by Erika Furlong

I recently attended the June 29th-30th FDA advisory committee meeting that voted for a reduction in the maximum daily over-the-counter (OTC) dose of acetaminophen and the ‘unbundling’ of narcotic-acetaminophen prescription medications. While I agree ultimately with many of the recommendations that were made, I can’t help but feel that there is a larger problem that remains unaddressed. There is a growing disparity between FDA expectations for prescription drugs and expectations for OTC drugs and dietary supplements. As requirements for prescription drugs increasingly reflect the ability of the pharmaceutical industry to design and manufacture safer drugs, requirements for OTC drugs appear stagnant, and dietary supplements continue to be deemed safe until proven otherwise.

Most OTC painkillers were first made available at a time when modern drug development technologies and safety assessment techniques did not exist – and even though these technologies and techniques are now available, FDA hasn’t required OTC drug manufacturers to apply them to their products. The popularity of these drugs over the years has illustrated that the public considers them to be of great utility in offering readily available treatment for pain conditions. Yet, these drugs account for a huge proportion of the adverse events that are seen with all pharmaceutical agents, due in part to their widespread use. By all accounts (clinical trials, retrospective studies and medical surveillance systems) these compounds have ‘important’ health risks associated with their use, most notably to the liver, kidney and gastrointestinal tract. Not surprisingly, these adverse events constitute a substantial (and potentially avoidable) public safety issue with important implications in terms of health care costs.

This begs the question: do these drugs still reflect current safety and efficacy standards? And, shouldn’t they? 

Technology to improve on the safety profiles of these medications exists, but manufacturers have few incentives to use it. Many of these drugs might not meet current FDA requirements for new drug formulations, so one might argue that industry has in fact been conditioned to rely on inaction and bank on the fact that the tradition of using these outdated medications is enough to surmount what would be considered for any other group of non-lifesaving medications an unfavorable safety profile.

For example, let’s consider acetaminophen, the active ingredient in Tylenol and other painkillers. It is a derivative of coal tar, which first became available in the 1950s when its parent compound, phenacetin (also an analgesic/antipyretic), was determined to have substantial side effects. FDA staff member Dr. John Senior reminded members of the FDA’s 2002 Nonprescription Drug Advisory Committee of the drug’s history:

Recall that this drug, acetaminophen, was approved before there was even a requirement to show efficacy, so that there were never any really [proper]  dose ranging studies done for safety purposes. And the methods and techniques available in 1950 were very limited.

Since the 1950s, researchers have determined that when the body breaks down acetaminophen it produces a reactive metabolite. It is this metabolite that then causes liver toxicity – and the higher the dose, the greater toxicity. In technical terms, acetaminophen is a dose-dependent hepatotoxin. FDA has said that dose-dependent hepatotoxins present too great a risk of hepatotoxicity and are now generally ‘discovered and rejected during preclinical testing.’ But more importantly, there now exist ways to design drugs around the development of a reactive metabolite. This is achieved by screening multiple and often times thousands of related compounds to find the ones that cause the fewest adverse effects and that are least likely to result in the formation of reactive metabolites. In fact, as early as the mid-1980s a scientist proposed that by just slightly modifying the chemical structure of acetaminophen the analgesic properties could be retained but the metabolite would never be formed. So why has this not been done? 

Part of the problem may be that not only is the FDA setting a low bar for OTC drug manufacturers, but industry may consider current efficacy and safety standards too prohibitive to tempt the development of improved formulations, which would now require extensive safety and efficacy testing (never before done on many of these compounds). An estimated 42,000 people are hospitalized each year due to acetaminophen, of which four to five hundred die. Thousands of people are also afflicted with potentially life threatening gastrointestinal bleeds because of NSAIDs (another type of pain drug, which includes aspirin, ibuprofen, and naproxen sodium). But with billions of dollars in sales, it is not too hard to imagine why this industry might not want to mess with a good thing, despite the casualties left in its wake. 

Clearly something should be done here. With baby boomers feeling the aches and pains of older age, the need for OTC pain relievers is great. But the ease of their OTC status should not be an obstacle to the development of safer, more effective alternatives. Acetaminophen was first developed and recognized as safe at a time when cars didn’t have seatbelts and there were ashtrays in the Surgeon General’s office. Since that time, drug design has improved by leaps and bounds and safety expectations have risen accordingly. So too should improvements and technological innovations be applied to the development of safer OTC pain relievers. Instead of trying to patch the problem with stricter warnings and inadequately funded educational campaigns, regulators should consider a combination of penalties and incentives to drive safety improvements to OTC pain relievers.

Erika Furlong is a scientific analyst for a Manhattan-based law firm. She has worked on litigations involving both NSAIDs and acetaminophen.

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