Acetaminophen. Paracetemol. APAP. Tylenol. Any way you say it, this drug has become synonymous with pain and fever relief. And this week, Tylenol turns 50. What began as a children’s elixir has now hit middle age.
The story of its discovery is steeped in the organic chemistry of urine metabolites of the analgesics in use during the 1890’s. It was not until decades later that scientists realized acetaminophen was far less toxic than other alternatives:
In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and Julius Axelrod were assigned to investigate why non-aspirin agents were associated with the development of methemoglobinemia, a non-lethal blood condition. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol (acetaminophen), since it did not have the toxic effects of acetanilide.
The product went on sale in the United States in 1955 under the brand name Tylenol.
It’s been ingested by billions, and prescribed by some of us just yesterday. But how it works is still not clearly understood:
Paracetamol has long been suspected of having a similar mechanism of action to aspirin because of the similarity in structure. That is, it has been assumed that paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX) enzyme.
However, there are important differences between the effects of aspirin and paracetamol. Prostaglandins participate in the inflammatory response, but paracetamol has no appreciable anti-inflammatory action. Furthermore, COX also produces thromboxanes which aid in blood clotting – aspirin reduces blood clotting, but paracetamol does not. Finally, aspirin and the other NSAIDs commonly have detrimental effects on the stomach lining, where prostaglandins serve a protective role, but paracetamol is safe.
Indeed, while aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme’s active site, Boutaud et al. (2002) found that paracetamol indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why paracetamol is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides.
Swierkosz et al. (2002) reported data suggesting that paracetamol selectively blocks a variant of the COX enzyme that is different from the then known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works.
Despite the ambiguity around its mechanism of action, Tylenol was safe and became a trusted brand. It helped that its introduction coincided with new data regarding aspirin and childhood fevers (the dreaded but rare Reye’s Syndrome).
It’s hard to believe there was ever a time when drugstores didn’t have a dozen different versions of tylenol (Extra Strength, PM, Flu, Liquid, Capsule, Gel-Cap, Tablet, and so on). But Tylenol’s marketing was originally quire limited:
Acetaminophen had been used in Europe since 1893, but was little known in the United States when the Tylenol brand was launched in 1955. McEvoy said Tylenol was the first Aspirin-free, non-narcotic pain reliever on sale in the U.S. – only available by prescription, for children and in liquid form. McNeil, acquired by Johnson & Johnson in 1959, rolled out the first Tylenol for adults in 1961.
In terms of marketing, Tylenol has an impressive record. Despite having lost much of its patent protection, the brand does very well, and continues to gain share (especially since the COX-2 inhibitor debacles).
But it wasn’t always so rosy for Tylenol. Today’s medical students may not remember this, but there was a time when Tylenol was feared:
Tylenol’s biggest challenge, the 1982 cyanide tampering scare in Chicago that killed seven people, is considered “a case study of how to deal with a brand crisis,” said Mark Bard, president of Manhattan Research. He said pharmaceutical companies such as Vioxx maker Merck & Co. and Bextra maker Pfizer Inc. “could learn some lessons from what happened 20 years ago.”
J&J had its sales force remove 264,000 Tylenol bottles from Chicago area stores; consumers also were urged to return any Tylenol they had for a safe bottle, and prompt alerts from J&J and the FDA kept the public informed, recalled Dr. Anthony Temple, head of medical affairs for McNeil Consumer in 1982.
“If you leave people in the dark, you have a real risk of them never being able to trust you” again, said Temple, now senior medical consultant for McNeil Consumer. It took just a few months to regain public confidence, he said.
Bard said it was worth it for Johnson & Johnson to spend around $100 million on the recall to save its brand, given that non-prescription drugs are on the market for decades, compared with prescription drugs that lose patent protection, and thus most of their sales, in 10 to 15 years at most.
The culprit was never caught, but McNeil prevented a recurrence by developing containers protected by multiple seals.
“They made tamperproof packaging, which we take for granted today” on everything from non-prescription drugs to pickle jars, Bard said.
Tylenol continues to innovate in marketing, discreetly sponsoring minimalist indie scenes like the “Tylenol Bowl” :
It has become a “pain partner” with underground event organizers of skateboarding events, film festivals and breakdancing competitions. And it’s all done with barely a mention of the brand. Yet the brand has, in fact, been embraced with users of a Tylenol-built but unbranded skateboard bowl referring to it as the Tylenol Bowl. The brand has even made its way into the song lyrics of a Ben Kweller tune (called Tylenol) sold on Apple’s music store. To reach this audience, a media buy would be pointless because this group makes heavy use of all available ad blocking tools and even if any ads do slip through, they are viewed with great skepticism.
With a new generation on board, and competitor painkillers facing scandals, stomach pains, or addiction, it seems like Tylenol is well positioned to be the analgesic of choice for the next fifty years.
That’s all for this week. Have a pain-free weekend and join us Monday for more medgadgets!