Women, Children and Some Ethnic Groups at More Risk from NSAID

By Pat Anson, PNN Editor

Health experts have known for over a decade that diclofenac, a non-steroidal anti-inflammatory drug (NSAID), raises the risk of heart failure, stroke and other cardiovascular problems. Because of that, oral formulations of diclofenac are only available by prescription in the U.S. and some European nations, although the drug is still widely available as an over-the-counter pain reliever in Asia, Africa and the Middle East.

“Most patients who are using diclofenac have arthritis, and many of them are at risk of heart disease,” says Bhagwat Prasad, PharmD, an associate professor in the Washington State University College of Pharmacy and Pharmaceutical Sciences. “So there is a concern that taking diclofenac may be putting them at even greater risk of cardiovascular events such as heart attack and stroke.”

Prasad is senior author of a study, recently published in the journal Clinical Pharmacology & Therapeutics, that found women, children and some ethnic groups are more at risk from diclofenac because they have low levels of an enzyme that helps metabolize the drug in their intestines.

The enzyme – known as UGT2B17 – is present at much lower levels in women than in men, which helps explain why there are more reports of women suffering heart damage after taking diclofenac. UGT2B17 is mostly absent in children under the age of nine.

Ethnic differences also play a role. In studies on human liver and intestinal samples, WSU researchers found that up to 90% of people of Japanese descent lack the gene for the enzyme, compared to just 20% of Caucasian people.

“No one knew why this heart toxicity is happening in some individuals,” said first author Deepak Ahire, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences. “Our study showed, for the first time, that UGT2B17 is important in diclofenac metabolism and suggests that differences in UGT2B17 expression are what makes people’s response to diclofenac so variable, leading to toxicity in some whereas for others the drug simply does not work.”

Ahire and his colleagues hope to confirm their findings in a clinical trial. They also want to work with large hospitals to further study the connection between diclofenac and patients with heart problems. One way they suggest to reduce the risk of cardiovascular problems is to use genetic testing to screen patients who may have problems metabolizing diclofenac.

According to the FDA’s Adverse Events Reporting System, there have been over 27,000 serious medical cases involving diclofenac since 2010, including 2,827 deaths. The number of U.S. cases has tripled in recent years, with women involved in nearly twice as many adverse events as men.

In 2020, the FDA approved the use of diclofenac in Voltaren, a topical OTC gel that contains a small dose of diclofenac absorbed through the skin. The WSU study involved higher dose diclofenac tablets that are taken orally and absorbed in the digestive system. About half the prescriptions written for diclofenac in the U.S. are for tablets.

A large 2018 study in Denmark found that people who used diclofenac were 50 percent more likely to have cardiovascular problems within 30 days of taking the drug than those who took nothing. The risk of gastrointestinal bleeding was also higher. The authors of that study recommended that diclofenac not be available OTC and should only be prescribed with prominent warning labels.

Fizzy Pain Relievers Are Bad for the Heart

By Pat Anson PNN Editor

Long-term use of the pain reliever acetaminophen has long been associated with liver, kidney, heart and blood pressure problems.  A new study has also found that some acetaminophen tablets are so loaded with salt that they significantly raise the risk of a heart attack or stroke in as little as one year.

At issue are dissolvable acetaminophen tablets that are mostly used to treat cold and flu symptoms, as well as minor aches and pains. The tablets quickly dissolve in water because of their high salt (sodium) content, creating a fizzy, effervescent drink that is absorbed more quickly in the digestive system than a standard tablet.

Some of the fizzy tablets contain as much as 440 milligrams of sodium per pill. A recommended daily dose of two tablets taken four times a day adds up to over 3,500 milligrams – more sodium than three McDonald’s Big Macs – and nearly double the daily amount recommended for healthy adults.

Since high salt content has long been associated with cardiovascular problems, a team of researchers looked at the health records of 300,000 people enrolled in Britain’s National Health Service who were prescribed acetaminophen (paracetamol) to see what impact the medications may have.

Their findings, recently published in the European Heart Journal, showed that patients with a history of high blood pressure (hypertension) taking fizzy acetaminophen tablets were up to 45% more likely to suffer a heart attack, stroke or heart failure within a year. Just one prescription for the tablets increased their risk of dying by 177 percent, and those with five or more prescriptions were 264% more likely to die.

The risk of a heart attack, stroke or death for patients without high blood pressure also rose with a prescription for fizzy acetaminophen, but to a lesser degree.

“The direct message from this study is clear—there are likely to be millions of people worldwide taking paracetamol on a daily basis in a ‘fast-acting’ effervescent or soluble formulation who are increasing their risks of cardiovascular disease and premature death,” wrote Aletta Schutte, PhD, and Bruce Neal, PhD, in an accompanying editorial.

“Fortunately, only a small proportion of paracetamol formulations contain sodium but, with ‘fast-acting’ and ‘fizzy’ medications increasing in popularity, the adverse effects of medication-related sodium intake look set to rise rather than fall.”

The risk isn’t limited to fizzy tablets with acetaminophen. Other effervescent medications containing aspirin, ibuprofen and even vitamins also contain high levels of sodium.  

With or without salt, long-term acetaminophen use can be risky. A recent study at the University of Edinburgh found that acetaminophen significantly raised the risk of heart disease and stroke in people with high blood pressure. Researchers said the increased risk of cardiovascular problems was similar to that seen with non-steroidal anti-inflammatory drugs (NSAIDs).

Acetaminophen is the most widely used over-the-counter pain reliever in the world — and is the active ingredient in Tylenol, Excedrin, and hundreds of pain medications. But a 2021 review found little or no evidence to support the use acetaminophen for most pain conditions.

Widespread Pain Raises Risk of Dementia and Stroke

By Pat Anson, PNN Editor

Widespread body pain caused by fibromyalgia and other chronic pain conditions raises the risk of stroke and dementia, including Alzheimer’s disease, according to a new study.

Researchers looked at health data for nearly 2,500 second generation participants in the long-running, community-based Framingham Heart Study. Participants in the “offspring” phase of the study were given a comprehensive check-up that included a physical exam, lab tests and detailed pain assessment when they enrolled in the early 1990’s. They were then reassessed every four years for signs of cognitive decline, dementia or stroke.

Over the next two decades, 188 of the participants were diagnosed with some form of dementia and 139 had a stroke.

While the number of cases was small, researchers found an association between pain and cognitive decline. Participants with widespread pain were 43% more likely to have some type of dementia, 47% more likely to have Alzheimer’s disease, and 29% more likely to have a stroke compared to those without widespread pain (WSP). 

“These findings provide convincing evidence that WSP may be a risk factor for all-cause dementia, AD dementia (Alzheimer’s), and stroke,” researchers concluded. “While it is known that chronic pain or persistent pain without detailed classification is associated with poorer cognitive performance in cross-sectional or cohort studies, our study was based on much more accurate assessments for pain at a longitudinal population level. The specific presence of WSP… has long-term implications for dementia and AD.”

The researchers said there were three possible explanations for the link between pain and cognitive decline. First are lifestyle factors associated with pain, such as reduced physical activity, poor diet, alcohol and weight gain. Second is that stress caused by widespread pain may impair cognitive function; and third is that WSP may be a “preclinical phase” of dementia and AD.

Previous studies have also linked chronic pain to dementia. A large 2017 study found that older people with chronic pain experience faster declines in memory and are more likely to develop dementia. A more recent study suggests that people with chronic pain are at higher risk of memory loss and cognitive decline if they have lower levels of education, income and access to healthcare.

Antidepressants, anti-psychotics, antihistamines and other common medications may also cause confusion and disorientation that is mistaken for dementia, especially in older adults. When patients are taken off the drugs, their cognitive function may improve.  

Previous studies have also linked widespread pain to cancer, peripheral arterial disease, cardiovascular disease and increased mortality.

Use of NSAIDs Risky for Osteoarthritis Patients

By Pat Anson, PNN Editor

It’s long been known that nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen can raise the risk of cardiovascular problems. A large new study in Canada has documented how NSAIDs can significantly raise the risk of heart disease, congestive heart failure and stroke in people with osteoarthritis.

Osteoarthritis (OA) is a joint disorder that leads to thinning of cartilage and progressive joint damage. NSAIDs are frequently used to treat the pain and inflammation caused by OA.

The Canadian study, published in the journal Arthritis & Rheumatology, looked at nearly 7,750 osteoarthritis patients in British Columbia and compared them with a control group of over 23,000 patients without OA. The average age of the participants was 65 and a little over half were women.

The risk of developing cardiovascular disease was found to be about 23% higher among people with OA than the control group. Researchers attributed about 41% of that increased risk to the use of NSAIDs.

NSAIDs appeared to play a significant role in several cardiovascular problems. The risk of congestive heart failure was 42% higher among people with OA, followed by a 17% greater risk of heart disease and a 14% greater risk of stroke.

"To the best of our knowledge, this is the first longitudinal study to evaluate the mediating role of NSAID use in the relationship between osteoarthritis and cardiovascular disease in a large population-based sample," said senior author Aslam Anis, PhD, of the School of Population and Public Health at the University of British Columbia.

"Our results indicate that osteoarthritis is an independent risk factor for cardiovascular disease and suggest a substantial proportion of the increased risk is due to the use of NSAIDs. This is highly relevant because NSAIDs are some of the most commonly used drugs to manage pain in patients with osteoarthritis."

The association of cardiovascular disease with NSAIDs is consistent with previous research.  A large international study in 2017, for example, found that prescription strength NSAIDs raises the risk of a heart attack as soon as the first week of use.

NSAIDs are used to alleviate pain and reduce inflammation, and are found in a wide variety of over-the-counter products, including cold and flu remedies. They are found in so many products -- such as Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

Canada adopted guidelines in 2017 that recommend NSAIDs as an alternative to opioid pain medication. The guideline makes no mention of the health risks associated with NSAIDs, but focuses on their cost effectiveness.

“NSAID-based treatment may have lower mean costs and higher effectiveness relative to opioids,” the guideline states. “Naproxen-based regimens in particular may be more cost effective compared to opioids and other NSAIDs, such as ibuprofen and celecoxib.”

Opioid guidelines released in 2016 by the U.S. Centers for Disease Control and Prevention also recommend NSAIDs as an alternative to opioids, but acknowledge the medications “do have risks, including gastrointestinal bleeding or perforation as well as renal and cardiovascular risks.”

In 2015, the Food and Drug Administration ordered warning labels for all NSAIDs to indicate they increase the risk of a fatal heart attack or stroke. The FDA warning does not apply to aspirin.

The European Society of Cardiology recommends limited use of NSAIDs by patients who are at risk of heart failure. People already diagnosed with heart failure should refrain from using NSAIDs altogether.

Aspirin Risky for Seniors 75 and Older

By Pat Anson, Editor

The old cliché about a doctor telling you to “take two aspirin and call me in the morning” isn’t such great advice after all. Especially for seniors aged 75 and older.

A daily dose of aspirin has long been recommended as a way to prevent a heart attack or stroke. But British researchers at the University of Oxford say the blood thinning effects of aspirin substantially raise the risk of gastrointestinal bleeding as patients grow older.

Their study, published in The Lancet medical journal, estimates that aspirin causes over 3,000 deaths in the U.K. annually.

“We have known for some time that aspirin increases the risk of bleeding for elderly patients. But our new study gives us a much clearer understanding of the size of the increased risk and of the severity and consequences of bleeds,” said lead author Professor Peter Rothwell.

“Previous studies have shown there is a clear benefit of short term anti-platelet treatment following a heart attack or stroke. But our findings raise questions about the balance of risk and benefit of long-term daily aspirin use in people aged 75 or over.”

Rothwell and his colleagues followed over 3,100 patients for 10 years who were prescribed a daily aspirin after a heart attack or stroke. For the patients under 65, the annual rate of bleeding severe enough to require hospitalization was about 1.5 percent. For patients aged 75-84, the annual rate rose to 3.5 percent and for patients over 85 it was 5 percent.

The researchers are not recommending that seniors stop taking aspirin. But they suggest that a proton-pump inhibitor – heartburn drugs – be prescribed along with aspirin to reduce the risk of bleeding.  They estimate that proton-pump inhibitors (PPIs) could reduce upper gastrointestinal bleeding by as much as 90% in patients receiving long-term aspirin treatment.

“While there is some evidence that PPIs might have some small long-term risks, this study shows that the risk of bleeding without them at older ages is high, and the consequences significant,” said Rothwell.

About half of adults aged 75 or older in the U.S. and Europe take aspirin or another anti-platelet drug daily .

Researchers Say NSAIDs Cause Heart Damage

By Pat Anson, Editor

Researchers have known for many years that non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of heart attack and stroke. Now they may finally be learning why the pain relievers can be harmful.

In experiments on heart cells from rats and mice, scientists at the University of California, Davis, found that NSAIDs reduced the activity of cardiac cells at pharmacological levels found in humans. Their study was recently published in the Journal of Molecular and Cellular Cardiology.

“We knew these non-steroidal anti-inflammatories had negative side effects for heart disease and stroke risk, “ said lead author Aldrin Gomes, a UC Davis associate professor of Neurobiology, Physiology and Behavior. “But now we have an idea of some of the mechanisms behind it.”

NSAIDs are widely used to treat everything from fever and headache to low back pain and arthritis. They are found in so many different products -- such as ibuprofen, Advil and Motrin -- that many consumers may not be aware how often they use NSAIDs. 

Several studies have found that NSAIDs increase the risk of cardiovascular disease and other health problems, but the exact cause has been unclear.

The UC Davis researchers compared naproxen, considered the safest over-the-counter NSAID, with a more potent anti-inflammatory, the prescription drug meclofenamate sodium (MS).

They found that MS increased reactive oxygen species, impaired mitochondrial function, decreased proteasome function, and increased cardiac cell death. Naproxen did not affect proteasome function or cause heart cells to die, but it did impair mitochondrial function and increase reactive oxygen species produced in cardiac cells.

“We were surprised to see that many of the NSAIDs we tested were causing the cardiac cell to die when used for prolonged periods,” said Gomes. “Some people are taking these drugs too often, and this is a problem. These drugs are abused.”

For moderate pain, Gomes suggests rubbing an anti-inflammatory topically onto the pained area, which would not expose the entire body to the drug. Taking an antioxidant like vitamin C before ingesting a NSAID may also reduce cardiac cell death.

Last year the U.S. Food and Drug Administration ordered warning labels for all NSAIDs to be strengthened to indicate they increase the risk of a fatal heart attack or stroke. The agency said studies have shown the risk of serious side effects can occur in the first few weeks of using NSAIDs and could increase the longer people use the drugs. The revised warning does not apply to aspirin.

The FDA said people who have a history of heart disease, particularly those who recently had a heart attack or cardiac bypass surgery, are at the greatest risk. But the risk is also present for people who don't have heart problems.

“Everyone may be at risk – even people without an underlying risk for cardiovascular disease,” said Judy Racoosin, MD, deputy director of FDA’s Division of Anesthesia, Analgesia, and Addiction Products.

In a major study published recently in the European Heart Journal, a number of leading heart specialists warned that there is no "solid evidence" that NSAIDs are safe.

"When doctors issue prescriptions for NSAIDs, they must in each individual case carry out a thorough assessment of the risk of heart complications and bleeding. NSAIDs should only be sold over the counter when it comes with an adequate warning about the associated cardiovascular risks. In general, NSAIDs are not be used in patients who have or are at high-risk of cardiovascular diseases," said co-author Christian Torp-Pedersen, a professor in cardiology at Aalborg University in Denmark.