The dark side of acetaminophen

There is a drug — probably sitting in your purse, desk drawer or medicine cabinet — that is widely considered one of the world’s safest painkillers. But over the last decade, it has killed hundreds of Canadians, hospitalized tens of thousands and cost the health-care system tens of millions, a Toronto Star investigation has found.

Acetaminophen has spent more than half a century as one of Canada’s top-selling non-prescription drugs. It can be found in nearly 500 products and billions of doses are taken safely every year.

But few Canadians appreciate the potential dangers of acetaminophen — the ingredient that made Tylenol famous but can be found in everything from Nyquil and NeoCitran to prescription painkillers such as Percocet. This is a drug many consumers take as casually as M&Ms — both of which can be bought at any gas station or drugstore, sometimes in packages containing hundreds.

While Health Canada tried to address these issues by updating label warnings in 2009, it ignored stronger changes recommended by its own scientists, according to internal documents obtained by the Star — language that was also opposed by the non-prescription drug industry.

Related: Reports offer insight into acetaminophen overdoses

Canadians’ lack of understanding, compounded by a culture of overmedicating, can turn a safe drug into something dangerous. Acetaminophen is often used in suicides — nearly 300 between 2000 and 2009, according to a Statistics Canada database — but a Star investigation has found that Canadians are also dying by accident.

How many? This question was impossible to accurately answer, both because of the difficulty in determining why someone fatally overdosed and a lack of co-ordinated surveillance across the country. Instead, a patchwork of databases, each with its own gaps and flaws, prevails.

“There’s nobody really systematically looking at it. It’s not really seen as a public policy issue,” said Dr. Michael Rieder, a pediatric clinical pharmacologist and scientist with Western University’s Robarts Research Institute. “It’s the kind of thing where if no one sees it, no one sees it, right? So that’s the problem.”

The Star has spent months analyzing numerous data sources and the resulting figures provide a troubling — and surprising — toll:

In all cases, the data sources behind these statistics have shortcomings that complicate the numbers (see “Behind the Numbers” sidebar). And the real figures may be higher.

“It’s an old drug, been around for a long time, used forever. And for what it’s used for, it’s pretty effective,” Reider said. “But it’s got a dark side. And this dark side is what happens in overdose.”

Those at highest risk of unintentional overdose include chronic drinkers, the malnourished and people with liver disease — but infants and seniors are also at “relatively greatest risk,” noted an internal 2009 Health Canada report obtained by the Star.

This report also found a dozen cases in Health Canada’s adverse drug events database where people suffered liver injury or damage after taking acetaminophen for several days — despite taking doses below the daily limit.

These findings have never been made public. Nor have any findings from a Health Canada working group studying the drug since 2010 but still finalizing its first report. Health Canada plans to release a summary of the report sometime this winter — it also declined to provide the names of the group’s 18 scientists, citing privacy concerns.

Acetaminophen is exceptionally safe when taken appropriately. As a painkiller, many health professionals prefer it over its competitors, ibuprofen and aspirin, which can cause stomach bleeding, even at recommended doses.

McNeil Consumer Healthcare, the makers of Tylenol and a division of Johnson & Johnson, said in a written statement that acetaminophen has a “remarkable record of safety” and is “one of the most studied and well-understood over-the-counter medicines.”

Acetaminophen’s death toll is also tiny considering the billions of tablets taken every year. In 2008 alone, manufacturers sold an estimated 4.1 billion doses to Canadian hospitals and pharmacies, according to a Health Canada report. In 2012, hospitals and pharmacies purchased $122.6 million worth of acetaminophen, according to health information company IMS Brogan. Last year, Canadians spent $148 million buying the drug from retailers and pharmacies, according to market research firm Nielsen.

But acetaminophen is older than today’s regulatory standards — it was first used as medicine in 1893 and became widely available in the early 1950s.

If it entered the market today, it probably would not be approved as an over-the-counter drug. Even in 1975, an editorial in the leading medical journal The Lancet stated that, had acetaminophen been introduced that year, it “would not be approved by the (British) Committee on Safety of Medicines and it would certainly never be freely available without prescription.”

“Toxicity can result in death or transplant — it’s not just fevers or a day off work,” noted Dr. Paul Marotta, head of the liver transplant unit at London Health Sciences Centre in London, Ont. “So that would be a product that would probably have a very strict indication, would not be over-the-counter.”

American drug regulators have expressed concern with the drug’s “narrow therapeutic window,” as recently reported by investigative journalism centre ProPublica — meaning the dose that damages is relatively close to the dose recommended on your pill bottles. ProPublica recently reported on issues surrounding acetaminophen in the U.S. and aided the Star on this story.

“With acetaminophen you have a drug that is virtually spotless when used as directed,” said Gerry Harrington, director of public affairs for Consumer Health Products Canada, a drug industry group representing large over-the-counter drug and natural health product makers.

“But there’s a sharp veering into danger if you’re reckless with it. It is, in that respect, a real standout.”

As the drug’s popularity grows — dosages bought by hospital and drugstores grew by 26 per cent between 2004 and 2008, according to a Health Canada report — so does the potential for error.

More than a third of Canadians misused over-the-counter drugs, according to a 2004 survey commissioned by Health Canada. Seventy-five per cent of consumers and even health professionals also considered non-prescription drugs to be “generally, if not completely, safe,” the survey found.

Deaths are just one piece of the problem.

“That’s only the tip of the iceberg,” said gastroenterologist, liver specialist and intensive care physician Dr. Constantine Karvellas with the University of Alberta, who is researching acetaminophen. “If you look at it as a societal problem, it’s a much bigger issue.”

The next layer down would be the acute liver failures — a rare, sudden and often fatal condition that frequently requires a liver transplant. Karvellas has treated more than 50 cases of acute liver failure over the last three years — 60 per cent caused by acetaminophen.

More common are hospitalizations for acetaminophen-induced liver injuries, which can often be treated with a very effective antidote, one that McNeil helped develop. Across Canada, acetaminophen overdoses were linked to 10,340 emergency room visits between 2009 and 2012, according to data from the Canadian Institute for Health Information (CIHI). The same time period saw nearly 13,000 hospitalizations — to the tune of an estimated $43.3 million.

There are untold numbers of overdoses that never get treated or reported. People may call one of Canada’s five poison control centres — in 2012, they answered more than 23,000 calls about acetaminophen, according to data provided by the centres.

The calls range from the relatively minor (a mom worried about her baby swallowing an acetaminophen pill) to the serious (suicide attempts). In Alberta, Saskatchewan and Quebec, more people are calling about unintentional overdoses than intentional ones, the data shows.

“Acetaminophen is by far and away the most common medication or drug-related call that we receive at our poison centre,” said Dr. Mark Yarema, the Alberta poison centre’s medical director. “That’s all age groups — so from pediatrics all the way up to seniors.”

Globally, acetaminophen is the No. 1 ingredient suspected in drug-induced liver injury deaths, Health Canada noted in its 2009 report, citing a World Health Organization adverse drug events database.

In the United Kingdom, acetaminophen is the most common drug taken in overdose — mostly in suicides — and stores that aren’t pharmacies can only sell the drug in packages of up to 16 extra-strength pills. In other European countries, such as Germany and France, acetaminophen can only be purchased in pharmacies — and never in the 100- or 200-pill bottles available in Canada.

In the United States, ProPublica has reported that acetaminophen sends 78,000 Americans to emergency rooms every year. It is also the No. 1 cause of acute liver failure in the U.S. — roughly half of all cases are caused by accidental acetaminophen overdoses.

Last year, McNeil took the unusual step of going beyond FDA rules and it began printing “CONTAINS ACETAMINOPHEN” warnings in red on the caps of extra-strength Tylenol bottles. The Star has learned that McNeil is also planning to introduce cap warnings in Canada for Tylenol products and cough and cold medications that contain acetaminophen.

The U.S. Food and Drug Administration has described acetaminophen overdoses as a “serious public health problem.” After decades of reviews, recommendations and delays, it is considering a recommendation to lower the daily limit from the current standard of four grams, the equivalent of eight extra-strength pills. The FDA also recently banned prescription drugs from containing more than 325 mg of acetaminophen per dose.

The last time Canadian regulators changed the rules for acetaminophen was in 2009 when Health Canada released its current labelling guide. Senior medical adviser Dr. Supriya Sharma says Canada’s guidelines are now among the toughest in the world.

But some feel that more can — and should — be done.

“That was a step in the right direction. I think it still remains a huge problem,” said James Lunney, Conservative MP for Nanaimo-Alberni and a former chiropractor. “I think we need the strongest possible warnings.”

Health Canada has been more worried about acetaminophen than many Canadians may realize.

“Definitely there’s a concern (with acetaminophen),” said Sharma in a phone interview. “The challenge is we’ve got a product that’s been on the market for a long period of time.”

“That’s why we’re doing as much as we are.”

But none of the acetaminophen researchers, toxicologists or drug safety experts contacted by the Star knew about Health Canada’s working group or the upcoming report. Lunney — who petitioned Parliament for stronger acetaminophen warnings seven years ago — also didn’t know what Health Canada has been doing on this issue.

In 2006, a couple from Lunney’s riding, Chuck and Tammie Campbell, received a phone call from their daughter’s roommate: something was wrong with Ashley.

Their daughter Ashley, then 19, was going through a typical teenage phase: she was arguing with her parents, had moved into her own apartment and was struggling with boy troubles.

At Ashley’s apartment, they discovered their daughter dazed and confused. An empty bottle of Tylenol was in the bathroom; Ashley said she had “taken Tylenol and nothing else.”

At the hospital, Ashley told her parents she wanted to get better. It never occurred to them that she would not — until the doctor told them Ashley’s liver had been destroyed.

Blood tests revealed alcohol and cocaine in Ashley’s system. But the doctors said it was the Tylenol that was killing her.

“Tylenol!!! Regular strength, over-the-counter, buy it by the bushel load, Tylenol,” Campbell wrote on a website created in the memory of his daughter. “My head was reeling — I had been a policeman for 25 years and never heard of such a thing.”

Ashley’s death took three agonizing days. Her father remembers how her brain swelled, her organs shut down and her blood stopped clotting. Ashley would shake and bolt upright, screaming in pain. Everything swelled; her belly, filled with gas that released in “long awful belch-like bursts of air”; her tongue, so thick her mouth couldn’t close; her eyes, which oozed with “red-yellow goo.”

The coroner who investigated Ashley’s death noted her history of depression and her claim to have taken Tylenol “in response to sudden despondency over some personal issues.” But Ashley “later adamantly denied this was her intention,” Dr. David Sherstone wrote in his coroner’s report. “As her intentions were not clear, an accidental overdose cannot be ruled out.”

Sherstone ultimately classified Ashley’s death as accidental. Her father agrees and insists Ashley never wanted to die; her last words to her mother were: “I love you, too, Mom and I’m fighting for you.”

Chuck Campbell doesn’t think Ashley understood the risks of Tylenol. At the time of her death in 2006, acetaminophen labels only warned that “it is hazardous to exceed the maximum recommended dose unless advised by a physician.”

Campbell was shocked to discover that in British Columbia, acetaminophen was the No. 1 pharmaceutical involved in intentional and unintentional drug poisonings.

“We realized we had to do something,” Campbell said. “It’s just wrong and people don’t know.”

He reached out to Lunney, who presented two petitions to the House of Commons in 2007 and 2008, calling for stronger warning labels on acetaminophen products. In March 2008, Tony Clement, then Canada’s health minister, responded by stating that acetaminophen labels were under review and new rules would soon be released.

One year later, the current “Acetaminophen Labelling Standard” came into effect. Today, acetaminophen labels carry clearer warnings (“Taking more than the maximum daily dose may cause severe or possibly fatal liver damage”), caution against combining products (“DO NOT USE with other drugs containing acetaminophen”) and instruct consumers to take two pills only if the first dose of a single tablet didn’t work.

Lunney’s petitions also triggered Health Canada to search its adverse reactions database, which is voluntary and cannot be used to prove causality. This resulted in a 48-page internal report in 2009 called “Special Project: Acetaminophen and Hepatoxicity,” which the Star has obtained.

Health Canada found 115 reports of adverse drug reactions associated with acetaminophen over five years. Most were associated with suicide attempts, intentional overdoses or alcohol abuse — but 39 cases were not and 16 of these were fatal.

The health agency also discovered a dozen instances where people suffered liver injuries after taking doses of less than four grams, the daily recommended maximum, for between one and 60 days. Six of these people suffered serious liver injury or failure.

For the Health Canada department responsible for monitoring drug safety, these findings prompted them in July 2009 to recommend changing acetaminophen labels to warn of “severe or even fatal LIVER INJURY, even at doses less than the maximum recommended dose” (emphasis theirs).

This language has never appeared on Canadian labels.

They also recommended clarifying the risk of combining acetaminophen products, as well as listing the symptoms of overdose: “nausea, vomiting, weakness, excessive sweating, anorexia, abdominal pain, or pale lips, tongue, mouth, palms, or impaired cognition.”

These recommendations were not adopted.

Health Canada has not explained why it chose not to adopt the recommendations. According to Gerry Harrington of Consumer Health Products Canada, the recommendations were opposed by representatives of non-prescription drug manufacturers, who participated in Health Canada’s labelling review.

Harrington said there were many heated conversations with Health Canada, as industry representatives felt too many “really low-probability scenarios” were being proposed.

“The worry was, how do you get all of that on the label without it being absolutely unreadable?” Harrington said. “We were saying . . . is it really prioritizing the risks in the consumer’s mind?’”

Since 2010, the acetaminophen working group has been collecting evidence on the drug’s safety and working to pin down Canadian statistics.

The Star has obtained two versions of the working group’s “key scientific questions” that guides its research. They indicate the matters of greatest urgency for Health Canada, including:

“You would think that after (50 years) of availability, they would have already addressed these topics long ago,” said Dr. David Juurlink, a toxicologist and drug safety expert with Sunnybrook hospital.

“I’m glad they’re paying attention to it but it’s something that warranted attention a few decades ago.”

Health Canada is also seeking to answer: “What are the root causes underlying unintentional overdoses of acetaminophen in Canada?”

But first — what is a “safe” dose? Fifty years on, health regulators are still wringing their hands over what acetaminophen’s “safe” daily dose should be. Dosages are calculated on weight and some people are more susceptible to toxicity — perhaps due to health problems, alcoholism or, in rare cases, a genetic disorder that may make people more vulnerable to acetaminophen poisoning.

The current daily limit is four grams but an FDA advisory panel has recommended lowering it in the United States. Health Canada is also re-evaluating the evidence.

“The four grams per day is for a 70-kilogram male,” said the University of Alberta’s Karvellas. “That doesn’t apply to everyone; that’s an average.”

A toxic dose for adults is generally considered between 7.5 and 10 grams, with the latter equivalent to roughly 30 regular-strength acetaminophen pills. Anyone who takes that much at once is probably attempting suicide — but it is also possible to hit 10 grams a day without realizing it.

Taking 30 acetaminophen tablets over the course of a day or two sounds like a lot but it’s “not a stretch” for some people, says Marotta of London Health Sciences Centre — especially for those in acute pain or the one in five Canadians struggling with chronic pain.

Consider, for example, someone who had a painful root canal and decided to take regular-strength Tylenol every three hours instead of every four.

“And instead of two pills, they take three, because God, it’s got to be better and it’s just an over-the-counter medicine,” Marotta said. “Suddenly — at 10 three-hour intervals at three pills — you’ve hit 30.

“A lot of people understand that that’s a lot. But it’s not unreasonable given the huge volumes that are out there.”

Alcohol and acetaminophen can make for a dangerous cocktail. Between 2006 and 2010, Statistics Canada’s coroner and medical examiners database recorded 107 accidental deaths caused by “therapeutic misadventure” with acetaminophen and nearly half involved alcohol.

In Canada, roughly 20 per cent of men and 8 per cent of women consume more than two drinks daily — but the FDA has warned that drinking three alcoholic beverages a day while regularly taking acetaminophen can result in severe liver damage.

Taking more than one product containing acetaminophen is also risky and “double dipping” was linked to roughly half of the 107 accidental acetaminophen deaths recorded by the Statistics Canada’s coroners database. Canada now has 407 over-the-counter acetaminophen products, according to Health Canada’s online drug database.

Consider, for example, someone who has a cold and takes eight extra-strength Tylenols in one day. If this person also drinks a mug of NeoCitran before bed, they have blown the daily limit.

If they continue this for four or five days, they could potentially suffer from a “staggered overdose” and the risk of liver injury becomes very real, said Karvellas. He estimates that roughly half of the acute liver failure cases he sees caused by acetaminophen are “therapeutic misadventures” — and about half of those people double dipped.

Staggered overdoses are dangerous because people don’t realize they are overdosing and are slower to seek treatment. Studies have shown that people who overdose accidentally are more likely to die than those who attempt suicide by swallowing up to twice as much acetaminophen.

People may also double dip with prescription opioids that contain acetaminophen, such as Percocet. Of the 107 accidental deaths in the Statistics Canada’s coroners database, roughly 14 were linked to opioid combination products.

“These substances are habit forming,” explains Sunnybrook’s Juurlink. “(If) someone has a habit and they’re taking 20 tablets of Percocet a day — they’re taking a lot of acetaminophen with that too.” (Twenty Percocets would contain the same amount of acetaminophen as 20 regular-strength Tylenols.)

And then there are people like Ashley Campbell — young people, often women, who take too much acetaminophen on an impulse without necessarily wanting to kill themselves.

“It’s particularly tragic when they show up two days later and they’ve missed the window of treatment with the antidote,” said Dr. Marco Sivilotti, an associate professor with Queen’s University who is studying acetaminophen overdoses. “They reach for acetaminophen primarily because it’s readily available.”

Marotta at London Health Sciences Centre says his hospital has seen an uptick in accidental acetaminophen overdoses recently — but he questions how this problem should be addressed.

“In the scheme of things, this is a tiny problem,” Marotta said. “To get a huge public awareness out there about perfect dosing of Tylenol — the cost and the ability to do that, and the bang you would get for your buck — is probably not what our society wants to spend our money on when you’ve got major public health issues out there already like alcohol and smoking.”

Juurlink echoes a concern raised in Health Canada’s 2009 report — by restricting access to acetaminophen, consumers will turn to alternatives like aspirin and ibuprofen, which can be damaging even at recommended doses.

“Those drugs have their own side effects and I would say they are much more likely to cause harm than acetaminophen,” Juurlink said. “So the alternatives are almost certainly worse, even when taken as directed, than acetaminophen.”

It is difficult to compare acetaminophen overdose deaths with those caused by ibuprofen or aspirin, Juurlink said — the latter may cause heart failure or stomach bleeding, more common issues that doctors may not recognize as being drug induced.

For Juurlink, the bigger problem is society’s attitude that “for every problem there is a pill.” The real message, he said, should be for people to take fewer drugs overall.

But he agrees that more should be done to tackle purely accidental overdoses from acetaminophen.

“It’s people who weren’t trying to hurt themselves, they were just doing something they thought was totally safe,” he said. “The real question is: What can we do to prevent that from happening?”

For Dr. Joel Lexchin, a York University professor and one of Canada’s leading drug experts, health regulators should have a lower risk threshold when it comes to something as widely available as acetaminophen.

“This particular product is widely available in large quantities without a prescription — so that puts it in a somewhat different class,” Lexchin said. “Some of the cancer drugs are extremely toxic. But, on the other hand, you can’t walk into a drugstore and buy them just because you want them.”

He points out that Health Canada has taken more drastic action on drugs associated with far fewer deaths than acetaminophen. For several months in 2005, Health Canada suspended market authorization for Adderall XR, a treatment for attention deficit hyperactivity disorder, after it was linked with a dozen pediatric deaths in the U.S.

“It raises the question that, given the amount of harm that acetaminophen is causing, why hasn’t there been more being done about it — at least insofar as alerting the public, alerting doctors?” Lexchin asks.

Health Canada’s own experts raised the same question in the internal 2009 report.

“To ensure safe use of over-the-counter products, such as acetaminophen, there is increased necessity to provide consumers with clear, pointed information — including product labelling and educational material — to allow them to make well informed decisions regarding their medical health.”

Other countries have tried implementing stronger warnings or smaller packages to prevent accidental overdoses. But every expert interviewed by the Star agreed that an important solution is perhaps the most difficult one: to make people aware.

In the United States, the FDA has undertaken a public education offensive in recent years, creating videos, an educational campaign, issuing consumer updates and serving as an adviser for an awareness campaign called Know Your Dose.

Health Canada directed the Star to an “It’s Your Health” website, which currently has a broken link. Aside from notices about specific products, the most recent awareness advisory, “Reminding Canadians About Using Acetaminophen Safely,” was issued in 2011.

“When it comes to broader education campaigns on the (over-the-counter side), there’s not a ton of history there (with Health Canada),” said Harrington with Consumer Health Products Canada. “It’s just not something they focus on. And industry has to step up as well.”

After Ashley died, Campbell and his wife flushed all of their acetaminophen pills down the toilet. But over time, especially as his arthritis started flaring up, he came to realize that acetaminophen was the best drug for him to relieve his pain.

The difference is now he has a fierce appreciation for the potential dangers. Campbell understands the risks — he only wishes he could have communicated them to his daughter.

“As a father, that’s the legacy I’m left with, the guilt,” Campbell said. “I thought about pot, I thought about booze, I thought about boyfriends, I thought about staying out at night, I thought about sex — all the things a dad thinks about with a daughter.

“I did not think about acetaminophen.”

Jennifer Yang can be reached at jyang@thestar.ca

Robert Cribb can be reached at rcribb@thestar.ca