April 18Over-the-counter painkillers known as nonsteroidal anti-inflammatory drugs under the well-known brand names of Advil, Motrin and Aleve, to name a few are among the most commonly used drugs on the planet as temporary treatment for headaches, arthritis, gout, muscle aches, athletic injuries and other discomforts.
But many users aren't aware, or choose to ignore, the fact that relieving pain or reducing fever with ibuprofen and other such drugs pose serious health risks, including heart problems. This is especially the case for people taking large doses over several months or even years.
That's why a recent Danish study and commentary published in the European Heart Journal recommended these drugs known as NSAIDs no longer be sold over the counter.
"Allowing these drugs to be purchased without a prescription, and without any advice or restrictions, sends a message to the public that they must be safe," said Gunnar H. Gislason of Copenhagen University Hospital in Denmark, commenting about his team's study findings verifying the drugs' side effects. "Previous studies have shown that NSAIDs are related to increased cardiovascular risk, which is a concern because they are widely used."
Use of any variety of NSAID, save for aspirin, is associated in the study with a 31 percent elevated risk of cardiac arrest. Ibuprofen (Motrin and Advil), which accounts for more than half of total NSAID usage, brings a 50 percent higher risk of cardiac arrest. The study recommends daily doses of ibuprofen no higher than 1,200 milligrams.
A typical Advil capsule or pill, for example, is 200 milligrams.
Naproxen (Aleve) was safest among all NSAIDs, the study found, with no occurrence of cardiac arrest. But even that drug wasn't fully exonerated due to smaller sample size.
Other NSAID drugs include ketoprofen (Actron, Orudis) and diplofenac (Voltaren), the latter of which the study showed to have a 31 percent elevated risk of heart problems.
"The findings are a stark reminder that NSAIDs are not harmless," Mr. Gislason stated in commentary about the study, noting they "should be used with caution and for a valid indication" and "should also be avoided in patients with cardiovascular disease or cardiovascular risk factors."
The U.S. Food and Drug Administration put a boxed warning on the drugs in 2005 and strengthened the warning in 2015, noting that they can "increase the chance of heart attack or stroke, either of which can cause death."
"Those serious side effects can occur as early as the first few weeks of using an NSAID, and the risk might rise the longer people take NSAIDs," the FDA says, adding that the warning does not apply to aspirin, which also is an NSAID. In fact, the FDA goes even further in stating that there is no period of use shown to be without risk and the higher the dose and longer the usage, the greater the risk.
Ajay D. Wasan, vice chair for pain medicine in the University of Pittsburgh Department of Anesthesiology, said the Danish study conclusions long have been known, especially when high doses of the drugs are used for extended periods of time.
Still, the drugs serve as important treatments for controlling pain. While banning over-the-counter sale of the drugs might have some merit, they are generally considered safe when used as directed.
"There are not a whole lot of alternatives, and the alternatives are not great either. All have their own risks. For instance, there are times when low-dose opioids are safer than NSAIDs for chronic pain," said Dr. Wasan, who also is a professor of anesthesiology and psychiatry at the Pitt School of Medicine. "This is one of the huge struggles and problems with formulating a sustainable plan for chronic pain care. Studies are consistent in showing difficulties in treating chronic pain."
Biology of concern
The anti-inflammation and pain-relieving components of NSAIDs result from their inhibition of the Cox-2 enzyme, which develops a fat compound involved in generating inflammation and sensitizing neurons in the spinal cord to pain.
Garret A. FitzGerald, director of Pitt's Institute for Translational Medicine & Therapeutics, did an early study that predicted that NSAIDS, by their impact on blood vessels, would cause heart problems. His research was prophetic.
He said studies now show the drugs present "a cardiovascular hazard similar in magnitude to that resulting from being a smoker or having diabetes" given the human tendency to "take whatever doses are necessary to relieve pain." Other risks can include gastrointestinal problems and kidney failure, among others. Yet other studies show it can cause acid reflux.
"If used as intended" in moderate doses taken transiently, cardiovascular risk is minimal to nonexistent. When higher doses are taken chronically, the person should seek a doctor's advice," Dr. FitzGerald said. High-risk patients with heart disease, kidney disease or diabetes should avoid NSAIDs.
Banning their sale over the counter "certainly is a legitimate consideration," he said, adding however that "we all have had headaches or sprains, and we're glad to get ibuprofen." In those cases, "the risk is minimal."
Rofecoxib (Vioxx) was removed from the market in 2004 due to health concerns. Celebrex, made from a similar compound (celecoxib) is prescription only, although Pfizer, its manufacturer, is working to make it available over the counter.
"Once over the counter, anything can happen," Dr. FitzGerald said.
Naproxen is probably the safest of this class of pain reliever, experts say, with the study limiting the dose to no more than 500 milligrams a day.
The study also provides reasons why such drugs increase the risk of heart attacks, including aggregation of platelets in the blood, blood clots, constricted arteries, fluid retention and higher blood pressure. Dr. FitzGerald said his early study showed that the drugs remove nitric oxide, which provides elasticity to blood vessels, while also affecting cells in a way that causes blood vessels to stiffen.
Given the science, David Gortler, a drug safety expert with FormerFDA.com, said he thinks such over-the-counter medications probably need even stronger cautions on medication packaging.
"The question is, with what we now know about NSAIDs, they likely would have been prescription-only had these long-term cardiovascular effects been known back then," when they received FDA approval decades ago.
One alternative is acetaminophen (Tylenol) that doesn't reduce inflammation but blocks pain signaling to the brain.
"The problem is, people see a tablet in the palm of the hand and don't understand the vastly complicated pharmacology and science that goes into its development," he said.
Mr. Gortler, who holds two doctoral degrees, said while the drugs generally are safe when used as directed, the "government can't monitor what patients do with their medication once they take it home. But if consumers continue being irresponsible and there is an increase in deaths, the possibility of quantity restriction or prescription-only status for NSAIDs might have to be explored."
Danish study author Dr. Gislason said NSAIDs' wide availability simply sends the wrong public message.
"If you can buy these drugs in a convenience store then you probably think, 'they must be safe for me,' " he stated. "Our study adds to the evidence about the adverse cardiovascular effects of NSAIDs and confirms that they should be taken seriously and used only after consulting a health care professional."
David Templeton: firstname.lastname@example.org or 412-263-1578.
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