Wednesday, July 8, 2009

Acetaminophen Debacle; Much Ado About Very Little

Last week the FDA convened a panel to consider serious adverse events — poisonings, liver damage, and deaths — that have been associated with acetaminophen during many years. The panel recommended placing severe restrictions on the distribution of OTC acetaminophen products and the banning of Rx opioid-acetaminophen combination products. While acknowledging that the risk to individual patients of developing liver injury is very low, the FDA noted that acetaminophen-containing products are used extensively and “the absolute number of liver injury cases is a public health concern.”

How Big is the Public Health Concern?

The FDA had assembled considerable background data for its panel and the several hundred pages of documentation can be accessed at The FDA’s data can be viewed from different perspectives, and there are always limitations; however, based on our examination, the validity and necessity of the panel’s recommendations should be questioned.

According to the FDA’s most recent data, in 2005 there were a remarkable 28 billion doses of products containing acetaminophen distributed in the United States. Using further data one can estimate the overall harm potential:
  • Assuming an average per-dose amount of 500 mg, there were 14 billion grams of acetaminophen distributed in 2005 (28 billion x .5 g).

  • FDA data indicate that the average median acetaminophen amount associated with liver injury was 6.25 grams (range 5-7.5 g), which suggests that there was a worst-case potential for 2.24 million severe adverse events in 2005 (14 billion g / 6.25 g/event).

  • Based on various summaries in the FDA data, during 2005 there were about 2,700 acetaminophen-associated poisoning/liver-failure cases and an estimated 460 deaths or a total 3,160 severe adverse events. This is merely 0.14% of the total potential adverse events (3,160 / 2.24 million).

  • Put another way, during 2005, taking into account a conservative, worst-case scenario, 99.86% of the time acetaminophen products were used safely. And, presumably, the trends have not changed significantly since 2005, according to the FDA’s documentation.

Even a single case of liver failure or death attributed to a product is cause for alarm and concern. However, does a 0.14% incidence rate, affecting roughly 0.001% of the U.S. population, signal a public health threat of such proportions that it requires an immediate, rigorous, and widespread governmental response that limits access to important analgesics?

These and other data from the FDA can be employed in alternate analyses but, due to the colossal number of acetaminophen doses distributed each year (denominator) and the relatively minuscule incidence of adverse events (numerator), the ultimate dimensions of the problem or risk are always quite small. In fact, this same sort of analytical perspective could (should?) be applied to risks associated with opioid analgesics, which are currently under scrutiny as part of the FDA’s REMS (Risk Evaluation and Mitigation Strategy) initiative directed at those medications.

Addressing the Wrong Questions

Both for acetaminophen and the opioid-REMS initiative, it seems that the wrong questions are being addressed. Rather than asking, “How can the public be better educated on safely using vital pain relievers?” the question pursued by the FDA seems to be, “How should access for all persons to certain analgesics be further controlled so as to prevent a minority of persons from misusing them and doing themselves harm?”

Acetaminophen products have very favorable safety profiles when used as directed. Most adverse events are accidental, relating to taking too much of the drug or in combination with alcohol. Black box warnings, lowering the maximum dose, and other restrictive measures recommended for acetaminophen by the FDA panel will do no good unless consumers attend to and can clearly understand such directives; however, there were no recommendations proffered for how to more effectively communicate safety information and better educate consumers. Instead, the government approach to risk reduction appears to be directly or indirectly limiting or denying access to analgesics of concern.

All medicines are potentially poisonous to some extent; 100% safe use is an unrealistic goal. Yet, nearly 300 years ago it was recognized that, "In the hands of the wise, poison is medicine. In the hands of a fool, medicine is poison." What is most needed when it comes to acetaminophen safety (as well as for opioids) is not more regulation, but better education of patients/consumers and the healthcare providers who serve them. You be the judge, and let your representatives in Congress know what you think.