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.

Older Adults Look Beyond Western Medicine for Help With Joint Pain

By Pat Anson, PNN Editor

Most older Americans use over-the-counter pain medication and exercise to manage their joint pain, according to a large new survey of adults over age 50. Marijuana, opioids and non-steroidal anti-inflammatory drugs (NSAIDs) were rated the most effective pain relievers among those who used them.

The survey of 2,277 adults aged 50 to 80 was conducted online and over the phone early this year as part of the University of Michigan’s National Poll on Healthy Aging. It found that many older adults looked beyond conventional Western medicine for help with their joint pain, but few talked to their doctors about it.

Eight out of ten people (80%) with joint pain said they were confident they could manage it on their own. The survey found that two-thirds (66%) used over-the-counter pain relievers such as NSAID’s or acetaminophen.

The vast majority (89%) also used non-pharmacologic treatments to manage their symptoms, including exercise (64%), massage (26%), physical therapy (24%), splints or braces (13%), and acupuncture or acupressure (5%).

One in four (26%) said they take supplements, such as glucosamine, chondroitin and turmeric, while 11% use cannabidiol (CBD) products and 9% use marijuana.

Only a minority use prescription-based treatments, such as non-opioid pain relievers (18%), steroid joint injections (19%), oral steroids (14%), opioids (14%) and disease-modifying anti-rheumatic drugs (4%).

NATIONAL POLL ON HEALTHY AGING

“There are sizable risks associated with many of these treatment options, especially when taken long-term or in combination with other drugs. Yet 60 percent of those taking two or more substances for their joint pain said their health care provider hadn’t talked with them about risks, or they couldn’t recall if they had,” said Beth Wallace, MD, Assistant Professor of Internal Medicine at Michigan Medicine and a staff rheumatologist at the VA Ann Arbor Healthcare System.

“This suggests a pressing need for providers to talk with their patients about how to manage their joint pain, and what interactions and long-term risks might arise if they use medications to do so.”

Both NSAIDs and oral steroids have health risks, especially for older adults. Chronic NSAID use can worsen medical conditions such as hypertension, kidney disease, gastrointestinal bleeding and cardiovascular disease. Short-term use of oral steroids is associated with similar problems, as well as increased risk of developing diabetes, cataracts, insomnia, depression, and anxiety.

The risks are even greater if NSAIDs and oral steroids are taken together. Despite this, about one in four older adults taking oral steroids for joint pain said they had not discussed the potential risks with their provider.

Joint pain is common among older adults, including those who have not been formally diagnosed with arthritis. Nearly half of those surveyed reported joint pain that limited their daily activities, but few rated their symptoms as severe and most regarded joint pain as a normal part of aging.

Those with severe joint pain were somewhat fatalistic about it, with nearly half (49%) agreeing with the statement that “there is nothing a person with arthritis or joint pain can do to make their symptoms better.” Only 10% of those with mild joint pain agreed there was nothing they could do about it.

“Older adults with fair or poor physical or mental health were much more likely to agree with the statement that there’s nothing that someone with joint pain can do to ease their symptoms, which we now know to be untrue. Health providers need to raise the topic of joint pain with their older patients, and help them make a plan for care that might work for them,” said poll director Preeti Malani, MD, a Michigan Medicine physician who specializes in geriatrics and infectious diseases.

Widely Used Painkiller Raises Risk of Heart Problems

By Pat Anson, Editor

The most widely used painkiller in the world should be banned as an over-the-counter drug because it significantly raises the risk of cardiovascular problems and gastrointestinal bleeding, according to a large new study published in the British Medical Journal (BMJ).

Diclofenac is not well-known in the United States, but it is the most widely used non-steroidal anti-inflammatory drug (NSAID) in the world. It is sold both as a prescription and over-the-counter medication under various brand names such as Voltaren, Cambia, Zorvolex and Solaraze.

Researchers looked at healthcare data from over 6 million people in Denmark from 1996 to 2016 and found that those who used diclofenac were 50 percent more likely to have cardiovascular problems such as atrial fibrillation, heart failure and stroke in the first 30 days compared to those who took nothing. Their risk of gastrointestinal bleeding was also higher.

Out of every 1,000 people who used diclofenac, the study estimated that four additional people would develop a major health problem within a year.

"It is time to acknowledge the potential health risk of diclofenac and to reduce its use. Diclofenac should not be available over the counter, and when prescribed, should be accompanied by an appropriate front package warning about its potential risks," wrote lead author Morten Schmidt, MD, Aarhus University Hospital.

"Treatment of pain and inflammation with NSAIDs may be worthwhile for some patients to improve quality of life despite potential side effects. Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs."

This is not the first time that researchers have warned about the health risks associated with diclofenac and other NSAIDs.

In 2016, researchers at 14 European universities and hospitals, including a number of leading heart specialists, warned that some NSAID’s raise cardiovascular risk and that there is no "solid evidence" the drugs are safe.

Some of the greatest cardiovascular risk comes from a class of NSAIDs known as COX-2 inhibitors. A COX-2 inhibitor called Vioxx was voluntarily pulled from the market by Merck in 2004, but many other COX-2 inhibitors, such as diclofenac, are still widely used for pain relief.   

Another 2016 study published in the BMJ found that use of any NSAID was associated with a 20 percent higher risk of being hospitalized with heart failure. These seven NSAIDs were found to be the riskiest:

• diclofenac
• ibuprofen
• indomethacin
• ketorolac
• naproxen
• nimesulide
• piroxicam

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

In 2015, 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 FDA said studies found 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 European Society of Cardiology recommends limited use of NSAIDs by patients who are at increased risk of heart failure. Those already diagnosed with heart failure should refrain from using NSAIDs completely.

1 in 6 Seniors Take Risky Drug Combinations

By Pat Anson, Editor

One in six older adults now regularly use potentially deadly combinations of prescription drugs, over-the-counter (OTC) medications and supplements, a two-fold increase over a five-year period, according to new research published in JAMA Internal Medicine.

Researchers at the University of Illinois at Chicago surveyed over 2,200 Americans between the ages of 62 and 85 and found that over half (54%) were taking some type of pain reliever in 2011.

Over 40 percent used aspirin; nearly 14% took non-steroidal anti-inflammatory drugs (NSAIDs); and about 11% used an opioid analgesic.

Only 44% were using a pain reliever in 2006.

Researchers identified 15 potentially life-threatening drug combinations of the most commonly used medications and supplements. Statins, anti-platelet drugs such as aspirin, and supplements (specifically omega-3 fish oil) accounted for the vast majority of interacting drug medications, some of which worsen cardiovascular problems. Opioids were not listed among the 15 risky combinations.

Nearly 15% of older adults regularly used at least one of the dangerous drug combinations in 2011, compared to 8% five years earlier.

"The risk seems to be growing, and public awareness is lacking," said Dima Mazen Qato, an assistant professor of pharmacy systems at the University of Illinois.

"Many older patients seeking to improve their cardiovascular health are also regularly using interacting drug combinations that may worsen cardiovascular risk. For example, the use of clopidogrel in combination with the proton-pump inhibitor omeprazole, aspirin, or naproxen -- all over-the-counter medications -- is associated with an increased risk of heart attacks, bleeding complications, or death.”

As Pain News Network reported, European researchers also warned last week that aspirin and some types of NSAID’s could be harmful to patients with heart or kidney problems. The researchers said NSAIDs, in particular, raise cardiovascular risk and there is no "solid evidence" the drugs 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,” said Christian Torp-Pedersen, a professor in cardiology at Aalborg University in Denmark.

In opioid prescribing guidelines released last week, the Centers for Disease Control and Prevention recommends "nonopioid pharmacologic therapy" such as acetaminophen and NSAIDs as the "preferred" treatments for chronic pain. Only briefly do the CDC guidelines even mention that NSAIDs have been associated with cardiovascular risks or that acetaminophen may cause liver failure. Instead, the 52-page guideline focuses on the risks of opioid addiction and abuse.

Over half of the risky drug combinations in the University of Illinois study involved over-the-counter medications or dietary supplements.

New Warning About Over-the-Counter Pain Relievers

By Pat Anson, Editor

At a time when the U.S. Centers for Disease Control and Prevention is recommending that non-opioid pain relievers such as non-steroidal anti-inflammatory drugs (NSAIDs) be used to treat chronic and acute pain, European researchers are warning about health risks associated with those same over-the-counter pain medications.

In guidelines for primary care physicians released on Tuesday, the CDC said "nonopioid pharmacologic therapy" such as acetaminophen and NSAIDs are "preferred" treatments for chronic pain.

Only briefly do the CDC guidelines even mention that NSAIDs “have been associated with hepatic, gastrointestinal, renal, and cardiovascular risks” and that acetaminophen may cause liver failure. The 52-page guideline instead focus on the risks of addiction and abuse associated with opioids.

But in a major new study published this week in the European Heart Journal, researchers at 14 European universities and hospitals, including a number of leading heart specialists, warn that some NSAID’s raise cardiovascular risk and that there is no "solid evidence" the drugs 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.

Some of the greatest cardiovascular risk comes from a class of NSAIDs known as COX-2 inhibitors. A COX-2 inhibitor called Vioxx was voluntarily pulled from the market by Merck in 2004, but many other COX-2 inhibitors, such as Diclofenac, are still widely used around the world for pain relief.   

"It's been well-known for a number of years that newer types of NSAIDs - what are known as COX-2 inhibitors, increase the risk of heart attacks. For this reason, a number of these newer types of NSAIDs have been taken off the market again. We can now see that some of the older NSAID types, particularly Diclofenac, are also associated with an increased risk of heart attack and apparently to the same extent as several of the types that were taken off the market," said Morten Schmidt, MD, a postdoctoral research fellow at Aarhus University in Denmark.

Diclofenac is the most widely used NSAID in the world. It is sold under a number of different brand names, including Cambia, Voltaren and Zorvolex.

A second study of NSAIDs, published this week in the New England Journal of Medicine, found that emergency room admissions can be significantly reduced if doctors stopped the “high-risk prescribing” of NSAIDs.

Researchers enrolled a group of primary care physicians in Scotland in an educational program aimed at reducing the exposure of patients with heart or kidney problems to NSAIDs like ibuprofen and aspirin, especially if the patients were taking anticoagulant drugs like warfarin. The study involved over 33,000 high risk patients.

After 48 weeks, the rate of hospital admissions for gastrointestinal ulcers or bleeding was significantly reduced, as was the rate of admissions for heart failure.

"Our previous work has shown that high-risk prescribing is common and often causes important harm. This new study shows that relatively simple interventions can significantly reduce high-risk prescribing in a lasting way, and are associated with reductions in emergency hospital admission for related complications,” said Professor Bruce Guthrie of the University of Dundee in Scotland.

High-risk prescribing and preventable drug-related complications are major concerns for healthcare providers around the world. Up to 4 per cent of emergency hospital admissions are caused by preventable adverse drug events, and in the United States the avoidable cost of drug-related hospital admissions was estimated at $19.6 billion in 2013.

The majority of drug-related emergency admissions to hospitals are caused by commonly prescribed drugs such as NSAIDs and acetaminophen.  Over 50 million people in the U.S. use acetaminophen each week for pain and fever – many not knowing the medication has long been associated with liver injury and allergic reactions such as skin rash. Over 50,000 emergency room visits each year in the U.S. are blamed on acetaminophen overdoses.

A recent study in the British Medical Journal  found that acetaminophen was ineffective in treating low back pain and provides little benefit to people with osteoarthritis. And in a survey of over 2,000 pain patients by Pain News Network and the International Pain Foundation, 76 percent said that over-the-counter pain relievers “did not help at all” in relieving their pain.

FDA: 'Everyone May Be at Risk' from NSAIDs

By Pat Anson, Editor

Warning that "everyone may be at risk," the U.S. Food and Drug Administration has ordered warning labels for non-steroidal anti-inflammatory drugs(NSAIDs) to be strengthened to indicate they increase the risk of a fatal heart attack or stroke.

The warning applies to ibuprofen, Advil, Motrin and other popular pain relievers sold over-the-counter, as well as prescriptions drugs containing NSAIDs. Many multi-symptom cold and flu products also contain NSAIDs.

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.

“There is no period of use shown to be without risk,” says Judy Racoosin, MD, deputy director of FDA’s Division of Anesthesia, Analgesia, and Addiction Products.

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 for a serious cardiovascular event associated with NSAIDs. 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,” Racoosin said.

NSAIDs are widely used to treat everything from fever and headache to low back pain and arthritis. They are in so many different pain relieving products that health officials believe many consumers may not be aware how often they use NSAIDs. 

“Be careful not to take more than one product that contains an NSAID at a time,” said Karen Mahoney, MD, deputy director of FDA’s Division of Nonprescription Drug Products.

The labels for both prescription and over-the-counter NSAIDs already have information warning of heart attack and stroke risk. In the coming months, FDA will require drug manufacturers to update their labels with more specific information warning that the risk is heightened even in the first few weeks of use.

“Consumers must carefully read the Drug Facts label for all nonprescription drugs. Consumers should carefully consider whether the drug is right for them, and use the medicine only as directed. Take the lowest effective dose for the shortest amount of time possible," Mahoney said.

Several recent studies have found that NSAIDs increase the risk or heart attack and other health problems. The exact cause is unclear, but researchers believe NSAIDs may raise blood pressure and fluid retention, which can affect how the heart functions.  

A 2013 study published in The Lancet warned that high doses of NSAIDs may increase the risk of heart problems by about a third. In a review of over 600 clinical trials involving more than 353,000 patients, researchers found that NSAIDs doubled the risk for heart failure. People on high doses of the drugs also had up to four times greater risk for bleeding ulcers or gastrointestinal problems.

Another large study at the University of Florida in 2014 found that the over-the counter pain reliever naproxen raises the risk of a heart attack, stroke and death in postmenopausal women. Naproxen is a NSAID and the active ingredient in Aleve and other pain relievers commonly used to treat arthritis.

Studying data from over 160,000 postmenopausal women participating in a study funded by the National Institutes of Health, researchers estimated that using naproxen just twice a week raises the risk of cardiovascular problems by about 10 percent. The same study did not find a higher risk of a heart attack, stroke and death associated with ibuprofen, another type of NSAID.

Aleve & Other Pain Relievers Reduce Fertility in Women

By Pat Anson, Editor

Health experts have warned for years about the side effects of over-the-counter pain relievers – everything from liver failure to heart disease to hearing loss.

Now researchers are saying that Aleve and some other non-steroidal anti-inflammatory drugs (NSAIDs) reduce the fertility of women so significantly they could potentially be used as an emergency form of contraception.

The results of a small study presented at the European League Against Rheumatism Annual Congress show that three NSAIDs --  naproxen, diclofenac, and etoricoxib -- inhibited ovulation in women after just a few days of treatment.

Naproxen, diclofenac, and etoricoxib are the active ingredients in several brand name drugs sold around the world, including Aleve, Voltaren, and Arcoxia, respectively. Etoricoxib is not approved for use in the United States.

Thirty nine Iraqi women of childbearing age who suffered from back pain took part in the study; receiving diclofenac (100mg once daily), naproxen (500mg twice daily), etoricoxib (90mg once daily), or a placebo.

Treatment was given for 10 days from day 10 of the onset of their menstrual cycle, with their progesterone levels and follicle diameter analyzed via blood sample and sonography.

“After just ten days of treatment we saw a significant decrease in progesterone, a hormone essential for ovulation, across all treatment groups, as well as functional cysts in one third of patients,” said study investigator Professor Sami Salman, Department of Rheumatology, University of Baghdad.

“These findings show that even short-term use of these popular, over-the-counter drugs could have a significant impact on a woman's ability to have children. This needs to be better communicated to patients with rheumatic diseases, who may take these drugs on a regular basis with little awareness of the impact.”

Of the women receiving NSAIDs, only 6.3% taking diclofenac, 25% taking naproxen, and 27.3% taking etoricoxib ovulated, compared with 100% of the control group that was not taking a pain reliever.

The dominant follicle remained unruptured in 75% of the women taking diclofenac, 25% taking naproxen and 33% of the patients receiving etoricoxib. Rupturing of the dominant follicle and the subsequent release of an oocyte (unfertilized egg), is essential for ovulation to occur.

“These findings highlight the harmful effects NSAIDs may have on fertility, and could open the door for research into a new emergency contraception with a more favorable safety profile than those currently in use,” said Salman.

NSAIDs are among the most common pain relief medicines in the world. Every day more than 30 million Americans use them to relieve pain, lower fever and reduce inflammation.