Risk of Harm from Motrin, Aleve, Advil - Better Odds in a Crap Shoot

Complications from non-steroidal anti-inflammatory drugs, or NSAID, have been linked to 103,000 hospitalizations and more than 16,000 deaths per year in the US, according to a study published in the American Journal of Therapeutics.

A lack of information, experts say, is the root cause of the lack of concern over the health risks associated with NSAIDs. A report in the January 16, 2005, Science Daily said: "More people die each year from NSAIDs-related complications than from AIDS and cervical cancer in the United States."

Experts say the risk of their many adverse effects increase and vary depending on the patient's age, dosage, and duration of use. NSAIDs include:

• Ibuprofen (Advil, Motrin, Nuprin).
• Naproxen (Aleve, Naprosyn).
• Indomethacin (Indocin).
• Ketoprofen (Orudis).
• Piroxicam (Feldene).

A January 2003, Over-the-Counter Pain Medication Study, by the National Consumer League, determined that NSAIDs make up the largest share of the OTC pain medication market. About 110 million Americans who take OTC pain medications take NSAIDs most often. In fact, the study found, Americans are twice as likely to take NSAIDs than they are to take acetaminophen-based products including Tylenol.

There are also many OTC products that contain ibuprofen such as: Advil Cold And Sinus, Advil Cold, Advil Allergy Sinus, Children's Advil Allergy Sinus, Ibuprohm Cold and Sinus, Sine-Aid IB, Children's Motrin Cold.

Products that contain naproxen include Aleve, Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, and Naprapac (copackaged with lansoprazole).

A new study, published in the June 27, 2006 journal, Circulation, is the fifth study in a little over a year to claim that NSAIDs cause heart problems. The researchers in Circulation say NSAIDs can greatly and quickly increase the risk of death in persons who have already had one heart attack.

Dr Gunnar Gislason, from the Gentofte University Hospital in Hellerup Denmark, and colleagues gathered the medical records from the Danish National Patient Registry on 58,432 patients 30 and older who had survived a heart attack between 1994 and 2002.

They then examined the Danish Registry of Medicinal Product Statistics for information regarding prescriptions of NSAIDs, their dosages, and how long they were prescribed.

With high daily doses of NSAIDs, the study found the likelihood of dying was doubled or quadrupled depending on the specific drug, and the risk of another heart attack went up 22% to 89%.

"In addition," Dr Gislason told Heartwire on June 21, 2006, "the average time of treatment in our study was just one month, so it appears that even short courses of these drugs are dangerous in patients with known heart disease."

"This is not just a problem associated with chronic treatment," he said.

The study found any use of ibuprofen upped the risk of death by 1.5-fold, and high doses (over 1,200 milligrams a day) increased the risk by 2.2-fold. Diclofenac increased the death risk by 2.4-fold, and at high doses the increase was 4.4-fold.

Experts advise that these risks are not small for heart attack survivors. They amount to one patient harmed for every 24 patients who took diclofenac, and one in every 45 patients who took ibuprofen.

A year ago in June 2005, a British study of more than 9000 people who had suffered a previous heart attack found NSAIDs increased the risk of another heart attack by between 24% to 55%.

In that study published in the June 2005, British Medical Journal, researchers at the University of Nottingham identified 9,218 patients across England, Scotland and Wales, who had suffered a heart attack for the first time, over a specific 4-year period, with ages ranging from 25 to 100.

The researchers examined the prescribing patterns, and took into account other risk factors such as age, smoking habits, and obesity, and found that for patients prescribed the drugs in the three month immediately before the heart attack, the risk increased when compared to patients who had not taken the drugs. With ibuprofen, the risk increased by 24% and with diclofenac the risk increased by 55%.

According to the researchers, given the high prevalence of the use of the drugs by elderly people with an increased risk of heart attack due to age, the findings have considerable implications for public health.

Enough "concerns exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs", they said.

In the May 23, 2006 online version of the journal Heart, researchers reported that taking NSAIDs could increase the risk of heart failure among the elderly by almost a third.

For this study, researchers from the Spanish Centre for Pharmacoepidemiologic Research in Madrid reviewed the medical records of 228,660 patients beginning on January 1, 1997, and followed the patients until the end of 2000.

Dr Consuelo Huerta and colleagues compared NSAID use among 1,396 patients between the ages of 60 and 84, who were hospitalized for non-fatal heart failure and a random sample of 5,000 subjects.

Of the patients admitted to the hospital, 14% were on NSAIDs at the time of their admission compared to 10% of randomly selected patients. Over half of those admitted to the hospital were in the age group of 70 to 79.

The research team determined that taking NSAIDs increases the risk of getting heart failure by 30%, after other factors are taken into consideration. The results mean that for every 1,000 people aged 60 to 84, taking NSAIDs leads to one extra hospital admission.

But according to the researchers, the number could rise to 3 among older patients with other health problems such as diabetes, high blood pressure or kidney failure. "Even a small increase in the risk can translate into a significant disease burden in the general population," the researchers noted.

They point out that their findings are compatible with those of other studies indicating that NSAIDs aggravate heart failure symptoms, leading to more hospitalization for susceptible patients, such as those with a history of cardiovascular disease or a previous heart failure.

And finally, on June 3, 2006, researchers in another study from the Clinical Trial Service Unit at the University of Oxford, together with colleagues from the University of Rome, published in the British Medical Journal, determined that ibuprofen doubles the risk of a heart attack in patients who take it at high doses over a long period of time.

The study is reportedly the largest and most definitive of its kind into the effect of NSAIDs on the heart, and involves 138 trials covering 140,000 patients. The study combined the results of all trials in order to provide the most reliable estimate of the increased risk.

Two NSAIDs - ibuprofen and the prescription-only diclofenac - increased the risk of a heart attack by almost as much as the Coxib drugs like as Vioxx.

The researchers noted that most of the patients did not have pre-existing heart disease and the increased risk amounted to three extra heart attacks in every 1,000 people taking ibuprofen or diclofenac every year. Overall they increased the risk of any vascular event - heart attack or stroke -by 40%.

Experts says the growing body of evidence indicating the certainty of heart problems caused by the use of these drugs is particularly disturbing, because their use has drastically increased since Vioxx and Bextra were withdrawn from the market.

There are also a host of other serious health problems associated with taking NSAIDs that include kidney, liver, and stomach problems, particularly stomach bleeding and ulcers, and high blood pressure.

According to a study published January 3, 2005, in the American Gastroenterological Association journal Clinical Gastroenterology and Hepatology, chronic users of NSAIDs have an increased risk of bleeding and visible damage to their small intestine.

The study analyzed 43 relatively healthy patients, who used NSAIDs daily for relief of pain associated with rheumatoid arthritis, osteoarthritis, or non-specific arthritis, and a control group who did not use NSAIDs or aspirin for their arthritis symptoms.

Results show that 71% of those exposed to NSAIDs for more than 90 days had visible injury to their small intestine ranging from small erosions to severe ulcers.

"We have always known that NSAIDs can cause potentially deadly stomach complications, but the extent of the impact on the small intestine was largely unknown until now," Dr David Graham, MD, lead author of the study told Science Daily.

According to Dr Thomas Stuttaford, in the May 26, 2006, UK Times Online, the hazards of NSAIDs "causing an exacerbation of indigestion and the gastro-intestinal complications associated with it, such as gastro-intestinal bleeding and even perforation, are well known."

"Care is needed," he warned, "when prescribing these drugs for patients over 65, especially if there is any history of peptic ulceration, whether gastric or duodenal, or of chronic indigestion."

In May 2005, WebMD reported that "for people with high blood pressure, some types of nonsteroidal anti-inflammatory drugs (NSAIDs) can be risky."

People with high blood pressure are at special risk, according to WebMD, because some of the NSAIDs reduce the blood flow to the kidneys, which filter the blood, causing them to work more slowly which causes fluid to build up in the body. As a result, the increased fluid drives up blood pressure.

In addition, if taken often enough and at a high enough dose, the WebMD article warned, "they can seriously damage the kidneys."

"People with high blood pressure don't know the risks of taking some of these painkillers," Dr Nieca Goldberg, MD, a cardiologist and spokesperson for the American Heart Association told WebMD.

"They assume that anything you can buy over the counter is safe," he said. "But these drugs are chemicals that can cause side effects."

"When I have patients with heart disease that suddenly gets much worse," he advised, "the first thing I ask them is if they've used an over-the-counter pain medicine."

In August 2005, research published in Hypertension: Journal of the American Heart Association warned that women who consume higher doses of non-aspirin painkillers were much more likely to develop high blood pressure than women who do not use the medications.

The study was conducted to determine whether higher doses of pain relief drugs, specifically acetaminophen, NSAIDs, and aspirin, increase a woman's risk of developing new-onset high blood pressure.

"Because high blood pressure is among the most important causes of death and disease in the United States, and analgesics are the most frequently used medications, a relationship between the two would be important from a public health standpoint," said lead author John Forman, MD, instructor in medicine, Harvard Medical School, and associate physician, renal division, Brigham and Women's Hospital, Boston, MA.

Researchers studied 1,903 women ages 51-77, and 3,220 women ages 34-53, who did not have high blood pressure when the studies began. They recorded information about whether the women used pain relief drugs, which type, at what dosage, and for what use, and then tracked whether the women developed high blood pressure. The NSAIDs taken were mostly ibuprofen and naproxen.

The study found that older women ages 51-77, who used an average of 400 mg of NSAIDs (2 ibuprofin tablets) or more per day were about 78% more likely to develop high blood pressure compared to older women who did not use the drugs.

Younger women ages 34-53, who used more than 400 mg a day of NSAIDs, were found to have a 60% higher chance of developing high blood pressure.

The risk of developing high blood pressure for women not taking any of the painkillers was only about 1 to 3% a year, researchers found.

The most surprising finding was the development of high blood pressure in women taking acetaminophen (Tylenol). Women ages 51-77 who took an average daily dose of more than 500 milligrams (one extra-strength Tylenol), had a 93% higher risk of developing high blood pressure within about 3 years. Among women 34-53 who took an average of more than 500 mg a day had a 99% higher risk, the study found.

The results of this study held up even when researchers excluded women who were taking pills for headaches, something that could itself be a result of very high blood pressure, said Dr Gary Curhan, one of the study's authors from Harvard Medical School.

In May 2005, WebMD warned all people with high blood pressure not to use ibuprofen or naproxen, unless a doctor explicitly said they could. The drugs, WebMD advised, "can also impair the effectiveness of common blood pressure medicines like ace inhibitors (such as Lotensin, Capoten, and Vasotec) and beta blockers (such as Coreg, Lopressor, and Corgard.)"

But as it turns out, this is nothing new. According to Dr Stuttaford, in the May 26, 2006 Times Online: "Research carried out well over twenty years ago showed that the NSAIDs also had a tendency to increase blood pressure."

"This tendency," he said, "was more likely to be evident in those patients who had been treated with medication to reduce blood pressure."

In addition, a 2005 study reported in High Blood Connection, found that NSAIDs also increase the risk for kidney failure, and that the risk is significantly greater for patients with hypertension.

Patients who took diuretics along with NSAIDs, the study found, had 11.6 times the risk of developing acute kidney failure compared to non-NSAID users. The relative risk for calcium channel blockers and NSAIDs was 7.8. The researchers warned that NSAIDs should be used with caution in patients with hypertension or heart failure.

Because there is no mandatory reporting system for post marketing adverse affects for drugs, only between 1% and 10% of all adverse reactions to medications are ever reported to the FDA, which means the actual number of patients harmed by NSAIDs is impossible to determine.

For this reason, the accurate number of cases of Stevens Johnson Syndrome caused by NSAIDs in the US are unavailable. Described in many package inserts as a "serious skin condition," SJS is a devastating allergic reaction to a drug described by some as "a fate worse than death."

SJS is characterized by an extremely painful skin rash and blistering sores in the mouth, throat, nostrils, eyes, and anal and genital areas. In the most serious cases, a patient's skin peels off in sheets from large areas of the body, much like what happens to severe burn patients.

According to experts, SJS causes the immune system to turn on itself to rid the body of the offending drug, in effect burning the patient from the inside out. SJS results in death in 10 to 30% of the cases.

Although SJS was once a rare condition, it is becoming far more common. According to the February 15, 2005 Pittsburgh Post-Gazette, there are now between 600-2,000 new cases in the US each year.

Some of the lasting effects of SJS include blindness, dry-eye syndrome, arthritis, lung damage, asthma, photophobia, chronic obstructive pulmonary disease, loss of nail beds, scarring of the esophagus and other mucous membranes, and chronic fatigue syndrome.

Over a year ago, on April 7, 2005, the FDA asked manufacturers of OTC NSAIDs to revise their labeling to include more specific information to assist consumers in the safe use of the drugs.

"This includes," the FDA said, "instructions about which patients should seek the advice of a physician before using these drugs, stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician, and a warning about potential skin reactions."

In the new labeling, the FDA instructed manufacturers to include: (1) more specific information about the potential CV and GI risks; (2) instructions about which patients should seek the advice of a physician before using these drugs; (3) stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician; and (4) a warning about potential skin reactions.

In addition, the agency ordered Black Box warnings about the risk of SJS on all OTC NSAIDs. The FDA's decision to add the strongest warning label available, followed two pediatric cases of SJS where one 9-year-old child died, and another 7-year-old became blind after using OTC NSAIDs.

Although experts are now saying to cut back on NSAIDs, on June 14, 2006, Wyeth began hawking its new product, Advil PM, promoting its use to battle sleeplessness "a few nights a week or more."

According to the company's press release, a survey conducted by the National Sleep Foundation found that almost 20% of Americans (42 million) experienced nighttime pain or physical discomfort that disrupted their sleep a few nights a week or more. In fact, it said, 68% of Americans currently are getting less than eight hours of sleep on weeknights, while the US Department of Health and Human Services recommends at least eight hours of uninterrupted sleep.

The profits up for grabs are as always obscene. According to Wyeth, 15% of Americans are turning to sleep aids, making the sleep aid market a $3.1 billion business annually in the US, of which more than $260 million can be attributed to OTC drugs.