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How Much Does It Hurt?

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That same year, after extensive consultation with the FDA, a company in California submitted its application to market yet another high-dose, long-acting opioid painkiller. To the puzzlement of many, the FDA did not require Zogenix, Inc., to create a tamper-resistant form of the drug (the agency now says “the science is still evolving”). That’s when people like Lewis Nelson began to fear that Zohydro, as the new drug would be called, might be OxyContin all over again.

Sharon Walsh began to hear about the prescription-painkiller problem more than a decade ago, when she was studying IV-drug addicts as a researcher at Johns Hopkins University School of Medicine. She figured she should read up on how addictive the legal narcotics were compared with heroin and was stunned to discover that nobody really knew. “I realized that some of the fundamental questions had never been asked or answered,” Walsh recalls. She was particularly interested in hydrocodone. It is the most-prescribed drug in the country (roughly 130 million prescriptions a year), and physicians dispensed those prescriptions believing that it was less potent and less addictive than oxycodone. “But I really couldn’t find evidence for that,” she says. So she started to do rigorous, blinded studies of a drug that Americans had been using for decades, first in Baltimore and later in Kentucky, when she took a job in 2005 at the University of Kentucky. As she soon discovered, the eastern part of that state “happened to be the epicenter of the prescription-drug-abuse problem.”

Walsh has since become an expert on legal opioids and has served on FDA advisory panels. When the FDA began to consider tighter restrictions, the agency asked her to assess how addictive hydrocodone, the opioid in Zohydro, was compared with morphine and oxycodone, the active ingredient in OxyContin.

These “abuse potential” tests have a set of metrics all their own: After recruiting volunteers with “appropriate drug-use histories,” Walsh and her colleagues dosed them with hydrocodone, oxycodone, and morphine in both pill form and IV. While the subjects were high, the researchers measured “pupil diameter” (opioids typically cause “pinpoint” pupils) and rate of breathing (opioids suppress breathing, which is how most overdose victims die). They asked subjects to rate the drug’s “likability” and to estimate its street value. They even gathered data on something called “coasting,” which Walsh described as “a relaxed, calm feeling that is recognizable by opiate abusers.” By the time her lab gathered all this data, Walsh had reached two conclusions: In the view of drug addicts, hydrocodone was “virtually identical” to oxycodone, contrary to what many doctors thought. And if a new hydrocodone product got to market, she said, “it might produce problems just like oxycodone.”

Walsh noticed another paradox: the lack of evidence for the effectiveness of long-term opioid use, which other pain experts had also zeroed in on. Writing in the British Medical Journal, David N. Juurlink, head of clinical pharmacology and toxicology at the Sunnybrook Research Institute in Toronto, and two colleagues made the following point: “Many physicians are unaware that there is no evidence from randomised controlled trials to support the popular assertion that the benefits of long-term opioid therapy outweigh the risks.”

That wasn’t the way the manufacturer saw it. Zogenix argued that its product would fill a vital niche for chronic-pain patients. It served an “unmet need,” offering an alternative to existing painkillers, and added one more option for “opioid rotation,” the practice of switching to another painkiller when patients stop responding to their current medication. It would come in a long-acting formulation, so patients would only have to take two pills a day instead of four or six Vicodin. Perhaps most important, it would be the first long-acting hydrocodone that didn’t have acetaminophen, the active ingredient in Tylenol. As the company pointed out in its FDA application, many chronic-pain patients couldn’t get sufficient relief from Percocet or Vicodin because they came packaged with acetaminophen, which can cause liver toxicity and produce its own fatal overdoses.

Those issues set the stage for a compelling debate when the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee met on December 7, 2012, to consider Zohydro.

There is a lovely bureaucratic Kabuki that plays out whenever the FDA convenes one of its advisory-committee meetings. During these daylong public sessions, the “sponsor” (the drug company) arrives with a cheerful army of personnel to give a well-rehearsed presentation that makes its clinical data seem irresistibly convincing. An FDA official usually gives a crisp, dry, and often astute analysis of the data. A panel of outside experts—the “advisory committee”—picks at the data with polite, occasionally pointed questions to the drug-company representatives. The key moment occurs at the end of the day, when the advisory-­committee members discuss the safety and efficacy of the new drug and then vote on whether the FDA should approve it. As countless news stories have noted over the years, the FDA usually follows the recommendations of these advisory committees but is not legally bound to do so.


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