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The Best of Pill Pushing - Tylenol - The deadliest over-the-counter pain killer - (3/22/2018)

Pill Pushing
The ways in which medications have changed our culture
Ron Gasbarro, PharmD

Tylenol® (acetaminophen)
Society at that time: In the 1960s, the burgeoning pharmaceutical industry was well aware of the popularity of taking a safe, effective pill for everyday aches and pains. Products such as Anacin®, Bufferin®, and Alka-Seltzer® were runaway successes in this regard. And they all shared one main ingredient: acetylsalicylic acid (aka aspirin – which initially came from willow tree bark). During that decade and into the early 1970s, the results of clinical studies were emerging to reveal that aspirin was the cause of peptic ulcers [Chapman, 1969; Gillies, 1969]. Prior to the introduction of cimetidine (Tagamet®) and ranitidine (Zantac®), which were formulated to decrease the acid production of the stomach and reduce symptoms, surgery was often performed to cure peptic ulcer disease. This often involved removing large portions of the stomach, considered a standard treatment for those for whom antacids were ineffective. The operation involved hospital time, a mountain of money (often $10,000-$20,000 or more) and punishing dietary restrictions. Thus, the search was on for an analgesic that was as effective as aspirin but without the propensity for painful, life-threatening gastric erosion. 
The drug in question:  In the spring of 1955, McNeil Pharmaceuticals introduced Tylenol Elixir for Children, the company's first single ingredient acetaminophen product. The outstanding success of Tylenol (also known as paracetamol in many countries), was attributed to a unique marketing strategy: to inform health care professionals of aspirin’s undesirable effects and ask them to recommend Tylenol to patients vulnerable to these effects. By 1970, Johnson & Johnson, which acquired the brand, enjoyed sales of Tylenol that were growing approximately 25% a year, with revenues projected to reach $60 million by 1975. With the release of a number of clinical studies in the early 1970s which questioned the wisdom of widespread dependency on aspirin as a painkiller, the use of acetaminophen accelerated. Consumers usually became familiar with acetaminophen through hospitals, where it was used extensively, not necessarily because it was the best medication for the job. Rather, because it was generally less expensive than other analgesics and less interactive with other medications than aspirin.
The good, the bad, and/or the ugly: The 1982 Tylenol murders was the type of publicity no company wants. Beginning Wednesday, September 29, 1982, 7 people in the Chicago, Illinois area, died suddenly after ingesting Extra-Strength Tylenol capsules, the company’s best-selling product [Fletcher, 2009]. Investigation confirmed that an unknown person or persons replaced the contents of 8 bottles of Extra-Strength Tylenol capsules with cyanide-laced capsules. It was believed the unknown party removed Tylenol bottles from a number of pharmacies and markets in and around Chicago and returned the tampered bottles to shelves at a later date. Before this event, Tylenol was the most successful over-the-counter product in the United States with over 100 million users. Tylenol was responsible for 19% of Johnson & Johnson’s corporate profits during the first 3 quarters of 1982 and accounted for more than 30% of the company’s year-to-year profit growth. Tylenol controlled 37% of the OTC pain killer market with revenue of about $1.2 million. Immediately after the cyanide poisonings, Tylenol’s market share nosedived to 7%. Despite this tragedy, Johnson & Johnson successfully rebuilt their brand and recovered 70% of its consumers.
Impact of drug on culture: The Tylenol murders did have a measurable, positive impact: a revolution in product safety standards. In the wake of the Tylenol poisonings, pharmaceutical and food industries dramatically improved their packaging, instituting tamperproof seals and indicators and increasing security controls during the manufacturing process. What set apart Johnson & Johnson's handling of the crisis from others? It placed consumers above profits by recalling 31 million bottles of Tylenol capsules from store shelves and offering replacement product in the safer tablet form free of charge – the first company to recall a pharmaceutical product [Rehak, 2003]. "Before 1982, nobody ever recalled anything," said Albert Tortorella, a managing director at Burson-Marsteller Inc., the New York public relations firm that advised Johnson & Johnson. "Companies often fiddle while Rome burns."
Where the drug is today: Now owned by McNeil Consumer Healthcare, Tylenol and the many generic forms that are available as acetaminophen remains one of the most popular over-the-counter painkillers. Combining it with the narcotic hydrocodone (Vicodin, Norco) has made it the number one prescribed medication in the United States for the last 5 years. Yet, problems remain. According to the US Food and Drug Administration (FDA), acetaminophen can cause serious and potentially fatal liver damage if too much is used [FDA, 2014]. In 2011, the FDA required manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury [FDA, 2011] and launched a public education program to help consumers avoid overdose. The possibility may be heightened by chronic alcohol abuse. Acetaminophen toxicity is the foremost cause of acute liver failure among the industrialized countries and accounts for most drug overdoses in the United States. However, acetaminophen may be safe if used correctly, that is, less than 4 grams a day (4,000 mg, or 8 extra-strength 500 mg tablets/day). However, taking the drug 7 days in a row or even longer does nothing to cheer up one’s liver. McNeil, in an effort to minimize the risk of liver toxicity, states in its packaging that no more than 3,000 mg be ingested in one day. 
In 2009, another Tylenol recall occurred. A nauseating "moldy" odor has sickened some people using Tylenol Arthritis Pain Caplet 100-count bottles with red EZ-Open caps. The manufacturer recalled this entire product, which was easily recognized by its distinctive red cap. McNeill says consumers reported the product had "an unusual moldy, musty, or mildew-like odor" linked to symptoms of nausea, stomach pain, vomiting, and diarrhea. The source of the odor appears to come from the breakdown product of a chemical used to treat the wooden pallets on which the product's packaging materials were transported and stored. The culprit was the hardy gram-negative bacteria Burkholderia cepacia which can cause serious infections if ingested. Despite the fact that no trace of the bacteria was found in the tablets as such, recalls of Tylenol in 2009 seriously wounded sales of that product. In 2008, before the recalls started, Tylenol had 56% of the US market share for the brand acetaminophen. In 2012, that was down to 24%. At the same time, private-label generic market share has grown from 32% to 62%. No surprise for that ubiquitous, and cheaply made molecule!
Nevertheless and despite hefty sales, this drug appears to do more harm than good. A 2015 review of the literature showed that acetaminophen was no more effective than placebo in patients with hip or knee osteoarthritis [Ennis, 2015]. The investigators concluded that acetaminophen was not efficacious in the treatment of chronic pain conditions. Most experts and health officials agree that when taken as recommended, Tylenol and other medications containing acetaminophen are relatively risk-free. However, as a new report points out, taking twice or sometimes even just a little bit more than the daily recommended dose of 4 grams of Tylenol over the course of a few days can result in severe illness and even death.
A report by the FDA says that taking even 5 grams a day of Tylenol could damage your liver. In other words, the difference between a safe dose and a dangerous one could be just two tablets of Extra Strength Tylenol. In contrast, one would need to take several times the recommended dose of other popular over-the-counter painkillers – 20 times the recommended dose of Ibuprofen (Advil, Motrin) and about 6 to 8 times that of aspirin – to cause toxicity. Between 2001 and 2010, more than 1,500 people in the US died from accidental acetaminophen overdoses, says the CDC. This makes it more deadly than any other over-the-counter pain reliever.
Pet Alert! Keep Tylenol away from pets. The drug is extremely toxic to both cats and dogs. Cat’s bodies lack the necessary enzymes to break acetaminophen down and excrete it safely. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, the blood cannot transport oxygen which causes suffocation [Allen, 2003]. In dogs, the effects of acetaminophen poisoning are quite serious, often causing non-repairable liver damage [Villar, 1998]. The most common symptoms that you may notice in pets suffering from acetaminophen toxicity include: brownish-gray colored gums, labored breathing, swollen face, neck or limbs, hypothermia (reduced body temperature), vomiting, jaundice (yellowish color to skin, whites of eyes), due to liver damage, coma. Medical help should be immediate. In the meantime, keep a jar of activated charcoal handy which will absorb some of the drug. But do get to a vet – or in the case of a human to an emergency room immediately. 
By and large, Tylenol is safe if not taken in great quantities especially over a long period of time. But ask your pharmacist for safer alternatives. 
Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Write him with any ideas or comments at ron@rx-press.com.  
References
Allen AL. The diagnosis of acetaminophen toxicosis in a cat. Can Vet J. 2003;44: 509–10.
Chapman BL, Duggan JM. Aspirin and uncomplicated peptic ulcer. Gut. 1969;10:443-50.
Ennis ZN, Dideriksen D, Vaegter HB, Handberg G, Pottegård A. Acetaminophen for chronic pain: A systematic review on efficacy. Basic Clin Pharmacol Toxicol. 2015 Nov 17. doi: 10.1111/bcpt.12527. [Epub ahead of print]
FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings [press release]. Silver Spring, MD: US FDA; January 13, 2011. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm  
Fletcher D. A brief history of the Tylenol poisonings. Time magazine. February 9, 2009.
Gillies MA, Skyring A. Gastric and duodenal ulcer. The association between aspirin ingestion, smoking and family history of ulcer. Med J Aust. 1969;2:280-5. 
Rehak J. Tylenol made a hero of Johnson & Johnson: The recall that started them all. New York Times. March 23, 2002.
US FDA. Acetaminophen information; 2015. Available at: www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm  
Villar D, Buck WB, Gonzalez JM. Ibuprofen, aspirin, and acetaminophen toxicosis and treatment in dogs and cats. Vet Hum Toxicol. 1998;40:156-62.


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