CLEVELAND, Ohio -- It's time to think twice about reaching for a pain reliever when your child has a low-grade fever or minor aches and pains.

The use of acetaminophen -- a pain reliever popularly sold under the brand name of Tylenol -- may be contributing to the rise in childhood asthma, according to a recent editorial in the scientific journal Pediatrics.

"People who take even low levels have a vastly increased risk of also having asthma," the journal states. "If people say they take acetaminophen once a month, generally their risk of having asthma has doubled."

Even worse, because acetaminophen metabolizes in a way that may affect a person's airways, the pain reliever can actually cause more harm than good when taken by someone with an upper respiratory illness or a history of wheezing, research shows.

"Who would think that Tylenol would be a problem?" asked Dr. John McBride, author of the editorial (pdf) and a pediatric pulmonologist at Akron Children's Hospital.

McBride, who has treated children for more than three decades, said that he was "really very skeptical" of the possible link between acetaminophen and asthma before he began reviewing the literature. But after analyzing more than a decade's worth of studies, McBride said he was stunned by his conclusion: He no longer recommends giving acetaminophen to any child with asthma or a family history of asthma.

Know your pain relievers

Over-the-counter pain relievers work by hindering the body's ability to produce an enzyme known commonly as COX, or cyclooxygenase. COX helps the body produce prostaglandins, which provide a number of protective functions in the body. The prostaglandins also can cause pain, inflammation and fever when a cell is injured by communicating with the body's nervous system.

There are two main types of pain relievers in the over-the-counter market: Acetaminophen and other non-steroidal anti-inflammatory drugs, or NSAIDs.

Acetaminophen drugs

Popularly sold under the brand name Tylenol and a main ingredient in products such as NyQuil.

Acetaminophen, unlike other over-the-counter pain relievers, blocks the brain's messages that are primarily sent to the central nervous system. This makes the drug effective for headaches, fever and minor aches and pains but not, for example, inflammation from a muscle sprain.

Pros:

Effective for reducing fevers and alleviating headaches and other pain. It's not as likely to irritate the stomach or affect platelet function as other pain relievers.

Cons:

Can cause liver failure because it reduces the body's natural supply of a peptide called glutathione. Some studies also suggest that the reduction of glutathione is associated with oxidant damage in the lungs, thus promoting existing asthma symptoms.

Nonsteroidal anti-inflammatory drugs

Sold in three main subgroups:

Aspirin

. Name brands include Bayer, Excedrin

Ibuprofen

. Name brands include Advil, Motrin

Naproxen

. Name brand is Aleve.

These drugs also inhibit the production of the COX enzyme that allows the brain to send messages by way of prostaglandins. But non-steroidal anti-inflammatories, also known as NSAIDs, block the prostaglandins that work with the body's peripheral nervous system as well as those that work with the central nervous system.

Pros:

This type of medication is most effective for reducing inflammation and muscle pain. It can also reduce fevers.

Cons:

The most common side effects can include upset stomach, diarrhea, heartburn and constipation. In some cases, it may also affect blood platelets, the cells that help your blood clot normally. The use of aspirin for children with viral illnesses has been associated with Reye's syndrome, a swift-acting and potentially fatal disease that causes swelling in the liver and brain.

"Every study shows the association between acetaminophen and asthma," McBride said, adding that "it seems to me it's time to tell people about this." Asthma, which is one of the most common chronic diseases in the United States, is a relatively new epidemic.

Since the late 1970s, the prevalence and death rates of asthma have increased nationwide, according to a Centers for Disease Control and Prevention surveillance study. While an average of 6.8 million people self-reported asthma in 1980, the number rose to an average 13.7 million by the end of 1994, according to the CDC study. By 2009, the U.S. Department of Health and Human Services reported that about 8.2 percent of the U.S. population, or 24.6 million children and adults, had asthma.

In Ohio, an estimated 252,944 children had asthma in 2008, according to the CDC.

Concerns about acetaminophen have been raised before by researchers who have studied asthma in juveniles.

In August 2010, The New York Times reported that young teenagers who use acetaminophen even once a month developed asthma symptoms more than twice as often as those who never take it. The report came from the International Study of Asthma and Allergies in Childhood, or ISAAC, and was based on data from more than 322,000 children age 13 and 14 from 50 countries.

There was also a large study of children with fevers -- between 6 months and 12 years old -- that pointed to the differences between acetaminophen and ibuprofen, another common over-the-counter pain medication. Between 1991 and 1993 the Boston University Fever Study randomly gave nearly 84,000 feverish children low doses of acetaminophen or ibuprofen and recorded the results. For asthmatic children with a respiratory infection, the need to go to the doctor after taking acetaminophen was 2.3 times higher than in those treated with ibuprofen.

After reviewing these studies and others, McBride said he "just could not believe that I didn't know more about this and that asthma experts of the world hadn't made more of it."

What's a parent to do?

Most parents have heard advice from pediatricians to alternate ibuprofen and acetaminophen when a child is running a fever or has some pain. But Dr. John McBride of Akron Children's Hospital warns that this may actually cause more harm — especially if the child is suffering from an upper-respiratory virus.

First, he said, it's not necessary to give a child pain reliever for fevers lower than 103 degrees. To ease the child's discomfort, McBride advises using only an ibuprofen product such as Motrin or Advil.

If parents still choose to give their child another pain reliever with acetaminophen, be careful not to overdose by using it too often or combining it with other drugs. Acetaminophen is in so many over-the-counter drugs that you may unwittingly be overdosing by simply giving your child a combination allergy medicine with a separate dose of pain reliever.

To find out which medications contain acetaminophen, Tylenol offers a helpful search site:

A logical biological link



To understand why feverish or asthmatic children who take acetaminophen may have worse outcomes, it helps to understand how the drug works in our bodies.

Acetaminophen works with the nervous system and brain to block messages of pain. Separately, when acetaminophen is being metabolized, it generates a compound that combines with and depletes the body's level of glutathione, an antioxidant produced by cells. The depletion is well known and is the reason federal regulators have warned that an overdose of acetaminophen causes liver failure, which can be fatal.

But glutathione is not only found in the body's liver, according to a 2005 study out of England. It is also found in high concentrations of the lung's airway linings, and evidence suggests that decreased glutathione levels are associated with damage in the lungs, according to that study.

For folks with asthma, which means you have sensitive airways, the body's decrease of glutathione means the possible loss of a protective mechanism, McBride said.

Dr. John Carl, section head of the Cleveland Clinic's Center for Pediatric Pulmonary Medicine, said that the biological cause makes sense.

"This is not John McBride being outrageous," he said.

Concerns about acetaminophen's ability to reduce glutathione and cause liver failure were so strong that the U.S. Food and Drug Administration decided in 2009 to make major changes in the way the pain reliever is sold. An FDA advisory panel made up of scientists, doctors and consumer representatives announced new limits on the amount of acetaminophen in over-the-counter pain relievers and warned that too much of the drug could cause serious liver damage.

In January, the FDA again announced limits on the amount of acetaminophen in products such as Tylenol and NyQuil and again proposed the agency's strongest warnings be added to prescription drug labels because of continued reports of liver injury.

Carl said patients should consider the risk of any drug. Aspirin has been linked to the rare but serious Reye's syndrome -- a potentially fatal disease that causes swelling of the brain and liver -- in children and teens. Ibuprofen has been known to irritate the stomach.

Carl said he would not recommend using acetaminophen for someone with asthma or other respiratory problems.

Differing viewpoints



Since publishing his editorial in December, McBride has recognized that some people aren't in agreement. He even has been invited to debate his findings at the annual American Thoracic Society meeting later this year.

Lots of people take acetaminophen on a regular basis and have no breathing problems or symptoms of asthma. It's not uncommon for a pediatrician to recommend that parents alternate the use of acetaminophen and ibuprofen to lessen the pain of teething or to reduce a fever.

And McBride admits that most of the studies he reviewed were cross-sectional epidemiological studies that cannot prove causation. Only one was a controlled trial. In his editorial, McBride recommends a well-designed controlled trial to lay to rest any questions about the link.

In response to an inquiry about the safety of the product, Johnson & Johnson, the parent company of Tylenol, responded with an email that stated the product "has over 50 years of clinical history to support its safety and efficacy." The statement went on to say that Tylenol was safer than other over-the-counter pain medications when used as directed.

"While we are aware of the article published in the December issue of Pediatrics, there are no prospective, randomized controlled studies that show a causal link between acetaminophen, the active ingredient in Tylenol, and asthma," the company wrote.

Dr. Kristie Ross, a pediatric pulmonologist at University Hospitals Rainbow Babies & Children's Hospital, said she'll wait for a conclusive controlled study before changing her recommendations.

"If they use appropriate doses [one dose per four- to six-hour period] for a short period of time in otherwise healthy children, I'm not concerned," she said.

Ross agrees that there is a biologic plausibility to the idea that acetaminophen could cause asthma or respiratory symptoms. "That's what makes the idea so intriguing," Ross said.

But for a drug that has been shown to be safe and effective for years, she said she doesn't feel comfortable telling parents definitely not to use it.

While the epidemiological studies can show an association, there are a lot of other factors that potentially could have led to children in those studies having poor outcomes, Ross said. Studies of asthma over the years have pointed to everything from genetics to the environment as contributing factors to the chronic illness.

McBride said that, yes, there likely are many contributing factors to asthma. But, why, he asked, risk giving acetaminophen when ibuprofen is available or, in many cases, no drug may be necessary?

Indeed, McBride, Carl and Ross all agreed that parents can often be too quick to give pain relievers or to treat fever. Chicken soup and cold liquids can also provide comfort, they said.

In addition, Ross says that it's important to remember that fever is a natural response to an infection.

"The mere fact that a child has a fever does not mean they need pain reliever," she said. "The idea that fever in and of itself is going to hurt the child is a myth."

The rise of acetaminophen



Acetaminophen was a relatively little-used pain reliever before the mid-1970s, when fear that aspirin was linked to Reye's syndrome caused people to look for an alternative.

Today, acetaminophen is the most commonly used children's medicine for reducing pain and fever, according to the Consumer Healthcare Products Association. A 2005-2006 telephone survey by the organization found that 12 percent of children under the age of 12 had taken acetaminophen the prior week.

That 2005 study out of England -- authored by researchers out of the University of Nottingham in London, the National Institute of Public Health in The Netherlands, and Cornell University in New York -- found that use of neither aspirin nor ibuprofen was associated with the prevalence of asthma. However, it hypothesized that "regular users of acetaminophen may, through depletion of glutathione, be at an increased risk of lung tissue damage and ultimately of respiratory disease."

McBride, who is nearing retirement, said he felt it was important to start a national discussion about acetaminophen's safety -- even if not all doctors agree.

"I want to do the right thing, and to me this is so important," McBride said, adding: "As a parent, it's not acceptable to me that we wait until there is more evidence."