author, first Sir Richard Doll Professor and senior academic advisor in FAU's Schmidt College of Medicine. "Moreover, the relatively favorable side effect profile of aspirin and extremely low costs compared with other prescription drug therapies may provide additional clinical options for primary health care providers treating acute as well as recurrent migraine headaches."

Common symptoms of migraine include a headache that often begins as a dull pain and then grows into a throbbing pain, which can be incapacitating and often occurs with nausea and vomiting, and sensitivity to sound, light and smell. Migraines can last anywhere from four to 72 hours and may occur as many times as several times a week to only once a year.

"Migraine headaches are among the most common and potentially debilitating disorders encountered by primary health care providers," said Bianca Biglione, first author and a second-year medical student in FAU's Schmidt College of Medicine. "In fact, about 1 in 10 primary care patients present with headache and three out of four are migraines. Aspirin is readily available without a prescription, is inexpensive, and based on our review, was shown to be effective in many migraine patients when compared with alternative more expensive therapies."

Approximately 36 million Americans suffer from migraine headaches and the cause of this disabling disorder is not well understood. There is a higher prevalence in women (18 percent) than men (9 percent). In women, the prevalence is highest during childbearing age.

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